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 THAP12 protein O43422 UNIPROT EIF2S1 protein P05198 UNIPROT unknown phosphorylation Ser52 MILLSELsRRRIRSI -1 10542257 t lperfetto "The mammalian kinases PKR and HRI and the yeast kinase GCN2 specifically phosphorylate Ser-51 on the alpha subunit of the translation initiation factor eIF2. " SIGNOR-249029 TGM2 protein P21980 UNIPROT H3C1 protein P68431 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 BTO:0000150 16407273 t gcesareni "Tg2 is able to phosphorylate purified histone proteins, and h3 and h1 in chromatin preparations, and it is associated with chromatin in breast cancer cells." SIGNOR-143642 GNB1 protein P62873 UNIPROT GNG2 protein P59768 UNIPROT "up-regulates activity" binding 10696571 t "GNB1 dissociates from the receptor, bound with GNG2 as stable dimer" SIGNOR-251105 GNB1 protein P62873 UNIPROT PLCB2 protein Q00722 UNIPROT up-regulates binding 9606 BTO:0000142 1465133 t 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 THBS1 protein P07996 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR down-regulates 17326328 f lperfetto "There are many naturally occurring proteins that can inhibit angiogenesis, including angiostatin, endostatin, interferon, platelet factor 4, thorombospondin, prolactin 16 kd fragment, and tissue inhibitor of metalloproteinase-1, -2, and -3" SIGNOR-252271 GNB1 protein P62873 UNIPROT PLCB1 protein Q9NQ66 UNIPROT down-regulates binding 9606 8870665 t gcesareni "These results indicate that g-protein beta gamma subunits constitute a mechanism by which g-protein mediate a rapid and transient plc- beta 1." SIGNOR-44369 NFIA protein Q12857 UNIPROT MYOD1 protein P15172 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165 32991581 t brain lperfetto "NFIA binds to and activates the brown-fat-specific enhancers even before differentiation and later facilitates the binding of PPARgamma|NFIA has at least three functions on the transcriptional regulation of brown fat [2]. First, NFIA activates adipogenesis per se, through activating the transcription of Pparg, which encodes PPARgamma. Second, NFIA also activates the brown-fat-specific gene expression (such as Ucp1 and Ppargc1a) independent of the degree of adipocyte differentiation, through facilitating the binding of PPARgamma to the brown-fat-specific enhancers. Third, NFIA represses myogenesis through suppression of myogenic transcription factors such as Myod1 as well as Myog," SIGNOR-263982 NFIA protein Q12857 UNIPROT MYOG protein P15173 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165 32991581 t brain lperfetto "NFIA binds to and activates the brown-fat-specific enhancers even before differentiation and later facilitates the binding of PPARgamma|NFIA has at least three functions on the transcriptional regulation of brown fat [2]. First, NFIA activates adipogenesis per se, through activating the transcription of Pparg, which encodes PPARgamma. Second, NFIA also activates the brown-fat-specific gene expression (such as Ucp1 and Ppargc1a) independent of the degree of adipocyte differentiation, through facilitating the binding of PPARgamma to the brown-fat-specific enhancers. Third, NFIA represses myogenesis through suppression of myogenic transcription factors such as Myod1 as well as Myog," SIGNOR-263983 CDH17 protein Q12864 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" binding 9606 21255999 t miannu "At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin" SIGNOR-265856 TIAM1 protein Q13009 UNIPROT RAC1 protein P63000 UNIPROT up-regulates binding 9606 12393875 t gcesareni "Lpa-induced rac activation requires tiam1" SIGNOR-94691 tiotropium chemical CHEBI:90960 ChEBI CHRM1 protein P11229 UNIPROT "down-regulates activity" "chemical inhibition" -1 8441333 t miannu "A newly developed compound, Ba 679 BR (abbreviated Ba 679) proved to be a highly potent muscarinic antagonist in guinea pig tracheal rings. Its binding to human receptors (Hm1, Hm2, Hm3) was characterized by KD-values in the 10(-10) M concentration range.he drug showed ""kinetic receptor subtype selectivity"" by having a more rapid dissociation from Hm2 than from Hm1 and Hm3 receptors." SIGNOR-258485 tiotropium chemical CHEBI:90960 ChEBI CHRM2 protein P08172 UNIPROT "down-regulates activity" "chemical inhibition" -1 8441333 t miannu "A newly developed compound, Ba 679 BR (abbreviated Ba 679) proved to be a highly potent muscarinic antagonist in guinea pig tracheal rings. Its binding to human receptors (Hm1, Hm2, Hm3) was characterized by KD-values in the 10(-10) M concentration range.he drug showed ""kinetic receptor subtype selectivity"" by having a more rapid dissociation from Hm2 than from Hm1 and Hm3 receptors." SIGNOR-258484 tiotropium chemical CHEBI:90960 ChEBI CHRM3 protein P20309 UNIPROT "down-regulates activity" "chemical inhibition" -1 8441333 t miannu "A newly developed compound, Ba 679 BR (abbreviated Ba 679) proved to be a highly potent muscarinic antagonist in guinea pig tracheal rings. Its binding to human receptors (Hm1, Hm2, Hm3) was characterized by KD-values in the 10(-10) M concentration range.he drug showed ""kinetic receptor subtype selectivity"" by having a more rapid dissociation from Hm2 than from Hm1 and Hm3 receptors." SIGNOR-258486 AIMP1 protein Q12904 UNIPROT SMURF2 protein Q9HAU4 UNIPROT up-regulates binding 9606 18448069 t lpetrilli "Here, we report that aimp1 negatively regulates tgf-? Signaling via stabilization of smurf2." SIGNOR-178498 PTPRJ protein Q12913 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 BTO:0000782 10734133 t gcesareni "Ptp-1b and t-cell ptp are physiological enzymes for the insulin receptor kinase." SIGNOR-76096 PTPRJ protein Q12913 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 10734133 t gcesareni "These results, combined with secondary dephosphorylation tests, confirm and extend earlier findings that ptp-1b and t-cell ptp are physiological enzymes for the insulin receptor kinase." SIGNOR-76100 PTPRJ protein Q12913 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 1715686 t gcesareni "Dephosphorylation of autophosphorylated insulin and epidermal-growth-factor receptors by two major subtypes of protein-tyrosine-phosphatase from human placenta." SIGNOR-21295 PTPRJ protein Q12913 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 1715686 t gcesareni "Dephosphorylation of autophosphorylated insulin and epidermal-growth-factor receptors by two major subtypes of protein-tyrosine-phosphatase from human placenta." SIGNOR-21299 PTPRJ protein Q12913 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 1715686 t gcesareni "Dephosphorylation of autophosphorylated insulin and epidermal-growth-factor receptors by two major subtypes of protein-tyrosine-phosphatase from human placenta." SIGNOR-21303 NUMA1 protein Q14980 UNIPROT TUBB6 protein Q9BUF5 UNIPROT up-regulates binding 9606 11956313 t miannu "Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules." SIGNOR-117109 PTPRJ protein Q12913 UNIPROT SRC protein P12931 UNIPROT "up-regulates activity" dephosphorylation Tyr530 FTSTEPQyQPGENL 10116 15735685 t "The rat tyrosine phosphatase eta increases cell adhesion by activating c-Src through dephosphorylation of its inhibitory phosphotyrosine residue" SIGNOR-248705 PTPRJ protein Q12913 UNIPROT FLT1 protein P17948 UNIPROT down-regulates dephosphorylation 9606 12771128 t gcesareni "Vegf acts by binding to two high affinity receptor tyrosine kinases: vegf receptor (vegfr)* 1 also called flt-1, and vegfr-2, also called flk-1/kdr a dominant-negative mutant of high cell densityenhanced ptp 1 (dep-1)//cd148 as well as reduction of its expression by rna interference partially restore vegfr-2 phosphorylation and map kinase activation." SIGNOR-101272 PTPRJ protein Q12913 UNIPROT PLCG1 protein P19174 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 11259588 t miannu "Cd148 can dephosphorylate lat and plc?1 In vitro. / plc?1 Undergoes inducible tyrosine phosphorylation following tcr stimulation (46), and this phosphorylation is required to stimulate its catalytic activity" SIGNOR-105790 PTPRJ protein Q12913 UNIPROT PLCG1 protein P19174 UNIPROT unknown dephosphorylation 9606 11259588 t "Protein tyrosine phosphatase CD148-mediated inhibition of T-cell receptor signal transduction is associated with reduced LAT and phospholipase Cgamma1 phosphorylation" SIGNOR-248706 TLR4 protein O00206 UNIPROT TICAM2 protein Q86XR7 UNIPROT up-regulates binding 9606 18221795 t fstefani "Mappit analysis of early toll-like receptor signalling events." SIGNOR-160424 PTPRJ protein Q12913 UNIPROT PI3K complex SIGNOR-C156 SIGNOR down-regulates dephosphorylation 9606 18348712 t gcesareni "As reduction of pi3k activity by cd148 or shp-1 [32] is not large (2540%), it is likely that these ptps may function as modulators of the pi3k pathway rather than suppressors." SIGNOR-252727 PTPN13 protein Q12923 UNIPROT STK25 protein O00506 UNIPROT "down-regulates activity" dephosphorylation 9606 17657516 t "To investigate dephosphorylation of CCM3 by FAP-1, phosphorylated GST-CCM3 was incubated with cdFAP-1, and reactions were analyzed by autoradiography. Again, GST-STK25 phosphorylated GST-CCM3 and possessed autophosphorylation activity. cdFAP-1 of 0.005 U were sufficient to dephosphorylate GST-CCM3 as well as the kinase GST-STK25.|More recently, the Golgi matrix protein GM130 was shown to function as a scaffold protein for STK25 and to activate STK25 through stimulation of autophosphorylation." SIGNOR-248711 PTPN13 protein Q12923 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 15611135 t gcesareni "We demonstrate that ptpl1, like ptp1b, interacts with and dephosphorylates a bis-phosphorylated insulin receptor peptide more efficiently than monophosphorylated peptides, indicating that ptpl1 may down-regulate the phosphatidylinositol 3-kinase pathway, by dephosphorylating insulin or growth factor receptors that contain tandem phosphotyrosines." SIGNOR-132551 TRAF2 protein Q12933 UNIPROT TRAF1 protein Q13077 UNIPROT up-regulates binding 9606 8069916 t amattioni "Our analysis indicates that traf1 and traf2 are associated with the cytoplasmic domain of tnf-r2 in a heterodimeric complex in which traf2 contacts the receptor directly. Traf1 interacts with tnf-r2 indirectly through heterodimer formation with traf2." SIGNOR-35881 TRAF2 protein Q12933 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates binding 9606 10346818 t amattioni "Oligomerization of the traf2 effector domain results in specific binding to mekk1, a protein kinase capable of jnk, p38, and ikk activation" SIGNOR-67552 TRAF2 protein Q12933 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates binding 9606 18635759 t gcesareni "Traf2, ubc13, and ikkgamma were required for complex assembly and activation of mekk1 and mapk cascades." SIGNOR-179476 TRAF2 protein Q12933 UNIPROT BIRC3 protein Q13489 UNIPROT up-regulates binding 9606 18621737 t gcesareni "A traf2 trimer interacts with one ciap2 both in the crystal and in solution through its death domain and amino-terminal region, tradd recruits rip1 (receptor-interacting protein), traf2, and through its interaction with traf2, c-iap1 and c-iap2 (13). Traf2 recruit ciap1 and ciap2. A traf2 trimer interacts with one ciap2 both in the crystal and in solution." SIGNOR-179452 FOXF1 protein Q12946 UNIPROT GH2 protein P01242 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599;BTO:0000798 16772323 f miannu "Overexpression of FOXF1 in BeWo and HepG2 cells induced the GHV promoter, whereas overexpression of FOXF2 was without effect. These studies indicate that FOXF1 induces GHV expression by interaction with a FOXF1/FOXF2 cis-element in the proximal promoter." SIGNOR-254175 FOXF2 protein Q12947 UNIPROT TBP protein P20226 UNIPROT "up-regulates activity" binding -1 9722567 t miannu "The human forkhead protein FREAC-2 contains two functionally redundant activation domains and interacts with TBP and TFIIB." SIGNOR-220373 FOXC1 protein Q12948 UNIPROT RBPJ protein Q06330 UNIPROT up-regulates binding 9606 BTO:0000671 21871448 t gcesareni "We demonstrate that physical interactions occur between wt1, foxc1/2 and rbpj, suggestive of the formation of multimeric transcriptional complexes." SIGNOR-176183 FOXI1 protein Q12951 UNIPROT CFTR protein P13569 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20972246 f miannu "Results of transiently transfected vas deferens cells with either the -33G wild-type or the -33A variant CFTR directed luciferase reporter gene confirmed that the -33A variant, which alters the FOXI1 (Forkhead box I1) binding, significantly decreases the CFTR promoter activity." SIGNOR-254176 TLRs proteinfamily SIGNOR-PF20 SIGNOR Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 20404851 f lperfetto "The negative regulation of TLR-induced responses is important for sup- pressing inflammation and deleterious immune responses." SIGNOR-216304 PPP1R8 protein Q12972 UNIPROT PPP1CA protein P62136 UNIPROT "down-regulates activity" binding -1 1322907 t "We have purified two of these nuclear inhibitors of PP-1 (NIPP-1a and NIPP-1b) until homogeneity." SIGNOR-255657 TNF protein P01375 UNIPROT GCH1 protein P30793 UNIPROT "up-regulates activity" 9606 9204951 f miannu "The de novo synthesis of 6-BH4 depends on the induction of GTP-CH-1, e.g., by tumor necrosis factor-alpha (TNF alpha)." SIGNOR-252210 TNFAIP3 protein P21580 UNIPROT RIPK1 protein Q13546 UNIPROT "down-regulates quantity" ubiquitination 9606 BTO:0000007 15258597 t "A20The carboxy-terminal domain of A20, composed of seven C2/C2 zinc fingers, then functions as a ubiquitin ligase by polyubiquitinating RIP with K48-linked ubiquitin chains, thereby targeting RIP for proteasomal degradation." SIGNOR-259977 TNFAIP3 protein P21580 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT "down-regulates activity" deubiquitination 9606 18164316 t lperfetto "A20 is a deubiquitinating enzyme (dub) for lys63-linked polyubiquitinated signaling mediators such as traf6" SIGNOR-160223 PPP1R8 protein Q12972 UNIPROT EZH2 protein Q15910 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 phosphorylation:Thr416 EANSRCQtPIKMKPN 23241245 t "Recruited NIPP1 enables the net phosphorylation of EZH2 by inhibiting its dephosphorylation by PP1." SIGNOR-255665 TNF protein P01375 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 9606 21514273 f "via a ?-catenin-dependent pathway" fspada "Tumor necrosis factor-? (TNF-alpha) Is known to suppress adipocyte differentiation via a Beta-catenin-dependent pathway." SIGNOR-173421 PPP1R8 protein Q12972 UNIPROT PP1 proteinfamily SIGNOR-PF54 SIGNOR "down-regulates activity" binding -1 1322907 t lperfetto "We have purified two of these nuclear inhibitors of PP-1 (NIPP-1a and NIPP-1b) until homogeneity." SIGNOR-264673 PTP4A2 protein Q12974 UNIPROT CDK2 protein P24941 UNIPROT up-regulates dephosphorylation 9606 14643450 t amattioni "Cells overexpressing prl-2 exhibited enhanced cyclin-dependent kinase 2 (cdk2) activity" SIGNOR-119478 TNF protein P01375 UNIPROT NOD2 protein Q9HC29 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003355 18647246 f miannu "NOD2, toll-like receptor 4 (TLR4) and the adapter protein receptor-interacting protein 2 (RIP2) are induced by tumor-necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in the bronchial epithelial cell line BEAS-2B." SIGNOR-252407 TNF protein P01375 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "up-regulates activity" 9606 8530143 f "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 GRIK3 protein Q13003 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000938 29953871 t miannu "Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial." SIGNOR-264944 MLLT11 protein Q13015 UNIPROT TCF7 protein P36402 UNIPROT "up-regulates activity" binding -1 26079538 t irozzo "Here, we show that AF1q specifically binds to T-cell-factor-7 (TCF7) in the Wnt signaling pathway and results in transcriptional activation of CD44 as well as multiple downstream targets of the TCF7/LEF1. Super-shift and electrophoretic mobility shift assay (EMSA) further confirmed that AF1q directly interacted with TCF7 and enhanced the binding affinity of the complex" SIGNOR-259108 TNF protein P01375 UNIPROT SCN2A protein Q99250 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0004102 26112872 f miannu "TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels." SIGNOR-253480 TNF protein P01375 UNIPROT SCN3A protein Q9NY46 UNIPROT "up-regulates activity" 10090 BTO:0004102 26112872 f miannu "TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels." SIGNOR-253494 STK4 protein Q13043 UNIPROT LATS1 protein O95835 UNIPROT up-regulates phosphorylation Thr1079 EHAFYEFtFRRFFDD 9606 BTO:0000007 15688006 t milica "We show that Mst2 and hWW45 interact with each other in human cells and that both Mst2 and Mst1 are able to phosphorylate Lats1 and Lats2, thereby stimulating Lats kinase activity." SIGNOR-133555 STK4 protein Q13043 UNIPROT ABL1 protein P00519 UNIPROT down-regulates phosphorylation Thr735 DTEWRSVtLPRDLQS 9606 18794806 t lperfetto "Here, we identify clk1, clk4, mst1, mst2 and ttk (also known as mps1) as novel thr735 kinases in vitro / phosphorylation of thr735 in c-abl is critical for binding to 14-3-3" SIGNOR-181060 STK4 protein Q13043 UNIPROT AR protein P10275 UNIPROT down-regulates 21512132 f lperfetto "Mst1 plays a critical role in the regulation of programmed cell death and it has been implicated in PCa development. Interestingly, MST1 has been detected in AR-chromatin complexes, and forced expression of MST1 reduces AR binding to androgen-responsive elements along the PSA promoter." SIGNOR-151712 TNF protein P01375 UNIPROT TNFRSF1A protein P19438 UNIPROT "up-regulates activity" binding 9606 17151142 t 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 TNF protein P01375 UNIPROT TNFRSF1A protein P19438 UNIPROT "up-regulates activity" binding 9606 21133840 t "simone vumbaca" "TNF alpha and IFN gamma exhibit a cross-talk at the level of TNFR1 to induce activation of macrophages" SIGNOR-256025 STK4 protein Q13043 UNIPROT STK4 protein Q13043 UNIPROT "up-regulates activity" phosphorylation Ser327 SEEDEMDsGTMVRAV 9534 BTO:0004055 12223493 t lperfetto "Mapping of MST1 kinase sites of phosphorylation. Activation and autophosphorylationwas also highly autophosphorylated at the newly identified Thr(177) and Thr(387) residues" SIGNOR-247569 STK4 protein Q13043 UNIPROT STK4 protein Q13043 UNIPROT "up-regulates activity" phosphorylation Thr177 VAGQLTDtMAKRNTV 9534 BTO:0004055 12223493 t lperfetto "Mapping of MST1 kinase sites of phosphorylation. Activation and autophosphorylationwas also highly autophosphorylated at the newly identified Thr(177) and Thr(387) residues" SIGNOR-247573 TNFRSF1A protein P19438 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates 9606 10795740 t "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 STK4 protein Q13043 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Ser872 HQRCLAHsLVGTPNY 9606 23431053 t milica "MST1/2 directly phosphorylate Lats1/2 at the hydrophobic motif (Lats1 T1079 and Lats2 T1041), and this phosphorylation is required for Lats1/2 activation" SIGNOR-201298 TNK2 protein Q07912 UNIPROT TNK2 protein Q07912 UNIPROT up-regulates phosphorylation Tyr284 LPQNDDHyVMQEHRK 9606 14506255 t llicata "Purified ack1 undergoes autophosphorylation, and autophosphorylation enhances kinase activity. We identified tyr284 in the activation loop of ack1 as the primary autophosphorylation site using mass spectrometry." SIGNOR-118201 TNK2 protein Q07912 UNIPROT TNK2 protein Q07912 UNIPROT "up-regulates activity" phosphorylation Tyr284 LPQNDDHyVMQEHRK -1 16472662 t "Purified ACK1 undergoes autophosphorylation at Tyr284, and autophosphorylation increases kinase activity" SIGNOR-251184 TRAF3 protein Q13114 UNIPROT MAP3K14 protein Q99558 UNIPROT "down-regulates quantity by destabilization" binding 10090 BTO:0000785 15084608 t lperfetto "Traf3 is physically associated with nik via a specific sequence motif located in the n-terminal region of nik; this molecular interaction appears to target nik for degradation by the proteasome." SIGNOR-124236 TRAF3 protein Q13114 UNIPROT TBK1 protein Q9UHD2 UNIPROT "up-regulates activity" binding 9606 24622840 t miannu "MAVS also interacts with STING that locates at the ER (endoplasmic reticulum), and induces the ubiquitination and dimerization of STING. The activated STING recruits TBK1 and IRF3 and contributes to the phosphorylation of IRF3 mediated by TBK1." SIGNOR-260156 "tofacitinib citrate" chemical CHEBI:71197 ChEBI JAK3 protein P52333 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207311 DUSP4 protein Q13115 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 8626452 t fstefani "Here we characterize a new map kinase phosphatase, mkp-2, that is induced in human peripheral blood t cells with phorbol 12-myristate 13-acetate and is expressed in a variety of nonhematopoietic tissues as well. We show that the in vivo substrate specificities of individual phosphatases are unique. Pac1, mkp-2, and mkp-1 recognize erk and p38, erk and jnk, and erk, p38, and jnk, respectively." SIGNOR-40926 Tomivosertib chemical CID:118598754 PUBCHEM MKNK1 protein Q9BUB5 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0002522 29526098 t "Simone Vumbaca" "Compound 23 (eFT508), an exquisitely selective, potent dual MNK1/2 inhibitor, was designed to assess the potential for control of oncogene signaling at the level of mRNA translation." SIGNOR-261116 Tomivosertib chemical CID:118598754 PUBCHEM MKNK2 protein Q9HBH9 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0002522 29526098 t "Simone Vumbaca" "Compound 23 (eFT508), an exquisitely selective, potent dual MNK1/2 inhibitor, was designed to assess the potential for control of oncogene signaling at the level of mRNA translation." SIGNOR-261117 TOP2A protein P11388 UNIPROT Chromosome_segregation phenotype SIGNOR-PH44 SIGNOR up-regulates 9606 20562910 f lperfetto "Topoisomerase IIalpha (topoIIalpha) is an essential mammalian enzyme that topologically modifies DNA and is required for chromosome segregation during mitosis." SIGNOR-242530 "torin 2" chemical CHEBI:90682 ChEBI MTOR protein P42345 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000551 23436801 t "ATP-competitive inhibitor" gcesareni "Torin2, a second generation atp-competitive inhibitor that is potent and selective for mtor.." SIGNOR-201499 "torin 2" chemical CHEBI:90682 ChEBI RPS6KB1 protein P23443 UNIPROT down-regulates 9606 BTO:0000551 23436801 f gcesareni "Torin2 inhibited mtorc1-dependent t389 phosphorylation on s6k (rps6kb1)" SIGNOR-201502 torkinib chemical CHEBI:90679 ChEBI MTOR protein P42345 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258268 TP53 protein P04637 UNIPROT BID protein P55957 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0002572 16151013 f "Nuclear p53" lperfetto "Bid is a p53 primary-response gene." SIGNOR-140248 TP53 protein P04637 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 24212651 f miannu "P53 is a nuclear transcription factor with a pro-apoptotic function" SIGNOR-255678 TP53 protein P04637 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 14963330 t gcesareni "Tp53 directly activated the proapoptotic bcl-2 protein bax in the absence of other proteins to permeabilize mitochondria and engage the apoptotic program" SIGNOR-121895 TP53 protein P04637 UNIPROT BAX protein Q07812 UNIPROT "up-regulates activity" binding 9606 14963330 t lperfetto "Tp53 directly activated the proapoptotic bcl-2 protein bax in the absence of other proteins to permeabilize mitochondria and engage the apoptotic program" SIGNOR-178690 TP53 protein P04637 UNIPROT BAK1 protein Q16611 UNIPROT up-regulates binding 9606 15077116 t gcesareni "P53 interacts with the pro-apoptotic mitochondrial membrane protein bak" SIGNOR-124122 PRKAA1 protein Q13131 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser811 IYISPLKsPYKISEG 9606 BTO:0000938 BTO:0000142 SIGNOR-C15 19217427 t gcesareni "Amp-activated protein kinase phosphorylates retinoblastoma protein. Rb phosphorylation sites, ser804 (ser811 in human), resembled the ampk consensus phosphorylation site." SIGNOR-184052 PRKAA1 protein Q13131 UNIPROT GLI1 protein P08151 UNIPROT "down-regulates activity" phosphorylation Ser102 LQTVIRTsPSSLVAF 9606 26190112 t Luana "AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This in turn leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency." SIGNOR-259861 ERBB4 protein Q15303 UNIPROT SHC3 protein Q92529 UNIPROT up-regulates relocalization 9606 16829981 t gcesareni "Like erbb1, erbb4 recruits grb2, shc and stat5." SIGNOR-147850 TP53 protein P04637 UNIPROT FASLG protein P48023 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150 9841917 f "Nuclear p53" amattioni "Cd95l, cd95, and the trail death receptors are induced by the tumour suppressor p53" SIGNOR-62379 TP53 protein P04637 UNIPROT CYCS protein P99999 UNIPROT up-regulates 9606 19007744 f "Translocation from Mitochondria to Cytosol" lperfetto "P53 translocation precedes changes of mitochondrial membrane potential, cytochrome c release and caspase activation" SIGNOR-140251 TP53 protein P04637 UNIPROT DRAM2 protein Q6UX65 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 30755245 f irozzo "DRAM2 plays an oncogenic role in NSCLC via regulating p53 expression. Knockdown of DRAM2 caused an increase of p53 and p21 expression, and overexpression of p53 caused a decrease of DRAM2 expression." SIGNOR-259148 PRKAA1 protein Q13131 UNIPROT POU2F1 protein P14859 UNIPROT down-regulates phosphorylation Ser385 RRRKKRTsIETNIRV 9606 1684878 t lperfetto "Mitosis-specific phosphorylation site in the homeodomain of oct-1 was phosphorylated in vitro by protein kinase a. Pka-mediated phosphorylation event was identified in the cns-specific pou domain protein brn-2/n-oct-3/pou3f2 (nieto et al. 2007). In this case, the modification, at a position homologous to oct1 s385, was found to alter binding specificity for complex dimeric sites." SIGNOR-20971 PRKAA1 protein Q13131 UNIPROT DNMT1 protein P26358 UNIPROT "down-regulates activity" phosphorylation Ser714 DNIPEMPsPKKMHQG -1 28143904 t lperfetto "Together, these results indicate that AMPK phosphorylated DNMT1-Ser730, RBBP7-Ser314, and HAT1-Ser190|AMPK decreased DNMT1 activity" SIGNOR-264783 TP53 protein P04637 UNIPROT OGG1 protein O15527 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001109 16293709 f miannu "Using gel-shift assays, we showed that p53 binds to its putative cis-elements within the hOGG1 promoter. In addition we demonstrated that supplementing p53 in HCT116p53-/- cells enhanced the transcription of hOGG1." SIGNOR-255440 TP53 protein P04637 UNIPROT NR4A3 protein Q92570 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 30455429 f miannu "We showed that p53 directly bound the promoter of NR4A3 gene and induced its transcription. p53 transactivates the NR4A3 promoter in H1299 cells." SIGNOR-256200 PRKAA1 protein Q13131 UNIPROT HNF4A protein P41235 UNIPROT "down-regulates activity" phosphorylation Ser303 DPDAKGLsDPGKIKR 9606 BTO:0001131 SIGNOR-C15 12740371 t lperfetto "Here we demonstrate that ampk directly phosphorylates hnf4 and represses its transcriptional activity. Ampk-mediated phosphorylation of hnf4 on serine 304 had a 2-fold effect" SIGNOR-101101 PRKAA1 protein Q13131 UNIPROT NAMPT protein P43490 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 BTO:0000165 18477450 f gcesareni "Activated AMPK was required to promote GR-induced transcription of the NAD+ biosynthetic enzyme Nampt" SIGNOR-238598 TP73 protein O15350 UNIPROT PMAIP1 protein Q13794 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17700533 f miannu "Dissociation of p73 and HDM2 leads to increased p73 transcriptional activity with upregulation of p73 target genes noxa, puma and p21, as well as enhanced apoptosis." SIGNOR-255469 TPO protein P07202 UNIPROT TG protein P01266 UNIPROT "up-regulates activity" "catalytic activity" 9606 BTO:0004709 23349248 t miannu "After transport through the apical membrane, I− is covalently bound to the tyrosyl residues of Tg by thyroid peroxidase (TPO)." SIGNOR-259914 TPR protein P12270 UNIPROT MAD2L1 protein Q13257 UNIPROT up-regulates binding 9606 BTO:0000567 18981471 t miannu "Tpr directly binds to mad1 and mad2. / depletion of tpr decreases the levels of mad1 at kinetochores during prometaphase, correlating with the inability of mad1 to activate mad2, which is required for inhibiting apc(cdc20)." SIGNOR-181975 TP73 protein O15350 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 17700533 f miannu "Like p53, its homolog p73 transactivates proapoptotic genes and induces cell death." SIGNOR-256665 PRKAA1 protein Q13131 UNIPROT FOXO1 protein Q12778 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C15 17900900 t gcesareni "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." SIGNOR-157941 PRKAA1 protein Q13131 UNIPROT ACACA protein Q13085 UNIPROT "down-regulates activity" phosphorylation Ser1201 IPTLNRMsFSSNLNH 10116 BTO:0000759 7907095 t miannu "We have isolated and purified from rat livers a novel kinase that phosphorylates and inactivates the carboxylase Ser1200 isphosphorylated by both CAMP-dependent protein kinase and AMP-activated protein kinase" SIGNOR-250400 PRKAA1 protein Q13131 UNIPROT PRKAA1 protein Q13131 UNIPROT "down-regulates activity" phosphorylation Ser486 DDEITEAKsGTATPQRS -1 17023420 t "We show that AMPK α-Ser485/491 can be a site for autophosphorylation, which may play a role in limiting AMPK activation in response to energy depletion or other regulators" SIGNOR-256114 PRKAA1 protein Q13131 UNIPROT CTBP1 protein Q13363 UNIPROT down-regulates phosphorylation Ser158 REGTRVQsVEQIREV 9606 SIGNOR-C15 23291169 t lperfetto "We found that an activated amp-activated protein kinase (ampk) phosphorylates ctbp1 on ser-158 upon metabolic stresses. Moreover, ampk-mediated phosphorylation of ctbp1 (s158) attenuates the repressive function of ctbp1" SIGNOR-200250 PRKAA1 protein Q13131 UNIPROT NR0B2 protein Q15466 UNIPROT up-regulates 9606 17909097 f gcesareni "We have concluded that metformin inhibits hepatic gluconeogenesis through ampk-dependent regulation of shp" SIGNOR-158071 PRKAA1 protein Q13131 UNIPROT CRY1 protein Q16526 UNIPROT down-regulates phosphorylation Ser71 ANLRKLNsRLFVIRG 9606 SIGNOR-C15 phosphorylation:Ser71 ANLRKLNsRLFVIRG 21892142 t gcesareni "Ampk was shown to regulate the stability of the core clock component cry1 though phosphorylation of cry1 ser71, which stimulates the direct binding of the fbox protein fbxl3 to cry1, targeting it for ubiquitin-mediated degradation" SIGNOR-176472 TRAF2 protein Q12933 UNIPROT BIRC3 protein Q13489 UNIPROT up-regulates binding 9606 18997794 t gcesareni "A traf2 trimer interacts with one ciap2 both in the crystal and in solution through its death domain and amino-terminal region, tradd recruits rip1 (receptor-interacting protein), traf2, and through its interaction with traf2, c-iap1 and c-iap2 (13). Traf2 recruit ciap1 and ciap2. A traf2 trimer interacts with one ciap2 both in the crystal and in solution." SIGNOR-182137 TRAF2 protein Q12933 UNIPROT MAP3K14 protein Q99558 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 20651737 t lperfetto "Under resting conditions cellular inhibitor of apoptosis (ciap) proteins target nuclear factor-kb (nf-kb)-inducing kinase (nik) for ubiquitylation and proteasomal degradation." SIGNOR-167066 PRKAA1 protein Q13131 UNIPROT RBBP7 protein Q16576 UNIPROT "up-regulates activity" phosphorylation Ser314 LKLHTFEsHKDEIFQ -1 28143904 t lperfetto "AMPK increased HAT1 activity through phosphorylation of HAT1-Ser190 and RBBP7-Ser314| interaction between RBBP7 and HAT1 is required for acetyltransferase activity" SIGNOR-264784 PRKAA1 protein Q13131 UNIPROT NRF1 protein Q16656 UNIPROT up-regulates 9606 BTO:0000887 15509864 f gcesareni "In muscle, it causes increased dna binding by the transcription factors nrf1 (bergeron et al., 2001) and mef2 (zheng et al., 2001), which may be involved in regulation of mitochondrial genes and glut4, respectively." SIGNOR-130076 PRKAA1 protein Q13131 UNIPROT ZNF692 protein Q9BU19 UNIPROT down-regulates phosphorylation Ser470 VAAHRSKsHPALLLA 9606 SIGNOR-C15 17097062 t gcesareni "Arebp is phosphorylated at ser(470) by ampk. Phosphorylation reduces the dna-binding activity of arebp." SIGNOR-150590 PRKAA1 protein Q13131 UNIPROT MFF protein Q9GZY8 UNIPROT "up-regulates activity" phosphorylation Ser155 GRLKRERsMSENAVR 9606 BTO:0001938 26816379 t gcesareni "A screen for substrates of AMPK identified mitochondrial fission factor (MFF), a mitochondrial outer-membrane receptor for DRP1, the cytoplasmic guanosine triphosphatase that catalyzes mitochondrial fission." SIGNOR-245953 PRKAA1 protein Q13131 UNIPROT MFF protein Q9GZY8 UNIPROT "up-regulates activity" phosphorylation Ser172 GQLVRNDsLWHRSDS 9606 BTO:0001938 26816379 t gcesareni "A screen for substrates of AMPK identified mitochondrial fission factor (MFF), a mitochondrial outer-membrane receptor for DRP1, the cytoplasmic guanosine triphosphatase that catalyzes mitochondrial fission." SIGNOR-249656 PRKAA1 protein Q13131 UNIPROT KLC2 protein Q9H0B6 UNIPROT up-regulates phosphorylation Ser582 PRMKRASsLNFLNKS 9606 SIGNOR-C15 21725060 t gcesareni "Consistent with phosphorylation of both ser545 and ser582 of klc2 contributing to its 14-3-3 binding, a ser545ala mutant of klc2 could be phosphorylated in vitro by ampk on ser582" SIGNOR-174681 PRKAA1 protein Q13131 UNIPROT MLXIPL protein Q9NP71 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C15 11724780 t gcesareni "Ampk has also been suggested to phosphorylate the glucose-sensitive transcription factor chrebpthe dna binding activity, as assayed in a gel-shift assay of the truncated chrebp, was gradually inactivated with time by treatment with ampk" SIGNOR-112289 PRKAA1 protein Q13131 UNIPROT MLXIPL protein Q9NP71 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C15 21892142 t gcesareni "Ampk has also been suggested to phosphorylate the glucose-sensitive transcription factor chrebpthe dna binding activity, as assayed in a gel-shift assay of the truncated chrebp, was gradually inactivated with time by treatment with ampk" SIGNOR-176494 PRKAA1 protein Q13131 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "up-regulates activity" phosphorylation Ser399 DNITLPPsQPSPTGG 9606 BTO:0000007 17711846 t gcesareni "Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization." SIGNOR-252975 PRKAA1 protein Q13131 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "up-regulates activity" phosphorylation Ser413 GLMQRSSsFPYTTKG 9606 BTO:0000007 17711846 t gcesareni "Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization." SIGNOR-252976 trastuzumab antibody DB00072 DRUGBANK ERBB2 protein P04626 UNIPROT "down-regulates activity" binding 9606 BTO:0000150 29017563 t miannu "HER2+ breast cancer is associated with poor prognosis and high mortality rates, but the development of HER2-targeted therapies, such as originator trastuzumab (Herceptin®), has substantially improved patient survival." SIGNOR-259904 PRKAA1 protein Q13131 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "up-regulates activity" phosphorylation Ser555 RALSNSVsNMGLSES 9606 BTO:0000007 17711846 t gcesareni "Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization." SIGNOR-252977 PRKAA1 protein Q13131 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "up-regulates activity" phosphorylation Ser588 QTLSDSLsGSSLYST 9606 BTO:0000007 17711846 t gcesareni "Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization." SIGNOR-252978 "trichostatin A" chemical CHEBI:46024 ChEBI HDAC1 protein Q13547 UNIPROT "down-regulates activity" "chemical inhibition" -1 17868033 t Luana "Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay." SIGNOR-257940 "trichostatin A" chemical CHEBI:46024 ChEBI HDAC7 protein Q8WUI4 UNIPROT "down-regulates activity" "chemical inhibition" -1 17868033 t Luana "Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay." SIGNOR-257938 PAK1 protein Q13153 UNIPROT PXN protein P49023 UNIPROT unknown phosphorylation Ser272 ELDELMAsLSDFKIQ 9606 16717130 t llicata "We show that p21-activated kinase (pak)-induced phosphorylation of serine 273 in paxillin is a critical regulator of this turnover." SIGNOR-146842 PAK1 protein Q13153 UNIPROT ARHGDIA protein P52565 UNIPROT down-regulates phosphorylation Ser101 LESFKKQsFVLKEGV 9606 BTO:0000142 15225553 t lperfetto "Pak1 binds and phosphorylates rhogdi both in vitro and in vivo at ser101 and ser174. This resulted in dissociation of rac1-rhogdi, but not rhoa-rhogdi, complexes, as determined by in vitro assays of complexation and in vivo by coimmunoprecipitation analysis. We observed that cdc42-induced rac1 activation is inhibited by expression of pak1 autoinhibitory domain. The dissociation of rac1 from rhogdi and its subsequent activation stimulated by pdgf or egf is also attenuated by pak1 autoinhibitory domain, and this is dependent on the ability of rhogdi to be phosphorylated at ser101/174." SIGNOR-126650 PAK1 protein Q13153 UNIPROT ARHGDIA protein P52565 UNIPROT down-regulates phosphorylation Ser174 KGMLARGsYSIKSRF 9606 BTO:0000142 15225553 t lperfetto "Pak1 binds and phosphorylates rhogdi both in vitro and in vivo at ser101 and ser174. This resulted in dissociation of rac1-rhogdi, but not rhoa-rhogdi, complexes, as determined by in vitro assays of complexation and in vivo by coimmunoprecipitation analysis. We observed that cdc42-induced rac1 activation is inhibited by expression of pak1 autoinhibitory domain. The dissociation of rac1 from rhogdi and its subsequent activation stimulated by pdgf or egf is also attenuated by pak1 autoinhibitory domain, and this is dependent on the ability of rhogdi to be phosphorylated at ser101/174." SIGNOR-126654 PAK1 protein Q13153 UNIPROT PLK1 protein P53350 UNIPROT up-regulates phosphorylation Ser49 EVLVDPRsRRRYVRG 9606 BTO:0000567 18427546 t llicata "We show here that pak1 is required for cell proliferation, mitotic progression and plk1 activity in hela cells. phosphorylation of plk1 on ser 49 is important for metaphase-associated events." SIGNOR-178353 PAK1 protein Q13153 UNIPROT PAK1 protein Q13153 UNIPROT "up-regulates activity" phosphorylation Ser199 PRPEHTKsVYTRSVI 9534 BTO:0000298 9032240 t miannu "Cdc42 and Rac1 cause alpha-PAK autophosphorylation and kinase activation." SIGNOR-250216 trimipramine chemical CHEBI:9738 ChEBI SLC6A3 protein Q01959 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 9537821 t miannu "At the human dopamine transporter, sertraline and nomifensine were the most potent with KD's of 25±2 and 56±3, respectively. Except for these two compounds, most antidepressants were not potent at the human dopamine transporter." SIGNOR-258740 trimipramine chemical CHEBI:9738 ChEBI SLC6A4 protein P31645 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 9537821 t miannu "Among the antidepressants that we tested, paroxetine, which is a serotonin selective re-uptake inhibitor based on animal data, was the most potent for the human serotonin transporter with a KD=0.13±0.01 nM. Some tricyclic antidepressants (clomipramine, imipramine and amitriptyline), as well as some other antidepressants (sertraline, fluoxetine, citalopram and fluvoxamine) and some of their metabolites (norfluoxetine, desmethylsertraline and desmethylcitalopram) were also very potent at the human serotonin transporter." SIGNOR-258741 PAK1 protein Q13153 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 10611223 t lperfetto "Pak phosphorylates bad in vitro and in vivo on ser112 and ser136, resulting in a markedly reduced interaction between bad and bcl-2 or bcl-x(l) and the increased association of bad with 14-3-3tau." SIGNOR-73529 PAK1 protein Q13153 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 10611223 t lperfetto "Pak phosphorylates bad in vitro and in vivo on ser112 and ser136, resulting in a markedly reduced interaction between bad and bcl-2 or bcl-x(l) and the increased association of bad with 14-3-3tau." SIGNOR-73533 PAK1 protein Q13153 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser74 VEIRSRHsSYPAGTE 9606 BTO:0000007 22096607 t lperfetto "Bad is a pro-apoptotic member of the bcl-2 family of proteins, which can be phosphorylated on numerous sites to modulate binding to bcl-2 and 14-3-3 proteins and inhibit its pro-apoptotic activities. Together, these findings demonstrate that pak1 phosphorylates bad directly at s111, but phosphorylated s112 through raf-1. These two sites of bad serve as redundant regulatory sites for bcl-2 binding" SIGNOR-177271 PAK1 protein Q13153 UNIPROT ARHGEF2 protein Q92974 UNIPROT down-regulates phosphorylation Ser886 PVDPRRRsLPAGDAL 9606 19667072 t gcesareni "We identify gef-h1 as a binding target and substrate for p21-activated kinase 1 (pak1), we show that phosphorylation of gef-h1 at ser(885) by pak1 induces 14-3-3 binding to the exchange factor and relocation of 14-3-3 to microtubules." SIGNOR-187573 PAK1 protein Q13153 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0001955 12876277 t lperfetto "We find that adhesion to fibronectin induces pak1-dependent phosphorylation of mek1 on s298 and that this phosphorylation is necessary for efficient activation of mek1 and subsequent mapk activation." SIGNOR-244924 FADD protein Q13158 UNIPROT CASP8 protein Q14790 UNIPROT "up-regulates activity" binding 9606 BTO:0000782 11717445 t amattioni "Fadd recruits caspase-8 through homotypic interactions of death-effector domains (deds), leading to caspase-8 activation and apoptosis. In turn, fadd recruits the zymogen form of the apoptosis-initiating protease caspase-8, through homophilic interaction of death effector domains." SIGNOR-112061 FADD protein Q13158 UNIPROT CASP10 protein Q92851 UNIPROT up-regulates binding 9606 BTO:0000782 11717445 t gcesareni "The death-effector domains ofcasp8and -10 bothinteractwith the death-effector domain offadd. Therefore, caspase-10 is recruited into the fas signaling complex and becomes activated like caspase-8" SIGNOR-112058 MAP2K5 protein Q13163 UNIPROT MAPK7 protein Q13164 UNIPROT up-regulates phosphorylation 9606 BTO:0000142 11782488 t gcesareni "Kato et al. reported that mek5 specifically activates bmk1 but not other mammalian map kinasesin vivo." SIGNOR-113770 MAP2K5 protein Q13163 UNIPROT MAPK7 protein Q13164 UNIPROT up-regulates phosphorylation 9606 12912994 t gcesareni "Mek5 is the mapk kinase that phosphorylates and activates erk5 in response to growth factors, oxidative stress, and hyperosmotic conditions." SIGNOR-104631 TTK protein P33981 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 19332559 t llicata "Ttk/hmps1 mediates the p53-dependent postmitotic checkpoint by phosphorylating p53 at thr18. phosphorylation at thr18 enhances p53-dependent activation of not only p21 but also lats2, two mediators of the postmitotic checkpoint." SIGNOR-184931 MAPK7 protein Q13164 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates phosphorylation Ser387 LSLPSTQsLNIKSEP 9606 BTO:0000887;BTO:0001260 9384584 t lperfetto "Bmk1 dramatically enhances the transactivation activity of mef2c by phosphorylating a serine residue at amino acid position 387 in this transcription factor." SIGNOR-53545 TULP3 protein O75386 UNIPROT GPR161 protein Q8N6U8 UNIPROT "up-regulates activity" relocalization 10090 BTO:0003913 23332756 t "Upon knockdown of Tulp3 using siRNA in IMCD3 cells, ciliary localization of Gpr161 was severely reduced" SIGNOR-259938 TUBB protein P07437 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" binding 9606 17429065 t lperfetto "Smad2/3 also binds to _-tubulin, which provides a negative regulatory mechanism controlling tgf-_ activity. the results showed that the mh2 domain of smad2 binds to _-tubulin with almost the same efficiency as the full-length (wild-type) smad2. Similar results were obtained for the smad3 binding to _-tubulin." SIGNOR-232113 TUBB protein P07437 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates binding 9606 17429065 t lpetrilli "Smad2/3 also binds to _-tubulin, which provides a negative regulatory mechanism controlling tgf-_ activity. the results showed that the mh2 domain of smad2 binds to _-tubulin with almost the same efficiency as the full-length (wild-type) smad2. Similar results were obtained for the smad3 binding to _-tubulin." SIGNOR-154316 PAK2 protein Q13177 UNIPROT ABL1 protein P00519 UNIPROT down-regulates phosphorylation Ser618 APTPPKRsSSFREMD 9606 18161990 t lperfetto "The interaction of c-abl with the abl interactor protein abi2 is shown to be negatively regulated by phosphorylation of serines 637 and 638. These serines are adjacent to the pxxp motif (ptppkrs637s638sfr) that binds the sh3 domain of abi. phosphorylation of c-abl by pak2 inhibits the interaction between the sh3 domain of abi2 and the pxxp motif of c-abl." SIGNOR-160215 PAK2 protein Q13177 UNIPROT ABL1 protein P00519 UNIPROT down-regulates phosphorylation Ser619 PTPPKRSsSFREMDG 9606 18161990 t lperfetto "The interaction of c-abl with the abl interactor protein abi2 is shown to be negatively regulated by phosphorylation of serines 637 and 638. These serines are adjacent to the pxxp motif (ptppkrs637s638sfr) that binds the sh3 domain of abi. phosphorylation of c-abl by pak2 inhibits the interaction between the sh3 domain of abi2 and the pxxp motif of c-abl." SIGNOR-160219 PAK2 protein Q13177 UNIPROT VIM protein P08670 UNIPROT "down-regulates activity" phosphorylation Ser66 GVYATRSsAVRLRSS -1 11895474 t miannu "In vitro analyses revealed that vimentin served as an excellent substrate for PAK. This phosphorylated vimentin lost the potential to form 10 nm filaments. We identified Ser25, Ser38, Ser50, Ser65 and Ser72 in the amino-terminal head domain as the major phosphorylation sites on vimentin for PAK. " SIGNOR-250241 PAK2 protein Q13177 UNIPROT VIM protein P08670 UNIPROT "down-regulates activity" phosphorylation Ser73 SAVRLRSsVPGVRLL -1 11895474 t miannu "In vitro analyses revealed that vimentin served as an excellent substrate for PAK. This phosphorylated vimentin lost the potential to form 10 nm filaments. We identified Ser25, Ser38, Ser50, Ser65 and Ser72 in the amino-terminal head domain as the major phosphorylation sites on vimentin for PAK. " SIGNOR-250243 PAK2 protein Q13177 UNIPROT SYN1 protein P17600 UNIPROT unknown phosphorylation Ser9 NYLRRRLsDSNFMAN 10116 12237306 t miannu "Recombinant PAK2 could also phosphorylate the Ser9 and Ser551 residues." SIGNOR-250236 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT "up-regulates activity" phosphorylation Ser19 PAPPVRMsSTIFSTG -1 10075701 t miannu "Eight autophosphorylation sites were identified in Cdc42-activated gamma-PAK, six of which are in common with those previously reported in alpha-PAK, while Ser-19 and Ser-165 appear to be uniquely phosphorylated in the gamma-form. Further, the phosphorylation of Ser-141, Ser-165, and Thr-402 was found to correlate with gamma-PAK activation. The information resulting from manual Edman degradation and from automated sequencing clearly identified Ser-192, Ser-197, and Thr-402 as the phosphorylation sites" SIGNOR-250224 PAK2 protein Q13177 UNIPROT MYLK protein Q15746 UNIPROT "down-regulates activity" phosphorylation Ser1208 MKSRRPKsSLPPVLG -1 10748018 t miannu "PAK2 can directly phosphorylate MLCK, inhibiting its activity and limiting the development of isometric tension. PAK2 catalyzes MLCK phosphorylation on serine residues 439 and 991." SIGNOR-250222 TXK protein P42681 UNIPROT TXK protein P42681 UNIPROT up-regulates phosphorylation Tyr91 KIQVKALyDFLPREP 9606 BTO:0000782 12081135 t lperfetto "Evidence of autophosphorylation in txk: y91 is an autophosphorylation site. the results suggest that phosphorylated txk is an active form to promote ifn-gamma synthesis" SIGNOR-89844 TXK protein P42681 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr113 SSFEEDDyESPNDDQ 9606 BTO:0000782 10660534 t lperfetto "Resting lymphocyte kinase (rlk/txk) targets lymphoid adaptor slp-76 in the cooperative activation of interleukin-2 transcription in t-cells. In this study, we report that rlk phosphorylates slp-76 at its n-terminal yesp/yepp sites. A third tyrosine within the amino-terminal region (y145) appears to be the most important for optimal slp-76 function" SIGNOR-74844 TXK protein P42681 UNIPROT LCP2 protein Q13094 UNIPROT "up-regulates activity" phosphorylation Tyr128 DGEDDGDyESPNEEE 9606 BTO:0000782 10660534 t lperfetto "Rlk phosphorylated the N-terminal region of SLP-76, a region that has been previously shown to serve as a target for ZAP-70. Loss of N-terminal YESP/YEPP sites of SLP-76 or the Rlk kinase activity attenuated cooperativity between Rlk and SLP-76" SIGNOR-246929 CBX3 protein Q13185 UNIPROT H3-4 protein Q16695 UNIPROT "up-regulates activity" binding 9606 methylation:Lys10 RTKQTARkSTGGKAP 19111658 t miannu "A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing." SIGNOR-264495 CBX3 protein Q13185 UNIPROT NIPBL protein Q6KC79 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 28167679 t miannu "The heterochromatin protein HP1γ (also known as CBX3) recruits NIPBL to DNA double-strand breaks (DSBs) through the corresponding HP1-binding motif within the N-terminus." SIGNOR-264524 STK3 protein Q13188 UNIPROT ABL1 protein P00519 UNIPROT down-regulates phosphorylation Thr735 DTEWRSVtLPRDLQS 9606 18794806 t lperfetto "Here, we identify clk1, clk4, mst1, mst2 and ttk (also known as mps1) as novel thr735 kinases in vitro / phosphorylation of thr735 in c-abl is critical for binding to 14-3-3" SIGNOR-181056 "tyrphostin AG 1478" chemical CHEBI:75404 ChEBI EGFR protein P00533 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189377 "tyrphostin B42" chemical CHEBI:131968 ChEBI EGFR protein P00533 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189386 "tyrphostin B42" chemical CHEBI:131968 ChEBI JAK2 protein O60674 UNIPROT "down-regulates activity" 9606 11368440 t gcesareni "the Janus kinase inhibitor, tyrphostine AG490, inhibits STAT3 activation, STAT3 DNA binding, and IL-2Ralpha mRNA and protein expression in parallel" SIGNOR-238293 "tyrphostin B42" chemical CHEBI:131968 ChEBI JAK2 protein O60674 UNIPROT "down-regulates activity" "chemical inhibition" 9606 11368440 t gcesareni "the Janus kinase inhibitor, tyrphostine AG490, inhibits STAT3 activation, STAT3 DNA binding, and IL-2Ralpha mRNA and protein expression in parallel" SIGNOR-238542 U0126.EtOH chemical CHEBI:90692 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207603 PSMD2 protein Q13200 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "form complex" binding 9606 BTO:0000007 29636472 t lperfetto "Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line" SIGNOR-263344 U69593 chemical CHEBI:73357 ChEBI OPRK1 protein P41145 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258827 TBX2 protein Q13207 UNIPROT MYOD1 protein P15172 UNIPROT "down-regulates activity" binding 9606 24470334 t "We have found that TBX2 is highly up regulated in both ERMS and ARMS subtypes of RMS and demonstrate that TBX2 is a repressor of myogenesis by binding to MyoD and myogenin and inhibiting their activity." SIGNOR-251560 TBX2 protein Q13207 UNIPROT MYOG protein P15173 UNIPROT "down-regulates activity" binding 9606 24470334 t "We have found that TBX2 is highly up regulated in both ERMS and ARMS subtypes of RMS and demonstrate that TBX2 is a repressor of myogenesis by binding to MyoD and myogenin and inhibiting their activity." SIGNOR-251561 UBE2I protein P63279 UNIPROT SOX6 protein P35712 UNIPROT "down-regulates activity" sumoylation Lys404 VSPTGIkNEKRGTS 9606 BTO:0000007 16442531 t "We show that SOX6 is modified in vitro and in vivo by small ubiquitin‐related modifier (SUMO) on two distinct sites. Mutation of both sites abolished SOX6 sumoylation and increased SOX6 transcriptional activity. SUMO dependent repression of SOX6 transcription was promoted by UBC9 whereas siRNA to UBC9, cotransfection of inactive UBC9 or a SUMO protease increased SOX6 transcriptional activity." SIGNOR-256129 UBE2I protein P63279 UNIPROT PLAG1 protein Q6DJT9 UNIPROT down-regulates sumoylation Lys244 NQELLKVkTEPVDFL 9606 15208321 t miannu "Sumoylation decreases the transcriptional activity of plag1 / plag1 is sumoylated at 2 specific lysine residues (lys-244 and lys-263)" SIGNOR-126044 UBE2I protein P63279 UNIPROT PLAG1 protein Q6DJT9 UNIPROT down-regulates sumoylation Lys263 CNVSVPIkDELLPVM 9606 15208321 t miannu "Sumoylation decreases the transcriptional activity of plag1 / plag1 is sumoylated at 2 specific lysine residues (lys-244 and lys-263)" SIGNOR-126048 MAP3K1 protein Q13233 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates phosphorylation Thr275 LVDSKAKtRSAGCAA 9606 9312068 t lperfetto "Here we show that jnkk2, a novel member of the map kinase kinase family, was phosphorylated and activated by mekk1" SIGNOR-51211 MAP3K1 protein Q13233 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 BTO:0000150 17563747 t lperfetto "Phosphorylation of s727 induces pin1 binding which increases transcription. Pin1 binding increases stat3 interaction with p300 and dna." SIGNOR-236346 MAP3K1 protein Q13233 UNIPROT MAP2K4 protein P45985 UNIPROT "up-regulates activity" phosphorylation Thr261 LVDSIAKtRDAGCRP 9606 BTO:0000007 9712898 t lperfetto "The gck-ctd-mekk1 interaction is sufficiently stable to support mekk1 s phosphorylation of its substrate, sek1" SIGNOR-236380 MAP3K1 protein Q13233 UNIPROT MAP2K4 protein P45985 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007 9712898 t lperfetto "The gck-ctd-mekk1 interaction is sufficiently stable to support mekk1 s phosphorylation of its substrate, SEK1" SIGNOR-236376 UBXN8 protein O00124 UNIPROT VCP protein P55072 UNIPROT "down-regulates quantity" relocalization 9606 BTO:0000567 21949850 t SARA "The human protein named Rep8 or Ubxd6 as a new cofactor of p97. Rep8 tethers p97 to the ER membrane for efficient ER-associated degradation." SIGNOR-261002 UCHL1 protein P09936 UNIPROT UBC protein P0CG48 UNIPROT "up-regulates quantity" cleavage 9606 BTO:0000938 9521656 t lperfetto "These data suggest that the physiological role of UCH is to hydrolyze small adducts of ubiquitin and to generate free monomeric ubiquitin from ubiquitin proproteins, but not to deubiquitinate ubiquitin-protein conjugates or disassemble polyubiquitin chains" SIGNOR-249693 UBXN1 protein Q04323 UNIPROT NGLY1 protein Q96IV0 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 15362974 t miannu "PNGase is directed to polyubiquitinated MGPs via VCP and the adaptor protein SAKS1, allowing PNGase to deglycosylate MGPs, which can then be degraded by the proteasome. PNGase itself is reported to bind to the S4 component of the 19 S proteasome." SIGNOR-261060 UBXN1 protein Q04323 UNIPROT Protein_degradation phenotype SIGNOR-PH96 SIGNOR up-regulates 9606 BTO:0000007 15362974 f miannu "Our working hypothesis is that SAKS1 acts as scaffolding protein to enhance the unfolding and proteolytic destruction of a subset of proteins. PNGase removes high-mannose-containing oligosaccharides from MGPs [30], and our results suggest this may be facilitated by the formation of a complex between PNGase, VCP, SAKS1 and ubiquitinated MGPs, as illustrated schematically in Figure 7(B). PNGase has been reported to bind to the S4 component of the proteasome [30], so that the deglycosylation of MGPs by PNGase, followed by VCP-catalysed unfolding, may facilitate their destruction by the proteasome." SIGNOR-261059 PRKG2 protein Q13237 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser82 RALSRQLsSGVSEIR 9606 19593530 t "10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro." lperfetto "Purified pkg isoforms ia, ib, and ii all caused incorporation of phosphate in recombinant hsp27 at ser-78, ser-82, and thr-143, but not ser-15.These Studies indicate that hsp27 is a genuine substrate for pkg and that pkg may mediate inhibition of platelet aggregation through phosphorylation of hsp27 and subsequent prevent of actin polymerization" SIGNOR-186943 PRKG2 protein Q13237 UNIPROT PLCB3 protein Q01970 UNIPROT "down-regulates activity" phosphorylation Ser1105 LDRKRHNsISEAKMR 10116 BTO:0004576 11278298 t lperfetto "PKG can directly phosphorylate PLC-beta2 and PLC-beta3 in vitro with purified proteins and in vivo with metabolic labeling. Phosphorylation of PLC-beta leads to the inhibition of G-protein-activated PLC-beta3 activity by 50-70% in COS-7 cell transfection assays. By using phosphopeptide mapping and site-directed mutagenesis, we further identified two key phosphorylation sites for the regulation of PLC-beta3 by PKG (Ser(26) and Ser(1105)). Mutation at these two sites (S26A and S1105A) of PLC-beta3 completely blocked the phosphorylation of PLC-beta3 protein catalyzed by PKG." SIGNOR-249078 PRKG2 protein Q13237 UNIPROT PTS protein Q03393 UNIPROT up-regulates phosphorylation Ser19 AQVSRRIsFSASHRL 9606 BTO:0000142 10531334 t gcesareni "Upon expression in cos-1 cells, ptps-s19a was stable but not phosphorylated and had a reduced activity of approximately 33% in comparison to wild-type ptps. Addition of cgmp stimulated phosphotransferase activity 2-fold. Extracts from transfected cos-1 cells overexpressing cgkii stimulated ser(19) phosphorylation more than 100-fold.In assays with purified enzymes, wild-type but not ptps-s19a was a specific substrate for the cgmp-dependent protein kinase (cgk) type i and ii. Upon expression in cos-1 cells, ptps-s19a was stable but not phosphorylated and had a reduced activity of approximately 33% in comparison to wild-type ptps" SIGNOR-71751 PRKG2 protein Q13237 UNIPROT LASP1 protein Q14847 UNIPROT unknown phosphorylation Ser146 MEPERRDsQDGSSYR 9606 BTO:0000132 12571245 t lperfetto "Recombinant human LASP was phosphorylated by cGMP- and cAMP-dependent protein kinase (cAK) in vitro. Cotransfection of PtK-2 cells with LASP and cGK confirmed phosphorylation of LASP in vivo. Studies with human LASP mutants identified serine 146 as a specific phosphorylation site for cGK and cAK in vivo. LASP is an actin-binding protein, and the phospho-LASP-mimicking mutant S146D showed reduced binding affinity for F-actin in cosedimentation experiments." SIGNOR-249197 NOG protein Q13253 UNIPROT GDF5 protein P43026 UNIPROT "down-regulates activity" binding 9606 21976273 t miannu "Growth and differentiation factor 5 (GDF5), a member of the bone morphogenetic protein (BMP) family, is essential for cartilage, bone, and joint formation. Antagonists such as noggin counteract BMP signaling by covering the ligand's BMP type I (BMPRI) and type II (BMPRII, ActRII, ActRIIB) interaction sites. The mutation GDF5-S94N is located within the BMPRII interaction site, the so-called knuckle epitope, and was identified in patients suffering from multiple synostoses syndrome (SYNS)." SIGNOR-252420 NOG protein Q13253 UNIPROT BMPR2 protein Q13873 UNIPROT "down-regulates activity" binding 9031 BTO:0000140 SIGNOR-C29 12478285 t "Create trimers (2 typeII and 1 typeI) with serine/threonine kinase function" lperfetto "Noggin binds the domain that is re-quired for bmp-7 to interact with bmp type i and type ii receptors (PMID 22298955). Noggin Inhibits bmp by blocking the molecular interfaces of the binding epitopes for both type i and type ii receptors" SIGNOR-219225 Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR CREB3L2 protein Q70SY1 UNIPROT up-regulates 9606 17178827 f miannu "Although bbf2h7 protein is not expressed under normal conditions, it is markedly induced at the translational level during er stress, suggesting that bbf2h7 might contribute to only the late phase of unfolded protein response signaling." SIGNOR-151312 Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR ERN1 protein O75460 UNIPROT up-regulates 9606 31226023 f miannu "Besides being activated like PERK via dissociation of GRP78, IRE1 is also activated by direct binding of the unfolded protein to its N-terminal luminal domain" SIGNOR-260175 Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR ERP44 protein Q9BS26 UNIPROT up-regulates 9606 11847130 f miannu "Like many ER folding factors, ERp44 transcripts are induced by agents that cause the accumulation of unfolded proteins in the ER." SIGNOR-261047 Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR HERPUD1 protein Q15011 UNIPROT "up-regulates quantity by expression" 9606 10922362 f miannu "We demonstrate a new target gene for upr-induced transcription, herp." SIGNOR-80156 Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR HSPA5 protein P11021 UNIPROT down-regulates 9606 31226023 f miannu "In the stressed ER, protein chaperone GRP78 binds to unfolded proteins and dissociates from the luminal domain of PERK, leading to oligomerization and activation of PERK by autophosphorylation." SIGNOR-260163 USF1 protein P22415 UNIPROT FOSL1 protein P15407 UNIPROT "down-regulates activity" binding 10090 BTO:0000095 9160889 t 2 miannu "USF specifically interacts with Fra1. USF was repressing this modest Fra1 transactivation" SIGNOR-240975 USF1 protein P22415 UNIPROT GCK protein P35557 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 9677331 f miannu "Cotransfection of an expression plasmid encoding USF1 into HepG2 hepatoma cells resulted in the activation of the glucokinase promoter, dependent on the integrity of the P2 element" SIGNOR-255597 USF1 protein P22415 UNIPROT GATA5 protein Q9BWX5 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002922 22625849 f miannu "The present study provides the first evidence that USF1 activates GATA5 gene expression through the E-box motif and suggests a potential mechanism (disruption of the E-box) by which GATA5 promoter methylation reduces GATA5 expression in cancer." SIGNOR-255596 NR5A1 protein Q13285 UNIPROT STAR protein P49675 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001555 19022561 f miannu "We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters." SIGNOR-254869 NMI protein Q13287 UNIPROT SOX10 protein P56693 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 16214168 t miannu "we identify an association of Sox10 with the N-myc interactor Nmi. Nmi modulated the transcriptional activity of Sox10 in reporter gene assays. Nmi effects varied between different Sox10 target gene promoters, indicating that Nmi function in vivo may be promoter-specific." SIGNOR-225602 PTK7 protein Q13308 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 23151663 t gcesareni "Ptk7 has been strongly implicated in pcp and, like many pcp activators, is a negative regulator of beta-catenin-dependent wnt." SIGNOR-199536 USP6 protein P35125 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates 9606 20418905 f miannu "These data confirm that tre17 activates nfkappab in a usp-dependent manner" SIGNOR-164949 SKP2 protein Q13309 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates ubiquitination 9606 15998794 t gcesareni "Up-regulation of skp2 by notch signaling enhances proteasome-mediated degradation of the ckis, p27 kip1 and p21 cip1, and causes premature entry into s phase." SIGNOR-138490 SKP2 protein Q13309 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates ubiquitination 9606 15998794 t gcesareni "Up-regulation of skp2 by notch signaling enhances proteasome-mediated degradation of the ckis, p27 kip1 and p21 cip1, and causes premature entry into s phase. ;the recognition of p27 by skp2/cks1 of the scfskp2 complex is dictated by cycline/cdk2, providing a high affinity binding site and the phosphorylation of p27 at t187, serving here we provide evidence suggesting that both cdk2/e and phosphorylation of thr(187) on p27 are essential for the recognition of p27 by the scf(skp2/cks1) complex, the ubiquitin-protein isopeptide ligase (e3)." SIGNOR-138493 ATM protein Q13315 UNIPROT PPM1G protein O15355 UNIPROT "up-regulates activity" phosphorylation Ser183 GTGEEPGsQGLNGEA -1 26324325 t "ATM indeed mediated PPM1G phosphorylation at S183, and mutation of this residue (S183A) abrogated detection with the phospho-specific antibody" SIGNOR-255591 ATM protein Q13315 UNIPROT FANCA protein O15360 UNIPROT up-regulates phosphorylation Ser1449 AAPDADLsQEPHLF 9606 19109555 t lperfetto "The s1449a mutant failed to completely correct a variety of fa-associated phenotypes. The dna damage response is coordinated by phosphorylation events initiated by apical kinases atm (ataxia telangectasia mutated) and atr (atm and rad3-related), and atr is essential for proper fa pathway function. Serine 1449 is in a consensus atm/atr site" SIGNOR-182949 ATM protein Q13315 UNIPROT BUB1 protein O43683 UNIPROT up-regulates phosphorylation Ser314 SHEDLPAsQERSEVN 9606 22099307 t lperfetto "We also demonstrate that mitotically activated atm phosphorylates bub1, a critical kinetochore protein, on ser314. Atm-mediated bub1 ser314 phosphorylation is required for bub1 activity and is essential for the activation of the spindle checkpoint" SIGNOR-177276 ATM protein Q13315 UNIPROT NBN protein O60934 UNIPROT up-regulates phosphorylation Ser343 TTPGPSLsQGVSVDE 9606 10608806 t lperfetto "In this report, we showed that atm phosphorylates a p95 peptide (ser-343) and a mre11 peptide (ser-264) in vitro, suggesting that atm may regulate the function of p95?Mre11? Rad50 repair complex in response to dna damage." SIGNOR-73432 ATM protein Q13315 UNIPROT NBN protein O60934 UNIPROT up-regulates phosphorylation Ser343 TTPGPSLsQGVSVDE 9606 10802669 t gcesareni "We show that atm physically interacts with and phosphorylates nibrin on serine 343 both in vivo and in vitro. Phosphorylation of this site appears to be functionally important because mutated nibrin (s343a) does not completely complement radiosensitivity in nbs cells." SIGNOR-77149 ATM protein Q13315 UNIPROT NBN protein O60934 UNIPROT up-regulates phosphorylation Ser278 VDTGITNsQTLIPDC 9606 10839544 t lperfetto "We have identified two residues of nbs1, ser 278 and ser 343 that are phosphorylated in vitro by atm and whose modification in vivo is essential for the cellular response to dna damage. This response includes s-phase checkpoint activation, formation of the nbs1/mrel1/rad50 nuclear foci and rescue of hypersensitivity to ionizing radiation." SIGNOR-78025 ATM protein Q13315 UNIPROT NBN protein O60934 UNIPROT up-regulates phosphorylation Ser397 EQKFRMLsQDAPTVK 9606 10839545 t lperfetto "We have identified two residues of nbs1, ser 278 and ser 343 that are phosphorylated in vitro by atm and whose modification in vivo is essential for the cellular response to dna damage. This response includes s-phase checkpoint activation, formation of the nbs1/mrel1/rad50 nuclear foci and rescue of hypersensitivity to ionizing radiation." SIGNOR-78030 ATM protein Q13315 UNIPROT NBN protein O60934 UNIPROT up-regulates phosphorylation Ser615 VPESSKIsQENEIGK 9606 10839545 t lperfetto "In vivo, nbs was phosphorylated on many serine residues, of which s343, s397 and s615 were phosphorylated by atm in vitro. Reconstituting nbs cells with a mutant form of nbs that cannot be phosphorylated at selected, atm-dependent serine residues led to a specific reduction in clonogenic survival after gamma-radiation." SIGNOR-78034 "UV stress" stimulus SIGNOR-ST7 SIGNOR CDKN2A protein P42771 UNIPROT up-regulates 9606 11830546 f miannu "The expression of the melanoma susceptibility gene product p16 is increased after UVR both in epidermally derived cell lines and in human skin. The increased expression of p16 after exposure to suberythemal doses of UVR is potentiated by α-MSH, a ligand for MC1R, and this effect is mimicked by cAMP, the intracellular mediator of α-MSH signaling via the MC1 receptor." SIGNOR-252376 "UV stress" stimulus SIGNOR-ST7 SIGNOR KRT14 protein P02533 UNIPROT up-regulates 9606 BTO:0000667 11875647 f miannu "UVB increases keratin 5 and keratin 14 expression through direct activation of the EGF receptor in SVHK." SIGNOR-251900 "UV stress" stimulus SIGNOR-ST7 SIGNOR MAP3K4 protein Q9Y6R4 UNIPROT up-regulates 9606 9305639 f lperfetto "Overexpression of a dominant-negative MTK1 mutant [MTK1(K/R)] strongly inhibited the activation of the p38 pathway by environmental stresses (osmotic shock, UV and anisomycin)[]These results indicate that MTK1 is a major mediator of environmental stresses that activate the p38 MAPK pathway" SIGNOR-226605 vatalanib chemical CHEBI:90620 ChEBI FLT1 protein P17948 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207642 vatalanib chemical CHEBI:90620 ChEBI KDR protein P35968 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258309 VCAM1 protein P19320 UNIPROT "A4/b1 integrin" complex SIGNOR-C162 SIGNOR "up-regulates activity" binding 9606 BTO:0000664 12123670 t lperfetto "We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1." SIGNOR-253241 VCP protein P55072 UNIPROT DDX58 protein O95786 UNIPROT "down-regulates quantity by destabilization" ubiquitination Lys181 ALEKERNkFSELWIV 9606 BTO:0000007 26471729 t lperfetto "Here, we report a new role for p97 with Npl4-Ufd1 as its cofactor in reducing antiviral innate immune responses by facilitating proteasomal degradation of RIG-I. The p97 complex is able to directly bind both non-ubiquitinated RIG-I and the E3 ligase RNF125, promoting K48-linked ubiquitination of RIG-I at residue K181." SIGNOR-261000 VCP protein P55072 UNIPROT NGLY1 protein Q96IV0 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 15362974 t simone "PNGase is directed to polyubiquitinated MGPs via VCP and the adaptor protein SAKS1, allowing PNGase to deglycosylate MGPs, which can then be degraded by the proteasome. PNGase itself is reported to bind to the S4 component of the 19 S proteasome." SIGNOR-261058 ATM protein Q13315 UNIPROT H2AX protein P16104 UNIPROT up-regulates phosphorylation Ser140 GKKATQAsQEY 9606 21690091 t gcesareni "Upon dna damage, h2ax is phosphorylated by ataxia telangiectasia mutated (atm) and atm-related kinases at serine 139, known as ?_?_?_-H2ax, which serves as a docking site to recruit the mediator of dna damage checkpoint protein 1 (mdc1) to sites of dna damage, named dna damage foci" SIGNOR-174442 ATM protein Q13315 UNIPROT CREB1 protein P16220 UNIPROT down-regulates phosphorylation Ser107 SVDSVTDsQKRREIL 9606 15073328 t lperfetto "Atm phosphorylated creb in vitro and in vivo in response to ionizing radiation (ir) and h(2)o(2) on a stress-inducible domain. Ir-induced phosphorylation of creb correlated with a decrease in creb transactivation potential and reduced interaction between creb and its transcriptional coactivator, creb-binding protein (cbp). A creb mutant containing ala substitutions at atm phosphorylation sites displayed enhanced transactivation potential," SIGNOR-124047 ATM protein Q13315 UNIPROT HNF1A protein P20823 UNIPROT up-regulates phosphorylation Ser249 IQRGVSPsQAQGLGS 9606 24821553 t lperfetto "Serine 249 phosphorylation by atm protein kinase regulates hepatocyte nuclear factor-1_ transactivation" SIGNOR-205087 VEGFD protein O43915 UNIPROT FLT4 protein P35916 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103;BTO:0000763 9435229 t gcesareni "Vegf-d is a ligand for both vegf receptors (vegfrs) vegfr-2 (flk1) and vegfr-3 (flt4) and can activate these receptors." SIGNOR-55065 VEGFD protein O43915 UNIPROT KDR protein P35968 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103;BTO:0000763 9435229 t gcesareni "Vegf-d is a ligand for both vegf receptors (vegfrs) vegfr-2 (flk1) and vegfr-3 (flt4) and can activate these receptors." SIGNOR-55163 ATM protein Q13315 UNIPROT MCM3 protein P25205 UNIPROT unknown phosphorylation Ser535 ATDDPNFsQEDQQDT 9606 15210935 t lperfetto "Atm phosphorylates mcm3 on s535 in response to ionizing radiation. Second, atr phosphorylates mcm2 on s108 in response to multiple forms of dna damage and stalling of replication forksthe functional consequences of mcm2 s108 and mcm3 s535 phosphorylation are not clear" SIGNOR-126308 veliparib chemical CHEBI:62880 ChEBI PARP1 protein P09874 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189183 "Vicriviroc Malate" chemical CID:10218922 PUBCHEM CCR5 protein P51681 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207657 vildagliptin chemical CHEBI:135285 ChEBI DPP4 protein P27487 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000783 19149538 t Luana "Various classes of structurally different DPP IV inhibitors are currently being explored and few of them such as Sitagliptin and Vildagliptin were successfully launched." SIGNOR-257812 "Vincristine sulfate" chemical CHEBI:79401 ChEBI FN1 protein P02751 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000144 30599272 t miannu "Vincristine is commonly administered as an effective anti-brain tumor drug. Vincristine treatment also impaired the microtubule-associated protein tubulin, and fibronectin, and downregulated MMP10 activity." SIGNOR-259252 Viral_replication stimulus SIGNOR-ST23 SIGNOR Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR up-regulates 9606 31226023 f miannu "Double-stranded RNA (dsRNA), a common intermediate during the replication of DNA and RNA viruses." SIGNOR-260587 vismodegib chemical CHEBI:66903 ChEBI SMO protein Q99835 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000527 21679342 t gcesareni "Cyclopamine with improved solubility (ipi-926), smo inhibitors that considerably differ in structure from cyclopamine (gdc-0499, lde225, bms-833923, xl-139, pf-0449913), inhibitors of the transformation of inactive smo into active smo (sant 74-75), and inhibitors of the transport of cytoplasmic inactive smo to cilia (sant 1-4) have been developed to date." SIGNOR-174417 Volasertib chemical CID:10461508 PUBCHEM PLK1 protein P53350 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190290 vorinostat chemical CHEBI:45716 ChEBI HDAC8 protein Q9BY41 UNIPROT "down-regulates activity" "chemical inhibition" -1 17868033 t Luana "Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay." SIGNOR-257920 ATM protein Q13315 UNIPROT SIAH1 protein Q8IUQ4 UNIPROT down-regulates phosphorylation Ser19 GTSKCPPsQRVPALT 9606 18536714 t llicata "Disruption of the hipk2-siah-1 complex is mediated by the atm/atr pathway and involves atm/atr-dependent phosphorylation of siah-1 at ser 19." SIGNOR-177945 ATM protein Q13315 UNIPROT TTC5 protein Q8N0Z6 UNIPROT "up-regulates activity" phosphorylation Ser203 TGQNPKIsQQALSAY 9606 BTO:0001938 15448695 t miannu "Here we report a new pathway in which ATM kinase signals the DNA damage response by targeting the transcriptional cofactor Strap. ATM phosphorylates Strap at a serine residue, stabilizing nuclear Strap and facilitating formation of a stress-responsive co-activator complex." SIGNOR-262645 ATM protein Q13315 UNIPROT COP1 protein Q8NHY2 UNIPROT down-regulates phosphorylation Ser387 SDDSRTAsQLDEFQE 9606 16931761 t lperfetto "Atm engages autodegradation of the e3 ubiquitin ligase cop1 after dna damage. We observed that in response to dna damage, atm phosphorylated cop1 on ser(387) and stimulated a rapid autodegradation mechanism" SIGNOR-149082 VX-745 chemical CHEBI:90528 ChEBI MAPK11 protein Q15759 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207684 ATM protein Q13315 UNIPROT RAD50 protein Q92878 UNIPROT unknown phosphorylation Ser635 KLFDVCGsQDFESDL 9606 17570479 t llicata "The ms/ms fragmentation spectra (figure s7) confirmed the phosphorylation of rad50 at the predicted atm substrate site, s635, in agreement with published data" SIGNOR-156077 WASF3 protein Q9UPY6 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR "up-regulates activity" 9534 BTO:0000298 17623672 f "We have also shown that Abl targets and phosphorylates four tyrosine residues in WAVE3 and that the Abl-dependent phosphorylation of WAVE3 is critical for the stimulation of lamellipodia formation and cell migration." SIGNOR-259078 WASHC1 protein A8K0Z3 UNIPROT "WASH complex" complex SIGNOR-C258 SIGNOR "form complex" binding 23721880 t lperfetto "The WASH complex is composed of five proteins: KIAA1033 (also known as SWIP), Strumpellin, FAM21, WASH1 and CCDC53." SIGNOR-261020 WASHC2C protein Q9Y4E1 UNIPROT "WASH complex" complex SIGNOR-C258 SIGNOR "form complex" binding 23721880 t lperfetto "The WASH complex is composed of five proteins: KIAA1033 (also known as SWIP), Strumpellin, FAM21, WASH1 and CCDC53." SIGNOR-261016 WASHC3 protein Q9Y3C0 UNIPROT "WASH complex" complex SIGNOR-C258 SIGNOR "form complex" binding 23721880 t lperfetto "The WASH complex is composed of five proteins: KIAA1033 (also known as SWIP), Strumpellin, FAM21, WASH1 and CCDC53." SIGNOR-261017 ATM protein Q13315 UNIPROT AVEN protein Q9NQS1 UNIPROT "up-regulates activity" phosphorylation Ser135 VNNESGEsQRGTDFS -1 18571408 t miannu "Aven is also a substrate of the ATM kinase. Mutation of ATM-mediated phosphorylation sites on Aven reduced its ability to activate ATM, suggesting that Aven activation of ATM after DNA damage is enhanced by ATM-mediated Aven phosphorylation. We found that mutating S135 and S308 sites to Alanine largely dampened Aven’s phosphorylation by ATM (though some phosphorylation remained, due to either a contaminating kinase or an unidentified ATM phosphorylation site)." SIGNOR-262636 ATM protein Q13315 UNIPROT RASSF1 protein Q9NS23 UNIPROT up-regulates phosphorylation Ser135 EWETPDLsQAEIEQK 9606 BTO:0000551 19962312 t llicata "We show that, upon dna damage, rassf1a is phosphorylated by atm on ser131 and is involved in the activation of both mst2 and lats1, leading to the stabilization of p73." SIGNOR-161934 WIPF1 protein O43516 UNIPROT "Early Endosome" complex SIGNOR-C246 SIGNOR up-regulates 9606 BTO:0000007 19121306 f lperfetto "However, we did detect WAFL binding to bothWIP and actin by immunoprecipitation (Fig. 4). In conclusion, we propose a model whereby WAFL associates toendocytic vesicles by its coiled-coil domain and is involved in actin-based movement of early endosomes via WIP and binding to actin." SIGNOR-260611 WIPF1 protein O43516 UNIPROT Endocytosis phenotype SIGNOR-PH123 SIGNOR up-regulates 9606 BTO:0000007 19121306 f lperfetto "However, we did detect WAFL binding to bothWIP and actin by immunoprecipitation (Fig. 4). In conclusion, we propose a model whereby WAFL associates toendocytic vesicles by its coiled-coil domain and is involved in actin-based movement of early endosomes via WIP and binding to actin." SIGNOR-260609 ATM protein Q13315 UNIPROT EXO1 protein Q9UQ84 UNIPROT up-regulates phosphorylation 9606 20019063 t gcesareni "The phosphorylation of exo1 by atm appears to regulate the activity of exo1 following resection, allowing optimal rad51 loading and the completion of hr repair." SIGNOR-162304 ATM protein Q13315 UNIPROT SMC3 protein Q9UQE7 UNIPROT unknown phosphorylation Ser1083 ESERGSGsQSSVPSV 9606 18442975 t llicata "Ser-1083 phosphorylation is ir-inducible, depends on atm and nijmegen breakage syndrome 1 (nbs1), and is required for intra-s phase checkpoint." SIGNOR-178479 ATM protein Q13315 UNIPROT ZNF148 protein Q9UQR1 UNIPROT up-regulates phosphorylation Ser202 GEKPFQCsQCDMRFI 9606 17560543 t lperfetto "Here we found that zbp-89 is phosphorylated by atm kinase in vitro and in vivo. Disruption of the atm phosphorylation motif (202)sq within the zinc finger domain of zbp-89 attenuated its ability to enhance p21(waf1) activation by butyrate. Moreover, disruption of the atm phosphorylation site abrogated the ability of zbp-89 to potentiate butyrate induction of endogenous p21(waf1) expression." SIGNOR-155634 MTA1 protein Q13330 UNIPROT MTA3 protein Q9BTC8 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000812 18719363 f miannu "MTA1 overexpression resulted in downregulation of E-cadherin and MTA3 expression and enhanced expression of the transcriptional repressors SNAIL and SLUG." SIGNOR-254595 MTA1 protein Q13330 UNIPROT "MTA1/DJ1 complex" complex SIGNOR-C123 SIGNOR "form complex" binding 9606 BTO:0000567 21368136 t 1 miannu "we found that the MTA1/DJ1 complex is required for optimum stimulation of the TH expression by paired like homeodomain transcription factor (Pitx3) homeodomain transcription factor and that the MTA1/DJ1 complex is recruited to the TH gene chromatin via the direct interaction of MTA1 with Pitx3." SIGNOR-239739 WNT3A protein P56704 UNIPROT FBN1 protein P35555 UNIPROT "up-regulates quantity by stabilization" 10090 17943183 f Regulation miannu "Wnt3a markedly stimulated matrix assembly of microfibrillar proteins, including Fbn-1, by cultured fibroblasts, suggesting that Wnts contribute to increased microfibrillar matrices in Tsk skin.Wnt3a stimulates Fbn-1 matrix formation." SIGNOR-251894 WNT3A protein P56704 UNIPROT FZD8 protein Q9H461 UNIPROT up-regulates binding 9606 22653731 t gcesareni "Structural basis of wnt recognition by frizzled." SIGNOR-197638 WNT3A protein P56704 UNIPROT Frizzled proteinfamily SIGNOR-PF11 SIGNOR "up-regulates activity" binding 9606 21078818 t gcesareni "Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt Beta-catenin signaling." SIGNOR-253128 PPP2R5C protein Q13362 UNIPROT RPS6KB1 protein P23443 UNIPROT down-regulates binding 9606 20444422 t gcesareni "The human homolog of pp2a-b', ppp2r5c, also counteracts s6k1 phosphorylation, indicating a conserved mechanism in mammals" SIGNOR-165224 PPP2R5C protein Q13362 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates binding 9606 16456541 t gcesareni "B56-containing pp2a dephosphorylate erk and their activity is controlled by the early gene iex-1 and erk" SIGNOR-144328 PPP2R5C protein Q13362 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates binding 9606 16456541 t gcesareni "B56-containing pp2a dephosphorylate erk and their activity is controlled by the early gene iex-1 and erk" SIGNOR-144325 CTBP1 protein Q13363 UNIPROT ZEB2 protein O60315 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 16061479 t miannu "Polycomb protein Pc2 acts as an SUMO E3 ligase for SIP1. SIP1 is an active transcription repressor for many transcription factors and target genes. SIP1 Sumoylation Disrupts the Recruitment of the Corepressor CtBP" SIGNOR-225484 WNT5A protein P41221 UNIPROT DVL1 protein O14640 UNIPROT "up-regulates activity" 9606 BTO:0000007 21078818 f gcesareni "Common mechanism that involves their wnt-dependent coupling to the frizzled (fzd) coreceptor and recruitment of shared components, including dishevelled (dvl), axin, and glycogen synthase kinase 3 (gsk3)." SIGNOR-169666 WNT5A protein P41221 UNIPROT ROR1 protein Q01973 UNIPROT up-regulates binding 9606 23151663 t gcesareni "Ror1 and ror2 bind wnt5a." SIGNOR-199644 MAPK8IP2 protein Q13387 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT up-regulates binding 9606 10490659 t gcesareni "Deletion analysis demonstrated that the cooh-terminal regions of jip1 and jip2 were sufficient for the formation of hetero-oligomeric complexes" SIGNOR-70863 ILK protein Q13418 UNIPROT ILK protein Q13418 UNIPROT "up-regulates activity" phosphorylation Ser343 SMADVKFsFQCPGRM 9606 BTO:0001332 11313365 t lperfetto "Although ilk has been shown to autophosphorylate serine 343 (s343) is in the hydrophobic motif fsf within the activation loop of the kinase domain and has previously been suggested to be the target of autophosphorylation (9). Mutation of serine 343 to alanine (s343a) resulted in the inability of ilk to stimulate phosphorylation of pkb/akt in cos cells (9)." SIGNOR-106838 WNT7B protein P56706 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15578921 t 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-131981 ROCK1 protein Q13464 UNIPROT DNM1L protein O00429 UNIPROT "up-regulates activity" phosphorylation Ser637 VPVARKLsAREQRDC 10090 BTO:0002295 31063459 t lperfetto "We have also previously reported that ROCK1-mediated Drp1S600 phosphorylation resulted in enhanced mitochondrial fission in podocytes" SIGNOR-262549 ROCK1 protein Q13464 UNIPROT GFAP protein P14136 UNIPROT "down-regulates activity" phosphorylation Ser13 ITSAARRsYVSSGEM -1 12686604 t lperfetto "We report here that aurora-b phosphorylates gfap and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. The sites phosphorylated by aurora-b;thr-7/ser-13/ser-38 of gfap, and thr-16 of desmin are common with those related to rho-associated kinase (rho-kinase), which has been reported to phosphorylate gfap and desmin at cleavage furrow during cytokinesis. We identified ser-59 of desmin to be a specific site phosphorylated by aurora-b in vitro." SIGNOR-100181 ROCK1 protein Q13464 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Thr567 QGRDKYKtLRQIRQG 9606 19386264 t lperfetto "Activation of ezrin is mediated by initial pip2 binding and subsequent phosphorylation of threonine 567. We performed an in vitro kinase assay with 80 selected kinases on an ezrin peptide containing the t567 phosphorylation site (figure 3a). In this screen, we identified the mst and rock kinases as the most potent kinases for the ezrin peptide" SIGNOR-185567 "WRC complex" complex SIGNOR-C191 SIGNOR F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 9606 20332100 f miannu "The activated WAVE complex at the leading edge of lamellipodia promotes actin polymerization at the plasma membrane by activating the Arp2/3 complex." SIGNOR-253578 WRN protein Q14191 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR "up-regulates activity" 9606 19652551 f "Our work provides the first demonstration of the major importance of WRN in repair of a specific class of DSB in human cells." SIGNOR-258983 ROCK1 protein Q13464 UNIPROT MYL12A protein P19105 UNIPROT "up-regulates activity" phosphorylation Thr18 KKRPQRAtSNVFAMF 9606 BTO:0000567 12185584 t miannu "Phosphorylation of myosin II regulatory light chain (MRLC) is important for cell motility and cytokinesis in nonmuscle cells. Although the regulation of monophosphorylated MRLC at serine 19 throughout the cell cycle was examined in detail, MRLC diphosphorylation at both threonine 18 and serine 19 is still unclear. Here we found that Rho-kinase has an activity for MRLC diphosphorylation in nonmuscle cells using sequential column chromatographies." SIGNOR-263074 ROCK1 protein Q13464 UNIPROT MAPK8 protein P45983 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007 15068801 t gcesareni "Instead, we found that rock activates jnk, which then phosphorylates c-jun and atf2 when bound to the c-jun promoter." SIGNOR-123717 WWTR1 protein Q9GZV5 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 23075495 f gcesareni "Yap and taz are two main downstream effectors of the hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis." SIGNOR-256668 ROCK1 protein Q13464 UNIPROT PTEN protein P60484 UNIPROT up-regulates phosphorylation Thr232 YSSNSGPtRREDKFM 9606 BTO:0000672 15793569 t llicata "In addition, active rhoa is able to stimulate the phospholipid phosphatase activity of pten in human embryonic kidney cells and leukocytes, and this regulation seems to require rhoa's downstream effector, rhoa-associated kinase (rock). together with the observation that individual substitution of ser 229 and thr 223 restored some of the rescuing ability (fig. 4b), we conclude that effective regulation of pten by sdf-1 may require more than one of these residues." SIGNOR-134855 ROCK1 protein Q13464 UNIPROT RND3 protein P61587 UNIPROT up-regulates phosphorylation Ser11 RRASQKLsSKSIMDP 9606 15775972 t lperfetto "We show that rock phosphorylates endogenous rhoe at serine 11 upon cell stimulation with platelet-derived growth factor. Phosphorylation has no effect on rhoe binding to rock i, but instead increases rhoe protein stability." SIGNOR-134703 ROCK1 protein Q13464 UNIPROT MYLK protein Q15746 UNIPROT up-regulates binding 9606 11283607 t gcesareni "Rock proteins are known to regulate mlc-phosphorylation, and apoptotic cells exhibit a gradual increase in levels of phosphorylated mlc concomitant with rock i cleavage." SIGNOR-106552 ROCK1 protein Q13464 UNIPROT DPYSL2 protein Q16555 UNIPROT unknown phosphorylation Thr555 DNIPRRTtQRIVAPP 9534 BTO:0000298 10818093 t lperfetto "We produced an antibody that specifically recognizes CRMP-2 phosphorylated at Thr-555. Using this antibody, we found that Rho-kinase phosphorylated CRMP-2 downstream of Rho in COS7 cells. " SIGNOR-249042 WZ4002 chemical CHEBI:61400 ChEBI EGFR protein P00533 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207827 ROCK1 protein Q13464 UNIPROT MPRIP protein Q6WCQ1 UNIPROT down-regulates phosphorylation 9606 17761936 t gcesareni "Enhanced rho kinase activity induces endothelial barrier dysfunction by a contractile mechanism via inactivation of myosin phosphatase (mp).." SIGNOR-157593 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT up-regulates phosphorylation 9606 16862148 t acerquone "Rock phosphorylates filgap, and this phosphorylation stimulates its racgap activity and is a requirement for filgap-mediated bleb formation" SIGNOR-148262 XIAP protein P98170 UNIPROT CASP3 protein P42574 UNIPROT "down-regulates activity" binding 9606 10548111 t amattioni "The linker region located adjacent to the bir2 domain also participates in the binding of xiap to the effector caspases (-3 and -7)." SIGNOR-71954 XIAP protein P98170 UNIPROT CASP3 protein P42574 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 11447297 t lperfetto "Xiap promotes the degradation of active-form caspase-3, but not procaspase-3, in living cells. Both the association of XIAP with caspase-3 and the RING finger domain of XIAP were essential for ubiquitination. XIAP promotes the degradation of caspase-3, which enhances its anti-apoptotic effect." SIGNOR-109243 XIAP protein P98170 UNIPROT CASP7 protein P55210 UNIPROT "down-regulates quantity by destabilization" binding -1 11257231 t lperfetto "Our crystal structure of the complex between xiap (linker-bir2) and caspase-7 surprisingly revealed that the linker is the major determinant of binding and inhibition for the caspase." SIGNOR-105732 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT "up-regulates activity" phosphorylation Ser415 HKLDVSRsPPLMVKK 9606 BTO:0000007 16862148 t lperfetto "ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS‚‚PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573‚‚577 (see Supplementary Information, Table S2)." SIGNOR-249307 XL147 chemical CHEBI:71957 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-252659 ACVR2B protein Q13705 UNIPROT ACVR1B protein P36896 UNIPROT "up-regulates activity" phosphorylation Thr206 VQRTVARtIVLQEII 9606 8622651 t 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 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT "up-regulates activity" phosphorylation Thr575 SNSCRSStTTCPEQD 9606 BTO:0000007 16862148 t lperfetto "ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS€“PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573€“577 (see Supplementary Information, Table S2)." SIGNOR-249299 Y-27632 chemical CHEBI:75393 ChEBI ROCK1 protein Q13464 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207890 YBX1 protein P67809 UNIPROT ABCB1 protein P08183 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003918 10644769 f miannu "these results indicate a role for both NF-Y and Sp1 in the transcriptional activation of the MDR1 gene by genotoxic stress, and indicate that YB-1, if involved, is not sufficient to mediate this activation." SIGNOR-253873 YBX1 protein P67809 UNIPROT MMP13 protein P45452 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 17822788 f miannu "YB-1 binds to the MMP-13 promoter sequence and represses MMP-13 transactivation via the AP-1 site." SIGNOR-255615 YBX1 protein P67809 UNIPROT CXCR4 protein P61073 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001023 17072343 f miannu "YB-1 knockdown by siRNA upregulated 344 genes, including MDR1, thymidylate synthetase, S100 calcium binding protein and cyclin B, and downregulated 534 genes, including CXCR4, N-myc downstream regulated gene 1, E-cadherin and phospholipase C." SIGNOR-255611 YBX1 protein P67809 UNIPROT NDRG1 protein Q92597 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001023 17072343 f miannu "YB-1 knockdown by siRNA upregulated 344 genes, including MDR1, thymidylate synthetase, S100 calcium binding protein and cyclin B, and downregulated 534 genes, including CXCR4, N-myc downstream regulated gene 1, E-cadherin and phospholipase C." SIGNOR-255612 FZD5 protein Q13467 UNIPROT LRP6 protein O75581 UNIPROT "up-regulates activity" binding 9606 18077588 t areggio "Here we show that both Fz and Dvl functions are critical for Wnt-induced Lrp6 phosphorylation through Fz-Lrp6 interaction." SIGNOR-258966 FZD5 protein Q13467 UNIPROT PPARG protein P37231 UNIPROT down-regulates 9606 BTO:0000222 10937998 f fspada "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-80610 FZD5 protein Q13467 UNIPROT CEBPA protein P49715 UNIPROT down-regulates 9606 BTO:0000222 10937998 f fspada "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-80607 "Yellow AB" chemical CHEBI:82554 ChEBI PTCH1 protein Q13635 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000584 17970037 t gcesareni "Anti-patched-1 antibodies suppress hedgehog signaling pathway and pancreatic cancer proliferation." SIGNOR-158650 FZD5 protein Q13467 UNIPROT DVL3 protein Q92997 UNIPROT "up-regulates activity" binding 9606 23151663 t 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-258963 YWHAQ protein P27348 UNIPROT CDC25C protein P30307 UNIPROT down-regulates relocalization 9606 20068082 t gcesareni "Cdc25c: nuclear exclusion/cytoplasmic sequestration via binding to 14-3-3 proteins." SIGNOR-163237 YWHAH protein Q04917 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates binding 9606 12042314 t miannu "14-3-3_, 14-3-3_, and 14-3-3_ (but not 14-3-3_ and 14-3-3_) could form a complex with p27kip1 / we discovered that akt-mediated p27kip1phosphorylation directly induces p27kip1binding to 14-3-3 and cytoplasmic localization through phosphorylating the newly identified thr198residue." SIGNOR-109771 NFATC2 protein Q13469 UNIPROT FST protein P19883 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165 15130492 t lperfetto "MyoD, CREB, and NFAT Mediate the Transcriptional Activation of the Follistatin Promoter Induced by TSA" SIGNOR-251729 NFATC2 protein Q13469 UNIPROT PTGS2 protein P35354 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21871017 t miannu "NFAT induces the transcription of the COX2 (cyclo-oxygenase-2) gene incancer cells thereby enhancing invasive migration" SIGNOR-264025 NFATC2 protein Q13469 UNIPROT MYOF protein Q9NZM1 UNIPROT up-regulates "transcriptional regulation" 9606 23612709 f "Activated NFATc2 stimulates myoblast fusion through the increased production of IL-4 and myoferlin" SIGNOR-255461 YY1 protein P25490 UNIPROT SURF1 protein Q15526 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10858544 f miannu "We show that although the Surf-1/Surf-2 promoter does not contain Myc binding sites (E-boxes), Myc over-expression, or the activation of a Myc-oestrogen receptor fusion protein, activates transcription in the Surf-1 direction and that this response to Myc requires a functional YY1 binding site. Our data suggest that the MAP kinase cascade is required for the stimulation of Surf-1 promoter activity and that the Myc-YY1 interaction mediates this response." SIGNOR-254614 YY1 protein P25490 UNIPROT PRC2 complex SIGNOR-C130 SIGNOR "up-regulates quantity by expression" 17158804 t "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 SMAD4 protein Q13485 UNIPROT SMAD1/4 complex SIGNOR-C85 SIGNOR "form complex" binding 9606 9436979 t lperfetto "Bone morphogenetic protein (BMP) receptors signal by phosphorylating Smad1, which then associates with Smad4; this complex moves into the nucleus and activates transcription." SIGNOR-103618 SMAD4 protein Q13485 UNIPROT SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR "form complex" binding 9606 9843571 t 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 YY1 protein P25490 UNIPROT SUZ12/EZH2/YY1 complex SIGNOR-C102 SIGNOR "form complex" binding 10090 BTO:0000165;BTO:0002314 20887952 t lperfetto "TNF-activated p38a kinase promotes the interaction between YY1 and PRC2, via threonine 372 phosphorylation of EZH2, the enzy- matic subunit of the complex, leading to the for- mation of repressive chromatin on Pax7 promoter." SIGNOR-235580 BIRC3 protein Q13489 UNIPROT CASP9 protein P55211 UNIPROT down-regulates binding 9606 9545235 t gcesareni "Xiap, birc2 and birc3 were shown to bind pro-casp9. Iaps may suppress casp9 by direct auto-activation of pro-caspase-11" SIGNOR-56481 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr113 SSFEEDDyESPNDDQ 9606 BTO:0000782 9047237 t lperfetto "Zap-70 phosphorylates slp-76 at specific sites that allow vav sh2 domain bindingwe also show by in vitro and in vivo analysis that two slp-76 pyesp motifs (y113 and y128) mediate binding, the first being more efficient." SIGNOR-46855 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT "up-regulates activity" phosphorylation Tyr145 PVEDDADyEPPPSND 9606 BTO:0000782 12817019 t lperfetto "Phosphorylation of slp-76 is required for prolonged erk activation in response to sdf-1_ cr signal transduction results in slp-76 tyrosine phosphorylation at the amino-terminal tyrosines 113, 128, and 145 via a mechanism requiring the zap-70 tyrosine kinase." SIGNOR-102515 BIRC2 protein Q13490 UNIPROT RIPK1 protein Q13546 UNIPROT "up-regulates activity" ubiquitination 9606 16603398 t amattioni "In this report, we show that ciap1 and ciap2 promote cancer cell survival by functioning as e3 ubiquitin ligases that maintain constitutive ubiquitination of the rip1 adaptor protein." SIGNOR-145036 BIRC2 protein Q13490 UNIPROT RIPK1 protein Q13546 UNIPROT "up-regulates activity" ubiquitination 9606 BTO:0000007 18570872 t amattioni "cIAP1 and cIAP2 directly ubiquitinate RIP1 and induce constitutive RIP1 ubiquitination in cancer cells and demonstrate that constitutively ubiquitinated RIP1 associates with the prosurvival kinase TAK1. In this way RIP1 functions as a prosurvival scaffold molecule instead of a proapoptotic adaptor protein" SIGNOR-179100 ZBTB14 protein O43829 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 10080939 f miannu "ZF5, which we have cloned as a transcriptional repressor on the mouse c-myc promoter" SIGNOR-220537 ZAP70 protein P43403 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" phosphorylation Tyr493 LGADDSYyTARSAGK 9606 BTO:0000782 16049944 t lperfetto "Zap-70 is modified by auto-phosphorylation of various tyrosine residues and is activated by specific phosphorylation of the tyrosine residue y-493" SIGNOR-139098 ZAP70 protein P43403 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" phosphorylation Tyr492 ALGADDSyYTARSAG 9606 BTO:0000782;BTO:0000776 8756661 t lperfetto "The data further support a model in which ZAP-70 is first phosphorylated by Lck at Tyr-493 to upregulate the catalytic activity of ZAP-70. This in turn per- mits additional phosphorylation of ZAP-70 mediated, in part, by autophosphorylation at sites including Tyr-292 and -492" SIGNOR-226624 PIN1 protein Q13526 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 BTO:0000150 19151708 t gcesareni "Prolyl-isomerase pin1 interacts with notch1 and affects notch1 activation. Pin1 potentiates notch1 cleavage by gamma-secretase, leading to an increased release of the active intracellular domain and ultimately enhancing notch1. pin1 potentiates notch1 cleavage by gamma-secretase" SIGNOR-183461 PIN1 protein Q13526 UNIPROT IRF3 protein Q14653 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 16699525 t lperfetto "Here we report that activation of IRF3 is negatively regulated by the peptidyl-prolyl isomerase Pin1. After stimulation by double-stranded RNA, induced phosphorylation of the Ser339–Pro340 motif of IRF3 led to its interaction with Pin1 and finally polyubiquitination and then proteasome-dependent degradation of IRF3. Suppression of Pin1 by RNA interference or genetic deletion resulted in enhanced IRF-3-dependent production of interferon-beta, with consequent reduction of virus replication." SIGNOR-252256 ZEB2 protein O60315 UNIPROT CDH1 protein P12830 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15311212 f miannu "known E-cadherin transcriptional repressors, such as SLUG (SNAI2), SIP1 (ZEB2), TWIST1, SNAIL (SNAI1) and ZEB1 (TCF8), but not E12/E47 (TCF3), had a lack of upregulation in cells expressing mutated E-cadherin compared to WT." SIGNOR-255159 ATR protein Q13535 UNIPROT RAD17 protein O75943 UNIPROT "up-regulates activity" phosphorylation Ser656 SASELPAsQPQPFSA 9606 BTO:0000567 11687627 t lperfetto "Here we demonstrate that atr but not atm phosphorylates the human rad17 (hrad17) checkpoint protein on ser(635) and ser(645) in vitro.The rfc-related checkpoint protein rad17, a phosphorylation substrate of atr, is critical for atr-mediated checkpoint signaling and cell survival." SIGNOR-111252 ZFAT protein Q4KMQ4 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates quantity" 10090 24663380 f francesca "Ano6 deficiency significantly reduces ERK/AKT phosphorylation. In addition, Ano6-KD also affected levels of phosphorylated and total AKT levels." SIGNOR-261215 ziprasidone chemical CHEBI:10119 ChEBI HTR1A protein P08908 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9760039 t miannu "Several compounds proposed as ‘atypical’ antipsychoticagents were found to exhibit agonist activity at 5-HT1A EC values were greater than the respective Kvalues50i .21.8""5.8-fold difference,ns10 and a high degree of correlation was observed. All the compounds displayed high or marked bind-ing affinity at CHO-h5-HT1A receptors except for olanzapine, which exhibited a micromolar Kvalue at h5-HTi1A receptors (table3)." SIGNOR-258833 "ZM 336372" chemical CID:5730 PUBCHEM RAF1 protein P04049 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207911 ZM447439 chemical CHEBI:91376 ChEBI AURKB protein Q96GD4 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207923 ZM447439 chemical CHEBI:91376 ChEBI AURKC protein Q9UQB9 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207926 ZNF76 protein P36508 UNIPROT TBP protein P20226 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 15280358 t miannu "we identified ZNF76 as a novel transcriptional repressor that targets TBP. ZNF76 interacts with TBP through both its N and C termini. ZNF76 targets TBP for transcriptional repression." SIGNOR-224650 ATR protein Q13535 UNIPROT MCM6 protein Q14566 UNIPROT up-regulates phosphorylation 9606 21070963 t gcesareni "Together these data strongly support the conclusion that mec1 directly targets the s/tq sites in mcm4 and mcm6, although it is formally possible that mec1 and mrc1 activate a different s/tq-directed kinase to target mcm4 and mcm6." SIGNOR-169450 ATR protein Q13535 UNIPROT ATRIP protein Q8WXE1 UNIPROT up-regulates phosphorylation Ser68 EELDTLAsQALSQCP 9606 15451423 t lperfetto "When dna is damaged, the atr-atrip complex is recruited to chromatin and is activated to transduce the checkpoint signal, but the precise kinase activation mechanism remains unknown. Here, we show that atrip is phosphorylated in an atr-dependent manner after genotoxic stimuli. The serine 68 and 72 residues are important for the phosphorylation in vivo and are required exclusively for direct modification by atr in vitro." SIGNOR-129469 RIPK1 protein Q13546 UNIPROT TNFRSF10A protein O00220 UNIPROT up-regulates 9606 18545270 f gcesareni "The death domain of the rip1 kinase binds to death receptors such as tumor necrosis factor-related apoptosis-inducing ligand receptor 1,trailr1." SIGNOR-177952 RIPK1 protein Q13546 UNIPROT MAP3K7 protein O43318 UNIPROT "up-regulates activity" binding 9606 21133840 t "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 RIPK1 protein Q13546 UNIPROT FAS protein P25445 UNIPROT "up-regulates activity" binding 9606 18545270 t lperfetto "The death domain of the rip1 kinase binds to death receptors such as fas that is required for caspase 8 activation and apoptosis" SIGNOR-177949 RIPK1 protein Q13546 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates phosphorylation 9606 BTO:0000661 11369754 t gcesareni "These findings strongly suggest that rip phosphorylates mekk1 at ser-957 and ser-994." SIGNOR-108260 RIPK1 protein Q13546 UNIPROT MAP3K1 protein Q13233 UNIPROT "up-regulates activity" phosphorylation Ser970 HSQCLNSsPLSHHSQ 9606 BTO:0000661 11369754 t lperfetto "These findings strongly suggest that rip phosphorylates mekk1 at ser-957 and ser-994." SIGNOR-108257 RIPK1 protein Q13546 UNIPROT CASP8 protein Q14790 UNIPROT "up-regulates activity" binding 9606 BTO:0000007;BTO:0000459 12887920 t amattioni "Tradd and rip1 associate with fadd and caspase-8, forming a cytoplasmic complex" SIGNOR-104255 RIPK1 protein Q13546 UNIPROT CASP8 protein Q14790 UNIPROT "up-regulates activity" binding 9606 BTO:0002025 21525013 t amattioni "Degradation of ciaps triggers the release of receptor interacting protein kinase (ripk1) from tnf receptor i (tnfr1) to form a caspase-8 activating complex" SIGNOR-173432 RIPK1 protein Q13546 UNIPROT DAB2IP protein Q5VWQ8 UNIPROT "up-regulates activity" phosphorylation Ser728 PSPARSSsYSEANEP 9913 BTO:0003247 17389591 t "We further show that RIP1 (the Ser/Thr protein kinase receptor-interacting protein) associates with the GAP domain of AIP1 and mediates TNF-induced AIP1 phosphorylation at Ser-604 and JNK/p38 activation as demonstrated by both overexpression and small interfering RNA knockdown of RIP1 in EC." SIGNOR-259976 zotepine chemical CHEBI:32316 ChEBI HTR1A protein P08908 UNIPROT "down-regulates activity" "chemical inhibition" 10116 BTO:0000601 8935801 t miannu "Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B." SIGNOR-258558 zotepine chemical CHEBI:32316 ChEBI SLC6A2 protein P23975 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 20223878 t Luana "These results collectively demonstrate that norZTP exerts more potent inhibitory action than ZTP on norepinephrine transporters both in vitro and in vivo, presumably accounting for its antidepressant-like effect and low EPS propensity." SIGNOR-257828 LMAN2 protein Q12907 UNIPROT SERPINA1 protein P01009 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000599 20477988 t miannu "Identification of α1‐antitrypsin as interaction partner of VIP36. The complex formed by VIP36 and alpha1-AT in the Golgi recycled back to the ER. The combined data are most consistent with a function of VIP36 in post-ER quality control of alpha1-AT. We propose that VIP36 acts in post‐ER quality control in the Golgi by binding incompletely folded α1‐AT, which inadvertently escaped ER quality control, and by recycling it back to the ER for an additional round of quality control." SIGNOR-261356 HDAC1 protein Q13547 UNIPROT EGR1 protein P18146 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000567 21983014 f "In conclusion we demonstrated that treatment of HeLa cells with DMC leads to an enhanced formation of a complex consisting of NF-κB and HDAC1 that binds to the EGR1 promoter resulting in downregulation of EGR1 expression which plays a major role for transcriptional inhibition of mGPES-1 expression." SIGNOR-254257 HDAC1 protein Q13547 UNIPROT FSHR protein P23945 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001238 23086931 f miannu "Chromatin modifier MTA2 participates in the down-regulation of FSHR transcription. MTA2 is a potent corepressor of FSHR transcription, because it can recruit histone deacetylase-1 onto the FSHR promoter and participates in the down-regulation of FSHR expression upon FSH treatment." SIGNOR-254225 HDAC1 protein Q13547 UNIPROT CCND1 protein P24385 UNIPROT up-regulates binding 9606 15713663 t gcesareni "Cyclin d1 bound hdac in vivo and preferentially physically associated with hdac1, hdac2, hdac3, and hdac5." SIGNOR-134059 HDAC1 protein Q13547 UNIPROT DNMT1 protein P26358 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001570 23242655 f "Our previous studies demonstrated that mutant p53 along with repression complex proteins including DNMT1, HDAC1 and MeCP2 is associated with ER-negative promoter in MDA-MB-468 cells." SIGNOR-254028 MT-ATP8 protein P03928 UNIPROT "ATP synthase" complex SIGNOR-C264 SIGNOR "form complex" binding 9606 21874297 t miannu "Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L." SIGNOR-261406 HDAC1 protein Q13547 UNIPROT CEBPA protein P49715 UNIPROT down-regulates "transcriptional regulation" 9606 16431920 t fspada "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-210013 HDAC1 protein Q13547 UNIPROT CEBPA protein P49715 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 16431920 f fspada "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-143955 SELENOF protein O60613 UNIPROT UGGT2 protein Q9NYU1 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 24415556 t miannu "The enzymatic activity of UGGT2 is enhanced by complex formation with Sep15" SIGNOR-261373 TGFBR1 protein P36897 UNIPROT VPS39 protein Q96JC1 UNIPROT "up-regulates activity" binding 9534 12941698 t miannu "TLP interacts with TGF-β and activin receptors in vivo. Endogenous TLP associates with both active and kinase-deficient TGF-beta and activin type II receptors, but interacts with the common-mediator Smad4 only in the presence of TGF-beta/activin signaling." SIGNOR-261375 REEP5 protein Q00765 UNIPROT CXCR1 protein P25024 UNIPROT "up-regulates activity" binding 9606 BTO:0000018 27966653 t miannu "In this study, we found that CXCR1 interacted with REEP5 and REEP6, but CXCR2 did not. Overexpression of REEP5 and REEP6 enhanced IL-8-stimulated cellular responses through CXCR1, whereas depletion of the proteins led to the downregulation of the responses." SIGNOR-261366 QSOX2 protein Q6ZRP7 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 18034316 f miannu "a pro-apoptotic member of the QSOX superfamily, QSOXN, was described (Wittke et al. 2003). QSOXN was shown to sensitize neuroblastoma cells to INFγ-induced apoptosis, by still unknown mechanisms. In this context, absence of QSOX in fetal epithelia may prevent apoptosis." SIGNOR-261365 HDAC1 protein Q13547 UNIPROT FLI1 protein Q01543 UNIPROT up-regulates deacetylation Lys380 PTESSMYkYPSDISY 9606 24058639 t miannu "Hdac1 interacts with fli1 and mediates its deacetylation / our previous studies have shown that pcaf-dependent acetylation of fli1 at lysine 380 decreases its protein stability / p300 promotes the interaction of fli1 with hdac1 and increases the dna binding ability of fli1 through deacetylation of lysine 380" SIGNOR-202689 HDAC1 protein Q13547 UNIPROT RELA protein Q04206 UNIPROT down-regulates binding 9606 SIGNOR-C13 17183360 t gcesareni "Phosphorylation at thr505 by the chk1 inhibits rela transactivation and results in its increased association with hdac1." SIGNOR-151425 HDAC1 protein Q13547 UNIPROT HES1 protein Q14469 UNIPROT "down-regulates quantity" "transcriptional regulation" 10090 BTO:0004428 BTO:0000759 18762022 f "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 HDAC1 protein Q13547 UNIPROT GAD1 protein Q99259 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 19029285 f miannu "induction of the reelin and GAD67 mRNAs is accompanied by the dissociation of repressor complexes containing all three DNMTs, MeCP2, and HDAC1 from the corresponding promoters and by increased local histone acetylation." SIGNOR-254576 HDAC1 protein Q13547 UNIPROT "CoREST-HDAC complex" complex SIGNOR-C105 SIGNOR "form complex" binding 9606 BTO:0000567 11171972 t miannu "Here we describe the components of a histone deacetylase (HDAC) complex that we term the CoREST-HDAC complex. CoREST Is a Component of an HDAC1/2 Complex. p40 is a Sox-like protein, p110b contains homology to polyamine oxidases, p110a is ZNF217, an eight-zinc finger protein, and p80 is a hypothetical protein of unknown function." SIGNOR-222124 HDAC1 protein Q13547 UNIPROT SMAD7/HDAC1/E2F-1 complex SIGNOR-C12 SIGNOR "form complex" binding 9606 23213415 t gcesareni "Furthermore, smad7 caused hdac-1 bind to e2f-1 to form a ternary complex on chromosomal dna containing an e2f-binding motif and leading to repression in the activity of the e2f target genes" SIGNOR-199958 HDAC1 protein Q13547 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates binding 9606 17183360 t lperfetto "Phosphorylation at thr505 by the chk1 inhibits rela transactivation and results in its increased association with hdac1." SIGNOR-217409 HDAC1 protein Q13547 UNIPROT "MBD2/NuRD complex" complex SIGNOR-C337 SIGNOR "form complex" binding 9606 27098840 t miannu "The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression." SIGNOR-263839 ATP5F1B protein P06576 UNIPROT "ATP synthase" complex SIGNOR-C264 SIGNOR "form complex" binding 9606 21874297 t miannu "Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L." SIGNOR-261397 ATP5F1C protein P36542 UNIPROT "ATP synthase" complex SIGNOR-C264 SIGNOR "form complex" binding 9606 21874297 t miannu "Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L." SIGNOR-261405 ATP5F1D protein P30049 UNIPROT "ATP synthase" complex SIGNOR-C264 SIGNOR "form complex" binding 9606 21874297 t miannu "Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L." SIGNOR-261402 ATP5MC1 protein P05496 UNIPROT "ATP synthase" complex SIGNOR-C264 SIGNOR "form complex" binding 9606 21874297 t miannu "Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L." SIGNOR-261409 ATP5MG protein O75964 UNIPROT "ATP synthase" complex SIGNOR-C264 SIGNOR "form complex" binding 9606 21874297 t miannu "Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L." SIGNOR-261408 ARRB2 protein P32121 UNIPROT INPP5D protein Q92835 UNIPROT "up-regulates activity" binding 9606 BTO:0000914 24817116 t lperfetto "We identified a new adaptor beta-arrestin 2 that associates with phosphorylated TIGIT and mediates recruitment of inositol phosphatase SHIP1 through the ITT-like motif (Fig. 7). Finally, SHIP1 impairs TRAF6 autoubiquitination to abolish NF-kappaB activation, leading to inhibition of IFN- gamma production in NK cells." SIGNOR-261428 CAMK2G protein Q13555 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser273 AGTRRREsLGKKAKR 9677319 t llicata "Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. By deletion and point mutation analysis we show that phosphorylation by CaMKII and PKA occurs on a single serine residue at position 273" SIGNOR-250703 CAMK2G protein Q13555 UNIPROT PLCB3 protein Q01970 UNIPROT unknown phosphorylation Ser537 PSLEPQKsLGDEGLN 11325525 t llicata "CaMK II phosphorylated PLCbeta3 but not PLCbeta1 in vitro. Phosphorylation occurred exclusively on 537Ser in the X-Y linker region of PLCbeta3. 537Ser was also phosphorylated in the basal state in cells and phosphorylation was enhanced by ionomycin treatment" SIGNOR-250702 CAMK2G protein Q13555 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser259 FPLRKTAsEPNLKVR 9606 BTO:0000887 11114197 t gcesareni "Camk phosphorylates serines -259 and -498 in hdac5, which subsequently serve as docking sites for 14-3-3. Our studies suggest that 14-3-3 binding to hdac5 is required for camk-dependent disruption of mef2hdac complexes and nuclear export of hdac5, and implicate 14-3-3 as a signal-dependent regulator of muscle cell differentiation." SIGNOR-85098 INTS11 protein Q5TA45 UNIPROT "Integrator complex" complex SIGNOR-C265 SIGNOR "form complex" binding 7227 26220997 t lperfetto "Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits) " SIGNOR-261462 CAMK2D protein Q13557 UNIPROT TPD52 protein P55327 UNIPROT unknown phosphorylation Ser176 KNSPTFKsFEEKVEN 9606 BTO:0000567 BTO:0000975;BTO:0000671 20032513 t gcesareni "Here we demonstrate, using site-specific mutations, that ca(2+)-sensitive phosphorylation at serine 136 modulates the accumulation of d52 at the plasma membrane within 2 min of cell stimulation" SIGNOR-162630 INTS13 protein Q9NVM9 UNIPROT "Integrator complex" complex SIGNOR-C265 SIGNOR "form complex" binding 7227 26220997 t lperfetto "Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits) " SIGNOR-261469 CAMK2D protein Q13557 UNIPROT TPD52 protein P55327 UNIPROT unknown phosphorylation Ser176 KNSPTFKsFEEKVEN 9606 20946871 t gcesareni "Here we demonstrate, using site-specific mutations, that ca(2+)-sensitive phosphorylation at serine 136 modulates the accumulation of d52 at the plasma membrane within 2 min of cell stimulation" SIGNOR-168550 CAMK2D protein Q13557 UNIPROT HDAC4 protein P56524 UNIPROT up-regulates phosphorylation Ser210 YGKTQHSsLDQSSPP 9606 BTO:0000887;BTO:0001103 17179159 t lperfetto "These results demonstrate that camkiideltab preferentially targets hdac4, and this involves serine 210overexpression of camkiideltab in primary neonatal cardiomyocytes increases the activity of the mef2 transcription factor and completely rescues hdac4-mediated repression of mef2" SIGNOR-151418 CAMK2D protein Q13557 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates 9606 BTO:0001103 19725819 f 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 CAMK2D protein Q13557 UNIPROT CACNB2 protein Q08289 UNIPROT up-regulates phosphorylation Thr554 RGLSRQEtFDSETQE 9606 20194790 t "The effect has been demonstrated using Q08289-2" gcesareni "We recently identified ca(v)1.2 beta(2a) residues critical for camkii phosphorylation (thr 498) beta(2a) thr 498 and leu 493 are required for ca(v)1.2 activation by camkii in native cells." SIGNOR-164067 CAMK2D protein Q13557 UNIPROT CAMK2D protein Q13557 UNIPROT up-regulates phosphorylation 9606 BTO:0001103 19725819 t 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 RIN1 protein Q13671 UNIPROT KRAS protein P01116 UNIPROT up-regulates binding 9606 11784866 t gcesareni "We demonstrate that the ras effector protein rin1 binds to activated ras with an affinity (k(d), 22 nm) similar to that observed for raf1." SIGNOR-113970 CAMK2D protein Q13557 UNIPROT SCN5A protein Q14524 UNIPROT down-regulates phosphorylation Ser516 LSLTRGLsRTSMKPR 9606 BTO:0000007 22514276 t miannu "A stable interaction between ?(C)-camkii and the intracellular loop between domains 1 and 2 of na(v)1.5 was observed. This region was also phosphorylated by ?(C)-camkii, specifically at the ser-516 and thr-594 sites.Wild-type (wt) and phosphomutant hna(v)1.5 were co-expressed with gfp-?(C)-camkii in hek293 cells, and i(na) was recorded. As observed in myocytes, camkii shifted wt i(na) availability to a more negative membrane potential and enhanced accumulation of i(na) into an intermediate inactivated state, but these effects were abolished by mutating either of these sites to non-phosphorylatable ala residues." SIGNOR-197058 "28S mitochondrial small ribosomal subunit" complex SIGNOR-C266 SIGNOR Protein_synthesis phenotype SIGNOR-PH29 SIGNOR up-regulates 9606 27023846 f miannu "Mitochondrial ribosomes (mitoribosomes) perform protein synthesis inside mitochondria, the organelles responsible for energy conversion and adenosine triphosphate production in eukaryotic cells." SIGNOR-261487 BRK1 protein Q8WUW1 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR down-regulates 9606 BTO:0000934 23939472 f lperfetto "We found that NRF-1 positively regulates FAM134C and ENOX1, but negatively regulates C3orf10 in human neuroblastoma IMR-32 cells and primary rat cortical neurons. In IMR-32 cells, FAM134C positively regulates and C3orf10 negatively regulates neurite outgrowth, but ENOX1 plays no role in neurite outgrowth regulation. " SIGNOR-261491 "Integrator complex" complex SIGNOR-C265 SIGNOR FOSL1 protein P15407 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000567 25675981 f lperfetto "The Integrator complex controls the termination of transcription at diverse classes of gene targets.|Following INTS3 or INTS9 knockdown, the levels of SDC4, JUNB, FOSL1, and GADD45B increased, suggesting that the Integrator complex negatively regulates the transcription of these genes." SIGNOR-261477 "Integrator complex" complex SIGNOR-C265 SIGNOR GADD45B protein O75293 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000567 25675981 f lperfetto "The Integrator complex controls the termination of transcription at diverse classes of gene targets.|Following INTS3 or INTS9 knockdown, the levels of SDC4, JUNB, FOSL1, and GADD45B increased, suggesting that the Integrator complex negatively regulates the transcription of these genes." SIGNOR-261478 DYRK1A protein Q13627 UNIPROT FOXO6 protein A8MYZ6 UNIPROT down-regulates phosphorylation 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni "Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity" SIGNOR-183680 DYRK1A protein Q13627 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser330 RLSPIMAsTELDEVQ 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni "Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity phosphorylation of foxos by akt, ikk, erk, ck1, cdk2, and dyrk1a universally leads to foxo's inhibition." SIGNOR-183674 DYRK1A protein Q13627 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates activity" phosphorylation Ser330 RLSPIMAsTELDEVQ 9606 19188143 t lperfetto "Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity phosphorylation of foxos by akt, ikk, erk, ck1, cdk2, and dyrk1a universally leads to foxo's inhibition." SIGNOR-106833 STK11 protein Q15831 UNIPROT MARK2 protein Q7KZI7 UNIPROT up-regulates phosphorylation 9606 17573348 t gcesareni "Here we show in vitro that lkb1 phosphorylates and activates mark2" SIGNOR-156126 PTPN1 protein P18031 UNIPROT ACTN1 protein P12814 UNIPROT up-regulates dephosphorylation Tyr12 DSQQTNDyMQPEEDW 9606 16291744 t gcesareni "Here we report that protein-tyrosine phosphatase 1b (ptp 1b) is an ?-Actinin phosphatase." SIGNOR-141634 TNFRSF1B protein P20333 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" 20887952 f "These results indicate that TNF-a-activated p38 pathway negatively controls the expansion of PAX7-positive SCs" SIGNOR-253603 DRD4 protein P21917 UNIPROT GNB5 protein O14775 UNIPROT "up-regulates activity" binding 9606 BTO:0004032 21303898 t miannu "The D2-class dopamine receptors (D2, D3, and D4) couple to the Gi/o family of G proteins and thus induce inhibition of AC" SIGNOR-264995 DDB2 protein Q92466 UNIPROT DDB2/DDB1 complex SIGNOR-C39 SIGNOR "form complex" binding 9606 BTO:0000567 9418871 t miannu "Ddb was identified as a heterodimeric protein (48 and 127 kda) that binds to uv-damaged dna" SIGNOR-54099 CSNK1D protein P48730 UNIPROT MDM2 protein Q00987 UNIPROT "down-regulates activity" phosphorylation Ser269 SEEGQELsDEDDEVY 9606 12167711 t gcesareni "Hypophosphorylation of mdm2 augments p53 stability." SIGNOR-91191 CREBBP protein Q92793 UNIPROT MYBL1 protein P10243 UNIPROT "up-regulates activity" binding 9534 BTO:0004055 9210395 t 2 miannu "CBP co-operates functionally with A-Myb" SIGNOR-240984 LHX2 protein P50458 UNIPROT MSX1 protein P28360 UNIPROT "down-regulates activity" binding -1 9697309 t 2 miannu "Protein complex formation between Msx1 and Lhx2 homeoproteins is incompatible with DNA binding activity" SIGNOR-241327 TNFRSF25 protein Q93038 UNIPROT TRADD protein Q15628 UNIPROT up-regulates binding 9606 14585074 t amattioni "Dr3 induces apoptosis by tradd-mediated recruitment of fadd and caspase-8" SIGNOR-100480 MNAT1 protein P51948 UNIPROT ESR1 protein P03372 UNIPROT "up-regulates activity" phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 10949034 t Manara "Human Estrogen Receptor α Is Phosphorylated at Serine 118 In Vivo by Cdk7" SIGNOR-260837 EFNB2 protein P52799 UNIPROT EPHB3 protein P54753 UNIPROT up-regulates binding 9606 9330863 t gcesareni "Lerk-5 is a ligand for both elk and hek and induces receptor phosphorylation" SIGNOR-52583 PRKAA2 protein P54646 UNIPROT ACACB protein O00763 UNIPROT "down-regulates activity" phosphorylation Ser222 PTMRPSMsGLHLVKR 9606 BTO:0000887 14613924 t miannu "ACCβ(Ser221) is a known target for AMPK in human skeletal muscle" SIGNOR-250316 SEMA3A protein Q14563 UNIPROT NRP1 protein O14786 UNIPROT down-regulates binding 9606 BTO:0000938 10196546 t gcesareni "Semaphorins a and e act as antagonists of neuropilin-1 and agonists of neuropilin-2 receptors." SIGNOR-66661 CASP8 protein Q14790 UNIPROT CASP7 protein P55210 UNIPROT up-regulates cleavage 9606 9727491 t gcesareni "Casp8 can activate downstream caspases like caspase-6, and caspase-7 by directly cleaving them." SIGNOR-58118 CASP8 protein Q14790 UNIPROT CASP9 protein P55211 UNIPROT "up-regulates activity" -1 10988287 f lperfetto "One indirect means through which caspase-8 might regulate caspase-9 activation is through a bcl-2-regulated pathway." SIGNOR-81811 IL23A protein Q9NPF7 UNIPROT IL12RB1 protein P42701 UNIPROT up-regulates binding 9606 BTO:0000782 12023369 t gcesareni "Like il-12, il-23 binds to the il-12r subunit il-12rbeta1." SIGNOR-87739 CASP8 protein Q14790 UNIPROT CASP6 protein P55212 UNIPROT up-regulates cleavage 9606 9727491 t gcesareni "Casp8 can activate downstream caspases like caspase-6, and caspase-7 by directly cleaving them." SIGNOR-59857 LPAR3 protein Q9UBY5 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 BTO:0000938 12531543 t gcesareni "Lpa3couples to gq" SIGNOR-97400 SEPTIN9 protein Q9UHD8 UNIPROT ARHGEF18 protein Q6ZSZ5 UNIPROT down-regulates binding 9606 BTO:0000567 15558029 t miannu "In transient expression analyses, sept9b inhibited sa-rhogef-dependent rho activation in cos7 and hela cells." SIGNOR-131184 GDF2 protein Q9UK05 UNIPROT ALPL protein P05186 UNIPROT up-regulates 9606 19175684 f gcesareni "Wnt3a and bmp-9 enhanced each other's ability to induce alp in mscs" SIGNOR-183535 TAOK2 protein Q9UL54 UNIPROT MAP2K3 protein P46734 UNIPROT "up-regulates activity" binding -1 10497253 t lperfetto "Cotransfection experiments suggested that tao2 selectively activates mek3 and mek6 but not meks 1, 4, or 7." SIGNOR-70947 NSFL1C protein Q9UNZ2 UNIPROT CTSL protein P07711 UNIPROT "down-regulates activity" binding -1 15498563 t lperfetto "The SEP domain of p47 acts as a reversible competitive inhibitor of cathepsin L." SIGNOR-265043 USP24 protein Q9UPU5 UNIPROT DDB2 protein Q92466 UNIPROT up-regulates deubiquitination 9606 23159851 t miannu "Usp24-mediated ddb2 deubiquitination prevents ddb2 degradation" SIGNOR-199731 MAPK8IP1 protein Q9UQF2 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates binding 9606 10490659 t gcesareni "Both jip1 and jip2 selectively bind the mapkk isoform mkk7." SIGNOR-70848 MAPK8IP1 protein Q9UQF2 UNIPROT MAP3K12 protein Q12852 UNIPROT down-regulates binding 9606 11432832 t gcesareni "Jip inhibits dlk dimerization." SIGNOR-109046 WNT6 protein Q9Y6F9 UNIPROT MYF5 protein P13349 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 9753670 f gcesareni "Wnt4, wnt5a and wnt6 exert an intermediate effect activating both myf5 and myod equivalently in paraxial mesoderm." SIGNOR-60415 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR SREBF1 protein P36956 UNIPROT up-regulates phosphorylation Ser439 AGSPFQSsPLSLGSR 9606 16880739 t lperfetto "Cdk1/cyclin b-mediated phosphorylation stabilizes srebp1 during mitosis." SIGNOR-216821 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR DFFB protein O76075 UNIPROT up-regulates cleavage 9606 BTO:0000567 9108473 t gcesareni "Casp3_ cleaves the 45 kda subunit at two sites to generate an active factor that produces_ dna_ fragmentation" SIGNOR-256463 mTORC1 complex SIGNOR-C3 SIGNOR HIF1A protein Q16665 UNIPROT up-regulates 9606 20670887 f gcesareni "Hif1alfa is the transcription factor downstream of mtorc1 in the control of glycolytic genes." SIGNOR-167187 ANKRD26 protein Q9UPS8 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 BTO:0002572 21669876 f lperfetto "Ankrd26 gene disruption enhances adipogenesis of mouse embryonic fibroblasts." SIGNOR-266071 "Caspase 7 complex" complex SIGNOR-C232 SIGNOR PARP1 protein P09874 UNIPROT down-regulates cleavage 9606 11058599 t amattioni "Caspase-7 cleaves parp;redundancy exists between the caspase-3 and -7 at the level of parp proteolysis." SIGNOR-256470 PKA proteinfamily SIGNOR-PF17 SIGNOR CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser100 HLSGRKLsLQERSQG 9606 22778263 t lperfetto "Pka phosphorylates ser-100, ser-495, and ser-511the camp/pka pathway can inhibit camkk2 activity" SIGNOR-198146 AKT proteinfamily SIGNOR-PF24 SIGNOR CASP9 protein P55211 UNIPROT "down-regulates activity" phosphorylation Ser196 KLRRRFSsLHFMVEV -1 9812896 t "Akt phosphorylated recombinant Casp9 in vitro on serine-196 and inhibited its protease activity." SIGNOR-251473 FOXO proteinfamily SIGNOR-PF27 SIGNOR CDKN1B protein P46527 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 BTO:0004245 10783894 t gcesareni "AFX transcriptionally activates p27kip1, resulting in increased protein levels." SIGNOR-252928 NOTCH proteinfamily SIGNOR-PF30 SIGNOR SNW1 protein Q13573 UNIPROT up-regulates binding 9606 10713164 t gcesareni "Notch signal transduction pathway genes, lfng, hey1, and hes1, are differen-tially regulated by bmp-2 and tgf-beta." SIGNOR-254337 mTORC1 complex SIGNOR-C3 SIGNOR NRBF2 protein Q96F24 UNIPROT "up-regulates activity" phosphorylation Ser113 AEDAEGQsPLSQKYS 9606 BTO:0001938 28059666 t miannu "Human NRBF2 is phosphorylated by MTORC1 at S113 and S120. Upon nutrient starvation or MTORC1 inhibition, NRBF2 phosphorylation is diminished. Phosphorylated NRBF2 preferentially interacts with PIK3C3/PIK3R4. Suppression of NRBF2 phosphorylation by MTORC1 inhibition alters its binding preference from PIK3C3/PIK3R4 to ATG14/BECN1, leading to increased autophagic PtdIns3K complex assembly, as well as enhancement of ULK1 protein complex association." SIGNOR-265876 mTORC1 complex SIGNOR-C3 SIGNOR NRBF2 protein Q96F24 UNIPROT "up-regulates activity" phosphorylation Ser120 SPLSQKYsPSTEKCL 9606 BTO:0001938 28059666 t miannu "Human NRBF2 is phosphorylated by MTORC1 at S113 and S120. Upon nutrient starvation or MTORC1 inhibition, NRBF2 phosphorylation is diminished. Phosphorylated NRBF2 preferentially interacts with PIK3C3/PIK3R4. Suppression of NRBF2 phosphorylation by MTORC1 inhibition alters its binding preference from PIK3C3/PIK3R4 to ATG14/BECN1, leading to increased autophagic PtdIns3K complex assembly, as well as enhancement of ULK1 protein complex association." SIGNOR-265877 GREB1 protein Q4ZG55 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 30154312 f miannu "GREB1 is an early estrogen-responsive gene, and its expression is correlated with estrogen levels in breast cancer patients. Additionally, GREB1 responds to androgen in prostate cancer cells, and can stimulate the proliferation of breast, ovarian, and prostate cancer cells." SIGNOR-265886 "Food intake" phenotype SIGNOR-PH152 SIGNOR "vitamin K" smallmolecule CHEBI:28384 ChEBI "up-regulates quantity" 31226734 f lperfetto "Vitamin K obtained from the diet is considered to reach the target tissues via lipid absorption and the transport system " SIGNOR-265899 AKT1 protein P31749 UNIPROT MVD protein P53602 UNIPROT "up-regulates activity" phosphorylation Ser96 LARKRRNsRDGDPLP 10090 BTO:0000802 25378391 t miannu "Akt modulated the pathway by phosphorylating mevalonate diphosphate decarboxylase (MDD) at Ser96. These data suggest that Akt regulates Rac1 activity by directly phosphorylating MDD at Ser96, which augments Rac1 geranylgeranylation." SIGNOR-265891 HSPA9 protein P38646 UNIPROT MVD protein P53602 UNIPROT "down-regulates activity" binding 9534 BTO:0000298 12646231 t miannu "Mortalin binds to mevalonate pyrophosphate decarboxyl ase in mammalian cell. Mot-2 inactivates MPD resulting in decreased amounts of the steady state Ras protein." SIGNOR-265890 MRE11 protein P49959 UNIPROT PIH1D1 protein Q9NWS0 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 phosphorylation:Ser688;Ser689;Ser561;Ser558 SKGVDFEsSEDDDDD;KGVDFESsEDDDDDP;MANDSDDsISAATNK;AEQMANDsDDSISAA 28436950 t miannu "Here we show that MRE11 directly interacts with PIH1D1, a subunit of heat-shock protein 90 cochaperone R2TP complex, which is required for the assembly of large protein complexes, such as RNA polymerase II, small nucleolar ribonucleoproteins and mammalian target of rapamycin complex 1. The MRE11-PIH1D1 interaction is dependent on casein kinase 2 (CK2) phosphorylation of two acidic sequences within the MRE11 C terminus containing serines 558/561 and 688/689." SIGNOR-265898 MVD protein P53602 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" lipidation 10090 BTO:0000802 25378391 t miannu "Akt modulated the pathway by phosphorylating mevalonate diphosphate decarboxylase (MDD) at Ser96. These data suggest that Akt regulates Rac1 activity by directly phosphorylating MDD at Ser96, which augments Rac1 geranylgeranylation." SIGNOR-265892 warfarin chemical CHEBI:10033 ChEBI VKORC1 protein Q9BQB6 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 27941861 t lperfetto "Warfarin and vitamin K compete for binding to Phe55 in human VKOR|Our results challenge the prevailing concept of noncompetitive warfarin inhibition because K vitamers and warfarin share binding sites on VKOR that include Phe55, a key residue binding either the substrate or inhibitor." SIGNOR-265911 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT "up-regulates activity" carboxylation 9606 31226734 t lperfetto "Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation." SIGNOR-265921 GGCX protein P38435 UNIPROT BGLAP protein P02818 UNIPROT "up-regulates activity" carboxylation 9606 31226734 t lperfetto "Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation." SIGNOR-265922 GGCX protein P38435 UNIPROT PROC protein P04070 UNIPROT "up-regulates activity" carboxylation 9606 28125048 t lperfetto "Gamma-carboxylation is essential in the activation and proper functioning of multiple VK-dependent proteins (VKDP), the most well-known of which are involved in blood clotting, including coagulation factors (FII, FVII, FIX and FX) and natural anti-clotting agents (protein C, protein S (ProS; OMIM*176880) and protein Z" SIGNOR-265925 GGCX protein P38435 UNIPROT PROS1 protein P07225 UNIPROT "up-regulates activity" carboxylation 9606 28125048 t lperfetto "Gamma-carboxylation is essential in the activation and proper functioning of multiple VK-dependent proteins (VKDP), the most well-known of which are involved in blood clotting, including coagulation factors (FII, FVII, FIX and FX) and natural anti-clotting agents (protein C, protein S (ProS; OMIM*176880) and protein Z" SIGNOR-265924 GGCX protein P38435 UNIPROT PROZ protein P22891 UNIPROT "up-regulates activity" carboxylation 9606 28125048 t lperfetto "Gamma-carboxylation is essential in the activation and proper functioning of multiple VK-dependent proteins (VKDP), the most well-known of which are involved in blood clotting, including coagulation factors (FII, FVII, FIX and FX) and natural anti-clotting agents (protein C, protein S (ProS; OMIM*176880) and protein Z" SIGNOR-265926 GGCX protein P38435 UNIPROT GAS6 protein Q14393 UNIPROT "up-regulates activity" carboxylation 9606 31226734 t lperfetto "Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation." SIGNOR-265923 BLOC-1 complex SIGNOR-C381 SIGNOR Melanosome_assembly phenotype SIGNOR-PH180 SIGNOR up-regulates 9606 BTO:0000847 22203680 f lperfetto "Lysosome-related organelles (LROs) 6 are present in a range of cells in multicellular eukaryotes and include lytic granules, lung lamellar bodies, platelet-dense granules, and melanosomes (1.). The melanosome of the pigment cells in the skin and eye is the best studied of the LROs (1., 2.). The biogenesis of the melanosome and other LROs requires the AP-3 adaptor complex, the class C Vps complex, and three BLOC (biogenesis of lysosome-related organelles complex) complexes" SIGNOR-265939 BLOC-1 complex SIGNOR-C381 SIGNOR Platelet_dense_granule_formation phenotype SIGNOR-PH181 SIGNOR up-regulates 9606 BTO:0000132 12019270 f lperfetto "BLOC-1, a novel complex containing the pallidin and muted proteins involved in the biogenesis of melanosomes and platelet-dense granules|Interestingly, immunofluorescence and in vitro binding experiments demonstrated that pallidin/BLOC-1 is able to associate with actin filaments. We propose that BLOC-1 mediates the biogenesis of lysosome-related organelles by a mechanism that may involve self-assembly and interaction with the actin cytoskeleton." SIGNOR-265940 "AP-3 complex" complex SIGNOR-C247 SIGNOR Melanosome_assembly phenotype SIGNOR-PH180 SIGNOR up-regulates 9606 BTO:0000847 22203680 f lperfetto "Lysosome-related organelles (LROs) 6 are present in a range of cells in multicellular eukaryotes and include lytic granules, lung lamellar bodies, platelet-dense granules, and melanosomes (1.). The melanosome of the pigment cells in the skin and eye is the best studied of the LROs (1., 2.). The biogenesis of the melanosome and other LROs requires the AP-3 adaptor complex, the class C Vps complex, and three BLOC (biogenesis of lysosome-related organelles complex) complexes" SIGNOR-265941 "AP-3 complex" complex SIGNOR-C247 SIGNOR Platelet_dense_granule_formation phenotype SIGNOR-PH181 SIGNOR up-regulates 9606 BTO:0000132 12019270 f lperfetto "BLOC-1, a novel complex containing the pallidin and muted proteins involved in the biogenesis of melanosomes and platelet-dense granules|Interestingly, immunofluorescence and in vitro binding experiments demonstrated that pallidin/BLOC-1 is able to associate with actin filaments. We propose that BLOC-1 mediates the biogenesis of lysosome-related organelles by a mechanism that may involve self-assembly and interaction with the actin cytoskeleton." SIGNOR-265942 SNAPIN protein O95295 UNIPROT BLOC-1 complex SIGNOR-C381 SIGNOR "form complex" binding 9606 BTO:0002946 22203680 t lperfetto "We show that BLOC-1 is an elongated complex that contains one copy each of the eight subunits pallidin, Cappuccino, dysbindin, Snapin, Muted, BLOS1, BLOS2, and BLOS3. The complex appears as a linear chain of eight globular domains, ∼300 A long and ∼30 A in diameter." SIGNOR-265935 BLOC1S1 protein P78537 UNIPROT BLOC-1 complex SIGNOR-C381 SIGNOR "form complex" binding 9606 BTO:0002946 22203680 t lperfetto "We show that BLOC-1 is an elongated complex that contains one copy each of the eight subunits pallidin, Cappuccino, dysbindin, Snapin, Muted, BLOS1, BLOS2, and BLOS3. The complex appears as a linear chain of eight globular domains, ∼300 A long and ∼30 A in diameter." SIGNOR-265936 BLOC1S3 protein Q6QNY0 UNIPROT BLOC-1 complex SIGNOR-C381 SIGNOR "form complex" binding 9606 BTO:0002946 22203680 t lperfetto "We show that BLOC-1 is an elongated complex that contains one copy each of the eight subunits pallidin, Cappuccino, dysbindin, Snapin, Muted, BLOS1, BLOS2, and BLOS3. The complex appears as a linear chain of eight globular domains, ∼300 A long and ∼30 A in diameter." SIGNOR-265934 BLOC1S2 protein Q6QNY1 UNIPROT BLOC-1 complex SIGNOR-C381 SIGNOR "form complex" binding 9606 BTO:0002946 22203680 t lperfetto "We show that BLOC-1 is an elongated complex that contains one copy each of the eight subunits pallidin, Cappuccino, dysbindin, Snapin, Muted, BLOS1, BLOS2, and BLOS3. The complex appears as a linear chain of eight globular domains, ∼300 A long and ∼30 A in diameter." SIGNOR-265937 BLOC1S5 protein Q8TDH9 UNIPROT BLOC-1 complex SIGNOR-C381 SIGNOR "form complex" binding 9606 BTO:0002946 22203680 t lperfetto "We show that BLOC-1 is an elongated complex that contains one copy each of the eight subunits pallidin, Cappuccino, dysbindin, Snapin, Muted, BLOS1, BLOS2, and BLOS3. The complex appears as a linear chain of eight globular domains, ∼300 A long and ∼30 A in diameter." SIGNOR-265938 DTNBP1 protein Q96EV8 UNIPROT BLOC-1 complex SIGNOR-C381 SIGNOR "form complex" binding 9606 BTO:0002946 22203680 t lperfetto "We show that BLOC-1 is an elongated complex that contains one copy each of the eight subunits pallidin, Cappuccino, dysbindin, Snapin, Muted, BLOS1, BLOS2, and BLOS3. The complex appears as a linear chain of eight globular domains, ∼300 A long and ∼30 A in diameter." SIGNOR-265933 KIF4A protein O95239 UNIPROT Spindle_assembly phenotype SIGNOR-PH60 SIGNOR up-regulates 9606 BTO:0000567 15297875 f miannu "These results suggest that KIF4 and its binding partner PRC1 play essential roles in the organization of central spindles and midzone formation. KIF4 deficiency leads to mislocalization of PRC1, MKLP1, CENP-E and chromosomal passenger proteins" SIGNOR-265986 CCP110 protein O43303 UNIPROT Centrosome_separation phenotype SIGNOR-PH177 SIGNOR down-regulates 9606 12361598 f miannu "Reduction in CP110 Protein Levels or Loss of CP110 Phosphorylation Promotes Centrosome Separation." SIGNOR-265964 CCP110 protein O43303 UNIPROT CETN3 protein O15182 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 16760425 t miannu "We report that CP110 interacts with two different Ca2+-binding proteins, calmodulin (CaM) and centrin, in vivo. our data demonstrate a functional role for CaM binding to CP110 and suggest that CP110 cooperates with CaM and centrin to regulate progression through cytokinesis." SIGNOR-265968 CCP110 protein O43303 UNIPROT CALM1 protein P0DP23 UNIPROT "up-regulates activity" binding 9606 16760425 t miannu "We report that CP110 interacts with two different Ca2+-binding proteins, calmodulin (CaM) and centrin, in vivo. our data demonstrate a functional role for CaM binding to CP110 and suggest that CP110 cooperates with CaM and centrin to regulate progression through cytokinesis." SIGNOR-265965 CCP110 protein O43303 UNIPROT CETN2 protein P41208 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 16760425 t miannu "We report that CP110 interacts with two different Ca2+-binding proteins, calmodulin (CaM) and centrin, in vivo. our data demonstrate a functional role for CaM binding to CP110 and suggest that CP110 cooperates with CaM and centrin to regulate progression through cytokinesis." SIGNOR-265967 CCP110 protein O43303 UNIPROT CETN1 protein Q12798 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 16760425 t miannu "We report that CP110 interacts with two different Ca2+-binding proteins, calmodulin (CaM) and centrin, in vivo. our data demonstrate a functional role for CaM binding to CP110 and suggest that CP110 cooperates with CaM and centrin to regulate progression through cytokinesis." SIGNOR-265966 CDK2 protein P24941 UNIPROT CCP110 protein O43303 UNIPROT "down-regulates activity" phosphorylation Ser366 GSYAKLPsPEPSMSP -1 12361598 t miannu "GST-tagged recombinant CP110 (GST-wt) was robustly phosphorylated by cyclin E/CDK2 (Figure 2A). Expression of a mutant derivative of CP110 refractory to CDK phosphorylation provokes marked polyploidy. We localized the majority (nine of ten) of potential CDK2 phosphorylation sites in CP110 to an amino-terminal fragment (GST-ΔN1; Figure 1B)" SIGNOR-265960 CDK2 protein P24941 UNIPROT CCP110 protein O43303 UNIPROT "down-regulates activity" phosphorylation Ser372 PSPEPSMsPKMHRRR -1 12361598 t miannu "GST-tagged recombinant CP110 (GST-wt) was robustly phosphorylated by cyclin E/CDK2 (Figure 2A). Expression of a mutant derivative of CP110 refractory to CDK phosphorylation provokes marked polyploidy. We localized the majority (nine of ten) of potential CDK2 phosphorylation sites in CP110 to an amino-terminal fragment (GST-ΔN1; Figure 1B)" SIGNOR-265962 CDK2 protein P24941 UNIPROT CCP110 protein O43303 UNIPROT "down-regulates activity" phosphorylation Ser516 ASSQCIAsPNFGTVS -1 12361598 t miannu "GST-tagged recombinant CP110 (GST-wt) was robustly phosphorylated by cyclin E/CDK2 (Figure 2A). Expression of a mutant derivative of CP110 refractory to CDK phosphorylation provokes marked polyploidy. We localized the majority (nine of ten) of potential CDK2 phosphorylation sites in CP110 to an amino-terminal fragment (GST-ΔN1; Figure 1B)" SIGNOR-265963 CDK2 protein P24941 UNIPROT CCP110 protein O43303 UNIPROT "down-regulates activity" phosphorylation Thr194 FPKTSSAtPQETLIS -1 12361598 t miannu "GST-tagged recombinant CP110 (GST-wt) was robustly phosphorylated by cyclin E/CDK2 (Figure 2A). Expression of a mutant derivative of CP110 refractory to CDK phosphorylation provokes marked polyploidy. We localized the majority (nine of ten) of potential CDK2 phosphorylation sites in CP110 to an amino-terminal fragment (GST-ΔN1; Figure 1B)" SIGNOR-265961 APC-c complex SIGNOR-C150 SIGNOR Mitotic_checkpoint phenotype SIGNOR-PH28 SIGNOR up-regulates 9606 BTO:0000567 25092294 f miannu "We then found that the joint action of TRIP13 and p31comet also promotes MCC disassembly, releases APC/C from checkpoint inhibition, and inactivates the mitotic checkpoint." SIGNOR-265978 PRC1 protein O43663 UNIPROT Spindle_assembly phenotype SIGNOR-PH60 SIGNOR up-regulates 9606 BTO:0000567 15297875 f miannu "These results suggest that KIF4 and its binding partner PRC1 play essential roles in the organization of central spindles and midzone formation. KIF4 deficiency leads to mislocalization of PRC1, MKLP1, CENP-E and chromosomal passenger proteins" SIGNOR-265987 KIF4A protein O95239 UNIPROT PRC1 protein O43663 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 15297875 t miannu "These results suggest that KIF4 and its binding partner PRC1 play essential roles in the organization of central spindles and midzone formation. KIF4 deficiency leads to mislocalization of PRC1, MKLP1, CENP-E and chromosomal passenger proteins" SIGNOR-265988 PRC1 protein O43663 UNIPROT KIF23 protein Q02241 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 15297875 t miannu "These data indicate that PRC1 binds to KIF4, MKLP1 and CENP-E during late mitosis; however, it apparently does not interact simultaneously with more than one of these motor proteins." SIGNOR-265989 PRC1 protein O43663 UNIPROT CENPE protein Q02224 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 15297875 t miannu "These data indicate that PRC1 binds to KIF4, MKLP1 and CENP-E during late mitosis; however, it apparently does not interact simultaneously with more than one of these motor proteins." SIGNOR-265990 ABCC4 protein O15439 UNIPROT BLOC-1 complex SIGNOR-C381 SIGNOR "up-regulates activity" binding 9606 BTO:0000132 23805129 t lperfetto "The multidrug transporter MRP4, a multidrug resistance protein, is found on platelet dense granules and is proposed to transport adenine nucleotides into these granules (Jedlitschky et al., 2004). Uptake of serotonin from platelet cytosol into dense granules is mediated by vesicular monoamine transporter 2 (VMAT2). " SIGNOR-265996 SLC18A2 protein Q05940 UNIPROT BLOC-1 complex SIGNOR-C381 SIGNOR "up-regulates activity" binding 9606 BTO:0000132 23805129 t lperfetto "The multidrug transporter MRP4, a multidrug resistance protein, is found on platelet dense granules and is proposed to transport adenine nucleotides into these granules (Jedlitschky et al., 2004). Uptake of serotonin from platelet cytosol into dense granules is mediated by vesicular monoamine transporter 2 (VMAT2). |VMAT2 also appears to mediate histamine transport into dense granules" SIGNOR-265997 BLOC-1 complex SIGNOR-C381 SIGNOR serotonin chemical CHEBI:28790 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000132 23805129 t lperfetto "The multidrug transporter MRP4, a multidrug resistance protein, is found on platelet dense granules and is proposed to transport adenine nucleotides into these granules (Jedlitschky et al., 2004). Uptake of serotonin from platelet cytosol into dense granules is mediated by vesicular monoamine transporter 2 (VMAT2). |VMAT2 also appears to mediate histamine transport into dense granules" SIGNOR-265999 F-actin_assembly phenotype SIGNOR-PH18 SIGNOR Platelet_degranulation phenotype SIGNOR-PH138 SIGNOR down-regulates 9606 BTO:0000132 23805129 f lperfetto "Inhibition of actin polymerization also augments the kinetics and degree of alpha-granule release (Flaumenhaft et al., 2005). These results suggest that F-actin disassembly might actually be required for normal granule secretion and that activation-mediated granule release is related to actin." SIGNOR-266000 AURKA protein O14965 UNIPROT KIF4A protein O95239 UNIPROT "up-regulates activity" phosphorylation Thr799 PPKLRRRtFSLTEVR -1 31881080 t miannu "We show that Aurora A phosphorylates the condensin I-dependent pool of KIF4A and thus actively promotes chromosome congression from the spindle poles to the metaphase plate. In vitro kinase assays showed that recombinant KIF4A can be phosphorylated by Aurora A and that this activity is inhibited by the specific Aurora A inhibitor MLN8537 (Fig. 7 C)." SIGNOR-265993 CDK1 protein P06493 UNIPROT KIF4A protein O95239 UNIPROT "up-regulates activity" phosphorylation Thr1161 FFNPVCAtPNSKILK 9606 BTO:0000567 29771379 t miannu "Identification of Cdk phosphorylation of Kif4A at T1161 in early mitosis. We show that Cdk phosphorylation of Kif4A licenses its chromosome localization." SIGNOR-265994 PRKAA1 protein Q13131 UNIPROT KIF4A protein O95239 UNIPROT "up-regulates activity" phosphorylation Ser801 KLRRRTFsLTEVRGQ -1 28992084 t miannu "We found that the strong direct substrate KIF4A is phosphorylated by AMPK at Ser801.Using in vitro kinase assays, we found that active AMPK and Aurora B phosphorylated KIF4A at Ser801 and Thr799 respectively in a time-dependent manner (Figure 5D). KIF4A is phosphoregulated by AMPK and Aurora B. Although AMPK phosphorylation increased the ATPase activity of KIF4A, Aurora B phosphorylation resulted in a stronger increase (Figure 5I), which might be consistent with the more powerful kinase function of Aurora B during mitosis." SIGNOR-265991 SPTB proteinfamily SIGNOR-PF73 SIGNOR "Non-erythrocytic spectrin" complex SIGNOR-C385 SIGNOR "form complex" binding 9606 24302288 t lperfetto "Spectrin is a large, cytoskeletal, and heterodimeric protein composed of modular structure of alpha and beta subunits, it typically contains 106 contiguous amino acid sequence motifs called “spectrin repeats”. Spectrin is crucial for maintaining the stability and structure of the cell membrane and the shape of a cell" SIGNOR-266027 "Erythrocytic spectrin" complex SIGNOR-C384 SIGNOR Membrane_disruption phenotype SIGNOR-PH151 SIGNOR down-regulates 9606 BTO:0000424 24302288 f lperfetto "Spectrin is multifunctional, and spectrin-based networks are important for maintaining the shape and mechanical properties of erythrocytes." SIGNOR-266028 "Non-erythrocytic spectrin" complex SIGNOR-C385 SIGNOR Membrane_disruption phenotype SIGNOR-PH151 SIGNOR down-regulates 9606 24302288 f lperfetto "Spectrin is a large, cytoskeletal, and heterodimeric protein composed of modular structure of alpha and beta subunits, it typically contains 106 contiguous amino acid sequence motifs called “spectrin repeats”. Spectrin is crucial for maintaining the stability and structure of the cell membrane and the shape of a cell" SIGNOR-266029 "Erythrocytic spectrin" complex SIGNOR-C384 SIGNOR F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates binding 9606 BTO:0000424 24302288 t lperfetto "Spectrin is a member of the F-actin-crosslinking protein superfamily." SIGNOR-266030 "Non-erythrocytic spectrin" complex SIGNOR-C385 SIGNOR F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates binding 9606 24302288 t lperfetto "Spectrin is a member of the F-actin-crosslinking protein superfamily." SIGNOR-266031 "Erythrocytic spectrin" complex SIGNOR-C384 SIGNOR Cell_shape phenotype SIGNOR-PH182 SIGNOR up-regulates 9606 BTO:0000424 24302288 f lperfetto "Spectrin is multifunctional, and spectrin-based networks are important for maintaining the shape and mechanical properties of erythrocytes." SIGNOR-266032 "Non-erythrocytic spectrin" complex SIGNOR-C385 SIGNOR Cell_shape phenotype SIGNOR-PH182 SIGNOR up-regulates 9606 24302288 f lperfetto "Spectrin is a large, cytoskeletal, and heterodimeric protein composed of modular structure of alpha and beta subunits, it typically contains 106 contiguous amino acid sequence motifs called “spectrin repeats”. Spectrin is crucial for maintaining the stability and structure of the cell membrane and the shape of a cell" SIGNOR-266033 "AIIB/b3 integrin" complex SIGNOR-C173 SIGNOR Platelet_aggregation phenotype SIGNOR-PH81 SIGNOR up-regulates 10090 BTO:0000132 18278053 f lperfetto "Activated alphaIIbbeta3 integrins bind fibrinogen, vWF and fibronectin, thus allowing firm platelet adhesion and platelet aggregation." SIGNOR-266067 KIFC1 protein Q9BW19 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000948 33361741 f miannu "Kinesin Family Member C1 (KIFC1) Regulated by Centrosome Protein E (CENPE) Promotes Proliferation, Migration, and Epithelial-Mesenchymal Transition of Ovarian Cancer" SIGNOR-266114 KIFC1 protein Q9BW19 UNIPROT Cell_migration phenotype SIGNOR-PH38 SIGNOR up-regulates 9606 BTO:0000948 33361741 f miannu "Kinesin Family Member C1 (KIFC1) Regulated by Centrosome Protein E (CENPE) Promotes Proliferation, Migration, and Epithelial-Mesenchymal Transition of Ovarian Cancer" SIGNOR-266115 KIFC1 protein Q9BW19 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 SIGNOR up-regulates 9606 BTO:0000948 33361741 f miannu "Kinesin Family Member C1 (KIFC1) Regulated by Centrosome Protein E (CENPE) Promotes Proliferation, Migration, and Epithelial-Mesenchymal Transition of Ovarian Cancer" SIGNOR-266117 POLR1D protein P0DPB6 UNIPROT "RNA Polymerase III" complex SIGNOR-C389 SIGNOR "form complex" binding 9606 BTO:0000567 12391170 t lperfetto "In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights." SIGNOR-266137 POLR2F protein P41584 UNIPROT "RNA Polymerase III" complex SIGNOR-C389 SIGNOR "form complex" binding 9606 BTO:0000567 12391170 t lperfetto "In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights." SIGNOR-266139 Polr2l protein P52436 UNIPROT "RNA Polymerase III" complex SIGNOR-C389 SIGNOR "form complex" binding 9606 BTO:0000567 12391170 t lperfetto "In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights." SIGNOR-266142 POLR1D protein P0DPB6 UNIPROT "RNA Polymerase I" complex SIGNOR-C390 SIGNOR "form complex" binding 22260999 t lperfetto "In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1). " SIGNOR-266146 POLR2F protein P41584 UNIPROT "RNA Polymerase I" complex SIGNOR-C390 SIGNOR "form complex" binding 22260999 t lperfetto "In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1). " SIGNOR-266148 Polr2l protein P52436 UNIPROT "RNA Polymerase I" complex SIGNOR-C390 SIGNOR "form complex" binding 22260999 t lperfetto "In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1). " SIGNOR-266151 POLR1G protein O15446 UNIPROT "RNA Polymerase I" complex SIGNOR-C390 SIGNOR "form complex" binding 22260999 t lperfetto "In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1). " SIGNOR-266155 POLR1H protein Q9P1U0 UNIPROT "RNA Polymerase I" complex SIGNOR-C390 SIGNOR "form complex" binding 22260999 t lperfetto "In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1). " SIGNOR-266156 POLR1F protein Q3B726 UNIPROT "RNA Polymerase I" complex SIGNOR-C390 SIGNOR "form complex" binding 22260999 t lperfetto "In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1). " SIGNOR-266157 POLR2M protein P0CAP2 UNIPROT "RNA Polymerase II" complex SIGNOR-C391 SIGNOR "form complex" binding 9606 BTO:0000567 9852112 t lperfetto "Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II" SIGNOR-266169 POLR2J2 protein Q9GZM3 UNIPROT "RNA Polymerase II" complex SIGNOR-C391 SIGNOR "form complex" binding 9606 BTO:0000567 9852112 t lperfetto "Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II" SIGNOR-266174 "RNA Polymerase I" complex SIGNOR-C390 SIGNOR rRNA_transcription phenotype SIGNOR-PH145 SIGNOR up-regulates 22260999 f lperfetto "In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1). " SIGNOR-266177 ZNF76 protein P36508 UNIPROT TCP1 protein P17987 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567 10893243 t Luana "The transcription from the minimalCcta promoter was up-regulated 3-fold by ZNF143 and 6-fold by ZNF76 when full-length proteins were co-expressed, indicating that both ZNF143 and ZNF76 can enhance Ccta transcription." SIGNOR-266221 ZNF143 protein P52747 UNIPROT TCP1 protein P17987 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567 10893243 t Luana "The transcription from the minimalCcta promoter was up-regulated 3-fold by ZNF143 and 6-fold by ZNF76 when full-length proteins were co-expressed, indicating that both ZNF143 and ZNF76 can enhance Ccta transcription." SIGNOR-266220 NFX1 protein Q12986 UNIPROT HLA-DRA protein P01903 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000567 7964459 t Luana "A novel cysteine-rich sequence-specific DNA-binding protein interacts with the conserved X-box motif of the human major histocompatibility complex class II genes via a repeated Cys-His domain and functions as a transcriptional repressor" SIGNOR-266224 NFIL3 protein Q16649 UNIPROT IL3 protein P08700 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9580 BTO:0000799 7565758 t Luana "NF-IL3A transactivates the IL-3 promoter through the A region sequences." SIGNOR-266222 TCF20 protein Q9UGU0 UNIPROT MMP3 protein P08254 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000944 7760812 t Luana "This result indicates that expression of SPBP is sufficient to transactivate a minimal promoter containing a single copy of the SPRE, as well as the full-length stromelysin promoter." SIGNOR-266223 CS protein O75390 UNIPROT citrate(3-) smallmolecule CHEBI:16947 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 3013232 t miannu "Citrate synthase catalyzes an important step within the cycle, the Claisen condensation of acetyl-Coenzyme A with oxaloacetate to form citrate; and it is the only enzyme in the cycle that can catalyze the formation of a carbon-carbon bond." SIGNOR-266240 citrate(3-) smallmolecule CHEBI:16947 ChEBI ACO1 protein P21399 UNIPROT "up-regulates activity" "chemical activation" 9606 24068518 t miannu "Citrate is converted to cis-aconitate. This is catalyzed by aconitase. Cis-aconitate is an intermediate and is further converted to isocitrate by aconitase. Aconitase is involved in both reactions. In which first dehydration and then rehydration occur and as a result final product isocitrate is obtained." SIGNOR-266241 ACO1 protein P21399 UNIPROT citrate(3-) smallmolecule CHEBI:16947 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 24068518 t miannu "Citrate is converted to cis-aconitate. This is catalyzed by aconitase. Cis-aconitate is an intermediate and is further converted to isocitrate by aconitase. Aconitase is involved in both reactions. In which first dehydration and then rehydration occur and as a result final product isocitrate is obtained." SIGNOR-266242 citrate(3-) smallmolecule CHEBI:16947 ChEBI ACO2 protein Q99798 UNIPROT "up-regulates activity" "chemical activation" 9606 24068518 t miannu "Citrate is converted to cis-aconitate. This is catalyzed by aconitase. Cis-aconitate is an intermediate and is further converted to isocitrate by aconitase. Aconitase is involved in both reactions. In which first dehydration and then rehydration occur and as a result final product isocitrate is obtained." SIGNOR-266243 ACO2 protein Q99798 UNIPROT citrate(3-) smallmolecule CHEBI:16947 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 24068518 t miannu "Citrate is converted to cis-aconitate. This is catalyzed by aconitase. Cis-aconitate is an intermediate and is further converted to isocitrate by aconitase. Aconitase is involved in both reactions. In which first dehydration and then rehydration occur and as a result final product isocitrate is obtained." SIGNOR-266244 D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI "Isocitrate Dehydrogenase" complex SIGNOR-C396 SIGNOR "up-regulates activity" "chemical activation" 9606 28139779 t miannu "Human NAD-dependent isocitrate dehydrogenase existing as the α2βγ heterotetramer, catalyzes the decarboxylation of isocitrate into α-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP." SIGNOR-266250 "(S)-malic acid" smallmolecule CHEBI:30797 ChEBI MDH1 protein P40925 UNIPROT "up-regulates activity" "chemical activation" 9606 24068518 t miannu "Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle" SIGNOR-266281 "(S)-malic acid" smallmolecule CHEBI:30797 ChEBI MDH2 protein P40926 UNIPROT "up-regulates activity" "chemical activation" 9606 24068518 t miannu "Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle" SIGNOR-266282 MDH1 protein P40925 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 24068518 t miannu "Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle" SIGNOR-266285 MDH1 protein P40925 UNIPROT NADH smallmolecule CHEBI:16908 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 24068518 t miannu "Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle" SIGNOR-266287 MDH1 protein P40925 UNIPROT "(S)-malic acid" smallmolecule CHEBI:30797 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 24068518 t miannu "Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle" SIGNOR-266283 MDH2 protein P40926 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 24068518 t miannu "Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle" SIGNOR-266286 MDH2 protein P40926 UNIPROT NADH smallmolecule CHEBI:16908 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 24068518 t miannu "Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle" SIGNOR-266288 MDH2 protein P40926 UNIPROT "(S)-malic acid" smallmolecule CHEBI:30797 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 24068518 t miannu "Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle" SIGNOR-266284 OGDC complex SIGNOR-C397 SIGNOR succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 15953811 t miannu "The α-ketoglutarate–dehydrogenase complex is a complex including multiple copies of three proteins: E1k (α-ketoglutarate dehydrogenase), E2k (dihydrolipoyl succinyltransferase), and E3 (dihydrolipoamide dehydrogenase) (Fig. 2). The consecutive action of the three catalytic components of KGDHC results in oxidative decarboxylation of 2-oxoglutarate, preserving the energy in the form of succinylCoA and NADH." SIGNOR-266258 SRC protein P12931 UNIPROT GRK2 protein P25098 UNIPROT "up-regulates activity" phosphorylation Tyr92 FYEEIKKyEKLETEE BTO:0000007 16725308 t miannu "Here, we demonstrate that c-Src kinase activity increases the interaction between GRK2 and Galphaq. Tyrosine phosphorylation of GRK2 appears to be critically involved in the modulation of this interaction since the stimulatory effect of c-Src is not observed with a GRK2 mutant with impaired tyrosine phosphorylation (GRK2 Y13,86,92F), whereas a mutant that mimics GRK2 tyrosine phosphorylation in these residues displays an increased interaction with Galphaq. " SIGNOR-266293 PRKACB protein P22694 UNIPROT GPKOW protein Q92917 UNIPROT "up-regulates activity" phosphorylation Ser27 SFGFTRTsARRRLAD 21880142 t miannu "Using yeast two-hybrid screening with the PKA Cβ2 subunit as bait we identified GPKOW, also known as MOS2 homolog or T54 protein, as an interaction partner for Cβ2. PKA phosphorylates GPKOW at S27 and T316 in vitro. GPKOWs ability to bind RNA is sensitive to mutations of its PKA phosphorylation sites." SIGNOR-266299 PRKACB protein P22694 UNIPROT GPKOW protein Q92917 UNIPROT "up-regulates activity" phosphorylation Thr316 GTASSRKtLWNQELY 21880142 t miannu "Using yeast two-hybrid screening with the PKA Cβ2 subunit as bait we identified GPKOW, also known as MOS2 homolog or T54 protein, as an interaction partner for Cβ2.PKA phosphorylates GPKOW at S27 and T316 in vitro. GPKOWs ability to bind RNA is sensitive to mutations of its PKA phosphorylation sites." SIGNOR-266298 GPKOW protein Q92917 UNIPROT DHX16 protein O60231 UNIPROT "up-regulates quantity" binding BTO:0000567 25296192 t miannu "In this report, we showed that GPKOW interacted directly with the DHX16/hPRP2 and with RNA. Immuno-depletion of GPKOW from HeLa nuclear extracts resulted in an inactive spliceosome that still bound DHX16." SIGNOR-266300 IFITM3 protein Q01628 UNIPROT gamma-secretase complex SIGNOR-C98 SIGNOR "up-regulates activity" binding 10090 BTO:0000938 32879487 t miannu "IFITM3 directly binds to γ-secretase. IFITM3 KO reduced γ-secretase activity for both Aβ40 and Aβ42 cleavages as compared to the EV (empty vector guide RNA) cell line by 36% and 27%, respectively (Fig. 2d, bar 1 and 3)." SIGNOR-266303 AMPK complex SIGNOR-C15 SIGNOR FH protein P07954 UNIPROT "up-regulates activity" phosphorylation Ser75 YGAQTVRsTMNFKIG -1 28628081 t miannu "Glucose deficiency induces AMPK activation, which phosphorylates FH at Ser75 and promotes its binding to ATF2 and the enrichment of the FH–ATF2 complex on the promoter regions of ATF2-targeted genes." SIGNOR-266313 CALM2 protein P0DP24 UNIPROT PPP3CA protein Q08209 UNIPROT up-regulates binding 9606 11796223 t miannu "Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain." SIGNOR-266327 CCP110 protein O43303 UNIPROT CALM3 protein P0DP25 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 16760425 t miannu "We report that CP110 interacts with two different Ca2+-binding proteins, calmodulin (CaM) and centrin, in vivo. our data demonstrate a functional role for CaM binding to CP110 and suggest that CP110 cooperates with CaM and centrin to regulate progression through cytokinesis." SIGNOR-266348 CALM3 protein P0DP25 UNIPROT CAMKK2 protein Q96RR4 UNIPROT up-regulates binding 9606 BTO:0000782 BTO:0000142 9822657 t miannu "The ca2+-calmodulin-dependent protein kinase (cam kinase) cascade includes three kinases: cam-kinase kinase (camkk);and the cam kinases camki and camkiv, which are phosphorylated and activated by camkk." SIGNOR-266345 CALM3 protein P0DP25 UNIPROT SCN8A protein Q9UQD0 UNIPROT "down-regulates activity" binding 9606 BTO:0000938 11807557 t miannu "Here we show that calmodulin (CaM), a ubiquitous Ca2+-sensing protein, binds to the carboxy-terminal 'IQ' domain of the human cardiac Na channel (hH1) in a Ca2+-dependent manner. This binding interaction significantly enhances slow inactivation-a channel-gating process linked to life-threatening idiopathic ventricular arrhythmias." SIGNOR-266346 CALM3 protein P0DP25 UNIPROT Calcineurin complex SIGNOR-C155 SIGNOR up-regulates binding 9606 11796223 t miannu "Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain." SIGNOR-266347 ULK1 protein O75385 UNIPROT ATG9A protein Q7Z3C6 UNIPROT "up-regulates activity" phosphorylation Ser761 QSIPRSAsYPCAAPR 9606 BTO:0000007 25266655 t miannu "Our data suggest that the localization of mammalian Atg9A to autophagosomes requires phosphorylation on the C terminus of Atg9A at S761, which creates a 14-3-3ζ docking site. Under basal conditions, this phosphorylation is maintained at a low level and is dependent on both ULK1 and AMPK." SIGNOR-266366 ULK1 protein O75385 UNIPROT ATG9A protein Q7Z3C6 UNIPROT "up-regulates activity" phosphorylation Ser14 EYQRLEAsYSDSPPG 9606 BTO:0000007 27934868 t miannu "Src phosphorylates mATG9 at Tyr8 to maintain its endocytic and constitutive trafficking in unstressed conditions. In response to starvation, phosphorylation of mATG9 at Tyr8 by Src and at Ser14 by ULK1 functionally cooperate to promote interactions between mATG9 and the AP1/2 complex, leading to redistribution of mATG9 from the plasma membrane and juxta-nuclear region to the peripheral pool for autophagy initiation." SIGNOR-266369 SRC protein P12931 UNIPROT ATG9A protein Q7Z3C6 UNIPROT "up-regulates activity" phosphorylation Tyr8 MAQFDTEyQRLEASY 9606 BTO:0000007 27934868 t miannu "Src phosphorylates mATG9 at Tyr8 to maintain its endocytic and constitutive trafficking in unstressed conditions. In response to starvation, phosphorylation of mATG9 at Tyr8 by Src and at Ser14 by ULK1 functionally cooperate to promote interactions between mATG9 and the AP1/2 complex, leading to redistribution of mATG9 from the plasma membrane and juxta-nuclear region to the peripheral pool for autophagy initiation." SIGNOR-266367 CCNF protein P41002 UNIPROT CCP110 protein O43303 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0001938 20596027 t miannu "Using a mode of substrate binding distinct from other F-box protein-substrate pairs, CP110 and Cyclin F physically associate on the centrioles during the G2 phase of the cell cycle, and CP110 is ubiquitylated by the SCF(Cyclin F) ubiquitin ligase complex, leading to its degradation." SIGNOR-266364 CCNF protein P41002 UNIPROT FZR1 protein Q9UM11 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 27653696 t miannu "We show that cyclin F, a cell-cycle-regulated substrate receptor (F-box protein) for the SCF, is targeted for degradation by APC/C. Furthermore, we establish that Cdh1 is itself a substrate of SCF(cyclin F). Cyclin F loss impairs Cdh1 degradation and delays S-phase entry, and this delay is reversed by simultaneous removal of Cdh1." SIGNOR-266363 ATG9A protein Q7Z3C6 UNIPROT YWHAE protein P62258 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 25266655 t miannu "Our data suggest that the localization of mammalian Atg9A to autophagosomes requires phosphorylation on the C terminus of Atg9A at S761, which creates a 14-3-3ζ docking site. Under basal conditions, this phosphorylation is maintained at a low level and is dependent on both ULK1 and AMPK." SIGNOR-266368 AMPK complex SIGNOR-C15 SIGNOR ATG9A protein Q7Z3C6 UNIPROT "up-regulates activity" phosphorylation Ser761 QSIPRSAsYPCAAPR 9606 BTO:0000007 25266655 t miannu "Our data suggest that the localization of mammalian Atg9A to autophagosomes requires phosphorylation on the C terminus of Atg9A at S761, which creates a 14-3-3ζ docking site. Under basal conditions, this phosphorylation is maintained at a low level and is dependent on both ULK1 and AMPK." SIGNOR-266365 APC-c complex SIGNOR-C150 SIGNOR CCNF protein P41002 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 27653696 t miannu "We show that cyclin F, a cell-cycle-regulated substrate receptor (F-box protein) for the SCF, is targeted for degradation by APC/C. Furthermore, we establish that Cdh1 is itself a substrate of SCF(cyclin F). Cyclin F loss impairs Cdh1 degradation and delays S-phase entry, and this delay is reversed by simultaneous removal of Cdh1." SIGNOR-266362 DHPS protein P49366 UNIPROT EIF5A protein P63241 UNIPROT "up-regulates activity" "post translational modification" -1 32142284 t miannu "Deoxyhypusine synthase (DHPS) utilizes spermidine and NAD as cofactors to incorporate a hypusine modification into the eukaryotic translation initiation factor 5A (eIF5A). Hypusine is essential for eIF5A activation, which, in turn, plays a key role in regulating protein translation of selected mRNA that are associated with the synthesis of oncoproteins, thereby enhancing tumor cell proliferation." SIGNOR-266374 EIF5A protein P63241 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9534 BTO:0000298 15371445 t miannu "eIF5A regulated p53 protein expression. Further analysis by reverse transcription PCR showed eIF5A-activated p53 transcription. The effect of eIF5A on p53 transcriptional activity was further demonstrated by the increasing expressions of p21 and Bax, well known target genes of p53." SIGNOR-266375 CSNK2A1 protein P68400 UNIPROT CCNF protein P41002 UNIPROT "down-regulates activity" phosphorylation Ser621 GYEGDQEsEGEKEGD 9606 BTO:0000007 29021214 t miannu "We determined that casein kinase II (CK2) can phosphorylate Ser621 and thereby regulate the E3 ligase activity of the SCF(cyclin F) complex." SIGNOR-266373 RIPK3 protein Q9Y572 UNIPROT DLD protein P09622 UNIPROT "up-regulates activity" phosphorylation Thr135 STAVKALtGGIAHLF -1 29358703 t miannu "Here, we show that RIP3 activates the pyruvate dehydrogenase complex (PDC, also known as PDH), the rate-limiting enzyme linking glycolysis to aerobic respiration, by directly phosphorylating the PDC E3 subunit (PDC-E3) on T135." SIGNOR-266372 AMPK complex SIGNOR-C15 SIGNOR ARMC10 protein Q8N2F6 UNIPROT "up-regulates activity" phosphorylation Ser45 LGIRSSKsAGALEEG 9606 BTO:0000007 30631047 t miannu "We validated one uncharacterized protein, ARMC10, and demonstrated that the S45 site of ARMC10 can be phosphorylated by AMPK both in vitro and in vivo. Moreover, ARMC10 overexpression was sufficient to promote mitochondrial fission, whereas ARMC10 knockout prevented AMPK-mediated mitochondrial fission. These results demonstrate that ARMC10 is an effector of AMPK that participates in dynamic regulation of mitochondrial fission and fusion." SIGNOR-266413 BRD4 protein O60885 UNIPROT P-TEFb complex SIGNOR-C238 SIGNOR "up-regulates activity" binding 9606 BTO:0000567 16109377 t miannu "Binding of Brd4 to Core P-TEFb Is Essential for Transcription." SIGNOR-266411 KIF14 protein Q15058 UNIPROT Cilium_assembly phenotype SIGNOR-PH64 SIGNOR up-regulates 9606 32348467 f miannu " We show that RNAi depletion of KIF14 specifically leads to defects in ciliogenesis and basal body (BB) biogenesis, as its absence hampers the efficiency of primary cilium formation and the dynamics of primary cilium elongation, and disrupts the localization of the distal appendage proteins SCLT1 and FBF1 and components of the IFT-B complex. " SIGNOR-266421 PRC1 protein O43663 UNIPROT KIF14 protein Q15058 UNIPROT "up-regulates activity" binding 9606 BTO:0000565 16431929 t miannu "KIF14 interacts with PRC1 and citron kinase. We find that KIF14 targets to the central spindle via its interaction with PRC1 and has an essential function in cytokinesis. I" SIGNOR-266423 MLKL protein Q8NB16 UNIPROT Necroptosis phenotype SIGNOR-PH174 SIGNOR "up-regulates activity" 9606 24316671 t gianni "Here, we report that MLKL forms a homotrimer through its amino-terminal coiled-coil domain and locates to the cell plasma membrane during TNF-induced necroptosis. By generating different MLKL mutants, we demonstrated that the plasma membrane localization of trimerized MLKL is critical for mediating necroptosis. Importantly, we found that the membrane localization of MLKL is essential for Ca(2+) influx, which is an early event of TNF-induced necroptosis." SIGNOR-266431 Z-RNA stimulus SIGNOR-ST29 SIGNOR ZBP1 protein Q9H171 UNIPROT "up-regulates activity" binding 10090 BTO:0002572 32200799 t gianni "Here, we show that replicating IAV generates Z-RNAs, which activate ZBP1 in the nucleus of infected cells. ZBP1 then initiates RIPK3-mediated MLKL activation in the nucleus, resulting in nuclear envelope disruption, leakage of DNA into the cytosol, and eventual necroptosis." SIGNOR-266432 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH13 protein P55290 UNIPROT "up-regulates activity" "chemical activation" 9606 22535893 t miannu "Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis." SIGNOR-265831 PCK2 protein Q16822 UNIPROT phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 24632615 t miannu "Phosphoenolpyruvate carboxykinase (PEPCK, EC 4.1.1.32) is a key enzyme of gluconeogenesis. Two isoforms exist, a cytoplasmic form (PCK1, PEPCK-C) and a mitochondrial isoform (PCK2, PEPCK-M). PEPCK activity is present at significant levels in the liver, but also in the kidney and in brown and white adipose tissue. PEPCK, which converts oxaloacetate (OAA) to PEP, has an important role in glucose formation, but also for the generation of glycerol and serine." SIGNOR-266557 G6PC3 protein Q9BUM1 UNIPROT "alpha-D-glucose 6-phosphate(2-)" smallmolecule CHEBI:58225 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 12093802 t miannu "Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis" SIGNOR-266570 G6P proteinfamily SIGNOR-PF81 SIGNOR "alpha-D-glucose 6-phosphate(2-)" smallmolecule CHEBI:58225 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 12093803 t miannu "Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis" SIGNOR-266571 ABL2 protein P42684 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 10090 BTO:0003102 33622779 f miannu "Here, using cultured hippocampal neurons pooled from both sexes of mice, we provide evidence that binding to cortactin tethers Abl2 in spines, where Abl2 and cortactin maintain the small pool of stable actin required for dendritic spine stability." SIGNOR-266594 CTTN protein Q14247 UNIPROT Dendritic_spine_morphogenesis phenotype SIGNOR-PH183 SIGNOR up-regulates 9606 BTO:0003102 14684878 f miannu "Cortactin is an F-actin binding protein and activator of the Arp2/3 actin nucleation machinery that also interacts with the postsynaptic density (PSD) protein Shank. Cortactin is concentrated in dendritic spines of cultured hippocampal neurons, and the N-terminal half of the protein containing the Arp2/3 and F-actin binding domains is necessary and sufficient for spine targeting." SIGNOR-266595 Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR Dendritic_spine_morphogenesis phenotype SIGNOR-PH183 SIGNOR up-regulates 9606 BTO:0000142 14684878 f miannu "Dendritic spines are small protrusions found on dendrites of principal neurons of mammalian brain. Serving as postsynaptic compartments for individual excitatory inputs, spines show rapid movements and shape changes that are influenced by synaptic activity. The structural modifications of spines are believed to represent morphological correlates of synaptic plasticity. The form and motility of spines are determined mainly by the actin cytoskeleton" SIGNOR-266596 F-actin_assembly phenotype SIGNOR-PH18 SIGNOR Dendritic_spine_morphogenesis phenotype SIGNOR-PH183 SIGNOR up-regulates 9606 BTO:0000142 14684878 f miannu "Dendritic spines are small protrusions found on dendrites of principal neurons of mammalian brain. Serving as postsynaptic compartments for individual excitatory inputs, spines show rapid movements and shape changes that are influenced by synaptic activity. The structural modifications of spines are believed to represent morphological correlates of synaptic plasticity. The form and motility of spines are determined mainly by the actin cytoskeleton" SIGNOR-266597 EID3 protein Q8N140 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR down-regulates 10090 23720823 f miannu "Here we show that, when over-expressed, FRG1 binds and interferes with the activity of the histone methyltransferase Suv4-20h1 both in mammals and Drosophila. Accordingly, FRG1 over-expression or Suv4-20h1 knockdown inhibits myogenesis. The novel inhibitor of differentiation Eid3 is an FRG1/Suv4-20h1 target involved in the myogenic defects caused by FRG1 over-expression. Eid3 is down-regulated upon muscle differentiation and behaves as a myogenic inhibitor gene." SIGNOR-266641 TM9SF4 protein Q92544 UNIPROT Autophagy phenotype SIGNOR-PH31 SIGNOR up-regulates 9606 BTO:0000007 29125601 f miannu "In the present study, we report a novel autophagy-related protein TM9SF4, which plays a functional role in the induction phase of autophagic process. Overexpression of TM9SF4 promoted autophagic flux in HEK293 cells." SIGNOR-266704 ADNP protein Q9H2P0 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates 10090 BTO:0000142 12888219 f miannu "Mouse ADNP was shown to be expressed at the time of neural tube closure, detected at E7.5 and increased on E9.5. Expression was augmented in the brain (E12.5), sustained throughout embryogenesis and regulated by VIP. In conclusion, ADNP is identified here as a new key gene essential for organogenesis in the developing embryo and may be implicated as a clinical target associated with proper neurodevelopment." SIGNOR-266758 GAP43 protein P17677 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 10090 BTO:0000596 21938722 f miannu "Growth associated protein 43 (Gap43) is a neuron-specific phosphoprotein, which plays critical role in axon growth and synapses functions during neurogenesis. " SIGNOR-266769 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR GAP43 protein P17677 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0000099 26865625 t miannu " In this study, we demonstrated for the first time that growth-associated protein 43 (GAP43), a well known growth cone protein that promotes axonal regeneration, can be induced in rat brain astrocytes by the proinflammatory endotoxin lipopolysaccharide via both nuclear factor-κB and signal transducer and activator of transcription 3-mediated transcriptional activation." SIGNOR-266770 GAP43 protein P17677 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates 10116 BTO:0000099 26865625 f miannu "Growth-associated protein 43 (GAP43), a protein kinase C (PKC)-activated phosphoprotein, is often implicated in axonal plasticity and regeneration. " SIGNOR-266771 MBD5 protein Q9P267 UNIPROT Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 BTO:0000964 20700456 f miannu "The human proteins MBD5 and MBD6 associate with heterochromatin but they do not bind methylated DNA.Our data suggest that MBD5 and MBD6 are unlikely to be methyl-binding proteins, yet they may contribute to the formation or function of heterochromatin. One isoform of MBD5 is highly expressed in oocytes, which suggests a possible role in epigenetic reprogramming after fertilization." SIGNOR-266773 TERF2 protein Q15554 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR down-regulates 10116 BTO:0001009 27117401 f miannu "During neuronal differentiation, use of an alternative splice site on the rat telomere repeat-binding factor 2 (TRF2) mRNA generates a short TRF2 protein isoform (TRF2-S) capable of derepressing neuronal genes." SIGNOR-266805 MYT1L protein Q9UL68 UNIPROT Demyelination phenotype SIGNOR-PH155 SIGNOR down-regulates 9606 BTO:0000938 29397565 f miannu "Myt1L (myelin transcription factor 1-like), mainly expressed in neurons, has been associated with intellectual disability, schizophrenia, and depression. In the present study, we found that Myt1L was expressed in oligodendrocyte lineage cells during myelination and remyelination." SIGNOR-266779 WDFY3 protein Q8IZQ1 UNIPROT Autophagy phenotype SIGNOR-PH31 SIGNOR up-regulates 9606 22653340 f miannu "ALFY is a large, scaffolding, multidomain protein implicated in the selective degradation of ubiquitinated protein aggregates by autophagy." SIGNOR-266794 AFF2 protein P51816 UNIPROT "RNA Polymerase II" complex SIGNOR-C391 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 17135274 t miannu "Here, we provide the first evidence for a direct role of AF4 in the regulation of transcriptional elongation by RNA polymerase II (Pol II). We demonstrate that mouse Af4 functions as a positive regulator of Pol II transcription elongation factor b (P-TEFb) kinase and, in complex with MLL fusion partners Af9, Enl and Af10, as a mediator of histone H3-K79 methylation by recruiting Dot1 to elongating Pol II. These pathways are interconnected and tightly regulated by the P-TEFb-dependent phosphorylation of Af4, Af9 and Enl which controls their transactivation activity and/or protein stability." SIGNOR-266797 EBNA1 protein P03211 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR "down-regulates activity" 9606 BTO:0002181 29659505 f scontino "EBNA1 has been reported to block p65 activation by inhibiting IKKα/β through an unknown mechanism, we suggest that, in NPC, NF-κB signaling and EBNA1 may form a regulatory loop which supports EBV latent gene expression, while also limiting NF-κB activity" SIGNOR-266802 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR EBNA1 protein P03211 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002181 29659505 t scontino "We found that EBV-encoded Qp-EBNA1 can be upregulated by NF-κB, while EBNA1 protein expression has been shown to negatively regulate NF-κB activation by inhibiting IKKα/β phosphorylation" SIGNOR-266803 PRC1 complex SIGNOR-C408 SIGNOR "Histone H2A" proteinfamily SIGNOR-PF70 SIGNOR "down-regulates activity" ubiquitination 9606 BTO:0000227 25519132 t miannu "Mechanism of transcriptional activation. PRC1 can monoubiquitinate H2AK119 through its RING1B component. " SIGNOR-266815 AUTS2 protein Q8WXX7 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 BTO:0000227 28505103 f miannu "Cytoplasmic AUTS2 regulates actin cytoskeleton to control neuronal migration and neurite extension, while nuclear AUTS2 controls transcription of various genes as a component of the polycomb complex 1 (PRC1)." SIGNOR-266816 AUTS2 protein Q8WXX7 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 BTO:0000227 25533347 f miannu "AUTS2 is involved in neurite outgrowth and branch formation in neurons." SIGNOR-266818 Tubulin proteinfamily SIGNOR-PF46 SIGNOR Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates 9606 BTO:0000142 28347630 f miannu "Microtubules are essential for the generation, migration and differentiation of neurons. Within dendrites microtubules have also been implicated in the formation and plasticity of spines. For instance, the treatment of hippocampal neurons with low doses of the microtubule destabilizing drug Nocodazole impairs BDNF induced dendritic spine formation" SIGNOR-266827 Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 BTO:0000142 28347630 f miannu "Microtubules are essential for the generation, migration and differentiation of neurons. Within dendrites microtubules have also been implicated in the formation and plasticity of spines. For instance, the treatment of hippocampal neurons with low doses of the microtubule destabilizing drug Nocodazole impairs BDNF induced dendritic spine formation" SIGNOR-266829 Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 BTO:0000142 28347630 f miannu "Microtubules are essential for the generation, migration and differentiation of neurons. Within dendrites microtubules have also been implicated in the formation and plasticity of spines. For instance, the treatment of hippocampal neurons with low doses of the microtubule destabilizing drug Nocodazole impairs BDNF induced dendritic spine formation" SIGNOR-266830 LMP2 protein P13285 UNIPROT IFNGR2/INFGR1 complex SIGNOR-C142 SIGNOR "down-regulates quantity by destabilization" 9606 19718044 f scontino "The EBV-encoded Latent Membrane Proteins, LMP2A and LMP2B, Limit the Actions of Interferon by Targeting Interferon Receptors for Degradation. LMP2A and LMP2B increase the turnover and degradation of IFNAR1 and IFNGR1. LMP2A and LMP2B reduce the half-life of IFNAR1 and IFNGR1." SIGNOR-266825 TBR1 protein Q16650 UNIPROT FOXP2 protein O15409 UNIPROT "up-regulates activity" binding 9606 BTO:0000142 25232744 t miannu "We show that TBR1 homodimerizes, that it interacts with FOXP2, a transcription factor implicated in speech/language disorders, and that this interaction is disrupted by pathogenic mutations affecting either protein." SIGNOR-266831 LMP2 protein P13285 UNIPROT IFNAR complex SIGNOR-C243 SIGNOR "down-regulates quantity by destabilization" 9606 19718044 f scontino "The EBV-encoded Latent Membrane Proteins, LMP2A and LMP2B, Limit the Actions of Interferon by Targeting Interferon Receptors for Degradation.LMP2A and LMP2B increase the turnover and degradation of IFNAR1 and IFNGR1. LMP2A and LMP2B reduce the half-life of IFNAR1 and IFNGR1." SIGNOR-266824 CACNA2D3 protein Q8IZS8 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0003041;BTO:0004491 31746409 f miannu "Overexpression of CACNA2D3 reduced proliferation and migration, but increased apoptosis and Ca2+ influx in Ishikawa and RL95-2 cells." SIGNOR-266854 CACNA2D3 protein Q8IZS8 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0003041;BTO:0004491 31746409 f miannu "Overexpression of CACNA2D3 reduced proliferation and migration, but increased apoptosis and Ca2+ influx in Ishikawa and RL95-2 cells." SIGNOR-266855 CACNA2D3 protein Q8IZS8 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR "up-regulates activity" 9606 BTO:0003041;BTO:0004491 31746409 f miannu "The results indicated that the overexpression of CACNA2D3 induced an increase in intracellular Ca2+ and increased the levels of p-p38 MAPK. These data indicated that the p38 MAPK pathway is activated by overexpression of CACNA2D3 and P4 induction." SIGNOR-266857 EGFL7 protein Q9UHF1 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates 9606 BTO:0000142 20372059 f miannu "EGFL7 drives the formation of neurons from neural stem cells. In the embryonic and adult brain this process is essential for neurogenesis and homeostasis of the nervous system. In this review, we discuss the implications of our findings for adult neurogenesis and illustrate the potential of EGFL7 to serve as an agent to increase neurogenesis and the self-renewal potential of the brain" SIGNOR-266859 ZBTB20 protein Q9HC78 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates 10090 BTO:0004102;BTO:0004185 29748916 f miannu "The transcription factor (TF) Zbtb20 is important for the hippocampal specification and the regulation of neurogenesis of neocortical projection neurons. Herein, we show a critical involvement of the TF Zbtb20 in the neurogenesis of both projection neurons and interneurons of the olfactory bulb during embryonic stages" SIGNOR-266866 VPS13B protein Q7Z7G8 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 10116 BTO:0003102 25492866 f miannu "Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. COH1 and RAB6 regulate neurite outgrowth in primary neurons" SIGNOR-266872 RAB6A protein P20340 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 10116 BTO:0003102 25492866 f miannu "Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. COH1 and RAB6 regulate neurite outgrowth in primary neurons" SIGNOR-266873 RAB6B protein Q9NRW1 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 10116 BTO:0003102 25492866 f miannu "Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. COH1 and RAB6 regulate neurite outgrowth in primary neurons" SIGNOR-266874 RAB6C protein Q9H0N0 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 10116 BTO:0003102 25492866 f miannu "Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. COH1 and RAB6 regulate neurite outgrowth in primary neurons" SIGNOR-266875 RAB6A protein P20340 UNIPROT Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR up-regulates 9534 BTO:0001444 20360680 f miannu "We show that BICDR-1 interacts with the dynein/dynactin motor complex, binds to kinesin-3 motor protein Kif1C and controls the pericentrosomal localization of Rab6-positive secretory vesicles." SIGNOR-266880 RAB6B protein Q9NRW1 UNIPROT Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR up-regulates 9534 BTO:0001444 20360680 f miannu "We show that BICDR-1 interacts with the dynein/dynactin motor complex, binds to kinesin-3 motor protein Kif1C and controls the pericentrosomal localization of Rab6-positive secretory vesicles." SIGNOR-266881 RAB6C protein Q9H0N0 UNIPROT Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR up-regulates 9534 BTO:0001444 20360680 f miannu "We show that BICDR-1 interacts with the dynein/dynactin motor complex, binds to kinesin-3 motor protein Kif1C and controls the pericentrosomal localization of Rab6-positive secretory vesicles." SIGNOR-266882 KIF1A protein Q12756 UNIPROT Dense-core_vesicle_exocytosis phenotype SIGNOR-PH184 SIGNOR up-regulates 10116 BTO:0003102 30021165 f miannu "To better understand how KIF1A-driven dense core vesicle (DCV) transport is regulated, we identified the KIF1A interactome and focused on three binding partners, the calcium binding protein calmodulin (CaM) and two synaptic scaffolding proteins: liprin-α and TANC2. We showed that calcium, acting via CaM, enhances KIF1A binding to DCVs and increases vesicle motility. In contrast, liprin-α and TANC2 are not part of the KIF1A-cargo complex but capture DCVs at dendritic spines" SIGNOR-266893 TANC1 protein Q9C0D5 UNIPROT Dendritic_spine_morphogenesis phenotype SIGNOR-PH183 SIGNOR up-regulates 10116 BTO:0000142 21068316 t miannu "In the present study, we provide evidence that TANC1 and its close relative TANC2 regulate dendritic spines and excitatory synapses. our results indicate that TANC-dependent spine/synapse maintenance requires TANC binding to PSD-95, which promotes synaptic localization of TANC proteins. Thus, it is likely that interaction with PSD-95 concentrates TANC proteins at synapses, where they play a role in mediating PSD-95-dependent maintenance of spines and synapses." SIGNOR-266896 TANC2 protein Q9HCD6 UNIPROT Dendritic_spine_morphogenesis phenotype SIGNOR-PH183 SIGNOR up-regulates 10116 BTO:0000142 21068316 t miannu "In the present study, we provide evidence that TANC1 and its close relative TANC2 regulate dendritic spines and excitatory synapses. our results indicate that TANC-dependent spine/synapse maintenance requires TANC binding to PSD-95, which promotes synaptic localization of TANC proteins. Thus, it is likely that interaction with PSD-95 concentrates TANC proteins at synapses, where they play a role in mediating PSD-95-dependent maintenance of spines and synapses." SIGNOR-266897 NR3C1 protein P04150 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR "up-regulates activity" 9606 BTO:0000567 25910399 f "Glucocorticoids (GCs) are the most commonly used anti-inflammatory agents to treat inflammatory and immune diseases [.. }The dogma that transrepression of genes, by tethering of the glucocorticoid receptor (GR) to DNA-bound pro-inflammatory transcription factors, is the main anti-inflammatory mechanism, is now challenged." SIGNOR-266901 glutamine chemical CHEBI:28300 ChEBI GLS protein O94925 UNIPROT "up-regulates activity" "chemical activation" 9606 22049910 t "Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia." SIGNOR-266906 glutamine chemical CHEBI:28300 ChEBI GLS2 protein Q9UI32 UNIPROT "up-regulates activity" "chemical activation" 9606 22049910 t "Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia." SIGNOR-266907 GLS protein O94925 UNIPROT glutamine chemical CHEBI:28300 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 22049910 t "Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia." SIGNOR-266908 GLS2 protein Q9UI32 UNIPROT glutamine chemical CHEBI:28300 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 22049910 t "Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia." SIGNOR-266909 SLC38A1 protein Q9H2H9 UNIPROT glutamine chemical CHEBI:28300 ChEBI "up-regulates quantity" relocalization 9606 26724577 t "Fourteen of them [[SLC transporters] , capable of transporting glutamine across the plasma membrane, are found in four families: SLC1, SLC6, SLC7, and SLC38. However, it is generally thought that the members of the SLC38 family are the principal transporters for glutamine." SIGNOR-266912 SLC38A2 protein Q96QD8 UNIPROT glutamine chemical CHEBI:28300 ChEBI "up-regulates quantity" relocalization 9606 26724577 t "Fourteen of them [[SLC transporters] , capable of transporting glutamine across the plasma membrane, are found in four families: SLC1, SLC6, SLC7, and SLC38. However, it is generally thought that the members of the SLC38 family are the principal transporters for glutamine." SIGNOR-266913 SLC1A5 protein Q15758 UNIPROT glutamine chemical CHEBI:28300 ChEBI "up-regulates quantity" relocalization 9606 26724577 t "Fourteen of them [[SLC transporters] , capable of transporting glutamine across the plasma membrane, are found in four families: SLC1, SLC6, SLC7, and SLC38. However, it is generally thought that the members of the SLC38 family are the principal transporters for glutamine." SIGNOR-266914 RFX3 protein P48380 UNIPROT Cilium_assembly phenotype SIGNOR-PH64 SIGNOR up-regulates 10090 BTO:0000401 32725242 f miannu "RFX2 and RFX3 are key regulators of ependymal cell ciliogenesis in vitro and in vivo. We show here that RFX2 and RFX3 have both redundant and specific functions in the biogenesis of motile cilia on mouse ependymal cells, whereas RFX1 does not seem to play a key regulatory role in this process." SIGNOR-266927 RFX2 protein P48378 UNIPROT Cilium_assembly phenotype SIGNOR-PH64 SIGNOR up-regulates 10090 BTO:0000401 32725242 f miannu "RFX2 and RFX3 are key regulators of ependymal cell ciliogenesis in vitro and in vivo. We show here that RFX2 and RFX3 have both redundant and specific functions in the biogenesis of motile cilia on mouse ependymal cells, whereas RFX1 does not seem to play a key regulatory role in this process." SIGNOR-266928 SLC5A5 protein Q92911 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI "up-regulates quantity" relocalization 10116 28192058 t scontino "Active iodide (I-) transport in both the thyroid and some extrathyroidal tissues is mediated by the Na+/I- symporter (NIS). In the thyroid, NIS-mediated I- uptake plays a pivotal role in thyroid hormone (TH) biosynthesis. " SIGNOR-266961 L-thyroxine smallmolecule CHEBI:18332 ChEBI DIO2 protein Q92813 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0004055 8755651 t scontino "Type II iodothyronine deiodinase (DII), which catalyzes deiodination of thyroxine (T4) exclusively on the outer ring (5’-position) to yield T3" SIGNOR-266948 Sin3B_complex complex SIGNOR-C409 SIGNOR H3-3A protein P84243 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 21041482 t miannu "We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin." SIGNOR-266970 Sin3B_complex complex SIGNOR-C409 SIGNOR H3-4 protein Q16695 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 21041483 t miannu "We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin." SIGNOR-266971 ACAN protein P16112 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 BTO:0000206 10922468 t lperfetto "Degradation of aggrecan, the major proteoglycan of the cartilage ECM responsible for the load-bearing and elastic properties of this tissue, is one of the earliest detectable events in arthritic cartilage degeneration. MMPs have been implicated in proteolysis and the subsequent loss of aggrecan from cartilage during arthritis" SIGNOR-266982 Sin3B_complex complex SIGNOR-C409 SIGNOR H3-5 protein Q6NXT2 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 21041484 t miannu "We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin." SIGNOR-266972 Sin3B_complex complex SIGNOR-C409 SIGNOR H3C1 protein P68431 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 21041485 t miannu "We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin." SIGNOR-266973 Sin3B_complex complex SIGNOR-C409 SIGNOR H3C15 protein Q71DI3 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 21041486 t miannu "We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin." SIGNOR-266974 Sin3B_complex complex SIGNOR-C409 SIGNOR H3Y1 protein P0DPK2 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 21041487 t miannu "We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin." SIGNOR-266975 Sin3B_complex complex SIGNOR-C409 SIGNOR H3Y2 protein P0DPK5 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 21041488 t miannu "We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin." SIGNOR-266976 ACAN protein P16112 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 BTO:0000206 16051604 t lperfetto "Cartilage oligomeric matrix protein/thrombospondin 5 (COMP/TSP5) is a major component of the extracellular matrix of the musculoskeletal system. " SIGNOR-266983 APOH protein P02749 UNIPROT cardiolipin chemical CHEBI:28494 ChEBI "down-regulates quantity by destabilization" binding 9606 BTO:0000131 9596664 t lperfetto "The most relevant physiological role of beta2GPI is supposed to be the regulation of the function of anionic phospholipids like cardiolipin (CL). |Anticardiolipin antibodies or lupus anticoagulants are strongly associated with thrombosis. In these autoimmune diseases with anti-phospholipid antibody syndrome, beta2GPI is a cofactor in the recognition of the phospholipid antigen, CL, by anti-CL antibodies." SIGNOR-266998 phosphatidylethanolamine chemical CHEBI:16038 ChEBI Outer_mitochondrial_membrane complex SIGNOR-C410 SIGNOR "form complex" binding 9606 25627476 t lperfetto "The OMM is comprised of a phospholipid bilayer that houses vital components such as metabolic enzymes and transport proteins|he OMM contains a variety of lipids. The major components of this bilayer include phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylinositol (PI) |It has been reported that in the mammalian OMM, the most prominent of these lipids are PC (~54 % of total), PE (~29 %) and PI (~14 %) (Daum and Vance 1997). The remaining lipids comprise approximately 3 % of the total OMM composition." SIGNOR-266999 phosphatidylcholine chemical CHEBI:64482 ChEBI Outer_mitochondrial_membrane complex SIGNOR-C410 SIGNOR "form complex" binding 9606 25627476 t lperfetto "The OMM is comprised of a phospholipid bilayer that houses vital components such as metabolic enzymes and transport proteins|he OMM contains a variety of lipids. The major components of this bilayer include phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylinositol (PI) |It has been reported that in the mammalian OMM, the most prominent of these lipids are PC (~54 % of total), PE (~29 %) and PI (~14 %) (Daum and Vance 1997). The remaining lipids comprise approximately 3 % of the total OMM composition." SIGNOR-267000 phosphatidylinositol chemical CHEBI:28874 ChEBI Outer_mitochondrial_membrane complex SIGNOR-C410 SIGNOR "form complex" binding 9606 25627476 t lperfetto "The OMM is comprised of a phospholipid bilayer that houses vital components such as metabolic enzymes and transport proteins|he OMM contains a variety of lipids. The major components of this bilayer include phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylinositol (PI) |It has been reported that in the mammalian OMM, the most prominent of these lipids are PC (~54 % of total), PE (~29 %) and PI (~14 %) (Daum and Vance 1997). The remaining lipids comprise approximately 3 % of the total OMM composition." SIGNOR-267001 phosphatidylethanolamine chemical CHEBI:16038 ChEBI Inner_mitochondrial_membrane complex SIGNOR-C411 SIGNOR "form complex" binding 9606 25627476 t lperfetto "The lipid composition of the IMM varies from that of the OMM. PC and PE are still the most abundant phospholipids in the IMM, comprising about 75 % of total lipids.|One of the biggest differences between OMM and IMM lipid composition is the greater concentration of CL that is found in the IMM. Here, CL makes up about 15–20 % of the total phospholipid mass" SIGNOR-267002 phosphatidylcholine chemical CHEBI:64482 ChEBI Inner_mitochondrial_membrane complex SIGNOR-C411 SIGNOR "form complex" binding 9606 25627476 t lperfetto "The lipid composition of the IMM varies from that of the OMM. PC and PE are still the most abundant phospholipids in the IMM, comprising about 75 % of total lipids.|One of the biggest differences between OMM and IMM lipid composition is the greater concentration of CL that is found in the IMM. Here, CL makes up about 15–20 % of the total phospholipid mass" SIGNOR-267003 cardiolipin chemical CHEBI:28494 ChEBI Inner_mitochondrial_membrane complex SIGNOR-C411 SIGNOR "form complex" binding 9606 25627476 t lperfetto "The lipid composition of the IMM varies from that of the OMM. PC and PE are still the most abundant phospholipids in the IMM, comprising about 75 % of total lipids.|One of the biggest differences between OMM and IMM lipid composition is the greater concentration of CL that is found in the IMM. Here, CL makes up about 15–20 % of the total phospholipid mass" SIGNOR-267004 Inner_mitochondrial_membrane complex SIGNOR-C411 SIGNOR Mitochondrial_biogenesis phenotype SIGNOR-PH32 SIGNOR up-regulates 25627476 f lperfetto "Mitochondrial phospholipids are important components of this system. Phospholipids make up the characteristic outer and inner membranes that give mitochondria their shape. " SIGNOR-267005 Inner_mitochondrial_membrane complex SIGNOR-C411 SIGNOR "Mitochondrial respiratory chain complex II" complex SIGNOR-C278 SIGNOR up-regulates relocalization 9606 25627476 t lperfetto "One of the main functions of the IMM is the housing of proteins that make up the electron transport chain (ETC) which ultimately produces ATP. " SIGNOR-267006 Inner_mitochondrial_membrane complex SIGNOR-C411 SIGNOR "Mitochondrial respiratory chain complex III" complex SIGNOR-C279 SIGNOR up-regulates relocalization 9606 25627476 t lperfetto "One of the main functions of the IMM is the housing of proteins that make up the electron transport chain (ETC) which ultimately produces ATP. " SIGNOR-267007 CRLS1 protein Q9UJA2 UNIPROT cardiolipin chemical CHEBI:28494 ChEBI up-regulates "small molecule catalysis" 10090 16678169 t lperfetto "The mitochondrial phospholipid cardiolipin is synthesized from cytidinediphosphate-diacylglycerol and phosphatidylglycerol, a process catalyzed by the enzyme cardiolipin synthase." SIGNOR-267028 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH15 protein P55291 UNIPROT "up-regulates activity" "chemical activation" 9606 22535893 t miannu "Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis." SIGNOR-265832 citrate(3-) smallmolecule CHEBI:16947 ChEBI ACACA protein Q13085 UNIPROT "up-regulates activity" binding 9606 6138356 t miannu "Citrate, an allosteric activator of acetyl-CoA carboxylase, induces polymerization of an inactive protomeric form of the enzyme into an active filamentous form composed of 10-20 protomers. " SIGNOR-267104 citrate(3-) smallmolecule CHEBI:16947 ChEBI ACLY protein P53396 UNIPROT "up-regulates activity" "chemical activation" 9606 19286649 t miannu "ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor." SIGNOR-267100 ACLY protein P53396 UNIPROT citrate(3-) smallmolecule CHEBI:16947 ChEBI "down-regulates quantity by destabilization" "small molecule catalysis" 9606 19286649 t miannu "ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor." SIGNOR-267101 TG protein P01266 UNIPROT Colloid phenotype SIGNOR-PH185 SIGNOR up-regulates 9606 BTO:0001379 24251883 f scontino "The thyroid gland is unique among endocrine glands in storing its principle hormonal product—the two very small thyroid hormones (TH)—as components of a 1000-fold larger precursor—thyroglobulin (Tg)—that is secreted and stored in the colloid, outside of the thyroid cell. Moreover, the thyroid cell is part of a layer of similar cells—the thyroid follicular epithelium—that completely encloses the secreted Tg and segregates it from the circulation." SIGNOR-267135 TSHR protein P16473 UNIPROT GNAS protein P63092 UNIPROT "up-regulates activity" binding 9606 BTO:0001379 25878058 t scontino "The primary signal transduction pathway for TSH receptor is activation of adenylate cyclase via a Gαs G protein-coupled receptor." SIGNOR-267136 KANSL3 protein Q9P2N6 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates 9606 BTO:0000567 26243146 f miannu "Here we uncover a novel function of the NSL complex members in mitosis. As the cell enters mitosis, KANSL1 and KANSL3 undergo a marked relocalisation from the chromatin to the mitotic spindle. By stabilizing microtubule minus ends in a RanGTP-dependent manner, they are essential for spindle assembly and chromosome segregation." SIGNOR-267169 "NSL histone acetyltransferase" complex SIGNOR-C413 SIGNOR H4C1 protein P62805 UNIPROT "down-regulates activity" acetylation Lys17 GLGKGGAkRHRKVLR 9606 20018852 t miannu "Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. by comparing the substrate specificities of the MSL and NSL complexes, we obtain evidence that MOF HAT activity is differentially regulated by assembly into the MSL complex, where it acetylates nucleosomal histone H4 on lysine 16, and the NSL complex, where it also acetylates nucleosomal histone H4 on lysines 5 and 8." SIGNOR-267166 "NSL histone acetyltransferase" complex SIGNOR-C413 SIGNOR H4C1 protein P62805 UNIPROT "down-regulates activity" acetylation Lys6 kGGKGLGK 9606 20018852 t miannu "Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. by comparing the substrate specificities of the MSL and NSL complexes, we obtain evidence that MOF HAT activity is differentially regulated by assembly into the MSL complex, where it acetylates nucleosomal histone H4 on lysine 16, and the NSL complex, where it also acetylates nucleosomal histone H4 on lysines 5 and 8." SIGNOR-267167 "NSL histone acetyltransferase" complex SIGNOR-C413 SIGNOR H4C1 protein P62805 UNIPROT "down-regulates activity" acetylation Lys9 SGRGKGGkGLGKGGA 9606 20018852 t miannu "Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. by comparing the substrate specificities of the MSL and NSL complexes, we obtain evidence that MOF HAT activity is differentially regulated by assembly into the MSL complex, where it acetylates nucleosomal histone H4 on lysine 16, and the NSL complex, where it also acetylates nucleosomal histone H4 on lysines 5 and 8." SIGNOR-267168 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser53 LPPFEDEsEGLLGTE 9606 19647517 t lperfetto "Phosphorylation of mcm2 by cdc7 promotes pre-replication complex assembly during cell-cycle re-entry" SIGNOR-187400 KANSL1 protein Q7Z3B3 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates 9606 BTO:0000567 26243146 f miannu "Here we uncover a novel function of the NSL complex members in mitosis. As the cell enters mitosis, KANSL1 and KANSL3 undergo a marked relocalisation from the chromatin to the mitotic spindle. By stabilizing microtubule minus ends in a RanGTP-dependent manner, they are essential for spindle assembly and chromosome segregation." SIGNOR-267170 KANSL3 protein Q9P2N6 UNIPROT Chromosome_segregation phenotype SIGNOR-PH44 SIGNOR up-regulates 9606 BTO:0000567 26243146 f miannu "Here we uncover a novel function of the NSL complex members in mitosis. As the cell enters mitosis, KANSL1 and KANSL3 undergo a marked relocalisation from the chromatin to the mitotic spindle. By stabilizing microtubule minus ends in a RanGTP-dependent manner, they are essential for spindle assembly and chromosome segregation." SIGNOR-267171 KANSL1 protein Q7Z3B3 UNIPROT Chromosome_segregation phenotype SIGNOR-PH44 SIGNOR up-regulates 9606 BTO:0000567 26243146 f miannu "Here we uncover a novel function of the NSL complex members in mitosis. As the cell enters mitosis, KANSL1 and KANSL3 undergo a marked relocalisation from the chromatin to the mitotic spindle. By stabilizing microtubule minus ends in a RanGTP-dependent manner, they are essential for spindle assembly and chromosome segregation." SIGNOR-267172 MED19 protein A0JLT2 UNIPROT "Core mediator complex" complex SIGNOR-C405 SIGNOR "form complex" binding 9606 28467824 t miannu "Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles." SIGNOR-266663 GXYLT2 protein A0PJZ3 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 22117070 t "Xylosylation in ER membrane" gcesareni "We have previously identified two human genes, gxylt1 and gxylt2, encoding glucoside xylosyltransferases responsible for the transfer of xylose to o-linked glucose. The identity of the enzyme further elongating the glycan to generate the final trisaccharide xylose-xylose-glucose, however, remained unknown. Here, we describe that the human gene c3orf21 encodes a udp-xylose:alfa-xyloside alfa1,3-xylosyltransferase, acting on xylose-alfa1,3-glucosebeta1-containing acceptor structures. We have, therefore, renamed it xxylt1 (xyloside xylosyltransferase 1). Xxylt1 cannot act on a synthetic acceptor containing an alfa-linked xylose alone, but requires the presence of the underlying glucose. Activity on notch egf repeats was proven by in vitro xylosylation of a mouse notch1 fragment recombinantly produced in sf9 insect cells, a bacterially expressed egf repeat from mouse notch2 modified in vitro by rumi and gxylt2 and in vivo by co-expression of the enzyme with the notch1 fragment. The enzyme was shown to be a typical type ii membrane-bound glycosyltransferase localized in the endoplasmic reticulum." SIGNOR-177717 ARHGAP10 protein A1A4S6 UNIPROT RHOA protein P61586 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260465 SYCE3 protein A1L190 UNIPROT Synaptonemal_complex complex SIGNOR-C351 SIGNOR "form complex" binding 9606 22394509 t miannu "The synaptonemal complex (SC) is a proteinaceous structure of chromosome bivalents whose assembly is indispensable for the successful progression of the first meiotic division of sexually reproducing organisms. four proteins were identified that locate specifically to the CE: SYCE1, SYCE2, SYCE3 and TEX12. These three proteins (SYCP1, SYCE1 and SYCE3) are essential for synapsis initiation, as no CE-structures are formed in the absence of any of these proteins. The final step, i.e. synapsis extension over the entire length of the homologs, requires loading of both SYCE2 and TEX12. In their absence, short pieces of CE-like structures composed of SYCP1, SYCE1 and SYCE3 are formed that, however, cannot mature to a SC central region." SIGNOR-264202 PLEKHG3 protein A1L390 UNIPROT CDC42 protein P60953 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260585 SH3PXD2B protein A1X283 UNIPROT NOXA1 protein Q86UR1 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 20943948 t lperfetto "Tks4 and Tks5 bind NoxA1 through their SH3 domains in a Rac-independent manner|NoxO1 is required for full Nox1 and Nox3 oxidase activity at least partially because of its role in the plasma membrane recruitment of the NoxA1 activator protein|Tks4 and Tks5 support Nox1- and Nox3-dependent ROS generation" SIGNOR-264707 NBAS protein A2RRP1 UNIPROT "NRZ complex" complex SIGNOR-C358 SIGNOR "form complex" binding 25364732 t lperfetto "NRZ complex, which comprises NAG, RINT1, and ZW10, is also involved in Golgi-to-ER retrograde transport, but each component of the complex has diverse cellular functions including endosome-to-Golgi transport, cytokinesis, cell cycle checkpoint, autophagy, and mRNA decay." SIGNOR-265024 DENND3 protein A2RUS2 UNIPROT RAB12 protein Q6IQ22 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 25925668 t lperfetto "ULK-mediated phosphorylation of the guanine nucleotide exchange factor DENND3 at serines 554 and 572 upregulates its GEF activity toward the small GTPase Rab12.|active Rab12 facilitates autophagosome trafficking, thus establishing a crucial role for the ULK/DENND3/Rab12 axis in starvation-induced autophagy." SIGNOR-264734 GRID2IP protein A4D2P6 UNIPROT GRID2 protein O43424 UNIPROT "up-regulates quantity" binding 9606 BTO:0004909 11826110 t miannu "We identified a novel GluRdelta2-interacting protein, named Delphilin, that contains a single PDZ domain and formin homology (FH) domains FH1 and FH2 plus coiled-coil structure. Delphilin is selectively localized at the postsynaptic junction site of the parallel fiber-Purkinje cell synapse and colocalized with GluRdelta2. Thus, Delphilin is a postsynaptic scaffolding protein at the parallel fiber-Purkinje cell synapse, where it may serve to link GluRdelta2 with actin cytoskeleton and various signaling molecules." SIGNOR-264475 BDP1 protein A6H8Y1 UNIPROT TFIIIB complex SIGNOR-C393 SIGNOR "form complex" binding 29378333 t lperfetto "Both in yeast and mammalian cells, TFIIIB consists of three subunits: TFIIB-related Brf1, TATA-box binding protein (TBP), common also for the other two RNA polymerases, and Pol III-specific subunit, Bdp1 (Table 1)." SIGNOR-266189 FAM83G protein A6ND36 UNIPROT CD2AP protein Q9Y5K6 UNIPROT "up-regulates activity" binding 9606 BTO:0001938 29175910 t lperfetto "PAWS1 interacts in a dynamic fashion with the actin/cytoskeletal regulator CD2AP at lamellae|Loss of PAWS1 causes severe defects in F-actin organization and distribution as well as in lamellipodial organization, resulting in impaired cell migration." SIGNOR-264768 NKX6-3 protein A6NJ46 UNIPROT GKN1 protein Q9NS71 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001007 26314965 t Luana " In particular, NKX6.3 transcriptional factor was found to bind specifically to the upstream sequences of GKN1, a gastric-specific tumor suppressor, and dramatically increase expression of the latter. " SIGNOR-266096 RIMBP3C protein A6NJZ7 UNIPROT RIMS1 protein Q86UR5 UNIPROT "down-regulates activity" binding 10116 BTO:0001009 11988172 t miannu "SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins." SIGNOR-264362 RIMBP3C protein A6NJZ7 UNIPROT RIMS3 protein Q9UJD0 UNIPROT "down-regulates activity" binding 10116 BTO:0001009 11988172 t miannu "SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins." SIGNOR-264372 RIMBP3C protein A6NJZ7 UNIPROT RIMS2 protein Q9UQ26 UNIPROT "down-regulates activity" binding 10116 BTO:0001009 11988172 t miannu "SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins." SIGNOR-264367 RIMBP3B protein A6NNM3 UNIPROT RIMS1 protein Q86UR5 UNIPROT "down-regulates activity" binding 10116 BTO:0001009 11988172 t miannu "SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins." SIGNOR-264364 RIMBP3B protein A6NNM3 UNIPROT RIMS3 protein Q9UJD0 UNIPROT "down-regulates activity" binding 10116 BTO:0001009 11988172 t miannu "SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins." SIGNOR-264374 RIMBP3B protein A6NNM3 UNIPROT RIMS2 protein Q9UQ26 UNIPROT "down-regulates activity" binding 10116 BTO:0001009 11988172 t miannu "SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins." SIGNOR-264369 CD300LB protein A8K4G0 UNIPROT GRB2 protein P62993 UNIPROT "up-regulates activity" binding 9534 BTO:0004055 20959446 t lperfetto "The CD300b receptor is a non-classical activating receptor able to deliver signals by associating with the transmembrane adaptor protein DAP-12 and the intracellular mediator Grb-2." SIGNOR-264833 CENPX protein A8MT69 UNIPROT FANCM protein Q8IYD8 UNIPROT up-regulates binding 9606 20347429 t gcesareni "We also provide biochemical evidence that mhf1 and mhf2 assemble into a heterodimer that binds dna and enhances the dna branch migration activity of fancm. These findings reveal critical roles of the mhf1-mhf2 dimer in dna damage repair and genome maintenance through fancm." SIGNOR-164729 BBIP1 protein A8MTZ0 UNIPROT "BBsome complex" complex SIGNOR-C288 SIGNOR "form complex" binding 9606 BTO:0004910 19081074 t lperfetto "We recently showed that seven highly conserved BBS proteins form a stable complex, the BBSome, that functions in membrane trafficking to and inside the primary cilium.|As a first step in characterizing this protein, we investigated the biochemical properties of its binding to the core BBSome (previously defined as the BBS1, -2, -4, -5, -7, -8, and -9 complex). We subjected the native LAP-BBS4 eluate to velocity sedimentation analysis (Figure 1C). BBIP10 clearly cosedimented with BBS4 at 14S, suggesting that BBIP10 strongly associates with the core BBSome" SIGNOR-262561 FOXO6 protein A8MYZ6 UNIPROT IDH1 protein O75874 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25648147 t miannu "We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH." SIGNOR-260103 FOXO6 protein A8MYZ6 UNIPROT IDH1 protein O75874 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25648147 t miannu "We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH." SIGNOR-260092 "2-deoxy-alpha-D-ribose 1-phosphate" smallmolecule CHEBI:11563 ChEBI PGM2 protein Q96G03 UNIPROT "up-regulates activity" "chemical activation" 9606 17804405 t miannu "Biochemical characterization of phosphoglucomutase (PGM) isozymes indicated that one of them, designated PGM2 in man (PGM1 in mouse) was more active as a phosphopentomutase than as a phosphoglucomutase, whereas mammalian PGM1 (equivalent to PGM2 in mouse) has a phosphopentomutase activity representing only about 0.2% of its phosphoglucomutase activity. Phosphopentomutase catalyzes the conversion of the nucleoside breakdown products ribose 1-phosphate and deoxyribose 1-phosphate to the corresponding 5-phosphopentoses." SIGNOR-267093 "lysophosphatidic acid" smallmolecule CHEBI:132742 ChEBI LPAR5 protein Q9H1C0 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257532 "lysophosphatidic acid" smallmolecule CHEBI:132742 ChEBI LPAR2 protein Q9HBW0 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257529 "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI RORB protein Q92753 UNIPROT "down-regulates activity" "chemical inhibition" 9606 12958591 t miannu "ATRA and related retinoids inhibit ROR beta but not ROR alpha transcriptional activity suggesting that high-affinity, subtype-specific ligands could be designed for the identification of ROR beta target genes. Our results identify ROR beta as a retinoid-regulated nuclear receptor, providing a novel pathway for retinoid action." SIGNOR-266845 "lysophosphatidic acid" smallmolecule CHEBI:132742 ChEBI LPAR3 protein Q9UBY5 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257530 "lysophosphatidylinositol 22:6" smallmolecule CHEBI:138556 ChEBI GPR55 protein Q9Y2T6 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257507 "precursor messenger RNA" smallmolecule CHEBI:139356 ChEBI "CFII complex" complex SIGNOR-C387 SIGNOR "up-regulates activity" "chemical activation" 9606 BTO:0000567 30139799 t lperfetto "Cleavage factor II (CF II) is a poorly characterized component of the multiprotein complex catalyzing 3' cleavage and polyadenylation of mammalian mRNA precursors. We have reconstituted CF II as a heterodimer of hPcf11 and hClp1. The heterodimer is active in partially reconstituted cleavage reactions" SIGNOR-266179 "precursor messenger RNA" smallmolecule CHEBI:139356 ChEBI "CFI complex" complex SIGNOR-C388 SIGNOR "up-regulates activity" "chemical activation" 9606 BTO:0000567 30139799 t lperfetto "Cleavage factor II (CF II) is a poorly characterized component of the multiprotein complex catalyzing 3' cleavage and polyadenylation of mammalian mRNA precursors. We have reconstituted CF II as a heterodimer of hPcf11 and hClp1. The heterodimer is active in partially reconstituted cleavage reactions" SIGNOR-266178 acetyl-CoA smallmolecule CHEBI:15351 ChEBI ACACB protein O00763 UNIPROT "up-regulates activity" "chemical activation" 9606 20952656 t miannu "ACC catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting and first committed step in de novo fatty acid biosynthesis. Two isoforms of ACC exist in mammals, ACC1 and ACC2, and both enzymes function to carboxylate acetyl-CoA to form malonyl-CoA" SIGNOR-267108 acetyl-CoA smallmolecule CHEBI:15351 ChEBI CS protein O75390 UNIPROT "up-regulates activity" "chemical activation" 9606 3013232 t miannu "Citrate synthase catalyzes an important step within the cycle, the Claisen condensation of acetyl-Coenzyme A with oxaloacetate to form citrate; and it is the only enzyme in the cycle that can catalyze the formation of a carbon-carbon bond." SIGNOR-266236 acetyl-CoA smallmolecule CHEBI:15351 ChEBI ACACA protein Q13085 UNIPROT "up-regulates activity" "chemical activation" 9606 20952656 t miannu "ACC catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting and first committed step in de novo fatty acid biosynthesis. Two isoforms of ACC exist in mammals, ACC1 and ACC2, and both enzymes function to carboxylate acetyl-CoA to form malonyl-CoA" SIGNOR-267107 pyruvate smallmolecule CHEBI:15361 ChEBI LDHA protein P00338 UNIPROT "up-regulates activity" "chemical activation" 9606 24929216 t "Glucose and alanine produce pyruvate which is reduced to lactate by lactate dehydrogenase in the cytoplasm without oxygen consumption. Lactate removal takes place via its oxidation to pyruvate by lactate dehydrogenase." SIGNOR-266920 pyruvate smallmolecule CHEBI:15361 ChEBI PC protein P11498 UNIPROT "up-regulates activity" "chemical activation" 9606 24363178 t miannu "As an alternative to decarboxylation by PDH, the second major fate of mitochondrial pyruvate is the irreversible, ATP-dependent carboxylation of pyruvate to oxaloacetate by pyruvate carboxylase (PC). Oxaloacetate is a critical intermediate in metabolism, linking carbohydrate, lipid, amino acid, and nucleotide metabolism (Fig. 2)" SIGNOR-266553 pyruvate smallmolecule CHEBI:15361 ChEBI PDH complex SIGNOR-C402 SIGNOR "up-regulates activity" "chemical activation" 9606 29059435 t miannu "The mitochondrial pyruvate dehydrogenase complex (PDC) irreversibly decarboxylates pyruvate to acetyl coenzyme A, thereby linking glycolysis to the tricarboxylic acid cycle and defining a critical step in cellular bioenergetics." SIGNOR-266542 "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI CYP26A1 protein O43174 UNIPROT "up-regulates activity" "chemical activation" 9606 31963453 t lperfetto "Cytochrome P450 (CYP) subfamily 26 of enzymes degrade the excess of RA to avoid detrimental effects [17]. Among the three subtypes (CYP26A1, CYP26B1, and CYP26C1), CYP26A1 is particularly important during embryonic development" SIGNOR-265138 "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI AFP protein P02771 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000972 9792724 f miannu "In this report, we show a distinctive effect of all-trans-retinoic acid (RA) in Hep3B cells. RA caused a marked decrease in AFP transcripts." SIGNOR-254443 "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI THBD protein P07204 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001321;BTO:0003160;BTO:0001061 22406829 f miannu "In carcinomas the expression of thrombomodulin (TM) is inversely correlated with tumour progression and metastasis. The expression of TM is negatively regulated by NF-?B- and GSK3-?-dependent signalling pathways and positively regulated by retinoic acid and transcription factor Sp1 in PrEC, LNCaP and PC-3 cells, but not in DU-145 cells." SIGNOR-255217 "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI RARA protein P10276 UNIPROT "up-regulates activity" "chemical activation" 9606 17132853 t miannu "The physiological effects of retinoic acids (RAs) are mediated by members of two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are encoded by three distinct human genes, RXRalpha, RXRbeta, and RXRgamma." SIGNOR-256194 "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI RARB protein P10826 UNIPROT "up-regulates activity" "chemical activation" 9606 17132853 t miannu "The physiological effects of retinoic acids (RAs) are mediated by members of two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are encoded by three distinct human genes, RXRalpha, RXRbeta, and RXRgamma." SIGNOR-256195 "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI RARB protein P10826 UNIPROT "up-regulates activity" "chemical activation" 9534 BTO:0000298 19058965 t Luana "Tazarotene and its analogue 8 are RAR-β,γ selective acetylenic retinoids, whereas analogue 9 is very active on the three subtypes. " SIGNOR-258137 "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI PML-RARalpha "fusion protein" SIGNOR-FP2 SIGNOR "down-regulates quantity by destabilization" "chemical inhibition" 9606 19029980 t "Retinoic acid and arsenic synergize to clear LICs through cooperative PML-RARA degradation, this combination does not enhance differentiation." SIGNOR-259926 "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI RAR proteinfamily SIGNOR-PF45 SIGNOR "up-regulates activity" "chemical activation" 9606 17132853 t miannu "The physiological effects of retinoic acids (RAs) are mediated by members of two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are encoded by three distinct human genes, RXRalpha, RXRbeta, and RXRgamma." SIGNOR-256197 ATP smallmolecule CHEBI:15422 ChEBI PRKAG1 protein P54619 UNIPROT down-regulates "chemical inhibition" 9606 SIGNOR-C15 21399626 t gcesareni "Atp promotes dephosphorylation of catalytic subunit, rendering the ampk enzyme inactive" SIGNOR-172822 ATP smallmolecule CHEBI:15422 ChEBI P2RX7 protein Q99572 UNIPROT up-regulates "chemical activation" 9606 18827222 t mrosina "Pericellular ATP activates P2XRs on the T cell in an autocrine fashion (step 4) and perhaps also P2X7 receptors on the APC in a paracrine fashion resulting in IL-1beta processing and release (step 5)." SIGNOR-254965 ATP smallmolecule CHEBI:15422 ChEBI AMPK complex SIGNOR-C15 SIGNOR down-regulates "chemical inhibition" 9606 21399626 t lperfetto "Atp promotes dephosphorylation of catalytic subunit, rendering the ampk enzyme inactive" SIGNOR-217481 glycine smallmolecule CHEBI:15428 ChEBI GLRA3 protein O75311 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0001175;BTO:0001279;BTO:0000146 18721822 t miannu "The glycine receptor chloride channel (GlyR), a member of the pentameric Cys-loop ion channel receptor family, mediates inhibitory neurotransmission in the spinal cord, brainstem and retina." SIGNOR-264982 glycine smallmolecule CHEBI:15428 ChEBI GLRA1 protein P23415 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0001175;BTO:0001279;BTO:0000146 18721822 t miannu "The glycine receptor chloride channel (GlyR), a member of the pentameric Cys-loop ion channel receptor family, mediates inhibitory neurotransmission in the spinal cord, brainstem and retina." SIGNOR-264980 glycine smallmolecule CHEBI:15428 ChEBI GLRA1 protein P23415 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000007 9009272 t miannu "For each mutant GlyR we examined the agonist efficacies of taurine and β-alanine relative to glycine, the concentration of each agonist required for half-maximal current activation (EC50) and, in mutant GlyRs where β-alanine and taurine exhibited partial or no agonist efficacy, the concentration required for half-maximal inhibition of glycine-gated currents (IC50).experiments described in this report were performed on human α1 homomeric GlyRs recombinantly expressed in mammalian HEK 293 cells. Taurine and β-alanine act as full agonists of human α1 GlyRs when expressed in this system." SIGNOR-258580 glycine smallmolecule CHEBI:15428 ChEBI GLRA2 protein P23416 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0001175;BTO:0001279;BTO:0000146 18721822 t miannu "The glycine receptor chloride channel (GlyR), a member of the pentameric Cys-loop ion channel receptor family, mediates inhibitory neurotransmission in the spinal cord, brainstem and retina." SIGNOR-264981 glycine smallmolecule CHEBI:15428 ChEBI GLRB protein P48167 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0001175;BTO:0001279;BTO:0000146 18721822 t miannu "The glycine receptor chloride channel (GlyR), a member of the pentameric Cys-loop ion channel receptor family, mediates inhibitory neurotransmission in the spinal cord, brainstem and retina." SIGNOR-264983 glycine smallmolecule CHEBI:15428 ChEBI GlyR proteinfamily SIGNOR-PF62 SIGNOR "up-regulates activity" "chemical activation" 9606 BTO:0001175;BTO:0001279;BTO:0000146 18721822 t miannu "The glycine receptor chloride channel (GlyR), a member of the pentameric Cys-loop ion channel receptor family, mediates inhibitory neurotransmission in the spinal cord, brainstem and retina." SIGNOR-264985 malonyl-CoA smallmolecule CHEBI:15531 ChEBI CPT1A protein P50416 UNIPROT "down-regulates activity" binding 9606 14517221 t miannu "Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C)." SIGNOR-267114 malonyl-CoA smallmolecule CHEBI:15531 ChEBI CPT1C protein Q8TCG5 UNIPROT "down-regulates activity" binding 9606 14517221 t miannu "Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C)." SIGNOR-267116 malonyl-CoA smallmolecule CHEBI:15531 ChEBI CPT1B protein Q92523 UNIPROT "down-regulates activity" binding 9606 14517221 t miannu "Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C)." SIGNOR-267115 15(S)-HETE smallmolecule CHEBI:15558 ChEBI PPARG protein P37231 UNIPROT "up-regulates activity" "chemical activation" 9606 12517954 t lperfetto "15(S)-HETE is a ligand for PPARγ in IL-4-stimulated A549 cells" SIGNOR-254095 "sedoheptulose 7-phosphate" smallmolecule CHEBI:15721 ChEBI TALDO1 protein P37837 UNIPROT "up-regulates activity" "chemical activation" 9606 19401148 t miannu "Transaldolase (TAL, sedoheptulose 7-phosphate: d-glyceraldehyde 3-phosphate dihydroxyacetone transferase; EC number 2.2.1.2) is a cofactor-less enzyme of the pentose phosphate pathway (PPP) (Fig. 1A and B). It catalyzes the reversible transfer of a three carbon unit (“dihydroxyacetone”) between various sugar phosphates (from 3 to 8 carbon atoms in length). Physiological donor compounds are ketose sugar phosphates as fructose 6-phosphate or sedoheptulose 7-phosphate. Acceptor compounds are aldose sugar phosphates as glyceraldehyde 3-phosphate and erythrose 4-phosphate." SIGNOR-267089 "hexadecanoic acid" smallmolecule CHEBI:15756 ChEBI FFAR1 protein O14842 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257488 tyramine smallmolecule CHEBI:15760 ChEBI CYP2D6 protein P10635 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000143 NBK536726 t brain lperfetto "Under specific conditions, dopamine can also be synthesized by a minor pathway, in which L-tyrosine is converted into p-tyramine (mediated by AADC), with subsequent hydroxylation to dopamine by the enzyme CYP2D6 (Cytochrome P450 2D6) which is found in the substantia nigra of human brain " SIGNOR-264176 L-dopa smallmolecule CHEBI:15765 ChEBI DDC protein P20711 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0004032 NBK536726 t brain lperfetto "Subsequently, L-DOPA is converted into 3,4-dihydroxyphenethylamine (dopamine) through decarboxylation by the enzyme L-3,4-dihydroxyphenylalanine decarboxylase (DOPA decarboxylase) in the pre-synaptic terminal" SIGNOR-264174 3,5-diiodo-L-tyrosine smallmolecule CHEBI:15768 ChEBI TPO protein P07202 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0001379 28153798 t scontino "The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a “donor” onto a DIT residue called an “acceptor”. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines." SIGNOR-267038 3,5-diiodo-L-tyrosine smallmolecule CHEBI:15768 ChEBI IYD protein Q6PHW0 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0001379 28153798 t scontino "MIT and DIT, which are deiodinated by iodotyrosine dehalogenase (DEHAL1) that seems to be present in the apical plasma membrane. MIT and DIT are liberated, and the deiodination of these molecules by DEHAL1 is important for providing a sustained source of intrathyroidal iodide." SIGNOR-267035 (R)-2-hydroxyglutarate(2-) smallmolecule CHEBI:15801 ChEBI TET2 protein Q6N021 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001883 29090344 t miannu "Various studies have tried to investigate how the accumulation of R2-HG promotes leukemogenesis in cooperation with other frequently observed mutations in AML. An important role appears to be the ability of R2-HG to competitively inhibit multiple αKG-dependent dioxygenases. While TET2 normally catalyzes the conversion of 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), inhibition of TET2 by R2-HG has been found to result in a hypermethylated gene signature in HSPCs, which overlaps with the signatures of both IDH and TET2-mutated leukemic cells." SIGNOR-261829 3-methoxytyramine smallmolecule CHEBI:1582 ChEBI MAOA protein P21397 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0004032;BTO:0002606 NBK536726 t brain lperfetto "Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells |dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO." SIGNOR-264178 3-methoxytyramine smallmolecule CHEBI:1582 ChEBI MAOB protein P27338 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0004032;BTO:0002606 NBK536726 t brain lperfetto "Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells |dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO." SIGNOR-264179 "arachidonic acid" smallmolecule CHEBI:15843 ChEBI FOS protein P01100 UNIPROT up-regulates 9606 15878913 f 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-255392 "arachidonic acid" smallmolecule CHEBI:15843 ChEBI PRKCA protein P17252 UNIPROT up-regulates "chemical activation" 9606 1357097 t miannu "These results suggest that the activation of protein kinase c by both arachidonic acid and phorbol esters may play a role in the potentiation of glutamate exocytosis." SIGNOR-17809 "arachidonic acid" smallmolecule CHEBI:15843 ChEBI PTGS2 protein P35354 UNIPROT up-regulates 9606 15878913 f 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 "arachidonic acid" smallmolecule CHEBI:15843 ChEBI PLA2G4A protein P47712 UNIPROT up-regulates 9606 15878913 f 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-255393 taurine smallmolecule CHEBI:15891 ChEBI GLRA1 protein P23415 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000007 9009272 t miannu "For each mutant GlyR we examined the agonist efficacies of taurine and β-alanine relative to glycine, the concentration of each agonist required for half-maximal current activation (EC50) and, in mutant GlyRs where β-alanine and taurine exhibited partial or no agonist efficacy, the concentration required for half-maximal inhibition of glycine-gated currents (IC50).experiments described in this report were performed on human α1 homomeric GlyRs recombinantly expressed in mammalian HEK 293 cells. Taurine and β-alanine act as full agonists of human α1 GlyRs when expressed in this system." SIGNOR-258579 GTP smallmolecule CHEBI:15996 ChEBI GNAI1 protein P63096 UNIPROT up-regulates "chemical activation" 9606 12040175 t gcesareni "Agonist binding triggers a conformational change in the receptor, which catalyses the dissociation of gdp from the alfa subunit followed by gtp-binding to galfa and the dissociation of galfa from gbetagamma subunits1. The alfa subunits of g proteins are divided into four subfamilies: galfas, galfai, galfaq and galfa12, and a single gpcr can couple to either one or more families of galfa proteins." SIGNOR-88238 GTP smallmolecule CHEBI:15996 ChEBI GNAS protein Q5JWF2 UNIPROT up-regulates "chemical activation" 9606 17095603 t gcesareni "Galfa subunits cycle between inactive (gdp-bound) and active (gtp-bound) states, and the lifetime of the active state is limited by gtp hydrolysis." SIGNOR-253071 "adenosine 5'-monophosphate" smallmolecule CHEBI:16027 ChEBI PRPS1 protein P60891 UNIPROT "down-regulates activity" "chemical inhibition" 29074724 t lperfetto "PRPS1 is inhibited by the nucleotide biosynthesis products ADP, AMP, and GDP" SIGNOR-265737 cholesterol smallmolecule CHEBI:16113 ChEBI SOAT1 protein P35610 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000759 31848472 t miannu "Excess cholesterol is esterified by acyl coenzyme A:cholesterol acyltransferase (ACAT; also known as SOAT) to cholesteryl esters" SIGNOR-265159 "2-deoxy-D-ribose 5-phosphate" smallmolecule CHEBI:16132 ChEBI DERA protein Q9Y315 UNIPROT "up-regulates activity" "chemical activation" 9606 25229427 t miannu "Deoxyribose-phosphate aldolase (EC 4.1.2.4), which converts 2-deoxy-d-ribose-5-phosphate into glyceraldehyde-3-phosphate and acetaldehyde, belongs to the core metabolism of living organisms. his study provides the first experimental evidence that DERA, which is mainly expressed in lung, liver and colon, is the human deoxyribose phosphate aldolase." SIGNOR-267096 "hydrogen peroxide" smallmolecule CHEBI:16240 ChEBI TXN protein P10599 UNIPROT up-regulates "chemical activation" 9606 15556622 t gcesareni "We show that 10 and 50 microm h2o2 and short-term exposure to shear stress significantly increased trx-1 mrna and protein levels in endothelial cells." SIGNOR-131049 "hydrogen peroxide" smallmolecule CHEBI:16240 ChEBI MAPK7 protein Q13164 UNIPROT up-regulates 9606 BTO:0000142 11782488 f gcesareni "These findings suggest that c-src mediated bmk1 activation by h(2)o(2) may counteract ischemic cellular damage probably through the activation of mef2c transcription factor." SIGNOR-113758 UDP-N-acetyl-alpha-D-glucosamine smallmolecule CHEBI:16264 ChEBI GNE protein Q9Y223 UNIPROT "up-regulates quantity" "chemical activation" 10745088 t lperfetto "UDP-GlcNAc 2-epimerase is a bifunctional enzyme and catalyzes the first two steps of neuraminic acid synthesis in the cytosol, the conversion of UDP-N-acetylglucosamine to ManAc and the phosphorylation to ManAc-6-phosphate." SIGNOR-266075 17beta-hydroxy-5alpha-androstan-3-one smallmolecule CHEBI:16330 ChEBI AR protein P10275 UNIPROT up-regulates "chemical activation" 9606 15861399 t miannu "Testosterone is the predominant circulating androgen in mammals and is converted to dihydrotestosterone (DHT) by 5α-reductase in certain tissues of the male urogenital tract, skin, and other target cells. DHT binds with highest affinity to AR and together with testosterone promotes AR transcriptional activity thereby ensuring the development and maintenance of male reproductive functions." SIGNOR-251533 adenosine smallmolecule CHEBI:16335 ChEBI PI4K2B protein Q8TCG2 UNIPROT "down-regulates activity" "chemical inhibition" -1 21704602 t Luana "Both PI4K2A and PI4K2B were inhibited by adenosine at concentrations that do not significantly inhibit PI4KA and PI4KB actitvity" SIGNOR-258316 adenosine smallmolecule CHEBI:16335 ChEBI PI4K2A protein Q9BTU6 UNIPROT "down-regulates activity" "chemical inhibition" -1 21704602 t Luana "Both PI4K2A and PI4K2B were inhibited by adenosine at concentrations that do not significantly inhibit PI4KA and PI4KB actitvity" SIGNOR-258317 "phosphatidic acid" smallmolecule CHEBI:16337 ChEBI CDS2 protein O95674 UNIPROT "up-regulates activity" "chemical activation" 9606 25375833 t lperfetto "CDP-diacylglycerol synthases (CDS) are critical enzymes that catalyze the formation of CDP-diacylglycerol (CDP-DAG) from phosphatidic acid (PA)." SIGNOR-267022 "phosphatidic acid" smallmolecule CHEBI:16337 ChEBI MAPK1 protein P28482 UNIPROT up-regulates "chemical activation" 9606 BTO:0000887;BTO:0001103 20231899 t gcesareni "In addition, extracellular signal-regulated kinase (erk) is stimulated by ampk-induced pld1 activation through the formation of phosphatidic acid (pa), which is a product of pld" SIGNOR-164289 "phosphatidic acid" smallmolecule CHEBI:16337 ChEBI MTOR protein P42345 UNIPROT up-regulates "chemical activation" 9606 11729323 t gcesareni "Pa directly interacted with the domain in mtor that is targeted by rapamycin, and this interaction was positively correlated with mtor's ability to activate downstream effectors." SIGNOR-112379 "phosphatidic acid" smallmolecule CHEBI:16337 ChEBI RAC1 protein P63000 UNIPROT up-regulates "chemical activation" 9606 18480413 t gcesareni "The c-terminal polybasic motif of rac1 is responsible for direct interaction with pa," SIGNOR-178632 "phosphatidic acid" smallmolecule CHEBI:16337 ChEBI PRKCZ protein Q05513 UNIPROT up-regulates "chemical activation" 9606 12401205 t gcesareni "The pkc isoform pkc-zeta appear to be activated by direct interactions with pa" SIGNOR-94867 "phosphatidic acid" smallmolecule CHEBI:16337 ChEBI SOS1 protein Q07889 UNIPROT up-regulates "chemical activation" 9606 17486115 t gcesareni "Phosphatidic acid interacts with a defined site in the sos ph domain with high affinity and specificity" SIGNOR-154676 "phosphatidic acid" smallmolecule CHEBI:16337 ChEBI CDS1 protein Q92903 UNIPROT "up-regulates activity" "chemical activation" 9606 25375833 t lperfetto "CDP-diacylglycerol synthases (CDS) are critical enzymes that catalyze the formation of CDP-diacylglycerol (CDP-DAG) from phosphatidic acid (PA)." SIGNOR-267019 (R)-carnitine smallmolecule CHEBI:16347 ChEBI CPT1A protein P50416 UNIPROT "up-regulates activity" "chemical activation" 9606 14517222 t miannu "Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C)." SIGNOR-267117 (R)-carnitine smallmolecule CHEBI:16347 ChEBI CPT1C protein Q8TCG5 UNIPROT "up-regulates activity" "chemical activation" 9606 14517224 t miannu "Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C)." SIGNOR-267119 (R)-carnitine smallmolecule CHEBI:16347 ChEBI CPT1B protein Q92523 UNIPROT "up-regulates activity" "chemical activation" 9606 14517223 t miannu "Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C)." SIGNOR-267118 iodide smallmolecule CHEBI:16382 ChEBI TPO protein P07202 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0004708 23349248 t miannu "After transport through the apical membrane, I− is covalently bound to the tyrosyl residues of Tg by thyroid peroxidase (TPO)." SIGNOR-259913 lipopolysaccharide smallmolecule CHEBI:16412 ChEBI TLR4 protein O00206 UNIPROT "up-regulates activity" "chemical activation" 10090 9851930 t "The mammalian Tlr4 protein has been adapted primarily to subserve the recognition of LPS and presumably transduces the LPS signal across the plasma membrane." SIGNOR-252075 oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI CS protein O75390 UNIPROT "up-regulates activity" "chemical activation" 9606 3013232 t miannu "Citrate synthase catalyzes an important step within the cycle, the Claisen condensation of acetyl-Coenzyme A with oxaloacetate to form citrate; and it is the only enzyme in the cycle that can catalyze the formation of a carbon-carbon bond." SIGNOR-266237 17beta-estradiol smallmolecule CHEBI:16469 ChEBI ESR1 protein P03372 UNIPROT up-regulates "chemical activation" 9606 BTO:0000150 17478088 t gcesareni "Oestrogen receptors (er)alpha and beta modify the expression of genes involved in cell growth, proliferation and differentiation through binding to oestrogen response elements (eres) located in a number of gene promoters." SIGNOR-154660 "nitric oxide" smallmolecule CHEBI:16480 ChEBI GUCY1A3-B2 complex SIGNOR-C139 SIGNOR "up-regulates activity" "chemical activation" 9606 15036565 t gcesareni "One of the most biologically relevant actions of NO is its binding to the heme moiety in the heterodimeric enzyme, soluble guanylyl cyclase (sGC). Activation of sGC by NO results in the production of the second messenger molecule, 3€²,5€²-cyclic guanosine monophosphate (cGMP)" SIGNOR-244113 "nitric oxide" smallmolecule CHEBI:16480 ChEBI GUCY1A3-B3 complex SIGNOR-C140 SIGNOR "up-regulates activity" "chemical activation" 9606 15036565 t gcesareni "One of the most biologically relevant actions of NO is its binding to the heme moiety in the heterodimeric enzyme, soluble guanylyl cyclase (sGC). Activation of sGC by NO results in the production of the second messenger molecule, 3€²,5€²-cyclic guanosine monophosphate (cGMP)" SIGNOR-243967 CHEK1 protein O14757 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 BTO:0001321 15659650 t lperfetto "CHK1 and CHK2 phosphorylate the p53 N terminus at Ser15, Thr18, Ser20, and Ser37" SIGNOR-217799 "1D-myo-inositol 1,4,5-trisphosphate" smallmolecule CHEBI:16595 ChEBI GSN protein P06396 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000132 12788695 t lperfetto "We further measured the ability of ppIs phosphorylated in positions D-3 and D-4 to release the F-actin capping proteins CapZ and gelsolin from OG-permeabilized platelets (Fig. 7A). Ten percent of platelet CapZ and gelsolin is found in the OG-insoluble fraction (4). PI3,4,5P3 and PI3,4P2 release both CapZ and gelsolin from these preparations." SIGNOR-261840 "1D-myo-inositol 1,4,5-trisphosphate" smallmolecule CHEBI:16595 ChEBI PRKCA protein P17252 UNIPROT up-regulates "chemical activation" 9606 18593525 t gcesareni "The hrh1 predominantly couples to g?q/11 proteins, leading to the activation of phospholipase c (plc) and subsequent release of the second messengers inositol trisphosphate (ip3) and diacylglycerol (dag) followed by the activation of pkc and the release of [ca2+]i." SIGNOR-179291 melatonin smallmolecule CHEBI:16796 ChEBI MTNR1B protein P49286 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257546 sedoheptulose smallmolecule CHEBI:16802 ChEBI SHPK protein Q9UHJ6 UNIPROT "up-regulates activity" "chemical activation" 9606 22682222 t miannu "The sedoheptulose kinase CARKL directs macrophage polarization through control of glucose metabolism. CARKL bridges glycolysis and PPP by catalyzing the formation of S7P from sedoheptulose" SIGNOR-267083 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI HIF1A protein Q16665 UNIPROT "up-regulates activity" "chemical activation" 20383689 t lperfetto "HIF prolyl hydroxylase-3 mediates alpha-ketoglutarate-induced apoptosis and tumor suppression|The hypoxia inducible factor (HIF) prolyl hydroxylases (PHDs) are enzymes that are functionally inactivated in hypoxia, as they use both oxygen and alpha-ketoglutarate as substrates to hydroxylate target prolyl residues." SIGNOR-253138 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI OGDC complex SIGNOR-C397 SIGNOR "up-regulates activity" "chemical activation" 9606 15953811 t miannu "The α-ketoglutarate–dehydrogenase complex is a complex including multiple copies of three proteins: E1k (α-ketoglutarate dehydrogenase), E2k (dihydrolipoyl succinyltransferase), and E3 (dihydrolipoamide dehydrogenase) (Fig. 2). The consecutive action of the three catalytic components of KGDHC results in oxidative decarboxylation of 2-oxoglutarate, preserving the energy in the form of succinylCoA and NADH." SIGNOR-266253 6-phospho-D-gluconate smallmolecule CHEBI:16863 ChEBI PGD protein P52209 UNIPROT "up-regulates activity" "chemical activation" 9606 34775382 t miannu "6 PG undergoes oxidative decarboxylation by 6-phosphogluconate dehydrogenase (6PGD) producing Ru5P and the second NADPH molecule." SIGNOR-267059 "gamma-aminobutyric acid" smallmolecule CHEBI:16865 ChEBI "GABA-A (a5-b1-g2) receptor" complex SIGNOR-C335 SIGNOR "up-regulates activity" "chemical activation" 9606 18790874 t brain lperfetto "Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS)." SIGNOR-263791 "gamma-aminobutyric acid" smallmolecule CHEBI:16865 ChEBI "GABA-B receptor" complex SIGNOR-C336 SIGNOR "up-regulates activity" "chemical activation" 9606 18790874 t miannu "Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS)." SIGNOR-264962 "gamma-aminobutyric acid" smallmolecule CHEBI:16865 ChEBI "GABA-B receptor" complex SIGNOR-C336 SIGNOR "up-regulates activity" "chemical activation" 9606 9872316 t brain lperfetto "GABA (gamma-aminobutyric acid) is the main inhibitory neurotransmitter in the mammalian central nervous system, where it exerts its effects through ionotropic (GABA(A/C)) receptors to produce fast synaptic inhibition and metabotropic (GABA(B)) receptors to produce slow, prolonged inhibitory signals." SIGNOR-263795 6-O-phosphono-D-glucono-1,5-lactone smallmolecule CHEBI:16938 ChEBI PGLS protein O95336 UNIPROT "up-regulates activity" "chemical activation" 9606 31586547 t miannu "The second enzyme in the oxiPPP, 6-phosphogluconolactonase (PGLS), converts 6PGL to 6-phosphogluconate (6PG)." SIGNOR-267056 beta-alanine smallmolecule CHEBI:16958 ChEBI GLRA1 protein P23415 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000007 9009272 t miannu "For each mutant GlyR we examined the agonist efficacies of taurine and β-alanine relative to glycine, the concentration of each agonist required for half-maximal current activation (EC50) and, in mutant GlyRs where β-alanine and taurine exhibited partial or no agonist efficacy, the concentration required for half-maximal inhibition of glycine-gated currents (IC50).experiments described in this report were performed on human α1 homomeric GlyRs recombinantly expressed in mammalian HEK 293 cells. Taurine and β-alanine act as full agonists of human α1 GlyRs when expressed in this system." SIGNOR-258581 11-deoxycorticosterone smallmolecule CHEBI:16973 ChEBI NR3C1 protein P04150 UNIPROT "up-regulates activity" "chemical activation" 9534 BTO:0001538 8282004 t miannu "The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4)." SIGNOR-258713 "glutamic acid" smallmolecule CHEBI:18237 ChEBI GRIA3 protein P42263 UNIPROT "up-regulates activity" "chemical activation" 9606 30825796 t miannu "In the mammalian brain the majority of fast excitatory neurotransmission is carried out by Œ±-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive ionotropic glutamate receptors located within the post-synaptic density of glutamatergic synapses" SIGNOR-264610 "glutamic acid" smallmolecule CHEBI:18237 ChEBI GRIA4 protein P48058 UNIPROT "up-regulates activity" "chemical activation" 9606 30825796 t miannu "In the mammalian brain the majority of fast excitatory neurotransmission is carried out by Œ±-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive ionotropic glutamate receptors located within the post-synaptic density of glutamatergic synapses" SIGNOR-264611 progesterone smallmolecule CHEBI:17026 ChEBI NR3C2 protein P08235 UNIPROT "down-regulates activity" "chemical inhibition" 9534 BTO:0001538 8282004 t miannu "The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4)." SIGNOR-258705 estrone smallmolecule CHEBI:17263 ChEBI ESR2 protein Q92731 UNIPROT "up-regulates activity" "chemical activation" -1 9048584 t miannu "In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes." SIGNOR-258583 "D-ribulose 5-phosphate" smallmolecule CHEBI:17363 ChEBI RPIA protein P49247 UNIPROT "up-regulates activity" "chemical activation" 9606 34775382 t miannu "The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux." SIGNOR-267064 "D-ribulose 5-phosphate" smallmolecule CHEBI:17363 ChEBI RPEL1 protein Q2QD12 UNIPROT "up-regulates activity" "chemical activation" 9606 34775382 t miannu "The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux." SIGNOR-267063 "D-ribulose 5-phosphate" smallmolecule CHEBI:17363 ChEBI RPE protein Q96AT9 UNIPROT "up-regulates activity" "chemical activation" 9606 34775382 t miannu "The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux." SIGNOR-267062 "3',5'-cyclic AMP" smallmolecule CHEBI:17489 ChEBI PRKAR2A protein P13861 UNIPROT "down-regulates activity" "chemical inhibition" 9606 26687711 t "Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets" SIGNOR-258761 "3',5'-cyclic AMP" smallmolecule CHEBI:17489 ChEBI PRKACA protein P17612 UNIPROT up-regulates "chemical activation" 9606 16293724 t 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 "3',5'-cyclic AMP" smallmolecule CHEBI:17489 ChEBI PRKAR1B protein P31321 UNIPROT "down-regulates activity" "chemical inhibition" 9606 26687711 t "Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets" SIGNOR-258760 "3',5'-cyclic AMP" smallmolecule CHEBI:17489 ChEBI PRKAR2B protein P31323 UNIPROT "down-regulates activity" "chemical inhibition" 9606 26687711 t "Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets" SIGNOR-258762 "3',5'-cyclic AMP" smallmolecule CHEBI:17489 ChEBI PKA proteinfamily SIGNOR-PF17 SIGNOR "up-regulates activity" "chemical activation" 9606 26687711 t "Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets" SIGNOR-258763 "1-phosphatidyl-1D-myo-inositol 4-phosphate" smallmolecule CHEBI:17526 ChEBI "AP-1/clathrin vescicle" complex SIGNOR-C251 SIGNOR "form complex" binding 9606 23103167 t lperfetto "Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors" SIGNOR-260675 GDP smallmolecule CHEBI:17552 ChEBI GNAS protein Q5JWF2 UNIPROT down-regulates "chemical inhibition" 9606 17095603 t gcesareni "Galfa subunits cycle between inactive (GDP-bound) and active (GTP-bound) states, and the lifetime of the active state is limited by GTP hydrolysis." SIGNOR-253072 O-phosphoethanolamine smallmolecule CHEBI:17553 ChEBI GABARAP protein O95166 UNIPROT up-regulates "chemical activation" 9606 16303767 t gcesareni "Three human atg8 (hatg8) homologs, lc3, gabarap, and gate-16, have been characterized as modifiers in reactions mediated by hatg7 (an e1-like enzyme) and hatg3 (an e2-like enzyme)" SIGNOR-142011 diiodine smallmolecule CHEBI:17606 ChEBI TPO protein P07202 UNIPROT "up-regulates activity" "chemical activation" 9606 16098474 t scontino "TPO plays a key role in thyroid hormone synthesis by catalyzing both the iodination of tyrosine residues to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) residues. The first step in the process of thyroid hormone synthesis is the binding of iodine to tyrosine residues in Tg, which yields MIT and DIT residues." SIGNOR-266958 cortisol smallmolecule CHEBI:17650 ChEBI NR3C1 protein P04150 UNIPROT "up-regulates activity" "chemical activation" 9534 BTO:0001538 8282004 t miannu "The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4)." SIGNOR-258708 cortisol smallmolecule CHEBI:17650 ChEBI NR3C2 protein P08235 UNIPROT "up-regulates activity" "chemical activation" 9534 BTO:0001538 8282004 t miannu "The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4)." SIGNOR-258707 5-hydroxy-L-tryptophan smallmolecule CHEBI:17780 ChEBI DDC protein P20711 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0006205 31024440 t brain lperfetto "In serotonergic neurons Trp serves as the precursor for 5-HT. The 5-HT metabolic pathway is initiated by Trp being hydroxylated to the intermediate 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated to become 5-HT" SIGNOR-264186 D-glucitol smallmolecule CHEBI:17924 ChEBI HNRNPA1 protein P09651 UNIPROT "down-regulates activity" relocalization 9606 BTO:0000312 33172210 f "We found that osmotic stress robustly induced nuclear loss of TDP-43, SPFQ, FUS, hnRNPA1 and hnRNPK, with characteristic changes in nucleocytoplasmic localisation in an RBP-dependent manne" SIGNOR-262814 D-glucitol smallmolecule CHEBI:17924 ChEBI FUS protein P35637 UNIPROT "down-regulates activity" relocalization 9606 BTO:0000312 33172210 f "We found that osmotic stress robustly induced nuclear loss of TDP-43, SPFQ, FUS, hnRNPA1 and hnRNPK, with characteristic changes in nucleocytoplasmic localisation in an RBP-dependent manne" SIGNOR-262813 D-glucitol smallmolecule CHEBI:17924 ChEBI TARDBP protein Q13148 UNIPROT "down-regulates activity" relocalization 9606 BTO:0000312 33172210 f "We found that osmotic stress robustly induced nuclear loss of TDP-43, SPFQ, FUS, hnRNPA1 and hnRNPK, with characteristic changes in nucleocytoplasmic localisation in an RBP-dependent manne" SIGNOR-262817 UDP-D-glucose smallmolecule CHEBI:18066 ChEBI P2RY14 protein Q15391 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257562 tyrosine smallmolecule CHEBI:18186 ChEBI TH protein P07101 UNIPROT "up-regulates activity" "chemical activation" 9606 NBK536726 t brain lperfetto "Tyrosine produced in the liver is then transported by an active transport mechanism into the dopaminergic neurons within the brain. This is followed by the conversion of L-tyrosine into L-DOPA through hydroxylation at the phenol ring by the enzyme tyrosine hydroxylase (TH)." SIGNOR-264173 tyrosine smallmolecule CHEBI:18186 ChEBI DDC protein P20711 UNIPROT "up-regulates activity" "chemical activation" 9606 NBK536726 t brain lperfetto "Under specific conditions, dopamine can also be synthesized by a minor pathway, in which L-tyrosine is converted into p-tyramine (mediated by AADC), with subsequent hydroxylation to dopamine by the enzyme CYP2D6 (Cytochrome P450 2D6) which is found in the substantia nigra of human brain¬†" SIGNOR-264175 "glutamic acid" smallmolecule CHEBI:18237 ChEBI GRM8 protein O00222 UNIPROT "up-regulates activity" "chemical activation" 9606 25042998 t miannu "Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate" SIGNOR-264073 "glutamic acid" smallmolecule CHEBI:18237 ChEBI GRM6 protein O15303 UNIPROT "up-regulates activity" "chemical activation" 9606 25042998 t miannu "Glutamate is the major excitatory neurotransmitter in the central nervous system. Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate." SIGNOR-264076 "glutamic acid" smallmolecule CHEBI:18237 ChEBI GRIK1 protein P39086 UNIPROT "up-regulates activity" "chemical activation" 9606 27586965 t miannu "Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) and exerts its biological activity through a variety of receptors. Glutamate receptors (GluRs) are divided into two major classes on the basis of the mechanism by which they relay their signal: the ionotropic glutamate receptors (iGluRs), which are ligand-gated cation channels, and the metabotropic glutamate receptors (mGluRs) that are G protein-coupled receptors" SIGNOR-264470 "glutamic acid" smallmolecule CHEBI:18237 ChEBI GRM5 protein P41594 UNIPROT "up-regulates activity" "chemical activation" 9606 25042998 t miannu "Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate" SIGNOR-264070 "glutamic acid" smallmolecule CHEBI:18237 ChEBI GRIA1 protein P42261 UNIPROT "up-regulates activity" "chemical activation" 10090 15115814 t lperfetto "AMPA glutamate receptor subunit (GluR1)" SIGNOR-261432 "glutamic acid" smallmolecule CHEBI:18237 ChEBI GRIA2 protein P42262 UNIPROT "up-regulates activity" "chemical activation" 9606 30825796 t miannu "In the mammalian brain the majority of fast excitatory neurotransmission is carried out by Œ±-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive ionotropic glutamate receptors located within the post-synaptic density of glutamatergic synapses" SIGNOR-264609 "glutamic acid" smallmolecule CHEBI:18237 ChEBI GRIK2 protein Q13002 UNIPROT "up-regulates activity" "chemical activation" 9606 27586965 t miannu "Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) and exerts its biological activity through a variety of receptors. Glutamate receptors (GluRs) are divided into two major classes on the basis of the mechanism by which they relay their signal: the ionotropic glutamate receptors (iGluRs), which are ligand-gated cation channels, and the metabotropic glutamate receptors (mGluRs) that are G protein-coupled receptors" SIGNOR-264471 "glutamic acid" smallmolecule CHEBI:18237 ChEBI GRIK3 protein Q13003 UNIPROT "up-regulates activity" "chemical activation" 9606 27586965 t miannu "Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) and exerts its biological activity through a variety of receptors. Glutamate receptors (GluRs) are divided into two major classes on the basis of the mechanism by which they relay their signal: the ionotropic glutamate receptors (iGluRs), which are ligand-gated cation channels, and the metabotropic glutamate receptors (mGluRs) that are G protein-coupled receptors" SIGNOR-264472 "glutamic acid" smallmolecule CHEBI:18237 ChEBI GRM1 protein Q13255 UNIPROT "up-regulates activity" "chemical activation" 9606 25042998 t miannu "Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate" SIGNOR-264069 "glutamic acid" smallmolecule CHEBI:18237 ChEBI GRM2 protein Q14416 UNIPROT "up-regulates activity" "chemical activation" 9606 25042998 t miannu "Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate" SIGNOR-264071 dopamine smallmolecule CHEBI:18243 ChEBI DRD2 protein P14416 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 8301582 t miannu "The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line." SIGNOR-258717 dopamine smallmolecule CHEBI:18243 ChEBI MAOA protein P21397 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0004032;BTO:0002606 NBK536726 t brain lperfetto "Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells |It undergoes oxidative deamination, catalyzed by the enzyme monoamine oxidase (MAO) in the presence of flavin adenine dinucleotide (FAD), to produce reactive aldehyde 3,4-dihydroxyphenylacetaldehyde (DOPAL)." SIGNOR-264180 histamine smallmolecule CHEBI:18295 ChEBI HRH1 protein P35367 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257512 L-thyroxine smallmolecule CHEBI:18332 ChEBI DIO1 protein P49895 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0004055 1400883 t scontino "The type I 5' iodothyronine deiodinase (5' DI) catalyzes the deiodination of T4 to the biologically active hormone T3 and accounts for a significant fraction of its production." SIGNOR-266943 L-thyroxine smallmolecule CHEBI:18332 ChEBI DIO3 protein P55073 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0004055 12746313 t scontino "Human type III iodothyronine deiodinase (D3) catalyzes the conversion of T(4) to rT(3) and of T(3) to 3, 3'-diiodothyronine (T2) by inner-ring deiodination. Like types I and II iodothyronine deiodinases, D3 protein contains selenocysteine (SeC) in the highly conserved core catalytic center at amino acid position 144." SIGNOR-266940 L-thyroxine smallmolecule CHEBI:18332 ChEBI DIO proteinfamily SIGNOR-PF83 SIGNOR "up-regulates activity" "chemical activation" 9606 BTO:0001379 34674502 t scontino "Thyroid hormone (TH) deiodinases play a pivotal role in the functional diversification of TH signaling. They are involved in development, growth, and metabolic processes, and act in a cell-specific manner in the fine regulation of TH homeostasis. TH deiodinases catalyze activation and inactivation of THs through the removal of one iodine atom in the outer or inner ring of the TH molecule. " SIGNOR-267042 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA2A protein P08913 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257453 nicotine smallmolecule CHEBI:18723 ChEBI CHRNB3 protein Q05901 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000227 28901280 t miannu "Neuronal nicotinic acetylcholine receptors (nAChRs) belong to a super-family of Cysloop ligand-gated ion channels that respond to endogenous acetylcholine (ACh) or other cholinergic ligands. These receptors are also the targets of drugs such as nicotine (the main addictive agent delivered by cigarette smoke) and are involved in a variety of physiological and pathophysiological processes." SIGNOR-264259 3-iodo-L-tyrosine smallmolecule CHEBI:27847 ChEBI TPO protein P07202 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0001379 28153798 t scontino "The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a “donor” onto a DIT residue called an “acceptor”. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines." SIGNOR-267037 3-iodo-L-tyrosine smallmolecule CHEBI:27847 ChEBI IYD protein Q6PHW0 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0001379 28153798 t scontino "MIT and DIT, which are deiodinated by iodotyrosine dehalogenase (DEHAL1) that seems to be present in the apical plasma membrane. MIT and DIT are liberated, and the deiodination of these molecules by DEHAL1 is important for providing a sustained source of intrathyroidal iodide." SIGNOR-267031 phenylalanine smallmolecule CHEBI:28044 ChEBI GCHFR protein P30047 UNIPROT "down-regulates activity" "chemical inhibition" 9606 11361142 t miannu "The enzyme activity of GTP cyclohydrolase I is controlled by a regulatory protein for this enzyme, GFRP, which is a pentamer of identical subunits. GFRP mediates feedback inhibition of GTP cyclohydrolase I activity by BH4, and the inhibition by BH4 is reversed by phenylalanine" SIGNOR-252205 "all-cis-5,8,11,14,17-icosapentaenoic acid" smallmolecule CHEBI:28364 ChEBI FBN1 protein P35555 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000951 16467281 f "Regulation of expression" miannu "it was found that EPA increased collagen and elastic fibers (tropoelastin and fibrillin-1) expression by increasing transformin growth factor-beta expression in aged human skin." SIGNOR-251910 "vitamin K epoxide" smallmolecule CHEBI:28371 ChEBI VKORC1L1 protein Q8N0U8 UNIPROT "up-regulates activity" "chemical activation" 9606 31226734 t lperfetto "This series of oxidation-reduction reactions begins with conversion of vitamin K from a stable oxidized form (quinone form) to a hydroquinone form by vitamin K epoxide reductase (VKOR)" SIGNOR-265916 "vitamin K epoxide" smallmolecule CHEBI:28371 ChEBI VKORC1L1 protein Q8N0U8 UNIPROT "up-regulates activity" "chemical activation" 9606 31226734 t lperfetto "The epoxide form of vitamin K is reduced by epoxide reductase (vitamin K epoxide reductase complex 1; VKORC1 or vitamin K epoxide reductase complex 1-like 1; VKORC1L1) to a reduced form and then to the reduced hydroquinone form" SIGNOR-265914 "vitamin K epoxide" smallmolecule CHEBI:28371 ChEBI VKORC1 protein Q9BQB6 UNIPROT "up-regulates activity" "chemical activation" 9606 31226734 t lperfetto "The epoxide form of vitamin K is reduced by epoxide reductase (vitamin K epoxide reductase complex 1; VKORC1 or vitamin K epoxide reductase complex 1-like 1; VKORC1L1) to a reduced form and then to the reduced hydroquinone form" SIGNOR-265913 "vitamin K" smallmolecule CHEBI:28384 ChEBI VKORC1 protein Q9BQB6 UNIPROT "up-regulates activity" "chemical activation" 9606 31226734 t lperfetto "This series of oxidation-reduction reactions begins with conversion of vitamin K from a stable oxidized form (quinone form) to a hydroquinone form by vitamin K epoxide reductase (VKOR)" SIGNOR-265915 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI THRA protein P10827 UNIPROT "up-regulates activity" "chemical activation" 10116 BTO:0000759 2158622 t miannu "We determined the affinity for T3 and analog binding characteristics of the translational products of c-erbA a- and /3-probes together with hepatic nuclear extracts." SIGNOR-258385 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI THRB protein P10828 UNIPROT "up-regulates activity" "chemical activation" 10116 BTO:0000759 2158622 t miannu "We determined the affinity for T3 and analog binding characteristics of the translational products of c-erbA a- and /3-probes together with hepatic nuclear extracts." SIGNOR-258384 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI DIO3 protein P55073 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0004055 12746313 t scontino "Human type III iodothyronine deiodinase (D3) catalyzes the conversion of T(4) to rT(3) and of T(3) to 3, 3'-diiodothyronine (T2) by inner-ring deiodination. Like types I and II iodothyronine deiodinases, D3 protein contains selenocysteine (SeC) in the highly conserved core catalytic center at amino acid position 144." SIGNOR-266946 (R)-adrenaline smallmolecule CHEBI:28918 ChEBI ADRB2 protein P07550 UNIPROT up-regulates "chemical activation" 9606 22863277 t gcesareni "In contrast, stimulation of gs-coupled receptors by glucagon or epinephrine activates lats1/2 kinase activity, thereby inhibiting yap function." SIGNOR-198501 (R)-adrenaline smallmolecule CHEBI:28918 ChEBI ADRA1D protein P25100 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 7651358 t miannu "Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1." SIGNOR-258459 (R)-adrenaline smallmolecule CHEBI:28918 ChEBI ADRA1A protein P35348 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 7651358 t miannu "Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1." SIGNOR-258458 (R)-adrenaline smallmolecule CHEBI:28918 ChEBI LATS2 protein Q9NRM7 UNIPROT up-regulates 9606 23075495 f gcesareni "On the other hand, galfas-coupled signals, such as epinephrine and glucagon, induce kinase activity of lats1/2, leading to phosphorylation and yap/taz." SIGNOR-199199 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH16 protein O75309 UNIPROT "up-regulates activity" "chemical activation" 9606 22535893 t miannu "Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis." SIGNOR-265833 calcium(2+) smallmolecule CHEBI:29108 ChEBI SLC25A12 protein O75746 UNIPROT "up-regulates activity" "chemical activation" 9606 12084073 t miannu "Aralar1 and citrin are members of the subfamily of calcium-binding mitochondrial carriers and correspond to two isoforms of the mitochondrial aspartate/glutamate carrier (AGC). These proteins are activated by Ca2+ acting on the external side of the inner mitochondrial membrane." SIGNOR-265152 calcium(2+) smallmolecule CHEBI:29108 ChEBI S100A8 protein P05109 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0001044 16690079 t miannu "S100 proteins comprise the largest family of calcium-binding proteins. Members of this family usually form homo- or heterodimers, which may associate to higher-order oligomers in a calcium-dependent manner. The heterodimers of S100A8 and S100A9 represent the major calcium-binding proteins in phagocytes. Both proteins regulate migration of these cells via modulation of tubulin polymerization." SIGNOR-261935 calcium(2+) smallmolecule CHEBI:29108 ChEBI GSN protein P06396 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000132 27871158 t lperfetto "Gelsolin is an actin binding protein that severs and caps the barbed-end actin filaments to prevent actin monomer exchange upon intracellular calcium increase in the initial step." SIGNOR-261844 calcium(2+) smallmolecule CHEBI:29108 ChEBI S100A9 protein P06702 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0001044 16690079 t miannu "S100 proteins comprise the largest family of calcium-binding proteins. Members of this family usually form homo- or heterodimers, which may associate to higher-order oligomers in a calcium-dependent manner. The heterodimers of S100A8 and S100A9 represent the major calcium-binding proteins in phagocytes. Both proteins regulate migration of these cells via modulation of tubulin polymerization." SIGNOR-261934 calcium(2+) smallmolecule CHEBI:29108 ChEBI CAPN1 protein P07384 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000590 25969760 t lperfetto "The data obtained from those studies suggest that the mechanisms leading to the formation of the hallmark lesions of AD might be linked. One of such mechanisms seems to be the dysregulation of calcium homeostasis that results in the abnormal activation of calpains. Calpains are a family of Ca2+-dependent cysteine proteases that play a key role in multiple cell functions including cell development, differentiation and proliferation, axonal guidance, growth cone motility, and cell death, among others." SIGNOR-251580 calcium(2+) smallmolecule CHEBI:29108 ChEBI CALM1 protein P0DP23 UNIPROT up-regulates "chemical activation" 10090 10448861 t 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 calcium(2+) smallmolecule CHEBI:29108 ChEBI CALM1 protein P0DP23 UNIPROT up-regulates "chemical activation" 9606 10884684 t 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 calcium(2+) smallmolecule CHEBI:29108 ChEBI CALM2 protein P0DP24 UNIPROT up-regulates "chemical activation" 10090 10448861 t miannu "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-266318 calcium(2+) smallmolecule CHEBI:29108 ChEBI CALM2 protein P0DP24 UNIPROT up-regulates "chemical activation" 9606 10884684 t miannu "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-266317 calcium(2+) smallmolecule CHEBI:29108 ChEBI CALM3 protein P0DP25 UNIPROT up-regulates "chemical activation" 10090 10448861 t miannu "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-266334 calcium(2+) smallmolecule CHEBI:29108 ChEBI CALM3 protein P0DP25 UNIPROT up-regulates "chemical activation" 9606 10884684 t miannu "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-266333 calcium(2+) smallmolecule CHEBI:29108 ChEBI PRKCA protein P17252 UNIPROT up-regulates "chemical activation" 9606 BTO:0000887;BTO:0001103 22944199 t gcesareni "The wnt/ca2+ signaling pathway is defined by the activation of plc (phospholipase c) through wnt/fzd resulting in an increase in intracellular ca2+ levels, which activate pkcs (protein kinase c) and camkii (calcium-calmodulin-dependent kinase ii) or cn (calcineurin), a phosphatase that activates the transcription factor nfat (nuclear factor of activated t cell)." SIGNOR-198822 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH2 protein P19022 UNIPROT "up-regulates activity" "chemical activation" 9606 22535893 t miannu "Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis." SIGNOR-265842 calcium(2+) smallmolecule CHEBI:29108 ChEBI FLNA protein P21333 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000132 27871158 t lperfetto "Gelsolin is an actin binding protein that severs and caps the barbed-end actin filaments to prevent actin monomer exchange upon intracellular calcium increase in the initial step. Cofilin also binds to actin and contributes to the disassembly of actin filaments and the subsequent release of actin monomers. The actin cross-linking complex, GP1b/IX-filamin, translocates from the plasma membrane to the cytoskeleton during this step." SIGNOR-261845 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH3 protein P22223 UNIPROT "up-regulates activity" "chemical activation" 9606 22535893 t miannu "Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis." SIGNOR-265843 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH5 protein P33151 UNIPROT "up-regulates activity" "chemical activation" 9606 22535893 t miannu "Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis." SIGNOR-265845 calcium(2+) smallmolecule CHEBI:29108 ChEBI PLA2G4A protein P47712 UNIPROT up-regulates relocalization 9606 8027085 t gcesareni "Cytosolic phospholipase a2 (cpla2) is a calcium-sensitive 85-kda enzyme that hydrolyzes arachidonic acid-containing membrane phospholipids to initiate the biosynthesis of eicosanoids and platelet-activating factor, potent inflammatory mediators. The calcium-dependent activation of the enzyme is mediated by an n-terminal c2 domain, which is responsible for calcium-dependent translocation of the enzyme to membranes and that enables the intact enzyme to hydrolyze membrane-resident substrates. cytosolic phospholipase a2 (cpla2) associates with natural membranes in response to physiological increases in ca2+, resulting in the selective hydrolysis of arachidonyl phospholipids." SIGNOR-35874 calcium(2+) smallmolecule CHEBI:29108 ChEBI PLA2G4A protein P47712 UNIPROT up-regulates relocalization 9606 9430701 t gcesareni "Cytosolic phospholipase a2 (cpla2) is a calcium-sensitive 85-kda enzyme that hydrolyzes arachidonic acid-containing membrane phospholipids to initiate the biosynthesis of eicosanoids and platelet-activating factor, potent inflammatory mediators. The calcium-dependent activation of the enzyme is mediated by an n-terminal c2 domain, which is responsible for calcium-dependent translocation of the enzyme to membranes and that enables the intact enzyme to hydrolyze membrane-resident substrates. cytosolic phospholipase a2 (cpla2) associates with natural membranes in response to physiological increases in ca2+, resulting in the selective hydrolysis of arachidonyl phospholipids." SIGNOR-54943 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH4 protein P55283 UNIPROT "up-regulates activity" "chemical activation" 9606 22535893 t miannu "Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis." SIGNOR-265844 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH6 protein P55285 UNIPROT "up-regulates activity" "chemical activation" 9606 22535893 t miannu "Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis." SIGNOR-265846 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH8 protein P55286 UNIPROT "up-regulates activity" "chemical activation" 9606 22535893 t miannu "Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis." SIGNOR-265848 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH11 protein P55287 UNIPROT "up-regulates activity" "chemical activation" 9606 22535893 t miannu "Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis." SIGNOR-265829 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH12 protein P55289 UNIPROT "up-regulates activity" "chemical activation" 9606 22535893 t miannu "Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis." SIGNOR-265830 calcium(2+) smallmolecule CHEBI:29108 ChEBI PPP3CA protein Q08209 UNIPROT up-regulates "chemical activation" 9606 21880741 t gcesareni "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-176367 calcium(2+) smallmolecule CHEBI:29108 ChEBI PPP3CA protein Q08209 UNIPROT up-regulates "chemical activation" 9606 22944199 t lperfetto "Non-canonical Wnt/Ca2+ pathway has also been implicated in multiple functions including cell adhesion and cell movements during gastrulation. In this signaling cascade, binding of Wnt to the Fzd receptor leads to the release of intracellular Ca2+, a process which is mediated through heterotrimeric G proteins, PLC (phospholipase C) and CamKII (calcium-calmodulin-dependent kinae II) as well as PKC (protein kinase C). The increased intracellular Ca2+ concentration also activates the calcineurin phosphatase, leading to activation of the transcription factor NFAT (nuclear factor of activated T cell)." SIGNOR-198819 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH17 protein Q12864 UNIPROT "up-regulates activity" "chemical activation" 9606 22535893 t miannu "Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis." SIGNOR-265834 calcium(2+) smallmolecule CHEBI:29108 ChEBI CAMK2G protein Q13555 UNIPROT up-regulates "chemical activation" 9606 22944199 t lperfetto "Non-canonical Wnt/Ca2+ pathway has also been implicated in multiple functions including cell adhesion and cell movements during gastrulation. In this signaling cascade, binding of Wnt to the Fzd receptor leads to the release of intracellular Ca2+, a process which is mediated through heterotrimeric G proteins, PLC (phospholipase C) and CamKII (calcium-calmodulin-dependent kinae II) as well as PKC (protein kinase C). The increased intracellular Ca2+ concentration also activates the calcineurin phosphatase, leading to activation of the transcription factor NFAT (nuclear factor of activated T cell)." SIGNOR-198816 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH18 protein Q13634 UNIPROT "up-regulates activity" "chemical activation" 9606 22535893 t miannu "Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis." SIGNOR-265835 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH24 protein Q86UP0 UNIPROT "up-regulates activity" "chemical activation" 9606 22535893 t miannu "Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis." SIGNOR-265840 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH19 protein Q9H159 UNIPROT "up-regulates activity" "chemical activation" 9606 22535893 t miannu "Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis." SIGNOR-265836 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH23 protein Q9H251 UNIPROT "up-regulates activity" "chemical activation" 9606 22535893 t miannu "Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis." SIGNOR-265839 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH20 protein Q9HBT6 UNIPROT "up-regulates activity" "chemical activation" 9606 22535893 t miannu "Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis." SIGNOR-265837 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH22 protein Q9UJ99 UNIPROT "up-regulates activity" "chemical activation" 9606 22535893 t miannu "Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis." SIGNOR-265838 calcium(2+) smallmolecule CHEBI:29108 ChEBI SLC25A13 protein Q9UJS0 UNIPROT "up-regulates activity" "chemical activation" 9606 12084073 t miannu "Aralar1 and citrin are members of the subfamily of calcium-binding mitochondrial carriers and correspond to two isoforms of the mitochondrial aspartate/glutamate carrier (AGC). These proteins are activated by Ca2+ acting on the external side of the inner mitochondrial membrane." SIGNOR-265153 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH9 protein Q9ULB4 UNIPROT "up-regulates activity" "chemical activation" 9606 22535893 t miannu "Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis." SIGNOR-265849 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH7 protein Q9ULB5 UNIPROT "up-regulates activity" "chemical activation" 9606 22535893 t miannu "Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis." SIGNOR-265847 calcium(2+) smallmolecule CHEBI:29108 ChEBI CAMK2A protein Q9UQM7 UNIPROT "up-regulates activity" "chemical activation" 15621017 t "It has been reported that Aβ can result in an increase in intracellular Ca2+, which in turn can activates CaMK." SIGNOR-255491 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH10 protein Q9Y6N8 UNIPROT "up-regulates activity" "chemical activation" 9606 22535893 t miannu "Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis." SIGNOR-265828 calcium(2+) smallmolecule CHEBI:29108 ChEBI Calcineurin complex SIGNOR-C155 SIGNOR up-regulates "chemical activation" 9606 22944199 t lperfetto "Non-canonical Wnt/Ca2+ pathway has also been implicated in multiple functions including cell adhesion and cell movements during gastrulation. In this signaling cascade, binding of Wnt to the Fzd receptor leads to the release of intracellular Ca2+, a process which is mediated through heterotrimeric G proteins, PLC (phospholipase C) and CamKII (calcium-calmodulin-dependent kinae II) as well as PKC (protein kinase C). The increased intracellular Ca2+ concentration also activates the calcineurin phosphatase, leading to activation of the transcription factor NFAT (nuclear factor of activated T cell)." SIGNOR-252320 calcium(2+) smallmolecule CHEBI:29108 ChEBI Calcineurin complex SIGNOR-C155 SIGNOR "up-regulates activity" "chemical activation" 9606 21880741 t mainnu "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 calcium(2+) smallmolecule CHEBI:29108 ChEBI "Calprotectin complex" complex SIGNOR-C293 SIGNOR "up-regulates activity" "chemical activation" 9606 BTO:0001044 16690079 t miannu "S100 proteins comprise the largest family of calcium-binding proteins. Members of this family usually form homo- or heterodimers, which may associate to higher-order oligomers in a calcium-dependent manner. The heterodimers of S100A8 and S100A9 represent the major calcium-binding proteins in phagocytes. Both proteins regulate migration of these cells via modulation of tubulin polymerization." SIGNOR-262826 fumarate(2-) smallmolecule CHEBI:29806 ChEBI FH protein P07954 UNIPROT "up-regulates activity" "chemical activation" 9606 30761759 t miannu "Fumarate hydratases (FHs, fumarases) catalyze the reversible conversion of fumarate into l-malate. FHs are distributed over all organisms and play important roles in energy production, DNA repair and as tumor suppressors." SIGNOR-266278 "lysophosphatidic acids" smallmolecule CHEBI:32957 ChEBI LPAR1 protein Q92633 UNIPROT up-regulates "chemical activation" 9606 16014605 t gcesareni "Lpa exerts its downstream signaling by binding to the lpa(1), lpa(2), and lpa(3) (formerly edg-2, -4, and -7) family of seven-transmembrane, segmented, heterotrimeric guanine nucleotide-binding protein (g protein)-coupled receptors." SIGNOR-138582 succinate(2-) smallmolecule CHEBI:30031 ChEBI SDH complex SIGNOR-C400 SIGNOR "up-regulates activity" "chemical activation" 9606 16143825 t miannu "Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. The human enzyme readily oxidizes succinate to fumarate, while the reverse reaction is hardly detectable in most human cells and tissues under standard conditions." SIGNOR-266275 ATP(4-) smallmolecule CHEBI:30616 ChEBI P2RY2 protein P41231 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257563 ATP(4-) smallmolecule CHEBI:30616 ChEBI P2RY4 protein P51582 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257564 ATP(4-) smallmolecule CHEBI:30616 ChEBI P2RY11 protein Q96G91 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257559 D-thyroxine smallmolecule CHEBI:30659 ChEBI THRA protein P10827 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0003736 6777394 t miannu "The high levels of circulating D-T4 and presumably of circulating D-T3 originating from the peripheral conversion of D-T4 achieved after the chronic administration of D-T4 (Choloxin) may be responsible for a high degree of saturation of the human pituitary nuclear T3 receptors, thus resulting in the suppression of the TRH-induced TSH response." SIGNOR-258402 D-thyroxine smallmolecule CHEBI:30659 ChEBI THRB protein P10828 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0003736 6777394 t miannu "The high levels of circulating D-T4 and presumably of circulating D-T3 originating from the peripheral conversion of D-T4 achieved after the chronic administration of D-T4 (Choloxin) may be responsible for a high degree of saturation of the human pituitary nuclear T3 receptors, thus resulting in the suppression of the TRH-induced TSH response." SIGNOR-258401 "oxaloacetic acid" smallmolecule CHEBI:30744 ChEBI CS protein O75390 UNIPROT "up-regulates activity" "chemical activation" 9606 3013232 t miannu "Citrate synthase catalyzes an important step within the cycle, the Claisen condensation of acetyl-Coenzyme A with oxaloacetate to form citrate; and it is the only enzyme in the cycle that can catalyze the formation of a carbon-carbon bond." SIGNOR-266548 "oxaloacetic acid" smallmolecule CHEBI:30744 ChEBI PCK2 protein Q16822 UNIPROT "up-regulates activity" "chemical activation" 9606 24632615 t miannu "Phosphoenolpyruvate carboxykinase (PEPCK, EC 4.1.1.32) is a key enzyme of gluconeogenesis. Two isoforms exist, a cytoplasmic form (PCK1, PEPCK-C) and a mitochondrial isoform (PCK2, PEPCK-M). PEPCK activity is present at significant levels in the liver, but also in the kidney and in brown and white adipose tissue. PEPCK, which converts oxaloacetate (OAA) to PEP, has an important role in glucose formation, but also for the generation of glycerol and serine." SIGNOR-266555 "2-oxoglutaric acid" smallmolecule CHEBI:30915 ChEBI OXGR1 protein Q96P68 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257555 bradykinin smallmolecule CHEBI:3165 ChEBI BDKRB1 protein P46663 UNIPROT up-regulates "chemical activation" 9606 BTO:0001130;BTO:0000189 17251915 t gcesareni "Neuropeptides such as grp, endothelin, bradykinin, neuromedin b (nmb), cholecystokinin (cck) and angiotensin ii activate their cognate gpcrs to stimulate cell proliferation in various cell types, and have a crucial role in many aggressive human cancers, including small-cell lung cancer (sclc), pancreatic cancer, hnscc and prostate cancer." SIGNOR-152588 bradykinin smallmolecule CHEBI:3165 ChEBI BDKRB1 protein P46663 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257464 "lysophosphatidic acids" smallmolecule CHEBI:32957 ChEBI LATS1 protein O95835 UNIPROT down-regulates 10090 BTO:0002572 22863277 f milica "Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2, thereby activating yap and taz transcription coactivators, which are oncoproteins repressed by lats1/2." SIGNOR-198517 "lysophosphatidic acids" smallmolecule CHEBI:32957 ChEBI LPAR1 protein Q92633 UNIPROT up-regulates "chemical activation" 9606 22863277 t gcesareni "Lpa binds to a family of gpcrs known as lpa receptors (lpa1-6) to initiate intracellular signaling. Lpa1 was highly expressed and lpa3 was detectable in hek293a cells compared to other lpa receptors." SIGNOR-198523 "lysophosphatidic acids" smallmolecule CHEBI:32957 ChEBI LPAR2 protein Q9HBW0 UNIPROT up-regulates "chemical activation" 9606 8276865 t gcesareni "Lpa activates its own g protein-coupled receptor(s) leading to stimulation of phospholipase c and inhibition of adenylate cyclase." SIGNOR-37368 "lysophosphatidic acids" smallmolecule CHEBI:32957 ChEBI LATS2 protein Q9NRM7 UNIPROT down-regulates 10090 BTO:0002572 22863277 f milica "Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2, thereby activating yap and taz transcription coactivators, which are oncoproteins repressed by lats1/2." SIGNOR-198520 "lysophosphatidic acids" smallmolecule CHEBI:32957 ChEBI LPAR3 protein Q9UBY5 UNIPROT up-regulates "chemical activation" 9606 16014605 t gcesareni "Lpa exerts its downstream signaling by binding to the lpa(1), lpa(2), and lpa(3) (formerly edg-2, -4, and -7) family of seven-transmembrane, segmented, heterotrimeric guanine nucleotide-binding protein (g protein)-coupled receptors." SIGNOR-138585 "lysophosphatidic acids" smallmolecule CHEBI:32957 ChEBI LPAR3 protein Q9UBY5 UNIPROT up-regulates "chemical activation" 9606 22863277 t gcesareni "Lpa binds to a family of gpcrs known as lpa receptors (lpa1-6) to initiate intracellular signaling. Lpa1 was highly expressed and lpa3 was detectable in hek293a cells compared to other lpa receptors." SIGNOR-198526 "beta-D-fructofuranose 1,6-bisphosphate(4-)" smallmolecule CHEBI:32966 ChEBI ALDOA protein P04075 UNIPROT "up-regulates activity" "chemical activation" 9606 16051738 t miannu "Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C." SIGNOR-266475 "beta-D-fructofuranose 1,6-bisphosphate(4-)" smallmolecule CHEBI:32966 ChEBI ALDOB protein P05062 UNIPROT "up-regulates activity" "chemical activation" 9606 16051738 t miannu "Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C." SIGNOR-266476 "beta-D-fructofuranose 1,6-bisphosphate(4-)" smallmolecule CHEBI:32966 ChEBI ALDOC protein P09972 UNIPROT "up-regulates activity" "chemical activation" 9606 16051738 t miannu "Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C." SIGNOR-266477 "beta-D-fructofuranose 1,6-bisphosphate(4-)" smallmolecule CHEBI:32966 ChEBI Aldolase proteinfamily SIGNOR-PF75 SIGNOR "up-regulates activity" "chemical activation" 9606 16051738 t miannu "Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C." SIGNOR-266478 adrenaline smallmolecule CHEBI:33568 ChEBI ADRB2 protein P07550 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000457 20590599 t Luana "Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline)" SIGNOR-257878 adrenaline smallmolecule CHEBI:33568 ChEBI ADRB1 protein P08588 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000457 20590599 t Luana "Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline)" SIGNOR-257876 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR2C protein P28335 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257523 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR1F protein P30939 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257520 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR7 protein P34969 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257526 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR2B protein P41595 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257522 "sphingosine 1-phosphate" smallmolecule CHEBI:37550 ChEBI S1PR2 protein O95136 UNIPROT "up-regulates activity" "chemical activation" 10116 10617617 t "We observed that S1P treatment significantly increased proliferation of HTC4 hepatoma cells stably transfected with human S1P receptor Edg3 or Edg5, which was attributable to stimulation of cell growth and inhibition of apoptosis caused by serum starvation." SIGNOR-261141 "sphingosine 1-phosphate" smallmolecule CHEBI:37550 ChEBI S1PR3 protein Q99500 UNIPROT "up-regulates activity" "chemical activation" 10116 10617617 t "We observed that S1P treatment significantly increased proliferation of HTC4 hepatoma cells stably transfected with human S1P receptor Edg3 or Edg5, which was attributable to stimulation of cell growth and inhibition of apoptosis caused by serum starvation." SIGNOR-261142 "sphingosine 1-phosphate" smallmolecule CHEBI:37550 ChEBI LATS2 protein Q9NRM7 UNIPROT down-regulates 9606 BTO:0000007 22863277 f milica "Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2, thereby activating yap and taz transcription coactivators, which are oncoproteins repressed by lats1/2." SIGNOR-198553 7alpha,25-dihydroxycholesterol smallmolecule CHEBI:37623 ChEBI GPR183 protein P32249 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257504 (S)-adrenaline smallmolecule CHEBI:40751 ChEBI ADRA1D protein P25100 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 7651358 t miannu "Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1." SIGNOR-258452 (S)-adrenaline smallmolecule CHEBI:40751 ChEBI ADRA1A protein P35348 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 7651358 t miannu "Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1." SIGNOR-258454 (S)-adrenaline smallmolecule CHEBI:40751 ChEBI ADRA1B protein P35368 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 7651358 t miannu "Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1." SIGNOR-258453 D-glucopyranose smallmolecule CHEBI:4167 ChEBI "adenosine 5'-monophosphate" smallmolecule CHEBI:16027 ChEBI down-regulates 9606 BTO:0000887;BTO:0001103 10409121 f gcesareni "The activation in response to glucose removal appeared to be due to changes in the concentration of the known regulators of the cascade, i.e. Amp and atp, since ampk activation was associated with a large increase in the cellular amp." SIGNOR-69249 D-ribofuranose smallmolecule CHEBI:47013 ChEBI RBKS protein Q9H477 UNIPROT "up-regulates activity" "chemical activation" 9606 25749547 t miannu "Human ribokinase (RK) is a member of the ribokinase family, and is the first enzyme responsible for D-ribose metabolism, since D-ribose must first be converted into D-ribose-5-phosphate to be further metabolized and incorporated into ATP or other high energy phosphorylated compounds." SIGNOR-267071 "Dynorphin A" smallmolecule CHEBI:4727 ChEBI OPRK1 protein P41145 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258794 "episterol ester" smallmolecule CHEBI:52393 ChEBI CNR1 protein P21554 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000142 29751000 t miannu "2-AG is an endocannabinoid that activates the cannabinoid CB1 receptor." SIGNOR-264266 succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI "Succinyl-CoA ATP variant" complex SIGNOR-C398 SIGNOR "up-regulates activity" "chemical activation" 9606 27487822 t miannu "In the citric acid cycle, succinyl-CoA synthetase (SCS) catalyzes the only step that provides substrate-level phosphorylation: succinyl-CoA + NDP + Pi = succinate + CoA + NTP, where N is adenosine or guanosine and the reaction requires magnesium ions." SIGNOR-266265 succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI "Succinyl-CoA GTP variant" complex SIGNOR-C399 SIGNOR "up-regulates activity" "chemical activation" 9606 27487822 t miannu "In the citric acid cycle, succinyl-CoA synthetase (SCS) catalyzes the only step that provides substrate-level phosphorylation: succinyl-CoA + NDP + Pi = succinate + CoA + NTP, where N is adenosine or guanosine and the reaction requires magnesium ions." SIGNOR-266266 palmitoyl-CoA(4-) smallmolecule CHEBI:57379 ChEBI CPT1A protein P50416 UNIPROT "up-regulates activity" "chemical activation" 9606 14517227 t miannu "Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C)." SIGNOR-267123 palmitoyl-CoA(4-) smallmolecule CHEBI:57379 ChEBI CPT1C protein Q8TCG5 UNIPROT "up-regulates activity" "chemical activation" 9606 14517227 t miannu "Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C)." SIGNOR-267125 palmitoyl-CoA(4-) smallmolecule CHEBI:57379 ChEBI CPT1B protein Q92523 UNIPROT "up-regulates activity" "chemical activation" 9606 14517227 t miannu "Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C)." SIGNOR-267124 "prostaglandin D2(1-)" smallmolecule CHEBI:57406 ChEBI PTGDR protein Q13258 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257568 "leukotriene B4(1-)" smallmolecule CHEBI:57461 ChEBI LTB4R protein Q15722 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257534 N(6)-(1,2-dicarboxylatoethyl)-AMP(4-) smallmolecule CHEBI:57567 ChEBI ADSL protein P30566 UNIPROT "up-regulates activity" "chemical activation" 9606 22812634 t miannu "ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case" SIGNOR-266610 "3-phosphonato-D-glyceroyl phosphate(4-)" smallmolecule CHEBI:57604 ChEBI PGK1 protein P00558 UNIPROT "up-regulates activity" "chemical activation" 9606 16051738 t miannu "Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa." SIGNOR-266499 "3-phosphonato-D-glyceroyl phosphate(4-)" smallmolecule CHEBI:57604 ChEBI PGK2 protein P07205 UNIPROT "up-regulates activity" "chemical activation" 9606 16051738 t miannu "Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa." SIGNOR-266500 "3-phosphonato-D-glyceroyl phosphate(4-)" smallmolecule CHEBI:57604 ChEBI PKG proteinfamily SIGNOR-PF77 SIGNOR "up-regulates activity" "chemical activation" 9606 16051738 t miannu "Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa." SIGNOR-266501 "beta-D-fructofuranose 6-phosphate(2-)" smallmolecule CHEBI:57634 ChEBI PFKM protein P08237 UNIPROT "up-regulates activity" "chemical activation" 9606 16051738 t miannu "Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35 Three different subunits have been identified in humans: PFK-M (muscle), PFK-L (liver), and PFK-P (platelet).The subunits are expressed in a tissue-specific manner and, in erythrocytes, 5 isoenzymes of varying subunit composition (M4, M3L1, M2L2, ML3, and L4) can be identified." SIGNOR-266463 "beta-D-fructofuranose 6-phosphate(2-)" smallmolecule CHEBI:57634 ChEBI PFKL protein P17858 UNIPROT "up-regulates activity" "chemical activation" 9606 16051738 t miannu "Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35 Three different subunits have been identified in humans: PFK-M (muscle), PFK-L (liver), and PFK-P (platelet).The subunits are expressed in a tissue-specific manner and, in erythrocytes, 5 isoenzymes of varying subunit composition (M4, M3L1, M2L2, ML3, and L4) can be identified." SIGNOR-266464 "beta-D-fructofuranose 6-phosphate(2-)" smallmolecule CHEBI:57634 ChEBI PFKP protein Q01813 UNIPROT "up-regulates activity" "chemical activation" 9606 16051738 t miannu "Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35." SIGNOR-266465 "beta-D-fructofuranose 6-phosphate(2-)" smallmolecule CHEBI:57634 ChEBI PFK proteinfamily SIGNOR-PF79 SIGNOR "up-regulates activity" "chemical activation" 9606 16051738 t miannu "Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35." SIGNOR-266466 "glycerone phosphate(2-)" smallmolecule CHEBI:57642 ChEBI TPI1 protein P60174 UNIPROT "up-regulates activity" "chemical activation" 9606 16051738 t miannu "Triosephosphate isomerase (TPI) is the glycolytic enzyme with the highest activity in vitro. TPI catalyzes the interconversion of glyceraldehyde-3-phosphate and DHAP (Figure 1). It consists of a dimer with 2 identical subunits of 248 amino acids (27 kDa)." SIGNOR-266491 4-oxobutanoate smallmolecule CHEBI:57706 ChEBI ALDH5A1 protein P51649 UNIPROT "up-regulates activity" "chemical activation" 9606 19300440 t miannu "Succinic semialdehyde dehydrogenase (SSADH) is involved in the final degradation step of the inhibitory neurotransmitter gamma-aminobutyric acid by converting succinic semialdehyde to succinic acid in the mitochondrial matrix." SIGNOR-266615 "alpha-D-ribose 1-phosphate(2-)" smallmolecule CHEBI:57720 ChEBI PGM2 protein Q96G03 UNIPROT "up-regulates activity" "chemical activation" 9606 17804405 t miannu "Phosphopentomutase catalyzes the conversion of the nucleoside breakdown products ribose 1-phosphate and deoxyribose 1-phosphate to the corresponding 5-phosphopentoses. The role of phosphopentomutase is to utilize ribose 1-phosphate and deoxyribose 1-phosphate, which are formed by purine nucleoside phosphorylase and uridine phosphorylase. Using catalytic efficiency as a criterion, PGM2 acted more than 10-fold better as a phosphopentomutase (both on deoxyribose 1-phosphate and on ribose 1-phosphate) than as a phosphoglucomutase." SIGNOR-267074 "D-xylulose 5-phosphate(2-)" smallmolecule CHEBI:57737 ChEBI TKT protein P29401 UNIPROT "up-regulates activity" "chemical activation" 9606 24929114 t miannu "Transketolase (TK, EC 2.2.1.1) is the key rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway of carbohydrate transformation. TKs (with the exception of the enzymes of mammalian origin) are characterized by broad substrate specificity. Xylulose 5-phosphate (X5P), fructose 6-phosphate (F6P), erythrulose 4-phosphate, and sedoheptulose 7-phosphate are typical donor substrates of TK; ribose 5-phosphate (R5P), glyceraldehyde 3-phosphate (G3P), and erythrose 4-phosphate are typical acceptor substrates." SIGNOR-267085 "1-acyl-sn-glycerol 3-phosphate(2-)" smallmolecule CHEBI:57970 ChEBI AGPAT4 protein Q9NRZ5 UNIPROT "up-regulates activity" "chemical activation" 9606 21173190 t lperfetto "The enzyme 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT) converts lysophosphatidic acid (LPA) to phosphatidic acid (PA). " SIGNOR-267016 "1-acyl-sn-glycerol 3-phosphate(2-)" smallmolecule CHEBI:57970 ChEBI AGPAT3 protein Q9NRZ7 UNIPROT "up-regulates activity" "chemical activation" 9606 21173190 t lperfetto "The enzyme 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT) converts lysophosphatidic acid (LPA) to phosphatidic acid (PA). " SIGNOR-267010 "1-acyl-sn-glycerol 3-phosphate(2-)" smallmolecule CHEBI:57970 ChEBI AGPAT5 protein Q9NUQ2 UNIPROT "up-regulates activity" "chemical activation" 9606 21173190 t lperfetto "The enzyme 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT) converts lysophosphatidic acid (LPA) to phosphatidic acid (PA). " SIGNOR-267013 UDP(3-) smallmolecule CHEBI:58223 ChEBI P2RY6 protein Q15077 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257565 "alpha-D-glucose 6-phosphate(2-)" smallmolecule CHEBI:58225 ChEBI GPI protein P06744 UNIPROT "up-regulates activity" "chemical activation" 9606 16051738 t miannu "Glucose 6-phosphate isomerase (GPI) catalyzes the interconversion of G6P into fructose-6-phosphate (F6P) in the second step of the Embden-Meyerhof pathway (Figure 1). As a result of this reversible reaction, products of the hexose-monophosphate shunt can be recycled to G6P." SIGNOR-266460 "alpha-D-glucose 6-phosphate(2-)" smallmolecule CHEBI:58225 ChEBI G6PD protein P11413 UNIPROT "up-regulates activity" "chemical activation" 9606 24769394 t miannu "G6PD catalyzes the oxidation of glucose-6-phosphate to 6-phosphogluconate and concomitantly reduces NADP+ to NADPH, which is the rate-limiting and primary control step of the NADPH-generating portion in the PPP. Thus, G6PD acts as a guardian of cellular redox potential during oxidative stress" SIGNOR-267049 "alpha-D-glucose 6-phosphate(2-)" smallmolecule CHEBI:58225 ChEBI G6PC1 protein P35575 UNIPROT "up-regulates activity" "chemical activation" 9606 12093795 t miannu "Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis" SIGNOR-266574 "alpha-D-glucose 6-phosphate(2-)" smallmolecule CHEBI:58225 ChEBI G6PC1 protein P35575 UNIPROT "up-regulates activity" "chemical activation" 9606 12093795 t miannu "Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis" SIGNOR-266560 "alpha-D-glucose 6-phosphate(2-)" smallmolecule CHEBI:58225 ChEBI G6PC3 protein Q9BUM1 UNIPROT "up-regulates activity" "chemical activation" 9606 12093795 t miannu "Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis" SIGNOR-266576 "alpha-D-glucose 6-phosphate(2-)" smallmolecule CHEBI:58225 ChEBI G6PC3 protein Q9BUM1 UNIPROT "up-regulates activity" "chemical activation" 9606 12093795 t miannu "Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis" SIGNOR-266562 "alpha-D-glucose 6-phosphate(2-)" smallmolecule CHEBI:58225 ChEBI G6PC2 protein Q9NQR9 UNIPROT "up-regulates activity" "chemical activation" 9606 12093795 t miannu "Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis" SIGNOR-266575 "alpha-D-glucose 6-phosphate(2-)" smallmolecule CHEBI:58225 ChEBI G6PC2 protein Q9NQR9 UNIPROT "up-regulates activity" "chemical activation" 9606 12093795 t miannu "Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis" SIGNOR-266561 SMAD7 protein O15105 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" binding 9606 9892110 t lperfetto "Smad6 and smad7, can prevent tgfb signaling by interacting either with the receptor or with smad2 and smad3." SIGNOR-64085 "alpha-D-glucose 6-phosphate(2-)" smallmolecule CHEBI:58225 ChEBI G6P proteinfamily SIGNOR-PF81 SIGNOR "up-regulates activity" "chemical activation" 9606 12093795 t miannu "Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis" SIGNOR-266577 "alpha-D-glucose 6-phosphate(2-)" smallmolecule CHEBI:58225 ChEBI G6P proteinfamily SIGNOR-PF81 SIGNOR "up-regulates activity" "chemical activation" 9606 12093795 t miannu "Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis" SIGNOR-266563 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI PGAM2 protein P15259 UNIPROT "up-regulates activity" "chemical activation" 9606 24786789 t miannu "Phosphoglycerate mutase (PGAM) is a glycolytic enzyme that catalyzes the reversible conversion of 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG; ref. 4). Human genome contains two PGAM genes, PGAM1 (also known as PGAM-B), which is expressed in brain and most other tissues, and PGAM2 (also known as PGAM-M), which is highly expressed in muscle." SIGNOR-266509 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI PGAM1 protein P18669 UNIPROT "up-regulates activity" "chemical activation" 9606 24786789 t miannu "Phosphoglycerate mutase (PGAM) is a glycolytic enzyme that catalyzes the reversible conversion of 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG; ref. 4). Human genome contains two PGAM genes, PGAM1 (also known as PGAM-B), which is expressed in brain and most other tissues, and PGAM2 (also known as PGAM-M), which is highly expressed in muscle." SIGNOR-266508 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI PGAM proteinfamily SIGNOR-PF78 SIGNOR "up-regulates activity" "chemical activation" 9606 24786789 t miannu "Phosphoglycerate mutase (PGAM) is a glycolytic enzyme that catalyzes the reversible conversion of 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG; ref. 4). Human genome contains two PGAM genes, PGAM1 (also known as PGAM-B), which is expressed in brain and most other tissues, and PGAM2 (also known as PGAM-M), which is highly expressed in muscle." SIGNOR-266510 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI ENO1 protein P06733 UNIPROT "up-regulates activity" "chemical activation" 9606 29767008 t miannu "Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: α-enolase (ENO1) is present in almost all mature tissues; β-enolase (ENO3) exists primarily in muscle tissues; and γ-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits." SIGNOR-266520 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI ENO2 protein P09104 UNIPROT "up-regulates activity" "chemical activation" 9606 29767008 t miannu "Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: α-enolase (ENO1) is present in almost all mature tissues; β-enolase (ENO3) exists primarily in muscle tissues; and γ-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits." SIGNOR-266521 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI ENO3 protein P13929 UNIPROT "up-regulates activity" "chemical activation" 9606 29767008 t miannu "Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: α-enolase (ENO1) is present in almost all mature tissues; β-enolase (ENO3) exists primarily in muscle tissues; and γ-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits." SIGNOR-266522 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI Enolase proteinfamily SIGNOR-PF74 SIGNOR "up-regulates activity" "chemical activation" 9606 29767008 t miannu "Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: α-enolase (ENO1) is present in almost all mature tissues; β-enolase (ENO3) exists primarily in muscle tissues; and γ-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits." SIGNOR-266523 "L-tyrosine zwitterion" smallmolecule CHEBI:58315 ChEBI TPO protein P07202 UNIPROT "up-regulates activity" "chemical activation" 9606 16098474 t scontino "TPO plays a key role in thyroid hormone synthesis by catalyzing both the iodination of tyrosine residues to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) residues. The first step in the process of thyroid hormone synthesis is the binding of iodine to tyrosine residues in Tg, which yields MIT and DIT residues." SIGNOR-266955 CDP-diacylglycerol(2-) smallmolecule CHEBI:58332 ChEBI PGS1 protein Q32NB8 UNIPROT "up-regulates activity" "chemical activation" 9606 29034233 t lperfetto "After activation of PA by the CDP-DAG synthase TAMM41 (Kutik et al., 2008), the phosphatidylglycerol phosphate synthase (PGS1) catalyzes the committed step by converting CDP-DAG to phosphatidylglycerol phosphate (PGP)" SIGNOR-267024 SAICAR(4-) smallmolecule CHEBI:58443 ChEBI ADSL protein P30566 UNIPROT "up-regulates activity" "chemical activation" 9606 22812634 t miannu "ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case" SIGNOR-266609 phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI PKM protein P14618 UNIPROT "up-regulates activity" "chemical activation" 9606 15996096 t miannu "Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A)." SIGNOR-266532 PIPP smallmolecule CID:24755493 PUBCHEM LRP6 protein O75581 UNIPROT up-regulates 9606 18772438 f gcesareni "Wnt3a stimulates the formation of phosphatidylinositol 4,5-bisphosphates [ptdins (4,5)p2] through frizzled and dishevelled, the latter of which directly interacted with and activated pip5ki. In turn, ptdins (4,5)p2 regulated phosphorylation of lrp6 at thr1479 and ser1490" SIGNOR-180797 phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI PKLR protein P30613 UNIPROT "up-regulates activity" "chemical activation" 9606 15996096 t miannu "Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A)." SIGNOR-266533 phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI PK proteinfamily SIGNOR-PF80 SIGNOR "up-regulates activity" "chemical activation" 9606 15996096 t miannu "Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A)." SIGNOR-266538 sapropterin smallmolecule CHEBI:59560 ChEBI GCHFR protein P30047 UNIPROT "up-regulates activity" "chemical activation" 9606 11361142 t miannu "The enzyme activity of GTP cyclohydrolase I is controlled by a regulatory protein for this enzyme, GFRP, which is a pentamer of identical subunits. GFRP mediates feedback inhibition of GTP cyclohydrolase I activity by BH4, and the inhibition by BH4 is reversed by phenylalanine" SIGNOR-252204 "D-glyceraldehyde 3-phosphate(2-)" smallmolecule CHEBI:59776 ChEBI GAPDHS protein O14556 UNIPROT "up-regulates activity" "chemical activation" 9606 11724794 t miannu "GAPDH is commonly known as a key enzyme in glycolysis (GAPDH catalyzes the NAD-mediated oxidative phosphorylation of glyceraldehyde 3-phosphate to 1,3-diphosphoglycerate), a number of intriguing intracellular roles have been reported including modulation of the cytoskeleton, kinase activity, and the promotion of vesicle fusion" SIGNOR-266496 "D-glyceraldehyde 3-phosphate(2-)" smallmolecule CHEBI:59776 ChEBI GAPDH protein P04406 UNIPROT "up-regulates activity" "chemical activation" 9606 11724794 t miannu "GAPDH is commonly known as a key enzyme in glycolysis (GAPDH catalyzes the NAD-mediated oxidative phosphorylation of glyceraldehyde 3-phosphate to 1,3-diphosphoglycerate), a number of intriguing intracellular roles have been reported including modulation of the cytoskeleton, kinase activity, and the promotion of vesicle fusion" SIGNOR-266493 "D-glyceraldehyde 3-phosphate(2-)" smallmolecule CHEBI:59776 ChEBI TALDO1 protein P37837 UNIPROT "up-regulates activity" "chemical activation" 9606 19401148 t miannu "Transaldolase (TAL, sedoheptulose 7-phosphate: d-glyceraldehyde 3-phosphate dihydroxyacetone transferase; EC number 2.2.1.2) is a cofactor-less enzyme of the pentose phosphate pathway (PPP) (Fig. 1A and B). It catalyzes the reversible transfer of a three carbon unit (“dihydroxyacetone”) between various sugar phosphates (from 3 to 8 carbon atoms in length). Physiological donor compounds are ketose sugar phosphates as fructose 6-phosphate or sedoheptulose 7-phosphate. Acceptor compounds are aldose sugar phosphates as glyceraldehyde 3-phosphate and erythrose 4-phosphate." SIGNOR-267090 "1-(3-sn-phosphatidyl)-sn-glycerol 3-phosphate(3-)" smallmolecule CHEBI:60110 ChEBI PTPMT1 protein Q8WUK0 UNIPROT "up-regulates activity" "chemical activation" 10090 21641550 t lperfetto "PGP is an essential intermediate in the biosynthetic pathway of cardiolipin, a mitochondrial-specific phospholipid regulating the membrane integrity and activities of the organelle. We further demonstrate that PTPMT1 specifically dephosphorylates PGP in vitro. Loss of PTPMT1 leads to dramatic diminution of cardiolipin, which can be partially reversed by the expression of catalytic active PTPMT1. Our study identifies PTPMT1 as the mammalian PGP phosphatase and points to its role as a regulator of cardiolipin biosynthesis." SIGNOR-267027 "sphingosine 1-phosphate(1-)" smallmolecule CHEBI:60119 ChEBI S1PR1 protein P21453 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257577 "sphingosine 1-phosphate(1-)" smallmolecule CHEBI:60119 ChEBI S1PR3 protein Q99500 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257579 phosphatidylglycerol(1-) smallmolecule CHEBI:60523 ChEBI CRLS1 protein Q9UJA2 UNIPROT "up-regulates activity" "chemical activation" 10090 16678169 t lperfetto "The mitochondrial phospholipid cardiolipin is synthesized from cytidinediphosphate-diacylglycerol and phosphatidylglycerol, a process catalyzed by the enzyme cardiolipin synthase." SIGNOR-267029 "prostaglandin E2(1-)" smallmolecule CHEBI:606564 ChEBI PTGER1 protein P34995 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257569 "prostaglandin E2(1-)" smallmolecule CHEBI:606564 ChEBI PTGER4 protein P35408 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257572 FGF17 protein O60258 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates binding 9606 8663044 t tpavlidou "Fgfs bind and activate high-affinity receptor tyrosine kinases. The cloning of fgf receptors (fgfrs) has identified four distinct genes" SIGNOR-42365 "prostaglandin E2(1-)" smallmolecule CHEBI:606564 ChEBI PTGER3 protein P43115 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257571 "prostaglandin E2(1-)" smallmolecule CHEBI:606564 ChEBI PTGER2 protein P43116 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257570 Kallidin smallmolecule CHEBI:6102 ChEBI BDKRB2 protein P30411 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257465 somatostatin smallmolecule CHEBI:64628 ChEBI SSTR5 protein P35346 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257585 MET-enkephalin smallmolecule CHEBI:6618 ChEBI OPRM1 protein P35372 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257554 MET-enkephalin smallmolecule CHEBI:6618 ChEBI OPRD1 protein P41143 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257551 Delta(9)-tetrahydrocannabinol smallmolecule CHEBI:66964 ChEBI CNR1 protein P21554 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000142 29751001 t miannu "Endocannabinoids (eCBs) are the body’s natural agonists for cannabinoid receptors (G protein-coupled CB1 and CB2) that also recognize Δ9-tetrahydrocannabinol (Δ9-THC), the psychoactive component of marijuana." SIGNOR-264267 Delta(9)-tetrahydrocannabinol smallmolecule CHEBI:66964 ChEBI CNR2 protein P34972 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000142 29751001 t miannu "Endocannabinoids (eCBs) are the body’s natural agonists for cannabinoid receptors (G protein-coupled CB1 and CB2) that also recognize Δ9-tetrahydrocannabinol (Δ9-THC), the psychoactive component of marijuana." SIGNOR-264268 "1-phospho-alpha-D-glucuronic acid" smallmolecule CHEBI:681 ChEBI DRD2 protein P14416 UNIPROT "up-regulates activity" "chemical activation" -1 7576010 t miannu "The affinities of D2 receptors for agonists and antagonists were compared for receptors labeled with [1251]-7-OHPIPAT and with [*251]-NCQ-298 under conditions that promote, respectively, coupling or uncoupling of receptors to G proteins. Table 1.Similarly, the affinities of D3 receptors for quinpirole and dopamine were much higher than the affinities of D:! receptors for the agonists in the presence of Gpp(NH)p and NaCl when [1251]-NCQ-298 was used to label receptors; however, when Gpp(NH)p and NaCl were not present, and when [12sI]-7-OH-PIPAT was used, receptors bound quinpirole and dopamine with nearly equal affinities (Table 1)." SIGNOR-258435 "1-phospho-alpha-D-glucuronic acid" smallmolecule CHEBI:681 ChEBI DRD3 protein P35462 UNIPROT "up-regulates activity" "chemical activation" -1 7576010 t miannu "The affinities of D2 receptors for agonists and antagonists were compared for receptors labeled with [1251]-7-OHPIPAT and with [*251]-NCQ-298 under conditions that promote, respectively, coupling or uncoupling of receptors to G proteins. Table 1.Similarly, the affinities of D3 receptors for quinpirole and dopamine were much higher than the affinities of D:! receptors for the agonists in the presence of Gpp(NH)p and NaCl when [1251]-NCQ-298 was used to label receptors; however, when Gpp(NH)p and NaCl were not present, and when [12sI]-7-OH-PIPAT was used, receptors bound quinpirole and dopamine with nearly equal affinities (Table 1)." SIGNOR-258434 "D-ribofuranose 5-phosphate(2-)" smallmolecule CHEBI:78346 ChEBI PRPS2 protein P11908 UNIPROT "up-regulates activity" "chemical activation" 9606 16939420 t miannu "PRPP (phosphoribosylpyrophosphate) is an important metabolite essential for nucleotide synthesis and PRS (PRPP synthetase) catalyses synthesis of PRPP from R5P (ribose 5-phosphate) and ATP." SIGNOR-267080 "D-ribofuranose 5-phosphate(2-)" smallmolecule CHEBI:78346 ChEBI TKT protein P29401 UNIPROT "up-regulates activity" "chemical activation" 9606 24929114 t miannu "Transketolase (TK, EC 2.2.1.1) is the key rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway of carbohydrate transformation. TKs (with the exception of the enzymes of mammalian origin) are characterized by broad substrate specificity. Xylulose 5-phosphate (X5P), fructose 6-phosphate (F6P), erythrulose 4-phosphate, and sedoheptulose 7-phosphate are typical donor substrates of TK; ribose 5-phosphate (R5P), glyceraldehyde 3-phosphate (G3P), and erythrose 4-phosphate are typical acceptor substrates." SIGNOR-267086 "D-ribofuranose 5-phosphate(2-)" smallmolecule CHEBI:78346 ChEBI PRPS1 protein P60891 UNIPROT "up-regulates activity" "chemical activation" 9606 16939420 t miannu "PRPP (phosphoribosylpyrophosphate) is an important metabolite essential for nucleotide synthesis and PRS (PRPP synthetase) catalyses synthesis of PRPP from R5P (ribose 5-phosphate) and ATP." SIGNOR-267077 oxytocin smallmolecule CHEBI:7872 ChEBI OXTR protein P30559 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257556 "Neuromedin B" smallmolecule CHEBI:80139 ChEBI NMBR protein P28336 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257547 Galanin smallmolecule CHEBI:80161 ChEBI GALR2 protein O43603 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257495 Galanin smallmolecule CHEBI:80161 ChEBI GALR3 protein O60755 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257496 Galanin smallmolecule CHEBI:80161 ChEBI GALR1 protein P47211 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257494 Bombesin smallmolecule CHEBI:80229 ChEBI GRPR protein P30550 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257509 Endothelin-1 smallmolecule CHEBI:80240 ChEBI EDNRB protein P24530 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257483 JAK2 protein O60674 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation 7888666 t 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 Endothelin-1 smallmolecule CHEBI:80240 ChEBI EDNRA protein P25101 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257482 "Urotensin II" smallmolecule CHEBI:80244 ChEBI UTS2R protein Q9UKP6 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257590 "Melanin-concentrating hormone" smallmolecule CHEBI:80254 ChEBI MCHR2 protein Q969V1 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257541 "Melanin-concentrating hormone" smallmolecule CHEBI:80254 ChEBI MCHR1 protein Q99705 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257540 Motilin smallmolecule CHEBI:80269 ChEBI MLNR protein O43193 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257542 "Parathyroid hormone-related peptide (1-36)" smallmolecule CHEBI:80274 ChEBI PTH1R protein Q03431 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257575 "Tuberoinfundibular peptide of 39 residues" smallmolecule CHEBI:80275 ChEBI PTH2R protein P49190 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257576 "Prolactin-releasing peptide-20" smallmolecule CHEBI:80301 ChEBI PRLHR protein P49683 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257566 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser41 RTDALTSsPGRDLPP 9606 BTO:0000567 16899510 t gcesareni "In the present study, we report the identification of cdc7/dbf4 phosphorylation sites on mcm2 and determine the functional role of cdc7/dbf4 phosphorylation of mcm2 in the initiation of dna replication in human cells." SIGNOR-148717 "Pituitary adenylate cyclase-activating peptide-27" smallmolecule CHEBI:80303 ChEBI ADCYAP1R1 protein P41586 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257445 Kisspeptin-10 smallmolecule CHEBI:80307 ChEBI KISS1R protein Q969F8 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257527 "Substance P" smallmolecule CHEBI:80308 ChEBI TACR1 protein P25103 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257586 "Neurokinin A" smallmolecule CHEBI:80311 ChEBI TACR2 protein P21452 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257587 "Neurokinin B" smallmolecule CHEBI:80312 ChEBI TACR3 protein P29371 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257588 "Reduced Vitamin K" smallmolecule CHEBI:8784 ChEBI GGCX protein P38435 UNIPROT "up-regulates activity" "chemical activation" 9606 31226734 t lperfetto "GGCX carboxylates the glutamic acid residues of vitamin K-dependent proteins (VKDP) to Gla using reduced vitamin K, while simultaneously oxidizing the reduced form of vitamin K to an epoxide form." SIGNOR-265917 quizartinib smallmolecule CHEBI:90217 ChEBI FLT3 protein P36888 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258270 2-[[3-[[2-(dimethylamino)phenyl]methyl]-2-pyridin-4-yl-1,3-diazinan-1-yl]methyl]-N,N-dimethylaniline smallmolecule CHEBI:94276 ChEBI GLI2 protein P10070 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000150;BTO:0001130 17494766 t gcesareni "Gant61 was able to efficiently block gli1 as well as gli2-induced transcription" SIGNOR-154756 4-(2,4,5-tripyridin-4-yl-3-thiophenyl)pyridine smallmolecule CHEBI:94284 ChEBI GLI1 protein P08151 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000150;BTO:0000551 19860666 t gcesareni "Gant58 is a gli antagonist that inhibits gli1-induced transcription" SIGNOR-188863 4-(2,4,5-tripyridin-4-yl-3-thiophenyl)pyridine smallmolecule CHEBI:94284 ChEBI GLI2 protein P10070 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000150;BTO:0000551 19860666 t gcesareni "Both molecules gant58 and gant61 were capable of interfering with gli1 as well as gli2-mediated transcription in a dose-dependent manner" SIGNOR-188866 Thrombin smallmolecule CHEBI:9574 ChEBI F2RL2 protein O00254 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257486 Thrombin smallmolecule CHEBI:9574 ChEBI F2RL3 protein Q96RI0 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257487 vasopressin smallmolecule CHEBI:9937 ChEBI AVPR2 protein P30518 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257463 vasopressin smallmolecule CHEBI:9937 ChEBI AVPR1A protein P37288 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257461 vasopressin smallmolecule CHEBI:9937 ChEBI AVPR1B protein P47901 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257462 VXJPSOQJNUZHDN-YJFQKBDPSA-N smallmolecule CID:118708139 PUBCHEM NMUR2 protein Q9GZQ4 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257592 VXJPSOQJNUZHDN-YJFQKBDPSA-N smallmolecule CID:118708139 PUBCHEM NMUR1 protein Q9HB89 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257591 2-[2-Amino-5-(3,4-dimethoxyphenyl)pyrimidin-4-yl]-5-[(4-bromobenzyl)oxy]phenol smallmolecule CID:135651766 PUBCHEM GIPR protein P48546 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257498 QYDAFJUKVGVEKO-PKOVDKIBSA-N smallmolecule CID:16132339 PUBCHEM MRGPRX1 protein Q96LB2 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257543 Cortistatin14 smallmolecule CID:16133803 PUBCHEM MRGPRX2 protein Q96LB1 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257544 Nutlin-3 smallmolecule CID:216345 PUBCHEM TP73 protein O15350 UNIPROT up-regulates 9606 17700533 t miannu "These results provide the first evidence that Nutlin-3 disrupts endogenous p73-HDM2 interaction and enhances the stability and proapoptotic activities of p73 and thus, provides a rationale for the use of Nutlin-3 in the large number of human tumors in which p53 is inactivated." SIGNOR-255472 Nutlin-3 smallmolecule CID:216345 PUBCHEM TP53 protein P04637 UNIPROT up-regulates 9606 17700533 t miannu "Nutlin, a class of small molecule antagonist of HDM2, binds to the p53-binding pocket of HDM2, preventing p53 from binding to HDM2 and thus, resulting in stabilization and activation of p53" SIGNOR-255471 Apelin smallmolecule CID:56841713 PUBCHEM APLNR protein P35414 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257460 "MSH release-inhibiting hormone" smallmolecule CID:56842142 PUBCHEM MC4R protein P32245 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257538 "MSH release-inhibiting hormone" smallmolecule CID:56842142 PUBCHEM MC5R protein P33032 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257539 "MSH release-inhibiting hormone" smallmolecule CID:56842142 PUBCHEM MC3R protein P41968 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257537 "MSH release-inhibiting hormone" smallmolecule CID:56842142 PUBCHEM MC1R protein Q01726 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257536 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCA protein P17252 UNIPROT up-regulates binding 9606 14967450 t "PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine." gcesareni "The molecular requirements for diacylglycerol (dag) and calcium (ca2+) to promote pkc membrane translocation, the hallmark of pkc activation, have been clarified." SIGNOR-121956 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCA protein P17252 UNIPROT up-regulates binding 9606 23630338 t "PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine." gcesareni "C1a domain is critical for the dag-induced activation of pkcalfa.Furthermore, calcium and diacylglycerol activate protein kinase c, resulting in the phosphorylation of a large variety of substrates." SIGNOR-202007 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCA protein P17252 UNIPROT up-regulates "chemical activation" 9606 18593525 t gcesareni "The increases in the membrane levels of nacholeate itself and of dag induce a translocation and overexpression of protein kinase c (pkc) and subsequent reductions of cyclin d, cyclin-dependent kinases 4 and 6 (cdks 4 and 6), hypophosphorylation of the retinoblastoma protein, inhibition of e2f1 and knockdown of dihydrofolate reductase (dhfr) impairing dna synthesis." SIGNOR-179279 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCA protein P17252 UNIPROT "up-regulates activity" binding 9606 12629049 t "Activation of PKC depends on the availability of DAG,a signaling lipid that is tightly and dynamically regulated." SIGNOR-251559 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCH protein P24723 UNIPROT "up-regulates activity" binding 9606 14967450 t "PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine." lperfetto "The molecular requirements for diacylglycerol (dag) and calcium (ca2+) to promote pkc membrane translocation, the hallmark of pkc activation, have been clarified." SIGNOR-242593 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCI protein P41743 UNIPROT "up-regulates activity" binding 9606 14967450 t "PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine." lperfetto "The molecular requirements for diacylglycerol (dag) and calcium (ca2+) to promote pkc membrane translocation, the hallmark of pkc activation, have been clarified." SIGNOR-242581 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCE protein Q02156 UNIPROT "up-regulates activity" binding 9606 14967450 t "PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine." lperfetto "The molecular requirements for diacylglycerol (dag) and calcium (ca2+) to promote pkc membrane translocation, the hallmark of pkc activation, have been clarified." SIGNOR-242590 "PAR-1 (Protease-Activated Receptor) Selective Activating Peptide" smallmolecule CID:71312048 PUBCHEM F2R protein P25116 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257484 "PAR-1 (Protease-Activated Receptor) Selective Activating Peptide" smallmolecule CID:71312048 PUBCHEM F2RL1 protein P55085 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257485 Sincalide smallmolecule CID:9833444 PUBCHEM CCKAR protein P32238 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257466 Sincalide smallmolecule CID:9833444 PUBCHEM CCKBR protein P32239 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "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-257467 ORF4b protein K9N643 UNIPROT TBK1 protein Q9UHD2 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 26631542 t miannu "Previous studies have shown that MERS-CoV ORF4b antagonizes the early antiviral alpha/beta interferon (IFN-α/β) response, which may significantly contribute to MERS-CoV pathogenesis; however, the underlying mechanism is poorly understood. Here, we found that ORF4b in the cytoplasm could specifically bind to TANK binding kinase 1 (TBK1) and IκB kinase epsilon (IKKε), suppress the molecular interaction between mitochondrial antiviral signaling protein (MAVS) and IKKε, and inhibit IFN regulatory factor 3 (IRF3) phosphorylation and subsequent IFN-β production. these results indicate that MERS-CoV ORF4b inhibits the induction of type I IFN through a direct interaction with IKKε/TBK1 in the cytoplasm" SIGNOR-260593 SGK1 protein O00141 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates activity" phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000007 11154281 t 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 SGK1 protein O00141 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates activity" phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 BTO:0000007 11154281 t 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 SGK1 protein O00141 UNIPROT NEDD4L protein Q96PU5 UNIPROT down-regulates phosphorylation Ser448 IRRPRSLsSPTVTLS 9606 15677482 t gcesareni "Nedd4-2 function is negatively regulated by phosphorylation via a serum- and glucocorticoid-inducible protein kinase (sgk1), which serves as a mechanism to inhibit the ubiquitination-dependent degradation of enac. Sgk1 catalyzed phosphorylation of hnedd4-2 at ser-468 maintaining hnedd4-2 in an inactive phosphorylated state." SIGNOR-133438 SGK1 protein O00141 UNIPROT NEDD4L protein Q96PU5 UNIPROT "down-regulates activity" phosphorylation Thr383 PSVAYVHtTPGLPSG -1 12911626 t miannu "Site‐directed mutagenesis of the SGK1 phosphorylation sites in the Nedd4‐2 protein (S382A,S468ANedd4‐2) and in the EAAT1 protein (T482AEAAT1, T482DEAAT1) significantly blunts the effect of S422DSGK1. Introduction of a negative charge at the SGK phosphorylation site in the EAAT1 protein leads to a strong stimulation of the carrier, whereas replacement with alanine markedly decreases the EAAT1‐mediated current. These observations suggest that SGK1 exerts its effect not only by phosphorylation of Nedd4‐2 but also by phosphorylation of EAAT1." SIGNOR-263076 SGK1 protein O00141 UNIPROT NEDD4L protein Q96PU5 UNIPROT "down-regulates activity" phosphorylation 9606 15586017 t "Regulation of localization" miannu "The serum and glucocorticoid inducible kinase 1 (SGK1) is induced in the aldosterone sensitive distal nephron (ASDN) where it may stimulate Na reabsorption, partly by inhibiting ubiquitin ligase Nedd4-2-mediated retrieval of epithelial Na+ channel ENaC from the luminal membrane." SIGNOR-251949 SGK1 protein O00141 UNIPROT NEDD4L protein Q96PU5 UNIPROT up-regulates phosphorylation Ser342 SSRLRSCsVTDAVAE 9606 11742982 t lperfetto "Here we show by expression studies in xenopus laevis oocytes that the aldosterone-induced sgk1 kinase interacts with the ubiquitin protein ligase nedd4-2 in a py motif-dependent manner and phosphorylates nedd4-2 on ser444 and, to a lesser extent, ser338. Such phosphorylation reduces the interaction between nedd4-2 and enac, leading to elevated enac cell surface expression." SIGNOR-113052 SGK1 protein O00141 UNIPROT MAP3K3 protein Q99759 UNIPROT "down-regulates activity" phosphorylation Ser166 EPRSRHLsVSSQNPG 9534 BTO:0001538 12392720 t miannu "It was shown that the recombinant MEKK3 protein and fluorescein-labeled MEKK3 peptides (FITC-(159)epRsRhlSVi(168) and FITC-(330)dpRgRlpSAd(339)) are phosphorylated by SGK1 in vitro. It was also observed that the intrinsic kinase activity of MEKK3 on Ser(189) of MKK3 (equivalent to Ser(207) of MKK6) decreased along with phosphorylation of Ser(166) and Ser(337) in MEKK3 in vitro and in vivo. Therefore, it is suggested that SGK1 inhibits MEKK3-MKK3/6 signal transduction by phosphorylation of MEKK3." SIGNOR-250004 SGK1 protein O00141 UNIPROT MAP3K3 protein Q99759 UNIPROT "down-regulates activity" phosphorylation Ser337 DPRGRLRsADSENAL 9534 BTO:0001538 12392720 t miannu "It was shown that the recombinant MEKK3 protein and fluorescein-labeled MEKK3 peptides (FITC-(159)epRsRhlSVi(168) and FITC-(330)dpRgRlpSAd(339)) are phosphorylated by SGK1 in vitro. It was also observed that the intrinsic kinase activity of MEKK3 on Ser(189) of MKK3 (equivalent to Ser(207) of MKK6) decreased along with phosphorylation of Ser(166) and Ser(337) in MEKK3 in vitro and in vivo. Therefore, it is suggested that SGK1 inhibits MEKK3-MKK3/6 signal transduction by phosphorylation of MEKK3." SIGNOR-250005 SGK1 protein O00141 UNIPROT MAP3K3 protein Q99759 UNIPROT "down-regulates activity" phosphorylation Ser166 EPRSRHLsVSSQNPG 9606 12761204 t lperfetto "Inhibition of mitogen-activated kinase kinase kinase 3 activity through phosphorylation by the serum- and glucocorticoid-induced kinase 1" SIGNOR-101211 SGK1 protein O00141 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000007 11154281 t 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-252987 SGK1 protein O00141 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Ser315 DFRSRTNsNASTVSG 9606 BTO:0000007 11154281 t 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-252989 SGK1 protein O00141 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 BTO:0000007 11154281 t 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-252988 HAX1 protein O00165 UNIPROT ATP2A2 protein P16615 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 18971376 t lperfetto "The anti-apoptotic protein HAX-1 interacts with SERCA2 and regulates its protein levels to promote cell survival.|Importantly, HAX-1 overexpression was associated with down-regulation of SERCA2 expression levels, resulting in significant reduction of apparent ER Ca(2+) levels." SIGNOR-262052 ARVCF protein O00192 UNIPROT CDH3 protein P22223 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0001109 14610055 t miannu "To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member." SIGNOR-252127 ARVCF protein O00192 UNIPROT CDH5 protein P33151 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0001109 14610055 t miannu "To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member." SIGNOR-252129 HRK protein O00198 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates binding 9606 9130713 t gcesareni "Hrk, physically interacts with the death-repressor proteins bcl2 and bcl2l1. Hrk activates cell death at least in part by interacting with and inhibiting the protection afforded by bcl2 and bcl2l1." SIGNOR-47797 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser40 RRTDALTsSPGRDLP 9606 19647517 t lperfetto "Phosphorylation of mcm2 by cdc7 promotes pre-replication complex assembly during cell-cycle re-entry" SIGNOR-187392 AP3B1 protein O00203 UNIPROT KIF3A protein Q9Y496 UNIPROT "up-regulates activity" binding 10090 BTO:0002572 19934039 t Giorgia "Here, we show that the beta subunit of AP-3, a clathrin-associated protein complex required for HIV-1 release, is a target of IP(7)-mediated pyrophosphorylation. We have identified Kif3A, a motor protein of the kinesin superfamily, as an AP3B1-binding partner and demonstrate that Kif3A, like the AP-3 complex, is involved in an intracellular process required for HIV-1 Gag release." SIGNOR-260398 AP3B1 protein O00203 UNIPROT "AP-3 complex" complex SIGNOR-C247 SIGNOR "form complex" binding 9606 21097499 t lperfetto "Key components of this system are the heterotetrameric adaptor protein (AP)4 complexes, AP-1 (gamma-beta1-mi1-sigma1), AP-2 (α-beta2-mi2-sigma2), AP-3 (delta-beta3-mi3-sigma3), and AP-4 (epsilon-beta4-mi4-sigma4) (subunit composition shown in parentheses)" SIGNOR-260681 TLR4 protein O00206 UNIPROT TLR4 protein O00206 UNIPROT "up-regulates activity" binding 10090 22664090 t 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-252066 TLR4 protein O00206 UNIPROT JUN protein P05412 UNIPROT "up-regulates activity" 9606 BTO:0000801 19592489 f lperfetto "The transcription factor AP-1 consists of a variety of dimers composed of members of the Jun, Fos, and ATF families of proteins. The Jun proteins can both homo- and heterodimerize with Fos members to form transcriptionally active complexes. The stimulation of macrophage TLR4 receptor rapidly activates not only the NF-kappaB pathway but also MAPK pathways, including JNK, ERK, and p38. Many of the downstream targets of MAPK pathways are transcription factors that include c-Jun." SIGNOR-249518 TLR4 protein O00206 UNIPROT TIRAP protein P58753 UNIPROT up-regulates binding 9606 11544529 t fstefani "Mal (myd88-adapter-like) is required for toll-like receptor-4 signal transduction." SIGNOR-110337 TLR4 protein O00206 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" phosphorylation 9606 28137827 t miannu "Binding of S100A9 to TLR4 stimulates the phosphorylation of JNK, ERK1/2, and p38 MAPK, which leads to the activation of c-Jun, CREB, and NF-κB. Activation of neutrophils by S100A9 also proceeds via p38 MAPK, JNK, and ERK1/2 phosphorylation." SIGNOR-263652 TLR4 protein O00206 UNIPROT TICAM1 protein Q8IUC6 UNIPROT "up-regulates activity" binding 10090 22664090 t 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 TLR4 protein O00206 UNIPROT MYD88 protein Q99836 UNIPROT "up-regulates activity" binding 10090 22664090 t 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 TLR4 protein O00206 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "up-regulates activity" 9606 BTO:0000801 7635431 f lperfetto "The activation of NF-kB is triggered by different stimuli, eg., lipopolysaccharides (LPSs), muramyl peptides, viruses,e inflammatory cytokines tumor necrosis factor-alpha(TNF-a) and interleukin (IL)-1b, irradiation, and reactive xygen intermediates (H2O2)." SIGNOR-249517 BMPR1B protein O00238 UNIPROT STAMBP protein O95630 UNIPROT "up-regulates activity" phosphorylation Ser243 SLKPGALsNSESIPT 9534 BTO:0000298 11483516 t llicata "BMP type I receptor activation stimulates AMSH phosphorylation | The exact position of phosphoserine residues in four phosphopeptides was identified by Edman degradation analysis; spot a for Ser243, Ser245 and Ser247, spot b for Ser2, and spots c and d for Ser48. To confirm the position of the phosphoserine residues, the serine residue(s) in each phosphopeptide was replaced by alanine residues. Then, each mutant as well as wild‐type AMSH was transfected into COS7 cells in the absence or presence of caALK6, and tryptic phosphopeptide mapping of each mutant was performed. As seen in Figure 7, each spot corresponding to the phosphopeptide containing phosphoserine disappeared in the tryptic phosphopeptide mapping. | Thus, AMSH promotes BMP signaling by negatively regulating the function of I‐Smads." SIGNOR-250597 BMPR1B protein O00238 UNIPROT STAMBP protein O95630 UNIPROT "up-regulates activity" phosphorylation Ser245 KPGALSNsESIPTID 9534 BTO:0000298 11483516 t llicata "BMP type I receptor activation stimulates AMSH phosphorylation | The exact position of phosphoserine residues in four phosphopeptides was identified by Edman degradation analysis; spot a for Ser243, Ser245 and Ser247, spot b for Ser2, and spots c and d for Ser48. To confirm the position of the phosphoserine residues, the serine residue(s) in each phosphopeptide was replaced by alanine residues. Then, each mutant as well as wild‐type AMSH was transfected into COS7 cells in the absence or presence of caALK6, and tryptic phosphopeptide mapping of each mutant was performed. As seen in Figure 7, each spot corresponding to the phosphopeptide containing phosphoserine disappeared in the tryptic phosphopeptide mapping. | Thus, AMSH promotes BMP signaling by negatively regulating the function of I‐Smads." SIGNOR-250598 BMPR1B protein O00238 UNIPROT STAMBP protein O95630 UNIPROT "up-regulates activity" phosphorylation Ser247 GALSNSEsIPTIDGL 9534 BTO:0000298 11483516 t llicata "BMP type I receptor activation stimulates AMSH phosphorylation | The exact position of phosphoserine residues in four phosphopeptides was identified by Edman degradation analysis; spot a for Ser243, Ser245 and Ser247, spot b for Ser2, and spots c and d for Ser48. To confirm the position of the phosphoserine residues, the serine residue(s) in each phosphopeptide was replaced by alanine residues. Then, each mutant as well as wild‐type AMSH was transfected into COS7 cells in the absence or presence of caALK6, and tryptic phosphopeptide mapping of each mutant was performed. As seen in Figure 7, each spot corresponding to the phosphopeptide containing phosphoserine disappeared in the tryptic phosphopeptide mapping. | Thus, AMSH promotes BMP signaling by negatively regulating the function of I‐Smads." SIGNOR-250599 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser41 RTDALTSsPGRDLPP 9606 16446360 t gcesareni "In the present study, we report the identification of cdc7/dbf4 phosphorylation sites on mcm2 and determine the functional role of cdc7/dbf4 phosphorylation of mcm2 in the initiation of dna replication in human cells." SIGNOR-143996 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser139 RRGLLYDsDEEDEER 9606 BTO:0000567 16899510 t gcesareni "In the present study, we report the identification of cdc7/dbf4 phosphorylation sites on mcm2 and determine the functional role of cdc7/dbf4 phosphorylation of mcm2 in the initiation of dna replication in human cells." SIGNOR-148709 BMPR1B protein O00238 UNIPROT STAMBP protein O95630 UNIPROT "up-regulates activity" phosphorylation Ser48 VEIIRMAsIYSEEGN 9534 BTO:0000298 11483516 t llicata "BMP type I receptor activation stimulates AMSH phosphorylation | The exact position of phosphoserine residues in four phosphopeptides was identified by Edman degradation analysis; spot a for Ser243, Ser245 and Ser247, spot b for Ser2, and spots c and d for Ser48. To confirm the position of the phosphoserine residues, the serine residue(s) in each phosphopeptide was replaced by alanine residues. Then, each mutant as well as wild‐type AMSH was transfected into COS7 cells in the absence or presence of caALK6, and tryptic phosphopeptide mapping of each mutant was performed. As seen in Figure 7, each spot corresponding to the phosphopeptide containing phosphoserine disappeared in the tryptic phosphopeptide mapping. | Thus, AMSH promotes BMP signaling by negatively regulating the function of I‐Smads." SIGNOR-250600 BMPR1B protein O00238 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation 9606 19620713 t gcesareni "Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression." SIGNOR-187190 BMPR1B protein O00238 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation Ser462 GSPHNPIsSVS 9606 9335504 t llicata "The c terminus of smad1, which is phosphorylated directly by the bmp type i receptor at the ssvs sequence in contrast to the bmp-stimulated phosphorylation of smad1, which affects carboxy-terminal serines and induces nuclear accumulation of smad1, erk-mediated phosphorylation specifically inhibits the nuclear accumulation of smad1." SIGNOR-52662 BMPR1B protein O00238 UNIPROT SMAD5 protein Q99717 UNIPROT up-regulates phosphorylation 9606 19620713 t gcesareni "Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression." SIGNOR-187193 BMPR1B protein O00238 UNIPROT SMAD5 protein Q99717 UNIPROT up-regulates 10090 BTO:0000165 10564272 f lperfetto "We found that both smad6 and smad7 inhibit the activation of smad1 and smad5 by bmpr-ia/alk-3 and bmpr-ib/alk-6, as well as that by alk-2" SIGNOR-235625 BMPR1B protein O00238 UNIPROT SMAD5 protein Q99717 UNIPROT "up-regulates activity" phosphorylation 9606 19620713 t lperfetto "Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression." SIGNOR-255260 AGRP protein O00253 UNIPROT MC4R protein P32245 UNIPROT "down-regulates activity" binding 9606 10318826 t miannu "AGRP is a potent antagonist of the melanocortin-3 receptor and the MC4R and has also been shown to have a lesser degree of inhibitory action at the melanocortin-5 receptor." SIGNOR-252379 AGRP protein O00253 UNIPROT MC3R protein P41968 UNIPROT down-regulates binding 9606 BTO:0001253 9311920 t gcesareni "Recombinant agouti-related protein was a potent, selective antagonist of mc3r and mc4r, melanocortin receptor subtypes implicated in weight regulation." SIGNOR-51067 AGRP protein O00253 UNIPROT MC3R protein P41968 UNIPROT "down-regulates activity" binding 9606 10318826 t miannu "AGRP is a potent antagonist of the melanocortin-3 receptor and the MC4R and has also been shown to have a lesser degree of inhibitory action at the melanocortin-5 receptor." SIGNOR-252380 F2RL2 protein O00254 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257301 F2RL2 protein O00254 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257146 F2RL2 protein O00254 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257234 F2RL2 protein O00254 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256904 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser27 GNDPLTSsPGRSSRR 9606 BTO:0000567 16899510 t gcesareni "In the present study, we report the identification of cdc7/dbf4 phosphorylation sites on mcm2 and determine the functional role of cdc7/dbf4 phosphorylation of mcm2 in the initiation of dna replication in human cells." SIGNOR-148713 F2RL2 protein O00254 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257033 F2RL2 protein O00254 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257409 F2RL2 protein O00254 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256761 MEN1 protein O00255 UNIPROT CDKN2C protein P42773 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15640349 f irozzo "Menin activates transcription by means of a mechanism involving recruitment of MLL to the p27Kip1 and p18Ink4c promoters and coding regions." SIGNOR-255888 MEN1 protein O00255 UNIPROT KMT2A protein Q03164 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 15640349 t irozzo "However, menin dramatically increases the amount of MLL bound at the p27Kip1 and p18Ink4c loci, suggesting that it either directly or indirectly promotes MLL recruitment to these targets. Once recruited, MLL could enhance transcription by a number of mechanisms.Overall, the data suggest that transcriptional regulation by menin involves increasing MLL protein association with target loci." SIGNOR-255890 MEN1 protein O00255 UNIPROT RELA protein Q04206 UNIPROT down-regulates binding 9606 SIGNOR-C13 11526476 t miannu "Menin represses p65-mediated transcriptional activation on nf-kappab sites in a dose-dependent and specific manner." SIGNOR-110067 MEN1 protein O00255 UNIPROT FANCD2 protein Q9BXW9 UNIPROT up-regulates binding 9606 12874027 t miannu "Menin interacts with fancd2 / loss of menin expression in mouse embryonic fibroblasts leads to increased sensitivity to dna damage. Furthermore, menin is localized to chromatin and nuclear matrix, and the association with nuclear matrix is enhanced by gamma-irradiation. Together, these results suggest that menin plays a critical role in repair of dna damage in concert with fancd2." SIGNOR-103947 MEN1 protein O00255 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates binding 9606 11526476 t lperfetto "Menin represses p65-mediated transcriptional activation on nf-kappab sites in a dose-dependent and specific manner." SIGNOR-217406 MEN1 protein O00255 UNIPROT "MLL Fusion" "fusion protein" SIGNOR-FP14 SIGNOR "up-regulates activity" binding 10090 BTO:0004730 16239140 t miannu "We demonstrate here that oncogenic MLL fusion proteins retain an ability to stably associate with menin through a high-affinity, amino-terminal, conserved binding motif and that this interaction is required for the initiation of MLL-mediated leukemogenesis.These results demonstrate that a human oncoprotein is critically dependent on direct physical interaction with a tumor suppressor protein for its oncogenic activity." SIGNOR-260130 HIP1 protein O00291 UNIPROT AR protein P10275 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001130 16027218 f miannu "Hip1 as a transcriptional regulator of the ar / silencing hip1 expression reduces the transcriptional activity and protein levels of the ar" SIGNOR-138820 HIP1 protein O00291 UNIPROT REST protein Q13127 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21832040 f miannu "HIPPI could bind to the promoter of REST and increased its expression in neuronal as well as non-neuronal cells. Such activation of REST down-regulated expression of REST target genes, such as brain-derived neurotrophic factor (BDNF) or proenkephalin (PENK)." SIGNOR-255076 EIF3F protein O00303 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates deubiquitination Lys1759 CGVLLSRkRRRQHGQ 9606 21124883 t gcesareni "The activated form of notch needs to be deubiquitinated before being processed by the gamma-secretase activity and entering the nucleus, where it fulfills its transcriptional function. The enzyme accounting for this deubiquitinase activity is eif3f, known so far as a translation initiation factor." SIGNOR-170158 EIF3F protein O00303 UNIPROT EIF3_complex complex SIGNOR-C401 SIGNOR "form complex" binding -1 16920360 t miannu "Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1)." SIGNOR-266395 EIF3F protein O00303 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates deubiquitination 9606 21124883 t gcesareni "The activated form of notch needs to be deubiquitinated before being processed by the gamma-secretase activity and entering the nucleus, where it fulfills its transcriptional function. The enzyme accounting for this deubiquitinase activity is eif3f, known so far as a translation initiation factor." SIGNOR-254327 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser139 RRGLLYDsDEEDEER 9606 16446360 t gcesareni "In the present study, we report the identification of cdc7/dbf4 phosphorylation sites on mcm2 and determine the functional role of cdc7/dbf4 phosphorylation of mcm2 in the initiation of dna replication in human cells." SIGNOR-143988 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser27 GNDPLTSsPGRSSRR 9606 16446360 t gcesareni "In the present study, we report the identification of cdc7/dbf4 phosphorylation sites on mcm2 and determine the functional role of cdc7/dbf4 phosphorylation of mcm2 in the initiation of dna replication in human cells." SIGNOR-143992 ARNTL protein O00327 UNIPROT VWF protein P04275 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000394 20658528 t lperfetto "We also show that major circadian transcriptional regulators CLOCK and Bmal1 directly regulate the activity of vWF promoter and that lack of Bmal1 results in upregulation of vWF both at mRNA and protein level. Here we report a direct regulation of vWF expression in endothelial cells by biological clock gene Bmal1. This study establishes a mechanistic connection between Bmal1 and cardiovascular phenotype." SIGNOR-253704 ARNTL protein O00327 UNIPROT PER3 protein P56645 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 22750052 f "Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins." SIGNOR-253630 ARNTL protein O00327 UNIPROT CRY1 protein Q16526 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 22750052 f "Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins." SIGNOR-253626 ARNTL protein O00327 UNIPROT CRY2 protein Q49AN0 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 22750052 f "Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins." SIGNOR-253627 ARNTL protein O00327 UNIPROT MAGEL2 protein Q9UJ55 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 22208286 t miannu "Magel2 represses the activity of the Clock:Bmal1 heterodimer in a Per2-luciferase assay. Magel2 interacts with Bmal1 and with Per2 as measured by co-immunoprecipitation in co-transfected cells, and exhibits a subcellular distribution consistent with these interactions when visualized by immunofluorescence. As well, Magel2 induces the redistribution of the subcellular localization of Clock towards the cytoplasm, in contrast to the nucleus-directed effect of Bmal1 on Clock subcellular localization." SIGNOR-253517 ARNTL protein O00327 UNIPROT CLOCK/ARNTL complex SIGNOR-C195 SIGNOR "form complex" binding -1 22653727 t lperfetto "Crystal structure of the heterodimeric CLOCK:BMAL1 transcriptional activator complex|The structure of the CLOCK:BMAL1 complex is a starting point for understanding at an atomic level the mechanism driving the mammalian circadian clock." SIGNOR-253708 PIK3CD protein O00329 UNIPROT PIK3CD protein O00329 UNIPROT down-regulates phosphorylation Ser1039 NWLAHNVsKDNRQ 9606 10064595 t gcesareni "Autophosphorylation of p110delta phosphoinositide 3-kinase: a new paradigm for the regulation of lipid kinases in vitro and in vivo in vitro autophosphorylation of p110delta completely down-regulates its lipid kinase activity." SIGNOR-65186 PDHX protein O00330 UNIPROT GCG protein P01275 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001731 12783165 f miannu "In glucagonoma cells transduced with a Pdx1-encoding lentiviral vector, insulin gene expression was induced while glucagon mRNA levels were reduced by 50 to 60%." SIGNOR-254901 PDHX protein O00330 UNIPROT INS protein P01308 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001731 12783165 f miannu "In glucagonoma cells transduced with a Pdx1-encoding lentiviral vector, insulin gene expression was induced while glucagon mRNA levels were reduced by 50 to 60%." SIGNOR-254902 PDHX protein O00330 UNIPROT PDH complex SIGNOR-C402 SIGNOR "form complex" binding 9606 20160912 t miannu "The human (h) pyruvate dehydrogenase complex (hPDC) consists of multiple copies of several components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2), dihydrolipoamide dehydrogenase (E3), E3-binding protein (BP), and specific kinases and phosphatases. Mammalian PDC has a well organized structure with an icosahedral symmetry of the central E2/BP core to which the other component proteins bind non-covalently." SIGNOR-266543 P2RY10 protein O00398 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257213 P2RY10 protein O00398 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256869 P2RY10 protein O00398 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257005 PIK3C2A protein O00443 UNIPROT "1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate" smallmolecule CHEBI:16618 ChEBI up-regulates "small molecule catalysis" 9606 BTO:0000150 23119004 t gcesareni "Pi3ks phosphorylate the d3 position of membrane phosphatidylinositides to generate phosphatidylinositol 3,4,5-triphosphate (pip3)." SIGNOR-199367 P2RY10 protein O00398 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257121 P2RY10 protein O00398 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256726 P2RY10 protein O00398 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257287 P2RY10 protein O00398 UNIPROT GNA13 protein Q14344 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257348 DCTN6 protein O00399 UNIPROT PLK1 protein P53350 UNIPROT "up-regulates activity" binding 9534 BTO:0004055 phosphorylation:Thr186 KTMKGSStPVKN 23455152 t lperfetto "Here, we show that the p27/p25 heterodimer undergoes mitotic phosphorylation by cyclin‐dependent kinase 1 (Cdk1) at a single site, p27 Thr186, to generate an anchoring site for polo‐like kinase 1 (Plk1) at kinetochores." SIGNOR-264798 WASL protein O00401 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR "up-regulates activity" binding 9606 BTO:0000567 20498093 t lperfetto "Members of the Wiskott-Aldrich syndrome protein (WASP) family, which includes WASP, N-WASP, WAVE (1–3), WHAMM, JMY, and WASH, control actin cytoskeletal dynamics throughout biology. They act in large part by regulating the actin nucleating activity of the ubiquitous Arp2/3 complex. WASP proteins stimulate Arp2/3 complex using a conserved C-terminal VCA (Verprolin homologous, central hydrophobic, and acidic) region. They contain distinct N-terminal elements, which facilitate integration into unique macromolecular complexes." SIGNOR-261003 IPO5 protein O00410 UNIPROT DSCAM protein O60469 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000938 30745319 t miannu "DSCAM and DSCAML1 specifically interacted with the importin beta IPO5, whereas deletion of the identified NLSs abolished this specific interaction and suppressed nuclear translocation of the DSCAM/L1 ICDs in cell lines and cultured neurons. This suggests a direct role of IPO5 in the nuclear import of the DSCAM/L1 ICDs." SIGNOR-264273 IPO5 protein O00410 UNIPROT DSCAML1 protein Q8TD84 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000938 30745319 t miannu "DSCAM and DSCAML1 specifically interacted with the importin beta IPO5, whereas deletion of the identified NLSs abolished this specific interaction and suppressed nuclear translocation of the DSCAM/L1 ICDs in cell lines and cultured neurons. This suggests a direct role of IPO5 in the nuclear import of the DSCAM/L1 ICDs." SIGNOR-264274 EEF2K protein O00418 UNIPROT EEF2K protein O00418 UNIPROT down-regulates phosphorylation Ser445 SGDSGYPsEKRGELD 9606 22669845 t gcesareni "The combination of eef2k autophosphorylation (targeting ser445) and a yet to be identified kinase (targeting ser441) would be needed to generate the eef2k phosphodegron specifically in response to dna damage." SIGNOR-197725 EEF2K protein O00418 UNIPROT EEF2 protein P13639 UNIPROT down-regulates phosphorylation Thr57 RAGETRFtDTRKDEQ 9606 BTO:0000007 12194824 t gcesareni "The activation of eef2 kinase by ampk, resulting in the phosphorylation and inactivation of eef2, provides a novel mechanism for the inhibition of protein synthesis." SIGNOR-91751 EEF2K protein O00418 UNIPROT EEF2 protein P13639 UNIPROT down-regulates phosphorylation Thr59 GETRFTDtRKDEQER 9606 2261989 t gcesareni "Ef-2 kinase phosphorylates ef-2 at 3 threonine residues: thr-53, thr-56, thr-58. Phosphorylation of thr56 and thr58 was found to be an ordered process, modification of thr56 preceding, and apparently being required for, phosphorylation of thr58." SIGNOR-22928 EEF2K protein O00418 UNIPROT EEF2 protein P13639 UNIPROT down-regulates phosphorylation Thr57 RAGETRFtDTRKDEQ 9606 8386634 t gcesareni "The eef-2 kinase could phosphorylate a synthetic peptide based on residues 49-60 of eef-2 (ragetrftdtrk), albeit only at a very low rate, and with a very high km, compared to eef-2 itself." SIGNOR-38552 EEF2K protein O00418 UNIPROT EEF2 protein P13639 UNIPROT down-regulates phosphorylation Thr59 GETRFTDtRKDEQER 9606 8386634 t gcesareni "Ef-2 kinase phosphorylates ef-2 at 3 threonine residues: thr-53, thr-56, thr-58. Phosphorylation of thr56 and thr58 was found to be an ordered process, modification of thr56 preceding, and apparently being required for, phosphorylation of thr58." SIGNOR-38556 DNM1L protein O00429 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR "up-regulates activity" binding 10090 BTO:0002295 31063459 t lperfetto "Importantly, we found that crosstalk between phosphorylated Drp1S600 (p-Drp1S600) and the actin-binding protein com- plex Arp2/3 is a required step in mitochondrial Drp1 recruitment and mitochondrial fission under HG conditions." SIGNOR-262550 PLK4 protein O00444 UNIPROT TUBGCP6 protein Q96RT7 UNIPROT "up-regulates activity" phosphorylation Ser1060 HGHVSDAsIRVGENV -1 22302995 t miannu "Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication." SIGNOR-262900 PLK4 protein O00444 UNIPROT TUBGCP6 protein Q96RT7 UNIPROT "up-regulates activity" phosphorylation Ser1087 HGHVSNAsISLGESV -1 22302995 t miannu "Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication." SIGNOR-262901 PLK4 protein O00444 UNIPROT TUBGCP6 protein Q96RT7 UNIPROT "up-regulates activity" phosphorylation Ser1114 HGHVSNAsIRVGENV -1 22302995 t miannu "Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication." SIGNOR-262902 PLK4 protein O00444 UNIPROT TUBGCP6 protein Q96RT7 UNIPROT "up-regulates activity" phosphorylation Ser1168 HGHVSDAsISLGESV -1 22302995 t miannu "Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication." SIGNOR-262903 PLK4 protein O00444 UNIPROT TUBGCP6 protein Q96RT7 UNIPROT "up-regulates activity" phosphorylation Ser1176 ISLGESVsDMAPARP -1 22302995 t miannu "Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication." SIGNOR-262904 PLK4 protein O00444 UNIPROT TUBGCP6 protein Q96RT7 UNIPROT "up-regulates activity" phosphorylation Ser1195 HGHVSDAsISLGESV -1 22302995 t miannu "Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication." SIGNOR-262905 PLK4 protein O00444 UNIPROT TUBGCP6 protein Q96RT7 UNIPROT "up-regulates activity" phosphorylation Ser1249 HGHVSDAsISLGEPV -1 22302995 t miannu "Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication." SIGNOR-262906 PLK4 protein O00444 UNIPROT TUBGCP6 protein Q96RT7 UNIPROT "up-regulates activity" phosphorylation Ser1437 RYPDSYEsMSEPPIA -1 22302995 t miannu "Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication." SIGNOR-262907 PLK4 protein O00444 UNIPROT TUBGCP6 protein Q96RT7 UNIPROT "up-regulates activity" phosphorylation Ser1465 PVDPQVQsAADETAV -1 22302995 t miannu "Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication." SIGNOR-262908 PLK4 protein O00444 UNIPROT TUBGCP6 protein Q96RT7 UNIPROT "up-regulates activity" phosphorylation Ser392 VSGASPEsISSLLSE -1 22302995 t miannu "Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication." SIGNOR-262909 PLK4 protein O00444 UNIPROT CENPJ protein Q9HC77 UNIPROT up-regulates phosphorylation Ser595 ISFSSNSsFVLKILE 9606 20531387 t lperfetto "Plk2 phosphorylates the s589 and s595 residues of cpap in vitro and in vivo. This phosphorylation is critical for procentriole formation during the centrosome cycle. Plk4 also phosphorylates s595 of cpap" SIGNOR-166007 AGRN protein O00468 UNIPROT CHRNB3 protein Q05901 UNIPROT "up-regulates activity" binding 9606 BTO:0002916 14502292 t miannu "Treatment of muscle cells with neural agrin causes tyrosine phosphorylation of the AChR β subunit and induces AChR clustering by promoting anchoring of the receptor protein to postsynaptic cytoskeleton. Regulation of acetylcholine receptor clustering by the tumor suppressor APC. By showing a direct requirement for APC in AChR clustering, our present study suggests that the Wnt/β-catenin pathway may crosstalk with the agrin signaling cascade during the formation of mammalian neuromuscular junction." SIGNOR-264260 NR5A2 protein O00482 UNIPROT CYP19A1 protein P11511 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001555 19022561 f miannu "We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters." SIGNOR-254872 NR5A2 protein O00482 UNIPROT CYP11B1 protein P15538 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002588 11564608 f miannu "The ability of LRH-1 to enhance transcription of the gene encoding human 11 beta- hydroxylase (hCYP11B1) was then examined using the H295R adrenal cell line. LRH-1 co-transfection with hCYP11B1 luciferase promoter constructs caused a 25-fold induction of luciferase activity. Furthermore, co-transfection of a hCYP11B1 reporter construct containing a mutation in the SF-1 binding cis-element abolished the stimulatory effect of both SF-1 and LRH-1. Electrophoretic mobility shift assay (EMSA) demonstrated that LRH-1 could bind to the SF-1 response element. Taken together, our data suggested that LRH-1 is expressed in the adrenal, and can substitute for SF-1 to enhance transcription of genes encoding certain of the steroid-metabolizing enzymes." SIGNOR-254880 NR5A2 protein O00482 UNIPROT HSD3B2 protein P26439 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001555 19022561 f miannu "We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters." SIGNOR-254873 CXCL11 protein O14625 UNIPROT CXCR3 protein P49682 UNIPROT "up-regulates activity" binding 9606 BTO:0000782 12750173 t miannu "The chemokines CXCL9, 10, and 11 exert their action via CXC chemokine receptor-3 (CXCR3), a receptor highly expressed on activated T cells." SIGNOR-260971 NR5A2 protein O00482 UNIPROT STAR protein P49675 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001555 19022561 f miannu "We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters." SIGNOR-254870 PSMD14 protein O00487 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "form complex" binding 9606 BTO:0000007 29636472 t lperfetto "Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line" SIGNOR-263346 STK25 protein O00506 UNIPROT CCM2 protein Q9BSQ5 UNIPROT up-regulates phosphorylation Ser384 GRGIITDsFGRHRRA 9606 BTO:0001757 22782892 t miannu "CCM2 can be phosphorylated by STK25, and the kinase activity of STK25 is required for death signaling." SIGNOR-263144 STK25 protein O00506 UNIPROT PDCD10 protein Q9BUL8 UNIPROT unknown phosphorylation Ser39 ELERVNLsAAQTLRA 9606 19370760 t llicata "Stk25 phosphorylates ccm3 at serine 39 and threonine 43" SIGNOR-185388 STK25 protein O00506 UNIPROT PDCD10 protein Q9BUL8 UNIPROT unknown phosphorylation Thr43 VNLSAAQtLRAAFIK 9606 19370760 t llicata "Stk25 phosphorylates ccm3 at serine 39 and threonine 43" SIGNOR-185392 BCL9 protein O00512 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates binding 9606 BTO:0000776 11955446 t amattioni "Bcl9 exert its function by physically linking pygo to beta-catenin. The recruitment of pygo permits beta-catenin to transcriptionally activate wnt target genes." SIGNOR-116552 BCL9 protein O00512 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates binding 9606 15208637 t amattioni "The transcriptional activity of beta-catenin depends on bcl-9. Bcl-9 functions in targeting beta-catenin to the nucleus and thus increases the transcriptional activity of beta-catenin" SIGNOR-126059 BCL9 protein O00512 UNIPROT PYGO1 protein Q9Y3Y4 UNIPROT up-regulates binding 9606 BTO:0000776 11955446 t miannu "Here we report the identification of two segment polarity genes in drosophila, legless (lgs), and pygopus (pygo), and we show that their products are required for wnt signal transduction at the level of nuclear beta-catenin. Lgs encodes the homolog of human bcl9, and we provide genetic and molecular evidence that these proteins exert their function by physically linking pygo to beta-catenin." SIGNOR-116577 CHL1 protein O00533 UNIPROT ANK1 protein P16157 UNIPROT "up-regulates quantity" relocalization 10116 BTO:0000227 7961622 t miannu "Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains." SIGNOR-266724 CHL1 protein O00533 UNIPROT ANK2 protein Q01484 UNIPROT "up-regulates quantity" relocalization 10116 BTO:0000227 7961622 t miannu "Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains." SIGNOR-266722 CHL1 protein O00533 UNIPROT ANK3 protein Q12955 UNIPROT "up-regulates quantity" relocalization 10116 BTO:0000227 7961622 t miannu "Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains." SIGNOR-266723 DLL1 protein O00548 UNIPROT NOTCH1 protein P46531 UNIPROT "up-regulates activity" binding 9606 BTO:0000776 16140393 t 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 DLL1 protein O00548 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 23111325 t gcesareni "In this study, we demonstrate that dll1 can activate notch signaling mostly through notch2 receptor and can contribute to drug resistance to bortezomib, both in murine and human mm cells." SIGNOR-199320 DLL1 protein O00548 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates binding BTO:0001103 12361602 t 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 DLL1 protein O00548 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates binding 23729744 t 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 DLL1 protein O00548 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR "up-regulates activity" binding 9606 BTO:0000776 16140393 t 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-254315 CACNA1A protein O00555 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000938 20655485 t miannu "The main G b/g-dependent effectors of presynaptic GABAB receptors are P/Q-and N-type voltage-dependent Ca2+ channels. GABAB receptors inhibit these Ca2+ channels at excitatory and inhibitory terminals, thereby restricting neurotransmitter release." SIGNOR-266708 CACNA1A protein O00555 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000227 30849329 t miannu "Voltage-gated calcium channels mediate the influx of calcium in response to membrane depolarization in excitable cells. In presynaptic nerve terminals, this calcium influx triggers transmitter release for synaptic transmission. Several neurological and cardiac disorders are caused by pathogenic variants in genes encoding α1-subunits of voltage-gated calcium channels, including CACNA1A (MIM: 601011) (familial hemiplegic migraine [MIM: 141500], episodic ataxia [MIM: 108500], and epilepsy [MIM: 617106]),3, 4, 5 CACNA1C (MIM: 114205) (Timothy syndrome [MIM: 601005]),6, 7 CACNA1D (MIM: 114206) (primary aldosteronism, neurodevelopmental disorders [MIM: 615474]),8, 9 and CACNA1G (MIM: 604065) (spinocerebellar ataxia [MIM: 616795])." SIGNOR-264323 MPHOSPH10 protein O00566 UNIPROT RPS5 protein P46782 UNIPROT "up-regulates activity" binding -1 28813493 t miannu "Mpp10 is able to bind the ribosome biogenesis factor Utp3/Sas10 through two conserved motifs in its N-terminal region. In addition, Mpp10 interacts with the ribosomal protein S5/uS7 using a short stretch within an acidic loop region. Thus, our findings reveal that Mpp10 provides a platform for the simultaneous interaction with multiple proteins in the 90S pre-ribosome." SIGNOR-261175 MPHOSPH10 protein O00566 UNIPROT IMP4 protein Q96G21 UNIPROT "up-regulates activity" binding -1 28813493 t miannu "Mpp10 represents a platform for the interaction of multiple factors within the 90S pre-ribosome. In eukaryotes, ribosome assembly is a highly complex process that involves more than 200 assembly factors that ensure the folding, modification and processing of the different rRNA species as well as the timely association of ribosomal proteins. One of these factors, Mpp10 associates with Imp3 and Imp4 to form a complex that is essential for the normal production of the 18S rRNA." SIGNOR-261174 MPHOSPH10 protein O00566 UNIPROT UTP3 protein Q9NQZ2 UNIPROT "up-regulates activity" binding -1 28813493 t miannu "Mpp10 is able to bind the ribosome biogenesis factor Utp3/Sas10 through two conserved motifs in its N-terminal region. In addition, Mpp10 interacts with the ribosomal protein S5/uS7 using a short stretch within an acidic loop region. Thus, our findings reveal that Mpp10 provides a platform for the simultaneous interaction with multiple proteins in the 90S pre-ribosome." SIGNOR-261176 MPHOSPH10 protein O00566 UNIPROT IMP3 protein Q9NV31 UNIPROT "up-regulates activity" binding -1 28813493 t miannu "Mpp10 represents a platform for the interaction of multiple factors within the 90S pre-ribosome. In eukaryotes, ribosome assembly is a highly complex process that involves more than 200 assembly factors that ensure the folding, modification and processing of the different rRNA species as well as the timely association of ribosomal proteins. One of these factors, Mpp10 associates with Imp3 and Imp4 to form a complex that is essential for the normal production of the 18S rRNA." SIGNOR-261173 MFNG protein O00587 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 10935626 t Fucosylation gcesareni "Manic fringe elongates the o-linked fucose saccharides on full-length notch1 and notch1 egf repeats 1923." SIGNOR-80555 MFNG protein O00587 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 11346656 t gcesareni "These observations indicate that the fringe proteins directly modify notch2, which is consistent with the recent finding that fringe is a glycosyltransferase that directly modifies notch (30, 31). It was further indicated that lfng does this at a site from the n terminus through the 15th egf repeat of notch2, and mfng does so at a site from the 23rd through the 29th egf repeat of notch2." SIGNOR-107708 PEX12 protein O00623 UNIPROT UBE2D1 protein P51668 UNIPROT "up-regulates activity" binding -1 19687296 t miannu "Here we report on the identification of the protein-ubiquitin ligases that are responsible for the ubiquitination of the peroxisomal protein import receptor Pex5. It is demonstrated that each of the three RING peroxins Pex2, Pex10, and Pex12 exhibits ubiquitin-protein isopeptide ligase activity. Our results show that Pex2 mediates the Ubc4-dependent polyubiquitination whereas Pex12 facilitates the Pex4-dependent monoubiquitination of Pex5.While polyubiquitinated Pex5 is degraded by the proteasome, monoubiquitinated Pex5 is destined for a new round of the receptor cycle." SIGNOR-253024 KPNA4 protein O00629 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates relocalization 9606 20454918 t gcesareni "Nicd binds via one of its four potential nuclear localization signals to importins alfa3, alfa4, and alfa7." SIGNOR-254322 SLN protein O00631 UNIPROT ATP2A1 protein O14983 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 28487373 t lperfetto "These results suggest that sAnk1 interacts with SLN both directly and in complex with SERCA1 and reduces SLN's inhibitory effect on SERCA1 activity." SIGNOR-265929 SLN protein O00631 UNIPROT ATP2A2 protein P16615 UNIPROT "down-regulates activity" binding -1 23455424 t lperfetto "The structure suggests a mechanism for selective Ca2+ loading and activation of SERCA, and provides new insight into how SLN and PLB inhibition arises from stabilization of this E1 intermediate state without bound Ca2+." SIGNOR-264779 NFIB protein O00712 UNIPROT NFIB protein O00712 UNIPROT "down-regulates activity" binding 9606 BTO:0000567 9099724 t 2 miannu "Coexpression of NFI-B3 with other isoforms of the NFI-B, -C, and -X family, however, led to a strong reduction of transcriptional activation compared with the expression of these factors alone. NFI-B3 apparently forms heterodimers with other NFI proteins thereby interfering with their function." SIGNOR-240883 NFIB protein O00712 UNIPROT NFIC protein P08651 UNIPROT "down-regulates activity" binding 9606 BTO:0000567 9099724 t 2 miannu "Coexpression of NFI-B3 with other isoforms of the NFI-B, -C, and -X family, however, led to a strong reduction of transcriptional activation compared with the expression of these factors alone. NFI-B3 apparently forms heterodimers with other NFI proteins thereby interfering with their function." SIGNOR-240880 NFIB protein O00712 UNIPROT NFIX protein Q14938 UNIPROT "down-regulates activity" binding 9606 BTO:0000567 9099724 t 2 miannu "Coexpression of NFI-B3 with other isoforms of the NFI-B, -C, and -X family, however, led to a strong reduction of transcriptional activation compared with the expression of these factors alone. NFI-B3 apparently forms heterodimers with other NFI proteins thereby interfering with their function." SIGNOR-240915 E2F3 protein O00716 UNIPROT TFDP1 protein Q14186 UNIPROT "up-regulates activity" binding 10029 BTO:0000246 8832394 t 2 miannu "The transcriptionally active forms of E2F are heterodimers composed of one polypeptide encoded by the E2F gene family and one polypeptide encoded by the DP gene family.In transfected cells, DP-1 did not accumulate in the nucleus unless it was coexpressed with the heterodimeric partners E2F-1, E2F-2, or E2F-3." SIGNOR-240553 PPP6C protein O00743 UNIPROT MAP3K7 protein O43318 UNIPROT down-regulates dephosphorylation Thr187 CDIQTHMtNNKGSAA 9606 17079228 t gcesareni "Our results demonstrate that pp6 specifically down-regulates tak1 through dephosphorylation of thr-187 in the activation loop, which is likely important for suppressing inflammatory responses via tak1 signaling pathways." SIGNOR-150408 PPP6C protein O00743 UNIPROT MAP3K7 protein O43318 UNIPROT "down-regulates activity" dephosphorylation Thr187 CDIQTHMtNNKGSAA 9606 BTO:0000007 17079228 t "Protein phosphatase 6 down-regulates TAK1 kinase activation in the IL-1 signaling pathway|From proteomic analysis of TAK1-binding proteins, we identified protein phosphatase 6 (PP6), a type-2A phosphatase, and demonstrated that PP6 associated with and inactivated TAK1 by dephosphorylation of Thr-187." SIGNOR-248292 WNT10B protein O00744 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15578921 t 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-131628 WNT10B protein O00744 UNIPROT FZD5 protein Q13467 UNIPROT up-regulates binding 9606 12055200 t fspada "Inhibition of adipogenesis by wnt10b is likely mediated by‚ wnt‚ receptors, frizzled 1, 2, and/or 5, and co-receptors low density lipoprotein receptor-related proteins 5 and 8" SIGNOR-210164 WNT10B protein O00744 UNIPROT FZD2 protein Q14332 UNIPROT up-regulates binding 9606 12055200 t fspada "Inhibition of adipogenesis by wnt10b is likely mediated by wnt receptors, frizzled 1, 2, and/or 5, and co-receptors low density lipoprotein receptor-related proteins 5 and 7" SIGNOR-89137 WNT10B protein O00744 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 t 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-131625 WNT10B protein O00744 UNIPROT FZD1 protein Q9UP38 UNIPROT up-regulates binding 9606 12055200 t fspada "Inhibition of adipogenesis by wnt10b is likely mediated by wnt receptors, frizzled 1, 2, and/or 5, and co-receptors low density lipoprotein receptor-related proteins 5 and 6" SIGNOR-89134 WNT7A protein O00755 UNIPROT FZD7 protein O75084 UNIPROT "up-regulates activity" binding 9606 BTO:0000887;BTO:0001103 22944199 t 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 WNT7A protein O00755 UNIPROT FZD7 protein O75084 UNIPROT "up-regulates activity" binding 9606 BTO:0002314 BTO:0001103 23290138 t 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 WNT7A protein O00755 UNIPROT FZD7 protein O75084 UNIPROT "up-regulates activity" binding 23290138 t "Simone Vumbaca" "Wnt7a-Fzd7 signaling stimulates symmetric stem cell divisions" SIGNOR-255646 WNT7A protein O00755 UNIPROT LRP5 protein O75197 UNIPROT "up-regulates activity" binding 9606 15578921 t 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-131900 WNT7A protein O00755 UNIPROT LRP6 protein O75581 UNIPROT "up-regulates activity" binding 9606 15578921 t 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-131903 WNT7A protein O00755 UNIPROT MYOD1 protein P15172 UNIPROT "up-regulates activity" 10090 BTO:0000887;BTO:0001103 22944199 f gcesareni "In explant cultures of mouse paraxial mesoderm, wnt1 induced expression of the mrf myf5, whereas wnt7a or wnt6 preferentially activated the mrf myod. Here we report that cells expressing wnt1 will preferentially activate myf5 while cells expressing wnt7a will preferentially activate myod" SIGNOR-198922 WNT7A protein O00755 UNIPROT MYOD1 protein P15172 UNIPROT "up-regulates activity" 10090 BTO:0000887;BTO:0001103 9753670 f gcesareni "Differential activation of Myf5 and MyoD by different Wnts in explants of mouse paraxial mesoderm and the later activation of myogenesis in the absence of Myf5" SIGNOR-60471 WNT7A protein O00755 UNIPROT PRKACA protein P17612 UNIPROT "up-regulates activity" 9606 BTO:0001103 21902831 f gcesareni "Wnt1 and wnt7a stimulation of precursor cells activates protein kinase a (pka), which, through the phosphorylation of creb, induces the expression of the myogenic transcription factors myf5, myod and pax3, resulting in the myogenic commitment of embryonic precursors." SIGNOR-176575 WNT7A protein O00755 UNIPROT SPRY4 protein Q9C004 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002058 15705594 f miannu "In NSCLC cells, Wnt-7a and Fzd-9 induced both cadherin and Sprouty-4 expression and stimulated the JNK pathway, but not beta-catenin/T cell factor activity." SIGNOR-253034 WNT7A protein O00755 UNIPROT FZD3 protein Q9NPG1 UNIPROT "up-regulates activity" binding 9606 15578921 t 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-131897 WNT7A protein O00755 UNIPROT Frizzled proteinfamily SIGNOR-PF11 SIGNOR "up-regulates activity" binding 9606 15578921 t 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-253130 ACACB protein O00763 UNIPROT acetyl-CoA smallmolecule CHEBI:15351 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 20952656 t miannu "ACC catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting and first committed step in de novo fatty acid biosynthesis. Two isoforms of ACC exist in mammals, ACC1 and ACC2, and both enzymes function to carboxylate acetyl-CoA to form malonyl-CoA" SIGNOR-267106 ACACB protein O00763 UNIPROT malonyl-CoA smallmolecule CHEBI:15531 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 20952656 t miannu "ACC catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting and first committed step in de novo fatty acid biosynthesis. Two isoforms of ACC exist in mammals, ACC1 and ACC2, and both enzymes function to carboxylate acetyl-CoA to form malonyl-CoA" SIGNOR-267110 DLGAP1 protein O14490 UNIPROT DLG4 protein P78352 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 9115257 t miannu "SAPAPs are specifically expressed in neuronal cells and enriched in the PSD fraction. SAPAPs induce the enrichment of PSD-95/SAP90 to the plasma membrane in transfected cells. Thus, SAPAPs may have a potential activity to maintain the structure of PSD by concentrating its components to the membrane area." SIGNOR-264209 CHD2 protein O14647 UNIPROT XRCC4 protein Q13426 UNIPROT "up-regulates quantity" relocalization 9606 BTO:0001938 26895424 t miannu "CHD2 Promotes the Recruitment of Core NHEJ Factors. overexpression of ATPase-dead CHD2 (K515R; Figure S5F), but not wild-type CHD2, also reduced the recruitment of XRCC4 (Figure 5E). Together, these findings suggest that the chromatin remodeling activity of CHD2 promotes the efficient assembly of NHEJ complexes at DSBs." SIGNOR-264528 ARID1A protein O14497 UNIPROT "SWI/SNF complex" complex SIGNOR-C92 SIGNOR "form complex" binding 9606 15627498 t miannu "We discuss recent insights in the functional differences between two evolutionary conserved subclasses of swi/snf-related chromatin remodeling factors. Onesubfamily comprises yeast swi/snf, fly bap and mammalian baf, whereas the other subfamily includes yeast rsc, fly pbap andmammalian pbaf. We review the subunit composition, conserved protein modules and biological functions of each of these subclasses ofswi/snf remodelers." SIGNOR-132919 CDK2AP1 protein O14519 UNIPROT CDK2 protein P24941 UNIPROT "down-regulates activity" binding 22427660 t lperfetto "The ubiquitously expressed CDK2AP1 protein is the only known specific inhibitor of CDK2, making it an important component of cell cycle regulation during G1-to-S phase transition." SIGNOR-264781 SDHD protein O14521 UNIPROT "Mitochondrial respiratory chain complex II" complex SIGNOR-C278 SIGNOR "form complex" binding 30030361 t lperfetto "Complex II (EC 1.3.5.1) or succinate dehydrogenase (quinone) is shared between the TCA cycle and the ETC and has no proton pumping activity. It is composed of four nDNA-encoded subunits. The two hydrophilic catalytic subunits are SDHA/SDH1 and SDHB/SDH2. Hydrophobic subunits SDHC/SDH3 and SDHD/SDH4 constitute the cII membrane anchor, containing a haem b group and two CoQ binding sites" SIGNOR-262187 SDHD protein O14521 UNIPROT SDH complex SIGNOR-C400 SIGNOR "form complex" binding 9606 16143825 t miannu "Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. Four nuclear genes encode the four subunits, SDHA (15 exons), SDHB (8 exons), SDHC (6 exons) and SDHD (4 exons), mapping on to chromosomes 5p15, 1p35-p36.1, 1q21 and 11q23, respectively." SIGNOR-266274 PTPRT protein O14522 UNIPROT STAT3 protein P40763 UNIPROT "down-regulates activity" dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0001109;BTO:0000182 17360477 t brain lperfetto "Identification of STAT3 as a substrate of receptor protein tyrosine phosphatase T|Phosphorylation of a tyrosine at amino acid Y705 is essential for the function of STAT3, and PTPRT specifically dephosphorylated STAT3 at this position." SIGNOR-263981 PTPRT protein O14522 UNIPROT PXN protein P49023 UNIPROT "down-regulates activity" dephosphorylation Tyr88 PQSSSPVyGSSAKTS 9606 BTO:0000182 27447856 t brain lperfetto "To this end, using a phospho-proteomics approach, we identified and validated paxillin and STAT3 as the substrates of PTPRT [15, 16]|the PTPRT target site on paxillin is a previously uncharacterized tyrosine-88 residue (paxillin Y88)|In this study, we also show how pY88 paxillin transduces a signal to activate Akt" SIGNOR-263978 FCHO1 protein O14526 UNIPROT "AP-2/clathrin vescicle" complex SIGNOR-C249 SIGNOR "up-regulates quantity by stabilization" binding 24789820 t lperfetto "Early recruitment of FCHo1/2, Eps15, epsin, and intersectin to the rims of assembling coated pits is essential for their stability and further growth" SIGNOR-260715 CUX2 protein O14529 UNIPROT OGG1 protein O15527 UNIPROT "up-regulates activity" binding 10090 BTO:0002572 26221032 t miannu "CUX2 Interacts Directly with OGG1 and Stimulate Its Binding to DNA Containing 8-OxoG" SIGNOR-263960 SOCS3 protein O14543 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates activity" binding 9606 24600449 t 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 GAPDHS protein O14556 UNIPROT "3-phosphonato-D-glyceroyl phosphate(4-)" smallmolecule CHEBI:57604 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 11724794 t miannu "GAPDH is commonly known as a key enzyme in glycolysis (GAPDH catalyzes the NAD-mediated oxidative phosphorylation of glyceraldehyde 3-phosphate to 1,3-diphosphoglycerate), a number of intriguing intracellular roles have been reported including modulation of the cytoskeleton, kinase activity, and the promotion of vesicle fusion" SIGNOR-266497 GAPDHS protein O14556 UNIPROT "D-glyceraldehyde 3-phosphate(2-)" smallmolecule CHEBI:59776 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 11724794 t miannu "GAPDH is commonly known as a key enzyme in glycolysis (GAPDH catalyzes the NAD-mediated oxidative phosphorylation of glyceraldehyde 3-phosphate to 1,3-diphosphoglycerate), a number of intriguing intracellular roles have been reported including modulation of the cytoskeleton, kinase activity, and the promotion of vesicle fusion" SIGNOR-266498 CIT protein O14578 UNIPROT MYL9 protein P24844 UNIPROT "up-regulates activity" phosphorylation Thr19 KKRPQRAtSNVFAMF -1 21457715 t Giulio "Activation of the catalytic ATPase domain residing in the N‐terminus of the heavy chain relies on the reversible phosphorylation of the associated MLC on Ser19 (monophosphorylation), or in some cases on both Thr18 and Ser19 (diphosphorylation)|We detected Ser19 of MLC as the common phosphorylation site for the catalytic domains of MRCK_/_, ROK_, MLCK and PAK_, but only ROK_ and CRIK are able to phosphorylate both Thr18 and Ser19 residues causing diphosphorylation." SIGNOR-260306 CIT protein O14578 UNIPROT KIF14 protein Q15058 UNIPROT "up-regulates activity" binding 9606 BTO:0000565 16431929 t miannu "We find that KIF14 targets to the central spindle via its interaction with PRC1 and has an essential function in cytokinesis. In KIF14-depleted cells, citron kinase but not other components of the central spindle and cleavage furrow fail to localize. Furthermore, the localization of KIF14 and citron kinase to the central spindle and midbody is codependent, and they form a complex depending on the activation state of citron kinase." SIGNOR-266424 CTDSP2 protein O14595 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" dephosphorylation Ser204 NHSMDAGsPNLSPNP 9606 BTO:0000007 17035229 t "Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity" SIGNOR-248293 CTDSP2 protein O14595 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" dephosphorylation Ser208 DAGSPNLsPNPMSPA 9606 BTO:0000007 17035229 t "Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity" SIGNOR-248294 CTDSP2 protein O14595 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" dephosphorylation Ser213 NLSPNPMsPAHNNLD 9606 BTO:0000007 17035229 t "Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity" SIGNOR-248295 CTDSP2 protein O14595 UNIPROT SMAD2 protein Q15796 UNIPROT "down-regulates activity" dephosphorylation Ser245 NQSMDTGsPAELSPT 9606 BTO:0000007 17035229 t "Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity" SIGNOR-248297 CTDSP2 protein O14595 UNIPROT SMAD2 protein Q15796 UNIPROT "down-regulates activity" dephosphorylation Ser250 TGSPAELsPTTLSPV 9606 BTO:0000007 17035229 t "Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity" SIGNOR-248298 CTDSP2 protein O14595 UNIPROT SMAD2 protein Q15796 UNIPROT "down-regulates activity" dephosphorylation Ser255 ELSPTTLsPVNHSLD 9606 BTO:0000007 17035229 t "Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity" SIGNOR-248299 CTDSP2 protein O14595 UNIPROT SMAD2 protein Q15796 UNIPROT "down-regulates activity" dephosphorylation Thr220 QSNYIPEtPPPGYIS 9606 BTO:0000007 17035229 t "Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity" SIGNOR-248296 CTDSP2 protein O14595 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates dephosphorylation 9606 16882717 t lpetrilli "In human cells, rnai-mediated depletion of scp1 and scp2 increases the extent and duration of smad1 phosphorylation in response to bmp, the transcriptional action of smad1, and the strength of endogenous bmp gene responses. The present identification of the scp family as smad c-terminal phosphatases sheds light on the events that attenuate smad signaling and reveals unexpected links to the essential phosphatases that control rna polymerase ii in eukaryotes." SIGNOR-148434 CTDSP2 protein O14595 UNIPROT SMAD1 protein Q15797 UNIPROT "down-regulates activity" dephosphorylation Ser187 NSHPFPHsPNSSYPN 9606 BTO:0000552 17085434 t "Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214)" SIGNOR-248300 CTDSP2 protein O14595 UNIPROT SMAD1 protein Q15797 UNIPROT "down-regulates activity" dephosphorylation Ser195 PNSSYPNsPGSSSST 9606 BTO:0000552 17085434 t "Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214)" SIGNOR-248301 CTDSP2 protein O14595 UNIPROT SMAD1 protein Q15797 UNIPROT "down-regulates activity" dephosphorylation Ser206 SSSTYPHsPTSSDPG 9606 BTO:0000552 17085434 t "Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214)" SIGNOR-248302 CTDSP2 protein O14595 UNIPROT SMAD1 protein Q15797 UNIPROT "down-regulates activity" dephosphorylation Ser214 PTSSDPGsPFQMPAD 9606 BTO:0000552 17085434 t "Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214)" SIGNOR-248303 AP3D1 protein O14617 UNIPROT "AP-3 complex" complex SIGNOR-C247 SIGNOR "form complex" binding 9606 21097499 t lperfetto "Key components of this system are the heterotetrameric adaptor protein (AP)4 complexes, AP-1 (gamma-beta1-mi1-sigma1), AP-2 (α-beta2-mi2-sigma2), AP-3 (delta-beta3-mi3-sigma3), and AP-4 (epsilon-beta4-mi4-sigma4) (subunit composition shown in parentheses)" SIGNOR-260683 DVL1 protein O14640 UNIPROT AXIN1 protein O15169 UNIPROT "down-regulates activity" binding 9534 BTO:0004055 SIGNOR-C110 10196136 t 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-219356 DVL1 protein O14640 UNIPROT LRP6 protein O75581 UNIPROT "up-regulates activity" binding 9606 17569865 t amattioni "The scaffold protein dishevelled (dvl) is required for lrp6 phosphorylation and aggregation. We propose that wnts induce coclustering of receptors and dvl in lrp6-signalosomes, which in turn triggers lrp6 phosphorylation to promote axin recruitment and beta-catenin stabilization." SIGNOR-156072 DVL1 protein O14640 UNIPROT JUN protein P05412 UNIPROT up-regulates binding 9606 BTO:0000007 18347071 t gcesareni "In this study, we discovered two novel interactions between dvl and c-jun and between dvl and beta-catenin in the nucleus that mediate the formation of a dvlc-junbeta-catenintcf functional complex." SIGNOR-178038 DVL1 protein O14640 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" binding 9606 15735151 t 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 DVL1 protein O14640 UNIPROT GSK3B protein P49841 UNIPROT "down-regulates activity" binding 9606 SIGNOR-C110 20837657 t gcesareni "In canonical wnt signaling, dsh phosphorylation inhibits the apcaxingsk3 complex, leading to beta-catenin stabilization." SIGNOR-167957 DVL1 protein O14640 UNIPROT RHOA protein P61586 UNIPROT "up-regulates activity" binding 9606 27571105 t areggio "Although there are other activators of PCP, Wnt5a can activate the PCP pathway by forming a complex with Fzd and Ror2 receptors, activating DVL, which in turn activates Rho-family small GTPases, including RhoA and Rac, and their downstream effectors, Rho-associated protein kinase (ROCK), the actin-binding protein, Filamin A and c-Jun N-terminal protein kinase (JNK)" SIGNOR-258971 DVL1 protein O14640 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" binding 9606 19365405 t 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 DVL1 protein O14640 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" 9606 23151663 f 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 DVL1 protein O14640 UNIPROT RND1 protein Q92730 UNIPROT up-regulates 9606 23151663 f 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-199387 DVL1 protein O14640 UNIPROT PLCB1 protein Q9NQ66 UNIPROT "up-regulates activity" 9606 19279717 t areggio "Dsh through PLC activates IP3, which leads to release of intracellular Ca2+, which in turn activates CamK11 and calcineurin" SIGNOR-258978 DVL1 protein O14640 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "down-regulates activity" binding 9606 20837657 t lperfetto "In canonical wnt signaling, dsh phosphorylation inhibits the apcaxingsk3 complex, leading to beta-catenin stabilization." SIGNOR-227914 DVL2 protein O14641 UNIPROT DVL2 protein O14641 UNIPROT "up-regulates activity" binding 9606 17529994 t amattioni "dix domain of dvl2 mediates dynamic polymerization, which is essential for the signaling activity of dvl2." SIGNOR-155224 DVL2 protein O14641 UNIPROT LRP6 protein O75581 UNIPROT "up-regulates activity" binding 9606 BTO:0000331 10196136 t amattioni "Dvl is required for lrp6 phosphorylation, which is essential for subsequent steps of signal transduction." SIGNOR-66362 DVL2 protein O14641 UNIPROT RBPJ protein Q06330 UNIPROT "down-regulates activity" binding 10029 BTO:0000457 23132247 t gcesareni "Mechanistically, Dishevelled binds and directly inhibits CSL transcription factors downstream of Notch receptors, reducing their activity. Furthermore, our data suggest that this crosstalk mechanism is conserved between vertebrate and invertebrate homologues. Thus, we identify a dual function for Dishevelled as an inhibitor of Notch signalling and an activator of the Wnt pathway that sharpens the distinction between opposing Wnt and Notch responses, allowing for robust cell-fate decisions." SIGNOR-243999 DVL2 protein O14641 UNIPROT PARD6A protein Q9NPB6 UNIPROT up-regulates binding 9606 23151663 t 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-199500 DVL2 protein O14641 UNIPROT PLCB1 protein Q9NQ66 UNIPROT "up-regulates activity" 9606 19279717 t areggio "Dsh through PLC activates IP3, which leads to release of intracellular Ca2+, which in turn activates CamK11 and calcineurin" SIGNOR-258979 CHD1 protein O14646 UNIPROT SF3a complex SIGNOR-C345 SIGNOR "up-regulates activity" binding 9606 BTO:0000567 18042460 t miannu "CHD1 was found to bridge core spliceosomal components to H3K4me3 via specific interactions with the SF3a sub-complex of U2 snRNP. The recruitment of SF3a and the efficiency of pre-mRNA splicing were perturbed upon reduction of CHD1 and H3K4me3." SIGNOR-263951 CHD2 protein O14647 UNIPROT H3-3A protein P84243 UNIPROT "up-regulates quantity" relocalization 9606 BTO:0001938 26895424 t miannu "Non-homologous end-joining (NHEJ) is the dominant DSB repair pathway in human cells, but our understanding of how it operates in chromatin is limited. Here, we define a mechanism that plays a crucial role in regulating NHEJ in chromatin. This mechanism is initiated by DNA damage-associated poly(ADP-ribose) polymerase 1 (PARP1), which recruits the chromatin remodeler CHD2 through a poly(ADP-ribose)-binding domain. CHD2 in turn triggers rapid chromatin expansion and the deposition of histone variant H3.3 at sites of DNA damage." SIGNOR-264527 APAF1 protein O14727 UNIPROT CASP9 protein P55211 UNIPROT "up-regulates activity" binding 9606 15829969 t lperfetto "During apoptosis, Apaf-1 binds to cytochrome c and in the presence of ATP/dATP forms an apoptosome, leading to the recruitment and activation of the initiator caspase, caspase-9 ." SIGNOR-135381 TOR1A protein O14656 UNIPROT SNAPIN protein O95295 UNIPROT "up-regulates activity" binding 9606 BTO:0000793 18167355 t Monia "In the present study, we used yeast two-hybrid analysis to identify a new binding partner of torsinA, the SNARE-associated protein snapin. We have reported that snapin shows a robust interaction with wild type and mutant torsinA. we have demonstrated that this portion of torsinA and/or the adjacent linker region has the additional role of recruiting snapin. we found that snapin, which binds SNAP-25 (synaptosome-associated protein of 25,000 Da) and enhances the association of the SNARE complex with synaptotagmin, is an interacting partner for both wild type and mutant torsinA." SIGNOR-261170 STX16 protein O14662 UNIPROT "LE-TGN SNARE" complex SIGNOR-C157 SIGNOR "form complex" binding 9606 BTO:0000567 18195106 t lperfetto "We show in human cells that a soluble NSF attachment protein receptor (SNARE) complex comprised of syntaxin 10 (STX10), STX16, Vti1a, and VAMP3 is required for this MPR transport" SIGNOR-253079 ADAM10 protein O14672 UNIPROT EGF protein P01133 UNIPROT "up-regulates activity" cleavage 9606 26284334 t miannu "Like ADAM17, ADAM10 has also been implicated in the activation of specific EGFR ligands, especially EGF and betacellulin" SIGNOR-259840 ADAM10 protein O14672 UNIPROT ERBB2 protein P04626 UNIPROT "up-regulates activity" cleavage 9606 26284334 t miannu "The ADAM proteases are best known for their role in shedding the extracellular domain of transmembrane proteins. Among the transmembrane proteins shed by ADAM10 are notch, HER2, E-cadherin, CD44, L1 and the EGFR ligands, EGF and betacellulin." SIGNOR-259845 ADAM10 protein O14672 UNIPROT CDH1 protein P12830 UNIPROT "up-regulates activity" cleavage 9606 26284334 t miannu "The ADAM proteases are best known for their role in shedding the extracellular domain of transmembrane proteins. Among the transmembrane proteins shed by ADAM10 are notch, HER2, E-cadherin, CD44, L1 and the EGFR ligands, EGF and betacellulin." SIGNOR-259846 ITGB1BP1 protein O14713 UNIPROT "A3/b1 integrin" complex SIGNOR-C161 SIGNOR "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257641 ITGB1BP1 protein O14713 UNIPROT "A4/b1 integrin" complex SIGNOR-C162 SIGNOR "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257642 ITGB1BP1 protein O14713 UNIPROT "A5/b1 integrin" complex SIGNOR-C163 SIGNOR "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257643 ITGB1BP1 protein O14713 UNIPROT "A6/b1 integrin" complex SIGNOR-C164 SIGNOR "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257644 ITGB1BP1 protein O14713 UNIPROT "A8/b1 integrin" complex SIGNOR-C165 SIGNOR "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257645 ITGB1BP1 protein O14713 UNIPROT "A9/b1 integrin" complex SIGNOR-C166 SIGNOR "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257646 ITGB1BP1 protein O14713 UNIPROT "A11/b1 integrin" complex SIGNOR-C168 SIGNOR "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257648 ITGB1BP1 protein O14713 UNIPROT "AL/b2 integrin" complex SIGNOR-C169 SIGNOR "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257650 ITGB1BP1 protein O14713 UNIPROT "AM/b2 integrin" complex SIGNOR-C170 SIGNOR "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257651 ITGB1BP1 protein O14713 UNIPROT "AX/b2 integrin" complex SIGNOR-C171 SIGNOR "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257652 ITGB1BP1 protein O14713 UNIPROT "AD/b2 integrin" complex SIGNOR-C172 SIGNOR "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257654 ITGB1BP1 protein O14713 UNIPROT "AIIB/b3 integrin" complex SIGNOR-C173 SIGNOR "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257655 ITGB1BP1 protein O14713 UNIPROT "A4/b7 integrin" complex SIGNOR-C187 SIGNOR "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257666 APAF1 protein O14727 UNIPROT CASP9 protein P55211 UNIPROT up-regulates binding 9606 9390557 t gcesareni "During apoptosis, apaf-1 binds to cytochrome c and in the presence of atp/datp forms an apoptosome, leading to the recruitment and activation of the initiator caspase, caspase-9 .in particular, caspase-9 is recruited and activated by apaf-1 .casp9 and apaf-1 bind to each other via their respective nh2-terminal ced-3 homologous domains in the presence of cycs and datp, an event that leads to casp9 activation." SIGNOR-53579 APAF1 protein O14727 UNIPROT CASP9 protein P55211 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 9390557 t lperfetto "Caspase-9 and Apaf-1 bind to each other via their respective NH2-terminal CED-3 homologous domains in the presence of cytochrome c and dATP, an event that leads to caspase-9 activation." SIGNOR-53576 APAF1 protein O14727 UNIPROT Apoptosome complex SIGNOR-C230 SIGNOR "form complex" binding -1 10206961 t lperfetto " APAF-1 binds and hydrolyzes ATP or dATP to ADP or dADP, respectively. The hydrolysis of ATP/dATP and the binding of cytochrome c promote APAF-1 oligomerization, forming a large multimeric APAF-1.cytochrome c complex. Such a complex can be isolated using gel filtration chromatography and is by itself sufficient to recruit and activate procaspase-9. " SIGNOR-256431 RIOK3 protein O14730 UNIPROT IFIH1 protein Q9BYX4 UNIPROT "down-regulates activity" phosphorylation Ser828 GRARADEsTYVLVAH 9606 BTO:0000007 25865883 t lperfetto "RIOK3 mediates phosphorylation of MDA5 Ser-828|RIOK3-mediated phosphorylation of MDA5 interferes with its assembly and attenuates the innate immune response" SIGNOR-264576 MAP2K7 protein O14733 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser312 TESITATsPASMVGG 9606 BTO:0000975 17360977 t lperfetto "Tyrosine phosphorylation of IRS-1 initiates insulin signaling, whereas serine/threonine phosphorylation alters the ability of IRS-1 to transduce the insulin signalInsulin increased the phosphorylation of Ser312, Ser616, Ser636, Ser892, Ser1101, and Ser1223 Ser312 can be phosphorylated by kinases, such as c-jun NH2-terminal kinase and inhibitor of _B kinase" SIGNOR-217920 MAP2K7 protein O14733 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates phosphorylation Thr183 AGTSFMMtPYVVTRY 9606 11062067 t amattioni "Jnk full activation requires the phosphorylation of a threonine and a tyrosine residue in a thr-pro-tyr motif, which can be catalysed by the protein kinases mitogen-activated protein kinase kinase (mkk)4 and mkk7. Mkk7 shows a striking preference for the threonine residue (thr-183)." SIGNOR-83736 MAP2K7 protein O14733 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates phosphorylation Thr183 AGTSFMMtPYVVTRY 9606 9312068 t gcesareni "Jnk is activated by jnk-activating kinase 1 (jnkk1), a dual specificity protein kinase that phosphorylates jnk on threonine 183 and tyrosine 185 residues." SIGNOR-51199 MAP2K7 protein O14733 UNIPROT MAPK9 protein P45984 UNIPROT "up-regulates activity" phosphorylation Ser407 STEQTLAsDTDSSLD -1 11062067 t "MKK7 also phosphorylates JNK2 alpha 2 at Thr-404 and Ser-407 in vitro. Stress-activated protein kinase 1 (SAPK1), also called c-Jun N-terminal kinase (JNK), becomes activated in vivo in response to pro-inflammatory cytokines or cellular stresses. Its full activation requires the phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif, which can be catalysed by the protein kinases mitogen-activated protein kinase kinase (MKK)4 and MKK7." SIGNOR-251416 MAP2K7 protein O14733 UNIPROT MAPK9 protein P45984 UNIPROT "up-regulates activity" phosphorylation Thr183 ACTNFMMtPYVVTRY -1 11062067 t "MKK7 phosphorylates SAPK2a p38 exclusively at Tyr-182. Stress-activated protein kinase 1 (SAPK1), also called c-Jun N-terminal kinase (JNK), becomes activated in vivo in response to pro-inflammatory cytokines or cellular stresses. Its full activation requires the phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif, which can be catalysed by the protein kinases mitogen-activated protein kinase kinase (MKK)4 and MKK7." SIGNOR-251417 MAP2K7 protein O14733 UNIPROT MAPK9 protein P45984 UNIPROT "up-regulates activity" phosphorylation Thr404 SSMSTEQtLASDTDS -1 11062067 t "MKK7 also phosphorylates JNK2 alpha 2 at Thr-404 and Ser-407 in vitro. Stress-activated protein kinase 1 (SAPK1), also called c-Jun N-terminal kinase (JNK), becomes activated in vivo in response to pro-inflammatory cytokines or cellular stresses. Its full activation requires the phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif, which can be catalysed by the protein kinases mitogen-activated protein kinase kinase (MKK)4 and MKK7." SIGNOR-251418 MAP2K7 protein O14733 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates phosphorylation 9606 11062067 t "Phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif" gcesareni "Here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1)these results indicate that hgk, a novel activator of the jnk pathway, may function through tak1, and that the hgk --> tak1 --> mkk4, mkk7 --> jnk kinase cascade may mediate the TNF-alphalpha signaling pathway." SIGNOR-83732 MAP2K7 protein O14733 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates phosphorylation Thr221 AGTSFMMtPYVVTRY 9606 15911620 t lperfetto "Two mapkks, sek1 and mkk7, synergistically activate jnk. Sek1 prefers the tyr-185 residue, and mkk7 prefers the thr-183 residue (17, 19)." SIGNOR-137609 MAP2K7 protein O14733 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates phosphorylation 9606 BTO:0000007 9890973 t "Phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif" gcesareni "Here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1)these results indicate that hgk, a novel activator of the jnk pathway, may function through tak1, and that the hgk --> tak1 --> mkk4, mkk7 --> jnk kinase cascade may mediate the TNF-alphalpha signaling pathway." SIGNOR-63972 MAP2K7 protein O14733 UNIPROT MAPK10 protein P53779 UNIPROT "up-regulates activity" phosphorylation Thr221 AGTSFMMtPYVVTRY -1 10715136 t "Activation of JNK3 alpha 1 requires both MKK4 and MKK7. both MKK4 and MKK7 were required for bisphosphorylation and maximal enzyme activity. a processive mechanism for JNK3R1 activation that requires phosphorylation of Thr 221 by MKK7 prior to phosphorylation of Tyr 223 by MKK4" SIGNOR-251422 MAP2K7 protein O14733 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR "up-regulates activity" phosphorylation 9606 11062067 t lperfetto "Here we report that MKK4 shows a striking preference for the tyrosine residue (Tyr-185), and MKK7 a striking preference for the threonine residue (Thr-183) in three SAPK1/JNK1 isoforms tested (JNK1 alpha 1, JNK2 alpha 2 and JNK3 alpha 1)." SIGNOR-83725 PRMT5 protein O14744 UNIPROT HOXA9 protein P31269 UNIPROT "up-regulates activity" methylation Arg140 KPEPLSArRGDCPTL 9606 BTO:0000007 22269951 t lperfetto "Hoxa9 methylation by prmt5 is essential for endothelial cell expression of leukocyte adhesion molecules. / prmt5 is a critical coactivator component in a newly defined, hoxa9-containing transcription complex./ Hoxa9 is methylated on arg140 by prmt5." SIGNOR-195526 SLC9A3R1 protein O14745 UNIPROT ADRB2 protein P07550 UNIPROT "up-regulates activity" binding -1 9671706 t lperfetto "The Na+/H+ exchanger regulatory factor (NHERF) binds to the tail of the beta2-adrenergic receptor and plays a role in adrenergic regulation of Na+/H+ exchange. NHERF contains two PDZ domains, the first of which is required for its interaction with the beta2 receptor." SIGNOR-262598 CHEK1 protein O14757 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" phosphorylation Ser366 PGGSRAHsSHLKSKK 9606 BTO:0001321 15659650 t lperfetto "Phosphorylation by chk1 of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage." SIGNOR-217853 CHEK1 protein O14757 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "down-regulates activity" 9606 28138032 f miannu "Mechanistically, Ras-MEK signaling drives Chk1 expression and promotes cancer cell growth that produces genotoxic stress that requires Chk1 to mediate a response to the consequent DNA damage. Reciprocally, Chk1 engages a negative feedback loop to prevent hyperactivation of Ras-MEK signaling, thereby limiting DNA damage. Ras–MEK signaling transcriptionally activates Chk1, which appears to sustain cancer cell growth by maintaining DNA damage levels below a threshold that would otherwise drive apoptosis." SIGNOR-263059 TNFRSF10B protein O14763 UNIPROT FADD protein Q13158 UNIPROT up-regulates binding 9606 14585074 t amattioni "Fadd binds to ligated trailr1 or trail-r2" SIGNOR-98565 GABRD protein O14764 UNIPROT "GABA-A (a4-b2-d) receptor" complex SIGNOR-C326 SIGNOR "form complex" binding 9606 BTO:0000227 18790874 t "brain, See table 3 for identified complexes" lperfetto "The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon." SIGNOR-263746 GABRD protein O14764 UNIPROT "GABA-A (a4-b3-d) receptor" complex SIGNOR-C327 SIGNOR "form complex" binding 9606 BTO:0000227 18790874 t "brain, See table 3 for identified complexes" lperfetto "The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon." SIGNOR-263749 GABRD protein O14764 UNIPROT "GABA-A (a6-b2-d) receptor" complex SIGNOR-C328 SIGNOR "form complex" binding 9606 BTO:0000227 18790874 t "brain, See table 3 for identified complexes" lperfetto "The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon." SIGNOR-263770 GABRD protein O14764 UNIPROT "GABA-A (a6-b3-d) receptor" complex SIGNOR-C329 SIGNOR "form complex" binding 9606 BTO:0000227 18790874 t "brain, See table 3 for identified complexes" lperfetto "The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon." SIGNOR-263773 GNB5 protein O14775 UNIPROT ADCY5 protein O95622 UNIPROT "down-regulates activity" binding 9606 BTO:0004032 21303898 t miannu "The D2-class dopamine receptors (D2, D3, and D4) couple to the Gi/o family of G proteins and thus induce inhibition of AC" SIGNOR-264998 GNB5 protein O14775 UNIPROT ADCY1 protein Q08828 UNIPROT "down-regulates activity" binding 9606 BTO:0004032 21303898 t miannu "The D2-class dopamine receptors (D2, D3, and D4) couple to the Gi/o family of G proteins and thus induce inhibition of AC" SIGNOR-264996 NDC80 protein O14777 UNIPROT "Ndc80 complex" complex SIGNOR-C361 SIGNOR "form complex" binding 27881301 t lperfetto "Kinetochores, multisubunit protein assemblies, connect chromosomes to spindle microtubules to promote chromosome segregation. The 10-subunit KMN assembly (comprising KNL1, MIS12, and NDC80 complexes, designated KNL1C, MIS12C, and NDC80C) binds microtubules and regulates mitotic checkpoint function through NDC80C and KNL1C, respectively. |NDC80C contains the NDC80, NUF2, SPC24, and SPC25 subunits" SIGNOR-265188 NRP1 protein O14786 UNIPROT PHACTR1 protein Q9C0D0 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21939755 f miannu "Recently, we identified a new Vascular Endothelial Growth Factor (VEGF)-A(165)-induced gene Phactr-1, (Phosphatase Actin Regulator-1). We found that neuropilin-1 (NRP-1) and VEGF-R1 depletion inhibited Phactr-1 mRNA expression while NRP-2 and VEGF-R2 depletion had no effect." SIGNOR-260061 TNFSF11 protein O14788 UNIPROT TNFRSF11B protein O00300 UNIPROT up-regulates binding 9606 11733492 t gcesareni "Receptor activator of nf-kappa b ligand (rankl, also known as odf and opgl), a member of the tumor necrosis factor (tnf) family, triggers osteoclastogenesis by forming a complex with its receptor, rank." SIGNOR-112539 TNFSF11 protein O14788 UNIPROT TNFRSF11A protein Q9Y6Q6 UNIPROT "up-regulates activity" binding 9606 12897775 t miannu "RANKL, a member of the tumour necrosis factor superfamily, is most abundantly expressed as a cell-surface protein by bone-marrow stromal cells. It interacts with its receptor RANK (which is encoded by Tnfrsf11a) on macrophages and mature osteoclasts." SIGNOR-253042 MSTN protein O14793 UNIPROT ACVR2B protein Q13705 UNIPROT "up-regulates activity" binding 10090 11459935 t 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 MSTN protein O14793 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" 9606 19357233 f miannu "In the current study, it was demonstrated that myostatin inhibits activation of Akt, in both myoblasts and myotubes." SIGNOR-255339 TNFRSF10C protein O14798 UNIPROT TNFSF10 protein P50591 UNIPROT down-regulates binding 9606 BTO:0000671 20103630 t amattioni "Albeit on binding the ligand, dcr1 and dcr2 do not transduce the apoptogenic signal," SIGNOR-163611 POLR3A protein O14802 UNIPROT "RNA Polymerase III" complex SIGNOR-C389 SIGNOR "form complex" binding 9606 BTO:0000567 12391170 t lperfetto "In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights." SIGNOR-266133 PSMA7 protein O14818 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "form complex" binding 9606 BTO:0000007 29636472 t lperfetto "Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line" SIGNOR-263365 FFAR1 protein O14842 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257338 FFAR1 protein O14842 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256799 FFAR3 protein O14843 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256678 FFAR3 protein O14843 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256957 WNT9A protein O14904 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 15578921 t 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-132076 WNT9A protein O14904 UNIPROT CHRNA1 protein P02708 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000887 22309736 t gcesareni "We identified five wnts (wnt9a, wnt9b, wnt10b, wnt11, and wnt16) that are able to stimulate achr clustering, of which wnt9a and wnt11 are expressed abundantly in developing muscles." SIGNOR-195972 WNT9A protein O14904 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 t 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-132070 WNT9B protein O14905 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15578921 t 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-132114 WNT9B protein O14905 UNIPROT CHRNA1 protein P02708 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000887 22309736 t gcesareni "We identified five wnts (wnt9a, wnt9b, wnt10b, wnt11, and wnt16) that are able to stimulate achr clustering, of which wnt9a and wnt11 are expressed abundantly in developing muscles." SIGNOR-195978 WNT9B protein O14905 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 t 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-132111 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT "down-regulates activity" phosphorylation Ser689 SQPGQLMsQPSTASN 9606 BTO:0000007 10195894 t "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-251279 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT "down-regulates activity" phosphorylation Ser692 GQLMSQPsTASNSLP 9606 BTO:0000007 10195894 t "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-251280 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT "down-regulates activity" phosphorylation Ser705 LPEPAKKsEELVAEA 9606 BTO:0000007 10195894 t "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-251283 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT "down-regulates activity" phosphorylation Ser733 TVREQDQsFTALDWS 9606 BTO:0000007;BTO:0000567 SIGNOR-C14 SIGNOR-C14 10195894 t 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-66344 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT "down-regulates activity" phosphorylation Ser740 SFTALDWsWLQTEEE 9606 BTO:0000567 SIGNOR-C14 SIGNOR-C14 10195894 t 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-236048 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT "down-regulates activity" phosphorylation Ser750 QTEEEEHsCLEQAS 9606 BTO:0000007;BTO:0000567 SIGNOR-C14 SIGNOR-C14 10195894 t 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-66352 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT "down-regulates activity" phosphorylation Ser756 HSCLEQAs 9606 BTO:0000007 10195894 t "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-251284 IKBKB protein O14920 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 BTO:0000150 15084260 t gcesareni "Ikkbeta phosphorylates foxo3a at ser644. Ikappab kinase (ikk) physically interacts with, phosphorylates, and inhibits foxo3a independent of akt and causes proteolysis of foxo3a via the ub-dependent proteasome pathway" SIGNOR-124207 IKBKB protein O14920 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni "Ikkbeta phosphorylates foxo3a at ser644. Ikappab kinase (ikk) physically interacts with, phosphorylates, and inhibits foxo3a independent of akt and causes proteolysis of foxo3a via the ub-dependent proteasome pathway" SIGNOR-183684 IKBKB protein O14920 UNIPROT NFKB1 protein P19838 UNIPROT "down-regulates activity" phosphorylation Ser923 DELRDSDsVCDSGVE 9606 BTO:0000007 SIGNOR-C13 11158290 t lperfetto "Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway." SIGNOR-104803 IKBKB protein O14920 UNIPROT NFKB1 protein P19838 UNIPROT "down-regulates activity" phosphorylation Ser927 DSDSVCDsGVETSFR 9606 BTO:0000007 SIGNOR-C13 11158290 t lperfetto "Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway." SIGNOR-104807 IKBKB protein O14920 UNIPROT NFKB1 protein P19838 UNIPROT "down-regulates activity" phosphorylation Ser932 CDSGVETsFRKLSFT 9606 BTO:0000007 SIGNOR-C13 11158290 t lperfetto "Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway." SIGNOR-104811 IKBKB protein O14920 UNIPROT NFKB1 protein P19838 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser923 DELRDSDsVCDSGVE 9606 BTO:0000459 SIGNOR-C13 10469655 t lperfetto "Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway." SIGNOR-70465 IKBKB protein O14920 UNIPROT NFKB1 protein P19838 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser927 DSDSVCDsGVETSFR 9606 BTO:0000459 SIGNOR-C13 10469655 t lperfetto "Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway." SIGNOR-70469 IKBKB protein O14920 UNIPROT NFKB1 protein P19838 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser932 CDSGVETsFRKLSFT 9606 BTO:0000459 SIGNOR-C13 10469655 t lperfetto "Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway." SIGNOR-70473 IKBKB protein O14920 UNIPROT COMT protein P21964 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000100 19291302 f "Regulation of expression" miannu "TNFα-dependent COMT downregulation was indeed mediated by the NF-κB pathway. Transient expression of p65, the essential component of NF-κB complexes, or IKKβ, the major positive regulator of NF-κB activition, significantly decreased P2-COMT reporter expression." SIGNOR-251965 IKBKB protein O14920 UNIPROT NFKBIA protein P25963 UNIPROT "down-regulates activity" phosphorylation 10090 BTO:0002572;BTO:0000801 SIGNOR-C14 21232017 t 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-235400 IKBKB protein O14920 UNIPROT NFKBIA protein P25963 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser32 LLDDRHDsGLDSMKD 11815618 t lperfetto "Nuclear factor-kappaB activation depends on phosphorylation and degradation of its inhibitor protein, IkapapB. The phosphorylation of I_Balpha on Ser32 and Ser36 is initiated by an IkapapB kinase (IKK) complex that includes a catalytic heterodimer composed of I_B kinase 1 (IKK-1) and IkapapB kinase 2 (IKK-2) as well as a regulatory adaptor subunit, NF-kappaB essential modulator." SIGNOR-249365 IKBKB protein O14920 UNIPROT NFKBIA protein P25963 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser36 RHDSGLDsMKDEEYE 11815618 t lperfetto "Nuclear factor-kappaB activation depends on phosphorylation and degradation of its inhibitor protein, IkapapB. The phosphorylation of I_Balpha on Ser32 and Ser36 is initiated by an IkapapB kinase (IKK) complex that includes a catalytic heterodimer composed of I_B kinase 1 (IKK-1) and IkapapB kinase 2 (IKK-2) as well as a regulatory adaptor subunit, NF-kappaB essential modulator." SIGNOR-249366 IKBKB protein O14920 UNIPROT YWHAB protein P31946 UNIPROT down-regulates phosphorylation Ser132 GDYFRYLsEVASGDN 9606 16024783 t gcesareni "We provide a mechanism for these observations through the phosphorylation of 14-3-3beta by ikkbeta and pkcdelta on serine residues ser132 and ser60, respectively, which interferes with its binding to ttp and hence the retention of ttp in the cytoplasm." SIGNOR-138608 IKBKB protein O14920 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser268 SDEFRPRsKSQSSSN -1 12351658 t "IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways." SIGNOR-251288 IKBKB protein O14920 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser270 EFRPRSKsQSSSNCS -1 12351658 t "IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways." SIGNOR-251289 IKBKB protein O14920 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser272 RPRSKSQsSSNCSNP -1 12351658 t "IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways." SIGNOR-251290 IKBKB protein O14920 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser312 TESITATsPASMVGG -1 12351658 t "IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways." SIGNOR-251293 IKBKB protein O14920 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser341 GTMSRPAsVDGSPVS -1 12351658 t "IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways." SIGNOR-251294 IKBKB protein O14920 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser345 RPASVDGsPVSPSTN -1 12351658 t "IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways." SIGNOR-251295 IKBKB protein O14920 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser527 RFRKRTHsAGTSPTI -1 12351658 t "IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways." SIGNOR-251296 IKBKB protein O14920 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser531 RTHSAGTsPTITHQK -1 12351658 t "IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways." SIGNOR-251297 IKBKB protein O14920 UNIPROT RELA protein Q04206 UNIPROT "up-regulates activity" phosphorylation Ser536 SGDEDFSsIADMDFS 9606 BTO:0000007 SIGNOR-C13 15489227 t 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-129935 IKBKB protein O14920 UNIPROT RELA protein Q04206 UNIPROT "up-regulates activity" phosphorylation Ser468 AVFTDLAsVDNSEFQ 9606 BTO:0000150;BTO:0000782 SIGNOR-C13 16046471 t lperfetto "Rela is phosphorylated at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k). We now present evidence that suggests that the upstream kinase ikkbeta plays an important role in tax-induced p53 inhibition through phosphorylation of p65/rela at ser-536. Ikkbeta plays an important role in tax-induced p53 inhibition through phosphorylation of p65/rela at ser-536." SIGNOR-138903 IKBKB protein O14920 UNIPROT TSC1 protein Q92574 UNIPROT down-regulates phosphorylation Ser487 AAISRELsEITTAEA 9606 BTO:0000150 17693255 t gcesareni "Here we show that ikkbeta, a major downstream kinase in the tnfalpha signaling pathway, physically interacts with and phosphorylates tsc1 at ser487 and ser511, resulting in suppression of tsc1phosphorylation of tsc2 (by akt and erk;refs. 28, 29) and tsc1(by ikkbeta;ref. 30) results in the disruption of the tsc1/2 complex, and thereby activates the oncogenic mtor signaling contributing to tumor progression." SIGNOR-157296 IKBKB protein O14920 UNIPROT TSC1 protein Q92574 UNIPROT down-regulates phosphorylation Ser511 DSPFYRDsLPGSQRK 9606 BTO:0000150 17693255 t gcesareni "Here we show that ikkbeta, a major downstream kinase in the tnfalpha signaling pathway, physically interacts with and phosphorylates tsc1 at ser487 and ser511, resulting in suppression of tsc1phosphorylation of tsc2 (by akt and erk;refs. 28, 29) and tsc1(by ikkbeta;ref. 30) results in the disruption of the tsc1/2 complex, and thereby activates the oncogenic mtor signaling contributing to tumor progression." SIGNOR-157300 IKBKB protein O14920 UNIPROT TSC1 protein Q92574 UNIPROT down-regulates phosphorylation Ser487 AAISRELsEITTAEA 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni "Here we show that ikkbeta, a major downstream kinase in the tnfalpha signaling pathway, physically interacts with and phosphorylates tsc1 at ser487 and ser511, resulting in suppression of tsc1phosphorylation of tsc2 (by akt and erk;refs. 28, 29) and tsc1(by ikkbeta;ref. 30) results in the disruption of the tsc1/2 complex, and thereby activates the oncogenic mtor signaling contributing to tumor progression." SIGNOR-183688 IKBKB protein O14920 UNIPROT TSC1 protein Q92574 UNIPROT down-regulates phosphorylation Ser511 DSPFYRDsLPGSQRK 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni "Here we show that ikkbeta, a major downstream kinase in the tnfalpha signaling pathway, physically interacts with and phosphorylates tsc1 at ser487 and ser511, resulting in suppression of tsc1phosphorylation of tsc2 (by akt and erk;refs. 28, 29) and tsc1(by ikkbeta;ref. 30) results in the disruption of the tsc1/2 complex, and thereby activates the oncogenic mtor signaling contributing to tumor progression." SIGNOR-183692 IKBKB protein O14920 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C14 23332762 t gcesareni "Ikk phosphorylates bad at serine-26 (ser26) and primes it for inactivation." SIGNOR-192614 IKBKB protein O14920 UNIPROT DOK1 protein Q99704 UNIPROT up-regulates phosphorylation Ser439 EPGTATGsGIKSHNS 9606 15574499 t amattioni "Ikkbeta phosphorylates dok1 s(439)s(443) and s(446)s(450) after tnf-alpha, il-1, or gamma-radiation. mutant dok1 a(439), a(443), a(446), and a(450) differed from wild-type dok1 in not inhibiting platelet-derived growth factor-induced extracellular signal-regulated kinase 1/2 phosphorylation or cell growth. Mutant dok1 a(439), a(443), a(446), and a(450) also did not promote cell motility whereas wild-type dok1 promoted cell motility." SIGNOR-131447 IKBKB protein O14920 UNIPROT DOK1 protein Q99704 UNIPROT up-regulates phosphorylation Ser443 ATGSGIKsHNSALYS 9606 15574499 t amattioni "Ikkbeta phosphorylates dok1 s(439)s(443) and s(446)s(450) after tnf-alpha, il-1, or gamma-radiation. mutant dok1 a(439), a(443), a(446), and a(450) differed from wild-type dok1 in not inhibiting platelet-derived growth factor-induced extracellular signal-regulated kinase 1/2 phosphorylation or cell growth. Mutant dok1 a(439), a(443), a(446), and a(450) also did not promote cell motility whereas wild-type dok1 promoted cell motility." SIGNOR-131451 IKBKB protein O14920 UNIPROT DOK1 protein Q99704 UNIPROT up-regulates phosphorylation Ser446 SGIKSHNsALYSQVQ 9606 15574499 t amattioni "Ikkbeta phosphorylates dok1 s(439)s(443) and s(446)s(450) after tnf-alpha, il-1, or gamma-radiation. mutant dok1 a(439), a(443), a(446), and a(450) differed from wild-type dok1 in not inhibiting platelet-derived growth factor-induced extracellular signal-regulated kinase 1/2 phosphorylation or cell growth. Mutant dok1 a(439), a(443), a(446), and a(450) also did not promote cell motility whereas wild-type dok1 promoted cell motility." SIGNOR-131455 IKBKB protein O14920 UNIPROT DOK1 protein Q99704 UNIPROT up-regulates phosphorylation Ser450 SHNSALYsQVQKSGA 9606 15574499 t amattioni "Ikkbeta phosphorylates dok1 s(439)s(443) and s(446)s(450) after tnf-alpha, il-1, or gamma-radiation. mutant dok1 a(439), a(443), a(446), and a(450) differed from wild-type dok1 in not inhibiting platelet-derived growth factor-induced extracellular signal-regulated kinase 1/2 phosphorylation or cell growth. Mutant dok1 a(439), a(443), a(446), and a(450) also did not promote cell motility whereas wild-type dok1 promoted cell motility." SIGNOR-131556 IKBKB protein O14920 UNIPROT CYLD protein Q9NQC7 UNIPROT "down-regulates activity" phosphorylation Ser418 TTENRFHsLPFSLTK 9606 BTO:0000661 15870263 t gianni "In response to cellular stimuli, CYLD undergoes rapid and transient phosphorylation, which is required for signal-induced TRAF2 ubiquitination and activation of downstream signaling events. Interestingly, the CYLD phosphorylation requires IkappaB kinase gamma (IKKgamma) and can be induced by IKK catalytic subunits." SIGNOR-266436 IKBKB protein O14920 UNIPROT CYLD protein Q9NQC7 UNIPROT "down-regulates activity" phosphorylation Ser418 TTENRFHsLPFSLTK 9606 BTO:0000938 24614225 t lperfetto "Thus, serine 418 is phosphorylated in vivo.Cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity." SIGNOR-204716 IKBKB protein O14920 UNIPROT CYLD protein Q9NQC7 UNIPROT "down-regulates activity" phosphorylation Ser432 KMPNTNGsIGHSPLS 9606 BTO:0000938 24614225 t lperfetto "The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity." SIGNOR-204724 ERBB2 protein P04626 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates binding 9606 1676673 t gcesareni "Activated egfr binds the sh2 domain of phospholipase c-gamma (plc-gamma), activating plc-gamma-mediated downstream signaling." SIGNOR-20815 IKBKB protein O14920 UNIPROT CYLD protein Q9NQC7 UNIPROT "down-regulates activity" phosphorylation Ser439 SIGHSPLsLSAQSVM 9606 BTO:0000938 24614225 t lperfetto "The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity." SIGNOR-204732 IKBKB protein O14920 UNIPROT CYLD protein Q9NQC7 UNIPROT "up-regulates activity" phosphorylation Ser422 RFHSLPFsLTKMPNT 9606 BTO:0000938 24614225 t lperfetto "The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity." SIGNOR-204720 IKBKB protein O14920 UNIPROT IKBKG protein Q9Y6K9 UNIPROT "down-regulates activity" phosphorylation Ser68 LRDAIRQsNQILRER 9606 SIGNOR-C14 SIGNOR-C14 17977820 t lperfetto "In this study we analyze the ikkbeta-mediated phosphorylation of the ikk-binding domain of nemo. In vitro, ikkbeta phosphorylates three serine residues in the domain of nemo at positions 43, 68, and 85. However, mutational analysis revealed that only the phosphorylation of serine 68 in the center of the ikk-binding domain plays an essential role for the formation and the function of the ikk complex. Thus, ser(68) phosphorylation attenuates the amino-terminal dimerization of nemo as well as the ikkbeta-nemo interaction. I" SIGNOR-158659 IKBKB protein O14920 UNIPROT IKBKG protein Q9Y6K9 UNIPROT "down-regulates activity" phosphorylation Ser85 ELLHFQAsQREEKEF 9606 SIGNOR-C14 SIGNOR-C14 17977820 t lperfetto "In this study we analyze the ikkbeta-mediated phosphorylation of the ikk-binding domain of nemo. In vitro, ikkbeta phosphorylates three serine residues in the domain of nemo at positions 43, 68, and 85. However, mutational analysis revealed that only the phosphorylation of serine 68 in the center of the ikk-binding domain plays an essential role for the formation and the function of the ikk complex. Thus, ser(68) phosphorylation attenuates the amino-terminal dimerization of nemo as well as the ikkbeta-nemo interaction. I" SIGNOR-158663 IKBKB protein O14920 UNIPROT IKBKG protein Q9Y6K9 UNIPROT unknown phosphorylation Ser31 QDVLGEEsPLGKPAM 9606 SIGNOR-C14 SIGNOR-C14 12657630 t "IKKbeta phosphorylates human IKKgamma at Ser-31, Ser-43, and Ser-376. IKK≈í‚⧠mediates IKK≈í‚â• phosphorylation under physiologic signaling conditions. IKK≈í‚â• is chronically phosphorylated in cells expressing the HTLV1 Tax oncoprotein, which interfaces directly with the I≈í‚à´B kinase complex.both Tax and TNF induce phosphorylation of human IKK≈í‚â• at Ser-31, Ser-43, and Ser-376." SIGNOR-251285 IKBKB protein O14920 UNIPROT IKBKG protein Q9Y6K9 UNIPROT unknown phosphorylation Ser376 PPAPAYLsSPLALPS 9606 SIGNOR-C14 SIGNOR-C14 12657630 t "IKKbeta phosphorylates human IKKgamma at Ser-31, Ser-43, and Ser-376. IKK≈í‚⧠mediates IKK≈í‚â• phosphorylation under physiologic signaling conditions. IKK≈í‚â• is chronically phosphorylated in cells expressing the HTLV1 Tax oncoprotein, which interfaces directly with the I≈í‚à´B kinase complex.both Tax and TNF induce phosphorylation of human IKK≈í‚â• at Ser-31, Ser-43, and Ser-376." SIGNOR-251286 IKBKB protein O14920 UNIPROT IKBKG protein Q9Y6K9 UNIPROT unknown phosphorylation Ser43 PAMLHLPsEQGAPET 9606 SIGNOR-C14 12657630 t "IKKbeta phosphorylates human IKKgamma at Ser-31, Ser-43, and Ser-376|Thus far, we have no compelling evidence that inducible phosphorylation of these IKKgamma domains is important for their assigned functions." SIGNOR-251287 IKBKB protein O14920 UNIPROT IKBKG protein Q9Y6K9 UNIPROT unknown phosphorylation Ser43 PAMLHLPsEQGAPET 9606 SIGNOR-C14 SIGNOR-C14 17977820 t lperfetto "In this study we analyze the ikkbeta-mediated phosphorylation of the ikk-binding domain of nemo. In vitro, ikkbeta phosphorylates three serine residues in the domain of nemo at positions 43, 68, and 85. However, mutational analysis revealed that only the phosphorylation of serine 68 in the center of the ikk-binding domain plays an essential role for the formation and the function of the ikk complex. Thus, ser(68) phosphorylation attenuates the amino-terminal dimerization of nemo as well as the ikkbeta-nemo interaction." SIGNOR-158655 IKBKB protein O14920 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000567 11971985 t "We demonstrated the in vitro phosphorylation of SRC-3 by the two catalytic subunits of the IKK complex, IKKα and IKKβ.  IKK kinase activity is required for synergistic activation with SRC-3" SIGNOR-251298 IKBKB protein O14920 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates phosphorylation 9606 11158290 t lperfetto "Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway." SIGNOR-217403 IKBKB protein O14920 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 15489227 t 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-217376 IKBKB protein O14920 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR "form complex" binding 9606 20300203 t gcesareni "The kinase(s) responsible for the phosphorylation of the ikb inhibitors remained elusive for many years, until the biochemical purification of a cytoplasmic high-molecular weight complex migrating around 700900 kda and containing two related catalytic subunits, ikkalfa and ikkbeta." SIGNOR-164509 IKBKB protein O14920 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 BTO:0000150 15084260 t gcesareni "Ikkbeta phosphorylates foxo3a at ser644. Ikappab kinase (ikk) physically interacts with, phosphorylates, and inhibits foxo3a independent of akt and causes proteolysis of foxo3a via the ub-dependent proteasome pathway" SIGNOR-252948 IKBKB protein O14920 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni "Ikkbeta phosphorylates foxo3a at ser644. Ikappab kinase (ikk) physically interacts with, phosphorylates, and inhibits foxo3a independent of akt and causes proteolysis of foxo3a via the ub-dependent proteasome pathway" SIGNOR-252947 HAT1 protein O14929 UNIPROT H4C1 protein P62805 UNIPROT "down-regulates activity" acetylation Lys6 kGGKGLGK -1 11585814 t lperfetto "During nucleosome assembly in vivo, newly synthesized histone H4 is specifically diacetylated on lysines 5 and 12 within the H4 NH(2)-terminal tail domain. The highly conserved ""K5/K12"" deposition pattern of acetylation is thought to be generated by the Hat1 histone acetyltransferase, which in vivo is found in the HAT-B complex." SIGNOR-264791 HAT1 protein O14929 UNIPROT H4C1 protein P62805 UNIPROT "down-regulates activity" acetylation Lys13 KGGKGLGkGGAKRHR -1 28143904 t lperfetto "Histone acetyltransferase 1 is the founding member of the histone acetyltransferase superfamily and catalyzes lysine acetylation of newly synthesized histone H4|Lys12 for direct attack of the acetyl group of the cofactor.| It is postulated that histone acetylation, through charge neutralization of the cationic histone tails, weakens nucleosomal electrostatic interactions with anionic DNA, thus destabilizing internucleosomal contacts and nucleosomal structure and facilitating access to the promoter region for RNA polymerase and transcription factors." SIGNOR-264790 CASK protein O14936 UNIPROT TBR1 protein Q16650 UNIPROT up-regulates binding 9534 BTO:0000298 10749215 t miannu "Here we report that, through its guanylate kinase domain, CASK interacts with Tbr-1, a T-box transcription factor that is involved in forebrain development. CASK enters the nucleus and binds to a specific DNA sequence (the T-element) in a complex with Tbr-1. CASK acts as a coactivator of Tbr-1 to induce transcription of T-element containing genes, including reelin, a gene that is essential for cerebrocortical development." SIGNOR-266835 EREG protein O14944 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 BTO:0001253 20513444 t "Epiregulin may be a mediator of localized cell proliferation" gcesareni "Remarkably, three members of the epidermal growth factor (egf) family (ereg, areg, and epgn) showed increased expression that was associated with elevated epidermal activation of the egf receptor (egfr) and stat3, a downstream effector of egfr signaling." SIGNOR-165782 EREG protein O14944 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 BTO:0000150 9419975 t "Epiregulin may be a mediator of localized cell proliferation" gcesareni "Chemical cross-linking experiments showed that [125i]epiregulin directly bound to each of egfr and erbb-4 but not to erbb-2 and erbb-3. remarkably, three members of the epidermal growth factor (egf) family (ereg, areg, and epgn) showed increased expression that was associated with elevated epidermal activation of the egf receptor (egfr) and stat3, a downstream effector of egfr signaling." SIGNOR-54351 EREG protein O14944 UNIPROT ERBB3 protein P21860 UNIPROT up-regulates binding 9606 16829981 t gcesareni "For example, betacellulin binds to and activates both erbb1 and erbb4, whereas epiregulin binds to erbb1, erbb3 and erbb4" SIGNOR-147856 EREG protein O14944 UNIPROT ERBB3 protein P21860 UNIPROT up-regulates binding 9606 BTO:0000150 22891299 t gcesareni "For example, betacellulin binds to and activates both erbb1 and erbb4, whereas epiregulin binds to erbb1, erbb3 and erbb4" SIGNOR-191785 EREG protein O14944 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 16829981 t gcesareni "For example, betacellulin binds to and activates both erbb1 and erbb4, whereas epiregulin binds to erbb1, erbb3 and erbb4." SIGNOR-147859 EREG protein O14944 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 BTO:0000150 22891299 t gcesareni "For example, betacellulin binds to and activates both erbb1 and erbb4, whereas epiregulin binds to erbb1, erbb3 and erbb4." SIGNOR-191788 TFEC protein O14948 UNIPROT MYH9 protein P35579 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567 11467950 f miannu "we have focused on element F of the NMHC-A gene. We have identified and characterized the factors which are capable of binding to element F. The basic helix_loop_helix leucine zipper (bHLH-LZ) proteins, TFEC-l and -s, which are alternatively spliced isoforms, TFE3, USF1, and USF2 have all been found to bind to element F with different binding activities and with different transcriptional activation potencies." SIGNOR-222551 UQCRQ protein O14949 UNIPROT "Mitochondrial respiratory chain complex III" complex SIGNOR-C279 SIGNOR "form complex" binding 30030361 t lperfetto "Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits" SIGNOR-262197 UQCR11 protein O14957 UNIPROT "Mitochondrial respiratory chain complex III" complex SIGNOR-C279 SIGNOR "form complex" binding 30030361 t lperfetto "Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits" SIGNOR-262196 HGS protein O14964 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates 9606 11094085 f gcesareni "Hgs and sara, are prerequisites for receptor-mediated activation of smad2" SIGNOR-84616 AURKA protein O14965 UNIPROT AURKA protein O14965 UNIPROT up-regulates phosphorylation Thr288 APSSRRTtLCGTLDY 9606 24867643 t lperfetto "The upstream pak1 kinase can phosphorylate aurora a at t288, autophosphorylation appears to be the essential mode of activation. Our experiments suggest that phosphorylation of t288 is important for regulation of the aurora2 kinase both for its activity and its stability" SIGNOR-205106 AURKA protein O14965 UNIPROT MBD3 protein O95983 UNIPROT up-regulates phosphorylation Ser24 REEVPRRsGLSAGHR 9606 BTO:0000567 12354758 t llicata "These results suggest that the biochemical changes of mbd3 may be intimately related to the targeting of mbd3 to centrosomes. aurora-a phosphorylates mbd3" SIGNOR-93693 AURKA protein O14965 UNIPROT TP53 protein P04637 UNIPROT down-regulates phosphorylation Ser215 DRNTFRHsVVVPYEP 9606 15469940 t llicata "Here we show that p53 is phosphorylated by the mitotic kinase aurora-a at serine 215. Unlike most identified phosphorylation sites of p53 that positively associate with p53 function (brooks, c. L., and gu, w. (2003) curr. Opin. Cell biol. 15, 164-171), the phosphorylation of p53 by aurora-a at ser-215 abrogates p53 dna binding and transactivation activity." SIGNOR-129809 AURKA protein O14965 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser106 SQKTYQGsYGFRLGF 9606 23201157 t gcesareni "Ser-106 phosphorylation of p53 decreases its interaction with mdm2 and prolongs the half-life of p53" SIGNOR-199939 AURKA protein O14965 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" phosphorylation Ser315 LPNNTSSsPQPKKKP 9606 24173284 t lperfetto "The N-terminus of E2F1 can interact directly with a region towards the C-terminus of p53, resulting in increased nuclear retention of p53 and p53-mediated transcription and apoptosis. This is inhibited by competition between p53 and cyclin A at the binding site within E2F19,10. The interaction between p53 and E2F1 is enhanced by phosphorylation of p53 on Ser315, a residue within the E2F1 binding region that is phosphorylated by cell cycle kinases such as cdk1, cdk2, cdk9 and Aurora kinase A" SIGNOR-120836 AURKA protein O14965 UNIPROT AR protein P10275 UNIPROT "up-regulates activity" phosphorylation Ser293 PLAECKGsLLDDSAG 9606 BTO:0001321 20713353 t miannu "Phosphorylation and activation of androgen receptor by Aurora-A.Aurora-A interacts with AR and phosphorylates AR at Thr(282) and Ser(293) in vitro and in vivo. Aurora-A induces AR transactivation activity in a phosphorylation-dependent manner." SIGNOR-259828 AURKA protein O14965 UNIPROT CDC25B protein P30305 UNIPROT up-regulates phosphorylation Ser353 VQNKRRRsVTPPEEQ 9606 16082213 t lperfetto "We show that bypass of the g2/m checkpoint by the chk1 kinase inhibitor ucn-01 results in the activation of aurora-a and phosphorylation of cdc25b on s353" SIGNOR-139396 AURKA protein O14965 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser308 KAEFCNKsKQPGLAR 9606 14990569 t lperfetto "Previous studies have shown that the brca1 breast cancer tumor suppressor also localizes to the centrosome and that brca1 inactivation results in loss of the g(2)-m checkpoint. We demonstrate here that aurora-a physically binds to and phosphorylates brca1. We propose that brca1 phosphorylation by aurora-a plays a role in g(2) to m transition of cell cycle" SIGNOR-123065 AURKA protein O14965 UNIPROT CETN2 protein P41208 UNIPROT up-regulates phosphorylation Ser170 LRIMKKTsLY 9606 BTO:0000150 21731694 t llicata "Our studies show that aurora a phosphorylates centrin at serine 170 in vitro and that the serine 170 phosphorylation affects the stability of centrin by regulating its interaction with apc/c. finally we demonstrated that phosphorylation of centrin serine 170 is an absolute requirement for aurora a-mediated centriole amplification." SIGNOR-174686 AURKA protein O14965 UNIPROT H3C1 protein P68431 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 12588998 t gcesareni "Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis." SIGNOR-98289 AURKA protein O14965 UNIPROT H3C1 protein P68431 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 14583461 t gcesareni "Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis." SIGNOR-118886 AURKA protein O14965 UNIPROT FADD protein Q13158 UNIPROT up-regulates phosphorylation Ser203 MSWNSDAsTSEAS 9606 21978935 t lperfetto "Here, we report that aur-a phosphorylates s203 of the fas associated with death domain protein (fadd)phosphorylation of s203 by aur-a serves to prime fadd for plk1-mediated phosphorylation at s194" SIGNOR-176739 AURKA protein O14965 UNIPROT PIN1 protein Q13526 UNIPROT "down-regulates activity" phosphorylation Ser16 PGWEKRMsRSSGRVY 9606 23970419 t llicata "Here, we found that aurora a can interact with and phosphorylate pin1 at ser16, which suppresses the g2/m function of pin1 by disrupting its binding ability and mitotic entry." SIGNOR-202487 AURKA protein O14965 UNIPROT NEDD9 protein Q14511 UNIPROT "up-regulates activity" phosphorylation Ser296 PVARRHQsLSPNHPP 9606 BTO:0000093 16184168 t miannu "HEF1 interacts with AurA and is required for the activation of AurA kinase. Together, these data suggest a model in which an initial interaction of HEF1 with AurA prior to mitotic entry activates AurA, which then phosphorylates HEF1, promoting dissociation of the two proteins." SIGNOR-262654 AURKA protein O14965 UNIPROT DLGAP5 protein Q15398 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser627 VKLFSGLsVSSEGPS 9606 BTO:0000007 15987997 t miannu "Phosphorylation and stabilization of HURP by Aurora-A. Four phosphorylated residues were identified, namely, HURP-S627, -S725, -S757, and -S830, with 65% amino acid sequence coverage. we propose here that Aurora-A may phosphorylate HURP and this probably attenuates the negative impact of cdk1 phosphorylation and by inhibiting subsequent proteasome activity and this will generate a longer HURP half-life." SIGNOR-262649 AURKA protein O14965 UNIPROT DLGAP5 protein Q15398 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser725 CLSSERMsLPLLAGG 9606 BTO:0000007 15987997 t miannu "Phosphorylation and stabilization of HURP by Aurora-A. Four phosphorylated residues were identified, namely, HURP-S627, -S725, -S757, and -S830, with 65% amino acid sequence coverage. we propose here that Aurora-A may phosphorylate HURP and this probably attenuates the negative impact of cdk1 phosphorylation and by inhibiting subsequent proteasome activity and this will generate a longer HURP half-life." SIGNOR-262650 AURKA protein O14965 UNIPROT DLGAP5 protein Q15398 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser757 EGMELNSsITSQDVL 9606 BTO:0000007 15987997 t miannu "Phosphorylation and stabilization of HURP by Aurora-A. Four phosphorylated residues were identified, namely, HURP-S627, -S725, -S757, and -S830, with 65% amino acid sequence coverage. we propose here that Aurora-A may phosphorylate HURP and this probably attenuates the negative impact of cdk1 phosphorylation and by inhibiting subsequent proteasome activity and this will generate a longer HURP half-life." SIGNOR-262651 AURKA protein O14965 UNIPROT DLGAP5 protein Q15398 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser830 QEHARHIsFGGNLIT 9606 BTO:0000007 15987997 t miannu "Phosphorylation and stabilization of HURP by Aurora-A. Four phosphorylated residues were identified, namely, HURP-S627, -S725, -S757, and -S830, with 65% amino acid sequence coverage. we propose here that Aurora-A may phosphorylate HURP and this probably attenuates the negative impact of cdk1 phosphorylation and by inhibiting subsequent proteasome activity and this will generate a longer HURP half-life." SIGNOR-262652 AURKA protein O14965 UNIPROT MAP9 protein Q49MG5 UNIPROT up-regulates phosphorylation Ser625 RKQKKRHsFLESEAL 9606 17925329 t llicata "Asap is a novel substrate of the oncogenic mitotic kinase aurora-a: phosphorylation on ser625 is essential to spindle formation and mitosis." SIGNOR-158210 AURKA protein O14965 UNIPROT SGO1 protein Q5FBB7 UNIPROT "up-regulates activity" phosphorylation -1 16824953 t lperfetto "Loss of INCENP/Aurora B in Mitosis Correlates with Delocalization of MEI-S332|MEI-S332 Is Phosphorylated by Aurora B In Vitro|Of these, MEI-S332S124,125,126A was a poor substrate for Aurora B kinase in vitro" SIGNOR-252046 AURKA protein O14965 UNIPROT WWC1 protein Q8IX03 UNIPROT unknown phosphorylation Ser539 TSLSPRSsLSSPSPP 9606 21878642 t llicata "We identified the highly conserved ser(539) as the primary phosphorylation site for aurora kinases." SIGNOR-176359 AURKA protein O14965 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Ser380 ATLARRDsLQKPGLE 9606 21822051 t lperfetto "In the present study, aurora a was demonstrated to phosphorylate lats2 on serine 380 (s380) during mitosistogether, the results suggest that the aurora a-lats1/2-aurora b axis might be a novel pathway that regulates accurate mitotic progression by ensuring the proper mitotic localization of lats2." SIGNOR-175939 AURKA protein O14965 UNIPROT RASSF1 protein Q9NS23 UNIPROT down-regulates phosphorylation Ser207 TSVRRRTsFYLPKDA 9606 17563743 t llicata "Aurora-a appears to phosphorylate rassf1a at threonine202 and/or serine203 that reside within the known microtubule-binding domain of rassf1a. Substitutions of these residues with glutamic acid at both positions, mimicking constitutive phosphorylation of rassf1a, disrupt rassf1a interactions with microtubules and abolish its ability to induce m-phase cell cycle arrest." SIGNOR-155815 AURKA protein O14965 UNIPROT RASSF1 protein Q9NS23 UNIPROT down-regulates phosphorylation Thr206 GTSVRRRtSFYLPKD 9606 17563743 t llicata "AuroraT-a appears to phosphorylate rassf1a at threonine202 and/or serine203 that reside within the known microtubule-binding domain of rassf1a. Substitutions of these residues with glutamic acid at both positions, mimicking constitutive phosphorylation of rassf1a, disrupt rassf1a interactions with microtubules and abolish its ability to induce m-phase cell cycle arrest." SIGNOR-155819 AURKA protein O14965 UNIPROT AURKAIP1 protein Q9NWT8 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser70 MLVPRKMsVSPLESW 9606 BTO:0000567 17957726 t miannu "AIP is phosphorylated on Serine 70 by Aurora‐A but not Aurora‐B and expression of phosphorylation mimic mutant of AIP results in prolonged protein stability compared to unphosphorylatable mutant. Phosphorylation of AIP Prolongs its Protein Stability" SIGNOR-262648 AURKA protein O14965 UNIPROT TPX2 protein Q9ULW0 UNIPROT "up-regulates activity" phosphorylation Ser121 PAQPQRRsLRLSAQK 9606 BTO:0000567 26240182 t lperfetto "Here we show that TPX2, a microtubule-bundling protein and activator of Aurora A, plays an important role. TPX2 was phosphorylated by Aurora A during mitosis. Its phospho-null mutant caused short metaphase spindles coupled with low microtubule flux rate. Interestingly, phosphorylation of TPX2 regulated its interaction with CLASP1 but not Kif2a.|This suggests that TPX2 phosphorylation positively regulates the function of CLASP1.| This is in accord with a phosphoproteomics study that identified S121 and S125 as potential phosphorylation sites for Aurora A in mitotic HeLa cells" SIGNOR-265089 AURKA protein O14965 UNIPROT KNSTRN protein Q9Y448 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0001938 22535524 t lperfetto "The protein astrin has been shown to remove Kif2b from kinetochores in metaphase through competitive binding of CLASP1 (Manning et al., 2010 blue right-pointing triangle). During prometaphase, Aurora B kinase activity prevents astrin from localizing to kinetochores (Manning et al., 2010 blue right-pointing triangle; Schmidt et al., 2010 blue right-pointing triangle). This permits Kif2b to localize to kinetochores to destabilize k-MT attachments to execute error correction through Plk1-dependent recruitment and activation." SIGNOR-252052 AURKA protein O14965 UNIPROT TACC3 protein Q9Y6A5 UNIPROT unknown phosphorylation Ser34 PEVTGRSsVLRVSQK -1 26134678 t lperfetto "To address whether the phosphorylation state of TACC3 influenced Aurora-A binding and activation, we generated TACC3 variants in which all three Aurora-A phosphorylation sites (S34, S552 and S558)| The SA mutant had strongly reduced levels of phosphorylation compared to the individual mutations|" SIGNOR-263697 AURKA protein O14965 UNIPROT TACC3 protein Q9Y6A5 UNIPROT unknown phosphorylation Ser552 GTSSFKEsALRKQSL -1 26134678 t lperfetto "In humans, Aurora-A phosphorylates TACC3 on three residues (S34, S552 and S558); these sites are conserved in Maskin and the S558 equivalent site is also present in D-TACC [26,27,30]. In mammalian cells, phosphorylation of S558 promotes accumulation of TACC3 on spindle MTs" SIGNOR-263698 ATP2A1 protein O14983 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "down-regulates quantity" relocalization 9986 BTO:0001103 28487373 t lperfetto "SERCA1, the sarco(endo)plasmic reticulum Ca2+-ATPase of skeletal muscle, is essential for muscle relaxation and maintenance of low resting Ca2+ levels in the myoplasm." SIGNOR-265928 MCF2L protein O15068 UNIPROT CDC42 protein P60953 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260560 MCF2L protein O15068 UNIPROT RHOA protein P61586 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260559 CEP290 protein O15078 UNIPROT RAB8A protein P61006 UNIPROT "up-regulates activity" binding 9606 18694559 t miannu "CEP290 cooperates with Rab8a to promote ciliogenesis and this function is antagonized by CP110. CEP290 recruits Rab8a to centrosomes. Depletion of CEP290 results in a significant decrease of Rab8a at the centrosome and at the cilium, raising the possibility that CEP290 first recruits Rab8a through direct protein-protein interactions to the centrosome in cycling cells and later promotes ciliogenesis by allowing the entry of Rab8a into the cilium" SIGNOR-252146 ARHGEF11 protein O15085 UNIPROT RHOA protein P61586 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260538 SMAD7 protein O15105 UNIPROT BMPR1B protein O00238 UNIPROT down-regulates 10090 BTO:0000165 10564272 f gcesareni "We found that both smad6 and smad7 inhibit the activation of smad1 and smad5 by bmpr-ia/alk-3 and bmpr-ib/alk-6, as well as that by alk-2" SIGNOR-236864 SMAD7 protein O15105 UNIPROT PPP1R15A protein O75807 UNIPROT up-regulates binding 9606 14718519 t lpetrilli "We found smad7 interacts with growth arrest and dna damage protein, gadd34, a regulatory subunit of the protein phosphatase 1 (pp1) holoenzyme, which subsequently recruits catalytic subunit of pp1 (pp1c) to dephosphorylate t?RI." SIGNOR-121280 SMAD7 protein O15105 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates 9606 BTO:0001130 15684397 f gcesareni "In the current study, our data indicate that both smad7 and p38 map kinase positively contributed to the accumulation of -catenin" SIGNOR-133447 SMAD7 protein O15105 UNIPROT TGFBR1 protein P36897 UNIPROT "down-regulates activity" binding 9606 30017632 t miannu "Smad7 inhibits both transforming growth factor β (TGF-β)- and BMP-induced Smad signaling. Smad7 can use both surfaces in its interaction with the ALK-2, -3, and -4 receptors, but only the basic groove is used in the interaction between Smad7 and the TGF-β type I receptor (TβRI, also known as ALK-5)." SIGNOR-260438 SMAD7 protein O15105 UNIPROT ACVRL1 protein P37023 UNIPROT down-regulates 9606 BTO:0000975 12023024 f gcesareni "Smad7, induced by alk1 activation, recruits pp1? To alk1 and thereby inhibits tgf-?/Alk1-induced smad1/5 phosphorylation in ecs." SIGNOR-87673 SMAD7 protein O15105 UNIPROT PPP1CA protein P62136 UNIPROT up-regulates binding 9606 16571110 t gcesareni "Smad7, induced by alk1 activation, recruits pp1? To alk1 and thereby inhibits tgf-?/Alk1-induced smad1/5 phosphorylation in ecs" SIGNOR-145389 CHUK protein O15111 UNIPROT NFKB1 protein P19838 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser927 DSDSVCDsGVETSFR 10090 BTO:0000944 SIGNOR-C14 SIGNOR-C13 11297557 t lperfetto "The i b kinase (ikk) complex rapidly phosphorylates nf- b1 p105 on serine 927 in the pest region romashkova et al. demonstrated that akt binds to and activates inhibitor of kappa b kinase-alfa (ikkalfa), which in turn phosphorylates and thereby promotes the degradation of the inhibitory cofactor of nf-kb, i-kb the scf-betatrcp complex is responsible for the ubiquitination of p100 and p105 following their phosphorylation by ikk." SIGNOR-235438 CHUK protein O15111 UNIPROT NFKB1 protein P19838 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser932 CDSGVETsFRKLSFT 10090 BTO:0000944 SIGNOR-C14 SIGNOR-C13 11297557 t lperfetto "The i b kinase (ikk) complex rapidly phosphorylates nf- b1 p105 on serine 927 in the pest region romashkova et al. demonstrated that akt binds to and activates inhibitor of kappa b kinase-alfa (ikkalfa), which in turn phosphorylates and thereby promotes the degradation of the inhibitory cofactor of nf-kb, i-kb the scf-betatrcp complex is responsible for the ubiquitination of p100 and p105 following their phosphorylation by ikk." SIGNOR-235442 CHUK protein O15111 UNIPROT CCND1 protein P24385 UNIPROT down-regulates phosphorylation Thr286 EEVDLACtPTDVRDV 9606 16103118 t gcesareni "Ikkalpha regulates subcellular localization and proteolysis of cyclin d1 by phosphorylation of cyclin d1 at thr286." SIGNOR-139570 CHUK protein O15111 UNIPROT NFKBIA protein P25963 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser32 LLDDRHDsGLDSMKD 9606 BTO:0000567 SIGNOR-C14 9346241 t 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-52875 CHUK protein O15111 UNIPROT NFKBIA protein P25963 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 BTO:0000567 SIGNOR-C14 9346241 t 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-52879 CHUK protein O15111 UNIPROT NFKB2 protein Q00653 UNIPROT "up-regulates activity" phosphorylation Ser870 KEDSAYGsQSVEQEA 10090 BTO:0000785 15084608 t lperfetto "Ikkalfa phosphorylates p100, leading to its proteasomal processing to p52." SIGNOR-124230 CHUK protein O15111 UNIPROT RELA protein Q04206 UNIPROT "up-regulates activity" phosphorylation Ser536 SGDEDFSsIADMDFS 9606 BTO:0000567 SIGNOR-C14 SIGNOR-C13 10521409 t 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-71270 CHUK protein O15111 UNIPROT RELA protein Q04206 UNIPROT "up-regulates activity" phosphorylation Ser536 SGDEDFSsIADMDFS 9606 BTO:0000007;BTO:0000567 SIGNOR-C14 SIGNOR-C13 15489227 t 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-129931 CHUK protein O15111 UNIPROT RELA protein Q04206 UNIPROT "up-regulates activity" phosphorylation Ser536 SGDEDFSsIADMDFS 9606 BTO:0000876 SIGNOR-C14 SIGNOR-C13 15611276 t 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-132568 CHUK protein O15111 UNIPROT TAX1BP1 protein Q86VP1 UNIPROT "up-regulates activity" phosphorylation Ser593 NYKELKRsLENPAER 10090 BTO:0002572 21765415 t "The effect has been demonstrated using Q86VP1-2" lperfetto "Here we demonstrate that tax1bp1 was inducibly phosphorylated on ser593 and ser624 in response to proinflammatory stimuli. The kinase ikkalpha, But not ikkbeta, was required for phosphorylation of tax1bp1 and directly phosphorylated tax1bp1 in response to stimulation with tumor necrosis factor (tnf) or interleukin 1 (il-1)." SIGNOR-175058 CHUK protein O15111 UNIPROT TAX1BP1 protein Q86VP1 UNIPROT "up-regulates activity" phosphorylation Ser666 RPPVRVPsWGLEDNV 10090 BTO:0002572 21765415 t "The effect has been demonstrated using Q86VP1-2" lperfetto "Here we demonstrate that tax1bp1 was inducibly phosphorylated on ser593 and ser624 in response to proinflammatory stimuli. The kinase ikkalpha, but not ikkbeta, was required for phosphorylation of tax1bp1 and directly phosphorylated tax1bp1 in response to stimulation with tumor necrosis factor (tnf) or interleukin 1 (il-1)." SIGNOR-175062 CHUK protein O15111 UNIPROT CREBBP protein Q92793 UNIPROT up-regulates binding 9606 12789342 t gcesareni "Ikk-alpha interacts with creb-binding protein and in conjunction with rel a is recruited to nf-kappab-responsive promoters and mediates the cytokine-induced phosphorylation and subsequent acetylation of specific residues in histone h3." SIGNOR-101539 CHUK protein O15111 UNIPROT MAP3K14 protein Q99558 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr559 TGDYIPGtETHMAPE 9606 BTO:0000776 20501937 t lperfetto "Upon activation by nik, ikkalfa phosphorylates nik, triggering its proteolysis." SIGNOR-165622 CHUK protein O15111 UNIPROT TRAF4 protein Q9BUZ4 UNIPROT down-regulates phosphorylation Ser426 KPGTWRGsLDESSLG 9606 22547678 t llicata "Traf4 is atypical within its family because it is the only traf family member to negatively regulate innate immune signaling. Ikk_'s phosphorylation of serine-426 on traf4 was required for this negative regulation." SIGNOR-197253 CHUK protein O15111 UNIPROT CYLD protein Q9NQC7 UNIPROT "down-regulates activity" phosphorylation Ser418 TTENRFHsLPFSLTK 9606 BTO:0000938 24614225 t lperfetto "Thus, serine 418 is phosphorylated in vivo. Cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity." SIGNOR-204688 CHUK protein O15111 UNIPROT CYLD protein Q9NQC7 UNIPROT "down-regulates activity" phosphorylation Ser432 KMPNTNGsIGHSPLS 9606 BTO:0000938 24614225 t lperfetto "The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity." SIGNOR-204696 CHUK protein O15111 UNIPROT CYLD protein Q9NQC7 UNIPROT "down-regulates activity" phosphorylation Ser436 TNGSIGHsPLSLSAQ 9606 BTO:0000938 24614225 t lperfetto "The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity." SIGNOR-204700 CRX protein O43186 UNIPROT RBP3 protein P10745 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10354480 f miannu "OTX2, as well as CRX, a homeodomain protein very similar to OTX2, activates the human IRBP promoter in co-transfection experiments." SIGNOR-254890 CHUK protein O15111 UNIPROT CYLD protein Q9NQC7 UNIPROT "down-regulates activity" phosphorylation Ser439 SIGHSPLsLSAQSVM 9606 BTO:0000938 24614225 t lperfetto "The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity." SIGNOR-204704 CHUK protein O15111 UNIPROT CYLD protein Q9NQC7 UNIPROT "down-regulates activity" phosphorylation Ser444 PLSLSAQsVMEELNT 9606 BTO:0000938 24614225 t lperfetto "The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity." SIGNOR-204712 CHUK protein O15111 UNIPROT CYLD protein Q9NQC7 UNIPROT "up-regulates activity" phosphorylation Ser422 RFHSLPFsLTKMPNT 9606 BTO:0000938 24614225 t lperfetto "The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity." SIGNOR-204692 CHUK protein O15111 UNIPROT CYLD protein Q9NQC7 UNIPROT "up-regulates activity" phosphorylation Ser441 GHSPLSLsAQSVMEE 9606 BTO:0000938 24614225 t lperfetto "The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity." SIGNOR-204708 CHUK protein O15111 UNIPROT FOXA2 protein Q9Y261 UNIPROT down-regulates phosphorylation Ser107 AGMGPHLsPSLSPLG 9606 22196886 t lperfetto "Here, we show that ikk_, an important downstream kinase of tnf_, interacts with and phosphorylates foxa2 at s107/s111, thereby suppressing foxa2 transactivation activity and leading to decreased numb expression" SIGNOR-195312 CHUK protein O15111 UNIPROT FOXA2 protein Q9Y261 UNIPROT down-regulates phosphorylation Ser111 PHLSPSLsPLGGQAA 9606 22196886 t lperfetto "Here, we show that ikk_, an important downstream kinase of tnf_, interacts with and phosphorylates foxa2 at s107/s111, thereby suppressing foxa2 transactivation activity and leading to decreased numb expression" SIGNOR-195316 CHUK protein O15111 UNIPROT NCOR2 protein Q9Y618 UNIPROT down-regulates phosphorylation Ser2407 AKVSGRPsSRKAKSP 9606 SIGNOR-C14 15494311 t "Translocation from Nucleus to Cytoplasm" gcesareni "Nf-kappab transcription requires ikkalpha to phosphorylate smrt on chromatin, stimulating the exchange of corepressor for coactivator complexes. Ikk directly phosphorylates smrt to stimulate nuclear export. Ikkalpha orchestrates smrt derepression, a prerequisite for nf-kappab transcription and survival." SIGNOR-129956 CHUK protein O15111 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates phosphorylation Ser857 PPYNRAVsLDSPVSV 9606 15383283 t gcesareni "Herein, we report the successful identification of six functional in vivo src-3 phosphorylation sites." SIGNOR-127064 MUSK protein O15146 UNIPROT WNT11 protein O96014 UNIPROT up-regulates binding 9606 23151663 t gcesareni "Like ror, musk has an extracellular region with homolgogy to the frizzled crd, binding of which by wnt11 stimulates a pcp-like pathway during neuromuscular development" SIGNOR-199518 MDM4 protein O15151 UNIPROT MDM2 protein Q00987 UNIPROT "up-regulates quantity by stabilization" 9606 15735705 f lperfetto "Mdm2 and mdmx function as cellular regulators of the p53 tumor suppressor protein. Intriguingly, the activities of these proteins are interdependent;mdmx stabilizes mdm2, enabling its activities towards p53" SIGNOR-134391 POLR1C protein O15160 UNIPROT "RNA Polymerase III" complex SIGNOR-C389 SIGNOR "form complex" binding 9606 BTO:0000567 12391170 t lperfetto "In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights." SIGNOR-266136 POLR1C protein O15160 UNIPROT "RNA Polymerase I" complex SIGNOR-C390 SIGNOR "form complex" binding 22260999 t lperfetto "In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1). " SIGNOR-266145 TRIM24 protein O15164 UNIPROT AR protein P10275 UNIPROT up-regulates binding 9606 BTO:0001130 19909775 t miannu "We found that trim24/transcriptional intermediary factor 1alpha (tif1alpha), which is known as a ligand-dependent nuclear receptor co-regulator, interacts with ar and enhances transcriptional activity of ar" SIGNOR-189113 AXIN1 protein O15169 UNIPROT AXIN1 protein O15169 UNIPROT "up-regulates activity" binding 9606 17529994 t amattioni "The axin dix domain has a novel structural fold largely composed of beta-strands that engage in head-to-tail self-interaction to form filaments in the crystal" SIGNOR-155218 AXIN1 protein O15169 UNIPROT APC protein P25054 UNIPROT "up-regulates activity" binding 9606 BTO:0000038 9734785 t amattioni "Axin, an inhibitor of the wnt pathway, interacts with beta-catenin, gsk-3beta and apc and reduces the beta-catenin level." SIGNOR-60043 AXIN1 protein O15169 UNIPROT BMPR1A protein P36894 UNIPROT down-regulates ubiquitination 9606 22298955 t gcesareni "Other proteins, such as the serine/threonine kinase fused (fu), can function in concert with the e3 ligase smurf to regulate ubiquitination and proteolysis of the bmp receptor" SIGNOR-195552 AXIN1 protein O15169 UNIPROT CSNK1D protein P48730 UNIPROT up-regulates binding 9606 SIGNOR-C110 12000790 t gcesareni "Complex of axin and casein kinase i (cki) induces beta-catenin phosphorylation at a single site: serine 45 (s45)." SIGNOR-87401 AXIN1 protein O15169 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates 9606 16601693 f gcesareni "Axin promotes smad3 phosphorylation;phosphorylated smad3 dissociates from the axin complex and then combines with smad4 to activate transcription in the nucleus." SIGNOR-145848 AXIN1 protein O15169 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates binding 9606 10829020 t gcesareni "We found that in contrast to axin, dvl2 activation of jnk does not require mekk1." SIGNOR-77591 AXIN1 protein O15169 UNIPROT RNF111 protein Q6ZNA4 UNIPROT up-regulates binding 9606 14657019 t gcesareni "Here, we show that axin activates tgf-beta signaling by forming a multimeric complex consisting of smad7 and ubiquitin e3 ligase arkadia. Axin is a scaffold protein in tgf-beta signaling that promotes degradation of smad7 by arkadia." SIGNOR-119660 NUAK1 protein O60285 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser392 FKTEGPDsD 9606 21317932 t gcesareni "Here we showed that in the presence of wild-type lkb1, nuak1 directly interacts with and phosphorylates p53 in vitro and in vivo." SIGNOR-172012 AXIN1 protein O15169 UNIPROT RNF111 protein Q6ZNA4 UNIPROT up-regulates binding 9606 16601693 t gcesareni "Here, we show that axin activates tgf-beta signaling by forming a multimeric complex consisting of smad7 and ubiquitin e3 ligase arkadia. Axin is a scaffold protein in tgf-beta signaling that promotes degradation of smad7 by arkadia." SIGNOR-145845 AXIN1 protein O15169 UNIPROT MAP3K4 protein Q9Y6R4 UNIPROT up-regulates binding 9606 BTO:0000007 12878610 t gcesareni "Mekk4, also binds to axin in vivo and mediates axin-induced jnk activation." SIGNOR-104003 AXIN1 protein O15169 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "form complex" binding 9606 BTO:0000586 9734785 t lperfetto "Axin, an inhibitor of the wnt pathway, interacts with beta-catenin, gsk-3beta and apc and reduces the beta-catenin level." SIGNOR-227292 CTDSPL protein O15194 UNIPROT RB1 protein P06400 UNIPROT "up-regulates activity" dephosphorylation Ser811 IYISPLKsPYKISEG 9606 15051889 t "ppRB (RB phosphorylated at Ser-807/811|Possible Mechanisms of HYA22 Action in Tumorigenesis: Dephosphorylation of RB by Transient Expression of HYA22 Isoforms." SIGNOR-248305 CTDSPL protein O15194 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" dephosphorylation Ser204 NHSMDAGsPNLSPNP 9606 BTO:0000007 17035229 t "Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity" SIGNOR-248306 CTDSPL protein O15194 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" dephosphorylation Ser208 DAGSPNLsPNPMSPA 9606 BTO:0000007 17035229 t "Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity" SIGNOR-248307 OGT protein O15294 UNIPROT "NSL histone acetyltransferase" complex SIGNOR-C413 SIGNOR "form complex" binding 9606 BTO:0000007 20018852 t miannu "Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. Two of its subunits, WD repeat domain 5 (WDR5) and host cell factor 1 (HCF1), are shared with members of the MLL/SET family of histone H3 lysine 4 (H3K4) methyltransferase complexes, and a third subunit, MCRS1, is shared with the human INO80 chromatin-remodeling complex." SIGNOR-267158 PPM1D protein O15297 UNIPROT TP53 protein P04637 UNIPROT down-regulates dephosphorylation Ser15 PSVEPPLsQETFSDL 9606 15870257 t lperfetto "PPM1D also dephosphorylates p53 at phospho-Ser 15. PPM1D dephosphorylations are correlated with reduced cellular intra-S and G2/M checkpoint activity in response to DNA damage induced by ultraviolet and ionizing radiation. Thus, a primary function of PPM1D may be to reverse the p53 and Chk1-induced DNA damage and cell cycle checkpoint responses and return the cell to a homeostatic state following completion of DNA repair." SIGNOR-135980 PPM1D protein O15297 UNIPROT TP53 protein P04637 UNIPROT "down-regulates activity" dephosphorylation Ser15 PSVEPPLsQETFSDL 9606 15870257 t "PPM1D binds Chk1 and dephosphorylates the ATR-targeted phospho-Ser 345, leading to decreased Chk1 kinase activity. PPM1D also dephosphorylates p53 at phospho-Ser 15. PPM1D dephosphorylations are correlated with reduced cellular intra-S and G2/M checkpoint activity in response to DNA damage induced by ultraviolet and ionizing radiation. Thus, a primary function of PPM1D may be to reverse the p53 and Chk1-induced DNA damage and cell cycle checkpoint responses and return the cell to a homeostatic state following completion of DNA repair." SIGNOR-248319 POLR3G protein O15318 UNIPROT "RNA Polymerase III" complex SIGNOR-C389 SIGNOR "form complex" binding 9606 BTO:0000567 12391170 t lperfetto "In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights." SIGNOR-266127 INPP4B protein O15327 UNIPROT "phosphatidylinositol bisphosphate" smallmolecule CHEBI:37328 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 BTO:0000356 21127264 t gcesareni "Collectively this data indicates INPP4B is the only PtdIns(3,4)P2 4-phosphatase expressed in breast cancer cells and suggests a correlation between INPP4B and hormone receptor status in human breast cancer" SIGNOR-252433 EIF3D protein O15371 UNIPROT EIF3_complex complex SIGNOR-C401 SIGNOR "form complex" binding -1 16920360 t miannu "Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1)." SIGNOR-266397 EIF3H protein O15372 UNIPROT EIF3_complex complex SIGNOR-C401 SIGNOR "form complex" binding -1 16920360 t miannu "Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1)." SIGNOR-266393 YY2 protein O15391 UNIPROT FOS protein P01100 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567 15087442 t Luana "YY2 activated the p53 promoter. However, in contrast to YY1, which represses the activity of c-Fos, YY2 increased the activity of the c-Fos promoter." SIGNOR-266212 YY2 protein O15391 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567 15087442 t Luana "YY2 activated the p53 promoter. However, in contrast to YY1, which represses the activity of c-Fos, YY2 increased the activity of the c-Fos promoter." SIGNOR-266213 GRIN2D protein O15399 UNIPROT "NMDA receptor_2D" complex SIGNOR-C350 SIGNOR "form complex" binding 9606 BTO:0000938 12871085 t miannu "The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. The NMDA receptor subtypes are encoded by three gene families that process mRNA transcripts to yield six distinct subunits (NR1, NR2A-2D, NR3A). Receptors are thought to be tetrameric complexes of two NR1 and two NR2 subunits" SIGNOR-264127 FOXP2 protein O15409 UNIPROT RELN protein P78509 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000142 25232744 t miannu "By interacting with CASK, TBR1 regulates several ASD candidate genes, such as GRIN2B, AUTS2 and RELN—all of which are recurrently mutated in ASD. In areas of the brain with overlapping expression patterns, such as in glutamatergic layer 6 neurons, the TBR1–FOXP2 interaction may result in co-ordinated regulation of common downstream targets." SIGNOR-266833 FOXP2 protein O15409 UNIPROT GRIN2B protein Q13224 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000142 25232744 t miannu "By interacting with CASK, TBR1 regulates several ASD candidate genes, such as GRIN2B, AUTS2 and RELN—all of which are recurrently mutated in ASD. In areas of the brain with overlapping expression patterns, such as in glutamatergic layer 6 neurons, the TBR1–FOXP2 interaction may result in co-ordinated regulation of common downstream targets." SIGNOR-266834 FOXP2 protein O15409 UNIPROT AUTS2 protein Q8WXX7 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000142 25232744 t miannu "By interacting with CASK, TBR1 regulates several ASD candidate genes, such as GRIN2B, AUTS2 and RELN—all of which are recurrently mutated in ASD. In areas of the brain with overlapping expression patterns, such as in glutamatergic layer 6 neurons, the TBR1–FOXP2 interaction may result in co-ordinated regulation of common downstream targets." SIGNOR-266832 ABCC4 protein O15439 UNIPROT "sphingosine 1-phosphate" smallmolecule CHEBI:37550 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000132 29304533 t lperfetto "Release of Platelet-Derived Sphingosine-1-Phosphate Involves Multidrug Resistance Protein 4 (MRP4/ABCC4) and Is Inhibited by Statins" SIGNOR-265912 POLR2D protein O15514 UNIPROT "RNA Polymerase II" complex SIGNOR-C391 SIGNOR "form complex" binding 9606 BTO:0000567 9852112 t lperfetto "Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II" SIGNOR-266164 PDPK1 protein O15530 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr412 NQVFLGFtYVAPSVL 9606 9445476 t miannu "A regulatory link between p70s6k and pkb was demonstrated, as pdk1 was found to selectively phosphorylate p70s6k at thr229. More importantly, pdk1 activated p70s6k in vitro and in vivo, whereas the catalytically inactive pdk1 blocked insulin-induced activation of p70s6k." SIGNOR-188911 PDPK1 protein O15530 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr412 NQVFLGFtYVAPSVL 9606 9445476 t gcesareni "A regulatory link between p70s6k and pkb was demonstrated, as pdk1 was found to selectively phosphorylate p70s6k at thr229. More importantly, pdk1 activated p70s6k in vitro and in vivo, whereas the catalytically inactive pdk1 blocked insulin-induced activation of p70s6k. one of the most studied signalling events controlled by ptdins(3,4,5)p3, comprises the activation of a group of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated." SIGNOR-55310 PDPK1 protein O15530 UNIPROT RPS6KB1 protein P23443 UNIPROT "up-regulates activity" phosphorylation Thr252 HDGTVTHtFCGTIEY -1 9445476 t gcesareni "The results presented here are consistent with PDK1 as the in vivo kinase responsible for mediating Thr252 phosphorylation in the catalytic domain of p70s6k." SIGNOR-243338 PDPK1 protein O15530 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000142 10226025 t acerquone "We have partially purified a kinase from brain extract that phosphorylates Ser473 of PKBalpha in a PtdIns(3,4,5)P3-dependent manner and that is immunoprecipitated with PDK1 antibodies." SIGNOR-67367 PDPK1 protein O15530 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0000142 10226025 t acerquone "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-67363 PDPK1 protein O15530 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Thr308 KDGATMKtFCGTPEY 9606 phosphorylation:Ser473 RPHFPQFsYSASGTA 12167717 t gcesareni "Together, these results suggest a mechanism in which 3' phosphoinositide lipid-dependent translocation of pkb to the plasma membrane promotes serine 473 phosphorylation, which is, in turn, necessary for pdk1-mediated phosphorylation of threonine 308 and, consequentially, full pkb activation." SIGNOR-91354 PDPK1 protein O15530 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Thr308 KDGATMKtFCGTPEY 9606 12808134 t 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-252611 PDPK1 protein O15530 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Thr308 KDGATMKtFCGTPEY 9606 21798082 t 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 PDPK1 protein O15530 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0000567 15718470 t 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-252612 PDPK1 protein O15530 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation Thr308 KDGATMKtFCGTPEY 19951971 t 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 PDPK1 protein O15530 UNIPROT AKT2 protein P31751 UNIPROT "up-regulates activity" phosphorylation Ser474 RTHFPQFsYSASIRE 9606 15743829 t 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. Pdk1 phosphorylates akt-2 at thr 309 in the catalytic domain, leading to enzymatic activation." SIGNOR-134481 PDPK1 protein O15530 UNIPROT AKT2 protein P31751 UNIPROT "up-regulates activity" phosphorylation Thr309 SDGATMKtFCGTPEY 9606 15743829 t 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. Pdk1 phosphorylates akt-2 at thr 309 in the catalytic domain, leading to enzymatic activation." SIGNOR-134485 PDPK1 protein O15530 UNIPROT AKT2 protein P31751 UNIPROT "up-regulates activity" phosphorylation Thr309 SDGATMKtFCGTPEY 9606 BTO:0000887;BTO:0001103;BTO:0001760 9512493 t lperfetto "The activation of pkbbeta and pkbgamma by pdk1 was accompanied by the phosphorylation of the residues equivalent to thr308 in pkbalpha, namely thr309 (pkbbeta) and thr305 (pkbgamma)" SIGNOR-236785 PDPK1 protein O15530 UNIPROT MAP2K2 protein P36507 UNIPROT up-regulates phosphorylation Ser226 LIDSMANsFVGTRSY 9606 15175348 t gcesareni "The identified pdk1 phosphorylation sites in mek1 and mek2 are ser222 and ser226, respectively, and are known to be essential for full activation." SIGNOR-125176 PDPK1 protein O15530 UNIPROT RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation Ser227 DHEKKAYsFCGTVEY 9606 10480933 t gcesareni "We characterize two monoclonal antibodies raised against phosphorylated forms of the n- and c-terminal domain of rsk2 (p-s227 and p-t577, respectively). Using these two antibodies, we show that stress signals, such as uv light, induce phosphorylation and activation of the three rsks." SIGNOR-70612 PDPK1 protein O15530 UNIPROT RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation Ser227 DHEKKAYsFCGTVEY 9606 19956600 t gcesareni "We characterize two monoclonal antibodies raised against phosphorylated forms of the n- and c-terminal domain of rsk2 (p-s227 and p-t577, respectively). Using these two antibodies, we show that stress signals, such as uv light, induce phosphorylation and activation of the three rsks." SIGNOR-161924 PDPK1 protein O15530 UNIPROT PLK1 protein P53350 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007;BTO:0001914 23887393 t gcesareni "Here, we report that PDK1 directly induces phosphorylation of Polo-like kinase 1 (PLK1), which in turn induces MYC phosphorylation and protein accumulation. We show that PDK1-PLK1-MYC signaling is critical for cancer cell growth and survival, and small-molecule inhibition of PDK1/PLK1 provides an effective approach for therapeutic targeting of MYC dependency" SIGNOR-243519 PDPK1 protein O15530 UNIPROT PRKCE protein Q02156 UNIPROT up-regulates phosphorylation Thr566 LNGVTTTtFCGTPDY 9606 11964154 t llicata "In the present study, we analysed the contribution of the phosphoinositide-dependent kinase 1 (pdk-1) and pkcepsilon kinase activity in controlling the phosphorylation of thr(566) and ser(729). pdk-1 phosphorylation of the activation loop triggers autophosphorylation of the hydrophobic motif" SIGNOR-117320 PDPK1 protein O15530 UNIPROT MAP2K1 protein Q02750 UNIPROT "up-regulates activity" phosphorylation Ser222 LIDSMANsFVGTRSY 9606 BTO:0000007 15175348 t lperfetto "In vitro kinase assay revealed that the direct targets of pdk1 in the mapk pathway were the upstream mapk kinases mek1 and mek2. The identified pdk1 phosphorylation sites in mek1 and mek2 are ser222 and ser226, respectively, and are known to be essential for full activation" SIGNOR-236633 PDPK1 protein O15530 UNIPROT PRKCQ protein Q04759 UNIPROT up-regulates phosphorylation 9606 BTO:0000782 15802604 t gcesareni "We demonstrate that 3-phosphoinositide-dependent kinase 1 (pdk1) has an essential role in this pathway by regulating the activation of pkc and through signal-dependent recruiting of both pkc and card11 to lipid rafts." SIGNOR-134869 PDPK1 protein O15530 UNIPROT PRKCZ protein Q05513 UNIPROT up-regulates phosphorylation Thr410 GPGDTTStFCGTPNY 9606 11141077 t gcesareni "Our findings suggest that insulin, via pip(3), provokes increases in pkc-zeta enzyme activity through (a) pdk-1-dependent t410 loop phosphorylation, (b) t560 autophosphorylationcytoskeletal reorganization;tnni1(induces);desmin(induces);tpm1(induces);myo1c(induces);tnnt1(induces);" SIGNOR-85501 PDPK1 protein O15530 UNIPROT PRKCD protein Q05655 UNIPROT "up-regulates activity" phosphorylation Thr507 FGESRAStFCGTPDY 9606 BTO:0000007 9748166 t miannu "PDK1 phosphorylated the activation loop sites of PKCzeta and PKCdelta in vitro and in a phosphoinositide 3-kinase (PI 3-kinase)-dependent manner in vivo in human embryonic kidney (293) cells. PKCδ was also phosphorylated in the activation loop site (T505)" SIGNOR-250269 PDPK1 protein O15530 UNIPROT PAK1 protein Q13153 UNIPROT "up-regulates activity" phosphorylation Thr423 PEQSKRStMVGTPYW 9534 BTO:0000298 10995762 t miannu "P21-activated kinase (PAK1) is phosphorylated and activated by 3-phosphoinositide-dependent kinase-1 (PDK1). We identify threonine 423, a conserved threonine in the activation loop of kinase subdomain VIII, as the PDK1 phosphorylation site on PAK1." SIGNOR-250267 PDPK1 protein O15530 UNIPROT RPS6KA1 protein Q15418 UNIPROT "up-regulates activity" phosphorylation Ser221 DHEKKAYsFCGTVEY 9534 BTO:0000298 10480933 t miannu "Full-length RSK1, RSK2, and RSK3 Are Activated when Coexpressed with PDK1 in COS7 Cells. Ser221 phosphorylation is increased 2–3-fold during ERK-mediated activation of RSK1 in COS1 cells" SIGNOR-250270 PDPK1 protein O15530 UNIPROT PKN1 protein Q16512 UNIPROT up-regulates phosphorylation Thr774 GYGDRTStFCGTPEF 9606 10753910 t miannu "It is shown that activation in vitro and in vivo involves the activation loop phosphorylation of prk1/2 by 3-phosphoinositide-dependent protein kinase-1 (pdk1) /pdk1 phosphorylates the prks at their conserved activation loop threonines (thr-774 and thr-816 for prk1 and prk2, respectively)" SIGNOR-76640 PDPK1 protein O15530 UNIPROT PKN2 protein Q16513 UNIPROT up-regulates phosphorylation Thr816 GYGDRTStFCGTPEF 9606 10753910 t miannu "It is shown that activation in vitro and in vivo involves the activation loop phosphorylation of prk1/2 by 3-phosphoinositide-dependent protein kinase-1 (pdk1) /pdk1 phosphorylates the prks at their conserved activation loop threonines (thr-774 and thr-816 for prk1 and prk2, respectively)" SIGNOR-76710 PDPK1 protein O15530 UNIPROT SGK3 protein Q96BR1 UNIPROT up-regulates phosphorylation 9606 15209375 t gcesareni "One of the most studied events controlled by ptdins(3,4,5)p3, comprises the activation of a of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated." SIGNOR-126236 PDPK1 protein O15530 UNIPROT SGK3 protein Q96BR1 UNIPROT up-regulates phosphorylation Thr320 AISDTTTtFCGTPEY 9606 16790420 t llicata "Full-length sgk3 contains a complete phox homology (px) domain that targets the protein to endosomes. Both a functional px domain and pi3k activation are necessary for phosphorylation of sgk3 at two regulatory sites (thr-320 and ser-486) and subsequent induction of kinase activity. Pdk1 phosphorylates endosome-associated sgk3 at thr-320" SIGNOR-147213 PDPK1 protein O15530 UNIPROT SGK3 protein Q96BR1 UNIPROT "up-regulates activity" phosphorylation Ser486 DDAFVGFsYAPPSED 10548550 t miannu "SGK2 and SGK3 are activated in vitro by PDK1, albeit more slowly than SGK1, and their activation is accompanied by the phosphorylation of Thr(193) and Thr(253) respectively. The PDK1-catalysed phosphorylation and activation of SGK2 and SGK3, like SGK1, is greatly potentiated by mutating Ser(356) and Ser(419) respectively to Asp, these residues being equivalent to the C-terminal phosphorylation site of PKB." SIGNOR-250278 PDPK1 protein O15530 UNIPROT SGK3 protein Q96BR1 UNIPROT "up-regulates activity" phosphorylation Thr320 AISDTTTtFCGTPEY 10548550 t miannu "SGK2 and SGK3 are activated in vitro by PDK1, albeit more slowly than SGK1, and their activation is accompanied by the phosphorylation of Thr(193) and Thr(253) respectively. The PDK1-catalysed phosphorylation and activation of SGK2 and SGK3, like SGK1, is greatly potentiated by mutating Ser(356) and Ser(419) respectively to Asp, these residues being equivalent to the C-terminal phosphorylation site of PKB." SIGNOR-250279 PDPK1 protein O15530 UNIPROT TSSK3 protein Q96PN8 UNIPROT "up-regulates activity" phosphorylation Thr168 SHRELSQtFCGSTAY -1 16336268 t Manara "We elucidated the mechanism of regulation of TSSK3 activity showing that autophosphorylation and PDK1 phosphorylation in the ‘activation loop’ are necessary for activation." SIGNOR-260786 PDPK1 protein O15530 UNIPROT CARD11 protein Q9BXL7 UNIPROT up-regulates phosphorylation 9606 BTO:0000782 15802604 t gcesareni "We demonstrate that 3-phosphoinositide-dependent kinase 1 (pdk1) has an essential role in this pathway by regulating the activation of pkc and through signal-dependent recruiting of both pkc and card11 to lipid rafts." SIGNOR-134866 PDPK1 protein O15530 UNIPROT SGK2 protein Q9HBY8 UNIPROT up-regulates phosphorylation 9606 15209375 t gcesareni "One of the most studiedevents controlled by ptdins(3,4,5)p3, comprises the activation of aof agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated." SIGNOR-126177 PDPK1 protein O15530 UNIPROT SGK2 protein Q9HBY8 UNIPROT "up-regulates activity" phosphorylation Ser416 SSAFLGFsYAPEDDD 10548550 t miannu "SGK2 and SGK3 are activated in vitro by PDK1, albeit more slowly than SGK1, and their activation is accompanied by the phosphorylation of Thr(193) and Thr(253) respectively. The PDK1-catalysed phosphorylation and activation of SGK2 and SGK3, like SGK1, is greatly potentiated by mutating Ser(356) and Ser(419) respectively to Asp, these residues being equivalent to the C-terminal phosphorylation site of PKB." SIGNOR-250376 PDPK1 protein O15530 UNIPROT SGK2 protein Q9HBY8 UNIPROT "up-regulates activity" phosphorylation Thr193 EPEDTTStFCGTPEY 10548550 t miannu "SGK2 and SGK3 are activated in vitro by PDK1, albeit more slowly than SGK1, and their activation is accompanied by the phosphorylation of Thr(193) and Thr(253) respectively. The PDK1-catalysed phosphorylation and activation of SGK2 and SGK3, like SGK1, is greatly potentiated by mutating Ser(356) and Ser(419) respectively to Asp, these residues being equivalent to the C-terminal phosphorylation site of PKB." SIGNOR-250277 PDPK1 protein O15530 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT up-regulates phosphorylation Thr228 HEGAVTHtFCGTIEY 9606 15209375 t gcesareni "A regulatory link between p70s6k and pkb was demonstrated, as pdk1 was found to selectively phosphorylate p70s6k at thr229. More importantly, pdk1 activated p70s6k in vitro and in vivo, whereas the catalytically inactive pdk1 blocked insulin-induced activation of p70s6k. one of the most studied signalling events controlled by ptdins(3,4,5)p3, comprises the activation of a group of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated." SIGNOR-126076 PDPK1 protein O15530 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT up-regulates phosphorylation Thr228 HEGAVTHtFCGTIEY 9606 9445476 t gcesareni "A regulatory link between p70s6k and pkb was demonstrated, as pdk1 was found to selectively phosphorylate p70s6k at thr229. More importantly, pdk1 activated p70s6k in vitro and in vivo, whereas the catalytically inactive pdk1 blocked insulin-induced activation of p70s6k. one of the most studied signalling events controlled by ptdins(3,4,5)p3, comprises the activation of a group of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated." SIGNOR-55371 PDPK1 protein O15530 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT "up-regulates activity" phosphorylation Ser370 TRQTPVDsPDDTALS -1 11733037 t miannu " Mutational analysis revealed that the phosphorylation of Thr241 and Thr401 in p70beta1 was indispensable for the kinase activity. In contrast, a p70beta1 mutant in which Ser383 was substituted with Gly (S383G) still retained nearly the half maximal activity. Sequential phosphorylation of wild-type and S383G mutant of p70beta1 with mTOR and 3-phosphoinositide-dependent protein kinase 1 (PDK1) in vitro synergistically activated their kinase activities." SIGNOR-250371 PDPK1 protein O15530 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT "up-regulates activity" phosphorylation Thr228 HEGAVTHtFCGTIEY -1 11733037 t miannu " Mutational analysis revealed that the phosphorylation of Thr241 and Thr401 in p70beta1 was indispensable for the kinase activity. In contrast, a p70beta1 mutant in which Ser383 was substituted with Gly (S383G) still retained nearly the half maximal activity. Sequential phosphorylation of wild-type and S383G mutant of p70beta1 with mTOR and 3-phosphoinositide-dependent protein kinase 1 (PDK1) in vitro synergistically activated their kinase activities." SIGNOR-250273 NUAK1 protein O60285 UNIPROT CASP6 protein P55212 UNIPROT "down-regulates activity" phosphorylation Ser257 TLVNRKVsQRRVDFC -1 15273717 t miannu "ARK5 negatively regulates procaspase-6 by phosphorylation at Ser257, leading to resistance to the FasL/Fas system." SIGNOR-250209 PDPK1 protein O15530 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT "up-regulates activity" phosphorylation Thr388 NQAFLGFtYVAPSVL -1 11733037 t miannu " Mutational analysis revealed that the phosphorylation of Thr241 and Thr401 in p70beta1 was indispensable for the kinase activity. In contrast, a p70beta1 mutant in which Ser383 was substituted with Gly (S383G) still retained nearly the half maximal activity. Sequential phosphorylation of wild-type and S383G mutant of p70beta1 with mTOR and 3-phosphoinositide-dependent protein kinase 1 (PDK1) in vitro synergistically activated their kinase activities." SIGNOR-250272 PDPK1 protein O15530 UNIPROT AKT3 protein Q9Y243 UNIPROT up-regulates phosphorylation Thr305 TDAATMKtFCGTPEY 9606 BTO:0000887;BTO:0001103;BTO:0001760 9512493 t gcesareni "The activation of pkbbeta and pkbgamma by pdk1 was accompanied by the phosphorylation of the residues equivalent to thr308 in pkbalpha, namely thr309 (pkbbeta) and thr305 (pkbgamma)" SIGNOR-55937 PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation 9606 21798082 t lperfetto "Positive feedback involves mtorc2, which phosphorylates akt at serine 473, a phosphorylation required for maximum activation of akt in addition to phosphorylation at threonine 308 by pdk1." SIGNOR-244396 PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Thr308 KDGATMKtFCGTPEY 10116 BTO:0000142 10226025 t 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 PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Thr308 KDGATMKtFCGTPEY 10090 12808134 t 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 PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0000567 15718470 t 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 PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation 9606 15743829 t 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 PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0000887;BTO:0001103;BTO:0001760 9512493 t 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 PDPK1 protein O15530 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 15175348 t lperfetto "The identified pdk1 phosphorylation sites in mek1 and mek2 are ser222 and ser226, respectively, and are known to be essential for full activation." SIGNOR-244938 PDPK1 protein O15530 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000007 15175348 t lperfetto "In vitro kinase assay revealed that the direct targets of pdk1 in the mapk pathway were the upstream mapk kinases mek1 and mek2. The identified pdk1 phosphorylation sites in mek1 and mek2 are ser222 and ser226, respectively, and are known to be essential for full activation" SIGNOR-244934 PDPK1 protein O15530 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR "up-regulates activity" phosphorylation Ser221 DHEKKAYsFCGTVEY 9534 BTO:0000298 10480933 t miannu "90-kDa ribosomal S6 kinase is phosphorylated and activated by 3-phosphoinositide-dependent protein kinase-1." SIGNOR-252763 PER1 protein O15534 UNIPROT SLC5A1 protein P13866 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000195 22526585 f miannu "Our findings suggest that PER1 exerts an indirect suppressive effect on SGLT1, possibly acting via other clock-controlled genes binding to non-E-box sites on the SGLT1 promoter." SIGNOR-254912 KDM6A protein O15550 UNIPROT HOXC11 protein O43248 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24561908 t miannu "Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters." SIGNOR-260026 KDM6A protein O15550 UNIPROT HOXC4 protein P09017 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24561908 t miannu "Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters." SIGNOR-260030 KDM6A protein O15550 UNIPROT HOXC6 protein P09630 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24561908 t miannu "Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters." SIGNOR-260028 KDM6A protein O15550 UNIPROT ERG protein P11308 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 29736013 t miannu "Our findings reveal a dual role for UTX in suppressing acute myeloid leukaemia via repression of oncogenic ETS and upregulation of tumor suppressive GATA programs. several ETS transcription factors, including Elf4, Etv6, Erg, Fli1, Ets2, Spi1 and Elk3 were upregulated immediately after Utx loss in the preleukaemic phase" SIGNOR-260033 KDM6A protein O15550 UNIPROT ETS2 protein P15036 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 29736013 t miannu "Our findings reveal a dual role for UTX in suppressing acute myeloid leukaemia via repression of oncogenic ETS and upregulation of tumor suppressive GATA programs. several ETS transcription factors, including Elf4, Etv6, Erg, Fli1, Ets2, Spi1 and Elk3 were upregulated immediately after Utx loss in the preleukaemic phase" SIGNOR-260035 KDM6A protein O15550 UNIPROT SPI1 protein P17947 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 29736013 t miannu "Our findings reveal a dual role for UTX in suppressing acute myeloid leukaemia via repression of oncogenic ETS and upregulation of tumor suppressive GATA programs. several ETS transcription factors, including Elf4, Etv6, Erg, Fli1, Ets2, Spi1 and Elk3 were upregulated immediately after Utx loss in the preleukaemic phase" SIGNOR-260036 KDM6A protein O15550 UNIPROT HOXA5 protein P20719 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24561908 t miannu "Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters." SIGNOR-260023 KDM6A protein O15550 UNIPROT HOXA7 protein P31268 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24561908 t miannu "Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters." SIGNOR-260024 KDM6A protein O15550 UNIPROT HOXA9 protein P31269 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24561908 t miannu "Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters." SIGNOR-260025 KDM6A protein O15550 UNIPROT HOXA11 protein P31270 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24561908 t miannu "Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters." SIGNOR-260021 KDM6A protein O15550 UNIPROT HOXA13 protein P31271 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24561908 t miannu "Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters." SIGNOR-260022 KDM6A protein O15550 UNIPROT HOXC8 protein P31273 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24561908 t miannu "Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters." SIGNOR-260029 KDM6A protein O15550 UNIPROT HOXC13 protein P31276 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24561908 t miannu "Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters." SIGNOR-260027 KDM6A protein O15550 UNIPROT ETV6 protein P41212 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 29736013 t miannu "Our findings reveal a dual role for UTX in suppressing acute myeloid leukaemia via repression of oncogenic ETS and upregulation of tumor suppressive GATA programs. several ETS transcription factors, including Elf4, Etv6, Erg, Fli1, Ets2, Spi1 and Elk3 were upregulated immediately after Utx loss in the preleukaemic phase" SIGNOR-260032 KDM6A protein O15550 UNIPROT ELK3 protein P41970 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 29736013 t miannu "Our findings reveal a dual role for UTX in suppressing acute myeloid leukaemia via repression of oncogenic ETS and upregulation of tumor suppressive GATA programs. several ETS transcription factors, including Elf4, Etv6, Erg, Fli1, Ets2, Spi1 and Elk3 were upregulated immediately after Utx loss in the preleukaemic phase" SIGNOR-260037 KDM6A protein O15550 UNIPROT HOXA1 protein P49639 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24561908 t miannu "Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters." SIGNOR-260019 KDM6A protein O15550 UNIPROT H3C1 protein P68431 UNIPROT "down-regulates activity" demethylation Lys28 LATKAARkSAPATGG 9606 24561908 t "This tri-methylation is associated with the downregulation of nearby genes via the formation of heterochromatic regions." miannu "Ubiquitously Transcribed Tetratricopeptide Repeat on chromosome X (UTX) and Jumonji D3 (JMJD3) as novel histone demethylases that catalyze the removal of di- and trimethyl groups on histone H3 lysine 27, thereby promoting target gene activation." SIGNOR-260017 KDM6A protein O15550 UNIPROT ZBTB16 protein Q05516 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 29736013 t miannu "UTX catalytic activity has been reported to upregulate expression of the master transcription factor PLZF and to modulate superenhancer accessibility in invariant natural killer T cells." SIGNOR-260038 KDM6A protein O15550 UNIPROT ELF4 protein Q99607 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 29736013 t miannu "Our findings reveal a dual role for UTX in suppressing acute myeloid leukaemia via repression of oncogenic ETS and upregulation of tumor suppressive GATA programs. several ETS transcription factors, including Elf4, Etv6, Erg, Fli1, Ets2, Spi1 and Elk3 were upregulated immediately after Utx loss in the preleukaemic phase" SIGNOR-260031 FFAR2 protein O15552 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257075 FFAR2 protein O15552 UNIPROT GNA15 protein P30679 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257276 PHF1 protein O43189 UNIPROT HOXA10 protein P31260 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 20565746 t miannu "These data support the proposed regulatory impact of particular PRC2-proteins in expression of HOXA9 and HOXA10 in NK/T-cells. In mammalian cells knockdown of PRC2 components EZH2 or PHF1 led to upregulated HOXA gene expression." SIGNOR-260071 FFAR2 protein O15552 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256946 FFAR2 protein O15552 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257188 FFAR2 protein O15552 UNIPROT GNA13 protein Q14344 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257397 FFAR2 protein O15552 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256803 MEFV protein O15553 UNIPROT "Pyrin inflammasome" complex SIGNOR-C226 SIGNOR "form complex" binding 30288079 t lperfetto "Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin." SIGNOR-256413 CYP26A1 protein O43174 UNIPROT "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI "down-regulates activity" "chemical inhibition" 9606 BTO:0001248 9716180 t Gianni "The RA-induced CYP26 was shown to be highly specific for the hydroxylation of all-trans-RA and did not recognize the 13-cis and 9-cis isomers. This substrate specificity is promising for finding retinoids that are not recognized by this enzyme and, therefore, could be more effective in growth inhibition of susceptible cancer cells." SIGNOR-266425 CYP26A1 protein O43174 UNIPROT "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 31963453 t lperfetto "Cytochrome P450 (CYP) subfamily 26 of enzymes degrade the excess of RA to avoid detrimental effects [17]. Among the three subtypes (CYP26A1, CYP26B1, and CYP26C1), CYP26A1 is particularly important during embryonic development" SIGNOR-265139 NDUFS4 protein O43181 UNIPROT "Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24]." SIGNOR-262178 ARHGAP6 protein O43182 UNIPROT RHOA protein P61586 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260462 ADAM12 protein O43184 UNIPROT SDC4 protein P31431 UNIPROT up-regulates binding 9606 BTO:0000975 12509413 t gcesareni "The adam12 cysteine-rich domain (radam12-cys) supports cell attachment using syndecan-4 as a primary cell surface receptor that subsequently triggers beta(1) integrin-dependent cell spreading, stress fiber assembly, and focal adhesion formation." SIGNOR-96931 CRX protein O43186 UNIPROT RS1 protein O15537 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003061 18927113 f miannu "Our in vitro and in vivo results indicate that two CRE sites in the minimal RS1 promoter region control retinal RS1 expression and establish CRX as a key factor driving this expression." SIGNOR-253822 CRX protein O43186 UNIPROT BEST1 protein O76090 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" -1 18849347 f miannu "Three OTX family proteins - OTX1, OTX2 and CRX - bound to both Sites 1 and 2 in vitro, and all of them increased BEST1 promoter activity." SIGNOR-253815 CRX protein O43186 UNIPROT RHO protein P08100 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000007 15277472 f miannu "KLF15 repressed transactivation of rhodopsin and IRBP promoters alone and in combination with the transcriptional activators Crx and/or Nrl." SIGNOR-253820 CRX protein O43186 UNIPROT RBP3 protein P10745 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000007 15277472 f miannu "KLF15 repressed transactivation of rhodopsin and IRBP promoters alone and in combination with the transcriptional activators Crx and/or Nrl." SIGNOR-253821 PHF1 protein O43189 UNIPROT HOXA9 protein P31269 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 20565746 t miannu "These data support the proposed regulatory impact of particular PRC2-proteins in expression of HOXA9 and HOXA10 in NK/T-cells. In mammalian cells knockdown of PRC2 components EZH2 or PHF1 led to upregulated HOXA gene expression." SIGNOR-260069 MLNR protein O43193 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257132 MLNR protein O43193 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256880 MLNR protein O43193 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256737 MLNR protein O43193 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257222 PSMD3 protein O43242 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "form complex" binding 9606 BTO:0000007 29636472 t lperfetto "Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line" SIGNOR-263353 ZNHIT1 protein O43257 UNIPROT H2AZ1 protein P0C0S5 UNIPROT unknown 9606 BTO:0000887 20473270 f gcesareni "The chromatin-remodelling complex snf2-related cbp activator protein (srcap) regulates chromatin structure in yeast by modulating the exchange of histone h2a for the h2a.z variant. We also show that p18hamlet is required for h2a.z accumulation into this genomic region and for subsequent muscle gene transcriptional activation." SIGNOR-165610 ZW10 protein O43264 UNIPROT DCTN2 protein Q13561 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000567 SIGNOR-C357 20462495 t lperfetto "ZW10 interacts with dynamitin, a subunit of the dynein-dynactin complex (Echeverri et al., 1996), thereby recruiting this motor to kinetochores" SIGNOR-265016 ZW10 protein O43264 UNIPROT "RZZ complex" complex SIGNOR-C357 SIGNOR "form complex" binding 9606 BTO:0000567 20462495 t lperfetto "The RZZ complex recruits dynein to kinetochores. We investigated structure, topology, and interactions of the RZZ subunits (ROD, ZWILCH, and ZW10) in vitro, in vivo, and in silico." SIGNOR-265012 ZW10 protein O43264 UNIPROT "NRZ complex" complex SIGNOR-C358 SIGNOR "form complex" binding 25364732 t lperfetto "NRZ complex, which comprises NAG, RINT1, and ZW10, is also involved in Golgi-to-ER retrograde transport, but each component of the complex has diverse cellular functions including endosome-to-Golgi transport, cytokinesis, cell cycle checkpoint, autophagy, and mRNA decay." SIGNOR-265023 GPAA1 protein O43292 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 32432756 f miannu "GPAA1 may contribute to the malignant progression of childhood ALL via activating c-myc. Luciferase reporter gene assay demonstrated that overexpression of c-myc remarkably attenuated the Luciferase activity of the wild-type GPAA1 vector without attenuating that of the mutant vector or empty vector, further demonstrating that GPAA1 can be targeted by c-myc." SIGNOR-261240 DAPK3 protein O43293 UNIPROT MYL12B protein O14950 UNIPROT up-regulates phosphorylation Ser20 KRPQRATsNVFAMFD 9606 1178183 t lperfetto "Hzipk phosphorylated the regulatory light chain of myosin ii (mrlc) at both ser19 and thr18 in vitro. Phosphorylation of mrlc is required to generate the driving force in the migration of the cells but not necessary for localization of myosin ii at the leading edge." SIGNOR-16043 DAPK3 protein O43293 UNIPROT MYL12B protein O14950 UNIPROT up-regulates phosphorylation Thr19 KKRPQRAtSNVFAMF 9606 1178183 t gcesareni "Hzipk phosphorylated the regulatory light chain of myosin ii (mrlc) at both ser19 and thr18 in vitro. Phosphorylation of mrlc is required to generate the driving force in the migration of the cells but not necessary for localization of myosin ii at the leading edge." SIGNOR-16047 DAPK3 protein O43293 UNIPROT MYL12B protein O14950 UNIPROT up-regulates phosphorylation Thr19 KKRPQRAtSNVFAMF 9606 BTO:0000567 12429016 t gcesareni "Hzipk phosphorylated the regulatory light chain of myosin ii (mrlc) at both ser19 and thr18 in vitro. Phosphorylation of mrlc is required to generate the driving force in the migration of the cells but not necessary for localization of myosin ii at the leading edge." SIGNOR-95524 DAPK3 protein O43293 UNIPROT DAPK3 protein O43293 UNIPROT up-regulates phosphorylation Ser311 EYTIKSHsSLPPNNS 9606 BTO:0000887;BTO:0001260 15611134 t lperfetto "Zipk autophosphorylates in vitrowe have identified six phosphorylation sites in zipk that regulate both its enzyme activity and localization, including thr180, thr225, thr265, thr299, thr306, and ser311." SIGNOR-132455 DAPK3 protein O43293 UNIPROT DAPK3 protein O43293 UNIPROT up-regulates phosphorylation Thr180 EFKNIFGtPEFVAPE 9606 BTO:0000887;BTO:0001260 15611134 t gcesareni "Mutational analysis showed that phosphorylation of thr180 in the kinase activation t-loop, thr225 in the substrate-binding groove, and thr265 in kinase subdomain x is essential for full zipk autophosphorylation and activity toward exogenous substrates." SIGNOR-132459 DAPK3 protein O43293 UNIPROT DAPK3 protein O43293 UNIPROT up-regulates phosphorylation Thr225 LGETKQEtLTNISAV 9606 BTO:0000887;BTO:0001260 15611134 t gcesareni "Mutational analysis showed that phosphorylation of thr180 in the kinase activation t-loop, thr225 in the substrate-binding groove, and thr265 in kinase subdomain x is essential for full zipk autophosphorylation and activity toward exogenous substrates." SIGNOR-132463 DAPK3 protein O43293 UNIPROT DAPK3 protein O43293 UNIPROT up-regulates phosphorylation Thr265 KDPKRRMtIAQSLEH 9606 BTO:0000887;BTO:0001260 15611134 t gcesareni "Mutational analysis showed that phosphorylation of thr180 in the kinase activation t-loop, thr225 in the substrate-binding groove, and thr265 in kinase subdomain x is essential for full zipk autophosphorylation and activity toward exogenous substrates." SIGNOR-132467 DAPK3 protein O43293 UNIPROT DAPK3 protein O43293 UNIPROT up-regulates phosphorylation Thr299 PERRRLKtTRLKEYT 9606 BTO:0000887;BTO:0001260 15611134 t lperfetto "Zipk autophosphorylates in vitrowe have identified six phosphorylation sites in zipk that regulate both its enzyme activity and localization, including thr180, thr225, thr265, thr299, thr306, and ser311.Abrogation of phosphorylation of thr299, thr306, and ser311 had little effect on enzyme activity, but mutation of thr299 and thr300 to alanine resulted in redistribution of zipk from the cytosol to the nucleus" SIGNOR-132471 DAPK3 protein O43293 UNIPROT DAPK3 protein O43293 UNIPROT up-regulates phosphorylation Thr306 TTRLKEYtIKSHSSL 9606 BTO:0000887;BTO:0001260 15611134 t lperfetto "Zipk autophosphorylates in vitrowe have identified six phosphorylation sites in zipk that regulate both its enzyme activity and localization, including thr180, thr225, thr265, thr299, thr306, and ser311" SIGNOR-132475 DAPK3 protein O43293 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser20 PLSQETFsDLWKLLP 9606 BTO:0000776 17339337 t gcesareni "A cell-free ser(20) phosphorylation site assay was used to identify a broad range of calcium calmodulin kinase superfamily members, including chk2, chk1, dapk-1, dapk-3, drak-1, and ampk, as ser(20) kinases.Evaluation of these calcium calmodulin kinase superfamily members as candidate ser(20) kinases in vivo has shown that only chk1 or dapk-1 can stimulate p53 transactivation and induce ser(20) phosphorylation of p53." SIGNOR-153495 DAPK3 protein O43293 UNIPROT MYL9 protein P24844 UNIPROT up-regulates phosphorylation Ser20 KRPQRATsNVFAMFD 9606 19851336 t lperfetto "More than a dozen kinases have been reported to phosphorylate the rlcs of nm ii (fig. 2), including myosin light chain kinase (mlck;also known as mylk), rho-associated, coiled coil-containing kinase (rock), citron kinase, leucine zipper interacting kinase (zipk;also known as dapk3) and myotonic dystrophy kinase-related cdc42-binding kinase (mrck;also known as cdc42bp)6,34,45,46. These kinases phosphorylate rlcs on ser19, thr18 or both, to relieve the inhibition imposed on the myosin molecule by unphosphorylated rlcs and the head_head interaction outlined above." SIGNOR-188789 DAPK3 protein O43293 UNIPROT MYL9 protein P24844 UNIPROT up-regulates phosphorylation Thr19 KKRPQRAtSNVFAMF 9606 19851336 t lperfetto "More than a dozen kinases have been reported to phosphorylate the rlcs of nm ii (fig. 2), including myosin light chain kinase (mlck;also known as mylk), rho-associated, coiled coil-containing kinase (rock), citron kinase, leucine zipper interacting kinase (zipk;also known as dapk3) and myotonic dystrophy kinase-related cdc42-binding kinase (mrck;also known as cdc42bp)6,34,45,46. These kinases phosphorylate rlcs on ser19, thr18 or both, to relieve the inhibition imposed on the myosin molecule by unphosphorylated rlcs and the head_head interaction outlined above." SIGNOR-188793 DAPK3 protein O43293 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr145 QGRKRRQtSMTDFYH -1 15001356 t llicata "ZIP kinase phosphorylates p21(WAF1) at Thr145 and alanine-substituted mutations in the p21(WAF1) phosphorylation site alter its ability to be phosphorylated by ZIP kinase. | Transfected ZIPK can promote the phosphorylation of p21(WAF1) at Thr145 in vivo and can increase the half-life of p21(WAF1)" SIGNOR-251085 DAPK3 protein O43293 UNIPROT RPL13A protein P40429 UNIPROT up-regulates phosphorylation Ser77 PYHFRAPsRIFWRTV 9606 BTO:0000801 18995835 t lperfetto "Zipk phosphorylates l13a in vitro / l13a is phosphorylated on ser77 in vitro" SIGNOR-182117 DAPK3 protein O43293 UNIPROT MDM2 protein Q00987 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser166 SSRRRAIsETEENSD 9606 15001356 t gcesareni "Zip kinase was able to phosphorylate mdm2 at ser166, a site previously reported to be modified by akt kinase, thus demonstrating that zip kinase is a bona fide mdm2-binding protein." SIGNOR-123159 SRGAP3 protein O43295 UNIPROT WASF1 protein Q92558 UNIPROT up-regulates binding 9606 12447388 t miannu "Wrp binds directly to wave-1 through its src homology domain 3 and specifically inhibits rac function in vivo." SIGNOR-95967 ZBTB43 protein O43298 UNIPROT BDP1 protein A6H8Y1 UNIPROT unknown binding 9606 16542149 t miannu "The zinc finger protein ZNF297B interacts with BDP1, a subunit of TFIIIB. Due to the essential role of BDP1 in Pol III transcription, we propose that ZNF297B may also regulate these transcriptional pathways." SIGNOR-225852 CCP110 protein O43303 UNIPROT CALM2 protein P0DP24 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 16760425 t miannu "We report that CP110 interacts with two different Ca2+-binding proteins, calmodulin (CaM) and centrin, in vivo. our data demonstrate a functional role for CaM binding to CP110 and suggest that CP110 cooperates with CaM and centrin to regulate progression through cytokinesis." SIGNOR-266332 ADCY6 protein O43306 UNIPROT "3',5'-cyclic AMP" smallmolecule CHEBI:17489 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 15385642 t miannu "Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions." SIGNOR-265001 TBX1 protein O43435 UNIPROT FLT4 protein P35916 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001176 20439995 f "Regulation of expression" miannu "Tbx1 plays a critical role in lymphatic vessel development and regulates the expression of Vegfr3, a gene that is essential for lymphangiogenesis. Tbx1 activates Vegfr3 transcription in endothelial cells (ECs) by binding to an enhancer element in the Vegfr3 gene." SIGNOR-251869 ARHGEF9 protein O43307 UNIPROT CDC42 protein P60953 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260534 MTSS1 protein O43312 UNIPROT GLI1 protein P08151 UNIPROT up-regulates binding 9606 BTO:0001253 15545630 t gcesareni "Mim is a shh-responsive gene that can potentiate gli transcriptional activity.MIM Appears to regulate target gene expression through its association with the gli complex" SIGNOR-130542 MTSS1 protein O43312 UNIPROT GLI1 protein P08151 UNIPROT up-regulates binding 9606 17845852 t gcesareni "Mim is a shh-responsive gene that can potentiate gli transcriptional activity.MIM Appears to regulate target gene expression through its association with the gli complex" SIGNOR-157650 MTSS1 protein O43312 UNIPROT SUFU protein Q9UMX1 UNIPROT up-regulates binding 9606 BTO:0001253 15545630 t miannu "We found that in vitro translated gli1 and sufu bind to gst-mim, but not gst-mim?N399 Or gst columns (fig. 4f). Indicative of the importance of the mim/gli complex interactions, the mim?N399 Mutant that fails to interact with gli and sufu showed a markedly reduced capacity to potentiate gli-dependent transcription (fig. 4g). Although these results indicate that a mim/gli/sufu complex is important for mim-mediated transcriptional potentiation" SIGNOR-130545 MAP3K7 protein O43318 UNIPROT IKBKB protein O14920 UNIPROT "up-regulates activity" phosphorylation Ser177 AKELDQGsLCTSFVG 9606 BTO:0000007 SIGNOR-C14 11460167 t lperfetto "Tak1 become activated and then phosphorylates and activates ikk2 which in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation. tak1 kinase complex phosphorylates and activates ikk in a manner that depends on traf6 and ubc13-uev1a our studies suggests that tak1_ acts as an upstream activating kinase for ikkbeta." SIGNOR-109490 MAP3K7 protein O43318 UNIPROT IKBKB protein O14920 UNIPROT "up-regulates activity" phosphorylation Ser181 DQGSLCTsFVGTLQY 9606 BTO:0000007 SIGNOR-C14 11460167 t lperfetto "Tak1 become activated and then phosphorylates and activates ikk2 which in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation. tak1 kinase complex phosphorylates and activates ikk in a manner that depends on traf6 and ubc13-uev1a our studies suggests that tak1_ acts as an upstream activating kinase for ikkbeta." SIGNOR-109494 MAP3K7 protein O43318 UNIPROT IKBKB protein O14920 UNIPROT "up-regulates activity" phosphorylation 9606 SIGNOR-C14 19632174 t lperfetto "Tak1 become activated and then phosphorylates and activates ikk2 which in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation. tak1 kinase complex phosphorylates and activates ikk in a manner that depends on traf6 and ubc13-uev1a our studies suggests that tak1_ acts as an upstream activating kinase for ikkbeta." SIGNOR-187242 MAP3K7 protein O43318 UNIPROT MAP3K7 protein O43318 UNIPROT "up-regulates activity" phosphorylation Ser192 HMTNNKGsAAWMAPE 9606 BTO:0000007 10702308 t 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 MAP3K7 protein O43318 UNIPROT MAP3K7 protein O43318 UNIPROT "up-regulates activity" phosphorylation Ser192 HMTNNKGsAAWMAPE -1 20538596 t 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 MAP3K7 protein O43318 UNIPROT MAP3K7 protein O43318 UNIPROT "up-regulates activity" phosphorylation Thr178 LKICDFGtACDIQTH -1 20538596 t 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 MAP3K7 protein O43318 UNIPROT MAP3K7 protein O43318 UNIPROT "up-regulates activity" phosphorylation Thr184 GTACDIQtHMTNNKG -1 20538596 t 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 MAP3K7 protein O43318 UNIPROT MAP3K7 protein O43318 UNIPROT "up-regulates activity" phosphorylation Thr187 CDIQTHMtNNKGSAA -1 20538596 t 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 MAP3K7 protein O43318 UNIPROT NFKB1 protein P19838 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567 9480845 f lperfetto "These results suggest that tak1 induces nf-kappa b activation through a novel nik-independent signaling pathway." SIGNOR-55713 MAP3K7 protein O43318 UNIPROT NFKBIA protein P25963 UNIPROT "down-regulates quantity by destabilization" 9606 BTO:0000567 9480845 f lperfetto "Overexpression of tak1 together with its activator protein, tak1 binding protein 1 (tab1), induced the nuclear translocation of nf-kappa b p50/p65 heterodimer accompanied by the degradation of i kappa b alpha and i kappa b beta, and the expression of kappa b-dependent reporter gene." SIGNOR-55716 MAP3K7 protein O43318 UNIPROT PTPN3 protein P26045 UNIPROT unknown phosphorylation Ser359 PAMRRSLsVEHLETK 9606 9341175 t gcesareni "Mutation of ser359 and ser853 to alanine significantly reduced the association between 14-3-3beta and ptph1. Furthermore, association of ptph1 and 14-3-3beta was detected in several cell lines and was regulated in response to extracellular signals" SIGNOR-52781 MAP3K7 protein O43318 UNIPROT MAP2K4 protein P45985 UNIPROT "up-regulates activity" phosphorylation 9606 9278437 t lperfetto "Mitogen-activated protein kinase kinase 4 (mkk4)/stress-activated protein kinase/extracellular signal-regulated kinase (sek1), a dual-specificity kinase that phosphorylates and activates jnk, synergized with tak1 in activating jnk.Taken together, these results identify TAK1 as a regulator in the HPK1 --> TAK1 --> MKK4/SEK1 --> JNK kinase cascade and indicate the involvement of JNK in the TGF-beta signaling pathway." SIGNOR-50618 MAP3K7 protein O43318 UNIPROT MAP2K3 protein P46734 UNIPROT "up-regulates activity" phosphorylation 10090 17299140 t 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 MAP3K7 protein O43318 UNIPROT MAP2K3 protein P46734 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000222 21902831 t 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 MAP3K7 protein O43318 UNIPROT RAB8A protein P61006 UNIPROT "up-regulates activity" phosphorylation Thr72 AGQERFRtITTAYYR -1 32227113 t lperfetto "In a screen for Rab8A kinases we identify TAK1 and MST3 kinases that can efficiently phosphorylate the Switch II residue Threonine72 (Thr72) in a similar manner as LRRK2 in vitro. |Overall our data suggests that the phosphorylation of Rab8A at Ser111 may influence Switch II-binding by regulators, thus disrupting interactions with its cognate GEF and moderately impairs its interaction with GAPs.|The antagonistic interplay between Ser111 phosphorylation and Thr72 phosphorylation is genetically concordant with how respective mutations in PINK1 and LRRK2 cause Parkinson’s disease" SIGNOR-260266 MAP3K7 protein O43318 UNIPROT NFKBIB protein Q15653 UNIPROT down-regulates phosphorylation 9606 9480845 t gcesareni "Overexpression oftak1together with its activator protein,tak1binding protein 1 (tab1), induced thenucleartranslocation of nf-kappa b p50/p65 heterodimer accompanied by the degradation of i kappa b alpha and i kappa b beta, and the expression of kappa b-dependent reporter gene." SIGNOR-55719 MAP3K7 protein O43318 UNIPROT KSR1 protein Q8IVT5 UNIPROT down-regulates phosphorylation Ser406 TRLRRTEsVPSDINN 9606 11741534 t gcesareni "C-tak1 constitutively associates with mammalian ksr1 and phosphorylates serine 392 to confer 14-3-3 binding and cytoplasmic sequestration of ksr1 in unstimulated cells. In response to signal activation, the phosphorylation state of s392 is reduced, allowing the ksr1 complex to colocalize with activated ras and raf-1 at the plasma membrane" SIGNOR-112779 MAP3K7 protein O43318 UNIPROT HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser155 FPLRKTVsEPNLKLR 9606 16980613 t lperfetto "We further show that emk and c-tak1 phosphorylate class iia hdacs on one of their multiple 14-3-3 binding sites and alter their subcellular localization and repressive function" SIGNOR-149579 MAP3K7 protein O43318 UNIPROT MAP3K14 protein Q99558 UNIPROT "up-regulates activity" phosphorylation 10094049 t lperfetto "The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathway|Activated TAK1 phosphorylates NIK, which stimulates IKK-alpha activity. Our results indicate that TAK1 links TRAF6 to the NIK-IKK cascade in the IL-1 signalling pathway." SIGNOR-262833 MAP3K7 protein O43318 UNIPROT NLK protein Q9UBE8 UNIPROT up-regulates phosphorylation 9606 BTO:0000007 12482967 t gcesareni "The tak1-nlk-mapk-related pathway antagonizes signalling between beta-catenin and transcription factor tcf." SIGNOR-96425 MAP3K7 protein O43318 UNIPROT IKBKG protein Q9Y6K9 UNIPROT "up-regulates activity" binding 9606 SIGNOR-C14 20038579 t lperfetto "This result suggests that ikkgamma/nemo binds to the polyubiquitinated tak1." SIGNOR-162634 MAP3K7 protein O43318 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR "up-regulates activity" phosphorylation 9606 21133840 t 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 MAP3K7 protein O43318 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR "up-regulates activity" phosphorylation 9606 21232017 t 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 MSI1 protein O43347 UNIPROT NUMB protein P49757 UNIPROT down-regulates binding 9606 20477901 t "Inhibits translation" gcesareni "The study confirmed p21(cip1) and numb proteins as targets of musashi1, suggesting additionally p27(kip1) in cell-cycle regulation and jagged-1 in notch ." SIGNOR-165617 RIPK2 protein O43353 UNIPROT RIPK2 protein O43353 UNIPROT "up-regulates activity" phosphorylation Ser176 KWRMMSLsQSRSSKS 9606 BTO:0000801 16824733 t amattioni "In summary, our results indicate that s176 is a regulatory autophosphorylation site for rip2 and that s176 phosphorylation can be used to monitor the activation state of rip2." SIGNOR-229701 RIPK2 protein O43353 UNIPROT IKBKG protein Q9Y6K9 UNIPROT "up-regulates activity" 9606 SIGNOR-C14 16493424 f miannu "In the case of NOD2, activation of RICK leads to K63 (Lys63)-linked polyubiquitylation of IKKgamma, the scaffold of the inhibitor of NF-kappaB (IkappaB)-kinase complex (the IKK complex), which also consists of IKKalpha and IKKbeta. This is followed by the phosphorylation of IKKbeta, as well as the phosphorylation of IkappaB and the release of nuclear factor-kappaB (NF-kappaB) for translocation to the nucleus. So, in activating the IKK complex, RICK either activates an E3 ubiquitin ligase that promotes K63-linked polyubiquitylation or inhibits an enzyme (such as cylindromatosis protein, CYLD) that de-ubiquitylates proteins that are modified with K63-linked polyubiquitin, so RICK does not require its own kinase activity for this function." SIGNOR-252413 GRID2 protein O43424 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000938 29953871 t miannu "Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial." SIGNOR-264952 SYNJ1 protein O43426 UNIPROT MYO1E protein Q12965 UNIPROT "up-regulates activity" binding 10116 BTO:0000142 17257598 t miannu "We describe binding of two PRD-containing endocytic proteins, dynamin and synaptojanin-1, to the SH3 domain of Myo1E. This interaction was detected both in vitro, using pull-downs of purified proteins, and in vivo, using immunoprecipitation of protein complexes from synapse-enriched brain extract and immunolocalization of Myo1E and dynamin. Our observation of the interaction between human Myo1E and endocytic proteins suggests that this longtailed myosin may play a role in clathrin-dependent endocytosis.Interaction between Myo1E SH3 domain and PRD-containing endocytic proteins may promote recruitment of Myo1E to clathrin-coated structures since an inactivating mutation in the SH3 domain reduced Myo1E localization to clathrin-containing puncta." SIGNOR-265423 ATP8B1 protein O43520 UNIPROT ATP2B2 protein Q01814 UNIPROT up-regulates 9606 BTO:0000630 19478059 f lperfetto "Consequently ATP8B1 deficiency, with a secondary disturbance of membrane lipid asymmetry, likely inhibits PMCA2 activity and affects the efficiency of mechanotransduction." SIGNOR-262584 SUV39H1 protein O43463 UNIPROT MYOD1 protein P15172 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002267 23435416 f lperfetto "The methyl marks H3K9me3 on the myoD promoter and H3K27me3 on the myogenin promoter have been shown to be under the control of the histone methyl transferase KMT1A and the HDM KDM4A, respectively, during normal myogenesis. In addition, KMT1A has recently been shown to play a role in ARMS by inhibiting myogenic differentiation" SIGNOR-249600 SUV39H1 protein O43463 UNIPROT MYOG protein P15173 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002267 23435416 f lperfetto "The methyl marks H3K9me3 on the myoD promoter and H3K27me3 on the myogenin promoter have been shown to be under the control of the histone methyl transferase KMT1A and the HDM KDM4A, respectively, during normal myogenesis. In addition, KMT1A has recently been shown to play a role in ARMS by inhibiting myogenic differentiation" SIGNOR-249601 HTRA2 protein O43464 UNIPROT XIAP protein P98170 UNIPROT down-regulates binding 9606 11583623 t gcesareni "Here we report that a serine protease called htra2/omi is released from mitochondria and inhibits the function of xiap by direct binding in a similar way to diablo." SIGNOR-110834 KLF4 protein O43474 UNIPROT SOD1 protein P00441 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002104 23370975 f miannu "The expression of superoxide dismutase (SOD) 1 in both mRNA and protein levels was found to be decreased by overexpressing KLF4, while increased by knockdown of KLF4" SIGNOR-254545 KLF4 protein O43474 UNIPROT TNF protein P01375 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000801 22378047 f 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 KLF4 protein O43474 UNIPROT THBD protein P07204 UNIPROT "up-regulates activity" "transcriptional regulation" 9606 19661484 f miannu "Thrombomodulin upregulation was independent of NF-kappaB signaling, a principal target of proteasome inhibitors, but was instead a direct consequence of increased expression of the Krüppel-like transcription factors, KLF2 and KLF4." SIGNOR-254546 KLF4 protein O43474 UNIPROT HSPA8 protein P11142 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165;BTO:0003292 18379898 f miannu "The results showed the upregulation of the HSP73 constitutive expression by KLF4 overexpression in both C2C12 cells and murine RAW264.7 macrophages; in response to heat stress, however, few changes were observed in the levels of HSP73 by KLF4 overexpression." SIGNOR-254544 KLF4 protein O43474 UNIPROT SRF protein P11831 UNIPROT down-regulates binding 9606 BTO:0000887;BTO:0001260 21673106 t gcesareni "Klf4 antagonizes contractile gene expression through diverse mechanisms including (i) inhibiting the binding of srf-myocd or srf-mrtfs to the carg box by direct association with srf." SIGNOR-174258 KLF4 protein O43474 UNIPROT STAT6 protein P42226 UNIPROT up-regulates 9606 BTO:0000801 22378047 f lperfetto "KLF4 cooperates with Stat6 to induce M2 genes (Arg-1, Mrc1, Fizz1, PPAR?) and inhibit M1 genes (TNFa, Cox-2, CCL5, iNOS) via sequestration of coactivators required for NF-kappaB activation." SIGNOR-249569 KLF4 protein O43474 UNIPROT NPNT protein Q6UXI9 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0005787 BTO:0001103 23612709 f 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 KLF4 protein O43474 UNIPROT MYOCD protein Q8IZQ8 UNIPROT down-regulates 9606 BTO:0000887;BTO:0001260 21673106 f gcesareni "Finally, we demonstrate that the basal expression of both myocd and mrtf-a is negatively regulated by klf4. . The mechanism of inhibition of myocd or mrtf-a by klf4 is currently unclear and warrants future study." SIGNOR-174255 CACNA1G protein O43497 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000227 30849329 t miannu "Voltage-gated calcium channels mediate the influx of calcium in response to membrane depolarization in excitable cells. In presynaptic nerve terminals, this calcium influx triggers transmitter release for synaptic transmission. Several neurological and cardiac disorders are caused by pathogenic variants in genes encoding α1-subunits of voltage-gated calcium channels, including CACNA1A (MIM: 601011) (familial hemiplegic migraine [MIM: 141500], episodic ataxia [MIM: 108500], and epilepsy [MIM: 617106]),3, 4, 5 CACNA1C (MIM: 114205) (Timothy syndrome [MIM: 601005]),6, 7 CACNA1D (MIM: 114206) (primary aldosteronism, neurodevelopmental disorders [MIM: 615474]),8, 9 and CACNA1G (MIM: 604065) (spinocerebellar ataxia [MIM: 616795])." SIGNOR-264324 CACNA1G protein O43497 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 10090 BTO:0002496 33393208 t miannu "Adult hippocampal neurogenesis plays an important role in neuronal plasticity and maintenance in mammals. Low-threshold voltage-gated T-type calcium channels produce calcium spikes that increase fast action potentials in newborn cells in the hippocampal dentate gyrus (DG)" SIGNOR-264032 RAD51C protein O43502 UNIPROT XRCC3 protein O43542 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000567 23438602 f lperfetto "It is likely that the recruitment of RAD51C to the sites of DNA lesions can promote XRCC3 phosphorylation and activate the DNA damage response pathway(s) in the S and G2 phases. " SIGNOR-263260 RAD51C protein O43502 UNIPROT RAD51B/RAD51C complex SIGNOR-C65 SIGNOR "form complex" binding 9606 11751636 t miannu "We show that two of them, rad51b and rad51c, are associated in a stable complex. Rad51b-rad51c complex has ssdna binding and ssdna-stimulated atpase activities." SIGNOR-113388 LAMTOR5 protein O43504 UNIPROT S100A4 protein P26447 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150 22740693 f miannu "It suggests that HBXIP is able to activate S100A4 promoter via interacting with STAT4 in breast cancer cells, leading to the up-regulation of S100A4." SIGNOR-255248 LAMTOR5 protein O43504 UNIPROT LIN28B protein Q6ZN17 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000093 23494474 f miannu "We found that HBXIP was able to upregulate Lin28B in breast cancer MCF-7 cells." SIGNOR-255251 MED7 protein O43513 UNIPROT "Core mediator complex" complex SIGNOR-C405 SIGNOR "form complex" binding 9606 28467824 t miannu "Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles." SIGNOR-266657 WIPF1 protein O43516 UNIPROT WASL protein O00401 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 10878810 t lperfetto "Recruitment of N-WASP to vaccinia is mediated by WASP-interacting protein (WIP), whereas in Shigella WIP is recruited by N-WASP. Our observations show that vaccinia and Shigella activate the Arp2/3 complex to achieve actin-based motility, by mimicking either the SH2/SH3-containing adaptor or Cdc42 signalling pathways to recruit the N-WASP-WIP complex." SIGNOR-261880 BCL2L11 protein O43521 UNIPROT BCL2 protein P10415 UNIPROT down-regulates binding 9606 15694340 t gcesareni "Bim can induce apoptosis by interacting with anti-apoptotic members of the bcl2 family, including bcl2, bcl-xl and mcl-1.. Bim binds prosurvival proteins comparably. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1" SIGNOR-133823 BCL2L11 protein O43521 UNIPROT BCL2 protein P10415 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 15694340 t lperfetto "Apoptosis is initiated when Bcl-2 and its prosurvival relatives are engaged by proapoptotic BH3-only proteins via interaction of its BH3 domain with a groove on the Bcl-2-like proteins. These interactions have been considered promiscuous, but our analysis of the affinity of eight BH3 peptides for five Bcl-2-like proteins has revealed that the interactions vary over 10,000-fold in affinity, and accordingly, only certain protein pairs associate inside cells. Bim and Puma potently engaged all the prosurvival proteins comparably. Bad, however, bound tightly to Bcl-2, Bcl-xL, and Bcl-w but only weakly to A1 and not to Mcl-1." SIGNOR-133820 BCL2L11 protein O43521 UNIPROT BCL2 protein P10415 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 18498746 t lperfetto "We show that mutation of the phosphorylation site Thr-112 causes decreased binding of Bim to the antiapoptotic protein Bcl2 and can increase cell survival." SIGNOR-178676 BCL2L11 protein O43521 UNIPROT BAX protein Q07812 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 11997495 t lperfetto "We have shown that the interaction of the bims and bimad isoforms with bax leads to a conformational change in this protein analogous to that triggered by the bh3-only protein bid.We find short peptides representing the alpha-helical bh3 domains of bid or bim are capable of inducing oligomerization of bak and bax to release cytochrome." SIGNOR-87280 BCL2L11 protein O43521 UNIPROT BAX protein Q07812 UNIPROT "up-regulates activity" binding 9606 17289999 t lperfetto "Contrary to the direct-activation model, we show that Bax and Bak can mediate apoptosis without discernable association with the putative BH3-only activators (Bim, Bid, and Puma), even in cells with no Bim or Bid and reduced Puma. Our results indicate that BH3-only proteins induce apoptosis at least primarily by engaging the multiple pro-survival relatives guarding Bax and Bak" SIGNOR-152986 BCL2L11 protein O43521 UNIPROT BAX protein Q07812 UNIPROT "up-regulates activity" binding 9606 22492984 t lperfetto "Bim, and puma bind with high affinity to all pro-survival proteins" SIGNOR-196935 BCL2L11 protein O43521 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates binding 9606 15694340 t gcesareni "Bim can induce apoptosis by interacting with anti-apoptotic members of the bcl2 family, including bcl2, bcl-xl and mcl-1.Bim binds bcl-2, bcl2l1, bcl2l2, mcl1 and a1 tightly." SIGNOR-133829 BCL2L11 protein O43521 UNIPROT BCL2L1 protein Q07817 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 18498746 t lperfetto "Bim can induce apoptosis by interacting with anti-apoptotic members of the bcl2 family, including bcl2, bcl-xl and mcl-1.Bim binds bcl-2, bcl2l1, bcl2l2, mcl1 and a1 tightly." SIGNOR-178679 BCL2L11 protein O43521 UNIPROT BAK1 protein Q16611 UNIPROT up-regulates binding 9606 22492984 t gcesareni "Bim, and puma bind with high affinity to all pro-survival proteins" SIGNOR-196932 BCL2L11 protein O43521 UNIPROT BCL2L2 protein Q92843 UNIPROT down-regulates binding 9606 15694340 t gcesareni "Bim binds prosurvival proteins comparably. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1." SIGNOR-133832 FOXO3 protein O43524 UNIPROT BCL2L11 protein O43521 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 14981546 f "Induction of Foxo3a phosphorylation by FLT3-ITD receptors in Ba/F3 cells correlates with the suppression of Foxo-target genes p27Kip1 and the proapoptotic Bcl-2 family member Bim" SIGNOR-261528 FOXO3 protein O43524 UNIPROT BCL2L11 protein O43521 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000938 12913110 f lperfetto "In addition, we find that FKHRL1 (FOXO3a) directly activates the bim promoter via two conserved FOXO binding sites and that mutation of these sites abolishes bim promoter activation after NGF withdrawal." SIGNOR-209657 FOXO3 protein O43524 UNIPROT FOXO3 protein O43524 UNIPROT "up-regulates quantity" "transcriptional regulation" BTO:0000759 22848740 t "We show that FOXO3 binds and activates its own promoter via a positive autoregulatory feedback loop" SIGNOR-255757 FOXO3 protein O43524 UNIPROT IDH1 protein O75874 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25648147 t miannu "We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH." SIGNOR-260089 FOXO3 protein O43524 UNIPROT IDH1 protein O75874 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25648147 t miannu "We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH." SIGNOR-260100 FOXO3 protein O43524 UNIPROT GALT protein P07902 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000975 17975019 f miannu "Our finding that FOXO3 regulates the expression of Galt and enhances its transcriptional activity indicates that it is the repression of FOXO3 by PRL acting through RS that prevents Galt expression in the ovary and causes follicular death." SIGNOR-254186 FOXO3 protein O43524 UNIPROT MYOD1 protein P15172 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000222 18854138 f 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-181618 FOXO3 protein O43524 UNIPROT CDKN1B protein P46527 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 14981546 f "Induction of Foxo3a phosphorylation by FLT3-ITD receptors in Ba/F3 cells correlates with the suppression of Foxo-target genes p27Kip1 and the proapoptotic Bcl-2 family member Bim" SIGNOR-261527 FOXO3 protein O43524 UNIPROT CDKN1B protein P46527 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 BTO:0004245 10783894 t gcesareni "AFX transcriptionally activates p27kip1, resulting in increased protein levels." SIGNOR-238610 FOXO3 protein O43524 UNIPROT NOTCH1 protein P46531 UNIPROT "down-regulates quantity" "transcriptional regulation" 10090 BTO:0002314 24749067 f gcesareni "We demonstrate that FOXO3, perhaps by activating Notch signaling, promotes the quiescent state during SC self-renewal in adult muscle regeneration." SIGNOR-244076 FOXO3 protein O43524 UNIPROT FASLG protein P48023 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10102273 f gcesareni "Within the nucleus, fkhrl1 triggers apoptosis most likely by inducing the expression of genes that are critical for cell death, such as the fas ligand gene." SIGNOR-66035 MAST3 protein O60307 UNIPROT PTEN protein P60484 UNIPROT unknown phosphorylation 9606 15951562 t gcesareni "Furthermore, binding of PTEN to the PDZ domains from microtubule-associated serine/threonine kinases facilitated PTEN phosphorylation at its C terminus by these kinases." SIGNOR-138080 FOXO3 protein O43524 UNIPROT RBL2 protein Q08999 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 BTO:0000944 11884591 t gcesareni "Here we show that the Forkheads AFX (FOXO4) and FKHR-L1 (FOXO3a) also directly control transcription of the retinoblastoma-like p130 protein and cause upregulation of p130 protein expression." SIGNOR-238606 FOXO3 protein O43524 UNIPROT TSC1 protein Q92574 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 20371605 t "FoxO3a binds to and transactivates the TSC1 promoter, indicating a key role for FoxO3a in regulating TSC1 expression. Together, these data demonstrate that FoxO3a regulates glycolysis downstream of Akt through transcriptional control of Tsc1" SIGNOR-259382 FOXO3 protein O43524 UNIPROT DIO2 protein Q92813 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 20978344 f "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 FOXO3 protein O43524 UNIPROT FBXO32 protein Q969P5 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165 15109499 f 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 FOXO3 protein O43524 UNIPROT FBXO32 protein Q969P5 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15109499 f 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 FOXO3 protein O43524 UNIPROT FBXO32 protein Q969P5 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887 21798082 f 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 FOXO3 protein O43524 UNIPROT TRIM63 protein Q969Q1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887 21798082 f 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 FOXO3 protein O43524 UNIPROT TSC22D3 protein Q99576 UNIPROT "up-regulates activity" "transcriptional regulation" 10090 15031210 t "We then characterized the human gilz promoter and showed that FoxO3 (Forkhead box class O3) binding to the Forkhead responsive elements identified in the promoter is necessary for induction of gilz expression upon IL-2 withdrawal" SIGNOR-256094 FOXO3 protein O43524 UNIPROT TSC22D3 protein Q99576 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001482 15705665 t "We have analyzed the promoter of human gilz (glucocorticoid-induced leucine zipper), a dexamethasone-inducible gene that is involved in regulating apoptosis, and identified six glucocorticoid (GC)-responsive elements and three Forkhead responsive elements (FHREs)." SIGNOR-255950 FOXO3 protein O43524 UNIPROT CITED2 protein Q99967 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150 18158893 f gcesareni "Foxo3a induces expression of cited2" SIGNOR-160127 FOXO3 protein O43524 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR "down-regulates quantity" "transcriptional regulation" 10090 BTO:0002314 24749067 f gcesareni "We demonstrate that FOXO3, perhaps by activating Notch signaling, promotes the quiescent state during SC self-renewal in adult muscle regeneration." SIGNOR-254320 KCNQ3 protein O43525 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000227 19298256 t miannu "KCNQ genes encode five Kv7 K+ channel subunits (Kv7.1–Kv7.5). Four of these (Kv7.2–Kv7.5) are expressed in the nervous system. Kv7.2 and Kv7.3 are the principal molecular components of the slow voltage-gated M-channel, which widely regulates neuronal excitability, although other subunits may contribute to M-like currents in some locations." SIGNOR-265984 KCNQ2 protein O43526 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000227 19298256 t miannu "KCNQ genes encode five Kv7 K+ channel subunits (Kv7.1–Kv7.5). Four of these (Kv7.2–Kv7.5) are expressed in the nervous system. Kv7.2 and Kv7.3 are the principal molecular components of the slow voltage-gated M-channel, which widely regulates neuronal excitability, although other subunits may contribute to M-like currents in some locations." SIGNOR-265982 SMAD6 protein O43541 UNIPROT MAP3K7 protein O43318 UNIPROT "down-regulates activity" binding 10116 BTO:0001009 11737269 t lperfetto "Smad6 interacts with tak1 and tab1, and smad7 with tab1. The interaction of i-smads with tak1 and/or tab1 implies that several mechanisms exist underlying the repression of the tak1-p38 kinase pathway by i-smads." SIGNOR-235571 SMAD6 protein O43541 UNIPROT HOXC8 protein P31273 UNIPROT "up-regulates activity" binding 9606 10722652 t gcesareni "Smad6 interacts with hox transcription factors as part of the negative feedback circuit in the bmp signaling pathway" SIGNOR-75823 SMAD6 protein O43541 UNIPROT BMPR1A protein P36894 UNIPROT down-regulates 10090 BTO:0000165 10564272 f gcesareni "We found that both smad6 and smad7 inhibit the activation of smad1 and smad5 by bmpr-ia/alk-3 and bmpr-ib/alk-6, as well as that by alk-2" SIGNOR-236861 SMAD6 protein O43541 UNIPROT TGFBR1 protein P36897 UNIPROT "down-regulates activity" binding 9606 20663871 t lperfetto "The inhibitory Smads (I-Smads), i.e. Smad6 and Smad7, are negative regulators of transforming growth factor-_ (TGF-_) family signaling. I-Smads inhibit TGF-_ family signaling principally through physical interaction with type I receptors (activin receptor-like kinases), so as to compete with receptor-regulated Smads (R-Smads) for activation." SIGNOR-167160 SMAD6 protein O43541 UNIPROT NR2C2 protein P49116 UNIPROT down-regulates binding 9606 11737269 t lperfetto "Smad6 interacts with tak1 and tab1, and smad7 with tab1" SIGNOR-112636 SMAD6 protein O43541 UNIPROT SMAD4 protein Q13485 UNIPROT "down-regulates activity" binding 9606 22298955 t "Create a non-functional complex with smad4 and competes with R-smad." lperfetto "On the other hand, Smad6 competes with R-Smad and forms a non-functional complex with Smad4, which will inhibit BMP signaling in bone formation. Smad6 is involved in a negative feedback loop regulating BMP signaling and is required to limit BMP signaling during endochondral bone formation." SIGNOR-195648 SMAD6 protein O43541 UNIPROT TAB1 protein Q15750 UNIPROT down-regulates binding 9606 11737269 t lpetrilli "Smad6 interacts with tak1 and tab1, and smad7 with tab1. The interaction of i-smads with tak1 and/or tab1 implies that several mechanisms exist underlying the repression of the tak1-p38 kinase pathway by i-smads." SIGNOR-112642 MAST3 protein O60307 UNIPROT PTEN protein P60484 UNIPROT up-regulates binding 9606 15951562 t miannu "Pten binds to and is phosphorylated by mast kinases./ Pdz domain-mediated binding to pten facilitates its phosphorylation by mast kinases / pdz domain binding increases pten protein stability." SIGNOR-138077 XRCC3 protein O43542 UNIPROT CHEK2 protein O96017 UNIPROT "up-regulates activity" 9606 BTO:0000567 23438602 f lperfetto "Interestingly, as with ATM (40, 41), XRCC3-deficient cells exhibited RDS and impaired CHK2 activation|Notably, early activation of CHK2 in S/G2 phase was downstream of XRCC3 recruitment as well as its phosphorylation at the sites of DSBs. NBS1 also has been shown to be involved in the early activation of CHK2 in response to IR (42). It is likely that NBS1-dependent CHK2 phosphorylation is mediated through XRCC3 activation." SIGNOR-263261 XRCC3 protein O43542 UNIPROT RAD51 protein Q06609 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000567 SIGNOR-C301 23438602 t lperfetto "We examined the effect of XRCC3 depletion on redistribution of RAD51 upon IR damage|Interestingly, cells expressing the XRCC3 S225A phosphomutant showed compromised chromatin loading of RAD51 upon IR damage (Fig. 4G) while the nuclear and cytosolic fractions of RAD51 were largely unchanged|It is likely that BRCA2 may directly participate in RAD51 recruitment and XRCC3 may stabilize the RAD51 filament which is in part mediated by phosphorylation." SIGNOR-263258 XRCC3 protein O43542 UNIPROT RAD51 protein Q06609 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000007 23438602 t miannu "XRCC3 activation is essential for the recruitment of RAD51 to the sites of DNA lesions. It is likely that BRCA2 may directly participate in RAD51 recruitment and XRCC3 may stabilize the RAD51 filament which is in part mediated by phosphorylation." SIGNOR-262667 XRCC3 protein O43542 UNIPROT "D1-D2-G-X3 complex" complex SIGNOR-C301 SIGNOR "form complex" binding 9606 18212739 t lperfetto "These results argue that FANCG has a role independent of the FA core complex, and we propose that phosphorylation of serine 7 is the signalling event required for forming a discrete complex comprising FANCD1/BRCA2-FANCD2-FANCG-XRCC3 (D1-D2-G-X3). " SIGNOR-263257 TNFSF14 protein O43557 UNIPROT TNFRSF14 protein Q92956 UNIPROT up-regulates binding 9606 BTO:0000763 10894944 t gcesareni "A member of the tumor necrosis factor (tnf) superfamily, human tnfsf14 (htnfsf14)/hvem-l (herpes virus entry mediator ligand) was isolated as a cellular ligand for hvem/tr2 and human lymphotoxin beta receptor (ltbetar). Tnfsf14 induces apoptosis and suppresses tumor formation" SIGNOR-79328 LAT protein O43561 UNIPROT PIK3R2 protein O00459 UNIPROT "up-regulates activity" binding 9606 phosphorylation:Tyr161;Tyr200 DDYHNPGyLVVLPDS;SMESIDDyVNVPESG 11368773 t lperfetto "By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively." SIGNOR-246055 LAT protein O43561 UNIPROT VAV1 protein P15498 UNIPROT "up-regulates activity" binding 9606 phosphorylation:Tyr255;Tyr220 EEEGAPDyENLQELN;SLDGSREyVNVSQEL 11368773 t lperfetto "By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively." SIGNOR-246045 LAT protein O43561 UNIPROT PLCG1 protein P19174 UNIPROT "up-regulates activity" binding 9606 phosphorylation:Tyr161;Tyr200 DDYHNPGyLVVLPDS;SMESIDDyVNVPESG 11368773 t lperfetto "By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively." SIGNOR-246060 LAT protein O43561 UNIPROT PIK3R1 protein P27986 UNIPROT "up-regulates activity" binding 9606 phosphorylation:Tyr161;Tyr200 DDYHNPGyLVVLPDS;SMESIDDyVNVPESG 11368773 t lperfetto "By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively." SIGNOR-246050 LAT protein O43561 UNIPROT PIK3CA protein P42336 UNIPROT "up-regulates activity" binding 9606 phosphorylation:Tyr161;Tyr200 DDYHNPGyLVVLPDS;SMESIDDyVNVPESG 11368773 t lperfetto "By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively." SIGNOR-246065 LAT protein O43561 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 BTO:0000661 10811803 t "Our results showed that three distal tyrosines, Tyr(171), Tyr(191), and Tyr(226), are responsible for Grb2-binding;" SIGNOR-251521 LAT protein O43561 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" binding 9606 11368773 t lperfetto "By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively." SIGNOR-252734 PSTPIP1 protein O43586 UNIPROT PTPN18 protein Q99952 UNIPROT "up-regulates activity" binding 9534 BTO:0004055 9422760 t lperfetto "These data confirm the importance of these residues to the binding interaction, and they suggest that much of the COOH-terminal region of PTP HSCF may be required for highest affinity binding to PST PIP.|Because this protein-protein interaction appears to be required for the dephosphorylation of PST PIP phosphotyrosines (20), it may be a potentially important new mechanism for the regulation of the cytoskeleton." SIGNOR-262594 PLRG1 protein O43660 UNIPROT HNRNPM protein P52272 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 20467437 t 1 miannu "hnRNP-M interacts directly with CDC5L and PLRG1 in vivo. we investigated whether the function of hnRNP-M in alternative splicing was affected by the central region mapped as essential for binding to the CDC5L/PLRG1 proteins. We conclude that loss of the CDC5L/PLRG1 interaction domain in hnRNP-M correlates with a loss of ability to modulate alternative splice site selection in this assay." SIGNOR-239444 XPOT protein O43592 UNIPROT NPC complex SIGNOR-C263 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 9660920 t miannu "Exportin-t Is Predominantly Nuclear, Binds NPCs, and Shuttles Rapidly between Nucleus and Cytoplasm. RanGTP appears to have at least two functions in this complex. First, it stabilizes the tRNA/exportin-t interaction (see Figure 4B). Second, exportin-t apparently has to bind RanGTP for rapid exit from the nucleus . RanGTP causing a conformational change in exportin-t, which increases the affinity for export sites at the NPC. Exportin-t probably makes a direct contact to the NPC and accounts for the interactions that drive translocation of the tRNA/exportin-t/RanGTP complex out of the nucleus." SIGNOR-261393 GALR2 protein O43603 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257136 GALR2 protein O43603 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256884 GALR2 protein O43603 UNIPROT GNA15 protein P30679 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257226 GALR2 protein O43603 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257020 GALR2 protein O43603 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256741 GALR2 protein O43603 UNIPROT GNA13 protein Q14344 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257356 SPRY1 protein O43609 UNIPROT SOS1 protein Q07889 UNIPROT down-regulates binding 9606 11585837 t gcesareni "Taken together, these results establish mammalian sprouty proteins as important negative regulators of growth factor signaling and suggest that sprouty proteins act downstream of the grb2.Sos Complex to selectively uncouple growth factor signals from ras activation and the map kinase pathway." SIGNOR-110948 HCRT protein O43612 UNIPROT HCRTR1 protein O43613 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 9491897 t gcesareni "Identification and initial biological characterization of two orexins as well as their two receptors" SIGNOR-53667 HCRTR1 protein O43613 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257294 NDUFB5 protein O43674 UNIPROT "Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and |The main ND4-module intermediate binds NDUFB1, NDUFB4, NDUFB5, NDUFB6, NDUFB10, NDUFB11 and MT-ND4" SIGNOR-262168 HCRTR1 protein O43613 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256876 HCRTR1 protein O43613 UNIPROT GNA15 protein P30679 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257354 HCRTR1 protein O43613 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257220 HCRTR1 protein O43613 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256733 HCRTR1 protein O43613 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257404 HCRTR2 protein O43614 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257290 HCRTR2 protein O43614 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256872 HCRTR2 protein O43614 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257008 HCRTR2 protein O43614 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257216 HCRTR2 protein O43614 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256729 HCRTR2 protein O43614 UNIPROT GNA13 protein Q14344 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257350 SNAI2 protein O43623 UNIPROT ESR1 protein P03372 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000150 20509143 f miannu "SLUG up-regulation engenders breast cancer cells with stem cell-like properties including enhanced expression of CD44 and Jagged-1 in conjunction with estrogen receptor alpha down-regulation, growth as mammospheres, and extracellular matrix invasiveness." SIGNOR-255154 SNAI2 protein O43623 UNIPROT VDR protein P11473 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000356 18485278 f miannu "We have shown here that the transcriptional repressor protein SLUG inhibits the expression of VDR in human breast cancer cells." SIGNOR-255177 SNAI2 protein O43623 UNIPROT CDH1 protein P12830 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15311212 f miannu "known E-cadherin transcriptional repressors, such as SLUG (SNAI2), SIP1 (ZEB2), TWIST1, SNAIL (SNAI1) and ZEB1 (TCF8), but not E12/E47 (TCF3), had a lack of upregulation in cells expressing mutated E-cadherin compared to WT." SIGNOR-255155 SNAI2 protein O43623 UNIPROT MMP9 protein P14780 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001033 22074556 f miannu "We demonstrated that forced expression of SLUG elevated CXCR4 and CXCL12 expression in human prostate cancer cell lines PC3, DU145, 22RV1, and LNCaP; conversely, reduced expression of SLUG by shRNA downregulated CXCR4 and CXCL12 expression at RNA and protein levels in prostate cancer cells. Furthermore, ectopic expression of SLUG increased MMP9 expression and activity in PC3, 22RV1, and DU-145 cells, and SLUG knockdown by shRNA downregulated MMP9 expression." SIGNOR-255170 SNAI2 protein O43623 UNIPROT HPGD protein P15428 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004078 17575121 f miannu "the Slug protein, but not ZEB1, binds to the PGDH promoter and represses transcription." SIGNOR-255172 SNAI2 protein O43623 UNIPROT CD44 protein P16070 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150 20509143 f miannu "SLUG up-regulation engenders breast cancer cells with stem cell-like properties including enhanced expression of CD44 and Jagged-1 in conjunction with estrogen receptor alpha down-regulation, growth as mammospheres, and extracellular matrix invasiveness." SIGNOR-255153 SNAI2 protein O43623 UNIPROT CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000356 21044962 f miannu "knockdown of SLUG in SLUG-high breast cancer cells elevated the levels of UbcH5c while decreasing the level of cyclin D1 protein. SLUG is recruited at the E2-box sequence at the UbcH5c gene promoter along with the corepressor CtBP1 and the effector HDAC1 to silence the expression of this gene." SIGNOR-255176 SNAI2 protein O43623 UNIPROT CXCL12 protein P48061 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001033 22074556 f miannu "We demonstrated that forced expression of SLUG elevated CXCR4 and CXCL12 expression in human prostate cancer cell lines PC3, DU145, 22RV1, and LNCaP; conversely, reduced expression of SLUG by shRNA downregulated CXCR4 and CXCL12 expression at RNA and protein levels in prostate cancer cells." SIGNOR-255169 SNAI2 protein O43623 UNIPROT CXCR4 protein P61073 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001033 22074556 f miannu "We demonstrated that forced expression of SLUG elevated CXCR4 and CXCL12 expression in human prostate cancer cell lines PC3, DU145, 22RV1, and LNCaP; conversely, reduced expression of SLUG by shRNA downregulated CXCR4 and CXCL12 expression at RNA and protein levels in prostate cancer cells." SIGNOR-255171 SNAI2 protein O43623 UNIPROT UBE2D3 protein P61077 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000356 21044962 f miannu "knockdown of SLUG in SLUG-high breast cancer cells elevated the levels of UbcH5c while decreasing the level of cyclin D1 protein. SLUG is recruited at the E2-box sequence at the UbcH5c gene promoter along with the corepressor CtBP1 and the effector HDAC1 to silence the expression of this gene." SIGNOR-255173 SNAI2 protein O43623 UNIPROT JAG1 protein P78504 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150 20509143 f miannu "SLUG up-regulation engenders breast cancer cells with stem cell-like properties including enhanced expression of CD44 and Jagged-1 in conjunction with estrogen receptor alpha down-regulation, growth as mammospheres, and extracellular matrix invasiveness." SIGNOR-255151 CHMP2A protein O43633 UNIPROT ESCRT-III complex SIGNOR-C379 SIGNOR "form complex" binding -1 26775243 t miannu "The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. ESCRT-III subunits (CHMPs, for Charged Multivesicular Body Proteins [32], or Chromatin Modifying Proteins [33]) transition between soluble and polymerising states, and assemble in a defined order to form a membrane-remodeling filament that brings about membrane fission." SIGNOR-265532 FOXS1 protein O43638 UNIPROT FASLG protein P48023 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9913 BTO:0004577 18288644 t Luana "As we expected, Fkhl18 suppressed, dose-dependently,human and mouseFasLpromoter in bovine vascularsmooth muscle cells" SIGNOR-261612 FOXS1 protein O43638 UNIPROT FOXO4 protein P98177 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9913 BTO:0004577 18288644 t Luana "Fkhl18 suppressed the transcriptional activity of FoxO3a and FoxO4." SIGNOR-261611 NDUFB3 protein O43676 UNIPROT "Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND5-module corresponds to the distal part of the membrane arm and it is composed of MT-ND5, NDUFB2, NDUFB3, NDUFB7, NDUFB8, NDUFB9 and NDUFAB1" SIGNOR-262166 NDUFC1 protein O43677 UNIPROT "Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND2-module is formed by an initial intermediate that contains MT-ND2, NDUFC1 and NDUFC2 bound to NDUFAF1/CIA30 [49,50], ECSIT [51] and ACAD9 [52,53]. Then, MT-ND3 is added together with TMEM126B [54], forming a larger intermediate to which subunits MT-ND6 and MT-ND4L bind. The latest assembly stages involve the incorporation of subunits NDUFA1, NDUFA10 and NDUFS5 [24,34]." SIGNOR-262173 NDUFA2 protein O43678 UNIPROT "Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24]." SIGNOR-262154 BUB1 protein O43683 UNIPROT H2AC11 protein P0C0S8 UNIPROT "up-regulates activity" phosphorylation Thr121 AVLLPKKtESHHKAK 9606 BTO:0000567 19965387 t lperfetto "the localization of hBub1 kinase usually defines the centromere-specific phosphorylation of H2A-T120. Accordingly, hSgo1 localized along the whole chromosome length in H2B-hBub1deltaN cells (Fig. 6D), indicating that H2A-pT120 plays a predominant role in defining shugoshin localization sites on the human chromosomes" SIGNOR-265261 BUB1 protein O43683 UNIPROT PLK1 protein P53350 UNIPROT up-regulates binding 9606 BTO:0000567 phosphorylation:Thr609 SAAQLAStPFHKLPV 16760428 t gcesareni "The plk1-bub1 interaction requires the polo-box domain (pbd) of plk1 and is enhanced by cyclin-dependent kinase 1 (cdk1)-mediated phosphorylation of bub1 at t609" SIGNOR-147061 BUB1 protein O43683 UNIPROT CENPE protein Q02224 UNIPROT "up-regulates activity" relocalization 11402067 t lperfetto "Spindle checkpoint protein Bub1 is required for kinetochore localization of Mad1, Mad2, Bub3, and CENP-E, independently of its kinase activity" SIGNOR-252016 BUB1 protein O43683 UNIPROT CDC20 protein Q12834 UNIPROT "down-regulates activity" phosphorylation Ser153 NRLKVLYsQKATPGS 9606 BTO:0000567 15525512 t llicata "Bub1 directly phosphorylates Cdc20 in vitro and inhibits the ubiquitin ligase activity of APC/C(Cdc20) catalytically. A Cdc20 mutant with all six Bub1 phosphorylation sites removed is refractory to Bub1-mediated phosphorylation and inhibition in vitro. " SIGNOR-250604 BUB1 protein O43683 UNIPROT CDC20 protein Q12834 UNIPROT "down-regulates activity" phosphorylation Ser161 QKATPGSsRKTCRYI 9606 BTO:0000567 15525512 t llicata "Bub1 directly phosphorylates Cdc20 in vitro and inhibits the ubiquitin ligase activity of APC/C(Cdc20) catalytically. A Cdc20 mutant with all six Bub1 phosphorylation sites removed is refractory to Bub1-mediated phosphorylation and inhibition in vitro. " SIGNOR-250605 BUB1 protein O43683 UNIPROT CDC20 protein Q12834 UNIPROT "down-regulates activity" phosphorylation Ser41 EAAGPAPsPMRAANR 9606 BTO:0000567 15525512 t llicata "Bub1 directly phosphorylates Cdc20 in vitro and inhibits the ubiquitin ligase activity of APC/C(Cdc20) catalytically. A Cdc20 mutant with all six Bub1 phosphorylation sites removed is refractory to Bub1-mediated phosphorylation and inhibition in vitro. " SIGNOR-250606 BUB1 protein O43683 UNIPROT CDC20 protein Q12834 UNIPROT "down-regulates activity" phosphorylation Ser72 SKVQTTPsKPGGDRY 9606 BTO:0000567 15525512 t llicata "Bub1 directly phosphorylates Cdc20 in vitro and inhibits the ubiquitin ligase activity of APC/C(Cdc20) catalytically. A Cdc20 mutant with all six Bub1 phosphorylation sites removed is refractory to Bub1-mediated phosphorylation and inhibition in vitro. " SIGNOR-250607 BUB1 protein O43683 UNIPROT CDC20 protein Q12834 UNIPROT "down-regulates activity" phosphorylation Ser92 AAQMEVAsFLLSKEN 9606 BTO:0000567 15525512 t llicata "Bub1 directly phosphorylates Cdc20 in vitro and inhibits the ubiquitin ligase activity of APC/C(Cdc20) catalytically. A Cdc20 mutant with all six Bub1 phosphorylation sites removed is refractory to Bub1-mediated phosphorylation and inhibition in vitro. " SIGNOR-250608 BUB1 protein O43683 UNIPROT CDC20 protein Q12834 UNIPROT "down-regulates activity" phosphorylation Thr157 VLYSQKAtPGSSRKT 9606 BTO:0000567 15525512 t llicata "Bub1 directly phosphorylates Cdc20 in vitro and inhibits the ubiquitin ligase activity of APC/C(Cdc20) catalytically. A Cdc20 mutant with all six Bub1 phosphorylation sites removed is refractory to Bub1-mediated phosphorylation and inhibition in vitro. " SIGNOR-250609 BUB1 protein O43683 UNIPROT MAD2L1 protein Q13257 UNIPROT "up-regulates activity" relocalization 11402067 t lperfetto "Spindle checkpoint protein Bub1 is required for kinetochore localization of Mad1, Mad2, Bub3, and CENP-E, independently of its kinase activity" SIGNOR-252018 BUB1 protein O43683 UNIPROT MAD1L1 protein Q9Y6D9 UNIPROT "up-regulates activity" relocalization 11402067 t lperfetto "Spindle checkpoint protein Bub1 is required for kinetochore localization of Mad1, Mad2, Bub3, and CENP-E, independently of its kinase activity" SIGNOR-252017 BUB3 protein O43684 UNIPROT MCC complex SIGNOR-C382 SIGNOR "form complex" binding 9606 BTO:0000567 25092294 t miannu "The mitotic (or spindle assembly) checkpoint system delays anaphase until all chromosomes are correctly attached to the mitotic spindle. When the checkpoint is active, a Mitotic Checkpoint Complex (MCC) assembles and inhibits the ubiquitin ligase Anaphase-Promoting Complex/Cyclosome (APC/C). MCC is composed of the checkpoint proteins Mad2, BubR1, and Bub3 associated with the APC/C activator Cdc20." SIGNOR-265975 TLX3 protein O43711 UNIPROT ETS1 protein P14921 UNIPROT "down-regulates activity" binding 9606 BTO:0002504 22516263 t irozzo "We show that the cortical thymic maturation arrest in T-lineage ALLs that overexpress TLX1 or TLX3 is due to binding of TLX1/TLX3 to ETS1, leading to repression of T cell receptor (TCR) α enhanceosome activity and blocked TCR-Jα rearrangement." SIGNOR-259098 PRKAB2 protein O43741 UNIPROT AMPK complex SIGNOR-C15 SIGNOR "form complex" binding 9606 16054041 t gcesareni "Gamma non-catalytic subunit mediates binding to amp, adp and atp, leading to activate or inhibit ampk: amp-binding results in allosteric activation of alpha catalytic subunit (prkaa1 or prkaa2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits." SIGNOR-139167 AP1G1 protein O43747 UNIPROT "AP-1 complex" complex SIGNOR-C248 SIGNOR "form complex" binding 9606 21097499 t lperfetto "Key components of this system are the heterotetrameric adaptor protein (AP)4 complexes, AP-1 (gamma-beta1-mi1-sigma1), AP-2 (α-beta2-mi2-sigma2), AP-3 (delta-beta3-mi3-sigma3), and AP-4 (epsilon-beta4-mi4-sigma4) (subunit composition shown in parentheses)" SIGNOR-260687 ENSA protein O43768 UNIPROT PPP2R2D protein Q66LE6 UNIPROT "down-regulates activity" binding -1 phosphorylation:Ser67 KGQKYFDsGDYNMAK 21164014 t gcesareni "We identified cyclic adenosine monophosphate€“regulated phosphoprotein 19 (Arpp19) and -Endosulfine as two substrates of Gwl that, when phosphorylated by this kinase, associate with and inhibit PP2A, thus promoting mitotic entry." SIGNOR-243735 DYRK3 protein O43781 UNIPROT AKT1S1 protein Q96B36 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C3 23415227 t lperfetto "When dyrk3 is active, it allows stress granule dissolution, releasing mtorc1 for signaling and promoting its activity by directly phosphorylating the mtorc1 inhibitor pras40" SIGNOR-201002 DYRK3 protein O43781 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR down-regulates phosphorylation 9606 23415227 t lperfetto "When dyrk3 is active, it allows stress granule dissolution, releasing mtorc1 for signaling and promoting its activity by directly phosphorylating the mtorc1 inhibitor pras40" SIGNOR-217571 SPOP protein O43791 UNIPROT EGLN2 protein Q96KS0 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0001033 28089830 t lperfetto "Tumor suppressor SPOP ubiquitinates and degrades EglN2 to compromise growth of prostate cancer cells" SIGNOR-261996 SPOP protein O43791 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT "down-regulates quantity by destabilization" binding 9606 24239470 t miannu "Mutations in SPOP represent the most common point mutations in primary prostate cancer,with recurrent mutations in SPOP in 6% to 15% of multiple independent cohorts. Wild-type SPOP will bind and promote the degradation of SRC-3,whereas prostate cancer–derived SPOP mutants lose this ability,leading to increased androgen signaling in certain model systems." SIGNOR-251529 NUDT21 protein O43809 UNIPROT "CFI complex" complex SIGNOR-C388 SIGNOR "form complex" binding 9606 BTO:0000567 8626397 t lperfetto "We report here the purification of CF Im from HeLa cell nuclear extracts. Three polypeptides of 68, 59, and 25 kDa copurified with CF Im activity." SIGNOR-266122 STRN protein O43815 UNIPROT PPP2CB protein P62714 UNIPROT "up-regulates activity" binding 10090 BTO:0000938 29802198 t miannu "The striatin family proteins interact with the structural (A) and catalytic (C) subunits of the protein phosphatase, PP2A, and are also termed the B‴ family of PP2A subunits (4). Within heterotrimeric PP2A complexes, striatins function as one of many regulatory B subunits thought to be responsible for substrate selection and localization of PP2A isoforms" SIGNOR-261700 STRN protein O43815 UNIPROT PPP2CA protein P67775 UNIPROT "up-regulates activity" binding 10090 BTO:0000938 29802198 t miannu "The striatin family proteins interact with the structural (A) and catalytic (C) subunits of the protein phosphatase, PP2A, and are also termed the B‴ family of PP2A subunits (4). Within heterotrimeric PP2A complexes, striatins function as one of many regulatory B subunits thought to be responsible for substrate selection and localization of PP2A isoforms" SIGNOR-261698 AKAP8 protein O43823 UNIPROT PRKACA protein P17612 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 19531803 t Giulio "To determine whether AKAP95 and p105 were present in a complex in mammalian cells, FLAG-tagged AKAP95 wascoexpressed with Myc-tagged p105 in human embryonic kidney (HEK) 293 cells. Immunoprecipitation of either protein pulled down a complex containing AKAP95, p105, and PKA-Ca (Fig. 6D).|The identification of a PKA phosphorylation site in the C-terminal region of p105 suggests that p105 is a candidate substrate for AKAP95-targeted PKA." SIGNOR-260302 ZBTB14 protein O43829 UNIPROT ZBTB14 protein O43829 UNIPROT "up-regulates activity" binding 9606 10080939 t miannu "ZF5, which we have cloned as a transcriptional repressor on the mouse c-myc promoter, has the POZ domain at the amino-terminus and the Kruppel-type zinc finger domain at the carboxy-terminus. We demonstrated that the POZ domain has a function mediating homomeric protein-protein interaction and this interaction requires the zinc finger domain." SIGNOR-220534 IDH3B protein O43837 UNIPROT "Isocitrate Dehydrogenase" complex SIGNOR-C396 SIGNOR "form complex" binding 9606 28139779 t miannu "Human NAD-dependent isocitrate dehydrogenase existing as the α2βγ heterotetramer, catalyzes the decarboxylation of isocitrate into α-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP." SIGNOR-266249 CALU protein O43852 UNIPROT GGCX protein P38435 UNIPROT "down-regulates activity" binding 10116 BTO:0000759 15075329 t lperfetto "Results are presented that demonstrate that the endoplasmic reticulum chaperone protein calumenin is associated with gamma-carboxylase and inhibits its activity." SIGNOR-265910 AHCYL1 protein O43865 UNIPROT SLC4A4 protein Q9Y6R1 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 21317537 t miannu "IRBIT opposed the effects of WNKs and SPAK by recruiting PP1 to the complex to dephosphorylate CFTR and NBCe1-B, restoring their cell surface expression, in addition to stimulating their activities." SIGNOR-263135 KIF1C protein O43896 UNIPROT RAB6A protein P20340 UNIPROT "up-regulates quantity" relocalization -1 20360680 t miannu "Here, we identify Bicaudal-D-related protein 1 (BICDR-1) as an effector of the small GTPase Rab6 and key component of the molecular machinery that controls secretory vesicle transport in developing neurons. BICDR-1 interacts with kinesin motor Kif1C, the dynein/dynactin retrograde motor complex, regulates the pericentrosomal localization of Rab6-positive secretory vesicles and is required for neural development in zebrafish. In young neurons, BICDR-1 accumulates Rab6 secretory vesicles around the centrosome, restricts anterograde secretory transport and inhibits neuritogenesis. Later during development, BICDR-1 expression is strongly reduced, which permits anterograde secretory transport required for neurite outgrowth. These results indicate an important role for BICDR-1 as temporal regulator of secretory trafficking during the early phase of neuronal differentiation." SIGNOR-266877 KIF1C protein O43896 UNIPROT RAB6C protein Q9H0N0 UNIPROT "up-regulates quantity" relocalization -1 20360680 t miannu "Here, we identify Bicaudal-D-related protein 1 (BICDR-1) as an effector of the small GTPase Rab6 and key component of the molecular machinery that controls secretory vesicle transport in developing neurons. BICDR-1 interacts with kinesin motor Kif1C, the dynein/dynactin retrograde motor complex, regulates the pericentrosomal localization of Rab6-positive secretory vesicles and is required for neural development in zebrafish. In young neurons, BICDR-1 accumulates Rab6 secretory vesicles around the centrosome, restricts anterograde secretory transport and inhibits neuritogenesis. Later during development, BICDR-1 expression is strongly reduced, which permits anterograde secretory transport required for neurite outgrowth. These results indicate an important role for BICDR-1 as temporal regulator of secretory trafficking during the early phase of neuronal differentiation." SIGNOR-266879 RAD21 protein O60216 UNIPROT "Cohesin complex" complex SIGNOR-C304 SIGNOR "form complex" binding 28430577 t lperfetto "Cohesin is an evolutionarily conserved complex composed of four core proteins (SMC1A, SMC3, RAD21 and either STAG2 or STAG1) that form a ring-shaped structure able to encircle chromatin" SIGNOR-263311 MED14 protein O60244 UNIPROT "Core mediator complex" complex SIGNOR-C405 SIGNOR "form complex" binding 9606 28467824 t miannu "Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles." SIGNOR-266676 KIF1C protein O43896 UNIPROT RAB6B protein Q9NRW1 UNIPROT "up-regulates quantity" relocalization -1 20360680 t miannu "Here, we identify Bicaudal-D-related protein 1 (BICDR-1) as an effector of the small GTPase Rab6 and key component of the molecular machinery that controls secretory vesicle transport in developing neurons. BICDR-1 interacts with kinesin motor Kif1C, the dynein/dynactin retrograde motor complex, regulates the pericentrosomal localization of Rab6-positive secretory vesicles and is required for neural development in zebrafish. In young neurons, BICDR-1 accumulates Rab6 secretory vesicles around the centrosome, restricts anterograde secretory transport and inhibits neuritogenesis. Later during development, BICDR-1 expression is strongly reduced, which permits anterograde secretory transport required for neurite outgrowth. These results indicate an important role for BICDR-1 as temporal regulator of secretory trafficking during the early phase of neuronal differentiation." SIGNOR-266878 NDUFS5 protein O43920 UNIPROT "Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND2-module is formed by an initial intermediate that contains MT-ND2, NDUFC1 and NDUFC2 bound to NDUFAF1/CIA30 [49,50], ECSIT [51] and ACAD9 [52,53]. Then, MT-ND3 is added together with TMEM126B [54], forming a larger intermediate to which subunits MT-ND6 and MT-ND4L bind. The latest assembly stages involve the incorporation of subunits NDUFA1, NDUFA10 and NDUFS5 [24,34]." SIGNOR-262179 EFNA2 protein O43921 UNIPROT EPHA2 protein P29317 UNIPROT up-regulates binding 9606 10072375 t tpavlidou "Ephrin-a ligands (named ephrin-a1_ephrin-a5) are anchored in the plasma membrane through a gpi-linkage, and each can bind any of the epha subclass of receptors (epha1_epha8)" SIGNOR-65413 EFNA2 protein O43921 UNIPROT EPHA8 protein P29322 UNIPROT up-regulates binding 9606 9330863 t gcesareni "The activation of eph receptors by their ligands, which are membrane-anchored molecules, involves a cell-cell recognition event that often causes cell repulsion. Therefore, eph receptors mediate signals that can override cell adhesion." SIGNOR-52269 EFNA2 protein O43921 UNIPROT EPHA5 protein P54756 UNIPROT up-regulates binding 9606 10072375 t tpavlidou "Ephrin-a ligands (named ephrin-a1_ephrin-a5) are anchored in the plasma membrane through a gpi-linkage, and each can bind any of the epha subclass of receptors (epha1_epha8)" SIGNOR-65416 EFNA2 protein O43921 UNIPROT EPHA4 protein P54764 UNIPROT up-regulates binding 9606 9330863 t tpavlidou "Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor" SIGNOR-52203 EFNA2 protein O43921 UNIPROT EPHA7 protein Q15375 UNIPROT up-regulates binding 9606 9330863 t gcesareni "The activation of eph receptors by their ligands, which are membrane-anchored molecules, involves a cell-cell recognition event that often causes cell repulsion." SIGNOR-52206 EFNA2 protein O43921 UNIPROT EPHA6 protein Q9UF33 UNIPROT up-regulates binding 9606 10072375 t tpavlidou "Ephrin-a ligands (named ephrin-a1_ephrin-a5) are anchored in the plasma membrane through a gpi-linkage, and each can bind any of the epha subclass of receptors (epha1_epha8)" SIGNOR-65419 PEX1 protein O43933 UNIPROT PEX5 protein P50542 UNIPROT "up-regulates activity" binding 10029 16314507 t "Pex1, Pex6, and Pex26 are involved in Pex5 export from peroxisomes., we found that Pex1 and Pex6 bind to Pex5 (Fig. ​(Fig.6). Therefore, it is conceivable that Pex1 and Pex6 pull out Pex5 from peroxisome membranes in an ATP-dependent manner." SIGNOR-253618 RAD21 protein O60216 UNIPROT APOB protein P04114 UNIPROT "down-regulates quantity" "transcriptional regulation" 9606 25575569 t "The promoter region of APOB bound RAD21 but not RAD21 p.622 Ala>Thr; expression of wild-type RAD21 in HEK293 cells repressed expression of APOB, compared with control vector." SIGNOR-259974 RAD21 protein O60216 UNIPROT ERG protein P11308 UNIPROT "down-regulates activity" relocalization 9606 BTO:0001545 26607380 t miannu "Large-scale AML genome re-sequencing efforts have identified novel recurrently mutated genes, including the members of the cohesin complex (RAD21, SMC3, SMC1A, and STAG2), implicated in the pathogenesis of this disease.Using ATAC-seq, we determined that mutant cohesin lead to a state of elevated chromatin accessibility and higher predicted binding at transcription factor binding sites for ERG, GATA2, and RUNX1. Moreover, using ChIP-Seq, we formally demonstrated increased binding of GATA2 and RUNX1 to these sites. Finally, we demonstrated that knockdown of these three TFs in human HSPC can revert the differentiation block induced by mutant cohesin. These results support a model in which mutant cohesin impairs hematopoietic differentiation and enforces stem cell programs through the modulation of ERG, GATA2, and RUNX1 chromatin accessibility, expression, and activity." SIGNOR-261515 RAD21 protein O60216 UNIPROT GATA2 protein P23769 UNIPROT "down-regulates activity" relocalization 9606 BTO:0001545 26607380 t miannu "Large-scale AML genome re-sequencing efforts have identified novel recurrently mutated genes, including the members of the cohesin complex (RAD21, SMC3, SMC1A, and STAG2), implicated in the pathogenesis of this disease.Using ATAC-seq, we determined that mutant cohesin lead to a state of elevated chromatin accessibility and higher predicted binding at transcription factor binding sites for ERG, GATA2, and RUNX1. Moreover, using ChIP-Seq, we formally demonstrated increased binding of GATA2 and RUNX1 to these sites. Finally, we demonstrated that knockdown of these three TFs in human HSPC can revert the differentiation block induced by mutant cohesin. These results support a model in which mutant cohesin impairs hematopoietic differentiation and enforces stem cell programs through the modulation of ERG, GATA2, and RUNX1 chromatin accessibility, expression, and activity." SIGNOR-261513 RAD21 protein O60216 UNIPROT RUNX1 protein Q01196 UNIPROT "down-regulates activity" relocalization 9606 BTO:0001545 26607380 t miannu "Large-scale AML genome re-sequencing efforts have identified novel recurrently mutated genes, including the members of the cohesin complex (RAD21, SMC3, SMC1A, and STAG2), implicated in the pathogenesis of this disease.Using ATAC-seq, we determined that mutant cohesin lead to a state of elevated chromatin accessibility and higher predicted binding at transcription factor binding sites for ERG, GATA2, and RUNX1. Moreover, using ChIP-Seq, we formally demonstrated increased binding of GATA2 and RUNX1 to these sites. Finally, we demonstrated that knockdown of these three TFs in human HSPC can revert the differentiation block induced by mutant cohesin. These results support a model in which mutant cohesin impairs hematopoietic differentiation and enforces stem cell programs through the modulation of ERG, GATA2, and RUNX1 chromatin accessibility, expression, and activity." SIGNOR-261514 RAD21 protein O60216 UNIPROT RUNX1 protein Q01196 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 24321385 t miannu "We observed that depletion of RAD21 (but not CTCF) enhanced RUNX1 transcription in human HL-60 myelocytic leukemia cells" SIGNOR-259973 PRKN protein O60260 UNIPROT GPR37 protein O15354 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000938 12666095 t lperfetto "Parkin is a protein of 465 amino acids, and its structure includes a ubiquitin homologous domain in its N terminus and two RING finger domains in its C terminus. Molecular studies have determined that parkin is an E3 ubiquitin ligase function, implicating parkin in the ubiquitin-proteasome system, and raising the possibility that mutations in the gene lead to loss or diminished function. Three substrates for the ubiquitin-ligase function of parkin have been identified to date.1. A 22kDa glycosolated form of alpha-synuclei|2. Parkin-associated endothelin receptor-like receptor (Pael-R)." SIGNOR-249706 PRKN protein O60260 UNIPROT SNCA protein P37840 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000938 12666095 t lperfetto "Parkin is a protein of 465 amino acids, and its structure includes a ubiquitin homologous domain in its N terminus and two RING finger domains in its C terminus. Molecular studies have determined that parkin is an E3 ubiquitin ligase function, implicating parkin in the ubiquitin-proteasome system, and raising the possibility that mutations in the gene lead to loss or diminished function. Three substrates for the ubiquitin-ligase function of parkin have been identified to date.1. A 22kDa glycosolated form of alpha-synuclei|2. Parkin-associated endothelin receptor-like receptor (Pael-R)." SIGNOR-249705 PRKN protein O60260 UNIPROT EPS15 protein P42566 UNIPROT "down-regulates activity" ubiquitination 10090 16862145 t gcesareni "Treatment of cells with EGF stimulates parkin binding to both Eps15 and the EGFR and promotes parkin-mediated ubiquitination of Eps15." SIGNOR-243282 PRKN protein O60260 UNIPROT EPS15 protein P42566 UNIPROT up-regulates ubiquitination 9606 BTO:0000938 BTO:0000142 16862145 t gcesareni "Treatment of cells with egf stimulates parkin binding to both eps15 and the egfr and promotes parkin-mediated ubiquitination of eps15" SIGNOR-148218 PRKN protein O60260 UNIPROT RANBP2 protein P49792 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 16332688 t irozzo "Our findings suggested that the intracellular levels of RanBP2 and its functional activity may be modulated by Parkin-mediated ubiquitination and proteasomal pathways. Furthermore, Parkin controls the intracellular levels of sumoylated HDAC4, as a result of the ubiquitination and degradation of RanBP2." SIGNOR-259116 PRKN protein O60260 UNIPROT HIF3A protein Q9Y2N7 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000793 27551449 t Parkinson miannu "Here we show that IPAS is a key molecule involved in neuronal cell death in Parkinson's disease (PD). IPAS was ubiquitinated by Parkin for proteasomal degradation following carbonyl cyanide m-chlorophenyl hydrazone treatment. Phosphorylation of IPAS at Thr12 by PTEN-induced putative kinase 1 (PINK1) was required for ubiquitination to occur." SIGNOR-263089 ADCY3 protein O60266 UNIPROT "3',5'-cyclic AMP" smallmolecule CHEBI:17489 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 15385642 t miannu "Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions." SIGNOR-265000 SPAG9 protein O60271 UNIPROT ABL1 protein P00519 UNIPROT unknown binding 9606 BTO:0000222 SIGNOR-C21 19470755 t lperfetto "We report that abl associates with both cdo and jlp during myoblast differentiation" SIGNOR-185765 SPAG9 protein O60271 UNIPROT MAPK11 protein Q15759 UNIPROT up-regulates binding 9606 BTO:0000222 17074887 t "p38 MAPK is activated by phosphorylation in response to CDO-BOC interactions. Activated p38 MAPK may translocate into the nucleus to further activate myogenic related transcription factors." gcesareni "Cdo, jlp, and p38alpha/beta form complexes in differentiating myoblasts, and cdo and jlp cooperate to enhance levels of active p38alpha/beta in transfectants." SIGNOR-150147 SPAG9 protein O60271 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" binding 9606 BTO:0000222 17074887 t "Activation of p38alpha/beta MAPK in myogenesis via binding of the scaffold protein JLP" lperfetto "Cdo, jlp, and p38alpha/beta form complexes in differentiating myoblasts, and cdo and jlp cooperate to enhance levels of active p38alpha/beta in transfectants." SIGNOR-149979 SPAG9 protein O60271 UNIPROT MAP3K5 protein Q99683 UNIPROT unknown binding 10090 BTO:0000165;BTO:0000222;BTO:0002181 SIGNOR-C21 22337877 t lperfetto "Cdo and jlp interacted with ask1 or tak1 in 293t cells and c2c12 myoblasts" SIGNOR-235545 SPAG9 protein O60271 UNIPROT CDON/SPAG9 complex SIGNOR-C21 SIGNOR "form complex" binding 9606 BTO:0000222 17074887 t gcesareni "In this study, we report that the cdo intracellular region interacts with jlp, a scaffold protein for the p38alpha/beta mapk pathway." SIGNOR-149178 SPAG9 protein O60271 UNIPROT CDO/JLP/P38 complex SIGNOR-C22 SIGNOR "form complex" binding 9606 BTO:0000222 17074887 t "p38 MAPK is activated by phosphorylation in response to CDO-BOC interactions. Activated p38 MAPK may translocate into the nucleus to further activate myogenic related transcription factors." gcesareni "Cdo, jlp, and p38alpha/beta form complexes in differentiating myoblasts, and cdo and jlp cooperate to enhance levels of active p38alpha/beta in transfectants." SIGNOR-150288 KIF5C protein O60282 UNIPROT TRAK2 protein O60296 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 24161670 t miannu "Trafficking kinesin proteins (TRAKs) are kinesin adaptors. They bind the cargo binding domain of kinesin-1 motor proteins forming a link between the motor and their cargoes. This supports the idea that the KIF5A–TRAK2 interaction is multivalent and could act to ensure stable motor-cargo interaction during intracellular trafficking; dimerization of both motor and adaptor molecules further enhances this stability (Fig. 6). A similar multivalent profile was found for the TRAK2 binding site within the kinesin-1 isoform, KIF5C." SIGNOR-264064 NUAK1 protein O60285 UNIPROT PPP1R12A protein O14974 UNIPROT down-regulates phosphorylation Ser445 LGLRKTGsYGALAEI 9606 20354225 t gcesareni "Phosphorylation of ser(445), ser(472), and ser(910) of mypt1 by nuak1 promoted the interaction of mypt1 with 14-3-3 adaptor proteins, thereby suppressing phosphatase activity." SIGNOR-164747 NUAK1 protein O60285 UNIPROT PPP1R12A protein O14974 UNIPROT down-regulates phosphorylation Ser472 AGVTRSAsSPRLSSS 9606 20354225 t gcesareni "Phosphorylation of ser(445), ser(472), and ser(910) of mypt1 by nuak1 promoted the interaction of mypt1 with 14-3-3 adaptor proteins, thereby suppressing phosphatase activity." SIGNOR-164751 NUAK1 protein O60285 UNIPROT PPP1R12A protein O14974 UNIPROT down-regulates phosphorylation Ser910 SLLGRSGsYSYLEER 9606 20354225 t gcesareni "Phosphorylation of ser(445), ser(472), and ser(910) of mypt1 by nuak1 promoted the interaction of mypt1 with 14-3-3 adaptor proteins, thereby suppressing phosphatase activity." SIGNOR-22572 NUAK1 protein O60285 UNIPROT LATS1 protein O95835 UNIPROT down-regulates phosphorylation Ser464 NIPVRSNsFNNPLGN 9606 19927127 t lperfetto "Moreover, we show that nuak1 phosphorylates lats1 at s464 and this has a role in controlling its stabilitycells that constitutively express nuak1 suffer gross aneuploidies and show diminished expression of the genomic stability regulator lats1" SIGNOR-161792 NUAK1 protein O60285 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 21317932 t gcesareni "Here we showed that in the presence of wild-type lkb1, nuak1 directly interacts with and phosphorylates p53 in vitro and in vivo." SIGNOR-172008 KDM1A protein O60341 UNIPROT H3C1 protein P68431 UNIPROT "up-regulates activity" demethylation Lys5 kQTARKST 9606 BTO:0000567 15620353 t miannu "Here, we provide evidence that LSD1 (KIAA0601), a nuclear homolog of amine oxidases, functions as a histone demethylase and transcriptional corepressor. LSD1 specifically demethylates histone H3 lysine 4, which is linked to active transcription." SIGNOR-264507 KDM1A protein O60341 UNIPROT H3-3A protein P84243 UNIPROT "up-regulates activity" demethylation Lys5 kQTARKST 9606 BTO:0000567 15620353 t miannu "Here, we provide evidence that LSD1 (KIAA0601), a nuclear homolog of amine oxidases, functions as a histone demethylase and transcriptional corepressor. LSD1 specifically demethylates histone H3 lysine 4, which is linked to active transcription." SIGNOR-264509 KDM1A protein O60341 UNIPROT H3-4 protein Q16695 UNIPROT "up-regulates activity" demethylation Lys5 kQTARKST 9606 15620353 t miannu "Here, we provide evidence that LSD1 (KIAA0601), a nuclear homolog of amine oxidases, functions as a histone demethylase and transcriptional corepressor. LSD1 specifically demethylates histone H3 lysine 4, which is linked to active transcription." SIGNOR-264508 KDM1A protein O60341 UNIPROT "CoREST-HDAC complex" complex SIGNOR-C105 SIGNOR "form complex" binding 9606 BTO:0000567 11171972 t miannu "Here we describe the components of a histone deacetylase (HDAC) complex that we term the CoREST-HDAC complex. CoREST Is a Component of an HDAC1/2 Complex. p40 is a Sox-like protein, p110b contains homology to polyamine oxidases, p110a is ZNF217, an eight-zinc finger protein, and p80 is a hypothetical protein of unknown function." SIGNOR-222121 KDM1A protein O60341 UNIPROT "BHC complex" complex SIGNOR-C353 SIGNOR "form complex" binding 9606 "BTO:0000567; BTO:0000007" 15325272 t miannu "BRAF–HDAC complex (BHC) consisting of six subunit proteins, BRAF35, BHC80, BHC110, HDAC1, HDAC2, and CoREST, has been purified from HeLa and HEK293 cells" SIGNOR-264501 TBC1D4 protein O60343 UNIPROT SLC2A4 protein P14672 UNIPROT down-regulates 9606 12637568 f gcesareni "These findings strongly indicate that insulin-stimulated phosphorylation of as160 is required for glut4 translocation and that this phosphorylation signals translocation through inactivation of the rab gap function." SIGNOR-99303 PHLPP1 protein O60346 UNIPROT RAF1 protein P04049 UNIPROT "down-regulates activity" dephosphorylation Ser338 RPRGQRDsSYYWEIE 10090 24530606 t gcesareni "PHLPP1 and PHLPP2 dephosphorylate RAF1 to reduce its signaling, increase the invasive and migratory activities of CRC cells, and activate the epithelial-mesenchymal transition. In Apc(Min) mice, loss of PHLPP1 promotes tumor progression." SIGNOR-237449 PHLPP1 protein O60346 UNIPROT PRKCB protein P05771 UNIPROT "down-regulates quantity" dephosphorylation Ser661 QNEFAGFsYTNPEFV 9606 BTO:0000067 18162466 t gcesareni "Here we show that the two PHLPP isoforms, PHLPP1 and PHLPP2, also dephosphorylate the hydrophobic motif on PKC betaII, an event that shunts PKC to the detergent-insoluble fraction, effectively terminating its life cycle" SIGNOR-237047 PHLPP1 protein O60346 UNIPROT PRKCB protein P05771 UNIPROT "down-regulates quantity by destabilization" dephosphorylation Ser661 QNEFAGFsYTNPEFV 9606 18162466 t "These data reveal that PHLPP controls the cellular levels of PKC by specifically dephosphorylating the hydrophobic motif, thus destabilizing the enzyme and promoting its degradation.|n contrast, results from siRNA depletion and overexpression experiments indicate that the hydrophobic motif site (Ser660) is regulated by PHLPP isoforms," SIGNOR-248326 PHLPP1 protein O60346 UNIPROT PRKCA protein P17252 UNIPROT "down-regulates quantity" dephosphorylation Ser657 QSDFEGFsYVNPQFV 9606 BTO:0000067 18162466 t gcesareni "In addition, knockdown of PHLPP expression reduces the rate of phorbol ester-triggered dephosphorylation of the hydrophobic motif, but not turn motif, of PKC alpha" SIGNOR-237043 PHLPP1 protein O60346 UNIPROT RPS6KB1 protein P23443 UNIPROT "down-regulates activity" dephosphorylation Thr390 DSKFTRQtPVDSPDD 9606 21986499 t gcesareni "Here we report the identification of ribosomal protein S6 kinase 1 (S6K1) as a novel substrate of PHLPP." SIGNOR-237454 PHLPP1 protein O60346 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000527 15808505 t gcesareni "Here, we identify a protein_ phosphatase, ph domain leucine-rich repeat protein_ phosphatase_ (phlpp), that specifically_ dephosphorylates_ the hydrophobic motif of_ akt_ (ser473 in akt1), triggering_ apoptosis_ and suppressing_ tumor_ growth." SIGNOR-252601 PHLPP1 protein O60346 UNIPROT AKT1 protein P31749 UNIPROT "down-regulates activity" dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0001544 19261608 t "The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells." SIGNOR-248327 PHLPP1 protein O60346 UNIPROT AKT2 protein P31751 UNIPROT down-regulates dephosphorylation 9606 17386267 t gcesareni "These data are consistent with phlpp terminating akt signaling by directly dephosphorylating and inactivating akt / phlpp1 specifically modulates the phosphorylation of hdm2 and gsk-3alpha through akt2, whereas phlpp2 specifically modulates the phosphorylation of p27 through akt3" SIGNOR-153935 PHLPP1 protein O60346 UNIPROT AKT2 protein P31751 UNIPROT "down-regulates activity" dephosphorylation Ser474 RTHFPQFsYSASIRE 9606 BTO:0001544 19261608 t "The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells." SIGNOR-248328 PHLPP1 protein O60346 UNIPROT AKT2 protein P31751 UNIPROT unknown dephosphorylation 9606 BTO:0000527 15808505 t gcesareni "These data are consistent with phlpp terminating akt signaling by directly dephosphorylating and inactivating akt / phlpp1 specifically modulates the phosphorylation of hdm2 and gsk-3alpha through akt2, whereas phlpp2 specifically modulates the phosphorylation of p27 through akt3" SIGNOR-135008 PHLPP1 protein O60346 UNIPROT STK4 protein Q13043 UNIPROT up-regulates binding 9606 23431053 t gcesareni "Here, we report that phlpp1 is a binding protein for mst1 and it modulates the hippo pathway by dephosphorylating mst1 at the inhibitory thr(387) of mst1." SIGNOR-201262 PHLPP1 protein O60346 UNIPROT STK4 protein Q13043 UNIPROT "up-regulates activity" dephosphorylation Thr387 TMKRRDEtMQPAKPS 9606 20513427 t "PHLPPs dephosphorylate Mst1 on the T387 inhibitory site, which activate Mst1 and its downstream effectors p38 and JNK to induce apoptosis." SIGNOR-248329 PHLPP1 protein O60346 UNIPROT AKT3 protein Q9Y243 UNIPROT "down-regulates activity" dephosphorylation Ser472 RPHFPQFsYSASGRE 9606 BTO:0001544 19261608 t "The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells." SIGNOR-248330 PHLPP1 protein O60346 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000527 15808505 t gcesareni "Here, we identify a protein_ phosphatase, ph domain leucine-rich repeat protein_ phosphatase_ (phlpp), that specifically_ dephosphorylates_ the hydrophobic motif of_ akt_ (ser473 in akt1), triggering_ apoptosis_ and suppressing_ tumor_ growth." SIGNOR-135005 PHLPP1 protein O60346 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" dephosphorylation 9606 BTO:0001544 19261608 t "The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells." SIGNOR-248331 FZD6 protein O60353 UNIPROT DVL1 protein O14640 UNIPROT "up-regulates activity" binding 9606 BTO:0000887;BTO:0001103 22944199 t 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-198828 NUPR1 protein O60356 UNIPROT ATF4 protein P18848 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567 19946894 f lperfetto "Nuclear protein 1 induced by ATF4 in response to various stressors acts as a positive regulator on the transcriptional activation of ATF4." SIGNOR-253731 HBP1 protein O60381 UNIPROT NCF1 protein P14598 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002181 15024088 t Luana "Together, these results indicate that HBP1 may contribute to the regulation of NADPH oxidase-dependent superoxide production through transcriptional repression of the p47phox gene. " SIGNOR-261614 EVI5 protein O60447 UNIPROT PLK1 protein P53350 UNIPROT down-regulates 9606 16439210 f gcesareni "Evi5 antagonizes scf(betatrcp)-dependent emi1 ubiquitination and destruction by binding to a site adjacent to emi1's dsgxxs degron and blocking both degron phosphorylation by polo-like kinases and subsequent betatrcp binding." SIGNOR-143683 NRP2 protein O60462 UNIPROT VEGFC protein P49767 UNIPROT up-regulates binding 9606 BTO:0000938 16816121 t gcesareni "By in vitro binding studies we found that both vegf-c and vegf-d interact with np2, vegf-c in a heparin-independent and vegf-d in a heparin-dependent manner." SIGNOR-147530 DSCAM protein O60469 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 30745319 t miannu "Our findings now further suggest that STAT3 and the adaptor protein SH2D2A interact with tyrosine‐containing motifs within the DSCAM/L1 ICDs. The SH2 domains of both STAT3 and SH2D2A are known to bind to phosphorylated tyrosine residues in the context of such motifs. Thus, the interactions between DSCAMs and SH2‐domain containing proteins seem to play a central and conserved role in Dscam signaling in the context of dynamic changes of tyrosine‐phosphorylation levels." SIGNOR-264277 DSCAM protein O60469 UNIPROT SH2D2A protein Q9NP31 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 30745319 t miannu "Our findings now further suggest that STAT3 and the adaptor protein SH2D2A interact with tyrosine‐containing motifs within the DSCAM/L1 ICDs. The SH2 domains of both STAT3 and SH2D2A are known to bind to phosphorylated tyrosine residues in the context of such motifs. Thus, the interactions between DSCAMs and SH2‐domain containing proteins seem to play a central and conserved role in Dscam signaling in the context of dynamic changes of tyrosine‐phosphorylation levels." SIGNOR-264279 DLX3 protein O60479 UNIPROT RUNX2 protein Q13950 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17060321 f gcesareni "Here we show that bmp2 induces dlx3, a homeodomain protein that activates runx2 gene transcription. Small interfering rna knockdown studies in osteoblasts validate that dlx3 is a potent regulator of runx2." SIGNOR-150177 STX10 protein O60499 UNIPROT "LE-TGN SNARE" complex SIGNOR-C157 SIGNOR "form complex" binding 9606 BTO:0000567 18195106 t lperfetto "We show in human cells that a soluble NSF attachment protein receptor (SNARE) complex comprised of syntaxin 10 (STX10), STX16, Vti1a, and VAMP3 is required for this MPR transport" SIGNOR-253080 ADCY9 protein O60503 UNIPROT "3',5'-cyclic AMP" smallmolecule CHEBI:17489 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 15385642 t miannu "Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions." SIGNOR-265005 CREBL2 protein O60519 UNIPROT PPARG protein P37231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000011 21728997 f Luana "Accordingly, the results of QPCR and immunoblot analysis showed that during adipogenesis, both the mRNA (Figures 4D and 4E) and protein (Figure 4F) levels of PPARγ , as well as C/EBPα, in 3T3-L1 preadipocytes transfected with either siCREBL2-1 or siCREBL2-2 were significantly decreased compared with the control (P < 0.05), suggesting that knockdown of CREBL2 protein suppress 3T3-L1 preadipocyte differentiation via inhibition of PPARγ and C/EBPα expression." SIGNOR-261573 CREBL2 protein O60519 UNIPROT CEBPA protein P49715 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000011 21728997 f Luana "Accordingly, the results of QPCR and immunoblot analysis showed that during adipogenesis, both the mRNA (Figures 4D and 4E) and protein (Figure 4F) levels of PPARγ , as well as C/EBPα, in 3T3-L1 preadipocytes transfected with either siCREBL2-1 or siCREBL2-2 were significantly decreased compared with the control (P < 0.05), suggesting that knockdown of CREBL2 protein suppress 3T3-L1 preadipocyte differentiation via inhibition of PPARγ and C/EBPα expression." SIGNOR-261574 PSPN protein O60542 UNIPROT GFRA4 protein Q9GZZ7 UNIPROT up-regulates binding 9606 BTO:0000938 11116144 t gcesareni "Glial cell line-derived neurotrophic factor (gdnf) family ligands signal through receptor complex consisting of a glycosylphosphatidylinositol-linked gdnf family receptor (gfr) alpha subunit and the transmembrane receptor tyrosine kinase ret." SIGNOR-85162 FOXD2 protein O60548 UNIPROT PRKAR1A protein P10644 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000661 12621056 t Luana "Elevating the amounts of FOXD2 expression vector up to 12-fold relative to the RIα1b reporter construct demonstrated that maximal induction of the RIα1b promoter by FOXD2 was at least 5.8-fold" SIGNOR-261605 CCNT1 protein O60563 UNIPROT HES1 protein Q14469 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15546612 f gcesareni "Cycc:cdk8 and cyct1:cdk9/p-tefb are recruited with notch and associated coactivators (mam, skip) to the hes1 promoter in signaling cells." SIGNOR-130634 CCNT1 protein O60563 UNIPROT "AEP complex" complex SIGNOR-C117 SIGNOR "form complex" binding 9606 BTO:0000664 20153263 t 1 miannu "These data demonstrate that AF4, AF5q31 and ENL associate in an endogenous higher-order complex (hereafter referred to as AEP for the AF4 family/ENL family/P-TEFb complex) containing P-TEFb in hematopoietic lineage cells." SIGNOR-239237 JAK2 protein O60674 UNIPROT PRMT5 protein O14744 UNIPROT down-regulates phosphorylation Tyr297 NRPPPNAyELFAKGY 9606 21316606 t llicata "Oncogenic jak2 kinases phosphorylate prmt5 in_vivo phosphorylation of prmt5 by jak2v617f greatly impairs its methyltransferase activity" SIGNOR-171994 BUB1B protein O60566 UNIPROT MCC complex SIGNOR-C382 SIGNOR "form complex" binding 9606 BTO:0000567 25092294 t miannu "The mitotic (or spindle assembly) checkpoint system delays anaphase until all chromosomes are correctly attached to the mitotic spindle. When the checkpoint is active, a Mitotic Checkpoint Complex (MCC) assembles and inhibits the ubiquitin ligase Anaphase-Promoting Complex/Cyclosome (APC/C). MCC is composed of the checkpoint proteins Mad2, BubR1, and Bub3 associated with the APC/C activator Cdc20." SIGNOR-265974 EIF4E2 protein O60573 UNIPROT "EIF4E2/GIGYF1 complex" complex SIGNOR-C256 SIGNOR "form complex" binding 9606 30917308 t lperfetto "4EHP forms complexes with the GYF domain-containing proteins GIGYF1 and GIGYF2, which are critical for this translational repression" SIGNOR-261010 EIF4E2 protein O60573 UNIPROT "EIF4E2/GIGYF2 complex" complex SIGNOR-C257 SIGNOR "form complex" binding 9606 BTO:0000568 22751931 t SARA "A Novel 4EHP-GIGYF2 Translational Repressor Complex Is Essential for Mammalian Development|GIGYF2 interacts specifically with m4EHP. The stabilities of m4EHP and GIGYF2 proteins are coregulated." SIGNOR-261008 TLR5 protein O60602 UNIPROT IL6 protein P05231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24709011 f miannu "These studies demonstrate a novel function of Toll-like receptor-5 (TLR5) in a human multiple myeloma (MM) cell line, KMS28BM. These cells express high levels of both TLR5 mRNA and protein. When cells were treated with the specific TLR5 ligand flagellin, proliferation was increased, and the secretion of IgG λ antibody and the expression of the pro-inflammatory cytokine IL-6 were increased via NF-κB activation through PI3K/AKT and p38 signaling." SIGNOR-259868 TLR2 protein O60603 UNIPROT TIRAP protein P58753 UNIPROT "up-regulates activity" binding 10090 22664090 t scontino "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-266745 TLR2 protein O60603 UNIPROT TICAM2 protein Q86XR7 UNIPROT "up-regulates activity" binding 10090 22664090 t scontino "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-266747 TLR2 protein O60603 UNIPROT TICAM1 protein Q8IUC6 UNIPROT "up-regulates activity" binding 10090 22664090 t scontino "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-266746 TLR2 protein O60603 UNIPROT MYD88 protein Q99836 UNIPROT "up-regulates activity" binding 10090 22664090 t miannu "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-266740 TLR2 protein O60603 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "down-regulates activity" 9606 BTO:0001025 19185596 f miannu "S protein is a ligand for human TLR2. S protein utilizes toll-like receptor 2(TLR 2) to increase IL-8 production.Our results show that SARS S protein in a soluble form increased IL-8 production through hTLR2 ligand interaction. we have provided evidence that S protein induces IL-8 in PBMC in vitro and in THP-1 cells. The ability of S protein to increase IL-8 mRNA was mediated by activation of NF-κB possibly via TLR2 ligand and could be inhibited by the NF-κB inhibitor TPCK. The ability to detect elevated NF-κB transcription factor activity in the nucleus in response to S protein suggests that this most likely occurs by the mechanism of induction. Moreover increased secretion of IL-8 and IL-6 cytokines indicated that levels of proinflammatory mediators could be enhanced by S protein interaction with monocyte macrophages and could stimulate NK, neutrophil and monocyte migration to the site of infection." SIGNOR-260973 DIAPH1 protein O60610 UNIPROT CDH4 protein P55283 UNIPROT "up-regulates activity" 9606 BTO:0000815 22820501 t lperfetto "Taken together, data obtained from MCF10A cells were consistent with the idea that Rho signaling to Dia1 and profilin-1 was essential for R-cadherin adherens junction formation." SIGNOR-253110 SNAP91 protein O60641 UNIPROT SYT1 protein P21579 UNIPROT "up-regulates quantity" binding 9606 BTO:0000938 26903854 t miannu " the monomeric adaptor proteins AP180/CALM and stonin-2 are required for the efficient retrieval of synaptobrevin II (sybII) and synaptotagmin-1 respectively .Stonin-2 and AP-2 are also Required for Efficient Synaptotagmin-1 Retrieval.  the monomeric adaptor proteins AP180/CALM and stonin-2 are required for the efficient retrieval of synaptobrevin II (sybII) and synaptotagmin-1 respectively." SIGNOR-264114 SNAP91 protein O60641 UNIPROT VAMP2 protein P63027 UNIPROT "up-regulates quantity" binding 9606 BTO:0000938 26903854 t miannu " the monomeric adaptor proteins AP180/CALM and stonin-2 are required for the efficient retrieval of synaptobrevin II (sybII) and synaptotagmin-1 respectively. Furthermore, recent studies have revealed that sybII and synaptotagmin-1 interact with other SV cargoes to ensure a high fidelity of retrieval." SIGNOR-264112 PLIN3 protein O60664 UNIPROT IGF2R protein P11717 UNIPROT "up-regulates activity" relocalization 9534 BTO:0004055 9590177 t lperfetto "TIP47 is present in cytosol and on endosomes and is required for MPR transport from endosomes to the trans-Golgi network in vitro and in vivo. TIP47 recognizes a phenylalanine/tryptophan signal in the tail of the cation-dependent MPR that is essential for its proper sorting within the endosomal pathway. These data suggest that TIP47 binds MPR cytoplasmic domains and facilitates their collection into transport vesicles destined for the Golgi." SIGNOR-253092 PLIN3 protein O60664 UNIPROT M6PR protein P20645 UNIPROT "up-regulates activity" relocalization 9534 BTO:0004055 9590177 t lperfetto "TIP47 is present in cytosol and on endosomes and is required for MPR transport from endosomes to the trans-Golgi network in vitro and in vivo. TIP47 recognizes a phenylalanine/tryptophan signal in the tail of the cation-dependent MPR that is essential for its proper sorting within the endosomal pathway. These data suggest that TIP47 binds MPR cytoplasmic domains and facilitates their collection into transport vesicles destined for the Golgi." SIGNOR-253093 RAD1 protein O60671 UNIPROT TOPBP1 protein Q92547 UNIPROT up-regulates binding 9606 18594563 t gcesareni "The 9-1-1 complex functions as a clamp, encircling the dna, and recruits the brct domain-containing protein topbp1 in a phospho-dependent manner" SIGNOR-179379 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT down-regulates phosphorylation Tyr317 TEQDLQLyCDFPNII 9606 BTO:0000007 19364823 t "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 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates activity" phosphorylation Tyr570 VRREVGDyGQLHETE 9606 BTO:0000007 15143187 t "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 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates activity" phosphorylation Tyr570 VRREVGDyGQLHETE 9606 21841788 t 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 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT unknown phosphorylation Tyr1007 VLPQDKEyYKVKEPG -1 9111318 t "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 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates phosphorylation Tyr221 IRAKIQDyHILTRKR 9606 BTO:0000007 15143187 t lperfetto "Autophosphorylation of jak2 on tyrosines 221 and 570 regulates its activity with phosphorylation of tyrosine 221 increasing kinase activity" SIGNOR-236506 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates phosphorylation Tyr868 GSVEMCRyDPLQDNT 9606 BTO:0000007 20304997 t lperfetto "Tyrosines 868, 966, and 972 in the kinase domain of jak2 are autophosphorylated and required for maximal jak2 kinase activity" SIGNOR-236298 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates phosphorylation Tyr966 QICKGMEyLGTKRYI 9606 BTO:0000007 20304997 t lperfetto "Tyrosines 868, 966, and 972 in the kinase domain of jak2 are autophosphorylated and required for maximal jak2 kinase activity" SIGNOR-236290 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT "up-regulates activity" phosphorylation Tyr813 NSLFTPDyELLTEND 9606 BTO:0000007 15121872 t "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 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT "up-regulates activity" phosphorylation Tyr221 IRAKIQDyHILTRKR 9606 BTO:0000007 15143187 t "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 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT "up-regulates activity" phosphorylation Tyr201 DQTPLAIyNSISYKT 9534 BTO:0000298 17027227 t "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 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT "up-regulates activity" phosphorylation Tyr637 KFGSLDTyLKKNKNC 9606 BTO:0000007 19364823 t "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 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT "up-regulates activity" phosphorylation Tyr972 EYLGTKRyIHRDLAT 9606 BTO:0000007 20304997 t lperfetto "Tyrosines 868, 966, and 972 in the kinase domain of jak2 are autophosphorylated and required for maximal jak2 kinase activity" SIGNOR-236294 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT "up-regulates activity" phosphorylation Tyr1007 VLPQDKEyYKVKEPG -1 9111318 t "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 JAK2 protein O60674 UNIPROT APOA1 protein P02647 UNIPROT "up-regulates activity" 9606 14668333 t miannu "ApoA-I interactions with ABCA1 and lipid efflux to apoA-I were substantially impaired by inhibiting or abolishing JAK2, whereas ABCA1 protein levels were unaffected, and ABCA1 cholesterol translocase activity was only slightly reduced. The most likely explanation for these findings is that JAK2 promotes apolipoprotein interactions with ABCA1 or a closely proximal site, and this facilitates the removal of cellular lipids. the interaction of apolipoproteins with ABCA1-expressing cells activates JAK2, which in turn activates a process that enhances apolipoprotein interactions with ABCA1 and lipid removal from cells" SIGNOR-252107 JAK2 protein O60674 UNIPROT RAF1 protein P04049 UNIPROT "up-regulates activity" phosphorylation Tyr340 RGQRDSSyYWEIEAS 10090 BTO:0001482 8876196 t " JAK2 phosphorylated Raf-1. e sites at 340/341 are indeed phosphorylated by JAK2 and that this phosphorylation represents a major component of the activation process." SIGNOR-251361 JAK2 protein O60674 UNIPROT RAF1 protein P04049 UNIPROT "up-regulates activity" phosphorylation Tyr341 GQRDSSYyWEIEASE 10090 BTO:0001482 8876196 t " JAK2 phosphorylated Raf-1. e sites at 340/341 are indeed phosphorylated by JAK2 and that this phosphorylation represents a major component of the activation process." SIGNOR-251362 JAK2 protein O60674 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation 9606 BTO:0001103 21576360 t "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 JAK2 protein O60674 UNIPROT IFNGR1 protein P15260 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000801 23898330 t 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 JAK2 protein O60674 UNIPROT CSF2RA protein P15509 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000801 8977526 t lperfetto "JAK2 is a primary kinase regulating all the known activities of GM-CSF. JAK2 mediates GM-CSF induced c-fos activation through receptor phosphorylation and Shc/PTP 1D activation." SIGNOR-249503 JAK2 protein O60674 UNIPROT CTLA4 protein P16410 UNIPROT "up-regulates quantity by stabilization" phosphorylation Tyr201 SPLTTGVyVKMPPTE 9606 10842319 t "Janus Kinase 2 (Jak2) was directly associated with a box 1-like motif in the cytoplasmic tail of CTLA-4 molecule. Jak2 phosphorylated Y-165 residue in the cytoplasmic region of CTLA-4. It has been reported that phosphorylation and dephosphorylation of tyrosine residue Y-165 in the cytoplasmic region of CTLA-4 play an important role in its negative signaling and cell surface expression. Some signaling molecules such as Src homology 2 protein tyrosine phosphatase 2 (SHP-2) and the p85 subunit of phosphatidylinositol 3 kinase (PI3 kinase) associate with phosphorylated tyrosine residue Y-165, through Src homology 2 (SH2) domains. On the other hand, the adapter complex proteins, AP-2 and AP-50 interact with the same tyrosine residue when unphosphorylated, resulting in clathrin-mediated endocytosis of CTLA-4 molecules." SIGNOR-251346 JAK2 protein O60674 UNIPROT EPOR protein P19235 UNIPROT "up-regulates activity" phosphorylation Tyr368 SEHAQDTyLVLDKWL 12441334 t "JAK2 in turn phosphorylates several tyrosine residues on the EpoR-cytosolic domain and probably on JAK2 itself that serve as docking sites for SH2 or protein tyrosine binding domains of downstream signal transduction proteins such as STAT5, phosphatidylinositol 3-kinase, Shc, and tyrosine phosphatases SHP1 and SHP2" SIGNOR-251348 JAK2 protein O60674 UNIPROT EPOR protein P19235 UNIPROT "up-regulates activity" phosphorylation Tyr426 ASAASFEyTILDPSS 12441334 t "JAK2 in turn phosphorylates several tyrosine residues on the EpoR-cytosolic domain and probably on JAK2 itself that serve as docking sites for SH2 or protein tyrosine binding domains of downstream signal transduction proteins such as STAT5, phosphatidylinositol 3-kinase, Shc, and tyrosine phosphatases SHP1 and SHP2" SIGNOR-251349 JAK2 protein O60674 UNIPROT EPOR protein P19235 UNIPROT "up-regulates activity" phosphorylation Tyr454 PTPPHLKyLYLVVSD 12441334 t "JAK2 in turn phosphorylates several tyrosine residues on the EpoR-cytosolic domain and probably on JAK2 itself that serve as docking sites for SH2 or protein tyrosine binding domains of downstream signal transduction proteins such as STAT5, phosphatidylinositol 3-kinase, Shc, and tyrosine phosphatases SHP1 and SHP2" SIGNOR-251350 JAK2 protein O60674 UNIPROT EPOR protein P19235 UNIPROT "up-regulates activity" phosphorylation Tyr456 PPHLKYLyLVVSDSG 12441334 t "JAK2 in turn phosphorylates several tyrosine residues on the EpoR-cytosolic domain and probably on JAK2 itself that serve as docking sites for SH2 or protein tyrosine binding domains of downstream signal transduction proteins such as STAT5, phosphatidylinositol 3-kinase, Shc, and tyrosine phosphatases SHP1 and SHP2" SIGNOR-251351 JAK2 protein O60674 UNIPROT EPOR protein P19235 UNIPROT "up-regulates activity" phosphorylation Tyr468 DSGISTDySSGDSQG 12441334 t "JAK2 in turn phosphorylates several tyrosine residues on the EpoR-cytosolic domain and probably on JAK2 itself that serve as docking sites for SH2 or protein tyrosine binding domains of downstream signal transduction proteins such as STAT5, phosphatidylinositol 3-kinase, Shc, and tyrosine phosphatases SHP1 and SHP2" SIGNOR-251352 JAK2 protein O60674 UNIPROT EPOR protein P19235 UNIPROT "up-regulates activity" phosphorylation Tyr485 GGLSDGPySNPYENS 12441334 t "JAK2 in turn phosphorylates several tyrosine residues on the EpoR-cytosolic domain and probably on JAK2 itself that serve as docking sites for SH2 or protein tyrosine binding domains of downstream signal transduction proteins such as STAT5, phosphatidylinositol 3-kinase, Shc, and tyrosine phosphatases SHP1 and SHP2" SIGNOR-251353 JAK2 protein O60674 UNIPROT EPOR protein P19235 UNIPROT "up-regulates activity" phosphorylation Tyr489 DGPYSNPyENSLIPA 12441334 t "JAK2 in turn phosphorylates several tyrosine residues on the EpoR-cytosolic domain and probably on JAK2 itself that serve as docking sites for SH2 or protein tyrosine binding domains of downstream signal transduction proteins such as STAT5, phosphatidylinositol 3-kinase, Shc, and tyrosine phosphatases SHP1 and SHP2" SIGNOR-251354 JAK2 protein O60674 UNIPROT EPOR protein P19235 UNIPROT "up-regulates activity" phosphorylation Tyr504 AEPLPPSyVACS 12441334 t "JAK2 in turn phosphorylates several tyrosine residues on the EpoR-cytosolic domain and probably on JAK2 itself that serve as docking sites for SH2 or protein tyrosine binding domains of downstream signal transduction proteins such as STAT5, phosphatidylinositol 3-kinase, Shc, and tyrosine phosphatases SHP1 and SHP2" SIGNOR-251355 JAK2 protein O60674 UNIPROT IFNGR2 protein P38484 UNIPROT "up-regulates activity" binding 9606 BTO:0000801 23898330 t 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 JAK2 protein O60674 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000599 9575217 t 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 JAK2 protein O60674 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000599 9575217 t 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 JAK2 protein O60674 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation Tyr701 DGPKGTGyIKTELIS 9606 BTO:0000567 15322115 t 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 JAK2 protein O60674 UNIPROT STAT6 protein P42226 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000801 18852293 t 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 JAK2 protein O60674 UNIPROT STAT5A protein P42229 UNIPROT up-regulates phosphorylation Tyr694 LAKAVDGyVKPQIKQ 4932 9575217 t 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 JAK2 protein O60674 UNIPROT STAT5A protein P42229 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000801 9575217 t lperfetto "Jak2 kinase induces tyrosine phosphorylation, dimerization, nuclear translocation, and dna binding of a concomitantly expressed stat5 protein" SIGNOR-249507 JAK2 protein O60674 UNIPROT SLC6A8 protein P48029 UNIPROT "down-regulates activity" relocalization 443947 BTO:0000964 22407360 t miannu "Janus-activated kinase-2 (JAK2) participates in the regulation of the Na⁺-coupled glucose transporter SGLT1 and the Na⁺-coupled amino acid transporter SLC6A19. JAK2 is a novel regulator of the creatine transporter SLC6A8, which downregulates the carrier, presumably by interference with carrier protein insertion into the cell membrane." SIGNOR-265781 JAK2 protein O60674 UNIPROT SLC6A8 protein P48029 UNIPROT "down-regulates activity" relocalization 443947 BTO:0000964 22407360 t miannu "Janus-activated kinase-2 (JAK2) participates in the regulation of the Na⁺-coupled glucose transporter SGLT1 and the Na⁺-coupled amino acid transporter SLC6A19. JAK2 is a novel regulator of the creatine transporter SLC6A8, which downregulates the carrier, presumably by interference with carrier protein insertion into the cell membrane." SIGNOR-265807 JAK2 protein O60674 UNIPROT LEPR protein P48357 UNIPROT "up-regulates activity" phosphorylation Tyr1141 SKKTFASyMPQFQTC 9606 BTO:0000007 11018044 t miannu "LRb signaling is initiated by leptin binding to the extracellular domain of the LRb dimer, leading to Jak2 transphosphorylation and activation. Activated Jak2 mediates the tyrosine phosphorylation of Tyr985 and Tyr1138of LRb. These phosphotyrosine residues immediately function as binding sites (double-ended lines) for SHP-2 and STAT3, both of which quickly become tyrosine-phosphorylated by Jak2." SIGNOR-263494 JAK2 protein O60674 UNIPROT LEPR protein P48357 UNIPROT "up-regulates activity" phosphorylation Tyr986 QRQPFVKyATLISNS 9606 BTO:0000007 11018044 t miannu "LRb signaling is initiated by leptin binding to the extracellular domain of the LRb dimer, leading to Jak2 transphosphorylation and activation. Activated Jak2 mediates the tyrosine phosphorylation of Tyr985 and Tyr1138of LRb. These phosphotyrosine residues immediately function as binding sites (double-ended lines) for SHP-2 and STAT3, both of which quickly become tyrosine-phosphorylated by Jak2." SIGNOR-263493 JAK2 protein O60674 UNIPROT GTF2I protein P78347 UNIPROT "up-regulates activity" phosphorylation Tyr248 EESEDPDyYQYNIQA 10090 BTO:0000944 11313464 t lperfetto "Jak2 activates tfii-i and regulates its interaction with extracellular signal-regulated kinase the interaction between tfii-i and erk, which is essential for its activity, can be regulated by jak2 through phosphorylation of tfii-i at tyrosine 248" SIGNOR-235313 JAK2 protein O60674 UNIPROT PTPN11 protein Q06124 UNIPROT "up-regulates activity" phosphorylation Tyr304 PNEPVSDyINANIIM 9534 BTO:0004055 8995399 t lperfetto "Tyrosine residues 304 and 327 in shp-2 are phosphorylated by jaks, and phosphorylated shp-2 can associate with the downstream adapter protein grb2" SIGNOR-236266 JAK2 protein O60674 UNIPROT PTPN11 protein Q06124 UNIPROT "up-regulates activity" phosphorylation Tyr327 NSKPKKSyIATQGCL 9534 BTO:0004055 8995399 t lperfetto "Tyrosine residues 304 and 327 in shp-2 are phosphorylated by jaks, and phosphorylated shp-2 can associate with the downstream adapter protein grb2" SIGNOR-236270 JAK2 protein O60674 UNIPROT STAT4 protein Q14765 UNIPROT up-regulates phosphorylation Tyr693 TERGDKGyVPSVFIP 9606 BTO:0000782 16324152 t gcesareni "Janus family tyrosine kinases jak2 and tyk2, which in turn phosphorylate stat4 on tyrosine 693. The p38 mitogen-activated protein kinase (mapk) signaling pathway is also activated in response to il-12, followed by phosphorylation of stat4 on serine 721, which is required for stat4 full transcriptional activity" SIGNOR-142736 JAK2 protein O60674 UNIPROT STAM protein Q92783 UNIPROT up-regulates phosphorylation 9606 9133424 t gcesareni "Stam is associated with jak3 and jak2 tyrosine kinases via its itam region and phosphorylated by jak3 and jak2 upon stimulation with il-2." SIGNOR-47834 JAK2 protein O60674 UNIPROT ATOH1 protein Q92858 UNIPROT "up-regulates quantity" phosphorylation Tyr80 CTARAAQyLLHSPEL 9606 BTO:0004328 29168692 t Gianni "We discovered tyrosine 78 of Atoh1 is phosphorylated by a Jak2-mediated pathway only in tumor-initiating cells and in human SHH-type medulloblastoma. Phosphorylation of tyrosine 78 stabilizes Atoh1, increases Atoh1’s transcriptional activity, and is independent of canonical Jak2 signaling." SIGNOR-262201 JAK2 protein O60674 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates phosphorylation Tyr718 IPERDSRySQPLHEE 9606 19287004 t lperfetto "Previously we have shown that tyrosine 718 of ask1 when phosphorylated is critical for socs1 binding and socs1-mediated degradation of ask1we identified jak2 and shp2 as a tyr-718-specific kinase and phosphatase, respectively." SIGNOR-184600 JAK2 protein O60674 UNIPROT STAP2 protein Q9UGK3 UNIPROT "up-regulates activity" phosphorylation Tyr250 PFLLDEDyEKVLGYV BTO:0000007 12540842 t lperfetto "To examine this possibility, STAP-2 was co-transfected with constitutively active tyrosine kinases in HEK-293 cells. STAP-2 was strongly phosphorylated by various tyrosine kinases, including v-Src (Fig.2 A-a), a JAK2 tyrosine kinase |On the other hand, the phosphorylation levels of Y22F, Y310F, and Y322F by GST-JH1 were reduced to 80€“60% of the levels of wild-type STAP-2, which suggests that these three are potential phosphorylation sites by activated JAK2." SIGNOR-249371 JAK2 protein O60674 UNIPROT STAP2 protein Q9UGK3 UNIPROT "up-regulates activity" phosphorylation Tyr310 LPNQEENyVTPIGDG BTO:0000007 12540842 t lperfetto "To examine this possibility, STAP-2 was co-transfected with constitutively active tyrosine kinases in HEK-293 cells. STAP-2 was strongly phosphorylated by various tyrosine kinases, including v-Src (Fig.2 A-a), a JAK2 tyrosine kinase |On the other hand, the phosphorylation levels of Y22F, Y310F, and Y322F by GST-JH1 were reduced to 80€“60% of the levels of wild-type STAP-2, which suggests that these three are potential phosphorylation sites by activated JAK2." SIGNOR-249372 LRP6 protein O75581 UNIPROT GSK3B protein P49841 UNIPROT "up-regulates activity" 15229249 f "We speculate that DKK1 produced by βAP-treated neurons suppresses the canonical Wnt signaling pathway by interacting with LRP5/6 and therefore facilitates GSK3β activation." SIGNOR-255484 JAK2 protein O60674 UNIPROT GAB2 protein Q9UQC2 UNIPROT up-regulates phosphorylation Tyr643 TSDEKVDyVQVDKEK 9606 BTO:0000130 18644434 t lperfetto "In vitro, activated jak2 directly phosphorylated specific gab2 tyrosine residues. Mutagenesis studies revealed that gab2 tyrosine 643 (y643) was a major target of jak2 in vitro, and a key residue for jak2-dependent phosphorylation in intact cells. Mutation of gab2 y643 inhibited g-csf-stimulated erk1/2 activation and shp2 binding to gab2." SIGNOR-179488 JAK2 protein O60674 UNIPROT IFNGR2/INFGR1 complex SIGNOR-C142 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000801 23898330 t 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 JAK2 protein O60674 UNIPROT CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000876 BTO:0001103 19436055 t 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 JAK2 protein O60674 UNIPROT CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000801 8977526 t irozzo "JAK2 is a primary kinase regulating all the known activities of GM-CSF. JAK2 mediates GM-CSF induced c-fos activation through receptor phosphorylation and Shc/PTP 1D activation." SIGNOR-256001 KPNA6 protein O60684 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates relocalization 9606 20454918 t gcesareni "Nicd binds via one of its four potential nuclear localization signals to importins alfa3, alfa4, and alfa7. importins alpha3, alpha4 (and to a lesser extent, alpha7) mediate nuclear import of nicd and thus are directly involved in notch signaling." SIGNOR-165343 ABCC9 protein O60706 UNIPROT "KATP channel" complex SIGNOR-C274 SIGNOR "form complex" binding 9606 28842488 t lperfetto "ATP-sensitive K+ (KATP) channels, found throughout the body, are generated as octameric complexes consisting of four pore-forming Kir6.1 or Kir6.2 subunits with four regulatory sulfonylurea receptor (SUR1 or SUR2) subunits." SIGNOR-262057 CTNND1 protein O60716 UNIPROT CDH2 protein P19022 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0003564 14610055 t miannu "To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member." SIGNOR-252125 CTNND1 protein O60716 UNIPROT CDH3 protein P22223 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0003564 14610055 t miannu "To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member." SIGNOR-252124 CTNND1 protein O60716 UNIPROT CDH5 protein P33151 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0003564 14610055 t miannu "To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member." SIGNOR-252126 CTNND1 protein O60716 UNIPROT RAC1 protein P63000 UNIPROT up-regulates binding 9606 22946057 t gcesareni "We demonstrate that p120-catenin participates in the stimulation of rac1 activity, binding directly to this protein. In addition we show that vav2 also binds to p120-catenin and is required for rac1 activation and for beta-catenin translocation to the nucleus.Vav2 And rac1 association with p120-catenin was modulated by phosphorylation of this protein, which was stimulated upon serine/threonine phosphorylation by ck1 and inhibited by tyrosine phosphorylation by src or fyn" SIGNOR-198938 CTNND1 protein O60716 UNIPROT ZBTB33 protein Q86T24 UNIPROT down-regulates 9606 23481205 f gcesareni "Nuclear signaling is affected by the interaction ofp120with kaiso, a transcription factor regulatingwnt-responsive genes. in addition, p120 cytoplasmic localization results in sequestration of kaiso in the cytoplasm and its inactivation" SIGNOR-192369 SLC24A1 protein O60721 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI "down-regulates quantity" relocalization 9606 BTO:0000938 30173760 t miannu "K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+)" SIGNOR-264395 SLC24A1 protein O60721 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "down-regulates quantity" relocalization 9606 BTO:0000938 30173760 t miannu "K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+)" SIGNOR-264390 CDC14B protein O60729 UNIPROT TP53 protein P04637 UNIPROT "down-regulates activity" dephosphorylation Ser315 LPNNTSSsPQPKKKP 9606 10644693 t "The human Cdc14 phosphatases interact with and dephosphorylate the tumor suppressor protein p53|. Furthermore, the hCdc14 phosphatases were found to dephosphorylate p53 specifically at the p34Cdc2/clb phosphorylation site (p53-phosphor-Ser315)|Earlier studies showed that Ser315 phosphorylation increases the sequence-specific DNA binding capacity of p53, suggesting that Ser315 phosphorylation is an activating modification" SIGNOR-248332 CDC14B protein O60729 UNIPROT APC protein P25054 UNIPROT up-regulates dephosphorylation 9606 SIGNOR-C110 18662541 t gcesareni "The phosphatase cdc14b translocates from the nucleolus to the nucleoplasm and induces the activation of the ubiquitin ligase apc/ccdh1" SIGNOR-179636 CDC14B protein O60729 UNIPROT SKP2 protein Q13309 UNIPROT "down-regulates quantity by destabilization" dephosphorylation Ser64 SNLGHPEsPPRKRLK 9606 18239684 t "The activity of SCF(Skp2) is regulated by the Cyclin-dependent kinase (CDK)2-mediated phosphorylation of Skp2 on Ser64 allows its expression in mid-G1 phase, even in the presence of active APC(Cdh1). Reciprocally, dephosphorylation of Skp2 by the mitotic phosphatase Cdc14B at the M --> G1 transition promotes its degradation by APC(Cdh1)." SIGNOR-248333 CDC14B protein O60729 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates dephosphorylation Ser684 IGIPQFHsPVGSPLK 9606 20236090 t lperfetto "Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3.alanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.we found that the phosphatases cdc14a and cdc14b (cdc is cell-division cycle) bind to erk3 and reverse its c-terminal phosphorylation in mitosis." SIGNOR-164471 CDC14B protein O60729 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates dephosphorylation Ser688 QFHSPVGsPLKSIQA 9606 20236090 t lperfetto "Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3.alanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.we found that the phosphatases cdc14a and cdc14b (cdc is cell-division cycle) bind to erk3 and reverse its c-terminal phosphorylation in mitosis." SIGNOR-164475 CDC14B protein O60729 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates dephosphorylation Ser705 TPSAMKSsPQIPHQT 9606 20236090 t lperfetto "Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3.alanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.we found that the phosphatases cdc14a and cdc14b (cdc is cell-division cycle) bind to erk3 and reverse its c-terminal phosphorylation in mitosis." SIGNOR-164479 CDC14B protein O60729 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates dephosphorylation Thr698 KSIQATLtPSAMKSS 9606 20236090 t lperfetto "Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3.alanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.we found that the phosphatases cdc14a and cdc14b (cdc is cell-division cycle) bind to erk3 and reverse its c-terminal phosphorylation in mitosis." SIGNOR-164483 CDC14B protein O60729 UNIPROT MAPK6 protein Q16659 UNIPROT "down-regulates quantity by destabilization" dephosphorylation Ser684 IGIPQFHsPVGSPLK 9606 20236090 t "Reciprocally, we found that the phosphatases Cdc14A and Cdc14B (Cdc is cell-division cycle) bind to ERK3 and reverse its C-terminal phosphorylation in mitosis. Importantly, alanine substitution of the four C-terminal phosphorylation sites markedly decreased the half-life of ERK3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.|In vitro phosphorylation of a series of ERK3-deletion mutants by mitotic cell extracts revealed that phosphorylation is confined to the unique C-terminal extension of the protein. Using MS analysis, we identified four novel phosphorylation sites, Ser684, Ser688, Thr698 and Ser705, located at the extreme C-terminus of ERK3." SIGNOR-248334 CDC14B protein O60729 UNIPROT MAPK6 protein Q16659 UNIPROT "down-regulates quantity by destabilization" dephosphorylation Ser688 QFHSPVGsPLKSIQA 9606 20236090 t "Reciprocally, we found that the phosphatases Cdc14A and Cdc14B (Cdc is cell-division cycle) bind to ERK3 and reverse its C-terminal phosphorylation in mitosis. Importantly, alanine substitution of the four C-terminal phosphorylation sites markedly decreased the half-life of ERK3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.|In vitro phosphorylation of a series of ERK3-deletion mutants by mitotic cell extracts revealed that phosphorylation is confined to the unique C-terminal extension of the protein. Using MS analysis, we identified four novel phosphorylation sites, Ser684, Ser688, Thr698 and Ser705, located at the extreme C-terminus of ERK3." SIGNOR-248335 CDC14B protein O60729 UNIPROT MAPK6 protein Q16659 UNIPROT "down-regulates quantity by destabilization" dephosphorylation Ser705 TPSAMKSsPQIPHQT 9606 20236090 t "Reciprocally, we found that the phosphatases Cdc14A and Cdc14B (Cdc is cell-division cycle) bind to ERK3 and reverse its C-terminal phosphorylation in mitosis. Importantly, alanine substitution of the four C-terminal phosphorylation sites markedly decreased the half-life of ERK3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.|In vitro phosphorylation of a series of ERK3-deletion mutants by mitotic cell extracts revealed that phosphorylation is confined to the unique C-terminal extension of the protein. Using MS analysis, we identified four novel phosphorylation sites, Ser684, Ser688, Thr698 and Ser705, located at the extreme C-terminus of ERK3." SIGNOR-248337 CDC14B protein O60729 UNIPROT MAPK6 protein Q16659 UNIPROT "down-regulates quantity by destabilization" dephosphorylation Thr698 KSIQATLtPSAMKSS 9606 20236090 t "Reciprocally, we found that the phosphatases Cdc14A and Cdc14B (Cdc is cell-division cycle) bind to ERK3 and reverse its C-terminal phosphorylation in mitosis. Importantly, alanine substitution of the four C-terminal phosphorylation sites markedly decreased the half-life of ERK3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.|In vitro phosphorylation of a series of ERK3-deletion mutants by mitotic cell extracts revealed that phosphorylation is confined to the unique C-terminal extension of the protein. Using MS analysis, we identified four novel phosphorylation sites, Ser684, Ser688, Thr698 and Ser705, located at the extreme C-terminus of ERK3." SIGNOR-248336 MITF protein O75030 UNIPROT TPSAB1 protein Q15661 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000830 20513998 t lperfetto "The transcription of tryptase gene in human mast cells is regulated by mi transcription factor |Using mutant constructs of tryptase promoter, we observed that two E-box (CANNTG) motifs including between -817 to -715 and -421 to -202 are able to involve in the transactivation of tryptase gene by MITF-A." SIGNOR-251725 CDC14B protein O60729 UNIPROT SIRT2 protein Q8IXJ6 UNIPROT unknown dephosphorylation Ser368 PNPSTSAsPKKSPPP 9606 17488717 t "Here, we demonstrate that SIRT2 is phosphorylated both in vitro and in vivo on serine 368 by the cell-cycle regulator, cyclin-dependent kinase 1, and dephosphorylated by the phosphatases CDC14A and CDC14B. Overexpression of SIRT2 mediates a delay in cellular proliferation that is dependent on serine 368 phosphorylation|Additionally, we found that SIRT2, like other Cdk1 targets, can be dephosphorylated by the phosphatases CDC14A and CDC14B. In contrast to a published report (8), we did not observe any degradation of SIRT2 by the 26 S proteasome in response to CDC14B overexpression|However, we cannot exclude the possibility that phosphorylation of serine 368 might affect the activity of SIRT2 on other unidentified acetylated substrates." SIGNOR-248338 CDC14B protein O60729 UNIPROT KMT5A protein Q9NQR1 UNIPROT "down-regulates quantity by destabilization" dephosphorylation Ser100 SKIYSYMsPNKCSGM 9606 20966048 t "The dephosphorylation of S29 during late mitosis by the Cdc14 phosphatases was required for APC(cdh1)-mediated ubiquitination of PR-Set7 and subsequent proteolysis." SIGNOR-248339 CDC14B protein O60729 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates dephosphorylation 9606 18662541 t lperfetto "The phosphatase cdc14b translocates from the nucleolus to the nucleoplasm and induces the activation of the ubiquitin ligase apc/ccdh1" SIGNOR-227927 GALR3 protein O60755 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257206 GALR3 protein O60755 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256862 GALR3 protein O60755 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256998 GALR3 protein O60755 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257114 GALR3 protein O60755 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256719 USO1 protein O60763 UNIPROT GOLGB1 protein Q14789 UNIPROT "up-regulates activity" binding 9606 23555793 t miannu "The “cis-golgin tether” is one of the most well-characterized golgin tether complexes. It is composed of the COPI vesicle-associated golgin giantin linked to Golgi membrane-associated GM130 via p115. GM130 is in turn linked to GRASP65 via a PDZ-like domain. GRASP65 is anchored to the Golgi membrane through N-terminal myristoylation as well as through binding to other Golgi proteins [10]. Together, these proteins appear to mediate vesicle tethering at the cis-Golgi membrane." SIGNOR-261237 MRPS14 protein O60783 UNIPROT "28S mitochondrial small ribosomal subunit" complex SIGNOR-C266 SIGNOR "form complex" binding 9606 BTO:0000934 25838379 t miannu "The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins." SIGNOR-261456 DKC1 protein O60832 UNIPROT TERT protein O14746 UNIPROT "up-regulates activity" binding 18680434 t lperfetto "Dyskerin was recently found to be associated with active human telomerase (34), and mutations in dyskerin or NOP10 or deletion of the H/ACA motif of hTERC result in diminished telomerase activity" SIGNOR-263332 MITF protein O75030 UNIPROT MLANA protein Q16655 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000848 12819038 f miannu "The results of the present work demonstrate that the essential melanocyte-specific transcription factor MITF regulates expression of the genes encoding the melanoma tumor markers MLANA and SILV. MITF up- or down-regulation is seen to correspondingly modulate expression of MLANA and SILV in parallel directions, at both mRNA and protein levels." SIGNOR-254590 MMP20 protein O60882 UNIPROT ACAN protein P16112 UNIPROT "down-regulates quantity by destabilization" cleavage Asn360 DFVDIPEnFFGVGGE -1 10922468 t lperfetto "Matrix metalloproteinases 19 and 20 cleave aggrecan and cartilage oligomeric matrix protein (COMP)|In this study we investigated the ability of MMP-19 and MMP-20 to cleave two of the macromolecules characterising the cartilage ECM, namely aggrecan and the cartilage oligomeric matrix protein (COMP). Both MMPs hydrolysed aggrecan efficiently at the well-described MMP cleavage site between residues Asn(341) and Phe(342), as shown by Western blotting using neo-epitope antibodies. Furthermore, the two enzymes cleaved COMP in a distinctive manner, generating a major proteolytic product of 60 kDa. Our results suggest that MMP-19 may participate in the degradation of aggrecan and COMP in arthritic disease, whereas MMP-20, due to its unique expression pattern, may primarily be involved in the turnover of these molecules during tooth development." SIGNOR-266979 MMP20 protein O60882 UNIPROT ACAN protein P16112 UNIPROT "down-regulates quantity by destabilization" cleavage -1 10922468 t lperfetto "Matrix metalloproteinases 19 and 20 cleave aggrecan and cartilage oligomeric matrix protein (COMP)|It has been suggested that MMPs play a role in the hydrolysis of COMP and, therefore, compromise the integrity of the cartilage ECM structure leading to the ultimate loss of joint function" SIGNOR-266981 BRD4 protein O60885 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr58 KKFELLPtPPLSPSR 9606 32482868 t lperfetto "We report that BRD4 phosphorylates MYC at Thr58, leading to MYC ubiquitination and degradation, thereby regulating MYC target genes." SIGNOR-262046 BRD4 protein O60885 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1616 TPQSPSYsPTSPSYS 9606 BTO:0000150;BTO:0001271;BTO:0000785 22509028 t llicata "We report that brd4 is an atypical kinase that binds to the carboxyl-terminal domain (ctd) of rna polymerase ii and directly phosphorylates its serine 2 (ser2) sites both in vitro and in vivo under conditions where other ctd kinases are inactive. our findings may provide a mechanistic basis for several functional studies that showed that loss of brd4 causes transcription termination and embryonic lethality" SIGNOR-197012 BRD4 protein O60885 UNIPROT KDM5C protein P41229 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 30921702 f miannu " KDM5C was transcriptionally upregulated by bromodomain-containing protein 4 (BRD4), and knockdown KDM5C sensitized the therapeutic effects of CRPC cells to the bromodomain and extraterminal (BET) inhibitor. " SIGNOR-264311 BRD4 protein O60885 UNIPROT EP300 protein Q09472 UNIPROT "up-regulates activity" binding 9606 32544088 t lperfetto "In this study, we explored the role of Brd4 and its interaction with the p300 acetyltransferase in the regulation of Nox4 and the in vivo efficacy of a BET inhibitor to reverse established age-associated lung fibrosis. |Together, these studies suggest that Brd4 enhances p300-mediated histone acetylation." SIGNOR-262064 NBN protein O60934 UNIPROT ATM protein Q13315 UNIPROT up-regulates binding 9606 15758953 t gcesareni "Nbs1 can also immobilize atm at the site of the dsb via direct binding of atm to a c-terminal atm interaction motif on nbs1 . the mre11/rad50/nbs1 (mrn) complex maintains genomic stability by bridging dna ends and initiating dna damage signaling through activation of the atm" SIGNOR-134508 NBN protein O60934 UNIPROT ATM protein Q13315 UNIPROT up-regulates binding 9606 18854157 t gcesareni "Nbs1 can also immobilize atm at the site of the dsb via direct binding of atm to a c-terminal atm interaction motif on nbs1 . the mre11/rad50/nbs1 (mrn) complex maintains genomic stability by bridging dna ends and initiating dna damage signaling through activation of the atm" SIGNOR-181631 NBN protein O60934 UNIPROT MRE11/RAD50/NBS1 complex SIGNOR-C147 SIGNOR "form complex" binding 17713585 t lperfetto "The mre11_rad50_nbs1 (mrn) complex is among the earliest respondents to dna double-strand breaks (dsbs). To organize the mrn complex, the mre11 exonuclease directly binds nbs1, dna, and rad50." SIGNOR-251505 MITF protein O75030 UNIPROT BEST1 protein O76090 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004595 14982938 f miannu "These studies define the VMD2 promoter region sufficient to drive RPE-specific expression in the eye, identify positive regulatory regions in vitro, and suggest that MITF as well as other E-box binding factors may act as positive regulators of VMD2 expression." SIGNOR-254586 MITF protein O75030 UNIPROT BEST1 protein O76090 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 20530484 f miannu "BEST1 promoter activity was increased by SOX9 overexpression and decreased by siRNA-mediated SOX9 knockdown. SOX9 physically interacted with MITF and OTX2 and orchestrated synergistic activation of the BEST1 promoter with the paired SOX site playing essential roles." SIGNOR-255185 MITF protein O75030 UNIPROT BCL2 protein P10415 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 12086670 t lperfetto "MITF directly occupies the BCL2 promoter in vivo and this suggest that BCL2 may be a direct transcriptional target of MITF" SIGNOR-249618 MITF protein O75030 UNIPROT ACP5 protein P13686 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0003292 11481336 f miannu "The combination of MITF and PU.1 synergistically activated the TRAP promoter in transient assays." SIGNOR-254584 MITF protein O75030 UNIPROT TYR protein P14679 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000847 10080955 f miannu "Microphthalmia transcription factor MITF, a melanocyte-specific basic helix-loop-helix protein, has been shown to transactivate tyrosinase and TRP-1 genes in vitro by binding to a shared regulatory sequence known as M box. both activation of positive factors such as MITF and inactivation of negative regulatory factors may be required for TRP-1 gene expression during melanocytic differentiation." SIGNOR-254593 MITF protein O75030 UNIPROT TYRP1 protein P17643 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000847 22371403 f miannu "MITF transcription factor regulates melanogenesis by activation of tyrosinase, TRP1 and TRP2 transcription." SIGNOR-254591 MITF protein O75030 UNIPROT SERPINF1 protein P36955 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001177 22115973 f miannu "Here we show that the basic-helix-loop-helix-leucine zipper microphthalmia-associated transcription factor (MITF), which plays central roles in the development and function of a variety of cell types including RPE cells, upregulates the expression of a multifunctional factor PEDF in RPE cells." SIGNOR-254587 MITF protein O75030 UNIPROT OCA2 protein Q04671 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000847 22234890 f miannu "the SNP rs12913832 has strong statistical association with human pigmentation. It is located within an intron of the nonpigment gene HERC2, 21 kb upstream of the pigment gene OCA2, and the region surrounding rs12913832 is highly conserved among animal species.In darkly pigmented human melanocytes carrying the rs12913832 T-allele, we detected binding of the transcription factors HLTF, LEF1, and MITF to the HERC2 rs12913832 enhancer, and a long-range chromatin loop between this enhancer and the OCA2 promoter that leads to elevated OCA2 expression." SIGNOR-254556 MITF protein O75030 UNIPROT TRPM1 protein Q7Z4N2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 14744763 f miannu "Mice homozygously mutated in MITF showed a dramatic decrease in TRPM1 expression. Finally, the slope of TRPM1 induction by MITF was particularly steep compared with other MITF target genes, suggesting it is a sensitive indicator of MITF expression and correspondingly of melanocytic differentiation." SIGNOR-254588 SRGAP2 protein O75044 UNIPROT CDC42 protein P60953 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260517 SRGAP2 protein O75044 UNIPROT RAC1 protein P63000 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260516 SDC3 protein O75056 UNIPROT NOTCH1 protein P46531 UNIPROT "up-regulates activity" binding 10090 BTO:0002314 20696709 t gcesareni "Furthermore, we show that Syndecan-3 interacts with Notch and is required for Notch processing by ADAM17/tumor necrosis factor-€“converting enzyme (TACE) and signal transduction. Together, our data support the conclusion that Syndecan-3 and Notch cooperate in regulating homeostasis of the satellite cell population and myofiber size." SIGNOR-244072 SDC3 protein O75056 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR "up-regulates activity" binding 10090 BTO:0002314 20696709 t gcesareni "Furthermore, we show that Syndecan-3 interacts with Notch and is required for Notch processing by ADAM17/tumor necrosis factor-€“converting enzyme (TACE) and signal transduction. Together, our data support the conclusion that Syndecan-3 and Notch cooperate in regulating homeostasis of the satellite cell population and myofiber size." SIGNOR-254329 DNAJC6 protein O75061 UNIPROT HSPA8 protein P11142 UNIPROT "up-regulates activity" relocalization 24789820 t lperfetto "Hsc70, recruited by the J-domain protein auxilin, mediates clathrin uncoating and release of a free vesicle, primed to fuse with a target membrane." SIGNOR-260719 CBFA2T3 protein O75081 UNIPROT ZNF652 protein Q9Y2D9 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 20116376 t "Previously we reported that a classical C2H2 zinc finger DNA binding protein ZNF652 functionally interacts with CBFA2T3 to repress transcription of genes containing ZNF652 consensus DNA binding sequence within the promoters of these target genes." SIGNOR-253954 CBFA2T3 protein O75081 UNIPROT CBFA2T3/ZNF651 complex SIGNOR-C197 SIGNOR "form complex" binding 9606 BTO:0000007 20116376 t "Previously we reported that a classical C2H2 zinc finger DNA binding protein ZNF652 functionally interacts with CBFA2T3 to repress transcription of genes containing ZNF652 consensus DNA binding sequence within the promoters of these target genes. Here we show that ZNF651 is a ZNF652 paralogue that shares a common DNA binding sequence with ZNF652 and represses target gene expression through the formation of a CBFA2T3-ZNF651 corepressor complex." SIGNOR-253956 FZD7 protein O75084 UNIPROT DVL1 protein O14640 UNIPROT up-regulates binding BTO:0001103 22179044 t 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 FZD7 protein O75084 UNIPROT FZD7/SDC4 complex SIGNOR-C216 SIGNOR "form complex" binding 9606 BTO:0002314 BTO:0001103 23290138 t 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 SLIT1 protein O75093 UNIPROT GPC1 protein P35052 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 10364234 t gcesareni "Slit family proteins are functional ligands of glypican-1 in nervous tissue and suggest that their interactions may be critical for certain stages of central nervous system histogenesis." SIGNOR-68327 SLIT1 protein O75093 UNIPROT ROBO proteinfamily SIGNOR-PF14 SIGNOR up-regulates binding 9606 16226035 t gcesareni "Here we describe and compare two human robo3 isoforms, robo3a and robo3b, which differ by the insertion of 26 amino acids at the n-terminus, and these forms appear to be evolutionary conserved. We investigated the bioactivity of these isoforms and show that they have different binding properties to slit." SIGNOR-141111 ROCK2 protein O75116 UNIPROT PPP1R12A protein O14974 UNIPROT "down-regulates activity" phosphorylation Thr853 PREKRRStGVSFWTQ -1 12220642 t lperfetto "Rho kinase is known to control smooth muscle contractility by phosphorylating the 110 kDa myosin-targetting subunit (MYPT1) of the myosin-associated form of protein phosphatase 1 (PP1M). Phosphorylation of MYPT1 at Thr695 has previously been reported to inhibit the catalytic activity of PP1. Here, we show that the phosphorylation of Thr850 by Rho kinase dissociates PP1M from myosin, providing a second mechanism by which myosin phosphatase activity is inhibited." SIGNOR-249164 ROCK2 protein O75116 UNIPROT MYL9 protein P24844 UNIPROT "up-regulates activity" phosphorylation Ser20 KRPQRATsNVFAMFD 9606 8702756 t miannu "Here we found that Rho-kinase stoichiometrically phosphorylated myosin light chain (MLC). Peptide mapping and phosphoamino acid analyses revealed that the primary phosphorylation site of MLC by Rho-kinase was Ser-19, which is the site phosphorylated by MLC kinase. Rho-kinase phosphorylated recombinant MLC, whereas it failed to phosphorylate recombinant MLC, which contained Ala substituted for both Thr-18 and Ser-19. We also found that the phosphorylation of MLC by Rho-kinase resulted in the facilitation of the actin activation of myosin ATPase." SIGNOR-261709 ROCK2 protein O75116 UNIPROT MYL9 protein P24844 UNIPROT "up-regulates activity" phosphorylation Ser20 KRPQRATsNVFAMFD 9606 8702756 t miannu "Here we found that Rho-kinase stoichiometrically phosphorylated myosin light chain (MLC). Peptide mapping and phosphoamino acid analyses revealed that the primary phosphorylation site of MLC by Rho-kinase was Ser-19, which is the site phosphorylated by MLC kinase. Rho-kinase phosphorylated recombinant MLC, whereas it failed to phosphorylate recombinant MLC, which contained Ala substituted for both Thr-18 and Ser-19. We also found that the phosphorylation of MLC by Rho-kinase resulted in the facilitation of the actin activation of myosin ATPase." SIGNOR-261719 PHF2 protein O75151 UNIPROT ARID5B protein Q14865 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 21532585 t miannu "We found that phosphorylated PHF2 then associates with ARID5B, a DNA-binding protein, and induce demethylation of methylated ARID5B. Assembly of the PHF2–ARID5B complex, its recruitment to target promoters, and its H3H9Me2 demethylase activity were dependent on PKA activity." SIGNOR-264514 ROCK2 protein O75116 UNIPROT MYL9 protein P24844 UNIPROT "up-regulates activity" phosphorylation Thr19 KKRPQRAtSNVFAMF 9606 8702756 t miannu "Here we found that Rho-kinase stoichiometrically phosphorylated myosin light chain (MLC). Peptide mapping and phosphoamino acid analyses revealed that the primary phosphorylation site of MLC by Rho-kinase was Ser-19, which is the site phosphorylated by MLC kinase. Rho-kinase phosphorylated recombinant MLC, whereas it failed to phosphorylate recombinant MLC, which contained Ala substituted for both Thr-18 and Ser-19. We also found that the phosphorylation of MLC by Rho-kinase resulted in the facilitation of the actin activation of myosin ATPase." SIGNOR-261718 ROCK2 protein O75116 UNIPROT MYL9 protein P24844 UNIPROT "up-regulates activity" phosphorylation Thr19 KKRPQRAtSNVFAMF 9606 8702756 t miannu "Here we found that Rho-kinase stoichiometrically phosphorylated myosin light chain (MLC). Peptide mapping and phosphoamino acid analyses revealed that the primary phosphorylation site of MLC by Rho-kinase was Ser-19, which is the site phosphorylated by MLC kinase. Rho-kinase phosphorylated recombinant MLC, whereas it failed to phosphorylate recombinant MLC, which contained Ala substituted for both Thr-18 and Ser-19. We also found that the phosphorylation of MLC by Rho-kinase resulted in the facilitation of the actin activation of myosin ATPase." SIGNOR-261708 ROCK2 protein O75116 UNIPROT IRF4 protein Q15306 UNIPROT up-regulates phosphorylation Ser447 YHRSIRHsSIQE 9606 BTO:0000782 20697158 t miannu "Carock2 phosphorylated irf4 at either of 2 distinct phosphorylation sites, s446 and s447 / rock2-mediated phosphorylation of irf4 regulated the synthesis of il-17 and il-21 and the differentiation of th17 cells." SIGNOR-167467 ROCK2 protein O75116 UNIPROT IRF4 protein Q15306 UNIPROT up-regulates phosphorylation Ser448 HRSIRHSsIQE 9606 BTO:0000782 20697158 t miannu "Carock2 phosphorylated irf4 at either of 2 distinct phosphorylation sites, s446 and s447 / rock2-mediated phosphorylation of irf4 regulated the synthesis of il-17 and il-21 and the differentiation of th17 cells." SIGNOR-167471 ROCK2 protein O75116 UNIPROT DPYSL2 protein Q16555 UNIPROT up-regulates phosphorylation Thr555 DNIPRRTtQRIVAPP 9606 BTO:0000938 10818093 t lperfetto "Rho-kinase phosphorylated crmp-2 at thr-555 in vitro.we demonstrated that crmp-2 is phosphorylated by rho-kinase in drg neurons during lpa-induced growth cone collapse." SIGNOR-77543 ROCK2 protein O75116 UNIPROT SH3GL2 protein Q99962 UNIPROT down-regulates phosphorylation Thr14 KKQFHKAtQKVSEKV 9606 16164598 t llicata "We identified the phosphorylation site of endophilin a1 at thr-14 endophilin t14d inhibited egf receptor internalization. Furthermore, phosphorylation of endophilin by rho-kinase inhibited the binding to cin85." SIGNOR-140466 CLASP2 protein O75122 UNIPROT CLIP1 protein P30622 UNIPROT "up-regulates activity" binding 9534 BTO:0004055 19638411 t lperfetto "CLASPs were originally identified as CLIP-170-interacting proteins and later found to be required for microtubule stabilisation at the cortical regions of epithelial cells|the C-terminal region of CLASP2 is known to interact with CLIP-170" SIGNOR-264827 CLASP2 protein O75122 UNIPROT IQGAP1 protein P46940 UNIPROT "up-regulates activity" binding 9534 BTO:0004055 19638411 t lperfetto "IQGAP1 is a novel CLASP2-interacting protein| nonphosphorylated CLASP2 on microtubules is allowed to associate with IQGAP1 for the coupling of microtubules to actin filaments at the front of migrating cells." SIGNOR-264828 CLASP2 protein O75122 UNIPROT MAPRE1 protein Q15691 UNIPROT "up-regulates activity" binding 9534 BTO:0004055 19638411 t lperfetto "GSK-3beta directly phosphorylates CLASP2 at Ser533 and Ser537 within the region responsible for the IQGAP1 binding. Phosphorylation of CLASP2 results in the dissociation of CLASP2 from IQGAP1, EB1 and microtubules.| CLASPs were originally identified as CLIP-170-interacting proteins and later found to be required for microtubule stabilisation at the cortical regions of epithelial cells" SIGNOR-264829 CLASP2 protein O75122 UNIPROT CLIP2 protein Q9UDT6 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 15631994 t lperfetto "CLIP-associating protein (CLASP) 1 and CLASP2 are mammalian microtubule (MT) plus-end binding proteins, which associate with CLIP-170 and CLIP-115.|We demonstrate that the middle part of CLASPs binds directly to EB1 and to MTs. | Both EB1- and cortex-binding domains of CLASP are required to promote MT stability." SIGNOR-265093 DEPDC5 protein O75140 UNIPROT GATOR1 complex SIGNOR-C192 SIGNOR "form complex" binding 9606 23723238 t miannu "Here, we identify GATOR as a complex that interacts with the Rags and is composed of two subcomplexes we call GATOR1 and 2. Inhibition of GATOR1 subunits (DEPDC5, Nprl2, and Nprl3) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of GATOR2 subunits (Mios, WDR24, WDR59, Seh1L, Sec13) suppresses mTORC1 signaling and epistasis analysis shows that GATOR2 negatively regulates DEPDC5" SIGNOR-255280 ATG13 protein O75143 UNIPROT ULK2 protein Q8IYT8 UNIPROT up-regulates binding 9606 19225151 t gcesareni "He mammalian atg13 binds both ulk1 and ulk2 and mediates the interaction of the ulk proteins with fip200. The binding of atg13 stabilizes and activates ulk and facilitates the phosphorylation of fip200 by ulk" SIGNOR-184123 ATG13 protein O75143 UNIPROT RB1CC1 protein Q8TDY2 UNIPROT up-regulates binding 9606 19225151 t gcesareni "Atg13 directly binds fip200." SIGNOR-184120 ATG13 protein O75143 UNIPROT ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR "form complex" binding 9606 23863160 t lperfetto "In mammals, two protein complexes, namely the ULK1-Atg13-FIP200 (200kDa focal adhesion kinase family-interacting protein) complex and the Beclin–Vps34 complex, function jointly to produce the phagophore membrane, the initial phase of autophagosome formation." SIGNOR-209884 PHF2 protein O75151 UNIPROT H3C1 protein P68431 UNIPROT "up-regulates activity" demethylation "Lys 10" RTKQTARkSTGGKAP 9606 BTO:0000007 21532585 t miannu "PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. This modification leads to targeting of the PHF2–ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark." SIGNOR-264521 PHF2 protein O75151 UNIPROT H3C1 protein P68431 UNIPROT "up-regulates activity" demethylation Lys5 kQTARKST 9606 BTO:0000007 21532585 t miannu "PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. This modification leads to targeting of the PHF2–ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark." SIGNOR-264516 PHF2 protein O75151 UNIPROT H3-3A protein P84243 UNIPROT "up-regulates activity" demethylation "Lys 10" RTKQTARkSTGGKAP 9606 BTO:0000007 21532585 t miannu "PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. This modification leads to targeting of the PHF2–ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark." SIGNOR-264519 PHF2 protein O75151 UNIPROT H3-3A protein P84243 UNIPROT "up-regulates activity" demethylation Lys5 kQTARKST 9606 BTO:0000007 21532585 t miannu "PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. This modification leads to targeting of the PHF2–ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark." SIGNOR-264518 PHF2 protein O75151 UNIPROT H3-4 protein Q16695 UNIPROT "up-regulates activity" demethylation "Lys 10" RTKQTARkSTGGKAP 9606 BTO:0000007 21532585 t miannu "PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. This modification leads to targeting of the PHF2–ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark." SIGNOR-264520 PHF2 protein O75151 UNIPROT H3-4 protein Q16695 UNIPROT "up-regulates activity" demethylation Lys5 kQTARKST 9606 21532585 t miannu "PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. This modification leads to targeting of the PHF2–ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark." SIGNOR-264517 CNOT3 protein O75175 UNIPROT CAND2 protein O75155 UNIPROT unknown binding 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001760 12207886 t lperfetto "Hnot3l is associated with tip120b / tip120b presumably affects tissue-specific transcriptional regulation via interaction with not3." SIGNOR-235593 CNOT3 protein O75175 UNIPROT TNFRSF11A protein Q9Y6Q6 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0003292 24550297 t Luana "Our results reveal that CNOT3 is a critical regulator of bone mass acting on bone resorption through posttranscriptional down-regulation of RANK mRNA stability, at least in part, even in aging-induced osteoporosis." SIGNOR-261572 SS18L1 protein O75177 UNIPROT CREBBP protein Q92793 UNIPROT up-regulates relocalization 9606 BTO:0000938 15488321 t miannu "The calcium-responsive transactivator recruits creb binding protein to nuclear bodies." SIGNOR-129926 SIN3B protein O75182 UNIPROT TP53 protein P04637 UNIPROT "down-regulates activity" binding 9606 BTO:0001109 26181367 t miannu "The present study shows that under bleomycin-induced stress, expression of Sin3B gets up-regulated and it gets recruited by p53 at its target promoters. Knockdown of Sin3B leads to impaired negative regulation of p53 target genes and thus exemplifies Sin3B as a critical player in down-regulation of p53 subset target genes." SIGNOR-266776 SIN3B protein O75182 UNIPROT Sin3B_complex complex SIGNOR-C409 SIGNOR "form complex" binding 9606 BTO:0000007 21041482 t miannu "We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin." SIGNOR-266967 LRP5 protein O75197 UNIPROT AXIN1 protein O15169 UNIPROT "down-regulates quantity" relocalization 10090 BTO:0000944 11336703 t amattioni "Axin is a protein that interacts with the intracellular domain of LRP-5. LRP-5 active form bind Axin and induce LEF-1 activation by destabilizing Axin and stabilizing beta-catenin." SIGNOR-236997 LRP5 protein O75197 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "down-regulates quantity by destabilization" relocalization 9606 11336703 t lperfetto "Lrp-5, a close homolog of lrp-6 (hey et al., 1998), functions as a coreceptor for wnt proteins in mammalian cells and that it can transduce the canonical wnt signals, at least in part by binding and recruiting axin to membranes" SIGNOR-227930 LRP5 protein O75197 UNIPROT LPR5/6 complex SIGNOR-C219 SIGNOR "form complex" binding 9606 27821587 t miannu "Low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/6) are co-receptors for Wnt ligands." SIGNOR-256176 NDUFS7 protein O75251 UNIPROT "Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The Q-module is built through the association of NDUFA5, NDUFS2 and NDUFS3 plus NDUFS7 and NDUFS8. The chaperones NDUFAF3/C3ORF60 and NDUFAF4/C6ORF66 [36,37] remain bound to this module until the final assembly steps [34]. NDUFAF6/C8ORF38 [38] also seems to participate in the assembly of the Q-module [24,39]. NDUFAF3, 4 and 6, are necessary to maintain normal MT-ND1 synthesis [40,41]. NDUFAF5 adds a hydroxyl group to Arg73 of NDUFS7 [42] and NDUFAF7 dimethylates NDUFS2 in Arg85 [43], an essential modification for cI assembly [44]. NUBPL/IND1 delivers [4Fe–4S] clusters specifically to the N- and Q-module subunits [45,46]." SIGNOR-262181 NDUFS2 protein O75306 UNIPROT "Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The Q-module is built through the association of NDUFA5, NDUFS2 and NDUFS3 plus NDUFS7 and NDUFS8. The chaperones NDUFAF3/C3ORF60 and NDUFAF4/C6ORF66 [36,37] remain bound to this module until the final assembly steps [34]. NDUFAF6/C8ORF38 [38] also seems to participate in the assembly of the Q-module [24,39]. NDUFAF3, 4 and 6, are necessary to maintain normal MT-ND1 synthesis [40,41]. NDUFAF5 adds a hydroxyl group to Arg73 of NDUFS7 [42] and NDUFAF7 dimethylates NDUFS2 in Arg85 [43], an essential modification for cI assembly [44]. NUBPL/IND1 delivers [4Fe–4S] clusters specifically to the N- and Q-module subunits [45,46]." SIGNOR-262176 CDH16 protein O75309 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" binding 9606 21255999 t miannu "At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin" SIGNOR-265855 SEMA7A protein O75326 UNIPROT PLXNC1 protein O60486 UNIPROT up-regulates binding 9606 BTO:0000938 10520995 t gcesareni "Plexin-c1 is a receptor for the gpi-anchored semaphorin sema7a. The cytoplasmic domain of plexins associates with a tyrosine kinase activity. Plexins may also act as ligands mediating repulsion in epithelial cells in vitro." SIGNOR-71260 TBCA protein O75347 UNIPROT Tubulin proteinfamily SIGNOR-PF46 SIGNOR "up-regulates quantity by stabilization" binding 9606 28158450 t miannu "These intermediates interact with a series of five tubulin-specific chaperones (termed TBCA-E); these function together as a nanomachine that assembles the α/β tubulin heterodimer" SIGNOR-261169 ZNF217 protein O75362 UNIPROT "CoREST-HDAC complex" complex SIGNOR-C105 SIGNOR "form complex" binding 9606 BTO:0000567 11171972 t miannu "Here we describe the components of a histone deacetylase (HDAC) complex that we term the CoREST-HDAC complex. CoREST Is a Component of an HDAC1/2 Complex. p40 is a Sox-like protein, p110b contains homology to polyamine oxidases, p110a is ZNF217, an eight-zinc finger protein, and p80 is a hypothetical protein of unknown function." SIGNOR-222118 PITX3 protein O75364 UNIPROT MTA1 protein Q13330 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 SIGNOR-C123 21368136 t 1 miannu "we found that the MTA1/DJ1 complex is required for optimum stimulation of the TH expression by paired like homeodomain transcription factor (Pitx3) homeodomain transcription factor and that the MTA1/DJ1 complex is recruited to the TH gene chromatin via the direct interaction of MTA1 with Pitx3." SIGNOR-239770 PTP4A3 protein O75365 UNIPROT KRT8 protein P05787 UNIPROT "down-regulates activity" dephosphorylation Ser432 SAYGGLTsPGLSYSL 9606 BTO:0000586 19115206 t "the cytoskeletal intermediate filament keratin 8 (KRT8) was identified as a physiological PRL-3-interacting protein. Indeed, treatment with the PRL-3 inhibitor effectively suppressed the phosphorylation of KRT8 at S73 and S431" SIGNOR-248341 PTP4A3 protein O75365 UNIPROT KRT8 protein P05787 UNIPROT "down-regulates activity" dephosphorylation Ser74 TVNQSLLsPLVLEVD 9606 BTO:0000586 19115206 t "the cytoskeletal intermediate filament keratin 8 (KRT8) was identified as a physiological PRL-3-interacting protein. Indeed, treatment with the PRL-3 inhibitor effectively suppressed the phosphorylation of KRT8 at S73 and S431|The site-specific phosphorylation of keratins induces the disassembly of these filaments, and the balance between their phosphorylation and dephosphorylation controls the continuous exchange of intermediate filament subunits between a soluble pool and polymerized filaments" SIGNOR-248340 PTP4A3 protein O75365 UNIPROT EZR protein P15311 UNIPROT "down-regulates activity" dephosphorylation Thr567 QGRDKYKtLRQIRQG 9606 BTO:0001109 18078820 t "Here we report the identification of Ezrin as a specific and direct cellular substrate of PRL-3. In HCT116 colon cancer cell line, Ezrin was identified among the cellular proteins whose phosphorylation level decreased upon ectopic over-expression of wtPRL-3 but not of catalytically inactive PRL-3 mutants. Although PRL-3 over-expression in HCT116 cells appeared to affect Ezrin phosphorylation status at both tyrosine residues and Thr567, suppression of the endogenous protein by RNA interference pointed to Ezrin-Thr567 as the residue primarily affected by PRL-3 action." SIGNOR-248342 NCOR1 protein O75376 UNIPROT SNAI2 protein O43623 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000094 18588516 f miannu "The down-regulation of slug in the ERalpha-positive MCF-7 cell line was mediated by direct repression of slug transcription by the formation of a co-repressor complex involving ligand-activated ERalpha protein, HDAC1 (histone deacetylase 1) and N-CoR (nuclear receptor co-repressor)." SIGNOR-254229 NCOR1 protein O75376 UNIPROT PPARG protein P37231 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 22395773 t 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 NCOR1 protein O75376 UNIPROT BCL6 protein P41182 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 10898795 t miannu "The POZ domains of BCL-6 and several other POZ proteins interact with corepressors N-CoR and SMRT." SIGNOR-252239 NDUFS6 protein O75380 UNIPROT "Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24]." SIGNOR-262180 PEX14 protein O75381 UNIPROT PEX7 protein O00628 UNIPROT "up-regulates activity" binding -1 15798189 t miannu "The peroxisomal docking complex is a key component of the import machinery for matrix proteins. The core protein of this complex, Pex14, is thought to represent the initial docking site for the import receptors Pex5 and Pex7." SIGNOR-253028 PEX14 protein O75381 UNIPROT PEX5 protein P50542 UNIPROT "up-regulates activity" binding -1 15798189 t miannu "The peroxisomal docking complex is a key component of the import machinery for matrix proteins. The core protein of this complex, Pex14, is thought to represent the initial docking site for the import receptors Pex5 and Pex7." SIGNOR-253027 PEX14 protein O75381 UNIPROT PEX13 protein Q92968 UNIPROT "up-regulates activity" binding -1 15798189 t miannu "Pex14 interacts via its proline-rich motif with the SH3 domain of Pex13. We conclude that the association of Pex13 with Pex14 is an essential step in peroxisomal protein import" SIGNOR-253029 ULK1 protein O75385 UNIPROT DENND3 protein A2RUS2 UNIPROT "up-regulates activity" phosphorylation Ser490 ELAPRNSsLRLTDTA 9606 BTO:0000007 25925668 t lperfetto "ULK-mediated phosphorylation of the guanine nucleotide exchange factor DENND3 at serines 554 and 572 upregulates its GEF activity toward the small GTPase Rab12." SIGNOR-264731 ULK1 protein O75385 UNIPROT GABARAP protein O95166 UNIPROT up-regulates binding 9606 BTO:0000567;BTO:0000938 BTO:0000142 11146101 t gcesareni "N-terminal proline/serine rich (ps) domain of ulk1 (amino acid 287-416) is required for ulk1-gate-16 and ulk1-gabarap protein interactions" SIGNOR-85614 ULK1 protein O75385 UNIPROT PRKAA2 protein P54646 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C15 21460634 t gcesareni "Here we report that ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity. Thus, we propose that ulk1 is not only involved in the induction of autophagy, but also in terminating signaling events that trigger autophagy. In our model, phosphorylation of ampk by ulk1 represents a negative feedback circuit." SIGNOR-173050 ULK1 protein O75385 UNIPROT PRKAA1 protein Q13131 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000007 SIGNOR-C15 21460634 t lperfetto "Ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity." SIGNOR-173047 ULK1 protein O75385 UNIPROT SEC23B protein Q15437 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser186 SCEGISKsYVFRGTK 9606 BTO:0000007 30596474 t lperfetto "Here, we show that the F-box protein FBXW5 targets SEC23B, a component of COPII, for proteasomal degradation and that this event limits the autophagic flux in the presence of nutrients. In response to starvation, ULK1 phosphorylates SEC23B on Serine 186, preventing the interaction of SEC23B with FBXW5 and, therefore, inhibiting SEC23B degradation." SIGNOR-265285 ULK1 protein O75385 UNIPROT RB1CC1 protein Q8TDY2 UNIPROT up-regulates phosphorylation 9606 19597335 t gcesareni "Ulk1 and ulk2 are the kinase phosphorylating their binding proteins atg13 and fip200. Atg13 directly binds fip200 and mediates the interaction between fip200 and ulks." SIGNOR-186992 ULK1 protein O75385 UNIPROT AMBRA1 protein Q9C0C7 UNIPROT up-regulates phosphorylation 9606 20921139 t gcesareni "When autophagy is induced, ulk1 phosphorylates ambra1, releasing the autophagy core complex from dynein. Its subsequent relocalization to the endoplasmic reticulum enables autophagosome nucleation. Ambra1-dlc1 dissociates from the dynein complex upon ulk1-dependent ambra1 phosphorylation." SIGNOR-168292 ULK1 protein O75385 UNIPROT PRKAG3 protein Q9UGI9 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C15 21460634 t gcesareni "Ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity phosphorylation of ampk by ulk1 represents a negative feedback circuit." SIGNOR-173053 ULK1 protein O75385 UNIPROT ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR "form complex" binding 9606 23863160 t lperfetto "In mammals, two protein complexes, namely the ULK1-Atg13-FIP200 (200kDa focal adhesion kinase family-interacting protein) complex and the Beclin–Vps34 complex, function jointly to produce the phagophore membrane, the initial phase of autophagosome formation." SIGNOR-209890 CS protein O75390 UNIPROT acetyl-CoA smallmolecule CHEBI:15351 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 3013232 t miannu "Citrate synthase catalyzes an important step within the cycle, the Claisen condensation of acetyl-Coenzyme A with oxaloacetate to form citrate; and it is the only enzyme in the cycle that can catalyze the formation of a carbon-carbon bond." SIGNOR-266238 CS protein O75390 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 3013232 t miannu "Citrate synthase catalyzes an important step within the cycle, the Claisen condensation of acetyl-Coenzyme A with oxaloacetate to form citrate; and it is the only enzyme in the cycle that can catalyze the formation of a carbon-carbon bond." SIGNOR-266239 CS protein O75390 UNIPROT "oxaloacetic acid" smallmolecule CHEBI:30744 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 3013232 t miannu "Citrate synthase catalyzes an important step within the cycle, the Claisen condensation of acetyl-Coenzyme A with oxaloacetate to form citrate; and it is the only enzyme in the cycle that can catalyze the formation of a carbon-carbon bond." SIGNOR-266549 MRPL33 protein O75394 UNIPROT "39S mitochondrial large ribosomal subunit" complex SIGNOR-C285 SIGNOR "form complex" binding -1 25838379 t lperfetto "We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules" SIGNOR-262364 NDUFB1 protein O75438 UNIPROT "Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and |The main ND4-module intermediate binds NDUFB1, NDUFB4, NDUFB5, NDUFB6, NDUFB10, NDUFB11 and MT-ND4" SIGNOR-262162 PMPCB protein O75439 UNIPROT PINK1 protein Q9BXM7 UNIPROT "down-regulates quantity by destabilization" cleavage 9606 BTO:0000007 22354088 t miannu "Using an unbiased RNA-mediated interference (RNAi)-based screen, we identified four mitochondrial proteases, mitochondrial processing peptidase (MPP), presenilin-associated rhomboid-like protease (PARL), m-AAA and ClpXP, involved in PINK1 degradation. We find that PINK1 turnover is particularly sensitive to even modest reductions in MPP levels. Moreover, PINK1 cleavage by MPP is coupled to import such that reducing MPP activity induces PINK1 accumulation at the mitochondrial surface, leading to Parkin recruitment and mitophagy." SIGNOR-261363 MAF protein O75444 UNIPROT MMP13 protein P45452 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20067416 f miannu "MMP-13 gene expression is regulated primarily at the transcriptional level. In this study, we investigated the role of c-maf in regulating MMP-13 transcription. Using transient transfection system with an c-maf construct, and MMP-13 promoter-luciferase constructs with specific mutations in transcription factor binding sites, we found that c-maf can significantly enhance MMP-13 promoter activity via the AP-1 sitecv" SIGNOR-254560 MED24 protein O75448 UNIPROT "Core mediator complex" complex SIGNOR-C405 SIGNOR "form complex" binding 9606 28467824 t miannu "Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles." SIGNOR-266666 ERN1 protein O75460 UNIPROT XBP-1S protein P17861_P17861-2 UNIPROT "up-regulates quantity by expression" "post transcriptional regulation" 9606 31226023 t miannu "Upon activation by oligomerization and autophosphorylation, the cytosolic RNase domain of IRE1 mediates an unconventional splicing of the mRNA of X-box-binding protein 1 (XBP1). The spliced and frameshifted transcript encodes XBP1S, a bZIP transcription factor inducing the expression of numerous UPR effector genes that enhance ER folding capacity." SIGNOR-260183 ERN1 protein O75460 UNIPROT TRAF2 protein Q12933 UNIPROT "up-regulates activity" binding 10090 BTO:0004488 18519638 t "P00441:p.Gly94Ala (mutation causing interaction); P00441:p.Gly86Arg (mutation causing interaction); P00441:p.Ala5Val (mutation causing interaction)" "Activated IRE1 has been demonstrated to recruit TRAF2 and ASK1 on the ER membrane and thus to activate ASK1|ASK1 was found to associate with IRE1 only in the presence of TRAF2 and SOD1mut (Fig. 4B), suggesting that SOD1mut induces formation of an IRE1–TRAF2–ASK1 complex on the ER membrane and thus activates ASK1 by triggering ER stress-induced IRE1 activation." SIGNOR-262790 ERN1 protein O75460 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR "down-regulates activity" 9606 31226023 f miannu "The kinase activity of IRE1 also activates a signaling cascade that ultimately activates c-Jun N-terminal kinase (JNK)" SIGNOR-260177 NR1I2 protein O75469 UNIPROT ABCB1 protein P08183 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000003 18540626 f miannu "Among approximately 40 kinds of phytochemicals, tangeretin and ginkgolides A and B markedly induced the PXR-dependent transcriptional activity and also the activity of the human MDR1 promoter. The expression levels of MDR1 mRNA as well as of CYP3A4 mRNA, another gene regulated by PXR, were significantly increased by these phytochemicals." SIGNOR-254834 NR1I2 protein O75469 UNIPROT CYP3A4 protein P08684 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000003 18540626 f miannu "Among approximately 40 kinds of phytochemicals, tangeretin and ginkgolides A and B markedly induced the PXR-dependent transcriptional activity and also the activity of the human MDR1 promoter. The expression levels of MDR1 mRNA as well as of CYP3A4 mRNA, another gene regulated by PXR, were significantly increased by these phytochemicals." SIGNOR-254835 NR1I2 protein O75469 UNIPROT RXRA protein P19793 UNIPROT up-regulates binding 9606 11706036 t gcesareni "The constitutive androstane receptor (car, nr1i4), like fxr and pxr, binds dna as a heterodimer with rxr?" SIGNOR-111624 LRP6 protein O75581 UNIPROT AXIN1 protein O15169 UNIPROT "down-regulates activity" relocalization 9606 BTO:0000007 18632848 t amattioni "The phosphorylation of lrp6 generates a docking site for axin and recruits it to the plasma membrane, where axin is inactivated and/or targeted for degradation by an unknown mechanism." SIGNOR-179469 NR1I2 protein O75469 UNIPROT UGT1A1 protein P22309 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18172616 f miannu "This study indicates that hepatocyte nuclear factor 1alpha (HNF1alpha) bound to the proximal promoter motif not only enhances the basal reporter activity of UGT1A1, including the distal (-3570/-3180) and proximal (-165/-1) regions, but also influences the transcriptional regulation of UGT1A1 by CAR, PXR, GR, and AhR to markedly enhance reporter activities." SIGNOR-254440 FRAT2 protein O75474 UNIPROT GSK3B protein P49841 UNIPROT "down-regulates activity" binding -1 11738041 t gcesareni "The structure of phosphorylated GSK-3beta complexed with a peptide, FRATtide, that inhibits beta-catenin phosphorylation." SIGNOR-244030 GPC4 protein O75487 UNIPROT WNT5A protein P41221 UNIPROT up-regulates binding 9606 22302992 t gcesareni "Gpc4 bound to wnt3a and wnt5a which activate the beta-catenin-dependent and -independent pathways, respectively, and colocalized with wnts on the cell surface. Expression of gpc4 enhanced the wnt3a-dependent beta-catenin pathway and the wnt5a-dependent beta-catenin-independent pathway, and knockdown of gpc4 suppressed both pathways" SIGNOR-195752 GPC4 protein O75487 UNIPROT WNT3A protein P56704 UNIPROT up-regulates binding 9606 22302992 t gcesareni "Gpc4 bound to wnt3a and wnt5a which activate the beta-catenin-dependent and -independent pathways, respectively, and colocalized with wnts on the cell surface. Expression of gpc4 enhanced the wnt3a-dependent beta-catenin pathway and the wnt5a-dependent beta-catenin-independent pathway, and knockdown of gpc4 suppressed both pathways" SIGNOR-195749 NDUFS3 protein O75489 UNIPROT "Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The Q-module is built through the association of NDUFA5, NDUFS2 and NDUFS3 plus NDUFS7 and NDUFS8. The chaperones NDUFAF3/C3ORF60 and NDUFAF4/C6ORF66 [36,37] remain bound to this module until the final assembly steps [34]. NDUFAF6/C8ORF38 [38] also seems to participate in the assembly of the Q-module [24,39]. NDUFAF3, 4 and 6, are necessary to maintain normal MT-ND1 synthesis [40,41]. NDUFAF5 adds a hydroxyl group to Arg73 of NDUFS7 [42] and NDUFAF7 dimethylates NDUFS2 in Arg85 [43], an essential modification for cI assembly [44]. NUBPL/IND1 delivers [4Fe–4S] clusters specifically to the N- and Q-module subunits [45,46]." SIGNOR-262177 GMNN protein O75496 UNIPROT CDT1 protein Q9H211 UNIPROT "down-regulates activity" binding 9606 BTO:0002181 11125146 t "Here we show that geminin interacts tightly with Cdt1, a recently identified replication initiation factor necessary for MCM loading." SIGNOR-261680 HSBP1 protein O75506 UNIPROT HSF1 protein Q00613 UNIPROT "down-regulates activity" binding 9606 BTO:0000567 9649501 t Monia "HSBP1 is nuclear-localized and interacts in vivo with the active trimeric state of HSF1 that appears during heat shock. During attenuation of HSF1 to the inert monomer, HSBP1 associates with Hsp70. HSBP1 negatively affects HSF1 DNA-binding activity, and overexpression of HSBP1 in mammalian cells represses the transactivation activity of HSF1. HSF1 interacts with HSBP1 in vivo and is a nuclear localized protein." SIGNOR-261181 EED protein O75530 UNIPROT PRC2 complex SIGNOR-C130 SIGNOR "form complex" binding 9606 23110252 t lperfetto "The PRC2 core, conserved from Drosophila to humans, is composed of four proteins that add up to about 230 kDa (Figure 1A) (see Margueron and Reinberg, 2010 for a recent review): EED (present in different isoforms), either one of the two methyltranferases Ezh1 or Ezh2 (Ezh1/2), Suz12, and either RbAp46 or RbAp48 (RbAp46/48)." SIGNOR-241897 EED protein O75530 UNIPROT SUZ12/EED complex SIGNOR-C76 SIGNOR "form complex" binding 9606 16712789 t miannu "Suz12 is a polycomb group protein that forms polycomb repressive complexes (prc2/3) together with eed and histone methyltransferase ezh2." SIGNOR-146755 CSDE1 protein O75534 UNIPROT FOS protein P01100 UNIPROT "down-regulates quantity" "post transcriptional regulation" 10090 BTO:0000944 15314026 t "By testing different classes of mammalian poly(A) nucleases, we identified CCR4 as a poly(A) nuclease involved in the mCRD-mediated rapid deadenylation in viv" SIGNOR-261145 DAB1 protein O75553 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 BTO:0000142 22394407 t lperfetto "The induction of disabled-1 (dab-1) tyrosine phosphorylation, and the subsequent activation of src family kinases, were found to be essential steps for the activation of notch-1 signaling by reelin" SIGNOR-196438 STX11 protein O75558 UNIPROT "STX11-SNAP23 SNARE complex" complex SIGNOR-C272 SIGNOR "form complex" binding 9606 BTO:0000132 22767500 t lperfetto "Coimmunoprecipitation experiments showed that syntaxin-11 can form SNARE complexes with both VAMP-8 and SNAP-23. " SIGNOR-261894 STX11 protein O75558 UNIPROT "STX11-VAMP8 SNARE complex" complex SIGNOR-C273 SIGNOR "form complex" binding 9606 BTO:0000132 22767500 t lperfetto "Coimmunoprecipitation experiments showed that syntaxin-11 can form SNARE complexes with both VAMP-8 and SNAP-23. " SIGNOR-261897 CRCP protein O75575 UNIPROT "RNA Polymerase III" complex SIGNOR-C389 SIGNOR "form complex" binding 9606 BTO:0000567 12391170 t lperfetto "In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights." SIGNOR-266134 ITGA10 protein O75578 UNIPROT "A10/b1 integrin" complex SIGNOR-C167 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253185 LRP6 protein O75581 UNIPROT DVL1 protein O14640 UNIPROT "up-regulates activity" binding 9606 23209147 t Gianni "The Wnt–FZD–LRP5/6 trimeric complex recruits Dishevelled (DVL) and Axin through the intracellular domains of FZD and LRP5/6, resulting in inhibition of β-catenin phosphorylation and thus ensuing β-catenin stabilization." SIGNOR-262526 LRP6 protein O75581 UNIPROT AXIN1 protein O15169 UNIPROT "down-regulates activity" relocalization 9606 BTO:0000007 12897152 t amattioni "The phosphorylation of lrp6 generates a docking site for axin and recruits it to the plasma membrane, where axin is inactivated and/or targeted for degradation by an unknown mechanism." SIGNOR-104493 LRP6 protein O75581 UNIPROT AXIN1 protein O15169 UNIPROT "down-regulates activity" relocalization 9606 BTO:0000007;BTO:0000567 16890161 t amattioni "The phosphorylation of lrp6 generates a docking site for axin and recruits it to the plasma membrane, where axin is inactivated and/or targeted for degradation by an unknown mechanism." SIGNOR-148668 NTRK1 protein P04629 UNIPROT NTRK1 protein P04629 UNIPROT up-regulates phosphorylation Tyr496 HIIENPQyFSDACVH 9606 9099755 t gcesareni "In vitro studies indicate that trka autophosphorylates at tyrosines 490, 670, 674, 675, and 785" SIGNOR-47167 LRP6 protein O75581 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "down-regulates activity" binding 9606 19107203 t "PPPSPxS motif in LRP6/5 must be phosphorylated." lperfetto "These observations demonstrate that phosphorylated lrp6/5 both recruits and directly inhibits gsk3beta using two distinct portions of its cytoplasmic sequence binding of wnts to the coreceptors frizzled and lrp6/5 leads to phosphorylation of pppspxs motifs in the lrp6/5 intracellular region and the inhibition of gsk3beta bound to the scaffold protein axin.These Observations demonstrate that phosphorylated lrp6/5 both recruits and directly inhibits gsk3beta using two distinct portions of its cytoplasmic sequence." SIGNOR-227942 LRP6 protein O75581 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "down-regulates quantity by destabilization" relocalization 9606 BTO:0000007 18632848 t lperfetto "The phosphorylation of lrp6 generates a docking site for axin and recruits it to the plasma membrane, where axin is inactivated and/or targeted for degradation by an unknown mechanism." SIGNOR-227939 LRP6 protein O75581 UNIPROT LPR5/6 complex SIGNOR-C219 SIGNOR "form complex" binding 9606 27821587 t miannu "Low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/6) are co-receptors for Wnt ligands." SIGNOR-256175 RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT unknown phosphorylation Ser750 RRKMKKTsTSTETRS 9606 15568999 t lperfetto "Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. ser-750, ser-752 and ser-758 are phosphorylated by the n-terminal kinase domain;however, their function is not known." SIGNOR-131399 RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT unknown phosphorylation Ser752 KMKKTSTsTETRSSS 9606 15568999 t lperfetto "Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. ser-750, ser-752 and ser-758 are phosphorylated by the n-terminal kinase domain;however, their function is not known." SIGNOR-131403 RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT unknown phosphorylation Ser758 TSTETRSsSSESSHS 9606 15568999 t lperfetto "Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. ser-750, ser-752 and ser-758 are phosphorylated by the n-terminal kinase domain;however, their function is not known." SIGNOR-131407 RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT "up-regulates activity" phosphorylation Ser212 DETERAYsFCGTIEY 9606 15568999 t lperfetto "Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. Of these sites, the n-terminal t-loop residue ser-212 and the 'hydrophobic motif' ser-376 are phosphorylated by the c-terminal kinase domain of msk1, and their phosphorylation is essential for the catalytic activity of the n-terminal kinase domain of msk1 and therefore for the phosphorylation of msk1 substrates in vitro." SIGNOR-131387 RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT "up-regulates activity" phosphorylation Ser376 EKLFQGYsFVAPSIL 9606 15568999 t lperfetto "Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. Of these sites, the n-terminal t-loop residue ser-212 and the 'hydrophobic motif' ser-376 are phosphorylated by the c-terminal kinase domain of msk1, and their phosphorylation is essential for the catalytic activity of the n-terminal kinase domain of msk1 and therefore for the phosphorylation of msk1 substrates in vitro." SIGNOR-131391 RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT "up-regulates activity" phosphorylation Ser381 GYSFVAPsILFKRNA 9606 15568999 t lperfetto "Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. Of these sites, the n-terminal t-loop residue ser-212 and the 'hydrophobic motif' ser-376 are phosphorylated by the c-terminal kinase domain of msk1, and their phosphorylation is essential for the catalytic activity of the n-terminal kinase domain of msk1 and therefore for the phosphorylation of msk1 substrates in vitro." SIGNOR-131395 RPS6KA5 protein O75582 UNIPROT HMGN1 protein P05114 UNIPROT "down-regulates activity" phosphorylation Ser7 sSAEGAAK 12213813 t lperfetto "HMGN1 (formerly known as HMG-14) phosphorylation at Ser6 occurs concomitantly with IE gene expression. | MSK2 seems to be the most important kinase responsible for this modification |Accordingly, it was suggested that HMGN1 phosphorylation reduces binding of the protein to the nucleosomes" SIGNOR-262988 RPS6KA5 protein O75582 UNIPROT TH protein P07101 UNIPROT up-regulates phosphorylation Ser40 GQGAPGPsLTGSPWP 9606 12421349 t "The effect has been demonstrated using P07101-3" gcesareni "Recombinant human tyrosine hydroxylase (hth1) was found to be phosphorylated by mitogen and stress-activated protein kinase 1 (msk1) at ser40 and by p38 regulated/activated kinase (prak) on ser19. Phosphorylation by msk1 induced an increase in vmax. studies on th from several species suggest that ser40 is the main site involved in direct activation of th" SIGNOR-95491 RPS6KA5 protein O75582 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser119 EILSRRPsYRKILND 9606 BTO:0000567 9687510 t lperfetto "Msk1 is localized in the nucleus of unstimulated or stimulated cells, and phosphorylates creb at ser133_ .MSK1 Is activated in vitro by mapk2/erk2 or sapk2/p38. Endogenous msk1 is activated in 293 cells by either growth factor/phorbol ester stimulation, or by exposure to uv radiation, and oxidative and chemical stres msk was the kinase responsible for phosphorylation of the transcription factor creb in response to tcr stimulation. Pka, ca2+-calmodulin-dependent kinase iv (camkiv), msk, p70s6k and rsk phosphorylate creb." SIGNOR-59458 RPS6KA5 protein O75582 UNIPROT ATF1 protein P18846 UNIPROT "up-regulates activity" phosphorylation Ser63 GILARRPsYRKILKD 10090 BTO:0000452 11909979 t lperfetto "Using embryonic fibroblasts derived from these mice we were able to demonstrate an important role for these enzymes in the activation of CREB and the closely related transcription factor ATF1. | Our results clearly demonstrate that MSK1 and MSK2 are the major, if not the only, protein kinases that mediate the phosphorylation of CREB at Ser133 and of ATF1 at Ser63 in fibroblasts" SIGNOR-249144 RPS6KA5 protein O75582 UNIPROT ATF1 protein P18846 UNIPROT "up-regulates activity" phosphorylation Ser63 GILARRPsYRKILKD 9606 12414794 t lperfetto "We find that activation of the c-jun promoter through the atf1 site requires phosphorylation of atf1 at serine 63. atf1 can be phosphorylated by mitogen- and stress-activated protein kinase 1 (msk1), which is activated by egf and erk1/2." SIGNOR-95318 RPS6KA5 protein O75582 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser383 IHFWSTLsPIAPRSP 9606 BTO:0000150 BTO:0000975 11145955 t gcesareni "Phosphorylation on ser383 and ser389 of elk-1 by mapk enhances this basal binding but, most importantly, elk-1 exhibits new interactions with p300." SIGNOR-85514 RPS6KA5 protein O75582 UNIPROT NR4A1 protein P22736 UNIPROT unknown phosphorylation Ser351 GRRGRLPsKPKQPPD 9606 BTO:0000007 16223362 t lperfetto "In the present paper, we have re-examined the phosphorylation of Nur77 on Ser354. Using a combination of cell-permeable kinase inhibitors and mouse knockin mutations, we show that Nur77 is phosphorylated by RSK in response to mitogenic stimulation of cells. Phosphorylation of Nur77 on Ser354 did not, however, appear to affect the transcriptional activity of Nur77, or its ability to bind 14-3-3 proteins in vivo." SIGNOR-249296 RPS6KA5 protein O75582 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 12763138 t gcesareni "The stat3-mediated transactivation was reduced by blocking the stat3 serine phosphorylation with the mek inhibitor u0126 or by expression of kinase-inactive msk1." SIGNOR-101251 RPS6KA5 protein O75582 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation 9606 20626350 t gcesareni "Msk (mitogen- and stress-activated kinase) 1 and 2 can directly phosphorylate and activate transcription factors such as creb, atf1, the nf- b isoform p65 and stat (signal transducer and activator of transcription) 1 and 3" SIGNOR-166664 RPS6KA5 protein O75582 UNIPROT PLA2G4A protein P47712 UNIPROT "up-regulates activity" phosphorylation Ser727 RQNPSRCsVSLSNVE 9606 BTO:0000007 10978317 t lperfetto "Serine 727 phosphorylation and activation of cytosolic phospholipase A2 by MNK1-related protein kinases." SIGNOR-249051 RPS6KA5 protein O75582 UNIPROT ETV1 protein P50549 UNIPROT "up-regulates activity" phosphorylation Ser216 PMYQRQMsEPNIPFP 9606 BTO:0002181 12213813 t lperfetto "Activated, overexpressed MSK1 was able to phosphorylate ER81 at Ser191 and Ser216. Mutation of these residues strongly impairs ER81-responsive promoter activity." SIGNOR-262987 RPS6KA5 protein O75582 UNIPROT H3C1 protein P68431 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 BTO:0000938 14625384 t gcesareni "Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun." SIGNOR-119237 RPS6KA5 protein O75582 UNIPROT H3C1 protein P68431 UNIPROT up-regulates phosphorylation Ser29 ATKAARKsAPATGGV 9606 BTO:0000938 20129940 t gcesareni "Upon activation of the erk and p38 mapk pathways, the msk1/2-mediated nucleosomal response, including h3 phosphorylation at serine 28 or 10, is coupled with the induction of immediate-early (ie) gene transcription." SIGNOR-163712 RPS6KA5 protein O75582 UNIPROT H3-3A protein P84243 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 10464286 t gcesareni "Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun." SIGNOR-70440 RPS6KA5 protein O75582 UNIPROT H3-3A protein P84243 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 BTO:0000938 14625384 t gcesareni "Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun." SIGNOR-119233 RPS6KA5 protein O75582 UNIPROT H3-3A protein P84243 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 15994958 t gcesareni "Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun." SIGNOR-138479 RPS6KA5 protein O75582 UNIPROT H3-3A protein P84243 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 BTO:0000938 18508628 t gcesareni "In addition to ser10, msk was also found to phosphorylate a second site on h3, ser28 (75). It should be noted that while both ser10 and ser28 in h3 are extensively phosphorylated during mitosis, this is independent of msks and is catalysed by aurora kinases. In contrast, msks only phosphorylate a small proportion of the total cellular histone h3 in response to mitogens or stress. The spatial distribution of ser10 and ser28 phosphorylation is very tightly regulated in cells. In vitro, msk1 will phosphorylate one histone h3 molecule on both ser10 and ser28. Surprisingly it has been shown that in cells msk phosphorylates either ser10 or ser28 but not both on individual nucleosomes." SIGNOR-178704 RPS6KA5 protein O75582 UNIPROT H3-3A protein P84243 UNIPROT up-regulates phosphorylation Ser29 ATKAARKsAPSTGGV 9606 BTO:0000938 18508628 t gcesareni "In addition to ser10, msk was also found to phosphorylate a second site on h3, ser28 (75). It should be noted that while both ser10 and ser28 in h3 are extensively phosphorylated during mitosis, this is independent of msks and is catalysed by aurora kinases. In contrast, msks only phosphorylate a small proportion of the total cellular histone h3 in response to mitogens or stress. The spatial distribution of ser10 and ser28 phosphorylation is very tightly regulated in cells. In vitro, msk1 will phosphorylate one histone h3 molecule on both ser10 and ser28. Surprisingly it has been shown that in cells msk phosphorylates either ser10 or ser28 but not both on individual nucleosomes." SIGNOR-178708 RPS6KA5 protein O75582 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser276 SMQLRRPsDRELSEP 9606 SIGNOR-C13 12628924 t gcesareni "Transcriptional activation of the nf-kappab p65 subunit by mitogen- and stress-activated protein kinase-1 (msk1)mutational analysis of p65 revealed ser276 as a target for phosphorylation and transactivation in response to tnf. Moreover, we identified msk1 as a nuclear kinase for p65, since msk1 associates with p65 in a stimulus-dependent way and phosphorylates p65 at ser276." SIGNOR-99210 RPS6KA5 protein O75582 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr45 PGGTLFStTPGGTRI -1 11777913 t lperfetto "Here, using mass spectrometry, we identify the serum-responsive, rapamycin-sensitive sites as Ser 65 and Thr 70. | Phosphorylation of Thr 37/Thr 46 is followed by Thr 70 phosphorylation, and Ser 65 is phosphorylated last. Finally, we show that phosphorylation of Ser 65 and Thr 70 alone is insufficient to block binding to eIF4E, indicating that a combination of phosphorylation events is necessary to dissociate 4E-BP1 from eIF4E." SIGNOR-249131 RPS6KA5 protein O75582 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Ser65 FLMECRNsPVTKTPP 12213813 t lperfetto "In response to UV-B irradiation, the translation factor 4E-BP1 (eukaryotic initiation factor 4E [eIF4E]-binding protein 1) was phosphorylated at Thr36, Thr45, Ser64 and Thr69. Using either p38 MAPK inhibitors or the MSK inhibitor H89, UV-B-irradiation-induced phosphorylation was blocked [43]. 4E-BP1 binds to eIF4E in resting cells to prevent formation of a functional eIF4F complex, which is essential for cap-dependent initiation of translation. Phosphorylation of 4E-BP1 leads to dissociation from eIF4E" SIGNOR-262993 RPS6KA5 protein O75582 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr37 PPGDYSTtPGGTLFS 12213813 t lperfetto "In response to UV-B irradiation, the translation factor 4E-BP1 (eukaryotic initiation factor 4E [eIF4E]-binding protein 1) was phosphorylated at Thr36, Thr45, Ser64 and Thr69. Using either p38 MAPK inhibitors or the MSK inhibitor H89, UV-B-irradiation-induced phosphorylation was blocked [43]. 4E-BP1 binds to eIF4E in resting cells to prevent formation of a functional eIF4F complex, which is essential for cap-dependent initiation of translation. Phosphorylation of 4E-BP1 leads to dissociation from eIF4E" SIGNOR-262991 RPS6KA5 protein O75582 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr46 GGTLFSTtPGGTRII 12213813 t lperfetto "In response to UV-B irradiation, the translation factor 4E-BP1 (eukaryotic initiation factor 4E [eIF4E]-binding protein 1) was phosphorylated at Thr36, Thr45, Ser64 and Thr69. Using either p38 MAPK inhibitors or the MSK inhibitor H89, UV-B-irradiation-induced phosphorylation was blocked [43]. 4E-BP1 binds to eIF4E in resting cells to prevent formation of a functional eIF4F complex, which is essential for cap-dependent initiation of translation. Phosphorylation of 4E-BP1 leads to dissociation from eIF4E" SIGNOR-262992 RPS6KA5 protein O75582 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr70 RNSPVTKtPPRDLPT 12213813 t lperfetto "In response to UV-B irradiation, the translation factor 4E-BP1 (eukaryotic initiation factor 4E [eIF4E]-binding protein 1) was phosphorylated at Thr36, Thr45, Ser64 and Thr69. Using either p38 MAPK inhibitors or the MSK inhibitor H89, UV-B-irradiation-induced phosphorylation was blocked [43]. 4E-BP1 binds to eIF4E in resting cells to prevent formation of a functional eIF4F complex, which is essential for cap-dependent initiation of translation. Phosphorylation of 4E-BP1 leads to dissociation from eIF4E" SIGNOR-262994 RPS6KA5 protein O75582 UNIPROT H3-4 protein Q16695 UNIPROT unknown phosphorylation Ser11 TKQTARKsTGGKAPR 10090 BTO:0000452 12773393 t lperfetto "The results presented here show that MSK2 and, to a lesser extent, MSK1 are the major protein kinases required for the phosphorylation of histone H3 at both Ser10 and Ser28" SIGNOR-249213 RPS6KA5 protein O75582 UNIPROT H3-4 protein Q16695 UNIPROT unknown phosphorylation Ser29 ATKVARKsAPATGGV 10090 BTO:0000452 12773393 t lperfetto "The results presented here show that MSK2 and, to a lesser extent, MSK1 are the major protein kinases required for the phosphorylation of histone H3 at both Ser10 and Ser28" SIGNOR-249214 RPS6KA5 protein O75582 UNIPROT H2AW protein Q7L7L0 UNIPROT "down-regulates activity" phosphorylation Ser2 sGRGKQGG -1 15010469 t miannu "We found that MSK1 phosphorylated histone H2A on serine 1, and mutation of serine 1 to alanine blocked the inhibition of transcription by MSK1. Furthermore, we found that acetylation of histone H3 by the p300 and CREB-binding protein associated factor, PCAF, suppressed the kinase-dependent inhibition of transcription. These results suggest that acetylation of histones may stimulate transcription by suppressing an inhibitory phosphorylation by a kinase as MSK1." SIGNOR-262942 RPS6KA5 protein O75582 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser118 GRELRRMsDEFVDSF 12213813 t lperfetto "Phosphorylation of Bad at Ser112 in response to growth factors or cytokines is generally linked to cell survival. Knockdown of MSK1 suppressed Bad phosphorylation after calcium ionophore A23187 treatment in neuronal cells" SIGNOR-262990 RPS6KA5 protein O75582 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 12628924 t lperfetto "Transcriptional activation of the nf-kappab p65 subunit by mitogen- and stress-activated protein kinase-1 (msk1)mutational analysis of p65 revealed ser276 as a target for phosphorylation and transactivation in response to tnf. Moreover, we identified msk1 as a nuclear kinase for p65, since msk1 associates with p65 in a stimulus-dependent way and phosphorylates p65 at ser276." SIGNOR-217424 MED6 protein O75586 UNIPROT "Core mediator complex" complex SIGNOR-C405 SIGNOR "form complex" binding 9606 28467824 t miannu "Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles." SIGNOR-266677 MYCBP2 protein O75592 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0001321 32814769 t miannu "We identified several E3 ligases as strong candidates responsible for AR and MYC protein loss as HECTD4, MYCBP2, and TRIM49. HECTD4 and MYCBP2 target AR and MYC for degradation while TRIM49 appears to promote AR and MYC stability. We have shown that these E3 ligases in turn are directly regulated by MYC. MYC in turn represses the expression of ubiquitin ligases, HECTD4 and MYCBP2 that promote AR and MYC protein degradation, further suppressing MYC and AR in a feed forward loop." SIGNOR-267147 MYCBP2 protein O75592 UNIPROT MYC protein P01106 UNIPROT "up-regulates activity" binding -1 9689053 t Monia "We have identified a large and highly conserved nuclear protein that interacts directly with the transcriptional activating domain of Myc (designated ‘‘protein associated with Myc’’ or Pam).Pam Binds to Myc but Not NMyc. the data indicate that the portion of Myc between amino acids 44 and 107 is essential for binding to Pam (Fig. 7B). We hypothesize that the binding of Pam plays a role in transcriptional activation by Myc, either as facilitator or regulator." SIGNOR-261201 MYCBP2 protein O75592 UNIPROT AR protein P10275 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0001321 32814769 t miannu "We identified several E3 ligases as strong candidates responsible for AR and MYC protein loss as HECTD4, MYCBP2, and TRIM49. HECTD4 and MYCBP2 target AR and MYC for degradation while TRIM49 appears to promote AR and MYC stability. We have shown that these E3 ligases in turn are directly regulated by MYC. MYC in turn represses the expression of ubiquitin ligases, HECTD4 and MYCBP2 that promote AR and MYC protein degradation, further suppressing MYC and AR in a feed forward loop." SIGNOR-267149 MYCBP2 protein O75592 UNIPROT RAN protein P62826 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 10090 26304119 t Monia "MYCBP2 Is a Nuclear GEF for Ran in DRG Neurons—Next, we studied whether or not MYCBP2 modulates the interaction between Ran/RanGAP1. MYCBP2 contains an N-terminal RCC1-like domain (Fig. 8C) (13), and RCC1 is a known GEF for Ran, indicating a potential functional interaction between MYCBP2 and Ran." SIGNOR-261204 MYCBP2 protein O75592 UNIPROT TSC1/TSC2 complex SIGNOR-C101 SIGNOR down-regulates ubiquitination 10116 BTO:0001009 14559897 t Monia "Pam Interacts with the Tuberin-Hamartin Complex—To examine the in vivo association of tuberin and Pam, we performed co-immunoprecipitation experiments in PC12 cells and rat embryonic brain. Immunoprecipitation of tuberin using an anti-tuberin antibody followed by immunoblot analysis showed that endogenous Pam co-immunoprecipitates with tuberin in PC12 cells and embryonic rat brain. Pam Homolog HIW Modulates Tsc1Tsc2 Activity in Drosophila. The enhancement of Tsc1Tsc2 phenotype by the removal of the hiw gene indicates that hiw negatively regulates Tsc1Tsc2 activity in Drosophila eye. Taken together, it is probable that Pam may function as an E3 ligase for tuberin and regulate the ubiquitination and proteasomal degradation of the tuberinhamartin complex particularly in the CNS" SIGNOR-261202 FOXH1 protein O75593 UNIPROT SMAD2 protein Q15796 UNIPROT "up-regulates activity" binding 9606 BTO:0001538 9858566 t lperfetto "FAST-2 also interacts directly with Smad2, a cytoplasmic protein which is translocated to the nucleus in response to TGF-beta, and forms a multimeric complex with Smad2 and Smad4 on the activin response element, a high-affinity binding site for FAST-1." SIGNOR-108333 GCM2 protein O75603 UNIPROT PTH protein P01270 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004712 20558332 f miannu "We found that GCMB binds to the PTH gene 5'-promoter (-390/-383 bp) and positively regulates its transcription." SIGNOR-254200 GCM2 protein O75603 UNIPROT CASR protein P41180 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004712 BTO:0000975 18712808 f miannu "we show that both promoters (P1 and P2) of the calcium-sensing receptor (CASR) gene, a differentiation marker for the parathyroid gland, are transactivated by wild-type GCM2." SIGNOR-254199 PRDM1 protein O75626 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 12032779 f miannu "Several different transcription factors have been implicated in the down-regulation of c-myc expression during differentiation, including C/EBPalpha, CTCF, BLIMP-1, and RFX1." SIGNOR-253828 PRDM1 protein O75626 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000776 12626569 f miannu "The positive regulatory domain i binding factor 1 (prdi-bf1 or blimp-1) protein represses the transcription of specific target genes, including c-myc, the mhc class ii trans-activator, pax-5, and cd23b" SIGNOR-99119 PRDM1 protein O75626 UNIPROT FCER2 protein P06734 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000776 11342629 f "In this study, we report that PRDI-BF1/Blimp1 can bind to the same functional element in the human CD23b promoter to which BCL-6 and IRF-4 had previously been shown to bind, and that, like BCL-6, Blimp1 can repress IRF-4-transactivating ability" SIGNOR-253926 PRDM1 protein O75626 UNIPROT CIITA protein P33076 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000776 12626569 f miannu "The positive regulatory domain i binding factor 1 (prdi-bf1 or blimp-1) protein represses the transcription of specific target genes, including c-myc, the mhc class ii trans-activator, pax-5, and cd23b" SIGNOR-99116 PRDM1 protein O75626 UNIPROT PAX5 protein Q02548 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000776 12052884 f miannu "Blimp-1-dependent repression of pax-5 is required for differentiation of b cells to immunoglobulin m-secreting plasma cells" SIGNOR-89032 FCN3 protein O75636 UNIPROT MASP2 protein O00187 UNIPROT "up-regulates activity" binding 17204478 t lperfetto "In the lectin pathway, mannose-binding lectin (MBL) and ficolins bind to pathogens and activate MBL-associated serine protease-2 (MASP-2)" SIGNOR-263412 FCN3 protein O75636 UNIPROT MASP1 protein P48740 UNIPROT "up-regulates activity" binding 9606 BTO:0000392 11907111 t lperfetto "H-ficolin binds to PSA, a polysaccharide produced by Aerococcus viridans. C4 was activated by H-ficolin preparations bound to PSA which had been coated on ELISA plates. These results indicate that H-ficolin is a second ficolin which is associated with MASPs and sMAP, and which activates the lectin pathway|Proteolytic activation of complement components by H-ficolin-MASP." SIGNOR-263410 RPS6KA4 protein O75676 UNIPROT RPS6KA4 protein O75676 UNIPROT up-regulates phosphorylation Ser196 EEKERTFsFCGTIEY 9606 BTO:0001253 17429437 t gcesareni "Ser-343 and ser-196 are autophosphorylated by the c-terminal kinase domain, and their phosphorylation is essential for the catalytic activity of the n-terminal kinase domain." SIGNOR-154324 RPS6KA4 protein O75676 UNIPROT FOS protein P01100 UNIPROT "up-regulates activity" phosphorylation Ser374 PSSDSLSsPTLLAL 16055710 t lperfetto "Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos" SIGNOR-263000 RPS6KA4 protein O75676 UNIPROT FOS protein P01100 UNIPROT "up-regulates activity" phosphorylation Ser362 AAAHRKGsSSNEPSS 9606 22187936 t gcesareni "Rsk1/2 stabilize c-fos and increases its activity." SIGNOR-191678 RPS6KA4 protein O75676 UNIPROT FOS protein P01100 UNIPROT "up-regulates activity" phosphorylation Ser362 AAAHRKGsSSNEPSS 9606 8248197 t gcesareni "Rsk1/2 phosphorylates the transcription factor c-fos on s362 and increases its activity." SIGNOR-37216 RPS6KA4 protein O75676 UNIPROT TP53 protein P04637 UNIPROT down-regulates 9606 19797274 f gcesareni "Mitogen- and stress-activated kinase 2 (msk2) inhibits the transcription factor p53, and we investigate here the mechanisms underlying this inhibition. In the absence of stress stimuli, msk2 selectively suppressed the expression of a subset of p53 target genes.Msk2 can also control the the transcriptional activity of p53 in a kinase-indipendent mannermsk2 can also control the the transcriptional activity of p53 in a kinase-indipendent manner" SIGNOR-188334 RPS6KA4 protein O75676 UNIPROT HMGN1 protein P05114 UNIPROT unknown phosphorylation Ser7 sSAEGAAK 10090 BTO:0000452 12773393 t lperfetto "The results presented here show that MSK2 and, to a lesser extent, MSK1 are the major protein kinases required for the phosphorylation of histone H3 at both Ser10 and Ser28 and HMG-14 at Ser6 after stimulation of primary embryonic fibroblasts by TPA or anisomycin." SIGNOR-249216 RPS6KA4 protein O75676 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser119 EILSRRPsYRKILND 9606 BTO:0000782 17668895 t gcesareni "Msk1 and msk2 directly phosphorilate and activete transcription factors such as creb1, atf1 msk was the kinase responsible for phosphorylation of the transcription factor creb in response to tcr stimulation." SIGNOR-157158 RPS6KA4 protein O75676 UNIPROT ATF1 protein P18846 UNIPROT up-regulates phosphorylation 9606 11909979 t gcesareni "Msk1 and msk2 directly phosphorilate and activate transcription factors such as creb1, atf1." SIGNOR-116252 RPS6KA4 protein O75676 UNIPROT ATF1 protein P18846 UNIPROT up-regulates phosphorylation 9606 20626350 t gcesareni "Msk1 and msk2 directly phosphorilate and activate transcription factors such as creb1, atf1." SIGNOR-166661 RPS6KA4 protein O75676 UNIPROT ATF1 protein P18846 UNIPROT "up-regulates activity" phosphorylation Ser63 GILARRPsYRKILKD 10090 BTO:0000452 11909979 t lperfetto "Using embryonic fibroblasts derived from these mice we were able to demonstrate an important role for these enzymes in the activation of CREB and the closely related transcription factor ATF1. | Our results clearly demonstrate that MSK1 and MSK2 are the major, if not the only, protein kinases that mediate the phosphorylation of CREB at Ser133 and of ATF1 at Ser63 in fibroblasts" SIGNOR-249145 RPS6KA4 protein O75676 UNIPROT H3-4 protein Q16695 UNIPROT unknown phosphorylation Ser11 TKQTARKsTGGKAPR 10090 BTO:0000452 12773393 t lperfetto "The results presented here show that MSK2 and, to a lesser extent, MSK1 are the major protein kinases required for the phosphorylation of histone H3 at both Ser10 and Ser28" SIGNOR-249211 RPS6KA4 protein O75676 UNIPROT H3-4 protein Q16695 UNIPROT unknown phosphorylation Ser29 ATKVARKsAPATGGV 10090 BTO:0000452 12773393 t lperfetto "The results presented here show that MSK2 and, to a lesser extent, MSK1 are the major protein kinases required for the phosphorylation of histone H3 at both Ser10 and Ser28" SIGNOR-249212 ABL1 protein P00519 UNIPROT GRAP protein Q13588 UNIPROT up-regulates binding 9606 BTO:0001271 23399893 t gcesareni "We show that the grb2-related adapter protein, gads, also associates with bcr-abl, specifically through y177 and demonstrate that bcr-abl-driven lymphoid disease requires gads" SIGNOR-200871 RPS6KA4 protein O75676 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 17183360 t lperfetto "Rela is phosphorylated at: ser276 by the catalytic subunit of protein kinase a (pkac), msk1 and msk2; at ser311 by the atypical pkczeta; at ser468 by ikkbeta, ikkepsilon and glycogen-synthase kinase-3beta (gsk3beta); at ser529 by ck2; and at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1)) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k) msk 1 and 2 can directly phosphorylate and activate transcription factors such as creb, atf1, the nf-kb isoform p65 and stat 1 and 3." SIGNOR-217373 PPM1B protein O75688 UNIPROT IKBKB protein O14920 UNIPROT down-regulates dephosphorylation Ser177 AKELDQGsLCTSFVG 9606 18930133 t lperfetto "Using a functional genomic approach, we have identified two protein serine/threonine phosphatases, ppm1a and ppm1b, as ikkbeta phosphatases. Overexpression of ppm1a or ppm1b results in dephosphorylation of ikkbeta at ser177 and ser181 and termination of ikkbeta-induced nf-kappab activation" SIGNOR-181663 PPM1B protein O75688 UNIPROT IKBKB protein O14920 UNIPROT down-regulates dephosphorylation Ser181 DQGSLCTsFVGTLQY 9606 18930133 t lperfetto "Using a functional genomic approach, we have identified two protein serine/threonine phosphatases, ppm1a and ppm1b, as ikkbeta phosphatases. Overexpression of ppm1a or ppm1b results in dephosphorylation of ikkbeta at ser177 and ser181 and termination of ikkbeta-induced nf-kappab activation" SIGNOR-181667 PPM1B protein O75688 UNIPROT IKBKB protein O14920 UNIPROT "down-regulates activity" dephosphorylation Ser177 AKELDQGsLCTSFVG 9606 BTO:0000007 18930133 t "PPM1A and PPM1B act as IKKbeta phosphatases to terminate TNFalpha-induced IKKbeta-NF-kappaB activation|Overexpression of PPM1A or PPM1B results in dephosphorylation of IKKbeta at Ser177 and Ser181 and termination of IKKbeta-induced NF-kappaB activation." SIGNOR-248343 PPM1B protein O75688 UNIPROT IKBKB protein O14920 UNIPROT "down-regulates activity" dephosphorylation Ser181 DQGSLCTsFVGTLQY 9606 BTO:0000007 18930133 t "PPM1A and PPM1B act as IKKbeta phosphatases to terminate TNFalpha-induced IKKbeta-NF-kappaB activation|Overexpression of PPM1A or PPM1B results in dephosphorylation of IKKbeta at Ser177 and Ser181 and termination of IKKbeta-induced NF-kappaB activation." SIGNOR-248344 PPM1B protein O75688 UNIPROT CDK9 protein P50750 UNIPROT unknown dephosphorylation Thr186 NSQPNRYtNRVVTLW 9606 18829461 t gcesareni "Taken together, our data indicate that PPM1A and to some extent PPM1B are important negative regulators of P-TEFb function" SIGNOR-181396 PPM1B protein O75688 UNIPROT PAX2 protein Q02962 UNIPROT "down-regulates activity" dephosphorylation 9606 BTO:0000007 25631048 t "PPM1B can dephosphorylate the Pax2 activation domain and displace the adaptor protein PTIP, thus inhibiting H3K4 methylation and gene activation" SIGNOR-251712 NUP155 protein O75694 UNIPROT NPC complex SIGNOR-C263 SIGNOR "form complex" binding 27016207 t lperfetto "The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2)." SIGNOR-262082 STK16 protein O75716 UNIPROT STK16 protein O75716 UNIPROT unknown phosphorylation Ser197 AAQRCTIsYRAPELF -1 18184589 t Manara "Indeed, our kinetic analysis of MPSK1 autophosphorylation showed that autophosphorylation is a slow process and that two of the three identified sites are largely buried in unphosphorylated MPSK1. However, two autophosphorylation sites are located in the P + 1 loop and phosphorylation at these locations might affect substrate recognition." SIGNOR-260804 STK16 protein O75716 UNIPROT STK16 protein O75716 UNIPROT unknown phosphorylation Thr185 EGSRQALtLQDWAAQ -1 18184589 t Manara "Indeed, our kinetic analysis of MPSK1 autophosphorylation showed that autophosphorylation is a slow process and that two of the three identified sites are largely buried in unphosphorylated MPSK1. However, two autophosphorylation sites are located in the P + 1 loop and phosphorylation at these locations might affect substrate recognition." SIGNOR-260803 STK16 protein O75716 UNIPROT STK16 protein O75716 UNIPROT unknown phosphorylation Tyr198 AQRCTISyRAPELFS -1 18184589 t Manara "Indeed, our kinetic analysis of MPSK1 autophosphorylation showed that autophosphorylation is a slow process and that two of the three identified sites are largely buried in unphosphorylated MPSK1. However, two autophosphorylation sites are located in the P + 1 loop and phosphorylation at these locations might affect substrate recognition." SIGNOR-260805 WDHD1 protein O75717 UNIPROT CLSPN protein Q9HAW4 UNIPROT "up-regulates activity" binding 9606 BTO:0001109 26082189 t miannu "And-1 is phosphorylated at T826 by ATR following replication stress, and this phosphorylation is required for And-1 to accumulate at the damage sites, where And-1 promotes the interaction between Claspin and Chk1, thereby stimulating efficient Chk1 activation by ATR. Significantly, And-1 binds directly to ssDNA and facilitates the association of Claspin with ssDNA." SIGNOR-262665 SLC25A12 protein O75746 UNIPROT "glutamic acid" smallmolecule CHEBI:18237 ChEBI "down-regulates quantity" relocalization 9606 12084073 t miannu "Aralar1 and citrin are members of the subfamily of calcium-binding mitochondrial carriers and correspond to two isoforms of the mitochondrial aspartate/glutamate carrier (AGC). These proteins are activated by Ca2+ acting on the external side of the inner mitochondrial membrane." SIGNOR-265154 SLC25A12 protein O75746 UNIPROT "aspartic acid" smallmolecule CHEBI:22660 ChEBI "up-regulates quantity" relocalization 9606 12084073 t miannu "Aralar1 and citrin are members of the subfamily of calcium-binding mitochondrial carriers and correspond to two isoforms of the mitochondrial aspartate/glutamate carrier (AGC). These proteins are activated by Ca2+ acting on the external side of the inner mitochondrial membrane." SIGNOR-265156 PPP1R15A protein O75807 UNIPROT PPP1CC protein P36873 UNIPROT up-regulates binding 9606 14718519 t gcesareni "We found smad7 interacts with growth arrest and dna damage protein, gadd34, a regulatory subunit of the protein phosphatase 1 (pp1) holoenzyme, which subsequently recruits catalytic subunit of pp1 (pp1c) to dephosphorylate tbetari." SIGNOR-120471 PPP1R15A protein O75807 UNIPROT PPP1CC protein P36873 UNIPROT up-regulates relocalization 9606 14718519 t lpetrilli "We found smad7 interacts with growth arrest and dna damage protein, gadd34, a regulatory subunit of the protein phosphatase 1 (pp1) holoenzyme, which subsequently recruits catalytic subunit of pp1 (pp1c) to dephosphorylate t?RI." SIGNOR-120734 PPP1R15A protein O75807 UNIPROT PPP1CC protein P36873 UNIPROT "up-regulates activity" binding 9606 27629041 t miannu "Dephosphorylation of eIF2α is central to ISR signal termination to restore protein synthesis and normal cell functioning 15. It is mediated by protein phosphatase 1 (PP1) complex that recruits a PP1 catalytic subunit (PP1c) and one of the two regulatory subunits. In mammals, phosphatase activity is regulated by either PPP1R15A (also known as growth arrest and DNA damage‐inducible protein, GADD34), which is induced as part of the ISR. the GADD34–PP1 complex acts as an important negative feedback loop to restore protein synthesis once the ER stress has been resolved, and as such aids in cell survival" SIGNOR-260174 EIF3G protein O75821 UNIPROT EIF3_complex complex SIGNOR-C401 SIGNOR "form complex" binding -1 16920360 t miannu "Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1)." SIGNOR-266394 EIF3J protein O75822 UNIPROT EIF3_complex complex SIGNOR-C401 SIGNOR "form complex" binding -1 16920360 t miannu "Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1)." SIGNOR-266391 KLF7 protein O75840 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9534 BTO:0004055 14729953 f miannu "KLF7 stimulates p21WAF1/Cip1 transcription" SIGNOR-224624 TNFSF13 protein O75888 UNIPROT TNFRSF13B protein O14836 UNIPROT up-regulates binding 9606 BTO:0000007 10956646 t gcesareni "Tumor necrosis factor (tnf) receptor superfamily member taci is a high affinity receptor for tnf family members april and blys." SIGNOR-81308 TNFSF13 protein O75888 UNIPROT TNFRSF17 protein Q02223 UNIPROT up-regulates binding 9606 BTO:0000782 10973284 t gcesareni "April is involved in stimulation of b and t cell function. April functions via binding to bcma and taci and competes with tall-i for receptor binding." SIGNOR-81386 GABBR2 protein O75899 UNIPROT "GABA-B receptor" complex SIGNOR-C336 SIGNOR "form complex" binding 9606 BTO:0000007 9872316 t brain lperfetto "Heterodimerization is required for the formation of a functional GABA(B) receptor.|These results indicate that, in vivo, functional brain GABA(B) receptors may be heterodimers composed of GABA(B)R1 and GABA(B)R2." SIGNOR-263743 CCNK protein O75909 UNIPROT CDK12/CCNK complex SIGNOR-C37 SIGNOR "form complex" binding 9606 22012619 t miannu "We identified a 70-kda cyclin k (cyck) that binds cdk12 and cdk13 to form two different complexes (cyck/cdk12 or cyck/cdk13) in human cells" SIGNOR-176783 CCNK protein O75909 UNIPROT CDK13/CCNK complex SIGNOR-C38 SIGNOR "form complex" binding 9606 22012619 t miannu "We identified a 70-kda cyclin k (cyck) that binds cdk12 and cdk13 to form two different complexes (cyck/cdk12 or cyck/cdk13) in human cells" SIGNOR-176786 PAK3 protein O75914 UNIPROT PAK3 protein O75914 UNIPROT "up-regulates activity" phosphorylation Ser154 VNNQKYMsFTSGDKS -1 11278486 t miannu "Both in vivo and in vitro analyses demonstrate that, although most phosphorylation events in the PAK N-terminal regulatory domain play no direct role in activation, a phosphorylation of alphaPAK serine 144 or betaPAK serine 139, which lie in the kinase inhibitory domain, significantly contribute to activation. " SIGNOR-250245 PAK3 protein O75914 UNIPROT SYN1 protein P17600 UNIPROT "up-regulates activity" phosphorylation Ser605 AGPTRQAsQAGPVPR 10116 BTO:0001009 12237306 t miannu "Synapsin I is phosphorylated at Ser603 by p21-activated kinases. the Ser603 residue must be one of the pivotal sites for the release" SIGNOR-250246 PAK3 protein O75914 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates phosphorylation Ser150 TLRRVRIsADAMMQA 9606 BTO:0000887 15769444 t lperfetto "In vitro addition of pak3 to skinned rat cardiac fibres increased myofilament ca2+ sensitivity with no change in maximal ca2+-activated force [67]. These effects were associated with pak3-induced phosphorylation of myofilament proteins, including ctni which was phosphorylated at a novel site, ser149, located in the region forming a ca2+-sensitive interaction with the n-terminal regulatory domain of tnc." SIGNOR-134593 PAK3 protein O75914 UNIPROT TNNI3 protein P19429 UNIPROT unknown phosphorylation Ser150 TLRRVRIsADAMMQA 9606 BTO:0000887 12242269 t llicata "Importantly, cardiac troponin i was found to be phosphorylated at serine 149 of human cardiac troponin i, representing a novel phosphorylation site. These findings suggest a novel mechanism of modulating the calcium sensitivity of cardiac muscle contraction." SIGNOR-92990 PAK3 protein O75914 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser714 EGVRNIKsMWEKGNV 9606 BTO:0000887;BTO:0001260 20858431 t gcesareni "We investigated the effects of phosphorylation by p(21)-activated kinase 3 (pak) and calmodulin on the 22 kda c-terminal fragment of caldesmon (cad22). We substituted the major pak sites, ser-672 and ser-702, with either alanine or aspartic acid to mimic nonphosphorylated and constitutively phosphorylated states of caldesmon, respectively. Phosphorylation at these sites weakened ca(2+)-calmodulin binding further and reduced the inhibitory activity of cad22 in the absence of ca(2+)-calmodulin." SIGNOR-167976 PAK3 protein O75914 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser744 GLKVGVSsRINEWLT 9606 BTO:0000887;BTO:0001260 20858431 t gcesareni "We investigated the effects of phosphorylation by p(21)-activated kinase 3 (pak) and calmodulin on the 22 kda c-terminal fragment of caldesmon (cad22). We substituted the major pak sites, ser-672 and ser-702, with either alanine or aspartic acid to mimic nonphosphorylated and constitutively phosphorylated states of caldesmon, respectively. Phosphorylation at these sites weakened ca(2+)-calmodulin binding further and reduced the inhibitory activity of cad22 in the absence of ca(2+)-calmodulin." SIGNOR-167980 PAK3 protein O75914 UNIPROT MYO6 protein Q9UM54 UNIPROT "up-regulates activity" phosphorylation Thr405 TAGGTKGtVIKVPLK -1 11517222 t miannu "P21-activated kinase 3 phosphorylated myosin VI, and the site was identified as Thr(406). The phosphorylation of myosin VI significantly facilitated the actin-translocating activity of myosin VI. " SIGNOR-250244 PIAS1 protein O75925 UNIPROT RPA2 protein P15927 UNIPROT up-regulates sumoylation 9606 20016603 t gcesareni "Pias1 and pias4 promote brca1 accumulation and sumoylation, rpa phosphorylation, and dsb repair" SIGNOR-162153 PIAS1 protein O75925 UNIPROT DDX5 protein P17844 UNIPROT down-regulates sumoylation Lys53 WNLDELPkFEKNFYQ 9606 17369852 t miannu "We demonstrate that the sumo e3 ligase pias1 interacts with p68 and enhances its sumo modification in vivo / sumo modification enhances p68 transcriptional repression activity and inhibits the ability of p68 to function as a coactivator of p53." SIGNOR-153723 PIAS1 protein O75925 UNIPROT DDX5 protein P17844 UNIPROT up-regulates sumoylation Lys53 WNLDELPkFEKNFYQ 9606 17369852 t miannu "We demonstrate that the sumo e3 ligase pias1 interacts with p68 and enhances its sumo modification in vivo / sumo modification enhances p68 transcriptional repression activity and inhibits the ability of p68 to function as a coactivator of p53." SIGNOR-153719 PIAS1 protein O75925 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" sumoylation Lys276 NVVYRDLkLENLMLD 10090 BTO:0002572 23884910 t gcesareni "Although multiple sites on Akt could be SUMOylated, K276 was identified as a major SUMO acceptor site. K276R or E278A mutation reduced SUMOylation of Akt but had little effect on its ubiquitination. Strikingly, these mutations also completely abolished Akt kinase activity. In support of these results, we found that expression of PIAS1 and SUMO1 increased Akt activity, whereas expression of SENP1 reduced Akt1 activity." SIGNOR-252735 PIAS1 protein O75925 UNIPROT STAT1 protein P42224 UNIPROT down-regulates binding 9606 14699505 t gcesareni "Pias1 inhibits binding of stat1 dimers to the response elements in the promoters of target genes" SIGNOR-120548 PIAS1 protein O75925 UNIPROT STAT1 protein P42224 UNIPROT down-regulates binding 9606 BTO:0000887;BTO:0001103 23663276 t 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-202039 PIAS1 protein O75925 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates sumoylation 9606 20016603 t gcesareni "Pias1 and pias4 are recruited to dna-damage sites and mediate 53bp1 recruitment and sumoylation." SIGNOR-162156 PIAS1 protein O75925 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates sumoylation 9606 15028714 t lperfetto "These data demonstrate that pias1 protein positively modulates tgf-beta responses as a sumo e3 ligase for smad4" SIGNOR-123462 PIAS1 protein O75925 UNIPROT FHL1 protein Q13642 UNIPROT down-regulates sumoylation Lys144 GTGSFFPkGEDFYCV 9606 17509614 t gcesareni "Pias1 (the protein inhibitor of activated stat1) interacts with kyot2 directly and attenuates kyot2-mediated transcriptional repression. We demonstrate that kyot2 is modified by sumoylation at two lysine residues, k144 and k171. Sumoylation of the transfected kyot2 is enhanced by pias1" SIGNOR-154801 PIAS1 protein O75925 UNIPROT FHL1 protein Q13642 UNIPROT down-regulates sumoylation Lys300 PRGPGLVkAPVWWPM 9606 17509614 t gcesareni "Pias1 (the protein inhibitor of activated stat1) interacts with kyot2 directly and attenuates kyot2-mediated transcriptional repression. We demonstrate that kyot2 is modified by sumoylation at two lysine residues, k144 and k171. Sumoylation of the transfected kyot2 is enhanced by pias1" SIGNOR-154805 PIAS1 protein O75925 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" sumoylation Lys276 NVVYRDLkLENLMLD 10090 BTO:0002572 23884910 t gcesareni "Although multiple sites on Akt could be SUMOylated, K276 was identified as a major SUMO acceptor site. K276R or E278A mutation reduced SUMOylation of Akt but had little effect on its ubiquitination. Strikingly, these mutations also completely abolished Akt kinase activity. In support of these results, we found that expression of PIAS1 and SUMO1 increased Akt activity, whereas expression of SENP1 reduced Akt1 activity." SIGNOR-252737 TRIO protein O75962 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260579 WFS1 protein O76024 UNIPROT ATP1B1 protein P05026 UNIPROT "up-regulates quantity" binding 9534 BTO:0000298 17947299 t SARA "Sodium-potassium ATPase 1 Subunit Is a Molecular Partner of Wolframin, an Endoplasmic Reticulum Protein Involved in ER Stress|We conclude that the interaction may be important for Na+/K+ ATPase beta1 subunit maturation" SIGNOR-260999 CDKL5 protein O76039 UNIPROT CDKL5 protein O76039 UNIPROT "up-regulates activity" phosphorylation Thr169 EGNNANYtEYVATRW -1 16935860 t gcesareni "Furthermore, we show that CDKL5 can self-associate and mediate the phosphorylation of its own TEY (Thr-Glu-Tyr) motif." SIGNOR-262289 CDKL5 protein O76039 UNIPROT CDKL5 protein O76039 UNIPROT "up-regulates activity" phosphorylation Tyr171 NNANYTEyVATRWYR -1 16935860 t miannu "Furthermore, we show that CDKL5 can self-associate and mediate the phosphorylation of its own TEY (Thr-Glu-Tyr) motif." SIGNOR-245876 CDKL5 protein O76039 UNIPROT AMPH protein P49418 UNIPROT "down-regulates activity" phosphorylation Ser293 PAPARPRsPSQTRKG 10090 23651931 t gcesareni "This 120-kDa protein was identified as amphiphysin 1 (Amph1) by LC-MS/MS analysis, and the site of phosphorylation by CDKL5 was determined to be Ser-293.| The phosphorylation mimic mutants, Amph1(S293E) and Amph1(S293D), showed significantly reduced affinity for endophilin, a protein involved in synaptic vesicle endocytosis" SIGNOR-245881 CDKL5 protein O76039 UNIPROT MECP2 protein P51608 UNIPROT unknown phosphorylation -1 16935860 t Luana "Phosphorylation assays performed with the wild-type protein confirm its capability to mediate the modification of MeCP2 in vitro, whereas Rett missense mutations within the conserved catalytic domain abrogate or significantly impair the enzymatic activity" SIGNOR-264702 CDKL5 protein O76039 UNIPROT LRRC4C protein Q9HCJ2 UNIPROT unknown phosphorylation Ser631 PLLIRMNsKDNVQET 9606 22922712 t llicata "Cdkl5 binds and phosphorylates the cell adhesion molecule ngl-1. This phosphorylation event ensures a stable association between ngl-1 and psd95." SIGNOR-192035 STC2 protein O76061 UNIPROT STAT3 protein P40763 UNIPROT up-regulates 10090 BTO:0000298 29207625 f lperfetto "STC2 activates STAT3 signaling pathway in the hypothalamus and GT1-7 cells" SIGNOR-260406 RNF8 protein O76064 UNIPROT L3MBTL2 protein Q969R5 UNIPROT "up-regulates activity" ubiquitination 9606 31225475 t miannu "L3MBTL2 links RNF8 and RNF168 in the DNA double strand break response. The protein kinase ATM phosphorylates L3MBTL2, which recruits it to the DNA lesion by promoting the interaction between MDC1 and L3MBTL2. L3MBTL2 is subsequently ubiquitinated by RNF8, which acts as a docking site for RNF168, thereby recruiting the ubiquitin ligase to the damage site. RNF168, in turn, ubiquitinates H2A-type histones to amplify the DNA damage response and recruit downstream DNA repair proteins for proper DSB signaling." SIGNOR-266787 RNF8 protein O76064 UNIPROT RAD18 protein Q9NS91 UNIPROT up-regulates binding 9606 19396164 t gcesareni "Rnf8 depletion also significantly reduced the accumulation of rad18 to chromatin fraction after ir" SIGNOR-185593 FGF18 protein O76093 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates binding 9606 8663044 t tpavlidou "Fgfs bind and activate high-affinity receptor tyrosine kinases. The cloning of fgf receptors (fgfrs) has identified four distinct genes" SIGNOR-42368 SRP72 protein O76094 UNIPROT SRP68 protein Q9UHB9 UNIPROT "up-regulates activity" binding -1 30649417 t miannu "Taken together our data show that binding of the SRP68/72 heterodimer follows an ultrasensitive response dependent on the SRP72 C-terminus. Although the large solenoids of SRP68/72 have not been structurally characterized due to intrinsic flexibility, they serve as important contact sites in ribosome interaction." SIGNOR-261164 MTA2 protein O94776 UNIPROT FSHR protein P23945 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001238 23086931 f miannu "Chromatin modifier MTA2 participates in the down-regulation of FSHR transcription. MTA2 is a potent corepressor of FSHR transcription, because it can recruit histone deacetylase-1 onto the FSHR promoter and participates in the down-regulation of FSHR expression upon FSH treatment." SIGNOR-254226 PCF11 protein O94913 UNIPROT "CFII complex" complex SIGNOR-C387 SIGNOR "form complex" binding 9606 BTO:0000567 30139799 t lperfetto "Cleavage factor II (CF II) is a poorly characterized component of the multiprotein complex catalyzing 3' cleavage and polyadenylation of mammalian mRNA precursors. We have reconstituted CF II as a heterodimer of hPcf11 and hClp1." SIGNOR-266119 MTA2 protein O94776 UNIPROT "MBD2/NuRD complex" complex SIGNOR-C337 SIGNOR "form complex" binding 9606 27098840 t miannu "The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression." SIGNOR-263841 MTA2 protein O94776 UNIPROT "MBD3/NuRD complex" complex SIGNOR-C338 SIGNOR "form complex" binding 9606 27098840 t miannu "The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression." SIGNOR-263853 DPM2 protein O94777 UNIPROT "DPM complex" complex SIGNOR-C289 SIGNOR "form complex" binding 9606 10835346 t lperfetto "Human dolichol-phosphate-mannose synthase consists of three subunits, DPM1, DPM2 and DPM3." SIGNOR-262564 USP1 protein O94782 UNIPROT FANCI protein Q9NVI1 UNIPROT "down-regulates activity" deubiquitination SIGNOR-C302 18985065 t lperfetto "Phosphorylation of FANCI may also turn the ubiquitinated ID complex into a poor substrate for deubiquitination by the USP1–UAF1 complex, resulting in increased levels of monoubiquitinated FANCD2." SIGNOR-263272 ALDH1A2 protein O94788 UNIPROT retinal smallmolecule CHEBI:15035 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 21621639 t lperfetto "All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step." SIGNOR-265125 ALDH1A2 protein O94788 UNIPROT "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 21621639 t lperfetto "All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step." SIGNOR-265126 STK10 protein O94804 UNIPROT MSN protein P26038 UNIPROT "up-regulates activity" phosphorylation Thr558 LGRDKYKtLRQIRQG 9606 19255442 t llicata "Evidence in jurkat cells that lok phosphorylates erm and that erm phosphorylation impedes migration." SIGNOR-184433 PRKD3 protein O94806 UNIPROT GIT1 protein Q9Y2X7 UNIPROT unknown phosphorylation Ser46 RSLGRHIsIVKHLRH 9606 22893698 t lperfetto "We propose that phosphorylation of git1 on serine 46 by pkd3 represents a molecular switch by which git1 localization, paxillin trafficking, and cellular protrusive activity are regulated." SIGNOR-191839 SLIT2 protein O94813 UNIPROT GPC1 protein P35052 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 10364234 t gcesareni "Slit family proteins are functional ligands of glypican-1 in nervous tissue and suggest that their interactions may be critical for certain stages of central nervous system histogenesis." SIGNOR-68428 SLIT2 protein O94813 UNIPROT ROBO4 protein Q8WZ75 UNIPROT up-regulates binding 9606 BTO:0000938 12941633 t gcesareni "We show that robo4 binds slit and inhibits cellular migration in a heterologous expression system, analogous to the role of known robo receptors in the nervous system." SIGNOR-86380 ATG12 protein O94817 UNIPROT ATG12/5/16L1 complex SIGNOR-C109 SIGNOR "form complex" binding 9606 BTO:0000007 18321988 t lperfetto "Atg12 is conjugated to atg5 and forms an approximately 800-kda protein complex with atg16l (referred to as atg16l complex)." SIGNOR-226689 TOMM70 protein O94826 UNIPROT HSP90AA1 protein P07900 UNIPROT "up-regulates activity" binding 9534 12526792 t miannu "The Tom70 receptor is a membrane-localized cochaperone that integrates the Hsp70/Hsp90 chaperones with mitochondrial preprotein targeting and translocation. In mammals, preprotein in the cytosol is associated with both Hsp90 and Hsp70 in a multichaperone complex, and docking of Hsp90 and/or Hsp70 onto Tom70 is essential for preprotein targeting." SIGNOR-261379 TOMM70 protein O94826 UNIPROT HSPA1A protein P0DMV8 UNIPROT "up-regulates activity" binding 9534 12526792 t miannu "The Tom70 receptor is a membrane-localized cochaperone that integrates the Hsp70/Hsp90 chaperones with mitochondrial preprotein targeting and translocation. In mammals, preprotein in the cytosol is associated with both Hsp90 and Hsp70 in a multichaperone complex, and docking of Hsp90 and/or Hsp70 onto Tom70 is essential for preprotein targeting." SIGNOR-261380 PLEKHG5 protein O94827 UNIPROT RHOA protein P61586 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260566 SEC24D protein O94855 UNIPROT "COPII vesicle" complex SIGNOR-C370 SIGNOR "form complex" binding 9606 BTO:0000567 30605680 t lperfetto "The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat" SIGNOR-265291 TSPOAP1 protein O95153 UNIPROT RIMS3 protein Q9UJD0 UNIPROT "down-regulates activity" binding 10116 BTO:0001009 11988172 t miannu "SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins." SIGNOR-264373 NFASC protein O94856 UNIPROT ANK1 protein P16157 UNIPROT "up-regulates quantity" relocalization 10116 BTO:0000227 7961622 t miannu "Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains." SIGNOR-266718 NFASC protein O94856 UNIPROT ANK2 protein Q01484 UNIPROT "up-regulates quantity" relocalization 10116 BTO:0000227 7961622 t miannu "Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains." SIGNOR-266716 NFASC protein O94856 UNIPROT ANK3 protein Q12955 UNIPROT "up-regulates quantity" relocalization 10116 BTO:0000227 7961622 t miannu "Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains." SIGNOR-266717 UFL1 protein O94874 UNIPROT H4C1 protein P62805 UNIPROT "up-regulates activity" ubiquitination Lys32 DNIQGITkPAIRRLA 9606 BTO:0000007;BTO:0001938 30886146 t lperfetto "Here we report that UFM1 specific ligase 1 (UFL1), an ufmylation E3 ligase, is important for ATM activation." SIGNOR-265072 UFL1 protein O94874 UNIPROT ATM protein Q13315 UNIPROT "up-regulates activity" ubiquitination 9606 BTO:0000007 30886146 t lperfetto "UFM1 specific ligase 1 (UFL1), an ufmylation E3 ligase, is important for ATM activation. UFL1 is recruited to double strand breaks by the MRE11/RAD50/NBS1 complex, and monoufmylates histone H4 following DNA damage." SIGNOR-265073 SUN1 protein O94901 UNIPROT NUP153 protein P49790 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 SIGNOR-C303 SIGNOR-C263 28831067 t lperfetto "The NXF1:NXT1 complex and NUP153 interact with the amino terminus of SUN1 |In analogy to a proposal made by Chang et al.4, Nesprins could help anchoring SUN1 near the NPC to enable it to fulfill its task in mRNA export." SIGNOR-263294 SUN1 protein O94901 UNIPROT MAJIN protein Q3KP22 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 SIGNOR-C303 SIGNOR-C305 33015044 t lperfetto "In this study, we found that SUN1 not only interacted with TERB1 but also interacted with MAJIN, and the interaction of SUN1 with MAJIN is stronger than TERB1. We also found that SUN1 interacted with SPDYA, an activator of CDK2. | It will be of great interest to test this hypothesis to fully understand the mechanisms of stable telomere–NE connection and telomere movement along the NE driven by the LINC complex." SIGNOR-263300 SUN1 protein O94901 UNIPROT SPDYA protein Q5MJ70 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 SIGNOR-C305 33015044 t lperfetto "In this study, we found that SUN1 not only interacted with TERB1 but also interacted with MAJIN, and the interaction of SUN1 with MAJIN is stronger than TERB1. We also found that SUN1 interacted with SPDYA, an activator of CDK2. | Taken together, we speculate that speedy A is likely capable of interacting with both telomeres and the LINC complex and thus might function as the missing linkage between telomeres and the LINC complex during prophase I, stabilizing the telomere–NE connection" SIGNOR-263301 SUN1 protein O94901 UNIPROT TERB1 protein Q8NA31 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 SIGNOR-C303 SIGNOR-C305 33015044 t lperfetto "In this study, we found that SUN1 not only interacted with TERB1 but also interacted with MAJIN, and the interaction of SUN1 with MAJIN is stronger than TERB1. We also found that SUN1 interacted with SPDYA, an activator of CDK2. | It will be of great interest to test this hypothesis to fully understand the mechanisms of stable telomere–NE connection and telomere movement along the NE driven by the LINC complex." SIGNOR-263299 SUN1 protein O94901 UNIPROT NXF1 protein Q9UBU9 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 SIGNOR-C303 28831067 t lperfetto "SUN1, a component of the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex, functions in mammalian mRNA export through the NXF1-dependent pathway. It associates with mRNP complexes by direct interaction with NXF1." SIGNOR-263296 SUN1 protein O94901 UNIPROT "LINC complex" complex SIGNOR-C303 SIGNOR "form complex" binding 24481844 t lperfetto "LINC complex couples the nuclear lamina to the cytoskeleton. SUN domain proteins, SUN1 and SUN2, located at the inner nuclear membrane (INM) interact with the nuclear lamins, Lamin A/C, B1, and B2, that line the nucleoplasmic face of the INM. SUN domain proteins interact with Nesprins in the perinuclear space (PNS). Nesprins protrude from the outer nuclear membrane (ONM) and interact with the cytoskeleton, often through an intermediate binding partner. Nesprin 1 giant (g) and Nesprin 2g potentially link the NE directly to the Z-disc (Z), whereas Nesprin 1alpha and 2alpha may connect via an unknown intermediate protein. In addition, the shorter isoforms of Nesprin 1 and Nesprin 2 may localize to the INM." SIGNOR-263282 DKK1 protein O94907 UNIPROT LRP6 protein O75581 UNIPROT down-regulates binding 9606 11448771 t gcesareni "We report that dkk-1 is a high-affinity ligand for lrp6 and inhibits wnt signaling by preventing fz-lrp6 complex formation induced by wnt. Dkk1 has been shown to inhibit wnt by binding to and antagonizing lrp5/6." SIGNOR-109247 DKK1 protein O94907 UNIPROT WNT3A protein P56704 UNIPROT down-regulates 9606 19874086 f "Antagonizes canonical Wnt signaling by inhibiting LRP5/6 interaction with Wnt and by forming a ternary complex with the transmembrane protein KREMEN that promotes internalization of LRP5/6." gcesareni "It has been shown that both sclerostin and dkk1 act physiologically as downstream molecules of bmp signaling to inhibit canonical wnt signaling and therefore negatively regulate bone mass." SIGNOR-188961 DKK1 protein O94907 UNIPROT KREMEN2 protein Q8NCW0 UNIPROT up-regulates binding 9606 12050670 t gcesareni "Dkk1 has been shown to inhibitwnt by binding to and antagonizing lrp5/6. Here we show that the transmembrane proteins kremen1 and kremen2 are high-affinity dkk1 receptors that functionally cooperate with dkk1 to blockwnt/beta-catenin . Kremen2 forms a ternary complex with dkk1 and lrp6, and induces rapid endocytosis and removal of thewntreceptor lrp6 from the plasma membranekremen2 forms a ternary complex with dkk1 and lrp6, and induces rapid endocytosis and removal of the wnt receptor lrp6 from the plasma membrane" SIGNOR-88882 DKK1 protein O94907 UNIPROT KREMEN1 protein Q96MU8 UNIPROT up-regulates binding 9606 12050670 t gcesareni "Dkk1 has been shown to inhibitwnt by binding to and antagonizing lrp5/6. Here we show that the transmembrane proteins kremen1 and kremen2 are high-affinity dkk1 receptors that functionally cooperate with dkk1 to blockwnt/betBeta-catenin. Kremen2 forms a ternary complex with dkk1 and lrp6, and induces rapid endocytosis and removal of thewntreceptor lrp6 from the plasma membrane." SIGNOR-88838 CDK14 protein O94921 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation Ser1490 AILNPPPsPATERSH 9606 20059949 t gcesareni "Low-density lipoprotein receptor related proteins 5 and 6 (lrp5/6) are transmembrane receptors that initiate wnt/beta-catenin signaling. Phosphorylation of pppsp motifs in the lrp6 cytoplasmic domain is crucial for signal transduction. Using a kinome-wide rnai screen, we show that pppsp phosphorylation requires the drosophila cyclin-dependent kinase (cdk) l63. L63 and its vertebrate homolog pftk are regulated by the membrane tethered g2/m cyclin, cyclin y, which mediates binding to and phosphorylation of lrp6." SIGNOR-162924 CDK14 protein O94921 UNIPROT TAGLN2 protein P37802 UNIPROT "down-regulates activity" phosphorylation Ser163 KENPRNFsDNQLQEG 21577206 t lperfetto "This newly identified oncogene–tumor suppressor cascade, where oncogenic PFTK1 inactivates a tumor suppressor gene TAGLN2 via phosphorylation|. Our data therefore underline much importance for S83 and S163 residues on TAGLN2 in its actin-binding capacity." SIGNOR-265105 CDK14 protein O94921 UNIPROT TAGLN2 protein P37802 UNIPROT "down-regulates activity" phosphorylation Ser83 PVKKIQAsTMAFKQM 21577206 t lperfetto "This newly identified oncogene–tumor suppressor cascade, where oncogenic PFTK1 inactivates a tumor suppressor gene TAGLN2 via phosphorylation|. Our data therefore underline much importance for S83 and S163 residues on TAGLN2 in its actin-binding capacity." SIGNOR-265103 GLS protein O94925 UNIPROT "glutamic acid" smallmolecule CHEBI:18237 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 22049910 t "Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia." SIGNOR-266910 GLS protein O94925 UNIPROT "glutamic acid" smallmolecule CHEBI:18237 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 22049910 t "Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia." SIGNOR-260001 HAUS5 protein O94927 UNIPROT "HAUS complex" complex SIGNOR-C281 SIGNOR "form complex" binding 9606 BTO:0000567 19369198 t lperfetto "Here, by using mass spectrometry, we identified the full human augmin complex of 8 subunits and show that it interacts with the gamma-tubulin ring complex (gamma-TuRC)" SIGNOR-262317 KDM4B protein O94953 UNIPROT AR protein P10275 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 23435229 f miannu "KDM4B enzymatic activity is required to enhance AR transcriptional activity" SIGNOR-254541 KDM4B protein O94953 UNIPROT CDKN1A protein P38936 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001109 28073943 f miannu "JMJD2B induction attenuates the transcription of key p53 transcriptional targets including p21, PIG3 and PUMA, and this modulation is dependent on the catalytic capacity of JMJD2B." SIGNOR-263730 KDM4B protein O94953 UNIPROT H3C1 protein P68431 UNIPROT "down-regulates activity" demethylation Lys10 RTKQTARkSTGGKAP 9606 30759871 t miannu "The KDM4 family of Jumonj domain histone demethylases specifically target di- and tri-methylated lysine 9 on histone H3 (H3K9me3), removing a modification central to defining heterochromatin and gene repression. The majority of studies regarding its function describe it as an activator that removes repressive H3K9me3 and H3K9me2 at or near regulated promoters in order to facilitate expression of the indicated pathways." SIGNOR-263734 KDM4B protein O94953 UNIPROT TP53I3 protein Q53FA7 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001109 28073943 f miannu "JMJD2B induction attenuates the transcription of key p53 transcriptional targets including p21, PIG3 and PUMA, and this modulation is dependent on the catalytic capacity of JMJD2B." SIGNOR-263731 KDM4B protein O94953 UNIPROT BBC3 protein Q96PG8 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001109 28073943 f miannu "JMJD2B induction attenuates the transcription of key p53 transcriptional targets including p21, PIG3 and PUMA, and this modulation is dependent on the catalytic capacity of JMJD2B." SIGNOR-263733 AP2A2 protein O94973 UNIPROT "AP-2 complex" complex SIGNOR-C245 SIGNOR "form complex" binding 31671891 t lperfetto "The most important endocytic adaptor is the heterotetrameric AP-2 complex made up of the large alpha- and beta2-adaptin subunits, the medium-sized mu2-subunit and a small sigma2-subunit" SIGNOR-260423 SEC31A protein O94979 UNIPROT "COPII vesicle" complex SIGNOR-C370 SIGNOR "form complex" binding 9606 BTO:0000567 30605680 t lperfetto "The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat" SIGNOR-265292 FAM13A protein O94988 UNIPROT RAC1 protein P63000 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260502 ARHGEF15 protein O94989 UNIPROT CDC42 protein P60953 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260541 ARHGEF15 protein O94989 UNIPROT RHOA protein P61586 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260540 UBR5 protein O95071 UNIPROT RNF168 protein Q8IYW5 UNIPROT "down-regulates quantity" ubiquitination 9606 BTO:0001938 22884692 t miannu "Here, we show that TRIP12 and UBR5, two HECT domain ubiquitin E3 ligases, control accumulation of RNF168, a rate-limiting component of a pathway that ubiquitylates histones after DNA breakage. We find that RNF168 can be saturated by increasing amounts of DSBs. Depletion of TRIP12 and UBR5 allows accumulation of RNF168 to supraphysiological levels, followed by massive spreading of ubiquitin conjugates and hyperaccumulation of ubiquitin-regulated genome caretakers such as 53BP1 and BRCA1." SIGNOR-266782 PAK4 protein O96013 UNIPROT PXN protein P49023 UNIPROT unknown phosphorylation Ser272 ELDELMAsLSDFKIQ 9606 BTO:0001130 20406887 t llicata "We find that pak4 is localised at focal adhesions, is immunoprecipitated with paxillin and phosphorylates paxillin on serine 272." SIGNOR-164889 ZNF202 protein O95125 UNIPROT POMGNT1 protein Q8WZA1 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 22419172 f miannu "Here, we describe the first dystroglycanopathy patient carrying an alteration in the promoter region of the POMGNT1 gene (protein O-mannose β-1,2-N-acetylglucosaminyltransferase 1), which involves a homozygous 9-bp duplication (-83_-75dup). Analysis of the downstream effects of this mutation revealed a decrease in the expression of POMGNT1 mRNA and protein because of negative regulation of the POMGNT1 promoter by the transcription factor ZNF202 (zinc-finger protein 202)." SIGNOR-255626 S1PR2 protein O95136 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257289 S1PR2 protein O95136 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256871 S1PR2 protein O95136 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257123 S1PR2 protein O95136 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257215 S1PR2 protein O95136 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256728 S1PR2 protein O95136 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257349 S1PR2 protein O95136 UNIPROT GNA13 protein Q14344 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257401 NDUFB6 protein O95139 UNIPROT "Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and |The main ND4-module intermediate binds NDUFB1, NDUFB4, NDUFB5, NDUFB6, NDUFB10, NDUFB11 and MT-ND4" SIGNOR-262169 TNFSF15 protein O95150 UNIPROT TNFRSF25 protein Q93038 UNIPROT up-regulates binding 9606 14585074 t amattioni "The ligand of dr3 is tl1a" SIGNOR-103078 TSPOAP1 protein O95153 UNIPROT RIMS1 protein Q86UR5 UNIPROT "down-regulates activity" binding 10116 BTO:0001009 11988172 t miannu "SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins." SIGNOR-264363 NTRK1 protein P04629 UNIPROT NTRK1 protein P04629 UNIPROT up-regulates phosphorylation Tyr676 FGMSRDIySTDYYRV 9606 9099755 t gcesareni "In vitro studies indicate that trka autophosphorylates at tyrosines 490, 670, 674, 675, and 785" SIGNOR-47171 TSPOAP1 protein O95153 UNIPROT RIMS2 protein Q9UQ26 UNIPROT "down-regulates activity" binding 10116 BTO:0001009 11988172 t miannu "SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins." SIGNOR-264368 ELP1 protein O95163 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates 9606 12058026 f gcesareni "Ikap efficiently and specifically enhanced jnk activation induced by ectopic expression of mekk1 and ask1, upstream activators of jnk" SIGNOR-89334 GABARAP protein O95166 UNIPROT GPHN protein Q9NQX3 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 25882190 t miannu "The GABA(A)R-associated protein GABARAP was found to bind to the gamma2 subunit of GABA(A)Rs. Here we show that GABARAP interacts with gephyrin in both biochemical assays and transfected cells. Our data indicate that GABARAP-gephyrin interactions are not important for postsynaptic GABA(A)R anchoring but may be implicated in receptor sorting and/or targeting mechanisms." SIGNOR-264971 GABARAP protein O95166 UNIPROT GABA-A proteinfamily SIGNOR-PF61 SIGNOR "up-regulates activity" binding 9606 BTO:0000938 25882190 t miannu "GABARAP was originally isolated as a binding partner of the GABAA receptor γ2-subunit in a yeast two-hybrid screen, and was suggested to have a role in the targeting and clustering of GABAA receptors." SIGNOR-264972 NDUFA3 protein O95167 UNIPROT "Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND1-module builds around the Q-module with the help of TIMMDC1/C3ORF1 [47,48], which remains bound to the Q/ND1 subassembly until the last maturation steps. MT-ND1 joins first and then NDUFA3, NDUFA8 and NDUFA13 are added" SIGNOR-262155 NDUFB4 protein O95168 UNIPROT "Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and |The main ND4-module intermediate binds NDUFB1, NDUFB4, NDUFB5, NDUFB6, NDUFB10, NDUFB11 and MT-ND4" SIGNOR-262167 NDUFB8 protein O95169 UNIPROT "Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND5-module corresponds to the distal part of the membrane arm and it is composed of MT-ND5, NDUFB2, NDUFB3, NDUFB7, NDUFB8, NDUFB9 and NDUFAB1" SIGNOR-262171 NDUFB2 protein O95178 UNIPROT "Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND5-module corresponds to the distal part of the membrane arm and it is composed of MT-ND5, NDUFB2, NDUFB3, NDUFB7, NDUFB8, NDUFB9 and NDUFAB1" SIGNOR-262165 NDUFA7 protein O95182 UNIPROT "Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24]." SIGNOR-262158 LETM1 protein O95202 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI "up-regulates quantity" relocalization 10090 BTO:0000938 29123128 t lperfetto "Others have suggested that LETM1 plays an essential role in mitochondrial K+ homeostasis by mediating the mitochondrial K+/H+ exchange" SIGNOR-262542 LETM1 protein O95202 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 10090 BTO:0000938 29123128 t lperfetto "LETM1 is a mitochondrial inner membrane protein and several reports suggest that it mediates mitochondrial Ca2+ uptake and extrusion in a gradient-dependent manner" SIGNOR-262541 LETM1 protein O95202 UNIPROT "Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR up-regulates 9606 BTO:0000567 18628306 f lperfetto "LETM1 knockdown obviously reduced the formation of the supercomplexes (Fig. 5C, arrowhead). Complexes I and IV failed to form, and the assembly of complex III was significantly decreased. By contrast, the assembly of complex II (succinate dehydrogenase) and complex V (ATP synthase) – which are not proton pumps – was unaffected." SIGNOR-262547 LETM1 protein O95202 UNIPROT "Mitochondrial respiratory chain complex III" complex SIGNOR-C279 SIGNOR up-regulates 9606 BTO:0000567 18628306 f lperfetto "LETM1 knockdown obviously reduced the formation of the supercomplexes (Fig. 5C, arrowhead). Complexes I and IV failed to form, and the assembly of complex III was significantly decreased. By contrast, the assembly of complex II (succinate dehydrogenase) and complex V (ATP synthase) – which are not proton pumps – was unaffected." SIGNOR-262546 LETM1 protein O95202 UNIPROT "Mitochondrial respiratory chain complex IV" complex SIGNOR-C280 SIGNOR up-regulates 9606 BTO:0000567 18628306 f lperfetto "LETM1 knockdown obviously reduced the formation of the supercomplexes (Fig. 5C, arrowhead). Complexes I and IV failed to form, and the assembly of complex III was significantly decreased. By contrast, the assembly of complex II (succinate dehydrogenase) and complex V (ATP synthase) – which are not proton pumps – was unaffected." SIGNOR-262548 ZWINT protein O95229 UNIPROT "RZZ complex" complex SIGNOR-C357 SIGNOR "form complex" binding 9606 BTO:0000567 20462495 t lperfetto "The RZZ complex recruits dynein to kinetochores. We investigated structure, topology, and interactions of the RZZ subunits (ROD, ZWILCH, and ZW10) in vitro, in vivo, and in silico." SIGNOR-265013 LRAT protein O95237 UNIPROT retinol smallmolecule CHEBI:50211 ChEBI "down-regulates quantity" "small molecule catalysis" 10090 18093970 t lperfetto "We investigated the role of retinyl ester formation catalyzed by lecithin:retinol acyltransferase (LRAT) in regulating retinoid homeostasis during embryogenesis" SIGNOR-265110 LRAT protein O95237 UNIPROT "all-trans-retinyl ester" smallmolecule CHEBI:63410 ChEBI "up-regulates quantity" "small molecule catalysis" 10090 18093970 t lperfetto "We investigated the role of retinyl ester formation catalyzed by lecithin:retinol acyltransferase (LRAT) in regulating retinoid homeostasis during embryogenesis" SIGNOR-265111 SPDEF protein O95238 UNIPROT MMP9 protein P14780 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0003160 22761428 f miannu "Transcriptional analysis of several genes associated with tumor metastasis, invasion, and the epithelial-mesenchymal transition demonstrated that SPDEF expression selectively down-regulated MMP9 and MMP13 in prostate cancer cells." SIGNOR-255218 SPDEF protein O95238 UNIPROT MMP13 protein P45452 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0003160 22761428 f miannu "Transcriptional analysis of several genes associated with tumor metastasis, invasion, and the epithelial-mesenchymal transition demonstrated that SPDEF expression selectively down-regulated MMP9 and MMP13 in prostate cancer cells." SIGNOR-255219 CHEK2 protein O96017 UNIPROT CHEK2 protein O96017 UNIPROT "up-regulates activity" phosphorylation Ser379 SKILGETsLMRTLCG 9606 BTO:0000007 18644861 t lperfetto "Regulation of chk2 ubiquitination and signaling through autophosphorylation of serine 379.Thus, auto-/transphosphorylation of s379 is required for chk2 ubiquitination and effector function" SIGNOR-179537 ATE1 protein O95260 UNIPROT HSPA5 protein P11021 UNIPROT "down-regulates quantity by destabilization" "post transcriptional regulation" 9606 BTO:0000567 29295953 t miannu "We showed that the molecular chaperone BiP (also known as GRP78) was short-lived under basal conditions and ER stress. The turnover of BiP was in part driven by its amino-terminal arginylation (Nt-arginylation) by the arginyltransferase ATE1, which generated an autophagic N-degron of the N-end rule pathway." SIGNOR-261345 TNKS protein O95271 UNIPROT AXIN1 protein O15169 UNIPROT "down-regulates quantity by destabilization" ADP-ribosylation 9606 BTO:0000007 19759537 t lperfetto "Together, these findings are consistent with the hypothesis that TNKS promotes the ubiquitination and degradation of axin, which may be mediated, at least in part, through the direct PARsylation of axin." SIGNOR-263379 TNKS protein O95271 UNIPROT AXIN1 protein O15169 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 19759537 t lperfetto "Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway." SIGNOR-187972 TNKS protein O95271 UNIPROT CASC3 protein O15234 UNIPROT "down-regulates quantity by destabilization" ADP-ribosylation 9606 BTO:0000007 21478859 t lperfetto "Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation." SIGNOR-263383 TNKS protein O95271 UNIPROT TERF1 protein P54274 UNIPROT "down-regulates activity" ADP-ribosylation -1 11739745 t lperfetto "Tankyrase 1 ADP-ribosylates TRF1, inhibiting its binding to telomeric DNA." SIGNOR-263377 TNKS protein O95271 UNIPROT TARDBP protein Q13148 UNIPROT "up-regulates quantity by stabilization" binding 10116 BTO:0000142 32409565 t lperfetto "Upon investigating the functional effect, we find that interaction with Tnks-1/2 inhibits the ubiquitination and proteasomal turnover of TDP-43, leading to its stabilization. We further show that proteasomal turnover of TDP-43 occurs preferentially in the nucleus; our data indicate that Tnks-1/2 stabilizes TDP-43 by promoting cytoplasmic accumulation, which sequesters the protein from nuclear proteasome degradation." SIGNOR-262115 TNKS protein O95271 UNIPROT PSMF1 protein Q92530 UNIPROT "down-regulates quantity by destabilization" ADP-ribosylation 9606 BTO:0000007 23622245 t lperfetto "We identify the ADP-ribosyltransferase tankyrase (TNKS) and the 19S assembly chaperones dp27 and dS5b as direct binding partners of the proteasome regulator PI31. TNKS-mediated ADP-ribosylation of PI31 drastically reduces its affinity for 20S proteasome alpha subunits to relieve 20S repression by PI31." SIGNOR-263387 TNKS protein O95271 UNIPROT BLZF1 protein Q9H2G9 UNIPROT "down-regulates quantity by destabilization" ADP-ribosylation 9606 BTO:0000007 21478859 t lperfetto "Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation." SIGNOR-263385 TNKS protein O95271 UNIPROT RNF146 protein Q9NTX7 UNIPROT "up-regulates activity" 9606 BTO:0000007 21478859 f lperfetto "Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation." SIGNOR-263338 TNKS protein O95271 UNIPROT AXIN2 protein Q9Y2T1 UNIPROT "down-regulates quantity by destabilization" ADP-ribosylation 9606 BTO:0000007 19759537 t lperfetto "Together, these findings are consistent with the hypothesis that TNKS promotes the ubiquitination and degradation of axin, which may be mediated, at least in part, through the direct PARsylation of axin." SIGNOR-263381 TNKS protein O95271 UNIPROT AXIN2 protein Q9Y2T1 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 19759537 t lperfetto "Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway." SIGNOR-187975 TNKS protein O95271 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "down-regulates quantity by destabilization" 9606 BTO:0000007 19759537 t "Using a quantitative chemical proteomic approach, we discovered that XAV939 stabilizes axin by inhibiting the poly-ADP-ribosylating enzymes tankyrase 1 and tankyrase 2. Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway." SIGNOR-261249 EPM2A protein O95278 UNIPROT GSK3B protein P49841 UNIPROT unknown dephosphorylation Ser9 SGRPRTTsFAESCKP 10090 16959610 t "Epm2a-encoded laforin is a phosphatase for GSK-3beta and an important repressor in the Wnt signaling pathway| only GSK-3β phosphorylation on Ser9 was affected by overexpression of laforin|Although GSK-3β is inactivated by phosphorylation at the Ser9 position, it is unclear if the inactivated enzyme can be reactivated by dephosphorylation." SIGNOR-248345 VAPB protein O95292 UNIPROT "VAPB-PTPIP51 complex" complex SIGNOR-C275 SIGNOR "form complex" binding 10116 BTO:0000142 30841933 t lperfetto "Here, we demonstrate that the VAPB-PTPIP51 tethers regulate synaptic activity. VAPB and PTPIP51 localise and form contacts at synapses, and stimulating neuronal activity increases ER-mitochondria contacts and the VAPB-PTPIP51 interaction." SIGNOR-262118 SNAPIN protein O95295 UNIPROT SNAP25 protein P60880 UNIPROT "up-regulates activity" binding 9606 BTO:0000793 18167355 t miannu "In the present study, we used yeast two-hybrid analysis to identify a new binding partner of torsinA, the SNARE-associated protein snapin. We have reported that snapin shows a robust interaction with wild type and mutant torsinA. we have demonstrated that this portion of torsinA and/or the adjacent linker region has the additional role of recruiting snapin. we found that snapin, which binds SNAP-25 (synaptosome-associated protein of 25,000 Da) and enhances the association of the SNARE complex with synaptotagmin, is an interacting partner for both wild type and mutant torsinA." SIGNOR-261171 NDUFC2 protein O95298 UNIPROT "Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND2-module is formed by an initial intermediate that contains MT-ND2, NDUFC1 and NDUFC2 bound to NDUFAF1/CIA30 [49,50], ECSIT [51] and ACAD9 [52,53]. Then, MT-ND3 is added together with TMEM126B [54], forming a larger intermediate to which subunits MT-ND6 and MT-ND4L bind. The latest assembly stages involve the incorporation of subunits NDUFA1, NDUFA10 and NDUFS5 [24,34]." SIGNOR-262174 NDUFA10 protein O95299 UNIPROT "Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND2-module is formed by an initial intermediate that contains MT-ND2, NDUFC1 and NDUFC2 bound to NDUFAF1/CIA30 [49,50], ECSIT [51] and ACAD9 [52,53]. Then, MT-ND3 is added together with TMEM126B [54], forming a larger intermediate to which subunits MT-ND6 and MT-ND4L bind. The latest assembly stages involve the incorporation of subunits NDUFA1, NDUFA10 and NDUFS5 [24,34]." SIGNOR-262151 PGLS protein O95336 UNIPROT 6-phospho-D-gluconate smallmolecule CHEBI:16863 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 31586547 t miannu "The second enzyme in the oxiPPP, 6-phosphogluconolactonase (PGLS), converts 6PGL to 6-phosphogluconate (6PG)." SIGNOR-267058 PGLS protein O95336 UNIPROT 6-O-phosphono-D-glucono-1,5-lactone smallmolecule CHEBI:16938 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 31586547 t miannu "The second enzyme in the oxiPPP, 6-phosphogluconolactonase (PGLS), converts 6PGL to 6-phosphogluconate (6PG)." SIGNOR-267057 SMC2 protein O95347 UNIPROT "Condensin I" complex SIGNOR-C341 SIGNOR "form complex" binding 9606 32445620 t miannu "The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction." SIGNOR-263903 SMC2 protein O95347 UNIPROT "Condensin II" complex SIGNOR-C342 SIGNOR "form complex" binding 9606 32445620 t miannu "The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction." SIGNOR-263908 ATG7 protein O95352 UNIPROT GABARAPL2 protein P60520 UNIPROT "up-regulates activity" binding -1 16303767 t lperfetto "Three human atg8 (hatg8) homologs, lc3, gabarap, and gate-16, have been characterized as modifiers in reactions mediated by hatg7 (an e1-like enzyme) and hatg3 (an e2-like enzyme)." SIGNOR-142002 ATG7 protein O95352 UNIPROT MAP1LC3C protein Q9BXW4 UNIPROT "up-regulates activity" binding 10090 BTO:0002572 22170151 t lperfetto "Lc3-i is activated by the same atg7 involved in atg12 conjugation, transferred to atg3, a second e2-like enzyme, and finally conjugated to pe" SIGNOR-191540 ATG7 protein O95352 UNIPROT MAP1LC3B protein Q9GZQ8 UNIPROT up-regulates binding 9606 22170151 t gcesareni "These results indicated that the fap motif of atg7 is indispensable for formation of the atg3-lc3 e2-substrate intermediate through the interaction of atg7 with atg3." SIGNOR-195239 ATG7 protein O95352 UNIPROT MAP1LC3A protein Q9H492 UNIPROT up-regulates binding 9606 22170151 t gcesareni "Lc3-i is activated by the same atg7 involved in atg12 conjugation, transferred to atg3, a second e2-like enzyme, and finally conjugated to pe" SIGNOR-195236 ZBTB7A protein O95365 UNIPROT CDKN2A protein Q8N726 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15662416 f miannu "Pokemon can specifically repress the transcription of the tumour suppressor gene ARF through direct binding." SIGNOR-225900 LYPLA2 protein O95372 UNIPROT GAP43 protein P17677 UNIPROT "down-regulates quantity by destabilization" deacetylation Cys3 cCMRRTKQ 9606 BTO:0000567 21152083 t miannu "Acyl-protein thioesterase 2 catalyzes the deacylation of peripheral membrane-associated GAP-43. In this work, we investigated the deacylation of growth-associated protein-43 (GAP-43), a dually acylated protein at cysteine residues 3 and 4. Thus, the results demonstrate that APT-2 is the protein thioesterase involved in the acylation/deacylation cycle operating in GAP-43 subcellular distribution.we demonstrated that the reduction in the protein level was abrogated when cells were also treated with proteasome inhibitors (chloroquine, MG132 and lactacystin) which strongly suggest that GAP-43 deacylation is an early and necessary step for its later ubiquitination and degradation by the proteasome. In addition, it also suggests that acyl-protein thioesterase levels not only regulate palmitate turnover but also global protein turnover of GAP-43." SIGNOR-266767 LYPLA2 protein O95372 UNIPROT GAP43 protein P17677 UNIPROT "down-regulates quantity by destabilization" deacetylation Cys4 cMRRTKQV 9606 BTO:0000567 21152083 t miannu "Acyl-protein thioesterase 2 catalyzes the deacylation of peripheral membrane-associated GAP-43. In this work, we investigated the deacylation of growth-associated protein-43 (GAP-43), a dually acylated protein at cysteine residues 3 and 4. Thus, the results demonstrate that APT-2 is the protein thioesterase involved in the acylation/deacylation cycle operating in GAP-43 subcellular distribution.we demonstrated that the reduction in the protein level was abrogated when cells were also treated with proteasome inhibitors (chloroquine, MG132 and lactacystin) which strongly suggest that GAP-43 deacylation is an early and necessary step for its later ubiquitination and degradation by the proteasome. In addition, it also suggests that acyl-protein thioesterase levels not only regulate palmitate turnover but also global protein turnover of GAP-43." SIGNOR-266768 MAP3K6 protein O95382 UNIPROT MAP3K6 protein O95382 UNIPROT "up-regulates activity" phosphorylation Thr806 GITPCTEtFTGTLQY 9606 17210579 t Manara "These results suggested that the induction of ASK2 phosphorylation in the presence of ASK1 is the consequence of autophosphorylation of ASK2. ASK1 thus appears to not only support the effective protein expression but also confer the kinase activity to ASK2." SIGNOR-260774 MAP3K6 protein O95382 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" phosphorylation Thr180 RHTDDEMtGYVATRW 9534 8622669 t Manara "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-260915 MAP3K6 protein O95382 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" phosphorylation Tyr182 RHTDDEMtGYVATRW 9534 8622669 t Manara "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-260916 MAP3K6 protein O95382 UNIPROT MAP3K5 protein Q99683 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr838 GINPCTEtFTGTLQY 9606 17210579 t Manara "ASK2 Activates ASK1 by Phosphorylation" SIGNOR-260832 GDF11 protein O95390 UNIPROT ACTR2 protein P61160 UNIPROT up-regulates binding 9606 16446785 t gcesareni "Here we demonstrate using genetic and biochemical studies that actriib and its subfamily receptor, actriia, cooperatively mediate the gdf11 signal in patterning the axial vertebrae, and that gdf11 binds to both actriia and actriib, and induces phosphorylation of smad2." SIGNOR-144147 GDF11 protein O95390 UNIPROT ACVR2B protein Q13705 UNIPROT up-regulates binding 9606 12414726 t gcesareni "Here we demonstrate using genetic and biochemical studies that actriib and its subfamily receptor, actriia, cooperatively mediate the gdf11 signal in patterning the axial vertebrae, and that gdf11 binds to both actriia and actriib, and induces phosphorylation of smad2" SIGNOR-95309 GDF11 protein O95390 UNIPROT ACVR2B protein Q13705 UNIPROT up-regulates binding 9606 BTO:0000671 16845371 t acerquone "The identity of the receptors that mediate gdf11 signalling during embryogenesis remains unclear. gdf11 could only bind directly to acvr2b but not to any type i receptor" SIGNOR-147940 BMP10 protein O95393 UNIPROT BMPR1A protein P36894 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000562 16049014 t acerquone "We showed that three orphan ligands known to be important for joint and cartilage formation (gdf6) (10), interneuron, sensory neurons, and seminal vesicle formation (gdf7) (11_13), and heart development (bmp10) (14) used the type i receptors alk3 or alk6 and the type ii receptors bmprii or actriia to activate the smad1/5/8 proteins." SIGNOR-139052 BMP10 protein O95393 UNIPROT ACVRL1 protein P37023 UNIPROT up-regulates binding 9606 17068149 t acerquone "Taken together, our results sug- gest that bmp9 and bmp10 are two spe- cific alk1 ligands that may physiologi- cally trigger the effects of alk1 on angiogenesis" SIGNOR-150201 RAPGEF3 protein O95398 UNIPROT RAP1B protein P61224 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9534 BTO:0000298 10777494 t miannu "Epac1 (cAMP-GEFI) and Epac2 (cAMP-GEFII) are closely related guanine nucleotide exchange factors (GEFs) for the small GTPase Rap1, which are directly regulated by cAMP. Here we show that both GEFs efficiently activate Rap2 as well." SIGNOR-263957 RAPGEF3 protein O95398 UNIPROT RAP1A protein P62834 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9534 BTO:0000298 10777494 t miannu "Epac1 (cAMP-GEFI) and Epac2 (cAMP-GEFII) are closely related guanine nucleotide exchange factors (GEFs) for the small GTPase Rap1, which are directly regulated by cAMP. Here we show that both GEFs efficiently activate Rap2 as well." SIGNOR-263956 MED26 protein O95402 UNIPROT "Core mediator complex" complex SIGNOR-C405 SIGNOR "form complex" binding 9606 28467824 t miannu "Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles." SIGNOR-266664 ZFYVE9 protein O95405 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" binding 9606 9865696 t 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-62874 ZFYVE9 protein O95405 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" relocalization 9606 20515759 t 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-59145 ZFYVE9 protein O95405 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" relocalization 9606 9865696 t 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 ZFYVE9 protein O95405 UNIPROT SMAD2 protein Q15796 UNIPROT "up-regulates activity" relocalization 9606 20515759 t 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 TNFRSF6B protein O95407 UNIPROT TNFSF15 protein O95150 UNIPROT down-regulates binding 9606 BTO:0000782 11911831 t amattioni "Tl1a, is a ligand for dr3 and decoy receptor tr6/dcr3. Tr6-fc protein antagonizes nf-kappab activation and apoptosis induced by tl1a" SIGNOR-116256 TNFRSF6B protein O95407 UNIPROT FASLG protein P48023 UNIPROT down-regulates binding 9606 BTO:0001271;BTO:0000661 BTO:0000763 10318773 t amattioni "Tr6 specifically binds fas ligand. Tr6 may play a regulatory role for suppressing in fasl- mediated cell death." SIGNOR-67434 BAG4 protein O95429 UNIPROT TNFRSF1A protein P19438 UNIPROT "down-regulates activity" binding 10090 BTO:0000801 12748303 t gcesareni "It was suggested that the silencer of death domains (SODD) protein constitutively associates intracellularly with TNFR1 and inhibits the recruitment of cytoplasmic signaling proteins to TNFR1 to prevent spontaneous aggregation of the cytoplasmic death domains of TNFR1 molecules that are juxtaposed in the absence of ligand stimulation" SIGNOR-245022 AHSA1 protein O95433 UNIPROT GCH1 protein P30793 UNIPROT "up-regulates activity" binding 9606 BTO:0001519 16696853 t miannu "The interaction of GCH1 with Aha1 may recruit GCH1 into the eNOS/Hsp90 complex so as to support local changes in nitric oxide production by endothelial cells." SIGNOR-252213 SLC34A2 protein O95436 UNIPROT EGF protein P01133 UNIPROT down-regulates 9606 BTO:0000195 BTO:0000763 11171583 f miannu "In vivo and in vitro studies showed that egf treatment decreased intestinal napi-iib mrna abundance by _50%, suggesting possible transcriptional regulation." SIGNOR-105161 CTDNEP1 protein O95476 UNIPROT BMPR1A protein P36894 UNIPROT up-regulates binding 9606 17141153 t lperfetto "We show that dullard promotes the ubiquitin-mediated proteosomal degradation of bmp receptors (bmprs). Dullard preferentially complexes with the bmp type ii receptor (bmprii) and partially colocalizes with the caveolin-1-positive compartment, suggesting that dullard promotes bmpr degradation via the lipid raft-caveolar pathway" SIGNOR-150998 CTDNEP1 protein O95476 UNIPROT LPIN1 protein Q14693 UNIPROT "up-regulates activity" dephosphorylation Ser106 IPMHLATsPILSEGA 9606 BTO:0001131 17420445 t "Dullard significantly dephosphorylates mouse lipin 1b only in BHK cells (Fig. 5A). This is most clearly seen by using the antibody prepared against the phosphorylation site Ser-106.|Dephosphorylation of lipin results in its translocation to the nuclear envelope and endoplasmic reticulum membranes from the cytosol and generation of diacylglycerol" SIGNOR-248346 ABCA1 protein O95477 UNIPROT APOA1 protein P02647 UNIPROT "up-regulates activity" binding 9606 15347662 t miannu "The stimulation of cellular cholesterol and phospholipid efflux by apolipoprotein A-I is mediated by the activity of the ATP-binding cassette transporter A1 (ABCA1). ABCA1 forms a high affinity complex with apoA-I by binding amphipathic helices within the apolipoprotein. VFVNFA sequence is required for ABCA1 to form a complex with apoA-I and to transfer cholesterol to the apolipoprotein." SIGNOR-252100 ABCA1 protein O95477 UNIPROT MEGF10 protein Q96KG7 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 17205124 t miannu "ABCA1 and MEGF10 interact during engulfment. MEGF10 function can be modulated by the ATP binding cassette transporter ABCA1, ortholog to CED-7. by the combined use of cellular and biochemical approaches we provide evidence that ABCA1 and MEGF10 interact at the molecular level." SIGNOR-265164 SEC24A protein O95486 UNIPROT "COPII vesicle" complex SIGNOR-C370 SIGNOR "form complex" binding 9606 BTO:0000567 30605680 t lperfetto "The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat" SIGNOR-265295 SEC24B protein O95487 UNIPROT "COPII vesicle" complex SIGNOR-C370 SIGNOR "form complex" binding 9606 BTO:0000567 30605680 t lperfetto "The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat" SIGNOR-265290 KLF8 protein O95600 UNIPROT CTBP2 protein P56545 UNIPROT "up-regulates activity" binding 10090 BTO:0000944 10756197 t miannu "Here we report the characterisation of KLF8/ZNF741/BKLF3 (KLF8). We demonstrate that this protein is able to bind CACCC-boxes in DNA and can repress gene expression by associating with CtBP co-repressors." SIGNOR-236962 KLF8 protein O95600 UNIPROT HBB protein P68871 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000944 10756197 t Luana "These results establish KLF8 as a CACCC-box binding protein that associates with CtBP and represses transcription." SIGNOR-266052 POLR1A protein O95602 UNIPROT "RNA Polymerase I" complex SIGNOR-C390 SIGNOR "form complex" binding 22260999 t lperfetto "In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1). " SIGNOR-266152 PCNT protein O95613 UNIPROT CDK5RAP2 protein Q96SN8 UNIPROT "up-regulates activity" binding 9606 BTO:0001938 18042621 t Giulio "Our observation that Cep215 may function downstream of pericentrin suggests that the two proteins affect centrosome cohesion through a common mechanism. |Finally, depletion of pericentrin caused an almost complete loss of Cep215 from centrosomes, a detectable reduction in centrosomal levels of Cep68 and rootletin, but no significant effect on C-Nap1 (Fig. 6C and Table 1). Taken together, these results point to functional (and perhaps molecular) interactions between (1) Cep68 and rootletin and (2) Cep215 and pericentrin." SIGNOR-260309 ADCY5 protein O95622 UNIPROT "3',5'-cyclic AMP" smallmolecule CHEBI:17489 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 15385642 t miannu "Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions." SIGNOR-264999 NTN1 protein O95631 UNIPROT UNC5C protein O95185 UNIPROT up-regulates binding 9606 10399920 t gcesareni "We provide evidence that netrin-1 triggers the formation of a receptor complex of dcc and unc5 proteins and simultaneously derepresses the interaction between their cytoplasmic domains, thereby converting dcc-mediated attraction to unc5/dcc-mediated repulsion." SIGNOR-69047 NFATC1 protein O95644 UNIPROT IL6 protein P05231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001260 17079331 t lperfetto "The calcineurin/nuclear factor of activated T cells (NFAT) signaling pathway has been found to play a role in regulating growth and differentiation in several cell types. However, the functional significance of NFAT in the vasculature is largely unclear. Here we show that NFATc1, NFATc3, and NFATc4 are expressed in human myometrial arteries. |Chronic inhibition of NFAT significantly reduced IL-6 production in intact myometrial arteries and inhibited cell proliferation in vascular smooth muscle cells cultured from explants from the same arteries." SIGNOR-251730 NFATC1 protein O95644 UNIPROT MYH7 protein P12883 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165 17111365 f Regulation miannu "Transient transfection assays demonstrated that the calcineurin/NFATc1 signaling pathway is essential for MyHCbeta promoter activation during transformation of C2C12 myotubes but is not sufficient for complete fast MyHCIId/x promoter inhibition. Along with NFATc1, myocyte enhancer factor-2D (MEF-2D) and the myogenic transcription factor MyoD transactivated the MyHCbeta promoter in calcium-ionophore-treated myotubes in a calcineurin-dependent manner." SIGNOR-251956 NFATC1 protein O95644 UNIPROT PTGS2 protein P35354 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21871017 t miannu "NFAT induces the transcription of the COX2 (cyclo-oxygenase-2) gene incancer cells thereby enhancing invasive migration" SIGNOR-264026 NFATC1 protein O95644 UNIPROT PLAUR protein Q03405 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 23015147 t "Inducible podocyte-specific expression of constitutively active NFATc1 increased podocyte uPAR expression by binding to the Plaur gene promoter (encoding uPAR) in chromatin immunoprecipitation assays." SIGNOR-253336 NFATC1 protein O95644 UNIPROT GPC6 protein Q9Y625 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150 21871017 t miannu "NFAT transcriptionally regulates GPC6 induction in breast cancer cells and binds to three regulatory elements in the GPC6 proximal promoter. Expression of GPC6 in response to NFAT signalling promotes invasive migration, whereas GPC6 silencing with shRNA (small-hairpin RNA) potently blocks this phenotype." SIGNOR-264022 CDS2 protein O95674 UNIPROT "phosphatidic acid" smallmolecule CHEBI:16337 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 25375833 t lperfetto "CDP-diacylglycerol synthases (CDS) are critical enzymes that catalyze the formation of CDP-diacylglycerol (CDP-DAG) from phosphatidic acid (PA)." SIGNOR-267021 CDS2 protein O95674 UNIPROT CDP-diacylglycerol(2-) smallmolecule CHEBI:58332 ChEBI up-regulates "small molecule catalysis" 9606 25375833 t lperfetto "CDP-diacylglycerol synthases (CDS) are critical enzymes that catalyze the formation of CDP-diacylglycerol (CDP-DAG) from phosphatidic acid (PA)." SIGNOR-267020 CEP43 protein O95684 UNIPROT MAPRE1 protein Q15691 UNIPROT up-regulates relocalization 9606 16314388 t miannu "Fop also binds to eb1 and is required for localizing eb1 to the centrosome" SIGNOR-142400 OXSR1 protein O95747 UNIPROT SLC12A2 protein P55011 UNIPROT up-regulates phosphorylation Thr203 HQHYYYDtHTNTYYL 9606 12145304 t gcesareni "The secretory na-k-cl cotransporter nkcc1 is activated by secretagogues through a phosphorylation-dependent mechanism. three phosphoacceptor sites were identified in the n-terminal domain of the protein (at thr184, thr189, and thr202) none of these residues occurs in the context of strong consensus sites for known ser/thr kinases." SIGNOR-90927 OXSR1 protein O95747 UNIPROT SLC12A2 protein P55011 UNIPROT up-regulates phosphorylation Thr212 TNTYYLRtFGHNTMD 9606 12145304 t gcesareni "Oxidative stress-responsive kinase-1 (osr1) is a known upstream regulator of n(k)ccs. these results suggest that, globally, osr1 is involved in the regulation of bp and renal tubular na(+) reabsorption mainly via the activation of nkcc1 and nkcc2." SIGNOR-90931 OXSR1 protein O95747 UNIPROT SLC12A2 protein P55011 UNIPROT up-regulates phosphorylation Thr203 HQHYYYDtHTNTYYL 9606 BTO:0000007 16669787 t miannu "We have identified three residues in nkcc1 (thr175/thr179/thr184 in shark or thr203/thr207/thr212 in human) that are phosphorylated by spak and osr1 / exposure of hek-293 (human embryonic kidney) cells to osmotic stress, which leads to phosphorylation and activation of nkcc1, increased phosphorylation of nkcc1 at the sites targeted by spak/osr1" SIGNOR-146513 OXSR1 protein O95747 UNIPROT SLC12A2 protein P55011 UNIPROT up-regulates phosphorylation Thr207 YYDTHTNtYYLRTFG 9606 BTO:0000007 16669787 t miannu "We have identified three residues in nkcc1 (thr175/thr179/thr184 in shark or thr203/thr207/thr212 in human) that are phosphorylated by spak and osr1 / exposure of hek-293 (human embryonic kidney) cells to osmotic stress, which leads to phosphorylation and activation of nkcc1, increased phosphorylation of nkcc1 at the sites targeted by spak/osr1" SIGNOR-146517 OXSR1 protein O95747 UNIPROT SLC12A2 protein P55011 UNIPROT up-regulates phosphorylation Thr212 TNTYYLRtFGHNTMD 9606 BTO:0000007 16669787 t miannu "We have identified three residues in nkcc1 (thr175/thr179/thr184 in shark or thr203/thr207/thr212 in human) that are phosphorylated by spak and osr1 / exposure of hek-293 (human embryonic kidney) cells to osmotic stress, which leads to phosphorylation and activation of nkcc1, increased phosphorylation of nkcc1 at the sites targeted by spak/osr1" SIGNOR-146521 OXSR1 protein O95747 UNIPROT SLC12A3 protein P55017 UNIPROT up-regulates phosphorylation Thr60 MRTFGYNtIDVVPTY 9606 BTO:0000007 BTO:0000671 18270262 t miannu "We demonstrate that the spak and osr1 kinases that are activated by wnk1 phosphorylate human ncc at three conserved residues (thr46, thr55 and thr60) / our results also indicate that phosphorylation of thr60 plays the most crucial role in triggering the activation of ncc in hek293 cells and its mutation also inhibits phosphorylation of the adjacent thr46 and thr55 sites." SIGNOR-160833 OXSR1 protein O95747 UNIPROT PAK1 protein Q13153 UNIPROT "down-regulates activity" phosphorylation Thr84 LPSDFEHtIHVGFDA 9606 BTO:0000567 14707132 t miannu "OSR1 phosphorylated threonine 84 in the N-terminal regulatory domain of PAK1. phosphorylation of PAK1 by OSR1 desensitizes PAK1 to activation by small G proteins, providing a modulatory input to PAK1 activity." SIGNOR-250210 DDX58 protein O95786 UNIPROT MAVS protein Q7Z434 UNIPROT "up-regulates activity" binding 9606 19052324 t miannu "Initially, RIG-I and MDA5 sense dsRNA in the cytoplasm, produced as a by-product of RNA virus replication.Once one or both of these sensors are activated, they interact with a mitochondrial membrane protein called MAVS (mitochondrial antiviral) (also called IPS1, Cardif, and VISA). They signal to the mitochondrial membrane protein MAVS, which in turn activates the kinases TBK1 and IKKɛ." SIGNOR-260139 BAG3 protein O95817 UNIPROT HSPA8 protein P11142 UNIPROT "up-regulates activity" binding -1 27474740 t lperfetto "Heat shock cognate protein 70 (Hsc70) regulates protein homeostasis through its reversible interactions with client proteins. Hsc70 has two major domains: a nucleotide-binding domain (NBD), that hydrolyzes ATP, and a substrate-binding domain (SBD), where clients are bound. Members of the BAG family of co-chaperones, including Bag1 and Bag3, are known to accelerate release of both ADP and client from Hsc70." SIGNOR-254116 BAG3 protein O95817 UNIPROT SIRT5 protein Q9NXA8 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 30910998 f Monia "Ectopic BAG3 expression decreases the interaction between GLS and SIRT5. we demonstrated that BAG3 overexpression decreased SIRT5 expression in HepG2 cells (Fig. 5d)." SIGNOR-261205 MAP4K4 protein O95819 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates binding 9606 10807933 t gcesareni "The existence of an at least trimolecular complex consisting of nik, tak1, and ikk2, although the precise sequence of activation as well as the possible location of the kinases within the signalosome remains to be elucidated." SIGNOR-77404 AIFM1 protein O95831 UNIPROT BAX protein Q07812 UNIPROT up-regulates 9606 21210296 f gcesareni "Permeabilization of the outer mitochondrial membrane allows the leakage of at least five apoptotic mediators from the mitochondrial intermembrane space, such as cyt c, (diablo/diablo), htra2/omi, apoptosis-inducing factors (aif), and endonuclease g. Such modifications result in their activation and translocation to outer mitochondrial membrane (omm) which helps it to interact with multidomain pro-apototic members, bax/baklike proteins, leading to their oligomerization and formation of pore." SIGNOR-170960 LATS1 protein O95835 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser127 PQHVRAHsSPASLQL 9606 22658639 t milica "In response to high cell densities, activated LATS1/2 phosphorylates the WW-domain containing transcriptional co-activators YAP at Ser127 and TAZ at Ser89, promoting 14-3-3 binding and thereby inhibiting their translocation into the nucleus." SIGNOR-197647 LATS1 protein O95835 UNIPROT YAP1 protein P46937 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser397 TYHSRDEsTDSGLSM 9606 BTO:0000007 20048001 t lperfetto "We show that YAP is phosphorylated by Lats on Ser 381 in one of the HXRXXS motifs, and this phosphorylation provides the priming signal for CK1delta/epsilon to phosphorylate a phosphodegron in YAP. The phosphorylated phosphodegron recruits beta-TRCP, leading to YAP ubiquitination and degradation under conditions of elevated Hippo pathway activity, such as cell contact inhibition" SIGNOR-218034 LATS1 protein O95835 UNIPROT VEPH1 protein Q14D04 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000938 22055343 f "In the neuronal differentiation" lperfetto "Melted represses warts transcription to disrupt hippo pathway activity and specify rh5 fate wts and melt repress each other s transcription in a double negative, bistable feedback loop that directs robust expression of either rh5 or rh6 in r8" SIGNOR-177068 ANGPTL1 protein O95841 UNIPROT TEK protein Q02763 UNIPROT down-regulates binding 9606 BTO:0004980 BTO:0000763 15284220 t gcesareni "In experiments with human endothelial cell lines, ang3 was identified as an antagonist of tie2 and ang4 was identified as an agonist of tie2." SIGNOR-127354 ANGPTL1 protein O95841 UNIPROT TEK protein Q02763 UNIPROT up-regulates binding 9606 10051567 t gcesareni "Ang3 and ang4 are agonists of tie2, but mouse ang3 has strong activity only on endothelial cells of its own species." SIGNOR-65110 SNAI1 protein O95863 UNIPROT CLDN7 protein O95471 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001570 19277896 f lperfetto "We propose that CtBP1 is recruited by SNAI1P at the CLDN7 gene promoter indirectly through another yet to be identified protein. Based on our observations, we propose a model for SNAI1P-mediated down regulation of human CLDN7 gene expression by chromatin remodeling" SIGNOR-254104 SNAI1 protein O95863 UNIPROT SERPINE1 protein P05121 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19055748 f lperfetto "We demonstrated by both cDNA microarrays and real-time quantitative RT-PCR that the functional blockade of SNAI1 induces a significant decrease of PAI-1 and uPA transcripts." SIGNOR-252262 SNAI1 protein O95863 UNIPROT CDH1 protein P12830 UNIPROT "down-regulates quantity" "transcriptional regulation" 9606 19055748 f lperfetto "Taken together these results suggest that SNAI1 functional blockade is leading to partial re-expression of E-cadherin (i.e. at the level of transcription), to a decrease in PAI-1 and to a more collective migration, while the parental cells expressing SNAI1 have less E-cadherin, more PAI 1, and migrate individually. We suggest that the present study establishes a relation between SNAI1 function, PAI-1 distribution and EMT status." SIGNOR-252260 SNAI1 protein O95863 UNIPROT CDH1 protein P12830 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15311212 f miannu "known E-cadherin transcriptional repressors, such as SLUG (SNAI2), SIP1 (ZEB2), TWIST1, SNAIL (SNAI1) and ZEB1 (TCF8), but not E12/E47 (TCF3), had a lack of upregulation in cells expressing mutated E-cadherin compared to WT." SIGNOR-255156 SNAI1 protein O95863 UNIPROT CTBP1 protein Q13363 UNIPROT "up-regulates activity" 9606 BTO:0001570 19277896 f lperfetto "We propose that CtBP1 is recruited by SNAI1P at the CLDN7 gene promoter indirectly through another yet to be identified protein. Based on our observations, we propose a model for SNAI1P-mediated down regulation of human CLDN7 gene expression by chromatin remodeling" SIGNOR-254103 SNAI1 protein O95863 UNIPROT PXDN protein Q92626 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000567 29305973 t miannu "TGF-β1 induced Snai1 binding to the PXDN promoter (as assessed by chromatin immunoprecipitation-PCR) and significantly repressed luciferase reporter gene expression, as did Snai1 overexpression." SIGNOR-265249 SNAI1 protein O95863 UNIPROT SNAIL/RELA/PARP1 complex SIGNOR-C198 SIGNOR "form complex" binding 9606 BTO:0000452;BTO:0002625 22223884 t 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 DLGAP3 protein O95886 UNIPROT DLG4 protein P78352 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 9115257 t miannu "SAPAPs are specifically expressed in neuronal cells and enriched in the PSD fraction. SAPAPs induce the enrichment of PSD-95/SAP90 to the plasma membrane in transfected cells. Thus, SAPAPs may have a potential activity to maintain the structure of PSD by concentrating its components to the membrane area." SIGNOR-264211 DLGAP3 protein O95886 UNIPROT SHANK3 protein Q9BYB0 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000938 28179641 t miannu "SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3)." SIGNOR-264594 DLGAP3 protein O95886 UNIPROT SHANK2 protein Q9UPX8 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000938 28179641 t miannu "SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3)." SIGNOR-264593 DLGAP3 protein O95886 UNIPROT SHANK1 protein Q9Y566 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000938 28179641 t miannu "SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3)." SIGNOR-264592 CBX7 protein O95931 UNIPROT CDH1 protein P12830 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000196 19706751 f miannu "We confirmed by coimmunoprecipitation that CBX7 physically interacts with the HDAC2 protein and is able to inhibit its activity. Then, we showed that both these proteins bind the E-cadherin promoter and that CBX7 up-regulates E-cadherin expression." SIGNOR-253767 BMP15 protein O95972 UNIPROT BMPR2 protein Q13873 UNIPROT up-regulates binding 9606 BTO:0000975 SIGNOR-C29 16446785 t gcesareni "Here we have performed a detailed in situ hybridization analysis of the spatial and temporal expression patterns of the bmp ligands (bmp-2, -3, -3b, -4, -6, -7, -15), receptors (bmpr-ia, -ib, -ii), and bmp antagonist, follistatin, in rat ovaries over the normal estrous cycle." SIGNOR-144098 BMP15 protein O95972 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates binding 9606 BTO:0000975 16446785 t lperfetto "Here we have performed a detailed in situ hybridization analysis of the spatial and temporal expression patterns of the bmp ligands (bmp-2, -3, -3b, -4, -6, -7, -15), receptors (bmpr-ia, -ib, -ii), and bmp antagonist, follistatin, in rat ovaries over the normal estrous cycle." SIGNOR-217538 MBD3 protein O95983 UNIPROT "MBD3/NuRD complex" complex SIGNOR-C338 SIGNOR "form complex" binding 9606 27098840 t miannu "The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression." SIGNOR-263847 TCL1B protein O95988 UNIPROT AKT2 protein P31751 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271 10983986 t gcesareni "In vivo, tcl1 forms trimers, which associate with akt. Tcl1 facilitates the oligomerization and activation of akt. Our data show that tcl1 is a novel akt kinase coactivator, which promotes akt-induced cell survival and proliferation." SIGNOR-81716 TCL1B protein O95988 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates binding 9606 BTO:0000782;BTO:0001271 10983986 t lperfetto "In vivo, tcl1 forms trimers, which associate with akt. Tcl1 facilitates the oligomerization and activation of akt. Our data show that tcl1 is a novel akt kinase coactivator, which promotes akt-induced cell survival and proliferation." SIGNOR-244452 NUDT3 protein O95989 UNIPROT AKT2 protein P31751 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271 10983986 t miannu "Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation" SIGNOR-81759 FAM107A protein O95990 UNIPROT AKT3 protein Q9Y243 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271 10983986 t miannu "Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation" SIGNOR-81800 APC2 protein O95996 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates binding 9606 SIGNOR-C110 9601641 t acerquone "Human axin (haxin) binds directly to beta-catenin, gsk3 beta, and apc in vitro, and the endogenous proteins are found in a complex in cells." SIGNOR-57673 APC2 protein O95996 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates quantity by destabilization" relocalization 9606 BTO:0000038 10980707 t lperfetto "The tumour-suppressing activity of apc largely involves facilitating the proteasome-mediated degradation of b-cateninit is possible that once exported from the nucleus, apc directs b-catenin along the cytoskeletal network to sites of degradation." SIGNOR-81545 APC2 protein O95996 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates binding 9606 9601641 t lperfetto "Human axin (haxin) binds directly to beta-catenin, gsk3 beta, and apc in vitro, and the endogenous proteins are found in a complex in cells." SIGNOR-227945 PTTG1 protein O95997 UNIPROT TIMP2 protein P16035 UNIPROT "down-regulates quantity" 9606 19351864 f miannu "Suppressing PTTG expression by siRNA decreased cell motility in both PTTG-HA/EC9706 and KYSE150 cells. By using mass spectrometric analysis, we identified that PTTG up-regulated S100A4 and galectin-1 secretion and down-regulated tissue inhibitor of metalloproteinase-2 secretion to the culture media." SIGNOR-255069 PTTG1 protein O95997 UNIPROT S100A4 protein P26447 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002430 19351864 f miannu "PTTG induced S100A4 and galectin-1 mRNA and protein expression as assessed by Western blot and reverse transcription-PCR." SIGNOR-255070 BCL10 protein O95999 UNIPROT IKBKG protein Q9Y6K9 UNIPROT up-regulates binding 9606 SIGNOR-C14 18287044 t gcesareni "Here, we show that bcl10 undergoes k63-linked polyubiquitination in response to t cell activation and subsequently binds nemo, the regulatory subunit of ikk." SIGNOR-160967 NDUFB10 protein O96000 UNIPROT "Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and |The main ND4-module intermediate binds NDUFB1, NDUFB4, NDUFB5, NDUFB6, NDUFB10, NDUFB11 and MT-ND4" SIGNOR-262163 ZBED1 protein O96006 UNIPROT RPS12 protein P25398 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567 17220279 t Luana "HDRE-like sequences act as positive regulatory elements for RP gene promoter activities in vivo. | Cotransfection of a plasmid expressing hDREF increased luciferase expression directed by each RP gene promoter more than 30% compared with the values obtained without the hDREF-expressing plasmid." SIGNOR-266084 ZBED1 protein O96006 UNIPROT GATA4 protein P43694 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 7227 BTO:0001138 22021382 f 1 miannu "XNP/dATRX physically interacts with DREF. our results show that DREF is required for the proper expression of pnr and that XNP/dATRX binds to DREF at the DRE sites, resulting in the repression of pnr gene expression." SIGNOR-239736 ZBED1 protein O96006 UNIPROT RPS10 protein P46783 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567 17220279 t Luana "HDRE-like sequences act as positive regulatory elements for RP gene promoter activities in vivo. | Cotransfection of a plasmid expressing hDREF increased luciferase expression directed by each RP gene promoter more than 30% compared with the values obtained without the hDREF-expressing plasmid." SIGNOR-266083 ZBED1 protein O96006 UNIPROT RPS6 protein P62753 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567 17220279 t Luana "HDRE-like sequences act as positive regulatory elements for RP gene promoter activities in vivo. | Cotransfection of a plasmid expressing hDREF increased luciferase expression directed by each RP gene promoter more than 30% compared with the values obtained without the hDREF-expressing plasmid." SIGNOR-266082 PAK4 protein O96013 UNIPROT SYNJ1 protein O43426 UNIPROT "up-regulates activity" phosphorylation -1 22371566 t miannu "We identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo." SIGNOR-263024 PAK4 protein O96013 UNIPROT PAK4 protein O96013 UNIPROT up-regulates phosphorylation Ser474 KEVPRRKsLVGTPYW 9606 20926745 t gcesareni "Intracellular localization;enzymatic activity, induced;cell growth, altered;" SIGNOR-168301 PAK4 protein O96013 UNIPROT PAK4 protein O96013 UNIPROT "up-regulates activity" phosphorylation Ser474 KEVPRRKsLVGTPYW 10090 BTO:0000944 11668177 t lperfetto "Here we demonstrate that PAK4 is frequently overexpressed in human tumor cell lines of various tissue origins. We also have identified serine (Ser-474) as the likely autophosphorylation site in the kinase domain of PAK4 in vivo. Mutation of this serine to glutamic acid (S474E) results in constitutive activation of the kinase." SIGNOR-235867 PAK4 protein O96013 UNIPROT FH protein P07954 UNIPROT "down-regulates quantity" phosphorylation Ser46 PNAARMAsQNSFRIE 9606 BTO:0002058 30683654 t miannu " FH is massively phosphorylated at the Ser 46 by PAK4 in non-small cell lung cancer (NSCLC) cells, and PAK4-phosphorylated FH binds to 14-3-3, resulting in cytosolic detention of FH and prohibition of FH/CSL/p53 complex formation. " SIGNOR-266315 PAK4 protein O96013 UNIPROT ITGB5 protein P18084 UNIPROT up-regulates phosphorylation Ser759 REFAKFQsERSRARY 9606 20507994 t llicata "Pak4 specifically phosphorylated the integrin beta5 subunit at ser-759 and ser-762 within the beta5-sers-motif. Point mutation of these two serine residues abolished the pak4-induced cell migration, indicating a functional role for these phosphorylations in migration." SIGNOR-165702 PAK4 protein O96013 UNIPROT ITGB5 protein P18084 UNIPROT up-regulates phosphorylation Ser762 AKFQSERsRARYEMA 9606 20507994 t llicata "Pak4 specifically phosphorylated the integrin beta5 subunit at ser-759 and ser-762 within the beta5-sers-motif. Point mutation of these two serine residues abolished the pak4-induced cell migration, indicating a functional role for these phosphorylations in migration." SIGNOR-165706 PAK4 protein O96013 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Ser675 QDYKKRLsVELTSSL 9606 22173096 t lperfetto "Pak4 interacts with and phosphorylates _-catenin on ser675, which promotes the tcf/lef transcriptional activity and stabilizes _-catenin through inhibition of its degradation." SIGNOR-191557 PAK4 protein O96013 UNIPROT RAN protein P62826 UNIPROT unknown phosphorylation Ser135 DRKVKAKsIVFHRKK 9606 20805321 t llicata "We show that ran is a substrate for p21-activated kinase 4 (pak4) and that its phosphorylation on serine-135 increases during mitosis. our study suggests that pak4-mediated phosphorylation of gdp- or gtp-bound ran regulates the assembly of ran-dependent complexes on the mitotic spindle" SIGNOR-167671 PAK4 protein O96013 UNIPROT RAN protein P62826 UNIPROT up-regulates phosphorylation Ser135 DRKVKAKsIVFHRKK 9606 20805321 t lperfetto "We show that ran is a substrate for p21-activated kinase 4 (pak4) and that its phosphorylation on serine-135 increases during mitosis.Altogether, our findings strongly suggest that pak4-mediated phosphorylation of gdp- or gtp-bound ran modulates the assembly of complexes that are required at specific subcellular localizations for ran to carry out its functions during mitotic progression." SIGNOR-167667 PAK4 protein O96013 UNIPROT PACSIN1 protein Q9BY11 UNIPROT "up-regulates activity" phosphorylation Ser346 SQAGDRGsVSSYDRG -1 22371566 t miannu "We identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo." SIGNOR-263023 WNT11 protein O96014 UNIPROT MUSK protein O15146 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000887 22309736 t gcesareni "We provide evidence that wnt9a and wnt11 bind directly to the extracellular domain of musk, to induce musk dimerization and subsequent tyrosine phosphorylation of the kinase" SIGNOR-195966 WNT11 protein O96014 UNIPROT MUSK protein O15146 UNIPROT up-regulates binding 9606 BTO:0000887 23151663 t gcesareni "Musk has an extracellular region with homology to the frizzled crd,binding of which by wnt11 stimulates a pcp-like pathway during neuromuscolar development. Here, we show that in vivo, wnt11r and wnt4a initiate musk translocation from muscle membranes to recycling endosomes we provide evidence that wnt9a and wnt11 bind directly to the extracellular domain of musk, to induce musk dimerization and subsequent tyrosine phosphorylation of the kinase" SIGNOR-199641 WNT11 protein O96014 UNIPROT FZD6 protein O60353 UNIPROT "up-regulates activity" binding 9606 BTO:0000551;BTO:0000848 16273260 t gcesareni "Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors." SIGNOR-141431 WNT11 protein O96014 UNIPROT FZD7 protein O75084 UNIPROT "up-regulates activity" binding 7227 10862746 t gcesareni "Consistent with this, xfz7 biochemically and functionally interacts with xwnt11" SIGNOR-78406 WNT11 protein O96014 UNIPROT LRP6 protein O75581 UNIPROT "up-regulates activity" binding 9606 15578921 t 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-131637 WNT11 protein O96014 UNIPROT CHRNA1 protein P02708 UNIPROT up-regulates 9606 BTO:0000938 BTO:0000887 22309736 f gcesareni "We identified five wnts (wnt9a, wnt9b, wnt10b, wnt11, and wnt16) that are able to stimulate achr clustering, of which wnt9a and wnt11 are expressed abundantly in developing muscles." SIGNOR-195963 WNT11 protein O96014 UNIPROT FZD3 protein Q9NPG1 UNIPROT "up-regulates activity" binding 9606 15578921 t 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-131634 WNT11 protein O96014 UNIPROT FZD3 protein Q9NPG1 UNIPROT "up-regulates activity" binding 9606 BTO:0000551;BTO:0000848 16273260 t gcesareni "Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors." SIGNOR-141428 WNT11 protein O96014 UNIPROT Frizzled proteinfamily SIGNOR-PF11 SIGNOR "up-regulates activity" binding 9606 BTO:0000551;BTO:0000848 16273260 t gcesareni "Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors." SIGNOR-253127 CHEK2 protein O96017 UNIPROT MDM4 protein O15151 UNIPROT down-regulates phosphorylation Ser342 SKLTHSLsTSDITAI 9606 16163388 t lperfetto "Phosphorylation of s342 and s367 in vivo require the chk2 kinase. Chk2 also stimulates mdmx ubiquitination and degradation by mdm2" SIGNOR-140417 CHEK2 protein O96017 UNIPROT MDM4 protein O15151 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser367 PDCRRTIsAPVVRPK 9606 18356162 t lperfetto "The chk1 and chk2 kinases have also been shown to phosphorylate ser367, leading to 14-3-3 binding (34_36, 38, 44). In both cases, the outcome differed: in chk1-mediated phosphorylation, mdmx was translocated to the cytoplasm;in chk2-mediated phosphorylation, mdmx was degraded (34_36, 38, 44). It is possible that the damage response is mediated through additional phosphorylation sites other than ser367 and that, depending on the type of damage, certain sites will be modified, leading to different outcomes." SIGNOR-178071 CHEK2 protein O96017 UNIPROT CHEK2 protein O96017 UNIPROT "up-regulates activity" phosphorylation Thr383 GETSLMRtLCGTPTY 9606 BTO:0000007 11901158 t gcesareni "Phosphorylation of thr-68 by the ataxia telangiectasia-mutated is necessary for efficient activation of chk2 when cells are exposed to ionizing radiation. By an unknown mechanism, this initial event promotes additional autophosphorylation events including modifications of thr-383 and thr-387" SIGNOR-116127 CHEK2 protein O96017 UNIPROT CHEK2 protein O96017 UNIPROT "up-regulates activity" phosphorylation Thr387 LMRTLCGtPTYLAPE 9606 BTO:0000007 11901158 t gcesareni "Phosphorylation of thr-68 by the ataxia telangiectasia-mutated is necessary for efficient activation of chk2 when cells are exposed to ionizing radiation. By an unknown mechanism, this initial event promotes additional autophosphorylation events including modifications of thr-383 and thr-387" SIGNOR-116131 CHEK2 protein O96017 UNIPROT CHEK2 protein O96017 UNIPROT "up-regulates activity" phosphorylation Thr68 SSLETVStQELYSIP 9606 BTO:0000007 11901158 t lperfetto "Thus, activation of chk2 in irradiated cells may occur through oligomerization of chk2 via binding of the thr-68-phosphorylated region of one chk2 to the fha domain of another. Oligomerization of chk2 may therefore increase the efficiency of trans-autophosphorylation resulting in the release of active chk2 monomers that proceed to enforce checkpoint control in irradiated cells." SIGNOR-116135 CHEK2 protein O96017 UNIPROT CHEK2 protein O96017 UNIPROT "up-regulates activity" phosphorylation Ser516 PQVLAQPsTSRKRPR 9606 BTO:0002201 12855706 t lperfetto "Chk2 is also autophosphorylated following dna damage. It is proposed that autophosphorylation of chk2 may contribute to chk2 activation. To fully understand the regulation of chk2, we mapped an in vitro chk2 autophosphorylation site at c-terminal serine 516 site (ser-516). Ser-516 of chk2 is phosphorylated following radiation in vivo, and this phosphorylation depends on the kinase activity of chk2." SIGNOR-103544 F2 protein P00734 UNIPROT F5 protein P12259 UNIPROT "up-regulates activity" 9606 BTO:0000131 29880919 t lperfetto "Thrombin also activates the cofactors FVIII (to FVIIIa) and FV (to FVa) and activates platelets such that they provide a procoagulant membrane surface to which these proteins then bind" SIGNOR-263530 CHEK2 protein O96017 UNIPROT SOD1 protein P00441 UNIPROT "up-regulates activity" phosphorylation Ser60 DNTAGCTsAGPHFNP 4932 24647101 t "ROS signaling is mediated by Mec1/ATM and its effector Dun1/Cds1 kinase, through Dun1 interaction with Sod1 and regulation of Sod1 by phosphorylation at S60, 99. In the nucleus, Sod1 binds to the promoters and regulates the expression of oxidative resistance and repair genes." SIGNOR-262794 CHEK2 protein O96017 UNIPROT SOD1 protein P00441 UNIPROT "up-regulates activity" phosphorylation Ser99 KDGVADVsIEDSVIS 4932 24647101 t "ROS signaling is mediated by Mec1/ATM and its effector Dun1/Cds1 kinase, through Dun1 interaction with Sod1 and regulation of Sod1 by phosphorylation at S60, 99. In the nucleus, Sod1 binds to the promoters and regulates the expression of oxidative resistance and repair genes." SIGNOR-262795 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" phosphorylation Ser20 PLSQETFsDLWKLLP 9606 17339337 t Manara "Evaluation of these calcium calmodulin kinase superfamily members as candidate Ser(20) kinases in vivo has shown that only CHK1 or DAPK-1 can stimulate p53 transactivation and induce Ser(20) phosphorylation of p53.| Thus, endogenous CHK1 is required for the majority of Ser20 site phosphorylation of ectopically expressed p53 in H1299 cells." SIGNOR-260776 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser15 PSVEPPLsQETFSDL 9606 10656682 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." SIGNOR-74823 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 10656682 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." SIGNOR-74831 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 10656682 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." SIGNOR-74839 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0000567 10673501 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." SIGNOR-75009 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser366 PGGSRAHsSHLKSKK 9606 BTO:0000567 10673501 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." SIGNOR-75013 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 BTO:0000567 10673501 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." SIGNOR-75017 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 BTO:0000567 10673501 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." SIGNOR-75025 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser15 PSVEPPLsQETFSDL 9606 10710310 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." SIGNOR-75629 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 10710310 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." SIGNOR-75637 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser378 SKKGQSTsRHKKLMF 9606 10710310 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." SIGNOR-75641 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 10710310 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." SIGNOR-75645 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser20 PLSQETFsDLWKLLP 9606 10801407 t gcesareni "The tumour suppressor protein p53 is stabilised and activated in response to ionising radiation. This is known to depend on the kinase atm;recent results suggest atm acts via the downstream kinase chk2/hcds1, which stabilises p53 at least in part by direct phosphorylation of residue serine 20" SIGNOR-77144 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser366 PGGSRAHsSHLKSKK 9606 BTO:0001321 15659650 t lperfetto "The cell cycle checkpoint kinases CHK1 and CHK2 have been shown to phosphorylate multiple sites in the N-terminal domain of p53, consequently leading to p53 stabilization and activation. Phosphorylation of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage." SIGNOR-75633 CHEK2 protein O96017 UNIPROT AATF protein Q9NY61 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser477 ELIERKTsSLDPNDQ 9606 BTO:0001109 17157788 t lperfetto "Three putative Chk2 phosphorylation sites (Stevens et al., 2003) are present in Che-1 at resides Ser141, Ser474, and Ser508. Thus, we performed in vitro Chk2 kinase assays utilizing the GST-Che-1 fusion peptides spanning these residues as substrates.| Taken together, these results indicate that Chk2 phosphorylates Che-1 and this phosphorylation contributes to increase Che-1 stability." SIGNOR-264417 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 15659650 t lperfetto "The cell cycle checkpoint kinases CHK1 and CHK2 have been shown to phosphorylate multiple sites in the N-terminal domain of p53, consequently leading to p53 stabilization and activation. Phosphorylation of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage. On activation, both of these kinases also phosphorylate multiple sites in the p53 N-terminal domain. These include Ser15, Thr18, Ser20, and Ser37, which are all DNA-damageinducible sites" SIGNOR-153475 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser378 SKKGQSTsRHKKLMF 9606 BTO:0001321 15659650 t lperfetto "The cell cycle checkpoint kinases CHK1 and CHK2 have been shown to phosphorylate multiple sites in the N-terminal domain of p53, consequently leading to p53 stabilization and activation. Phosphorylation of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage." SIGNOR-74835 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser378 SKKGQSTsRHKKLMF 9606 BTO:0000776 17339337 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." SIGNOR-153479 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 BTO:0000776 17339337 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." SIGNOR-153483 CHEK2 protein O96017 UNIPROT RB1 protein P06400 UNIPROT "up-regulates activity" phosphorylation Ser612 MYLSPVRsPKKKGST 9606 BTO:0000093 17380128 t lperfetto "Phosphorylation of prb at ser612 by chk1/2 leads to a complex between prb and e2f-1 after dna damageprb inhibits cell cycle progression through interactions with the e2f family of transcription factors. Here, we report that dna damage induced not only the dephosphorylation of prb at cdk phosphorylation sites and the binding of prb to e2f-1, but also the phosphorylation of prb at ser612. Phosphorylation of prb at ser612 enhanced the formation of a complex between prb and e2f-1" SIGNOR-153908 CHEK2 protein O96017 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser579 NVKSKIGsTENLKHQ 9606 21215781 t "The effect has been demonstrated using P10636-8" lperfetto "Tau pseudophosphorylation at specific sites such as s262, s293, s324 and s356 was reported to induce tau conformational change and attenuate tau binding to microtubules (fischer et al., 2009). Then, newly soluble tau proteins are targeted by post-translational modifications that directly or indirectly alter tau conformation, promoting tau dimerization in an anti-parallel manner. Stable tau dimers form tau oligomers, which continue in the aggregation process" SIGNOR-171026 CHEK2 protein O96017 UNIPROT KIT protein P10721 UNIPROT up-regulates phosphorylation 9606 22558186 t gcesareni "In this report, we characterize the binding of sh2(chk) to specific phosphotyrosine sites on the c-kit protein sequence. the sh2(chk) binding to the two sites is direct and not through phosphorylated intermediates such as fyn or shc. this indicates that chk binds to the same site on c-kit to which fyn binds, possibly bringing the two into proximity on associated c-kit subunits and leading to the down-regulation of fyn by chk." SIGNOR-197281 CHEK2 protein O96017 UNIPROT XRCC1 protein P18887 UNIPROT up-regulates phosphorylation Thr284 APTRTPAtAPVPARA 9606 18971944 t llicata "Chk2 formed a complex with xrcc1, the ber scaffold protein, and phosphorylated xrcc1 in vivo and in vitro at thr(284). our results are consistent with the phosphorylation of xrcc1 by atm-chk2 facilitating recruitment of downstream ber proteins to the initial damage recognition/excision step to promote ber." SIGNOR-181816 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT "down-regulates quantity" phosphorylation Ser124 PALKRSHsDSLDHDI 9606 12676583 t Manara "Chk2 phosphorylates a subset of the Chk1-targeted sites of Cdc25A | Phosphorylation of serines 123, 178, 278, and 292 regulates both basal and IR-induced accelerated proteolysis of Cdc25A" SIGNOR-260835 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT "down-regulates quantity" phosphorylation Ser178 LFTQRQNsAPARMLS 9606 12676583 t Manara "Chk2 phosphorylates a subset of the Chk1-targeted sites of Cdc25A | Phosphorylation of serines 123, 178, 278, and 292 regulates both basal and IR-induced accelerated proteolysis of Cdc25A" SIGNOR-260833 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT "down-regulates quantity" phosphorylation Ser279 VLKRPERsQEESPPG 9606 12676583 t Manara "Chk2 phosphorylates a subset of the Chk1-targeted sites of Cdc25A | Phosphorylation of serines 123, 178, 278, and 292 regulates both basal and IR-induced accelerated proteolysis of Cdc25A" SIGNOR-260834 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT "down-regulates quantity" phosphorylation Ser293 GSTKRRKsMSGASPK 9606 12676583 t Manara "Chk2 phosphorylates a subset of the Chk1-targeted sites of Cdc25A | Phosphorylation of serines 123, 178, 278, and 292 regulates both basal and IR-induced accelerated proteolysis of Cdc25A" SIGNOR-260836 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser124 PALKRSHsDSLDHDI 9606 11298456 t "Phosphorylation is the signal for ubiquitination" lperfetto "We show that IR-induced destruction of Cdc25A requires both ATM and the Chk2-mediated phosphorylation of Cdc25A on serine 123." SIGNOR-106808 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser124 PALKRSHsDSLDHDI 9606 11298456 t Manara "We conclude that Chk2-dependent phosphorylation of Cdc25A on Ser 123 represents a critical step in promoting its rapid destruction in response to IR-induced DNA damage." SIGNOR-260778 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser124 PALKRSHsDSLDHDI 9606 12676583 t "Phosphorylation is the signal for ubiquitination" gcesareni "We show that ir-induced destruction of cdc25a requires both atm and the chk2-mediated phosphorylation of cdc25a on serine 123. the basal turnover of cdc25a operating in unperturbed s phase required chk1-dependent phosphorylation of serines 123, 178, 278, and 292. Ir-induced acceleration of cdc25a proteolysis correlated with increased phosphate incorporation into these residues generated by a combined action of chk1 and chk2 kinases." SIGNOR-99721 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser178 LFTQRQNsAPARMLS 9606 12676583 t "Phosphorylation is the signal for ubiquitination" gcesareni "We show that ir-induced destruction of cdc25a requires both atm and the chk2-mediated phosphorylation of cdc25a on serine 123. the basal turnover of cdc25a operating in unperturbed s phase required chk1-dependent phosphorylation of serines 123, 178, 278, and 292. Ir-induced acceleration of cdc25a proteolysis correlated with increased phosphate incorporation into these residues generated by a combined action of chk1 and chk2 kinases." SIGNOR-99725 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser279 VLKRPERsQEESPPG 9606 12676583 t "Phosphorylation is the signal for ubiquitination" gcesareni "We show that ir-induced destruction of cdc25a requires both atm and the chk2-mediated phosphorylation of cdc25a on serine 123. the basal turnover of cdc25a operating in unperturbed s phase required chk1-dependent phosphorylation of serines 123, 178, 278, and 292. Ir-induced acceleration of cdc25a proteolysis correlated with increased phosphate incorporation into these residues generated by a combined action of chk1 and chk2 kinases." SIGNOR-99729 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser293 GSTKRRKsMSGASPK 9606 12676583 t "Phosphorylation is the signal for ubiquitination" gcesareni "We show that ir-induced destruction of cdc25a requires both atm and the chk2-mediated phosphorylation of cdc25a on serine 123. the basal turnover of cdc25a operating in unperturbed s phase required chk1-dependent phosphorylation of serines 123, 178, 278, and 292. Ir-induced acceleration of cdc25a proteolysis correlated with increased phosphate incorporation into these residues generated by a combined action of chk1 and chk2 kinases." SIGNOR-99733 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser178 LFTQRQNsAPARMLS 9606 14559997 t "Phosphorylation is the signal for ubiquitination" gcesareni "The order and fidelity of cell cycle events in mammals is intimately linked to the integrity of the Chk1 kinase-Cdc25A phosphatase pathway. Chk1 phosphorylation targets Cdc25A for destruction and, as shown here, inhibits interactions between Cdc25A and its mitotic substrate cyclin B1-Cdk1. Phosphorylation of Cdc25A on serine 178 and threonine 507 facilitates 14-3-3 binding, and Chk1 phosphorylates both residues in vitro." SIGNOR-118759 CHEK2 protein O96017 UNIPROT CDC25C protein P30307 UNIPROT "down-regulates activity" phosphorylation Ser216 SGLYRSPsMPENLNR 9606 12835754 t lperfetto "Activated chk2 in turn phosphorylates cdc25c at serine-216 contributing to the g2/m checkpoints. Cds1 phosphorylates and inactivates cdc25 in vitro|CDC25C is phosphorylated on Ser 216 throughout interphase, but not in mitosis. This creates a binding site for 14‐3‐3 proteins | It has been suggested that 14‐3‐3 protein binding is responsible for retaining Cdc25C in the cytoplasm during interphase, thereby contributing to the prevention of premature initiation of mitotic events" SIGNOR-102779 CHEK2 protein O96017 UNIPROT TTK protein P33981 UNIPROT unknown phosphorylation Thr288 SPDCDVKtDDSVVPC 9606 19151762 t llicata "Phosphorylation at ttk/hmps1 thr288 is enhanced by chk2 in vitro and in vivo after ir" SIGNOR-183470 CHEK2 protein O96017 UNIPROT TTK protein P33981 UNIPROT up-regulates phosphorylation Thr288 SPDCDVKtDDSVVPC 9606 19151762 t llicata "Phosphorylation at ttk/hmps1 thr288 is enhanced by chk2 in vitro and in vivo after ir" SIGNOR-242665 CHEK2 protein O96017 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser988 PPLFPIKsFVKTKCK 9606 BTO:0000150 14701743 t gcesareni "In this study, we tested the hypothesis that the brca1-mediated regulation of recombination requires the chk2- and atm-dependent phosphorylation sites." SIGNOR-120575 CHEK2 protein O96017 UNIPROT VHL protein P40337 UNIPROT up-regulates phosphorylation Ser111 GTGRRIHsYRGHLWL 9606 BTO:0000680 22071692 t llicata "We demonstrated that checkpoint kinase-2 (chk2) binds to the beta-domain of pvhl and phosphorylates ser 111 on dna damage. Notably, this modification enhances pvhl-mediated transactivation of p53 by recruiting p300 and tip60 to the chromatin of p53 target gene" SIGNOR-177091 CHEK2 protein O96017 UNIPROT E2F1 protein Q01094 UNIPROT "up-regulates activity" phosphorylation Ser364 PLLSRMGsLRAPVDE 9606 12717439 t Manara "Therefore, Chk2 phosphorylates and activates E2F-1 in response to DNA damage, resulting in apoptosis. | These results suggest that the Ser 364 site is phosphorylated by Chk2 and that anti-P-Ser 364 recognises the phosphorylated site in E2F-1." SIGNOR-260822 CHEK2 protein O96017 UNIPROT E2F1 protein Q01094 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser364 PLLSRMGsLRAPVDE 9606 12717439 t lperfetto "We report that checkpoint kinase 2 (chk2) regulates e2f-1 activity in response to the dna-damaging agent etoposide. A chk2 consensus phosphorylation site in e2f-1 is phosphorylated in response to dna damage" SIGNOR-100898 CHEK2 protein O96017 UNIPROT E2F1 protein Q01094 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser364 PLLSRMGsLRAPVDE 9606 22558186 t gcesareni "Among these effector proteins, chk1 phosphorylates tlk12 and rad51, while brca, pik3, pml and e2f1 are chk2 substrates." SIGNOR-197278 CHEK2 protein O96017 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Ser376 PLLPRVSsYLVPIQF 9606 BTO:0001938 17101782 t lperfetto "Chk2 mediates stabilization of the foxm1 transcription factor to stimulate expression of dna repair genesthis phosphorylation of foxm1 on serine residue 361 caused increased stability of the foxm1 protein" SIGNOR-150746 CHEK2 protein O96017 UNIPROT PPP2R5C protein Q13362 UNIPROT up-regulates phosphorylation 9606 BTO:0000007 15380617 t gcesareni "Found that chk2 associated with the b' regulatory subunit of protein phosphatase pp2a. In vitro kinase assays showed that b'gamma3 was a potent chk2 substrate. This phosphorylation increased the catalytic phosphatase activity of pp2a." SIGNOR-129255 CHEK2 protein O96017 UNIPROT RASGRF1 protein Q13972 UNIPROT down-regulates phosphorylation Ser287 PITHDDVsSIFLNSE 9606 17110335 t miannu "During interphase, cdc25 is inhibited by ser287 phosphorylation (xenopus cdc25;ser 216 in human cdc25c) and this inhibitory phosphorylation is maintained by dna-responsive checkpoints / s287 is targeted by many kinases, including chk1, chk2, ctak-1, pka, p38 and mapkap kinase-2 suggesting that phosphorylation of this site may integrate multiple signaling inputs." SIGNOR-150843 CHEK2 protein O96017 UNIPROT BECN1 protein Q14457 UNIPROT "up-regulates activity" phosphorylation Ser90 IPPARMMsTESANSF 9606 BTO:0002552 32187724 t lperfetto "We report that CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, thereby impairing Beclin 1-Bcl-2 autophagy-regulatory complex formation in a ROS-dependent fashion.|CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, promoting autophagy via Beclin 1 release from Bcl‐2 sequestration" SIGNOR-264557 CHEK2 protein O96017 UNIPROT BECN1 protein Q14457 UNIPROT "up-regulates activity" phosphorylation Ser93 ARMMSTEsANSFTLI 9606 BTO:0002552 32187724 t lperfetto "We report that CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, thereby impairing Beclin 1-Bcl-2 autophagy-regulatory complex formation in a ROS-dependent fashion.|CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, promoting autophagy via Beclin 1 release from Bcl‐2 sequestration" SIGNOR-264556 CHEK2 protein O96017 UNIPROT AATF protein Q9NY61 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser143 SKKSRSHsAKTPGFS 9606 BTO:0001109 17157788 t lperfetto "Three putative Chk2 phosphorylation sites (Stevens et al., 2003) are present in Che-1 at resides Ser141, Ser474, and Ser508. Thus, we performed in vitro Chk2 kinase assays utilizing the GST-Che-1 fusion peptides spanning these residues as substrates.| Taken together, these results indicate that Chk2 phosphorylates Che-1 and this phosphorylation contributes to increase Che-1 stability." SIGNOR-264416 CHEK2 protein O96017 UNIPROT AATF protein Q9NY61 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser510 KKVDRKAsKGRKLRF 9606 BTO:0001109 17157788 t lperfetto "Three putative Chk2 phosphorylation sites (Stevens et al., 2003) are present in Che-1 at resides Ser141, Ser474, and Ser508. Thus, we performed in vitro Chk2 kinase assays utilizing the GST-Che-1 fusion peptides spanning these residues as substrates.| Taken together, these results indicate that Chk2 phosphorylates Che-1 and this phosphorylation contributes to increase Che-1 stability." SIGNOR-264418 ACTL6A protein O96019 UNIPROT "SWI/SNF complex" complex SIGNOR-C92 SIGNOR "form complex" binding 9606 15627498 t miannu "We discuss recent insights in the functional differences between two evolutionary conserved subclasses of swi/snf-related chromatin remodeling factors. Onesubfamily comprises yeast swi/snf, fly bap and mammalian baf, whereas the other subfamily includes yeast rsc, fly pbap andmammalian pbaf. We review the subunit composition, conserved protein modules and biological functions of each of these subclasses ofswi/snf remodelers." SIGNOR-132916 CCNE2 protein O96020 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR "form complex" binding 9606 19665013 t lperfetto "The eukaryotic cell cycle is controlled by different cyclins and their associated kinases (murray and hunt, 1993). In mammalian cells, levels of cycline and its associated kinase, cdk2, rise in late g1/early s-phase when dna replication is initiated" SIGNOR-187454 NSD2 protein O96028 UNIPROT AR protein P10275 UNIPROT up-regulates binding 9606 BTO:0001130 19481544 t miannu "In this study, we discovered that nsd2 specifically interacts with the dna-binding domain of androgen receptor (ar) via its hmg domain, and the nuclear translocation of both nsd2 and ar is enhanced in the presence of ligand / the histone methyltransferase, nsd2, enhances androgen receptor-mediated transcription." SIGNOR-186045 MT-CYB protein P00156 UNIPROT "Mitochondrial respiratory chain complex III" complex SIGNOR-C279 SIGNOR "form complex" binding 30030361 t lperfetto "Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits" SIGNOR-262193 LDHA protein P00338 UNIPROT pyruvate smallmolecule CHEBI:15361 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 24929216 t "Glucose and alanine produce pyruvate which is reduced to lactate by lactate dehydrogenase in the cytoplasm without oxygen consumption. Lactate removal takes place via its oxidation to pyruvate by lactate dehydrogenase." SIGNOR-266918 LDHA protein P00338 UNIPROT (S)-lactate smallmolecule CHEBI:16651 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 24929216 t "Glucose and alanine produce pyruvate which is reduced to lactate by lactate dehydrogenase in the cytoplasm without oxygen consumption. Lactate removal takes place via its oxidation to pyruvate by lactate dehydrogenase." SIGNOR-266919 ALDH1A1 protein P00352 UNIPROT retinal smallmolecule CHEBI:15035 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 21621639 t lperfetto "All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step." SIGNOR-265122 ALDH1A1 protein P00352 UNIPROT "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 21621639 t lperfetto "All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step." SIGNOR-265123 PAH protein P00439 UNIPROT tyrosine smallmolecule CHEBI:18186 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 NBK536726 t brain lperfetto "L-phenylalanine is converted into L-tyrosine in the liver, by the enzyme phenylalanine hydroxylase (PH) in the presence of oxygen, iron, and tetrahydrobiopterin as cofactors" SIGNOR-263989 PAH protein P00439 UNIPROT phenylalanine smallmolecule CHEBI:28044 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 NBK536726 t brain lperfetto "L-phenylalanine is converted into L-tyrosine in the liver, by the enzyme phenylalanine hydroxylase (PH) in the presence of oxygen, iron, and tetrahydrobiopterin as cofactors" SIGNOR-263988 SOD1 protein P00441 UNIPROT ERN1 protein O75460 UNIPROT "up-regulates activity" binding 10090 BTO:0004488 18519638 t "P00441:p.Gly94Ala (mutation causing interaction); P00441:p.Gly86Arg (mutation causing interaction); P00441:p.Ala5Val (mutation causing interaction)" "SOD1mut-induced ER stress |we first examined whether SOD1mut induces ER stress in NSC34 motor neurons, as assessed by band-shift analyses of the ER transmembrane kinase receptors IRE1 and PERK. Adenovirus (Ad)-mediated expression of ALS-linked SOD1mut (SOD1G93A) was detectable within 48 h of infection (Supplemental Fig. S1A). SOD1mut (SOD1A4V, SOD1G85R, and SOD1G93A) but not wild-type SOD1 (SOD1wt) activated IRE1 and PERK" SIGNOR-262786 SOD1 protein P00441 UNIPROT BCL2 protein P10415 UNIPROT "up-regulates activity" binding 9606 BTO:0001279 15233914 t "P00441:p.Gly94Ala (mutation disrupting interaction)" "Familial amyotrophic lateral sclerosis (ALS)-linked mutations in the copper-zinc superoxide dismutase (SOD1) gene cause motor neuron death in about 3% of ALS cases. While the wild-type (wt) protein is anti-apoptotic, mutant SOD1 promotes apoptosis.|We now demonstrate that both wt and mutant SOD1 bind the anti-apoptotic protein Bcl-2, providing evidence of a direct link between SOD1 and an apoptotic pathway. This interaction is evident in vitro and in vivo in mouse and human spinal cord.|These findings provide new insights into the anti-apoptotic function of SOD1 and suggest that entrapment of Bcl-2 by large SOD1 aggregates may deplete motor neurons of this anti-apoptotic protein." SIGNOR-262799 SOD1 protein P00441 UNIPROT VDAC1 protein P21796 UNIPROT "down-regulates activity" binding 10090 BTO:0001279 20797535 t "P00441:p.Gly38Arg (mutation causing interaction)" "Misfolded Mutant SOD1 Directly Inhibits VDAC1 Conductance in a Mouse Model of Inherited ALS|With conformation-specific antibodies, we now demonstrate that misfolded mutant SOD1 binds directly to the voltage-dependent anion channel (VDAC1), an integral membrane protein imbedded in the outer mitochondrial membrane." SIGNOR-262798 SOD1 protein P00441 UNIPROT S100A4 protein P26447 UNIPROT "up-regulates quantity" 10116 BTO:0000452;BTO:0000099 BTO:0001279 31623154 f "P00441:p.Gly94Ala (mutation increasing interaction)" "We found that S100A4 was significantly up-regulated in astrocytes and microglia in the spinal cord of a transgenic rat SOD1-G93A model of amyotrophic lateral sclerosis" SIGNOR-262783 SOD1 protein P00441 UNIPROT S100A4 protein P26447 UNIPROT "up-regulates quantity" 9606 BTO:0000452 BTO:0001279 31623154 f "P00441:p.Gly94Ala (mutation increasing interaction)" "We demonstrated the increased expression of S100A4 also in fibroblasts derived from amyotrophic lateral sclerosis (ALS) patients carrying SOD1 pathogenic variants." SIGNOR-262784 SOD1 protein P00441 UNIPROT KARS1 protein Q15046 UNIPROT "down-regulates quantity by destabilization" binding 9534 BTO:0004055 18715867 t "P00441:p.Gly94Ala (mutation causing interaction); P00441:p.Gly86Arg (mutation causing interaction)" "In the presence of mutant SOD1, mitoKARS displays a high propensity to misfold and aggregate prior to its import into mitochondria, becoming a target for proteasome degradation." SIGNOR-262800 SOD1 protein P00441 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates 10090 BTO:0004488 18519638 f "P00441:p.Gly94Ala (mutation causing interaction); P00441:p.Gly86Arg (mutation causing interaction); P00441:p.Ala5Val (mutation causing interaction)" "To investigate the role of ASK1 in the motor neurotoxicity by SOD1mut, we examined whether SOD1mut activates ASK1 as assessed by in vitro kinase assay. Expression of SOD1mut, but not SOD1wt, activated endogenous ASK1 (Fig. 4A, top panel). We next examined whether SOD1mut-induced ASK1 activation is mediated by ER stress." SIGNOR-262789 SOD1 protein P00441 UNIPROT DERL1 protein Q9BUN8 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 18519638 t "P00441:p.Gly94Ala (mutation causing interaction); P00441:p.Gly86Arg (mutation causing interaction); P00441:p.Ala5Val (mutation causing interaction)" "Various proteins involved in ERAD have been identified recently (Meusser et al. 2005). Among them, components of the retro-translocation machinery including ATPase p97, its cofactors Ufd1 and Npl4, and the ER membrane proteins Derlin-1 and VIMP are of key importance to ERAD function |Here we show that SOD1(mut) specifically interacted with Derlin-1, a component of endoplasmic reticulum (ER)-associated degradation (ERAD) machinery and triggered ER stress through dysfunction of ERAD." SIGNOR-262785 SOD1 protein P00441 UNIPROT EIF2AK3 protein Q9NZJ5 UNIPROT "up-regulates activity" binding 10090 BTO:0004488 18519638 t "P00441:p.Gly94Ala (mutation causing interaction); P00441:p.Gly86Arg (mutation causing interaction); P00441:p.Ala5Val (mutation causing interaction)" "SOD1mut-induced ER stress |we first examined whether SOD1mut induces ER stress in NSC34 motor neurons, as assessed by band-shift analyses of the ER transmembrane kinase receptors IRE1 and PERK. Adenovirus (Ad)-mediated expression of ALS-linked SOD1mut (SOD1G93A) was detectable within 48 h of infection (Supplemental Fig. S1A). SOD1mut (SOD1A4V, SOD1G85R, and SOD1G93A) but not wild-type SOD1 (SOD1wt) activated IRE1 and PERK" SIGNOR-262787 CP protein P00450 UNIPROT SMO protein Q99835 UNIPROT down-regulates binding 9606 16885213 t gcesareni "Genetic and biochemical studies imply that smo can adopt an active conformation but that it is normally repressed by patched (ptch), a 12-transmembrane protein considered the receptor for hh" SIGNOR-148451 F8 protein P00451 UNIPROT "Factor VIIIa-IXa" complex SIGNOR-C320 SIGNOR "form complex" binding 10090 BTO:0000131 25769543 t lperfetto "The present data point to key roles of FVIII and FIX in FX activation at the site of a platelet thrombus by supporting: (i) thrombin generation, (ii) thrombus growth and platelet phosphatidylserine exposure, and (iii) fibrin formation at the platelet surface. The likely mechanism is that tenase activity via FVIIIa and FIXa, which is confined to the sites of platelet thrombi, generates FXa that directly catalyzes the conversion of prothrombin into thrombin." SIGNOR-263553 ABL1 protein P00519 UNIPROT APBB1 protein O00213 UNIPROT up-regulates phosphorylation Tyr547 VQKFQVYyLGNVPVA 9606 15031292 t lperfetto "The c-abl tyrosine kinase phosphorylates the fe65 adaptor protein to stimulate fe65/amyloid precursor protein nuclear signaling. Here, we show that active c-abl stimulates app/fe65-mediated gene transcription and that this effect is mediated by phosphorylation of fe65 on tyrosine 547 within its second ptb domain." SIGNOR-123476 ABL1 protein P00519 UNIPROT WASL protein O00401 UNIPROT unknown phosphorylation Tyr175 EITTNRFyGPQVNNI 10090 BTO:0002572 16199863 t gcesareni "Mutation of both tyrosines 175 and 256 to phenylalanine was required to abolish Abl-mediated phosphorylation of N-WASP in the presence of Grb2 [€] suggesting that phosphorylation at tyrosine 175 is not critical for comet tail formation by Shigella" SIGNOR-247666 ABL1 protein P00519 UNIPROT WASL protein O00401 UNIPROT "up-regulates activity" phosphorylation Tyr175 EITTNRFyGPQVNNI -1 16199863 t "Abl phosphorylates N-WASP on tyrosines 175 and 256. Phosphorylation at this site stabilizes the active conformation of N-WASP, resulting in comet tail elongation." SIGNOR-251436 ABL1 protein P00519 UNIPROT WASL protein O00401 UNIPROT "up-regulates activity" phosphorylation Tyr256 RETSKVIyDFIEKTG -1 16199863 t "Abl phosphorylates N-WASP on tyrosines 175 and 256. Phosphorylation at this site stabilizes the active conformation of N-WASP, resulting in comet tail elongation." SIGNOR-251437 ABL1 protein P00519 UNIPROT PSMA7 protein O14818 UNIPROT down-regulates phosphorylation Tyr153 QTDPSGTyHAWKANA 9606 16678104 t lperfetto "Proteasome-mediated proteolysis is a primary protein degradation pathway in cells. The present study demonstrates that c-abl and arg (abl-related gene) tyrosine kinases associate with and phosphorylate the proteasome psma7 (alpha4) subunit at tyr-153. Consequently, proteasome-dependent proteolysis is compromised" SIGNOR-146585 ABL1 protein P00519 UNIPROT PSMA7 protein O14818 UNIPROT "up-regulates quantity by stabilization" phosphorylation Tyr106 EDPVTVEyITRYIAS 9606 25620702 t Manara "PSMA7 degradation is suppressed by c-Abl-mediated tyrosine phosphorylation at Y106" SIGNOR-260937 ABL1 protein P00519 UNIPROT PLSCR1 protein O15162 UNIPROT unknown phosphorylation Tyr69 PVPNQPVyNQPVYNQ 9606 11390389 t lperfetto "C-abl tyrosine kinase binds and phosphorylates phospholipid scramblase 1. Phosphorylation was abolished by mutation of tyr residues tyr(69)/tyr(74) within the tandem repeat sequence (68)vynqpvynqp(77) of plscr1" SIGNOR-86013 ABL1 protein P00519 UNIPROT PLSCR1 protein O15162 UNIPROT unknown phosphorylation Tyr69 PVPNQPVyNQPVYNQ 9606 11390389 t Manara "Our data establish that the Abl SH3 domain binds to the N-terminal proline-rich segment of PLSCR1 and that ABL1 phosphorylates Tyr residues of the PLSCR1 polypeptide, most likely Tyr69 and Tyr74 within the tandem repeat sequence" SIGNOR-260807 ABL1 protein P00519 UNIPROT PLSCR1 protein O15162 UNIPROT unknown phosphorylation Tyr74 PVYNQPVyNQPVGAA 9606 11390389 t lperfetto "C-abl tyrosine kinase binds and phosphorylates phospholipid scramblase 1. Phosphorylation was abolished by mutation of tyr residues tyr(69)/tyr(74) within the tandem repeat sequence (68)vynqpvynqp(77) of plscr1" SIGNOR-86017 ABL1 protein P00519 UNIPROT PLSCR1 protein O15162 UNIPROT unknown phosphorylation Tyr74 PVYNQPVyNQPVGAA 9606 11390389 t Manara "Our data establish that the Abl SH3 domain binds to the N-terminal proline-rich segment of PLSCR1 and that ABL1 phosphorylates Tyr residues of the PLSCR1 polypeptide, most likely Tyr69 and Tyr74 within the tandem repeat sequence" SIGNOR-260808 ABL1 protein P00519 UNIPROT SPTLC1 protein O15269 UNIPROT down-regulates phosphorylation Tyr164 KTEEAIIySYGFATI 9606 23629659 t llicata "We demonstrated that the er-resident human protein serine palmitoyltransferase long chain-1 (sptlc1), which is the first enzyme of sphingolipid biosynthesis, is phosphorylated at tyr(164) by the tyrosine kinase abl. this occurred through the specific abl-mediated phosphorylation of sptlc1 on tyr164, leading to the attenuation of its activity." SIGNOR-202003 ABL1 protein P00519 UNIPROT TP73 protein O15350 UNIPROT up-regulates phosphorylation Tyr99 SVPTHSPyAQPSSTF 9606 10391251 t gcesareni "C-abl phosphorylates p73 on a tyrosine residue at position 99 both in vitro and in cells that have been exposed to ionizing radiation. Our results show that c-abl stimulates p73-mediated transactivation and apoptosis." SIGNOR-68931 ABL1 protein P00519 UNIPROT PSTPIP1 protein O43586 UNIPROT unknown phosphorylation Tyr345 PERNEGVyTAIAVQE 10090 BTO:0004055 11163214 t gcesareni "These data suggest that Tyr-344 is a major c-Abl phosphorylation site, or that phosphorylation of Tyr-344 is required for subsequent phosphorylation at other tyrosine residues." SIGNOR-246219 ABL1 protein P00519 UNIPROT PSTPIP1 protein O43586 UNIPROT unknown phosphorylation Tyr345 PERNEGVyTAIAVQE 9606 11163214 t Manara "PSTPIP1 was phosphorylated by ABL1, and growth factor–induced PSTPIP1 phosphorylation was diminished in Abl null fibroblasts." SIGNOR-260809 ABL1 protein P00519 UNIPROT PSTPIP1 protein O43586 UNIPROT "up-regulates activity" phosphorylation Tyr345 PERNEGVyTAIAVQE 9534 BTO:0004055 11163214 t "PSTPIP1 was phosphorylated by c-Abl. Tyr-344 is a major c-Abl phosphorylation site.PSTPIP1 was able to bridge c-Abl to the PEST-type PTPs." SIGNOR-251431 ABL1 protein P00519 UNIPROT PRKN protein O60260 UNIPROT down-regulates phosphorylation Tyr143 SPAGRSIyNSFYVYC 9606 BTO:0000142 20823226 t llicata "Here we show that the nonreceptor tyrosine kinase c-abl phosphorylates tyrosine 143 of parkin, inhibiting parkin's ubiquitin e3 ligase activity and protective function." SIGNOR-167853 ABL1 protein P00519 UNIPROT JAK2 protein O60674 UNIPROT "up-regulates activity" phosphorylation Tyr1007 VLPQDKEyYKVKEPG -1 11593427 t gcesareni "Jak2 peptide substrate studies indicated that the Bcr-Abl and Abl tyrosine kinases specifically phosphorylated Y1007 of Jak2 but only poorly phosphorylated Y1008. Phosphorylation of Y1007 of Jak2 is known to be critical for its tyrosine kinase activation." SIGNOR-245365 ABL1 protein P00519 UNIPROT AHSA1 protein O95433 UNIPROT "up-regulates activity" phosphorylation Tyr223 LTSPEELyRVFTTQE 9606 26235616 t Manara "Here, we show that c-Abl kinase phosphorylates Y223 in human Aha1 (hAha1), promoting its interaction with Hsp90. This, consequently, results in an increased Hsp90 ATPase activity" SIGNOR-260938 ABL1 protein P00519 UNIPROT ABL1 protein P00519 UNIPROT "up-regulates activity" phosphorylation Tyr393 FGLSRLMtGDTYTAH 9606 10964922 t Manara "We demonstrate here that autophosphorylation of ABL1 is intermolecular and stimulates Abl catalytic activity." SIGNOR-260781 ABL1 protein P00519 UNIPROT ABL1 protein P00519 UNIPROT "up-regulates activity" phosphorylation Tyr393 RLMTGDTyTAHAGAK 9606 11781820 t lperfetto "Phosphorylation of tyr412 can occur autocatalytically by a trans-mechanism and cause activation of otherwise inactive c-abl, suggesting a positive feedback loop on c-abl activity." SIGNOR-113659 ABL1 protein P00519 UNIPROT ABL1 protein P00519 UNIPROT "up-regulates activity" phosphorylation Tyr393 RLMTGDTyTAHAGAK 9606 BTO:0001271 8441409 t lperfetto "Sh1 domain autophosphorylation of p210 bcr/abl is required for transformation but not growth factor independence." SIGNOR-39142 ABL1 protein P00519 UNIPROT EGFR protein P00533 UNIPROT up-regulates phosphorylation Tyr1197 STAENAEyLRVAPQS 9606 16943190 t lperfetto "we show that activated Abl phosphorylates the EGFR primarily on tyrosine 1173Furthermore, we show that activated Abl allows the ligand-activated EGFR to escape Cbl-dependent down-regulation by inhibiting the accumulation of Cbl at the plasma membrane in response to epidermal growth factor stimulation and disrupting the formation of the EGFR.Cbl complex without affecting Cbl protein stability. These findings reveal a novel role for Abl in promoting increased cell-surface expression of the EGFR and suggest that Abl/EGFR signaling may cooperate in human" SIGNOR-149277 ABL1 protein P00519 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Tyr219 SIQGHNDyMCPATNQ 9606 BTO:0000150 20101225 t gcesareni "Eralpha can be phosphorylated on two sites, tyrosine 52 (y-52) and tyrosine 219 (y-219). Eralpha phosphorylation by c-abl stabilizes eralpha, resulting in enhanced eralpha transcriptional activity and increased expression of endogenous eralpha target genes." SIGNOR-163562 ABL1 protein P00519 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Tyr52 DSSKPAVyNYPEGAA 9606 BTO:0000150 20101225 t gcesareni "Eralpha can be phosphorylated on two sites, tyrosine 52 (y-52) and tyrosine 219 (y-219). Eralpha phosphorylation by c-abl stabilizes eralpha, resulting in enhanced eralpha transcriptional activity and increased expression of endogenous eralpha target genes." SIGNOR-163566 ABL1 protein P00519 UNIPROT CAT protein P04040 UNIPROT up-regulates phosphorylation Tyr231 NANGEAVyCKFHYKT 9606 12950161 t lperfetto "C-abl and arg phosphorylated catalase at tyr231 and tyr386 in vitro.catalase is a major effector in the defense of aerobic cells against oxidative stress. Recent studies have shown that catalase activity is stimulated by the c-abl and arg tyrosine kinases" SIGNOR-86581 ABL1 protein P00519 UNIPROT CAT protein P04040 UNIPROT up-regulates phosphorylation Tyr386 YRARVANyQRDGPMC 9606 12950161 t lperfetto "C-abl and arg phosphorylated catalase at tyr231 and tyr386 in vitrocatalase is a major effector in the defense of aerobic cells against oxidative stress. Recent studies have shown that catalase activity is stimulated by the c-abl and arg tyrosine kinases" SIGNOR-86585 ABL1 protein P00519 UNIPROT CAT protein P04040 UNIPROT "up-regulates activity" phosphorylation Tyr231 NANGEAVyCKFHYKT 9606 BTO:0000093 12777400 t lperfetto "The SH3 domains of c-Abl and Arg bound directly to catalase at a P293FNP site. c-Abl and Arg phosphorylated catalase at Tyr231 and Tyr386 in vitro and in the response of cells to H2O2" SIGNOR-101298 ABL1 protein P00519 UNIPROT CAT protein P04040 UNIPROT "up-regulates activity" phosphorylation Tyr386 YRARVANyQRDGPMC 9606 BTO:0000093 12777400 t lperfetto "C-abl and arg phosphorylated catalase at tyr231 and tyr386 in vitrocatalase is a major effector in the defense of aerobic cells against oxidative stress. Recent studies have shown that catalase activity is stimulated by the c-abl and arg tyrosine kinases" SIGNOR-101302 ABL1 protein P00519 UNIPROT CAT protein P04040 UNIPROT "up-regulates activity" phosphorylation Tyr386 YRARVANyQRDGPMC 9606 12777400 t Manara "These findings indicate that (i) ABL1 and Arg activate catalase by phosphorylation at both Tyr231 and Tyr386" SIGNOR-260770 ABL1 protein P00519 UNIPROT JUN protein P05412 UNIPROT unknown phosphorylation Tyr170 LHSEPPVyANLSNFN 9606 10637231 t gcesareni "After phosphorylation of c-Jun by Abl on Tyr170, both proteins interacted via the SH2 domain of Abl" SIGNOR-245370 ABL1 protein P00519 UNIPROT JUN protein P05412 UNIPROT "up-regulates activity" phosphorylation Tyr170 LHSEPPVyANLSNFN -1 10637231 t "Active nuclear Abl efficiently phosphorylate c-Jun. After phosphorylation of c-Jun by Abl on Tyr170, both proteins interacted via the SH2 domain of Abl." SIGNOR-251428 ABL1 protein P00519 UNIPROT RB1 protein P06400 UNIPROT unknown phosphorylation Tyr805 RIPGGNIyISPLKSP 9606 BTO:0001271 16158058 t llicata "Rb-induced apoptosis is compromised by abl-catalysed phosphorylation of rb at y805." SIGNOR-140396 ABL1 protein P00519 UNIPROT GPX1 protein P07203 UNIPROT "up-regulates activity" phosphorylation Tyr98 EILNSLKyVRPGGGF 9606 12893824 t lperfetto "GPx1 also functions as a substrate for c-Abl- and Arg-mediated phosphorylation on Tyr-96. The results further show that c-Abl and Arg stimulate GPx activity and that these kinases contribute to GPx-mediated protection of cells against oxidative stress." SIGNOR-104324 ABL1 protein P00519 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates phosphorylation Tyr686 IITEYCRyGDLVDYL 9606 BTO:0000150;BTO:0000527 19275932 t gcesareni "These data are exciting as they indicate that abl kinases not only are activated by pdgfr and promote pdgfr-mediated proliferation and migration,but also act in an intricate negative feedback loop to turn-off pdgfr-mediated chemotaxis." SIGNOR-184552 ABL1 protein P00519 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates phosphorylation Tyr970 GEGYKKKyQQVDEEF 9606 BTO:0000150;BTO:0000527 19275932 t gcesareni "These data are exciting as they indicate that abl kinases not only are activated by pdgfr and promote pdgfr-mediated proliferation and migration,but also act in an intricate negative feedback loop to turn-off pdgfr-mediated chemotaxis." SIGNOR-184556 ABL1 protein P00519 UNIPROT PDGFRB protein P09619 UNIPROT "down-regulates activity" phosphorylation Tyr934 PAHASDEiYEIMQKC 9606 19275932 t Manara "C-Abl phosphorylates three tyrosine residues on PDGFR-β (Y686, Y934, Y970) | These data are exciting as they indicate that abl kinases not only are activated by pdgfr and promote pdgfr-mediated proliferation and migration,but also act in an intricate negative feedback loop to turn-off pdgfr-mediated chemotaxis." SIGNOR-260931 ABL1 protein P00519 UNIPROT TOP1 protein P11387 UNIPROT "up-regulates activity" phosphorylation Tyr268 AKMLDHEyTTKEIFR 9606 15448168 t Manara "This study demonstrates that ABL1-dependent phosphorylation up-regulates topo I activity. The ABL1 SH3 domain bound directly to the N-terminal region of topo I. The results demonstrate that ABL1 phosphorylated topo I at Tyr268 in core subdomain II." SIGNOR-260775 ABL1 protein P00519 UNIPROT MYOD1 protein P15172 UNIPROT "down-regulates activity" phosphorylation Tyr30 FATTDDFyDDPCFDSP 9606 BTO:0000007 12415271 t "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 ABL1 protein P00519 UNIPROT CD19 protein P15391 UNIPROT "up-regulates activity" phosphorylation Tyr508 EDMRGILyAAPQLRS 10090 11120811 t gcesareni "The results revealed that only tyrosine (Y)490 of CD19 was phosphorylated by c-Abl." SIGNOR-245283 ABL1 protein P00519 UNIPROT VAV1 protein P15498 UNIPROT up-regulates phosphorylation 9606 BTO:0001271 11790798 t gcesareni "Thus, the c-terminal tail of vav serves as a direct substrate of bcr-abl in vitro." SIGNOR-114091 ABL1 protein P00519 UNIPROT MUC1 protein P15941 UNIPROT "up-regulates quantity by stabilization" phosphorylation Tyr1243 NGGSSLSyTNPAVAA 9606 16888623 t Manara "The results demonstrate that ABL1 phosphorylates MUC1 on Tyr-60 and forms a complex with MUC1 by binding of the ABL1 SH2 domain to the pTyr-60 site. " SIGNOR-260830 ABL1 protein P00519 UNIPROT NCK1 protein P16333 UNIPROT up-regulates phosphorylation Tyr105 VDPGERLyDLNMPAY 9606 22327338 t lperfetto "Activated c-abl reduces the amplitude of mitogen-activated protein kinases (erk1/2, jnks and p38) activation in a dose-dependent manner by a negative feedback mechanism. By analysis of the adaptor proteins nck1 and grb2 mutants we further show that the negative loop on p38 is mediated by c-abl phosphorylation at tyrosine 105 of the adaptor protein nck1" SIGNOR-196043 ABL1 protein P00519 UNIPROT CEBPB protein P17676 UNIPROT up-regulates phosphorylation Tyr78 RAIDFSPyLEPLGAP 9606 BTO:0000007 19563810 t gcesareni "The y79 amino acid residue of c/ebpbeta was phosphorylated by c-abl or arg. The phosphorylation of c/ebpbeta resulted in an increased c/ebpbeta stability and a potentiation of c/ebpbeta transcription activation activity in cells" SIGNOR-186423 ABL1 protein P00519 UNIPROT DDX5 protein P17844 UNIPROT up-regulates phosphorylation Tyr593 NGMNQQAyAYPATAA 9606 17018282 t llicata "These results suggested that p68 was phosphorylated by c-abl in ht-29 cells under stimulation of pdgf. we demonstrated that tyrosine phosphorylation of p68 at y593 mediated pdgf-stimulated epithelial-mesenchymal transition (emt). We showed that pdgf treatment led to phosphorylation of p68 at y593 in the cell nucleus. The y593-phosphorylated p68 (referred to as phosphor-p68) promotes beta-catenin nuclear translocation via a wnt-independent pathway." SIGNOR-149988 ABL1 protein P00519 UNIPROT LGALS3 protein P17931 UNIPROT unknown phosphorylation Tyr107 AYPATGPyGAPAGPL 9606 20600357 t llicata "In this report we have identified novel tyrosine phosphorylation sites in galectin-3 as well as the kinase responsible for its phosphorylation. Our results demonstrate that tyrosines at positions 79, 107 and 118 can be phosphorylated in vitro and in vivo by c-abl kinase. our results demonstrate that cells expressing galectin-3 y107f variant showed reduced migration in wound healing assay ( fig. 5). This result confirms the role of galectin-3 tyrosine phosphorylation in cell motility." SIGNOR-166493 ABL1 protein P00519 UNIPROT LGALS3 protein P17931 UNIPROT unknown phosphorylation Tyr118 AGPLIVPyNLPLPGG 9606 20600357 t llicata "In this report we have identified novel tyrosine phosphorylation sites in galectin-3 as well as the kinase responsible for its phosphorylation. Our results demonstrate that tyrosines at positions 79, 107 and 118 can be phosphorylated in vitro and in vivo by c-abl kinase. our results demonstrate that cells expressing galectin-3 y107f variant showed reduced migration in wound healing assay ( fig. 5). This result confirms the role of galectin-3 tyrosine phosphorylation in cell motility." SIGNOR-166497 ABL1 protein P00519 UNIPROT LGALS3 protein P17931 UNIPROT unknown phosphorylation Tyr79 GAPAPGVyPGPPSGP 9606 20600357 t llicata "In this report we have identified novel tyrosine phosphorylation sites in galectin-3 as well as the kinase responsible for its phosphorylation. Our results demonstrate that tyrosines at positions 79, 107 and 118 can be phosphorylated in vitro and in vivo by c-abl kinase. our results demonstrate that cells expressing galectin-3 y107f variant showed reduced migration in wound healing assay ( fig. 5). This result confirms the role of galectin-3 tyrosine phosphorylation in cell motility." SIGNOR-166501 ABL1 protein P00519 UNIPROT EPHB2 protein P29323 UNIPROT down-regulates phosphorylation 9606 BTO:0000938 11494128 t lperfetto "Two-hybrid screens identified regions of abl and arg that bind to the ephb2 and epha4 receptors, suggesting a novel signaling connection involving the two kinase families.The connection between EphB2 and Abl/Arg appears to be reciprocal. Activated EphB2 causes tyrosine phosphorylation of Abl and Arg, and vice versa. Interestingly, treatment of COS cells and B35 neuronal-like cells with ephrin-B1 to activate endogenous EphB2 decreased the kinase activity of endogenous Abl." SIGNOR-109668 ABL1 protein P00519 UNIPROT PTPN6 protein P29350 UNIPROT unknown phosphorylation Tyr564 SKHKEDVyENLHTKN -1 12468540 t gcesareni "Incorporation of Pmp at the 536 site led to 4-fold stimulation of the SHP-1 tyrosine phosphatase activity whereas incorporation at the 564 site led to no effect" SIGNOR-246240 ABL1 protein P00519 UNIPROT PTPN6 protein P29350 UNIPROT unknown phosphorylation Tyr564 SKHKEDVyENLHTKN 9606 BTO:0001412 8692915 t gcesareni "Treatment with ionizing radiation is associated with c-Abl-dependent tyrosine phosphorylation of SHPTP1. The results demonstrate that the SH3 domain of c-Abl interacts with a WPDHGVPSEP motif (residues 417-426) in the catalytic domain of SHPTP1 and that c-Abl phosphorylates C terminal Y536 and Y564 sites." SIGNOR-246231 ABL1 protein P00519 UNIPROT PTPN6 protein P29350 UNIPROT "up-regulates activity" phosphorylation Tyr536 QKGQESEyGNITYPP -1 12468540 t gcesareni "Incorporation of Pmp at the 536 site led to 4-fold stimulation of the SHP-1 tyrosine phosphatase activity whereas incorporation at the 564 site led to no effect" SIGNOR-246236 ABL1 protein P00519 UNIPROT PTPN6 protein P29350 UNIPROT "up-regulates activity" phosphorylation Tyr536 QKGQESEyGNITYPP 9606 BTO:0001412 8692915 t gcesareni "Treatment with ionizing radiation is associated with c-Abl-dependent tyrosine phosphorylation of SHPTP1. The results demonstrate that the SH3 domain of c-Abl interacts with a WPDHGVPSEP motif (residues 417-426) in the catalytic domain of SHPTP1 and that c-Abl phosphorylates C terminal Y536 and Y564 sites." SIGNOR-246227 ABL1 protein P00519 UNIPROT PTPN6 protein P29350 UNIPROT "up-regulates activity" phosphorylation Tyr536 QKGQESEyGNITYPP 9606 8692915 t Manara "The results demonstrate that the SH3 domain of ABL1 interacts with a WPDHGVPSEP motif (residues 417-426) in the catalytic domain of SHPTP1 and that ABL1 phosphorylates C terminal Y536 and Y564 sites." SIGNOR-260820 ABL1 protein P00519 UNIPROT PTPN6 protein P29350 UNIPROT "up-regulates activity" phosphorylation Tyr564 SKHKEDVyENLHTKN 9606 BTO:0001412 8692915 t "The SH3 domain of c-Abl interacts with a WPDHGVPSEP motif (residues 417-426) in the catalytic domain of SHPTP1 and that c-Abl phosphorylates C terminal Y536 and Y564 sites. The functional significance of the c-Abl-SHPTP1 interaction is supported by the demonstration that, like c-Abl, SHPTP1 regulates the induction of Jun kinase activity following DNA damage." SIGNOR-251433 ABL1 protein P00519 UNIPROT PTPN6 protein P29350 UNIPROT "up-regulates activity" phosphorylation Tyr564 SKHKEDVyENLHTKN 9606 8692915 t Manara "The results demonstrate that the SH3 domain of ABL1 interacts with a WPDHGVPSEP motif (residues 417-426) in the catalytic domain of SHPTP1 and that ABL1 phosphorylates C terminal Y536 and Y564 sites." SIGNOR-260821 ABL1 protein P00519 UNIPROT PPARG protein P37231 UNIPROT "up-regulates quantity" phosphorylation Tyr102 YDLKLQEyQSAIKVE 10090 BTO:0000007;BTO:0000011 25368164 t "We show that the tyrosine kinase Abelson murine leukemia viral oncogene (cAbl) is an adipogenic key regulator. c-Abl promotes adipogenesis by phosphorylation and subsequent stabilization of PPARγ." SIGNOR-262297 ABL1 protein P00519 UNIPROT PPARG protein P37231 UNIPROT "up-regulates quantity" phosphorylation Tyr78 SSISTPHyEDIPFTR 10090 25368164 t "We show that the tyrosine kinase Abelson murine leukemia viral oncogene (cAbl) is an adipogenic key regulator. c-Abl promotes adipogenesis by phosphorylation and subsequent stabilization of PPARγ." SIGNOR-255912 ABL1 protein P00519 UNIPROT MTOR protein P42345 UNIPROT down-regulates phosphorylation 9606 10753870 t gcesareni "Abl binds directly to raft1 and phosphorylates raft1 in vitro and in vivo. c-abl inhibits autophosphorylation of raft1 and raft1-mediated phosphorylation p70(s6k)." SIGNOR-76562 ABL1 protein P00519 UNIPROT ABL2 protein P42684 UNIPROT up-regulates phosphorylation Tyr261 GLVTTLHyPAPKCNK 9606 15735735 t lperfetto "The results show that arg is stabilized in response to 0.1 mm h2o2 by autophosphorylation of y-261, consistent with involvement of the arg kinase function in regulating arg levels. The results further demonstrate that c-abl-mediated phosphorylation of arg on y-261 similarly confers arg stabilization" SIGNOR-134396 ABL1 protein P00519 UNIPROT RAD52 protein P43351 UNIPROT "up-regulates activity" phosphorylation Tyr104 DLNNGKFyVGVCAFV 9606 BTO:0000007 12379650 t "C-Abl tyrosine kinase associates with and phosphorylates Rad52 on tyrosine 104. he functional significance of c-Abl-dependent phosphorylation of Rad52 is underscored by our findings that cells that express the phosphorylation-resistant Rad52 mutant, in which tyrosine 104 is replaced by phenylalanine, exhibit compromised nuclear foci formation in response to IR." SIGNOR-251435 ABL1 protein P00519 UNIPROT RAD52 protein P43351 UNIPROT "up-regulates activity" phosphorylation Tyr104 DLNNGKFyVGVCAFV 9606 BTO:0000007 12379650 t gcesareni "We show here that c-Abl tyrosine kinase associates with and phosphorylates Rad52 on tyrosine 104. Importantly, the very same site of Rad52 is phosphorylated on exposure of cells to ionizing radiation (IR)." SIGNOR-247661 ABL1 protein P00519 UNIPROT CRK protein P46108 UNIPROT "down-regulates activity" phosphorylation Tyr221 GGPEPGPyAQPSVNT 9606 21602891 t lperfetto "Abl induces phosphorylation at y251 in vivo, and that the kinetics of phosphorylation at y251 and the negative regulatory y221 site in vitro are similar." SIGNOR-173845 ABL1 protein P00519 UNIPROT CRK protein P46108 UNIPROT "down-regulates activity" phosphorylation Tyr221 GGPEPGPyAQPSVNT 9606 21779437 t lperfetto "Negative regulation of crk by abl is essential for the antitumorigenic effects of ephrinb2,similar pathways may operate for crkl" SIGNOR-175135 ABL1 protein P00519 UNIPROT CDKN1B protein P46527 UNIPROT "down-regulates activity" phosphorylation Tyr88 KGSLPEFyYRPPRPP -1 17254966 t "Lyn and Abl phosphorylate Y88 of p27 in vitro. phosphorylation of Y88 in p27 impaired its ability to inhibit the bound kinase complex" SIGNOR-251426 ABL1 protein P00519 UNIPROT CDKN1B protein P46527 UNIPROT "down-regulates quantity" phosphorylation Tyr88 KGSLPEFyYRPPRPP 9606 BTO:0000007;BTO:0000567 17254966 t gcesareni "A conserved tyrosine residue (Y88) in the Cdk-binding domain of p27 can be phosphorylated by the Src-family kinase Lyn and the oncogene product BCR-ABL" SIGNOR-245293 ABL1 protein P00519 UNIPROT YAP1 protein P46937 UNIPROT up-regulates phosphorylation Tyr407 SGLSMSSySVPRTPD 9606 18280240 t llicata "In this study, we show that c-abl directly phosphorylates yap1 at position y357 in response to dna damage. Tyrosine-phosphorylated yap1 is a more stable protein that displays higher affinity to p73 and selectively coactivates p73 proapoptotic target genes." SIGNOR-160860 ABL1 protein P00519 UNIPROT PLK1 protein P53350 UNIPROT "up-regulates activity" phosphorylation Tyr425 SDKYGLGyQLCDNSV 9606 27899378 t Manara "C-ABL can directly phosphorylate PLK1 and activate PLK1. | The above results indicate that c-ABL–mediated PLK1 Y425 phosphorylation regulates PLK1 ubiquitination and stability." SIGNOR-260935 ABL1 protein P00519 UNIPROT CASP9 protein P55211 UNIPROT up-regulates phosphorylation Tyr153 RGNADLAyILSMEPC 9606 15657060 t gcesareni "C-abl phosphorylates casp9 on tyr-153 in vitro and in vivo in response to dna damage.The Present results demonstrate that c-abl binds directly to casp9." SIGNOR-133260 ABL1 protein P00519 UNIPROT CASP9 protein P55211 UNIPROT "up-regulates activity" phosphorylation Tyr153 LAYILSMePCGHCLI 9606 15657060 t Manara "We show that ABL1 phosphorylates caspase-9 on Tyr-153 in vitro and in cells treated with DNA damaging agents. ! Moreover, inhibition of ABL1 with STI571 blocked DNA damage-induced autoprocessing of caspase-9 to the p35 subunit and activation of caspase-3." SIGNOR-260792 ABL1 protein P00519 UNIPROT RACK1 protein P63244 UNIPROT up-regulates phosphorylation Tyr52 LTRDETNyGIPQRAL 9606 19423701 t lperfetto "Phosphorylation of rack1 on tyrosine 52 by c-abl is required for insulin-like growth factor i-mediated regulation of focal adhesion kinase.Tyrosine 52 is further shown to be phosphorylated by c-abl kinase, and the c-abl inhibitor sti571 disrupts fak interaction with rack1" SIGNOR-185649 ABL1 protein P00519 UNIPROT CDK5 protein Q00535 UNIPROT "up-regulates activity" phosphorylation Tyr15 EKIGEGTyGTVFKAK 9534 BTO:0000298 10896159 t gcesareni "Phosphorylation of Cdk5 by c-Abl occurs on tyrosine 15 (Y15), which is stimulatory for p35/Cdk5 kinase activity." SIGNOR-245288 ABL1 protein P00519 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation Tyr276 SDEDDEVyQVTVYQA 9606 21081495 t lperfetto "Mdm2 has three known c-abl phosphorylation sites (tyr276, tyr394, and tyr405)these data show that c-abl is important for reducing mdm2 and mdmx protein levels after genotoxic stress and suggest another cellular mechanism for the stabilization and activation of p53." SIGNOR-169699 ABL1 protein P00519 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation Tyr405 STSSSIIySSQEDVK 9606 21081495 t lperfetto "Mdm2 has three known c-abl phosphorylation sites (tyr276, tyr394, and tyr405)these data show that c-abl is important for reducing mdm2 and mdmx protein levels after genotoxic stress and suggest another cellular mechanism for the stabilization and activation of p53." SIGNOR-169703 ABL1 protein P00519 UNIPROT MDM2 protein Q00987 UNIPROT "down-regulates activity" phosphorylation Tyr394 QSQESEDySQPSTSS 9606 12110584 t gcesareni "C-abl binds and phosphorylates mdm2 in vivo and in vitro;phosphorylation of mdm2 by c-abl impairs the inhibition of p53 by mdm2." SIGNOR-90512 ABL1 protein P00519 UNIPROT ERCC6 protein Q03468 UNIPROT "up-regulates activity" phosphorylation Tyr932 GANRVVIyDPDWNPS 9606 17626041 t Regulation miannu "N-terminal region of CSB interacts with the SH3 domain of c-Abl in vitro and in vivo. In addition, c-Abl kinase phosphorylates CSB at Tyr932. our results suggest that c-Abl interacts with and tyrosine phosphorylates CSB. This interaction may play an important role in the response to oxidative stress, resulting in activation of c-Abl, tyrosine phosphorylation of CSB and more efficient BER of oxidative DNA damage. Tyrosine-phosphorylated CSB may serve as a signal for repair proteins to localize to DNA damage and may help maintain active transcription in the nucleolus." SIGNOR-251933 ABL1 protein P00519 UNIPROT UBE3A protein Q05086 UNIPROT "down-regulates activity" phosphorylation Tyr659 GDSHPVLyQSLKDLL 9606 23581475 t Manara "Our results suggest that c-Abl protects p53 from HPV-E6-E6AP complex-mediated degradation by phosphorylating E6AP and impairing its E3 ligase activity" SIGNOR-260930 ABL1 protein P00519 UNIPROT BTK protein Q06187 UNIPROT "down-regulates activity" phosphorylation Tyr223 LKKVVALyDYMPMNA 9606 12445832 t Manara "In this report we describe for the first time that ABL1 and Btk physically interact and that ABL1 can phosphorylate tyrosine 223 in the SH3 domain of Btk. | This is presumably due to the negative regulatory effectof Btk SH3 domain phosphorylation caused by ABL1,which would result in a decreased catalytic activity ofBtk resulting in impaired autophosphorylation." SIGNOR-260801 ABL1 protein P00519 UNIPROT BTK protein Q06187 UNIPROT unknown phosphorylation Tyr223 LKKVVALyDYMPMNA 9606 BTO:0000567 12445832 t gcesareni "In this report we describe for the first time that c-Abl and Btk physically interact and that c-Abl can phosphorylate tyrosine 223 in the SH3 domain of Btk" SIGNOR-245278 ABL1 protein P00519 UNIPROT RAD51 protein Q06609 UNIPROT down-regulates phosphorylation Tyr54 HTVEAVAyAPKKELI 9606 9461559 t llicata "Here we demonstrate that c-abl interacts constitutively with rad51. We show that c-abl phosphorylates rad51 on tyr-54 in vitro. The results also show that treatment of cells with ionizing radiation induces c-abl-dependent phosphorylation of rad51. Phosphorylation of rad51 by c-abl inhibits the binding of rad51 to dna and the function of rad51 in atp-dependent dna strand exchange reactions." SIGNOR-55482 ABL1 protein P00519 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates phosphorylation 9606 10212258 t gcesareni "C-abl phosphorylates rad51 in vitro and in vivo. In assays using purified components, phosphorylation of rad51 by c-abl enhances complex formation between rad51 and rad52, which cooperates with rad51 in recombination and repair" SIGNOR-67069 ABL1 protein P00519 UNIPROT RAD51 protein Q06609 UNIPROT "up-regulates activity" phosphorylation Tyr315 ETRICKIyDSPCLPE 9534 BTO:0000298 10212258 t "C-Abl phosphorylates Rad51 in vitro and in vivo. phosphorylation of Rad51 by c-Abl enhances complex formation between Rad51 and Rad52, which cooperates with Rad51 in recombination and repair. c-Abl phosphorylates Rad51 Tyr315" SIGNOR-251434 ABL1 protein P00519 UNIPROT RAD51 protein Q06609 UNIPROT "up-regulates activity" phosphorylation Tyr315 ETRICKIyDSPCLPE 9534 BTO:0000298 10212258 t gcesareni "Mutation of Rad51 Tyr315, but not Tyr205, Tyr191, or Tyr54 to phenylalanine abolished Rad51 tyrosine phosphorylation by c-Abl (Fig. 3 b). These results strongly suggest that c-Abl phosphorylates Rad51 Tyr315 in vivo" SIGNOR-247594 ABL1 protein P00519 UNIPROT RAD51 protein Q06609 UNIPROT "up-regulates activity" phosphorylation Tyr315 ETRICKIyDSPCLPE 9606 10212258 t Manara "Tyrosine Phosphorylation of Rad51 by ABL1 Enhances the Interaction between Rad51 and Rad52 | our studies of Rad51·Rad52 complex formation in vitro and in vivo suggest that the ATM and ABL1-mediated signaling is likely to promote repair given the biochemical evidence that Rad51 acts in concert with Rad52 in homologous recombination" SIGNOR-260777 ABL1 protein P00519 UNIPROT RAD51 protein Q06609 UNIPROT "up-regulates activity" phosphorylation Tyr315 ETRICKIyDSPCLPE 10090 BTO:0002883 11684015 t gcesareni "Phosphorylation of the RAD51 Tyr-315 residue by BCR/ABL appears essential for enhanced DSB repair and drug resistance" SIGNOR-247599 ABL1 protein P00519 UNIPROT STK4 protein Q13043 UNIPROT "up-regulates activity" phosphorylation Tyr433 KIPQDGDyEFLKSWT 10116 21715626 t Manara "In the present study, we demonstrate that the protein kinase c-Abl phosphorylates MST1 at Y433, which triggers the stabilization and activation of MST1." SIGNOR-260927 ABL1 protein P00519 UNIPROT STK3 protein Q13188 UNIPROT up-regulates phosphorylation Tyr81 MQQCDSPyVVKYYGS 9606 BTO:0000938 22590567 t llicata "We demonstrate that c-abl kinase phosphorylates mst2 at an evolutionarily conserved site, y81, within the kinase domain. We further show that the phosphorylation of mst2 by c-abl leads to the disruption of the interaction with raf-1 proteins and the enhancement of homodimerization of mst2 proteins. It thereby enhances the mst2 activation and induces neuronal cell death." SIGNOR-197538 ABL1 protein P00519 UNIPROT ATR protein Q13535 UNIPROT up-regulates phosphorylation Tyr291 DTDQLKLyEEPLSKL 9606 20798688 t lperfetto "C-abl can phosphorylate atr on y291 and y310 and this phosphorylation appears to have a positive role in atr activation under genotoxic stress." SIGNOR-167632 ABL1 protein P00519 UNIPROT ATR protein Q13535 UNIPROT up-regulates phosphorylation Tyr310 FPFEAEAyRNIEPVY 9606 20798688 t lperfetto "C-abl can phosphorylate atr on y291 and y310 and this phosphorylation appears to have a positive role in atr activation under genotoxic stress." SIGNOR-167636 ABL1 protein P00519 UNIPROT RIN1 protein Q13671 UNIPROT up-regulates phosphorylation 9606 9144171 t gcesareni "We also report that the amino-terminal domain of rin1 contains sequences that can mediate interactions with the abl tyrosine kinase and that rin1 is itself tyrosine phosphorylated by c-abl." SIGNOR-48142 ABL1 protein P00519 UNIPROT RAPGEF1 protein Q13905 UNIPROT unknown phosphorylation Tyr504 APIPSVPyAPFAAIL 9606 20581864 t llicata "Activation of endogenous c-abl by oxidative stress was associated with phosphorylation of cellular c3g on y504. Inhibition of c3g expression and function using rnai or dominant-negative approaches inhibited c-abl-mediated cell death." SIGNOR-166422 ABL1 protein P00519 UNIPROT WRN protein Q14191 UNIPROT up-regulates phosphorylation 9606 BTO:0000567;BTO:0001271 12944467 t gcesareni "We thus hypothesized that wrn may interact with the abl tyrosine kinase in the dna damage response. Here, we provide evidence for a functional and physical interaction between wrn and c-abl, including wrn relocalization in response to dna damage, suggesting that this protein-protein interaction participates in a shared pathway of genome surveillance." SIGNOR-86497 ABL1 protein P00519 UNIPROT RBM39 protein Q14498 UNIPROT "up-regulates activity" phosphorylation Tyr95 DRRFRGRyRSPYSGP 9606 BTO:0000007 27018250 t miannu "In this paper, we report that RBM39 interacts with the nonreceptor tyrosine kinase c-Abl. Both the Src homology (SH) 2 and SH3 domains of c-Abl interact with RBM39. The major tyrosine phosphorylation sites on RBM39 that are phosphorylated by c-Abl are Y95 and Y99, as demonstrated by liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) and mutational analysis. c-Abl was shown boost the transcriptional coactivation activity of RBM39 for ERα and PRβ in a tyrosine kinase-dependent manner." SIGNOR-262609 ABL1 protein P00519 UNIPROT RBM39 protein Q14498 UNIPROT "up-regulates activity" phosphorylation Tyr99 RGRYRSPySGPKFNS 9606 BTO:0000007 27018250 t miannu "In this paper, we report that RBM39 interacts with the nonreceptor tyrosine kinase c-Abl. Both the Src homology (SH) 2 and SH3 domains of c-Abl interact with RBM39. The major tyrosine phosphorylation sites on RBM39 that are phosphorylated by c-Abl are Y95 and Y99, as demonstrated by liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) and mutational analysis. c-Abl was shown boost the transcriptional coactivation activity of RBM39 for ERα and PRβ in a tyrosine kinase-dependent manner." SIGNOR-262610 ABL1 protein P00519 UNIPROT LASP1 protein Q14847 UNIPROT up-regulates phosphorylation Tyr171 IPTSAPVyQQPQQQP 9606 BTO:0000150 15138294 t llicata "C-abl activation by apoptotic agents specifically promotes phosphorylation of lasp-1 at tyrosine 171, which is associated with the loss of lasp-1 localization to focal adhesions and induction of cell death. Thus, lasp-1 is a dynamic focal adhesion protein necessary for cell migration and survival in response to growth factors and ecm proteins." SIGNOR-124719 ABL1 protein P00519 UNIPROT PRKD1 protein Q15139 UNIPROT unknown phosphorylation Tyr432 KEGWMVHyTSKDTLR 9606 BTO:0000567 12637538 t gcesareni "Here we report that PKD is tyrosine-phosphorylated within the PH domain, leading to activation. [..] Mutation of the other two sites, Tyr432 and Tyr502, had no significant influence on PKD activity." SIGNOR-246211 ABL1 protein P00519 UNIPROT PRKD1 protein Q15139 UNIPROT unknown phosphorylation Tyr502 TTANVVYyVGENVVN 9606 BTO:0000567 12637538 t gcesareni "Here we report that PKD is tyrosine-phosphorylated within the PH domain, leading to activation. [..] Mutation of the other two sites, Tyr432 and Tyr502, had no significant influence on PKD activity." SIGNOR-246215 ABL1 protein P00519 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Tyr463 NDTGSRYyKEIPLSE 9606 12637538 t llicata "By using a phospho-specific antibody, we show that abl directly phosphorylates pkd at tyr(463) in vitro, and in cells phosphorylation of this site is sufficient to mediate full activation of pkd" SIGNOR-99255 ABL1 protein P00519 UNIPROT PRKD1 protein Q15139 UNIPROT "up-regulates activity" phosphorylation Tyr463 NDTGSRYyKEIPLSE 9606 BTO:0000567 12637538 t "Abl Phosphorylates and Activates PKD through Tyr463 Phosphorylation" SIGNOR-251430 ABL1 protein P00519 UNIPROT PRKD1 protein Q15139 UNIPROT "up-regulates activity" phosphorylation Tyr463 NDTGSRYyKEIPLSE 9606 12637538 t Manara "We show that Abl directly phosphorylates PKD at Tyr(463) in vitro, and in cells phosphorylation of this site is sufficient to mediate full activation of PKD" SIGNOR-260791 ABL1 protein P00519 UNIPROT MYLK protein Q15746 UNIPROT up-regulates phosphorylation Tyr231 NQDDVGVyTCLVVNG 9606 BTO:0000763 20861316 t lperfetto "Nonmuscle myosin light chain kinase (nmmlck), a multi-functional cytoskeletal protein critical to vascular homeostasis, is highly regulated by tyrosine phosphorylation. We identified multiple novel c-abl-mediated nmmlck phosphorylation sites by mass spectroscopy analysis (including y231, y464, y556, y846) and examined their influence on nmmlck function and human lung endothelial cell (ec) barrier regulation. Tyrosine phosphorylation of nmmlck increased kinase activity" SIGNOR-167989 ABL1 protein P00519 UNIPROT MYLK protein Q15746 UNIPROT up-regulates phosphorylation Tyr464 QEGSIEVyEDAGSHY 9606 BTO:0000763 20861316 t lperfetto "We identified multiple novel c-abl-mediated nmmlck phosphorylation sites by mass spectroscopy analysis (including y231, y464, y556, y846) and examined their influence on nmmlck function and human lung endothelial cell (ec) barrier regulation. Tyrosine phosphorylation of nmmlck increased kinase activity" SIGNOR-167993 ABL1 protein P00519 UNIPROT MYLK protein Q15746 UNIPROT up-regulates phosphorylation Tyr556 LNGQPIQyARSTCEA 9606 BTO:0000763 20861316 t lperfetto "Nonmuscle myosin light chain kinase (nmmlck), a multi-functional cytoskeletal protein critical to vascular homeostasis, is highly regulated by tyrosine phosphorylation. We identified multiple novel c-abl-mediated nmmlck phosphorylation sites by mass spectroscopy analysis (including y231, y464, y556, y846) and examined their influence on nmmlck function and human lung endothelial cell (ec) barrier regulation. Tyrosine phosphorylation of nmmlck increased kinase activity" SIGNOR-167997 ABL1 protein P00519 UNIPROT MYLK protein Q15746 UNIPROT up-regulates phosphorylation Tyr846 DGGGSDRyGSLRPGW 9606 BTO:0000763 20861316 t lperfetto "Nonmuscle myosin light chain kinase (nmmlck), a multi-functional cytoskeletal protein critical to vascular homeostasis, is highly regulated by tyrosine phosphorylation. We identified multiple novel c-abl-mediated nmmlck phosphorylation sites by mass spectroscopy analysis (including y231, y464, y556, y846) and examined their influence on nmmlck function and human lung endothelial cell (ec) barrier regulation. Tyrosine phosphorylation of nmmlck increased kinase activity" SIGNOR-168001 ABL1 protein P00519 UNIPROT RAPH1 protein Q70E73 UNIPROT "up-regulates activity" phosphorylation Tyr1226 GGSHISGyATLRRGP -1 20417104 t miannu "Here we show that phosphorylation of Lpd by c-Abl increases its interaction with Ena/VASP proteins. This analysis revealed that, in vitro, four Lpd peptides harboring tyrosines (Y426, Y456, Y513, Y1226) are highly phosphorylated, and eight additional peptides are phosphorylated to a lesser extent (Figure 1C)." SIGNOR-262605 GAST protein P01350 UNIPROT EGR1 protein P18146 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000269 22228178 f "Gastrin inhibited proliferation of colon cancer cells by suppressing expression of EGR1 and AE2 and by blocking ERK phosphorylation." SIGNOR-254252 ABL1 protein P00519 UNIPROT RAPH1 protein Q70E73 UNIPROT "up-regulates activity" phosphorylation Tyr426 LLRASGIyYVPKGKA -1 20417104 t miannu "Here we show that phosphorylation of Lpd by c-Abl increases its interaction with Ena/VASP proteins. This analysis revealed that, in vitro, four Lpd peptides harboring tyrosines (Y426, Y456, Y513, Y1226) are highly phosphorylated, and eight additional peptides are phosphorylated to a lesser extent (Figure 1C)." SIGNOR-262606 ABL1 protein P00519 UNIPROT RAPH1 protein Q70E73 UNIPROT "up-regulates activity" phosphorylation Tyr456 NVYYGQDyRNKYKAP -1 20417104 t miannu "Here we show that phosphorylation of Lpd by c-Abl increases its interaction with Ena/VASP proteins. This analysis revealed that, in vitro, four Lpd peptides harboring tyrosines (Y426, Y456, Y513, Y1226) are highly phosphorylated, and eight additional peptides are phosphorylated to a lesser extent (Figure 1C)." SIGNOR-262607 ABL1 protein P00519 UNIPROT RAPH1 protein Q70E73 UNIPROT "up-regulates activity" phosphorylation Tyr513 GKQLYMNyQEALKRT -1 20417104 t miannu "Here we show that phosphorylation of Lpd by c-Abl increases its interaction with Ena/VASP proteins. This analysis revealed that, in vitro, four Lpd peptides harboring tyrosines (Y426, Y456, Y513, Y1226) are highly phosphorylated, and eight additional peptides are phosphorylated to a lesser extent (Figure 1C)." SIGNOR-262608 ABL1 protein P00519 UNIPROT ABI1 protein Q8IZP0 UNIPROT up-regulates phosphorylation Tyr213 PPTVPNDyMTSPARL 9606 21320496 t lperfetto "Abi-1 is an adaptor protein for abelson kinase (c-abl). Here, we identified a new phosphorylation site (y398) in the sh3 domain of abi1, and disruption of y398, combined with the previously identified phosphorylation site y213, significantly weakens the binding of abi-1 to c-abl. Phosphorylation of abi-1 is dependent on c-abl kinase" SIGNOR-172017 ABL1 protein P00519 UNIPROT DGCR8 protein Q8WYQ5 UNIPROT "up-regulates activity" phosphorylation Tyr267 KRRTEEKyGGDSDHP 9606 BTO:0000007 26126715 t miannu "The kinase ABL phosphorylates the microprocessor subunit DGCR8 to stimulate primary microRNA processing in response to DNA damage. When coexpressed in HEK293T cells, ABL phosphorylated DGCR8 at Tyr(267)." SIGNOR-262604 ABL1 protein P00519 UNIPROT DDB2 protein Q92466 UNIPROT down-regulates phosphorylation 9606 12107171 t miannu "C-abl might act as a negative regulator of uv-ddb by phosphorylating ddb2" SIGNOR-90446 ABL1 protein P00519 UNIPROT HDAC2 protein Q92769 UNIPROT "up-regulates quantity by stabilization" phosphorylation Tyr222 IGAGKGKyYAVNFPM 10116 25219501 t Manara "C-Abl stabilizes HDAC2 levels by tyrosine phosphorylation repressing neuronal gene expression in Alzheimer's disease." SIGNOR-260928 ABL1 protein P00519 UNIPROT MAP4K1 protein Q92918 UNIPROT "up-regulates activity" phosphorylation Tyr232 FLMTKSGyQPPRLKE 9606 BTO:0000007 11278340 t "C-Abl phosphorylates HPK1 in cytoplasm and stimulates HPK1 activity. the c-Abl phosphorylation site (YXXP) in HPK1 (Y232QPP; aa 232–235) is localized in HPK1-KD" SIGNOR-251429 ABL1 protein P00519 UNIPROT YTHDC1 protein Q96MU7 UNIPROT down-regulates phosphorylation 9606 15175272 t lperfetto "We show that yt521-b is tyrosine phosphorylated by c-abl in the nucleus.We propose that tyrosine phosphorylation causes sequestration of YT521-B in an insoluble nuclear form, which abolishes the ability of YT521-B to change alternative splice sites." SIGNOR-125167 ABL1 protein P00519 UNIPROT RAD9A protein Q99638 UNIPROT up-regulates phosphorylation Tyr28 SRIGDELyLEPLEDG 9606 11971963 t gcesareni "C-abl phosphorylates the rad9 bcl-2 homology 3 domain (tyr-28) in vitro and in cells exposed to dna-damaging agents. The results also demonstrate that c-abl-mediated phosphorylation of rad9 induces binding of rad9 to the antiapototic bcl-x(l) protein" SIGNOR-86186 ABL1 protein P00519 UNIPROT RAD9A protein Q99638 UNIPROT "up-regulates activity" phosphorylation Tyr28 AVHSLSRiGDELYLE 9606 11971963 t Manara "The SH3 domain of c-Abl interacts directly with the C-terminal region of Rad9. c-Abl phosphorylates the Rad9 Bcl-2 homology 3 domain (Tyr-28) in vitro and in cells exposed to DNA-damaging agents. | c-Abl-mediated phosphorylation of Rad9 induces binding of Rad9 to Bcl-xL |these findings indicate that Rad9 is regulated by a c-Abl-dependent mechanism in the apoptotic response to genotoxic stress." SIGNOR-260843 ABL1 protein P00519 UNIPROT SRCIN1 protein Q9C0H9 UNIPROT unknown phosphorylation Tyr264 IYRKEPLyAAFPGSH 9606 BTO:0000142 23383002 t llicata "Furthermore, we identify abl as the major tyrosine kinase that can trigger p140cap phosphorylation on these sequences." SIGNOR-200854 ABL1 protein P00519 UNIPROT HIPK2 protein Q9H2X6 UNIPROT "up-regulates activity" phosphorylation Tyr367 TYLQSRYyRAPEIIL 9606 25944899 t Manara "The Tyrosine Kinase c-Abl Promotes Homeodomain-interacting Protein Kinase 2 (HIPK2) Accumulation and Activation in Response to DNA Damage" SIGNOR-260936 ABL1 protein P00519 UNIPROT TP63 protein Q9H3D4 UNIPROT "up-regulates quantity by stabilization" phosphorylation Tyr171 AIPSNTDyPGPHSFD 9606 19783996 t Manara "In cell lines, upon cisplatin treatment, c-Abl phosphorylates TAp63 on specific tyrosine residues. Such modifications affect p63 stability and induce a p63-dependent activation of proapoptotic promoters." SIGNOR-260932 ABL1 protein P00519 UNIPROT TP63 protein Q9H3D4 UNIPROT "up-regulates quantity by stabilization" phosphorylation Tyr290 RQSVLVPyEPPQVGT 9606 19783996 t Manara "In cell lines, upon cisplatin treatment, c-Abl phosphorylates TAp63 on specific tyrosine residues. Such modifications affect p63 stability and induce a p63-dependent activation of proapoptotic promoters." SIGNOR-260933 ABL1 protein P00519 UNIPROT WASF3 protein Q9UPY6 UNIPROT "up-regulates activity" phosphorylation Tyr151 KKDGLKFyTDPSYFF 9606 BTO:0000815 17623672 t "WAVE3-Abl interaction promotes the tyrosine phosphorylation of WAVE3 by Abl, and STI-571, a specific inhibitor of Abl kinase activity, abrogates the Abl-mediated phosphorylation of WAVE3." SIGNOR-262299 ABL1 protein P00519 UNIPROT WASF3 protein Q9UPY6 UNIPROT "up-regulates activity" phosphorylation Tyr248 HASDVTDySYPATPN 9606 BTO:0000815 17623672 t "WAVE3-Abl interaction promotes the tyrosine phosphorylation of WAVE3 by Abl, and STI-571, a specific inhibitor of Abl kinase activity, abrogates the Abl-mediated phosphorylation of WAVE3." SIGNOR-262300 ABL1 protein P00519 UNIPROT WASF3 protein Q9UPY6 UNIPROT "up-regulates activity" phosphorylation Tyr337 LPAQIIEyYNPSGPP 9606 BTO:0000815 17623672 t "WAVE3-Abl interaction promotes the tyrosine phosphorylation of WAVE3 by Abl, and STI-571, a specific inhibitor of Abl kinase activity, abrogates the Abl-mediated phosphorylation of WAVE3." SIGNOR-262301 ABL1 protein P00519 UNIPROT WASF3 protein Q9UPY6 UNIPROT "up-regulates activity" phosphorylation Tyr486 SRRIAVEySDSDDDS 9606 17623672 t "WAVE3-Abl interaction promotes the tyrosine phosphorylation of WAVE3 by Abl, and STI-571, a specific inhibitor of Abl kinase activity, abrogates the Abl-mediated phosphorylation of WAVE3." SIGNOR-259077 ABL1 protein P00519 UNIPROT ROBO1 protein Q9Y6N7 UNIPROT down-regulates phosphorylation Tyr1073 PSGQPTPyATTQLIQ 9606 10892742 t gcesareni "Abl functions to antagonize robo signaling both abl and ena can directly bind to robo's cytoplasmic domain." SIGNOR-78993 GAST protein P01350 UNIPROT CCKBR protein P32239 UNIPROT up-regulates binding 9606 BTO:0000142 10368033 t gcesareni "A segment of five amino acids in the second extracellular loop of the cck-b receptor was shown to be essential for the high affinity of the natural peptide agonits, gastrin," SIGNOR-66987 ABL1 protein P00519 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates phosphorylation Tyr1357 HPQAASIyQSSEMKG 9606 18765637 t lperfetto "Tyrosine phosphorylation of the nuclear receptor coactivator aib1/src-3 is enhanced by abl kinase and is required for its activity in cancer cellstyrosine kinase directly phosphorylates aib1/src-3 at y1357 and modulates the association of aib1 with c-abl, eralpha, the transcriptional cofactor p300," SIGNOR-180571 EGFR protein P00533 UNIPROT SCAMP3 protein O14828 UNIPROT unknown phosphorylation Tyr41 QYATLDVyNPFETRE -1 9658162 t llicata "SCAMP3 Is Tyrosine Phosphorylated by EGFR in Vitro" SIGNOR-251096 EGFR protein P00533 UNIPROT SCAMP3 protein O14828 UNIPROT "up-regulates activity" phosphorylation Tyr41 QYATLDVyNPFETRE -1 9658162 t miannu "In our efforts to identify cellular tyrosine kinases that phosphorylate SCAMPs, we are quite intrigued by the observation that among a number of kinases, only the EGFR exhibits activity toward SCAMPs. EGF catalyzes the progressive phosphorylation of the SCAMPs up to 1 h poststimulation and may enhance colocalization of the EGFR and SCAMP3 within the cell interior. EGF also induces SCAMP-EGFR association, as detected by coimmunoprecipitation, and phosphorylation of SCAMP3 is stimulated by the EGFR in vitro. These results suggest that phosphorylation of SCAMPs, either directly or indirectly, may be functionally linked to the internalization/down-regulation of the EGFR. we have observed that there are two tyrosines conserved in SCAMP1 and SCAMP3, which are not found in SCAMP2. Of these two tyrosines (Tyr37 and Tyr73 in SCAMP1; Tyr 41 and Tyr83 in SCAMP3), we consider Tyr37/41 to be a more likely site for tyrosine phosphorylation" SIGNOR-262858 EGFR protein P00533 UNIPROT PLD2 protein O14939 UNIPROT "up-regulates activity" phosphorylation Tyr179 RLLTMSFyRNYHAMT 9606 BTO:0000007 9837959 t llicata "Using transiently transfected human embryonic kidney fibroblasts (HEK293), we demonstrate here that PLD1 activity, and to a lesser extent PLD2 activity, is stimulated in response to epidermal growth factor (EGF). PLD2, but not PLD1, associates with the EGF receptor in a ligand-independent manner and becomes tyrosine-phosphorylated upon EGF receptor activation. Tyrosine 11 (Tyr-11) of PLD2 was identified as the specific phosphorylation site. Mutation of this residue to phenylalanine enhanced basal activity almost 2-fold" SIGNOR-251095 EGFR protein P00533 UNIPROT HGS protein O14964 UNIPROT "up-regulates activity" phosphorylation Tyr334 ARYLNRNyWEKKQEE 9606 BTO:0000567 12953068 t lperfetto "We have analysed hrs phosphorylation in response to epidermal growth factor (egf) stimulation and show that the evolutionary conserved tyrosines y329 and y334 provide the principal phosphorylation sitesover-expression of wild-type hrs or a double mutant, y329/334f, defective in egf-dependent phosphorylation, substantially retard egf receptor (egfr) degradation" SIGNOR-100246 EGFR protein P00533 UNIPROT SCAMP1 protein O15126 UNIPROT "up-regulates activity" phosphorylation Tyr37 VPPGLDEyNPFSDSR -1 9658162 t miannu "In our efforts to identify cellular tyrosine kinases that phosphorylate SCAMPs, we are quite intrigued by the observation that among a number of kinases, only the EGFR exhibits activity toward SCAMPs. EGF catalyzes the progressive phosphorylation of the SCAMPs up to 1 h poststimulation and may enhance colocalization of the EGFR and SCAMP3 within the cell interior. EGF also induces SCAMP-EGFR association, as detected by coimmunoprecipitation, and phosphorylation of SCAMP3 is stimulated by the EGFR in vitro. These results suggest that phosphorylation of SCAMPs, either directly or indirectly, may be functionally linked to the internalization/down-regulation of the EGFR. we have observed that there are two tyrosines conserved in SCAMP1 and SCAMP3, which are not found in SCAMP2. Of these two tyrosines (Tyr37 and Tyr73 in SCAMP1; Tyr 41 and Tyr83 in SCAMP3), we consider Tyr37/41 to be a more likely site for tyrosine phosphorylation" SIGNOR-262857 EGFR protein P00533 UNIPROT RGS16 protein O15492 UNIPROT up-regulates phosphorylation Tyr177 RFLKSPAyRDLAAQA 9606 BTO:0002181 11602604 t lperfetto "Rgs16 contains two conserved tyrosine residues in the rgs box, tyr(168) and tyr(177), which are predicted sites of phosphorylation. Rgs16 underwent phosphorylation in response to m2 muscarinic receptor or egfr stimulation in hek 293t or cos-7 cells, which required egfr kinase activity. Mutational analysis suggested that rgs16 was phosphorylated on both tyrosine residues (tyr(168) tyr(177)) after egf stimulation.Phosphorylated rgs16 demonstrated enhanced gtpase accelerating (gap) activity on galpha(i). Mutation of tyr(168) to phenylalanine resulted in a 30% diminution in rgs16 gap activity mutation of tyr(177) to phenylalanine had no effect on rgs16 gap activity but also abolished its regulation of g(i)-mediated signal transduction in these cells." SIGNOR-111024 EGFR protein P00533 UNIPROT RGS16 protein O15492 UNIPROT up-regulates phosphorylation Tyr168 TLMEKDSyPRFLKSP 9606 BTO:0000093 12588871 t gcesareni "Phosphorylation on tyr(168) was mediated by the epidermal growth factor receptor (egfr). We show here that endogenous rgs16 is phosphorylated after epidermal growth factor stimulation of mcf-7 cells." SIGNOR-98267 EGFR protein P00533 UNIPROT NCK2 protein O43639 UNIPROT up-regulates binding 9606 10026169 t esanto "Growth factor binding to receptor protein tyrosine kinases (r-ptks)1 induces their dimerization and trans-phosphorylation, creating docking sites for proteins containing sh2 and ptb protein interaction domains. Nck binds to the pdgf and egfr receptors (figure 3c)." SIGNOR-64731 EGFR protein P00533 UNIPROT JAK2 protein O60674 UNIPROT "up-regulates activity" 10090 BTO:0000667 15284024 f "JAK activation occurs upon ligand-mediated receptor multimerization because two JAKs are brought into close proximity, allowing trans-phosphorylation. The activated JAKs subsequently phosphorylate additional targets, including both the receptors and the major substrates, STATs." lperfetto "Two possibilities for STAT activation exist: a janus kinase (JAK)-dependent and a JAK-independent mechanism. Herein, we demonstrate that EGFR overexpression in primary esophageal keratinocytes activates STAT in a JAK-dependent fashion" SIGNOR-235870 EGFR protein P00533 UNIPROT STAM2 protein O75886 UNIPROT unknown phosphorylation Tyr192 HTETKSLyPSSEIQL -1 11687594 t llicata "Another major tyrosine phosphorylation site of STAM2 was identified as Tyr-192" SIGNOR-251097 EGFR protein P00533 UNIPROT ABCA1 protein O95477 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser2054 GGNKRKLsTAMALIG 9606 BTO:0000567 12196520 t lperfetto "We further provide in vitro evidence that epidermal growth factor receptor (EGFR)-mediated phosphorylation regulated ABCA1 ubiquitination |The EGFR selective inhibitor PD168393 blocked the EGFR-ABCA1 interaction and abolished ABCA1Ser2054 phosphorylation|" SIGNOR-264419 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr1069 EDSFLQRySSDPTGA 9606 10635327 t llicata "Initially, an autophosphorylation reaction creates docking sites for several signaling proteins, including a Cbl binding site at tyrosine 1045 of EGFR." SIGNOR-251093 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr1016 DVVDADEyLIPQQGF 9606 BTO:0000567 10653583 t "Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer" lperfetto "After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine." SIGNOR-236475 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr1092 TFLPVPEyINQSVPK 9606 BTO:0000567 10653583 t "Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer" lperfetto "After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine." SIGNOR-236479 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr1172 ISLDNPDyQQDFFPK 9606 BTO:0000567 10653583 t "Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer" lperfetto "After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine." SIGNOR-236467 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr1197 STAENAEyLRVAPQS 9606 BTO:0000567 10653583 t "Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer" lperfetto "After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine." SIGNOR-236471 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr869 LGAEEKEyHAEGGKV 9606 BTO:0000567 10653583 t "Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer" lperfetto "After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine." SIGNOR-236487 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr1016 DVVDADEyLIPQQGF 10090 BTO:0002882 16122376 t "Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer" lperfetto "EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work" SIGNOR-236527 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr1092 TFLPVPEyINQSVPK 10090 BTO:0002882 16122376 t "Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer" lperfetto "EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work" SIGNOR-236523 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr1110 GSVQNPVyHNQPLNP 10090 BTO:0002882 16122376 t "Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer" lperfetto "EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work" SIGNOR-236516 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr1172 ISLDNPDyQQDFFPK 10090 BTO:0002882 16122376 t "Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer" lperfetto "EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work" SIGNOR-236531 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr1197 STAENAEyLRVAPQS 10090 BTO:0002882 16122376 t "Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer" lperfetto "EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work" SIGNOR-235951 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr869 LGAEEKEyHAEGGKV 10090 BTO:0002882 16122376 t "Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer" lperfetto "EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work" SIGNOR-235956 EGFR protein P00533 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 11887937 t gcesareni "Activation of estrogen receptor-alpha (eralpha) by growth factors in the absence of estrogen is a well-documented phenomenon.Egfr tyrosine kinase in vitro stimulated the phosphorylation of recombinant er" SIGNOR-115734 EGFR protein P00533 UNIPROT ANXA1 protein P04083 UNIPROT up-regulates phosphorylation Tyr21 IENEEQEyVQTVKSS 9606 24103589 t lperfetto "The authors identified several phosphorylated residues by a combination of peptide mapping and sequence analysis and showed that recombinant pp60c-src phosphorylates annexin a1 near its amino terminus, at tyrosine 21 (tyr21). Also polyoma virus middle t/pp60c-src complex, recombinant pp50v-abl, and the egf receptor/kinase phosphorylated the same tyrosine residue. It was also shown that serine 27 residue of anxa1 is the primary site phosphorylated by protein kinase c (pkc). In the same study, the threonine 41 residue has been identified as a pkc substrate as well. The adenosine cyclic 3_,5_-phosphate dependent protein kinase a (pka) phosphorylates anxa1 in its carboxyl-terminal core at the threonine 216 residue (thr216) [2].Finally in 2013 caron et al. showed the relevance of y21 phosphorylation for the anxa1 stability. In fact the authors demonstrated that the tyrosine 21 phosphorylation is crucial for anxa1 sumoylation induced by egf" SIGNOR-202776 EGFR protein P00533 UNIPROT ERBB2 protein P04626 UNIPROT "up-regulates activity" phosphorylation Tyr1248 PTAENPEyLGLDVPV 9606 BTO:0000356 12354693 t llicata "Induction of cancer cell migration by epidermal growth factor is initiated by specific phosphorylation of tyrosine 1248 of c-erbB-2 receptor via EGFR. | In summary, c-erbB-2 up-regulation switches on the cell migration program by modulating the time course of PLC-gamma1 activation." SIGNOR-251094 EGFR protein P00533 UNIPROT GSTP1 protein P09211 UNIPROT up-regulates phosphorylation Tyr199 AFLASPEyVNLPING 9606 BTO:0000150 19254954 t llicata "Taken together, these results and those of the ms/ms analyses confirmed tyr-3, tyr-7, and tyr-198 to be primary residues phosphorylated by egfr in the gstp1 protein. The phosphorylation increased gstp1 enzymatic activity significantly," SIGNOR-184379 EGFR protein P00533 UNIPROT GSTP1 protein P09211 UNIPROT up-regulates phosphorylation Tyr4 yTVVYFPV 9606 BTO:0000150 19254954 t llicata "Taken together, these results and those of the ms/ms analyses confirmed tyr-3, tyr-7, and tyr-198 to be primary residues phosphorylated by egfr in the gstp1 protein. The phosphorylation increased gstp1 enzymatic activity significantly," SIGNOR-184383 TNF protein P01375 UNIPROT PIK3CD protein O00329 UNIPROT up-regulates 9606 10485710 f gcesareni "Tnf activates phosphatidylinositol-3-oh kinase (pi(3)k)" SIGNOR-70622 EGFR protein P00533 UNIPROT GSTP1 protein P09211 UNIPROT up-regulates phosphorylation Tyr8 MPPYTVVyFPVRGRC 9606 BTO:0000150 19254954 t llicata "Taken together, these results and those of the ms/ms analyses confirmed tyr-3, tyr-7, and tyr-198 to be primary residues phosphorylated by egfr in the gstp1 protein. The phosphorylation increased gstp1 enzymatic activity significantly," SIGNOR-184387 EGFR protein P00533 UNIPROT CALM1 protein P0DP23 UNIPROT down-regulates phosphorylation Tyr100 FDKDGNGyISAAELR 9606 3415247 t lperfetto "Phosphorylation of calmodulin by the epidermal-growth-factor-receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule." SIGNOR-24778 EGFR protein P00533 UNIPROT CALM1 protein P0DP23 UNIPROT down-regulates phosphorylation Tyr100 FDKDGNGyISAAELR 9606 7925415 t lperfetto "Phosphorylation of calmodulin by the epidermal-growth-factor-receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule." SIGNOR-34691 EGFR protein P00533 UNIPROT CALM2 protein P0DP24 UNIPROT down-regulates phosphorylation Tyr100 FDKDGNGyISAAELR 9606 3415247 t miannu "Phosphorylation of calmodulin by the epidermal-growth-factor-receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule." SIGNOR-266319 EGFR protein P00533 UNIPROT CALM3 protein P0DP25 UNIPROT down-regulates phosphorylation Tyr100 FDKDGNGyISAAELR 9606 3415247 t miannu "Phosphorylation of calmodulin by the epidermal-growth-factor-receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule." SIGNOR-266335 EGFR protein P00533 UNIPROT EPB41 protein P11171 UNIPROT down-regulates phosphorylation Tyr660 RLDGENIyIRHSNLM 9606 1647028 t lperfetto "The phosphorylation site has been localized to the 8-kda domain, which has one tyrosine, tyrosine-418. The 8-kda region is required for the assembly of the spectrin/actin complex, and phosphorylation by egfr reduced the ability of protein 4.1 to promote the assembly of the spectrin/actin/protein 4.1 ternary complex" SIGNOR-20452 EGFR protein P00533 UNIPROT PCNA protein P12004 UNIPROT up-regulates phosphorylation Tyr211 QLTFALRyLNFFTKA 9606 BTO:0000150 17115032 t lperfetto "Here, we show that the chromatin-bound pcna protein is phosphorylated on tyr 211, which is required for maintaining its function on chromatin and is dependent on the tyrosine kinase activity of egf receptor (egfr) in the nucleus. Phosphorylation on tyr 211 by egfr stabilizes chromatin-bound pcna protein and associated functions." SIGNOR-150852 EGFR protein P00533 UNIPROT EZR protein P15311 UNIPROT unknown phosphorylation Tyr146 KEVHKSGyLSSERLI 9606 BTO:0000017 15647376 t lperfetto "Here we report the identification of the tyrosine phosphorylation sites in ezrin using bacterially expressed protein as a substrate for in vitro phosphorylation with the egf receptor. tyrosines 145 and 353 were identified as the sites of phosphorylation. but as of yet the role of ezrin phosphorylation at y145 is unknown." SIGNOR-133219 EGFR protein P00533 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Tyr354 LMLRLQDyEEKTKKA 9606 BTO:0000017 15647376 t lperfetto "Ezrin was initially identified as a substrate for tyrosine phosphorylation by egfr (bretscher, 1989) and phosphorylation of residues y145 and y353 were detected to high stoichiometry after egf treatment . Phosphorylation of ezrin at y353 has been delineated to signal survival during epithelial cell differentiation via the phosphatidylinositol 3-kinase (pi3k)/akt pathway." SIGNOR-133215 EGFR protein P00533 UNIPROT MUC1 protein P15941 UNIPROT "up-regulates activity" phosphorylation Tyr1229 SSTDRSPyEKVSAGN 9606 BTO:0000150 11483589 t lperfetto "We also show that the activated egf-r phosphorylates the muc1 cytoplasmic tail on tyrosine at a yekv motif that functions as a binding site for the c-src sh2 domain. The results demonstrate that egf-r-mediated phosphorylation of muc1 induces binding of muc1 to c-src in cells" SIGNOR-109538 EGFR protein P00533 UNIPROT NCK1 protein P16333 UNIPROT up-regulates 9606 9362449 f "Nck interacts witn ErbB1 through SH2 and SH3 domains" gcesareni "We found that nck does not directly bind to egf receptor, instead it binds via its sh2 domain to a 62 kda phosphotyrosine protein" SIGNOR-52954 EGFR protein P00533 UNIPROT NCK1 protein P16333 UNIPROT "up-regulates activity" binding 10090 BTO:0000944 1333047 t "We show that epidermal growth factor or platelet-derived growth factor stimulation of intact human or murine cells leads to phosphorylation of Nck protein on tyrosine, serine, and threonine residues" SIGNOR-252089 EGFR protein P00533 UNIPROT PTPN1 protein P18031 UNIPROT up-regulates phosphorylation Tyr66 LHQEDNDyINASLIK 9606 9355745 t llicata "After binding to egfr, ptp1b becomes tyrosine-phosphorylated at tyr-66 phosphorylation of ptp1b by egfr enhances its catalytic activity" SIGNOR-52950 EGFR protein P00533 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates phosphorylation Tyr1253 EGSFESRyQQPFEDF 9606 BTO:0000142 1689310 t llicata "We have identified the sites phosphorylated in vitro by epidermal growth factor (egf) receptor kinase in bovine brain phospholipase c-gamma (plc-gamma). They are tyrosine residues 472, 771, 783, and 1254. we propose, therefore, that the phosphorylation of plc-gamma by egf receptor kinase alters its interaction with putative inhibitory proteins and leads to its activation." SIGNOR-20976 EGFR protein P00533 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates phosphorylation Tyr472 KLAEGSAyEEVPTSM 9606 BTO:0000142 1689310 t llicata "We have identified the sites phosphorylated in vitro by epidermal growth factor (egf) receptor kinase in bovine brain phospholipase c-gamma (plc-gamma). They are tyrosine residues 472, 771, 783, and 1254. we propose, therefore, that the phosphorylation of plc-gamma by egf receptor kinase alters its interaction with putative inhibitory proteins and leads to its activation." SIGNOR-20980 EGFR protein P00533 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates phosphorylation Tyr783 EGRNPGFyVEANPMP 9606 9176240 t gcesareni "In contrast, egf-induced tyrosine phosphorylation of plc-gamma 1 was rather small, indicating that tyrosine phosphorylation of plc-gamma 1 is not proportional to changes in plc activity. These results suggest that autophosphorylation of theegfr may induce a conformational change of its kinase domain which enhances its kinase activity with exogenous substrates and may induce association with phospholipase c-gamma by increasing its affinity to a domain containing tyr-771." SIGNOR-48872 Angiotensin-2 protein P01019_PRO_0000032458 UNIPROT AGTR2 protein P50052 UNIPROT "up-regulates activity" binding 9606 32201502 t MIANNU "Ang II initiates most of the RAS-attributed physiologic effects through selective interactions with G-proteincoupled Ang II type 1 (AT1) or type 2 (AT2) receptors and subsequent activation of distinct intra cellular signaling pathways" SIGNOR-260237 EGFR protein P00533 UNIPROT RASA1 protein P20936 UNIPROT unknown phosphorylation Tyr460 TVDGKEIyNTIRRKT 9606 1850098 t llicata "We conclude that tyr-460 is a site of gap tyrosine phosphorylation by the egf receptor in vitro and likely in vivo. Gap tyr-460 is located immediately c terminal to the second gap sh2 domain, suggesting that its phosphorylation might have a role in regulating protein-protein interactions." SIGNOR-21875 EGFR protein P00533 UNIPROT ERBB3 protein P21860 UNIPROT up-regulates phosphorylation Tyr1276 GGGPGGDyAAMGACP 9606 BTO:0000150 7929151 t lperfetto "The erbb3 protein which possesses little or no intrinsic protein tyrosine kinase activiity is phosphorylated by the activated egf receptor protein tyrosine kinase on tyrosine residues within the yxxm sequence motif. These phosphorylated tyrosine residues interact with the p85 regulatory subunit of pi 3-kinase, which could result in the activation of the p110 catalytic subunit via a conformational mechanism." SIGNOR-34748 EGFR protein P00533 UNIPROT ERBB3 protein P21860 UNIPROT up-regulates phosphorylation Tyr1289 CPASEQGyEEMRAFQ 9606 BTO:0000150 7929151 t lperfetto "The erbb3 protein which possesses little or no intrinsic protein tyrosine kinase activiity is phosphorylated by the activated egf receptor protein tyrosine kinase on tyrosine residues within the yxxm sequence motif. These phosphorylated tyrosine residues interact with the p85 regulatory subunit of pi 3-kinase, which could result in the activation of the p110 catalytic subunit via a conformational mechanism." SIGNOR-34752 EGFR protein P00533 UNIPROT CBL protein P22681 UNIPROT up-regulates relocalization 9606 11823423 t "Cbl binds directly to Tyr1045 receptors" gcesareni "Consistent with a negative role for c-Cbl, here we report that defective Tyr1045 of EGFR, an inducible c-Cbl docking site, enhances the mitogenic response to EGF" SIGNOR-114701 EGFR protein P00533 UNIPROT CBL protein P22681 UNIPROT up-regulates relocalization 9606 16829981 t "Cbl binds directly to Tyr1045 receptors" gcesareni "Likewise, cbl is recruited to erbb1 either directly (tyr1045), or indirectly, trough grb2" SIGNOR-147826 EGFR protein P00533 UNIPROT JAK1 protein P23458 UNIPROT "up-regulates activity" 10090 BTO:0000667 15284024 f "JAK activation occurs upon ligand-mediated receptor multimerization because two JAKs are brought into close proximity, allowing trans-phosphorylation. The activated JAKs subsequently phosphorylate additional targets, including both the receptors and the major substrates, STATs." lperfetto "Two possibilities for STAT activation exist: a janus kinase (JAK)-dependent and a JAK-independent mechanism. Herein, we demonstrate that EGFR overexpression in primary esophageal keratinocytes activates STAT in a JAK-dependent fashion" SIGNOR-235655 EGFR protein P00533 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates binding 9606 BTO:0000093 BTO:0000150 26918608 t lperfetto "p85alpha promotes nucleolin transcription and subsequently enhances EGFR mRNA stability and EGF-induced malignant cellular transformation." SIGNOR-33633 EGFR protein P00533 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 10090 BTO:0000944 7518560 t lperfetto "Both competition experiments with synthetic phosphopeptides and dephosphorylation protection analysis demonstrated that y-1173 and y-992 are major and minor binding sites, respectively, for shc on the egfr." SIGNOR-235481 EGFR protein P00533 UNIPROT SHC1 protein P29353 UNIPROT "up-regulates activity" binding 9606 11350724 t lperfetto "Adaptors such as Shc, Grb2, Crk or the recently characterised Dok-R protein (Jones Dumont 1999) show a modular structure containing protein– protein interaction domains and putative phosphorylation sites and act as signalling platforms which extend the receptor’s repertoire of activated intracellular pathways." SIGNOR-107712 EGFR protein P00533 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000150 22693070 t lperfetto "The transcription factors stat1, stat3, and stat5 are directly phosphorylated by erbb-1, subsequent to which they dimerize through phosphotyrosine-sh2 domain interactions and translocate to the nucleus to activate gene trascription critical for proliferation." SIGNOR-235692 EGFR protein P00533 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation 9606 14967450 t lperfetto "The transcription factors stat1, stat3, and stat5 are directly phosphorylated by erbb-1, subsequent to which they dimerize through phosphotyrosine-sh2 domain interactions and translocate to the nucleus to activate gene trascription critical for proliferation" SIGNOR-121962 EGFR protein P00533 UNIPROT STAT5A protein P42229 UNIPROT up-regulates binding 9606 BTO:0000017 10358079 t gcesareni "We identified stat5 as a direct binding partner to egfr and erbb4 and discovered new recognition motifs for shc and stat5.Egf stimulation and subsequent phosphorylation of egfr at tyrosine y978, y998 and y869 would then subsequently lead to recruitment and activation of stat5." SIGNOR-68159 EGFR protein P00533 UNIPROT STAT5A protein P42229 UNIPROT up-regulates binding 9606 16729043 t gcesareni "We identified stat5 as a direct binding partner to egfr and erbb4 and discovered new recognition motifs for shc and stat5.Egf stimulation and subsequent phosphorylation of egfr at tyrosine y978, y998 and y869 would then subsequently lead to recruitment and activation of stat5." SIGNOR-146852 EGFR protein P00533 UNIPROT EPS15 protein P42566 UNIPROT up-regulates phosphorylation Tyr849 NFANFSAyPSEEDMI 9606 24269888 t lperfetto "Earlier studies have shown that eps15 at tyr-849 is phosphorylated in egf-stimulated cells and partly controls the internalization of mono-ubiquitinated egfr via uim domains of eps15 [10]. It has also been shown that active egfr phosphorylates tyr-849 directly;" SIGNOR-203311 EGFR protein P00533 UNIPROT CRK protein P46108 UNIPROT "down-regulates activity" phosphorylation Tyr221 GGPEPGPyAQPSVNT 9606 BTO:0000007 9642287 t llicata "To address these questions, we have developed an antibody that specifically recognizes the CrkII protein phosphorylated on Tyr221, and we found that the EGF receptor directly phosphorylates CrkII on Tyr221. Furthermore, we observed that the phosphorylation of Tyr221 of CrkII correlated with its dissociation from the EGF receptor, implicating the phosphorylation of Tyr221 in the negative feedback of binding to the EGF receptor." SIGNOR-251091 EGFR protein P00533 UNIPROT SOX2 protein P48431 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19882665 f miannu "We show that egfr-mediated signaling promotes sox2 expression, which in turn binds to the egfr promoter and directly upregulates egfr expression." SIGNOR-189033 EGFR protein P00533 UNIPROT STAT5B protein P51692 UNIPROT up-regulates phosphorylation Tyr743 PQAHYNMyPQNPDSV 9606 BTO:0000007;BTO:0000150 11751923 t llicata "Novel activation of stat5b in response to epidermal growth factor. novel activation of stat5b in response to epidermal growth factor." SIGNOR-113401 EGFR protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates phosphorylation Tyr659 VADERVDyVVVDQQK 9606 BTO:0000527;BTO:0000017 9890893 t lperfetto "Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689)." SIGNOR-236404 EGFR protein P00533 UNIPROT STAT5B protein P51692 UNIPROT "up-regulates activity" phosphorylation Tyr699 TAKAVDGyVKPQIKQ 9606 BTO:0000007;BTO:0000356 11751923 t llicata "We have shown that EGF activates STAT5b not only in a HEK293 cell model in which the EGFR is stably overexpressed but also in the MDA-MB468 breast cancer cell line. Furthermore, EGF (but not GH) is able to activate tyrosine phosphorylation of a Tyr-699 mutant of STAT5b. | Fig. 2 A (bottom panels) demonstrates that EGF-induced phosphorylation of tyrosine 699 (the well-described site of STAT5b phosphorylation) is detected only in the EGFR-overexpressing MDA-MB468 cells and not the MCF-7 cells." SIGNOR-251098 EGFR protein P00533 UNIPROT VAV2 protein P52735 UNIPROT up-regulates phosphorylation Tyr142 TENDDDVyRSLEELA 9606 12454019 t miannu "To understand the mechanism of egf-dependent vav2 activation, we examined first the egf-dependent phosphorylation sites on vav2 and the nature of interaction of vav2 with the activated egf receptor. Based on our in vitro and in vivo data all three tyrosine residues (142, 159, and 172) in the n-terminal domain of vav2 can be phosphorylated by the egf receptor." SIGNOR-95972 EGFR protein P00533 UNIPROT VAV2 protein P52735 UNIPROT up-regulates phosphorylation Tyr159 HDLGEDIyDCVPCED 9606 12454019 t miannu "To understand the mechanism of egf-dependent vav2 activation, we examined first the egf-dependent phosphorylation sites on vav2 and the nature of interaction of vav2 with the activated egf receptor. Based on our in vitro and in vivo data all three tyrosine residues (142, 159, and 172) in the n-terminal domain of vav2 can be phosphorylated by the egf receptor." SIGNOR-95976 EGFR protein P00533 UNIPROT VAV2 protein P52735 UNIPROT up-regulates phosphorylation Tyr172 EDGGDDIyEDIIKVE 9606 12454019 t miannu "To understand the mechanism of egf-dependent vav2 activation, we examined first the egf-dependent phosphorylation sites on vav2 and the nature of interaction of vav2 with the activated egf receptor. Based on our in vitro and in vivo data all three tyrosine residues (142, 159, and 172) in the n-terminal domain of vav2 can be phosphorylated by the egf receptor." SIGNOR-95980 EGFR protein P00533 UNIPROT PKIA protein P61925 UNIPROT up-regulates phosphorylation Tyr8 MTDVETTyADFIASG 9606 1956339 t lperfetto "The difference in inhibitory potency between pki_ and pki_ has been attributed to the absence of a tyrosine residue (tyr7) in pki_ that is present in the nh2-terminal region of pki_. This suggests that the absence of a single amino acid residue can result in variations in how the catalytic subunit of camp-dependent protein kinase interacts with pki which ultimately can result in alterations in pki inhibitory potency." SIGNOR-22455 EGFR protein P00533 UNIPROT GRB2 protein P62993 UNIPROT unknown phosphorylation Tyr209 TGMFPRNyVTPVNRN 9606 BTO:0000017 11726515 t lperfetto "Phosphorylation of grb2 by bcr/abl or egf receptor reduced its sh3-dependent binding to sos in vivo, but not its sh2-dependent binding to bcr/abl. Tyr209 within the c-terminal sh3 domain of grb2 was identified as one of the tyrosine phosphorylation sites" SIGNOR-235738 EGFR protein P00533 UNIPROT GRB2 protein P62993 UNIPROT "up-regulates activity" binding -1 BTO:0000567 16729043 t lperfetto "We determined interaction partners to all cytosolic tyrosine residues of the four members of the ErbB-receptor family in an unbiased fashion by quantitative proteomics using pull-down experiments with pairs of phosphorylated and nonphosphorylated synthetic peptides. Each receptor had characteristic preferences for interacting proteins and most interaction partners had multiple binding sites on each receptor. EGFR and ErbB4 had several docking sites for Grb2, while ErbB3 was characterized by six binding sites for PI3K." SIGNOR-236327 EGFR protein P00533 UNIPROT GRB2 protein P62993 UNIPROT "up-regulates activity" binding 10090 BTO:0000944 7518560 t lperfetto "Erbb1 recruites grb2 through sh2 domain;from these studies, we concluded that grb2 binds directly to the egfr at y-1068, to a lesser extent at y-1086, and indirectly at y-1173. Egfr has six binding sites for the adapter protein grb2, and erbb4 has five, each with different binding strength several tyrosine-based motifs recruit a number of signal transducers to the phosphorylated form of erbb1 such as the adaptor proteins growth-factor-receptor bound-2 (grb2) and src-homology-2-containing (shc)." SIGNOR-235721 EGFR protein P00533 UNIPROT SHC2 protein P98077 UNIPROT up-regulates binding 9606 11350724 t miannu "Shc exists in three different isoforms, p46shc, p52shc and p66shc which are tyrosine phosphorylated upon egf stimulation and bind to the activated egfr and grb2. Interestingly, while the 46 and 52 kda isoforms increase mitogenic signalling after egf stimulation and are able to transform nih3t3 cells (pelicci et al. 1992), p66shc has no transforming potential and negatively influences egf-induced c-fos transcription" SIGNOR-107750 EGFR protein P00533 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr5 yLDPNLNH 9606 20802513 t llicata "In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate fak on tyr194 in the ferm domain collectively, this study provides the first example to explain how fak is activated by receptor tyrosine kinases." SIGNOR-167650 EGFR protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates phosphorylation Tyr285 TEADGELyVFNTPSG 9606 BTO:0000527;BTO:0000017 9890893 t lperfetto "Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689)." SIGNOR-236400 EGFR protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates phosphorylation Tyr406 DASSQDCyDIPRAFP 9606 BTO:0000527;BTO:0000017 9890893 t lperfetto "Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689)." SIGNOR-236396 EGFR protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates phosphorylation Tyr447 SEELDENyVPMNPNS 9606 BTO:0000527;BTO:0000017 9890893 t lperfetto "Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689)." SIGNOR-236420 EGFR protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates phosphorylation Tyr627 KGDKQVEyLDLDLDS 9606 BTO:0000527;BTO:0000017 9890893 t lperfetto "Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689)." SIGNOR-236392 F2 protein P00734 UNIPROT F5 protein P12259 UNIPROT "up-regulates activity" cleavage Arg737 LAAALGIrSFRNSSL -1 10026263 t lperfetto "Thrombin is considered the physiological activator of factor V and is the most potent activator, catalyzing the cleavage of three peptide bonds at Arg709, Arg1018, and Arg1545" SIGNOR-263632 EGFR protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr472 EPIQEANyVPMTPGT 9606 BTO:0000527;BTO:0000017 9890893 t lperfetto "Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689)." SIGNOR-236412 EGFR protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr589 SHDSEENyVPMNPNL 9606 BTO:0000527;BTO:0000017 9890893 t lperfetto "Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689)." SIGNOR-236416 EGFR protein P00533 UNIPROT TRIP13 protein Q15645 UNIPROT "up-regulates quantity" phosphorylation Tyr56 HNIVFGDyTWTEFDE 9606 BTO:0000007 32860853 t lperfetto "Reciprocally, TRIP13 was phosphorylated at tyrosine(Y) 56 by EGFRvIII and EGF-activated EGFR. Abrogating TRIP13 Y56 phosphorylation dramatically attenuated TRIP13 expression-enhanced EGFR signaling and GBM cell growth." SIGNOR-265083 EGFR protein P00533 UNIPROT LRRK1 protein Q38SD2 UNIPROT "down-regulates activity" phosphorylation Tyr971 TQQTEEQyFQFLAKF 9534 BTO:0000298 22337768 t miannu "In this study, we demonstrate that EGFR regulates the kinase activity of LRRK1 via tyrosine phosphorylation and that this is required for proper endosomal trafficking of EGFR. Phosphorylation of LRRK1 at Tyr-944 results in reduced LRRK1 kinase activity." SIGNOR-262856 EGFR protein P00533 UNIPROT CCDC50 protein Q8IVM0 UNIPROT "down-regulates activity" phosphorylation Tyr217 MAEEKKAyKKAKERE 9606 BTO:0000567 19059208 t miannu "We also detected tyrosine phosphorylation of Ymer by EGF stimulation as previously reported (Fig. 1A). Furthermore, we verified that EGF receptor-mediated tyrosine phosphorylation of Ymer is inhibited by AG1478, which is known as an EGF receptor tyrosine kinase inhibitor (Fig. 1B). A luciferase reporter assay showed that mutation of tyrosines on Ymer (YmerY217/279/304F) results in loss of the inhibitory activity for NF-kappaB signaling." SIGNOR-262850 EGFR protein P00533 UNIPROT CCDC50 protein Q8IVM0 UNIPROT "down-regulates activity" phosphorylation Tyr279 TDGEDADyTHFTNQQ 9606 BTO:0000567 19059208 t miannu "We also detected tyrosine phosphorylation of Ymer by EGF stimulation as previously reported (Fig. 1A). Furthermore, we verified that EGF receptor-mediated tyrosine phosphorylation of Ymer is inhibited by AG1478, which is known as an EGF receptor tyrosine kinase inhibitor (Fig. 1B). A luciferase reporter assay showed that mutation of tyrosines on Ymer (YmerY217/279/304F) results in loss of the inhibitory activity for NF-kappaB signaling." SIGNOR-262851 EGFR protein P00533 UNIPROT CCDC50 protein Q8IVM0 UNIPROT "down-regulates activity" phosphorylation Tyr304 SSHKGFHyKH 9606 BTO:0000567 19059208 t miannu "We also detected tyrosine phosphorylation of Ymer by EGF stimulation as previously reported (Fig. 1A). Furthermore, we verified that EGF receptor-mediated tyrosine phosphorylation of Ymer is inhibited by AG1478, which is known as an EGF receptor tyrosine kinase inhibitor (Fig. 1B). A luciferase reporter assay showed that mutation of tyrosines on Ymer (YmerY217/279/304F) results in loss of the inhibitory activity for NF-kappaB signaling." SIGNOR-262852 EGFR protein P00533 UNIPROT SHC3 protein Q92529 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 24212772 t "GRB2 recruit indirectly through PTB domain-mediated binding of the Shc adaptor" gcesareni "Several tyrosine-based motifs recruit a number of signal transducers to the phosphorylated form of erbb1 such as the adaptor proteins growth-factor-receptor bound-2 (grb2) and src-homology-2-containing (shc)." SIGNOR-55861 EGFR protein P00533 UNIPROT HDAC6 protein Q9UBN7 UNIPROT down-regulates phosphorylation Tyr570 SSNFDSIyICPSTFA 9606 20029029 t gcesareni "A negative feedback loop consisting of egfr-mediated phosphorylation of hdac6 tyr(570) resulted in reduced deacetylase activity and increased acetylation of alpha-tubulin." SIGNOR-162431 EGFR protein P00533 UNIPROT ERRFI1 protein Q9UJM3 UNIPROT "up-regulates activity" phosphorylation Tyr394 KKVSSTHyYLLPERP 10090 BTO:0000944 phosphorylation:Tyr395 KVSSTHYyLLPERPP 26280531 t """here we found that the epidermal growth factor receptor (EGFR) phosphorylates Mig6 on Y394 and that this phosphorylation is primed by prior phosphorylation of an adjacent residue, Y395, by Src.""" SIGNOR-252091 EGFR protein P00533 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0000093 BTO:0000150 26918608 t lperfetto "P85alpha promotes nucleolin transcription and subsequently enhances EGFR mRNA stability and EGF-induced malignant cellular transformation." SIGNOR-252671 MOS protein P00540 UNIPROT MAP2K1 protein Q02750 UNIPROT "up-regulates activity" phosphorylation Ser222 LIDSMANsFVGTRSY 10090 7731726 t Manara "Our data indicate that Mos activated MEK1 in vitro as well as in vivo by phosphorylating Ser 222." SIGNOR-260920 PGK1 protein P00558 UNIPROT "3-phosphonato-D-glyceroyl phosphate(4-)" smallmolecule CHEBI:57604 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 16051738 t miannu "Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa." SIGNOR-266502 PGK1 protein P00558 UNIPROT 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 16051738 t miannu "Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa." SIGNOR-266505 F2 protein P00734 UNIPROT F2RL2 protein O00254 UNIPROT up-regulates binding 9606 BTO:0001253 11356985 t gcesareni "as noted previously, the human form of par-3 activated phosphoinositide signaling in response to thrombin when overexpressed in cos-7 cells" SIGNOR-108225 F2 protein P00734 UNIPROT F8 protein P00451 UNIPROT "up-regulates activity" cleavage Arg1708 EDENQSPrSFQKKTR -1 10350471 t lperfetto "Activation of factor VIII by thrombin occurs via limited proteolysis at R372, R740, and R1689." SIGNOR-263639 F2 protein P00734 UNIPROT F8 protein P00451 UNIPROT "up-regulates activity" cleavage Arg391 SPSFIQIrSVAKKHP -1 10350471 t lperfetto "Activation of factor VIII by thrombin occurs via limited proteolysis at R372, R740, and R1689." SIGNOR-263640 F2 protein P00734 UNIPROT F8 protein P00451 UNIPROT "up-regulates activity" cleavage Arg759 KNNAIEPrSFSQNSR -1 10350471 t lperfetto "Activation of factor VIII by thrombin occurs via limited proteolysis at R372, R740, and R1689." SIGNOR-263641 F2 protein P00734 UNIPROT F7 protein P08709 UNIPROT "up-regulates activity" 9606 BTO:0000131 29880919 t lperfetto "Thrombin also activates the cofactors FVIII (to FVIIIa) and FV (to FVa) and activates platelets such that they provide a procoagulant membrane surface to which these proteins then bind" SIGNOR-263529 F2 protein P00734 UNIPROT F5 protein P12259 UNIPROT "up-regulates activity" cleavage Arg1046 HHAPLSPrTFHPLRS -1 10026263 t lperfetto "Thrombin is considered the physiological activator of factor V and is the most potent activator, catalyzing the cleavage of three peptide bonds at Arg709, Arg1018, and Arg1545" SIGNOR-263631 F2 protein P00734 UNIPROT F2R protein P25116 UNIPROT "down-regulates activity" cleavage Phe43 ATLDPRSfLLRNPND -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site." SIGNOR-263570 F2 protein P00734 UNIPROT F2R protein P25116 UNIPROT up-regulates binding 9606 BTO:0000150;BTO:0001130;BTO:0000848 23450633 t gcesareni "Thrombin, actin through par1 promotes tumor cell proliferation, migration and contributes to the metastatic potenital of breast, prostate, gastrointestinal cancers and melanoma." SIGNOR-199788 F2 protein P00734 UNIPROT F2R protein P25116 UNIPROT up-regulates cleavage 9606 22972936 t "Thrombin acts on protease-activated receptors (PARs), a subfamily of G protein-coupled receptors (GPCR) that participate in a variety of biological process, including chemokine and cytokine release, tissue remodeling, inflammation, proliferation, and angiogenesis." gcesareni "The par1 receptor subtype is activated when the n terminus is proteolytically cleaved by the serine protease thrombin, resulting in an irreversible activation of the receptor. Thrombin activates platelets by binding and cleaving protease-activated receptors 1 and 4 (par1 and par4)." SIGNOR-199007 F2 protein P00734 UNIPROT F2R protein P25116 UNIPROT "up-regulates activity" cleavage Arg25 PLLSARTrARRPESK -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus" SIGNOR-263568 F2 protein P00734 UNIPROT F2R protein P25116 UNIPROT "up-regulates activity" cleavage Arg41 TNATLDPrSFLLRNP -1 10978167 t lperfetto "Thrombin cleaved PAR1E at the Arg41-Ser42 activation site at concentrations known to induce cellular activation, supporting a native conformation of the recombinant polypeptide." SIGNOR-263569 F2 protein P00734 UNIPROT F2R protein P25116 UNIPROT "up-regulates activity" cleavage -1 10978167 t lperfetto "Thrombin selectively cleaves PAR1, PAR3, and PAR4 to induce activation of platelets and vascular cells," SIGNOR-263608 F2 protein P00734 UNIPROT F2RL1 protein P55085 UNIPROT up-regulates binding 9606 BTO:0001253 11356985 t gcesareni "Other major aspects of par-2 are highlighted, in particular the ability of several serine protease enzymes, in addition to trypsin, to function as activators of par-2." SIGNOR-108183 F2 protein P00734 UNIPROT F2RL3 protein Q96RI0 UNIPROT up-regulates binding 9606 22318735 t gcesareni "Thrombin activates platelets by binding and cleaving protease-activated receptors 1 and 4 (par1 and par4)." SIGNOR-196003 F2 protein P00734 UNIPROT "GPIb-IX-V complex" complex SIGNOR-C270 SIGNOR "up-regulates activity" binding 9606 BTO:0000132 25297919 t lperfetto "Besides VWF as a main ligand, GPIbα also binds multiple ligands such as thrombospondin, Factor XII, Factor XI, thrombin, High Molecular Weight kininogen, P-selectin and Mac-1." SIGNOR-261859 F2 protein P00734 UNIPROT Fibrinogen complex SIGNOR-C311 SIGNOR "up-regulates activity" cleavage 9606 BTO:0000131 29880919 t lperfetto "Thrombin is a key enzyme in the pathway and cleaves fibrinogen to fibrin, which spontaneously forms the insoluble polymer that is the basis for the haemostatic plug." SIGNOR-263525 F2 protein P00734 UNIPROT Thrombin-Thrombomodulin complex SIGNOR-C316 SIGNOR "form complex" binding 9606 BTO:0000131 29880919 t lperfetto "Thrombin also activates the negative regulators of the cascade, after complexing with thrombomodulin (TM) and endothelial protein C receptor (EPCR), to activate protein C (PC) to activated PC (APC)." SIGNOR-263549 F2 protein P00734 UNIPROT Thrombin-Thrombomodulin complex SIGNOR-C316 SIGNOR "form complex" binding 9606 BTO:0000131 29880919 t lperfetto "Thrombin also activates the negative regulators of the cascade, after complexing with thrombomodulin (TM) and endothelial protein C receptor (EPCR), to activate protein C (PC) to activated PC (APC)." SIGNOR-263550 C1R protein P00736 UNIPROT "Complement C1 complex" complex SIGNOR-C309 SIGNOR "form complex" binding -1 29449492 t lperfetto "The complement system is part of our innate immune system. The classical complement pathway is triggered by activation of the C1 initiation complex upon binding to cell surfaces. C1, or C1qr2s2, consists of four proteases, C1r and C1s, that associate with C1q, which contains antibody-binding sites.|The reconstruction reveals densities for all C1q collagen-like triple helices and gC1q modules, C1r and C1s proteases" SIGNOR-263395 HP protein P00738 UNIPROT APOA1 protein P02647 UNIPROT "up-regulates quantity by stabilization" binding 9606 17824618 t miannu "Haptoglobin binding to apolipoprotein A-I prevents damage from hydroxyl radicals on its stimulatory activity of the enzyme lecithin-cholesterol acyl-transferase. haptoglobin, when circulating at enhanced levels with free Hb during the acute phase of inflammation, might protect ApoA-I structure and function against hydroxyl radicals." SIGNOR-252106 HP protein P00738 UNIPROT HBB protein P68871 UNIPROT "down-regulates quantity" binding 9606 9315856 t "Regulation of binding" miannu "Haptoglobin forms a complex of extremely high affinity with Hb via a well-characterized globin site. Our results show that upon Hb-haptoglobin binding, the globin radical, loses its ability to be terminated by forming globin dimers." SIGNOR-251815 HP protein P00738 UNIPROT HBA1 protein P69905 UNIPROT "down-regulates quantity" binding 9606 9315856 t "Regulation of binding" miannu "Haptoglobin forms a complex of extremely high affinity with Hb via a well-characterized globin site. Our results show that upon Hb-haptoglobin binding, the globin radical, loses its ability to be terminated by forming globin dimers." SIGNOR-251816 F9 protein P00740 UNIPROT F7 protein P08709 UNIPROT "up-regulates activity" cleavage Arg212 NASKPQGrIVGGKVC 9606 BTO:0000131 12524220 t lperfetto "The factor VII zymogen is cleaved at arginine 152 by a variety of proteases, including thrombin, factor IXa, factor Xa, and factor VIIa–tissue factor to produce the serine protease factor VIIa." SIGNOR-263522 F9 protein P00740 UNIPROT "Factor VIIIa-IXa" complex SIGNOR-C320 SIGNOR "form complex" binding 10090 BTO:0000131 25769543 t lperfetto "The present data point to key roles of FVIII and FIX in FX activation at the site of a platelet thrombus by supporting: (i) thrombin generation, (ii) thrombus growth and platelet phosphatidylserine exposure, and (iii) fibrin formation at the platelet surface. The likely mechanism is that tenase activity via FVIIIa and FIXa, which is confined to the sites of platelet thrombi, generates FXa that directly catalyzes the conversion of prothrombin into thrombin." SIGNOR-263552 F10 protein P00742 UNIPROT F2 protein P00734 UNIPROT "up-regulates activity" cleavage 10090 BTO:0000131 25769543 t lperfetto "The present data point to key roles of FVIII and FIX in FX activation at the site of a platelet thrombus by supporting: (i) thrombin generation, (ii) thrombus growth and platelet phosphatidylserine exposure, and (iii) fibrin formation at the platelet surface. The likely mechanism is that tenase activity via FVIIIa and FIXa, which is confined to the sites of platelet thrombi, generates FXa that directly catalyzes the conversion of prothrombin into thrombin." SIGNOR-263539 F10 protein P00742 UNIPROT APOH protein P02749 UNIPROT "down-regulates activity" cleavage Lys336 HSSLAFWKTDASDVK -1 9596664 t lperfetto "In the previous study, we found that factor Xa can produce the nicked form by cleaving Lys 317-Thr 318, using recombinant human domain V (r-Domain V). |The cleavage was completely inhibited by plasmin inhibitor (alpha2PI). The nicked form was demonstrated to show reduced affinity for CL with a dissociation constant of one order of magnitude larger than that of the intact beta2GPI." SIGNOR-266997 F10 protein P00742 UNIPROT F7 protein P08709 UNIPROT "up-regulates activity" cleavage Arg212 NASKPQGrIVGGKVC 9606 BTO:0000131 12524220 t lperfetto "The factor VII zymogen is cleaved at arginine 152 by a variety of proteases, including thrombin, factor IXa, factor Xa, and factor VIIa–tissue factor to produce the serine protease factor VIIa." SIGNOR-263523 CFD protein P00746 UNIPROT CFB protein P00751 UNIPROT "up-regulates activity" cleavage Arg259 GPGEQQKrKIVLDPS 9606 BTO:0000089 26489954 t lperfetto "The resulting proconvertase C3bB is subsequently cleaved by factor D (FD), generating the AP C3 convertase C3bBb" SIGNOR-263487 CFD protein P00746 UNIPROT CFB protein P00751 UNIPROT "up-regulates activity" cleavage Thr25 LLSGGVTtTPWSLAR 9606 BTO:0000089 26489954 t lperfetto "The resulting proconvertase C3bB is subsequently cleaved by factor D (FD), generating the AP C3 convertase C3bBb" SIGNOR-263488 PLG protein P00747 UNIPROT PLAT protein P00750 UNIPROT "up-regulates activity" cleavage Arg310 QYSQPQFrIKGGLFA 9606 BTO:0000131 1447176 t lperfetto "The conversion of plasminogen to plasmin can occur by several different mechanisms, but it appears that the most important in uiuo activator is tPA (2). tPA, M, = 70,000, is present in plasma as a single-chain serine protease, but proteolytic cleavage of the Agr275-Ile276 bond in tPA by plasmin yields a disulfide-linked two-chain enzyme" SIGNOR-263534 PLG protein P00747 UNIPROT APOH protein P02749 UNIPROT "down-regulates activity" cleavage Lys336 HSSLAFWKTDASDVK 9606 BTO:0000131 9596664 t lperfetto "Plasmin can reduce the function of human beta2 glycoprotein I by cleaving domain V into a nicked form| The cleavage site of r-Domain V and beta2GPI by plasmin was proved to be Lys 317-Thr 318 by amino acid sequence analysis of the digest and of the C-terminal peptide isolated by high-performance liquid chromatography. The cleavage was completely inhibited by plasmin inhibitor (alpha2PI). The nicked form was demonstrated to show reduced affinity for CL with a dissociation constant of one order of magnitude larger than that of the intact beta2GPI." SIGNOR-266996 PLG protein P00747 UNIPROT F2R protein P25116 UNIPROT "down-regulates activity" cleavage Arg70 ESGLTEYrLVSINKS -1 10978167 t lperfetto "Plasmin mediates the lysis of fibrin clots and could in different studies activate platelets or inhibit the responses induced by thrombin (41-43). Our study favors a net inactivating effect on PAR1 despite minor cleavage at Arg41, on the basis of preferential cleavage at positions Arg70 and Lys76, COOH-terminal to the Arg41-Ser42 activation site." SIGNOR-263572 PLG protein P00747 UNIPROT F2R protein P25116 UNIPROT "down-regulates activity" cleavage Lys76 YRLVSINkSSPLQKQ -1 10978167 t lperfetto "Plasmin mediates the lysis of fibrin clots and could in different studies activate platelets or inhibit the responses induced by thrombin (41-43). Our study favors a net inactivating effect on PAR1 despite minor cleavage at Arg41, on the basis of preferential cleavage at positions Arg70 and Lys76, COOH-terminal to the Arg41-Ser42 activation site." SIGNOR-263574 PLG protein P00747 UNIPROT F2R protein P25116 UNIPROT "up-regulates activity" cleavage Arg41 TNATLDPrSFLLRNP -1 10978167 t lperfetto "Plasmin mediates the lysis of fibrin clots and could in different studies activate platelets or inhibit the responses induced by thrombin (41-43). Our study favors a net inactivating effect on PAR1 despite minor cleavage at Arg41, on the basis of preferential cleavage at positions Arg70 and Lys76, COOH-terminal to the Arg41-Ser42 activation site." SIGNOR-263571 PLG protein P00747 UNIPROT F2R protein P25116 UNIPROT "up-regulates activity" cleavage Lys32 RARRPESkATNATLD -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus" SIGNOR-263573 F12 protein P00748 UNIPROT F11 protein P03951 UNIPROT "up-regulates activity" cleavage 9606 BTO:0000131 8427954 t lperfetto "Activation of factor XI in plasma is dependent on factor XII | Similar kinetics of factor XI cleavage are seen when 40 nmol/L factor XIIa (equal to 10% of factor XII activation) is added to factor XII-deficient plasma if an activating surface is provided." SIGNOR-263519 F12 protein P00748 UNIPROT KLKB1 protein P03952 UNIPROT "up-regulates activity" cleavage Arg390 CTTKTSTrIVGGTNS 9606 BTO:0000131 28966616 t lperfetto "FXIIa activates two serine proteinases, factor XI (FXI) and plasma prekallikrein (PK) that drive the coagulation and kallikrein–kinin systems, respectively" SIGNOR-263518 PLAU protein P00749 UNIPROT PLAUR protein Q03405 UNIPROT up-regulates binding 9606 16456079 t gcesareni "The urokinase plasminogen activator binds to its cellular receptor with high affinity and initiates signaling cascades that are implicated in pathological processes including tumor growth, metastasis, and inflammation." SIGNOR-144306 PLAT protein P00750 UNIPROT PLG protein P00747 UNIPROT "up-regulates activity" binding 9606 BTO:0000131 1447176 t lperfetto "The conversion of plasminogen to plasmin can occur by several different mechanisms, but it appears that the most important in uiuo activator is tPA (2). tPA, M, = 70,000, is present in plasma as a single-chain serine protease, but proteolytic cleavage of the Agr275-Ile276 bond in tPA by plasmin yields a disulfide-linked two-chain enzyme" SIGNOR-263533 CFB protein P00751 UNIPROT "C3 convertase complex (C3bBb)" complex SIGNOR-C314 SIGNOR "form complex" binding 9606 BTO:0000089 cleavage:Arg259 GPGEQQKrKIVLDPS 26489954 t "complement factor B, b fragment: PRO_0000027547" lperfetto "Surface‐associated C3b recruits FB, which leads to FB activation and the formation of C3bBb, the AP C3 convertase, which cleaves more C3 and amplifies complement activation. In addition to the surface‐bound C3 convertase, a fluid‐phase convertase can be formed by association of water‐reacted C3, termed C3(H20), to FB thus constantly maintaining a low level of complement activation in solution (tick‐over)" SIGNOR-263486 REN protein P00797 UNIPROT ATP6AP2 protein O75787 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0000142;BTO:0000671;BTO:0001260 12045255 t gcesareni "We report the expression cloning of the human renin receptor complementary dna encoding a 350-amino acid protein with a single transmembrane domain and no homology with any known membrane protein. Transfected cells stably expressing the receptor showed renin- and prorenin-specific binding. The binding of renin induced a fourfold increase of the catalytic efficiency of angiotensinogen conversion to angiotensin i and induced an intracellular signal with phosphorylation of serine and tyrosine residues associated to an activation of map kinases erk1 and erk2" SIGNOR-88416 REN protein P00797 UNIPROT AGT protein P01019 UNIPROT "up-regulates activity" cleavage 9606 16816138 t "Angiotensinogen, an _-glycoprotein, is released from the liver (152, 250, 444) and is cleaved in the circulation by the enzyme renin that is secreted from the juxtaglomerular apparatus of the kidney (245, 250, 540, 631) to form the decapeptide angiotensin (ANG) I" SIGNOR-252297 REN protein P00797 UNIPROT Angiotensin-1 protein P01019_PRO_0000032457 UNIPROT "up-regulates quantity" cleavage 9606 32201502 t miannu "Renin is an aspartic protease that enzymatically cleaves its substrate angiotensinogen, which is produced by the liver, to form an inactive peptide: angiotensin (Ang)I or Ang (1–10)." SIGNOR-260225 SERPINC1 protein P01008 UNIPROT F2 protein P00734 UNIPROT "down-regulates activity" cleavage 31030036 t lperfetto "Antithrombin (AT), a member of the serine protease inhibitor (SERPIN) superfamily, is a major circulating inhibitor of blood coagulation proteases such as factor (F) IIa (known as thrombin), FXa and, to a lesser extent, FIXa, FXIa and FXIIa. SERPINC1, which encodes AT in humans, is located on chromosome 1q25.1" SIGNOR-264136 SERPINC1 protein P01008 UNIPROT F9 protein P00740 UNIPROT "down-regulates activity" cleavage 31030036 t lperfetto "Antithrombin (AT), a member of the serine protease inhibitor (SERPIN) superfamily, is a major circulating inhibitor of blood coagulation proteases such as factor (F) IIa (known as thrombin), FXa and, to a lesser extent, FIXa, FXIa and FXIIa. SERPINC1, which encodes AT in humans, is located on chromosome 1q25.1" SIGNOR-264140 SERPINC1 protein P01008 UNIPROT F10 protein P00742 UNIPROT "down-regulates activity" cleavage 31030036 t lperfetto "Antithrombin (AT), a member of the serine protease inhibitor (SERPIN) superfamily, is a major circulating inhibitor of blood coagulation proteases such as factor (F) IIa (known as thrombin), FXa and, to a lesser extent, FIXa, FXIa and FXIIa. SERPINC1, which encodes AT in humans, is located on chromosome 1q25.1" SIGNOR-264138 SERPINC1 protein P01008 UNIPROT F12 protein P00748 UNIPROT "down-regulates activity" cleavage 31030036 t lperfetto "Antithrombin (AT), a member of the serine protease inhibitor (SERPIN) superfamily, is a major circulating inhibitor of blood coagulation proteases such as factor (F) IIa (known as thrombin), FXa and, to a lesser extent, FIXa, FXIa and FXIIa. SERPINC1, which encodes AT in humans, is located on chromosome 1q25.1" SIGNOR-264139 SERPINC1 protein P01008 UNIPROT F11 protein P03951 UNIPROT "down-regulates activity" cleavage 31030036 t lperfetto "Antithrombin (AT), a member of the serine protease inhibitor (SERPIN) superfamily, is a major circulating inhibitor of blood coagulation proteases such as factor (F) IIa (known as thrombin), FXa and, to a lesser extent, FIXa, FXIa and FXIIa. SERPINC1, which encodes AT in humans, is located on chromosome 1q25.1" SIGNOR-264137 SERPINA1 protein P01009 UNIPROT F2 protein P00734 UNIPROT "down-regulates activity" binding 9606 BTO:0000131 17635716 t lperfetto "Alpha1PI, historically known as alpha1-antitrypsin, is a 51 kDa, 394 amino acid glycoprotein, synthesized in the liver, circulating at c. 1.3 mg mL-1 with a half-life of 4.5 days" SIGNOR-263524 SERPINA1 protein P01009 UNIPROT F12 protein P00748 UNIPROT "down-regulates activity" binding 9606 BTO:0000131 26707513 t lperfetto "C1INH is a serine protease inhibitor (serpin) that acts on both the complement pathway and the contact system and is the main inhibitor of the contact system by targeting both FXIIa and PK 9. Additionally, FXIIa can be inhibited by α1‐antitrypsin and plasminogen activator inhibitor‐1 (PAI‐1)." SIGNOR-263515 AGT protein P01019 UNIPROT REN protein P00797 UNIPROT "up-regulates activity" binding 9606 32201502 t miannu "Renin is an aspartic protease that enzymatically cleaves its substrate angiotensinogen, which is produced by the liver, to form an inactive peptide: angiotensin (Ang)I or Ang (1–10)." SIGNOR-260224 AGT protein P01019 UNIPROT AGTR1 protein P30556 UNIPROT up-regulates binding 9606 BTO:0001130 16597412 t gcesareni "Endothelin-1 (et-1) and angiotensin ii (angii), two potent vasoactive peptides involved in the regulation of cardiovascular homeostasis, also induce mitogenic and pro-angiogenic responses in vitro and in vivo. Both peptides are produced by cleavage of inactive precursors by metalloproteases (endothelin-converting enzyme and angiotensin-converting enzyme, respectively) and activate two subtypes of membrane receptors (eta-r and etb-r for et-1, at1r and at2r for angii) that all belong to the superfamily of g-protein coupled receptors." SIGNOR-145677 AGT protein P01019 UNIPROT AGTR1 protein P30556 UNIPROT "up-regulates activity" binding 10116 BTO:0004578 17346243 t "AT(1) receptor (AngII type-1 receptor), a G-protein-coupled receptor, mediates most of the physiological and pathophysiological actions of AngII, and this receptor is predominantly expressed in cardiovascular cells, such as VSMCs (vascular smooth muscle cells)" SIGNOR-252293 AGT protein P01019 UNIPROT AGTR2 protein P50052 UNIPROT up-regulates 9606 BTO:0001130 16597412 f gcesareni "Endothelin-1 (et-1) and angiotensin ii (angii), two potent vasoactive peptides involved in the regulation of cardiovascular homeostasis, also induce mitogenic and pro-angiogenic responses in vitro and in vivo. Both peptides are produced by cleavage of inactive precursors by metalloproteases (endothelin-converting enzyme and angiotensin-converting enzyme, respectively) and activate two subtypes of membrane receptors (eta-r and etb-r for et-1, at1r and at2r for angii) that all belong to the superfamily of g-protein coupled receptors." SIGNOR-145680 AGT protein P01019 UNIPROT TRPC6 protein Q9Y210 UNIPROT "up-regulates activity" 9606 24850910 f "We demonstrated that Ang II evokes concentration-dependent activation of podocyte TRPC6 channels" SIGNOR-253331 Angiotensin-1 protein P01019_PRO_0000032457 UNIPROT ACE protein P12821 UNIPROT "up-regulates activity" binding 9606 32201502 t MIANNU "Ang I is subsequently converted into the major RAS effector peptide Ang II or Ang (1–8), through activity of the zinc-dependent protease ACE, which hydrolyzes two amino acids from the carboxy terminus of Ang I" SIGNOR-260231 Angiotensin-1 protein P01019_PRO_0000032457 UNIPROT ACE2 protein Q9BYF1 UNIPROT "up-regulates activity" binding 9606 32201502 t miannu "At first, ACE2 has been demonstrated to induce conversion of Ang I into Ang (1–7) by means of intermediate production of Ang (1–9), a fragment with unknown function." SIGNOR-260226 Angiotensin-2 protein P01019_PRO_0000032458 UNIPROT AGTR1 protein P30556 UNIPROT "up-regulates activity" binding 9606 32201502 t MIANNU "Ang II initiates most of the RAS-attributed physiologic effects through selective interactions with G-proteincoupled Ang II type 1 (AT1) or type 2 (AT2) receptors and subsequent activation of distinct intra cellular signaling pathways" SIGNOR-260238 "Angiotensin 1-7" protein P01019_PRO_0000420660 UNIPROT MAS1 protein P04201 UNIPROT "up-regulates activity" binding 9606 23488800 t miannu "Recent advances have improved our understanding of the renin-angiotensin system (RAS). These have included the recognition that angiotensin (Ang)-(1-7) is a biologically active product of the RAS cascade. The identification of the ACE homologue ACE2, which forms Ang-(1-7) from Ang II, and the GPCR Mas as an Ang-(1-7) receptor have provided the necessary biochemical and molecular background and tools to study the biological significance of Ang-(1-7)." SIGNOR-260229 A2M protein P01023 UNIPROT MMP2 protein P08253 UNIPROT "down-regulates activity" binding -1 9344465 t lperfetto "Both PZP and a2M collagenase complexes incubated with gelatin demonstrated a significant inhibition of the catalytic activity| MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP." SIGNOR-261803 A2M protein P01023 UNIPROT MMP9 protein P14780 UNIPROT "down-regulates activity" binding -1 9344465 t lperfetto "Both PZP and a2M collagenase complexes incubated with gelatin demonstrated a significant inhibition of the catalytic activity| MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP." SIGNOR-261801 C3 protein P01024 UNIPROT C3 protein P01024 UNIPROT "up-regulates activity" cleavage Arg671 QPAARRRrSVQLTEK 9606 BTO:0000089 26806831 t lperfetto "C3 autoactivates in a process known as “tick-over,” which is characterized by spontaneous hydrolysis of a reactive thiol-ester to generate C3(H2O). Although C3(H2O)Bb produces only relatively small amounts of C3b compared to the other C3 convertases, it nevertheless generates enough C3b to set the C3 convertase amplification loop in motion." SIGNOR-263483 C3 protein P01024 UNIPROT C3 protein P01024 UNIPROT "up-regulates activity" cleavage Arg748 ASHLGLArSNLDEDI 9606 BTO:0000089 26806831 t lperfetto "C3 autoactivates in a process known as “tick-over,” which is characterized by spontaneous hydrolysis of a reactive thiol-ester to generate C3(H2O). Although C3(H2O)Bb produces only relatively small amounts of C3b compared to the other C3 convertases, it nevertheless generates enough C3b to set the C3 convertase amplification loop in motion." SIGNOR-263484 C3 protein P01024 UNIPROT C3AR1 protein Q16581 UNIPROT "up-regulates activity" binding 9606 cleavage:Arg671;Arg748 QPAARRRrSVQLTEK;ASHLGLArSNLDEDI 8765043 t "complement C3a fragment: PRO_0000005910" lperfetto "A cDNA clone encoding the human C3a anaphylatoxin receptor (C3aR) was isolated from a pcDNAI/Amp expression library prepared from U-937 cells|The cDNA clone contained an insert of 4.3 kbp and was able to confer to transfected human HEK-293 cells the capacity to bind specifically iodinated human C3a." SIGNOR-263451 C3 protein P01024 UNIPROT "C5 convertase complex" complex SIGNOR-C312 SIGNOR "form complex" binding cleavage:Arg748 ASHLGLArSNLDEDI 31331124 t "complement C3b fragment: PRO_0000005911" lperfetto "C3b associates with C3 convertase to form C5 convertase and cleaves C5." SIGNOR-263448 C3 protein P01024 UNIPROT "C3 convertase complex (C3bBb)" complex SIGNOR-C314 SIGNOR "form complex" binding 9606 BTO:0000089 cleavage:Arg748 ASHLGLArSNLDEDI 26489954 t "complement C3b fragment: PRO_0000005911" lperfetto "Surface‐associated C3b recruits FB, which leads to FB activation and the formation of C3bBb, the AP C3 convertase, which cleaves more C3 and amplifies complement activation. In addition to the surface‐bound C3 convertase, a fluid‐phase convertase can be formed by association of water‐reacted C3, termed C3(H20), to FB thus constantly maintaining a low level of complement activation in solution (tick‐over)" SIGNOR-263485 C3 protein P01024 UNIPROT "C5 convertase complex (C3bBbC3b)" complex SIGNOR-C315 SIGNOR "form complex" binding 9606 BTO:0000089 cleavage:Arg748 ASHLGLArSNLDEDI 26489954 t "complement C3b fragment: PRO_0000005911" lperfetto "In addition to the surface‐bound C3 convertase, a fluid‐phase convertase can be formed by association of water‐reacted C3, termed C3(H20), to FB thus constantly maintaining a low level of complement activation in solution (tick‐over). Both of the surface‐bound C3 convertases can bind a C3b molecule whereby the C5 convertases are formed. These cleave C5 into C5a and C5b, thus initiating the terminal pathway and leading to formation of the membrane attack complex (MAC)." SIGNOR-263480 C5 protein P01031 UNIPROT C5AR1 protein P21730 UNIPROT "up-regulates activity" binding 9606 cleavage:Arg751;Arg677 HKDMQLGrLHMKTLL;KEILRPRrTLQKKIE 1847994 t "complement C5a (anaphylatoxin) fragment: PRO_0000005988" lperfetto "The chemotactic receptor for human C5a anaphylatoxin|The human C5a receptor was cloned from U937 and HL-60 cells and identified by high affinity binding when expressed in COS-7 cells." SIGNOR-263457 C5 protein P01031 UNIPROT C5AR2 protein Q9P296 UNIPROT up-regulates binding 9606 cleavage:Arg751;Arg677 HKDMQLGrLHMKTLL;KEILRPRrTLQKKIE 11773063 t "complement C5a (anaphylatoxin) fragment: PRO_0000005988" gcesareni "Here we report that the orphan receptor c5l2/gpr77, which shares 35% amino acid identity with cd88, binds c5a with high affinity." SIGNOR-113558 C5 protein P01031 UNIPROT "Membrane attack complex" complex SIGNOR-C313 SIGNOR "form complex" binding -1 cleavage:Arg751 HKDMQLGrLHMKTLL 30552328 t "complement C5b fragment: PRO_0000005989" lperfetto "The human MAC pore was formed on liposomes from individual complement proteins. |The maps were further subdivided into three components: an asymmetric region (C5b, C6, C7, and C8), a hinge region (C7, C8, and two C9 molecules), and a C9 oligomer" SIGNOR-263440 KNG1 protein P01042 UNIPROT BDKRB2 protein P30411 UNIPROT "up-regulates activity" binding 9606 cleavage:Arg381;Arg389 GMISLMKrPPGFSPF;PPGFSPFrSSRIGEI 28966616 t lperfetto "BK binds receptor B2 (B2R) and triggers inflammation, edema, and symptoms of anaphylaxis." SIGNOR-263554 KNG1 protein P01042 UNIPROT "GPIb-IX-V complex" complex SIGNOR-C270 SIGNOR "up-regulates activity" binding 9606 BTO:0000132 25297919 t lperfetto "Besides VWF as a main ligand, GPIbα also binds multiple ligands such as thrombospondin, Factor XII, Factor XI, thrombin, High Molecular Weight kininogen, P-selectin and Mac-1." SIGNOR-261858 FOS protein P01100 UNIPROT JUN protein P05412 UNIPROT "up-regulates activity" binding 10090 BTO:0000095 2516828 t "The cFos proto-oncoprotein associates with cJun to form a heterodimer with increased DNA binding and transcriptional activities." SIGNOR-252087 IFNA2 protein P01563 UNIPROT "ISGF3 complex" complex SIGNOR-C124 SIGNOR "up-regulates quantity by stabilization" 9606 22171011 t 2 miannu "IFN-I (IFN-_ and IFN-_) induces the assembly of IFN-stimulated gene factor 3 (ISGF3), a multimeric transcriptional activation complex composed of STAT1, STAT2, and IFN regulatory factor 9." SIGNOR-240684 FOS protein P01100 UNIPROT AP1 complex SIGNOR-C154 SIGNOR "form complex" binding 9606 1904542 t irozzo "The proteins encoded by the proto-oncogenes c-fos and c-jun (Fos and Jun, respectively) form a heterodimeric complex that regulates transcription by interacting with the DNA-regulatory element known as the activator protein 1 (AP-1) binding site." SIGNOR-256364 FOS protein P01100 UNIPROT AP1 complex SIGNOR-C154 SIGNOR "form complex" binding -1 2467839 t irozzo "The protein products of the fos (Fos) and jun (Jun) proto-oncogenes have been shown to associate with a DNA element known as the transcription factor activator protein-1 (AP-1) binding site. Jun (previously known as the Fos-binding protein p39) and Fos form a protein complex in the nucleus. These data demonstrate a cooperative interaction between the protein products of two proto-oncogenes with a DNA element involved in transcriptional regulation." SIGNOR-256362 FOS protein P01100 UNIPROT AP1 complex SIGNOR-C154 SIGNOR "form complex" binding -1 3142692 t irozzo "The c-Jun and c-fos proto-oncogenes encode proteins that form a complex which regulates transcription from promoters containing AP-1 activation elements. c-Jun has specific DNA binding activity, while c-Fos has homology to the putative DNA binding domain of c-Jun." SIGNOR-256366 MYC protein P01106 UNIPROT PRODH protein O43272 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 22615405 f miannu "MYC not only inhibited POX/PRODH, but also markedly increased the enzymes of proline biosynthesis from glutamine, including P5C synthase and P5C reductase 1." SIGNOR-254608 MYC protein P01106 UNIPROT BRD4 protein O60885 UNIPROT "down-regulates activity" 9606 BTO:0000567 32482868 t lperfetto "Conversely, MYC inhibits BRD4's HAT activity, suggesting that MYC regulates its own transcription by limiting BRD4-mediated chromatin remodeling of its locus." SIGNOR-262047 MYC protein P01106 UNIPROT MYCBP2 protein O75592 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001321 32814769 t miannu "We identified several E3 ligases as strong candidates responsible for AR and MYC protein loss as HECTD4, MYCBP2, and TRIM49. HECTD4 and MYCBP2 target AR and MYC for degradation while TRIM49 appears to promote AR and MYC stability. We have shown that these E3 ligases in turn are directly regulated by MYC. MYC in turn represses the expression of ubiquitin ligases, HECTD4 and MYCBP2 that promote AR and MYC protein degradation, further suppressing MYC and AR in a feed forward loop." SIGNOR-267145 MYC protein P01106 UNIPROT DKK1 protein O94907 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 "BTO:0004896; BTO:0004300" 17485441 f gcesareni "c-Myc suppresses the Wnt inhibitors DKK1 and SFRP1, and derepression of DKK1 or SFRP1 reduces Myc-dependent transforming activity" SIGNOR-245355 MYC protein P01106 UNIPROT LDHA protein P00338 UNIPROT "up-regulates quantity" "transcriptional regulation" 10116 9192621 t "Our studies have linked c-Myc to the induction of LDH-A, whose expression increases lactate production and is necessary for c-Myc-mediated transformation" SIGNOR-259367 MYC protein P01106 UNIPROT HLA-B protein P01889 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000848 8206526 f miannu "In melanoma, HLA class I expression is suppressed by overexpression of the c-myc oncogene. We show here that transcription of the HLA-B locus, which is mainly affected by c-Myc, is downmodulated at the level of initiation of transcription." SIGNOR-254606 MYC protein P01106 UNIPROT HLA-C protein P04222 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000848 8206526 f miannu "In melanoma, HLA class I expression is suppressed by overexpression of the c-myc oncogene." SIGNOR-254602 MYC protein P01106 UNIPROT ENO1 protein P06733 UNIPROT "up-regulates quantity" "transcriptional regulation" 10116 10823814 t "C-Myc directly transactivates genes encoding GLUT1, phosphofructokinase, and enolase and increases glucose uptake in Rat1 fibroblasts. Nuclear run-on studies confirmed that the GLUT1 transcriptional rate is elevated by c-Myc. Our findings suggest that overexpression of the c-Myc oncoprotein deregulates glycolysis through the activation of several components of the glucose metabolic pathway." SIGNOR-259989 MYC protein P01106 UNIPROT PFKM protein P08237 UNIPROT "up-regulates quantity" "transcriptional regulation" 10116 10823814 t "C-Myc directly transactivates genes encoding GLUT1, phosphofructokinase, and enolase and increases glucose uptake in Rat1 fibroblasts. Nuclear run-on studies confirmed that the GLUT1 transcriptional rate is elevated by c-Myc. Our findings suggest that overexpression of the c-Myc oncoprotein deregulates glycolysis through the activation of several components of the glucose metabolic pathway." SIGNOR-259988 MYC protein P01106 UNIPROT SLC2A1 protein P11166 UNIPROT "up-regulates quantity" "transcriptional regulation" 10116 10823814 t "C-Myc directly transactivates genes encoding GLUT1, phosphofructokinase, and enolase and increases glucose uptake in Rat1 fibroblasts. Nuclear run-on studies confirmed that the GLUT1 transcriptional rate is elevated by c-Myc. Our findings suggest that overexpression of the c-Myc oncoprotein deregulates glycolysis through the activation of several components of the glucose metabolic pathway." SIGNOR-259987 MYC protein P01106 UNIPROT CDK4 protein P11802 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001271 12835716 f gcesareni "C-myc directly activates transcription of cyclin d1, cyclin d2 and cdk4, and leads to cdk 4/6 activation" SIGNOR-102734 MYC protein P01106 UNIPROT HLA-E protein P13747 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000848 8206526 f miannu "In melanoma, HLA class I expression is suppressed by overexpression of the c-myc oncogene." SIGNOR-254604 MYC protein P01106 UNIPROT VEGFA protein P15692 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 12368264 f "These defects are intrinsic to c-Myc, and are in part associated with a requirement for c-Myc for the expression of vascular endothelial growth factor (VEGF), as VEGF can partially rescue these defects." SIGNOR-259369 MYC protein P01106 UNIPROT HLA-G protein P17693 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000848 8206526 f miannu "In melanoma, HLA class I expression is suppressed by overexpression of the c-myc oncogene." SIGNOR-254607 MYC protein P01106 UNIPROT CCNA2 protein P20248 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001271 12835716 f gcesareni "These results suggest that e2f1 and cyclin a2 may be induced by c-myc to mediate the onset of mammary cancer, whereas overexpression of cyclins d1 and e may occur later to facilitate tumor progression." SIGNOR-102728 MYC protein P01106 UNIPROT CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001271 12835716 f gcesareni "C-myc directly activates transcription of cyclin d1, cyclin d2 and cdk4, and leads to cdk 4/6 activation" SIGNOR-102731 MYC protein P01106 UNIPROT CCNE1 protein P24864 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9188852 f gcesareni "Our results suggest that this activation may involve at least two myc-dependent steps: the induction of cyclin e gene transcription followed by accumulation of cyclin e mrna in a protein synthesis-independent manner and the p27(kip1) association with cyce/cdk2 complexes containing newly synthesised cyce." SIGNOR-49130 MYC protein P01106 UNIPROT CCND2 protein P30279 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 7526316 f gcesareni "C-myc directly activates transcription of cyclin d1, cyclin d2 and cdk4, and leads to cdk 4/6 activation." SIGNOR-27446 MYC protein P01106 UNIPROT CDC25A protein P30304 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000093 11154267 f lperfetto "Expression of Cdc25A is transcriptionally regulated by Myc and E2F-1 , both of which are expressed in MCF-7 cells in response to estrogen" SIGNOR-245465 MYC protein P01106 UNIPROT HLA-F protein P30511 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000848 8206526 f miannu "In melanoma, HLA class I expression is suppressed by overexpression of the c-myc oncogene." SIGNOR-254605 MYC protein P01106 UNIPROT BMI1 protein P35226 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000093 23239878 t gcesareni "DKK1 led to up-regulation of WNT target c-Myc, which in turn further led to transcriptional autoactivation of BMI1" SIGNOR-245347 MYC protein P01106 UNIPROT CDKN1A protein P38936 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001271 12835716 f gcesareni "C-myc also directly represses transcription of cdk kinase inhibitors including p27kip1, p21cip1, p15ink4b and p16ink4a" SIGNOR-102740 MYC protein P01106 UNIPROT CDKN2B protein P42772 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001271 12835716 f gcesareni "Miz1 is a zinc finger transcription factor with an n-terminal poz domain. Complexes with myc, bcl-6 or gfi-1 repress expression of genes like cdkn2b (p15(ink4)) or cdkn1a (p21(cip1))." SIGNOR-102746 MYC protein P01106 UNIPROT CDKN1B protein P46527 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000150;BTO:0000782 BTO:0000887;BTO:0001260 11313917 f amattioni "P27(kip1) gene is a target of transcriptional repression by c-myc." SIGNOR-107032 MYC protein P01106 UNIPROT HK2 protein P52789 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 17785433 t "Here, using the P493-6 Burkitt's lymphoma model with an inducible MYC, we demonstrate that HIF-1 cooperates with dysregulated c-Myc to promote glycolysis by induction of hexokinase 2, which catalyzes the first step of glycolysis, and pyruvate dehydrogenase kinase 1, which inactivates pyruvate dehydrogenase and diminishes mitochondrial respiration." SIGNOR-259986 MYC protein P01106 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" binding 9606 11804592 t gcesareni "Through its direct interaction with smads, c-myc binds to the sp1-smad complex on the promoter of the p15(ink4b) gene, thereby inhibiting the tgf-beta-induced transcriptional activity of sp1 and smad/sp1-dependent transcription of the p15(ink4b) gene. These results suggest that oncogenic c-myc promotes cell growth and cancer development partly by inhibiting the growth inhibitory functions of smads." SIGNOR-114284 MYC protein P01106 UNIPROT CDK6 protein Q00534 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001271 12835716 f gcesareni "The degradation of c-myc protein decreases the expression of the cell cycle regulators cdk4 and cdk6, which reversibly slows down the cell cycle." SIGNOR-102737 MYC protein P01106 UNIPROT CUL1 protein Q13616 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001271 12835716 f gcesareni "Furthermore, c-myc activation can also promote the degradation of p27kip1 protein by directly activating the cul1 gene, which encodes a critical component of the ubiquitin ligase scfskp2" SIGNOR-102749 MYC protein P01106 UNIPROT ITGA7 protein Q13683 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000165;BTO:0000222;BTO:0001760 14525975 t lperfetto "This report provides evidence that alpha7 gene expression during muscle differentiation is regulated by the c-Myc transcription factor. In myoblasts, alpha7 is expressed at basal levels, but following conversion to myotubes the expression of the integrin is strongly elevated. The increased alpha7 mRNA and protein levels following myogenic differentiation are inversely correlated with c-Myc expression. Transfection of myoblasts with the c-Myc transcription factor down-regulated alpha7 expression" SIGNOR-241769 MYC protein P01106 UNIPROT SURF1 protein Q15526 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10858544 f miannu "We show that although the Surf-1/Surf-2 promoter does not contain Myc binding sites (E-boxes), Myc over-expression, or the activation of a Myc-oestrogen receptor fusion protein, activates transcription in the Surf-1 direction and that this response to Myc requires a functional YY1 binding site. Our data suggest that the MAP kinase cascade is required for the stimulation of Surf-1 promoter activity and that the Myc-YY1 interaction mediates this response." SIGNOR-254615 MYC protein P01106 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates 9606 11804592 f "in cancer" lperfetto "Oncogenic c-myc promotes cell growth and cancer development partly by inhibiting the growth inhibitory functions of smads" SIGNOR-114281 MYC protein P01106 UNIPROT SIRT2 protein Q8IXJ6 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000584 23175188 f miannu "Here we demonstrated that the class III histone deacetylase SIRT2 was upregulated by N-Myc in neuroblastoma cells and by c-Myc in pancreatic cancer cells, and that SIRT2 enhanced N-Myc and c-Myc protein stability and promoted cancer cell proliferation." SIGNOR-255146 MYC protein P01106 UNIPROT SFRP1 protein Q8N474 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 "BTO:0004896; BTO:0004300" 17485441 f gcesareni "c-Myc suppresses the Wnt inhibitors DKK1 and SFRP1, and derepression of DKK1 or SFRP1 reduces Myc-dependent transforming activity" SIGNOR-245360 MYC protein P01106 UNIPROT MYCT1 protein Q8N699 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 11909865 t miannu "MT-MC1 is a widely expressed nuclear protein whose overexpression, unlike that of c-Myc targets reported previously, recapitulates multiple c-Myc phenotypes. These include promotion of apoptosis, alteration of morphology, enhancement of anchorage-independent growth, tumorigenic conversion, promotion of genomic instability, and inhibition of hematopoietic differentiation. The MT-MC1 promoter is a direct c-Myc target; it contains two consensus E-box elements, both of which bind c-Myc." SIGNOR-261736 HRAS protein P01112 UNIPROT ARAF protein P10398 UNIPROT up-regulates binding 9606 21779497 t lperfetto "The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases." SIGNOR-175183 MYC protein P01106 UNIPROT USP22 protein Q9UPT9 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 26049753 t "USP22 expression was regulated by c-MYC and contributed to c-MYC mediated reduction in SIRT1 polyubiquitination and degradation. USP22 directly interacted with and removing polyubiquitin chains from SIRT1 to increase SIRT1 protein stabilization and expression. These results support a role for USP22 in MYC-mediated increase in SIRT1 protein stabilization, and indicate that FLT3-ITD, c-MYC and USP22 form an oncogenic network that enhances SIRT1 expression and activity in leukemic cells." SIGNOR-261560 MYC protein P01106 UNIPROT HECTD4 protein Q9Y4D8 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001321 32814769 t miannu "We identified several E3 ligases as strong candidates responsible for AR and MYC protein loss as HECTD4, MYCBP2, and TRIM49. HECTD4 and MYCBP2 target AR and MYC for degradation while TRIM49 appears to promote AR and MYC stability. We have shown that these E3 ligases in turn are directly regulated by MYC. MYC in turn represses the expression of ubiquitin ligases, HECTD4 and MYCBP2 that promote AR and MYC protein degradation, further suppressing MYC and AR in a feed forward loop." SIGNOR-267144 MYC protein P01106 UNIPROT DNMT3A protein Q9Y6K1 UNIPROT "up-regulates activity" binding 9606 19786833 t irozzo "Based on one of these publications, we here showed that the interaction of Dnmt3a with c-myc promote the specific methylation of CG dinucleotides localized in c-myc boxes of promoter regions of CDKN2a, CCND1 and TIMP2 genes. Acellular experiments corroborated and complemented these results by revealing that the specificity of consensus sequence for DNA methylation of Dnmt3a is increased in presence of c-myc." SIGNOR-255806 NRAS protein P01111 UNIPROT RAF1 protein P04049 UNIPROT up-regulates relocalization 9606 21779497 t "Translocation from Cytosol to Membrane" gcesareni "The raf family of proteins (raf-1, a-raf, and b-raf) bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases." SIGNOR-175231 NRAS protein P01111 UNIPROT GLI1 protein P08151 UNIPROT up-regulates 9606 17845852 f gcesareni "Ras and akt signaling enhances the nuclear localization of gli1, counteracting its suppression by other modifiers that retain it in the cytoplasm, such as suppressor of fused (sufu)" SIGNOR-157773 NRAS protein P01111 UNIPROT ARAF protein P10398 UNIPROT up-regulates binding 9606 21779497 t gcesareni "The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases." SIGNOR-175216 NRAS protein P01111 UNIPROT BRAF protein P15056 UNIPROT "up-regulates activity" binding 9606 21779497 t lperfetto "The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases." SIGNOR-175219 NRAS protein P01111 UNIPROT PIK3CA protein P42336 UNIPROT "up-regulates activity" binding 9606 21779497 t lperfetto "Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k" SIGNOR-175222 NRAS protein P01111 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates binding 9606 21779497 t gcesareni "Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k" SIGNOR-175225 NRAS protein P01111 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 21779497 t gcesareni "Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. It was also described that ras interacts with pi3k in a direct manner.llysine residue 227 is essential for the interaction of ras with pi3k" SIGNOR-175228 NRAS protein P01111 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" binding 9606 21779497 t lperfetto "Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k" SIGNOR-252700 HRAS protein P01112 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 9020159 t lperfetto "We have examined whether the other two members of the Raf family, A-Raf and B-Raf, are regulated in a similar way to Raf-1. A-Raf behaves like Raf-1, being weakly activated by oncogenic Ras more strongly activated by oncogenic Src, and these signals synergize to give maximal activation. B-Raf by contrast is strongly activated by oncogenic Ras alone and is not activated by oncogenic Src." SIGNOR-235786 HRAS protein P01112 UNIPROT JUN protein P05412 UNIPROT "up-regulates activity" phosphorylation Ser63 KNSDLLTsPDVGLLK 10090 BTO:0000944 12169099 t lperfetto "c-Jun was first shown to be phosphorylated in its transactivation domain (Ser-63 and Ser-73) by ERKs and p54-JNK. This is consistent with other studies which show that PD98059 inhibits up-regulation of c-Jun protein in Ras-transformed NIH-3T3 cells" SIGNOR-235522 HRAS protein P01112 UNIPROT JUN protein P05412 UNIPROT "up-regulates activity" phosphorylation Ser73 VGLLKLAsPELERLI 10090 BTO:0000944 12169099 t lperfetto "c-Jun was first shown to be phosphorylated in its transactivation domain (Ser-63 and Ser-73) by ERKs and p54-JNK. This is consistent with other studies which show that PD98059 inhibits up-regulation of c-Jun protein in Ras-transformed NIH-3T3 cells" SIGNOR-235526 HRAS protein P01112 UNIPROT JUN protein P05412 UNIPROT "up-regulates activity" phosphorylation Ser63 KNSDLLTsPDVGLLK 10116 BTO:0000452 1749429 t lperfetto "Expression of oncogenic ha-ras augments transactivation by c-jun and stimulates its phosphorylation. Here we describe the mapping of the ha-ras-responsive phosphorylation sites to serines 63 and 73 of c-jun. Site-directed mutagenesis indicates that phosphorylation of these serines is essential for stimulation of c-jun activity and for cooperation with ha-ras in ocogenic transformation." SIGNOR-236682 HRAS protein P01112 UNIPROT JUN protein P05412 UNIPROT "up-regulates activity" phosphorylation Ser73 VGLLKLAsPELERLI 10116 BTO:0000452 1749429 t lperfetto "Expression of oncogenic ha-ras augments transactivation by c-jun and stimulates its phosphorylation. Here we describe the mapping of the ha-ras-responsive phosphorylation sites to serines 63 and 73 of c-jun. Site-directed mutagenesis indicates that phosphorylation of these serines is essential for stimulation of c-jun activity and for cooperation with ha-ras in ocogenic transformation." SIGNOR-236686 HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates binding 9606 18098337 t lperfetto "BRAF kinase is a downstream target of KRAS and activates the MAPK pathway." SIGNOR-160043 HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates binding 10090 BTO:0000944 7706312 t lperfetto "Association of B-Raf with immobilized Ras occurred independently of prior stimulation of cells with serum, suggesting that primarily the production of GTP-Ras by mitogen stimulation is critical for the formation of B-Raf_GTP-Ras complexes." SIGNOR-235478 HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT "up-regulates activity" binding 9606 21779497 t lperfetto "The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases." SIGNOR-147327 HRAS protein P01112 UNIPROT GATA2 protein P23769 UNIPROT "up-regulates activity" Ser192 PSTTGAAsPASSSAG 9606 25056917 f "Oncogenic Ras enhanced S192-dependent GATA-2 phosphorylation, nuclear foci localization, and transcriptional activation. These studies define a mechanism that controls a key regulator of hematopoiesis and a dual mode of impairing GATA-2-dependent genetic networks: mutational disruption of chromatin occupancy yielding insufficient GATA-2, and oncogenic Ras-mediated amplification of GATA-2 activity" SIGNOR-259945 HRAS protein P01112 UNIPROT PIK3CA protein P42336 UNIPROT "up-regulates activity" binding 9534 BTO:0004055 8052307 t lperfetto "In vivo, dominant negative ras mutant n17 inhibits growth factor induced production of 3' phosphorylated phosphoinositides in pc12 cells, and transfection of ras, but not raf, into cos cells results in a large elevation in the level of these lipids. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. it was also described that ras interacts with pi3k in a direct manner. lysine residue 227 is essential for the interaction of ras with pi3k" SIGNOR-236443 HRAS protein P01112 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 21779497 t gcesareni "Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. it was also described that ras interacts with pi3k in a direct manner. lysine residue 227 is essential for the interaction of ras with pi3k we show here, however, that in vivo there are marked quantitative differences in the ability of ki- and ha-ras to activate raf-1 and phosphoinositide 3 kinase. the mechanism of raf-1 activation is complex, but it is clear that one important role of ras is to recruit raf-1 to the plasma membrane where a series of events is initiated that ultimately leads to full raf-1 activation. These events include tyrosine, serine, and threonine phosphorylation plus interactions with ras, phospholipids, 14-3-3 proteins and their associated proteins, and possibly dimerization." SIGNOR-175195 HRAS protein P01112 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 9727023 t gcesareni "Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. it was also described that ras interacts with pi3k in a direct manner. lysine residue 227 is essential for the interaction of ras with pi3k we show here, however, that in vivo there are marked quantitative differences in the ability of ki- and ha-ras to activate raf-1 and phosphoinositide 3 kinase. the mechanism of raf-1 activation is complex, but it is clear that one important role of ras is to recruit raf-1 to the plasma membrane where a series of events is initiated that ultimately leads to full raf-1 activation. These events include tyrosine, serine, and threonine phosphorylation plus interactions with ras, phospholipids, 14-3-3 proteins and their associated proteins, and possibly dimerization." SIGNOR-59816 HRAS protein P01112 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" binding 9534 BTO:0004055 8052307 t lperfetto "In vivo, dominant negative ras mutant n17 inhibits growth factor induced production of 3' phosphorylated phosphoinositides in pc12 cells, and transfection of ras, but not raf, into cos cells results in a large elevation in the level of these lipids. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. it was also described that ras interacts with pi3k in a direct manner. lysine residue 227 is essential for the interaction of ras with pi3k" SIGNOR-252689 KRAS protein P01116 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 BTO:0000938 10882715 t gcesareni "Among other effectors, active ras binds and activates the raf kinase, iniziating a kinase cascade involving serine phosporylation of mek1/2 (mapkk) and tyrosine and threonine phosphorylation of erk1/2. the raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases.. Association of ras with the mapk kinase kinase, raf, initiates the raf mek erk map kinase cascade." SIGNOR-78911 KRAS protein P01116 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 16293107 t gcesareni "Among other effectors, active ras binds and activates the raf kinase, iniziating a kinase cascade involving serine phosporylation of mek1/2 (mapkk) and tyrosine and threonine phosphorylation of erk1/2. the raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases.. Association of ras with the mapk kinase kinase, raf, initiates the raf mek erk map kinase cascade." SIGNOR-141641 KRAS protein P01116 UNIPROT BRAF protein P15056 UNIPROT "up-regulates activity" binding 9606 21779497 t miannu "The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases." SIGNOR-156906 KRAS protein P01116 UNIPROT TCF3 protein P15923 UNIPROT up-regulates phosphorylation 9606 BTO:0000776 9528794 t gcesareni "Our results are consistent with a model in which notch and deltex act on e47 by inhibiting signaling through ras." SIGNOR-56144 KRAS protein P01116 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 21779497 t gcesareni "Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k phosphatidylinositol 3-kinase (pi3k) is one of the main effector pathways of ras, regulating cell growth, cell cycle entry, cell survival, cytoskeleton reorganization, and metabolism." SIGNOR-175204 KRAS protein P01116 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates binding 9606 7744823 t fstefani "Mitogen-activated protein kinase kinase kinase (mekk1) is a serine-threonine kinase that regulates sequential protein kinase pathways involving stress-activated protein kinases and mitogen-activated protein kinases. Mekk1 is activated in response to growth factor stimulation of cells and by expression of activated ras. mekk1 directly binds ras.GTP. Thus, ras interacts with protein kinases of both the raf and mekk families." SIGNOR-32620 KRAS protein P01116 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates phosphorylation Ser67 RQLRKVRsVELDQLP 9606 12228228 t gcesareni "Activation of ras may lead to two distinct ras-dependent pathways involving either a raf1/mek/mapk module or a mekk/sek/sapk module; jnk/sapk binds to the d domain near the nh2 terminus of mekk1 from approximately residues 6270 (9, 10). Pak1 can phosphorylate mekk1 on serine 67 within its jnk/sapk-binding d domain. Phosphorylation of mekk1 on serine 67 alters the state of the d domain, thereby decreasing its affinity for jnk/sapk. Under these conditions jnk/sapk is not recruited into the mekk1 signaling module." SIGNOR-92793 KRAS protein P01116 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates phosphorylation Ser67 RQLRKVRsVELDQLP 9606 BTO:0000776;BTO:0000785 8649450 t gcesareni "Activation of ras may lead to two distinct ras-dependent pathways involving either a raf1/mek/mapk module or a mekk/sek/sapk module; jnk/sapk binds to the d domain near the nh2 terminus of mekk1 from approximately residues 6270 (9, 10). Pak1 can phosphorylate mekk1 on serine 67 within its jnk/sapk-binding d domain. Phosphorylation of mekk1 on serine 67 alters the state of the d domain, thereby decreasing its affinity for jnk/sapk. Under these conditions jnk/sapk is not recruited into the mekk1 signaling module." SIGNOR-41953 KRAS protein P01116 UNIPROT NFIL3 protein Q16649 UNIPROT up-regulates 10090 BTO:0003104 10082541 f lperfetto "A constitutively active Ras protein [Ras(G12V)] regulates the stable expression of the NFIL3 transcription factor through both the Raf-MAPK and PI3-K pathways." SIGNOR-242757 KRAS protein P01116 UNIPROT MINK1 protein Q8N4C8 UNIPROT up-regulates 9606 16337592 f gcesareni "Mink is activated after ras induction via a mechanism involving reactive oxygen species and mediates stimulation of the stress-activated protein kinase p38 mapk downstream of the raf/erk pathway." SIGNOR-142985 KRAS protein P01116 UNIPROT RASSF1 protein Q9NS23 UNIPROT "up-regulates activity" binding 9606 22195963 t lperfetto "Mutant K-Ras promotes MST2 activation in two ways (i.e., by direct disruption of the inhibitory Raf-1-MST2 complex (Matallanas et al., 2008) and by forming an activating (i.e., by direct disruption of the inhibitory Raf-1-MST2 complex K-Ras-RASSF1A€“MST2 complex, as reported here" SIGNOR-249585 KRAS protein P01116 UNIPROT MAP4K5 protein Q9Y4K4 UNIPROT up-regulates 9606 BTO:0001271 9949177 f fstefani "Bcr-abl_mediated ras activation is crucial for the ability of bcr-abl to activate gckr and is consistent with the previously known requirement for ras in bcr-abl_induced sapk activation how ras activates gckr remains enigmatic." SIGNOR-64262 KRAS protein P01116 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 21779497 t gcesareni "Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k phosphatidylinositol 3-kinase (pi3k) is one of the main effector pathways of ras, regulating cell growth, cell cycle entry, cell survival, cytoskeleton reorganization, and metabolism." SIGNOR-252698 EGF protein P01133 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 12648462 t lperfetto "The mammalian ligands that bind the egf receptor (egfr [her1, erb-b1]) include egf, transforming growth factor- (tgf), heparin-binding egf-like growth factor (hb-egf), amphiregulin (ar), betacellulin (btc), epiregulin (epr), and epigen" SIGNOR-22716 EGF protein P01133 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" binding 9606 12297050 t lperfetto "Epidermal growth factor (egf) regulates cell proliferation and differentiation by binding to the egf receptor (egfr) extracellular region, comprising domains i-iv, with the resultant dimerization of the receptor tyrosine kinase." SIGNOR-186159 EGF protein P01133 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates binding 9606 11279155 t tpavlidou "To better understand the role of the egfr tyrosine kinase, we analyzed signaling by a kinase-inactive egfr (k721m) in erbb-devoid 32d cells. K721m alone exhibited no detectable signaling capacity, whereas coexpression of k721m with erbb2, but not erbb3 or erbb4, resulted in egf-dependent mitogen-activated protein kinase (mapk) activation. The kinase activity, but not tyrosine phosphorylation, of erbb2 was required for egf-induced mapk activation." SIGNOR-106497 TGFA protein P01135 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" binding 9606 BTO:0000584 16585207 t "Transforming growth factor alpha expression drives constitutive epidermal growth factor receptor pathway activation and sensitivity to gefitinib (Iressa) in human pancreatic cancer cell lines" gcesareni "Our data indicate that a subset of cell lines is dependent on TGF-_-mediated activation of the EGFR for cell proliferation and strongly suggest that pancreatic tumors expressing high levels of TGF-_ and phosphorylated (activated) EGFR are EGFR-dependent in vitro and in vivo." SIGNOR-93199 TGFB1 protein P01137 UNIPROT TGFB1 protein P01137 UNIPROT "up-regulates activity" binding 9606 16885528 t lperfetto "The active form of TGF-beta is a dimer stabilized by hydrophobic interactions and usually further strengthened by an intersubunit disulfide bridge." SIGNOR-148605 TGFB1 protein P01137 UNIPROT TSHB protein P01222 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 14623893 t miannu "TGF-β inhibits thyroid-stimulated hormone (TSH)-induced NIS mRNA and protein levels in a dose-dependent manner. This effect takes place at the transcriptional level, as TGF-β inhibits TSH-induced transcription" SIGNOR-251991 TGFB1 protein P01137 UNIPROT COL4A1 protein P02462 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000764 20846954 f Regulation miannu "We used diploid human lung fibroblasts (WI38 cells) induced by TGFβ to differentiate into myofibroblast-like cells. In order to characterize this system, we first studied the expression of the myofibroblast marker genes ACTA2 (coding for smooth muscle α-actin; SMA), COL4A1 (encoding collagen type IV α1) and SM22A (coding for smooth muscle protein 22-α). As shown in Figure 1A and B, TGFβ induced the expression all three genes." SIGNOR-251922 TGFB1 protein P01137 UNIPROT KRT1 protein P04264 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 16258965 f Regulation miannu "TGFβ1 and TGFβ2 induce loss of epithelial morphology, cytokeratin, and membrane-associated Zonula Occludens-1 and increase the smooth muscle markers calponin and caldesmon" SIGNOR-251884 TGFB1 protein P01137 UNIPROT LPL protein P06858 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000801 11742878 f "Regulation of expression" miannu "TGF-β1 inhibited gene expression and cell surface activity of LPL. TGF-β1 did not have an effect on LPL activity when it was added directly to the LPL activity assay (data not shown); however, as shown in the Table, TGF-β1 significantly reduced LPL mRNA by 55.0%" SIGNOR-251847 TGFB1 protein P01137 UNIPROT SFTPB protein P07988 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004299 18003659 f miannu "TGF-beta represses transcription of pulmonary surfactant protein-B gene in lung epithelial cells." SIGNOR-254170 TGFB1 protein P01137 UNIPROT COL1A2 protein P08123 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 8182090 f gcesareni "Tgf-beta stimulates transcription of the human alpha 2(i) collagen gene (col1a2) promoter by increasing the affinity of an sp1-containing protein complex for its cognate dna-binding site" SIGNOR-36783 TGFB1 protein P01137 UNIPROT CDK4 protein P11802 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000763 8402878 f gcesareni "Here we show that tgf beta 1 induces suppression of cdk4 synthesis in g1 in mink lung epithelial cells." SIGNOR-39045 TGFB1 protein P01137 UNIPROT ITGA2 protein P17301 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001596 1744142 f lperfetto "TGF-beta 1 decreases the biosynthesis of alpha 3 subunit but increases the production of alpha 2 subunit. IL-1 beta potentiates the effects of TGF-beta 1. Furthermore, in the presence of TGF-beta 1 the increase in the expression of alpha 1 subunit by IL-1 beta is even larger. Thus, IL-1 beta and TGF-beta 1, which usually have antagonistic functions in connective tissue, can regulate integrin expression in a synergistic way." SIGNOR-253354 TGFB1 protein P01137 UNIPROT ENG protein P17813 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002741 21146604 f miannu "In hepatic stellate cells, TGF-β1 upregulates endoglin expression most likely via the ALK5 pathway and requires the SP1 transcription factor." SIGNOR-255202 TGFB1 protein P01137 UNIPROT ENPP1 protein P22413 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000249 20930330 f miannu "TGF-β1 was shown to stimulate ANK and PC-1 expression in articular chondrocytes, and subsequent ePPi level, as well as to increase ePi uptake by inducing PiT-1 expression in a chondrogenic cell line." SIGNOR-252200 TGFB1 protein P01137 UNIPROT CDK2 protein P24941 UNIPROT down-regulates 9606 SIGNOR-C16 10611320 f gcesareni "Tgf-beta treatment resulted in the specific inactivation of cyclin cdk2 complexes caused by absence of the activating thr(160) phosphorylation on cdk2." SIGNOR-73537 TGFB1 protein P01137 UNIPROT ITGA3 protein P26006 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001596 1744142 f lperfetto "TGF-beta 1 decreases the biosynthesis of alpha 3 subunit but increases the production of alpha 2 subunit. IL-1 beta potentiates the effects of TGF-beta 1. Furthermore, in the presence of TGF-beta 1 the increase in the expression of alpha 1 subunit by IL-1 beta is even larger. Thus, IL-1 beta and TGF-beta 1, which usually have antagonistic functions in connective tissue, can regulate integrin expression in a synergistic way." SIGNOR-253353 TGFB1 protein P01137 UNIPROT PAX6 protein P26367 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001874 17251190 f Regulation miannu "The effect of TGFbeta on Pax6 expression was studied in the FHL124 lens epithelial cell line and was found to cause up to a 50% reduction in Pax6 mRNA levels within 24 h. Pax6-stimulated activity of the Pax6 promoter is repressed by TGFβ signalling." SIGNOR-251874 TGFB1 protein P01137 UNIPROT PIK3R1 protein P27986 UNIPROT "up-regulates activity" binding 9606 19114990 t lperfetto "While association of the TGF_RI receptor with p85 requires TGF-_ stimulation." SIGNOR-217960 TGFB1 protein P01137 UNIPROT SHC1 protein P29353 UNIPROT "up-regulates activity" 10090 BTO:0000944 17673906 f lperfetto "We report that upon TGF__ stimulation, the activated TGF__ type I receptor (T_RI) recruits and directly phosphorylates ShcA proteins on tyrosine and serine. This dual phosphorylation results from an intrinsic T_RI tyrosine kinase activity that complements its well_defined serine_threonine kinase function. TGF___induced ShcA phosphorylation induces ShcA association with Grb2 and Sos, thereby initiating the well_characterised pathway linking receptor tyrosine kinases with Erk MAP kinases." SIGNOR-242631 TGFB1 protein P01137 UNIPROT TGFBR1 protein P36897 UNIPROT "up-regulates activity" binding 9606 22326956 t "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 TGFB1 protein P01137 UNIPROT TGFBR1 protein P36897 UNIPROT "up-regulates activity" binding 9606 22326956 t 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 TGFB1 protein P01137 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates binding 9606 26194464 t "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 TGFB1 protein P01137 UNIPROT TGFBR2 protein P37173 UNIPROT "up-regulates activity" binding 9534 BTO:0004055 1310899 t 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 TGFB1 protein P01137 UNIPROT CDKN2B protein P42772 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 7592908 f gcesareni "The steadystate level of p15ink4b mrna was induced 30-fold upon tgf-beta treatment, implicating p15ink4b as a primary effector of the tgf-beta-mediated cell cycle arrest" SIGNOR-29582 TGFB1 protein P01137 UNIPROT CDKN1B protein P46527 UNIPROT "up-regulates quantity by expression" 9606 17283133 f gcesareni "In normal primary endometrial epithelial cells (eecs), tgfbeta directly induced a dose-dependent increase in p27 protein levels and its nuclear localization" SIGNOR-152945 TGFB1 protein P01137 UNIPROT PIK3CG protein P48736 UNIPROT "up-regulates activity" 9606 19114990 f lperfetto "First, TGF-beta can rapidly activate PI3K, as indicated by the phosphorylation of its downstream effector Akt" SIGNOR-217812 TGFB1 protein P01137 UNIPROT ACTA2 protein P62736 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000764 20846954 f Regulation miannu "We used diploid human lung fibroblasts (WI38 cells) induced by TGFβ to differentiate into myofibroblast-like cells. In order to characterize this system, we first studied the expression of the myofibroblast marker genes ACTA2 (coding for smooth muscle α-actin; SMA), COL4A1 (encoding collagen type IV α1) and SM22A (coding for smooth muscle protein 22-α). As shown in Figure 1A and B, TGFβ induced the expression all three genes." SIGNOR-251923 TGFB1 protein P01137 UNIPROT PPP2R2A protein P63151 UNIPROT "up-regulates activity" binding 9606 19114990 t lperfetto "The Balpha subunit interacts directly with activated T_RI. The Balpha interaction with the receptor is expected to result in enhanced protein phosphatase 2A activity" SIGNOR-217894 TGFB1 protein P01137 UNIPROT HBB protein P68871 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 8142649 f Regulation miannu "Basic fibroblast growth factor (bFGF) and transforming growth factor-beta 1 (TGF-beta) have both been shown to act on hematopoietic progenitor cells. bFGF antagonized the TGF-beta-mediated induction of hemoglobin in a dose-dependent manner, with 0.1 ng/mL bFGF inhibiting hemoglobin induction by 40% and 10 ng/mL bFGF completely abrogating hemoglobin production." SIGNOR-251797 TGFB1 protein P01137 UNIPROT HBA1 protein P69905 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 8142649 f Regulation miannu "Basic fibroblast growth factor (bFGF) and transforming growth factor-beta 1 (TGF-beta) have both been shown to act on hematopoietic progenitor cells. bFGF antagonized the TGF-beta-mediated induction of hemoglobin in a dose-dependent manner, with 0.1 ng/mL bFGF inhibiting hemoglobin induction by 40% and 10 ng/mL bFGF completely abrogating hemoglobin production." SIGNOR-251798 TGFB1 protein P01137 UNIPROT TFAP4 protein Q01664 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000452 21228219 f miannu "TGFβ effectively inhibits expression of SALL2 and its regulator AP4 when added to quiescent fibroblasts." SIGNOR-255428 TGFB1 protein P01137 UNIPROT TAGLN protein Q01995 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000764 20846954 f Regulation miannu "We used diploid human lung fibroblasts (WI38 cells) induced by TGFβ to differentiate into myofibroblast-like cells. In order to characterize this system, we first studied the expression of the myofibroblast marker genes ACTA2 (coding for smooth muscle α-actin; SMA), COL4A1 (encoding collagen type IV α1) and SM22A (coding for smooth muscle protein 22-α). As shown in Figure 1A and B, TGFβ induced the expression all three genes." SIGNOR-251924 TGFB1 protein P01137 UNIPROT PAX8 protein Q06710 UNIPROT "down-regulates activity" binding 9606 14623893 t miannu "DNA Binding Activity of Pax8 to the NIS Promoter Is Reduced by Smad3. TGF-β decreases Pax8 DNA binding to the NIS promoter and also found a physical interaction between Pax8 and Smad3." SIGNOR-251993 TGFB1 protein P01137 UNIPROT SKP2 protein Q13309 UNIPROT down-regulates 9606 21212736 f gcesareni "Skp2, a f-box protein that determines the substrate specificity for scf ubiquitin ligase, has recently been demonstrated to be degraded by cdh1/apc in response to tgfbeta signaling." SIGNOR-171013 TGFB1 protein P01137 UNIPROT RUNX2 protein Q13950 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001593 11331591 f lperfetto "Tgf-b caused a 50% reduction of cbfa1 mrna." SIGNOR-235998 TGFB1 protein P01137 UNIPROT RNF111 protein Q6ZNA4 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 14657019 f lpetrilli "Expression of arkadia is down-regulated by tgf-beta." SIGNOR-119669 TGFB1 protein P01137 UNIPROT DNAH10 protein Q8IVF4 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000667 31836722 f miannu "The protein expression of DNAH10 was assessed by Western blot analysis after stimulation of primary keratinocytes (P4) with inflammatory cytokine TNFα or growth factor TGF-β1 and their combination (Fig. 5C). Treatment with TNFα, TGF-β1, and their combination down regulated the expression of DNAH10 in keratinocytes after a 24-h-stimulation." SIGNOR-265552 TGFB1 protein P01137 UNIPROT MYOCD protein Q8IZQ8 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887;BTO:0001260 21673106 f gcesareni "These results indicate that (i) tgf- and klf4 regulate myocd transcription positively and negatively, respectively. When __90% of smad4 was down-regulated myocd mrna induction by tgf- was abolished, suggesting that smad4 plays a critical role in transcriptional activation of the myocd gene" SIGNOR-174396 TGFB1 protein P01137 UNIPROT SLC20A1 protein Q8WUM9 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000249 20930330 f miannu "TGF-β1 was shown to stimulate ANK and PC-1 expression in articular chondrocytes, and subsequent ePPi level, as well as to increase ePi uptake by inducing PiT-1 expression in a chondrogenic cell line." SIGNOR-252202 TGFB1 protein P01137 UNIPROT SLC5A5 protein Q92911 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 14623893 f miannu "The sodium/iodide symporter mediates the active transport of iodide in thyroid follicular cells. A number of agents regulate NIS expression; among these, TGF-β is a potent inhibitor of both iodide uptake and NIS gene expression" SIGNOR-259912 TGFB1 protein P01137 UNIPROT LPP protein Q93052 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887;BTO:0001260 22886954 f miannu "Tgf-_1-induced lpp expression dependant on rho kinase during differentiation and migration of bone marrow-derived smooth muscle progenitor cells" SIGNOR-191768 TGFB1 protein P01137 UNIPROT OMD protein Q99983 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 16970923 f miannu "We found tgf-beta1 to down regulate osad" SIGNOR-149565 TGFB1 protein P01137 UNIPROT SALL2 protein Q9Y467 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000452 21228219 f miannu "TGFβ effectively inhibits expression of SALL2 and its regulator AP4 when added to quiescent fibroblasts." SIGNOR-255427 TGFB1 protein P01137 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" binding 9606 19114990 t lperfetto "While association of the TGF_RI receptor with p85 requires TGF-_ stimulation." SIGNOR-252729 TGFB1 protein P01137 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR "down-regulates activity" 9606 10611320 f lperfetto "Tgf-beta treatment resulted in the specific inactivation of cyclin cdk2 complexes caused by absence of the activating thr(160) phosphorylation on cdk2." SIGNOR-217502 NGF protein P01138 UNIPROT NTRK1 protein P04629 UNIPROT up-regulates binding 9606 11114882 t gcesareni "Ngf is the preferred ligand for trka, bdnf and nt4/5 are preferred for trkb, and nt3 for trkc (barbacid 1994). These specificities are not absolute, and nt3 is also a ligand for trka and trkb." SIGNOR-85114 NGF protein P01138 UNIPROT NGFR protein P08138 UNIPROT up-regulates binding 9606 BTO:0000007 10764727 t gcesareni "The low affinity neurotrophin receptor p75ntr can mediate cell survival as well as cell death of neural cells by ngf and other neurotrophins." SIGNOR-76832 NGF protein P01138 UNIPROT GCH1 protein P30793 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0001676 16190874 f miannu "We examined intracellular signals required for NGF-induced expression of the GCH gene in PC12D cells. The activity of GCH was increased up to 5-fold after the NGF treatment. The human GCH promoter activity was significantly enhanced by NGF treatment." SIGNOR-252228 NGF protein P01138 UNIPROT SCN9A protein Q15858 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0003306 24493753 f miannu "Long-term (more than 24 h) treatment with nerve growth factor (NGF) upregulated Nav1.7 functional expression in the strongly metastatic MAT-LyLu rat PCa cell line; acute application had no effect" SIGNOR-253495 GNRH1 protein P01148 UNIPROT AR protein P10275 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 17202804 t miannu "GnRH antagonizes testosterone activation of the human androgen receptor in SCL60 cells. Gonadotropin-Releasing Hormone Functionally Antagonizes Testosterone Activation of the Human Androgen Receptor in Prostate Cells through Focal Adhesion Complexes Involving Hic-5" SIGNOR-259267 NPPA protein P01160 UNIPROT NPR1 protein P16066 UNIPROT up-regulates binding 9606 15911069 t gcesareni "Natriuretic peptide receptor-a (npra) is the biological receptor of the peptide hormones atrial natriuretic peptide (anp) and brain natriuretic peptide (bnp)" SIGNOR-137600 OXT protein P01178 UNIPROT OXTR protein P30559 UNIPROT up-regulates binding 9606 1313946 t gcesareni "The oxytocin receptor, expressed in xenopus oocytes, specifically responds to oxytocin and induces an inward membrane current" SIGNOR-16758 AVP protein P01185 UNIPROT AVPR2 protein P30518 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0000671;BTO:0001260 1560825 t gcesareni "We report here the cloning of a complementary dna encoding the hepatic v1a arginine vasopressin receptor. The liver cdna encodes a protein with seven putative transmembrane domains, which binds arginine vasopressin." SIGNOR-20185 POMC protein P01189 UNIPROT NFKB1 protein P19838 UNIPROT "down-regulates activity" 9606 BTO:0000848 16274845 f miannu "Alpha-MSH is an anti-inflammatory peptide which signals by binding to the melanocortin-1 receptor (MC1R) and elevating cyclic AMP in several different cells and tissues. The carboxyl terminal peptides of alpha-MSH (KPV/GKPV) are the smallest minimal sequences that prevent inflammation, but it is not known if they operate via MC1R or cyclic AMP. Immobilized alpha-melanocyte stimulating hormone 10-13 (GKPV) inhibits tumor necrosis factor-alpha stimulated NF-kappaB activity." SIGNOR-252371 POMC protein P01189 UNIPROT MC4R protein P32245 UNIPROT "up-regulates activity" binding 9606 20694162 t miannu "α-MSH can activate both melanocortin 4 receptors (MC4R) and melanocortin 1 receptors (MC1R)" SIGNOR-252373 POMC protein P01189 UNIPROT MC5R protein P33032 UNIPROT up-regulates binding 9606 BTO:0000007 11785979 t gcesareni "The purpose of this study was to identify the peptide that functions as a natural ligand at the mc5r in the skin. alpha-msh, acth1-39, acth1-17, acth1-10, and acth4-10 all increased the production of camp in hek293 cells transfected with the mouse mc5r. alpha-msh and acth1-17 were the most potent in this respect. In addition, all peptides stimulated a rapid and transient increase in [ca(2+)](i)." SIGNOR-114058 POMC protein P01189 UNIPROT OPRD1 protein P41143 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258409 POMC protein P01189 UNIPROT OPRK1 protein P41145 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258410 POMC protein P01189 UNIPROT MC3R protein P41968 UNIPROT "up-regulates activity" binding BTO:0000614 17702843 t lperfetto "Centrally administered melanotan II (MTII), a synthetic melanocortin 3/4-receptor agonist, decreases adiposity beyond that accountable by food intake decreases." SIGNOR-253073 POMC protein P01189 UNIPROT MC1R protein Q01726 UNIPROT "up-regulates activity" binding 9606 BTO:0000847 19656324 t miannu "Alpha-melanocyte stimulating hormone (alpha-MSH) binds to melanocortin-1 receptor (MC1R) on melanocytes to stimulate pigmentation and modulate various cutaneous inflammatory responses." SIGNOR-252370 PDYN protein P01213 UNIPROT OPRM1 protein P35372 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258414 PDYN protein P01213 UNIPROT OPRD1 protein P41143 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258415 PDYN protein P01213 UNIPROT OPRK1 protein P41145 UNIPROT "up-regulates activity" binding 10029 BTO:0000246 9262330 t miannu "We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined.. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine." SIGNOR-258411 PDYN protein P01213 UNIPROT OPRK1 protein P41145 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258416 CGA protein P01215 UNIPROT TSHR protein P16473 UNIPROT up-regulates binding 9606 12045258 t miannu "Human thyrotropin (tsh), follitropin (fsh), lutropin (lh), and chorionic gonadotropin (cg) are members of the glycoprotein hormone family derived from heterodimerization of a common ? Subunit with hormone-specific ? Subunits. These hormones were originally purified from the anterior pituitary (tsh, lh, and fsh) and placenta (human cg) and shown to activate specific g protein_coupled receptors in the thyroid (tsh receptor) and gonads (lh and fsh receptors), respectively" SIGNOR-88519 CGA protein P01215 UNIPROT TSH complex SIGNOR-C412 SIGNOR "form complex" binding 9606 BTO:0001379 8196184 t scontino "TSH is a heterodimer composed of common alpha subunit and unique beta subunit encoded by genes located on different chromosomes. It is known that the expression of these subunit genes is regulated in different mechanism by several extracellular factors." SIGNOR-267046 TSHB protein P01222 UNIPROT SLC5A5 protein Q92911 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 14623893 t miannu "I– uptake is stimulated by TSH, the master hormone for thyroid gland regulation. TSH stimulation results, at least in part, from the cAMP-mediated increase in NIS biosynthesis. TSH not only stimulates NIS transcription and biosynthesis but is also required for modulating the NIS phosphorylation pattern, maintaining its half-life, and retaining NIS at the thyrocyte plasma membrane" SIGNOR-251995 TSHB protein P01222 UNIPROT SLC5A5 protein Q92911 UNIPROT "up-regulates quantity by stabilization" 9606 14623893 f miannu "Uptake is stimulated by TSH, the master hormone for thyroid gland regulation. TSH stimulation results, at least in part, from the cAMP-mediated increase in NIS biosynthesis. TSH not only stimulates NIS transcription and biosynthesis but is also required for modulating the NIS phosphorylation pattern, maintaining its half-life, and retaining NIS at the thyrocyte plasma membrane" SIGNOR-251994 TSHB protein P01222 UNIPROT TSH complex SIGNOR-C412 SIGNOR "form complex" binding 9606 BTO:0001379 8196184 t scontino "TSH is a heterodimer composed of common alpha subunit and unique beta subunit encoded by genes located on different chromosomes. It is known that the expression of these subunit genes is regulated in different mechanism by several extracellular factors." SIGNOR-267047 CGB protein P01233 UNIPROT LHCGR protein P22888 UNIPROT up-regulates binding 9606 10446903 t gcesareni "The ?-Subunit of human choriogonadotropin interacts with the exodomain of the luteinizing hormone/choriogonadotropin receptor" SIGNOR-69400 PRL protein P01236 UNIPROT KRT14 protein P02533 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000667 20103718 f Regulation miannu "PRL up-regulated expression of keratins K5 and K14 and the epithelial stem cell-associated keratins K15 and K19 in organ-cultured HFs and/or isolated HF keratinocytes." SIGNOR-251902 PRL protein P01236 UNIPROT KRT19 protein P08727 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000667 20103718 f Regulation miannu "PRL up-regulated expression of keratins K5 and K14 and the epithelial stem cell-associated keratins K15 and K19 in organ-cultured HFs and/or isolated HF keratinocytes." SIGNOR-251905 PRL protein P01236 UNIPROT KRT15 protein P19012 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000667 20103718 f Regulation miannu "PRL up-regulated expression of keratins K5 and K14 and the epithelial stem cell-associated keratins K15 and K19 in organ-cultured HFs and/or isolated HF keratinocytes." SIGNOR-251904 GH1 protein P01241 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001939 15665309 t Luana "Autocrine hGH increased the transcription and subsequent mRNA level and protein expression of c-Myc, Cyclin D1, and Bcl-2 in human mammary epithelial cells" SIGNOR-261627 GH1 protein P01241 UNIPROT BCL2 protein P10415 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001939 15665309 t Luana "Autocrine hGH increased the transcription and subsequent mRNA level and protein expression of c-Myc, Cyclin D1, and Bcl-2 in human mammary epithelial cells" SIGNOR-261628 GH1 protein P01241 UNIPROT CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001939 15665309 t Luana "Autocrine hGH increased the transcription and subsequent mRNA level and protein expression of c-Myc, Cyclin D1, and Bcl-2 in human mammary epithelial cells" SIGNOR-261629 GCG protein P01275 UNIPROT LATS1 protein O95835 UNIPROT up-regulates 9606 23075495 f gcesareni "On the other hand, galfas-coupled signals, such as epinephrine and glucagon, induce kinase activity of lats1/2, leading to phosphorylation and yap/taz." SIGNOR-199202 GCG protein P01275 UNIPROT GLP1R protein P43220 UNIPROT up-regulates binding 9606 BTO:0000776 7937318 t gcesareni "In the present study we stably expressed the rat b-cell glp-i receptor in cho cells and studied binding characteristics and receptor activation utilizing the naturally occurring receptor agonist glp-i(7-36)-amide (glp-i), the proglucagon-derived glp-i-related peptide oxyntomodulin, the glp-i receptor agonist exendin-4, and the specific antagonist exendin" SIGNOR-34855 GCG protein P01275 UNIPROT GCGR protein P47871 UNIPROT up-regulates binding 9606 12529935 t fspada "Mutation of a highly conserved d64 residue in the n-terminal portion of the rat glucagon receptor completely eliminates glucagon binding. This residue corresponds to a mutated asp residue at amino acid 60 in the growth hormone releasing hormone receptor that gives rise to the little mouse phenotype (lin et al.1993). Antisera directed against amino acid sequences 126_137 of the n-terminal region, and agai residues 206_219 of the first extracellular loop block [125i]-glucagon binding and interfere with glucagon-induced adenylyl cyclase generation in rat liver membranes." SIGNOR-97338 GCG protein P01275 UNIPROT GCGR protein P47871 UNIPROT up-regulates binding 9606 BTO:0000007 22863277 t milica "In contrast, stimulation of gs-coupled receptors by glucagon or epinephrine activates lats1/2 kinase activity, thereby inhibiting yap function." SIGNOR-198504 GCG protein P01275 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates 9606 23075495 f gcesareni "On the other hand, galfas-coupled signals, such as epinephrine and glucagon, induce kinase activity of lats1/2, leading to phosphorylation and yap/taz." SIGNOR-199205 VIP protein P01282 UNIPROT VIPR1 protein P32241 UNIPROT up-regulates binding 9606 11897681 t gcesareni "Pacap binds to a pacap-specific receptor (pac1) and to vpac receptors (vpac1 and vpac2), which share high affinity for vasoactive intestinal polypeptide (vip)." SIGNOR-116122 PPY protein P01298 UNIPROT NPY4R protein P50391 UNIPROT up-regulates binding 9606 BTO:0000142 7592911 t gcesareni "Human y4 bound human pp family members in i-pyy membrane binding assays with a distinctive rank order (table 1): pp > pyy > npy > npy free acid." SIGNOR-24230 NPY protein P01303 UNIPROT NPY1R protein P25929 UNIPROT up-regulates binding 9606 9549761 t gcesareni "Analogs of npy and pyy have been synthesized that contain a proline residue in position 34 of the molecule, i.e., [leu31, pro34]npy (fuhlendorff et al., 1990) or [pro34]pyy (grandt et al., 1994b), and are much more potent at y1 than y2receptors." SIGNOR-56522 NPY protein P01303 UNIPROT NPY2R protein P49146 UNIPROT up-regulates binding 9606 9549761 t gcesareni "Analogs of npy and pyy have been synthesized that contain a proline residue in position 34 of the molecule, i.e., [leu31, pro34]npy (fuhlendorff et al., 1990) or [pro34]pyy (grandt et al., 1994b), and are much more potent at y1 than y2receptors." SIGNOR-56568 NPY protein P01303 UNIPROT NPY4R protein P50391 UNIPROT up-regulates binding 9606 BTO:0000142 7592911 t gcesareni "Human y4 bound human pp family members in i-pyy membrane binding assays with a distinctive rank order (table 1): pp > pyy > npy > npy free acid." SIGNOR-29633 INS protein P01308 UNIPROT APOB protein P04114 UNIPROT "down-regulates quantity by destabilization" 9606 23721961 f miannu "Insulin decreases ApoB secretion by promoting ApoB degradation in the hepatocyte. Though insulin does not alter ApoB mRNA levels, it inhibits ApoB translation by promoting the trafficking of ApoB mRNA into P-bodies, aggregates of translationally repressed mRNAs" SIGNOR-252114 INS protein P01308 UNIPROT INSR protein P06213 UNIPROT "up-regulates activity" binding 10029 BTO:0000246 16956584 t lperfetto "Insulin binds to the alpha subunit of the insulin receptor (IR) on the cell surface." SIGNOR-236748 INS protein P01308 UNIPROT INSR protein P06213 UNIPROT "up-regulates activity" binding 9606 2550426 t 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 INS protein P01308 UNIPROT LPL protein P06858 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001487 21966368 f Regulation miannu "Insulin has a major effect on LPL regulation in adipose tissue since in mature adipocytes insulin not only increases the level of LPL mRNA but also regulates LPL activity through both posttranscriptional and posttranslational mechanisms" SIGNOR-251857 INS protein P01308 UNIPROT IGF1R protein P08069 UNIPROT up-regulates binding 9606 BTO:0000887 1851182 t fspada "Because of the sequence homology and tertiary structure similarities between proinsulin (pi) and insulin-like growth factor-i (igf-i), it is possible that pi interacts with the igf-i receptor with higher affinity than insulin." SIGNOR-22083 INS protein P01308 UNIPROT SLC2A4 protein P14672 UNIPROT "up-regulates activity" 9606 BTO:0000887 9415393 f lperfetto "Studies in adipose cells have demonstrated that insulin stimulates its receptor to phosphorylate tyrosine residues in irs-1, leading to activation of phosphatidylinositol 3-kinase, which plays a necessary role in mediating the translocation of the insulin-responsive glucose transporter glut4 to the cell surface." SIGNOR-236781 INS protein P01308 UNIPROT RHOQ protein P17081 UNIPROT up-regulates 9606 12687004 f gcesareni "Exo70 translocates to the plasma membrane in response to insulin through the activation of tc10, where it assembles a multiprotein complex that includes sec6 and sec8" SIGNOR-100483 INS protein P01308 UNIPROT CEBPB protein P17676 UNIPROT up-regulates 10090 BTO:0000011 11279134 f 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-250565 INS protein P01308 UNIPROT COMT protein P21964 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000542 17612537 f "Regulation of expression" miannu "Catechol O-methyltransferase expression in granulosa cells was up-regulated by insulin, DHT, and ATRA." SIGNOR-251961 INS protein P01308 UNIPROT GATA2 protein P23769 UNIPROT down-regulates 9606 BTO:0000876 15837948 f fspada "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-135617 INS protein P01308 UNIPROT AKT1 protein P31749 UNIPROT up-regulates 10090 12530968 f lperfetto "The forkhead transcription factor foxo1 is regulated by insulin via akt-dependent phosphorylation and nuclear exclusion." SIGNOR-252627 INS protein P01308 UNIPROT PPARG protein P37231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000011 11279134 f 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-235619 INS protein P01308 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates 9606 15209375 f gcesareni "The interaction ofinsulin and growth factors with their receptors on the outside surface of a cell, leads to the activation of phosphatidylinositol 3-kinase (pi 3-kinase) and generation of the phosphatidylinositol 3,4,5-trisphosphate (ptdins(3,4,5)p3) second messenger at the inner surface of the cell membrane." SIGNOR-126063 INS protein P01308 UNIPROT CEBPA protein P49715 UNIPROT up-regulates 9606 11279134 f fspada "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-250570 INS protein P01308 UNIPROT GSK3B protein P49841 UNIPROT down-regulates 9606 BTO:0000887;BTO:0001103 8250835 f gcesareni "The results suggest that ser-9 phosphorylation underlies the reported gsk3 beta inhibition by insulin and that gsk3 may represent a point of convergence of two major growth-factor-stimulated protein kinase cascades." SIGNOR-37220 INS protein P01308 UNIPROT FOXO1 protein Q12778 UNIPROT "down-regulates activity" 9606 10358076 f lperfetto "Insulin disrupts irs-dependent transactivation by fkhr, and phosphorylation of ser-256 by pkb is necessary and sufficient to mediate this effect." SIGNOR-68155 INS protein P01308 UNIPROT TRIP10 protein Q15642 UNIPROT up-regulates 9606 12242347 f gcesareni "The specific interaction of active tc10 with cip4 2 suggested thatinsulinmight induce a change in the subcellular localization of cip4 2" SIGNOR-93062 INS protein P01308 UNIPROT DUSP6 protein Q16828 UNIPROT down-regulates 9606 22521266 f gcesareni "In conclusion,insulinlikely promotes mkp-3 protein degradation" SIGNOR-197203 INS protein P01308 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" 9606 10358076 f lperfetto "Insulin disrupts irs-dependent transactivation by fkhr, and phosphorylation of ser-256 by pkb is necessary and sufficient to mediate this effect." SIGNOR-252952 IGF2 protein P01344 UNIPROT IGF1R protein P08069 UNIPROT "up-regulates activity" binding 9606 22810696 t lperfetto "These results strongly suggest that the IGF2–IGF1R–IRS2 axis signals to PI3K in CRC and imply that therapeutic targeting of the pathway could act to block PI3K activity in this subset of patients." SIGNOR-251495 IGF2 protein P01344 UNIPROT IGF2R protein P11717 UNIPROT up-regulates binding 9606 11867533 t fspada "Insulin-like growth factor ii receptor (igf2r) is a multifunctional cell surface receptor implicated in tumour suppression. Its growth inhibitory activity has been associated with an ability to bind igf-ii." SIGNOR-115250 GAST protein P01350 UNIPROT SLC4A2 protein P04920 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000269 22228178 f "Gastrin inhibited proliferation of colon cancer cells by suppressing expression of EGR1 and AE2 and by blocking ERK phosphorylation." SIGNOR-254251 TNF protein P01375 UNIPROT RIPK2 protein O43353 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003355 18647246 f miannu "NOD2, toll-like receptor 4 (TLR4) and the adapter protein receptor-interacting protein 2 (RIP2) are induced by tumor-necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in the bronchial epithelial cell line BEAS-2B." SIGNOR-252409 TNF protein P01375 UNIPROT SNAI2 protein O43623 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150 20509143 f miannu "we show that TNFα treatment of human breast cancer cells up-regulates SLUG with a dependency on canonical NF-κB/HIF1α signaling, which is strongly enhanced by p53 inactivation." SIGNOR-255152 TNF protein P01375 UNIPROT TNFRSF21 protein O75509 UNIPROT up-regulates binding 9606 BTO:0000142 9714541 t gcesareni "We report the identification and initial characterization of dr6, a new member of the tnf receptor family possessing a cytoplasmic death domain." SIGNOR-59745 TNF protein P01375 UNIPROT SERPINA3 protein P01011 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002600 11027208 f miannu "We characterize a molecular mechanism responsible for both IL-1 and TNF-induced expression of ACT gene in astrocytes. We identify the 5' distal IL-1/TNF-responsive enhancer of the ACT gene located 13 kb upstream of the transcription start site. This 413-bp-long enhancer contains three elements, two of which bind nuclear factor kB (NF-kB) and one that binds activating protein 1 (AP-1). All of these elements contribute to the full responsiveness of the ACT gene to both cytokines, as determined by deletion and mutational analysis. The 5' NF-kB high-affinity binding site and AP-1 element contribute most to the enhancement of gene transcription in response to TNF and IL-1." SIGNOR-254809 TNF protein P01375 UNIPROT IL6 protein P05231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 32446778 f "doi: 10.1016/j.cytogfr.2020.05.003" miannu "Interleukin-6 (IL-6) deserves a more extensive discussion in view of its involvement in the coronavirus-induced cytokine storm. The production of this cytokine is increased by IL-1β and tumor necrosis factor (TNF- α)" SIGNOR-260856 TNF protein P01375 UNIPROT LPL protein P06858 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 16106106 f Regulation miannu "TNF-α and IL-6 inhibit lipoprotein lipase" SIGNOR-251855 TNF protein P01375 UNIPROT LPL protein P06858 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 3063839 f "Regulation of expression" miannu "Cytokines, notably TNF and IL-1, suppress synthesis of lipoprotein lipase which decreases the rate of TGFA clearance." SIGNOR-251853 TNF protein P01375 UNIPROT BMP4 protein P12644 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000018 17350185 f Luana "TNF-alpha represses the activity of a human Bmp4 promoter-luciferase construct, transfected into A549 and H441 cells." SIGNOR-266085 TNF protein P01375 UNIPROT TNFRSF1A protein P19438 UNIPROT "up-regulates activity" binding 9606 10634209 t lperfetto "TNF-induced apoptosis is mediated primarily through the activation of type I receptors" SIGNOR-226676 TNF protein P01375 UNIPROT TNFRSF1A protein P19438 UNIPROT "up-regulates activity" binding 9606 11502070 t lperfetto "Binding of tnf to the extracellular domain of tnfrsf1a leads to homotrimerization." SIGNOR-109716 TNF protein P01375 UNIPROT TNFRSF1A protein P19438 UNIPROT "up-regulates activity" binding 9606 14732063 t 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 TNF protein P01375 UNIPROT TNFRSF1A protein P19438 UNIPROT "up-regulates activity" binding 9606 23070005 t 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 TNF protein P01375 UNIPROT TNFRSF1B protein P20333 UNIPROT "up-regulates activity" binding 9606 12040173 t lperfetto "The binding of tnf to tnf-r1 triggers a series of intracellular events that ultimately result in the activation of two major transcription factors, nuclear factor kb (nf-kb) and c-jun." SIGNOR-88216 TNF protein P01375 UNIPROT TNFRSF1B protein P20333 UNIPROT "up-regulates activity" binding 14732063 t "[...] 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-253594 TNF protein P01375 UNIPROT TNFRSF1B protein P20333 UNIPROT "up-regulates activity" binding 17151142 t "These data indicate that myogenic activation of p38 requires TNF-alpha receptor-mediated signaling" SIGNOR-253592 TNF protein P01375 UNIPROT COMT protein P21964 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10116 BTO:0000099 19291302 f "Regulation of expression" miannu "COMT gene expression is downregulated by TNFα in primary rat astrocytes at both protein and mRNA levels." SIGNOR-251963 TNF protein P01375 UNIPROT AKT1 protein P31749 UNIPROT up-regulates 9606 11287630 f lperfetto "Tumor necrosis factor (tnf) inhibited insulin-promoted tyrosine phosphorylation of irs-1 and activated the akt/protein kinase b serine-threonine kinase, a downstream target for phosphatidylinositol 3-kinase" SIGNOR-106593 TNF protein P01375 UNIPROT AKT2 protein P31751 UNIPROT up-regulates 9606 11287630 f lperfetto "Tumor necrosis factor (tnf) inhibited insulin-promoted tyrosine phosphorylation of irs-1 and activated the akt/protein kinase b serine-threonine kinase, a downstream target for phosphatidylinositol 3-kinase" SIGNOR-106596 TNF protein P01375 UNIPROT SCN1A protein P35498 UNIPROT "up-regulates activity" 10090 BTO:0004102 26112872 f miannu "TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels." SIGNOR-253487 TNF protein P01375 UNIPROT SCN1A protein P35498 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0004102 26112872 f miannu "TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels." SIGNOR-253478 IFNA10 protein P01566 UNIPROT LPL protein P06858 UNIPROT "down-regulates activity" 10090 BTO:0000944 1632769 f Regulation miannu "Interleukin-1 and interferon-alpha and gamma induce lipolysis and decrease LPL activity but do not stimulate much PG production. These results demonstrate that cytokines enhance lipolysis and decrease LPL activity in 3T3 adipocytes by a PG independent mechanism." SIGNOR-251859 TNF protein P01375 UNIPROT SCN4A protein P35499 UNIPROT "up-regulates activity" 10090 BTO:0004102 26112872 f miannu "TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels." SIGNOR-253490 TNF protein P01375 UNIPROT SCN4A protein P35499 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0004102 26112872 f miannu "TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. VGSCs were up-regulated at both the mRNA and protein levels." SIGNOR-253481 TNF protein P01375 UNIPROT IRS1 protein P35568 UNIPROT down-regulates 9606 11287630 f gcesareni "Irs-1 tyrosine phosphorylation by tnf was blocked by rapamycin, an inhibitor of the mammalian target of rapamycin (mtor), a downstream target of akt. these results suggest that tnf impairs insulin signaling through irs-1" SIGNOR-106599 TNF protein P01375 UNIPROT SCNN1A protein P37088 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0005760 16877633 f "Regulation of expression" miannu "TNF, a proinflammatory cytokine present in several lung pathologies, decreases the expression and activity of the epithelial Na(+) channel (ENaC) by approximately 70% in alveolar epithelial cells." SIGNOR-251954 TNF protein P01375 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates 9606 10485710 f gcesareni "Tnf activates phosphatidylinositol-3-oh kinase (pi(3)k)." SIGNOR-70619 TNF protein P01375 UNIPROT CTSK protein P43235 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 11920402 f lperfetto "This is supported by our finding that inflammatory cytokines such as IL-1b and TNFa increase the expres- sion of cathepsin K mRNA 􏰌6–8-fold and increase the secretion of the mature enzyme." SIGNOR-253317 TNF protein P01375 UNIPROT NOTCH1 protein P46531 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004914 14586405 f "We found that TNF induced the expression of Notch-1, Notch-4, and Jagged-2 in RSF. The expression of these proteins was detected in the RA synovial tissues." SIGNOR-253606 TNF protein P01375 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 10485710 t gcesareni "Tnf activates phosphatidylinositol-3-oh kinase (pi(3)k)" SIGNOR-70625 TNF protein P01375 UNIPROT MC1R protein Q01726 UNIPROT "down-regulates activity" "transcriptional regulation" 9606 BTO:0000847 9767234 f miannu "MSH receptor (MSH-R) binding activity was upregulated by UVB, IL-1alpha, -1beta and ET-1, but was downregulated by TNF-alpha.Northern blotanalysis showed that MC1-R mRNA expression was induced 24 h after UVB irradiation in a dose-dependent manner, and that 24-h treatment with ET-1 also induced an expression of MC1-R mRNA,whereas TNF-a downregulated the expression. In addition, IL-1a and -1b have a small but real inductiveeffect on MC1-R mRNA expression." SIGNOR-252381 TNF protein P01375 UNIPROT REL protein Q04864 UNIPROT up-regulates 9606 BTO:0000782 10823840 f miannu "C-rel emerges as the main nf-kb family member stimulated by tnf_ in the context of physiologic activation of resting t cells." SIGNOR-77547 TNF protein P01375 UNIPROT HES1 protein Q14469 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004914 22190977 f "Exposure of RA FLSs to TNF-α (10 ng/ml) led to increase of Hes-1, a target gene of Notch signaling, and a marked upregulation of Notch 2, Delta-like 1, and Delta-like 3 mRNA levels." SIGNOR-253605 TNF protein P01375 UNIPROT SCN5A protein Q14524 UNIPROT "up-regulates activity" 10090 BTO:0004102 26112872 f miannu "TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels." SIGNOR-253486 TNF protein P01375 UNIPROT SCN5A protein Q14524 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0004102 26112872 f miannu "TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels." SIGNOR-253477 TNF protein P01375 UNIPROT SCN9A protein Q15858 UNIPROT "up-regulates activity" 10090 BTO:0004102 26112872 f miannu "TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels." SIGNOR-253488 TNF protein P01375 UNIPROT SCN9A protein Q15858 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0004102 26112872 f miannu "TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels." SIGNOR-253479 TNF protein P01375 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" 9606 16813528 f lperfetto "These observations suggest that tnf-alpha activates p38 map kinase during the inflammatory response at the injured growth plate, and tnf-alpha-p38 signaling seems to be required for marrow mesenchymal cell proliferation and migration at the growth plate injury site and in cell culture." SIGNOR-147369 TNF protein P01375 UNIPROT DNAH10 protein Q8IVF4 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000667 31836722 f miannu "The protein expression of DNAH10 was assessed by Western blot analysis after stimulation of primary keratinocytes (P4) with inflammatory cytokine TNFα or growth factor TGF-β1 and their combination (Fig. 5C). Treatment with TNFα, TGF-β1, and their combination down regulated the expression of DNAH10 in keratinocytes after a 24-h-stimulation." SIGNOR-265551 TNF protein P01375 UNIPROT LZTR1 protein Q8N653 UNIPROT "down-regulates quantity by destabilization" 9606 16356934 f "Induction of Apoptosis by Staurosporine, TNFŒ±, and TRAIL Induces Degradation of LZTR-1 by Caspase- and Proteasome-dependent Pathways" SIGNOR-253612 APOB protein P04114 UNIPROT LDLR protein P01130 UNIPROT up-regulates binding 9606 11986215 t gcesareni "In the case of ldl, binding of apolipoprotein b (apob) to the ldl-r18-20 and proteoglycans17 21 initiates plasma clearance and lipoprotein degradation" SIGNOR-87035 TNF protein P01375 UNIPROT SCN2A protein Q99250 UNIPROT "up-regulates activity" 10090 BTO:0004102 26112872 f miannu "TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels." SIGNOR-253489 TNF protein P01375 UNIPROT NOTCH4 protein Q99466 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004914 14586405 f "We found that TNF induced the expression of Notch-1, Notch-4, and Jagged-2 in RSF. The expression of these proteins was detected in the RA synovial tissues." SIGNOR-253607 TNF protein P01375 UNIPROT SCN3A protein Q9NY46 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0004102 26112872 f miannu "TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels." SIGNOR-253485 TNF protein P01375 UNIPROT SCN11A protein Q9UI33 UNIPROT "up-regulates activity" 10090 BTO:0004102 26112872 f miannu "TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels." SIGNOR-253492 TNF protein P01375 UNIPROT SCN11A protein Q9UI33 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0004102 26112872 f miannu "TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels." SIGNOR-253483 TNF protein P01375 UNIPROT SCN8A protein Q9UQD0 UNIPROT "up-regulates activity" 10090 BTO:0004102 26112872 f miannu "TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels." SIGNOR-253491 TNF protein P01375 UNIPROT SCN8A protein Q9UQD0 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0004102 26112872 f miannu "TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels." SIGNOR-253482 TNF protein P01375 UNIPROT JAG2 protein Q9Y219 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004914 14586405 f "We found that TNF induced the expression of Notch-1, Notch-4, and Jagged-2 in RSF. The expression of these proteins was detected in the RA synovial tissues." SIGNOR-253608 TNF protein P01375 UNIPROT SCN10A protein Q9Y5Y9 UNIPROT "up-regulates activity" 10090 BTO:0004102 26112872 f miannu "TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels." SIGNOR-253493 TNF protein P01375 UNIPROT SCN10A protein Q9Y5Y9 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0004102 26112872 f miannu "TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels." SIGNOR-253484 TNF protein P01375 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" 10090 10485710 f lperfetto "Tnf activates phosphatidylinositol-3-oh kinase (pi(3)k)." SIGNOR-252733 TNF protein P01375 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates 9606 11287630 f lperfetto "Tumor necrosis factor (tnf) inhibited insulin-promoted tyrosine phosphorylation of irs-1 and activated the akt/protein kinase b serine-threonine kinase, a downstream target for phosphatidylinositol 3-kinase" SIGNOR-244458 IFNA1 protein P01562 UNIPROT IFNAR1 protein P17181 UNIPROT up-regulates binding 9606 8181059 t fspada "The present study describes a novel type i ifn receptor having the ability to bind and respond to several subtypes of ifn-a as well as to ifn-8. This 102 kda-51 kda receptor is essential for the activity of many type i ifns, as demonstrated with anti-receptor antibodies." SIGNOR-36622 IFNA1 protein P01562 UNIPROT IFNAR2 protein P48551 UNIPROT up-regulates binding 9606 11278538 t gcesareni "Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2." SIGNOR-104641 IFNA1 protein P01562 UNIPROT IFNAR2 protein P48551 UNIPROT "up-regulates activity" binding 9534 BTO:0004055 11278538 t lperfetto "Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2." SIGNOR-219298 IFNA1 protein P01562 UNIPROT "ISGF3 complex" complex SIGNOR-C124 SIGNOR "up-regulates quantity by stabilization" 9606 22171011 f 2 miannu "IFN-I (IFN-_ and IFN-_) induces the assembly of IFN-stimulated gene factor 3 (ISGF3), a multimeric transcriptional activation complex composed of STAT1, STAT2, and IFN regulatory factor 9." SIGNOR-240610 IFNA1 protein P01562 UNIPROT IFNAR complex SIGNOR-C243 SIGNOR "up-regulates activity" binding 9606 11278538 t miannu "Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2." SIGNOR-260334 IFNA2 protein P01563 UNIPROT HLA-B protein P01889 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 2507660 f Regulation miannu "HLA-B (class I) and C13 gene expression was transcriptionally activated by IFN-gamma and IFN-alpha 2" SIGNOR-251925 IFNB1 protein P01574 UNIPROT MGMT protein P16455 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000711 17564708 f miannu "we observed that IFN-beta sensitized TMZ-resistant glioma cells with the unmethylated MGMT promoter and that the mechanism of action was possibly due to attenuation of MGMT expression via induction of TP53. In this context, IFN-beta inactivates MGMT via p53 gene induction and enhances the therapeutic efficacy to TMZ." SIGNOR-255438 IFNB1 protein P01574 UNIPROT IFNAR1 protein P17181 UNIPROT up-regulates binding 9606 11278538 t gcesareni "Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2." SIGNOR-104663 IFNB1 protein P01574 UNIPROT IFNAR1 protein P17181 UNIPROT "up-regulates activity" binding 9534 BTO:0004055 11278538 t lperfetto "Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2." SIGNOR-219301 IFNB1 protein P01574 UNIPROT JAK1 protein P23458 UNIPROT up-regulates 9606 10918594 f gcesareni "Early events in type i ifn signaling are tyrosine phosphorylation of the type i ifn receptor subunits (ifnar1 and ifnar2), and the activation of the receptor-associated tyk-2 and jak-1 janus kinases" SIGNOR-80100 IFNB1 protein P01574 UNIPROT TYK2 protein P29597 UNIPROT up-regulates 9606 10918594 f gcesareni "Early events in type i ifn signaling are tyrosine phosphorylation of the type i ifn receptor subunits (ifnar1 and ifnar2), and the activation of the receptor-associated tyk-2 and jak-1 janus kinases." SIGNOR-80103 IFNB1 protein P01574 UNIPROT IFNAR2 protein P48551 UNIPROT up-regulates binding 9606 11278538 t gcesareni "Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2." SIGNOR-105934 IFNB1 protein P01574 UNIPROT IFNAR2 protein P48551 UNIPROT "up-regulates activity" binding 9534 BTO:0004055 11278538 t lperfetto "Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2." SIGNOR-219304 IFNB1 protein P01574 UNIPROT IFNAR complex SIGNOR-C243 SIGNOR "up-regulates activity" binding 9606 11278538 t miannu "Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2." SIGNOR-260335 IFNG protein P01579 UNIPROT SOCS1 protein O15524 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000552 19482358 f lperfetto "IFN-_ induces socs1 gene expression through an inducible factor" SIGNOR-236809 IFNG protein P01579 UNIPROT RIPK2 protein O43353 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003355 18647246 f miannu "NOD2, toll-like receptor 4 (TLR4) and the adapter protein receptor-interacting protein 2 (RIP2) are induced by tumor-necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in the bronchial epithelial cell line BEAS-2B." SIGNOR-252410 IFNG protein P01579 UNIPROT HLA-B protein P01889 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 2507660 f Regulation miannu "HLA-B (class I) and C13 gene expression was transcriptionally activated by IFN-gamma and IFN-alpha 2" SIGNOR-251926 IFNG protein P01579 UNIPROT LPL protein P06858 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0001030 10909770 f "Regulation of expression" miannu "The suppression of lipoprotein lipase expression in J774.2 macrophages by IFN-gamma and TNF-alpha is mediated at the transcriptional level." SIGNOR-251854 IFNG protein P01579 UNIPROT LPL protein P06858 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000801 2114181 f Regulation miannu "Interferon-gamma inhibits lipoprotein lipase in human monocyte-derived macrophages. The data indicate that IFN-gamma is inhibiting macrophage LPL at least in part via a reduction of LPL synthesis" SIGNOR-251848 IFNG protein P01579 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates 9606 BTO:0001760 11009425 f gcesareni "In contrast, in differentiated myotubes, tnf plus interferon-gamma (ifn-gamma) signaling was required for nf-kappab-dependent down-regulation of myod and dysfunction of skeletal myofibers." SIGNOR-82467 IFNG protein P01579 UNIPROT IFNGR1 protein P15260 UNIPROT up-regulates binding 9606 12438563 t 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 IFNG protein P01579 UNIPROT IFNGR1 protein P15260 UNIPROT "up-regulates activity" binding 9606 BTO:0000801 23898330 t 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 IFNG protein P01579 UNIPROT GCH1 protein P30793 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000142 20525234 f miannu "Pro-inflammatory cytokines like interferon-γ (IFN-γ) induce expression of GTP-cyclohydrolase I in various brain cells." SIGNOR-252223 IFNG protein P01579 UNIPROT IFNGR2 protein P38484 UNIPROT up-regulates binding 9606 7673114 t 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 IFNG protein P01579 UNIPROT RFX5 protein P48382 UNIPROT "up-regulates activity" 9606 BTO:0000567 9177217 f 2 miannu "Transcriptional Activation by the RFX5 Activation Domain Is IFN-_-Inducible in HeLa Cells." SIGNOR-241368 IFNG protein P01579 UNIPROT SLC11A1 protein P49279 UNIPROT up-regulates 9606 BTO:0000801 11909746 f "Functional studies in Nramp1 transfected macrophages have demonstrated that the Nramp1 protein plays a vital role in early macrophage activation [10,29,30]. Nramp1 is constitutively expressed in macrophage cell lines of the myeloid lineage (isolated peritoneal, splenic, and liver resident macrophages), and can be induced by treatment of macrophages with IFN-γ, or IFN-γ plus lipopolysaccharide (LPS)" SIGNOR-254038 IFNG protein P01579 UNIPROT S100A10 protein P60903 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567;BTO:0002923 12645529 f miannu "The effect of interferon (IFN)-gamma on p11 expression was studied in two human epithelial cell lines (BEAS-2B and HeLa). Treatment with IFN-gamma resulted in increased steady-state levels of p11 mRNA and protein expression, with a time-dependent and dose-dependent effect." SIGNOR-255236 ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT "up-regulates activity" phosphorylation Tyr1248 PTAENPEyLGLDVPV -1 1706616 t " Y1023 and Y1248, Y1139 and Y1222 also serve as autophosphorylation sites of HER2." SIGNOR-251128 IFNG protein P01579 UNIPROT NOD2 protein Q9HC29 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003355 18647246 f miannu "NOD2, toll-like receptor 4 (TLR4) and the adapter protein receptor-interacting protein 2 (RIP2) are induced by tumor-necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in the bronchial epithelial cell line BEAS-2B." SIGNOR-252408 IFNG protein P01579 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "down-regulates activity" 10090 BTO:0004732 23667107 f "Early inhibition of IL-1β expression by IFN-γ is mediated by impaired binding of NF-κB to the IL-1β promoter but is independent of nitric oxide." SIGNOR-255937 IFNG protein P01579 UNIPROT IFNGR2/INFGR1 complex SIGNOR-C142 SIGNOR "up-regulates activity" binding 9606 BTO:0000801 23898330 t 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 IL1A protein P01583 UNIPROT SERPINA3 protein P01011 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002600 11027208 f miannu "We characterize a molecular mechanism responsible for both IL-1 and TNF-induced expression of ACT gene in astrocytes. We identify the 5' distal IL-1/TNF-responsive enhancer of the ACT gene located 13 kb upstream of the transcription start site. This 413-bp-long enhancer contains three elements, two of which bind nuclear factor kB (NF-kB) and one that binds activating protein 1 (AP-1). All of these elements contribute to the full responsiveness of the ACT gene to both cytokines, as determined by deletion and mutational analysis. The 5' NF-kB high-affinity binding site and AP-1 element contribute most to the enhancement of gene transcription in response to TNF and IL-1." SIGNOR-254807 IL1A protein P01583 UNIPROT TNF protein P01375 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000667 19005488 f miannu "UVB and proinflammatory cytokines synergistically activate TNF-alpha production in keratinocytes through enhanced gene transcription. UVB and IL-1alpha treatment synergistically enhanced TNF-alpha secretion and mRNA levels in human keratinocytes, similar to the findings reported previously in human fibroblasts." SIGNOR-252209 IL1A protein P01583 UNIPROT IL1R1 protein P14778 UNIPROT "up-regulates activity" binding 9606 BTO:0000876 7964161 t lperfetto "Interleukin-1 receptor (il-1r) is a cytokine receptor which binds interleukin 1." SIGNOR-35077 IL1A protein P01583 UNIPROT IL1R1 protein P14778 UNIPROT "up-regulates activity" binding 9606 BTO:0001573 9565970 t lperfetto "Il-1ri is responsible for il-1 signaling" SIGNOR-56718 IL1A protein P01583 UNIPROT FBN1 protein P35555 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000452 9036927 f Regulation miannu "UVB irradiation (50 mJ) of cultured skin fibroblasts suppressed fibrillin mRNA by 50%, consistent with a direct effect of radiation. UVB irradiation (50 mJ) of cultured skin fibroblasts suppressed fibrillin mRNA by 50%, consistent with a direct effect of radiation. Addition to the cultured fibroblasts of several cytokines upregulated by UVB showed that IL-1alpha had no effect on fibrillin mRNA in unirradiated cells, but in irradiated cells, this cytokine enhanced the suppression of fibrillin mRNA." SIGNOR-251890 IL1A protein P01583 UNIPROT MC1R protein Q01726 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000847 9767234 f miannu "MSH receptor (MSH-R) binding activity was upregulated by UVB, IL-1alpha, -1beta and ET-1, but was downregulated by TNF-alpha.Northern blotanalysis showed that MC1-R mRNA expression was induced 24 h after UVB irradiation in a dose-dependent manner, and that 24-h treatment with ET-1 also induced an expression of MC1-R mRNA,whereas TNF-a downregulated the expression. In addition, IL-1a and -1b have a small but real inductiveeffect on MC1-R mRNA expression." SIGNOR-252387 IL1B protein P01584 UNIPROT SERPINA3 protein P01011 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002600 11027208 f miannu "We characterize a molecular mechanism responsible for both IL-1 and TNF-induced expression of ACT gene in astrocytes. We identify the 5' distal IL-1/TNF-responsive enhancer of the ACT gene located 13 kb upstream of the transcription start site. This 413-bp-long enhancer contains three elements, two of which bind nuclear factor kB (NF-kB) and one that binds activating protein 1 (AP-1). All of these elements contribute to the full responsiveness of the ACT gene to both cytokines, as determined by deletion and mutational analysis. The 5' NF-kB high-affinity binding site and AP-1 element contribute most to the enhancement of gene transcription in response to TNF and IL-1." SIGNOR-254806 IL1B protein P01584 UNIPROT KRT1 protein P04264 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 17982242 f "Regulation of expression" miannu "IL-1β alone decreased the expression of E-cadherin and cytokeratin" SIGNOR-251883 IL1B protein P01584 UNIPROT IL6 protein P05231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 32446778 f "doi: 10.1016/j.cytogfr.2020.05.003" miannu "Interleukin-6 (IL-6) deserves a more extensive discussion in view of its involvement in the coronavirus-induced cytokine storm. The production of this cytokine is increased by IL-1β and tumor necrosis factor (TNF- α)" SIGNOR-260855 IL1B protein P01584 UNIPROT IL1R1 protein P14778 UNIPROT up-regulates binding 9606 BTO:0001253 9625767 t 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 IL1B protein P01584 UNIPROT IL1R1 protein P14778 UNIPROT "up-regulates activity" binding 9606 BTO:0000801 24166242 t 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 IL1B protein P01584 UNIPROT ITGA2 protein P17301 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001596 1744142 f lperfetto "TGF-beta 1 decreases the biosynthesis of alpha 3 subunit but increases the production of alpha 2 subunit. IL-1 beta potentiates the effects of TGF-beta 1. Furthermore, in the presence of TGF-beta 1 the increase in the expression of alpha 1 subunit by IL-1 beta is even larger. Thus, IL-1 beta and TGF-beta 1, which usually have antagonistic functions in connective tissue, can regulate integrin expression in a synergistic way." SIGNOR-253356 IL1B protein P01584 UNIPROT ITGA3 protein P26006 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001596 1744142 f lperfetto "TGF-beta 1 decreases the biosynthesis of alpha 3 subunit but increases the production of alpha 2 subunit. IL-1 beta potentiates the effects of TGF-beta 1. Furthermore, in the presence of TGF-beta 1 the increase in the expression of alpha 1 subunit by IL-1 beta is even larger. Thus, IL-1 beta and TGF-beta 1, which usually have antagonistic functions in connective tissue, can regulate integrin expression in a synergistic way." SIGNOR-253355 IL1B protein P01584 UNIPROT IL1R2 protein P27930 UNIPROT down-regulates binding 9606 BTO:0000876 8332913 t 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 IL1B protein P01584 UNIPROT GCH1 protein P30793 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000766 10435048 f miannu "IL-1 beta induces expression of GTP cyclohydrolase-1 which leads to increased generation of BH4 and activation of eNOS." SIGNOR-252224 IL1B protein P01584 UNIPROT SCNN1A protein P37088 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0005760 15755725 f "Regulation of transcription" miannu "Interleukin-1beta decreases expression of the epithelial sodium channel alpha-subunit in alveolar epithelial cells via a p38 MAPK-dependent signaling pathway." SIGNOR-251947 IL1B protein P01584 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" 9606 BTO:0002417 32454942 f miannu "IL-1β, an inflammatory cytokine primarily expressed in activated macrophages, monocytes, and microglia, significantly contributes to MS development. IL-1β promotes differentiation of T cells into Th17 cells via the STAT3 pathway and thereby promotes and aggravates the inflammatory environment in the CNS" SIGNOR-263820 IL1B protein P01584 UNIPROT GDF5 protein P43026 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0003742 19818765 f Regulation miannu "GDF-5 is suppressed by IL-1beta and enhances TGF-beta3-mediated chondrogenic differentiation in human rheumatoid fibroblast-like synoviocytes." SIGNOR-251864 IL1B protein P01584 UNIPROT MC1R protein Q01726 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000847 9767234 f miannu "MSH receptor (MSH-R) binding activity was upregulated by UVB, IL-1alpha, -1beta and ET-1, but was downregulated by TNF-alpha.Northern blotanalysis showed that MC1-R mRNA expression was induced 24 h after UVB irradiation in a dose-dependent manner, and that 24-h treatment with ET-1 also induced an expression of MC1-R mRNA,whereas TNF-a downregulated the expression. In addition, IL-1a and -1b have a small but real inductiveeffect on MC1-R mRNA expression." SIGNOR-252385 IL1B protein P01584 UNIPROT IL1RAP protein Q9NPH3 UNIPROT up-regulates binding 9606 9820540 t 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 EPO protein P01588 UNIPROT HBB protein P68871 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000574 9168989 f Regulation miannu "We describe the roles of Stat5 and of these tyrosine residues in the EPOR in the erythroid differentiation of murine hematopoietic cell line SKT6 which produces hemoglobin in response to EPO. Chimeric receptors carrying the extracellular domain of the EGF receptor and the intracellular domain of the EPOR were introduced into SKT6 cells. Like EPO, EGF equally activated Stat5 and induced hemoglobin." SIGNOR-251783 EPO protein P01588 UNIPROT HBA1 protein P69905 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000574 9168989 f Regulation miannu "We describe the roles of Stat5 and of these tyrosine residues in the EPOR in the erythroid differentiation of murine hematopoietic cell line SKT6 which produces hemoglobin in response to EPO. Chimeric receptors carrying the extracellular domain of the EGF receptor and the intracellular domain of the EPOR were introduced into SKT6 cells. Like EPO, EGF equally activated Stat5 and induced hemoglobin." SIGNOR-251786 COL1A1 protein P02452 UNIPROT DDR1 protein Q08345 UNIPROT up-regulates binding 9606 9659900 t gcesareni "We report that the collagens serve as ligands for the previously orphan family of discoidin domain-containing receptor-like tyrosine kinases." SIGNOR-58779 COL1A1 protein P02452 UNIPROT "A1/b1 integrin" complex SIGNOR-C159 SIGNOR "up-regulates activity" binding 9606 BTO:0000664 12123670 t lperfetto "We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1." SIGNOR-253247 COL1A1 protein P02452 UNIPROT "A2/b1 integrin" complex SIGNOR-C160 SIGNOR up-regulates binding 9606 7688313 t gcesareni "Both a2b1- and a1b1- inegrins are implicated in chondrocyte adhesion to native collagene i and ii" SIGNOR-31787 COL1A1 protein P02452 UNIPROT "A11/b1 integrin" complex SIGNOR-C168 SIGNOR "up-regulates activity" binding 10090 BTO:0000165 12496264 t lperfetto "Modeling of the alpha I domain-collagen peptide complexes could partially explain the observed preference of different I domains for certain GFOGER sequence variations. In summary, our data indicate that the GFOGER sequence in fibrillar collagens is a common recognition motif used by alpha(1)beta(1), alpha(2)beta(1), and also alpha(11)beta(1) integrins." SIGNOR-253345 COL2A1 protein P02458 UNIPROT "A2/b1 integrin" complex SIGNOR-C160 SIGNOR up-regulates binding 9606 7688313 t gcesareni "Both a2b1- and a1b1- integrins are implicated in chondrocyte adhesion to native collagene i and ii" SIGNOR-31881 COL2A1 protein P02458 UNIPROT "A10/b1 integrin" complex SIGNOR-C167 SIGNOR "up-regulates activity" binding 9606 BTO:0000249 25169886 t lperfetto "Isolation, cloning, and sequence analysis of the integrin subunit alpha10, a beta1-associated collagen binding integrin expressed on chondrocytes." SIGNOR-253347 COL3A1 protein P02461 UNIPROT ADGRG1 protein Q9Y653 UNIPROT "up-regulates activity" binding 22238662 t "Using the N-terminal fragment of GPR56 (GPR56(N)) as a probe, we have recently demonstrated that collagen III is the ligand of GPR56 in the developing brain. In this report, we discover a new functional domain in GPR56(N), the ligand binding domain." SIGNOR-253979 COL4A1 protein P02462 UNIPROT "A2/b1 integrin" complex SIGNOR-C160 SIGNOR "up-regulates activity" binding 9606 BTO:0000664 12123670 t lperfetto "We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1." SIGNOR-253242 CRYAA protein P02489 UNIPROT CRYBB2 protein P43320 UNIPROT "up-regulates activity" binding 9606 22982024 t miannu "Aberrant protein interactions can lead to aggregation and insolubilization, such as occurs during cataract formation. Deamidation, a prevalent age-related modification in the lens of the eye, decreases stability of the major lens proteins, crystallins. Deamidation did not disrupt specific αA/βB2 interactions but favored aggregation before complex formation with αA. We conclude that deamidation contributes to cataract formation through destabilization of crystallins before they can be rescued by α-crystallin." SIGNOR-252155 FGA protein P02671 UNIPROT Fibrinogen complex SIGNOR-C311 SIGNOR "form complex" binding -1 25427968 t lperfetto "Fibrinogen is a plasma glycoprotein mainly synthesised by hepatocytes and circulating as a 340-kDa hexamer consisting of two sets of three different polypeptide chains (Aalpha, Bbeta, and gamma, encoded by the FGA, FGB, and FGG gene, respectively)." SIGNOR-263392 CRYAB protein P02511 UNIPROT CRYGC protein P07315 UNIPROT "up-regulates activity" binding -1 20621668 t miannu "Human gamma-crystallins are long-lived, unusually stable proteins of the eye lens exhibiting duplicated, double Greek key domains. The lens also contains high concentrations of the small heat shock chaperone alpha-crystallin, which suppresses aggregation of model substrates in vitro. Mature-onset cataract is believed to represent an aggregated state of partially unfolded and covalently damaged crystallins. The alphaB-crystallin oligomers formed long-lived stable complexes with their gammaD-crystallin substrates. These in vitro results provide support for protein unfolding/protein aggregation models for cataract, with alpha-crystallin suppressing aggregation of damaged or unfolded proteins through early adulthood but becoming saturated with advancing age." SIGNOR-253622 CRYAB protein P02511 UNIPROT CRYGD protein P07320 UNIPROT "up-regulates activity" binding -1 20621668 t miannu "Human gamma-crystallins are long-lived, unusually stable proteins of the eye lens exhibiting duplicated, double Greek key domains. The lens also contains high concentrations of the small heat shock chaperone alpha-crystallin, which suppresses aggregation of model substrates in vitro. Mature-onset cataract is believed to represent an aggregated state of partially unfolded and covalently damaged crystallins. The alphaB-crystallin oligomers formed long-lived stable complexes with their gammaD-crystallin substrates. These in vitro results provide support for protein unfolding/protein aggregation models for cataract, with alpha-crystallin suppressing aggregation of damaged or unfolded proteins through early adulthood but becoming saturated with advancing age." SIGNOR-253621 CRYAB protein P02511 UNIPROT CRYGS protein P22914 UNIPROT "up-regulates activity" binding -1 20621668 t miannu "Human gamma-crystallins are long-lived, unusually stable proteins of the eye lens exhibiting duplicated, double Greek key domains. The lens also contains high concentrations of the small heat shock chaperone alpha-crystallin, which suppresses aggregation of model substrates in vitro. Mature-onset cataract is believed to represent an aggregated state of partially unfolded and covalently damaged crystallins. The alphaB-crystallin oligomers formed long-lived stable complexes with their gammaD-crystallin substrates. These in vitro results provide support for protein unfolding/protein aggregation models for cataract, with alpha-crystallin suppressing aggregation of damaged or unfolded proteins through early adulthood but becoming saturated with advancing age." SIGNOR-253623 KRT14 protein P02533 UNIPROT TNFRSF1A protein P19438 UNIPROT "down-regulates activity" binding 9606 11684708 t Regulation miannu "TRADD specifically bound K18 and K14, type I (acidic) keratins. it is possible that epidermal K14 may function as an inhibitor of TNF–TNFR1 signaling through an association with TRADD." SIGNOR-251906 KRT14 protein P02533 UNIPROT TRADD protein Q15628 UNIPROT "down-regulates activity" binding 9606 11684708 t "Regulation of binding" miannu "TRADD specifically bound K18 and K14, type I (acidic) keratins. it is possible that epidermal K14 may function as an inhibitor of TNF–TNFR1 signaling through an association with TRADD." SIGNOR-251907 LMNA protein P02545 UNIPROT SUN2 protein Q9UH99 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000567 16380439 t Sara "In the case of Sun2, there is some evidence that A-type lamins might contribute to Sun2 localization in the INM. We report that an interaction between subunits of the HOPS complex and the ERM (ezrin, radixin, moesin) proteins is required for the delivery of EGF receptor (EGFR) to lysosomes. Inhibiting either ERM proteins or the HOPS complex leads to the accumulation of the EGFR into early endosomes, delaying its degradation." SIGNOR-261310 SPTA1 protein P02549 UNIPROT "Erythrocytic spectrin" complex SIGNOR-C384 SIGNOR "form complex" binding 9606 BTO:0000424 24302288 t lperfetto "Spectrin is a large, cytoskeletal, and heterodimeric protein composed of modular structure of alpha and beta subunits, it typically contains 106 contiguous amino acid sequence motifs called “spectrin repeats”. Spectrin is crucial for maintaining the stability and structure of the cell membrane and the shape of a cell" SIGNOR-266025 APOA1 protein P02647 UNIPROT JAK2 protein O60674 UNIPROT "up-regulates activity" 9606 14668333 f miannu "ApoA-I Stimulates JAK2 Autophosphorylation. the interaction of apolipoproteins with ABCA1-expressing cells activates JAK2, which in turn activates a process that enhances apolipoprotein interactions with ABCA1 and lipid removal from cells" SIGNOR-252108 APOA1 protein P02647 UNIPROT ABCA1 protein O95477 UNIPROT "up-regulates quantity by stabilization" binding 9606 12869555 t miannu "ApoA-I stabilization of ABCA1 is mediated by reduced PEST sequence phosphorylation, which in turn leads to decreased calpain proteolysis of ABCA1." SIGNOR-252101 APOA1 protein P02647 UNIPROT APOE protein P02649 UNIPROT "up-regulates activity" relocalization 9606 20642861 t miannu "ApoA-I stimulates apoE secretion in mature human adipocytes. The regulation of apoE secretion by apoA-I, is neither dependent upon an increase in gene transcription, nor upon increased release from the Golgi. It may therefore be assumed that, in macrophage models, apoE is stored mainly in the cytoplasm and/or on the cell surface, with apoA-I enabling secretion of this cytoplasmic pool" SIGNOR-252105 APOA1 protein P02647 UNIPROT LCAT protein P04180 UNIPROT "up-regulates activity" binding 9606 19860440 t miannu "Activation of LCAT by apolipoprotein (apo) A-I on nascent (discoidal) high density lipoproteins (HDL) is essential for formation of mature (spheroidal) HDL during the antiatherogenic process of reverse cholesterol transport. After attachment of LCAT to discoidal HDL, the helix 5/5 domains in apoA-I form amphipathic presentation tunnels for migration of hydrophobic acyl chains and amphipathic UC from the bilayer to the phospholipase A2-like and esterification active sites of LCAT, respectively." SIGNOR-252103 APOE protein P02649 UNIPROT MAPT protein P10636 UNIPROT "up-regulates activity" binding 7566652 t lperfetto "Isoform specific interactions of ApoE have been shown with the microtubule-associated protein tau, which forms the neurofibrillary tangle in this disease.|Phosphorylation of serine262 in domain I of tau decreases tau binding to microtubules and also abolishes binding by ApoE3." SIGNOR-262588 APOE protein P02649 UNIPROT VLDLR protein P98155 UNIPROT up-regulates binding 9606 11278667 t gcesareni "Several ligands for the vldl receptor have been identified in addition to tfpi. These include apolipoprotein e (apoe)" SIGNOR-106221 APOE protein P02649 UNIPROT SORL1 protein Q92673 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001260 11557679 t gcesareni "Lr11 binds the apolipoprotein e (apoe)-rich lipoproteins, beta-very low density lipoproteins (vldls), with a high affinity similar to that of other members, such as the ldlr and vldl receptor.Incubation For 48 hours with beta-vldl of lr11-overexpressing cells, but not of control cells, promotes the appearance of numerous intracellular lipid droplets." SIGNOR-110555 APOC2 protein P02655 UNIPROT LPL protein P06858 UNIPROT "up-regulates activity" 9606 19956660 f Regulation miannu "Triglycerides in VLDL are hydrolyzed by lipoprotein lipase, which in turn is activated by apolipoprotein CII on the surface but inhibited by apolipoprotein CIII." SIGNOR-251846 FGB protein P02675 UNIPROT Fibrinogen complex SIGNOR-C311 SIGNOR "form complex" binding -1 25427968 t lperfetto "Fibrinogen is a plasma glycoprotein mainly synthesised by hepatocytes and circulating as a 340-kDa hexamer consisting of two sets of three different polypeptide chains (Aalpha, Bbeta, and gamma, encoded by the FGA, FGB, and FGG gene, respectively)." SIGNOR-263391 FGG protein P02679 UNIPROT VTN protein P04004 UNIPROT "down-regulates activity" binding 9606 2243140 t Regulation miannu "Fibrinogen y-chain carboxyterminal (GQQHHLGGAKQAGDV) peptides inhibit fibrinogen, fibronectin (Fn), vitronectin, and von Willebrand factor (vWF) binding to the platelet glycoprotein Ilb-Illa complex (GP lIbII1a)." SIGNOR-251969 FGG protein P02679 UNIPROT VWF protein P04275 UNIPROT "down-regulates activity" binding 9606 2243140 t Regulation miannu "Fibrinogen y-chain carboxyterminal (GQQHHLGGAKQAGDV) peptides inhibit fibrinogen, fibronectin (Fn), vitronectin, and von Willebrand factor (vWF) binding to the platelet glycoprotein Ilb-Illa complex (GP lIbII1a)." SIGNOR-251968 FGG protein P02679 UNIPROT Fibrinogen complex SIGNOR-C311 SIGNOR "form complex" binding -1 25427968 t lperfetto "Fibrinogen is a plasma glycoprotein mainly synthesised by hepatocytes and circulating as a 340-kDa hexamer consisting of two sets of three different polypeptide chains (Aalpha, Bbeta, and gamma, encoded by the FGA, FGB, and FGG gene, respectively)." SIGNOR-263393 GYPA protein P02724 UNIPROT "Ankyrin complex" complex SIGNOR-C383 SIGNOR "form complex" binding 9606 BTO:0000424 22465511 t lperfetto "The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB)) " SIGNOR-266018 SLC4A1 protein P02730 UNIPROT "Ankyrin complex" complex SIGNOR-C383 SIGNOR "form complex" binding 9606 BTO:0000424 22465511 t lperfetto "The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB)) " SIGNOR-266015 SLC4A1 protein P02730 UNIPROT "4.1 complex" complex SIGNOR-C386 SIGNOR "form complex" binding 9606 BTO:0000424 33187473 t lperfetto "The cytoskeleton plays a key role in maintaining the morphology and function of erythrocyte membranes. Many proteins, such as ankyrin, spectrin alpha- and beta-chains, proteins 4.1, or 4.1R and actin, cover the inner surface of the erythrocyte membrane to form two protein complexes, the ankyrin and protein 4.1 complex| the latter consists of Band 3 dimers binding Adducins alpha and beta, Glycophorin C, GLUT1 and Stomatin [15, 16]" SIGNOR-266036 CRP protein P02741 UNIPROT LPL protein P06858 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000801 18708524 f "Regulation of expression" miannu "C-reactive protein enhances macrophage lipoprotein lipase expression." SIGNOR-251852 CRP protein P02741 UNIPROT CXCL8 protein P10145 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004910 26961257 f miannu "In this study, we provide mechanistic insight into how CRP contributes to the development of AMD. In particular, we show that monomeric CRP (mCRP) but not the pentameric form (pCRP) upregulates IL-8 and CCL2 levels in retinal pigment epithelial cells. Further, we show that complement factor H (FH) binds mCRP to dampen its proinflammatory activity. FH from AMD patients carrying the “risk” His402 polymorphism displays impaired binding to mCRP, and therefore proinflammatory effects of mCRP remain unrestrained." SIGNOR-252143 CRP protein P02741 UNIPROT CCL2 protein P13500 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004910 26961257 f miannu "In this study, we provide mechanistic insight into how CRP contributes to the development of AMD. In particular, we show that monomeric CRP (mCRP) but not the pentameric form (pCRP) upregulates IL-8 and CCL2 levels in retinal pigment epithelial cells. Further, we show that complement factor H (FH) binds mCRP to dampen its proinflammatory activity. FH from AMD patients carrying the “risk” His402 polymorphism displays impaired binding to mCRP, and therefore proinflammatory effects of mCRP remain unrestrained." SIGNOR-252144 CRP protein P02741 UNIPROT IL10 protein P22301 UNIPROT "down-regulates quantity by repression" "translation regulation" 9606 BTO:0000801 16917108 f Regulation miannu "CRP significantly decreased IL-10 mRNA stability" SIGNOR-251824 CRP protein P02741 UNIPROT NOS3 protein P29474 UNIPROT "down-regulates quantity by destabilization" 17942113 f miannu "C-reactive protein (CRP), a cardiovascular risk marker, induces endothelial dysfunction. CRP decreases endothelial nitric oxide synthase (eNOS) expression and bioactivity in human aortic endothelial cells (HAECs). CRP treatment significantly decreased levels of BH4 thereby promoting eNOS uncoupling. we found that CRP decreased the eNOS dimer/monomer ratio further supporting eNOS uncoupling." SIGNOR-252217 CRP protein P02741 UNIPROT GCH1 protein P30793 UNIPROT "down-regulates activity" 9606 BTO:0004602 17942113 f miannu "The gene expression and enzymatic activity of GTPCH1, the first enzyme in the de novo biosynthesis of BH(4), were significantly inhibited by CRP. Importantly, GTPCH1 is known to be regulated by cAMP-mediated pathway. In the present study, CRP-mediated inhibition of GTPCH1 activity was reversed by pretreatment with cAMP analogues." SIGNOR-252215 CRP protein P02741 UNIPROT GCH1 protein P30793 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004602 17942113 f miannu "The gene expression and enzymatic activity of GTPCH1, the first enzyme in the de novo biosynthesis of BH(4), were significantly inhibited by CRP." SIGNOR-252216 C1QA protein P02745 UNIPROT "Complement C1q" complex SIGNOR-C308 SIGNOR "form complex" binding -1 29449492 t lperfetto "C1q comprises 18 polypeptide chains; three chains of C1q-A, -B, and -C trimerize to form six collagen-like triple helices connected to six globular (trimeric) ligand-recognition (gC1q) modules (fig. S1B) (1)." SIGNOR-263390 C1QB protein P02746 UNIPROT "Complement C1q" complex SIGNOR-C308 SIGNOR "form complex" binding -1 29449492 t lperfetto "C1q comprises 18 polypeptide chains; three chains of C1q-A, -B, and -C trimerize to form six collagen-like triple helices connected to six globular (trimeric) ligand-recognition (gC1q) modules (fig. S1B) (1)." SIGNOR-263388 C1QC protein P02747 UNIPROT "Complement C1q" complex SIGNOR-C308 SIGNOR "form complex" binding -1 29449492 t lperfetto "C1q comprises 18 polypeptide chains; three chains of C1q-A, -B, and -C trimerize to form six collagen-like triple helices connected to six globular (trimeric) ligand-recognition (gC1q) modules (fig. S1B) (1)." SIGNOR-263389 C9 protein P02748 UNIPROT "Membrane attack complex" complex SIGNOR-C313 SIGNOR "form complex" binding -1 30552328 t lperfetto "The human MAC pore was formed on liposomes from individual complement proteins. |The maps were further subdivided into three components: an asymmetric region (C5b, C6, C7, and C8), a hinge region (C7, C8, and two C9 molecules), and a C9 oligomer" SIGNOR-263441 CRP protein P02741 UNIPROT IL10 protein P22301 UNIPROT "down-regulates quantity" "post transcriptional regulation" 9606 16917108 f Regulation miannu "CRP significantly decreased IL-10 mRNA stability" SIGNOR-251825 FN1 protein P02751 UNIPROT "A5/b1 integrin" complex SIGNOR-C163 SIGNOR "up-regulates activity" binding 9606 BTO:0000664 12123670 t lperfetto "We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1." SIGNOR-253250 FN1 protein P02751 UNIPROT "A8/b1 integrin" complex SIGNOR-C165 SIGNOR "up-regulates activity" binding 15721307 t lperfetto "Integrin alpha8beta1-fibronectin interactions promote cell survival via PI3 kinase pathway." SIGNOR-253304 FN1 protein P02751 UNIPROT "A8/b1 integrin" complex SIGNOR-C165 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 7559467 t lperfetto "The human integrin alpha 8 beta 1 functions as a receptor for tenascin, fibronectin, and vitronectin." SIGNOR-253305 FN1 protein P02751 UNIPROT "Av/b6 integrin" complex SIGNOR-C179 SIGNOR up-regulates binding 9606 1532572 t gcesareni "Integrin alpha v beta 6 binds to fibronectin, but not to vitronectin or collagen i. cell adhesion assays show that fg-2 cell attachment to fibronectin is only partially inhibited by anti-beta 1 integrin antibodies, implying that other fibronectin receptors may be involved." SIGNOR-19793 FN1 protein P02751 UNIPROT FN1/SDC4 complex SIGNOR-C210 SIGNOR "form complex" binding 23290138 t apalma "We found that binding of ECM glycoprotein Fibronectin (FN) to Sdc4 stimulates the ability of Wnt7a to induce the symmetric expansion of satellite stem cells" SIGNOR-255285 RBP4 protein P02753 UNIPROT retinol smallmolecule CHEBI:50211 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000089 31963453 t lperfetto "In the blood, serum retinol travels in association with Retinol-binding protein 4 (RBP4)" SIGNOR-265106 PPBP protein P02775 UNIPROT OPRM1 protein P35372 UNIPROT "down-regulates activity" "chemical inhibition" 10029 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258413 PPBP protein P02775 UNIPROT OPRD1 protein P41143 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258412 CXCL10 protein P02778 UNIPROT CXCR3 protein P49682 UNIPROT "up-regulates activity" binding 9606 BTO:0000782 12750173 t miannu "The chemokines CXCL9, 10, and 11 exert their action via CXC chemokine receptor-3 (CXCR3), a receptor highly expressed on activated T cells." SIGNOR-260969 HPX protein P02790 UNIPROT HBB protein P68871 UNIPROT "down-regulates activity" 9606 20617898 f Regulation miannu "The endogenous molecule hemoglobin and its derivative heme are often released into tissue compartments where there is infection in the presence of degrading blood. We found that hemoglobin synergizes with multiple TLR agonists to induce high levels of tumor necrosis factor and interleukin-6 from macrophages and that this synergy is independent of TLR4 and MyD88. In contrast, heme synergized with some but not all TLR agonists studied. Furthermore, the synergy of both hemoglobin and heme with lipopolysaccharide was suppressed by hemopexin, a plasma heme-binding protein." SIGNOR-251811 BPLF1 protein P03186 UNIPROT NFKBIA protein P25963 UNIPROT "down-regulates activity" deubiquitination 9606 24586164 t scontino "In the current study, we have found that BPLF1 interferes with innate immune activation by targeting multiple intermediates along the TLR signal transduction pathway, including TRAF6, NEMO, and IκBα. BPLF1 can remove ubiquitin tags from proteins in the TLR signaling cascade. This inhibits TLR signaling and decreases the expression of immune response genes." SIGNOR-266744 BPLF1 protein P03186 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT "down-regulates activity" deubiquitination 9606 BTO:0000007 23365429 t scontino "EBV-encoded BPLF1 interacts with and deubiquitinates TRAF6 to inhibit NF-κB signaling during lytic infection. Once lytic replication is induced, BPLF1 then deubiquitinates and inactivates TRAF6 to further block NF-κB signaling, promoting efficient viral genome replication." SIGNOR-266739 BPLF1 protein P03186 UNIPROT IKBKG protein Q9Y6K9 UNIPROT "down-regulates activity" deubiquitination 9606 24586164 t scontino "In the current study, we have found that BPLF1 interferes with innate immune activation by targeting multiple intermediates along the TLR signal transduction pathway, including TRAF6, NEMO, and IκBα. BPLF1 can remove ubiquitin tags from proteins in the TLR signaling cascade. This inhibits TLR signaling and decreases the expression of immune response genes." SIGNOR-266743 BLLF1 protein P03200 UNIPROT CR2 protein P20023 UNIPROT "up-regulates activity" binding 9606 BTO:0000776 18786993 t scontino "The binding of the Epstein-Barr virus glycoprotein gp350 by complement receptor type 2 (CR2) is critical for viral attachment to B lymphocytes." SIGNOR-266624 BZLF1 protein P03206 UNIPROT IRF7 protein Q92985 UNIPROT "down-regulates activity" binding 9606 BTO:0002181 20381110 t scontino "We have shown that Epstein-Barr virus (EBV) IE protein Zta (BZLF1) physically interacts with IRF7, inhibiting its ability to activate the IFN-α, IFN-β, and Tap2 promoters" SIGNOR-266643 BRLF1 protein P03209 UNIPROT IFNB1 protein P01574 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002181 20381110 t scontino "Epstein-Barr Virus BRLF1 Inhibits Transcription of IRF3 and IRF7 and Suppresses Induction of Interferon-β. These results suggest that EBV Rta is capable of regulating the activation of the IFN-β promoter." SIGNOR-266646 BRLF1 protein P03209 UNIPROT IRF3 protein Q14653 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002181 20381110 t scontino "EBV Rta selectively down-regulates the expression of IRF3 and IRF7, the main regulators of the Type I IFNs." SIGNOR-266644 BRLF1 protein P03209 UNIPROT IRF7 protein Q92985 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002181 20381110 t scontino "EBV Rta selectively down-regulates the expression of IRF3 and IRF7, the main regulators of the Type I IFNs." SIGNOR-266645 BGLF5 protein P03217 UNIPROT TLR2 protein O60603 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0002181 26428381 t scontino "The RNA degradation induced by EBV BGLF5 can affect immunologically relevant proteins, including TLR2. Alkaline exonuclease involved in host shutoff, downregulates TLR2." SIGNOR-266741 RLN2 protein P04090 UNIPROT RXFP2 protein Q8WXD0 UNIPROT up-regulates binding 9606 BTO:0000142 11809971 t gcesareni "Lgr7 and lgr8, are capable of mediating the action of relaxin through an adenosine 3',5'-monophosphate (camp)-dependent pathway." SIGNOR-114585 BGLF5 protein P03217 UNIPROT TLR9 protein Q9NR96 UNIPROT "down-regulates quantity by destabilization" "post transcriptional regulation" 9606 BTO:0000007 21191071 t scontino "The EBV lytic-phase protein BGLF5 reduces TLR9 expression through mRNA degradation. We established that the EBV early protein BGLF5 degrades TLR9 mRNA in vitro, providing a mechanism for its contribution to TLR9 downregulation." SIGNOR-266633 LMP1 protein P03230 UNIPROT UBE2I protein P63279 UNIPROT "up-regulates activity" binding 9606 BTO:0002181 22951831 t scontino "One mechanism by which LMP1 regulates cellular activation is through the induction of protein posttranslational modifications. We have now identified a specific target of LMP1-induced sumoylation, interferon regulatory factor 7 (IRF7). We hypothesize that during EBV latency, LMP1 induces the sumoylation of IRF7, limiting its transcriptional activity and modulating the activation of innate immune responses. We recently documented that LMP1 induces a third major protein modification by physically interacting with the SUMO-conjugating enzyme Ubc9 through CTAR3 and inducing the sumoylation of cellular proteins in latently infected cells. we identified that IRF7 is sumoylated at lysine 452." SIGNOR-266838 LMP1 protein P03230 UNIPROT IRF7 protein Q92985 UNIPROT "down-regulates activity" sumoylation 9606 BTO:0002181 22951831 t scontino "One mechanism by which LMP1 regulates cellular activation is through the induction of protein posttranslational modifications. We have now identified a specific target of LMP1-induced sumoylation, interferon regulatory factor 7 (IRF7). We hypothesize that during EBV latency, LMP1 induces the sumoylation of IRF7, limiting its transcriptional activity and modulating the activation of innate immune responses." SIGNOR-266951 LMP1 protein P03230 UNIPROT TLR9 protein Q9NR96 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000726 20980631 f scontino "We determined that the EBV oncoprotein latent membrane protein 1 (LMP1) is a strong inhibitor of TLR9 transcription. These data show that the oncoprotein LMP1 downregulates TLR9 promoter activity in B cells." SIGNOR-266804 ESR1 protein P03372 UNIPROT PIK3R2 protein O00459 UNIPROT up-regulates binding 9606 BTO:0000150 16169518 t gcesareni "Recently, it has been known that er activates phosphatidylinositol-3-oh kinase (pi3k) through binding with the p85 regulatory subunit of pi3k." SIGNOR-140473 ESR1 protein P03372 UNIPROT SNAI2 protein O43623 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000095 18588516 f miannu "The down-regulation of slug in the ERalpha-positive MCF-7 cell line was mediated by direct repression of slug transcription by the formation of a co-repressor complex involving ligand-activated ERalpha protein, HDAC1 (histone deacetylase 1) and N-CoR (nuclear receptor co-repressor)." SIGNOR-254230 ESR1 protein P03372 UNIPROT KDM4B protein O94953 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001248 20682797 f miannu "Here, we show the histone demethylase JMJD2B is regulated by both ERalpha and HIF-1alpha, drives breast cancer cell proliferation in normoxia and hypoxia, and epigenetically regulates the expression of cell cycle genes such as CCND1, CCNA1, and WEE1. these data indicate that JMJD2B is a bona fide target of ERα and its expression in ER-positive breast cancer cells is mainly dependent on ERα." SIGNOR-263737 ESR1 protein P03372 UNIPROT F12 protein P00748 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 9794469 f miannu "Transcription of the FXII gene is stimulated by estrogens through specific interaction of the estrogen receptor alpha (ER alpha) with an estrogen response element present on FXII promoter." SIGNOR-254072 ESR1 protein P03372 UNIPROT MYC protein P01106 UNIPROT unknown "transcriptional regulation" 9606 BTO:0000356 11517191 f "ER beta and ER alpha induced the expression of several endogenous genes such as pS2, TGF alpha, or the cyclin kinase inhibitor p21 but, in contrast to ER alpha, ER beta was unable to regulate c-myc proto-oncogene expression" SIGNOR-253941 ESR1 protein P03372 UNIPROT TGFA protein P01135 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000356 11517191 f "ER beta and ER alpha induced the expression of several endogenous genes such as pS2, TGF alpha, or the cyclin kinase inhibitor p21 but, in contrast to ER alpha, ER beta was unable to regulate c-myc proto-oncogene expression" SIGNOR-253942 ESR1 protein P03372 UNIPROT TFF1 protein P04155 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000356 11517191 f "ER beta and ER alpha induced the expression of several endogenous genes such as pS2, TGF alpha, or the cyclin kinase inhibitor p21 but, in contrast to ER alpha, ER beta was unable to regulate c-myc proto-oncogene expression" SIGNOR-253938 ESR1 protein P03372 UNIPROT AR protein P10275 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 11000528 f gcesareni "Inhibition of ar-induced transactivation that was er cdna dose-responsive and estradiol dependent" SIGNOR-82158 ESR1 protein P03372 UNIPROT UGT1A4 protein P22310 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 19546240 f miannu "our data indicate that up-regulation of UGT1A4 expression by E(2) is mediated by both ER alpha and Sp1 and is a potential mechanism contributing to the enhanced elimination of lamotrigine in pregnancy." SIGNOR-254075 ESR1 protein P03372 UNIPROT CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150 15808510 t gcesareni "Ikkalpha in conjunction with eralpha and aib1/src-3, is important in activating the transcription of estrogen-responsive genes, including cyclin d1." SIGNOR-135053 ESR1 protein P03372 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates binding 9606 BTO:0000150 16169518 t gcesareni "Recently, it has been known that er activates phosphatidylinositol-3-oh kinase (pi3k) through binding with the p85 regulatory subunit of pi3k." SIGNOR-140470 ESR1 protein P03372 UNIPROT SCN1A protein P35498 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000938 BTO:0001264 22169964 f miannu "17β-Estradiol regulates the gene expression of voltage-gated sodium channels. . In this study, we investigate the mRNA expressions of Nav channel subtypes mediated differentially by the ERs in the DRGs of wild-type (WT) and estrogen receptor knockout (αERKO and βERKO) mice. In the present study, by means of quantitative real-time PCR, we found that the expressions of Nav1.1, Nav1.7, Nav1.8, and Nav1.9 subtypes were elevated in αERKO and βERKO mice" SIGNOR-253468 ESR1 protein P03372 UNIPROT PPARG protein P37231 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000150;BTO:0000093;BTO:0000567 16144913 t lperfetto "Our data show for the first time that eralpha binds to ppar response element and represses its transactivation" SIGNOR-140233 ESR1 protein P03372 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000356 11517191 f "ER beta and ER alpha induced the expression of several endogenous genes such as pS2, TGF alpha, or the cyclin kinase inhibitor p21 but, in contrast to ER alpha, ER beta was unable to regulate c-myc proto-oncogene expression" SIGNOR-253940 RLN2 protein P04090 UNIPROT RXFP1 protein Q9HBX9 UNIPROT up-regulates binding 9606 BTO:0000142 11809971 t gcesareni "Lgr7 and lgr8, are capable of mediating the action of relaxin through an adenosine 3',5'-monophosphate (camp)-dependent pathway" SIGNOR-114549 ESR1 protein P03372 UNIPROT SCN5A protein Q14524 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000093 BTO:0001264 24493753 f miannu "The effects of β-oestradiol (E2), the biologically active form of oestrogen, are classically mediated by two types of oestrogen receptor (ER): ERα and ERβ. E2 has both non-genomic and genomic effects upon VGSC expression/activity; and (ii) transcriptionally, E2 (via ERα) downregulates functional VGSC (nNav1.5) expression in BCa cells." SIGNOR-253467 ESR1 protein P03372 UNIPROT NR0B2 protein Q15466 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 10648597 f gcesareni "We demonstrate that shp variants, carrying either interaction-defective nr box mutations or a deletion of the repressor domain, have lost the capacity to inhibit agonist-dependent transcriptional estrogen receptor activation." SIGNOR-74288 ESR1 protein P03372 UNIPROT NCOA2 protein Q15596 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11477071 f lperfetto "Er_ mutants unable to bind coactivators drastically decrease estradiol regulation of ap-1-mediated transcription and overexpression of the coactivator grip1" SIGNOR-109520 ESR1 protein P03372 UNIPROT SCN9A protein Q15858 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000938 BTO:0001264 22169964 f miannu "17β-Estradiol regulates the gene expression of voltage-gated sodium channels. . In this study, we investigate the mRNA expressions of Nav channel subtypes mediated differentially by the ERs in the DRGs of wild-type (WT) and estrogen receptor knockout (αERKO and βERKO) mice. In the present study, by means of quantitative real-time PCR, we found that the expressions of Nav1.1, Nav1.7, Nav1.8, and Nav1.9 subtypes were elevated in αERKO and βERKO mice" SIGNOR-253469 ESR1 protein P03372 UNIPROT GREB1 protein Q4ZG55 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000356 17666587 f miannu "Long-range activation of GREB1 by estrogen receptor via three distal consensus estrogen-responsive elements in breast cancer cells. . GREB1 (gene regulated by estrogen in breast cancer 1) is an ER target gene that regulates estrogen-induced proliferation in breast cancer cells." SIGNOR-254074 ESR1 protein P03372 UNIPROT ESR2 protein Q92731 UNIPROT up-regulates binding 9606 10022879 t tpavlidou "It was recently shown that er? And er? Could form a heterodimer complex both in vitro and in vivo" SIGNOR-64427 ESR1 protein P03372 UNIPROT SCN11A protein Q9UI33 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000938 BTO:0001264 22169964 f miannu "17β-Estradiol regulates the gene expression of voltage-gated sodium channels. . In this study, we investigate the mRNA expressions of Nav channel subtypes mediated differentially by the ERs in the DRGs of wild-type (WT) and estrogen receptor knockout (αERKO and βERKO) mice. In the present study, by means of quantitative real-time PCR, we found that the expressions of Nav1.1, Nav1.7, Nav1.8, and Nav1.9 subtypes were elevated in αERKO and βERKO mice" SIGNOR-253471 ESR1 protein P03372 UNIPROT SCN8A protein Q9UQD0 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000938 22169964 f miannu "In this study, quantitative real-time PCR analysis showed that the gene expression levels of TTX-S (Nav1.1 and Nav1.7) and TTX-R (Nav1.8 and Nav1.9) sodium channel subtypes were elevated in DRGs of αERKO and βERKO mice, whereas Nav1.6 mRNA decreased in αERKOs but showed no changes in βERKO mice" SIGNOR-253476 ESR1 protein P03372 UNIPROT SCN10A protein Q9Y5Y9 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000938 BTO:0001264 22169964 f miannu "17β-Estradiol regulates the gene expression of voltage-gated sodium channels. . In this study, we investigate the mRNA expressions of Nav channel subtypes mediated differentially by the ERs in the DRGs of wild-type (WT) and estrogen receptor knockout (αERKO and βERKO) mice. In the present study, by means of quantitative real-time PCR, we found that the expressions of Nav1.1, Nav1.7, Nav1.8, and Nav1.9 subtypes were elevated in αERKO and βERKO mice" SIGNOR-253470 ESR1 protein P03372 UNIPROT AP1 complex SIGNOR-C154 SIGNOR "up-regulates activity" binding 9606 18247370 t miannu "The primary conclusion of the results reported here is that ERα and c‐jun, c‐fos and ATF‐2, but not Fra‐2 AP‐1 factors interact “in vivo” with specific estrogen‐responsive regulatory sequences and AP‐1 cis‐elements within the F promoter of the human ERα gene in osteoblast‐like SaOS‐2 cells." SIGNOR-263656 MT-ND1 protein P03886 UNIPROT "Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The Q-module is built through the association of NDUFA5, NDUFS2 and NDUFS3 plus NDUFS7 and NDUFS8. The chaperones NDUFAF3/C3ORF60 and NDUFAF4/C6ORF66 [36,37] remain bound to this module until the final assembly steps [34]. NDUFAF6/C8ORF38 [38] also seems to participate in the assembly of the Q-module [24,39]. NDUFAF3, 4 and 6, are necessary to maintain normal MT-ND1 synthesis [40,41]. NDUFAF5 adds a hydroxyl group to Arg73 of NDUFS7 [42] and NDUFAF7 dimethylates NDUFS2 in Arg85 [43], an essential modification for cI assembly [44]. NUBPL/IND1 delivers [4Fe–4S] clusters specifically to the N- and Q-module subunits [45,46]." SIGNOR-262143 MT-ND2 protein P03891 UNIPROT "Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND2-module is formed by an initial intermediate that contains MT-ND2, NDUFC1 and NDUFC2 bound to NDUFAF1/CIA30 [49,50], ECSIT [51] and ACAD9 [52,53]. Then, MT-ND3 is added together with TMEM126B [54], forming a larger intermediate to which subunits MT-ND6 and MT-ND4L bind. The latest assembly stages involve the incorporation of subunits NDUFA1, NDUFA10 and NDUFS5 [24,34]." SIGNOR-262144 MT-ND3 protein P03897 UNIPROT "Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND2-module is formed by an initial intermediate that contains MT-ND2, NDUFC1 and NDUFC2 bound to NDUFAF1/CIA30 [49,50], ECSIT [51] and ACAD9 [52,53]. Then, MT-ND3 is added together with TMEM126B [54], forming a larger intermediate to which subunits MT-ND6 and MT-ND4L bind. The latest assembly stages involve the incorporation of subunits NDUFA1, NDUFA10 and NDUFS5 [24,34]." SIGNOR-262145 MT-ND4L protein P03901 UNIPROT "Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND2-module is formed by an initial intermediate that contains MT-ND2, NDUFC1 and NDUFC2 bound to NDUFAF1/CIA30 [49,50], ECSIT [51] and ACAD9 [52,53]. Then, MT-ND3 is added together with TMEM126B [54], forming a larger intermediate to which subunits MT-ND6 and MT-ND4L bind. The latest assembly stages involve the incorporation of subunits NDUFA1, NDUFA10 and NDUFS5 [24,34]." SIGNOR-262147 NTRK1 protein P04629 UNIPROT NTRK1 protein P04629 UNIPROT up-regulates phosphorylation Tyr680 RDIYSTDyYRVGGRT 9606 9099755 t gcesareni "In vitro studies indicate that trka autophosphorylates at tyrosines 490, 670, 674, 675, and 785" SIGNOR-47175 MT-ND4 protein P03905 UNIPROT "Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and |The main ND4-module intermediate binds NDUFB1, NDUFB4, NDUFB5, NDUFB6, NDUFB10, NDUFB11 and MT-ND4" SIGNOR-262146 MT-ND6 protein P03923 UNIPROT "Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND2-module is formed by an initial intermediate that contains MT-ND2, NDUFC1 and NDUFC2 bound to NDUFAF1/CIA30 [49,50], ECSIT [51] and ACAD9 [52,53]. Then, MT-ND3 is added together with TMEM126B [54], forming a larger intermediate to which subunits MT-ND6 and MT-ND4L bind. The latest assembly stages involve the incorporation of subunits NDUFA1, NDUFA10 and NDUFS5 [24,34]." SIGNOR-262149 F11 protein P03951 UNIPROT F9 protein P00740 UNIPROT "up-regulates activity" cleavage 9606 BTO:0000131 20110423 t lperfetto "Factor XI (FXI) is the zymogen of an enzyme (FXIa) that contributes to hemostasis by activating factor IX.|The characterization of the apple disk structure, and its relationship to the catalytic domain, have provided new insight into the mechanism of FXI activation, the interaction of FXIa with the substrate factor IX, and the binding of FXI to platelets." SIGNOR-263537 F11 protein P03951 UNIPROT HGF protein P14210 UNIPROT "up-regulates activity" cleavage Arg424 KNMEDLHrHIFWEPD -1 12372819 t miannu "the ability of plasma kallikrein and FXIa to activate pro-HGF in vitro raises the possibility that mediators of inflammation and blood coagulation may also regulate processes that involve the HGF/c-Met pathway, such as tissue repair and angiogenesis.Unlike other known activators, both FXIa and kallikrein processed pro-HGF by cleavage at two sites. Using N-terminal sequencing they were identified as the normal cleavage site Arg(494)-Val(495) and the novel site Arg(424)-His(425) located in the K4 domain of the alpha-chain." SIGNOR-256515 F11 protein P03951 UNIPROT HGF protein P14210 UNIPROT "up-regulates activity" cleavage Arg494 CAKTKQLrVVNGIPT -1 12372819 t miannu "the ability of plasma kallikrein and FXIa to activate pro-HGF in vitro raises the possibility that mediators of inflammation and blood coagulation may also regulate processes that involve the HGF/c-Met pathway, such as tissue repair and angiogenesis.Unlike other known activators, both FXIa and kallikrein processed pro-HGF by cleavage at two sites. Using N-terminal sequencing they were identified as the normal cleavage site Arg(494)-Val(495) and the novel site Arg(424)-His(425) located in the K4 domain of the alpha-chain." SIGNOR-256514 F11 protein P03951 UNIPROT "GPIb-IX-V complex" complex SIGNOR-C270 SIGNOR "up-regulates activity" binding 9606 BTO:0000132 25297919 t lperfetto "Besides VWF as a main ligand, GPIbα also binds multiple ligands such as thrombospondin, Factor XII, Factor XI, thrombin, High Molecular Weight kininogen, P-selectin and Mac-1." SIGNOR-261857 KLKB1 protein P03952 UNIPROT F12 protein P00748 UNIPROT "up-regulates activity" cleavage Arg353 EQPPSLTrNGPLSCG 9606 BTO:0000131 28966616 t lperfetto "FXIIa converts PK to the active protease PKa, which reciprocally activates more FXII|In addition, PKa can initiate a further proteolysis of FXIIa into a ~30 kDa light chain fragment, termed β-FXIIa. The cleavage takes place at the peptide bond Arg353–Val354 and consequently, the active site released from the heavy chain and thus from surfaces." SIGNOR-263520 KLKB1 protein P03952 UNIPROT KNG1 protein P01042 UNIPROT "up-regulates activity" cleavage Arg381 GMISLMKrPPGFSPF 9606 BTO:0000131 cleavage:Arg390 CTTKTSTrIVGGTNS 28966616 t lperfetto "Bradykinin is a nonapeptide composed of the sequence Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg and functions as an inflammatory mediator. BK is the product of the kallikrein–kinin system following activation of FXII. FXIIa leads to proteolysis of PK, and the resulting PKa cleaves HK to generate BK (Figure 1)." SIGNOR-263547 KLKB1 protein P03952 UNIPROT KNG1 protein P01042 UNIPROT "up-regulates activity" cleavage Arg389 PPGFSPFrSSRIGEI 9606 BTO:0000131 cleavage:Arg390 CTTKTSTrIVGGTNS 28966616 t lperfetto "Bradykinin is a nonapeptide composed of the sequence Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg and functions as an inflammatory mediator. BK is the product of the kallikrein–kinin system following activation of FXII. FXIIa leads to proteolysis of PK, and the resulting PKa cleaves HK to generate BK (Figure 1)." SIGNOR-263548 RAF1 protein P04049 UNIPROT MAP2K2 protein P36507 UNIPROT up-regulates phosphorylation Ser222 VSGQLIDsMANSFVG 9606 8157000 t gcesareni "To understand the mechanism of activation of MAPKK, we have identified Ser217 and Ser221 of MAPKK1 as the sites phosphorylated by p74raf-1." SIGNOR-262292 RAF1 protein P04049 UNIPROT MAP2K2 protein P36507 UNIPROT up-regulates phosphorylation Ser226 LIDSMANsFVGTRSY 9606 8157000 t "Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases." gcesareni "To understand the mechanism of activation of MAPKK, we have identified Ser217 and Ser221 of MAPKK1 as the sites phosphorylated by p74raf-1." SIGNOR-36553 RAF1 protein P04049 UNIPROT MAP2K1 protein Q02750 UNIPROT "up-regulates activity" phosphorylation Ser218 VSGQLIDsMANSFVG 9606 BTO:0000975 10359597 t lperfetto "Among other effectors, active ras binds and activates the raf kinase, iniziating a kinase cascade involving serine phosporylation of mek1/2 (mapkk) and tyrosine and threonine phosphorylation of erk1/2 active raf phosphorylates mek phospholpeptide analysis demostrated that serine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf." SIGNOR-235987 RAF1 protein P04049 UNIPROT MAP2K1 protein Q02750 UNIPROT "up-regulates activity" phosphorylation Ser222 LIDSMANsFVGTRSY 9606 BTO:0000975 10359597 t lperfetto "Among other effectors, active ras binds and activates the raf kinase, iniziating a kinase cascade involving serine phosporylation of mek1/2 (mapkk) and tyrosine and threonine phosphorylation of erk1/2 ras activation leads to raf and subsequently mek activation. Phospholipide analysis demostrated that serine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf." SIGNOR-235991 RAF1 protein P04049 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 15849194 t "Ser112 corresponds to EIRSRHSsYPAGTED" lperfetto "Raf-1 protects cells from apoptosis, independently of its signals to MEK and ERK, by translocating to the mitochondria where it binds Bcl-2 and displaces BAD|Upon phosphorylation by Pak1, Raf-1 translocates to mitochondria and phosphorylates BAD at Ser-112." SIGNOR-81165 RAF1 protein P04049 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates binding 9606 11427728 t gcesareni "Raf-1 interacts with the proapoptotic, stress-activated protein kinase ask1 (apoptosis signal-regulating kinase 1) in vitro and in vivo." SIGNOR-109023 RAF1 protein P04049 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 11018021 t "Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases." lperfetto "The best characterized Raf substrates are MEK1 and MEK2. The activation of MEK1/2 by Raf is required to mediate many of the cellular responses to Raf activation, suggesting that MEK1/2 are the dominant Raf effector proteins." SIGNOR-244952 RAF1 protein P04049 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000975 11018021 t lperfetto "The best characterized Raf substrates are MEK1 and MEK2. The activation of MEK1/2 by Raf is required to mediate many of the cellular responses to Raf activation, suggesting that MEK1/2 are the dominant Raf effector proteins." SIGNOR-244945 PROC protein P04070 UNIPROT F7 protein P08709 UNIPROT "down-regulates activity" cleavage 9606 BTO:0000131 29880919 t lperfetto "Activated protein C (APC), which cleaves and inactivates both FVIIIa and FVa, thereby shutting down both the tenase and prothrombinase complexes" SIGNOR-263527 PROC protein P04070 UNIPROT F5 protein P12259 UNIPROT "down-regulates activity" cleavage 9606 BTO:0000131 29880919 t lperfetto "Activated protein C (APC), which cleaves and inactivates both FVIIIa and FVa, thereby shutting down both the tenase and prothrombinase complexes" SIGNOR-263528 PROC protein P04070 UNIPROT F5 protein P12259 UNIPROT "down-regulates activity" cleavage Arg334 KNCPKKTrNLKKITR -1 7989361 t lperfetto "The mechanism of inactivation of human factor V and human factor Va by activated protein C|Membrane-bound human factor V (250 nM) is cleaved by APC (2.5 nM) to give M(r) = 200,000, 70,000, 45,000, and 30,000 fragments and an M(r) = 22/20,000 doublet. These fragments are released after four sequential cleavages of the membrane-bound procofactor at Arg306, Arg506, Arg679, and Lys994." SIGNOR-263628 PROC protein P04070 UNIPROT F5 protein P12259 UNIPROT "down-regulates activity" cleavage Arg534 KSRSLDRrGIQRAAD -1 7989361 t lperfetto "The mechanism of inactivation of human factor V and human factor Va by activated protein C|Membrane-bound human factor V (250 nM) is cleaved by APC (2.5 nM) to give M(r) = 200,000, 70,000, 45,000, and 30,000 fragments and an M(r) = 22/20,000 doublet. These fragments are released after four sequential cleavages of the membrane-bound procofactor at Arg306, Arg506, Arg679, and Lys994." SIGNOR-263629 PROC protein P04070 UNIPROT F5 protein P12259 UNIPROT "down-regulates activity" cleavage Arg707 ESTVMATrKMHDRLE -1 7989361 t lperfetto "The mechanism of inactivation of human factor V and human factor Va by activated protein C|Membrane-bound human factor V (250 nM) is cleaved by APC (2.5 nM) to give M(r) = 200,000, 70,000, 45,000, and 30,000 fragments and an M(r) = 22/20,000 doublet. These fragments are released after four sequential cleavages of the membrane-bound procofactor at Arg306, Arg506, Arg679, and Lys994." SIGNOR-263630 PROC protein P04070 UNIPROT F5 protein P12259 UNIPROT "down-regulates activity" cleavage Lys1022 GGKSRLKkSQFLIKT -1 7989361 t lperfetto "The mechanism of inactivation of human factor V and human factor Va by activated protein C|Membrane-bound human factor V (250 nM) is cleaved by APC (2.5 nM) to give M(r) = 200,000, 70,000, 45,000, and 30,000 fragments and an M(r) = 22/20,000 doublet. These fragments are released after four sequential cleavages of the membrane-bound procofactor at Arg306, Arg506, Arg679, and Lys994." SIGNOR-263627 ALDOA protein P04075 UNIPROT "beta-D-fructofuranose 1,6-bisphosphate(4-)" smallmolecule CHEBI:32966 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 16051738 t miannu "Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C." SIGNOR-266487 ALDOA protein P04075 UNIPROT "glycerone phosphate(2-)" smallmolecule CHEBI:57642 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 16051738 t miannu "Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C." SIGNOR-266483 ALDOA protein P04075 UNIPROT "D-glyceraldehyde 3-phosphate(2-)" smallmolecule CHEBI:59776 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 16051738 t miannu "Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C." SIGNOR-266479 ANXA1 protein P04083 UNIPROT TNF protein P01375 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 27426034 f miannu "Our study demonstrates that ANXA1 can be phosphorylated by PKC and is subsequently translocated to the nucleus of BV-2 microglial cells after OGD/R, resulting in the induction of pro-inflammatory cytokines. we set out to examine the relationship between the different subcellular distributions of ANXA1 and the upregulation of inflammatory cytokines. When BV-2 microglial cells were transfected with ANXA1-S27A constructs following by OGD/R treatment, the pro-inflammatory cytokines, IL-1β, IL-6, and TNF-α, were found to be expressed at lower levels than those of control groups" SIGNOR-261941 ANXA1 protein P04083 UNIPROT IL1B protein P01584 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 27426034 f miannu "Our study demonstrates that ANXA1 can be phosphorylated by PKC and is subsequently translocated to the nucleus of BV-2 microglial cells after OGD/R, resulting in the induction of pro-inflammatory cytokines. we set out to examine the relationship between the different subcellular distributions of ANXA1 and the upregulation of inflammatory cytokines. When BV-2 microglial cells were transfected with ANXA1-S27A constructs following by OGD/R treatment, the pro-inflammatory cytokines, IL-1β, IL-6, and TNF-α, were found to be expressed at lower levels than those of control groups" SIGNOR-261940 ANXA1 protein P04083 UNIPROT IL6 protein P05231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 27426034 f miannu "Our study demonstrates that ANXA1 can be phosphorylated by PKC and is subsequently translocated to the nucleus of BV-2 microglial cells after OGD/R, resulting in the induction of pro-inflammatory cytokines. we set out to examine the relationship between the different subcellular distributions of ANXA1 and the upregulation of inflammatory cytokines. When BV-2 microglial cells were transfected with ANXA1-S27A constructs following by OGD/R treatment, the pro-inflammatory cytokines, IL-1β, IL-6, and TNF-α, were found to be expressed at lower levels than those of control groups" SIGNOR-261939 ANXA1 protein P04083 UNIPROT FPR1 protein P21462 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 15187149 t "We show that the mimetic N-terminal annexin 1 peptide Ac1-25 is able to activate and desensitize not only FPR but also FPRL1 and FPRL2." SIGNOR-259439 ANXA1 protein P04083 UNIPROT FPR3 protein P25089 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 15187149 t "We show that the mimetic N-terminal annexin 1 peptide Ac1-25 is able to activate and desensitize not only FPR but also FPRL1 and FPRL2." SIGNOR-259438 ANXA1 protein P04083 UNIPROT FPR2 protein P25090 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 15187149 t "We show that the mimetic N-terminal annexin 1 peptide Ac1-25 is able to activate and desensitize not only FPR but also FPRL1 and FPRL2." SIGNOR-259437 PDGFA protein P04085 UNIPROT PDGFRA protein P16234 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0000763 11803579 t 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 CSF2 protein P04141 UNIPROT CSF2RA protein P15509 UNIPROT up-regulates binding 9606 10572088 t gcesareni "We have determined the nmr structure of a ligand-binding domain of the granulocyte colony-stimulating factor (g-csf) receptor comparisons between the spectra of the 15n-labelled domain with and without g-csf indicate that the major ligand-recognition site is on the fg loop just upstream of the wsxws sequence." SIGNOR-72458 CSF2 protein P04141 UNIPROT CSF2RA protein P15509 UNIPROT up-regulates binding 9606 9187659 t gcesareni "We have determined the nmr structure of a ligand-binding domain of the granulocyte colony-stimulating factor (g-csf) receptor comparisons between the spectra of the 15n-labelled domain with and without g-csf indicate that the major ligand-recognition site is on the fg loop just upstream of the wsxws sequence." SIGNOR-49126 CSF2 protein P04141 UNIPROT CSF2RA protein P15509 UNIPROT "up-regulates activity" binding 9606 BTO:0000801 18551128 t lperfetto "The GM-CSF receptor (CSF2R) is a heterodimer composed of a specific ligand-binding subunit (CSF2Ralpha) and a common signal-transduction subunit (CSF2Rbeta)" SIGNOR-249501 CSF2 protein P04141 UNIPROT HBG2 protein P69892 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001571 2479426 f "Regulation of expression" miannu "Granulocyte-macrophage colony-stimulating factor reactivates fetal hemoglobin synthesis in erythroblast clones from normal adults." SIGNOR-251776 CSF2 protein P04141 UNIPROT CSF3R protein Q99062 UNIPROT up-regulates binding 9606 BTO:0000130 16492764 t gcesareni "A g-csfr expression plasmid was introduced into interleukin-3 (il-3)-dependent mouse myeloid precursor fdc-p1 cells that normally do not respond to g-csf. G-csf stimulated proliferation of the transformants. These results suggested that the g-csfr, but not the il-3/gm-csf receptors, transduced the neutrophilic differentiation signal into cells" SIGNOR-144740 CSF2 protein P04141 UNIPROT CSF3R protein Q99062 UNIPROT up-regulates binding 9606 BTO:0000130 7691413 t gcesareni "A g-csfr expression plasmid was introduced into interleukin-3 (il-3)-dependent mouse myeloid precursor fdc-p1 cells that normally do not respond to g-csf. G-csf stimulated proliferation of the transformants these results suggested that the g-csfr, but not the il-3/gm-csf receptors, transduced the neutrophilic differentiation signal into cells." SIGNOR-31963 CSF2 protein P04141 UNIPROT CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR up-regulates binding 9606 BTO:0000876 BTO:0001103 9680354 t apalma "GM-CSF elicits these diverse responses through the GM-CSF receptor (GMR)." SIGNOR-255581 NR3C1 protein P04150 UNIPROT SGK1 protein O00141 UNIPROT "up-regulates quantity" "transcriptional regulation" 10116 BTO:0000632 15793248 f "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 NR3C1 protein P04150 UNIPROT FOXO3 protein O43524 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 BTO:0000759 22848740 t 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 NR3C1 protein P04150 UNIPROT JUN protein P05412 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 8639160 t gcesareni "We have described how the receptor uses several means to achieve repression of the genes regulated by AP-1 and NF-KB proteins" SIGNOR-251679 NR3C1 protein P04150 UNIPROT LCK protein P06239 UNIPROT up-regulates binding 9606 16888650 t gcesareni "The present study shows that the GC receptor is part of a TCR-linked multiprotein complex containing heat-shock protein (HSP)90, LCK and FYN, which is essential for TCR-dependent LCK/FYN activation." SIGNOR-251685 NR3C1 protein P04150 UNIPROT NR3C2 protein P08235 UNIPROT up-regulates 9606 11154266 f lperfetto "These results indicate that functional interactions between the glucocorticoid and mineralocorticoid receptors in activating specific gene transcription are probably more complex than has been previously appreciated." SIGNOR-85987 NR3C1 protein P04150 UNIPROT CEBPB protein P17676 UNIPROT "up-regulates activity" binding 10090 BTO:0000011 11279134 t 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 NR3C1 protein P04150 UNIPROT CEBPB protein P17676 UNIPROT "up-regulates activity" binding 10116 9428795 t "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 NR3C1 protein P04150 UNIPROT CEBPB protein P17676 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000746 27777311 f "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 NR3C1 protein P04150 UNIPROT RXRA protein P19793 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12573484 f gcesareni "Physiological concentrations of glucocorticoids increase cellular cyp2c9 (and cyp3a5) but also car, rxr and pxr levels via a gr-mediated mechanism" SIGNOR-98102 NR3C1 protein P04150 UNIPROT NFKB1 protein P19838 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 8639160 t gcesareni "We have described how the receptor uses several means to achieve repression of the genes regulated by AP-1 and NF-KB proteins" SIGNOR-251680 NR3C1 protein P04150 UNIPROT UGT1A1 protein P22309 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18172616 f miannu "This study indicates that hepatocyte nuclear factor 1alpha (HNF1alpha) bound to the proximal promoter motif not only enhances the basal reporter activity of UGT1A1, including the distal (-3570/-3180) and proximal (-165/-1) regions, but also influences the transcriptional regulation of UGT1A1 by CAR, PXR, GR, and AhR to markedly enhance reporter activities." SIGNOR-254439 NR3C1 protein P04150 UNIPROT NR4A1 protein P22736 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15591535 f gcesareni "Our data suggest a mechanism for transrepression between two nuclear receptors, gr and ngfi-b." SIGNOR-132251 NR3C1 protein P04150 UNIPROT NR2F2 protein P24468 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 14739255 f gcesareni "Gralpha, but not grbeta, enhanced coup-tfii-induced transactivation of the simple coup-tfii-responsive 7alpha-hydroxylase promoter through the transcriptional activity of its activation function-1 domain, whereas coup-tfii repressed gralpha-induced transactivation of the glucocorticoid-responsive promoter by attracting the silencing mediator for retinoid and thyroid hormone receptors." SIGNOR-121422 NR3C1 protein P04150 UNIPROT NFKBIA protein P25963 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 7569975 f "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 NR3C1 protein P04150 UNIPROT MAPK3 protein P27361 UNIPROT "down-regulates activity" 10090 BTO:0000944 11742987 f gcesareni "Both induction of MKP-1 expression and inhibition of its degradation are necessary for glucocorticoid-mediated inhibition of Erk-1/2 activation." SIGNOR-251677 NR3C1 protein P04150 UNIPROT MAPK1 protein P28482 UNIPROT "down-regulates activity" 10090 BTO:0000944 11742987 f gcesareni "Glucocorticoids inhibit MAP kinase via increased expression and decreased degradation of MKP-1|Both induction of MKP-1 expression and inhibition of its degradation are necessary for glucocorticoid-mediated inhibition of Erk-1/2 activation. In NIH-3T3 fibroblasts, although glucocorticoids up-regulate the MKP-1 level, they do not attenuate the proteasomal degradation of this protein and consequently they are unable to inhibit Erk-1/2 activity." SIGNOR-251678 NR3C1 protein P04150 UNIPROT DUSP1 protein P28562 UNIPROT "up-regulates quantity" 10090 BTO:0000944 11742987 t gcesareni "Glucocorticoids inhibit MAP kinase via increased expression and decreased degradation of MKP-1|Both induction of MKP-1 expression and inhibition of its degradation are necessary for glucocorticoid-mediated inhibition of Erk-1/2 activation. In NIH-3T3 fibroblasts, although glucocorticoids up-regulate the MKP-1 level, they do not attenuate the proteasomal degradation of this protein and consequently they are unable to inhibit Erk-1/2 activity." SIGNOR-253546 NR3C1 protein P04150 UNIPROT PCK1 protein P35558 UNIPROT "up-regulates quantity" "transcriptional regulation" 10116 BTO:0004428 11069927 t "In the liver, glucocorticoids induce a 10-15-fold increase in the rate of transcription of the phosphoenolpyruvate carboxykinase (PEPCK) gene, which encodes a key gluconeogenic enzyme" SIGNOR-253056 NR3C1 protein P04150 UNIPROT PCK1 protein P35558 UNIPROT "up-regulates quantity" "transcriptional regulation" 9600 BTO:0000567 26652733 t "These results reveal that CRTC2 plays an essential role in the regulation of hepatic gluconeogenesis through coordinated regulation of the glucocorticoid/GR- and glucagon/CREB-signaling pathways on the key genes G6P and PEPCK." SIGNOR-256107 NR3C1 protein P04150 UNIPROT G6PC1 protein P35575 UNIPROT "up-regulates quantity" "transcriptional regulation" 9600 BTO:0000567 26652733 t "Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB" SIGNOR-256104 NR3C1 protein P04150 UNIPROT PPARG protein P37231 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 BTO:0000011 8754811 f 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 NR3C1 protein P04150 UNIPROT PPARG protein P37231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000011 10649448 f gcesareni "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-255753 NR3C1 protein P04150 UNIPROT PPARG protein P37231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000011 11279134 f 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-250561 NR3C1 protein P04150 UNIPROT PPARG protein P37231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000746 27777311 f "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 NR3C1 protein P04150 UNIPROT HNF4A protein P41235 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17978169 t gcesareni "Electrophoretic mobility shift, chromatin immunoprecipitation (ChIP), and streptavidin DNA binding assays revealed that DEX increased binding of HNF4alpha to the HNF4-RE and that an interaction of GR and HNF4alpha occurred at this site." SIGNOR-251684 NR3C1 protein P04150 UNIPROT STAT5A protein P42229 UNIPROT up-regulates binding 9606 8878484 t fspada "We show here that the glucocorticoid receptor can act as a transcriptional co-activator for stat5 and enhance stat5-dependent transcription. Stat5 forms a complex with the gluco-corticoid receptor which binds to dna independently of the gre. This complex formation between stat5 and the glucocorticoid receptor diminishes the glucocorticoid response of a gre-con-taining promoter." SIGNOR-44376 NR3C1 protein P04150 UNIPROT NR4A2 protein P43354 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15591535 f gcesareni "We now show that the other nur factors, nurr1 and nor-1, are also subject to antagonism by gr and that this transrepression appears to involve direct protein-protein interactions between the dbds of gr and nur factors." SIGNOR-132254 NR3C1 protein P04150 UNIPROT CEBPA protein P49715 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000011 11279134 f 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-235346 NR3C1 protein P04150 UNIPROT CEBPA protein P49715 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000746 27777311 t "We show that in addition, DEX-bound GR directly promotes the expression of adipogenic TFs, including C/EBPβ, Klf5, Klf9, and C/EBPα" SIGNOR-256116 ERBB2 protein P04626 UNIPROT CDK1 protein P06493 UNIPROT down-regulates phosphorylation Tyr15 EKIGEGTyGVVYKGR 9606 BTO:0000150 12049736 t lperfetto "Phosphorylation on tyrosine-15 of p34(cdc2) by erbb2 inhibits p34(cdc2) activation and is involved in resistance to taxol-induced apoptosis" SIGNOR-88671 NR3C1 protein P04150 UNIPROT CEBPD protein P49716 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 BTO:0000011 10649448 t gcesareni "We conclude that glucocorticoid-induced adipogenesis from bone marrow stromal cells is mediated through a reaction cascade in which dexamethasone transcriptionally activates C/EBPδ; C/EBPδ then binds to PPARγ2 promoter and transactivates PPARγ2 gene expression." SIGNOR-253061 NR3C1 protein P04150 UNIPROT CEBPD protein P49716 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 BTO:0000011 1840554 t "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 NR3C1 protein P04150 UNIPROT CAV1 protein Q03135 UNIPROT up-regulates binding 9606 23339905 t gcesareni "He mGR appears to reside in caveolae and its association with caveolin-1 (Cav-1) was clearly detected in two of the four cell lines investigated using double recognition proximity ligation assay." SIGNOR-251683 NR3C1 protein P04150 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates binding 10116 BTO:0004428 BTO:0000759 18762022 t "The GR directly interferes with Hes1 promoter activity, triggering the recruitment of histone deacetylase (HDAC) activities to the Hes1 gene" SIGNOR-253057 NR3C1 protein P04150 UNIPROT KLF9 protein Q13886 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000746 27777311 t "We show that in addition, DEX-bound GR directly promotes the expression of adipogenic TFs, including C/EBPβ, Klf5, Klf9, and C/EBPα" SIGNOR-256119 NR3C1 protein P04150 UNIPROT KLF5 protein Q13887 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000746 27777311 t "We show that in addition, DEX-bound GR directly promotes the expression of adipogenic TFs, including C/EBPβ, Klf5, Klf9, and C/EBPα" SIGNOR-256118 NR3C1 protein P04150 UNIPROT NCOA1 protein Q15788 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9590696 t gcesareni "Transactivation of these templates depends on the association of the GR with co-activators such as SRC-1/NcoA1, GRIP-1/TIF-2/NcoA2 and p300/CBP." SIGNOR-251682 NR3C1 protein P04150 UNIPROT MAPK14 protein Q16539 UNIPROT "down-regulates activity" 10090 11742987 f gcesareni "The MAP kinase p38 is also a target for negative regulation by glucocorticoids" SIGNOR-251675 NR3C1 protein P04150 UNIPROT NR4A3 protein Q92570 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15591535 f gcesareni "We now show that the other nur factors, nurr1 and nor-1, are also subject to antagonism by gr and that this transrepression appears to involve direct protein-protein interactions between the dbds of gr and nur factors." SIGNOR-132309 NR3C1 protein P04150 UNIPROT TRIM63 protein Q969Q1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 18612045 f 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 NR3C1 protein P04150 UNIPROT TSC22D3 protein Q99576 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001372 9430225 f "In thymocytes and peripheral T cells, GILZ gene expression is induced by DEX" SIGNOR-253295 NR3C1 protein P04150 UNIPROT KLF15 protein Q9UIH9 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0002572 20956975 f lperfetto "We identified glucocorticoid response element sites in the first intron of KLF15 by bioinformatical promoter analysis and confirmed their functional relevance by demonstrating GR interaction by chromatin immunoprecipitation" SIGNOR-236212 NR3C1 protein P04150 UNIPROT IRAK3 protein Q9Y616 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 25585690 t "We show that glucocorticoids and non-typeable Haemophilus influenzae synergistically upregulate IRAK-M expression via mutually and synergistically enhancing p65 and glucocorticoid receptor binding to the IRAK-M promoter" SIGNOR-259287 NR3C1 protein P04150 UNIPROT NR3C1/STAT5A complex SIGNOR-C84 SIGNOR "form complex" binding 9606 8878484 t fspada "We show here that the glucocorticoid receptor can act as a transcriptional co-activator for stat5 and enhance stat5-dependent transcription. Stat5 forms a complex with the gluco-corticoid receptor which binds to dna independently of the gre. This complex formation between stat5 and the glucocorticoid receptor diminishes the glucocorticoid response of a gre-con-taining promoter." SIGNOR-44373 OAT protein P04181 UNIPROT L-ornithine smallmolecule CHEBI:15729 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 BTO:0000452 BTO:0001103 14617280 t 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 OAT protein P04181 UNIPROT proline smallmolecule CHEBI:26271 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 14617280 t 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 MYCN protein P04198 UNIPROT ABCB1 protein P08183 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000793;BTO:0002104 7923112 f miannu "Decreased expression of the N-myc oncogene in neuroblastoma cell lines SH-SY5Y and BE(2)-C, following treatment with retinoic acid, was paralleled by down-regulation of MRP gene expression, contrasting with increased expression of the MDR1 gene." SIGNOR-254616 MYCN protein P04198 UNIPROT MEF2C protein Q06413 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000661 21261500 f miannu "HOXA9/HOXA10 activated expression of NMYC which in turn mediated MEF2C repression, indicating an indirect mode of regulation via NMYC interactor (NMI) and STAT5." SIGNOR-254214 MYCN protein P04198 UNIPROT SIRT2 protein Q8IXJ6 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000931 23175188 f miannu "Here we demonstrated that the class III histone deacetylase SIRT2 was upregulated by N-Myc in neuroblastoma cells and by c-Myc in pancreatic cancer cells, and that SIRT2 enhanced N-Myc and c-Myc protein stability and promoted cancer cell proliferation." SIGNOR-255145 MAS1 protein P04201 UNIPROT FLNA protein P21333 UNIPROT "up-regulates activity" binding 9606 26460884 t miannu "We further determined that GPCRs, AT1R, and MAS directly recruited FLNa and promoted its phosphorylation by cellular S/T kinases in an agonist-dependent manner. Our studies thus provide a structural framework for filamin in GPCR signaling, potentially regulating a variety of cellular responses. MAS likely binds filamin constitutively and hence leads to constitutive filamin phosphorylation. These results emphasize that it is the active receptor that mediates filamin phosphorylation by PKA or other cellular S/T kinases" SIGNOR-260627 MAS1 protein P04201 UNIPROT AGTR1 protein P30556 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 15809376 t miannu "our findings demonstrate that the protein encoded by the Mas proto-oncogene exhibits direct antagonistic properties on the AT1 receptor in vitro and that this oligomeric interaction may represent a natural state for these receptors in vivo in some tissues. the present findings in native tissues suggest that the Mas receptor can act as an in vivo functional antagonist of the AT1 receptor owing to formation of a hetero-oligomeric complex" SIGNOR-260626 CD74 protein P04233 UNIPROT CXCR4 protein P61073 UNIPROT up-regulates binding 9606 BTO:0000007;BTO:0000876 19665027 t miannu "Cd74 forms functional complexes with cxcr4 that mediate mif-specific signaling." SIGNOR-187461 CD3D protein P04234 UNIPROT TCR complex SIGNOR-C153 SIGNOR "form complex" binding 9606 12507424 t miannu "The T cell receptor-CD3 complex (TCR-CD3) serves a critical role in the differentiation, survival, and function of T cells, and receptor triggering elicits a complex set of biological responses that serve to protect the organism from infectious agents. The receptor is composed of six different chains that form the TCR heterodimer responsible for ligand recognition, as well as the CD3γε, CD3δε, and ζζ signaling modules.the TCRα-CD3δε and TCRβ-CD3γε interactions are similar since both require a lysine in the TM region of the respective TCR chain and both acidic TM residues in the relevant CD3 heterodimer. Nevertheless, formation of fully assembled αβ TCR-CD3 complexes containing the ζ-chain strictly required both CD3γ and δ" SIGNOR-255295 KRT1 protein P04264 UNIPROT MPO protein P05164 UNIPROT "up-regulates quantity" binding 9606 17591979 t "Regulation of binding" miannu "CK1 and CK9 specifically bind MPO. MPO is internalized by endothelial cells through a direct interaction with the endothelial surface protein CK1" SIGNOR-251886 KRT1 protein P04264 UNIPROT APC protein P25054 UNIPROT "up-regulates activity" phosphorylation 9606 18359618 t "Regulation of catabolism" miannu "Phosphorylation of this central repeat region of APC significantly enhances its affinity for β-catenin. When the repeats are phosphorylated by the cooperative action of CK1 and GSK3β, the binding interaction is significantly altered and enhanced." SIGNOR-251879 VWF protein P04275 UNIPROT F8 protein P00451 UNIPROT "up-regulates activity" binding 9606 23020315 t miannu "Binding of FVIII to VWF is needed to maintain appropriate plasma levels, as FVIII plasma levels and half-life are remarkably reduced in the absence of VWF" SIGNOR-251967 VWF protein P04275 UNIPROT F8 protein P00451 UNIPROT "up-regulates quantity by stabilization" 9606 32644488 f lperfetto "VWF plays a crucial role in hemostasis through platelet adhesion facilitation and coagulation factor VIII stabilization" SIGNOR-261865 VWF protein P04275 UNIPROT "AIIB/b3 integrin" complex SIGNOR-C173 SIGNOR "up-regulates activity" binding 9606 BTO:0000132 25297919 t lperfetto "Many studies have contributed to shed light on the importance of von Willebrand factor (VWF) interaction with its platelet receptors, glycoprotein (GP) Ib-IX-V and αIIbβ3 integrin, in promoting primary platelet adhesion and aggregation following vessel injury" SIGNOR-261854 VWF protein P04275 UNIPROT "GPIb-IX-V complex" complex SIGNOR-C270 SIGNOR "up-regulates activity" binding 9606 BTO:0000132 25297919 t lperfetto "Many studies have contributed to shed light on the importance of von Willebrand factor (VWF) interaction with its platelet receptors, glycoprotein (GP) Ib-IX-V and αIIbβ3 integrin, in promoting primary platelet adhesion and aggregation following vessel injury" SIGNOR-261853 GAPDH protein P04406 UNIPROT "3-phosphonato-D-glyceroyl phosphate(4-)" smallmolecule CHEBI:57604 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 11724794 t miannu "GAPDH is commonly known as a key enzyme in glycolysis (GAPDH catalyzes the NAD-mediated oxidative phosphorylation of glyceraldehyde 3-phosphate to 1,3-diphosphoglycerate), a number of intriguing intracellular roles have been reported including modulation of the cytoskeleton, kinase activity, and the promotion of vesicle fusion" SIGNOR-266494 GAPDH protein P04406 UNIPROT "D-glyceraldehyde 3-phosphate(2-)" smallmolecule CHEBI:59776 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 11724794 t miannu "GAPDH is commonly known as a key enzyme in glycolysis (GAPDH catalyzes the NAD-mediated oxidative phosphorylation of glyceraldehyde 3-phosphate to 1,3-diphosphoglycerate), a number of intriguing intracellular roles have been reported including modulation of the cytoskeleton, kinase activity, and the promotion of vesicle fusion" SIGNOR-266495 ERBB2 protein P04626 UNIPROT MSI1 protein O43347 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150 BTO:0000149 20443831 f gcesareni "We investigated the possibilities that erbb2 may regulate downstream mediators of notch1 signaling to induce musashi1 (which enhances notch1 signaling)." SIGNOR-165195 ERBB2 protein P04626 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 8816440 t gcesareni "Although erbb-2 binds neither ligand, even in a heterodimeric receptor complex, it is the preferred heterodimer partner of the three other members, and it favors interaction with erbb-3." SIGNOR-147838 ERBB2 protein P04626 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 15173068 t gcesareni "The results presented here show for the first time that er redistribution to the cytoplasm and its interaction with her2 are important downstream effects of her2 overexpression, that erk1/2 is important for er cytoplasmic localization, and that subcellular localization of er may play a mechanistic role in determining the responsiveness of breast cancer cells to tamoxifen." SIGNOR-124962 ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates phosphorylation Tyr1112 DPSPLQRySEDPTVP 9606 BTO:0000149 1706616 t gcesareni "However, each of these peptides contains tyrosines that correspond to major autophosphorylation sites of the epidermal growth factor receptor, suggesting that, in addition to y1023 and y1248, y1139 and y1222 also serve as autophosphorylation sites of her2." SIGNOR-21211 ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates phosphorylation Tyr1196 GAVENPEyLTPQGGA 9606 BTO:0000150 15156151 t gcesareni "Stimulation of these molecules, however, failed to induce efficient cell migration in the absence of neu/erbb2 phosphorylation at tyr 1201 or tyr 1227" SIGNOR-124856 ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates phosphorylation Tyr1221 SPAFDNLyYWDQDPP 9606 BTO:0000149 1706616 t gcesareni "However, each of these peptides contains tyrosines that correspond to major autophosphorylation sites of the epidermal growth factor receptor, suggesting that, in addition to y1023 and y1248, y1139 and y1222 also serve as autophosphorylation sites of her2." SIGNOR-21199 ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates phosphorylation Tyr1248 PTAENPEyLGLDVPV 9606 BTO:0000149 1706616 t gcesareni "However, each of these peptides contains tyrosines that correspond to major autophosphorylation sites of the epidermal growth factor receptor, suggesting that, in addition to y1023 and y1248, y1139 and y1222 also serve as autophosphorylation sites of her2." SIGNOR-21203 ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT "up-regulates activity" phosphorylation Tyr1023 DLVDAEEyLVPQQGF 9606 1706616 t "Y1023 and Y1248, Y1139 and Y1222 also serve as autophosphorylation sites of HER2." SIGNOR-251129 ERBB2 protein P04626 UNIPROT ERBB3 protein P21860 UNIPROT up-regulates binding 9606 12648465 t "Most breast, skin, lung, ovary, and gastrointestinal tract tumors express ErbB-3, and heterodimerization of this receptor with ErbB-2, may be involved in some cancers." gcesareni "Although ErbB-2 binds no known ligand, when recruited into heterodimers it increases ligand binding affinity" SIGNOR-99569 ERBB2 protein P04626 UNIPROT ERBB3 protein P21860 UNIPROT up-regulates binding 9606 8816440 t "Most breast, skin, lung, ovary, and gastrointestinal tract tumors express ErbB-3, and heterodimerization of this receptor with ErbB-2, may be involved in some cancers." gcesareni "Although erbb-2 binds neither ligand, even in a heterodimeric receptor complex, it is the preferred heterodimer partner of the three other members, and it favors interaction with erbb-3." SIGNOR-43841 ERBB2 protein P04626 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 9606 10085134 t gcesareni "Shc interacts with and is an excellent substrate for erbb2 and appears to play an important role in mitogenic signaling through this receptor tyrosine kinase" SIGNOR-65579 ERBB2 protein P04626 UNIPROT GRB2 protein P62993 UNIPROT up-regulates relocalization 9606 14967450 t gcesareni "All erbb ligands and receptors couple to activation of the ras-mapk pathway, either directly through sh2 domain-mediated recruitment of grb-2 or indirectly through ptb domain-mediated binding of the shc adaptor" SIGNOR-121968 ERBB2 protein P04626 UNIPROT SHC3 protein Q92529 UNIPROT up-regulates relocalization 9606 16729043 t gcesareni "Erbb3 is characterized by a large number of binding sites for phosphatidylinositol-3-kinase (pi3k), while erbb2 has only few interaction partners with shc as the most frequent one." SIGNOR-146855 ERBB2 protein P04626 UNIPROT DOCK7 protein Q96N67 UNIPROT up-regulates phosphorylation Tyr1257 METVPQLyDFTETHN 9606 18426980 t llicata "We show that the nrg1 receptor erbb2 directly binds and activates dock7 by phosphorylating tyr-1118. thus, dock7 functions as an intracellular substrate for erbb2 to promote schwann cell migration. This provides an unanticipated mechanism through which ligand-dependent tyrosine phosphorylation can trigger the activation of rho gtpase-gefs of the dock180 family." SIGNOR-178348 ERBB2 protein P04626 UNIPROT NOTCH3 protein Q9UM47 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150 21743488 f gcesareni "We demonstrate that her2 overexpression in this cellular model of dcis drives transcriptional upregulation of multiple components of the notch survival pathway. Importantly, luminal filling required upregulation of a signaling pathway comprising notch3, its cleaved intracellular domain and the transcriptional regulator hes1." SIGNOR-174747 WNT1 protein P04628 UNIPROT FZD6 protein O60353 UNIPROT "up-regulates activity" binding 9606 BTO:0000887;BTO:0001103 22944199 t gcesareni "Distinctly, wnt1 signals through fzd receptors 1 and 6 in the epaxial domain of the somite, to regulate myf5 expression via the canonical bcatenin pathway." SIGNOR-198846 WNT1 protein P04628 UNIPROT LRP5 protein O75197 UNIPROT "up-regulates activity" binding 9606 15578921 t 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-131574 WNT1 protein P04628 UNIPROT LRP5 protein O75197 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 21078818 t gcesareni "Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt?Beta-catenin signaling." SIGNOR-169645 WNT1 protein P04628 UNIPROT LRP6 protein O75581 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 21078818 t gcesareni "Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt?Beta-catenin signaling." SIGNOR-169648 WNT1 protein P04628 UNIPROT MYF5 protein P13349 UNIPROT "up-regulates activity" 10090 BTO:0000887;BTO:0001103 22944199 f gcesareni "In explant cultures of mouse paraxial mesoderm, Wnt1 induced expression of the MRF Myf5, whereas Wnt7a or Wnt6 preferentially activated the MRF MyoD" SIGNOR-198849 WNT1 protein P04628 UNIPROT MYF5 protein P13349 UNIPROT "up-regulates activity" 10090 BTO:0000887;BTO:0001103 9753670 f gcesareni "Differential activation of Myf5 and MyoD by different Wnts in explants of mouse paraxial mesoderm and the later activation of myogenesis in the absence of Myf5" SIGNOR-60285 WNT1 protein P04628 UNIPROT PRKACA protein P17612 UNIPROT "up-regulates activity" 9606 BTO:0001103 21902831 f gcesareni "Wnt1 and wnt7a stimulation of precursor cells activates protein kinase a (pka), which, through the phosphorylation of creb, induces the expression of the myogenic transcription factors myf5, myod and pax3, resulting in the myogenic commitment of embryonic precursors." SIGNOR-176572 WNT1 protein P04628 UNIPROT RYK protein P34925 UNIPROT up-regulates binding 9606 15454084 t lperfetto "Mammalian ryk is a wnt coreceptor required for stimulation of neurite outgrowth" SIGNOR-129577 WNT1 protein P04628 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates 10116 11149923 f gcesareni "Wnt-1 signaling inhibited the cytochrome c release and the subsequent caspase-9 activation induced by chemotherapeutic drugs, including both vincristine and vinblastine. Furthermore, we found that wnt-1-mediated cell survival was dependent on the activation of beta-catenin/t cell factor (tcf) transcription" SIGNOR-85760 WNT1 protein P04628 UNIPROT FZD1 protein Q9UP38 UNIPROT "up-regulates activity" binding 9606 15578921 t 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-131568 WNT1 protein P04628 UNIPROT FZD1 protein Q9UP38 UNIPROT "up-regulates activity" binding 10090 BTO:0000887 16936075 t lperfetto "Here, we report that the Wnt signal is transduced in muscle progenitor cells by at least two Frizzled (Fz) receptors (Fz1 and/or Fz6)" SIGNOR-217827 WNT1 protein P04628 UNIPROT FZD1 protein Q9UP38 UNIPROT "up-regulates activity" binding 9606 BTO:0000887;BTO:0001103 22944199 t gcesareni "Distinctly, wnt1 signals through fzd receptors 1 and 6 in the epaxial domain of the somite, to regulate myf5 expression via the canonical _-catenin pathway" SIGNOR-198843 WNT1 protein P04628 UNIPROT Frizzled proteinfamily SIGNOR-PF11 SIGNOR "up-regulates activity" binding 10090 BTO:0000887 16936075 t lperfetto "Here, we report that the Wnt signal is transduced in muscle progenitor cells by at least two Frizzled (Fz) receptors (Fz1 and/or Fz6)" SIGNOR-253126 NTRK1 protein P04629 UNIPROT ARHGAP32 protein A7KAX9 UNIPROT up-regulates relocalization 9606 BTO:0000938 BTO:0000142 12446789 t gcesareni "Grit translocation was regulated by receptor stimulation" SIGNOR-95809 NTRK1 protein P04629 UNIPROT ABL1 protein P00519 UNIPROT up-regulates binding 9606 BTO:0000938 10708759 t esanto "Autophosphorylated trka binds directly to plc?, Abl, and shc." SIGNOR-75402 TP53 protein P04637 UNIPROT BCL2 protein P10415 UNIPROT "down-regulates activity" binding 9606 19007744 t "Cytosolic p53" lperfetto "Mechanistic insights into the mitochondrial function of wtp53 came when it was realized that mitochondrially translocated p53 interacts directly with members of the Bcl-2 family, which are central in governing the induction of mitochondrial outer membrane permeabilization. In response to stress, wtp53 interacts with and neutralizes the anti-apoptotic members Bcl-xL and Bcl-2. This interaction stimulates MOMP and subsequent apoptosis" SIGNOR-99712 TP53 protein P04637 UNIPROT VCAN protein P13611 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12438652 f miannu "By using in vitro and in vivo assays, we showed CSPG2 to be directly transactivated by p53." SIGNOR-255441 TP53 protein P04637 UNIPROT ETS1 protein P14921 UNIPROT "down-regulates activity" binding 9606 14586398 t miannu "We demonstrate that p53 and ets-1 coregulate TXSA in an antagonistic and inter-related manner, with ets-1 being a potent transcriptional activator and p53 inhibiting ets-1-dependent transcription. We show that ets-1 and p53 associate physically in vitro and in vivo and that their interaction, rather than a direct binding of p53 to the TXSA promoter, is required for transcriptional repression of TXSA by wild-type p53." SIGNOR-254087 TP53 protein P04637 UNIPROT MGMT protein P16455 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000711 17564708 f miannu "we observed that IFN-beta sensitized TMZ-resistant glioma cells with the unmethylated MGMT promoter and that the mechanism of action was possibly due to attenuation of MGMT expression via induction of TP53. In this context, IFN-beta inactivates MGMT via p53 gene induction and enhances the therapeutic efficacy to TMZ." SIGNOR-255437 TP53 protein P04637 UNIPROT GADD45A protein P24522 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 23576563 f gcesareni "P53 acetylated at k120 subsequently bound to the promoters of its target apoptotic genes, bax and gadd45, to promote their expression and lead to apoptosis." SIGNOR-201679 TP53 protein P04637 UNIPROT TBXAS1 protein P24557 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 14586398 f miannu "We demonstrate that p53 and ets-1 coregulate TXSA in an antagonistic and inter-related manner, with ets-1 being a potent transcriptional activator and p53 inhibiting ets-1-dependent transcription." SIGNOR-254086 TP53 protein P04637 UNIPROT FAS protein P25445 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150 9841917 t "Nuclear p53" amattioni "In an attempt to understand how CD95 expression is regulated by p53, we identified a p53-responsive element within the first intron of the CD95 gene, as well as three putative elements within the promoter. The intronic element conferred transcriptional activation by p53 and cooperated with p53-responsive elements in the promoter of the CD95 gene. wt p53 bound to and transactivated the CD95 gene," SIGNOR-62376 TP53 protein P04637 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 14522900 f miannu " In this study, we found that a subset of ING family members strongly repressed human alpha-fetoprotein (AFP) promoter activity but stimulated the p21(WAF1) promoter in parallel experiments in the same cell type, similar to the effects of p53. Both ING1 and p53 were able to suppress AFP transcription and cause p21 induction; hSIR2, a negative regulator of the p53 protein, showed the opposite effects on the AFP promoter and, like HDAC1, repressed p21 promoter activity." SIGNOR-254484 TP53 protein P04637 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 7566157 t gcesareni "The p21 gene is under the transcriptional control of p53 (ref. 5), suggesting that p21 might promote p53-dependent cell cycle arrest or apoptosis. p21cip1 is a cyclin-dependent kinase (cdk) inhibitor that is transcriptionally activated by p53 in response to dna damage. p53 then transcriptionally upregulates the expression of target genes, of which p21 is critical for inhibiting g1/s entry." SIGNOR-29248 TP53 protein P04637 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000142 8242752 t lperfetto "The ability of p53 to activate transcription from specific sequences suggests that genes induced by p53 may mediate its biological role as a tumor suppressor. Using a subtractive hybridization approach, we identified a gene, named WAF1, whose induction was associated with wild-type but not mutant p53 gene expression in a human brain tumor cell line. The WAF1 gene was localized to chromosome 6p21.2, and its sequence, structure, and activation by p53 was conserved in rodents." SIGNOR-37145 TP53 protein P04637 UNIPROT MLH1 protein P40692 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 15781865 t ".... numerous potentially novel targets, including the DNA mismatch repair genes MLH1 and PMS2. Both of these genes were determined to be responsive to DNA damage and p53 activation in normal human fibroblasts, and have p53-response elements within their first intron." SIGNOR-257605 TP53 protein P04637 UNIPROT FNTA protein P49354 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 26469958 f lperfetto "In this study, we provided evidence that p53 induces the expression of a group of enzymes of the MVA pathway including 3'-hydroxy-3'-methylglutaryl-coenzyme A reductase, MVA kinase, farnesyl diphosphate synthase and farnesyl diphosphate farnesyl transferase 1, in the human glioblastoma multiforme cell line, U343 cells, and in normal human astrocytes, NHAs." SIGNOR-242408 TP53 protein P04637 UNIPROT FNTB protein P49356 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 26469958 f lperfetto "In this study, we provided evidence that p53 induces the expression of a group of enzymes of the MVA pathway including 3'-hydroxy-3'-methylglutaryl-coenzyme A reductase, MVA kinase, farnesyl diphosphate synthase and farnesyl diphosphate farnesyl transferase 1, in the human glioblastoma multiforme cell line, U343 cells, and in normal human astrocytes, NHAs." SIGNOR-242353 TP53 protein P04637 UNIPROT LRBA protein P50851 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15064745 f miannu "We also show that LRBA promoter activity and endogenous LRBA mRNA levels are reduced by p53 and increased by E2F1, indicating that mutations in the tumor suppressors p53 and Rb could contribute to the deregulation of LRBA." SIGNOR-253847 TP53 protein P04637 UNIPROT PMS2 protein P54278 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 15781865 t ".... numerous potentially novel targets, including the DNA mismatch repair genes MLH1 and PMS2. Both of these genes were determined to be responsive to DNA damage and p53 activation in normal human fibroblasts, and have p53-response elements within their first intron." SIGNOR-257604 TP53 protein P04637 UNIPROT NFKB2 protein Q00653 UNIPROT up-regulates binding 9606 16990795 t gcesareni "P52 cooperates with p53 to regulate other known p53 target genes." SIGNOR-149811 HSPA1A protein P0DMV8 UNIPROT FLCN protein Q8NFG4 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000007 27353360 t "These data suggest that inhibition of Hsp70 does not lead to an increase in misfolded FLCN but instead to its degradation." SIGNOR-256506 ALDOB protein P05062 UNIPROT "glycerone phosphate(2-)" smallmolecule CHEBI:57642 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 16051738 t miannu "Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C." SIGNOR-266484 ALDOB protein P05062 UNIPROT "D-glyceraldehyde 3-phosphate(2-)" smallmolecule CHEBI:59776 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 16051738 t miannu "Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C." SIGNOR-266480 APP protein P05067 UNIPROT GSK3A protein P49840 UNIPROT up-regulates 9606 BTO:0000938 16446437 f gcesareni "These results suggest a direct relationship between app proteolytic processing, but not amyloid-_, in gsk-3_ activation and tau phosphorylation in human neurons." SIGNOR-144057 APP protein P05067 UNIPROT NAE1 protein Q13564 UNIPROT "up-regulates activity" binding 9606 BTO:0000590 25568892 t lperfetto "Alzheimer's disease (AD) is the gradual loss of the cognitive function due to neuronal death. Currently no therapy is available to slow down, reverse or prevent the disease. Here we analyze the existing data in literature and hypothesize that the physiological function of the Amyloid Precursor Protein (APP) is activating the AppBp1 pathway and this function is gradually lost during the progression of AD pathogenesis." SIGNOR-251577 ARG1 protein P05089 UNIPROT L-ornithine smallmolecule CHEBI:15729 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 BTO:0000452 BTO:0001103 14617280 t 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 ITGB3 protein P05106 UNIPROT PTK2 protein Q05397 UNIPROT "up-regulates activity" 9606 15688067 f miannu "Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin." SIGNOR-257718 ITGB3 protein P05106 UNIPROT "AIIB/b3 integrin" complex SIGNOR-C173 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253198 ITGB3 protein P05106 UNIPROT "Av/b3 integrin" complex SIGNOR-C177 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253206 ITGB2 protein P05107 UNIPROT PTK2 protein Q05397 UNIPROT "up-regulates activity" 9606 15688067 f miannu "Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin." SIGNOR-257711 ITGB2 protein P05107 UNIPROT "AL/b2 integrin" complex SIGNOR-C169 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253190 ITGB2 protein P05107 UNIPROT "AM/b2 integrin" complex SIGNOR-C170 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253192 ITGB2 protein P05107 UNIPROT "AX/b2 integrin" complex SIGNOR-C171 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253194 PRKCG protein P05129 UNIPROT GRM5 protein P41594 UNIPROT "up-regulates activity" phosphorylation Thr841 RSAFTTStVVRMHVG -1 15894802 t lperfetto "Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839." SIGNOR-249289 ITGB2 protein P05107 UNIPROT "AD/b2 integrin" complex SIGNOR-C172 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253196 S100A8 protein P05109 UNIPROT TLR4 protein O00206 UNIPROT "down-regulates activity" binding 9606 BTO:0001545 28137827 t miannu "Interestingly, in the present study, we report that extracellular S100A9 induces terminal differentiation of myeloid leukemia cells in human and murine AMLs after TLR4 activation, which is highly expressed by primary myelomonocytic and monocytic leukemia cells. In contrast, anti-S100A8 induced the differentiation of AML cells, suggesting that the differentiation-promoting effect of S100A9 is inhibited by S100A8. ) S100A8 could bind to TLR4 and activate different signaling pathways, leading to the inhibition of cellular differentiation induced by S100A9." SIGNOR-261921 S100A8 protein P05109 UNIPROT "Calprotectin complex" complex SIGNOR-C293 SIGNOR "form complex" binding 9867828 t lperfetto "Using the two-hybrid system we analyzed the dimerization of MRP8 (S100A8) and MRP14 (S100A9), two S100 proteins expressed in myeloid cells. It is reported that the MRP8-MRP14 heteromer is the clearly preferred complex in both man and mouse." SIGNOR-262832 S100A8 protein P05109 UNIPROT Tubulin proteinfamily SIGNOR-PF46 SIGNOR "up-regulates quantity by stabilization" binding 9606 BTO:0000876 16690079 t miannu "Calcium-induced complexes of S100A8 and S100A9 have been shown to colocalize with microtubules (MTs) during activation of monocytes. Functional analyses demonstrated that the complexes are involved in cytoskeletal organization and that they directly bind to tubulin and promote tubulin polymerization in a calcium-dependent manner" SIGNOR-261937 INHA protein P05111 UNIPROT TGFBR3 protein Q03167 UNIPROT down-regulates binding 9606 10746731 t gcesareni "Type iii tgf-beta receptor, betaglycan, can function as an inhibin co-receptor with actrii. Betaglycan binds inhibin with high affinity and enhances binding in cells co-expressing actrii and betaglycan. ability of betaglycan to facilitate inhibin antagonism of activin" SIGNOR-76470 IL4 protein P05112 UNIPROT IL4R protein P24394 UNIPROT up-regulates binding -1 10219247 t 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 IL4 protein P05112 UNIPROT IL4R protein P24394 UNIPROT "up-regulates activity" binding 9606 BTO:0000801 18852293 t 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 IL4 protein P05112 UNIPROT IL2RG protein P31785 UNIPROT up-regulates binding 9606 11418623 t gcesareni "The common gamma-chain (gamma(c)) is an indispensable subunit of the functional receptor complexes for il-4, il-7, il-9, and il-15 as well as il-2. Here we show that the gamma(c) is also shared with the il-21r complex" SIGNOR-108861 IL4 protein P05112 UNIPROT IL13RA1 protein P78552 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000801;BTO:0000876 BTO:0000887;BTO:0000763;BTO:0001260 12704343 t milica "It is now known that this alternate receptor is a heterodimer, the type ii il-4 receptor or the il-13 receptor, which is comprised of IL-4R And IL-13R1." SIGNOR-100759 SERPINE1 protein P05121 UNIPROT F12 protein P00748 UNIPROT "down-regulates activity" binding 9606 BTO:0000131 26707513 t lperfetto "C1INH is a serine protease inhibitor (serpin) that acts on both the complement pathway and the contact system and is the main inhibitor of the contact system by targeting both FXIIa and PK 9. Additionally, FXIIa can be inhibited by α1‐antitrypsin and plasminogen activator inhibitor‐1 (PAI‐1)." SIGNOR-263516 PRKCG protein P05129 UNIPROT STK17B protein O94768 UNIPROT "down-regulates activity" phosphorylation Ser351 PEDSSMVsKRFRFDD 10090 BTO:0000944 18084041 t miannu "These results suggest that phosphorylation of Ser350 plays an essential role in regulating translocation of DRAK2 to the nucleus from the cytoplasm, possibly by affecting the activity of the NLS. Ectopic expression of PKC-gamma induced cytoplasmic localization of DRAK2 and PKC-gamma phosphorylated Ser350 flanking the NLS." SIGNOR-263178 PRKCG protein P05129 UNIPROT VTN protein P04004 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser381 RNRKGYRsQRGHSRG -1 9030777 t lperfetto "Phosphorylation of vitronectin on Ser362 by protein kinase C attenuates its cleavage by plasmin." SIGNOR-248964 PRKCG protein P05129 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser619 SLPKINRsASEPSLH 9606 8288587 t gcesareni "Pkc can effectively phosphorylate raf-1, this is a direct effect of activated pkc and not the result of raf-1 autophosphorylation." SIGNOR-37545 PRKCG protein P05129 UNIPROT ANXA1 protein P04083 UNIPROT up-regulates phosphorylation Ser27 EYVQTVKsSKGGPGS 9606 24103589 t lperfetto "The authors identified several phosphorylated residues by a combination of peptide mapping and sequence analysis and showed that recombinant pp60c-src phosphorylates annexin a1 near its amino terminus, at tyrosine 21 (tyr21). Also polyoma virus middle t/pp60c-src complex, recombinant pp50v-abl, and the egf receptor/kinase phosphorylated the same tyrosine residue. It was also shown that serine 27 residue of anxa1 is the primary site phosphorylated by protein kinase c (pkc). In the same study, the threonine 41 residue has been identified as a pkc substrate as well. The adenosine cyclic 3_,5_-phosphate dependent protein kinase a (pka) phosphorylates anxa1 in its carboxyl-terminal core at the threonine 216 residue (thr216) [2].The phosphorylation of serine 27 is essential for annexin a1 membrane localization." SIGNOR-202788 PRKCG protein P05129 UNIPROT HSP90AA1 protein P07900 UNIPROT down-regulates phosphorylation Thr115 GTIAKSGtKAFMEAL 9606 24117238 t lperfetto "Threonine residue set, thr(115)/thr(425)/thr(603), of hsp90_ is specifically phosphorylated by pkc_phosphorylation of hsp90_ by pkc_ decreases the binding affinity of hsp90_ towards atp and co-chaperones such as cdc37 (cell-division cycle 37), thereby decreasing its chaperone activity." SIGNOR-202812 PRKCG protein P05129 UNIPROT HSP90AA1 protein P07900 UNIPROT down-regulates phosphorylation Thr425 KKCLELFtELAEDKE 9606 24117238 t lperfetto "Threonine residue set, thr(115)/thr(425)/thr(603), of hsp90_ is specifically phosphorylated by pkc_, and, more interestingly, this threonine residue set serves as a 'phosphorylation switch' for hsp90_ binding or release of pkc_. Moreover, phosphorylation of hsp90_ by pkc_ decreases the binding affinity of hsp90_ towards atp and co-chaperones such as cdc37 (cell-division cycle 37), thereby decreasing its chaperone activity." SIGNOR-202816 JUN protein P05412 UNIPROT TCF4 protein P15884 UNIPROT up-regulates binding 9606 16007074 t gcesareni "Phosphorylation-dependent interaction between c-jun and tcf4;c-jun and tcf4 cooperatively activated the c-jun promoter in reporter assays" SIGNOR-138544 PRKCG protein P05129 UNIPROT HSP90AA1 protein P07900 UNIPROT down-regulates phosphorylation Thr603 PCCIVTStYGWTANM 9606 24117238 t lperfetto "Threonine residue set, thr(115)/thr(425)/thr(603), of hsp90_ is specifically phosphorylated by pkc_, and, more interestingly, this threonine residue set serves as a 'phosphorylation switch' for hsp90_ binding or release of pkc_. Moreover, phosphorylation of hsp90_ by pkc_ decreases the binding affinity of hsp90_ towards atp and co-chaperones such as cdc37 (cell-division cycle 37), thereby decreasing its chaperone activity." SIGNOR-202820 PRKCG protein P05129 UNIPROT TOP2A protein P11388 UNIPROT "up-regulates activity" phosphorylation Ser29 EDAKKRLsVERIYQK 9606 BTO:0000567 12569090 t lperfetto "Here, we have shown that the enzymatic activity of topoisomerase II alpha protein purified from HeLa cell nuclei was strongly enhanced following phosphorylation by protein kinase C. | Site-directed mutagenesis studies indicated that phosphorylation of serine 29 generated both of these phosphopeptides." SIGNOR-249196 PRKCG protein P05129 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates phosphorylation Ser42 AKKKSKIsASRKLQL 9606 BTO:0000887 15769444 t lperfetto "Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction." SIGNOR-134632 PRKCG protein P05129 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates phosphorylation Ser44 KKSKISAsRKLQLKT 9606 BTO:0000887 15769444 t lperfetto "Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction." SIGNOR-134636 PRKCG protein P05129 UNIPROT GRK2 protein P25098 UNIPROT "up-regulates activity" phosphorylation Ser29 ATPAARAsKKILLPE 9606 BTO:0000007 11042191 t lperfetto "Phosphorylation of GRK2 by protein kinase C abolishes its inhibition by calmodulin. In vitro, GRK2 was preferentially phosphorylated by PKC isoforms alpha, gamma, and delta. Two-dimensional peptide mapping of PKCalpha-phosphorylated GRK2 showed a single site of phosphorylation, which was identified as serine 29 by HPLC-MS. A S29A mutant of GRK2 was not phosphorylated by PKC in vitro and showed no phorbol ester-stimulated phosphorylation when transfected into human embryonic kidney (HEK)293 cells." SIGNOR-249060 PRKCG protein P05129 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser464 LLKHVTQsSRKLIRA 9606 BTO:0000938 15381704 t "The effect has been demonstrated using P28329-3" gcesareni "We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation." SIGNOR-129316 PRKCG protein P05129 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser465 LKHVTQSsRKLIRAD 9606 BTO:0000938 15381704 t "The effect has been demonstrated using P28329-3" gcesareni "We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation." SIGNOR-129320 PRKCG protein P05129 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser558 VPTYESAsIRRFQEG 9606 BTO:0000938 15381704 t "The effect has been demonstrated using P28329-3" gcesareni "We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation." SIGNOR-129324 PRKCG protein P05129 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser594 HKAAVPAsEKLLLLK 9606 BTO:0000938 15381704 t "The effect has been demonstrated using P28329-3" gcesareni "We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation." SIGNOR-129328 PRKCG protein P05129 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Thr373 TVLVKDStNRDSLDM 9606 BTO:0000938 15381704 t "The effect has been demonstrated using P28329-3" gcesareni "We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation." SIGNOR-129332 PRKCG protein P05129 UNIPROT PEBP1 protein P30086 UNIPROT "up-regulates activity" phosphorylation Ser153 RGKFKVAsFRKKYEL 10116 BTO:0003036 12551925 t lperfetto "Here we report that one mechanism involves dissociation of Raf kinase inhibitory protein (RKIP) from Raf-1. Classic and atypical but not novel PKC isoforms phosphorylate RKIP at serine 153 (Ser-153). RKIP Ser-153 phosphorylation by PKC either in vitro or in response to 12-O-tetradecanoylphorbol-13-acetate or epidermal growth factor causes release of RKIP from Raf-1, whereas mutant RKIP (S153V or S153E) remains bound. I" SIGNOR-249190 PRKCG protein P05129 UNIPROT SDC2 protein P34741 UNIPROT unknown phosphorylation Ser187 DLGERKPsSAAYQKA -1 9244383 t lperfetto "We investigated phosphorylation of syndecan-2 cytoplasmic domain by PKC | Peptide mapping and substitution studies showed that both serines were phosphoacceptors, but each had slightly different affinity, with that of serine-197 being higher than serine-198." SIGNOR-248975 PRKCG protein P05129 UNIPROT SDC2 protein P34741 UNIPROT unknown phosphorylation Ser188 LGERKPSsAAYQKAP -1 9244383 t lperfetto "We investigated phosphorylation of syndecan-2 cytoplasmic domain by PKC | Peptide mapping and substitution studies showed that both serines were phosphoacceptors, but each had slightly different affinity, with that of serine-197 being higher than serine-198." SIGNOR-248978 PRKCG protein P05129 UNIPROT GRM5 protein P41594 UNIPROT "up-regulates activity" phosphorylation Ser840 VRSAFTTsTVVRMHV -1 15894802 t lperfetto "Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839." SIGNOR-249282 PRKCG protein P05129 UNIPROT KIR3DL1 protein P43629 UNIPROT down-regulates phosphorylation Ser415 QRKITRPsQRPKTPP 9606 17911614 t gcesareni "Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of ser(394) by protein kinase c slightly suppresses kir3dl1 inhibitory function, and reduces receptor internalization and turnover." SIGNOR-158133 PRKCG protein P05129 UNIPROT PSEN1 protein P49768 UNIPROT "up-regulates activity" phosphorylation Ser346 EWEAQRDsHLGPHRS 9606 BTO:0000007 14576165 t lperfetto "A phosphorylation site at serine residue 346 was identified that is selectively phosphorylated by PKC but not by PKA. This site is localized within a recognition motif for caspases, and phosphorylation strongly inhibits proteolytic processing of PS1 by caspase activity during apoptosis." SIGNOR-249238 PRKCG protein P05129 UNIPROT STXBP1 protein P61764 UNIPROT "down-regulates activity" phosphorylation Ser313 SLKDFSSsKRMNTGE 9913 BTO:0000259 12519779 t lperfetto "Munc18a is essential for neurotransmitter release by exocytosis and can be phosphorylated by PKC in vitro on Ser-306 and Ser-313. We demonstrate that it is phosphorylated on Ser-313 in response to phorbol ester treatment in adrenal chromaffin cells. Mutation of both phosphorylation sites to glutamate reduces its affinity for syntaxin and so acts as a phosphomimetic mutation." SIGNOR-249187 PRKCG protein P05129 UNIPROT STXBP1 protein P61764 UNIPROT unknown phosphorylation Ser306 VSQEVTRsLKDFSSS -1 12519779 t lperfetto "Munc18a is essential for neurotransmitter release by exocytosis and can be phosphorylated by PKC in vitro on Ser-306 and Ser-313. We demonstrate that it is phosphorylated on Ser-313 in response to phorbol ester treatment in adrenal chromaffin cells. Mutation of both phosphorylation sites to glutamate reduces its affinity for syntaxin and so acts as a phosphomimetic mutation." SIGNOR-249184 PRKCG protein P05129 UNIPROT DAB2 protein P98082 UNIPROT unknown phosphorylation Ser24 QAAPKAPsKKEKKKG 9534 BTO:0004055 10542228 t lperfetto "We have mapped the TPA-induced DOC-2/DAB2 protein phosphorylation site to Ser24, which appears to modulate the DOC-2/DAB2 inhibition of AP-1 transcription activity. Results indicate that phosphorylation of Ser24 is mediated by PKCbetaII, PKC_, and PKCdelta, but not CKII. This suggests that the PKC phosphorylation of Ser24 in DOC-2/DAB2 may be an underlying mechanisms for its tumor-suppressive function." SIGNOR-249027 PRKCG protein P05129 UNIPROT HABP4 protein Q5JVS0 UNIPROT "down-regulates activity" phosphorylation Thr354 RKPANDItSQLEINF 9606 BTO:0004974 14699138 t lperfetto "We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation" SIGNOR-249249 PRKCG protein P05129 UNIPROT HABP4 protein Q5JVS0 UNIPROT "down-regulates activity" phosphorylation Thr375 GRGARGGtRGGRGRI 9606 BTO:0004974 14699138 t lperfetto "We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation" SIGNOR-249255 PRKCG protein P05129 UNIPROT NRGN protein Q92686 UNIPROT "up-regulates activity" phosphorylation Ser36 AAAKIQAsFRGHMAR -1 8080473 t lperfetto "Phosphorylation of RC3 by PKC alpha, beta, or gamma was stimulated by Ca2+, phospholipid, and diacylglycerol. A single site, Ser36, which is adjacent to the predicted calmodulin (CaM)-binding domain, was phosphorylated by these enzymes. Phosphorylation of RC3 by PKC or PKM, a protease-degraded PKC, was inhibited by CaM. The effect of CaM apparently targets at RC3, as phosphorylation of protamine sulfate by PKM was not inhibited by CaM." SIGNOR-248915 PRKCG protein P05129 UNIPROT CYTH2 protein Q99418 UNIPROT "down-regulates activity" phosphorylation Ser392 AARKKRIsVKKKQEQ 9606 BTO:0000567 10531036 t lperfetto "ARNO is phosphorylated in vivo by PKC on a single serine residue, S392, located within the carboxy-terminal polybasic domain. Mutation of S392 to alanine does not prevent ARNO-mediated actin rearrangements, suggesting that phosphorylation does not lead to ARNO activation [6]. Here, we report that phosphorylation negatively regulates ARNO exchange activity through a 'PH domain electrostatic switch'." SIGNOR-249025 PRKCG protein P05129 UNIPROT PA2G4 protein Q9UQ80 UNIPROT unknown phosphorylation Thr366 QSSASRKtQKKKKKK 9606 BTO:0004737 11325528 t lperfetto "We found that Ebp1 was basally phosphorylated in AU565 breast cancer cells on serine/threonine residues and that this phosphorylation was enhanced by heregulin treatment. Both serine and threonine residues of a GST-Ebp1 fusion protein were phosphorylated by PKC in vitro. In vivo, we demonstrated that basal Ebp1 phosphorylation was dependent upon PKC." SIGNOR-249094 SERPINA5 protein P05154 UNIPROT FN1 protein P02751 UNIPROT "down-regulates activity" binding 9606 BTO:0000594 24388360 t miannu "SERPINA5 inhibits HCC cell migration by directly interacting with fibronectin. SERPINA5 disrupts the fibronectin–integrin β1 signaling pathway." SIGNOR-265881 SERPING1 protein P05155 UNIPROT F12 protein P00748 UNIPROT "down-regulates activity" binding 9606 BTO:0000131 26707513 t lperfetto "C1INH is a serine protease inhibitor (serpin) that acts on both the complement pathway and the contact system and is the main inhibitor of the contact system by targeting both FXIIa and PK 9. Additionally, FXIIa can be inhibited by α1‐antitrypsin and plasminogen activator inhibitor‐1 (PAI‐1)." SIGNOR-263517 MPO protein P05164 UNIPROT APOA1 protein P02647 UNIPROT "down-regulates activity" oxidation 9606 20043647 t miannu "When apolipoprotein A-I (apoA-I), the major HDL protein, was oxidized by MPO, its ability to promote cellular cholesterol efflux by ABCA1 was impaired. Moreover, oxidized apoA-I was unable to activate lecithin:cholesterol acyltransferase (LCAT), which rapidly converts free cholesterol to cholesteryl ester, a critical step in HDL maturation" SIGNOR-252102 EIF2S1 protein P05198 UNIPROT ATF4 protein P18848 UNIPROT "down-regulates quantity" "transcriptional regulation" 9606 27629041 t miannu "ER stress, viral infection, and other cellular stress signals activate PERK, PKR, HRI, and GCN2 kinases that converge on phosphorylation of eIF2alpha, the core of ISR. This leads to global attenuation of Cap dependent translation while concomitantly initiates the preferential translation of ISR specific mRNAs, such as ATF4. ATF4 is the main effector of the ISR. eIF2alpha phosphorylation causes a reduction in global protein synthesis while allowing the translation of selected genes including activating transcription factor 4 (ATF4), aiding cell survival and recovery" SIGNOR-260169 INSR protein P06213 UNIPROT GRB7 protein Q14451 UNIPROT up-regulates binding 9606 10803466 t gcesareni "Insulin induces the ir-grb7 interaction in cells expressing physiological levels of the proteins, suggesting that grb7 is implicated in insulin signaling." SIGNOR-77153 FGF1 protein P05230 UNIPROT FGFR1 protein P11362 UNIPROT "up-regulates activity" binding 9606 BTO:0001487 18940940 t fspada "Together these data highlight the unique nature of the role of FGF-1 during the earliest stages of adipogenesis and establish a role for FGFR1 in human adipogenesis, identifying FGFR1 as a potential therapeutic target to reduce obesity." SIGNOR-236936 FGF1 protein P05230 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates binding 9606 10618369 t lperfetto "We have crystallized a complex between human FGF1 and a two-domain extracellular fragment of human FGFR2." SIGNOR-73811 FGF1 protein P05230 UNIPROT FGFR4 protein P22455 UNIPROT up-regulates binding 9606 1385111 t gcesareni "Our results establish an fgf binding profile for fgfr-4 with afgf having the highest affinity, followed by k-fgf/hst-1 and bfgf. In addition, fgf-6 was found to bind to fgfr-4 in ligand competition experiments. Ligands binding to fgfr-4 induced receptor autophosphorylation and phosphorylation of a set of cellular polypeptides." SIGNOR-18454 FGF1 protein P05230 UNIPROT FGFR3 protein P22607 UNIPROT up-regulates binding 9606 22298955 t gcesareni "Reports also show that fgf/fgfr3 signals mediate some of the effects of tgf-beta on embryonic bone formation" SIGNOR-195585 IL6 protein P05231 UNIPROT IL6R protein P08887 UNIPROT up-regulates binding 9606 15895091 t 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 IL6 protein P05231 UNIPROT IL6R protein P08887 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103 23663276 t 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 IL6 protein P05231 UNIPROT IL6R protein P08887 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 8676083 t 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 IL6 protein P05231 UNIPROT IL6R protein P08887 UNIPROT "up-regulates activity" binding 9606 18923185 t 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 IL6 protein P05231 UNIPROT GCH1 protein P30793 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 12859689 f miannu "CT-1 exerted these effects by decreasing tyrosine hydroxylase, GTP cyclohydrolase (GCH) and NE transporter mRNAs, while IL-6 lowered only GCH mRNA." SIGNOR-252220 IL6 protein P05231 UNIPROT IL6ST protein P40189 UNIPROT "up-regulates activity" binding 9606 BTO:0001271 15895091 t 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 IL6 protein P05231 UNIPROT IL6ST protein P40189 UNIPROT "up-regulates activity" -1 8511589 f 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 IL6 protein P05231 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" 10116 BTO:0001103 23869758 f "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 EDN1 protein P05305 UNIPROT MYH7 protein P12883 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12847114 f "Regulation of expression" miannu "βMHC expression was markedly augmented by PE and ET, suggesting the transformation of myosin. endothelin-1 (ET)" SIGNOR-251955 JUN protein P05412 UNIPROT SERPINA3 protein P01011 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002600 11027208 f miannu "We characterize a molecular mechanism responsible for both IL-1 and TNF-induced expression of ACT gene in astrocytes. We identify the 5' distal IL-1/TNF-responsive enhancer of the ACT gene located 13 kb upstream of the transcription start site. This 413-bp-long enhancer contains three elements, two of which bind nuclear factor kB (NF-kB) and one that binds activating protein 1 (AP-1). All of these elements contribute to the full responsiveness of the ACT gene to both cytokines, as determined by deletion and mutational analysis. The 5' NF-kB high-affinity binding site and AP-1 element contribute most to the enhancement of gene transcription in response to TNF and IL-1." SIGNOR-254808 JUN protein P05412 UNIPROT ABCB1 protein P08183 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000093 10369069 f miannu "Co-transfection of WT cells with a c-jun expression vector and either of the AP-1 luciferase constructs demonstrated that c-jun could activate gene expression from both the consensus and the MDR1 AP-1 sites in a dose dependent manner." SIGNOR-254534 JUN protein P05412 UNIPROT KRT16 protein P08779 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000552 12954631 f miannu "these results suggest that Sp1 and AP1 sites in the essential promoter region are critical for EGF response, and Sp1 showed a functional cooperation with c-Jun and coactivators p300/CBP in driving the transcriptional regulation of EGF-induced keratin 16 gene expression. The coactivators p300/CBP could collaborate with Sp1 and c-Jun in the activation of keratin 16 promoter." SIGNOR-253905 JUN protein P05412 UNIPROT CYP19A1 protein P11511 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001555 19022561 f miannu "We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters." SIGNOR-254876 JUN protein P05412 UNIPROT FOSL1 protein P15407 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004603 13679379 t Luana "Members of the AP1 family distinctly regulated the fra-1 promoter. In particular, coexpression of c-Jun, Jun-D, and Fra-2 up-regulated fra-1 transcription. " SIGNOR-261604 INSR protein P06213 UNIPROT DOK4 protein Q8TEW6 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103;BTO:0000671 12730241 f gcesareni "Irs5/dok4 and irs6/dok5 represent two new signaling proteins with potential roles in insulin and igf-1 action." SIGNOR-101005 JUN protein P05412 UNIPROT GOT1 protein P17174 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 8454627 t "Tumor necrosis factor (TNF)-stimulated gene 6 (TSG-6) encodes a protein expressed during inflammation. We have previously shown that transcription factors of the NF-IL6 and AP-1 families cooperatively modulate activation of the TSG-6 gene by TNF or interleukin 1 (IL-1) through a promoter region that contains an NF-IL6 site (-106 to -114) and an AP-1 element" SIGNOR-254052 JUN protein P05412 UNIPROT SPI1 protein P17947 UNIPROT "up-regulates activity" binding 9606 BTO:0004136 12393465 t apalma "These results indicate that AML1-ETO competes c-Jun away from binding to the β3β4 domain of PU.1. Thus, the c-Jun coactivation function of PU.1 is down-regulated and this in turn down-regulates transcriptional activity of PU.1." SIGNOR-255660 JUN protein P05412 UNIPROT LORICRIN protein P23490 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000667 12200429 f miannu "Mutation and DNA-protein analyses show that Sp1, c-Jun, an unidentified regulator, and the co-activator p300/CREB-binding protein up-regulate whereas Sp3, CREB-1/CREMalpha/ATF-1, Jun B, and an AP2-like protein (termed the keratinocyte-specific repressor-1 (KSR-1)) suppress loricrin promoter activity." SIGNOR-254536 JUN protein P05412 UNIPROT HSD3B2 protein P26439 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001555 19022561 f miannu "We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters." SIGNOR-254874 JUN protein P05412 UNIPROT GCH1 protein P30793 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16149046 f miannu "Constitutively active mutants of activating transcription factor 2 (ATF2) and c-Jun additionally stimulated GTP cyclohydrolase I promoter activity, but to a lesser extent than the constitutively active CREB mutant. Enzymatic reactions that require tetrahydrobiopterin as cofactor are therefore indirectly controlled by signaling cascades involving the signal-responsive transcription factors CREB, c-Jun, and ATF2." SIGNOR-252225 JUN protein P05412 UNIPROT AP1 complex SIGNOR-C154 SIGNOR "form complex" binding -1 2467839 t irozzo "The protein products of the fos (Fos) and jun (Jun) proto-oncogenes have been shown to associate with a DNA element known as the transcription factor activator protein-1 (AP-1) binding site. Jun (previously known as the Fos-binding protein p39) and Fos form a protein complex in the nucleus. These data demonstrate a cooperative interaction between the protein products of two proto-oncogenes with a DNA element involved in transcriptional regulation." SIGNOR-256361 JUN protein P05412 UNIPROT AP1 complex SIGNOR-C154 SIGNOR "form complex" binding -1 3142692 t irozzo "The c-Jun and c-fos proto-oncogenes encode proteins that form a complex which regulates transcription from promoters containing AP-1 activation elements. c-Jun has specific DNA binding activity, while c-Fos has homology to the putative DNA binding domain of c-Jun." SIGNOR-256365 POLR3D protein P05423 UNIPROT "RNA Polymerase III" complex SIGNOR-C389 SIGNOR "form complex" binding 9606 BTO:0000567 12391170 t lperfetto "In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights." SIGNOR-266130 TFAP2A protein P05549 UNIPROT CRYAB protein P02511 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21556774 t miannu "Aberrant expression of CRYAB has been shown to be associated with several neurological diseases and malignant neoplasms. To identify transcriptional regulators of CRYAB expression, we examined its promoter for binding sites of transcription factors and identified four potential AP-2 binding sites in addition to a p53 binding site reported previously|Taken together, our results indicate that AP-2_ up-regulates the transcription of the CRYAB gene through stabilizing p53" SIGNOR-253636 TFAP2A protein P05549 UNIPROT CRABP2 protein P29373 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002828 17187826 f miannu "Comparative cDNA microarray hybridization identified a set of genes induced by overexpression of AP2alpha and AP2gamma in HMECs. The up-regulation of cellular retinoic acid-binding protein 2 (CRABPII), EST-1, and ECM1 was induced by overexpression of AP2alpha, AP2gamma, or a chimeric AP2 factor in which the activation domain of AP2alpha was replaced by the activation domain of herpesvirus VP16." SIGNOR-255400 TFAP2A protein P05549 UNIPROT ADM protein P35318 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9480831 t "These findings suggest that NF-IL6 and AP-2 sites in the promoter region are the functional elements in the transcriptional regulation of human AM gene in vascular endothelial cells." SIGNOR-254048 TFAP2A protein P05549 UNIPROT LNPEP protein Q9UIQ6 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003420 15894523 f miannu "Activator protein-2 (AP-2) and Ikaros transcription factors play significant roles in exerting high promoter activity of P-LAP/OTase in the trophoblastic cells. Moreover, P-LAP/OTase is transcriptionally regulated in a trophoblast-differentiation-dependent fashion via up-regulation of AP-2, putatively AP-2alpha." SIGNOR-255402 ITGB1 protein P05556 UNIPROT PTK2 protein Q05397 UNIPROT "up-regulates activity" 9606 15688067 f miannu "Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin." SIGNOR-257700 ITGB1 protein P05556 UNIPROT "a7/b1 integrin" complex SIGNOR-C126 SIGNOR "form complex" binding 9606 BTO:0000222;BTO:0002319 10199978 t lperfetto "The alpha7beta1 integrin is a laminin receptor on the surface of skeletal myoblasts and myofibers. Alternative forms of both the alpha7 and beta1 chains are expressed in a developmentally regulated fashion during myogenesis. These different alpha7beta1 isoforms localize at specific sites on myofibers and appear to have distinct functions in skeletal muscle." SIGNOR-241512 PRKCB protein P05771 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser619 SLPKINRsASEPSLH 9606 8288587 t gcesareni "Pkc can effectively phosphorylate raf-1, this is a direct effect of activated pkc and not the result of raf-1 autophosphorylation. the sites of pkc-mediated raf-1 phosphorylation are deduced to be ser497 and ser619." SIGNOR-37478 INSR protein P06213 UNIPROT PIK3R3 protein Q92569 UNIPROT unknown phosphorylation Tyr341 NEDADENyFINEEDE 9606 BTO:0000142;BTO:0000671 7542745 t llicata "This pattern of 32p-tyr release unambiguously identified tyr-341 in p55pik as a major in vitro phosphorylation site." SIGNOR-28791 ITGB1 protein P05556 UNIPROT "A1/b1 integrin" complex SIGNOR-C159 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253170 ITGB1 protein P05556 UNIPROT "A2/b1 integrin" complex SIGNOR-C160 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253172 ITGB1 protein P05556 UNIPROT "A3/b1 integrin" complex SIGNOR-C161 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253174 ITGB1 protein P05556 UNIPROT "A4/b1 integrin" complex SIGNOR-C162 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253176 ITGB1 protein P05556 UNIPROT "A6/b1 integrin" complex SIGNOR-C164 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253180 ITGB1 protein P05556 UNIPROT "A8/b1 integrin" complex SIGNOR-C165 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253182 ITGB1 protein P05556 UNIPROT "A9/b1 integrin" complex SIGNOR-C166 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253184 ITGB1 protein P05556 UNIPROT "A10/b1 integrin" complex SIGNOR-C167 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253186 ITGB1 protein P05556 UNIPROT "A11/b1 integrin" complex SIGNOR-C168 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253188 ITGB1 protein P05556 UNIPROT "Av/b1 integrin" complex SIGNOR-C175 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253202 PRKCB protein P05771 UNIPROT PRKCB protein P05771 UNIPROT unknown phosphorylation Ser16 PPSEGEEsTVRFARK -1 2377895 t lperfetto "Thus four peptides containing six major sites of intrapeptide autophosphorylation of protein kinase C have been identified. | Phosphoamino acid analyses indicated that only the NH2-terminal peptide contained phosphoserine. The modified residue was determined to be Ser16" SIGNOR-248863 PRKCB protein P05771 UNIPROT PRKCB protein P05771 UNIPROT unknown phosphorylation Thr17 PSEGEEStVRFARKG -1 2377895 t lperfetto "Thus four peptides containing six major sites of intrapeptide autophosphorylation of protein kinase C have been identified. | Phosphoamino acid analyses indicated that only the NH2-terminal peptide contained phosphoserine. The modified residue was determined to be Ser16" SIGNOR-248868 PRKCB protein P05771 UNIPROT PRKCB protein P05771 UNIPROT up-regulates phosphorylation Thr642 TRQPVELtPTDKLFI 9606 17115692 t lperfetto "The catalytic or kinase domain requires phosphorylation at three sites for full activation (24, 25): ? Phosphorylation of threonine 500 (thr-500) in the activation loop by the upstream kinase pdk-1 is a prerequisite for the maturation of the enzyme (26), which subsequently leads to autophosphorylation at threonine 641 (thr-641) in the turn motif and serine 660 (ser-660) in the hydrophobic motif" SIGNOR-150865 PRKCB protein P05771 UNIPROT CD5 protein P06127 UNIPROT unknown phosphorylation Thr436 FHRNHTAtVRSHAEN 9606 BTO:0000661 11123317 t lperfetto "Here, we present a selective mutagenesis analysis of two conserved threonine residues (T410 and T412) located at the membrane-proximal cytoplasmic region of CD5. These residues are contained within consensus phosphorylation motifs for protein kinase C and are shown here to be critical for in vivo protein kinase C-mediated phosphorylation of CD5. " SIGNOR-249075 PRKCB protein P05771 UNIPROT EIF4E protein P06730 UNIPROT unknown phosphorylation Ser209 DTATKSGsTTKNRFV 10090 BTO:0000944 8662663 t lperfetto "Phosphorylation of eIF-4E on serine 209 by protein kinase C is inhibited by the translational repressors, 4E-binding proteins." SIGNOR-248946 PRKCB protein P05771 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser303 RGAPPRRsSIRNAHS 9606 BTO:0000130 12056906 t lperfetto "Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation." SIGNOR-89182 PRKCB protein P05771 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser304 GAPPRRSsIRNAHSI 9606 BTO:0000130 12056906 t lperfetto "Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation." SIGNOR-89186 PRKCB protein P05771 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser315 AHSIHQRsRKRLSQD 9606 BTO:0000130 12056906 t lperfetto "Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation." SIGNOR-89193 PRKCB protein P05771 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser320 QRSRKRLsQDAYRRN 9606 BTO:0000130 12056906 t lperfetto "Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation." SIGNOR-89197 PRKCB protein P05771 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser328 QDAYRRNsVRFLQQR 9606 BTO:0000130 12056906 t lperfetto "Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation." SIGNOR-89201 PRKCB protein P05771 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser379 DLILNRCsESTKRKL 9606 BTO:0000130 12056906 t lperfetto "Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation." SIGNOR-89213 PRKCB protein P05771 UNIPROT TYR protein P14679 UNIPROT up-regulates phosphorylation Ser527 DYHSLYQsHL 9606 BTO:0000848 10347209 t llicata "We conclude that pkc-beta activates tyrosinase directly by phosphorylating serine residues at positions 505 and 509 in the cytoplasmic domain of this melanosome-associated protein. our results strongly suggest that direct phosphorylation of tyrosinase by pkc-_ leads to its activation." SIGNOR-67870 PRKCB protein P05771 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser25 QAFELILsPRSKESV 9606 BTO:0001271 7637391 t gcesareni "Op18 is multisite phosphorylated on four ser residues during mitosis;two of these ser residues, ser-25 and ser-38, are targets for cyclin-dependent protein kinases. our findings suggest that stathmin phosphorylation in reh6 cells could be in part mediated by pkc activation." SIGNOR-30353 PRKCB protein P05771 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 BTO:0001271 7637391 t gcesareni "Op18 is multisite phosphorylated on four ser residues during mitosis;two of these ser residues, ser-25 and ser-38, are targets for cyclin-dependent protein kinases. our findings suggest that stathmin phosphorylation in reh6 cells could be in part mediated by pkc activation." SIGNOR-30357 PRKCB protein P05771 UNIPROT GRIN2B protein Q13224 UNIPROT "up-regulates activity" phosphorylation Ser1323 ALAPRSVsLKDKGRF -1 11306676 t lperfetto "These results indicate that PKC can directly phosphorylate S1303 and S1323 in the NR2B C terminus, leading to enhanced currents through NMDA receptor channels." SIGNOR-249087 PRKCB protein P05771 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser25 QAFELILsPRSKESV 9606 9271428 t gcesareni "Op18 is multisite phosphorylated on four ser residues during mitosis;two of these ser residues, ser-25 and ser-38, are targets for cyclin-dependent protein kinases. our findings suggest that stathmin phosphorylation in reh6 cells could be in part mediated by pkc activation." SIGNOR-50594 PRKCB protein P05771 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 9271428 t gcesareni "Op18 is multisite phosphorylated on four ser residues during mitosis;two of these ser residues, ser-25 and ser-38, are targets for cyclin-dependent protein kinases. our findings suggest that stathmin phosphorylation in reh6 cells could be in part mediated by pkc activation." SIGNOR-50598 PRKCB protein P05771 UNIPROT GJA1 protein P17302 UNIPROT "down-regulates activity" phosphorylation Ser368 QRPSSRAsSRASSRP 10116 10871288 t lperfetto "Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication.|These data strongly suggest that PKC directly phosphorylates Cx43 on S368 in vivo, which results in a change in single channel behavior that contributes to a decrease in intercellular communication." SIGNOR-249049 PRKCB protein P05771 UNIPROT GAP43 protein P17677 UNIPROT unknown phosphorylation Ser41 AATKIQAsFRGHITR -1 2140056 t lperfetto "We conclude that serine-41 is the protein kinase C phosphorylation site of neuromodulin and that phosphorylation of this amino acid residue blocks binding of calmodulin to neuromodulin." SIGNOR-248859 PRKCB protein P05771 UNIPROT TFEB protein P19484 UNIPROT "up-regulates activity" phosphorylation Ser467 KASSRRSsFSMEEGD 10090 BTO:0000968 23599343 t "This occurs following PKCβ phosphorylation of TFEB on three serine residues located in its last 15 amino acids. This post-translational modification stabilizes and increases the activity of this transcription factor." SIGNOR-255316 PRKCB protein P05771 UNIPROT LMNB1 protein P20700 UNIPROT unknown phosphorylation Ser395 LKLSPSPsSRVTVSR -1 8034666 t lperfetto "Beta II PKC-mediated phosphorylation of lamin B is confined to two sites, Ser395 and Ser405 | Comparative tryptic phosphopeptide mapping demonstrates that the beta II PKC site, Ser405, is a prominent target of mitotic lamin B phosphorylation in vivo. beta II PKC translocates to the nucleus during the G2/M phase of cell cycle concomitant with phosphorylation of Ser405, indicating a physiologic role for nuclear beta II PKC activation in mitotic lamin B phosphorylation in vivo." SIGNOR-248911 PRKCB protein P05771 UNIPROT LMNB1 protein P20700 UNIPROT unknown phosphorylation Ser405 VTVSRASsSRSVRTT 9606 BTO:0001271 8034666 t lperfetto "Beta II PKC-mediated phosphorylation of lamin B is confined to two sites, Ser395 and Ser405 | Comparative tryptic phosphopeptide mapping demonstrates that the beta II PKC site, Ser405, is a prominent target of mitotic lamin B phosphorylation in vivo. beta II PKC translocates to the nucleus during the G2/M phase of cell cycle concomitant with phosphorylation of Ser405, indicating a physiologic role for nuclear beta II PKC activation in mitotic lamin B phosphorylation in vivo." SIGNOR-248912 PRKCB protein P05771 UNIPROT C5AR1 protein P21730 UNIPROT down-regulates phosphorylation Ser334 SVVRESKsFTRSTVD 9606 17145764 t lperfetto "Dynamics of protein kinase c-mediated phosphorylation of the complement c5a receptor on serine 334. Analysis of c5ar ser/ala mutants that possess a single intact serine residue either at position 334 or at neighboring positions 327, 332, or 338 revealed functional redundancy of c-terminal phosphorylation sites since all 4 serine residues could individually support c5ar internalization and desensitization" SIGNOR-151011 PRKCB protein P05771 UNIPROT ITGB7 protein P26010 UNIPROT unknown phosphorylation Thr783 PLYKSAItTTINPRF 10090 BTO:0001825 12682249 t lperfetto "Beta7 subunit is phosphorylated even in unstimulated TK-1 cells. Activation of TK-1 cells with anti-CD3 (Fig. 5_A) and PDBu (Fig. 5_B) increased the phosphorylation 15€“20%. | The result shows that the fourth amino acid of the tryptic peptide was phosphorylated. This phosphorylated threonine residue is most likely the first threonine (Thr782) of threonine triplet (Thr782€“784)." SIGNOR-249200 PRKCB protein P05771 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Thr373 TVLVKDStNRDSLDM 9606 BTO:0000938 BTO:0000142 12486117 t "The effect has been demonstrated using P28329-3" gcesareni "We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation." SIGNOR-96632 PRKCB protein P05771 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser464 LLKHVTQsSRKLIRA 9606 BTO:0000938 15381704 t "The effect has been demonstrated using P28329-3" gcesareni "Protein kinase c isoforms differentially phosphorylate human choline acetyltransferase regulating its catalytic activity." SIGNOR-129280 PRKCB protein P05771 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Thr373 TVLVKDStNRDSLDM 9606 BTO:0000938 15381704 t "The effect has been demonstrated using P28329-3" gcesareni "We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation." SIGNOR-129296 PRKCB protein P05771 UNIPROT NOS3 protein P29474 UNIPROT "down-regulates activity" phosphorylation Thr495 TGITRKKtFKEVANA 9606 BTO:0001853 24379783 t lperfetto "The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites" SIGNOR-251630 PRKCB protein P05771 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser163 KRFSFKKsFKLSGFS -1 8422248 t lperfetto "These results indicate that in vitro, PKC phosphorylates MARCKS only at three sites, but not at Ser160 as that reported previously, and there was no preferential phosphorylation of MARCKS by either PKC isozyme I, II or III" SIGNOR-248926 PRKCB protein P05771 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser170 SFKLSGFsFKKNKKE -1 8422248 t lperfetto "These results indicate that in vitro, PKC phosphorylates MARCKS only at three sites, but not at Ser160 as that reported previously, and there was no preferential phosphorylation of MARCKS by either PKC isozyme I, II or III." SIGNOR-248929 PRKCB protein P05771 UNIPROT SDC2 protein P34741 UNIPROT unknown phosphorylation Ser187 DLGERKPsSAAYQKA -1 9244383 t lperfetto "We investigated phosphorylation of syndecan-2 cytoplasmic domain by PKC | Peptide mapping and substitution studies showed that both serines were phosphoacceptors, but each had slightly different affinity, with that of serine-197 being higher than serine-198." SIGNOR-248974 PRKCB protein P05771 UNIPROT SDC2 protein P34741 UNIPROT unknown phosphorylation Ser188 LGERKPSsAAYQKAP -1 9244383 t lperfetto "We investigated phosphorylation of syndecan-2 cytoplasmic domain by PKC | Peptide mapping and substitution studies showed that both serines were phosphoacceptors, but each had slightly different affinity, with that of serine-197 being higher than serine-198." SIGNOR-248977 PRKCB protein P05771 UNIPROT CASR protein P41180 UNIPROT "down-regulates activity" phosphorylation Thr888 FKVAARAtLRRSNVS 9606 BTO:0000007 12356761 t lperfetto "Expression of a mutant CaR in which the major PKC phosphorylation site is altered by substitution of alanine for threonine (T888A) eliminated oscillatory behavior, producing [Ca(2+)](i) responses almost identical to those produced by the wild type CaR exposed to PKC inhibitors. These results support a model in which phosphorylation of the CaR at the inhibitory threonine 888 by PKC provides the negative feedback needed to cause [Ca(2+)](i) oscillations mediated by this receptor." SIGNOR-249176 PRKCB protein P05771 UNIPROT GRM5 protein P41594 UNIPROT "up-regulates activity" phosphorylation Ser840 VRSAFTTsTVVRMHV -1 15894802 t lperfetto "Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839." SIGNOR-249279 PRKCB protein P05771 UNIPROT GRM5 protein P41594 UNIPROT "up-regulates activity" phosphorylation Thr841 RSAFTTStVVRMHVG -1 15894802 t lperfetto "Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839." SIGNOR-249286 PRKCB protein P05771 UNIPROT SLC6A9 protein P48067-2 UNIPROT "down-regulates activity" phosphorylation Thr19 GAVPSEAtKRDQNLK 9823 21864610 t miannu "We demonstrated that the isoforms GlyT1a, GlyT1b, and GlyT1c were constitutively phosphorylated, and that phosphorylation was dramatically enhanced, in a time dependent fashion, after PKC activation by phorbol ester. The phosphorylation was PKC-dependent, since pre-incubation of the cells with bisindolylmaleimide I, a selective PKC inhibitor, abolished the phorbol ester-induced phosphorylation. Blotting with specific anti-phospho-tyrosine antibodies did not yield any signal that could correspond to GlyT1 tyrosine phosphorylation, suggesting that the phosphorylation occurs at serine and/or threonine residues. These results together suggest that conventional PKCα and/or β are responsible for the downregulation of glycine transport. We further analyzed the effect of more specific inhibitors to PKCα and PKCβ on the GlyT1 activity. As shown in Fig. 4, panels C-F, incubation of the cells with varying concentrations of the PKCβ inhibitors (referred as PKCβ inhibitor and LY333531) or the PKCα/γ (HDBBE) inhibitors did not prevent the reduction of glycine uptake triggered by PMA, suggesting that PKCα and PKCβ together regulate GlyT1 activity." SIGNOR-262925 PRKCB protein P05771 UNIPROT SLC6A9 protein P48067-2 UNIPROT "down-regulates activity" phosphorylation Thr276 DGIMYYLtPQWDKIL 9823 21864610 t miannu "We demonstrated that the isoforms GlyT1a, GlyT1b, and GlyT1c were constitutively phosphorylated, and that phosphorylation was dramatically enhanced, in a time dependent fashion, after PKC activation by phorbol ester. The phosphorylation was PKC-dependent, since pre-incubation of the cells with bisindolylmaleimide I, a selective PKC inhibitor, abolished the phorbol ester-induced phosphorylation. Blotting with specific anti-phospho-tyrosine antibodies did not yield any signal that could correspond to GlyT1 tyrosine phosphorylation, suggesting that the phosphorylation occurs at serine and/or threonine residues. These results together suggest that conventional PKCα and/or β are responsible for the downregulation of glycine transport. We further analyzed the effect of more specific inhibitors to PKCα and PKCβ on the GlyT1 activity. As shown in Fig. 4, panels C-F, incubation of the cells with varying concentrations of the PKCβ inhibitors (referred as PKCβ inhibitor and LY333531) or the PKCα/γ (HDBBE) inhibitors did not prevent the reduction of glycine uptake triggered by PMA, suggesting that PKCα and PKCβ together regulate GlyT1 activity." SIGNOR-262926 PRKCB protein P05771 UNIPROT SLC6A9 protein P48067-2 UNIPROT "down-regulates activity" phosphorylation Thr590 PALLEHRtGRYAPTI 9823 21864610 t miannu "We demonstrated that the isoforms GlyT1a, GlyT1b, and GlyT1c were constitutively phosphorylated, and that phosphorylation was dramatically enhanced, in a time dependent fashion, after PKC activation by phorbol ester. The phosphorylation was PKC-dependent, since pre-incubation of the cells with bisindolylmaleimide I, a selective PKC inhibitor, abolished the phorbol ester-induced phosphorylation. Blotting with specific anti-phospho-tyrosine antibodies did not yield any signal that could correspond to GlyT1 tyrosine phosphorylation, suggesting that the phosphorylation occurs at serine and/or threonine residues. These results together suggest that conventional PKCα and/or β are responsible for the downregulation of glycine transport. We further analyzed the effect of more specific inhibitors to PKCα and PKCβ on the GlyT1 activity. As shown in Fig. 4, panels C-F, incubation of the cells with varying concentrations of the PKCβ inhibitors (referred as PKCβ inhibitor and LY333531) or the PKCα/γ (HDBBE) inhibitors did not prevent the reduction of glycine uptake triggered by PMA, suggesting that PKCα and PKCβ together regulate GlyT1 activity." SIGNOR-262927 PRKCB protein P05771 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser214 LVRSREVsVDEGRAC -1 9677319 t lperfetto "Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases." SIGNOR-249001 PRKCB protein P05771 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser273 AGTRRREsLGKKAKR -1 9677319 t lperfetto "Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases." SIGNOR-249005 PRKCB protein P05771 UNIPROT LASP1 protein Q14847 UNIPROT "down-regulates activity" phosphorylation Ser146 MEPERRDsQDGSSYR 9606 12571245 t lperfetto "Actin binding of human lim and sh3 protein is regulated by cgmp- and camp-dependent protein kinase phosphorylation on serine 146. Phosphorylation of lasp at ser-146 leads to a redistribution of the actin-bound protein from the tips of the cell membrane to the cytosol, accompanied with a reduced cell migration" SIGNOR-97942 PRKCB protein P05771 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser290 GRIVARNsRKMAFRA -1 9677319 t lperfetto "Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases." SIGNOR-249007 PRKCB protein P05771 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser299 KMAFRAKsKSCHDLS -1 9677319 t lperfetto "Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases." SIGNOR-249009 PRKCB protein P05771 UNIPROT EIF6 protein P56537 UNIPROT "up-regulates activity" phosphorylation Thr234 AQPSTIAtSMRDSLI 9534 BTO:0000298 14654845 t lperfetto "PKC stimulation led to eIF6 phosphorylation, and mutation of a serine residue in the carboxy terminus of eIF6 impaired RACK1/PKC-mediated translational rescue. | Data showed that the S235A mutant repressed translation and could not fully rescue it upon PKC stimulation" SIGNOR-249245 PRKCB protein P05771 UNIPROT STXBP1 protein P61764 UNIPROT "down-regulates activity" phosphorylation Ser313 SLKDFSSsKRMNTGE 9913 BTO:0000259 12519779 t lperfetto "Munc18a is essential for neurotransmitter release by exocytosis and can be phosphorylated by PKC in vitro on Ser-306 and Ser-313. We demonstrate that it is phosphorylated on Ser-313 in response to phorbol ester treatment in adrenal chromaffin cells. Mutation of both phosphorylation sites to glutamate reduces its affinity for syntaxin and so acts as a phosphomimetic mutation." SIGNOR-249186 PRKCB protein P05771 UNIPROT STXBP1 protein P61764 UNIPROT unknown phosphorylation Ser306 VSQEVTRsLKDFSSS -1 12519779 t lperfetto "Munc18a is essential for neurotransmitter release by exocytosis and can be phosphorylated by PKC in vitro on Ser-306 and Ser-313. We demonstrate that it is phosphorylated on Ser-313 in response to phorbol ester treatment in adrenal chromaffin cells. Mutation of both phosphorylation sites to glutamate reduces its affinity for syntaxin and so acts as a phosphomimetic mutation." SIGNOR-249183 PRKCB protein P05771 UNIPROT DAB2 protein P98082 UNIPROT unknown phosphorylation Ser24 QAAPKAPsKKEKKKG 9534 BTO:0004055 10542228 t lperfetto "We have mapped the TPA-induced DOC-2/DAB2 protein phosphorylation site to Ser24, which appears to modulate the DOC-2/DAB2 inhibition of AP-1 transcription activity. Results indicate that phosphorylation of Ser24 is mediated by PKCbetaII, PKC_, and PKCdelta, but not CKII. This suggests that the PKC phosphorylation of Ser24 in DOC-2/DAB2 may be an underlying mechanisms for its tumor-suppressive function." SIGNOR-249026 PRKCB protein P05771 UNIPROT EWSR1 protein Q01844 UNIPROT "down-regulates activity" phosphorylation Ser266 SSYGQQSsFRQDHPS 9606 9341188 t miannu "Here we report thatews, a nuclearrna-bindingprooncoprotein, contains an iq domain, is phosphorylated byproteinkinase c, and interacts with calmodulin. Interestingly, pkc phosphorylation of ews inhibits its binding to rna homopolymers, and conversely,rna binding to ews interferes with pkc phosphorylation./ these data indicate that ews contains an iq domain with ser266 acting as the primary site for pkc phosphorylation." SIGNOR-52854 PRKCB protein P05771 UNIPROT KCNC4 protein Q03721 UNIPROT down-regulates phosphorylation Ser15 SSYRGRKsGNKPPSK 9606 7993631 t gcesareni "We found that pkc specifically eliminates rapid inactivation of a cloned human a-type k+ channel (hkv3.4), converting this channel from a rapidly inactivating a type to a noninactivating delayed rectifier type." SIGNOR-35622 PRKCB protein P05771 UNIPROT KCNC4 protein Q03721 UNIPROT down-regulates phosphorylation Ser21 KSGNKPPsKTCLKEE 9606 7993631 t gcesareni "We found that pkc specifically eliminates rapid inactivation of a cloned human a-type k+ channel (hkv3.4), converting this channel from a rapidly inactivating a type to a noninactivating delayed rectifier type." SIGNOR-35626 PRKCB protein P05771 UNIPROT KCNC4 protein Q03721 UNIPROT down-regulates phosphorylation Ser15 SSYRGRKsGNKPPSK 9606 9649584 t gcesareni "This study investigated the molecular physiology of the nh2-terminal phosphorylation sites that regulate inactivation gating of an a-type k+ channel. The main results show that: (a) pkc acts on four phosphate acceptors (s8, s9, s15, and s21) within the inactivation domain because mutation of these residues to alanine is necessary and sufficient to remove the action of pkc on channel inactivation." SIGNOR-58498 PRKCB protein P05771 UNIPROT KCNC4 protein Q03721 UNIPROT down-regulates phosphorylation Ser21 KSGNKPPsKTCLKEE 9606 9649584 t gcesareni "This study investigated the molecular physiology of the nh2-terminal phosphorylation sites that regulate inactivation gating of an a-type k+ channel. The main results show that: (a) pkc acts on four phosphate acceptors (s8, s9, s15, and s21) within the inactivation domain because mutation of these residues to alanine is necessary and sufficient to remove the action of pkc on channel inactivation." SIGNOR-58502 PRKCB protein P05771 UNIPROT BTK protein Q06187 UNIPROT "down-regulates activity" phosphorylation Ser180 GSLKPGSsHRKTKKP 9606 BTO:0003076 11598012 t lperfetto "We provide direct evidence that PKCbeta acts as a feedback loop inhibitor of Btk activation. Inhibition of PKCbeta results in a dramatic increase in B-cell receptor (BCR)-mediated Ca2+ signaling. We identified a highly conserved PKCbeta serine phosphorylation site in a short linker within the Tec homology domain of Btk. Mutation of this phosphorylation site led to enhanced tyrosine phosphorylation and membrane association of Btk, and augmented BCR and FcepsilonRI-mediated signaling in B and mast cells, respectively. | This deductive analysis indicated that PKCbeta phosphorylates S180 in the region bisecting the Btk motif (BM) and the PRR of the TH domain." SIGNOR-249110 PRKCB protein P05771 UNIPROT ILF3 protein Q12906 UNIPROT "up-regulates activity" phosphorylation Ser647 RGRGRGGsIRGRGRG 9606 20870937 t llicata "Upon T cell activation, NF90 translocates from the nucleus into the cytoplasm, where it binds to the AU-rich element-containing 3' untranslated regions of IL-2 mRNA and stabilizes it.|Our results support a model in which PMA stimulation activates PKCβI to phosphorylate NF90-Ser647, and this phosphorylation triggers NF90 relocation to the cytoplasm and stabilize IL-2 mRNA." SIGNOR-168173 PRKCB protein P05771 UNIPROT GRIN2B protein Q13224 UNIPROT "up-regulates activity" phosphorylation Ser1303 NKLRRQHsYDTFVDL -1 11306676 t lperfetto "These results indicate that PKC can directly phosphorylate S1303 and S1323 in the NR2B C terminus, leading to enhanced currents through NMDA receptor channels." SIGNOR-249084 PRKCB protein P05771 UNIPROT NFE2L2 protein Q16236 UNIPROT up-regulates phosphorylation Ser40 SREVFDFsQRRKEYE 9606 12198130 t miannu "Phosphorylation of nrf2 at ser-40 by protein kinase c regulates antioxidant response element-mediated transcription / recently we reported evidence for the involvement of protein kinase c (pkc) in phosphorylating nrf2 and triggering its nuclear translocation in response to oxidative stress" SIGNOR-91830 PRKCB protein P05771 UNIPROT OCLN protein Q16625 UNIPROT "up-regulates activity" phosphorylation Ser340 DKRFYPEsSYKSTPV 9615 BTO:0000837 11502742 t lperfetto "Protein kinase C regulates the phosphorylation and cellular localization of occludin. Ser(338) of occludin was identified as an in vitro protein kinase C phosphorylation site using peptide mass fingerprint analysis and electrospray ionization tandem mass spectroscopy. Both the phosphorylation of occludin and its incorporation into tight junctions induced by calcium switch were markedly inhibited by the PKC inhibitor GF-109203X." SIGNOR-249106 PRKCB protein P05771 UNIPROT HABP4 protein Q5JVS0 UNIPROT "down-regulates activity" phosphorylation Thr354 RKPANDItSQLEINF 9606 BTO:0004974 14699138 t lperfetto "We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation" SIGNOR-249247 PRKCB protein P05771 UNIPROT HABP4 protein Q5JVS0 UNIPROT "down-regulates activity" phosphorylation Thr375 GRGARGGtRGGRGRI 9606 BTO:0004974 14699138 t lperfetto "We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation" SIGNOR-249253 PRKCB protein P05771 UNIPROT NRGN protein Q92686 UNIPROT "up-regulates activity" phosphorylation Ser36 AAAKIQAsFRGHMAR -1 8080473 t lperfetto "Phosphorylation of RC3 by PKC alpha, beta, or gamma was stimulated by Ca2+, phospholipid, and diacylglycerol. A single site, Ser36, which is adjacent to the predicted calmodulin (CaM)-binding domain, was phosphorylated by these enzymes. Phosphorylation of RC3 by PKC or PKM, a protease-degraded PKC, was inhibited by CaM. The effect of CaM apparently targets at RC3, as phosphorylation of protamine sulfate by PKM was not inhibited by CaM." SIGNOR-248914 PRKCB protein P05771 UNIPROT CYTH2 protein Q99418 UNIPROT "down-regulates activity" phosphorylation Ser392 AARKKRIsVKKKQEQ 9606 BTO:0000567 10531036 t lperfetto "ARNO is phosphorylated in vivo by PKC on a single serine residue, S392, located within the carboxy-terminal polybasic domain. Mutation of S392 to alanine does not prevent ARNO-mediated actin rearrangements, suggesting that phosphorylation does not lead to ARNO activation [6]. Here, we report that phosphorylation negatively regulates ARNO exchange activity through a 'PH domain electrostatic switch'." SIGNOR-249024 PRKCB protein P05771 UNIPROT IBTK protein Q9P2D0 UNIPROT down-regulates phosphorylation Ser1200 ASSLHSVsSKSFRDF 9606 BTO:0000776 21482705 t llicata "We found that ibtk_ is phosphorylated at serines 87 and 90 by pkc on bcr engagement;this phosphorylation causes the dissociation of the btk:ibtk_ complex and allows btk to translocate to the plasma membrane." SIGNOR-173383 PRKCB protein P05771 UNIPROT IBTK protein Q9P2D0 UNIPROT down-regulates phosphorylation Ser1203 LHSVSSKsFRDFLLE 9606 BTO:0000776 21482705 t llicata "We found that ibtk_ is phosphorylated at serines 87 and 90 by pkc on bcr engagement;this phosphorylation causes the dissociation of the btk:ibtk_ complex and allows btk to translocate to the plasma membrane." SIGNOR-173387 PRKCB protein P05771 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT unknown phosphorylation Ser473 PPSGTKKsKRGRGRP 9606 12529391 t llicata "Pkc-mediated phosphorylation at s486 does not affect s6k activity but eliminates the function of its nuclear localization signal and causes retention of an activated form of the kinase in the cytoplasm." SIGNOR-97283 PRKCB protein P05771 UNIPROT PA2G4 protein Q9UQ80 UNIPROT unknown phosphorylation Ser363 ALLQSSAsRKTQKKK 9606 BTO:0004737 11325528 t lperfetto "We found that Ebp1 was basally phosphorylated in AU565 breast cancer cells on serine/threonine residues and that this phosphorylation was enhanced by heregulin treatment. Both serine and threonine residues of a GST-Ebp1 fusion protein were phosphorylated by PKC in vitro. In vivo, we demonstrated that basal Ebp1 phosphorylation was dependent upon PKC." SIGNOR-249090 GYPB protein P06028 UNIPROT "Ankyrin complex" complex SIGNOR-C383 SIGNOR "form complex" binding 9606 BTO:0000424 22465511 t lperfetto "The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB)) " SIGNOR-266021 INSR protein P06213 UNIPROT IRS4 protein O14654 UNIPROT "up-regulates activity" phosphorylation 10090 25905389 t lperfetto "The binding of insulin to the subunit of IR not only concentrates insulin at its site of action, but also induces conformational changes in the receptor, which in turn stimulates the tyrosine kinase activity intrinsic to the _ subunit of the IR and triggers the signaling cascades (Fig. 3). Insulin receptors trans phosphorylate several immediate substrates (on Tyr residues) including IRS1-4, Shc, and Gab 1, Cbl, APS, and P60dok." SIGNOR-217897 INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT "up-regulates activity" phosphorylation Tyr1185 FGMTRDIyETDYYRK -1 2449432 t 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 INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT "up-regulates activity" phosphorylation Tyr1189 RDIYETDyYRKGGKG -1 2449432 t 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 INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT "up-regulates activity" phosphorylation Tyr1011 DVFPCSVyVPDEWEV -1 3166375 t 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 INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT "up-regulates activity" phosphorylation Tyr1355 SLGFKRSyEEHIPYT -1 3166375 t 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 INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT "up-regulates activity" phosphorylation Tyr1361 SYEEHIPyTHMNGGK -1 3166375 t 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 INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT "up-regulates activity" phosphorylation Tyr992 DGPLGPLyASSNPEY -1 3166375 t 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 INSR protein P06213 UNIPROT ADRB2 protein P07550 UNIPROT "down-regulates activity" phosphorylation Tyr132 CVIAVDRyFAITSPF 10029 BTO:0000246 8557631 t "Insulin (10 nM)-stimulated rIR-catalyzed phosphorylation of β2-adrenergic receptor peptides was found prominently in peptides L339 (Tyr350 and Tyr354), T362 (Tyr364), and to a lesser extent peptides Y132 (Tyr132 and Tyr141), and I135 (Tyr141). G-protein-linked receptors and intrinsic tyrosine-kinase growth receptors represent two prominent modalities in cell signaling. Cross-regulation among members of both receptor superfamilies has been reported, including the counter-regulatory effects of insulin on β-adrenergic catecholamine action. Cells stimulated by insulin show loss of function and increased phosphotyrosine content of β2-adrenergic receptors." SIGNOR-251299 INSR protein P06213 UNIPROT ADRB2 protein P07550 UNIPROT "down-regulates activity" phosphorylation Tyr141 AITSPFKyQSLLTKN 10029 BTO:0000246 8557631 t "Insulin (10 nM)-stimulated rIR-catalyzed phosphorylation of β2-adrenergic receptor peptides was found prominently in peptides L339 (Tyr350 and Tyr354), T362 (Tyr364), and to a lesser extent peptides Y132 (Tyr132 and Tyr141), and I135 (Tyr141). G-protein-linked receptors and intrinsic tyrosine-kinase growth receptors represent two prominent modalities in cell signaling. Cross-regulation among members of both receptor superfamilies has been reported, including the counter-regulatory effects of insulin on β-adrenergic catecholamine action. Cells stimulated by insulin show loss of function and increased phosphotyrosine content of β2-adrenergic receptors." SIGNOR-251300 INSR protein P06213 UNIPROT ADRB2 protein P07550 UNIPROT "down-regulates activity" phosphorylation Tyr350 RRSSLKAyGNGYSSN 10029 BTO:0000246 8557631 t "Insulin (10 nM)-stimulated rIR-catalyzed phosphorylation of β2-adrenergic receptor peptides was found prominently in peptides L339 (Tyr350 and Tyr354), T362 (Tyr364), and to a lesser extent peptides Y132 (Tyr132 and Tyr141), and I135 (Tyr141). G-protein-linked receptors and intrinsic tyrosine-kinase growth receptors represent two prominent modalities in cell signaling. Cross-regulation among members of both receptor superfamilies has been reported, including the counter-regulatory effects of insulin on β-adrenergic catecholamine action. Cells stimulated by insulin show loss of function and increased phosphotyrosine content of β2-adrenergic receptors." SIGNOR-251301 INSR protein P06213 UNIPROT ADRB2 protein P07550 UNIPROT "down-regulates activity" phosphorylation Tyr354 LKAYGNGySSNGNTG 10029 BTO:0000246 8557631 t "Insulin (10 nM)-stimulated rIR-catalyzed phosphorylation of β2-adrenergic receptor peptides was found prominently in peptides L339 (Tyr350 and Tyr354), T362 (Tyr364), and to a lesser extent peptides Y132 (Tyr132 and Tyr141), and I135 (Tyr141). G-protein-linked receptors and intrinsic tyrosine-kinase growth receptors represent two prominent modalities in cell signaling. Cross-regulation among members of both receptor superfamilies has been reported, including the counter-regulatory effects of insulin on β-adrenergic catecholamine action. Cells stimulated by insulin show loss of function and increased phosphotyrosine content of β2-adrenergic receptors." SIGNOR-251302 INSR protein P06213 UNIPROT CALM1 protein P0DP23 UNIPROT down-regulates phosphorylation Tyr100 FDKDGNGyISAAELR 9606 3415247 t lperfetto "The in vitro phosphorylation of calmodulin by the insulin receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule." SIGNOR-24782 INSR protein P06213 UNIPROT CALM2 protein P0DP24 UNIPROT down-regulates phosphorylation Tyr100 FDKDGNGyISAAELR 9606 3415247 t miannu "The in vitro phosphorylation of calmodulin by the insulin receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule." SIGNOR-266320 INSR protein P06213 UNIPROT CALM3 protein P0DP25 UNIPROT down-regulates phosphorylation Tyr100 FDKDGNGyISAAELR 9606 3415247 t miannu "The in vitro phosphorylation of calmodulin by the insulin receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule." SIGNOR-266336 INSR protein P06213 UNIPROT GYS1 protein P13807 UNIPROT "up-regulates activity" 9606 BTO:0000887;BTO:0001103 10909964 f lperfetto "In skeletal muscle, insulin activates glycogen synthase by reducing phosphorylation at both NH2- and COOH-terminal sites of the enzyme and by elevating the levels of glucose-6-phosphate, an allosteric activator of glycogen synthase." SIGNOR-236803 INSR protein P06213 UNIPROT FABP4 protein P15090 UNIPROT unknown phosphorylation Tyr20 SSENFDDyMKEVGVG -1 1648089 t "Adipocyte lipid-binding protein is phosphorylated on tyrosine 19 in an insulin-stimulated fashion by the insulin receptor" SIGNOR-251309 INSR protein P06213 UNIPROT PTPN1 protein P18031 UNIPROT "up-regulates activity" phosphorylation Tyr152 ISEDIKSyYTVRQLE -1 11506178 t lperfetto "Tyrosine residues 66, 152 and/or 153 of PTP1B are phosphorylated by the activated insulin receptor and are also necessary for formation of the PTP1B:insulin receptor complex| Furthermore, tyrosine phosphorylation of PTP1B by the insulin receptor tyrosine kinase increases the catalytic activity of PTP1B" SIGNOR-249368 INSR protein P06213 UNIPROT PTPN1 protein P18031 UNIPROT "up-regulates activity" phosphorylation Tyr153 SEDIKSYyTVRQLEL -1 11506178 t lperfetto "Tyrosine residues 66, 152 and/or 153 of PTP1B are phosphorylated by the activated insulin receptor and are also necessary for formation of the PTP1B:insulin receptor complex| Furthermore, tyrosine phosphorylation of PTP1B by the insulin receptor tyrosine kinase increases the catalytic activity of PTP1B" SIGNOR-249369 INSR protein P06213 UNIPROT CBL protein P22681 UNIPROT "up-regulates activity" phosphorylation Tyr371 TQEQYELyCEMGSTF 10090 BTO:0000944 11997497 t "Insulin receptor phosphorylates Cbl on tyrosines 371, 700, and 774 in the presence of APS. This phosphorylation event is required for the recruitment of Crk to the CAP/Cbl complex and for the subsequent activation of GLUT4 translocation." SIGNOR-251304 INSR protein P06213 UNIPROT CBL protein P22681 UNIPROT "up-regulates activity" phosphorylation Tyr774 SENEDDGyDVPKPPV 10090 BTO:0000944 11997497 t "Insulin receptor phosphorylates Cbl on tyrosines 371, 700, and 774 in the presence of APS. This phosphorylation event is required for the recruitment of Crk to the CAP/Cbl complex and for the subsequent activation of GLUT4 translocation." SIGNOR-251306 INSR protein P06213 UNIPROT PIK3R1 protein P27986 UNIPROT "up-regulates activity" phosphorylation Tyr368 STKMHGDyTLTLRKG 9534 BTO:0000298 8385099 t "The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor." SIGNOR-251320 INSR protein P06213 UNIPROT PIK3R1 protein P27986 UNIPROT "up-regulates activity" phosphorylation Tyr580 LRKTRDQyLMWLTQK 9534 BTO:0000298 8385099 t "The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor." SIGNOR-251321 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT "up-regulates activity" phosphorylation Tyr1229 SSEDLSAyASISFQK 9606 BTO:0000443 12220227 t lperfetto "Here we show that stimulation by insulin of freshly isolated primary adipocytes resulted in the expected rapid tyrosine phosphorylation of the insulin receptor, IRS-1 and IRS-3. Inhibition of PI 3-kinase enhanced the insulin-stimulated phosphorylation of IRS-1 on (i) Tyr(612) and Tyr(941) (p85 binding sites), concomitant with an increased association of the p85 subunit of PI 3-kinase; (ii) Tyr(896) (a Grb2 binding site); and (iii) Tyr(1229) (an SHP-2 binding site), although little or no binding of SHP-2 to IRS-1 was detectable under any conditions." SIGNOR-235983 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT "up-regulates activity" phosphorylation Tyr1229 SSEDLSAyASISFQK 10029 BTO:0000246 7651388 t lperfetto "Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir)." SIGNOR-236752 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT "up-regulates activity" phosphorylation Tyr612 TLHTDDGyMPMSPGV 10029 BTO:0000246 7651388 t lperfetto "Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir)." SIGNOR-236756 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT "up-regulates activity" phosphorylation Tyr632 GRKGSGDyMPMSPKS 10029 BTO:0000246 7651388 t lperfetto "Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir)." SIGNOR-236741 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT "up-regulates activity" phosphorylation Tyr896 EPKSPGEyVNIEFGS 10029 BTO:0000246 7651388 t lperfetto "Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir)." SIGNOR-236745 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT "up-regulates activity" phosphorylation Tyr941 EETGTEEyMKMDLGP 10116 BTO:0000443 7651388 t lperfetto "All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin receptors A previous study using phosphopeptides suggested that tyrosine-phosphorylated YXXM motifs at positions 608 and 939 in rat IRS-1 bind with high affinity to SH2 domains of p85, and motifs at positions 460 and 987 bind with lower affinity (10)." SIGNOR-235975 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT "up-regulates activity" phosphorylation Tyr989 VPSSRGDyMTMQMSC 10116 BTO:0000443 7651388 t lperfetto "All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin receptors A previous study using phosphopeptides suggested that tyrosine-phosphorylated YXXM motifs at positions 608 and 939 in rat IRS-1 bind with high affinity to SH2 domains of p85, and motifs at positions 460 and 987 bind with lower affinity (10)." SIGNOR-235979 INSR protein P06213 UNIPROT PTK2 protein Q05397 UNIPROT "up-regulates activity" phosphorylation Tyr576 RYMEDSTyYKASKGK -1 9507031 t "P125(Fak) sequence comprising amino acids 568-582, which contains tyrosines 576 and 577 of the kinase domain regulatory loop, is phosphorylated by the insulin receptor. p125(Fak) phosphorylation by the receptor results in its activation." SIGNOR-251323 INSR protein P06213 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr589 SHDSEENyVPMNPNL 10090 BTO:0000944 10978177 t "HGab-1 was phosphorylated by IR at eight tyrosine residues (Y242, Y285, Y373, Y447, Y472, Y619, Y657, and Y689). t Gab-1 is the major binding partner of PI-3 kinase in 3T3L1 cells when stimulated with insulin" SIGNOR-251315 INSR protein P06213 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr627 KGDKQVEyLDLDLDS 10090 BTO:0000944 10978177 t "HGab-1 was phosphorylated by IR at eight tyrosine residues (Y242, Y285, Y373, Y447, Y472, Y619, Y657, and Y689). t Gab-1 is the major binding partner of PI-3 kinase in 3T3L1 cells when stimulated with insulin" SIGNOR-251316 INSR protein P06213 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr659 VADERVDyVVVDQQK 10090 BTO:0000944 10978177 t "HGab-1 was phosphorylated by IR at eight tyrosine residues (Y242, Y285, Y373, Y447, Y472, Y619, Y657, and Y689). t Gab-1 is the major binding partner of PI-3 kinase in 3T3L1 cells when stimulated with insulin" SIGNOR-251317 INSR protein P06213 UNIPROT DOK1 protein Q99704 UNIPROT "up-regulates activity" phosphorylation Tyr362 DPKEDPIyDEPEGLA 10029 BTO:0000246 11551902 t "Insulin receptor-mediated p62dok tyrosine phosphorylation at residues 362 and 398. p62(dok) is a direct substrate for the IR tyrosine kinase and that phosphorylation at Tyr(362) and Tyr(398) plays an essential role for p62(dok) to interact with its effectors and negatively regulate the insulin signaling pathway." SIGNOR-251307 INSR protein P06213 UNIPROT DOK1 protein Q99704 UNIPROT "up-regulates activity" phosphorylation Tyr398 ARVKEEGyELPYNPA 10029 BTO:0000246 11551902 t "Insulin receptor-mediated p62dok tyrosine phosphorylation at residues 362 and 398. p62(dok) is a direct substrate for the IR tyrosine kinase and that phosphorylation at Tyr(362) and Tyr(398) plays an essential role for p62(dok) to interact with its effectors and negatively regulate the insulin signaling pathway." SIGNOR-251308 INSR protein P06213 UNIPROT DOK5 protein Q9P104 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103;BTO:0000671 12730241 f lperfetto "Irs5/dok4 and irs6/dok5 represent two new signaling proteins with potential roles in insulin and igf-1 action" SIGNOR-101038 INSR protein P06213 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" phosphorylation Tyr580 LRKTRDQyLMWLTQK 9534 BTO:0000298 8385099 t "The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor." SIGNOR-252691 INSR protein P06213 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" phosphorylation Tyr607 NENTEDQySLVEDDE 9534 BTO:0000298 8385099 t "The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor." SIGNOR-252693 LCK protein P06239 UNIPROT LAT protein O43561 UNIPROT up-regulates phosphorylation Tyr200 SMESIDDyVNVPESG 9606 BTO:0000782 16938345 t gcesareni "Evidence of lat as a dual substrate for lck and syk in t lymphocytes.Lat is a linker protein essential for activation of t lymphocytes. Its rapid tyrosine-phosphorylation upon t cell receptor (tcr) stimulation recruits downstream signaling molecules for membrane targeting and activation." SIGNOR-149182 LCK protein P06239 UNIPROT LAT protein O43561 UNIPROT up-regulates phosphorylation Tyr220 SLDGSREyVNVSQEL 9606 BTO:0000782 16938345 t gcesareni "Evidence of lat as a dual substrate for lck and syk in t lymphocytes.Lat is a linker protein essential for activation of t lymphocytes. Its rapid tyrosine-phosphorylation upon t cell receptor (tcr) stimulation recruits downstream signaling molecules for membrane targeting and activation." SIGNOR-149186 LCK protein P06239 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Tyr537 CKNVVPLyDLLLEML 9606 10571988 t gcesareni "On the basis of these data and other reports describing the structure and activity of y537 mutations, as well as knowledge of the three-dimensional structure of the her ligand binding domain, we propose an alternate model wherein y537f mutation favors an open pocket conformation, affecting the estrogen binding kinetics and stability of the hormone-bound, transcriptionally active closed pocket conformation." SIGNOR-72373 LCK protein P06239 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Tyr537 CKNVVPLyDLLLEML 9606 BTO:0000150;BTO:0000567 9500442 t gcesareni "On the basis of these data and other reports describing the structure and activity of y537 mutations, as well as knowledge of the three-dimensional structure of the her ligand binding domain, we propose an alternate model wherein y537f mutation favors an open pocket conformation, affecting the estrogen binding kinetics and stability of the hormone-bound, transcriptionally active closed pocket conformation." SIGNOR-55853 LCK protein P06239 UNIPROT CD3D protein P04234 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0000782 2470098 t "Last, we demonstrate directly that members of the CD3 complex, including the gamma, delta, and epsilon chains, as well as a putative zeta subunit, can be phosphorylated at tyrosine residues by the CD4/CD8.p56lck complex." SIGNOR-259929 LCK protein P06239 UNIPROT CD5 protein P06127 UNIPROT "up-regulates activity" phosphorylation Tyr453 ASHVDNEySQPPRNS 9606 BTO:0000782 11298344 t lperfetto "Tyrosine phosphorylation of cd5 requires lck activity. We propose that t cell activation mediates cd5 tyrosine phosphorylation at residues y429 and y463 mainly through the activation of lck" SIGNOR-106799 LCK protein P06239 UNIPROT CD5 protein P06127 UNIPROT "up-regulates activity" phosphorylation Tyr487 DNSSDSDyDLHGAQR 9606 BTO:0000782 11298344 t lperfetto "Tyrosine phosphorylation of cd5 requires lck activity. We propose that t cell activation mediates cd5 tyrosine phosphorylation at residues y429 and y463 mainly through the activation of lck" SIGNOR-106803 LCK protein P06239 UNIPROT CD3E protein P07766 UNIPROT "up-regulates activity" phosphorylation Tyr188 PPVPNPDyEPIRKGQ 9534 BTO:0004055 11855827 t "Tyrosine Phosphorylation of CD8- Chimeras by Lck and ZAP-70 in COS Cells. both Y170F and Y181F chimeric proteins could be efficiently phosphorylated by Lck in vivo. phosphorylation of Y170 and Y181 within CD3- –ITAM provides to CD3- the potential to interact with multiple downstream effectors and signaling pathways." SIGNOR-251368 LCK protein P06239 UNIPROT CD3G protein P09693 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0000782 2470098 t "Last, we demonstrate directly that members of the CD3 complex, including the gamma, delta, and epsilon chains, as well as a putative zeta subunit, can be phosphorylated at tyrosine residues by the CD4/CD8.p56lck complex." SIGNOR-259931 LCK protein P06239 UNIPROT CD28 protein P10747 UNIPROT up-regulates phosphorylation Tyr191 SRLLHSDyMNMTPRR 9606 22936936 t lperfetto "We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tail, in contrast to lck, which phosphorylates only tyrosine 173. Together with evidence that in vivo, tyrosines other than tyrosine 173 become phosphorylated following cd28 stimulation, this finding suggests that, like lck, one function of emt during cd28 signaling is phosphorylation of the receptor" SIGNOR-198755 LCK protein P06239 UNIPROT CD28 protein P10747 UNIPROT up-regulates phosphorylation Tyr191 SRLLHSDyMNMTPRR 9606 BTO:0000782;BTO:0001271 8992971 t lperfetto "We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tail, in contrast to lck, which phosphorylates only tyrosine 173. Together with evidence that in vivo, tyrosines other than tyrosine 173 become phosphorylated following cd28 stimulation, this finding suggests that, like lck, one function of emt during cd28 signaling is phosphorylation of the receptor" SIGNOR-45524 LCK protein P06239 UNIPROT IL2RB protein P14784 UNIPROT unknown phosphorylation Tyr381 EIEACQVyFTYDPYS -1 10214954 t "Recombinant p56(lck) phosphorylates in vitro tyrosine residues within the IL-2Rbeta chain. p56(lck) phosphorylates tyrosine residues 355, 358 and 361 but not 338 of the IL-2Rbeta chain acidic subdomain. p56(lck) also phosphorylates very efficiently the two tyrosines present in the IL-2Rbeta chain C-terminal region, Tyr-392 and Tyr-510." SIGNOR-251375 LCK protein P06239 UNIPROT ITK protein Q08881 UNIPROT up-regulates phosphorylation Tyr512 RFVLDDQyTSSTGTK -1 9312162 t "Lck phosphorylates the activation loop tyrosine of the Itk kinase domain and activates Itk kinase activity. The major site of Lck phosphorylation on Itk was mapped to the conserved tyrosine (Tyr511) in the activation loop of the Itk kinase domain." SIGNOR-251380 LCK protein P06239 UNIPROT IL2RB protein P14784 UNIPROT unknown phosphorylation Tyr384 ACQVYFTyDPYSEED -1 10214954 t "Recombinant p56(lck) phosphorylates in vitro tyrosine residues within the IL-2Rbeta chain. p56(lck) phosphorylates tyrosine residues 355, 358 and 361 but not 338 of the IL-2Rbeta chain acidic subdomain. p56(lck) also phosphorylates very efficiently the two tyrosines present in the IL-2Rbeta chain C-terminal region, Tyr-392 and Tyr-510." SIGNOR-251376 LCK protein P06239 UNIPROT IL2RB protein P14784 UNIPROT unknown phosphorylation Tyr387 VYFTYDPySEEDPDE -1 10214954 t "Recombinant p56(lck) phosphorylates in vitro tyrosine residues within the IL-2Rbeta chain. p56(lck) phosphorylates tyrosine residues 355, 358 and 361 but not 338 of the IL-2Rbeta chain acidic subdomain. p56(lck) also phosphorylates very efficiently the two tyrosines present in the IL-2Rbeta chain C-terminal region, Tyr-392 and Tyr-510." SIGNOR-251377 LCK protein P06239 UNIPROT IL2RB protein P14784 UNIPROT unknown phosphorylation Tyr418 LSGEDDAyCTFPSRD -1 10214954 t "Recombinant p56(lck) phosphorylates in vitro tyrosine residues within the IL-2Rbeta chain. p56(lck) phosphorylates tyrosine residues 355, 358 and 361 but not 338 of the IL-2Rbeta chain acidic subdomain. p56(lck) also phosphorylates very efficiently the two tyrosines present in the IL-2Rbeta chain C-terminal region, Tyr-392 and Tyr-510." SIGNOR-251378 LCK protein P06239 UNIPROT IL2RB protein P14784 UNIPROT unknown phosphorylation Tyr536 LPLNTDAyLSLQELQ -1 10214954 t "Recombinant p56(lck) phosphorylates in vitro tyrosine residues within the IL-2Rbeta chain. p56(lck) phosphorylates tyrosine residues 355, 358 and 361 but not 338 of the IL-2Rbeta chain acidic subdomain. p56(lck) also phosphorylates very efficiently the two tyrosines present in the IL-2Rbeta chain C-terminal region, Tyr-392 and Tyr-510." SIGNOR-251379 LCK protein P06239 UNIPROT EZR protein P15311 UNIPROT unknown phosphorylation Tyr146 KEVHKSGyLSSERLI -1 12560083 t "Lck phosphorylated ezrin in vitro, and the major phosphotyrosine was identified as Y145. Whether tyrosine phosphorylation of ezrin is an alternative mechanism to regulate dynamic changes of the actin cytoskeleton, as has been suggested in EGF-, PDGF- or HGF-treated epithelial cells, is still unclear. Alternatively, Lck-induced tyrosine phosphorylation of ezrin may be linked to its other functions, including participation in signaling pathways that control proliferation and apoptosis" SIGNOR-251374 LCK protein P06239 UNIPROT MUC1 protein P15941 UNIPROT "up-regulates activity" phosphorylation Tyr1229 SSTDRSPyEKVSAGN BTO:0000661 14766232 t lperfetto "The present results demonstrate that Lck phosphorylation of MUC1 on Y-46 also increases binding of MUC1 and beta-catenin. The results further show that ZAP-70 phosphorylation of MUC1-CD stimulates the interaction of MUC1 and beta-catenin" SIGNOR-249358 LCK protein P06239 UNIPROT MUC1 protein P15941 UNIPROT "up-regulates activity" phosphorylation Tyr1229 SSTDRSPyEKVSAGN 9606 14766232 t lperfetto "The present results demonstrate that Lck phosphorylation of MUC1 on Y-46 also increases binding of MUC1 and _-catenin. The results further show that ZAP-70 phosphorylation of MUC1-CD stimulates the interaction of MUC1 and _-catenin" SIGNOR-247058 LCK protein P06239 UNIPROT PECAM1 protein P16284 UNIPROT "up-regulates activity" phosphorylation Tyr713 KKDTETVySEVRKAV 9534 9624175 t miannu "We demonstrated that phosphorylation of PECAM-1 by Src or Csk family kinases was sufficient to trigger its association with SHP-2. Moreover, it was able to promote binding of PECAM-1 to SHP-1, a SHP-2-related protein-tyrosine phosphatase expressed in hemopoietic cells. Taken together, these findings indicated that the Src and Csk families of kinases are strong candidates for mediating tyrosine phosphorylation of PECAM-1 and triggering its association with SH2 domain-containing phosphatases under physiological circumstances." SIGNOR-262742 LCK protein P06239 UNIPROT CTLA4 protein P16410 UNIPROT unknown phosphorylation Tyr218 CEKQFQPyFIPIN 9606 BTO:0000007 9973379 t "Lck and Fyn, but not ZAP70, induce tyrosine phosphorylation of CTLA-4 in the cell line HEK293. Phosphorylation of CTLA-4 occurs on both Y201 and Y218.the role of Y218 in CTLA-4 biology is not known at the present" SIGNOR-251371 LCK protein P06239 UNIPROT CTLA4 protein P16410 UNIPROT "up-regulates quantity by stabilization" phosphorylation Tyr201 SPLTTGVyVKMPPTE 9606 9973379 t "Lck and Fyn, but not ZAP70, induce tyrosine phosphorylation of CTLA-4 in the cell line HEK293. Phosphorylation of CTLA-4 occurs on both Y201 and Y218. Phosphorylation of Y201 correlated with accumulation of CTLA-4 on the cell surface." SIGNOR-251370 LCK protein P06239 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates phosphorylation Tyr753 ERDINSLyDVSRMYV 9606 12181444 t gcesareni "In vitro phosphorylation experiments with recombinant plcgamma2 and recombinant lck, fyn, and lyn tyrosine kinases showed that phosphorylation of plcgamma2 led to activation of the recombinant enzyme." SIGNOR-91473 LCK protein P06239 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates phosphorylation Tyr759 LYDVSRMyVDPSEIN 9606 12181444 t gcesareni "In vitro phosphorylation experiments with recombinant plcgamma2 and recombinant lck, fyn, and lyn tyrosine kinases showed that phosphorylation of plcgamma2 led to activation of the recombinant enzyme." SIGNOR-91477 LCK protein P06239 UNIPROT CD33 protein P20138 UNIPROT up-regulates phosphorylation Tyr340 EMDEELHyASLNFHG 9606 10887109 t lperfetto "Human cd33 has two tyrosine residues in its cytoplasmic domain (y340 and y358). When phosphorylated, these tyrosines could function as docking sites for the phosphatases, shp-1 and/or shp-2, enabling cd33 to function as an inhibitory receptor. Lck is effective at phosphorylating y340" SIGNOR-78960 LCK protein P06239 UNIPROT CD247 protein P20963 UNIPROT up-regulates phosphorylation 9606 BTO:0000782 8626561 t amattioni "During tcr signaling, lck interacts with numerous molecules, including tcr-zeta. The binding of lck to the tyrosine-phosphorylated zeta chain of the tcr would serve to strengthen the interaction of the associated cd4 and the tcr complex, leading to increased avidity for the antigen-major histocompatibility protein complex." SIGNOR-41361 LCK protein P06239 UNIPROT ACP1 protein P24666 UNIPROT "up-regulates activity" phosphorylation Tyr132 QLIIEDPyYGNDSDF 9534 BTO:0004055 9038134 t "In co-transfected COS cells, Lck and Fyn caused phosphorylation of LMPTP. Most of the phosphate was located at Tyr-131, and some was also located at Tyr-132. Site-directed mutagenesis showed that Tyr-131 is important for the catalytic activity of LMPTP, and that thiophosphorylation of Tyr-131, and to a lesser degree Tyr-132, is responsible for the activation." SIGNOR-251366 LCK protein P06239 UNIPROT ADAM15 protein Q13444 UNIPROT up-regulates phosphorylation Tyr715 LVMLGASyWYRARLH 9606 BTO:0000661 11741929 t lperfetto "Hck, and to a lesser extent lck, phosphorylated the adam15. Deletion and point mutation analysis of the adam15 cytoplasmic domain confirmed the importance of the proline-rich motifs for grb2 and lck binding and indicated the regulatory nature of tyr(715) and tyr(735). These data demonstrate selective, phosphorylation-dependent interactions of adam15 with src family ptks and grb2, which highlight the potential for integration of adam functions and cellular signaling." SIGNOR-112931 LCK protein P06239 UNIPROT PIK3R1 protein P27986 UNIPROT "down-regulates activity" phosphorylation Tyr688 FAEPYNLySSLKELV 9534 BTO:0004055 9461588 t "the regulatory p85 subunit of phosphatidylinositol 3-kinase is phosphorylated on tyrosine residues. We report that this phosphorylation event is readily catalyzed by the Abl and Lck protein-tyrosine kinases in vitro, by Bcr-Abl or a catalytically activated Lck-Y505F in co-transfected COS cells. we have mapped a major phosphorylation site to Tyr-688 in the C-terminal SH2 domain of p85. Tyrosine phosphorylation of p85 in vitro or in vivo was not associated with detectable change in the enzymatic activity of the phosphatidylinositol 3-kinase heterodimer, but correlated with a strong reduction in the binding of some, but not all, phosphoproteins to the SH2 domains of p85." SIGNOR-251383 LCK protein P06239 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates phosphorylation Tyr564 SKHKEDVyENLHTKN 9606 BTO:0000782 8114715 t llicata "The two sites (y-536 and y-564) which are directly phosphorylated by lck in vitro are also phosphorylated in vivo in lstra cells. One of these sites (y-564) is phosphorylated in t cells in response to lck activation." SIGNOR-36121 LCK protein P06239 UNIPROT PTPN6 protein P29350 UNIPROT "up-regulates activity" phosphorylation Tyr536 QKGQESEyGNITYPP 10090 BTO:0000782 8114715 t "Two sites (Y-536 and Y-564) which are directly phosphorylated by Lck in vitro are also phosphorylated in vivo in LSTRA cells. ." SIGNOR-251387 LCK protein P06239 UNIPROT SHC1 protein P29353 UNIPROT "up-regulates activity" phosphorylation Tyr427 ELFDDPSyVNVQNLD 9606 BTO:0000782 9710204 t "We show that during TCR signaling, the tyrosines Y239, Y240 and Y317 of Shc are the primary sites of tyrosine phosphorylation. CD4/Lck-dependent tyrosine phosphorylation on Shc was markedly diminished when Y317 was mutated, suggesting a preference of Lck for the Y317 site. tyrosine phosphorylation of Shc may play a key role in T lymphocyte proliferation via interaction of phosphorylated Shc with downstream molecules involved in activation of Ras and Myc proteins" SIGNOR-251388 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT unknown phosphorylation Tyr178 EEAERKLySGAQTDG 9606 BTO:0000661 7961936 t "We show that ZAP-70 has a primary autophosphorylation site at Tyr-292, with a secondary site at Tyr-126. We also show additional phosphorylation at Tyr-69, Tyr-178, Tyr-492, and Tyr-493 upon the addition of the protein tyrosine kinase, p56lck." SIGNOR-251392 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT unknown phosphorylation Tyr69 ERQLNGTyAIAGGKA 9606 BTO:0000661 7961936 t "We show that ZAP-70 has a primary autophosphorylation site at Tyr-292, with a secondary site at Tyr-126. We also show additional phosphorylation at Tyr-69, Tyr-178, Tyr-492, and Tyr-493 upon the addition of the protein tyrosine kinase, p56lck." SIGNOR-251396 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" phosphorylation Tyr319 TSVYESPySDPEELK 10090 BTO:0000782 10037717 t "the protein tyrosine kinase (PTK) ZAP-70 is rapidly phosphorylated on several tyrosine residues, presumably by two mechanisms: an autophosphorylation and a trans-phosphorylation by the Src-family PTK Lck. we demonstrate that phosphorylation of Tyr319 is required for the positive regulation of ZAP-70 function" SIGNOR-251393 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" phosphorylation Tyr492 ALGADDSyYTARSAG 9606 BTO:0000782 7642520 t lperfetto "When expressed in COS cells, Y493F-mutated ZAP-70 demonstrated normal basal kinase activity, but, unlike wild type ZAP-70, could not be activated by tyrosine phosphorylation induced by incubation with pervanadate or by co-expression of constitutively activated Lck" SIGNOR-30429 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" phosphorylation Tyr493 LGADDSYyTARSAGK 9606 BTO:0000661 7961936 t "We show that ZAP-70 has a primary autophosphorylation site at Tyr-292, with a secondary site at Tyr-126. We also show additional phosphorylation at Tyr-69, Tyr-178, Tyr-492, and Tyr-493 upon the addition of the protein tyrosine kinase, p56lck." SIGNOR-251395 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" phosphorylation Tyr474 VLLVNRHyAKISDFG 9606 BTO:0000661 9685404 t lperfetto "We show that ZAP-70 has a primary autophosphorylation site at Tyr-292, with a secondary site at Tyr-126. We also show additional phosphorylation at Tyr-69, Tyr-178, Tyr-492, and Tyr-493 upon the addition of the protein tyrosine kinase, p56lck" SIGNOR-249375 LCK protein P06239 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 BTO:0000782 14583609 t gcesareni "Endogenous notch-1 associates with p56(lck) and pi3k. p56(lck) is required for the notch-1-mediated activation of akt/pkb function" SIGNOR-118902 LCK protein P06239 UNIPROT PRKCD protein Q05655 UNIPROT "up-regulates activity" phosphorylation Tyr313 SSEPVGIyQGFEKKT 9534 BTO:0000298 11381116 t "The tyrosine phosphorylation sites of PKC delta in the H(2)O(2)-treated cells were identified as Tyr-311, Tyr-332, and Tyr-512 by mass spectrometric analysis with the use of the precursor-scan method and by immunoblot analysis with the use of phosphorylation site-specific antibodies. Tyr-311 was the predominant modification site among them. In an in vitro study, phosphorylation at this site by Lck, a non-receptor-type tyrosine kinase, enhanced the basal enzymatic activity and elevated its maximal velocity in the presence of diacylglycerol. phosphorylation at Tyr-311 between the regulatory and catalytic domains is a critical step for generation of the active PKC delta in response to H(2)O(2)." SIGNOR-251384 LCK protein P06239 UNIPROT PRKCD protein Q05655 UNIPROT "up-regulates activity" phosphorylation Tyr334 MQDNSGTyGKIWEGS 9534 BTO:0000298 11381116 t "The tyrosine phosphorylation sites of PKC delta in the H(2)O(2)-treated cells were identified as Tyr-311, Tyr-332, and Tyr-512 by mass spectrometric analysis with the use of the precursor-scan method and by immunoblot analysis with the use of phosphorylation site-specific antibodies. Tyr-311 was the predominant modification site among them. In an in vitro study, phosphorylation at this site by Lck, a non-receptor-type tyrosine kinase, enhanced the basal enzymatic activity and elevated its maximal velocity in the presence of diacylglycerol. phosphorylation at Tyr-311 between the regulatory and catalytic domains is a critical step for generation of the active PKC delta in response to H(2)O(2)." SIGNOR-251385 LCK protein P06239 UNIPROT PRKCD protein Q05655 UNIPROT "up-regulates activity" phosphorylation Tyr514 TFCGTPDyIAPEILQ 9534 BTO:0000298 11381116 t "The tyrosine phosphorylation sites of PKC delta in the H(2)O(2)-treated cells were identified as Tyr-311, Tyr-332, and Tyr-512 by mass spectrometric analysis with the use of the precursor-scan method and by immunoblot analysis with the use of phosphorylation site-specific antibodies. Tyr-311 was the predominant modification site among them. In an in vitro study, phosphorylation at this site by Lck, a non-receptor-type tyrosine kinase, enhanced the basal enzymatic activity and elevated its maximal velocity in the presence of diacylglycerol. phosphorylation at Tyr-311 between the regulatory and catalytic domains is a critical step for generation of the active PKC delta in response to H(2)O(2)." SIGNOR-251386 FYN protein P06241 UNIPROT GRIN2B protein Q13224 UNIPROT unknown phosphorylation Tyr1474 GSSNGHVyEKLSSIE 9606 BTO:0000007 11024032 t "Tyr-1252, Tyr-1336, and Tyr-1472 of GluRε2 are phosphorylated in 293T cells when active Fyn is co-expressed." SIGNOR-251175 LCK protein P06239 UNIPROT CCDC50 protein Q8IVM0 UNIPROT "down-regulates activity" phosphorylation Tyr217 MAEEKKAyKKAKERE 9606 BTO:0000567 19059208 t miannu "We found that Ymer was considerably phosphorylated on tyrosine residues also via Src family kinases such as Lck. A luciferase reporter assay showed that mutation of tyrosines on Ymer (YmerY217/279/304F) results in loss of the inhibitory activity for NF-kappaB signaling." SIGNOR-262853 LCK protein P06239 UNIPROT CCDC50 protein Q8IVM0 UNIPROT "down-regulates activity" phosphorylation Tyr279 TDGEDADyTHFTNQQ 9606 BTO:0000567 19059208 t miannu "We found that Ymer was considerably phosphorylated on tyrosine residues also via Src family kinases such as Lck. A luciferase reporter assay showed that mutation of tyrosines on Ymer (YmerY217/279/304F) results in loss of the inhibitory activity for NF-kappaB signaling." SIGNOR-262854 LCK protein P06239 UNIPROT CCDC50 protein Q8IVM0 UNIPROT "down-regulates activity" phosphorylation Tyr304 SSHKGFHyKH 9606 BTO:0000567 19059208 t miannu "We found that Ymer was considerably phosphorylated on tyrosine residues also via Src family kinases such as Lck. A luciferase reporter assay showed that mutation of tyrosines on Ymer (YmerY217/279/304F) results in loss of the inhibitory activity for NF-kappaB signaling." SIGNOR-262855 LCK protein P06239 UNIPROT SIGLEC10 protein Q96LC7 UNIPROT unknown phosphorylation Tyr691 PKGTQADyAEVKFQ 9606 11733002 t lperfetto "These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. however, it is not clear whether y691 is capable of binding sap or a similar protein. Future studies will attempt to elucidate the signaling activities associated with y691" SIGNOR-112499 LCK protein P06239 UNIPROT SIGLEC10 protein Q96LC7 UNIPROT up-regulates phosphorylation Tyr597 RHSTILDyINVVPTA 9606 11733002 t lperfetto "These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. Y597 and y667 are likely involved in intracellular signaling" SIGNOR-112491 LCK protein P06239 UNIPROT DEF6 protein Q9H4E7 UNIPROT "up-regulates activity" phosphorylation Tyr144 MVPDEVEyLLKKVLS 9606 BTO:0000661 18976935 t lperfetto "Here, we report that the T cell receptor (TCR)-induced translocation of SLAT to the immunological synapse required Lck-mediated phosphorylation of two tyrosine residues located in an immunoreceptor tyrosine-based activation motif-like sequence but was independent of the SLAT PH domain. This subcellular relocalization was coupled to, and necessary for, activation of the NFAT pathway|These results indicate that SLAT undergoes Lck-dependent phosphorylation on Tyr-144 and Tyr-133 upon TCR and CD28 stimulation." SIGNOR-253368 LCK protein P06239 UNIPROT SH2D2A protein Q9NP31 UNIPROT "up-regulates activity" phosphorylation Tyr280 PKPSNPIyNEPDEPI 9606 BTO:0000782 18541536 t miannu "Here we mapped Lck phosphorylation and interaction sites on TSAd and evaluated their functional importance. The three C-terminal TSAd tyrosines Tyr(280), Tyr(290), and Tyr(305) were phosphorylated by Lck and functioned as docking sites for the Lck Src homology 2 (SH2) domain. Lck binds to TSAd prolines and phosphorylates and interacts with the three C-terminal TSAd tyrosines. We propose that through multivalent interactions with Lck, TSAd diverts Lck from phosphorylating other substrates, thus modulating its functional activity through substrate competition." SIGNOR-262888 LCK protein P06239 UNIPROT SH2D2A protein Q9NP31 UNIPROT "up-regulates activity" phosphorylation Tyr290 PDEPIAFyAMGRGSP 9606 BTO:0000782 18541536 t miannu "Here we mapped Lck phosphorylation and interaction sites on TSAd and evaluated their functional importance. The three C-terminal TSAd tyrosines Tyr(280), Tyr(290), and Tyr(305) were phosphorylated by Lck and functioned as docking sites for the Lck Src homology 2 (SH2) domain. Lck binds to TSAd prolines and phosphorylates and interacts with the three C-terminal TSAd tyrosines. We propose that through multivalent interactions with Lck, TSAd diverts Lck from phosphorylating other substrates, thus modulating its functional activity through substrate competition." SIGNOR-262889 LCK protein P06239 UNIPROT TCR complex SIGNOR-C153 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000661 8626561 t "The binding of Lck to the tyrosine-phosphorylated zeta chain of the TcR would serve to strengthen the interaction of the associated CD4 and the TcR complex, leading to increased avidity for the antigen-major histocompatibility protein complex" SIGNOR-252305 LCK protein P06239 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "down-regulates activity" phosphorylation Tyr688 FAEPYNLySSLKELV 9534 BTO:0004055 9461588 t "The regulatory p85 subunit of phosphatidylinositol 3-kinase is phosphorylated on tyrosine residues. We report that this phosphorylation event is readily catalyzed by the Abl and Lck protein-tyrosine kinases in vitro, by Bcr-Abl or a catalytically activated Lck-Y505F in co-transfected COS cells. we have mapped a major phosphorylation site to Tyr-688 in the C-terminal SH2 domain of p85. Tyrosine phosphorylation of p85 in vitro or in vivo was not associated with detectable change in the enzymatic activity of the phosphatidylinositol 3-kinase heterodimer, but correlated with a strong reduction in the binding of some, but not all, phosphoproteins to the SH2 domains of p85." SIGNOR-252699 FYN protein P06241 UNIPROT CD300LB protein A8K4G0 UNIPROT "up-regulates activity" phosphorylation Tyr188 EPGEQPIyMNFSEPL 9534 BTO:0004055 16920917 t lperfetto "As CD300b phosphorylation was occurring only in the presence of both c-Fyn and DAP-12, we addressed whether tyrosine phosphorylation was required for association of CD300b and DAP-12. For this purpose, we generated a set of HA-tagged CD300b mutants affecting the transmembrane lysine (K158L), the cytoplasmic tyrosine (Y188F) or both residues.|As expected, the CD300b double mutant could neither recruit DAP-12 nor become phosphorylated in the presence of c-Fyn kinase (Fig. 5⇑C). Association between CD300b and DAP-12 was maintained in absence of the c-Fyn kinase, indicating that phosphorylation of the adaptor was not essential for the formation of the complex (data not shown)" SIGNOR-264771 FYN protein P06241 UNIPROT ARHGAP33 protein O14559 UNIPROT down-regulates phosphorylation Tyr406 PLLTYQLyGKFSEAM 9606 BTO:0000142 16777849 t acerquone "Tcgap interacted with fyn and was phosphorylated by fyn, with tyr-406 in the gap domain as a major fyn-mediated phosphorylation site. Fyn suppressed the gap activity of wild-type tcgap" SIGNOR-147156 FYN protein P06241 UNIPROT TGFB1I1 protein O43294 UNIPROT "up-regulates activity" phosphorylation Tyr60 SGDKDHLySTVCKPR 9534 BTO:0000298 10838081 t miannu "Hic-5 is a CAKbeta-binding protein localized at focal adhesions. Here we show that overexpression of CAKbeta or Fyn, but not FAK, enhanced the tyrosine phosphorylation of coexpressed Hic-5 in COS-7 cells. The Y60F mutant of Hic-5 was not phosphorylated, and Hic-5 phosphorylated on tyrosine 60 was bound specifically to the SH2 domain of Csk. Specific phosphorylation of Hic-5 by CAKbeta and Fyn may activate a signaling pathway mediated by Hic-5." SIGNOR-262875 FYN protein P06241 UNIPROT LAT protein O43561 UNIPROT up-regulates phosphorylation Tyr200 SMESIDDyVNVPESG 9606 BTO:0000782 16938345 t gcesareni "Both lck and syk, phosphorylate the itam-like motifs on lat at y171y191, which is essential for induction of the interaction of lat with downstream signaling molecules such as grb2, plc-gamma1 and c-cbl, and for activation of mapk-erk." SIGNOR-149174 FYN protein P06241 UNIPROT FYN protein P06241 UNIPROT "up-regulates activity" phosphorylation Tyr28 SLNQSSGyRYGTDPT -1 9425276 t "Activated Fyn furthermore undergoes autophosphorylation on Tyr30, Tyr39 and Tyr420. Tyr28 This site is also a Fyn autophosphorylation site When Fyn mutants with Tyr28, Tyr30 or Tyr39 replaced with phenylalanine residues were transfected into NIH3T3 cells a decreased activation after PDGF stimulation was seen, suggesting a functional importance of the N-terminal tyrosine phosphorylation of Fyn." SIGNOR-251168 FYN protein P06241 UNIPROT FYN protein P06241 UNIPROT "up-regulates activity" phosphorylation Tyr30 NQSSGYRyGTDPTPQ -1 9425276 t "Activated Fyn furthermore undergoes autophosphorylation on Tyr30, Tyr39 and Tyr420. Tyr28 This site is also a Fyn autophosphorylation site When Fyn mutants with Tyr28, Tyr30 or Tyr39 replaced with phenylalanine residues were transfected into NIH3T3 cells a decreased activation after PDGF stimulation was seen, suggesting a functional importance of the N-terminal tyrosine phosphorylation of Fyn." SIGNOR-251165 FYN protein P06241 UNIPROT FYN protein P06241 UNIPROT "up-regulates activity" phosphorylation Tyr39 TDPTPQHyPSFGVTS -1 9425276 t "Activated Fyn furthermore undergoes autophosphorylation on Tyr30, Tyr39 and Tyr420. Tyr28 This site is also a Fyn autophosphorylation site When Fyn mutants with Tyr28, Tyr30 or Tyr39 replaced with phenylalanine residues were transfected into NIH3T3 cells a decreased activation after PDGF stimulation was seen, suggesting a functional importance of the N-terminal tyrosine phosphorylation of Fyn." SIGNOR-251166 FYN protein P06241 UNIPROT FYN protein P06241 UNIPROT "up-regulates activity" phosphorylation Tyr420 RLIEDNEyTARQGAK -1 9425276 t "Activated Fyn furthermore undergoes autophosphorylation on Tyr30, Tyr39 and Tyr420. Tyr28 This site is also a Fyn autophosphorylation site When Fyn mutants with Tyr28, Tyr30 or Tyr39 replaced with phenylalanine residues were transfected into NIH3T3 cells a decreased activation after PDGF stimulation was seen, suggesting a functional importance of the N-terminal tyrosine phosphorylation of Fyn." SIGNOR-251167 FYN protein P06241 UNIPROT CD79A protein P11912 UNIPROT "up-regulates activity" phosphorylation Tyr199 NLDDCSMyEDISRGL -1 9531288 t "Lyn and Fyn phosphorylated the CD79a cytoplasmic portion of the fusion proteins well, with >80% of phosphorylation occurring at Y182. CD79a and CD79b function as transducers of B cell antigen receptor signals via a cytoplasmic sequence, termed the immunoreceptor tyrosine-based activation motif (ITAM)." SIGNOR-251153 FYN protein P06241 UNIPROT FCGR2A protein P12318 UNIPROT "up-regulates activity" phosphorylation Tyr304 TDDDKNIyLTLPPND -1 8756631 t lperfetto "To identify the FcgammaRII-phosphorylating protein tyrosine kinase (PTK), we used the combination of an in vitro and an in vivo approach. In an in vitro assay using recombinant cytoplasmic tails of the different FcgammaRII isoforms as well as tyrosine exchange mutants, we show that each of the BCR-associated PTKs (Lyn, Blk, Fyn, and Syk) shows different phosphorylation patterns with regard to the different FcgammaR isoforms and point|Fyn and Blk definitely phosphorylate Y-282 in the ITAM of Fc_RIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addi-tion to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation." SIGNOR-249337 FYN protein P06241 UNIPROT CTLA4 protein P16410 UNIPROT "up-regulates quantity by stabilization" phosphorylation Tyr201 SPLTTGVyVKMPPTE 9606 9973379 t "CTLA-4 can associate with the Src kinases Fyn and Lck and that transfection of Fyn or Lck, but not the unrelated kinase ZAP70, can induce tyrosine phosphorylation of CTLA-4 on residues Y201 and Y218.¬† Phosphorylation of CTLA-4 Y201 in Jurkat cells correlated with cell surface accumulation of CTLA-4." SIGNOR-251161 FYN protein P06241 UNIPROT MAG protein P20916 UNIPROT "up-regulates activity" phosphorylation Tyr620 LTEELAEyAEIRVK 10090 BTO:0000142 7525550 t "Fyn constitutively binds to MAG in a latent form. Ligand stimulation of L-MAG would result in activation of Fyn kinase and phosphorylation of Tyr-620. Binding and activation of PLC y through this phosphotyrosine residue would contribute to the signaling pathway involved in the regulation of myelination." SIGNOR-251178 FYN protein P06241 UNIPROT ACP1 protein P24666 UNIPROT "up-regulates activity" phosphorylation Tyr132 QLIIEDPyYGNDSDF 9534 BTO:0004055 9038134 t "We identify Tyr-131 as the major phosphorylation site and Tyr-132 as a minor site and the Src family PTKs Lck and Fyn as enzymes capable of phosphorylating these sites in vivo and in vitro. Both Tyr-131 and Tyr-132 are located next to the catalytic pocket of LMPTP, and especially, Tyr-131 seems to be important for the activity of LMPTP. Phosphorylation of Tyr-131 or Tyr-132, particularly the former, caused an increase in the activity of LMPTP." SIGNOR-251149 FYN protein P06241 UNIPROT ACP1 protein P24666 UNIPROT "up-regulates activity" phosphorylation Tyr133 LIIEDPYyGNDSDFE 9534 BTO:0004055 9038134 t "We identify Tyr-131 as the major phosphorylation site and Tyr-132 as a minor site and the Src family PTKs Lck and Fyn as enzymes capable of phosphorylating these sites in vivo and in vitro. Both Tyr-131 and Tyr-132 are located next to the catalytic pocket of LMPTP, and especially, Tyr-131 seems to be important for the activity of LMPTP. Phosphorylation of Tyr-131 or Tyr-132, particularly the former, caused an increase in the activity of LMPTP." SIGNOR-251150 FYN protein P06241 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr349 EEPPDHQyYNDFPGK 9606 BTO:0000782 9710204 t lperfetto "Syk and zap-70 were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site. Of the two potential grb2 binding sites (y239 and y317), y239 appears to play a greater role in recruiting sos through grb2." SIGNOR-59623 FYN protein P06241 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr350 EPPDHQYyNDFPGKE 9606 BTO:0000782 9710204 t lperfetto "Syk and zap-70 were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site. Of the two potential grb2 binding sites (y239 and y317), y239 appears to play a greater role in recruiting sos through grb2." SIGNOR-59627 FYN protein P06241 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr427 ELFDDPSyVNVQNLD 9606 BTO:0000782 9710204 t lperfetto "Syk and zap-70 were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site. Of the two potential grb2 binding sites (y239 and y317), y239 appears to play a greater role in recruiting sos through grb2." SIGNOR-59631 FYN protein P06241 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr427 ELFDDPSyVNVQNLD 9606 9741627 t lperfetto "Shc is subsequently phosphorylated at tyrosine 317 and recruits grb2" SIGNOR-60160 FYN protein P06241 UNIPROT NMT1 protein P30419 UNIPROT unknown phosphorylation Tyr180 YTLLNENyVEDDDNM -1 11594778 t "Human NMT was found to be phosphorylated by non-receptor tyrosine kinase family members of Lyn, Fyn and Lck. Tyr100 is the principle phosphorylation site on hNMT for Lyn and Fyn. The significance of a phosphorylation-dependent interaction between NMT and a tyrosine kinase is not known at present." SIGNOR-251179 FYN protein P06241 UNIPROT FCGR2C protein P31995 UNIPROT "up-regulates activity" phosphorylation Tyr294 YETADGGyMTLNPRA -1 8756631 t miannu "Fyn and Blk definitely phosphorylate Y-282 in the ITAM of FcgRIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addition to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation" SIGNOR-262677 FYN protein P06241 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Tyr142 AVVNLINyQDDAELA -1 12640114 t "Interaction of beta-catenin with alpha-catenin is regulated by the phosphorylation of beta-catenin Tyr-142. This residue can be phosphorylated in vitro by Fer or Fyn tyrosine kinases.  Transfection of these kinases to epithelial cells disrupted the association between both catenins." SIGNOR-251162 FYN protein P06241 UNIPROT CD79B protein P40259 UNIPROT "up-regulates activity" phosphorylation Tyr196 GMEEDHTyEGLDIDQ -1 9531288 t "CD79b cytoplasmic tail-containing GST fusion proteins were phosphorylated in vitro by baculovirus-produced Fyn, >80% of phosphorylation occurred on the N-terminal ITAM tyrosine. CD79a and CD79b function as transducers of B cell antigen receptor signals via a cytoplasmic sequence, termed the immunoreceptor tyrosine-based activation motif (ITAM). pY195 and pY206 in CD79b" SIGNOR-251154 FYN protein P06241 UNIPROT CD79B protein P40259 UNIPROT "up-regulates activity" phosphorylation Tyr207 DIDQTATyEDIVTLR -1 9531288 t "CD79b cytoplasmic tail-containing GST fusion proteins were phosphorylated in vitro by baculovirus-produced Fyn, >80% of phosphorylation occurred on the N-terminal ITAM tyrosine. CD79a and CD79b function as transducers of B cell antigen receptor signals via a cytoplasmic sequence, termed the immunoreceptor tyrosine-based activation motif (ITAM). pY195 and pY206 in CD79b" SIGNOR-251155 FYN protein P06241 UNIPROT CNN1 protein P51911 UNIPROT "down-regulates activity" phosphorylation Tyr261 SQRGMTVyGLPRQVY 9534 BTO:0000298 15206927 t "We identify, for the first time, tyrosine-phosphorylated calponin h3 within COS 7 cells, before and after their transfection with the pSV vector containing cDNA encoding the cytoplasmic, Src-related, tyrosine kinase, Fyn. we have localized the tyrosines phosphorylated without actin to Tyr261 in calponin h3 and to Tyr261 and Tyr182 in calponin h1. Tyrosine phosphorylation of calponins inhibits their binding to F-actin" SIGNOR-251158 FYN protein P06241 UNIPROT CHN2 protein P52757 UNIPROT down-regulates phosphorylation Tyr21 VSSDAEEyQPPIWKS 9606 17560670 t llicata "Ere we report that beta2-chimaerin is tyrosine-phosphorylated by src-family kinases (sfks) upon cell stimulation with epidermal growth factor (egf). these results suggest tyr-21 phosphorylation as a novel, sfk-dependent mechanism that negatively regulates beta2-chimaerin rac-gap activity." SIGNOR-155709 FYN protein P06241 UNIPROT DLG4 protein P78352 UNIPROT up-regulates phosphorylation Tyr523 REDSVLSyETVTQME 9606 BTO:0000938 BTO:0000142 18721130 t llicata "Psd-95 is phosphorylated either by purified src/fyn kinases in vitro or by co-expression of constitutively active src/fyn in cos7 cells. psd-95 tyr(523) phosphorylation contributes to the post-ischaemic over-activation of nmda receptors." SIGNOR-180449 FYN protein P06241 UNIPROT H3-3A protein P84243 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 15537652 t gcesareni "Here we provide evidence that fyn kinase, a member of the src kinase family, is involved in the uvb-induced phosphorylation of histone h3 at serine 10" SIGNOR-130274 FYN protein P06241 UNIPROT IFITM3 protein Q01628 UNIPROT "up-regulates quantity" phosphorylation Tyr20 NSGQPPNyEMLKEEH 10090 BTO:0000452 24627473 t miannu "We determined that both mouse and human IFITM3 are phosphorylated by the protein-tyrosine kinase FYN on tyrosine 20 (Tyr(20)). Phosphorylation of IFITM3 on Tyr20 Leads to Plasma Membrane Accumulation." SIGNOR-266304 FYN protein P06241 UNIPROT CAV1 protein Q03135 UNIPROT "down-regulates activity" phosphorylation Tyr14 VDSEGHLyTVPIREQ 9606 12921535 t lperfetto "Caveolin-1 is phosphorylated on tyr(14) in response to both oxidative and hyperosmotic stress. In the present paper, we show that this phosphorylation requires activation of the src family kinase fyn.Therefore," SIGNOR-118003 FYN protein P06241 UNIPROT PRKCQ protein Q04759 UNIPROT up-regulates phosphorylation 9606 BTO:0000782 10383400 t miannu "Further indications of direct interaction are that p59fyn potentiates ?PKC Catalytic activity and that ?PKC Is a substrate for tyrosine phosphorylation by p59fyn." SIGNOR-68798 FYN protein P06241 UNIPROT GRIN2A protein Q12879 UNIPROT "up-regulates activity" phosphorylation Tyr1105 CSEVERTyLKTKSSS -1 10195142 t lperfetto "To gain further insight into the roles of Src and Fyn in the phosphorylation and regulation of the NMDA receptor, we have characterized the tyrosine phosphorylation of NR2A and NR2B by exogenous Src and FynIn the case of NR2A, three potential tyrosine phosphorylation sites have been proposed: Tyr1105, Tyr1267 and Tyr1387 (Zheng et al. 1998; Bi et al. 2000), all of which are similarly located in the C-terminal, cytoplasmic domain." SIGNOR-247151 FYN protein P06241 UNIPROT GRIN2A protein Q12879 UNIPROT "up-regulates activity" phosphorylation Tyr1267 PATGEQVyQQDWAQN -1 10195142 t lperfetto "To gain further insight into the roles of Src and Fyn in the phosphorylation and regulation of the NMDA receptor, we have characterized the tyrosine phosphorylation of NR2A and NR2B by exogenous Src and FynIn the case of NR2A, three potential tyrosine phosphorylation sites have been proposed: Tyr1105, Tyr1267 and Tyr1387 (Zheng et al. 1998; Bi et al. 2000), all of which are similarly located in the C-terminal, cytoplasmic domain." SIGNOR-247155 FYN protein P06241 UNIPROT GRIN2B protein Q13224 UNIPROT unknown phosphorylation Tyr1070 ISTHTVTyGNIEGNA -1 11024032 t "Tyr-932, Tyr-1039, Tyr-1070, Tyr-1109, Tyr-1252, Tyr-1336, and Tyr-1472 are Fyn-mediated phosphorylation sites in GluRε2 in vitro." SIGNOR-251170 FYN protein P06241 UNIPROT GRIN2B protein Q13224 UNIPROT unknown phosphorylation Tyr1109 FDEIELAyRRRPPRS -1 11024032 t "Tyr-932, Tyr-1039, Tyr-1070, Tyr-1109, Tyr-1252, Tyr-1336, and Tyr-1472 are Fyn-mediated phosphorylation sites in GluRε2 in vitro." SIGNOR-251171 FYN protein P06241 UNIPROT GRIN2B protein Q13224 UNIPROT unknown phosphorylation Tyr1252 CKKAGNLyDISEDNS 9606 BTO:0000007 11024032 t "Tyr-1252, Tyr-1336, and Tyr-1472 of GluRε2 are phosphorylated in 293T cells when active Fyn is co-expressed." SIGNOR-251172 FYN protein P06241 UNIPROT GRIN2B protein Q13224 UNIPROT unknown phosphorylation Tyr1336 RFMDGSPyAHMFEMS 9606 BTO:0000007 11024032 t "Tyr-1252, Tyr-1336, and Tyr-1472 of GluRε2 are phosphorylated in 293T cells when active Fyn is co-expressed." SIGNOR-251173 RB1 protein P06400 UNIPROT E2F1 protein Q01094 UNIPROT "down-regulates activity" binding 9606 8255752 t amattioni "E2f binds rb. E2f activation domain is the target for rb-induced repression. Rb can silence the 57 residue e2f activation domain. Rb can mask e2f residues involved in the activation process, possibly by mimicking a component of the transcriptional machinery" SIGNOR-37305 RB1 protein P06400 UNIPROT E2F2 protein Q14209 UNIPROT down-regulates binding 9606 22569856 t gcesareni "Cyclin-dependent kinase (cdk) phosphorylation of the retinoblastoma protein (rb) drives cell proliferation through rb complexes with e2f transcription factors and other regulatory proteins." SIGNOR-197328 RB1 protein P06400 UNIPROT TRIP11 protein Q15643 UNIPROT down-regulates binding 9606 9256431 t miannu "The wild-type rb is able to interact with the rb-binding domain of trip230 / rb represses trip230-mediated activation of tr-regulated transcription." SIGNOR-50266 PGR protein P06401 UNIPROT ESR1 protein P03372 UNIPROT up-regulates binding 9606 BTO:0000150 12612073 t gcesareni "Here we identify two domains of prb, erid-i and -ii, mediating a direct interaction with the ligand-binding domain of eralpha." SIGNOR-98807 PGR protein P06401 UNIPROT KLK4 protein Q9Y5K2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001248 19147544 f miannu "we have shown that K4.pPRE interacts directly with the PR to up-regulate KLK4 gene expression in T47D cells." SIGNOR-254913 PTMA protein P06454 UNIPROT CASP9 protein P55211 UNIPROT down-regulates binding 9606 BTO:0000567 12522243 t "PHAP proteins promoted caspase-9 activation after apoptosome formation, whereas ProT negatively regulated caspase-9 activation by inhibiting apoptosome formation." SIGNOR-259079 CDK1 protein P06493 UNIPROT CDC7 protein O00311 UNIPROT up-regulates phosphorylation Thr376 QVAPRAGtPGFRAPE 9606 10846177 t gcesareni "Hucdc7 and ask proteins can also be phosphorylated by cdks in vitro. Among four possible cdk phosphorylation sites of hucdc7, replacement of thr-376, corresponding to the activating threonine of cdk, with alanine (t376a mutant) dramatically reduces kinase activity, indicative of kinase activation by phosphorylation of this residue." SIGNOR-78311 CDK1 protein P06493 UNIPROT DCTN6 protein O00399 UNIPROT "up-regulates activity" phosphorylation Thr186 KTMKGSStPVKN -1 23455152 t lperfetto "Here, we show that the p27/p25 heterodimer undergoes mitotic phosphorylation by cyclin‐dependent kinase 1 (Cdk1) at a single site, p27 Thr186, to generate an anchoring site for polo‐like kinase 1 (Plk1) at kinetochores." SIGNOR-264777 CDK1 protein P06493 UNIPROT PIK3C2A protein O00443 UNIPROT "down-regulates activity" phosphorylation Ser259 KVSNLQVsPKSEDIS 9606 BTO:0000567 12719431 t lperfetto "Mitotic and stress-induced phosphorylation of HsPI3K-C2alpha targets the protein for degradation. Stress-dependent and mitotic phosphorylation of hspik3-c2alpha occurs on the same serine residue (ser259) within a recognition motif for proline-directed kinases. Mitotic phosphorylation of hspik3-c2alpha can be attributed to cdc2 activity, and stress-induced phosphorylation of hspik3-c2alpha is mediated by jnk/sapk" SIGNOR-100903 CDK1 protein P06493 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates phosphorylation Ser286 TSGGVSEsPSGFSKH 9606 21765472 t lperfetto "Chk1 itself is also subject to cdk-mediated phosphorylation at serines 286 and 301 (s286 and 301). We show that chk1 s301 phosphorylation increases as cells progress through s and g2 and that both cdk1 and cdk2 are likely to contribute to this modification in vivo. We also find that substitution of s286 and s301 with non-phosphorylatable alanine residues strongly attenuates dna damage-induced chk1 activation and g2 checkpoint proficiency" SIGNOR-175071 CDK1 protein P06493 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates phosphorylation Ser301 IQSNLDFsPVNSASS 9606 21765472 t lperfetto "Chk1 itself is also subject to cdk-mediated phosphorylation at serines 286 and 301 (s286 and 301). We show that chk1 s301 phosphorylation increases as cells progress through s and g2 and that both cdk1 and cdk2 are likely to contribute to this modification in vivo. We also find that substitution of s286 and s301 with non-phosphorylatable alanine residues strongly attenuates dna damage-induced chk1 activation and g2 checkpoint proficiency" SIGNOR-175075 CDK1 protein P06493 UNIPROT SYN3 protein O14994 UNIPROT up-regulates phosphorylation Ser470 PQGQQPLsPQSGSPQ 9606 BTO:0000938 14732590 t lperfetto "A rare, missense polymorphism, s470n, was identified in the synapsin iii gene and appeared more frequently in individuals with schizophrenia than in controls. Ser470, was determined to be a substrate for mitogen-activated protein kinase, a downstream effector of neurotrophin action." SIGNOR-121398 CDK1 protein P06493 UNIPROT MDM4 protein O15151 UNIPROT down-regulates phosphorylation Ser96 SFSVKDPsPLYDMLR 9606 15735705 t lperfetto "Cdc2p34 phosphorylates mdmx on ser 96 in vitro. Mutation within this site (mdmx(s96a)) impairs, whereas phosphomimic substitution (mdmx(s96d)) increases the cytoplasmic localization of mdmx, suggesting that cdk2/cdc2p34 phosphorylation is required for export of mdmx from the nucleus" SIGNOR-134388 CDK1 protein P06493 UNIPROT FANCG protein O15287 UNIPROT up-regulates phosphorylation Ser387 PRFSPPPsPPGPCMP 9606 15367677 t gcesareni "S387a mutant abolished fancg fusion protein phosphorylation by cdc2." SIGNOR-129061 CDK1 protein P06493 UNIPROT TP73 protein O15350 UNIPROT "down-regulates activity" phosphorylation Thr86 AASASPYtPEHAASV 9606 SIGNOR-C17 12676926 t gcesareni "Cyclin-dependent kinases phosphorylate p73 at threonine 86 in a cell cycle-dependent manner and negatively regulate p73.Furthermore, cyclin a/cdk1/2, cyclin b/cdk1/2, and cyclin e/cdk2 complexes can phosphorylate multiple p73 isoforms in vitro at threonine 86." SIGNOR-99742 CDK1 protein P06493 UNIPROT BIRC5 protein O15392 UNIPROT up-regulates phosphorylation Thr34 FLEGCACtPERMAEA 9606 11861764 t gcesareni "Survivin is a member of the inhibitor of apoptosis gene family that has been implicated in both apoptosis inhibition and regulation of mitosisin synchronized cultures, cytosolic survivin abruptly increased at mitosis, physically associated with p34(cdc2), and was phosphorylated by p34(cdc2) on thr(34), in vivo" SIGNOR-115129 CDK1 protein P06493 UNIPROT BUB1 protein O43683 UNIPROT up-regulates phosphorylation Thr609 SAAQLAStPFHKLPV 9606 BTO:0000567 16760428 t gcesareni "The plk1-bub1 interaction requires the polo-box domain (pbd) of plk1 and is enhanced by cyclin-dependent kinase 1 (cdk1)-mediated phosphorylation of bub1 at t609" SIGNOR-147065 CDK1 protein P06493 UNIPROT BUB1B protein O60566 UNIPROT up-regulates phosphorylation Thr620 RAARFVStPFHEIMS 9606 17785528 t lperfetto "Here, we demonstrate that bubr1 is phosphorylated on the cdk1 site t620, which triggers the recruitment of plk1 and phosphorylation of bubr1 by plk1 both in vitro and in vivo. Phosphorylation does not appear to be required for spindle checkpoint function but instead is important for the stability of kinetochore-microtubule (kt-mt) interactions" SIGNOR-157642 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Thr67 LSILSGGtPKRCLDL 9606 SIGNOR-C17 10864927 t gcesareni "Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b." SIGNOR-78432 CDK1 protein P06493 UNIPROT SUN1 protein O94901 UNIPROT "down-regulates activity" phosphorylation Ser48 KLDPVFDsPRMSRRS 9606 BTO:0000567 25482198 t miannu "Here, we show that SUN1, located in the INM, undergoes mitosis-specific phosphorylation on at least 3 sites within its nucleoplasmic N-terminus. We further identify Cdk1 as the kinase responsible for serine 48 and 333 phosphorylation, while serine 138 is phosphorylated by Plk1. Together, these data support a model whereby mitotic phosphorylation of SUN1 disrupts interactions with nucleoplasmic binding partners, promoting disassembly of the nuclear lamina and, potentially, its chromatin interactions." SIGNOR-263099 CDK1 protein P06493 UNIPROT NFAT5 protein O94916 UNIPROT up-regulates phosphorylation Thr135 TVQQHPStPKRHTVL 9606 BTO:0000007 21209322 t lperfetto "High nacl-induced activation of cdk5 increases phosphorylation of the osmoprotective transcription factor tonebp/orebp at threonine 135, which contributes to its rapid nuclear localization. we performed in vitro kinase assays using the tonebp/orebp peptide containing t135 as substrate (figure 3b, right panel) and various recombinant kinases. The peptide is strongly phosphorylated by cdk5, less by cdk1." SIGNOR-170882 CDK1 protein P06493 UNIPROT KAT7 protein O95251 UNIPROT up-regulates phosphorylation Thr85 TRSQQQPtPVTPKKY 9606 18250300 t lperfetto "Here, we show that the interaction between plk1 and hbo1 is mitosis-specific and that plk1 phosphorylates hbo1 on ser-57 in vitro and in vivo. During mitosis, cdk1 phosphorylates hbo1 on thr-85/88, creating a docking site for plk1 to be recruited. Significantly, the overexpression of hbo1 mutated at the plk1 phosphorylation site (s57a) leads to cell-cycle arrest in the g1/s phase, inhibition of chromatin loading of the minichromosome maintenance (mcm) complex, and a reduced dna replication rate." SIGNOR-160743 CDK1 protein P06493 UNIPROT KAT7 protein O95251 UNIPROT up-regulates phosphorylation Thr88 QQQPTPVtPKKYPLR 9606 18250300 t lperfetto "Here, we show that the interaction between plk1 and hbo1 is mitosis-specific and that plk1 phosphorylates hbo1 on ser-57 in vitro and in vivo. During mitosis, cdk1 phosphorylates hbo1 on thr-85/88, creating a docking site for plk1 to be recruited. Significantly, the overexpression of hbo1 mutated at the plk1 phosphorylation site (s57a) leads to cell-cycle arrest in the g1/s phase, inhibition of chromatin loading of the minichromosome maintenance (mcm) complex, and a reduced dna replication rate." SIGNOR-160747 CDK1 protein P06493 UNIPROT LATS1 protein O95835 UNIPROT up-regulates phosphorylation Ser613 EKKQITTsPITVRKN 9606 SIGNOR-C17 12372621 t lperfetto "Warts is a serine/threonine kinase and a dynamic component of the mitotic apparatus. We have found that cdc2/cyclin b forms a complex with a fraction of warts in the centrosome and phosphorylates the ser613 site of warts during mitosisit can be speculated that phosphorylation of warts by cdc2/cyclin b promotes a protein complex formation on the mitotic apparatus at early mitosis, which may be required for subsequent activation of warts kinase at the metaphase-anaphase transition." SIGNOR-94160 CDK1 protein P06493 UNIPROT EGFR protein P00533 UNIPROT down-regulates phosphorylation Ser1026 PQQGFFSsPSTSRTP 9606 BTO:0000017 8360196 t gcesareni "Using a synthetic peptide corresponding to the sequence surrounding ser-1002, p34cdc2 was identified as a kinase capable of phosphorylating this serine residue. phosphorylation of the egf receptor by p34cdc2 was associated with a decrease in its tyrosine protein kinase activity." SIGNOR-38313 CDK1 protein P06493 UNIPROT LMNA protein P02545 UNIPROT up-regulates phosphorylation Ser22 QASSTPLsPTRITRL 9606 18815303 t gcesareni "Phosphorylation by mitotic cdc2 kinase at ser-22, ser-390, and ser-392 residues on lamin a/c, or by protein kinase c (pkc) during apoptosis, leads to the depolymerization of lamin (disassembly of the nuclear lamina), which may lead to their release from the inm" SIGNOR-181310 CDK1 protein P06493 UNIPROT LMNA protein P02545 UNIPROT up-regulates phosphorylation Ser390 EEERLRLsPSPTSQR 9606 18815303 t gcesareni "Phosphorylation by mitotic cdc2 kinase at ser-22, ser-390, and ser-392 residues on lamin a/c, or by protein kinase c (pkc) during apoptosis, leads to the depolymerization of lamin (disassembly of the nuclear lamina), which may lead to their release from the inm" SIGNOR-181314 CDK1 protein P06493 UNIPROT LMNA protein P02545 UNIPROT up-regulates phosphorylation Ser392 ERLRLSPsPTSQRSR 9606 18815303 t gcesareni "Phosphorylation by mitotic cdc2 kinase at ser-22, ser-390, and ser-392 residues on lamin a/c, or by protein kinase c (pkc) during apoptosis, leads to the depolymerization of lamin (disassembly of the nuclear lamina), which may lead to their release from the inm" SIGNOR-181318 CDK1 protein P06493 UNIPROT TK1 protein P04183 UNIPROT down-regulates phosphorylation Ser13 LPTVLPGsPSKTRGQ 9606 BTO:0000567 12435275 t gcesareni "Given that the dimeric form of tk1 is less active than the tetrameric, we propose that mitotic phosphorylation of serine-13 is of physiological importance, in that it may counteract atp-dependent activation of tk1 by affecting its quaternary structure, thus attenuating its enzymatic function at the g2/m phase." SIGNOR-95574 CDK1 protein P06493 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" phosphorylation Ser315 LPNNTSSsPQPKKKP 9606 24173284 t lperfetto "The N-terminus of E2F1 can interact directly with a region towards the C-terminus of p53, resulting in increased nuclear retention of p53 and p53-mediated transcription and apoptosis. This is inhibited by competition between p53 and cyclin A at the binding site within E2F19,10. The interaction between p53 and E2F1 is enhanced by phosphorylation of p53 on Ser315, a residue within the E2F1 binding region that is phosphorylated by cell cycle kinases such as cdk1, cdk2, cdk9 and Aurora kinase A" SIGNOR-84256 CDK1 protein P06493 UNIPROT KRT18 protein P05783 UNIPROT up-regulates phosphorylation Ser34 RPVSSAAsVYAGAGG 9606 9524113 t lperfetto "We identified k18 ser33 as an interphase phosphorylation site, which increases its phosphorylation during mitosis in cultured cells and regenerating liver, and as an in vitro cdc2 kinase phosphorylation site. K18 ser33 phosphorylation dictates binding to 14_3_3 proteins" SIGNOR-55994 CDK1 protein P06493 UNIPROT KRT8 protein P05787 UNIPROT up-regulates phosphorylation Ser432 SAYGGLTsPGLSYSL 9606 9524113 t lperfetto "With regard to k8 phosphorylation at ser-431, it increases dramatically upon stimulation of cells with epidermal growth factor (egf) or after mitotic arrest and is the major k8 phosphorylated residue after incubating k8 immunoprecipitates with mitogen-activated protein or cdc2 kinases." SIGNOR-56054 CDK1 protein P06493 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser249 AVIPINGsPRTPRRG 9606 1756735 t lperfetto "The retinoblastoma gene product (prb) is a nuclear phosphoprotein that is thought to play a key role in the negative regulation of cellular proliferation. The active form of prb is underphosphorylated. Using synthetic peptides corresponding to potential cdc2 phosphorylation sites, we have developed a strategy which has allowed the identification of five sites. S249, t252, t373, s807 and s811 are phosphorylated in vivo, and in each case these sites correspond closely to the consensus sequence for phosphorylation by p34cdc2." SIGNOR-21548 CDK1 protein P06493 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser807 PGGNIYIsPLKSPYK 9606 1756735 t lperfetto "The retinoblastoma gene product (prb) is a nuclear phosphoprotein that is thought to play a key role in the negative regulation of cellular proliferation. The active form of prb is underphosphorylated. Using synthetic peptides corresponding to potential cdc2 phosphorylation sites, we have developed a strategy which has allowed the identification of five sites. S249, t252, t373, s807 and s811 are phosphorylated in vivo, and in each case these sites correspond closely to the consensus sequence for phosphorylation by p34cdc2." SIGNOR-21552 CDK1 protein P06493 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser811 IYISPLKsPYKISEG 9606 1756735 t gcesareni "The retinoblastoma gene product (prb) is a nuclear phosphoprotein that is thought to play a key role in the negative regulation of cellular proliferation. The active form of prb is underphosphorylated. Using synthetic peptides corresponding to potential cdc2 phosphorylation sites, we have developed a strategy which has allowed the identification of five sites. S249, t252, t373, s807 and s811 are phosphorylated in vivo, and in each case these sites correspond closely to the consensus sequence for phosphorylation by p34cdc2." SIGNOR-21556 CDK1 protein P06493 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Thr252 PINGSPRtPRRGQNR 9606 1756735 t lperfetto "The retinoblastoma gene product (prb) is a nuclear phosphoprotein that is thought to play a key role in the negative regulation of cellular proliferation. The active form of prb is underphosphorylated. Using synthetic peptides corresponding to potential cdc2 phosphorylation sites, we have developed a strategy which has allowed the identification of five sites. S249, t252, t373, s807 and s811 are phosphorylated in vivo, and in each case these sites correspond closely to the consensus sequence for phosphorylation by p34cdc2." SIGNOR-21560 CDK1 protein P06493 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Thr373 VNVIPPHtPVRTVMN 9606 1756735 t lperfetto "The retinoblastoma gene product (prb) is a nuclear phosphoprotein that is thought to play a key role in the negative regulation of cellular proliferation. The active form of prb is underphosphorylated. Using synthetic peptides corresponding to potential cdc2 phosphorylation sites, we have developed a strategy which has allowed the identification of five sites. S249, t252, t373, s807 and s811 are phosphorylated in vivo, and in each case these sites correspond closely to the consensus sequence for phosphorylation by p34cdc2." SIGNOR-21564 CDK1 protein P06493 UNIPROT NPM1 protein P06748 UNIPROT "down-regulates activity" phosphorylation Thr199 VKKSIRDtPAKNAQK 9606 SIGNOR-C17 12058066 t llicata "However, under the experimental conditions used here, the t199 residue was the most likely candidate to be phosphorylated by cyclin b/cdc2 these results strongly support the concept that the rna binding activity of b23.1 is inactivated by cyclin b/cdc2-mediated phosphorylation." SIGNOR-89605 CDK1 protein P06493 UNIPROT NPM1 protein P06748 UNIPROT "down-regulates activity" phosphorylation Thr234 SFKKQEKtPKTPKGP 9606 SIGNOR-C17 12058066 t gcesareni "Both subtypes of B23 proteins were phosphorylated during mitosis by cyclin B/cdc2. The RNA binding activity of B23.1 was repressed through cyclin B/cdc2-mediated phosphorylation at specific sites in B23. Thus, the RNA binding activity of B23.1 is stringently modulated by its phosphorylation and subtype association." SIGNOR-89597 CDK1 protein P06493 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr739 SEGSGTAtPSALITT 9606 BTO:0000887;BTO:0001260 SIGNOR-C17 20150555 t gcesareni "Moreover, we showed that sp1 is a novel mitotic substrate of cdk1/cyclin b1 and is phosphorylated by it at thr 739 before the onset of mitosis." SIGNOR-163738 CDK1 protein P06493 UNIPROT VIM protein P08670 UNIPROT down-regulates phosphorylation Ser55 TSRSLYAsSPGGVYA 9606 7983050 t llicata "These results strongly suggest that cdc2 kinase is the kinase which phosphorylates vimentin ser55 in the entire cytoplasm during mitosis and that the appearance of immunoreactivities with antibody 4a4 in cell staining indeed reflect the vimentin phosphorylation by cdc2 kinase. immunofluorescent evidence using antibody 4a4 and biochemical analysis using vimentin ser55 peptide showed that the degree of disassembly of vimentin filament of various cell types at early mitotic phase correlated well with the amount of mitotically activated cdc2 kinase." SIGNOR-35492 CDK1 protein P06493 UNIPROT AR protein P10275 UNIPROT up-regulates phosphorylation Ser83 QQQQQETsPRQQQQQ 9606 BTO:0001130 21799006 t gcesareni "At first, the data show that cdk5 enables phosphorylation of ar at ser-81 site through direct biochemical interaction and, therefore, results in the stabilization of ar proteins although ar was reported as substrates for cdk9 (5) as well as cdk1" SIGNOR-175692 CDK1 protein P06493 UNIPROT BCL2 protein P10415 UNIPROT "down-regulates activity" phosphorylation Thr56 FSSQPGHtPHPAASR 9606 10766756 t gcesareni "Using synthetic peptides and mutant cell lines, we identified threonine 56, one of two consensus sites for cdc2 within the bcl-2 sequence, as a residue phosphorylated by cdc2. Mutation at threonine 56 abrogated the cell cycle inhibitory effect of bcl-2 without affecting anti-apoptotic function.Taken together, our present findings indicate that phosphorylation of bcl-2 at threonine 56 by cdc2 is required for bcl-2-mediated cell cycle inhibition, which may have some roles during mitosis in the normal cell cycle." SIGNOR-76837 CDK1 protein P06493 UNIPROT TOP2A protein P11388 UNIPROT unknown phosphorylation Ser1247 KNENTEGsPQEDGVE 9606 BTO:0000567 7635160 t llicata "We show that many of the sites phosphorylated on topoisomerase iia in vivo correspond to sites phosphorylated in vitro by both p3pdcz and mitogen-activated protein (map) kinase. similarly, phosphopeptide 4 was absent from a mutant protein lacking ser1246" SIGNOR-30244 CDK1 protein P06493 UNIPROT TOP2A protein P11388 UNIPROT unknown phosphorylation Ser1354 DFVPSDAsPPKTKTS 9606 BTO:0000567 7635160 t llicata "We show that many of the sites phosphorylated on topoisomerase iia in vivo correspond to sites phosphorylated in vitro by both p3pdcz and mitogen-activated protein (map) kinase. we have also shown that phosphorylation of ser1353 and ser1360 yields different phosphopeptide maps depending upon whether one or both of these sites are phosphorylated." SIGNOR-30248 CDK1 protein P06493 UNIPROT TOP2A protein P11388 UNIPROT unknown phosphorylation Ser1361 SPPKTKTsPKLSNKE 9606 BTO:0000567 7635160 t llicata "We show that many of the sites phosphorylated on topoisomerase iia in vivo correspond to sites phosphorylated in vitro by both p3pdcz and mitogen-activated protein (map) kinase. we have also shown that phosphorylation of ser1353 and ser1360 yields different phosphopeptide maps depending upon whether one or both of these sites are phosphorylated." SIGNOR-30252 CDK1 protein P06493 UNIPROT RPA2 protein P15927 UNIPROT "up-regulates activity" phosphorylation Ser29 QSPGGFGsPAPSQAE 9606 1318195 t llicata "Cdc2 family kinases phosphorylate a human cell dna replication factor, rpa, and activate dna replication. therefore, the serines on rpa p34 that were necessary for phosphorylation by cdc2 kinase were also necessary for phosphorylation in the cell" SIGNOR-16975 CDK1 protein P06493 UNIPROT HMGA1 protein P17096 UNIPROT down-regulates phosphorylation Ser36 PRKQPPVsPGTALVG 9606 17960875 t gcesareni "Here, we found that hipk2 phosphorylates hmga1a at ser-35, thr-52, and thr-77, and hmga1b at thr-41 and thr-66. In addition, we demonstrated that cdc2, which is known to phosphorylate hmga1 proteins, could induce the phosphorylation of hmga1 proteins at the same ser/thr sites. we found that the hipk2-phosphorylated hmga1a reduced the binding affinity of hmga1a to human germ line promoter, and the drop in binding affinity induced by hipk2 phosphorylation was lower than that introduced by cdc2 phosphorylation." SIGNOR-158604 CDK1 protein P06493 UNIPROT HMGA1 protein P17096 UNIPROT down-regulates phosphorylation Thr53 KEPSEVPtPKRPRGR 9606 17960875 t gcesareni "Here, we found that hipk2 phosphorylates hmga1a at ser-35, thr-52, and thr-77, and hmga1b at thr-41 and thr-66. In addition, we demonstrated that cdc2, which is known to phosphorylate hmga1 proteins, could induce the phosphorylation of hmga1 proteins at the same ser/thr sites. we found that the hipk2-phosphorylated hmga1a reduced the binding affinity of hmga1a to human germ line promoter, and the drop in binding affinity induced by hipk2 phosphorylation was lower than that introduced by cdc2 phosphorylation." SIGNOR-158608 CDK1 protein P06493 UNIPROT HMGA1 protein P17096 UNIPROT down-regulates phosphorylation Thr78 KTRKTTTtPGRKPRG 9606 1939057 t lperfetto "Phosphorylation of the dna-binding domain of nonhistone high-mobility group i protein by cdc2 kinase: reduction of binding affinity" SIGNOR-22338 CDK1 protein P06493 UNIPROT PTPN2 protein P17706 UNIPROT unknown phosphorylation Ser304 LSPAFDHsPNKIMTE 9606 15030318 t llicata "Our studies identify ser-304 as a major phosphorylation site in human tcptp, and the tc45 variant as a novel mitotic cdk substrate." SIGNOR-123467 CDK1 protein P06493 UNIPROT PTPN1 protein P18031 UNIPROT unknown phosphorylation Ser386 LRGAQAAsPAKGEPS 9606 BTO:0000567 8491187 t llicata "Ptp1b is phosphorylated on ser386 by p34cdc2 in vivo." SIGNOR-39233 CDK1 protein P06493 UNIPROT RCC1 protein P18754 UNIPROT "up-regulates activity" phosphorylation Ser387 GQDEDAWsPVEMMGK -1 15014043 t miannu "We show here that Cdc2 kinase phosphorylates the serines located in or near the nuclear localization signal (NLS) of human RCC1, the nucleotide exchange factor for Ran. This phosphorylation is necessary for RCC1 to generate RanGTP on mitotic chromosomes in mammalian cells, which in turn is required for spindle assembly and chromosome segregation. However, when both S2 and S11 were simultaneously mutated to As, the resulting 6His-RCC1S2,11A failed to be phosphorylated, whereas all of the other double mutants were phosphorylated (Fig. 1C). As expected, mutating all four sites to As (the 6His-RCC1S2,11,387A-T274A) also blocked phosphorylation (Fig. 1C)." SIGNOR-262703 CDK1 protein P06493 UNIPROT RCC1 protein P18754 UNIPROT "up-regulates activity" phosphorylation Thr274 SNYHQLGtPGTESCF -1 15014043 t miannu "We show here that Cdc2 kinase phosphorylates the serines located in or near the nuclear localization signal (NLS) of hum an RCC1, the nucleotide exchange factor for Ran. This phosphorylation is necessary for RCC1 to generate RanGTP on mitotic chromosomes in mammalian cells, which in turn is required for spindle assembly and chromosome segregation. However, when both S2 and S11 were simultaneously mutated to As, the resulting 6His-RCC1S2,11A failed to be phosphorylated, whereas all of the other double mutants were phosphorylated (Fig. 1C). As expected, mutating all four sites to As (the 6His-RCC1S2,11,387A-T274A) also blocked phosphorylation (Fig. 1C)." SIGNOR-262704 CDK1 protein P06493 UNIPROT LIG1 protein P18858 UNIPROT "up-regulates activity" phosphorylation Ser76 EEEDEALsPAKGQKP 9606 BTO:0000567 12851383 t lperfetto "We show that three residues (ser51, ser76, and ser91), which are part of cyclin-dependent kinase sites, are phosphorylated in a cell cycle-dependent manner." SIGNOR-103242 CDK1 protein P06493 UNIPROT UBA1 protein P22314 UNIPROT up-regulates phosphorylation Ser4 sPLSKKRR 9606 BTO:0000150 7673335 t lperfetto "Ubiquitin-activating enzyme, e1, is phosphorylated in mammalian cells by the protein kinase cdc2. Each serine residue was independently mutated to an alanine and analyzed by two-dimensional electrophoresis;only serine 4 was phosphorylated. Disruption of the basic amino acids within the nls resulted in loss of exclusive nuclear localization and a 90-95% decrease in the phosphorylation of ha1-e1" SIGNOR-31157 CDK1 protein P06493 UNIPROT UBA1 protein P22314 UNIPROT up-regulates phosphorylation Ser835 ELKATLPsPDKLPGF 9606 BTO:0000567 7724583 t lperfetto "Ubiquitin-activating enzyme, e1, is phosphorylated in mammalian cells by the protein kinase cdc2. Thus, the serine at position 835 is a phosphorylation site. Taking these findings into consideration, we consider that cyclin b might be one of the substrates targeted by the specific ubiquitin conjugation pathway activated by the phosphorylation of e1 with cdc2 kinase." SIGNOR-32225 CDK1 protein P06493 UNIPROT UBA1 protein P22314 UNIPROT up-regulates phosphorylation Ser4 sPLSKKRR 9606 9099746 t lperfetto "Ubiquitin-activating enzyme, e1, is phosphorylated in mammalian cells by the protein kinase cdc2. Each serine residue was independently mutated to an alanine and analyzed by two-dimensional electrophoresis;only serine 4 was phosphorylated. Disruption of the basic amino acids within the nls resulted in loss of exclusive nuclear localization and a 90-95% decrease in the phosphorylation of ha1-e1" SIGNOR-47162 CDK1 protein P06493 UNIPROT RPS3 protein P23396 UNIPROT up-regulates phosphorylation Thr221 KDEILPTtPISEQKG 9606 21871177 t gcesareni "These results suggest that the phosphorylation of rps3 by cdk1 occurs at thr221 during g2/m phase and, moreover, that this event is important for nuclear accumulation of rps3." SIGNOR-176131 CDK1 protein P06493 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr444 RFIGSPRtPVSPVKF 9606 BTO:0000887;BTO:0001103 11705993 t gcesareni "Interestingly, phosphorylation at several ser/thr residues within the c-terminal autoinhibitory tail appears to either activate or inhibit s6k1, depending on the cell cycle phase. phosphorylation of those residues (featured by the thr-421/ser-424 site) during mitosis pursued by cdk1 inactivates s6k1 we then assessed the phosphorylation status of the mitosis-specific inhibitory residue of s6k1, thr-421/ser-424, which is targeted by mitotic cdk1." SIGNOR-111507 CDK1 protein P06493 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser394 TRQTPVDsPDDSTLS 9606 BTO:0000567 12586835 t gcesareni "A physical interaction exists between cdc2 and s6k1, and this interaction is enhanced in mitotic cells. These results suggest that cdc2 provides a signal that triggers inactivation of s6k1 in mitosis, presumably serving to spare energy for costly mitotic processes at the expense of ribosomal protein synthesis." SIGNOR-98211 CDK1 protein P06493 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser434 SFEPKIRsPRRFIGS 9606 BTO:0000567 9271440 t gcesareni "The activation of p70s6k is associated with multiple phosphorylations at two sets of sites. The first set, s411, s418, t421, and s424, reside within the autoinhibitory domain, mutations of s371 abolished kinase activity. In mitotic hela cells, when the activity of cdc2 is high, s6k1 is phosphorylated at multiple ser/thr, pro (s/tp) sites, including ser(371), ser(411), thr(421), and ser(424)." SIGNOR-50607 CDK1 protein P06493 UNIPROT DNMT1 protein P26358 UNIPROT up-regulates phosphorylation Ser154 AKPEPSPsPRITRKS 9606 21565170 t gcesareni "We report that cyclin-dependent kinases (cdks) 1, 2 and 5 can phosphorylate ser154 of human dnmt1 in vitro. Further evidence of phosphorylation of endogenous dnmt1 at position 154 by cdks is also found in 293 cells treated with roscovitine, a specific inhibitor of cdk1, 2 and 5" SIGNOR-173677 CDK1 protein P06493 UNIPROT MAP4 protein P27816 UNIPROT down-regulates phosphorylation Ser787 KAPEKRAsPSKPASA 9606 10791892 t gcesareni "Ser787 in the proline-rich region of human map4 is a critical phosphorylation site that reduces its activity to promote tubulin polymerization. Phosphorylation on ser-787 negatively regulates map4 activity to promote microtubule assembly." SIGNOR-77087 CDK1 protein P06493 UNIPROT MAP4 protein P27816 UNIPROT down-regulates phosphorylation Ser696 PNKELPPsPEKKTKP 9606 BTO:0000567 9398320 t lperfetto "Map4 is phosphorylated by cdc2 kinase in mitotic hela/ phosphorylation by cdc2 kinase decreased the microtubule-stabilizing ability of map4, suggesting that there are critical phosphorylation sites among the five major cdc2 kinase-dependent phosphorylation sites [spots 4 (ser-696), 5, 6, 9, and 10 (ser-787)]." SIGNOR-53735 CDK1 protein P06493 UNIPROT MAP4 protein P27816 UNIPROT down-regulates phosphorylation Ser787 KAPEKRAsPSKPASA 9606 BTO:0000567 9398320 t lperfetto "Map4 is phosphorylated by cdc2 kinase in mitotic hela/ phosphorylation by cdc2 kinase decreased the microtubule-stabilizing ability of map4, suggesting that there are critical phosphorylation sites among the five major cdc2 kinase-dependent phosphorylation sites [spots 4 (ser-696), 5, 6, 9, and 10 (ser-787)]." SIGNOR-53739 CDK1 protein P06493 UNIPROT EEF1D protein P29692 UNIPROT unknown phosphorylation Ser133 APQTQHVsPMRQVEP 9606 12551973 t gcesareni "The sequence flanking ser-133 of ef-1delta completely matches the consensus phosphorylation site for a cellular protein kinase, cdc2, and in vitro kinase assays revealed that purified cdc2 phosphorylates ser-133 of ef-1delta." SIGNOR-97733 CDK1 protein P06493 UNIPROT CDC27 protein P30260 UNIPROT up-regulates phosphorylation Ser426 TQPNINDsLEITKLD 9606 14657031 t lperfetto "Apc activation is thought to depend on apc phosphorylation and cdc20 binding. We have identified 43 phospho_sites on apc of which at least 34 are mitosis specific. Of these, 32 sites are clustered in parts of apc1 and the tetratricopeptide repeat (tpr) subunits cdc27, cdc16, cdc23 and apc7. In vitro, at least 15 of the mitotic phospho_sites can be generated by cyclin_dependent kinase 1 (cdk1), and 3 by polo_like kinase 1 (plk1). Apc phosphorylation by cdk1, but not by plk1, is sufficient for increased cdc20 binding and apc activation" SIGNOR-119873 CDK1 protein P06493 UNIPROT WEE1 protein P30291 UNIPROT down-regulates phosphorylation Ser123 EEGFGSSsPVKSPAA 9606 16085715 t gcesareni "We show that phosphorylation of S123 (pS123) by CDK promoted the binding of Wee1A to beta-TrCP through three independent mechanisms. The pS123 not only directly interacted with basic residues in the WD40 repeat domain of beta-TrCP but also primed phosphorylation by two independent protein kinases, Plk1 and CK2 (formerly casein kinase 2)" SIGNOR-139465 CDK1 protein P06493 UNIPROT CDC25A protein P30304 UNIPROT up-regulates phosphorylation Ser18 RRLLFACsPPPASQP 9606 12411508 t lperfetto "Mitotic stabilization of cdc25a reflects its phosphorylation on ser17 and ser115 by cyclin b-cdk1, modifications required to uncouple cdc25a from its ubiquitin-proteasome-mediated turnover." SIGNOR-95260 CDK1 protein P06493 UNIPROT CDC25B protein P30305 UNIPROT up-regulates phosphorylation Ser160 PVRLLGHsPVLRNIT 9606 SIGNOR-C17 12107172 t lperfetto "We demonstrate that serine 146 is required for two crucial features of cdc25b1. It is essential for cdc25b1 to function as a mitotic inducer and to prevent cdc25b1 export from the nucleus. We also show that serine 146 is phosphorylated in vitro by cdk1-cyclin b. Serine 146 phosphorylation is proposed to be a key event in the regulation of the cdc25b function" SIGNOR-90451 CDK1 protein P06493 UNIPROT CDC25B protein P30305 UNIPROT up-regulates phosphorylation Ser321 KCQRLFRsPSMPCSV 9606 20801879 t gcesareni "Ser(321) is phosphorylated in mitosis by cdk1. The mitotic phosphorylation of ser(321) acts to maintain full activation of cdc25b by disrupting 14-3-3 binding to ser(323) and enhancing the dephosphorylation of ser(323) to block 14-3-3 binding to this site." SIGNOR-167641 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT down-regulates phosphorylation Ser168 SEMKYLGsPITTVPK 9606 10037602 t gcesareni "Phosphorylation at thr-48, thr-67, ser-122, thr-130, ser-168 and ser-214 occurs at g2 and g2-m transition and is catalyzed by cdk1. Ser-168 phosphorylation levels are lower than those at the other 5 cdk1 sites. Phosphorylation by cdk1 leads to increased activity." SIGNOR-64972 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT down-regulates phosphorylation Ser168 SEMKYLGsPITTVPK 9606 8119945 t gcesareni "Phosphorylation at thr-48, thr-67, ser-122, thr-130, ser-168 and ser-214 occurs at g2 and g2-m transition and is catalyzed by cdk1. Ser-168 phosphorylation levels are lower than those at the other 5 cdk1 sites. Phosphorylation by cdk1 leads to increased activity." SIGNOR-36279 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Ser214 SRSGLYRsPSMPENL 9606 10037602 t gcesareni "Phosphorylation at thr-48, thr-67, ser-122, thr-130, ser-168 and ser-214 occurs at g2 and g2-m transition and is catalyzed by cdk1. Ser-168 phosphorylation levels are lower than those at the other 5 cdk1 sites. Phosphorylation by cdk1 leads to increased activity." SIGNOR-64960 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Thr48 VCPDVPRtPVGKFLG 9606 10037602 t gcesareni "Phosphorylation at thr-48, thr-67, ser-122, thr-130, ser-168 and ser-214 occurs at g2 and g2-m transition and is catalyzed by cdk1. Ser-168 phosphorylation levels are lower than those at the other 5 cdk1 sites. Phosphorylation by cdk1 leads to increased activity." SIGNOR-64964 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Thr67 LSILSGGtPKRCLDL 9606 10037602 t gcesareni "Phosphorylation at thr-48, thr-67, ser-122, thr-130, ser-168 and ser-214 occurs at g2 and g2-m transition and is catalyzed by cdk1. Ser-168 phosphorylation levels are lower than those at the other 5 cdk1 sites. Phosphorylation by cdk1 leads to increased activity." SIGNOR-64968 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Ser122 DQHLMKCsPAQLLCS 9606 SIGNOR-C17 10864927 t gcesareni "Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b." SIGNOR-78416 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Thr48 VCPDVPRtPVGKFLG 9606 SIGNOR-C17 10864927 t gcesareni "Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b." SIGNOR-78428 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Ser214 SRSGLYRsPSMPENL 9606 8119945 t gcesareni "Phosphorylation at thr-48, thr-67, ser-122, thr-130, ser-168 and ser-214 occurs at g2 and g2-m transition and is catalyzed by cdk1. Ser-168 phosphorylation levels are lower than those at the other 5 cdk1 sites. Phosphorylation by cdk1 leads to increased activity." SIGNOR-36267 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Thr48 VCPDVPRtPVGKFLG 9606 8119945 t gcesareni "Phosphorylation at thr-48, thr-67, ser-122, thr-130, ser-168 and ser-214 occurs at g2 and g2-m transition and is catalyzed by cdk1. Ser-168 phosphorylation levels are lower than those at the other 5 cdk1 sites. Phosphorylation by cdk1 leads to increased activity." SIGNOR-36271 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Thr67 LSILSGGtPKRCLDL 9606 8119945 t gcesareni "Phosphorylation at thr-48, thr-67, ser-122, thr-130, ser-168 and ser-214 occurs at g2 and g2-m transition and is catalyzed by cdk1. Ser-168 phosphorylation levels are lower than those at the other 5 cdk1 sites. Phosphorylation by cdk1 leads to increased activity." SIGNOR-36275 CDK1 protein P06493 UNIPROT RRM2 protein P31350 UNIPROT down-regulates phosphorylation Thr33 SLVDKENtPPALSGT 9606 22632967 t gcesareni "We found that, during g2, following cdk-mediated phosphorylation of thr33, rrm2 is degraded via scf(cyclin f) to maintain balanced dntp pools and genome stability." SIGNOR-197630 CDK1 protein P06493 UNIPROT RRM2 protein P31350 UNIPROT unknown phosphorylation Ser20 DPQQLQLsPLKGLSL 9606 9990288 t llicata "Ribonucleotide reductase r2 protein is phosphorylated at serine-20 by p34cdc2 kinase. comparison of ribonucleotide reductase activities between wild type and mutated forms of the r2 proteins suggested that mutation at serine-20 did not significantly affect enzyme activity." SIGNOR-64312 CDK1 protein P06493 UNIPROT STIP1 protein P31948 UNIPROT "down-regulates activity" phosphorylation Ser189 LLGVDLGsMDEEEEI 10090 BTO:0000944 14754904 t miannu "Inactivation and phosphorylation mimicking of potential phosphorylation sites in mSTI1 altered the nuclear translocation. Mimicking of phosphorylation at the mSTI1 CKII phosphorylation site (S189E) promoted nuclear localization of mSTI1-EGFP. Mimicking phosphorylation at the cdc2 kinase phosphorylation site (T198E) promoted cytoplasmic localization of mSTI1-EGFP at the G1/S-phase transition,whereas removal of this site (T198A) promoted the nuclear localization of mSTI1-EGFP under the same conditions." SIGNOR-262729 CDK1 protein P06493 UNIPROT STIP1 protein P31948 UNIPROT "down-regulates activity" phosphorylation Thr198 DEEEEIAtPPPPPPP 10090 BTO:0000944 14754904 t miannu "Inactivation and phosphorylation mimicking of potential phosphorylation sites in mSTI1 altered the nuclear translocation. Mimicking of phosphorylation at the mSTI1 CKII phosphorylation site (S189E) promoted nuclear localization of mSTI1-EGFP. Mimicking phosphorylation at the cdc2 kinase phosphorylation site (T198E) promoted cytoplasmic localization of mSTI1-EGFP at the G1/S-phase transition,whereas removal of this site (T198A) promoted the nuclear localization of mSTI1-EGFP under the same conditions. A lower level of phosphorylation was observed for the double mutant, suggesting that T332 might also be phosphorylated by cdc2 kinase." SIGNOR-262727 CDK1 protein P06493 UNIPROT STIP1 protein P31948 UNIPROT "down-regulates activity" phosphorylation Thr332 KSLAEHRtPDVLKKC 10090 BTO:0000944 14754904 t miannu "Inactivation and phosphorylation mimicking of potential phosphorylation sites in mSTI1 altered the nuclear translocation. Mimicking of phosphorylation at the mSTI1 CKII phosphorylation site (S189E) promoted nuclear localization of mSTI1-EGFP. Mimicking phosphorylation at the cdc2 kinase phosphorylation site (T198E) promoted cytoplasmic localization of mSTI1-EGFP at the G1/S-phase transition,whereas removal of this site (T198A) promoted the nuclear localization of mSTI1-EGFP under the same conditions. A lower level of phosphorylation was observed for the double mutant, suggesting that T332 might also be phosphorylated by cdc2 kinase." SIGNOR-262728 CDK1 protein P06493 UNIPROT MCM4 protein P33991 UNIPROT "down-regulates activity" phosphorylation Thr19 GSRRGRAtPAQTPRS 9606 BTO:0000567 12714602 t lperfetto "We report here that human mcm4, a subunit of the putative dna replicative helicase, is extensively phosphorylated in hela cells when they are incubated in the presence of inhibitors of dna synthesis or are exposed to uv irradiation. The data presented here indicate that the consecutive actions of atr-chk1 and cdk2 kinases are involved in this phosphorylation in the presence of hydroxyurea. Phosphorylation of t19 correlates with lowered level of dna helicase activity of the purified mcm4,6,7 complex." SIGNOR-100877 CDK1 protein P06493 UNIPROT RFC1 protein P35251 UNIPROT "down-regulates activity" phosphorylation Thr506 KESKLERtPQKNVQG 9534 BTO:0004055 12930972 t lperfetto "Phosphorylation of the PCNA binding domain of the large subunit of replication factor C on Thr506 by cyclin-dependent kinases regulates binding to PCNA|Replication factor C (RF-C) complex binds to DNA primers and loads PCNA onto DNA, thereby increasing the processivity of DNA polymerases. |Phosphorylation of either RF-Cp145 as a part of the RF-C complex or RF-Cp145 domain B by cdk-cyclin kinases inhibits their ability to bind PCNA." SIGNOR-265504 CDK1 protein P06493 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1189 QKGELSRsPSPFTHT 9606 BTO:0000150 10550055 t gcesareni "However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci." SIGNOR-72083 CDK1 protein P06493 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1497 EPGVERSsPSKCPSL 9606 BTO:0000150 10550055 t gcesareni "However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci." SIGNOR-72087 CDK1 protein P06493 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1189 QKGELSRsPSPFTHT 9606 BTO:0000551 19683496 t gcesareni "However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci." SIGNOR-187595 CDK1 protein P06493 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1191 GELSRSPsPFTHTHL 9606 BTO:0000551 19683496 t gcesareni "However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci." SIGNOR-187599 CDK1 protein P06493 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1497 EPGVERSsPSKCPSL 9606 BTO:0000551 19683496 t gcesareni "However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci." SIGNOR-187603 CDK1 protein P06493 UNIPROT FEN1 protein P39748 UNIPROT "down-regulates activity" phosphorylation Ser187 MDCLTFGsPVLMRHL 9606 BTO:0000007 12853968 t lperfetto "Phosphorylation of human fen1 by cyclin-dependent kinase modulates its role in replication fork regulation.As a functional consequence of phosphorylation by cdk1-cyclin a in vitro, endo- and exonuclease activities of fen1 are reduced whereas its dna binding is not affected." SIGNOR-103535 CDK1 protein P06493 UNIPROT CUX1 protein P39880 UNIPROT down-regulates phosphorylation Ser1237 TEYSQGAsPQPQHQL 9606 11584018 t lperfetto "Phosphorylation of serines 1237 and 1270 caused inhibition of dna binding in vitro. In cotransfection studies, cyclin a-cdk1 inhibited cdp/cux stable dna binding and prevented repression of the p21(waf1) reporter." SIGNOR-110908 CDK1 protein P06493 UNIPROT CUX1 protein P39880 UNIPROT down-regulates phosphorylation Ser1270 YQQKPYPsPKTIEDL 9606 11584018 t lperfetto "Phosphorylation of serines 1237 and 1270 caused inhibition of dna binding in vitro. In cotransfection studies, cyclin a-cdk1 inhibited cdp/cux stable dna binding and prevented repression of the p21(waf1) reporter." SIGNOR-110912 CDK1 protein P06493 UNIPROT RANGAP1 protein P46060 UNIPROT up-regulates phosphorylation Ser428 EPAPVLSsPPPADVS 9606 SIGNOR-C17 15037602 t lperfetto "Here, we show that rangap1 is phosphorylated on residues t409, s428, and s442. Phosphorylation occurs before nuclear envelope breakdown and is maintained throughout mitosis . Alternatively, phosphorylated rangap1 may recruit specific sumo target proteins to ranbp2's catalytic domain." SIGNOR-123516 CDK1 protein P06493 UNIPROT RANGAP1 protein P46060 UNIPROT up-regulates phosphorylation Thr409 GQGEKSAtPSRKILD 9606 SIGNOR-C17 15037602 t lperfetto "Here, we show that rangap1 is phosphorylated on residues t409, s428, and s442. Phosphorylation occurs before nuclear envelope breakdown and is maintained throughout mitosis. The m-phase kinase cyclin b/cdk1 phosphorylates rangap1 efficiently in vitro, and t409 phosphorylation correlates with nuclear accumulation of cyclin b1 in vivo." SIGNOR-123524 CDK1 protein P06493 UNIPROT RAP1GAP protein P47736 UNIPROT unknown phosphorylation Ser484 SLIVPGKsPTRKKSG 9606 1406653 t lperfetto "Two of the sites of phosphorylation by cyclic amp (camp)-dependent kinase were localized to serine residues 490 and 499, and one site of phosphorylation by p34cdc2 was localized to serine 484." SIGNOR-18735 CDK1 protein P06493 UNIPROT UBE2A protein P49459 UNIPROT up-regulates phosphorylation Ser120 LDEPNPNsPANSQAA 9606 11953320 t llicata "Hhr6a is phosphorylated in vitro by cdk-1 and -2 on ser120, a residue conserved in all hhr6a homologues, resulting in a 4-fold increase in its ubiquitin-conjugating activity." SIGNOR-116504 CDK1 protein P06493 UNIPROT RANBP2 protein P49792 UNIPROT "up-regulates activity" phosphorylation Ser2251 ASPLASSerPVRKNL -1 26051540 t irozzo "Cdk1 phosphorylates conserved sites within RanBP2 and activates BicD2 binding and early dynein recruitment." SIGNOR-259119 CDK1 protein P06493 UNIPROT RANBP2 protein P49792 UNIPROT "up-regulates activity" phosphorylation Ser2276 SFKSALSerPSKSPA -1 26051540 t irozzo "Cdk1 phosphorylates conserved sites within RanBP2 and activates BicD2 binding and early dynein recruitment." SIGNOR-259120 CDK1 protein P06493 UNIPROT RANBP2 protein P49792 UNIPROT "up-regulates activity" phosphorylation Ser2280 LSPSKSerPAKLN -1 26051540 t irozzo "Cdk1 phosphorylates conserved sites within RanBP2 and activates BicD2 binding and early dynein recruitment." SIGNOR-259121 CDK1 protein P06493 UNIPROT RANBP2 protein P49792 UNIPROT "up-regulates activity" phosphorylation Thr2153 LDIPLQThrPHKLVD -1 26051540 t irozzo "Cdk1 phosphorylates conserved sites within RanBP2 and activates BicD2 binding and early dynein recruitment." SIGNOR-259117 CDK1 protein P06493 UNIPROT ERF protein P50548 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C17 7588608 t lperfetto "Consistent with the in vivo phosphorylation and inactivation by ras, erf is efficiently phosphorylated in vitro by erk2 and cdc2/cyclin b kinases, at sites similar to those detected in vivo. Furthermore, a single mutation at position 526 results in the loss of a specific phosphopeptide both in in vivo and in vitro (by erk2) labeling. Substitution of thr526 for glutamic acid also decreases the repression ability of erf" SIGNOR-29501 CDK1 protein P06493 UNIPROT KIF11 protein P52732 UNIPROT up-regulates phosphorylation Thr926 LDIPTGTtPQRKSYL 9606 9235942 t lperfetto "The kinesin-related motor hseg5 is essential for centrosome separation, and its association with centrosomes appears to be regulated by phosphorylation of tail residue threonine 927 by the p34(cdc2) protein kinase.Phosphorylation also enhanced the specific binding of p150(glued) to the tail domain of hseg5 in vitro" SIGNOR-50169 CDK1 protein P06493 UNIPROT HMGA2 protein P52926 UNIPROT down-regulates phosphorylation Ser44 QEPTGEPsPKRPRGR 9606 10636877 t lperfetto "Architecture of high mobility group protein i-c dna complex and its perturbation upon phosphorylation by cdc2 kinase. Phosphorylation by cdc2 reduces binding strength of the mammalian and insect hmgi proteins to dna. After phosphorylation of the protein at ser-43 and ser-58 by cdc2 kinase multiple contacts of dbds, especially with the bases, are impaired and the protein binds to dna in a different way, extending the contacts to the sugar-phosphate backbone." SIGNOR-74094 CDK1 protein P06493 UNIPROT HMGA2 protein P52926 UNIPROT down-regulates phosphorylation Ser59 PKGSKNKsPSKAAQK 9606 10636877 t lperfetto "Architecture of high mobility group protein i-c dna complex and its perturbation upon phosphorylation by cdc2 kinase. Phosphorylation by cdc2 reduces binding strength of the mammalian and insect hmgi proteins to dna. After phosphorylation of the protein at ser-43 and ser-58 by cdc2 kinase multiple contacts of dbds, especially with the bases, are impaired and the protein binds to dna in a different way, extending the contacts to the sugar-phosphate backbone." SIGNOR-74098 CSF1 protein P09603 UNIPROT CSF3R protein Q99062 UNIPROT up-regulates binding 9606 16492764 t gcesareni "A crystal structure of the signaling complex between human granulocyte colony-stimulating factor (gcsf) and a ligand binding region of gcsf receptor (gcsf-r), has been determined to 2.8 a resolution" SIGNOR-144737 CDK1 protein P06493 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Thr125 PEVLRPEtPRPVDIG 9606 SIGNOR-C17 16287866 t gcesareni "Here, we show that the apoptotic initiator protease caspase-9 is regulated during the cell cycle through periodic phosphorylation at an inhibitory site, thr125. This site is phosphorylated by cdk1/cyclin b1 during mitosis and in response to microtubule poisons that arrest cells at this stage of the cell cycle." SIGNOR-141621 CDK1 protein P06493 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Thr125 PEVLRPEtPRPVDIG 9606 SIGNOR-C17 17466630 t gcesareni "Here, we show that the apoptotic initiator protease caspase-9 is regulated during the cell cycle through periodic phosphorylation at an inhibitory site, thr125. This site is phosphorylated by cdk1/cyclin b1 during mitosis and in response to microtubule poisons that arrest cells at this stage of the cell cycle." SIGNOR-154626 CDK1 protein P06493 UNIPROT PRPS1 protein P60891 UNIPROT "up-regulates activity" phosphorylation Ser103 RQDKKDKsRAPISAK 31253668 t lperfetto "CDK1 contributes to upregulation of PRPS1 activity by phosphorylating PRPS1 at S103|In conclusion, compared with upregulation of PRPS1 expression levels, increased PRPS1 activity, which is marked by S103 phosphorylation" SIGNOR-265728 CDK1 protein P06493 UNIPROT RAB5B protein P61020 UNIPROT unknown phosphorylation Ser123 KELQRQAsPSIVIAL 9606 10403367 t lperfetto "Cdc2 kinase preferentially phosphorylates ser-123 of rab5b. More work will be required to establish how phosphorylation of the three rab5 isoforms influences their function in the endocytic pathway" SIGNOR-69233 CDK1 protein P06493 UNIPROT PPP1CA protein P62136 UNIPROT "down-regulates activity" phosphorylation Thr320 NPGGRPItPPRNSAK 9606 12202491 t gcesareni "Both of these pp1 isoforms contain an arg-pro-ile/val-thr-pro-pro-arg sequence near the c terminus, a known site of phosphorylation by cdc/cdk kinases, and phosphorylation attenuates phosphatase activity." SIGNOR-151799 CDK1 protein P06493 UNIPROT RAB1A protein P62820 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000567 1902553 t Giulio "We now present biochemical evidence for a mitosis-specific p34cdc2 phosphorylation of RablAp and Rab4p.We also show that the distribution of RablAp and Rab4p between cytosolic and membrane-bound forms is different in interphase and mitotic cells." SIGNOR-261284 CDK1 protein P06493 UNIPROT CSNK2B protein P67870 UNIPROT up-regulates phosphorylation Ser209 QAASNFKsPVKTIR 9606 BTO:0000785 7578274 t lperfetto "In cells, the casein kinase ii beta-subunit is phosphorylated at an autophosphorylation site and at a site (ser-209) that is maximally phosphorylated in mitotic cells. These studies provide strong biochemical evidence that p34cdc2 is the enzyme that phosphorylates ser-209 on the beta-subunit of ckii in mitotic cells." SIGNOR-29462 CDK1 protein P06493 UNIPROT CSNK2A1 protein P68400 UNIPROT up-regulates phosphorylation Ser362 ISSVPTPsPLGPLAG 9606 BTO:0000527 19941816 t gcesareni "The mitotic phosphorylation sites on the alpha subunit of casein kinase ii can be phosphorylated in vitro by p34cdc2." SIGNOR-161839 CDK1 protein P06493 UNIPROT CSNK2A1 protein P68400 UNIPROT up-regulates phosphorylation Thr360 SGISSVPtPSPLGPL 9606 BTO:0000527 19941816 t gcesareni "It has been shown that the c-terminal domains of ck2? Are phosphorylated by cdc2 and interact with the peptidyl-prolyl isomerase pin1 in a cell cycle-dependent manner" SIGNOR-161843 CDK1 protein P06493 UNIPROT CSNK2A1 protein P68400 UNIPROT up-regulates phosphorylation Ser370 PLGPLAGsPVIAAAN 9606 7592773 t lperfetto "Four residues within this domain, thr-344, thr-360, ser-362, and ser-370, conform to the minimal consensus sequence for p34cdc2 phosphorylationthe high stoichiometry of phosphorylation suggests that phosphorylation could regulate functional properties of ckii and that it could in some way participate in the burst of phosphorylation that accompanies the activation of p34graphic at the ggraphic-m transition" SIGNOR-29521 CDK1 protein P06493 UNIPROT CSNK2A1 protein P68400 UNIPROT up-regulates phosphorylation Thr344 SSMPGGStPVSSANM 9606 7592773 t lperfetto "Four residues within this domain, thr-344, thr-360, ser-362, and ser-370, conform to the minimal consensus sequence for p34cdc2 phosphorylationthe high stoichiometry of phosphorylation suggests that phosphorylation could regulate functional properties of ckii and that it could in some way participate in the burst of phosphorylation that accompanies the activation of p34graphic at the ggraphic-m transition" SIGNOR-29525 CDK1 protein P06493 UNIPROT EIF4G2 protein P78344 UNIPROT "up-regulates activity" phosphorylation Thr508 AQPPRTQtPPLGQTP 9606 BTO:0000007 29530922 t miannu "To test whether CDK1 phosphorylates T508, Flag-DAP5 was purified from dox-induced HEK293 cells and incubated with active recombinant JNK2 or CDK1 in the presence of ATP (Fig. 3G). DAP5(T508) was phosphorylated only upon incubation with CDK1 (Fig. 3G)." SIGNOR-266387 CDK1 protein P06493 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates phosphorylation Ser332 TDSATIVsPPPSSPP 9606 8087847 t lperfetto "Association of e2f with rb inhibits its transactivation potential. phosphorylation of e2f-1 on serine residues 332 and 337 prevented its interaction with rbthese residues were phosphorylated in vivo and by p34cdc2 kinase in vitro." SIGNOR-36022 CDK1 protein P06493 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates phosphorylation Ser337 IVSPPPSsPPSSLTT 9606 8087847 t lperfetto "Association of e2f with rb inhibits its transactivation potential. phosphorylation of e2f-1 on serine residues 332 and 337 prevented its interaction with rbthese residues were phosphorylated in vivo and by p34cdc2 kinase in vitro." SIGNOR-36026 CDK1 protein P06493 UNIPROT FOXK2 protein Q01167 UNIPROT up-regulates phosphorylation Ser373 SSRSAPAsPNHAGVL 9606 20810654 t gcesareni "We have mapped two cdk phosphorylation sites, serines 368 and 423, which play a role in defining foxk2 function through regulating its stability and its activity as a transcriptional repressor protein. These two cdk sites appear vital for foxk2 function because expression of a mutant lacking these sites cannot be tolerated and causes apoptosis." SIGNOR-167822 CDK1 protein P06493 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser266 QYLGSIAsPSVHPAT 9606 16046550 t "The effect has been demonstrated using Q01196-8." gcesareni "Phosphorylation of ser-48, ser-303, and ser-424 by cyclin-dependent kinases (cdks) increases runx1 trans-activation activity without perturbing p300 interaction." SIGNOR-138912 CDK1 protein P06493 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Thr273 SPSVHPAtPISPGRA 9606 16046550 t "The effect has been demonstrated using Q01196-8." gcesareni "Phosphorylation of ser-48, ser-303, and ser-424 by cyclin-dependent kinases (cdks) increases runx1 trans-activation activity without perturbing p300 interaction." SIGNOR-138920 CDK1 protein P06493 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser21 TPPSTALsPGKMSEA 9606 BTO:0000007 SIGNOR-C17 21059642 t "The effect has been demonstrated using Q01196-8" gcesareni "Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20)." SIGNOR-169318 CDK1 protein P06493 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser397 SMVGGERsPPRILPP 9606 BTO:0000007 SIGNOR-C17 21059642 t "The effect has been demonstrated using Q01196-8" gcesareni "Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20)." SIGNOR-169322 CDK1 protein P06493 UNIPROT RUNX1 protein Q01196 UNIPROT "up-regulates activity" phosphorylation Ser276 VHPATPIsPGRASGM 9606 16046550 t "The effect has been demonstrated using Q01196-8." gcesareni "Phosphorylation of ser-48, ser-303, and ser-424 by cyclin-dependent kinases (cdks) increases runx1 trans-activation activity without perturbing p300 interaction." SIGNOR-138916 CDK1 protein P06493 UNIPROT MAP2K1 protein Q02750 UNIPROT down-regulates phosphorylation Thr286 VEGDAAEtPPRPRTP 9606 8114697 t gcesareni "P34cdc2 catalyzes the in vitro phosphorylation of mkk1 on both of these threonine residues and inactivates mkk1 enzymatic activity. Both sites are phosphorylated in vivo as well" SIGNOR-36112 CDK1 protein P06493 UNIPROT MAP2K1 protein Q02750 UNIPROT down-regulates phosphorylation Thr292 ETPPRPRtPGRPLSS 9606 8114697 t gcesareni "P34cdc2 catalyzes the in vitro phosphorylation of mkk1 on both of these threonine residues and inactivates mkk1 enzymatic activity. Both sites are phosphorylated in vivo as well" SIGNOR-36116 CDK1 protein P06493 UNIPROT APLP2 protein Q06481 UNIPROT unknown phosphorylation Thr736 VEVDPMLtPEERHLN 9606 BTO:0000142 9109675 t lperfetto "A cytoplasmic domain peptide from aplp2 is phosphorylated in vitro by protein kinase c and cdc2 kinase. Aplp2 is phosphorylated by cdc2 kinase at a site homologous to the cdc2 kinase site phosphorylated in app." SIGNOR-47483 CDK1 protein P06493 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Thr611 ETLPISStPSKSVLP 9606 SIGNOR-C17 19737929 t lperfetto "A conserved phosphorylation site within the forkhead domain of foxm1b is required for its activation by cyclin-cdk1further analysis reveals that the leu-641 residue within an lxl motif is required for the recruitment of the cyclin-cdk complex, and the thr-596 residue is a critical cdk1 phosphorylation site within the activation domain of foxm1b. Cdk-dependent phosphorylation stimulates the foxm1b transcriptional activity" SIGNOR-187880 CDK1 protein P06493 UNIPROT GOLGA2 protein Q08379 UNIPROT down-regulates phosphorylation Ser37 REYQQRNsPGVPTGA 9606 9753325 t lperfetto "Cdc2 kinase directly phosphorylates the cis-golgi matrix protein gm130 and is required for golgi fragmentation in mitosis. Mitotic fragmentation of the golgi apparatus can be largely explained by disruption of the interaction between gm130 and the vesicle-docking protein p115. Here we identify a single serine (ser-25) in gm130 as the key phosphorylated target and cdc2 as the responsible kinase" SIGNOR-60281 CDK1 protein P06493 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates phosphorylation Ser249 EGGKSGKsPRRRAAS 9606 BTO:0001130 18408765 t gcesareni "Overexpression of cdk1 inhibits the transcriptional activity of foxo1 in pca cells through s249 phosphorylation on foxo1." SIGNOR-178202 CDK1 protein P06493 UNIPROT TP53BP1 protein Q12888 UNIPROT "down-regulates activity" phosphorylation Ser1678 ITSEEERsPAKRGRK -1 30685087 t lperfetto "Nuclear import of 53BP1 is required for proper localization of 53BP1 and maintenance of genome integrity. 53BP1 has a classical bipartite nuclear localization signal (NLS) of sequence 1666-GKRKLITSEEERSPAKRGRKS-1686. Ser1678 within the 53BP1 NLS can be phosphorylated by CDK1/cyclin B, and a phosphomimetic substitution of Ser1678 with aspartate has been shown to negatively regulate nuclear import of 53BP1." SIGNOR-264412 CDK1 protein P06493 UNIPROT DLG1 protein Q12959 UNIPROT unknown phosphorylation Ser158 FVSHSHIsPIKPTEA 9606 19066288 t llicata "We also show that dlg1 is phosphorylated by both cdk1 and cdk2 on ser158 and ser442. These phosphorylated sites together affect the nuclear localisation of the protein, and implicate the role of phosphorylation on ser158 and ser442 in its putative nuclear functions as a tumour suppressor." SIGNOR-182753 CDK1 protein P06493 UNIPROT DLG1 protein Q12959 UNIPROT unknown phosphorylation Ser443 FLGQTPAsPARYSPV 9606 19066288 t llicata "We also show that dlg1 is phosphorylated by both cdk1 and cdk2 on ser158 and ser442. These phosphorylated sites together affect the nuclear localisation of the protein, and implicate the role of phosphorylation on ser158 and ser442 in its putative nuclear functions as a tumour suppressor." SIGNOR-182757 CDK1 protein P06493 UNIPROT CDC16 protein Q13042 UNIPROT up-regulates phosphorylation Ser560 KTLKNIIsPPWDFRE 9606 14657031 t lperfetto "Apc activation is thought to depend on apc phosphorylation and cdc20 binding. We have identified 43 phospho_sites on apc of which at least 34 are mitosis specific. Of these, 32 sites are clustered in parts of apc1 and the tetratricopeptide repeat (tpr) subunits cdc27, cdc16, cdc23 and apc7. In vitro, at least 15 of the mitotic phospho_sites can be generated by cyclin_dependent kinase 1 (cdk1), and 3 by polo_like kinase 1 (plk1). Apc phosphorylation by cdk1, but not by plk1, is sufficient for increased cdc20 binding and apc activation" SIGNOR-119762 CDK1 protein P06493 UNIPROT ORC1 protein Q13415 UNIPROT up-regulates phosphorylation Ser258 TSCASLDsPGRIKRK 9606 11931757 t lperfetto "Horc1p contains three (s/t)px(k/r) consensus sites for cdk phosphorylation (ser258, ser273, and thr375). These data combined strongly suggest that skp2 promotes horc1p turnover and that the n-terminal domain of horc1p, containing most of the phosphorylation sites and overlapping with one of the skp2-interacting domains, is a regulatory element for horc1p stability." SIGNOR-116321 CDK1 protein P06493 UNIPROT ZC3HC1 protein Q86WB0 UNIPROT down-regulates phosphorylation Ser395 PGLEVPSsPLRKAKR 9606 SIGNOR-C17 17389604 t gcesareni "Moreover, we found cyclin b1/cdk1 to phosphorylate nipa at ser-395 in mitosis. Mutation of both ser-359 and ser-395 impaired effective inactivation of the scfnipa complex, resulting in reduced levels of mitotic cyclin b1" SIGNOR-154047 CDK1 protein P06493 UNIPROT ORC1 protein Q13415 UNIPROT up-regulates phosphorylation Ser273 VAFSEITsPSKRSQP 9606 11931757 t lperfetto "Horc1p contains three (s/t)px(k/r) consensus sites for cdk phosphorylation (ser258, ser273, and thr375). These data combined strongly suggest that skp2 promotes horc1p turnover and that the n-terminal domain of horc1p, containing most of the phosphorylation sites and overlapping with one of the skp2-interacting domains, is a regulatory element for horc1p stability." SIGNOR-116325 CDK1 protein P06493 UNIPROT STIM1 protein Q13586 UNIPROT down-regulates phosphorylation Ser668 IGEETDSsPGRKKFP 9606 19881501 t gcesareni "Stim1 is phosphorylated during mitosis. Removal of ten mpm-2 recognition sites by truncation at amino acid 482 abolished mpm-2 recognition of mitotic stim1, and significantly rescued stim1 rearrangement and soce response in mitosis. We identified ser 486 and ser 668 as mitosis-specific phosphorylation sites, and stim1 containing mutations of these sites to alanine also significantly rescued mitotic soce." SIGNOR-189017 CDK1 protein P06493 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates phosphorylation Ser465 MVPGGDRsPSRMLPP 9606 BTO:0000150;BTO:0001130 16407259 t llicata "In vitro kinase assays using recombinant cdc2 kinase showed that runx2 was phosphorylated at ser(451) the cdc2 inhibitor roscovitine dose dependently inhibited in vivo runx2 dna-binding activity during mitosis and the runx2 mutant s451a exhibited lower dna-binding activity and reduced stimulation of anchorage-independent growth relative to wild type runx2." SIGNOR-143586 CDK1 protein P06493 UNIPROT ESPL1 protein Q14674 UNIPROT down-regulates phosphorylation Ser1126 IAPSTNSsPVLKTKP 9606 11747808 t lperfetto "Both cdc2/cyclinb1 and mapk (erk2) efficiently phosphorylate separase at its major inhibitory site in vitro" SIGNOR-113126 CDK1 protein P06493 UNIPROT LBR protein Q14739 UNIPROT down-regulates phosphorylation Ser71 KGGSTSSsPSRRRGS 9606 14718546 t lperfetto "The binding of the nk fragment to chromatin pretreated with an s-phase extract was suppressed by incubation with an m-phase extract. Enzyme inhibitor experiments revealed that multiple kinases participate in the suppression. One of these kinases was shown to be cdc2 experiments involving a mutant nk fragment showed that the phosphorylation of serine 71 by cdc2 kinase is responsible for the suppression." SIGNOR-121335 CDK1 protein P06493 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates phosphorylation Ser387 YLEMDLSsPQTRYIP 9606 BTO:0000149 SIGNOR-C17 20937773 t lperfetto "In this study, we demonstrate that procaspase-8 is phosphorylated in mitotic cells by cdk1na interference-mediated silencing of cyclin b1 or treatment with the cdk1 inhibitor ro-3306 enhances the fas-mediated activation and processing of procaspase-8 in mitotic cells/cyclin b1 on ser-387" SIGNOR-168446 CDK1 protein P06493 UNIPROT PLEC protein Q15149 UNIPROT down-regulates phosphorylation Thr4539 GGLIEPDtPGRVPLD 9606 BTO:0000567 SIGNOR-C17 19709076 t lperfetto "Identification of plectin as a substrate of p34cdc2 kinase and mapping of a single phosphorylation site. threonine 4542 was identified as the major target for the kinase. Phosphorylation of plectin by cyclin-dependent kinase 1/cyclin b (cdk1/cycb) kinase has been reported to abolish its cross-linking function during mitosis. Here, we induced phosphorylation of plectin in prepared fractions of hela cells by adding activated cdk1/cycb kinase. Consequently, there was significant dissociation of the centrosome from the nuclear membrane." SIGNOR-187766 CDK1 protein P06493 UNIPROT PLEC protein Q15149 UNIPROT down-regulates phosphorylation Thr4539 GGLIEPDtPGRVPLD 9606 BTO:0000567 SIGNOR-C17 8626512 t lperfetto "Identification of plectin as a substrate of p34cdc2 kinase and mapping of a single phosphorylation site. threonine 4542 was identified as the major target for the kinase. Phosphorylation of plectin by cyclin-dependent kinase 1/cyclin b (cdk1/cycb) kinase has been reported to abolish its cross-linking function during mitosis. Here, we induced phosphorylation of plectin in prepared fractions of hela cells by adding activated cdk1/cycb kinase. Consequently, there was significant dissociation of the centrosome from the nuclear membrane." SIGNOR-41319 CDK1 protein P06493 UNIPROT EZH2 protein Q15910 UNIPROT down-regulates phosphorylation Thr487 APAEDVDtPPRKKKR 9606 21659531 t lperfetto "Cdk1, which phosphorylates ezh2 at threonines 345 and 487.Phosphorylation of thr-345 and thr-487 promotes ezh2 ubiquitination and subsequent degradation by the proteasome" SIGNOR-174058 CDK1 protein P06493 UNIPROT MAPK6 protein Q16659 UNIPROT up-regulates phosphorylation Ser684 IGIPQFHsPVGSPLK 9606 SIGNOR-C17 20236090 t lperfetto "Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3. All four sites are followed by a proline residue. We have shown that purified cyclin b-cdk1 (cyclindependent kinase 1) phosphorylates these sitesalanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase." SIGNOR-164487 CDK1 protein P06493 UNIPROT MAPK6 protein Q16659 UNIPROT up-regulates phosphorylation Ser688 QFHSPVGsPLKSIQA 9606 SIGNOR-C17 20236090 t lperfetto "Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3. All four sites are followed by a proline residue. We have shown that purified cyclin b-cdk1 (cyclindependent kinase 1) phosphorylates these sitesalanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase." SIGNOR-164491 CDK1 protein P06493 UNIPROT MAPK6 protein Q16659 UNIPROT up-regulates phosphorylation Ser705 TPSAMKSsPQIPHQT 9606 SIGNOR-C17 20236090 t lperfetto "Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3. All four sites are followed by a proline residue. We have shown that purified cyclin b-cdk1 (cyclindependent kinase 1) phosphorylates these sitesalanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase." SIGNOR-164495 CDK1 protein P06493 UNIPROT MAPK6 protein Q16659 UNIPROT up-regulates phosphorylation Thr698 KSIQATLtPSAMKSS 9606 SIGNOR-C17 20236090 t lperfetto "Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3. All four sites are followed by a proline residue. We have shown that purified cyclin b-cdk1 (cyclindependent kinase 1) phosphorylates these sitesalanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase." SIGNOR-164499 CDK1 protein P06493 UNIPROT SIRT2 protein Q8IXJ6 UNIPROT down-regulates phosphorylation Ser368 PNPSTSAsPKKSPPP 9606 17488717 t gcesareni "Here, we demonstrate that sirt2 is phosphorylated both in vitro and in vivo on serine 368 by the cell-cycle regulator, cyclin-dependent kinase 1. Overexpression of sirt2 mediates a delay in cellular proliferation that is dependent on serine 368 phosphorylation." SIGNOR-154681 CDK1 protein P06493 UNIPROT ABI1 protein Q8IZP0 UNIPROT "down-regulates activity" phosphorylation Ser216 VPNDYMTsPARLGSQ 9606 BTO:0000567 21900237 t lperfetto "We identified serine 216 of Abi1 as a target of CDK1/cyclin B kinase that is phosphorylated in cells at the onset of mitosis.|Bcr-Abl-induced actin polymerization requires the Abi1 pathway, as the blockade of the signal transduction from Bcr-Abl to Abi1 abolishes the F-actin assembly|serine phosphorylation of Abi1 by CDK1/cyclin B serves as a cell cycle-dependent regulatory mechanism that inhibits actin assembly" SIGNOR-264421 CDK1 protein P06493 UNIPROT MPLKIP protein Q8TAP9 UNIPROT up-regulates phosphorylation Ser104 SQQQFGYsPGQQQTH 9606 17310276 t lperfetto "Ttdn1 is phosphorylated by cdk1 in vitro and in vivo. Ttdn1 is phosphorylated at multiple residues, including ser93 and ser104. Mutation of thr120 of ttdn1 abolishes its interaction with plk1, suggesting phosphorylation of thr120 in the consensus plk1-binding motif is required for its interaction with plk1" SIGNOR-153300 CDK1 protein P06493 UNIPROT MPLKIP protein Q8TAP9 UNIPROT up-regulates phosphorylation Ser93 YPGSYSRsPAGSQQQ 9606 17310276 t lperfetto "Ttdn1 is phosphorylated by cdk1 in vitro and in vivo. Ttdn1 is phosphorylated at multiple residues, including ser93 and ser104. Mutation of thr120 of ttdn1 abolishes its interaction with plk1, suggesting phosphorylation of thr120 in the consensus plk1-binding motif is required for its interaction with plk1" SIGNOR-153304 CDK1 protein P06493 UNIPROT MPLKIP protein Q8TAP9 UNIPROT up-regulates phosphorylation Thr120 QGSPRTStPFGSGRV 9606 17310276 t lperfetto "Ttdn1 is phosphorylated by cdk1 in vitro and in vivo. Ttdn1 is phosphorylated at multiple residues, including ser93 and ser104. Mutation of thr120 of ttdn1 abolishes its interaction with plk1, suggesting phosphorylation of thr120 in the consensus plk1-binding motif is required for its interaction with plk1" SIGNOR-153308 CDK1 protein P06493 UNIPROT NUP210 protein Q8TEM1 UNIPROT "up-regulates activity" phosphorylation Ser1881 SPPSGLWsPAYASH -1 8672508 t miannu "In vitro phosphorylation of GST fusion protein containing the carboxyl-terminal domain of gp210 by cyclin B-p34cdc2 protein kinase generates a phosphopeptide that comigrates with a mitosis-specific phosphopeptide. Ser1880 Is the Mitotic Phosphorylation Site of Gp210." SIGNOR-262699 CDK1 protein P06493 UNIPROT CKAP2 protein Q8WWK9 UNIPROT up-regulates phosphorylation Thr623 FKELKFLtPVRRSRR 9606 SIGNOR-C17 19369249 t llicata "Among these, thr-622 was specifically phosphorylated by cdk1-cyclin b1 both in vitro and in vivo. these findings suggest that cdk1-cyclin b1-mediated phosphorylation of tmap is important for and contributes to proper regulation of microtubule dynamics and establishment of functional bipolar spindles during mitosis." SIGNOR-185317 CDK1 protein P06493 UNIPROT TSC1 protein Q92574 UNIPROT down-regulates phosphorylation Ser584 ETSIFTPsPCKIPPP 9606 BTO:0000680;BTO:0001573;BTO:0001286 SIGNOR-C17 14551205 t lperfetto "Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin b.Cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (thr417) is in the hamartin-tuberin interaction domain. Tuberin interacts with phosphohamartin, and tuberin expression attenuates the phosphorylation of exogenous hamartin. Hamartin with alanine mutations in the three cyclin-dependent kinase 1 phosphorylation sites increased the inhibition of p70s6 kinase by the hamartin-tuberin complex" SIGNOR-118576 CDK1 protein P06493 UNIPROT TSC1 protein Q92574 UNIPROT down-regulates phosphorylation Thr1047 SSSSELStPEKPPHQ 9606 BTO:0000680;BTO:0001573;BTO:0001286 SIGNOR-C17 14551205 t lperfetto "Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin b.Cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (thr417) is in the hamartin-tuberin interaction domain. Tuberin interacts with phosphohamartin, and tuberin expression attenuates the phosphorylation of exogenous hamartin. Hamartin with alanine mutations in the three cyclin-dependent kinase 1 phosphorylation sites increased the inhibition of p70s6 kinase by the hamartin-tuberin complex" SIGNOR-118580 CDK1 protein P06493 UNIPROT TSC1 protein Q92574 UNIPROT down-regulates phosphorylation Thr417 SLPQATVtPPRKEER 9606 BTO:0000680;BTO:0001573;BTO:0001286 SIGNOR-C17 14551205 t lperfetto "Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin b.Cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (thr417) is in the hamartin-tuberin interaction domain. Tuberin interacts with phosphohamartin, and tuberin expression attenuates the phosphorylation of exogenous hamartin. Hamartin with alanine mutations in the three cyclin-dependent kinase 1 phosphorylation sites increased the inhibition of p70s6 kinase by the hamartin-tuberin complex" SIGNOR-118584 CDK1 protein P06493 UNIPROT TSC1 protein Q92574 UNIPROT unknown phosphorylation Thr1047 SSSSELStPEKPPHQ 9606 BTO:0000680;BTO:0001573;BTO:0001286 14551205 t llicata "In vitro assays showed that cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (thr417) is in the hamartin-tuberin interaction domain." SIGNOR-117339 CDK1 protein P06493 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates phosphorylation Ser540 HVSEDSSsPERTSPP 9606 SIGNOR-C17 19107194 t gcesareni "We identified cyclinb/cdk1 as a cell cycle-dependent kinase that forms a complex with and phosphorylates sirt1. Mutation of two residues phosphorylated by cyclin b/cdk1 (threonine 530 and serine 540) disturbs normal cell cycle progression and fails to rescue proliferation defects in sirt1-deficient cells" SIGNOR-182863 CDK1 protein P06493 UNIPROT MASTL protein Q96GX5 UNIPROT "up-regulates activity" phosphorylation Thr207 PRQDYSRtPGQVLSL 8355 22354989 t gcesareni "We propose a model in which the initiating event for Gwl activation is phosphorylation by MPF of the proline-directed sites T193 and T206 in the presumptive activation loop" SIGNOR-249653 CDK1 protein P06493 UNIPROT VCPIP1 protein Q96JH7 UNIPROT "down-regulates activity" phosphorylation Ser768 TPTKAPYsPTTSKEK 23500464 t lperfetto "We clarified that VCIP135, an essential factor in both p97 membrane fusion pathways, is phosphorylated on Threonine-760 and Serine-767 by Cdc2 at mitosis and that this phosphorylated VCIP135 does not bind to p97. " SIGNOR-265038 CDK1 protein P06493 UNIPROT VCPIP1 protein Q96JH7 UNIPROT "down-regulates activity" phosphorylation Thr761 GPSSAPAtPTKAPYS 23500464 t lperfetto "We clarified that VCIP135, an essential factor in both p97 membrane fusion pathways, is phosphorylated on Threonine-760 and Serine-767 by Cdc2 at mitosis and that this phosphorylated VCIP135 does not bind to p97. " SIGNOR-265037 PRSS1 protein P07477 UNIPROT F2RL1 protein P55085 UNIPROT "up-regulates activity" cleavage Arg36 TNRSSKGrSLIGKVD -1 10978167 t lperfetto "Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3." SIGNOR-263602 CDK1 protein P06493 UNIPROT KIF20B protein Q96Q89 UNIPROT "up-regulates activity" phosphorylation Thr1644 VKHPGCTtPVTVKIP 9606 11470801 t miannu "Here we report the identification of a novel KRP, termed KRMP1, which undergoes in vivo phosphorylation. The carboxyl-terminal globular tail domain is strongly phosphorylated by mitotic kinase activities almost attributed to cdc2 kinase, which is responsible for phosphorylation on residue Thr-1604 of KRMP1." SIGNOR-262695 CDK1 protein P06493 UNIPROT ATAD5 protein Q96QE3 UNIPROT "down-regulates activity" phosphorylation Ser653 TVPFDSEsPIRMKFT 9606 BTO:0000007 31875566 t miannu "To determine whether mitotic CDK phosphorylates ATAD5, a CDK1 inhibitor (RO3306) was applied to nocodazole-arrested cells (Figure S3F). CDK1 inhibition resulted in a loss of S653 phosphorylation (Figure S3F). These data meant that the S653 residue in the BET BD of ATAD5 is phosphorylated by mitotic CDK. This result suggested that the BRD4-ATAD5 interaction is inhibited during mitosis." SIGNOR-266410 CDK1 protein P06493 UNIPROT RAD9A protein Q99638 UNIPROT "up-regulates activity" phosphorylation Ser277 SHSQDLGsPERHQPV 9606 BTO:0000567 12734188 t lperfetto "Here we present evidence that thr292 of hrad9 is subject to cdc2-dependent phosphorylation in mitosis. Furthermore, our data are also consistent with four other hrad9 phosphorylation sites (ser277, ser328, ser336, and thr355) being regulated in part by cdc2. We also identify ser387 as a novel site of hrad9 constitutive phosphorylation and show that phosphorylation at ser387 is a prerequisite for one form of dna damage-induced hyperphosphorylation of hrad9." SIGNOR-101043 CDK1 protein P06493 UNIPROT RAD9A protein Q99638 UNIPROT "up-regulates activity" phosphorylation Ser328 VLPSISLsPGPQPPK 9606 BTO:0000567 12734188 t lperfetto "Here we present evidence that thr292 of hrad9 is subject to cdc2-dependent phosphorylation in mitosis. Furthermore, our data are also consistent with four other hrad9 phosphorylation sites (ser277, ser328, ser336, and thr355) being regulated in part by cdc2. We also identify ser387 as a novel site of hrad9 constitutive phosphorylation and show that phosphorylation at ser387 is a prerequisite for one form of dna damage-induced hyperphosphorylation of hrad9." SIGNOR-101047 CDK1 protein P06493 UNIPROT RAD9A protein Q99638 UNIPROT "up-regulates activity" phosphorylation Ser336 PGPQPPKsPGPHSEE 9606 BTO:0000567 12734188 t lperfetto "Here we present evidence that thr292 of hrad9 is subject to cdc2-dependent phosphorylation in mitosis. Furthermore, our data are also consistent with four other hrad9 phosphorylation sites (ser277, ser328, ser336, and thr355) being regulated in part by cdc2. We also identify ser387 as a novel site of hrad9 constitutive phosphorylation and show that phosphorylation at ser387 is a prerequisite for one form of dna damage-induced hyperphosphorylation of hrad9." SIGNOR-101051 CDK1 protein P06493 UNIPROT KIF2C protein Q99661 UNIPROT down-regulates phosphorylation Thr537 LGQNKAHtPFRESKL 9606 20368358 t llicata "We show here that cyclin-dependent kinase 1 (cdk1) phosphorylates t537 in the core domain of mcak and attenuates its microtubule-destabilizing activity in vitro and in vivo. Phosphorylation of mcak by cdk1 promotes the release of mcak from centrosomes and is required for proper spindle formation." SIGNOR-164761 CDK1 protein P06493 UNIPROT GORASP1 protein Q9BQQ3 UNIPROT "down-regulates activity" phosphorylation Ser274 DPLPGPGsPSHSAPD 10116 BTO:0000951 15834132 t miannu "Here we show that GRASP65 is phosphorylated on serine 277 in interphase cells, and this is strongly enhanced in response to the addition of serum or epidermal growth factor. This is directly mediated by ERK suggesting that GRASP65 has some role in growth factor signal transduction. Phosphorylation of Ser-277 is also dramatically increased during mitosis, however this is mediated by Cdk1 and not by ERK. These results argue against Ser-277 phosphorylation alone causing the dissolution of GRASP65 oligomers and cisternal unstacking, although it may make a significant contribution to these events." SIGNOR-262840 CDK1 protein P06493 UNIPROT WAC protein Q9BTA9 UNIPROT "up-regulates activity" phosphorylation Thr244 AETHSSStPVQHPIK 9606 BTO:0000567 30021153 t lperfetto "Cyclin-dependent kinase 1 (Cdk1) phosphorylates WAC, priming its direct interaction with the polo-box domain of Plk1. Knockdown of WAC compromises Plk1 activity and delays mitotic entry." SIGNOR-265032 CDK1 protein P06493 UNIPROT WAC protein Q9BTA9 UNIPROT "up-regulates activity" phosphorylation Thr457 YVSPRIStPQTNTVP 9606 BTO:0000567 30021153 t lperfetto "Cyclin-dependent kinase 1 (Cdk1) phosphorylates WAC, priming its direct interaction with the polo-box domain of Plk1. Knockdown of WAC compromises Plk1 activity and delays mitotic entry." SIGNOR-265035 CDK1 protein P06493 UNIPROT WAC protein Q9BTA9 UNIPROT "up-regulates activity" phosphorylation Thr471 PIKPLIStPPVSSQP 9606 BTO:0000567 30021153 t lperfetto "Cyclin-dependent kinase 1 (Cdk1) phosphorylates WAC, priming its direct interaction with the polo-box domain of Plk1. Knockdown of WAC compromises Plk1 activity and delays mitotic entry." SIGNOR-265034 CDK1 protein P06493 UNIPROT WAC protein Q9BTA9 UNIPROT "up-regulates activity" phosphorylation Thr482 SSQPKVStPVVKQGP 9606 BTO:0000567 30021153 t lperfetto "Cyclin-dependent kinase 1 (Cdk1) phosphorylates WAC, priming its direct interaction with the polo-box domain of Plk1. Knockdown of WAC compromises Plk1 activity and delays mitotic entry." SIGNOR-265033 CDK1 protein P06493 UNIPROT NUSAP1 protein Q9BXS6 UNIPROT down-regulates phosphorylation Thr300 HKRSLTKtPARKSAH 9606 22101338 t llicata "We report here that cdk1 phosphorylates nusap at threonine 300 and 338 in early mitosis. Phosphorylation of nusap inhibits its microtubule-binding activity in vitro and in vivo." SIGNOR-177545 CDK1 protein P06493 UNIPROT NUSAP1 protein Q9BXS6 UNIPROT down-regulates phosphorylation Thr338 GNSAAVItPFKLTTE 9606 22101338 t llicata "We report here that cdk1 phosphorylates nusap at threonine 300 and 338 in early mitosis. Phosphorylation of nusap inhibits its microtubule-binding activity in vitro and in vivo." SIGNOR-177549 CDK1 protein P06493 UNIPROT NIFK protein Q9BYG3 UNIPROT "up-regulates activity" phosphorylation Thr238 QGPTPVCtPTFLERR -1 16244663 t miannu "The forkhead-associated (FHA) domain of human Ki67 interacts with the human nucleolar protein hNIFK, recognizing a 44-residue fragment, hNIFK226-269, phosphorylated at Thr234. Here we show that high-affinity binding requires sequential phosphorylation by two kinases, CDK1 and GSK3, yielding pThr238, pThr234 and pSer230. phosphorylation of Thr234 by GSK3 proceeds only after Thr238 is already phosphorylated by CDK1." SIGNOR-262696 CDK1 protein P06493 UNIPROT ANAPC1 protein Q9H1A4 UNIPROT up-regulates phosphorylation Ser355 AALSRAHsPALGVHS 9606 14657031 t lperfetto "Apc activation is thought to depend on apc phosphorylation and cdc20 binding. We have identified 43 phospho_sites on apc of which at least 34 are mitosis specific. Of these, 32 sites are clustered in parts of apc1 and the tetratricopeptide repeat (tpr) subunits cdc27, cdc16, cdc23 and apc7. In vitro, at least 15 of the mitotic phospho_sites can be generated by cyclin_dependent kinase 1 (cdk1), and 3 by polo_like kinase 1 (plk1). Apc phosphorylation by cdk1, but not by plk1, is sufficient for increased cdc20 binding and apc activation" SIGNOR-119705 CD3E protein P07766 UNIPROT NCK1 protein P16333 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000661 12110186 t "We present strong evidence that ligand engagement of TCR-CD3 induces a conformational change that exposes a proline-rich sequence in CD3ϵ and results in recruitment of the adaptor protein Nck." SIGNOR-259934 CDK1 protein P06493 UNIPROT NUCKS1 protein Q9H1E3 UNIPROT "down-regulates activity" phosphorylation Ser181 LKATVTPsPVKGKGK -1 12413487 t miannu "putative phosphorylation site for Cdk1 is present in the DNA-binding domain peptide. This site, corresponding to Ser 181 in the NUCKS primary structure, is phosphorylated in vitro by Cdk1 with a Km of approximately 35 μM [7]. Phosphorylation of Ser 181 in the synthetic, DNA-binding domain peptide reduces its affinity for DNA-by 100%." SIGNOR-261959 CDK1 protein P06493 UNIPROT KMT5A protein Q9NQR1 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser100 SKIYSYMsPNKCSGM 9606 20966048 t miannu "We found that PR-Set7 is phosphorylated at Ser 29 (S29) specifically by the cyclin-dependent kinase 1 (cdk1)/cyclinB complex, primarily from prophase through early anaphase, subsequent to global accumulation of H4K20me1. While S29 phosphorylation did not affect PR-Set7 methyltransferase activity, this event resulted in the removal of PR-Set7 from mitotic chromosomes. S29 phosphorylation also functions to stabilize PR-Set7 by directly inhibiting its interaction with the anaphase-promoting complex (APC), an E3 ubiquitin ligase." SIGNOR-259832 CDK1 protein P06493 UNIPROT INCENP protein Q9NQS7 UNIPROT up-regulates phosphorylation Thr412 DTEIANStPNPKPAA 9606 16378098 t gcesareni "Here, we report that cdk1 phosphorylates thr 59 and thr 388 on inner centromere protein (incenp), which regulates the localization and kinase activity of aurora-b from prophase to metaphase. The replacement of endogenous incenp with t388a resulted in the delay of progression from metaphase to anaphase." SIGNOR-143387 CDK1 protein P06493 UNIPROT NDE1 protein Q9NXR1 UNIPROT up-regulates phosphorylation 9606 16682949 t gcesareni "We found that nde1 is subjected to phosphorylation in vivo. In particular, we identified six putative cdc2 phosphorylation sites in nde1 and found that alteration of these sites diminishes phosphorylation by cdc2 in vitro and affects the stability of su48-nde1 interactions and the centrosomal localization of nde1." SIGNOR-146734 CDK1 protein P06493 UNIPROT PTTG2 protein Q9NZH5 UNIPROT "up-regulates activity" phosphorylation Ser165 LFQLGPPsPVKMPSP 9606 BTO:0000567 10656688 t miannu "HPTTG is phosphorylated by Cdc2 at Ser165. we show that hPTTG is phosphorylated during mitosis. The direct phosphorylation of hPTTG by Cdc2 is interesting in itself since the substrates of this master mitotic kinase are supposed to play important roles in the initiation and progression of mitosis." SIGNOR-262700 CDK1 protein P06493 UNIPROT CDC23 protein Q9UJX2 UNIPROT up-regulates phosphorylation Thr565 NQGETPTtEVPAPFF 9606 14657031 t lperfetto "Apc activation is thought to depend on apc phosphorylation and cdc20 binding. We have identified 43 phospho_sites on apc of which at least 34 are mitosis specific. Of these, 32 sites are clustered in parts of apc1 and the tetratricopeptide repeat (tpr) subunits cdc27, cdc16, cdc23 and apc7. In vitro, at least 15 of the mitotic phospho_sites can be generated by cyclin_dependent kinase 1 (cdk1), and 3 by polo_like kinase 1 (plk1). Apc phosphorylation by cdk1, but not by plk1, is sufficient for increased cdc20 binding and apc activation" SIGNOR-119821 CDK1 protein P06493 UNIPROT NUP50 protein Q9UKX7 UNIPROT down-regulates phosphorylation Ser221 KVAAETQsPSLFGST 9606 19767751 t gcesareni "These results suggest that both ERK and Cdk1 directly phosphorylate Nup50 at Ser221 in intact cells|Notably, erk phosphorylation of the fg repeat region of nup50 reduced its affinity for importin-beta family proteins, importin-beta and transportin." SIGNOR-188061 CDK1 protein P06493 UNIPROT TPX2 protein Q9ULW0 UNIPROT "down-regulates activity" phosphorylation Thr72 NLQQAIVtPLKPVDN -1 25688093 t lperfetto "In this study, we characterize the phosphorylation of threonine 72 (Thr(72)) in human TPX2, a residue highly conserved across species. We find that Cdk1/2 phosphorylate TPX2 in vitro and in vivo. |Endogenous TPX2 phosphorylated at Thr(72) does not associate with the mitotic spindle. Furthermore, ectopic GFP-TPX2 T72A preferentially concentrates on the spindle" SIGNOR-265096 CDK1 protein P06493 UNIPROT EPN1 protein Q9Y6I3 UNIPROT "down-regulates activity" phosphorylation Ser382 FSDPWGGsPAKPSTN 10029 BTO:0000246 10764745 t miannu "Phosphorylation of POB1 and Epsin by p34cdc2 kinase. Their phosphorylation sites (Ser411 of POB1 and Ser357 of Epsin) were determined. Phosphorylated Epsin and EpsinS357D formed a complex with α-adaptin less efficiently than wild type Epsin." SIGNOR-262723 CDK1 protein P06493 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT down-regulates phosphorylation Ser728 VVKQEQLsPKKKENN 9606 SIGNOR-C17 22163316 t gcesareni "We demonstrate that aib1 is phosphorylated on ser728 and ser867 by cdk1/cyclin b at the onset of mitosis and remains phosphorylated until exit from m phase." SIGNOR-195233 CDK1 protein P06493 UNIPROT CyclinB/CDK1 complex SIGNOR-C17 SIGNOR "form complex" binding 9606 25603287 t lperfetto "The central mitotic kinase, cyclin-dependent kinase-1 (human cdk1 is present through all stages of the cell cycle, but its activity is cell-cycle regulated by phosphorylation/dephosphorylation and cyclin binding.Cdk1-cyclin b phosphorylates ser/thr residues directly preceding pro; thus, it is classified as a proline-directed kinase." SIGNOR-205593 CDK1 protein P06493 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates phosphorylation 9606 8114697 t lperfetto "P34cdc2 catalyzes the in vitro phosphorylation of mkk1 on both of these threonine residues and inactivates mkk1 enzymatic activity. Both sites are phosphorylated in vivo as well" SIGNOR-244847 CDK1 protein P06493 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser249 EGGKSGKsPRRRAAS 9606 BTO:0001130 18408765 t gcesareni "Overexpression of cdk1 inhibits the transcriptional activity of foxo1 in pca cells through s249 phosphorylation on foxo1." SIGNOR-252890 CDK1 protein P06493 UNIPROT PP1 proteinfamily SIGNOR-PF54 SIGNOR "down-regulates activity" phosphorylation 9606 12202491 t lperfetto "Both of these pp1 isoforms contain an arg-pro-ile/val-thr-pro-pro-arg sequence near the c terminus, a known site of phosphorylation by cdc/cdk kinases, and phosphorylation attenuates phosphatase activity." SIGNOR-264648 C2 protein P06681 UNIPROT "C3 convertase complex" complex SIGNOR-C310 SIGNOR "form complex" binding -1 cleavage:Arg243 KTKESLGrKIQIQRS 17204478 t "complement C2a fragment: PRO_0000027612" lperfetto "However, following cleavage of C4, C2 binds tightly to C4b to form the C4b2 complex" SIGNOR-263399 S100A9 protein P06702 UNIPROT TLR4 protein O00206 UNIPROT "up-regulates activity" binding 9606 BTO:0001545 28137827 t miannu "RAGE and TLR4 are well-characterized S100A8 and S100A9 receptors and expressed in AML cells. S100A9 binds to TLR4 and induces signaling pathways,promoting leukemic cell differentiation and proliferation arrest. Binding of S100A9 to TLR4 stimulates the phosphorylation of JNK, ERK1/2, and p38 MAPK, which leads to the activation of c-Jun, CREB, and NF-kB." SIGNOR-261918 S100A9 protein P06702 UNIPROT AGER protein Q15109 UNIPROT "up-regulates activity" binding 9606 BTO:0001545 28137827 t miannu "RAGE and TLR4 are well-characterized S100A8 and S100A9 receptors and expressed in AML cells Once secreted, S100A8 and S100A9 induce immune and inflammatory responses9 through interaction with receptors such as Toll-like receptor 4 (TLR4), receptor for advanced glycation end-product (RAGE), and CD33" SIGNOR-261920 IGF1R protein P08069 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates 9606 BTO:0001103 15829723 f apalma "Mechanical loading increases IGF-I release, and IGF-I can stimulate Ca2+ influx and thereby activate calcineurin" SIGNOR-255100 ENO1 protein P06733 UNIPROT 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 29767008 t miannu "Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: α-enolase (ENO1) is present in almost all mature tissues; β-enolase (ENO3) exists primarily in muscle tissues; and γ-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits." SIGNOR-266528 ENO1 protein P06733 UNIPROT phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 29767008 t miannu "Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: α-enolase (ENO1) is present in almost all mature tissues; β-enolase (ENO3) exists primarily in muscle tissues; and γ-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits." SIGNOR-266524 ENO1 protein P06733 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9534 BTO:0000318 2005901 t Luana "This result suggests that MBP-1 in vivo acts as a sequence-specific repressor." SIGNOR-261594 GPI protein P06744 UNIPROT "beta-D-fructofuranose 6-phosphate(2-)" smallmolecule CHEBI:57634 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 16051738 t miannu "Glucose 6-phosphate isomerase (GPI) catalyzes the interconversion of G6P into fructose-6-phosphate (F6P) in the second step of the Embden-Meyerhof pathway (Figure 1). As a result of this reversible reaction, products of the hexose-monophosphate shunt can be recycled to G6P." SIGNOR-266462 GPI protein P06744 UNIPROT "alpha-D-glucose 6-phosphate(2-)" smallmolecule CHEBI:58225 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 16051738 t miannu "Glucose 6-phosphate isomerase (GPI) catalyzes the interconversion of G6P into fructose-6-phosphate (F6P) in the second step of the Embden-Meyerhof pathway (Figure 1). As a result of this reversible reaction, products of the hexose-monophosphate shunt can be recycled to G6P." SIGNOR-266461 NPM1 protein P06748 UNIPROT HEXIM1 protein O94992 UNIPROT "down-regulates activity" binding 9606 BTO:0001545 18371977 t miannu "We identified NPM as a novel HEXIM1-binding protein. NPM functioned as a negative regulator of HEXIM1. cytoplasmic localization of endogenous HEXIM1 is detected in an acute myeloid leukemia (AML) cell line containing the NPMc+ mutation, suggesting the physiological importance of HEXIM1-NPMc+ interaction." SIGNOR-260134 NPM1 protein P06748 UNIPROT HOXA9 protein P31269 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 30205049 t miannu "In AML cells, NPM1 mutations result in abnormal cytoplasmic localization of the mutant protein (NPM1c); however, it is unknown whether NPM1c is required to maintain the leukemic state. Here, we show that loss of NPM1c from the cytoplasm, either through nuclear relocalization or targeted degradation, results in immediate downregulation of homeobox (HOX) genes followed by differentiation." SIGNOR-260138 NPM1 protein P06748 UNIPROT CENPA protein P49450 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 19410544 t miannu "Here we demonstrate that prenucleosomal CENP-A is complexed with histone H4, nucleophosmin 1, and HJURPA minority of NPM1 cofractionated with prenucleosomal CENP-A, consistent with only a small proportion of total NPM1 stably associated with CENP-A. The partial overlap of NPM1 and HJURP with each other supports their formation of distinct prenucleosomal complexes with CENP-A. it is also possible that NPM1 plays a non essential role in the assembly of CENP-A nucleosomes or the nucleophosmin paralogues NPM2 and NPM3 may compensate for the absence of NPM1." SIGNOR-263708 NPM1 protein P06748 UNIPROT CDKN2A protein Q8N726 UNIPROT "up-regulates activity" binding 10090 16199867 t gcesareni "The Arf-NPM interaction seems to be critical in regulating the stability of both proteins. Arf, in fact, induces polyubiquitination and degradation of NPM and inhibits its effects on ribogenesis (18). NPM, instead, protects Arf from degradation and, surprisingly, antagonizes its ability to inhibit cell division" SIGNOR-245073 NPM1 protein P06748 UNIPROT FBXW7 protein Q969H0 UNIPROT "up-regulates quantity" binding 10090 BTO:0002572 18625840 t gcesareni "We report here that NPM regulates turnover of the c-Myc oncoprotein by acting on the F-box protein Fbw7 , a component of the E3 ligase complex involved in the ubiquitination and proteasome degradation of c-Myc. NPM was required for nucleolar localization and stabili- zation of Fbw7" SIGNOR-245084 ITGAV protein P06756 UNIPROT "Av/b1 integrin" complex SIGNOR-C175 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253201 ITGAV protein P06756 UNIPROT "Av/b2 integrin" complex SIGNOR-C176 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253203 ITGAV protein P06756 UNIPROT "Av/b6 integrin" complex SIGNOR-C179 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253209 FES protein P07332 UNIPROT BCR protein P11274 UNIPROT down-regulates phosphorylation Tyr283 YQPYQSIyVGGMMEG 9606 BTO:0000007 8955135 t lperfetto "In the present study, we demonstrate that bcr tyr-246 and at least one of the closely spaced tyrosine residues, tyr-279, tyr-283, and tyr- 289 (3y cluster), are phosphorylated by fes both in vitro and in 32p(i)- labeled cells. tyrosine phosphorylation of bcr by fes suppressed bcr serine/threonine kinase activity toward the 14-3-3 protein and bcr substrate, bap-1." SIGNOR-45343 ITGAV protein P06756 UNIPROT "Av/b8 integrin" complex SIGNOR-C185 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253289 CRH protein P06850 UNIPROT CRHR1 protein P34998 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142;BTO:0001253 11416224 t gcesareni "Crf and ucn bind and activate crf-r1 with similarly high affinities." SIGNOR-108713 TH protein P07101 UNIPROT L-dopa smallmolecule CHEBI:15765 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 BTO:0004032 NBK536726 t brain lperfetto "Tyrosine produced in the liver is then transported by an active transport mechanism into the dopaminergic neurons within the brain. This is followed by the conversion of L-tyrosine into L-DOPA through hydroxylation at the phenol ring by the enzyme tyrosine hydroxylase (TH)." SIGNOR-263991 TH protein P07101 UNIPROT tyrosine smallmolecule CHEBI:18186 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 NBK536726 t brain lperfetto "Tyrosine produced in the liver is then transported by an active transport mechanism into the dopaminergic neurons within the brain. This is followed by the conversion of L-tyrosine into L-DOPA through hydroxylation at the phenol ring by the enzyme tyrosine hydroxylase (TH)." SIGNOR-263990 NEFL protein P07196 UNIPROT "Neurofilament L/H" complex SIGNOR-C208 SIGNOR "form complex" binding 9606 BTO:0000938 19468066 t miannu "Neurofilaments are obligate heteropolymers that are minimally comprised of the low molecular neurofilament protein L (NFL) plus the medium and/or high molecular weight proteins neurofilament protein M (NFM) and neurofilament protein H" SIGNOR-255272 TPO protein P07202 UNIPROT 3,5-diiodo-L-tyrosine smallmolecule CHEBI:15768 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 BTO:0001379 16098474 t scontino "TPO plays a key role in thyroid hormone synthesis by catalyzing both the iodination of tyrosine residues to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) residues. The first step in the process of thyroid hormone synthesis is the binding of iodine to tyrosine residues in Tg, which yields MIT and DIT residues." SIGNOR-267030 TPO protein P07202 UNIPROT diiodine smallmolecule CHEBI:17606 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 28153798 t scontino "TPO is considered the key enzyme in thyroid hormonogenesis. It catalyzes the oxidation of iodide that is necessary for the iodinationof the TG tyrosyl residues (the organification reaction)." SIGNOR-266959 TPO protein P07202 UNIPROT L-thyroxine smallmolecule CHEBI:18332 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 BTO:0001379 28153798 t scontino "The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a “donor” onto a DIT residue called an “acceptor”. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines." SIGNOR-267040 TPO protein P07202 UNIPROT 3-iodo-L-tyrosine smallmolecule CHEBI:27847 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 16098474 t scontino "TPO plays a key role in thyroid hormone synthesis by catalyzing both the iodination of tyrosine residues to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) residues. The first step in the process of thyroid hormone synthesis is the binding of iodine to tyrosine residues in Tg, which yields MIT and DIT residues." SIGNOR-266957 TPO protein P07202 UNIPROT 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 BTO:0001379 28153798 t scontino "The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a “donor” onto a DIT residue called an “acceptor”. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines." SIGNOR-267039 TPO protein P07202 UNIPROT "L-alanine zwitterion" smallmolecule CHEBI:57972 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 BTO:0001379 28153798 t scontino "The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a “donor” onto a DIT residue called an “acceptor”. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines." SIGNOR-267041 TPO protein P07202 UNIPROT "L-tyrosine zwitterion" smallmolecule CHEBI:58315 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 16098474 t scontino "TPO plays a key role in thyroid hormone synthesis by catalyzing both the iodination of tyrosine residues to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) residues. The first step in the process of thyroid hormone synthesis is the binding of iodine to tyrosine residues in Tg, which yields MIT and DIT residues." SIGNOR-266956 PGK2 protein P07205 UNIPROT "3-phosphonato-D-glyceroyl phosphate(4-)" smallmolecule CHEBI:57604 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 16051738 t miannu "Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa." SIGNOR-266503 PGK2 protein P07205 UNIPROT 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 16051738 t miannu "Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa." SIGNOR-266506 PROS1 protein P07225 UNIPROT AXL protein P30530 UNIPROT up-regulates binding 9606 7867073 t gcesareni "We report the identification of ligands for tyro 3 (alternatively called sky, rse, brt, or tif) and axl (alternatively, ark or ufo), members of a previously orphan family of receptor-like tyrosine kinases. These ligands correspond to protein s, a protease regulator that is a potent anticoagulant, and gas6, a protein related to protein s but lacking any known function." SIGNOR-34483 FES protein P07332 UNIPROT BCR protein P11274 UNIPROT down-regulates phosphorylation Tyr246 SCGVDGDyEDAELNP 9606 BTO:0000007 8955135 t lperfetto "In the present study, we demonstrate that bcr tyr-246 and at least one of the closely spaced tyrosine residues, tyr-279, tyr-283, and tyr- 289 (3y cluster), are phosphorylated by fes both in vitro and in 32p(i)- labeled cells. tyrosine phosphorylation of bcr by fes suppressed bcr serine/threonine kinase activity toward the 14-3-3 protein and bcr substrate, bap-1." SIGNOR-45330 FES protein P07332 UNIPROT BCR protein P11274 UNIPROT down-regulates phosphorylation Tyr279 PPLEYQPyQSIYVGG 9606 BTO:0000007 8955135 t lperfetto "In the present study, we demonstrate that bcr tyr-246 and at least one of the closely spaced tyrosine residues, tyr-279, tyr-283, and tyr- 289 (3y cluster), are phosphorylated by fes both in vitro and in 32p(i)- labeled cells. tyrosine phosphorylation of bcr by fes suppressed bcr serine/threonine kinase activity toward the 14-3-3 protein and bcr substrate, bap-1." SIGNOR-45334 FES protein P07332 UNIPROT BCR protein P11274 UNIPROT "down-regulates activity" phosphorylation Tyr177 ADAEKPFyVNVEFHH 9606 BTO:0000007 8955135 t "Mutagenesis of BCR Tyr-177 to Phe completely abolished FES-induced BCR binding to the GRB2 SH2 domain, identifying Tyr-177 as an additional phosphorylation site for FES. Co-expression of BCR and FES in human 293T cells stimulated the tyrosine autophosphorylation of FES. By contrast, tyrosine phosphorylation of BCR by FES suppressed BCR serine/threonine kinase activity toward the 14-3-3 protein and BCR substrate, BAP-1." SIGNOR-251136 FES protein P07332 UNIPROT BCR protein P11274 UNIPROT "down-regulates activity" phosphorylation Tyr246 SCGVDGDyEDAELNP 9606 BTO:0000007 8955135 t "In the present study, we demonstrate that BCR Tyr-246 and at least one of the closely spaced tyrosine residues, Tyr-279, Tyr-283, and Tyr-289 (3Y cluster), are phosphorylated by FES both in vitro and in 32Pi-labeled cells. Co-expression of BCR and FES in human 293T cells stimulated the tyrosine autophosphorylation of FES. By contrast, tyrosine phosphorylation of BCR by FES suppressed BCR serine/threonine kinase activity toward the 14-3-3 protein and BCR substrate, BAP-1. " SIGNOR-251137 FES protein P07332 UNIPROT PECAM1 protein P16284 UNIPROT "up-regulates activity" phosphorylation Tyr690 PLNSDVQyTEVQVSS 9606 BTO:0000007 12972546 t miannu "PECAM-1 Is Phosphorylated by Fer and, To a Lesser Extent, by Fes. These results suggest that Fer not only functions as a tyrosine kinase for PECAM-1 but also that Fer modulates the downstream signaling of PECAM-1 by inducing phosphorylation of SHP-2 and Gab1." SIGNOR-262867 FES protein P07332 UNIPROT PECAM1 protein P16284 UNIPROT "up-regulates activity" phosphorylation Tyr713 KKDTETVySEVRKAV 9606 BTO:0000007 12972546 t miannu "PECAM-1 Is Phosphorylated by Fer and, To a Lesser Extent, by Fes. These results suggest that Fer not only functions as a tyrosine kinase for PECAM-1 but also that Fer modulates the downstream signaling of PECAM-1 by inducing phosphorylation of SHP-2 and Gab1." SIGNOR-262868 CSF1R protein P07333 UNIPROT SOCS1 protein O15524 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000876 BTO:0001103 24890514 f 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 CSF1R protein P07333 UNIPROT CSF1R protein P07333 UNIPROT down-regulates phosphorylation Tyr561 ESYEGNSyTFIDPTQ 9606 BTO:0001271 15297464 t lperfetto "Csf-1-mediated wild-type (wt)-csf-1r phosphorylation was not markedly affected by sfk inhibition, indicating that lack of sfk binding is not responsible for diminished y559f phosphorylation. Unexpectedly, cells expressing y559f were hyperproliferative in response to csf-1. Hyperproliferation correlated with prolonged activation of akt, erk, and stat5 in the y559f mutant. Consistent with a defect in receptor negative regulation, c-cbl tyrosine phosphorylation and csf-1r/c-cbl co-association were almost undetectable in the y559f mutant. Furthermore, y559f underwent reduced multiubiquitination and delayed receptor internalization and degradation. In conclusion, we propose that tyr559 is a switch residue that functions in kinase regulation, signal transduction and, indirectly, receptor down-regulation." SIGNOR-127622 CSF1R protein P07333 UNIPROT CSF1R protein P07333 UNIPROT down-regulates phosphorylation Tyr969 PLLQPNNyQFC 9606 BTO:0001271 15297464 t 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) following ligand binding, the csf-1r is rapidly internalized and degraded. This process begins with multiubiquitination of the csf-1r mediated by c-cbl (20), an e3-type ubiquitin ligase" SIGNOR-127626 CSF1R protein P07333 UNIPROT CSF1R protein P07333 UNIPROT up-regulates phosphorylation Tyr708 NIHLEKKyVRRDSGF 9606 BTO:0001271 15297464 t 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 CSF1R protein P07333 UNIPROT CSF1R protein P07333 UNIPROT up-regulates phosphorylation Tyr723 SSQGVDTyVEMRPVS 9606 BTO:0001271 15297464 t 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 CSF1R protein P07333 UNIPROT CSF1R protein P07333 UNIPROT up-regulates phosphorylation Tyr809 DIMNDSNyIVKGNAR 9606 BTO:0001271 15297464 t 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 TUBB protein P07437 UNIPROT SMAD2 protein Q15796 UNIPROT "down-regulates activity" binding 9606 17429065 t lperfetto "Smad2/3 also binds to _-tubulin, which provides a negative regulatory mechanism controlling tgf-_ activity. the results showed that the mh2 domain of smad2 binds to _-tubulin with almost the same efficiency as the full-length (wild-type) smad2. Similar results were obtained for the smad3 binding to _-tubulin." SIGNOR-217631 IGF1R protein P08069 UNIPROT IRS4 protein O14654 UNIPROT up-regulates phosphorylation 9606 BTO:0000671 9553137 t gcesareni "Insulin-like growth factor i acting through its receptor was as effective as insulin in eliciting tyrosine phosphorylation of irs-4." SIGNOR-56604 CTSD protein P07339 UNIPROT protein B4DGD0 UNIPROT "down-regulates quantity by destabilization" cleavage Ala617 ISEVKMDaEFRHDSG -1 8943232 t lperfetto "FIG. 4. Schematic representation of the major cathepsin D cleavage sites in FLAG-bAPP156-bFGF and in bAPP100-FLAG. The amino acid sequences for the FLAG-bAPP156-bFGF and bAPP100-FLAG substrates are shown. Large arrows denote major cleavage sites. Unique cathepsin D cleavage sites in urea-denatured FLAG-bAPP156-bFGF are labeled (U). Small arrowheads denote minor bAPP100-FLAG cleavage sites determined by mass spectral analysis.|Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism." SIGNOR-261737 CTSD protein P07339 UNIPROT protein B4DGD0 UNIPROT "down-regulates quantity by destabilization" cleavage Asp572 PWHSFGAdSVPANTE -1 8943232 t lperfetto "FIG. 4. Schematic representation of the major cathepsin D cleavage sites in FLAG-bAPP156-bFGF and in bAPP100-FLAG. The amino acid sequences for the FLAG-bAPP156-bFGF and bAPP100-FLAG substrates are shown. Large arrows denote major cleavage sites. Unique cathepsin D cleavage sites in urea-denatured FLAG-bAPP156-bFGF are labeled (U). Small arrowheads denote minor bAPP100-FLAG cleavage sites determined by mass spectral analysis.|Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism." SIGNOR-261761 CTSD protein P07339 UNIPROT protein B4DGD0 UNIPROT "down-regulates quantity by destabilization" cleavage Asp638 KLVFFAEdVGSNKGA -1 8943232 t lperfetto "FIG. 4. Schematic representation of the major cathepsin D cleavage sites in FLAG-bAPP156-bFGF and in bAPP100-FLAG. The amino acid sequences for the FLAG-bAPP156-bFGF and bAPP100-FLAG substrates are shown. Large arrows denote major cleavage sites. Unique cathepsin D cleavage sites in urea-denatured FLAG-bAPP156-bFGF are labeled (U). Small arrowheads denote minor bAPP100-FLAG cleavage sites determined by mass spectral analysis.|Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism." SIGNOR-261764 CTSD protein P07339 UNIPROT protein B4DGD0 UNIPROT "down-regulates quantity by destabilization" cleavage Asp683 HHGVVEVdAAVTPEE -1 8943232 t lperfetto "The precise cathepsin D cleavage sites within these recombinant betaAPP substrates were identified using this technique. Both recombinant substrates were cleaved at the following sites: Leu49-Val50, Asp68-Ala69, Phe93-Phe94. | two additional cleavage sites near the amino terminus of betaA4, Glu-3-Val-2 and Glu3-Phe4, were observed, indicating that cathepsin D cleavage of betaAPP is influenced by the structural integrity of the substrate. Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism." SIGNOR-261765 CTSD protein P07339 UNIPROT protein B4DGD0 UNIPROT "down-regulates quantity by destabilization" cleavage Gln711 PTYKFFEqMQN -1 8943232 t lperfetto "FIG. 4. Schematic representation of the major cathepsin D cleavage sites in FLAG-bAPP156-bFGF and in bAPP100-FLAG. The amino acid sequences for the FLAG-bAPP156-bFGF and bAPP100-FLAG substrates are shown. Large arrows denote major cleavage sites. Unique cathepsin D cleavage sites in urea-denatured FLAG-bAPP156-bFGF are labeled (U). Small arrowheads denote minor bAPP100-FLAG cleavage sites determined by mass spectral analysis.|Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism." SIGNOR-261790 CTSD protein P07339 UNIPROT protein B4DGD0 UNIPROT "down-regulates quantity by destabilization" cleavage Glu612 IKTEEISeVKMDAEF -1 8943232 t lperfetto "The precise cathepsin D cleavage sites within these recombinant betaAPP substrates were identified using this technique. Both recombinant substrates were cleaved at the following sites: Leu49-Val50, Asp68-Ala69, Phe93-Phe94. | two additional cleavage sites near the amino terminus of betaA4, Glu-3-Val-2 and Glu3-Phe4, were observed, indicating that cathepsin D cleavage of betaAPP is influenced by the structural integrity of the substrate. Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism." SIGNOR-261766 CTSD protein P07339 UNIPROT protein B4DGD0 UNIPROT "down-regulates quantity by destabilization" cleavage Glu618 SEVKMDAeFRHDSGY -1 8943232 t lperfetto "The precise cathepsin D cleavage sites within these recombinant betaAPP substrates were identified using this technique. Both recombinant substrates were cleaved at the following sites: Leu49-Val50, Asp68-Ala69, Phe93-Phe94. | two additional cleavage sites near the amino terminus of betaA4, Glu-3-Val-2 and Glu3-Phe4, were observed, indicating that cathepsin D cleavage of betaAPP is influenced by the structural integrity of the substrate. Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism." SIGNOR-261767 CTSD protein P07339 UNIPROT protein B4DGD0 UNIPROT "down-regulates quantity by destabilization" cleavage Leu664 ATVIVITlVMLKKKQ -1 8943232 t lperfetto "The precise cathepsin D cleavage sites within these recombinant betaAPP substrates were identified using this technique. Both recombinant substrates were cleaved at the following sites: Leu49-Val50, Asp68-Ala69, Phe93-Phe94. | two additional cleavage sites near the amino terminus of betaA4, Glu-3-Val-2 and Glu3-Phe4, were observed, indicating that cathepsin D cleavage of betaAPP is influenced by the structural integrity of the substrate. Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism." SIGNOR-261784 CTSD protein P07339 UNIPROT protein B4DGD0 UNIPROT "down-regulates quantity by destabilization" cleavage Met666 VIVITLVmLKKKQYT -1 8943232 t lperfetto "FIG. 4. Schematic representation of the major cathepsin D cleavage sites in FLAG-bAPP156-bFGF and in bAPP100-FLAG. The amino acid sequences for the FLAG-bAPP156-bFGF and bAPP100-FLAG substrates are shown. Large arrows denote major cleavage sites. Unique cathepsin D cleavage sites in urea-denatured FLAG-bAPP156-bFGF are labeled (U). Small arrowheads denote minor bAPP100-FLAG cleavage sites determined by mass spectral analysis.|Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism." SIGNOR-261789 CTSD protein P07339 UNIPROT protein B4DGD0 UNIPROT "down-regulates quantity by destabilization" cleavage Phe619 EVKMDAEfRHDSGYE -1 8943232 t lperfetto "FIG. 4. Schematic representation of the major cathepsin D cleavage sites in FLAG-bAPP156-bFGF and in bAPP100-FLAG. The amino acid sequences for the FLAG-bAPP156-bFGF and bAPP100-FLAG substrates are shown. Large arrows denote major cleavage sites. Unique cathepsin D cleavage sites in urea-denatured FLAG-bAPP156-bFGF are labeled (U). Small arrowheads denote minor bAPP100-FLAG cleavage sites determined by mass spectral analysis.|Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism." SIGNOR-261769 CTSD protein P07339 UNIPROT protein B4DGD0 UNIPROT "down-regulates quantity by destabilization" cleavage Phe708 YENPTYKfFEQMQN -1 8943232 t lperfetto "The precise cathepsin D cleavage sites within these recombinant betaAPP substrates were identified using this technique. Both recombinant substrates were cleaved at the following sites: Leu49-Val50, Asp68-Ala69, Phe93-Phe94. | two additional cleavage sites near the amino terminus of betaA4, Glu-3-Val-2 and Glu3-Phe4, were observed, indicating that cathepsin D cleavage of betaAPP is influenced by the structural integrity of the substrate. Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism." SIGNOR-261776 CTSD protein P07339 UNIPROT protein B4DGD0 UNIPROT "up-regulates activity" cleavage Ala657 MVGGVVIaTVIVITL -1 10605825 t lperfetto "In this work, we used a sensitive in vitro method of detection to investigate the role of cathepasin D in the proteolytic processing of a 100-amino acid C-terminal fragment (C100) inclusive of βA4 and cytoplasmic domain of APP. Digestion of C100 with cathepsin D resulted in cleavage at the amyloidogenic γ-cleavage sites. This occurred preferentially at Thr43–Val44 and at Ala42–Thr43, generating full length βA4 43 and βA4 42 amyloid peptides, respectively. Cathepsin D was also found to cleave the substrate at the following nonamyloidogenic sites; Leu34–Met35, Thr48–Leu49 and Leu49–Val50. A high concentration of cathepsin D resulted in cleavage also occurring at Phe19–Phe20, Phe20–Ala21 and Phe93–Phe94 of the C100, suggesting that these sites are somewhat less sensitive to the action of cathepsin D." SIGNOR-261738 CTSD protein P07339 UNIPROT protein B4DGD0 UNIPROT "up-regulates activity" cleavage Leu649 NKGAIIGlMVGGVVI -1 10605825 t lperfetto "In this work, we used a sensitive in vitro method of detection to investigate the role of cathepasin D in the proteolytic processing of a 100-amino acid C-terminal fragment (C100) inclusive of βA4 and cytoplasmic domain of APP. Digestion of C100 with cathepsin D resulted in cleavage at the amyloidogenic γ-cleavage sites. This occurred preferentially at Thr43–Val44 and at Ala42–Thr43, generating full length βA4 43 and βA4 42 amyloid peptides, respectively. Cathepsin D was also found to cleave the substrate at the following nonamyloidogenic sites; Leu34–Met35, Thr48–Leu49 and Leu49–Val50. A high concentration of cathepsin D resulted in cleavage also occurring at Phe19–Phe20, Phe20–Ala21 and Phe93–Phe94 of the C100, suggesting that these sites are somewhat less sensitive to the action of cathepsin D." SIGNOR-261783 CTSD protein P07339 UNIPROT protein B4DGD0 UNIPROT "up-regulates activity" cleavage Phe634 VHHQKLVfFAEDVGS -1 10605825 t lperfetto "In this work, we used a sensitive in vitro method of detection to investigate the role of cathepasin D in the proteolytic processing of a 100-amino acid C-terminal fragment (C100) inclusive of βA4 and cytoplasmic domain of APP. Digestion of C100 with cathepsin D resulted in cleavage at the amyloidogenic γ-cleavage sites. This occurred preferentially at Thr43–Val44 and at Ala42–Thr43, generating full length βA4 43 and βA4 42 amyloid peptides, respectively. Cathepsin D was also found to cleave the substrate at the following nonamyloidogenic sites; Leu34–Met35, Thr48–Leu49 and Leu49–Val50. A high concentration of cathepsin D resulted in cleavage also occurring at Phe19–Phe20, Phe20–Ala21 and Phe93–Phe94 of the C100, suggesting that these sites are somewhat less sensitive to the action of cathepsin D." SIGNOR-261771 CTSD protein P07339 UNIPROT protein B4DGD0 UNIPROT "up-regulates activity" cleavage Phe635 HHQKLVFfAEDVGSN -1 10605825 t lperfetto "In this work, we used a sensitive in vitro method of detection to investigate the role of cathepasin D in the proteolytic processing of a 100-amino acid C-terminal fragment (C100) inclusive of βA4 and cytoplasmic domain of APP. Digestion of C100 with cathepsin D resulted in cleavage at the amyloidogenic γ-cleavage sites. This occurred preferentially at Thr43–Val44 and at Ala42–Thr43, generating full length βA4 43 and βA4 42 amyloid peptides, respectively. Cathepsin D was also found to cleave the substrate at the following nonamyloidogenic sites; Leu34–Met35, Thr48–Leu49 and Leu49–Val50. A high concentration of cathepsin D resulted in cleavage also occurring at Phe19–Phe20, Phe20–Ala21 and Phe93–Phe94 of the C100, suggesting that these sites are somewhat less sensitive to the action of cathepsin D." SIGNOR-261774 CTSD protein P07339 UNIPROT protein B4DGD0 UNIPROT "up-regulates activity" cleavage Phe709 ENPTYKFfEQMQN -1 10605825 t lperfetto "In this work, we used a sensitive in vitro method of detection to investigate the role of cathepasin D in the proteolytic processing of a 100-amino acid C-terminal fragment (C100) inclusive of βA4 and cytoplasmic domain of APP. Digestion of C100 with cathepsin D resulted in cleavage at the amyloidogenic γ-cleavage sites. This occurred preferentially at Thr43–Val44 and at Ala42–Thr43, generating full length βA4 43 and βA4 42 amyloid peptides, respectively. Cathepsin D was also found to cleave the substrate at the following nonamyloidogenic sites; Leu34–Met35, Thr48–Leu49 and Leu49–Val50. A high concentration of cathepsin D resulted in cleavage also occurring at Phe19–Phe20, Phe20–Ala21 and Phe93–Phe94 of the C100, suggesting that these sites are somewhat less sensitive to the action of cathepsin D." SIGNOR-261778 CTSD protein P07339 UNIPROT protein B4DGD0 UNIPROT "up-regulates activity" cleavage Thr658 VGGVVIAtVIVITLV -1 10605825 t lperfetto "In this work, we used a sensitive in vitro method of detection to investigate the role of cathepasin D in the proteolytic processing of a 100-amino acid C-terminal fragment (C100) inclusive of βA4 and cytoplasmic domain of APP. Digestion of C100 with cathepsin D resulted in cleavage at the amyloidogenic γ-cleavage sites. This occurred preferentially at Thr43–Val44 and at Ala42–Thr43, generating full length βA4 43 and βA4 42 amyloid peptides, respectively. Cathepsin D was also found to cleave the substrate at the following nonamyloidogenic sites; Leu34–Met35, Thr48–Leu49 and Leu49–Val50. A high concentration of cathepsin D resulted in cleavage also occurring at Phe19–Phe20, Phe20–Ala21 and Phe93–Phe94 of the C100, suggesting that these sites are somewhat less sensitive to the action of cathepsin D." SIGNOR-261792 IGF1R protein P08069 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates phosphorylation Tyr373 SEDDEDCyGNYDNLL -1 BTO:0000150 20044479 t lperfetto "IGF-1R Directly Interacts with and Phosphorylates PDK1 in Vitro" SIGNOR-236548 CTSD protein P07339 UNIPROT protein B4DGD0 UNIPROT "up-regulates activity" cleavage Thr663 IATVIVItLVMLKKK -1 10605825 t lperfetto "In this work, we used a sensitive in vitro method of detection to investigate the role of cathepasin D in the proteolytic processing of a 100-amino acid C-terminal fragment (C100) inclusive of βA4 and cytoplasmic domain of APP. Digestion of C100 with cathepsin D resulted in cleavage at the amyloidogenic γ-cleavage sites. This occurred preferentially at Thr43–Val44 and at Ala42–Thr43, generating full length βA4 43 and βA4 42 amyloid peptides, respectively. Cathepsin D was also found to cleave the substrate at the following nonamyloidogenic sites; Leu34–Met35, Thr48–Leu49 and Leu49–Val50. A high concentration of cathepsin D resulted in cleavage also occurring at Phe19–Phe20, Phe20–Ala21 and Phe93–Phe94 of the C100, suggesting that these sites are somewhat less sensitive to the action of cathepsin D." SIGNOR-261793 CTSD protein P07339 UNIPROT protein B4DGD0 UNIPROT "up-regulates activity" cleavage Phe709 ENPTYKFfEQMQN -1 8943232 t lperfetto "FIG. 4. Schematic representation of the major cathepsin D cleavage sites in FLAG-bAPP156-bFGF and in bAPP100-FLAG. The amino acid sequences for the FLAG-bAPP156-bFGF and bAPP100-FLAG substrates are shown. Large arrows denote major cleavage sites. Unique cathepsin D cleavage sites in urea-denatured FLAG-bAPP156-bFGF are labeled (U). Small arrowheads denote minor bAPP100-FLAG cleavage sites determined by mass spectral analysis.|Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism." SIGNOR-261777 CTSD protein P07339 UNIPROT BGLAP protein P02818 UNIPROT "down-regulates quantity by destabilization" cleavage Ala92 DHIGFQEaYRRFYGP -1 9076588 t miannu "This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42." SIGNOR-256319 C8A protein P07357 UNIPROT "Membrane attack complex" complex SIGNOR-C313 SIGNOR "form complex" binding -1 30552328 t lperfetto "The human MAC pore was formed on liposomes from individual complement proteins. |The maps were further subdivided into three components: an asymmetric region (C5b, C6, C7, and C8), a hinge region (C7, C8, and two C9 molecules), and a C9 oligomer" SIGNOR-263445 C8B protein P07358 UNIPROT "Membrane attack complex" complex SIGNOR-C313 SIGNOR "form complex" binding -1 30552328 t lperfetto "The human MAC pore was formed on liposomes from individual complement proteins. |The maps were further subdivided into three components: an asymmetric region (C5b, C6, C7, and C8), a hinge region (C7, C8, and two C9 molecules), and a C9 oligomer" SIGNOR-263444 GP1BA protein P07359 UNIPROT "GPIb-IX-V complex" complex SIGNOR-C270 SIGNOR "form complex" binding 9606 BTO:0000132 16293600 t lperfetto "The GPIb-V-IX receptor consists of 4 transmembrane subunits: GPIbα, disulfide-linked to GPIbβ, and the noncovalently associated GPIX and GPV components, in ratios of 2:2:2:1." SIGNOR-261847 C8G protein P07360 UNIPROT "Membrane attack complex" complex SIGNOR-C313 SIGNOR "form complex" binding -1 30552328 t lperfetto "The human MAC pore was formed on liposomes from individual complement proteins. |The maps were further subdivided into three components: an asymmetric region (C5b, C6, C7, and C8), a hinge region (C7, C8, and two C9 molecules), and a C9 oligomer" SIGNOR-263446 CAPN1 protein P07384 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" cleavage 9606 BTO:0000590 25969760 t lperfetto "Besides tau phosphorylation, calpain activation might play a role in tau-mediated neurodegeneration by inducing tau cleavage. In vitro studies have shown that both fetal and adult tau isoforms are rapidly proteolyzed by calpains" SIGNOR-251584 CAPN1 protein P07384 UNIPROT F2R protein P25116 UNIPROT "down-regulates activity" cleavage Lys76 YRLVSINkSSPLQKQ -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site." SIGNOR-263560 CAPN1 protein P07384 UNIPROT GSK3A protein P49840 UNIPROT "up-regulates activity" cleavage 9606 BTO:0000590 25969760 t lperfetto "Thus, it has been shown that calpain cleaves the inhibitory domain of GSK3 generating two fragments of 40 and 30 kDa. This cleavage enhanced activity of the kinase" SIGNOR-251585 CAPN1 protein P07384 UNIPROT GSK3B protein P49841 UNIPROT "up-regulates activity" cleavage 9606 BTO:0000590 25969760 t lperfetto "Thus, it has been shown that calpain cleaves the inhibitory domain of GSK3 generating two fragments of 40 and 30 kDa. This cleavage enhanced activity of the kinase" SIGNOR-251586 CAPN1 protein P07384 UNIPROT F2RL1 protein P55085 UNIPROT "down-regulates activity" cleavage Phe59 GVTVETVfSVDEFSA -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3" SIGNOR-263580 CAPN1 protein P07384 UNIPROT CDK5R1 protein Q15078 UNIPROT "up-regulates activity" cleavage 9606 BTO:0000590 25969760 t lperfetto "Calpains also modulate the activity of CDK5. Physiologically, CDK 5 is activated by p35 and its cleaved product p25. The latter has a longer half life than p35 and therefore it is a more potent activator of CDK5. The cleavage of p35 to p25 is mediated by calpain" SIGNOR-251583 CAPN1 protein P07384 UNIPROT CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR "up-regulates activity" cleavage 9606 BTO:0000590 25969760 t lperfetto "Calpains also modulate the activity of CDK5. Physiologically, CDK 5 is activated by p35 and its cleaved product p25. The latter has a longer half life than p35 and therefore it is a more potent activator of CDK5. The cleavage of p35 to p25 is mediated by calpain" SIGNOR-251581 TUBB protein P07437 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates binding 9606 17429065 t lpetrilli "Smad2/3 also binds to _-tubulin, which provides a negative regulatory mechanism controlling tgf-_ activity. the results showed that the mh2 domain of smad2 binds to _-tubulin with almost the same efficiency as the full-length (wild-type) smad2. Similar results were obtained for the smad3 binding to _-tubulin." SIGNOR-154319 PRSS1 protein P07477 UNIPROT F2RL1 protein P55085 UNIPROT "up-regulates activity" cleavage Lys34 QGTNRSSkGRSLIGK -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3" SIGNOR-263605 PRSS2 protein P07478 UNIPROT F2RL1 protein P55085 UNIPROT "up-regulates activity" cleavage Arg36 TNRSSKGrSLIGKVD -1 10978167 t lperfetto "Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3." SIGNOR-263603 PRSS2 protein P07478 UNIPROT F2RL1 protein P55085 UNIPROT "up-regulates activity" cleavage Lys34 QGTNRSSkGRSLIGK -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3" SIGNOR-263606 ADRB2 protein P07550 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256952 ADRB2 protein P07550 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257081 ADRB2 protein P07550 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 14500986 t "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 ADRB2 protein P07550 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256809 DCN protein P07585 UNIPROT FBN1 protein P35555 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0000951 17200203 f Regulation miannu "Decorin Induces Fibrillin-1 Protein Expression in NRK Cells via IGF-IR. we report a novel mechanism of action that involves two key molecules: decorin, a small leucine-rich proteoglycan, and the IGF-IR. These two players, together with the downstream signaling pathway evoked by decorin-mediated activation of the receptor, lead to an enhanced translation of fibrillin-1 and its deposition in the extracellular environment both in vitro and in vivo." SIGNOR-251893 CTSL protein P07711 UNIPROT BGLAP protein P02818 UNIPROT "down-regulates quantity by destabilization" cleavage Arg94 IGFQEAYrRFYGPV -1 9076588 t miannu "This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42." SIGNOR-256322 CTSL protein P07711 UNIPROT BGLAP protein P02818 UNIPROT "down-regulates quantity by destabilization" cleavage Gly58 RYLYQWLgAPVPYPD -1 9076588 t miannu "This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42." SIGNOR-256321 CTSL protein P07711 UNIPROT S protein P0DTC2 UNIPROT "up-regulates activity" cleavage 9606 BTO:0000195 32142651 t miannu "SARS-2-S can use both CatB/L as well as TMPRSS2 for priming in these cell lines." SIGNOR-260737 CTSL protein P07711 UNIPROT S protein P59594 UNIPROT "up-regulates activity" cleavage -1 16081529 t miannu "A cell-free membrane-fusion system demonstrates that engagement of receptor followed by proteolysis is required for SARS-CoV membrane fusion and indicates that cathepsin L is sufficient to activate membrane fusion by SARS-CoV S. These results suggest that SARS-CoV infection results from a unique, three-step process: receptor binding and induced conformational changes in S glycoprotein followed by cathepsin L proteolysis within endosomes. The requirement for cathepsin L proteolysis identifies a previously uncharacterized class of inhibitor for SARS-CoV infection." SIGNOR-260218 PFN1 protein P07737 UNIPROT CDH4 protein P55283 UNIPROT "up-regulates activity" 9606 BTO:0000815 22820501 t lperfetto "Taken together, data obtained from MCF10A cells were consistent with the idea that Rho signaling to Dia1 and profilin-1 was essential for R-cadherin adherens junction formation." SIGNOR-253111 CTSB protein P07858 UNIPROT BGLAP protein P02818 UNIPROT "down-regulates quantity by destabilization" cleavage Arg95 GFQEAYRrFYGPV -1 9076588 t miannu "This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42." SIGNOR-256320 CTSB protein P07858 UNIPROT BGLAP protein P02818 UNIPROT "down-regulates quantity by destabilization" cleavage Gly58 RYLYQWLgAPVPYPD -1 9076588 t miannu "This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42." SIGNOR-256318 CTSB protein P07858 UNIPROT S protein P0DTC2 UNIPROT "up-regulates activity" cleavage 9606 BTO:0000195 32142651 t miannu "SARS-2-S can use both CatB/L as well as TMPRSS2 for priming in these cell lines." SIGNOR-260738 HSP90AA1 protein P07900 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates binding 9606 21511880 t gcesareni "We report the crucial underlying role of the intranuclear heat shock protein 90 molecular chaperone complex in pulsatile GR regulation. Pharmacological interference of heat shock protein 90 (HSP90) with geldanamycin during the intranuclear chaperone cycle completely ablated GR's cyclical activity, cyclical cAMP response element-binding protein (CREB) binding protein (CBP)/p300 recruitment, and the associated cyclical acetylation at the promoter region." SIGNOR-251667 HSP90AA1 protein P07900 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates binding 9606 18591668 t lpetrilli "The data in fig. 5 suggest that hsp90 specifically interacts with t?RI And t?RII In vitro and in vivo. Coupled with our data showing that loss of hsp90 function decreases t?R Levels and blocks tgf?-Induced smad2/3 activation and transcription, this result suggests that hsp90 controls tgf? Signaling as an essential component for stabilizing t?Rs." SIGNOR-179271 HSP90AA1 protein P07900 UNIPROT PAFAH1B1 protein P43034 UNIPROT "up-regulates quantity by stabilization" binding 9606 20133715 t miannu "The type I lissencephaly gene product LIS1, a key regulator of cytoplasmic dynein, is critical for cell proliferation, survival, and neuronal migration. However, little is known about the regulation of LIS1. Here, we identify a previously uncharacterized mammalian homolog of Aspergillus NudC, NudCL2 (NudC-like protein 2), as a regulator of LIS1. NudCL2 is localized to the centrosome in interphase, and spindle poles and kinetochores during mitosis, a pattern similar to the localization of LIS1 and cytoplasmic dynein. Depletion of NudCL2 destabilized LIS1 and led to phenotypes resembling those of either dynein or LIS1 deficiency. NudCL2 complexed with and enhanced the interaction between LIS1 and Hsp90. Either disruption of the LIS1-Hsp90 interaction with the C terminus of NudCL2 or inhibition of Hsp90 chaperone function by geldanamycin decreased LIS1 stability." SIGNOR-252168 HSP90AA1 protein P07900 UNIPROT PPP5C protein P53041 UNIPROT up-regulates binding 9606 15577939 t miannu "Hsp90 causes substantial activation of ppp5 by competing for tpr_phosphatase domain contacts and allowing access to the catalytic site." SIGNOR-131564 HSP90AA1 protein P07900 UNIPROT FLCN protein Q8NFG4 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000007 27353360 t "Here we show that the stability of the tumour suppressor folliculin (FLCN) depends on the chaperone function of Hsp90." SIGNOR-256505 HSP90AA1 protein P07900 UNIPROT NOD2 protein Q9HC29 UNIPROT "up-regulates quantity by stabilization" binding 9606 23019338 t miannu "Nod2 is constitutively associated with a chaperone protein, Hsp90, which is required for Nod2 stability and protects Nod2 from degradation." SIGNOR-252414 UQCRH protein P07919 UNIPROT "Mitochondrial respiratory chain complex III" complex SIGNOR-C279 SIGNOR "form complex" binding 30030361 t lperfetto "Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits" SIGNOR-262195 LAMB1 protein P07942 UNIPROT Laminin-8 complex SIGNOR-C181 SIGNOR "form complex" binding 10809728 t lperfetto "Laminins are a large family of heterotrimeric extracellular matrix glycoproteins that, in addition to having structural roles, take part in the regulation of processes such as cell migration, differentiation, and proliferation. The laminin alpha(4) chain is widely distributed both in adults and during development in tissues such as cardiac, skeletal and smooth muscle fibers, vascular endothelia, lungs, and in peripheral nerves. It can associate with laminin beta(1)/gamma(1) chains to form laminin-8 and with the beta(2)/gamma(1) chains to form laminin-9." SIGNOR-253227 LYN protein P07948 UNIPROT LPXN protein O60711 UNIPROT "up-regulates activity" phosphorylation Tyr72 NIQELNVySEAQEPK 9606 BTO:0000007 17640867 t miannu "Of a total of 11 tyrosine sites in LPXN, we mutated Tyr(22), Tyr(72), Tyr(198), and Tyr(257) to phenylalanine and demonstrated that LPXN was phosphorylated by Lyn only at Tyr(72) and that this tyrosine site is proximal to the LD3 domain. We further show that LPXN suppressed the secretion of interleukin-2 by BCR-activated A20 B cells and that this inhibition was abrogated in the Y72F LPXN mutant, indicating that the phosphorylation of Tyr(72) is critical for the biological function of LPXN." SIGNOR-262892 LYN protein P07948 UNIPROT SLC4A1 protein P02730 UNIPROT unknown phosphorylation Tyr359 AKPDSSFyKGLDLNG -1 10942405 t "Lyn phosphorylates Y904 and Y359 of band 3. The primary phosphorylation of band 3 catalyzed by p72syk generates the SH2 binding motifs that are a prerequisite for the following recruitment of Lyn. p72syk as the most likely candidate to perform this task and indicates Y8 and Y21. Syk and Lyn phosphorylate band 3 at both cytosolic and membrane domains, Y-phosphorylation/dephosphorylation is likely involved in the regulation of several erythrocyte functions (ie, glycolysis, cell shape, cytoskeleton movements, and anion transport." SIGNOR-251412 LYN protein P07948 UNIPROT SLC4A1 protein P02730 UNIPROT unknown phosphorylation Tyr904 EEEGRDEyDEVAMPV -1 10942405 t "Lyn phosphorylates Y904 and Y359 of band 3. The primary phosphorylation of band 3 catalyzed by p72syk generates the SH2 binding motifs that are a prerequisite for the following recruitment of Lyn. p72syk as the most likely candidate to perform this task and indicates Y8 and Y21. Syk and Lyn phosphorylate band 3 at both cytosolic and membrane domains, Y-phosphorylation/dephosphorylation is likely involved in the regulation of several erythrocyte functions (ie, glycolysis, cell shape, cytoskeleton movements, and anion transport." SIGNOR-251414 LYN protein P07948 UNIPROT LYN protein P07948 UNIPROT "up-regulates activity" phosphorylation Tyr397 RVIEDNEyTAREGAK -1 8530369 t "Lyn is a member of the Src family of protein-tyrosine kinases that can readily undergo autophosphorylation in vitro. The site of autophosphorylation is Tyr397. Autophosphorylation results in a 17-fold increase in protein-tyrosine kinase activity." SIGNOR-251402 LYN protein P07948 UNIPROT CD79A protein P11912 UNIPROT "up-regulates activity" phosphorylation Tyr188 EYEDENLyEGLNLDD -1 9531288 t "Y182 of CD79a appears to be the initial and preferred site of Ag receptor phosphorylation by Src family kinases. In vitro, Src family Lyn and Fyn predominantly phosphorylate this residue in CD79a, and Y195 does so in CD79b. phosphorylation of Y182 alone can lead to further kinase activation and/or effector focusing necessary for phosphorylation of certain downstream targets, such as p62, p110, and Shc, but not others, such as Vav." SIGNOR-251397 LYN protein P07948 UNIPROT FCGR2A protein P12318 UNIPROT "up-regulates activity" phosphorylation Tyr304 TDDDKNIyLTLPPND -1 8756631 t lperfetto "Phosphorylation of FcgammaRIIa/c by Lyn is clearly dependent on the presence of Y-298, since all mutants lacking this residue are not phosphorylated by this PTK. This result suggests that Y-298 might be the only tyrosine residue of FcgammaRIIa/c phos- phorylated by Lyn." SIGNOR-249379 LYN protein P07948 UNIPROT CD19 protein P15391 UNIPROT "up-regulates activity" phosphorylation Tyr500 TSLGSQSyEDMRGIL 10090 BTO:0000776 10933394 t lperfetto "Experiments with purified proteins demonstrated that CD19-Y513 was Lyn's initial phosphorylation and binding site. This led to processive phosphorylation of CD19-Y482, which recruited a second Lyn molecule, allowing for transphosphorylation and amplification of Lyn activation|Tyrosine phosphorylation of CD19 following BCR and/or CD19 ligation provides Src homology 2 (SH2) recognition motifs that recruit regulatory molecules to the cell surface. CD19 dually phosphorylated at CD19€“Y482 and CD19€“Y513 binds the tandem SH2 domains of phosphatidylinositol 3-kinase (PI 3-kinase) p85 subuni" SIGNOR-249376 LYN protein P07948 UNIPROT CD19 protein P15391 UNIPROT "up-regulates activity" phosphorylation Tyr531 HEEDADSyENMDNPD 10090 BTO:0000776 10933394 t lperfetto "Experiments with purified proteins demonstrated that CD19-Y513 was Lyn's initial phosphorylation and binding site. This led to processive phosphorylation of CD19-Y482, which recruited a second Lyn molecule, allowing for transphosphorylation and amplification of Lyn activation|Tyrosine phosphorylation of CD19 following BCR and/or CD19 ligation provides Src homology 2 (SH2) recognition motifs that recruit regulatory molecules to the cell surface. CD19 dually phosphorylated at CD19€“Y482 and CD19€“Y513 binds the tandem SH2 domains of phosphatidylinositol 3-kinase (PI 3-kinase) p85 subuni" SIGNOR-249377 LYN protein P07948 UNIPROT CD19 protein P15391 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0000776 25673924 t lperfetto "CD19 has an extracellular region containing two C2-type Ig-like domains and a cytoplasmic region of ~240 amino acids with 9 conserved tyrosine residues24. Lyn, a Src-family protein tyrosine kinase member, is the dominant kinase that phosphorylates CD19 upon stimulation. Once tyrosyl-phosphorylated, CD19 serves as a membrane-bound adaptor protein for Src homology 2-containing signaling molecules such as Lyn, Vav, and phosphatidylinositol 3-kinase, which further mediate downstream activation cascades." SIGNOR-242891 LYN protein P07948 UNIPROT PLCG1 protein P19174 UNIPROT "up-regulates activity" phosphorylation Tyr771 IGTAEPDyGALYEGR -1 7682059 t lperfetto "The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors." SIGNOR-249381 LYN protein P07948 UNIPROT PLCG1 protein P19174 UNIPROT "up-regulates activity" phosphorylation Tyr783 EGRNPGFyVEANPMP -1 7682059 t lperfetto "The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors." SIGNOR-249382 LYN protein P07948 UNIPROT PDIA3 protein P30101 UNIPROT unknown phosphorylation Tyr467 KKLNPKKyEGGRELS -1 8631326 t miannu "Lyn phosphorylates tyrosine residues Y444, Y453 and Y466 which are located in a highly acidic region of the protein at the C-terminus. Upon phosphorylation, p57 forms a complex with Lyn which can be immunoprecipitated with anti-Lyn IgG. The association which occurs between the phosphorylated substrate and the SH2 domain of the kinase is consistent with the suggested 'processive phosphorylation' model, which implies that a primary phosphorylation site of the substrate binds to the SH2 domain of the enzyme and triggers the phosphorylation at secondary site(s)." SIGNOR-262896 LYN protein P07948 UNIPROT FCGR2C protein P31995 UNIPROT "up-regulates activity" phosphorylation Tyr310 TDDDKNIyLTLPPND -1 8756631 t miannu "Fyn and Blk definitely phosphorylate Y-282 in the ITAM of FcgRIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addition to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation" SIGNOR-262676 LYN protein P07948 UNIPROT CD79B protein P40259 UNIPROT "up-regulates activity" phosphorylation Tyr196 GMEEDHTyEGLDIDQ -1 9531288 t "Y182 of CD79a appears to be the initial and preferred site of Ag receptor phosphorylation by Src family kinases. In vitro, Src family Lyn and Fyn predominantly phosphorylate this residue in CD79a, and Y195 does so in CD79b" SIGNOR-251398 LYN protein P07948 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Tyr88 KGSLPEFyYRPPRPP 9606 21423214 t gcesareni "We previously reported that y88 phosphorylation of p27(kip1) by oncogenic tyrosine kinases impairs p27(kip1)-mediated cdk inhibition, and initiates its ubiquitin-dependent proteasomal degradation." SIGNOR-172904 LYN protein P07948 UNIPROT PRKCD protein Q05655 UNIPROT "down-regulates activity" phosphorylation Tyr567 IRVDTPHyPRWITKE -1 11812791 t "Src, Fyn, or Lyn are the essential kinases that tyrosine phosphorylate and inactivate PKC δ. Lyn phosphorylates tyrosine residue 565 in vitro" SIGNOR-251407 LYN protein P07948 UNIPROT PRKCD protein Q05655 UNIPROT "up-regulates activity" phosphorylation Tyr52 VQKKPTMyPEWKSTF -1 9692543 t "Lyn was found to phosphorylate Lyn-associated and recombinant PKC-delta in vitro and the tyrosine 52 phosphorylated PKC-delta was recruited to associate with the Lyn SH2 domain." SIGNOR-251408 LYN protein P07948 UNIPROT BTK protein Q06187 UNIPROT up-regulates phosphorylation Tyr551 RYVLDDEyTSSVGSK 9606 BTO:0000776 8630736 t lperfetto "Phosphorylation at y551 requires lyn kinase activity, indicating that y551 is a transphosphorylation site \ this transphosphorylation at y551 is followed by phosphorylation at a second site, which is dependent on btk catalytic activity." SIGNOR-41607 LYN protein P07948 UNIPROT PPP1R8 protein Q12972 UNIPROT "down-regulates activity" phosphorylation Tyr264 FAFSGGLyGGLPPTH -1 11104670 t "Tyrosine phosphorylation of NIPP1 by Lyn was abolished by the Tyr-264 to Asp mutation." SIGNOR-251405 LYN protein P07948 UNIPROT PPP1R8 protein Q12972 UNIPROT "down-regulates activity" phosphorylation Tyr335 NEPKKKKyAKEAWPG -1 11104670 t "Lyn phosphorylates both Tyr-264 and Tyr-335, but that the phosphorylation of Tyr-335 is dependent on the association of NIPP1 with RNA. The inhibitory potency of the C-terminal site of NIPP1 was decreased by phosphorylation of Tyr-335 and by the addition of RNA." SIGNOR-251406 LYN protein P07948 UNIPROT PAG1 protein Q9NWQ8 UNIPROT "up-regulates activity" phosphorylation Tyr387 SEEPEPDyEAIQTLN 9534 16920712 t miannu "Here we show that Lyn interacts with C-terminal Src kinase-binding protein (Cbp), an adaptor protein that recruits negative regulators C-terminal Src kinase (Csk)/Csk-like protein-tyrosine kinase (Ctk). Lyn phosphorylated Cbp on several tyrosine residues, including Tyr314, which recruited Csk/Ctk to suppress Lyn kinase activity.Thus, a single phosphotyrosine residue on Cbp coordinates a two-phase process involving distinct negative regulatory pathways to inactivate, then degrade, Lyn." SIGNOR-262893 LYN protein P07948 UNIPROT PAG1 protein Q9NWQ8 UNIPROT "up-regulates activity" phosphorylation Tyr417 LVPKENDyESISDLQ 9534 16920712 t miannu "Here we show that Lyn interacts with C-terminal Src kinase-binding protein (Cbp), an adaptor protein that recruits negative regulators C-terminal Src kinase (Csk)/Csk-like protein-tyrosine kinase (Ctk). Lyn phosphorylated Cbp on several tyrosine residues, including Tyr314, which recruited Csk/Ctk to suppress Lyn kinase activity.Thus, a single phosphotyrosine residue on Cbp coordinates a two-phase process involving distinct negative regulatory pathways to inactivate, then degrade, Lyn." SIGNOR-262899 LYN protein P07948 UNIPROT DAPP1 protein Q9UN19 UNIPROT "up-regulates activity" phosphorylation Tyr139 KVEEPSIyESVRVHT BTO:0000776 10880360 t lperfetto "Src family kinases mediate receptor-stimulated, phosphoinositide 3-kinase-dependent, tyrosine phosphorylation of dual adaptor for phosphotyrosine and 3-phosphoinositides-1 in endothelial and B cell lines|yrosine phosphorylation of DAPP-1 appears important for appropriate intracellular targeting and creates a potential binding site for Src homology 2 domain-containing proteins." SIGNOR-249378 RET protein P07949 UNIPROT PDPK1 protein O15530 UNIPROT "up-regulates activity" phosphorylation Tyr9 ARTTSQLyDAVPIQS 10029 BTO:0000246 12738763 t lperfetto "Ret/ptc (rearranged in transformation/papillary thyroid carcinomas) tyrosine kinase phosphorylates and activates phosphoinositide-dependent kinase 1 (pdk1) ret/ptc phosphorylates a specific tyrosine (y9) residue located in the n-terminal region of pdk1." SIGNOR-235863 RET protein P07949 UNIPROT RET protein P07949 UNIPROT unknown phosphorylation Tyr1029 TPSDSLIyDDGLSEE 9534 BTO:0004055 8621380 t lperfetto "Based on the phosphopeptide maps, we can identify six tyrosine phosphorylation sites in RET: Tyr-687, Tyr-826, Tyr-1062, Tyr-1096, Tyr-1015, and Tyr-1029. By comparing the peptide map of each mutant to the wild-type receptor, we can tentatively assign each tryptic peptide containing phosphorylation sites to individual P-labeled spots on the two-dimensional map " SIGNOR-248940 RET protein P07949 UNIPROT RET protein P07949 UNIPROT unknown phosphorylation Tyr687 AQAFPVSySSSGARR 9534 BTO:0004055 8621380 t lperfetto "Based on the phosphopeptide maps, we can identify six tyrosine phosphorylation sites in RET: Tyr-687, Tyr-826, Tyr-1062, Tyr-1096, Tyr-1015, and Tyr-1029. By comparing the peptide map of each mutant to the wild-type receptor, we can tentatively assign each tryptic peptide containing phosphorylation sites to individual P-labeled spots on the two-dimensional map " SIGNOR-248941 RET protein P07949 UNIPROT RET protein P07949 UNIPROT unknown phosphorylation Tyr826 SRKVGPGyLGSGGSR 9534 BTO:0004055 8621380 t lperfetto "Based on the phosphopeptide maps, we can identify six tyrosine phosphorylation sites in RET: Tyr-687, Tyr-826, Tyr-1062, Tyr-1096, Tyr-1015, and Tyr-1029. By comparing the peptide map of each mutant to the wild-type receptor, we can tentatively assign each tryptic peptide containing phosphorylation sites to individual P-labeled spots on the two-dimensional map " SIGNOR-248942 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr1062 TWIENKLyGMSDPNW 9606 14711813 t lperfetto "Mass spectrometric analysis revealed that ret tyr806, tyr809, tyr900, tyr905, tyr981, tyr1062, tyr1090, and tyr1096 were autophosphorylation sitesret short and middle isoforms contain 16 tyrosine residues in their intracellular domains, and ret long isoforms have two additional tyrosines in the c-terminal tail. Among these tyrosines, tyr905, tyr1015, tyr1062, and tyr1096 are thought to be phosphorylated to become binding sites for grb7/grb10, phospholipase c_, shc/snt(frs2)/enigma, and grb2, respectively." SIGNOR-121141 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr809 LIVEYAKyGSLRGFL 9606 14711813 t llicata "Mass spectrometric analysis revealed that ret tyr(806), tyr(809), tyr(900), tyr(905), tyr(981), tyr(1062), tyr(1090), and tyr(1096) were autophosphorylation sites. these facts suggest that tyr806 and tyr809, located in this unique position, play a novel supplemental role for the activation loop upon phosphorylation." SIGNOR-121157 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr900 FGLSRDVyEEDSYVK 9606 14711813 t gcesareni "Mass spectrometric analysis revealed that ret tyr(900) was autophosphorylation site. Tyr900 can partially replace the function of tyr905 as a local switch for kinase activation" SIGNOR-121161 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr905 DVYEEDSyVKRSQGR 9606 14711813 t llicata "Mass spectrometric analysis revealed that ret tyr(806), tyr(809), tyr(900), tyr(905), tyr(981), tyr(1062), tyr(1090), and tyr(1096) were autophosphorylation sites. taken together, the results suggest that phosphorylation of tyr981 is not obligatorily required for the catalytic activity but plays a supplementary role in initiating autophosphorylation of tyr905, which brings about the overall kinase activity." SIGNOR-121165 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr981 DNCSEEMyRLMLQCW 9606 14711813 t lperfetto "Mass spectrometric analysis revealed that ret tyr806, tyr809, tyr900, tyr905, tyr981, tyr1062, tyr1090, and tyr1096 were autophosphorylation sitesthe results suggest that phosphorylation of tyr981 is not obligatorily required for the catalytic activity but plays a supplementary role in initiating autophosphorylation of tyr905, which brings about the overall kinase activity." SIGNOR-121169 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr900 FGLSRDVyEEDSYVK 9606 16928683 t gcesareni "Mass spectrometric analysis revealed that ret tyr(900) was autophosphorylation site. Tyr900 can partially replace the function of tyr905 as a local switch for kinase activation" SIGNOR-148992 RET protein P07949 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates phosphorylation Tyr187 HTGFLTEyVATRWYR 9606 16153436 t gcesareni "We hypothesized that ret could directly phosphorylate fak and erk. erk 2 could be phosphorylated at y187 (y204 in erk1)." SIGNOR-140294 RET protein P07949 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 9606 8183561 t gcesareni "We have shown that the sh2 domain of the adaptor protein shc coimmunoprecipitates with all the ret." SIGNOR-36902 RET protein P07949 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Tyr315 TFCGTPEyLAPEVLE 9606 BTO:0000944 15994200 t lperfetto "The PKB Y315 residue, which is known to be phosphorylated by Src tyrosine kinase, was also a major site of phosphorylation by RET/PTC. RET/PTC-mediated tyrosine phosphorylation results in the activation of PKB kinase activity" SIGNOR-252619 RET protein P07949 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr576 RYMEDSTyYKASKGK 9606 21454698 t gcesareni "The identification of focal adhesion kinase (fak) as a direct substrate for ret kinase revealed (i) a ret-fak transactivation mechanism consisting of direct phosphorylation of fak tyr-576/577 by ret and a reciprocal phosphorylation of ret by fak, which crucially is able to rescue the kinase-impaired ret k758m mutant and (ii) that fak binds ret via its ferm domain. Interestingly, this interaction is abolished upon ret phosphorylation, indicating that ret binding to the ferm domain of fak is a priming step for ret-fak transactivation." SIGNOR-173013 RET protein P07949 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr577 YMEDSTYyKASKGKL 9606 21454698 t gcesareni "The identification of focal adhesion kinase (fak) as a direct substrate for ret kinase revealed (i) a ret-fak transactivation mechanism consisting of direct phosphorylation of fak tyr-576/577 by ret and a reciprocal phosphorylation of ret by fak, which crucially is able to rescue the kinase-impaired ret k758m mutant and (ii) that fak binds ret via its ferm domain. Interestingly, this interaction is abolished upon ret phosphorylation, indicating that ret binding to the ferm domain of fak is a priming step for ret-fak transactivation." SIGNOR-173017 RET protein P07949 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Tyr182 TDDEMTGyVATRWYR 9606 17548358 t gcesareni "Dually phosphorylated on thr-180 and tyr-182 by the map2ks map2k3/mkk3, map2k4/mkk4 and map2k6/mkk6 in response to inflammatory citokines, environmental stress or growth factors, which activates the enzyme." SIGNOR-155381 RET protein P07949 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Thr180 RHTDDEMtGYVATRW 9606 7535770 t gcesareni "Dually phosphorylated on thr-180 and tyr-182 by the map2ks map2k3/mkk3, map2k4/mkk4 and map2k6/mkk6 in response to inflammatory citokines, environmental stress or growth factors, which activates the enzyme." SIGNOR-28059 RET protein P07949 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Tyr182 TDDEMTGyVATRWYR 9606 7535770 t gcesareni "Dually phosphorylated on thr-180 and tyr-182 by the map2ks map2k3/mkk3, map2k4/mkk4 and map2k6/mkk6 in response to inflammatory citokines, environmental stress or growth factors, which activates the enzyme." SIGNOR-28063 RET protein P07949 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Thr180 RHTDDEMtGYVATRW 9606 8622669 t gcesareni "Dually phosphorylated on thr-180 and tyr-182 by the map2ks map2k3/mkk3, map2k4/mkk4 and map2k6/mkk6 in response to inflammatory citokines, environmental stress or growth factors, which activates the enzyme." SIGNOR-40493 RET protein P07949 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Tyr182 TDDEMTGyVATRWYR 9606 8622669 t gcesareni "Dually phosphorylated on thr-180 and tyr-182 by the map2ks map2k3/mkk3, map2k4/mkk4 and map2k6/mkk6 in response to inflammatory citokines, environmental stress or growth factors, which activates the enzyme." SIGNOR-40497 RET protein P07949 UNIPROT DOK6 protein Q6PKX4 UNIPROT up-regulates binding 9606 BTO:0000671 15286081 t gcesareni "These data identify dok-6 as a novel dok-4/5-related adaptor molecule that may function in vivo to transduce signals that regulate ret-mediated processes such as axonal projection." SIGNOR-127382 RET protein P07949 UNIPROT AFAP1L2 protein Q8N4X5 UNIPROT "up-regulates activity" phosphorylation Tyr54 SSSSDEEyIYMNKVT 9606 BTO:0000007 19060924 t miannu "RET/PTC induced robust tyrosine phosphorylation of XB130, which promoted its subsequent association with the p85alpha subunit of phosphatidylinositol 3-kinase (PI 3-kinase). We identified tyrosine 54 of XB130 as the major target of RET/PTC-mediated phosphorylation and a critical binding site for the SH2 domains of p85alpha." SIGNOR-263192 RET protein P07949 UNIPROT DOK4 protein Q8TEW6 UNIPROT up-regulates binding 9606 BTO:0000938 11470823 t gcesareni "We identified two new family members, dok-4 and dok-5, that can directly associate with y1062 of c-ret dok-4 and dok-5 enhance c-ret-dependent activation of mitogen-activated protein kinase" SIGNOR-109513 RET protein P07949 UNIPROT FRS2 protein Q8WU20 UNIPROT up-regulates binding 9606 11360177 t gcesareni "Tyrosine 1062 in ret provides a site for the interaction of multiple signaling molecules and that the balance of shc and snt/frs2 binding may affect the nature of the intracellular signaling for cell proliferation, differentiation and survival induced by activated ret" SIGNOR-108244 RET protein P07949 UNIPROT DOK1 protein Q99704 UNIPROT up-regulates binding 9606 12087092 t amattioni "Dok proteins directly associate with tyrosine 1062 of ret and could be its substrates. Phosphorylation of dok1 is necessary for interaction with ras-gap in vitro and in vivo. Dok1 is a negative regulator for the ras/erk signaling pathway activated by ret." SIGNOR-90158 RET protein P07949 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 16153436 t lperfetto "We hypothesized that ret could directly phosphorylate fak and erk. erk 2 could be phosphorylated at y187 (y204 in erk1)." SIGNOR-244643 FH protein P07954 UNIPROT fumarate(2-) smallmolecule CHEBI:29806 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 30761759 t miannu "Fumarate hydratases (FHs, fumarases) catalyze the reversible conversion of fumarate into l-malate. FHs are distributed over all organisms and play important roles in energy production, DNA repair and as tumor suppressors." SIGNOR-266279 FH protein P07954 UNIPROT "(S)-malic acid" smallmolecule CHEBI:30797 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 30761759 t miannu "Fumarate hydratases (FHs, fumarases) catalyze the reversible conversion of fumarate into l-malate. FHs are distributed over all organisms and play important roles in energy production, DNA repair and as tumor suppressors." SIGNOR-266280 FH protein P07954 UNIPROT ATF2 protein P15336 UNIPROT "up-regulates activity" binding -1 28628081 t miannu "Glucose deficiency induces AMPK activation, which phosphorylates FH at Ser75 and promotes its binding to ATF2 and the enrichment of the FH–ATF2 complex on the promoter regions of ATF2-targeted genes." SIGNOR-266314 SP1 protein P08047 UNIPROT CACNA1G protein O43497 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001909 23868804 t miannu "Consistent with this, Sp1 over-expression enhanced promoter activity while siRNA-mediated Sp1 silencing significantly decreased the level of CaV 3.1 protein and reduced the amplitude of whole-cell T-type Ca(2+) currents expressed in the N1E-115 cells. These results provide new insights into the molecular mechanisms that control CaV 3.1 channel expression." SIGNOR-264034 IGF1R protein P08069 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates phosphorylation Tyr376 DEDCYGNyDNLLSQF 9606 BTO:0000150 20044479 t lperfetto "We have described that upon ligand binding, igf-1r directly interacts with and phosphorylates pdk1 at tyr373/376" SIGNOR-236544 SP1 protein P08047 UNIPROT SOD1 protein P00441 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 8921911 f miannu "Studies using two mutant versions of this promoter, in which the Sp1 and C/EBP-related factor binding sites were deleted, respectively, revealed that Sp1 and C/EBP-related factors activate the transcription of SOD1 gene. the binding of Sp1 to the proximal upstream region of the Cu/Zn SOD might explain the expression of Cu/Zn SOD in a wide variety of cells." SIGNOR-253899 SP1 protein P08047 UNIPROT TGFB1 protein P01137 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000944 23936544 t 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-β 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-β production" SIGNOR-251740 SP1 protein P08047 UNIPROT KLK3 protein P07288 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001033 15708372 t "We characterized four Sp1/Sp3 binding sites in the proximal promoter of the PSA gene. In a luciferase assay, these sites contributed to the basal promoter activity in prostate cancer cells. In an electrophoretic mobility shift assay and chromatin immunoprecipitation assay, we confirmed that Sp1 and Sp3 bind to these sites. Overexpression of wild-type Sp1 and Sp3 further upregulated the promoter activity, whereas overexpression of the Sp1 dominant-negative form or addition of mithramycin A significantly reduced the promoter activity and the endogenous mRNA level of PSA." SIGNOR-253664 SP1 protein P08047 UNIPROT KRT16 protein P08779 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000552 12954631 f miannu "these results suggest that Sp1 and AP1 sites in the essential promoter region are critical for EGF response, and Sp1 showed a functional cooperation with c-Jun and coactivators p300/CBP in driving the transcriptional regulation of EGF-induced keratin 16 gene expression. The coactivators p300/CBP could collaborate with Sp1 and c-Jun in the activation of keratin 16 promoter." SIGNOR-253903 SP1 protein P08047 UNIPROT ALOX5 protein P09917 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19781662 f "The 5-LO promoter possesses a unique GC-rich region which contains consensus sequences for the transcription factors Sp1 and Egr-1 (GC-boxes) which are important for basal transcriptional activity" SIGNOR-254032 SP1 protein P08047 UNIPROT HGF protein P14210 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 9223667 t lperfetto "Furthermore, in transient cotransfection assays, overexpression of Sp1 and/or Sp3 stimulated HGF promoter activity independently and additively through binding to the Sp1 binding site in the HGF gene promoter region." SIGNOR-251739 SP1 protein P08047 UNIPROT POR protein P16435 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0004428 8660656 f miannu "Regulation of the NADPH-cytochrome P-450 oxidoreductase gene is controlled by both positive and negative regulatory elements, and, of the nine Sp1 consensus sites, the two proximal sites are sufficient to support basal transcription." SIGNOR-255213 SP1 protein P08047 UNIPROT ENG protein P17813 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002741 21146604 f miannu "In hepatic stellate cells, TGF-β1 upregulates endoglin expression most likely via the ALK5 pathway and requires the SP1 transcription factor." SIGNOR-255201 SP1 protein P08047 UNIPROT NDUFV2 protein P19404 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000931 17786189 f miannu "Sp1 role in the regulation of complex I subunits, was demonstrated by the ability of the Sp1/DNA binding inhibitor, mithramycin, to inhibit the transcription of NDUFV1 and NDUFV2, in neuroblastoma cells. In addition, Sp1 activated NDUFV2 promoter by binding to its three GC-boxes. Both activation and binding were inhibited by mithramycin." SIGNOR-255207 SP1 protein P08047 UNIPROT TBXA2R protein P21731 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000565 19747485 f "Collectively, data establish that regulated WT1 followed by sequential Egr1 and Sp1 binding to elements within Prm1 mediate repression and subsequent induction of TPα during differentiation into the megakaryocytic phenotype, shedding significant insights into factors regulating TPα expression therein." SIGNOR-254254 SP1 protein P08047 UNIPROT UGT1A4 protein P22310 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 19546240 f miannu "our data indicate that up-regulation of UGT1A4 expression by E(2) is mediated by both ER alpha and Sp1 and is a potential mechanism contributing to the enhanced elimination of lamotrigine in pregnancy." SIGNOR-254076 SP1 protein P08047 UNIPROT LORICRIN protein P23490 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000667 12200429 f miannu "Mutation and DNA-protein analyses show that Sp1, c-Jun, an unidentified regulator, and the co-activator p300/CREB-binding protein up-regulate whereas Sp3, CREB-1/CREMalpha/ATF-1, Jun B, and an AP2-like protein (termed the keratinocyte-specific repressor-1 (KSR-1)) suppress loricrin promoter activity." SIGNOR-254538 SP1 protein P08047 UNIPROT PON1 protein P27169 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 15380450 f miannu "These data suggest that Sp1 acts as a positive regulator of PON1 transcription, and that an interaction between Sp1 and PKC is a key mechanism for the effect of Sp1 on PON1 transcription." SIGNOR-255212 SP1 protein P08047 UNIPROT MAOB protein P27338 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11259630 f miannu "Cotransfection experiments show that Sp1 and its closely related family member Sp4 can trans-activate MAO B promoter activity through the proximal cluster of Sp1 sites and its activation can be repressed by the over-expression of Sp3 and a related family member BTEB2." SIGNOR-253868 SP1 protein P08047 UNIPROT CD34 protein P28906 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 7227 10989198 t lperfetto "Activation of the CD34 promoter by Sp1 requires the presence of a binding domain at -48 bp as well as the 5' untranslated region, which also binds Sp1" SIGNOR-241481 SP1 protein P08047 UNIPROT CBS protein P35520 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12427542 f miannu "We previously described essential transactivating roles for specificity protein 1 (Sp1), Sp3, nuclear factor Y (NF-Y), and USF-1 in the regulation of the CBS-1b promoter." SIGNOR-254812 SP1 protein P08047 UNIPROT SCNN1A protein P37088 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004299 12684058 f "Regulation of expression" miannu "Transcription factors Sp1 and Sp3 activate alpha-ENaC2 transcription through a GC-rich element (Sp1-binding site) in the promoter. Sp1 and Sp3 are essential for alpha-ENaC2 transcription in lung epithelial cells and that dephosphorylation of the Sp transcription factors by PP1 suppresses alpha-ENaC2 expression." SIGNOR-251950 SP1 protein P08047 UNIPROT ID1 protein P41134 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18025157 f "We show that the ID1 and ID2 promoters are activated by PML-RARalpha but, unexpectedly, not by wild-type RARalpha/RXR. Our data support a model in which the PML-RARalpha fusion protein regulates a novel class of target genes by interaction with the Sp1 and NF-Y transcription factors, without directly binding to the DNA, defining a gain-of-function for the oncoprotein." SIGNOR-255748 SP1 protein P08047 UNIPROT SLC19A1 protein P41440 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 15652157 f "Collectively, these results identify transcriptionally important regions in the hRFC-C minimal promoter that include a GC-box and CCAAT-box, and suggest that cooperative interactions between Sp1 and C/EBP beta are essential for hRFC-C transactivation." SIGNOR-254064 SP1 protein P08047 UNIPROT CDKN2B protein P42772 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11013220 f irozzo "In this system, the basal transcription level from the p15Ink4B promoter was increased with increasing levels of Sp1, and Sp1 was required for transcriptional induction by Smads. Finally, inactivation of the Sp1 binding sites in the p15Ink4B promoter decreased the basal transcription level and TGF-β responsiveness." SIGNOR-256289 SP1 protein P08047 UNIPROT SLC9A3 protein P48764 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 7227 BTO:0001677 16464174 f "Co-transfection of Sp1 or Sp3 into SL2 cells activated the NHE3-reporter constructs, suggesting that Sp1 and Sp3 act as positive regulators of the NHE3 expression. In addition, overexpression of EGR-1 was sufficient to transactivate the NHE3-reporter gene activity" SIGNOR-254270 SP1 protein P08047 UNIPROT PCYT1A protein P49585 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 7227 BTO:0001677 10744779 t Luana "Sp1 and Sp3 function as transcriptional activators of the Ctpct promoter" SIGNOR-266231 SP1 protein P08047 UNIPROT NDUFV1 protein P49821 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000931 17786189 f miannu "Sp1 role in the regulation of complex I subunits, was demonstrated by the ability of the Sp1/DNA binding inhibitor, mithramycin, to inhibit the transcription of NDUFV1 and NDUFV2, in neuroblastoma cells. In addition, Sp1 activated NDUFV2 promoter by binding to its three GC-boxes. Both activation and binding were inhibited by mithramycin." SIGNOR-255206 SP1 protein P08047 UNIPROT GFER protein P55789 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 18513187 f miannu "We also confirmed that activation and repression of hHSS transcription induced by Sp1 and HNF4alpha resulted from binding of these factors to these two cis-elements respectively. Overexpression of HNF4alpha led to a dramatic repression of the promoter activity and, in contrast, the activity was markedly elevated by overexpression of Sp1." SIGNOR-254450 SP1 protein P08047 UNIPROT ATP2C1 protein P98194 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000667 15955096 f miannu "when Sp1 or YY1 was overexpressed in keratinocytes, an obvious increase in ATP2C1 promoter activity was observed, which was in contrast with the case where a mutant promoter lacking the binding sites for Sp1 and YY1 was used as the reporter." SIGNOR-255194 SP1 protein P08047 UNIPROT FMR1 protein Q06787 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15479157 f miannu "we show that Sp1 (specificity protein 1) and Sp3 are also strong positive regulators of FMR1 promoter activity." SIGNOR-255204 SP1 protein P08047 UNIPROT HYAL1 protein Q12794 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004796 18718911 f miannu "in cells which do not express HYAL-1, we found SP1 binding to the HYAL-1 promoter. Because both SP1 and Egr-1 have two overlapping binding sites within the promoter (Fig. 5), it appears that although SP1 binding to the methylated HYAL-1 promoter turns off transcription, binding of Erg-1 (and also AP-2) to the unmethylated promoter turns on transcription." SIGNOR-253879 SP1 protein P08047 UNIPROT UGCG protein Q16739 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000738 15342415 f miannu "the results suggest that transcriptional up-regulation of GCS through DOX-induced activation of Sp1 is one potential mechanism to regulate ceramide increase and apoptosis in HL-60/ADR cells." SIGNOR-255205 SP1 protein P08047 UNIPROT SLC5A8 protein Q8N695 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20082847 t "Luciferase reporter assays of deletion mutants of SLC5A8 promoter demonstrated that a 295-bp region is essential for the basal promoter activity of the SLC5A8 gene. Further analysis indicated that the CCAAT boxes and GC boxes were involved in positive regulation of SLC5A8 promoter. Overexpression of two transcription factors, CCAAT/enhancer binding protein beta (C/EBPbeta) and specific transcription factor 1 (Sp1), upregulated the activities of the human SLC5A8 promoter and protein expression, suggesting that both C/EBPbeta and Sp1 transcription factors might have functions in SLC5A8 transcription." SIGNOR-254059 SP1 protein P08047 UNIPROT GGH protein Q92820 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 31739835 t miannu "Overexpression of Sp1 led to enhanced GGH promoter activity and GGH mRNA expression in allele-specific manners. These findings suggested that Sp1 acted as a positive regulator of human GGH transcription through the rs3758149 polymorphism in CEM/C1 cells." SIGNOR-261350 SP1 protein P08047 UNIPROT SLC19A3 protein Q9BZV2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 7227 BTO:0001677 15217784 f miannu "In transiently transfected Drosophila SL2 cells, both SP1 and SP3 transactivated the SLC19A3 minimal promoter in a dose-dependent manner and in combination demonstrated an additive stimulatory effect." SIGNOR-255215 SP1 protein P08047 UNIPROT GP6 protein Q9HCN6 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001549 12359731 f miannu "Deletion analyses and site-directed mutagenesis identified Sp1(227), GATA(177), and Ets(48) sites as essential for GPVI expression. We show that transcription factors GATA-1, Fli-1, and Sp1 can bind to and activate this promoter." SIGNOR-254159 SP1 protein P08047 UNIPROT PDGFC protein Q9NRA1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0001685 15247255 f "The PDGF family of ligands is comprised of A, B, C, and D chains. Here, we provide the first functional characterization of the PDGF-C promoter. We examined 797 bp of the human PDGF-C promoter and identified several putative recognition elements for Sp1, Ets Egr-1, and Smad.|These findings thus demonstrate that PDGF-C transcription, activated by FGF-2, is mediated by Egr-1 and its upstream kinase ERK.|Egr-1 and Sp1 specifically bind the PDGF-C promoter" SIGNOR-254272 SP1 protein P08047 UNIPROT ITGA11 protein Q9UKX5 UNIPROT "up-regulates quantity by expression" 9606 BTO:0001282 16300938 t lperfetto "We speculate that the ""mesenchymal signature"" of alpha11 integrin gene expression is controlled by the activity of Sp1/Sp3, fibroblast-specific combinations of Ets family members and yet unidentified enhancer-binding transcription factors." SIGNOR-253350 IGF1R protein P08069 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates phosphorylation Tyr373 SEDDEDCyGNYDNLL 9606 20643654 t 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 IGF1R protein P08069 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates phosphorylation Tyr376 DEDCYGNyDNLLSQF 9606 20643654 t 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 IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT up-regulates phosphorylation Tyr1165 RDIYETDyYRKGGKG 9606 7493944 t 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 IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT up-regulates phosphorylation Tyr973 RLGNGVLyASVNPEY -1 7493944 t 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 IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT "up-regulates activity" phosphorylation Tyr1161 FGMTRDIyETDYYRK 9606 7493944 t 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 IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT "up-regulates activity" phosphorylation Tyr1166 DIYETDYyRKGGKGL 9606 7493944 t 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 IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT "up-regulates activity" phosphorylation Tyr1161 FGMTRDIyETDYYRK -1 8940173 t 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 IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT "up-regulates activity" phosphorylation Tyr1166 DIYETDYyRKGGKGL -1 8940173 t 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 IGF1R protein P08069 UNIPROT SHC1 protein P29353 UNIPROT "up-regulates activity" binding -1 7541045 t lperfetto "In our present work, we show that both IRS-1 and SHC interact directly with the juxtamembrane region of the IGFIR in a phosphotyrosine-dependent manner. |We propose a model in which IGFIR autophosphorylation of Tyr-950 forms a direct binding site for the amino-terminal receptor binding domains of SHC and IRS-1. This interaction is presumed to facilitate tyrosine phosphorylation of SHC on Tyr-317 leading to GRB2/SOS interaction" SIGNOR-262587 IGF1R protein P08069 UNIPROT FBN1 protein P35555 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0000951 17200203 f "Indirect:regulation of expression" miannu "Decorin and IGF-I induce fibrillin-1 protein synthesis in normal rat kidney fibroblasts" SIGNOR-251863 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation 9606 BTO:0001103 15829723 t 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 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr1179 GLENGLNyIDLDLVK 9606 17827393 t 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 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr1229 SSEDLSAyASISFQK 9606 17827393 t 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 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr465 GEEELSNyICMGGKG 9606 17827393 t 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 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr612 TLHTDDGyMPMSPGV 9606 17827393 t 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 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr632 GRKGSGDyMPMSPKS 9606 17827393 t 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 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr896 EPKSPGEyVNIEFGS 9606 17827393 t 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 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr941 EETGTEEyMKMDLGP 9606 17827393 t 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 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr989 VPSSRGDyMTMQMSC 9606 17827393 t 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 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation 9606 21798082 t 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 IGF1R protein P08069 UNIPROT CSK protein P41240 UNIPROT up-regulates 9606 10026153 f lperfetto "The results suggest that c-src and csk are involved in igf-ir and ir signaling and that the interaction of csk with the igf-ir may play a role in the decrease in c-src activity following igf-i stimulation" SIGNOR-64676 IGF1R protein P08069 UNIPROT CRK protein P46108 UNIPROT "down-regulates activity" phosphorylation Tyr221 GGPEPGPyAQPSVNT 10090 BTO:0000944 9480911 t "On activation of the IGF-I receptor, Crk-II binds to phosphorylated tyrosine residues, especially in the juxtamembrane region. As a result of this binding, the IGF-I receptor kinase phosphorylates Tyr-221 of Crk-II, resulting in a change in intramolecular folding and binding of the SH2 domain to the phosphorylated Tyr-221, which causes rapid disassociation of the Crk-II-IGF-I receptor complex." SIGNOR-251273 IGF1R protein P08069 UNIPROT SIRPA protein P78324 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001260 11779860 f gcesareni "These studies indicate that igf-ir stimulates phosphorylation of shps-1 which is critical for shp-2 recruitment to the plasma membrane and for its recruitment to the igf-ir" SIGNOR-113640 IGF1R protein P08069 UNIPROT PIK3R3 protein Q92569 UNIPROT up-regulates binding 9606 phosphorylation:Tyr1346 SFDERQPyAHMNGGR 9415396 t gcesareni "Moreover, we found that the insulin-like growth factor-1 receptor (igf-ir) bound to p55pik;the interaction occurred at the receptor tyrosine 1316 and involved both p55pik sh2 domains." SIGNOR-52683 IGF1R protein P08069 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 18595745 t gcesareni "Igf-1 activated both the pi3k and the extracellular signal-regulated kinase [?] (erk [?]) Pathways as evidenced by phosphorylation of either akt or erk1 [?]/2 (respectively)" SIGNOR-252690 IGF1R protein P08069 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" 10090 BTO:0000165 11715022 f lperfetto "we show that IGF-1 unexpectedly acts via Akt to antagonize calcineurin signalling during myotube hypertrophy." SIGNOR-244403 RHO protein P08100 UNIPROT GNAT1 protein P11488 UNIPROT "up-regulates activity" binding 9606 8673138 t "We report that his affected descendants carry a missense mutation in the gene encoding the a subunit of rod transducin — the G-protein that couples rhodopsin to cGMP-phosphodiesterase in the phototransduction cascade." SIGNOR-260007 COL1A2 protein P08123 UNIPROT "A1/b1 integrin" complex SIGNOR-C159 SIGNOR "up-regulates activity" binding 9606 BTO:0000664 12123670 t lperfetto "We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1." SIGNOR-253248 COL1A2 protein P08123 UNIPROT "A11/b1 integrin" complex SIGNOR-C168 SIGNOR "up-regulates activity" binding 10090 BTO:0000165 12496264 t lperfetto "Modeling of the alpha I domain-collagen peptide complexes could partially explain the observed preference of different I domains for certain GFOGER sequence variations. In summary, our data indicate that the GFOGER sequence in fibrillar collagens is a common recognition motif used by alpha(1)beta(1), alpha(2)beta(1), and also alpha(11)beta(1) integrins." SIGNOR-253346 NGFR protein P08138 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates 9606 14699954 f amattioni "Jnk3 is expressed exclusively in the nervous system and recent evidence indicates that this jnk isoform may be required for p75ntr-mediated cell death" SIGNOR-120561 GLI1 protein P08151 UNIPROT MYCN protein P04198 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150;BTO:0000551 19860666 f gcesareni "GLI activators bind to GACCACCCA motif to regulate transcription of GLI1, PTCH1, PTCH2, HHIP1, MYCN, CCND1, CCND2, BCL2, CFLAR, FOXF1, FOXL1, PRDM1 (BLIMP1), JAG2, GREM1, and Follistatin" SIGNOR-188872 GLI1 protein P08151 UNIPROT GLI1 protein P08151 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0002572 16571352 f lperfetto "Primary mouse embryonic fibroblasts responded to Shh stimulation with the induction of Hh target genes Gli1, Ptc1, and Hip1.These observations support the previously advanced notion of a functional redundancy or cooperativity between Gli2 and Gli1 in activation of target genes [18] and [43] and indicate a functional cooperation between Gli3 and Gli1." SIGNOR-209617 GLI1 protein P08151 UNIPROT CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150;BTO:0000551 19860666 f gcesareni "GLI activators bind to GACCACCCA motif to regulate transcription of GLI1, PTCH1, PTCH2, HHIP1, MYCN, CCND1, CCND2, BCL2, CFLAR, FOXF1, FOXL1, PRDM1 (BLIMP1), JAG2, GREM1, and Follistatin" SIGNOR-188869 GLI1 protein P08151 UNIPROT CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 23074268 f gcesareni "Canonical hh signaling plays an essential role in cell proliferation throught introduction of the genes encoding cyclin d1 and n-myc" SIGNOR-199126 GLI1 protein P08151 UNIPROT PTCH1 protein Q13635 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0002572 16571352 f lperfetto "Primary mouse embryonic fibroblasts responded to Shh stimulation with the induction of Hh target genes Gli1, Ptc1, and Hip1.These observations support the previously advanced notion of a functional redundancy or cooperativity between Gli2 and Gli1 in activation of target genes [18] and [43] and indicate a functional cooperation between Gli3 and Gli1." SIGNOR-209620 GLI1 protein P08151 UNIPROT PTCH1 protein Q13635 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150;BTO:0000551 19860666 f gcesareni "Gli activators bind to gaccaccca motif to regulate transcription of gli1, ptch1, ptch2, hhip1, mycn, ccnd1, ccnd2, bcl2, cflar, foxf1, foxl1, prdm1 (blimp1), jag2, grem1, and follistatin" SIGNOR-188875 GLI1 protein P08151 UNIPROT HHIP protein Q96QV1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0002572 16571352 f lperfetto "Primary mouse embryonic fibroblasts responded to Shh stimulation with the induction of Hh target genes Gli1, Ptc1, and Hip1.These observations support the previously advanced notion of a functional redundancy or cooperativity between Gli2 and Gli1 in activation of target genes [18] and [43] and indicate a functional cooperation between Gli3 and Gli1." SIGNOR-209623 CHRM2 protein P08172 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256828 CHRM2 protein P08172 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256685 CHRM4 protein P08173 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256829 CHRM4 protein P08173 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256965 CHRM4 protein P08173 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256686 CD55 protein P08174 UNIPROT ADGRE5 protein P48960 UNIPROT up-regulates binding 9606 BTO:0000142 12417446 t gcesareni "This interaction may facilitate cell activation and migration through the blood-brain barrier. In addition, cd97-cd55 interactions in the parenchyma of the brain may contribute to the inflammation." SIGNOR-95458 NR3C2 protein P08235 UNIPROT ATP1B1 protein P05026 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000318 9694812 f miannu "Together these data indicate that the 21-base pair sequence represents a true MRE/GRE and that optimal activation of the human Na/K-ATPase beta1 promoter is controlled by mineralocorticoid and glucocorticoid hormones. It appears that an interaction of MR with GR on the beta1 promoter effectively down-regulates transcription." SIGNOR-254865 PFKM protein P08237 UNIPROT "beta-D-fructofuranose 1,6-bisphosphate(4-)" smallmolecule CHEBI:32966 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 16051738 t miannu "Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35." SIGNOR-266471 PFKM protein P08237 UNIPROT "beta-D-fructofuranose 6-phosphate(2-)" smallmolecule CHEBI:57634 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 16051738 t miannu "Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35." SIGNOR-266467 HSP90AB1 protein P08238 UNIPROT APAF1 protein O14727 UNIPROT down-regulates binding 9606 10944114 t gcesareni "The present studies demonstrate that heat shock protein 90 (hsp90) forms a cytosolic complex with apaf-1 and thereby inhibits the formation of the active complex." SIGNOR-81043 HSP90AB1 protein P08238 UNIPROT AR protein P10275 UNIPROT "up-regulates activity" binding 9606 15861399 t miannu "The unliganded AR resides predominately in the cytoplasm as a heteromeric complex with hsp90 and other chaperone proteins. These chaperone proteins maintain AR in a form that is receptive to ligand binding. Regulation of gene expression by androgen-activated AR occurs through receptor nuclear translocation, dimerization, and binding to androgen response elements (AREs) in the DNA of target genes." SIGNOR-251535 HSP90AB1 protein P08238 UNIPROT NOS3 protein P29474 UNIPROT "up-regulates activity" binding 9606 9580552 t miannu "Here we show that Hsp90 associates with endothelial nitric oxide synthase (eNOS) and is rapidly recruited to the eNOS complex by agonists that stimulate production of nitric oxide, namely vascular endothelial growth factor, histamine and fluid shear stress. Moreover, the binding of Hsp90 to eNOS enhances the activation of eNOS." SIGNOR-252214 PTPRC protein P08575 UNIPROT LCK protein P06239 UNIPROT "up-regulates activity" dephosphorylation Tyr505 FTATEGQyQPQP 10090 BTO:0000782 17719247 t "CD45 differentially regulates the negatively acting pTyr-505 and positively acting pTyr-394 p56(lck) tyrosine kinase phosphorylation sites. We propose that high wild-type CD45 expression is necessary to dephosphorylate p56(lck) pTyr-394, suppressing CD4 T+ cell lineage commitment and hyperactivity." SIGNOR-259933 HSP90AB1 protein P08238 UNIPROT FLCN protein Q8NFG4 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000007 27353360 t miannu "Heat shock protein-90 (Hsp90) is an essential molecular chaperone in eukaryotes involved in maintaining the stability and activity of numerous signalling proteins, also known as clients. Hsp90 ATPase activity is essential for its chaperone function and it is regulated by co-chaperones. Here we show that the tumour suppressor FLCN is an Hsp90 client protein and its binding partners FNIP1/FNIP2 function as co-chaperones. FNIPs decelerate the chaperone cycle, facilitating FLCN interaction with Hsp90, consequently ensuring FLCN stability." SIGNOR-261417 HSP90AB1 protein P08238 UNIPROT FLCN protein Q8NFG4 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000007 27353360 t miannu "Heat shock protein-90 (Hsp90) is an essential molecular chaperone in eukaryotes involved in maintaining the stability and activity of numerous signalling proteins, also known as clients. Hsp90 ATPase activity is essential for its chaperone function and it is regulated by co-chaperones. Here we show that the tumour suppressor FLCN is an Hsp90 client protein and its binding partners FNIP1/FNIP2 function as co-chaperones. FNIPs decelerate the chaperone cycle, facilitating FLCN interaction with Hsp90, consequently ensuring FLCN stability." SIGNOR-261418 ELANE protein P08246 UNIPROT AGT protein P01019 UNIPROT "up-regulates activity" cleavage Phe41 DRVYIHPfHLVIHNE -1 11747312 t miannu "Cathepsin G, elastase, and proteinase 3 are serine proteinases released by activated neutrophils. Cathepsin G can cleave angiotensinogen to release angiotensin II, but this activity has not been previously reported for elastase or proteinase 3. In this study we show that elastase and proteinase 3 can release angiotensin I from angiotensinogen and release angiotensin II from angiotensin I and angiotensinogen." SIGNOR-256313 ELANE protein P08246 UNIPROT F5 protein P12259 UNIPROT "down-regulates activity" cleavage Ala369 DYAPVIPaNMDKKYR -1 9242537 t lperfetto "Human neutrophil elastase activates human factor V but inactivates thrombin-activated human factor V|NH2-terminal sequence analysis of F.Va treated with HNE indicated cleavage at Ala341, Ile508, and Thr1767 under conditions, which the cofactor became inactivated, as measured by prothrombinase activity." SIGNOR-263635 ELANE protein P08246 UNIPROT F5 protein P12259 UNIPROT "down-regulates activity" cleavage Ile536 RSLDRRGiQRAADIE -1 9242537 t lperfetto "Human neutrophil elastase activates human factor V but inactivates thrombin-activated human factor V|NH2-terminal sequence analysis of F.Va treated with HNE indicated cleavage at Ala341, Ile508, and Thr1767 under conditions, which the cofactor became inactivated, as measured by prothrombinase activity." SIGNOR-263636 ELANE protein P08246 UNIPROT F5 protein P12259 UNIPROT "down-regulates activity" cleavage Thr1795 SRSSWRLtSSEMKKS -1 9242537 t lperfetto "Human neutrophil elastase activates human factor V but inactivates thrombin-activated human factor V|NH2-terminal sequence analysis of F.Va treated with HNE indicated cleavage at Ala341, Ile508, and Thr1767 under conditions, which the cofactor became inactivated, as measured by prothrombinase activity." SIGNOR-263634 ELANE protein P08246 UNIPROT F5 protein P12259 UNIPROT "up-regulates activity" cleavage Ile1512 KEFNPLViVGLSKDG -1 9242537 t lperfetto "Human neutrophil elastase activates human factor V but inactivates thrombin-activated human factor V|NH2-terminal sequence analysis of F.V treated with HNE indicated cleavage at Ile819 and Ile1484 under conditions during which the procofactor expressed enhanced cofactor activity in the prothrombinase complex." SIGNOR-263633 ELANE protein P08246 UNIPROT F5 protein P12259 UNIPROT "up-regulates activity" cleavage Ile847 LQPDVTGiRLLSLGA -1 9242537 t lperfetto "Human neutrophil elastase activates human factor V but inactivates thrombin-activated human factor V|NH2-terminal sequence analysis of F.V treated with HNE indicated cleavage at Ile819 and Ile1484 under conditions during which the procofactor expressed enhanced cofactor activity in the prothrombinase complex." SIGNOR-263637 ELANE protein P08246 UNIPROT F2R protein P25116 UNIPROT "down-regulates activity" cleavage Ala86 PLQKQLPaFISEDAS -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site." SIGNOR-263566 ELANE protein P08246 UNIPROT F2R protein P25116 UNIPROT "down-regulates activity" cleavage Val72 GLTEYRLvSINKSSP -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site." SIGNOR-263567 ELANE protein P08246 UNIPROT F2R protein P25116 UNIPROT "up-regulates activity" cleavage Ala36 PESKATNaTLDPRSF -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus" SIGNOR-263565 ELANE protein P08246 UNIPROT F2RL1 protein P55085 UNIPROT "down-regulates activity" cleavage Thr74 SVLTGKLtTVFLPIV -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3" SIGNOR-263587 HSPA1A protein P0DMV8 UNIPROT NOD2 protein Q9HC29 UNIPROT "up-regulates quantity by stabilization" binding 9606 24790089 t miannu "The molecular chaperone HSP70 binds to and stabilizes NOD2, an important protein involved in Crohn disease." SIGNOR-252416 ELANE protein P08246 UNIPROT F2RL1 protein P55085 UNIPROT "down-regulates activity" cleavage Val42 GRSLIGKvDGTSHVT -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3" SIGNOR-263588 ELANE protein P08246 UNIPROT F2RL1 protein P55085 UNIPROT "down-regulates activity" cleavage Val48 KVDGTSHvTGKGVTV -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3" SIGNOR-263589 ELANE protein P08246 UNIPROT F2RL1 protein P55085 UNIPROT "down-regulates activity" cleavage Val53 SHVTGKGvTVETVFS -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3" SIGNOR-263590 ELANE protein P08246 UNIPROT F2RL1 protein P55085 UNIPROT "down-regulates activity" cleavage Val58 KGVTVETvFSVDEFS -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3" SIGNOR-263591 ELANE protein P08246 UNIPROT F2RL1 protein P55085 UNIPROT "down-regulates activity" cleavage Val76 LTGKLTTvFLPIVYT -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3" SIGNOR-263592 MMP2 protein P08253 UNIPROT A2M protein P01023 UNIPROT "down-regulates quantity by destabilization" cleavage Arg719 VMGRGHArLVHVEEP -1 9344465 t lperfetto "The complex formation was confirmed by the use of 125I-labeled matrix metalloproteinase-2. The cleavage sites in the ""bait"" regions following formation of high-molecular-weight complexes of matrix metalloproteinases with the alpha-macroglobulins were determined by protein sequence analysis. Pregnancy zone protein was cleaved at Thr693-Tyr694 and alpha2-macroglobulin at Gly679-Leu680 and Arg696-Leu697 by matrix metalloproteinase-2. Matrix metalloproteinase-9 cleaved alpha2-macroglobulin at the same site as matrix metalloproteinase-2, but cleavage of pregnancy zone protein was at Leu753-Ser754.|MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP." SIGNOR-261739 MMP2 protein P08253 UNIPROT A2M protein P01023 UNIPROT "down-regulates quantity by destabilization" cleavage Gly702 YEMHGPEgLRVGFYE -1 9344465 t lperfetto "The complex formation was confirmed by the use of 125I-labeled matrix metalloproteinase-2. The cleavage sites in the ""bait"" regions following formation of high-molecular-weight complexes of matrix metalloproteinases with the alpha-macroglobulins were determined by protein sequence analysis. Pregnancy zone protein was cleaved at Thr693-Tyr694 and alpha2-macroglobulin at Gly679-Leu680 and Arg696-Leu697 by matrix metalloproteinase-2. Matrix metalloproteinase-9 cleaved alpha2-macroglobulin at the same site as matrix metalloproteinase-2, but cleavage of pregnancy zone protein was at Leu753-Ser754.|MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP." SIGNOR-261780 MMP2 protein P08253 UNIPROT DCN protein P07585 UNIPROT "down-regulates quantity by destabilization" cleavage Glu30 GLFDFMLeDEASGIG -1 9148753 t miannu "Degradation of decorin by matrix metalloproteinases. These data indicate proteolytic degradation of DCN by MMP-2, MMP-3 and MMP-7, and suggest the possibility that, under pathophysiological conditions, the digestion by the MMPs may induce tissue reactions mediated by TGF-beta1 released from DCN in the connective tissues." SIGNOR-256349 MMP2 protein P08253 UNIPROT DCN protein P07585 UNIPROT "down-regulates quantity by destabilization" cleavage Ser240 ISRVDAAsLKGLNNL -1 9148753 t miannu "Degradation of decorin by matrix metalloproteinases. These data indicate proteolytic degradation of DCN by MMP-2, MMP-3 and MMP-7, and suggest the possibility that, under pathophysiological conditions, the digestion by the MMPs may induce tissue reactions mediated by TGF-beta1 released from DCN in the connective tissues." SIGNOR-256350 MMP2 protein P08253 UNIPROT HAPLN1 protein P10915 UNIPROT "down-regulates quantity by destabilization" cleavage His31 LDHDRAIhIQAENGP -1 7694569 t miannu "Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix." SIGNOR-256327 MMP2 protein P08253 UNIPROT PZP protein P20742 UNIPROT "down-regulates quantity by destabilization" cleavage Thr718 PYVPQLGtYNVIPLN -1 9344465 t lperfetto "The complex formation was confirmed by the use of 125I-labeled matrix metalloproteinase-2. The cleavage sites in the ""bait"" regions following formation of high-molecular-weight complexes of matrix metalloproteinases with the alpha-macroglobulins were determined by protein sequence analysis. Pregnancy zone protein was cleaved at Thr693-Tyr694 and alpha2-macroglobulin at Gly679-Leu680 and Arg696-Leu697 by matrix metalloproteinase-2. Matrix metalloproteinase-9 cleaved alpha2-macroglobulin at the same site as matrix metalloproteinase-2, but cleavage of pregnancy zone protein was at Leu753-Ser754.|MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP." SIGNOR-261796 MMP3 protein P08254 UNIPROT DCN protein P07585 UNIPROT "down-regulates quantity by destabilization" cleavage Ser240 ISRVDAAsLKGLNNL -1 9148753 t miannu "Degradation of decorin by matrix metalloproteinases. These data indicate proteolytic degradation of DCN by MMP-2, MMP-3 and MMP-7, and suggest the possibility that, under pathophysiological conditions, the digestion by the MMPs may induce tissue reactions mediated by TGF-beta1 released from DCN in the connective tissues." SIGNOR-256353 MMP3 protein P08254 UNIPROT SPP1 protein P10451 UNIPROT "up-regulates activity" cleavage 25545242 t lperfetto "In this study, we found a novel motif, LRSKSRSFQVSDEQY, in the C-terminal fragment of MMP-3/7-cleaved mouse OPN binds to α9β1 integrin. Importantly, this novel motif is involved in the development of anti-type II collagen antibody-induced arthritis (CAIA). This study provides the first in vitro and in vivo evidence that OPN cleavage by MMP-3/7 is an important regulatory mechanism for CAIA." SIGNOR-253320 MMP3 protein P08254 UNIPROT HAPLN1 protein P10915 UNIPROT "down-regulates quantity by destabilization" cleavage His31 LDHDRAIhIQAENGP -1 7694569 t miannu "Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix." SIGNOR-256330 MMP3 protein P08254 UNIPROT ACAN protein P16112 UNIPROT "down-regulates quantity by destabilization" cleavage Asn360 DFVDIPEnFFGVGGE 9606 BTO:0000206 9202061 t lperfetto "Aggrecan Degradation in Human Cartilage Evidence for both Matrix Metalloproteinase and Aggrecanase Activity in Normal, Osteoarthritic, and Rheumatoid Joints|Stromelysin-1 (MMP-3), as well as other MMPs, cleave aggrecan in the interglobular domain between Asn341 and Phe342 to generate a G1 fragment with the COOH terminus VDIPEN341 (11–13). This fragment has been isolated and identified by NH2-terminal sequence analysis from human OA cartilage (11). A second proteolytic activity identified as “aggrecanase” also cleaves aggrecan in the interglobular domain, but between Glu373 and Ala374 (19–24), generating a G1 fragment with a COOH terminus of NITEGE374" SIGNOR-266986 CTSG protein P08311 UNIPROT AGT protein P01019 UNIPROT "up-regulates activity" cleavage Phe41 DRVYIHPfHLVIHNE -1 11747312 t miannu "Cathepsin G, elastase, and proteinase 3 are serine proteinases released by activated neutrophils. Cathepsin G can cleave angiotensinogen to release angiotensin II, but this activity has not been previously reported for elastase or proteinase 3. In this study we show that elastase and proteinase 3 can release angiotensin I from angiotensinogen and release angiotensin II from angiotensin I and angiotensinogen." SIGNOR-256312 CTSG protein P08311 UNIPROT C3 protein P01024 UNIPROT "up-regulates activity" cleavage Arg748 ASHLGLArSNLDEDI 9606 BTO:0001412 1861080 t miannu "Plasma membrane elastase and cathepsin G from U937 cells cleave C3 into C3a- and C3b-like fragments; further incubation leads to C3c- and C3dg-like fragments, as judged from SDS-PAGE analysis of the digests. Sequencing of the C3b-like fragment purified by reverse phase chromatography indicates that initial cleavage of C3 by purified cathepsin G occurs at two positions in the amino-terminal part of the alpha-chain, at a Arg-Ser bond located between residues 748 and 749 and at a Leu-Asp bond between residues 751 and 752. These proteases are, thus, able to generate, on the U937 surface, active fragments of C3, which are likely to be involved in cell-protein and cell-cell interactions." SIGNOR-256347 CTSG protein P08311 UNIPROT C3 protein P01024 UNIPROT "up-regulates activity" cleavage Leu751 LGLARSNlDEDIIAE 9606 BTO:0001412 1861080 t miannu "Plasma membrane elastase and cathepsin G from U937 cells cleave C3 into C3a- and C3b-like fragments; further incubation leads to C3c- and C3dg-like fragments, as judged from SDS-PAGE analysis of the digests. Sequencing of the C3b-like fragment purified by reverse phase chromatography indicates that initial cleavage of C3 by purified cathepsin G occurs at two positions in the amino-terminal part of the alpha-chain, at a Arg-Ser bond located between residues 748 and 749 and at a Leu-Asp bond between residues 751 and 752." SIGNOR-256348 CTSG protein P08311 UNIPROT SERPIND1 protein P05546 UNIPROT "down-regulates activity" cleavage Val458 QATTVTTvGFMPLST -1 2318847 t miannu "Amino acid sequence analysis led to the conclusion that both neutrophil elastase and cathepsin G cleave HC at Ile66, which does not affect HC activity, and at Val439, near the reactive site Leu444, which inactivates HC." SIGNOR-256509 CTSG protein P08311 UNIPROT F2R protein P25116 UNIPROT "down-regulates activity" cleavage Tyr69 NESGLTEyRLVSINK -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site." SIGNOR-263564 CTSG protein P08311 UNIPROT F2R protein P25116 UNIPROT "up-regulates activity" cleavage Arg41 TNATLDPrSFLLRNP -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Arg41-Ser42 activation site" SIGNOR-263561 CTSG protein P08311 UNIPROT F2RL1 protein P55085 UNIPROT "down-regulates activity" cleavage Leu38 RSSKGRSlIGKVDGT -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3" SIGNOR-263584 CTSG protein P08311 UNIPROT F2RL1 protein P55085 UNIPROT "down-regulates activity" cleavage Phe59 GVTVETVfSVDEFSA -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3" SIGNOR-263585 CTSG protein P08311 UNIPROT F2RL1 protein P55085 UNIPROT "down-regulates activity" cleavage Phe64 TVFSVDEfSASVLTG -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3" SIGNOR-263586 INHBA protein P08476 UNIPROT ACVR2A protein P27037 UNIPROT "up-regulates activity" binding 9606 1646080 t gcesareni "A protein of 494 amino acids comprising a ligand-binding extracellular domain, a single membrane-spanning domain, and an intracellular kinase domain with predicted serine/threonine specificity. 125I-activin A binds to transfected COS cells with an affinity of 180 pM and can be competed by activin A, activin B, and inhibin A, but not by transforming growth factor beta 1." SIGNOR-235138 ITGA2B protein P08514 UNIPROT "AIIB/b3 integrin" complex SIGNOR-C173 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253197 PDHA1 protein P08559 UNIPROT PDH complex SIGNOR-C402 SIGNOR "form complex" binding 9606 20160912 t miannu "The human (h) pyruvate dehydrogenase complex (hPDC) consists of multiple copies of several components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2), dihydrolipoamide dehydrogenase (E3), E3-binding protein (BP), and specific kinases and phosphatases. Mammalian PDC has a well organized structure with an icosahedral symmetry of the central E2/BP core to which the other component proteins bind non-covalently." SIGNOR-266544 COL4A2 protein P08572 UNIPROT "A2/b1 integrin" complex SIGNOR-C160 SIGNOR "up-regulates activity" binding 9606 BTO:0000664 12123670 t lperfetto "We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1." SIGNOR-253243 CYC1 protein P08574 UNIPROT "Mitochondrial respiratory chain complex III" complex SIGNOR-C279 SIGNOR "form complex" binding 30030361 t lperfetto "Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits" SIGNOR-262192 PTPRC protein P08575 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates activity" dephosphorylation Tyr1007 VLPQDKEyYKVKEPG 10090 11201744 t "CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling|these results show that CD45 dephosphorylates functionally important tyrosine residues. It should be noted that, as with our phosphatase assays in vitro, Tyr 1022 and Tyr 1023 of JAK1, Tyr 1007 and Tyr 1008 of JAK2, and Tyr 1054 and Tyr 1055 of Tyk2 are indeed hyperphosphorylated in cd45-deficient cells" SIGNOR-248348 PTPRC protein P08575 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates activity" dephosphorylation Tyr1008 LPQDKEYyKVKEPGE 10090 11201744 t "CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling|these results show that CD45 dephosphorylates functionally important tyrosine residues. It should be noted that, as with our phosphatase assays in vitro, Tyr 1022 and Tyr 1023 of JAK1, Tyr 1007 and Tyr 1008 of JAK2, and Tyr 1054 and Tyr 1055 of Tyk2 are indeed hyperphosphorylated in cd45-deficient cells" SIGNOR-248349 PTPRC protein P08575 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates activity" dephosphorylation 9606 24252238 t miannu "Src homology-2 (SH2) containing tyrosine phosphatase and CD45 tyrosine phosphatase play a major role in modulating JAK-STAT pathway. SH2 containing tyrosine phosphatases include SHP1 and SHP2 (shatterproof 1 & 2). Their SH2 domains allow attachment to the phospho-tyrosine residues present on activated receptors, JAKs or STAT proteins, leading to dephosphorylation of the substrates." SIGNOR-255679 PTPRC protein P08575 UNIPROT LCK protein P06239 UNIPROT "down-regulates activity" dephosphorylation Tyr394 RLIEDNEyTAREGAK 9606 11259588 t "Importantly, and in disagreement with the model that CD45 only activates Lck in vivo, the kinase activity of Lck from cells lacking CD45 was substantially increased. These results support a model in which CD45 dephosphorylates both Tyr505 and Tyr394, the net effect in normal thymocytes being a decrease in enzymatic activity" SIGNOR-248351 PTPRC protein P08575 UNIPROT LCK protein P06239 UNIPROT "down-regulates activity" dephosphorylation Tyr505 FTATEGQyQPQP 9606 11259588 t "Importantly, and in disagreement with the model that CD45 only activates Lck in vivo, the kinase activity of Lck from cells lacking CD45 was substantially increased. These results support a model in which CD45 dephosphorylates both Tyr505 and Tyr394, the net effect in normal thymocytes being a decrease in enzymatic activity" SIGNOR-248350 PTPRC protein P08575 UNIPROT FYN protein P06241 UNIPROT "up-regulates activity" dephosphorylation Tyr531 FTATEPQyQPGENL 9606 BTO:0000782 11909961 t "On the membrane SKAP55, via its phosphorylated Tyr-271, further binds the SH2 domain of Fyn to replace the low-affinity bound inhibitory site of the kinase. Consequently, CD45 may have transiently disassociated with the Tyr-232 residue of SKAP55 through dephosphorylation and simultaneously interacted with the released the phosphorylated inhibitory tyrosine residue of Fyn for dephosphorylation, resulting in activation of the Src family kinase Fyn and initiation of TCR-engaged signal transduction." SIGNOR-248352 PTPRC protein P08575 UNIPROT LYN protein P07948 UNIPROT "down-regulates activity" dephosphorylation Tyr397 RVIEDNEyTAREGAK 10090 BTO:0000776 10415030 t "CD45 negatively regulates lyn activity by dephosphorylating both positive and negative regulatory tyrosine residues in immature B cells.| Phosphoamino acid analysis confirmed that Lyn is tyrosine phosphorylated with little serine or threonine phosphorylation. In CD45-negative cells, two bands at 8.2 and 4.1 kDa were phosphorylated in the absence of B cell Ag receptor (BCR) ligation. The 8.2-kDa band corresponded to a fragment containing the positive regulatory site (Tyr397), as assessed by its size and its phosphorylation in an in vitro kinase assay. The 4.1-kDa band was phosphorylated by COOH-terminal Src kinase, suggesting that it contains the COOH-terminal negative regulatory site (Tyr508)" SIGNOR-248353 PTPRC protein P08575 UNIPROT LYN protein P07948 UNIPROT "down-regulates activity" dephosphorylation Tyr508 YTATEGQyQQQP 10090 BTO:0000776 10415030 t "CD45 negatively regulates lyn activity by dephosphorylating both positive and negative regulatory tyrosine residues in immature B cells.| Phosphoamino acid analysis confirmed that Lyn is tyrosine phosphorylated with little serine or threonine phosphorylation. In CD45-negative cells, two bands at 8.2 and 4.1 kDa were phosphorylated in the absence of B cell Ag receptor (BCR) ligation. The 8.2-kDa band corresponded to a fragment containing the positive regulatory site (Tyr397), as assessed by its size and its phosphorylation in an in vitro kinase assay. The 4.1-kDa band was phosphorylated by COOH-terminal Src kinase, suggesting that it contains the COOH-terminal negative regulatory site (Tyr508)" SIGNOR-248354 PTPRC protein P08575 UNIPROT JAK1 protein P23458 UNIPROT "down-regulates activity" dephosphorylation Tyr1035 IETDKEYyTVKDDRD 10090 11201744 t "CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling|these results show that CD45 dephosphorylates functionally important tyrosine residues. It should be noted that, as with our phosphatase assays in vitro, Tyr 1022 and Tyr 1023 of JAK1, Tyr 1007 and Tyr 1008 of JAK2, and Tyr 1054 and Tyr 1055 of Tyk2 are indeed hyperphosphorylated in cd45-deficient cells" SIGNOR-248356 PTPRC protein P08575 UNIPROT JAK1 protein P23458 UNIPROT up-regulates dephosphorylation 9606 BTO:0000776;BTO:0003076 11994288 t gcesareni "These negative regulatory effects on ig class switching were concomitant with the ability of cd45 to dephosphorylate the induced phosphorylation of jak1, jak3," SIGNOR-87154 PTPRC protein P08575 UNIPROT TYK2 protein P29597 UNIPROT "down-regulates activity" dephosphorylation Tyr1054 AVPEGHEyYRVREDG 10090 11201744 t "CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling|these results show that CD45 dephosphorylates functionally important tyrosine residues. It should be noted that, as with our phosphatase assays in vitro, Tyr 1022 and Tyr 1023 of JAK1, Tyr 1007 and Tyr 1008 of JAK2, and Tyr 1054 and Tyr 1055 of Tyk2 are indeed hyperphosphorylated in cd45-deficient cells" SIGNOR-248357 PTPRC protein P08575 UNIPROT TYK2 protein P29597 UNIPROT "down-regulates activity" dephosphorylation Tyr1055 VPEGHEYyRVREDGD 10090 11201744 t "CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling|these results show that CD45 dephosphorylates functionally important tyrosine residues. It should be noted that, as with our phosphatase assays in vitro, Tyr 1022 and Tyr 1023 of JAK1, Tyr 1007 and Tyr 1008 of JAK2, and Tyr 1054 and Tyr 1055 of Tyk2 are indeed hyperphosphorylated in cd45-deficient cells" SIGNOR-248358 PTPRC protein P08575 UNIPROT JAK3 protein P52333 UNIPROT up-regulates dephosphorylation 9606 BTO:0000776;BTO:0003076 11994288 t gcesareni "These negative regulatory effects on ig class switching were concomitant with the ability of cd45 to dephosphorylate the induced phosphorylation of jak1, jak3," SIGNOR-87157 PTPRC protein P08575 UNIPROT SKAP1 protein Q86WV1 UNIPROT "up-regulates activity" dephosphorylation Tyr232 EEEKEETyDDIDGFD 9606 BTO:0000661 11909961 t "Mutational analysis demonstrated the pivotal role of Tyr-232 in SKAP55 in the association with CD45. In Jurkat cells, anti-CD3 antibody stimulation promoted SKAP55 tyrosine phosphorylation and translocation from the cytoplasm to the membrane. Overexpression of SKAP55 in these cells induced transcriptional activation of the IL-2 promoter, while mutant SKAP55-Y232F totally suppressed the promoter activity. Furthermore, overexpression of SKAP55-Y232F also caused the tyrosine hyperphosphorylation of Fyn with a decreased kinase activity. Thus, SKAP55 is an essential adapter to couple CD45 with the Src family kinases for dephosphorylation and, thus, positively regulates TCR signaling." SIGNOR-248360 MET protein P08581 UNIPROT MET protein P08581 UNIPROT up-regulates phosphorylation Tyr1234 RDMYDKEyYSVHNKT 9606 8302603 t lperfetto "Previous work has shown that autophosphorylation of p190met enhances its enzymatic activity and that the major phosphorylation site is tyr1235, located in the catalytic domainonly the replacement of both tyr1234 and tyr1235 yielded a mutant which completely lost the ability to be activated by autophosphorylation" SIGNOR-37723 MET protein P08581 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr194 ALEKKSNyEVLEKDV 9606 16782899 t gcesareni "Here we report that fak directly interacts with the hepatocyte growth factor receptor c-met. Phosphorylation of c-met at tyr-1349 and, to a lesser extent, tyr-1356 is required for its interaction with the band 4.1 and ezrin/radixin/moesin homology domain (ferm domain) of fak. met-fak interaction leads to fak activation and subsequent contribution to hepatocyte growth factor-induced cell motility and cell invasion." SIGNOR-147179 MET protein P08581 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr397 SVSETDDyAEIIDEE 9606 16782899 t llicata "Met-mediated fak phosphorylation could further activate fak. Indeed, we found that met phosphorylates fak at its known phosphorylation sites, including tyr-576 and tyr-577, both of which are located in the activating loop within the catalytic domain" SIGNOR-147183 MET protein P08581 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr577 YMEDSTYyKASKGKL 9606 16782899 t llicata "Met-mediated fak phosphorylation could further activate fak. Indeed, we found that met phosphorylates fak at its known phosphorylation sites, including tyr-576 and tyr-577, both of which are located in the activating loop within the catalytic domain" SIGNOR-147195 MET protein P08581 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr861 PIGNQHIyQPVGKPD 9606 16782899 t llicata "Met-mediated fak phosphorylation could further activate fak. Indeed, we found that met phosphorylates fak at its known phosphorylation sites, including tyr-576 and tyr-577, both of which are located in the activating loop within the catalytic domain" SIGNOR-147199 MET protein P08581 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr925 DRSNDKVyENVTGLV 9606 16782899 t llicata "Met-mediated fak phosphorylation could further activate fak. Indeed, we found that met phosphorylates fak at its known phosphorylation sites, including tyr-576 and tyr-577, both of which are located in the activating loop within the catalytic domain" SIGNOR-147203 MET protein P08581 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr194 ALEKKSNyEVLEKDV 9606 20802513 t gcesareni "In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate fak on tyr194 in the ferm domain (band 4.1 and ezrin/radixin/moesin homology domain)." SIGNOR-167654 MET protein P08581 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr285 TEADGELyVFNTPSG 9606 BTO:0000018 10734310 t miannu "Gab-1 is phosphorylated on the same residues by HGF and EGF receptors. Among 16 peptides only nine were phosphorylated by the EGF and HGF receptors, namely peptides containing the tyrosine residues 285, 307, 373, 407, 448, 473, 590, 628 and 660. we show that in the response to HGF or EGF, Gab1 is phosphorylated in vivo on the same residues. However, a sustained activation of signaling pathways downstream to Gab1 (as a result of its sustained phosphorylation) is achieved only in response to HGF." SIGNOR-250552 MET protein P08581 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr589 SHDSEENyVPMNPNL 9606 BTO:0000018 10734310 t miannu "Gab-1 is phosphorylated on the same residues by HGF and EGF receptors. Among 16 peptides only nine were phosphorylated by the EGF and HGF receptors, namely peptides containing the tyrosine residues 285, 307, 373, 407, 448, 473, 590, 628 and 660. we show that in the response to HGF or EGF, Gab1 is phosphorylated in vivo on the same residues. However, a sustained activation of signaling pathways downstream to Gab1 (as a result of its sustained phosphorylation) is achieved only in response to HGF." SIGNOR-250288 MET protein P08581 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr627 KGDKQVEyLDLDLDS 9606 BTO:0000018 10734310 t miannu "Gab-1 is phosphorylated on the same residues by HGF and EGF receptors. Among 16 peptides only nine were phosphorylated by the EGF and HGF receptors, namely peptides containing the tyrosine residues 285, 307, 373, 407, 448, 473, 590, 628 and 660. we show that in the response to HGF or EGF, Gab1 is phosphorylated in vivo on the same residues. However, a sustained activation of signaling pathways downstream to Gab1 (as a result of its sustained phosphorylation) is achieved only in response to HGF." SIGNOR-250289 MET protein P08581 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr659 VADERVDyVVVDQQK 9606 BTO:0000018 10734310 t miannu "Gab-1 is phosphorylated on the same residues by HGF and EGF receptors. Among 16 peptides only nine were phosphorylated by the EGF and HGF receptors, namely peptides containing the tyrosine residues 285, 307, 373, 407, 448, 473, 590, 628 and 660. we show that in the response to HGF or EGF, Gab1 is phosphorylated in vivo on the same residues. However, a sustained activation of signaling pathways downstream to Gab1 (as a result of its sustained phosphorylation) is achieved only in response to HGF." SIGNOR-250290 MET protein P08581 UNIPROT GLMN protein Q92990 UNIPROT down-regulates relocalization 9606 11571281 t gcesareni "Significantly, nonphosphorylated hgf receptor prevents fap68 from stimulating p70s6k. fap68 binding to met requires the last 30 amino acids of the c-terminal tail, which are unique to the hgf receptor." SIGNOR-110726 ADRB1 protein P08588 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257030 ADRB1 protein P08588 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256901 ADRB1 protein P08588 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256758 CFH protein P08603 UNIPROT CFB protein P00751 UNIPROT "down-regulates activity" binding 9606 19050261 t miannu "As a regulator of the alternative pathway, FH binds to C3b and inhibits the binding of factor B to C3b, acts as a cofactor for the factor I-mediated cleavage of C3b to iC3b (cofactor activity), and accelerates the decay of C3bBb, the alternative pathway C3 convertase (decay-accelerating activity)" SIGNOR-252142 CFH protein P08603 UNIPROT C3 protein P01024 UNIPROT "down-regulates activity" binding 9606 19050261 t miannu "As a regulator of the alternative pathway, FH binds to C3b and inhibits the binding of factor B to C3b, acts as a cofactor for the factor I-mediated cleavage of C3b to iC3b (cofactor activity), and accelerates the decay of C3bBb, the alternative pathway C3 convertase (decay-accelerating activity)" SIGNOR-252141 HCK protein P08631 UNIPROT BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR "up-regulates activity" phosphorylation Tyr730 PNLFVALyDFVASGD 9606 16912036 t Manara "Src family kinases phosphorylate the Bcr-Abl SH3-SH2 region and modulate Bcr-Abl transforming activity. | Tyrosine phosphorylation of the SH3-SH2 region is essential for full Bcr-Abl biological activity." SIGNOR-260810 CFH protein P08603 UNIPROT CRP protein P02741 UNIPROT "down-regulates activity" binding 9606 BTO:0004910 26961257 t miannu "In this study, we provide mechanistic insight into how CRP contributes to the development of AMD. In particular, we show that monomeric CRP (mCRP) but not the pentameric form (pCRP) upregulates IL-8 and CCL2 levels in retinal pigment epithelial cells. Further, we show that complement factor H (FH) binds mCRP to dampen its proinflammatory activity. FH from AMD patients carrying the “risk” His402 polymorphism displays impaired binding to mCRP, and therefore proinflammatory effects of mCRP remain unrestrained." SIGNOR-252145 FGF4 protein P08620 UNIPROT FGFR4 protein P22455 UNIPROT up-regulates binding 9606 1385111 t gcesareni "Our results establish an fgf binding profile for fgfr-4 with afgf having the highest affinity, followed by k-fgf/hst-1 and bfgf. In addition, fgf-6 was found to bind to fgfr-4 in ligand competition experiments. Ligands binding to fgfr-4 induced receptor autophosphorylation and phosphorylation of a set of cellular polypeptides." SIGNOR-18567 HCK protein P08631 UNIPROT HCK protein P08631 UNIPROT up-regulates phosphorylation Tyr411 RVIEDNEyTAREGAK 9606 BTO:0000007 10934191 t gcesareni "Tyr(416) is the autophosphorylation site in the activation loop. Autophosphorylation of tyr(416) is required for hck activation." SIGNOR-80340 HCK protein P08631 UNIPROT HCK protein P08631 UNIPROT "up-regulates activity" phosphorylation Tyr411 RVIEDNEyTAREGAK 9606 BTO:0000007 10934191 t "Hck transiently expressed in human embryonic kidney 293T cells was found to be phosphorylated at Tyr-29 and Tyr-388, proving that Hck can also undergo autophosphorylation at both sites in vivo. autophosphorylation of Tyr-29 contributes significantly to the activation of Hck." SIGNOR-251266 HCK protein P08631 UNIPROT HCK protein P08631 UNIPROT "up-regulates activity" phosphorylation Tyr51 ASPHCPVyVPDPTST 9606 BTO:0000007 10934191 t "Hck transiently expressed in human embryonic kidney 293T cells was found to be phosphorylated at Tyr-29 and Tyr-388, proving that Hck can also undergo autophosphorylation at both sites in vivo. autophosphorylation of Tyr-29 contributes significantly to the activation of Hck." SIGNOR-251265 HCK protein P08631 UNIPROT PLCG2 protein P16885 UNIPROT "up-regulates activity" phosphorylation Tyr759 LYDVSRMyVDPSEIN -1 7682059 t lperfetto "The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors." SIGNOR-249364 HCK protein P08631 UNIPROT PLCG1 protein P19174 UNIPROT "up-regulates activity" phosphorylation Tyr1253 EGSFESRyQQPFEDF -1 7682059 t lperfetto "The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors." SIGNOR-249360 HCK protein P08631 UNIPROT ADAM15 protein Q13444 UNIPROT up-regulates phosphorylation Tyr735 LKGPTCQyRAAQSGP 9606 BTO:0000661 11741929 t lperfetto "Hck, and to a lesser extent lck, phosphorylated the adam15. Deletion and point mutation analysis of the adam15 cytoplasmic domain confirmed the importance of the proline-rich motifs for grb2 and lck binding and indicated the regulatory nature of tyr(715) and tyr(735). These data demonstrate selective, phosphorylation-dependent interactions of adam15 with src family ptks and grb2, which highlight the potential for integration of adam functions and cellular signaling." SIGNOR-112923 HCK protein P08631 UNIPROT RAPGEF1 protein Q13905 UNIPROT up-regulates phosphorylation Tyr504 APIPSVPyAPFAAIL 9606 24396067 t llicata "We also showed that ctla-4 receptor signaling mediates tyrosine phosphorylation in the c3g protein, and that this is required for augmented activation of rap1 and increased adhesion mediated by leukocyte function-associated antigen type 1 (lfa-1). ctla-4 signaling leads to phosphorylation of c3g tyrosine 504. the src family member hck phosphorylates c3g downstream of ctla-4." SIGNOR-203613 HCK protein P08631 UNIPROT ELMO1 protein Q92556 UNIPROT up-regulates phosphorylation Tyr18 AIEWPGAyPKLMEID 9606 15952790 t llicata "We previously showed that elmo1 binds directly to the hck sh3 domain and is phosphorylated by hck. In this study, we used mass spectrometry to identify the following sites of elmo1 phosphorylation: tyr 18, tyr 216, tyr 511, tyr 395, and tyr 720. Mutant forms of elmo1 lacking these sites were defective in their ability to promote phagocytosis and migration in fibroblasts." SIGNOR-138142 HCK protein P08631 UNIPROT ELMO1 protein Q92556 UNIPROT up-regulates phosphorylation Tyr216 VLNSHDLyQKVAQEI 9606 15952790 t llicata "We previously showed that elmo1 binds directly to the hck sh3 domain and is phosphorylated by hck. In this study, we used mass spectrometry to identify the following sites of elmo1 phosphorylation: tyr 18, tyr 216, tyr 511, tyr 395, and tyr 720. Mutant forms of elmo1 lacking these sites were defective in their ability to promote phagocytosis and migration in fibroblasts." SIGNOR-138146 HCK protein P08631 UNIPROT ELMO1 protein Q92556 UNIPROT up-regulates phosphorylation Tyr395 AKHHQDAyIRIVLEN 9606 15952790 t llicata "We previously showed that elmo1 binds directly to the hck sh3 domain and is phosphorylated by hck. In this study, we used mass spectrometry to identify the following sites of elmo1 phosphorylation: tyr 18, tyr 216, tyr 511, tyr 395, and tyr 720. Mutant forms of elmo1 lacking these sites were defective in their ability to promote phagocytosis and migration in fibroblasts." SIGNOR-138150 HCK protein P08631 UNIPROT CSF3R protein Q99062 UNIPROT "up-regulates activity" phosphorylation Tyr752 GTSDQVLyGQLLGSP -1 9790917 t "Hck becomes activated upon G-CSF treatment and is, in turn, able to phosphorylate the G-CSF-R, indicating a clear functional and physical involvement in G-CSF signaling. the ability of Hck to phosphorylate the G-CSF-R in vitro, both Y728 and Y763 fit the Src consensus phosphorylation site" SIGNOR-251263 HCK protein P08631 UNIPROT CSF3R protein Q99062 UNIPROT "up-regulates activity" phosphorylation Tyr787 LTPSPKSyENLWFQA -1 9790917 t "Hck becomes activated upon G-CSF treatment and is, in turn, able to phosphorylate the G-CSF-R, indicating a clear functional and physical involvement in G-CSF signaling. the ability of Hck to phosphorylate the G-CSF-R in vitro, both Y728 and Y763 fit the Src consensus phosphorylation site. we investigated the activation of Hck by the G-CSF-R in intact cells as well as in vitro. These studies revealed recruitment of Hck to activated G-CSF-R, mediated by direct binding via its SH2 domain to multiple phosphotyrosines of the receptor. In addition, we show that Hck becomes activated upon G-CSF treatment and is, in turn, able to phosphorylate the G-CSF-R, indicating a clear functional and physical involvement in G-CSF signaling." SIGNOR-251264 RARB protein P10826 UNIPROT RXRB protein P28702 UNIPROT up-regulates binding 9606 1310351 t gcesareni "Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins." SIGNOR-16581 HCK protein P08631 UNIPROT BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR "up-regulates activity" phosphorylation Tyr775 QGWVPSNyITPVNSL 9606 16912036 t Manara "Src family kinases phosphorylate the Bcr-Abl SH3-SH2 region and modulate Bcr-Abl transforming activity. | Tyrosine phosphorylation of the SH3-SH2 region is essential for full Bcr-Abl biological activity." SIGNOR-260811 HCK protein P08631 UNIPROT BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR "up-regulates activity" phosphorylation Tyr788 SLEKHSWyHGPVSRN 9606 16912036 t Manara "Src family kinases phosphorylate the Bcr-Abl SH3-SH2 region and modulate Bcr-Abl transforming activity. | Tyrosine phosphorylation of the SH3-SH2 region is essential for full Bcr-Abl biological activity." SIGNOR-260813 HCK protein P08631 UNIPROT BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR "up-regulates activity" phosphorylation Tyr798 VSRNAAEyLLSSGIN 9606 16912036 t Manara "Src family kinases phosphorylate the Bcr-Abl SH3-SH2 region and modulate Bcr-Abl transforming activity. | Tyrosine phosphorylation of the SH3-SH2 region is essential for full Bcr-Abl biological activity." SIGNOR-260812 HCK protein P08631 UNIPROT BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR "up-regulates activity" phosphorylation Tyr832 LRYEGRVyHYRINTA 9606 16912036 t Manara "Src family kinases phosphorylate the Bcr-Abl SH3-SH2 region and modulate Bcr-Abl transforming activity. | Tyrosine phosphorylation of the SH3-SH2 region is essential for full Bcr-Abl biological activity." SIGNOR-260814 HCK protein P08631 UNIPROT BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR "up-regulates activity" phosphorylation Tyr845 TASDGKLyVSSESRF 9606 16912036 t Manara "Src family kinases phosphorylate the Bcr-Abl SH3-SH2 region and modulate Bcr-Abl transforming activity. | Tyrosine phosphorylation of the SH3-SH2 region is essential for full Bcr-Abl biological activity." SIGNOR-260815 FCGR3A protein P08637 UNIPROT TNF protein P01375 UNIPROT "up-regulates quantity by expression" 9606 BTO:0000801 10728755 f lperfetto "This study suggests a dominant role for FcgammaRIIIA in the induction of both TNFalpha and IL-1alpha production by human macrophages in rheumatoid arthritis following receptor ligation by small immune complexes. The signaling of TNFalpha production may require the ligation of either 3 FcgammaRIIIA receptors or only 2 FcgammaRIIIA receptors, where one interaction must involve binding via an Fc domain." SIGNOR-249526 ITGA5 protein P08648 UNIPROT "A5/b1 integrin" complex SIGNOR-C163 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253177 IL3 protein P08700 UNIPROT IL3RA protein P26951 UNIPROT up-regulates binding 9606 11700046 t gcesareni "The results demonstrate that both the association and dissociation rates for the binding of il-3 to the il-3ralpha are altered by truncation and by amino acid substitution at individual sites. Intracellular signaling studies using k116w and e43n demonstrate that differences in the il-3alpha binding characteristics are reflected in magnitude and kinetics of stat5 phosphorylation." SIGNOR-111404 F7 protein P08709 UNIPROT F9 protein P00740 UNIPROT "up-regulates activity" binding 9606 BTO:0000131 SIGNOR-C319 29880919 t lperfetto "TF has a high affinity for FVII and enables the trace levels (∼1% of the total FVII) of activated FVII (FVIIa) in the blood to cleave specific sites in the serine proteases FIX and FX, activating them into FIXa and FXa, respectively." SIGNOR-263544 F7 protein P08709 UNIPROT F10 protein P00742 UNIPROT "up-regulates activity" binding 9606 BTO:0000131 SIGNOR-C319 29880919 t lperfetto "TF has a high affinity for FVII and enables the trace levels (∼1% of the total FVII) of activated FVII (FVIIa) in the blood to cleave specific sites in the serine proteases FIX and FX, activating them into FIXa and FXa, respectively." SIGNOR-263545 F7 protein P08709 UNIPROT "Factor FVIIa:TF" complex SIGNOR-C319 SIGNOR "form complex" binding 9606 BTO:0000131 32665005 t lperfetto "During vascular injury, TF is exposed to the blood, where it functions as a cofactor for the circulating zymogen factor VII (FVII). This TF:FVIIa complex can then bind and activate either factor IX (FIX) or factor X (FX), triggering a cascade that generates fibrin and activates platelets, resulting in a hemostatic plug at the site of injury." SIGNOR-263555 GNAI3 protein P08754 UNIPROT TNFAIP8 protein O95379 UNIPROT "up-regulates activity" binding 9606 20607800 t "TNFAIP8: a new effector for Galpha(i) coupling to reduce cell death and induce cell transformation" SIGNOR-256490 GNAI3 protein P08754 UNIPROT ADCY1 protein Q08828 UNIPROT down-regulates binding 9606 8327893 t gcesareni "Concentration-dependent inhibition of adenylyl cyclases by purified Gi alpha subunits is described. Activated Gi alpha but not G(o) alpha was effective, and myristoylation of Gi alpha was required" SIGNOR-38032 GNAI3 protein P08754 UNIPROT ADCY1 protein Q08828 UNIPROT down-regulates binding 9606 8327893 t gcesareni "Concentration-dependent inhibition of adenylyl cyclases by purified Gi alpha subunits is described. Activated Gi alpha but not G(o) alpha was effective, and myristoylation of Gi alpha was required" SIGNOR-38029 GNAI3 protein P08754 UNIPROT ADCY1 protein Q08828 UNIPROT "down-regulates activity" binding 9606 19703466 t "Adenylate cyclase is regulated by stimulatory hormones through Gs(alpha s beta gamma) and inhibitory hormones through Gi(alpha i beta gamma)" SIGNOR-256500 RPSA protein P08865 UNIPROT "40S cytosolic small ribosomal subunit" complex SIGNOR-C286 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262414 IL6R protein P08887 UNIPROT JAK2 protein O60674 UNIPROT "up-regulates activity" phosphorylation 9606 23869758 t miannu "On binding of IL-6 to its receptor IL-6R, JAK2 is phosphorylated, then STAT3 is phosphorylated by JAK2" SIGNOR-254405 IL6R protein P08887 UNIPROT IL6ST protein P40189 UNIPROT up-regulates binding 9606 BTO:0000785 11238858 t 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 CSF1 protein P09603 UNIPROT CSF1R protein P07333 UNIPROT "up-regulates activity" binding 9606 BTO:0000876 BTO:0001103 24890514 t 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 HTR1A protein P08908 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257088 HTR1A protein P08908 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256693 CHRM5 protein P08912 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257217 CHRM5 protein P08912 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256730 ADRA2A protein P08913 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256841 ADRA2A protein P08913 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256977 ADRA2A protein P08913 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257093 NMB protein P08949 UNIPROT NMBR protein P28336 UNIPROT up-regulates binding 9606 BTO:0001130;BTO:0000551 11313903 t gcesareni "These neuropeptides, including gastrin-releasing peptide, neuromedin b, neurotensin, gastrin, cholecystokinin and arginine vasopressin bind seven transmembrane-spanning receptors that couple to heterotrimeric g proteins." SIGNOR-107022 MRPL3 protein P09001 UNIPROT "39S mitochondrial large ribosomal subunit" complex SIGNOR-C285 SIGNOR "form complex" binding -1 25838379 t lperfetto "We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules" SIGNOR-262366 FGF2 protein P09038 UNIPROT TGFB1 protein P01137 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15780951 f gcesareni "Fgf-2 and fgf-9 increased expression of other osteogenic factors bmp-2 and tgf-beta1, and endogenous fgf/ fgfr signaling is a positive upstream regulator of the bmp-2 gene in calvarial osteoblasts" SIGNOR-134791 FGF2 protein P09038 UNIPROT ALPL protein P05186 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004473 19049325 f miannu "FGF2 increases PC-1 and Ank expression while inhibiting Tnap expression in primary pre-osteoblast cells. Additionally, we show that the induction of PC-1 by FGF2 is cell type specific and mediated by the transcription factor, Runx2." SIGNOR-252194 PARP1 protein P09874 UNIPROT THBD protein P07204 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002423 21489980 f miannu "Silencing of PARP1 resulted in a strong down-regulation of TM expression in Met-5A cells, while restoring TM expression in H28 cells." SIGNOR-254892 FGF2 protein P09038 UNIPROT BMP2 protein P12643 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15780951 f lperfetto "Furthermore, FGF-2 and FGF-9 increased expression of other osteogenic factors BMP-2 and TGFbeta-1. Meanwhile, blocking endogenous FGF signaling, using a virally transduced dominant-negative FGF receptor (FgfR), resulted in drastically reduced expression of the BMP-2 gene, demonstrating for the first time that endogenous FGF/FgfR signaling is a positive upstream regulator of the BMP-2 gene in calvarial osteoblasts" SIGNOR-134785 FGF2 protein P09038 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates binding 9606 11390973 t lperfetto "we determined the crystal structures of these two FGFR2 mutants in complex with fibroblast growth factor 2 (FGF2).These structures demonstrate that both mutations introduce additional interactions between FGFR2 and FGF2, thereby augmenting FGFR2-FGF2 affinity." SIGNOR-86121 FGF2 protein P09038 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates binding 10116 BTO:0001130 7687739 t lperfetto "The FGF-R2(IIIb) isoform displays high affinity for stromal cell-derived FGF-7, whereas the FGF-R2(IIIc) isoform does not recognize FGF-7 but has high affinity for the FGF-2 member of the FGF ligand family" SIGNOR-236033 FGF2 protein P09038 UNIPROT ENPP1 protein P22413 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004473 19049325 f miannu "FGF2 increases PC-1 and Ank expression while inhibiting Tnap expression in primary pre-osteoblast cells. Additionally, we show that the induction of PC-1 by FGF2 is cell type specific and mediated by the transcription factor, Runx2." SIGNOR-252191 FGF2 protein P09038 UNIPROT FGFR4 protein P22455 UNIPROT up-regulates binding 9606 1385111 t gcesareni "Our results establish an fgf binding profile for fgfr-4 with afgf having the highest affinity, followed by k-fgf/hst-1 and bfgf. In addition, fgf-6 was found to bind to fgfr-4 in ligand competition experiments. Ligands binding to fgfr-4 induced receptor autophosphorylation and phosphorylation of a set of cellular polypeptides." SIGNOR-18564 FGF2 protein P09038 UNIPROT FGFR3 protein P22607 UNIPROT up-regulates binding 9606 15780951 t gcesareni "Fgf-2 and fgf-9 increased expression of other osteogenic factors bmp-2 and tgf-beta1, and endogenous fgf/fgfr signaling is a positive upstream regulator of the bmp-2 gene in calvarial osteoblasts." SIGNOR-134788 FGF2 protein P09038 UNIPROT FGFR3 protein P22607 UNIPROT up-regulates binding 9606 22298955 t gcesareni "Fgf-2 and fgf-9 increased expression of other osteogenic factors bmp-2 and tgf-beta1, and endogenous fgf/fgfr signaling is a positive upstream regulator of the bmp-2 gene in calvarial osteoblasts." SIGNOR-195588 FGF2 protein P09038 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates 9606 20974802 f gcesareni "We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. External stimuli, which control the activity of mapks, such as phorbol esters and fibroblast growth factor 2 (fgf2) control the choice of the lrp6-ppps/tp kinase and regulate the amplitude of lrp6 phosphorylation and wnt/beta-catenin-dependent transcription." SIGNOR-168995 FGF2 protein P09038 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates 9606 20974802 f gcesareni "We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. External stimuli, which control the activity of mapks, such as phorbol esters and fibroblast growth factor 2 (fgf2) control the choice of the lrp6-ppps/tp kinase and regulate the amplitude of lrp6 phosphorylation and wnt/beta-catenin-dependent transcription" SIGNOR-168989 FGF2 protein P09038 UNIPROT MMP13 protein P45452 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15564063 f miannu "Increased expression of RUNX2 in OA cartilage may contribute to increased expression of MMP-13. FGF2, which is present in OA synovial fluid, activated RUNX2 via the MEK/ERK pathway and increased MMP-13 expression." SIGNOR-255079 FGF2 protein P09038 UNIPROT HBA1 protein P69905 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 8142649 f Regulation miannu "Basic fibroblast growth factor (bFGF) and transforming growth factor-beta 1 (TGF-beta) have both been shown to act on hematopoietic progenitor cells. bFGF antagonized the TGF-beta-mediated induction of hemoglobin in a dose-dependent manner, with 0.1 ng/mL bFGF inhibiting hemoglobin induction by 40% and 10 ng/mL bFGF completely abrogating hemoglobin production." SIGNOR-251796 FGF2 protein P09038 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 20974802 f gcesareni "We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. External stimuli, which control the activity of mapks, such as phorbol esters and fibroblast growth factor 2 (fgf2) control the choice of the lrp6-ppps/tp kinase and regulate the amplitude of lrp6 phosphorylation and wnt/beta-catenin-dependent transcription." SIGNOR-168992 FGF2 protein P09038 UNIPROT ANKH protein Q9HCJ1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004473 19049325 f miannu "FGF2 increases PC-1 and Ank expression while inhibiting Tnap expression in primary pre-osteoblast cells. Additionally, we show that the induction of PC-1 by FGF2 is cell type specific and mediated by the transcription factor, Runx2." SIGNOR-252193 ENO2 protein P09104 UNIPROT 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 29767008 t miannu "Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: α-enolase (ENO1) is present in almost all mature tissues; β-enolase (ENO3) exists primarily in muscle tissues; and γ-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits." SIGNOR-266529 ENO2 protein P09104 UNIPROT phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 29767008 t miannu "Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: α-enolase (ENO1) is present in almost all mature tissues; β-enolase (ENO3) exists primarily in muscle tissues; and γ-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits." SIGNOR-266525 SRP19 protein P09132 UNIPROT SRP72 protein O76094 UNIPROT "up-regulates activity" binding -1 30649418 t miannu "Mammalian SRP comprises the highly base-paired SRP RNA (also referred to as 7SL RNA) of ∼300 nt and six proteins (SRP9, SRP14, SRP19, SRP54, SRP68 and SRP72) (Figure ​(Figure1A).1A). The hierarchy of protein addition always starts with the scaffolding protein SRP19 (together with SRP9/14 for the entire SRP) followed by SRP68/72 and finally by SRP54." SIGNOR-261166 SRP19 protein P09132 UNIPROT SRP54 protein P61011 UNIPROT "up-regulates activity" binding -1 30649418 t miannu "Mammalian SRP comprises the highly base-paired SRP RNA (also referred to as 7SL RNA) of ∼300 nt and six proteins (SRP9, SRP14, SRP19, SRP54, SRP68 and SRP72) (Figure ​(Figure1A).1A). The hierarchy of protein addition always starts with the scaffolding protein SRP19 (together with SRP9/14 for the entire SRP) followed by SRP68/72 and finally by SRP54." SIGNOR-261168 SRP19 protein P09132 UNIPROT SRP68 protein Q9UHB9 UNIPROT "up-regulates activity" binding -1 30649418 t miannu "Mammalian SRP comprises the highly base-paired SRP RNA (also referred to as 7SL RNA) of ∼300 nt and six proteins (SRP9, SRP14, SRP19, SRP54, SRP68 and SRP72) (Figure ​(Figure1A).1A). The hierarchy of protein addition always starts with the scaffolding protein SRP19 (together with SRP9/14 for the entire SRP) followed by SRP68/72 and finally by SRP54." SIGNOR-261167 DBH protein P09172 UNIPROT dopamine smallmolecule CHEBI:18243 ChEBI "down-regulates quantity" "small molecule catalysis" 10090 BTO:0000047 7961964 t brain lperfetto "Dopamine beta-hydroxylase (DBH; EC 1.14.17.1) catalyzes the production of the neurotransmitter and hormone norepinephrine in the third step of the catecholamine biosynthesis pathway." SIGNOR-264005 DBH protein P09172 UNIPROT noradrenaline smallmolecule CHEBI:33569 ChEBI "up-regulates quantity" "small molecule catalysis" 10090 BTO:0000047 7961964 t brain lperfetto "Dopamine beta-hydroxylase (DBH; EC 1.14.17.1) catalyzes the production of the neurotransmitter and hormone norepinephrine in the third step of the catecholamine biosynthesis pathway." SIGNOR-264006 MMP7 protein P09237 UNIPROT DCN protein P07585 UNIPROT "down-regulates quantity by destabilization" cleavage Glu273 ANTPHLReLHLDNNK -1 9148753 t miannu "Degradation of decorin by matrix metalloproteinases. These data indicate proteolytic degradation of DCN by MMP-2, MMP-3 and MMP-7, and suggest the possibility that, under pathophysiological conditions, the digestion by the MMPs may induce tissue reactions mediated by TGF-beta1 released from DCN in the connective tissues." SIGNOR-256352 MMP7 protein P09237 UNIPROT SPP1 protein P10451 UNIPROT "up-regulates activity" cleavage 25545242 t lperfetto "In this study, we found a novel motif, LRSKSRSFQVSDEQY, in the C-terminal fragment of MMP-3/7-cleaved mouse OPN binds to α9β1 integrin. Importantly, this novel motif is involved in the development of anti-type II collagen antibody-induced arthritis (CAIA). This study provides the first in vitro and in vivo evidence that OPN cleavage by MMP-3/7 is an important regulatory mechanism for CAIA." SIGNOR-253321 MMP7 protein P09237 UNIPROT HAPLN1 protein P10915 UNIPROT "down-regulates quantity by destabilization" cleavage Leu40 QAENGPHlLVEAEQA -1 7694569 t miannu "Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix." SIGNOR-256329 MMP10 protein P09238 UNIPROT HAPLN1 protein P10915 UNIPROT "down-regulates quantity by destabilization" cleavage His31 LDHDRAIhIQAENGP -1 7694569 t miannu "Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix." SIGNOR-256331 MMP10 protein P09238 UNIPROT HAPLN1 protein P10915 UNIPROT "down-regulates quantity by destabilization" cleavage Leu40 QAENGPHlLVEAEQA -1 7694569 t miannu "Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix." SIGNOR-256332 CXCL1 protein P09341 UNIPROT GLI2 protein P10070 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16885213 f gcesareni "The data suggest that smo is in fact the source of two signals relevant to the activation of gli: one involving g(i) and the other involving events at smo's c-tail independent of g(i)." SIGNOR-148457 CXCL1 protein P09341 UNIPROT GLI3 protein P10071 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16885213 f gcesareni "The data suggest that smo is in fact the source of two signals relevant to the activation of gli: one involving g(i) and the other involving events at smo's c-tail independent of g(i)." SIGNOR-148460 CXCL1 protein P09341 UNIPROT PRKACA protein P17612 UNIPROT down-regulates binding 9606 17251915 t gcesareni "As pka suppresses the activity of gli, smo might use the stimulation of pi3k by galfai and gbetagamma subu- nits to block pka in cells that have high levels of camp." SIGNOR-152594 CXCL1 protein P09341 UNIPROT PLCE1 protein Q9P212 UNIPROT up-regulates binding 9606 17251915 t gcesareni "In the non-canonical wnt pathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor." SIGNOR-152591 HMGB1 protein P09429 UNIPROT TLR4 protein O00206 UNIPROT "up-regulates activity" binding 9606 BTO:0000801 20547845 t gcesareni "Here we show that Toll-like receptor 4 (TLR4), a pivotal receptor for activation of innate immunity and cytokine release, is required for HMGB1-dependent activation of macrophage TNF release." SIGNOR-252057 CSF1 protein P09603 UNIPROT CSF2RA protein P15509 UNIPROT up-regulates binding 9606 10572088 t gcesareni "Granulocyte-macrophage colony-stimulating factor (gm-csf) is an important hematopoietic cytokine that exerts its effects by interaction with the gm-csf receptor (gmr) on the surface of responsive cells. The gm-csf receptor consists of two subunits: gmralpha, which binds gm-csf with low affinity, and gmrbeta, which lacks intrinsic ligand-binding capability but complexes with gmralpha to form a high-affinity receptor (gmralpha/beta)." SIGNOR-72455 HMGB1 protein P09429 UNIPROT IL2RA protein P01589 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000661 7862168 f 2 miannu "The interleukin 2 receptor alpha-chain (IL-2R alpha) gene is rapidly and potently induced in T cells in response to mitogenic stimuli. Previously, an inducible enhancer between nucleotides -299 and -228 that contains NF-kappa B and CArG motifs was identified. We now report the characterization of a second essential positive regulatory element located between nucleotides -137 and -64 that binds Elf-1 and HMG-I(Y). Transcription from the IL-2R alpha promoter was inhibited when either the Elf-1 or the HMG-I(Y) binding site was mutated. Coexpression of both proteins activated transcription of the -137 to -64 element in COS-7 cells." SIGNOR-240113 HMGB1 protein P09429 UNIPROT HOXD9 protein P28356 UNIPROT "up-regulates activity" binding 10090 BTO:0000944 8890171 t miannu "We show that HMG1 interacts with proteins encoded by the HOX gene family by establishing protein-protein contacts between the HMG box domains and the HOX homeodomain.ƒ‚‚ The functional role of these interactions was studied using the transcriptional activity of the human HOXD9 protein as a model. HMG1 enhances, in a dose-dependent fashion, the sequence-specific DNA binding activity in vitro, and the transcriptional activation in a co-transfection assay in vivo, of the HOXD9 protein." SIGNOR-236956 HMGB1 protein P09429 UNIPROT HOXD3 protein P31249 UNIPROT "up-regulates activity" binding -1 8890171 t miannu "We show that HMG1 interacts with proteins encoded by the HOX gene family by establishing protein-protein contacts between the HMG box domains and the HOX homeodomain. The functional role of these interactions was studied using the transcriptional activity of the human HOXD9 protein as a model. HMG1 enhances, in a dose-dependent fashion, the sequence-specific DNA binding activity in vitro, and the transcriptional activation in a co-transfection assay in vivo, of the HOXD9 protein." SIGNOR-219980 HMGB1 protein P09429 UNIPROT HOXD11 protein P31277 UNIPROT "up-regulates activity" binding -1 8890171 t 2 miannu "We show that HMG1 interacts with proteins encoded by the HOX gene family by establishing protein-protein contacts between the HMG box domains and the HOX homeodomain. HMG1 enhances, in a dose-dependent fashion, the sequence-specific DNA binding activity in vitro, and the transcriptional activation in a co-transfection assay in vivo, of the HOXD9 protein." SIGNOR-240559 RBP1 protein P09455 UNIPROT retinol smallmolecule CHEBI:50211 ChEBI "up-regulates quantity" relocalization 31963453 t lperfetto "Once in the cytosol, retinol molecules are sequestered by membrane systems and bind to Cellular retinol-binding protein 1 (CRBP1), which plays a role in vitamin A cytoplasmic trafficking" SIGNOR-265108 GNAO1 protein P09471 UNIPROT NDN protein Q99608 UNIPROT "up-regulates activity" 9606 BTO:0002036 25012566 f lperfetto "We subsequently analyzed whether Gαo modulates the cellular activities of Necdin. Notably, expression of Gαo significantly augmented Necdin-mediated cellular responses, such as proliferation and differentiation. Moreover, activation of type 1 cannabinoid receptor (CB1R), a Gi/oα-coupled receptor, augmented cell growth suppression, which was mediated by Gαo and Necdin in U87MG cells containing CB1R, Gαo, and Necdin as normal components." SIGNOR-253388 GNAO1 protein P09471 UNIPROT TAOK2 protein Q9UL54 UNIPROT up-regulates 9606 BTO:0000007 12665513 f lperfetto "These results suggest that go alpha q205l activates p38 through taos and mek3/6." SIGNOR-235542 GNAO1 protein P09471 UNIPROT Tubulin proteinfamily SIGNOR-PF46 SIGNOR "up-regulates activity" binding -1 10224115 t "G protein alpha subunits Gi1alpha, Gsalpha, and Goalpha are shown to activate the GTPase activity of tubulin, inhibit microtubule assembly, and accelerate microtubule dynamics." SIGNOR-256540 CLTA protein P09496 UNIPROT "AP-2/clathrin vescicle" complex SIGNOR-C249 SIGNOR "form complex" binding 9606 24789820 t lperfetto "AP2 adaptor complexes, associated at the membrane with PtdIns(4,5)P2 (PIP2), recruit clathin triskelions to initiate lattice assembly. " SIGNOR-260667 CLTA protein P09496 UNIPROT "AP-3/clathrin vescicle" complex SIGNOR-C250 SIGNOR "form complex" binding 9606 23103167 t lperfetto "Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors" SIGNOR-260672 CLTA protein P09496 UNIPROT "AP-1/clathrin vescicle" complex SIGNOR-C251 SIGNOR "form complex" binding 9606 23103167 t lperfetto "Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors" SIGNOR-260678 CLTB protein P09497 UNIPROT "AP-2/clathrin vescicle" complex SIGNOR-C249 SIGNOR "form complex" binding 9606 24789820 t lperfetto "AP2 adaptor complexes, associated at the membrane with PtdIns(4,5)P2 (PIP2), recruit clathin triskelions to initiate lattice assembly. " SIGNOR-260666 CLTB protein P09497 UNIPROT "AP-1/clathrin vescicle" complex SIGNOR-C251 SIGNOR "form complex" binding 9606 23103167 t lperfetto "Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors" SIGNOR-260677 WNT2 protein P09544 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 15578921 t 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-131730 HMOX1 protein P09601 UNIPROT heme smallmolecule CHEBI:30413 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 16115609 t "The microsomal heme oxygenase system consists of heme oxygenase (HO) and NADPH-cytochrome P450 reductase, and plays a key role in the physiological catabolism of heme which yields biliverdin, carbon monoxide, and iron as the final products. Heme degradation proceeds essentially as a series of autocatalytic oxidation reactions involving heme bound to HO" SIGNOR-259333 HMOX1 protein P09601 UNIPROT BCL2 protein P10415 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 26722274 f irozzo "The results of the present study indicated that knockdown of HMOX-1 significantly enhanced doxorubicin-induced apoptosis and downregulated the expression of Bcl-2 and Bcl-xL in breast cancer cells." SIGNOR-256303 HMOX1 protein P09601 UNIPROT STC2/HMOX1 complex SIGNOR-C244 SIGNOR "form complex" binding BTO:0000298 22503972 t Giorgia "Stanniocalcin 2, forms a complex with heme oxygenase 1, binds hemin and is a heat shock protein.|Taken together, our findings point to three novel functions of STC2, and suggest that STC2 interacts with HO1 to form a eukaryotic 'stressosome' involved in the degradation of heme." SIGNOR-260388 PDGFRB protein P09619 UNIPROT FYN protein P06241 UNIPROT "up-regulates activity" phosphorylation Tyr28 SLNQSSGyRYGTDPT -1 9425276 t miannu "PDGF-induced phosphorylation of Tyr28 in the N-terminus of Fyn affects Fyn activation. We show here that Fyn, a member of the Src family, is phosphorylated on Tyr28 in the unique N-terminal part of the molecule after interaction with the intracellular domain of the PDGF beta-receptor. Activated Fyn furthermore undergoes autophosphorylation on Tyr30, Tyr39 and Tyr420. When Fyn mutants with Tyr28, Tyr30 or Tyr39 replaced with phenylalanine residues were transfected into NIH3T3 cells a decreased activation after PDGF stimulation was seen, suggesting a functional importance of the N-terminal tyrosine phosphorylation of Fyn." SIGNOR-250253 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT unknown phosphorylation Tyr751 SKDESVDyVPMLDMK 9606 2550144 t llicata "We have identified two platelet-derived growth factor (pdgf)-dependent autophosphorylation sites in the beta subunit of the human pdgf receptor (pdgf-r). The major site of phosphorylation (tyr-857) corresponds to the major autophosphorylation site in many other tyrosine kinases. Tyr-751, which lies within the kinase insert region, is a second in vivo site and the major in vitro site." SIGNOR-22993 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT unknown phosphorylation Tyr857 DIMRDSNyISKGSTF 9606 2550144 t llicata "We have identified two platelet-derived growth factor (pdgf)-dependent autophosphorylation sites in the beta subunit of the human pdgf receptor (pdgf-r). The major site of phosphorylation (tyr-857) corresponds to the major autophosphorylation site in many other tyrosine kinases. Tyr-751, which lies within the kinase insert region, is a second in vivo site and the major in vitro site." SIGNOR-22997 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT "up-regulates activity" phosphorylation Tyr775 SSNYMAPyDNYVPSA -1 8940081 t miannu "The SH2 domain of Grb7 can directly bind to the autophosphorylated PDGF beta-receptor in vitro. Grb7 association to the PDGF beta-receptor was dramatically reduced by replacement of tyrosine residues 716 or 775 with phenylalanine residues." SIGNOR-250259 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT "up-regulates activity" phosphorylation Tyr579 VSSDGHEyIYVDPMQ 9606 BTO:0000599 9642269 t miannu "We used two platelet-derived growth factor beta-receptor (beta-PDGFR) mutants to identify events that are required for full engagement (autophosphorylation and activation of the kinase activity) of the beta-PDGFR kinase. The F79/81 receptor (Tyr to Phe substitution at 579 and 581 in the juxtamembrane domain of the receptor) was capable of only very modest ligand-dependent autophosphorylation and also failed to associate with numerous SH2 domain-containing proteins." SIGNOR-250254 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT "up-regulates activity" phosphorylation Tyr581 SDGHEYIyVDPMQLP 9606 BTO:0000599 9642269 t miannu "We used two platelet-derived growth factor beta-receptor (beta-PDGFR) mutants to identify events that are required for full engagement (autophosphorylation and activation of the kinase activity) of the beta-PDGFR kinase. The F79/81 receptor (Tyr to Phe substitution at 579 and 581 in the juxtamembrane domain of the receptor) was capable of only very modest ligand-dependent autophosphorylation and also failed to associate with numerous SH2 domain-containing proteins." SIGNOR-250255 PDGFRB protein P09619 UNIPROT SRC protein P12931 UNIPROT "up-regulates activity" phosphorylation Tyr419 RLIEDNEyTARQGAK 9606 BTO:0002057 15489898 t gcesareni "The increased Src activity is mainly due to the phosphorylation of Tyr-419, rather than the dephosphorylation of Tyr-530 of Src protein. PDGFR, not FAK or EGFR, appears to be the upstream protein tyrosine kinase responsible for the detachment-induced Src activation in the lung tumor cells." SIGNOR-247979 PDGFRB protein P09619 UNIPROT NCK1 protein P16333 UNIPROT up-regulates binding 9606 10026169 t esanto "Growth factor binding to receptor protein tyrosine kinases (r-ptks)1 induces their dimerization and trans-phosphorylation, creating docking sites for proteins containing sh2 and ptb protein interaction domains. Nck binds to the pdgf and egfr receptors (figure 3c)." SIGNOR-64737 PDGFRB protein P09619 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates phosphorylation 9606 7535778 t miannu "Tyrosine phosphorylation has been shown to increase the enzymatic activity of plc-? / we show that the human pdgf ?- And ?-Receptors differ quantitatively in their abilities to associate with and phosphorylate plc-? And to stimulate inositol phosphate production." SIGNOR-28179 PDGFRB protein P09619 UNIPROT RASA1 protein P20936 UNIPROT up-regulates binding 9606 11896619 t miannu "The gtpase activating protein (gap) of ras binds only to beta-receptors / we have previously shown that the binding site for gtpase activating protein of ras (rasgap) in the pdgf beta-receptor, tyr771, is phosphorylated to a much lower extent in the heterodimeric configuration of pdgf alpha- and beta-receptors, compared to the pdgf beta-receptor homodimer. / the decreased recruitment of the rasgap to the receptor leads to prolonged activation of the ras/map kinase pathway" SIGNOR-115843 PDGFRB protein P09619 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation 9606 8195171 t gcesareni "In this study, we have characterized the interaction between the pdgf beta-receptor and shc. multiple autophosphorylation sites in the pdgf beta-receptor are responsible for the binding of shc." SIGNOR-36906 PDGFRB protein P09619 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 7935391 t fspada "A pathway leading to activation of the gtp-binding protein ras involves the adaptor molecule grb2. Here we show that tyr-716, a novel autophosphorylation site in the pdgf beta-receptor kinase insert, mediates direct binding of grb2 in vitro and in vivo." SIGNOR-34765 PDGFRB protein P09619 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr194 ALEKKSNyEVLEKDV 9606 20802513 t llicata "In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate fak on tyr194 in the ferm domain collectively, this study provides the first example to explain how fak is activated by receptor tyrosine kinases." SIGNOR-167658 PDGFRB protein P09619 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr5 yLDPNLNH 9606 20802513 t llicata "In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate fak on tyr194 in the ferm domain collectively, this study provides the first example to explain how fak is activated by receptor tyrosine kinases." SIGNOR-167662 PDGFRB protein P09619 UNIPROT PTPN11 protein Q06124 UNIPROT "up-regulates activity" phosphorylation Tyr542 SKRKGHEyTNIKYSL 10090 BTO:0000944 8041791 t miannu "Upon PDGF stimulation, SHPTP2 binds to the PDGFR and becomes tyrosine-phosphorylated. We have identified tyrosine-542 (pY542TNI) as the major in vivo site of SHPTP2 tyrosine phosphorylation. phosphorylation of SHPTP2 couples Grb2 to PDGFR in vivo, providing a mechanism for Ras activation by PDGFR and for positive signaling via SHPTP2 and Csw." SIGNOR-250260 DLD protein P09622 UNIPROT OGDC complex SIGNOR-C397 SIGNOR "form complex" binding 9606 15953811 t miannu "The α-ketoglutarate–dehydrogenase complex is a complex including multiple copies of three proteins: E1k (α-ketoglutarate dehydrogenase), E2k (dihydrolipoyl succinyltransferase), and E3 (dihydrolipoamide dehydrogenase) (Fig. 2). The consecutive action of the three catalytic components of KGDHC results in oxidative decarboxylation of 2-oxoglutarate, preserving the energy in the form of succinylCoA and NADH." SIGNOR-266256 DLD protein P09622 UNIPROT PDH complex SIGNOR-C402 SIGNOR "form complex" binding 9606 20160912 t miannu "The human (h) pyruvate dehydrogenase complex (hPDC) consists of multiple copies of several components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2), dihydrolipoamide dehydrogenase (E3), E3-binding protein (BP), and specific kinases and phosphatases. Mammalian PDC has a well organized structure with an icosahedral symmetry of the central E2/BP core to which the other component proteins bind non-covalently." SIGNOR-266545 HOXB7 protein P09629 UNIPROT FGF2 protein P09038 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567 8756643 t Luana "Band shift and cotransfection experiments showed that HOXB7 directly transactivates the hFGF gene through one out of five putative homeodomain binding sites present in its promoter." SIGNOR-261639 HOXB7 protein P09629 UNIPROT PRKDC protein P78527 UNIPROT "up-regulates activity" binding 9606 BTO:0002419 SIGNOR-C106 17308091 t miannu "Ku70 and Ku80 associated with HOXB7 in vivo. Ku70/Ku80 heterodimer formation is a prerequisite for HOXB7 binding. interaction between Ku70/80 and HOXB7 may affect the catalytic activity of DNA-PK. HOXB7 stimulates DNA-PK activity" SIGNOR-226063 HOXC6 protein P09630 UNIPROT S100B protein P04271 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002253 17488478 t Luana "HOXC6 and HOXC11 increase transcription of S100beta gene in BrdU-induced in vitro differentiation of GOTO neuroblastoma cells into Schwannian cells." SIGNOR-261646 HNRNPA1 protein P09651 UNIPROT TRA2B protein P62995 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000586 31311954 t lperfetto "HnRNPA1 interacts with G-quadruplex in the TRA2B promoter and stimulates its transcription in human colon cancer cells." SIGNOR-262280 CTSH protein P09668 UNIPROT BGLAP protein P02818 UNIPROT "down-regulates quantity by destabilization" cleavage Arg94 IGFQEAYrRFYGPV -1 9076588 t miannu "This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42." SIGNOR-256325 CTSH protein P09668 UNIPROT BGLAP protein P02818 UNIPROT "down-regulates quantity by destabilization" cleavage Gly58 RYLYQWLgAPVPYPD -1 9076588 t miannu "This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42." SIGNOR-256324 CD3G protein P09693 UNIPROT RPS6KA4 protein O75676 UNIPROT up-regulates 9606 BTO:0000782 17668895 f gcesareni "Tcr stimulation also activates the mitogen- and stress-activated kinases (msk) downstream of erk1/2." SIGNOR-157148 FGR protein P09769 UNIPROT HCLS1 protein P14317 UNIPROT unknown phosphorylation Tyr222 MEAPTTAyKKTTPIE -1 10066823 t "We have now identified tyrosine 222 as the HS1 residue phosphorylated by the Src family protein kinases c-Fgr and Lyn. this interaction is weakened by phosphorylation of Tyr-222, through an allosteric mechanism that ultimately causes the detachment of fully phosphorylated HS1 from c-Fgr." SIGNOR-251144 FGR protein P09769 UNIPROT SDHA protein P31040 UNIPROT unknown phosphorylation Tyr543 CGKISKLyGDLKHLK -1 17997986 t miannu "Here, we provide evidence that the flavoprotein of succinate dehydrogenase and aconitase are ""in vitro"" substrates of Fgr tyrosine kinase. Fgr phosphorylates flavoprotein of succinate dehydrogenase at Y535 and Y596 and aconitase at Y71, Y544 and Y665. Further experiments will be necessary to verify if Fgr is the tyrosine kinase responsible for the tyrosine phosphorylation of these proteins in vivo and to elucidate the role of these phosphorylations." SIGNOR-262872 FGR protein P09769 UNIPROT SDHA protein P31040 UNIPROT unknown phosphorylation Tyr604 YKVRIDEyDYSKPIQ -1 17997986 t miannu "Here, we provide evidence that the flavoprotein of succinate dehydrogenase and aconitase are ""in vitro"" substrates of Fgr tyrosine kinase. Fgr phosphorylates flavoprotein of succinate dehydrogenase at Y535 and Y596 and aconitase at Y71, Y544 and Y665. Further experiments will be necessary to verify if Fgr is the tyrosine kinase responsible for the tyrosine phosphorylation of these proteins in vivo and to elucidate the role of these phosphorylations." SIGNOR-262873 FGR protein P09769 UNIPROT ACO2 protein Q99798 UNIPROT unknown phosphorylation Tyr544 FDPGQDTyQHPPKDS -1 17997986 t miannu "Here, we provide evidence that the flavoprotein of succinate dehydrogenase and aconitase are ""in vitro"" substrates of Fgr tyrosine kinase. Fgr phosphorylates flavoprotein of succinate dehydrogenase at Y535 and Y596 and aconitase at Y71, Y544 and Y665. Further experiments will be necessary to verify if Fgr is the tyrosine kinase responsible for the tyrosine phosphorylation of these proteins in vivo and to elucidate the role of these phosphorylations." SIGNOR-262869 FGR protein P09769 UNIPROT ACO2 protein Q99798 UNIPROT unknown phosphorylation Tyr665 VVIGDENyGEGSSRE -1 17997986 t miannu "Here, we provide evidence that the flavoprotein of succinate dehydrogenase and aconitase are ""in vitro"" substrates of Fgr tyrosine kinase. Fgr phosphorylates flavoprotein of succinate dehydrogenase at Y535 and Y596 and aconitase at Y71, Y544 and Y665. Further experiments will be necessary to verify if Fgr is the tyrosine kinase responsible for the tyrosine phosphorylation of these proteins in vivo and to elucidate the role of these phosphorylations." SIGNOR-262870 PARP1 protein P09874 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" relocalization 9606 17891139 t miannu "We identify the major poly(ADP-ribosyl)ated sites of p53 by PARP-1 and find that PARP-1-mediated poly(ADP-ribosyl)ation blocks the interaction between p53 and the nuclear export receptor Crm1, resulting in nuclear accumulation of p53. These findings molecularly link PARP-1 and p53 in the DNA-damage response, providing the mechanism for how p53 accumulates in the nucleus in response to DNA damage.|PARP-1 is super-activated by binding to damaged DNA, and poly(ADP-ribosyl)ates p53. Poly(ADP-ribosyl)ation probably induces a structural change that mask the NES, and thus Crm1 can no longer target p53 to the nuclear export machinery, resulting in accumulation of p53 in the nucleus." SIGNOR-261321 PARP1 protein P09874 UNIPROT THBD protein P07204 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001289 21489980 f miannu "Silencing of PARP1 resulted in a strong down-regulation of TM expression in Met-5A cells, while restoring TM expression in H28 cells. We propose that methylation of the TM promoter is responsible for silencing of TM expression in MM tissue, a process that is regulated by PARP1." SIGNOR-254893 PARP1 protein P09874 UNIPROT POLA1 protein P09884 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 9518481 t Federica "We provide evidence that in proliferating cells: (i) PARP is physically associated with the catalytic subunit of the DNA polymerase α–primase tetramer, an association confirmed by confocal microscopy, demonstrating that both enzymes are co-localized at the nuclear periphery of HeLa cells.|(iii) PARP-deficient cells derived from PARP knock-out mice exhibited reduced DNA polymerase activity," SIGNOR-261270 PARP1 protein P09874 UNIPROT SERPINF1 protein P36955 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001949 18312852 f miannu "Upregulation of PEDF expression by PARP inhibition contributes to the decrease in hyperglycemia-induced apoptosis in HUVECs." SIGNOR-254891 ALOX5 protein P09917 UNIPROT "leukotriene A4" smallmolecule CHEBI:15651 ChEBI up-regulates "small molecule catalysis" 9606 11751058 t gcesareni "5-lipoxygenase catalyzes the production of leukotriene (lt) a4, from 5- hydroperoxyeicosatetraenoic acid (5-hpete) as well as the nitial oxidation of arachidonic acid to this hydroperoxy in-termediate" SIGNOR-113198 CSF3 protein P09919 UNIPROT CSF2RA protein P15509 UNIPROT up-regulates binding 9606 10572088 t gcesareni "Granulocyte-macrophage colony-stimulating factor (gm-csf) is an important hematopoietic cytokine that exerts its effects by interaction with the gm-csf receptor (gmr) on the surface of responsive cells. The gm-csf receptor consists of two subunits: gmralpha, which binds gm-csf with low affinity, and gmrbeta, which lacks intrinsic ligand-binding capability but complexes with gmralpha to form a high-affinity receptor (gmralpha/beta)." SIGNOR-72511 CSF3 protein P09919 UNIPROT CSF3R protein Q99062 UNIPROT up-regulates binding 9606 16492764 t gcesareni "The gcsf:gcsf-r complex formed a 2:2 stoichiometry by means of a cross-over interaction between the ig-like domains of gcsf-r and gcsf. the ig-like domain cross-over structure necessary for gcsf-r activation is consistent with previously reported thermodynamic and mutational analyses." SIGNOR-144743 FURIN protein P09958 UNIPROT VWF protein P04275 UNIPROT "up-regulates activity" cleavage BTO:0001538 8218226 t Giorgia "Like PACE,PACE4 was able to process pro-vWF to its mature form, and efficient cleavage required both the P4 arginine and the P2 lysine" SIGNOR-260368 FURIN protein P09958 UNIPROT INSR protein P06213 UNIPROT "up-regulates activity" cleavage 9606 BTO:0000666 25527501 t Giorgia "Here we demonstrate that the two IR isoforms are similarly cleaved by furin, but when this furin-dependent maturation is inefficient, IR proforms move to the cell surface where the proprotein convertase PACE4 selectively supports IRB maturation." SIGNOR-260365 FURIN protein P09958 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 22479394 t "Cleavage in Golgi" gcesareni "The proteolytic activity of furin responsible for processing full length notch-1 (p300) plays a critical role in notch signaling." SIGNOR-196914 ALDOC protein P09972 UNIPROT "beta-D-fructofuranose 1,6-bisphosphate(4-)" smallmolecule CHEBI:32966 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 16051738 t miannu "Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C." SIGNOR-266489 ALDOC protein P09972 UNIPROT "glycerone phosphate(2-)" smallmolecule CHEBI:57642 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 16051738 t miannu "Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C." SIGNOR-266485 ALDOC protein P09972 UNIPROT "D-glyceraldehyde 3-phosphate(2-)" smallmolecule CHEBI:59776 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 16051738 t miannu "Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C." SIGNOR-266481 C4A protein P0C0L4 UNIPROT "C3 convertase complex" complex SIGNOR-C310 SIGNOR "form complex" binding -1 cleavage:Arg756;Gly1446 KGQAGLQrALEILQE;TPLQLFEgRRNRRRR 17204478 t "complement C4b fragment: PRO_0000005970" lperfetto "However, following cleavage of C4, C2 binds tightly to C4b to form the C4b2 complex" SIGNOR-263400 C4B protein P0C0L5 UNIPROT "C3 convertase complex" complex SIGNOR-C310 SIGNOR "form complex" binding -1 cleavage:Arg756;Gly1446 KGQAGLQrALEILQE;TPLQLFEgRRNRRRR 17204478 t "complement C4b fragment:PRO_0000042703" lperfetto "However, following cleavage of C4, C2 binds tightly to C4b to form the C4b2 complex" SIGNOR-263398 H2AC11 protein P0C0S8 UNIPROT SGO1 protein Q5FBB7 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000567 phosphorylation:Thr121 AVLLPKKtESHHKAK phosphorylation:Thr346 LEEGVHLtPFRQKVS 24055156 t lperfetto "The complex between shugoshin and protein phosphatase 2A (Sgo1-PP2A) localizes to centromeres in mitosis, binds to cohesin in a reaction requiring Cdk-dependent phosphorylation of Sgo1, dephosphorylates cohesin-bound sororin, and protects a centromeric pool of cohesin from mitotic kinases and the cohesin inhibitor Wapl.|The centromeric localization of Sgo1 requires histone H2A phosphorylation at T120 (H2A-pT120) by the kinase Bub1." SIGNOR-265262 "Papain-like proteinase" protein P0C6X7_PRO_0000037311 UNIPROT TRAF3 protein Q13114 UNIPROT "down-regulates activity" deubiquitination 9606 31226023 t miannu "Overexpressing PLPro of SARS-CoV or MERS-CoV significantly reduced the expression of IFN-β and proinflammatory cytokines in MDA5-stimulated 293T cells (83).Also, SARS-CoVPLPro catalyzed deubiquitination of TNF-receptor-associated factor3 (TRAF3) and TRAF6, thereby suppressing IFN-I and proinflammatory cytokines induced by TLR7 agonist (63). The deubiquitinating activity of SARS-CoV PLPro also suppressed a constitutively active phosphomimetic IRF3, suggesting its involvement in the postactivation signaling of IRF3" SIGNOR-260246 "Papain-like proteinase" protein P0C6X7_PRO_0000037311 UNIPROT IRF3 protein Q14653 UNIPROT "down-regulates activity" binding 9606 17761676 t lperfetto "PLpro interacts with IRF-3, and inhibits the phosphorylation and nuclear translocation of IRF-3, thereby disrupting the activation of type I IFN responses through either Toll-like receptor 3 or retinoic acid inducible gene I/melanoma differentiation-associated gene 5 pathways." SIGNOR-260276 "Papain-like proteinase" protein P0C6X7_PRO_0000037311 UNIPROT IRF3 protein Q14653 UNIPROT "down-regulates activity" deubiquitination 9606 25481026 t miannu "Here we show that PLpro also inhibits IRF3 activation at a step after phosphorylation and that this inhibition is dependent on the de-ubiquitination (DUB) activity of PLpro. We found that PLpro is able to block the type I IFN induction of a constitutively active IRF3, but does not inhibit IRF3 dimerization, nuclear localization or DNA binding. However, inhibition of PLpro’s DUB activity by mutagenesis blocked the IRF3 inhibition activity of PLpro, suggesting a role for IRF3 ubiquitination in induction of a type I IFN innate immune response." SIGNOR-260249 HSPA1A protein P0DMV8 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates 9606 16172114 f gcesareni "Hsp70 inhibited stress-induced jnk activation and jnk with sp600125 or by expression of a dominant negative mutant of jnk-blocked bax translocation as effectively as hsp70 overexpression" SIGNOR-140553 "3C-like proteinase" protein P0C6X7_PRO_0000037312 UNIPROT ATP6V1G1 protein O75348 UNIPROT "down-regulates activity" cleavage -1 16226257 t lperfetto "Cleavage of the V-ATPase G1 fusion protein by SARS-CoV 3CLpro was found in this study (Fig. 3), implying that 3CLpro potentially cleaves the cellular V-ATPase G1, and affects the function of vacuolar H(+)-ATPase. Meanwhile, a significant intracellular acidification has been demonstrated in the 3CLpro-expressing cells (Fig. 4D). The result correlated well with previous reports in that V-ATPase-specific inhibitors cause acidic pHi [28], [29], and influences cell apoptosis" SIGNOR-260264 "Non-structural protein 10" protein P0C6X7_PRO_0000037317 UNIPROT MT-CO2 protein P00403 UNIPROT "down-regulates activity" binding 9606 BTO:0000764 16157265 t lperfetto "This result suggests that the nsp10 protein could affect the activities of NADH and cytochrome oxidase II via a direct interaction while being involved in viral replication." SIGNOR-260254 "Non-structural protein 10" protein P0C6X7_PRO_0000037317 UNIPROT MT-ND4L protein P03901 UNIPROT "down-regulates activity" binding 9606 BTO:0000764 16157265 t lperfetto "This result suggests that the nsp10 protein could affect the activities of NADH and cytochrome oxidase II via a direct interaction while being involved in viral replication." SIGNOR-260253 "Non-structural protein 10" protein P0C6X7_PRO_0000037317 UNIPROT IFTAP protein Q86VG3 UNIPROT unknown binding 4932 18433331 t lperfetto "In our previous work, we isolated a gene from a cDNA library of human embryo lung tissue, which en- coded a novel protein that specifically interacted with nsp-10 of SARS-CoV in a yeast trap experiment.|Since nsp- 10 of SARS-CoV is involved in viral genomic replica- tion and was observed to interact with ATF5, the cellular initiation factor of the RNA pol II complex (13), we in- ferred that HEPIS may also be involved in cellular gene transcription. Therefore, the significance of HEPIS ex- pression in cells needed to be further investigated. The work we describe here suggests that HEPIS represses cel- lular transcription initiation through interaction with a component of the RNA pol II complex" SIGNOR-260251 "Uridylate-specific endoribonuclease" protein P0C6X7_PRO_0000037321 UNIPROT EIF2AK2 protein P19525 UNIPROT "down-regulates activity" 9606 28158275 f miannu "Here we show that the coronavirus endonuclease (EndoU) activity is key to prevent early induction of double-stranded RNA (dsRNA) host cell responses. Replication of EndoU-deficient coronaviruses is greatly attenuated in vivo and severely restricted in primary cells even during the early phase of the infection. Collectively our results demonstrate that the coronavirus EndoU efficiently prevents simultaneous activation of host cell dsRNA sensors, such as Mda5, OAS and PKR. It is thus tempting to propose that viral dsRNA represents the natural substrate of the coronavirus EndoU. However, it remains to be determined which kind of viral dsRNA is cleaved by the EndoU or triggers Mda5, OAS, and PKR activation." SIGNOR-260348 "Uridylate-specific endoribonuclease" protein P0C6X7_PRO_0000037321 UNIPROT IFIH1 protein Q9BYX4 UNIPROT "down-regulates activity" 9606 28158275 f miannu "Here we show that the coronavirus endonuclease (EndoU) activity is key to prevent early induction of double-stranded RNA (dsRNA) host cell responses. Replication of EndoU-deficient coronaviruses is greatly attenuated in vivo and severely restricted in primary cells even during the early phase of the infection. Collectively our results demonstrate that the coronavirus EndoU efficiently prevents simultaneous activation of host cell dsRNA sensors, such as Mda5, OAS and PKR. It is thus tempting to propose that viral dsRNA represents the natural substrate of the coronavirus EndoU. However, it remains to be determined which kind of viral dsRNA is cleaved by the EndoU or triggers Mda5, OAS, and PKR activation." SIGNOR-260245 "Papain-like proteinase" protein P0C6X9_PRO_0000037340 UNIPROT IFNB1 protein P01574 UNIPROT "down-regulates quantity by repression" 9606 BTO:0000007 17761676 f lperfetto "SARS-CoV PLpro domain inhibits activation of IFN-β promoter following engagement of TLR3 or RIG-I pathways independent of its protease activity" SIGNOR-260277 LF2 protein P0C725 UNIPROT IRF7 protein Q92985 UNIPROT "down-regulates activity" binding 9606 BTO:0002181 18987133 t scontino "EBV LF2 tegument protein specifically interacts with the central inhibitory association domain of IRF7, and this interaction leads to inhibition of the dimerization of IRF7, which suppresses IFN-alpha production and IFN-mediated immunity." SIGNOR-266632 UBC protein P0CG48 UNIPROT PRKN protein O60260 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 26161729 t lperfetto "Mechanism of phospho-ubiquitin-induced PARKIN activation|PhosphoUb binding leads to straightening of a helix in the RING1 domain, and the resulting conformational changes release the Ubl domain from the PARKIN core; this activates PARKIN|Our results show that PINK1-dependent phosphorylation of both parkin and ubiquitin is sufficient for full activation of parkin E3 activity. These findings demonstrate that phosphorylated ubiquitin is a parkin activator." SIGNOR-249692 LIMS3 protein P0CW19 UNIPROT "IPP complex" complex SIGNOR-C380 SIGNOR "up-regulates activity" binding 16493410 t lperfetto "Integrin-linked kinase (ILK), PINCH and parvin form a ternary complex (the IPP complex) that binds to ECM-ligated integrins. This complex regulates signalling pathways and connects the ECM with the actin cytoskeleton." SIGNOR-265765 ADORA3 protein P0DMS8 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256671 HSPA1A protein P0DMV8 UNIPROT GSTA4 protein O15217 UNIPROT "up-regulates activity" relocalization phosphorylation:Thr193;Ser189 VKLSNIPtIKRFLEP;QEYTVKLsNIPTIKR 21929724 t lperfetto "Model showing Ser189/Thr193 protein kinase dependent phosphorylation of GST A4‐4 has increased affinity for chaperone Hsp70 which activates mitochondrial competent import signals for GSTA4‐4. |Protein kinase A mediated phosphorylation of serine residues of CYPs increases the affinity of proteins for binding to cytoplasmic chaperones such as heat shock proteins (Hsp), Hsp70/Hsp90, resulting in increased mitochondrial translocation" SIGNOR-264799 HSPA1A protein P0DMV8 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates binding 9606 21730050 t gcesareni "Interestingly, FKBP51 forms complexes in mitochondria with the glucocorticoid receptor and the Hsp90/Hsp70-based chaperone heterocomplex" SIGNOR-251668 HSPA1A protein P0DMV8 UNIPROT ENPP1 protein P22413 UNIPROT "up-regulates quantity" "post transcriptional regulation" 9606 19083193 t miannu "We demonstrated the binding of heat shock protein 70 (HSP70) to ENPP1-3'UTR. Through this binding, HSP70 stabilizes ENPP1 mRNA and increases ENPP1 transcript and protein levels. This positive modulation of ENPP1 expression is paralleled by a reduced insulin-induced IR and IRS-1 phosphorylation." SIGNOR-252197 HSPA1B protein P0DMV9 UNIPROT GSTA4 protein O15217 UNIPROT "up-regulates activity" relocalization phosphorylation:Thr193;Ser189 VKLSNIPtIKRFLEP;QEYTVKLsNIPTIKR 21929724 t lperfetto "Model showing Ser189/Thr193 protein kinase dependent phosphorylation of GST A4‐4 has increased affinity for chaperone Hsp70 which activates mitochondrial competent import signals for GSTA4‐4. |Protein kinase A mediated phosphorylation of serine residues of CYPs increases the affinity of proteins for binding to cytoplasmic chaperones such as heat shock proteins (Hsp), Hsp70/Hsp90, resulting in increased mitochondrial translocation" SIGNOR-264800 HSPA1B protein P0DMV9 UNIPROT ENPP1 protein P22413 UNIPROT "up-regulates quantity" "post transcriptional regulation" 9606 19083193 t miannu "We demonstrated the binding of heat shock protein 70 (HSP70) to ENPP1-3'UTR. Through this binding, HSP70 stabilizes ENPP1 mRNA and increases ENPP1 transcript and protein levels. This positive modulation of ENPP1 expression is paralleled by a reduced insulin-induced IR and IRS-1 phosphorylation." SIGNOR-252198 CALM1 protein P0DP23 UNIPROT EEF2K protein O00418 UNIPROT up-regulates binding 9606 11015200 t gcesareni "The calmodulin-binding region is located between amino acids 51 and 96" SIGNOR-82505 CALM1 protein P0DP23 UNIPROT PPP3CB protein P16298 UNIPROT up-regulates binding 9606 11796223 t gcesareni "Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain." SIGNOR-114101 CALM1 protein P0DP23 UNIPROT NOS3 protein P29474 UNIPROT "up-regulates activity" binding 9606 24379783 t lperfetto "Electrons flow from the C-terminal reductase domain of one NOS monomer to the N-terminal oxygenase domain of the other NOS monomer (Siddhanta et al., 1998). The primary mode of enzyme activation is the binding of calcium-bound calmodulin to the N-terminal CaM-binding domain. This facilitates a structure change and the flow of electrons from NADPH through the flavins to the oxygenase domain of the other eNOS monomer" SIGNOR-251615 CALM1 protein P0DP23 UNIPROT PPP3CC protein P48454 UNIPROT up-regulates binding 9606 11796223 t gcesareni "Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain." SIGNOR-114104 CALM1 protein P0DP23 UNIPROT GEM protein P55040 UNIPROT "up-regulates activity" binding 10116 14701738 t miannu "Inhibition of voltage-gated calcium channels by Gem requires GTP and calmodulin binding, but not phosphorylation of serine 261 or 289. Calmodulin binding in the C-terminal extension of Gem is required for maximal inhibition of HVA Ca2+ channels by ectopically expressed Gem, as determined by measurement of electrical activity in primary neurons and by Ca2+-evoked secretion in PC12 cells." SIGNOR-261716 CALM1 protein P0DP23 UNIPROT GEM protein P55040 UNIPROT "up-regulates activity" binding 10116 14701738 t miannu "Inhibition of voltage-gated calcium channels by Gem requires GTP and calmodulin binding, but not phosphorylation of serine 261 or 289. Calmodulin binding in the C-terminal extension of Gem is required for maximal inhibition of HVA Ca2+ channels by ectopically expressed Gem, as determined by measurement of electrical activity in primary neurons and by Ca2+-evoked secretion in PC12 cells." SIGNOR-261726 CALM1 protein P0DP23 UNIPROT PPP3CA protein Q08209 UNIPROT up-regulates binding 9606 11796223 t gcesareni "Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain." SIGNOR-114098 CALM1 protein P0DP23 UNIPROT KIF1A protein Q12756 UNIPROT "up-regulates activity" binding 10116 BTO:0003102 30021165 t miannu "To better understand how KIF1A-driven dense core vesicle (DCV) transport is regulated, we identified the KIF1A interactome and focused on three binding partners, the calcium binding protein calmodulin (CaM) and two synaptic scaffolding proteins: liprin-α and TANC2. We showed that calcium, acting via CaM, enhances KIF1A binding to DCVs and increases vesicle motility. We show that Ca2+/CaM-dependent modulation on KIF1A allows for binding to vesicular cargo. Our results indicate that at low calcium concentrations, the tail domain of KIF1A does not bind to vesicular cargo, whereas at high calcium concentrations, CaM binds KIF1A, allowing for subsequent DCV motility." SIGNOR-266888 CALM1 protein P0DP23 UNIPROT CAMKK1 protein Q8N5S9 UNIPROT up-regulates binding 9606 10770941 t lperfetto "The binding of Ca2+/CaM to CaM-KK is absolutely required for its activation and efficient phosphorylation of target protein kinases" SIGNOR-232178 CALM1 protein P0DP23 UNIPROT CAMKK2 protein Q96RR4 UNIPROT up-regulates binding 9606 9822657 t gcesareni "The ca2+-calmodulin-dependent protein kinase (cam kinase) cascade includes three kinases: cam-kinase kinase (camkk);and the cam kinases camki and camkiv, which are phosphorylated and activated by camkk." SIGNOR-61922 CALM1 protein P0DP23 UNIPROT SCN8A protein Q9UQD0 UNIPROT "down-regulates activity" binding 9606 11807557 t miannu "Here we show that calmodulin (CaM), a ubiquitous Ca2+-sensing protein, binds to the carboxy-terminal 'IQ' domain of the human cardiac Na channel (hH1) in a Ca2+-dependent manner. This binding interaction significantly enhances slow inactivation-a channel-gating process linked to life-threatening idiopathic ventricular arrhythmias." SIGNOR-253410 CALM1 protein P0DP23 UNIPROT Calcineurin complex SIGNOR-C155 SIGNOR up-regulates binding 9606 11796223 t gcesareni "Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain." SIGNOR-252337 CALM2 protein P0DP24 UNIPROT EEF2K protein O00418 UNIPROT up-regulates binding 9606 11015200 t miannu "The calmodulin-binding region is located between amino acids 51 and 96" SIGNOR-266321 CALM2 protein P0DP24 UNIPROT PPP3CB protein P16298 UNIPROT up-regulates binding 9606 11796223 t miannu "Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain." SIGNOR-266322 CALM2 protein P0DP24 UNIPROT NOS3 protein P29474 UNIPROT "up-regulates activity" binding 9606 BTO:0001853 24379783 t miannu "Electrons flow from the C-terminal reductase domain of one NOS monomer to the N-terminal oxygenase domain of the other NOS monomer (Siddhanta et al., 1998). The primary mode of enzyme activation is the binding of calcium-bound calmodulin to the N-terminal CaM-binding domain. This facilitates a structure change and the flow of electrons from NADPH through the flavins to the oxygenase domain of the other eNOS monomer" SIGNOR-266323 CALM2 protein P0DP24 UNIPROT PPP3CC protein P48454 UNIPROT up-regulates binding 9606 11796223 t miannu "Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain." SIGNOR-266324 CALM2 protein P0DP24 UNIPROT GEM protein P55040 UNIPROT "up-regulates activity" binding 10116 BTO:0001009 14701738 t miannu "Inhibition of voltage-gated calcium channels by Gem requires GTP and calmodulin binding, but not phosphorylation of serine 261 or 289. Calmodulin binding in the C-terminal extension of Gem is required for maximal inhibition of HVA Ca2+ channels by ectopically expressed Gem, as determined by measurement of electrical activity in primary neurons and by Ca2+-evoked secretion in PC12 cells." SIGNOR-266326 CALM2 protein P0DP24 UNIPROT GEM protein P55040 UNIPROT "up-regulates activity" binding 10116 BTO:0001009 14701738 t miannu "Inhibition of voltage-gated calcium channels by Gem requires GTP and calmodulin binding, but not phosphorylation of serine 261 or 289. Calmodulin binding in the C-terminal extension of Gem is required for maximal inhibition of HVA Ca2+ channels by ectopically expressed Gem, as determined by measurement of electrical activity in primary neurons and by Ca2+-evoked secretion in PC12 cells." SIGNOR-266325 CALM2 protein P0DP24 UNIPROT KIF1A protein Q12756 UNIPROT "up-regulates activity" binding 10116 BTO:0003102 30021165 t miannu "To better understand how KIF1A-driven dense core vesicle (DCV) transport is regulated, we identified the KIF1A interactome and focused on three binding partners, the calcium binding protein calmodulin (CaM) and two synaptic scaffolding proteins: liprin-α and TANC2. We showed that calcium, acting via CaM, enhances KIF1A binding to DCVs and increases vesicle motility. In contrast, liprin-α and TANC2 are not part of the KIF1A-cargo complex but capture DCVs at dendritic spines" SIGNOR-266889 CALM2 protein P0DP24 UNIPROT CAMKK1 protein Q8N5S9 UNIPROT up-regulates binding 9606 10770941 t miannu "The binding of Ca2+/CaM to CaM-KK is absolutely required for its activation and efficient phosphorylation of target protein kinases" SIGNOR-266328 CALM2 protein P0DP24 UNIPROT CAMKK2 protein Q96RR4 UNIPROT up-regulates binding 9606 BTO:0000782 BTO:0000142 9822657 t miannu "The ca2+-calmodulin-dependent protein kinase (cam kinase) cascade includes three kinases: cam-kinase kinase (camkk);and the cam kinases camki and camkiv, which are phosphorylated and activated by camkk." SIGNOR-266329 CALM2 protein P0DP24 UNIPROT SCN8A protein Q9UQD0 UNIPROT "down-regulates activity" binding 9606 BTO:0000938 11807557 t miannu "Here we show that calmodulin (CaM), a ubiquitous Ca2+-sensing protein, binds to the carboxy-terminal 'IQ' domain of the human cardiac Na channel (hH1) in a Ca2+-dependent manner. This binding interaction significantly enhances slow inactivation-a channel-gating process linked to life-threatening idiopathic ventricular arrhythmias." SIGNOR-266330 CALM2 protein P0DP24 UNIPROT Calcineurin complex SIGNOR-C155 SIGNOR up-regulates binding 9606 11796223 t miannu "Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain." SIGNOR-266331 CALM3 protein P0DP25 UNIPROT EEF2K protein O00418 UNIPROT up-regulates binding 9606 11015200 t miannu "The calmodulin-binding region is located between amino acids 51 and 96" SIGNOR-266337 CALM3 protein P0DP25 UNIPROT PPP3CB protein P16298 UNIPROT up-regulates binding 9606 11796223 t miannu "Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain." SIGNOR-266338 CALM3 protein P0DP25 UNIPROT NOS3 protein P29474 UNIPROT "up-regulates activity" binding 9606 BTO:0001853 24379783 t miannu "Electrons flow from the C-terminal reductase domain of one NOS monomer to the N-terminal oxygenase domain of the other NOS monomer (Siddhanta et al., 1998). The primary mode of enzyme activation is the binding of calcium-bound calmodulin to the N-terminal CaM-binding domain. This facilitates a structure change and the flow of electrons from NADPH through the flavins to the oxygenase domain of the other eNOS monomer" SIGNOR-266339 CALM3 protein P0DP25 UNIPROT PPP3CC protein P48454 UNIPROT up-regulates binding 9606 11796223 t miannu "Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain." SIGNOR-266340 CALM3 protein P0DP25 UNIPROT GEM protein P55040 UNIPROT "up-regulates activity" binding 10116 BTO:0001009 14701738 t miannu "Inhibition of voltage-gated calcium channels by Gem requires GTP and calmodulin binding, but not phosphorylation of serine 261 or 289. Calmodulin binding in the C-terminal extension of Gem is required for maximal inhibition of HVA Ca2+ channels by ectopically expressed Gem, as determined by measurement of electrical activity in primary neurons and by Ca2+-evoked secretion in PC12 cells." SIGNOR-266342 CALM3 protein P0DP25 UNIPROT GEM protein P55040 UNIPROT "up-regulates activity" binding 10116 BTO:0001009 14701738 t miannu "Inhibition of voltage-gated calcium channels by Gem requires GTP and calmodulin binding, but not phosphorylation of serine 261 or 289. Calmodulin binding in the C-terminal extension of Gem is required for maximal inhibition of HVA Ca2+ channels by ectopically expressed Gem, as determined by measurement of electrical activity in primary neurons and by Ca2+-evoked secretion in PC12 cells." SIGNOR-266341 CALM3 protein P0DP25 UNIPROT PPP3CA protein Q08209 UNIPROT up-regulates binding 9606 11796223 t miannu "Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain." SIGNOR-266343 CALM3 protein P0DP25 UNIPROT KIF1A protein Q12756 UNIPROT "up-regulates activity" binding 10116 BTO:0003102 30021165 t miannu "To better understand how KIF1A-driven dense core vesicle (DCV) transport is regulated, we identified the KIF1A interactome and focused on three binding partners, the calcium binding protein calmodulin (CaM) and two synaptic scaffolding proteins: liprin-α and TANC2. We showed that calcium, acting via CaM, enhances KIF1A binding to DCVs and increases vesicle motility. In contrast, liprin-α and TANC2 are not part of the KIF1A-cargo complex but capture DCVs at dendritic spines. we can conclude that TANC2 and liprin-α are enriched in dendritic spines and interact with various synaptic proteins. TANC2 and Liprin-α2 Act as Immobile Postsynaptic Posts Able to Recruit KIF1A in a Subset of Dendritic Spines" SIGNOR-266890 CALM3 protein P0DP25 UNIPROT CAMKK1 protein Q8N5S9 UNIPROT up-regulates binding 9606 10770941 t miannu "The binding of Ca2+/CaM to CaM-KK is absolutely required for its activation and efficient phosphorylation of target protein kinases" SIGNOR-266344 POLR1D protein P0DPB5 UNIPROT "RNA Polymerase I" complex SIGNOR-C390 SIGNOR "form complex" binding 22260999 t lperfetto "In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1). " SIGNOR-266158 M protein P0DTC5 UNIPROT MAVS protein Q7Z434 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 33110251 t miannu "Here, we identified SARS-CoV-2 membrane glycoprotein M as a negative regulator of the innate immune response. We found that the M protein interacted with the central adaptor protein MAVS in the innate immune response pathways. This interaction impaired MAVS aggregation and its recruitment of downstream TRAF3, TBK1, and IRF3, leading to attenuation of the innate antiviral response. Our findings reveal a mechanism by which SARS-CoV-2 evades the innate immune response and suggest that the M protein of SARS-CoV-2 is a potential target for the development of SARS-CoV-2 interventions." SIGNOR-262515 "Host translation inhibitor nsp1" protein P0DTD1_PRO_0000449619 UNIPROT RPS2 protein P15880 UNIPROT "down-regulates activity" binding -1 33188728 t miannu "Nsp1 Locks the 40S in a Conformation Incompatible with mRNA Loading and Disrupts Initiation Factor Binding. Molecular interactions between C-Nsp1 and 40S ribosome components, including uS3, h18, and uS5." SIGNOR-262508 THRA protein P10827 UNIPROT RARA protein P10276 UNIPROT up-regulates binding 9606 15650024 t gcesareni "We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs." SIGNOR-133240 Helicase protein P0DTD1_PRO_0000449630 UNIPROT TBK1 protein Q9UHD2 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 32979938 t miannu "We use unbiased screening to identify SARS-CoV-2 proteins that antagonize type I interferon (IFN-I) response. We found three proteins that antagonize IFN-I production via distinct mechanisms: nonstructural protein 6 (nsp6) binds TANK binding kinase 1 (TBK1) to suppress interferon regulatory factor 3 (IRF3) phosphorylation, nsp13 binds and blocks TBK1 phosphorylation, and open reading frame 6 (ORF6) binds importin Karyopherin α 2 (KPNA2) to inhibit IRF3 nuclear translocation. the results indicate that (1) nsp6 binds to TBK1 without affecting TBK1 phosphorylation, but the nsp6/TBK1 interaction decreases IRF3 phosphorylation, which leads to reduced IFN-β production; and (2) nsp13 binds and inhibits TBK1 phosphorylation, resulting in decreased IRF3 activation and IFN-β production (Figure 2F)." SIGNOR-262511 Helicase protein P0DTD1_PRO_0000449630 UNIPROT TBK1 protein Q9UHD2 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 32979938 t miannu "We use unbiased screening to identify SARS-CoV-2 proteins that antagonize type I interferon (IFN-I) response. We found three proteins that antagonize IFN-I production via distinct mechanisms: nonstructural protein 6 (nsp6) binds TANK binding kinase 1 (TBK1) to suppress interferon regulatory factor 3 (IRF3) phosphorylation, nsp13 binds and blocks TBK1 phosphorylation, and open reading frame 6 (ORF6) binds importin Karyopherin α 2 (KPNA2) to inhibit IRF3 nuclear translocation. the results indicate that (1) nsp6 binds to TBK1 without affecting TBK1 phosphorylation, but the nsp6/TBK1 interaction decreases IRF3 phosphorylation, which leads to reduced IFN-β production; and (2) nsp13 binds and inhibits TBK1 phosphorylation, resulting in decreased IRF3 activation and IFN-β production (Figure 2F)." SIGNOR-262512 GLI2 protein P10070 UNIPROT GLI1 protein P08151 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0002572 16571352 f lperfetto "Primary mouse embryonic fibroblasts responded to Shh stimulation with the induction of Hh target genes Gli1, Ptc1, and Hip1.These observations support the previously advanced notion of a functional redundancy or cooperativity between Gli2 and Gli1 in activation of target genes [18] and [43] and indicate a functional cooperation between Gli3 and Gli1." SIGNOR-209629 GLI2 protein P10070 UNIPROT BMP2 protein P12643 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16880529 f gcesareni "The zinc finger transcription factor gli2 mediates bone morphogenetic protein 2 expression in osteoblasts in response to hedgehog signaling" SIGNOR-148346 GLI2 protein P10070 UNIPROT PPARG protein P37231 UNIPROT down-regulates BTO:0004300 29205155 f areggio "Molecularly, Gli2 is the principle transcription factor in the Gli family to mediate the anti-adipogenic and anti-lipogenic effects of Hh signaling" SIGNOR-256224 GLI2 protein P10070 UNIPROT FOXF1 protein Q12946 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0005738 23034409 f miannu "we propose that chromatin looping between SDR and FOXF1 allows GLI2 to increase FOXF1 activity specifically in lung endothelium." SIGNOR-254216 GLI2 protein P10070 UNIPROT PTCH1 protein Q13635 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0002572 16571352 f lperfetto "Primary mouse embryonic fibroblasts responded to Shh stimulation with the induction of Hh target genes Gli1, Ptc1, and Hip1.These observations support the previously advanced notion of a functional redundancy or cooperativity between Gli2 and Gli1 in activation of target genes [18] and [43] and indicate a functional cooperation between Gli3 and Gli1." SIGNOR-209632 GLI2 protein P10070 UNIPROT HHIP protein Q96QV1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0002572 16571352 f lperfetto "Primary mouse embryonic fibroblasts responded to Shh stimulation with the induction of Hh target genes Gli1, Ptc1, and Hip1.These observations support the previously advanced notion of a functional redundancy or cooperativity between Gli2 and Gli1 in activation of target genes [18] and [43] and indicate a functional cooperation between Gli3 and Gli1." SIGNOR-209635 GLI3 protein P10071 UNIPROT MYCN protein P04198 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 17419683 f gcesareni "Gli activators bind to gaccaccca motif to regulate transcription of gli1, ptch1, ptch2, hhip1, mycn, ccnd1, ccnd2, bcl2, cflar, foxf1, foxl1, prdm1 (blimp1), jag2, grem1, and follistatin. .Hedgehog Signals induce cellular proliferation through upregulation of n-myc, cyclin d/e, and foxm1." SIGNOR-154237 GLI3 protein P10071 UNIPROT MYCN protein P04198 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000150;BTO:0000551 19860666 f gcesareni "Gli activators bind to gaccaccca motif to regulate transcription of gli1, ptch1, ptch2, hhip1, mycn, ccnd1, ccnd2, bcl2, cflar, foxf1, foxl1, prdm1 (blimp1), jag2, grem1, and follistatin. .Hedgehog Signals induce cellular proliferation through upregulation of n-myc, cyclin d/e, and foxm1." SIGNOR-188881 GLI3 protein P10071 UNIPROT GLI1 protein P08151 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0002572 16571352 f lperfetto "The basal expression of Gli1, Ptc1, and Hip1 was positively associated with the loss of Gli3 alleles.These findings implicate Gli3 as a repressor of Hh target gene expression." SIGNOR-209638 GLI3 protein P10071 UNIPROT CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17419683 f gcesareni "Gli activators bind to gaccaccca motif to regulate transcription of gli1, ptch1, ptch2, hhip1, mycn, ccnd1, ccnd2, bcl2, cflar, foxf1, foxl1, prdm1 (blimp1), jag2, grem1, and follistatin." SIGNOR-154234 GLI3 protein P10071 UNIPROT CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150;BTO:0000551 19860666 f gcesareni "Gli activators bind to gaccaccca motif to regulate transcription of gli1, ptch1, ptch2, hhip1, mycn, ccnd1, ccnd2, bcl2, cflar, foxf1, foxl1, prdm1 (blimp1), jag2, grem1, and follistatin." SIGNOR-188878 GLI3 protein P10071 UNIPROT PTCH1 protein Q13635 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0002572 16571352 f lperfetto "Primary mouse embryonic fibroblasts responded to Shh stimulation with the induction of Hh target genes Gli1, Ptc1, and Hip1.These observations support the previously advanced notion of a functional redundancy or cooperativity between Gli2 and Gli1 in activation of target genes [18] and [43] and indicate a functional cooperation between Gli3 and Gli1." SIGNOR-209641 GLI3 protein P10071 UNIPROT PTCH1 protein Q13635 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17419683 f lperfetto "Binding of n-shh to ptch1 inhibits repression of smo, leading to activationof some genes and de-repression of others through the effects of smo on the gli family of transcription factors." SIGNOR-154240 GLI3 protein P10071 UNIPROT PTCH1 protein Q13635 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19860666 t gcesareni "GLI activators bind to GACCACCCA motif to regulate transcription of GLI1, PTCH1, PTCH2, HHIP1, MYCN, CCND1, CCND2, BCL2, CFLAR, FOXF1, FOXL1, PRDM1 (BLIMP1), JAG2, GREM1, and Follistatin" SIGNOR-188884 AR protein P10275 UNIPROT UBE2C protein O00762 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19632176 t miannu "The evolution of prostate cancer from an androgen-dependent state (ADPCa) to one that is androgen-independent (AIPCa) marks its lethal progression. The androgen receptor (AR) is essential in both, though its function in AIPCa is poorly understood. We have defined the direct AR-dependent target genes in both AIPCa and ADPCa by generating AR-dependent gene expression profiles and AR cistromes. In contrast to ADPCa, AR selectively up-regulates M-phase cell cycle genes in AIPCa including UBE2C, a gene that inactivates the M-phase checkpoint." SIGNOR-251543 AR protein P10275 UNIPROT TMPRSS2 protein O15393 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001321 20308527 t lperfetto "We demonstrate that CHD8 directly associates with AR and that CHD8 and AR simultaneously localize to the TMPRSS2 enhancer after androgen treatment. In the LNCaP cell line, reduction of CHD8 levels by small interfering RNA treatment severely diminishes androgen-dependent activation of the TMPRSS2 gene. We demonstrate that the recruitment of AR to the TMPRSS2 promoter in response to androgen treatment requires CHD8" SIGNOR-253686 AR protein P10275 UNIPROT TMPRSS2 protein O15393 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0005556 21761340 t lperfetto "The prostate-specific TMPRSS2 gene, while upregulated by AR activity in luminal cells, is also transcribed in basal populations, confirming that AR acts as an expression modulator." SIGNOR-253687 AR protein P10275 UNIPROT TMPRSS2 protein O15393 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24505269 t miannu "Recurrent gene fusion between the androgen-regulated gene TMPRSS2 and members of the ETS transcription factor family, most commonly ERG, are present in about 50% of prostate cancer cases. Presence of this fusion gene is a critical event in the development of prostate cancer. the more aggressive phenotype that arises with the presence of TMPRSS2-ERG at least in part is caused by changes in the tumor stroma." SIGNOR-251545 AR protein P10275 UNIPROT CYP7B1 protein O75881 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000007 16630558 f miannu "DHT and overexpression of androgen receptor (AR) suppressed CYP7B1 promoter activity and CYP7B1-mediated catalysis in kidney-derived HEK293 cells." SIGNOR-253739 AR protein P10275 UNIPROT NRAS protein P01111 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001321 16281084 f "After AR antagonist flutamide treatment, three hundred and twenty-six genes (3.93%) expressed differentially, 97 down-regulated and 219 up-regulated. Among them, eight up-regulated genes might be cell cycle-related, namely CDC10, NRAS, BTG1, Wee1, CLK3, DKFZP564A122, CDKN1A and BTG2. The CDKN1A and BTG1 gene mRNA expression was confirmed to be higher in the experimental group by RT-PCR, while p53 mRNA expression had no significant changes." SIGNOR-253676 AR protein P10275 UNIPROT NR3C1 protein P04150 UNIPROT "down-regulates quantity by repression" binding 9606 9162033 t lperfetto "Androgen and glucocorticoid receptor heterodimer formation. A possible mechanism for mutual inhibition of transcriptional activity" SIGNOR-48513 AR protein P10275 UNIPROT ARG1 protein P05089 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001321 20711410 f miannu "The regulation of arginase expression following androgen stimulation was dependent on the androgen receptor (AR), as a siRNA treatment targeting the AR inhibited both ARG1 and ARG2 overexpression." SIGNOR-253738 AR protein P10275 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000938 11916967 f lperfetto "Transcription assays demonstrated that liganded ar repressed beta-catenin/t cell factor-responsive reporter gene activity" SIGNOR-116260 AR protein P10275 UNIPROT CDKN1A protein P38936 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001321 16281084 f "After AR antagonist flutamide treatment, three hundred and twenty-six genes (3.93%) expressed differentially, 97 down-regulated and 219 up-regulated. Among them, eight up-regulated genes might be cell cycle-related, namely CDC10, NRAS, BTG1, Wee1, CLK3, DKFZP564A122, CDKN1A and BTG2. The CDKN1A and BTG1 gene mRNA expression was confirmed to be higher in the experimental group by RT-PCR, while p53 mRNA expression had no significant changes." SIGNOR-253675 AR protein P10275 UNIPROT AKR1C3 protein P42330 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001321 22971343 f miannu "Both AR antagonism and androgen deprivation can upregulate AKR1C3." SIGNOR-253737 AR protein P10275 UNIPROT CLK3 protein P49761 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001321 16281084 f "After AR antagonist flutamide treatment, three hundred and twenty-six genes (3.93%) expressed differentially, 97 down-regulated and 219 up-regulated. Among them, eight up-regulated genes might be cell cycle-related, namely CDC10, NRAS, BTG1, Wee1, CLK3, DKFZP564A122, CDKN1A and BTG2. The CDKN1A and BTG1 gene mRNA expression was confirmed to be higher in the experimental group by RT-PCR, while p53 mRNA expression had no significant changes." SIGNOR-253672 AR protein P10275 UNIPROT UCN protein P55089 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001509 23801677 t lperfetto "When cells were treated with DHT alone, AR was upregulated and translocated into the nuclei, which might repress UCN1 expression via a potential androgen-responsive element found in human CRF family promoter|These data suggest that DHT differentially influences UCN1 levels under normal and inflammatory conditions in human umbilical vein endothelial cells, which involves AR-dependent and -independent mechanisms respectively." SIGNOR-253688 AR protein P10275 UNIPROT BTG2 protein P78543 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001321 16281084 f "After AR antagonist flutamide treatment, three hundred and twenty-six genes (3.93%) expressed differentially, 97 down-regulated and 219 up-regulated. Among them, eight up-regulated genes might be cell cycle-related, namely CDC10, NRAS, BTG1, Wee1, CLK3, DKFZP564A122, CDKN1A and BTG2. The CDKN1A and BTG1 gene mRNA expression was confirmed to be higher in the experimental group by RT-PCR, while p53 mRNA expression had no significant changes." SIGNOR-253674 AR protein P10275 UNIPROT NR5A1 protein Q13285 UNIPROT up-regulates binding 9606 11518799 t gcesareni "Ar suppresses transcription of the lhbeta subunit by interacting with steroidogenic factor-1." SIGNOR-109996 AR protein P10275 UNIPROT SEPTIN7 protein Q16181 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001321 16281084 f "After AR antagonist flutamide treatment, three hundred and twenty-six genes (3.93%) expressed differentially, 97 down-regulated and 219 up-regulated. Among them, eight up-regulated genes might be cell cycle-related, namely CDC10, NRAS, BTG1, Wee1, CLK3, DKFZP564A122, CDKN1A and BTG2. The CDKN1A and BTG1 gene mRNA expression was confirmed to be higher in the experimental group by RT-PCR, while p53 mRNA expression had no significant changes." SIGNOR-253677 AR protein P10275 UNIPROT NKX3-1 protein Q99801 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16697957 t miannu "Whereas androgen receptor (AR) positively regulates NKX3.1 expression, NKX3.1 negatively modulates AR transcription and consequently the AR-associated signaling events." SIGNOR-251546 RARA protein P10276 UNIPROT THRA protein P10827 UNIPROT up-regulates binding 9606 15650024 t gcesareni "We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs." SIGNOR-133231 RARA protein P10276 UNIPROT RXRG protein P48443 UNIPROT up-regulates binding 9606 1310351 t gcesareni "Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins" SIGNOR-16466 RARA protein P10276 UNIPROT RXRG protein P48443 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 1310351 f gcesareni "Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins" SIGNOR-16469 RARA protein P10276 UNIPROT CCNA1 protein P78396 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002136 11090075 t miannu "RARα is involved in the regulation of cyclin A1. Further studies using ligands selective for various retinoic acid receptors suggested that cyclin A1 expression is negatively regulated by activated RARα." SIGNOR-249636 ARAF protein P10398 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates phosphorylation Ser218 VSGQLIDsMANSFVG 9606 BTO:0000567 8621729 t lperfetto "Our data demonstrated that a-raf is, indeed, a mek1 activator and may play a role in growth factor signaling|The immunoprecipitates were assayed for GST-MEK1 activation. D, activation of MEK1 by A-Raf requires the presence of serine residue 218 and 222." SIGNOR-236451 ARAF protein P10398 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates phosphorylation Ser222 LIDSMANsFVGTRSY 9606 BTO:0000567 8621729 t lperfetto "Our data demonstrated that a-raf is, indeed, a mek1 activator and may play a role in growth factor signaling|The immunoprecipitates were assayed for GST-MEK1 activation. D, activation of MEK1 by A-Raf requires the presence of serine residue 218 and 222." SIGNOR-235944 ARAF protein P10398 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 21779497 t lperfetto "Active raf phosphorylates mek." SIGNOR-244809 ARAF protein P10398 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 BTO:0000567 8621729 t lperfetto "Our data demonstrated that a-raf is, indeed, a mek1 activator and may play a role in growth factor signaling." SIGNOR-244813 BCL2 protein P10415 UNIPROT CYCS protein P99999 UNIPROT "down-regulates activity" 9606 BTO:0000567 12624108 f lperfetto "Bcl-2 blocked the release of mitochondrial cytochrome c" SIGNOR-99063 BCL2 protein P10415 UNIPROT BAX protein Q07812 UNIPROT "down-regulates activity" binding 9606 BTO:0000776;BTO:0000785 8183370 t lperfetto "Bcl-2 has the unique oncogenic role of extending cell survival by inhibiting a variety of apoptotic deaths. Bcl-2 exerts its action through heterodimerization with bax." SIGNOR-36898 DLAT protein P10515 UNIPROT PDH complex SIGNOR-C402 SIGNOR "form complex" binding 9606 20160912 t miannu "The human (h) pyruvate dehydrogenase complex (hPDC) consists of multiple copies of several components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2), dihydrolipoamide dehydrogenase (E3), E3-binding protein (BP), and specific kinases and phosphatases. Mammalian PDC has a well organized structure with an icosahedral symmetry of the central E2/BP core to which the other component proteins bind non-covalently." SIGNOR-266546 PTPRF protein P10586 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 10734133 t gcesareni "Lar ptpase shows strong preference for dephosphorylation first at py5 (at tri-, di-, and monophosphotyrosyl levels). Initially this regioselectivity gives the y5(py9)(py10) diphospho regioisomer, followed by equal dephosphorylation at py9 or py10 to give the corresponding monophosphoryl species on the way to fully dephosphorylated product." SIGNOR-76013 PTPRF protein P10586 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 10734133 t lperfetto "Many cellular receptors signal via tyrosine phosphorylation. The tyrosine kinases required for this activity are often recruited upon ligand bindingAlternatively, receptors themselves have kinase activity, like insulin receptors. In either case, the receptors are returned to their original state through the activity of protein-tyrosine phosphatases (PTPs)The major candidate PTPs previously implicated in IRK dephosphorylation are PTP-1b and LAR." SIGNOR-76017 PTPRF protein P10586 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 1303753 t gcesareni "Lar ptpase shows strong preference for dephosphorylation first at py5 (at tri-, di-, and monophosphotyrosyl levels). Initially this regioselectivity gives the y5(py9)(py10) diphospho regioisomer, followed by equal dephosphorylation at py9 or py10 to give the corresponding monophosphoryl species on the way to fully dephosphorylated product." SIGNOR-16235 PTPRF protein P10586 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 1303753 t gcesareni "Lar ptpase shows strong preference for dephosphorylation first at py5 (at tri-, di-, and monophosphotyrosyl levels). Initially this regioselectivity gives the y5(py9)(py10) diphospho regioisomer, followed by equal dephosphorylation at py9 or py10 to give the corresponding monophosphoryl species on the way to fully dephosphorylated product." SIGNOR-16239 PTPRF protein P10586 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 1303753 t gcesareni "Lar ptpase shows strong preference for dephosphorylation first at py5 (at tri-, di-, and monophosphotyrosyl levels). Initially this regioselectivity gives the y5(py9)(py10) diphospho regioisomer, followed by equal dephosphorylation at py9 or py10 to give the corresponding monophosphoryl species on the way to fully dephosphorylated product." SIGNOR-16243 NR2F1 protein P10589 UNIPROT RXRA protein P19793 UNIPROT up-regulates binding 9606 10900149 t lperfetto "Arp-1/rxr, coup-tfi/rxr, and arp-1/coup-tfi heterodimers bound the fp330-3' site" SIGNOR-79440 CYP2D6 protein P10635 UNIPROT dopamine smallmolecule CHEBI:18243 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 BTO:0000143 NBK536726 t brain lperfetto "Under specific conditions, dopamine can also be synthesized by a minor pathway, in which L-tyrosine is converted into p-tyramine (mediated by AADC), with subsequent hydroxylation to dopamine by the enzyme CYP2D6 (Cytochrome P450 2D6) which is found in the substantia nigra of human brain " SIGNOR-263996 C7 protein P10643 UNIPROT "Membrane attack complex" complex SIGNOR-C313 SIGNOR "form complex" binding -1 30552328 t lperfetto "The human MAC pore was formed on liposomes from individual complement proteins. |The maps were further subdivided into three components: an asymmetric region (C5b, C6, C7, and C8), a hinge region (C7, C8, and two C9 molecules), and a C9 oligomer" SIGNOR-263443 PRKAR1A protein P10644 UNIPROT PRKACA protein P17612 UNIPROT "down-regulates activity" binding 9606 26687711 t "Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets" SIGNOR-258751 PRKAR1A protein P10644 UNIPROT PRKACB protein P22694 UNIPROT "down-regulates activity" binding 9606 26687711 t "Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets" SIGNOR-258755 TFPI protein P10646 UNIPROT VLDLR protein P98155 UNIPROT up-regulates binding 9606 11278667 t gcesareni "Binding studies revealed that full-length tfpi, but not the truncated tfpi molecule, is recognized by the very low density lipoprotein receptor (vldl receptor) indicating that this receptor is a novel high affinity endothelial cell receptor for tfpi" SIGNOR-106353 KIT protein P10721 UNIPROT JAK2 protein O60674 UNIPROT "up-regulates activity" binding 9606 BTO:0000830 15526160 t mainnu "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 KIT protein P10721 UNIPROT KIT protein P10721 UNIPROT up-regulates phosphorylation Tyr936 SESTNHIySNLANCS 9606 10377264 t miannu "Identification of tyr-703 and tyr-936 as autophosphorylation sites in c-kit/scfr" SIGNOR-68647 KIT protein P10721 UNIPROT KIT protein P10721 UNIPROT "up-regulates activity" phosphorylation Tyr568 EEINGNNyVYIDPTQ 9606 BTO:0001271 12824176 t lperfetto "Upon binding its ligand, stem cell factor (scf), c-kit forms an active dimer that autophosphorylates itself and activates a signaling cascade that induces cell growth./ Tyr-568 and tyr-570 are significantly phosphorylated" SIGNOR-102633 KIT protein P10721 UNIPROT GRB2 protein P62993 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 phosphorylation:Tyr703 DHAEAALyKNLLHSK 10377264 t gcesareni "We furthermore demonstrate that the adapter protein Grb2 is a specific binding partner for both phosphorylated Tyr-703 and phosphorylated Tyr-936, whereas the adapter protein Grb7 binds selectively to phosphorylated Tyr-936." SIGNOR-248283 KIT protein P10721 UNIPROT PTPN11 protein Q06124 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0002882 22806893 t irozzo "SHP2 can be phosphorylated at 2 C-terminal tyrosyl residues by receptor tyrosine kinases, including KIT as well as cytosolic tyrosine kinases, including Src and Abl. The level of tyrosyl phosphorylation of SHP2 has been associated with its recruitment to the receptor.Thus, pharmacologic inhibition of SHP2 phosphatase function might permit SHP2 to return to its inactive conformation resulting in reduced tyrosine phosphorylation." SIGNOR-256140 KIT protein P10721 UNIPROT SLA protein Q13239 UNIPROT "down-regulates activity" phosphorylation Tyr120 SETKKGFySLSVRHR 9534 BTO:0001538 24284075 t miannu "Oncogenic c-Kit-D816V phosphorylates SLAP on residues Y120, Y258 and Y273. Mutation of the SLAP tyrosine phosphorylation sites rescues its activity" SIGNOR-263140 KIT protein P10721 UNIPROT SLA protein Q13239 UNIPROT "down-regulates activity" phosphorylation Tyr273 SFFSSPPyFED 9534 BTO:0001538 24284075 t miannu "Oncogenic c-Kit-D816V phosphorylates SLAP on residues Y120, Y258 and Y273. Mutation of the SLAP tyrosine phosphorylation sites rescues its activity" SIGNOR-263142 KIT protein P10721 UNIPROT GRB7 protein Q14451 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 phosphorylation:Tyr936 SESTNHIySNLANCS 10377264 t gcesareni "We furthermore demonstrate that the adapter protein Grb2 is a specific binding partner for both phosphorylated Tyr-703 and phosphorylated Tyr-936, whereas the adapter protein Grb7 binds selectively to phosphorylated Tyr-936." SIGNOR-248291 KIT protein P10721 UNIPROT STAP1 protein Q9ULZ2 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007 10679268 t miannu "STAP-1 was tyrosine-phosphorylated by activated c-kit. An in vitro binding assay suggested that the STAP-1 SH2 domain interacted with several tyrosine-phosphorylated proteins including c-kit and STAT5. These suggest that STAP-1 functions as an adaptor molecule downstream of c-kit in hematopoietic stem cells." SIGNOR-261820 KIT protein P10721 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" binding 10090 BTO:0000141 18179858 t irozzo "KIT mutations within the carboxy-terminal region of the cytoplasmic tyrosine kinase domain (TK2), such as KITD816V, stabilize the KIT activation loop conformation in its active form.Previous studies have demonstrated hyperactivation of p85α regulatory subunit of class IA phosphatidylinositol-3-kinase (PI3K) in cell lines expressing the activation loop mutant of KIT. Although p85α is hyperphosphorylated and constitutively bound to KITD814V in cell-line models." SIGNOR-256121 KIT protein P10721 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000830 15526160 t 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 KIT protein P10721 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" 9534 BTO:0001538 7509796 t "Tyrosine residue 719 of the c-kit receptor is essential for binding of the P85 subunit of phosphatidylinositol (PI) 3-kinase and for c-kit-associated PI 3-kinase activity in COS-1 cells" SIGNOR-255949 KIT protein P10721 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "up-regulates activity" 9606 BTO:0000830 15526160 f 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 CD28 protein P10747 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 BTO:0000782 18006698 t gcesareni "Cd28 can bind directly to pi3k by a well-characterized ymnm binding motif in its cytoplasmic domain." SIGNOR-159322 RARB protein P10826 UNIPROT RXRA protein P19793 UNIPROT up-regulates binding 9606 1310351 t gcesareni "Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins." SIGNOR-16519 MCF2 protein P10911 UNIPROT CDC42 protein P60953 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260558 MCF2 protein P10911 UNIPROT RHOA protein P61586 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260556 MCF2 protein P10911 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260557 GHR protein P10912 UNIPROT MAP2K5 protein Q13163 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0005787 BTO:0001103 23612709 t 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 LAMC1 protein P11047 UNIPROT Laminin-9 complex SIGNOR-C180 SIGNOR "form complex" binding 10809728 t lperfetto "Laminins are a large family of heterotrimeric extracellular matrix glycoproteins that, in addition to having structural roles, take part in the regulation of processes such as cell migration, differentiation, and proliferation. The laminin alpha(4) chain is widely distributed both in adults and during development in tissues such as cardiac, skeletal and smooth muscle fibers, vascular endothelia, lungs, and in peripheral nerves. It can associate with laminin beta(1)/gamma(1) chains to form laminin-8 and with the beta(2)/gamma(1) chains to form laminin-9." SIGNOR-253225 LAMC1 protein P11047 UNIPROT Laminin-8 complex SIGNOR-C181 SIGNOR "form complex" binding 10809728 t lperfetto "Laminins are a large family of heterotrimeric extracellular matrix glycoproteins that, in addition to having structural roles, take part in the regulation of processes such as cell migration, differentiation, and proliferation. The laminin alpha(4) chain is widely distributed both in adults and during development in tissues such as cardiac, skeletal and smooth muscle fibers, vascular endothelia, lungs, and in peripheral nerves. It can associate with laminin beta(1)/gamma(1) chains to form laminin-8 and with the beta(2)/gamma(1) chains to form laminin-9." SIGNOR-253228 LAMC1 protein P11047 UNIPROT Laminin-10 complex SIGNOR-C182 SIGNOR "form complex" binding 11821406 t lperfetto "The laminin (LN) family of large heterotrimeric extracellular matrix glycoproteins has multiple functions: LNs take part in the regulation of processes such as cell migration, differentiation, and proliferation, in addition to contributing to the structure of basement membranes. LN-10, composed of alpha5, beta1, and gamma1 chains, is widely distributed in most basement membranes of both epithelia and endothelia." SIGNOR-253231 LAMC1 protein P11047 UNIPROT Laminin-1 complex SIGNOR-C183 SIGNOR "form complex" binding 7496033 t lperfetto "Laminin-1 is an extracellular matrix protein composed of three polypeptide chains that are designated alpha 1, beta 1, and gamma 1." SIGNOR-253234 PNMT protein P11086 UNIPROT adrenaline smallmolecule CHEBI:33568 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 BTO:0000047 7961964 t brain lperfetto "In the adrenal medulla NA (noradrenaline) is N-methylated by the enzyme phenylethanolamine N-methyl transferase (PNMT, EC 2.1.1.28) to form A (adrenaline)." SIGNOR-264007 PNMT protein P11086 UNIPROT noradrenaline smallmolecule CHEBI:33569 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 BTO:0000047 7961964 t brain lperfetto "In the adrenal medulla NA (noradrenaline) is N-methylated by the enzyme phenylethanolamine N-methyl transferase (PNMT, EC 2.1.1.28) to form A (adrenaline)." SIGNOR-264008 EGR2 protein P11161 UNIPROT CEBPB protein P17676 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16054051 t fspada "Ectopic expression of krox20 can transactivate the c/ebpbeta promoter and increase c/ebpbeta gene expression in 3t3-l1 preadipocytes" SIGNOR-139292 EGR2 protein P11161 UNIPROT NAB2 protein Q15742 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000848 20506119 f miannu "In melanoma and carcinoma cells EGR1 activates NAB2 expression. we investigated the influence of EGR2 and EGR3 on NAB2 expression in melanoma and carcinoma cells. Here, we show that like EGR1, EGR2 and EGR3 induced NAB2 expression in these cells. EGR1 and EGR3 act in concert on the NAB2 promoter and are more potent activators of NAB2 transcription than EGR2." SIGNOR-253883 EGR2 protein P11161 UNIPROT GFI1 protein Q99684 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 16923394 f miannu "Impairing Egr-2 or Nab-2 induction resulted in sustained expression of Gfi-1, demonstrating that Egr-2 and Nab-2 negatively regulate Gfi-1 expression . Importantly, the Gfi-1 promoter was repressed via the Egr site by coexpression of Egr-2 and Nab-2. Thus, Egr-2 and Nab-2 directly repress the Gfi-1 gene." SIGNOR-256041 SLC2A1 protein P11166 UNIPROT "Ankyrin complex" complex SIGNOR-C383 SIGNOR "form complex" binding 9606 BTO:0000424 22465511 t lperfetto "The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB)) " SIGNOR-266017 SLC2A1 protein P11166 UNIPROT "4.1 complex" complex SIGNOR-C386 SIGNOR "form complex" binding 9606 BTO:0000424 33187473 t lperfetto "The cytoskeleton plays a key role in maintaining the morphology and function of erythrocyte membranes. Many proteins, such as ankyrin, spectrin alpha- and beta-chains, proteins 4.1, or 4.1R and actin, cover the inner surface of the erythrocyte membrane to form two protein complexes, the ankyrin and protein 4.1 complex| the latter consists of Band 3 dimers binding Adducins alpha and beta, Glycophorin C, GLUT1 and Stomatin [15, 16]" SIGNOR-266038 EPB41 protein P11171 UNIPROT DLG1 protein Q12959 UNIPROT "up-regulates activity" relocalization 9615 BTO:0000837 12807908 t lperfetto "Together, our results demonstrate that in addition to the N-terminal targeting domain, the alternatively spliced I3 insertion plays a critical role in recruiting hDlg to the lateral membrane in epithelial cells via its interaction with protein 4.1R." SIGNOR-266011 MBL2 protein P11226 UNIPROT MASP1 protein P48740 UNIPROT "up-regulates activity" binding 9606 BTO:0000392 9087411 t lperfetto "The results (Fig. 3A) show that the anti-MBL antibody, in addition to binding MBL captures both MASP-1 and MASP-2|Our results emphasize the similarity between complement activation through the MBL, or 'MBLectin' pathway of the innate immune system and the classical pathway of complement activation (Fig. 5)." SIGNOR-263414 MBL2 protein P11226 UNIPROT S protein P59594 UNIPROT "down-regulates activity" binding 9606 BTO:0001370 20573835 t miannu "We have demonstrated that MBL selectively binds to SARS-S pseudotyped virus and can inhibit SARS-CoV infection in susceptible cell lines. Our results identified a single N-linked glycosylation site, N330, on S glycoprotein as the target for the specific interactions between MBL and SARS-CoV and provide evidence that the viral interaction with MBL did not affect its interaction with the ACE2 receptor. Binding to MBL did not affect SARS-S interactions with the ACE2 receptor. Furthermore, MBL-mediated inhibition occurred at a step prior to CTSL-mediated activation of SARS-S fusion. Thus, we suggest that the binding of the MBL may interfere with the induction of conformational changes within the S glycoprotein and thus prevent an early, postreceptor-binding event." SIGNOR-260285 CHRM1 protein P11229 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257130 CHRM1 protein P11229 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256878 CHRM1 protein P11229 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257014 BCR protein P11274 UNIPROT RAC1 protein P63000 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260526 SPTB protein P11277 UNIPROT "Erythrocytic spectrin" complex SIGNOR-C384 SIGNOR "form complex" binding 9606 BTO:0000424 24302288 t lperfetto "Spectrin is a large, cytoskeletal, and heterodimeric protein composed of modular structure of alpha and beta subunits, it typically contains 106 contiguous amino acid sequence motifs called “spectrin repeats”. Spectrin is crucial for maintaining the stability and structure of the cell membrane and the shape of a cell" SIGNOR-266024 ERG protein P11308 UNIPROT CLDN5 protein O00501 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004432 22235125 t Luana "ETS-related gene (ERG) controls endothelial cell permeability via transcriptional regulation of the claudin 5 (CLDN5) gene." SIGNOR-261596 ERG protein P11308 UNIPROT WNT11 protein O96014 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21242973 f miannu "ERG transcriptional networks in leukemia converge on WNT signaling targets. Specifically, WNT11 emerged as a direct target of ERG. Small interfering RNA (siRNA)-mediated knockdown of ERG confirmed downregulation of WNT11 transcripts." SIGNOR-254071 ERG protein P11308 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25277175 f miannu "Increased expression of ERG or other ETS factors under control of androgen responsive promoter (TMPRSS2) is an inevitable consequence of the fusion events, and it activates transcriptional program that contributes to oncogenesis by upregulating expression of, among others, MYC, EZH2 and SOX9 and repressing NKX3." SIGNOR-251554 ERG protein P11308 UNIPROT VWF protein P04275 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567 9444957 f miannu "Cotransfection of Ets-1 and Erg expression plasmids is sufficient to induce the -60/+19 vWF promoter activity in HeLa cells." SIGNOR-253914 ERG protein P11308 UNIPROT WNT1 protein P04628 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001321 23913826 t Luana "Interestingly, our data showed that ERG drastically induced Wnt ligand gene expression." SIGNOR-261597 ERG protein P11308 UNIPROT ICAM1 protein P05362 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 22235125 f miannu "It has been shown that ERG is a positive regulator of several EC-restricted genes including VE-cadherin, endoglin, and von Willebrand factor, and a negative regulator of other genes such as interleukin (IL)-8 and intercellular adhesion molecule (ICAM)-1." SIGNOR-253917 ERG protein P11308 UNIPROT VIM protein P08670 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000093;BTO:0000815 8895512 f miannu "Our results suggest that PEA3 specifically transactivates vimentin promoter through PEA3 site. Among members of the ETS transcription factor family only Erg showed ability to transactivate vimentin promoter besides PEA3." SIGNOR-254069 ERG protein P11308 UNIPROT CXCL8 protein P10145 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001949 19359602 f miannu "ERG can inhibit the activity of the IL-8 promoter in a dose dependent manner." SIGNOR-253912 ERG protein P11308 UNIPROT SPP1 protein P10451 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21669963 f miannu "Using in vitro and in vivo molecular assays, we showed that ERG increases OPN expression and binds to an EBS (nt -115 to -118) in the OPN promoter." SIGNOR-254066 ERG protein P11308 UNIPROT ERG protein P11308 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001106 21536859 f miannu "We further demonstrate that ERG expression in primary human T-ALL cells is mediated by the binding of other T-cell oncogenes SCL/TAL1, LMO2, and LYL1 in concert with ERG, FLI1, and GATA3 to the ERG +85 enhancer." SIGNOR-253925 ERG protein P11308 UNIPROT EZH2 protein Q15910 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25277175 f miannu "Increased expression of ERG or other ETS factors under control of androgen responsive promoter (TMPRSS2) is an inevitable consequence of the fusion events, and it activates transcriptional program that contributes to oncogenesis by upregulating expression of, among others, MYC, EZH2 and SOX9 and repressing NKX3." SIGNOR-251555 ERG protein P11308 UNIPROT NKX3-1 protein Q99801 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 25277175 f miannu "Increased expression of ERG or other ETS factors under control of androgen responsive promoter (TMPRSS2) is an inevitable consequence of the fusion events, and it activates transcriptional program that contributes to oncogenesis by upregulating expression of, among others, MYC, EZH2 and SOX9 and repressing NKX3." SIGNOR-251556 ERG protein P11308 UNIPROT TDRD1 protein Q9BXT4 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003215 23319146 f miannu "In the prostate cancer cell line VCaP, downregulation of ERG by shRNA lead to a lower expression level of TDRD1 and resulted in a decreased activity of the TDRD1 promoter." SIGNOR-254067 ERG protein P11308 UNIPROT TDRD1 protein Q9BXT4 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001033 23555854 f miannu "we report that ERG and TDRD1 are co-expressed in human prostate cancers and we provide a mechanistic explanation for the observed co-expression. We demonstrate that ERG activates TDRD1 transcription by inducing loss of DNA methylation at the TDRD1 promoter-associated CpG island." SIGNOR-254068 ERG protein P11308 UNIPROT EPB41L4B protein Q9H329 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20860828 f miannu "EPB41L3 downregulation and EPB41L4B upregulation were essentially restricted to the 22 cases with ERG overexpression." SIGNOR-253919 ERG protein P11308 UNIPROT ADAMTS1 protein Q9UHI8 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007 19396168 f miannu "ADAMTS1 and CXCR4, two candidate genes strongly associated with cell migration, were upregulated in the presence of ERG overexpression." SIGNOR-253910 ERG protein P11308 UNIPROT EPB41L3 protein Q9Y2J2 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 20860828 f miannu "EPB41L3 downregulation and EPB41L4B upregulation were essentially restricted to the 22 cases with ERG overexpression." SIGNOR-253918 PIM1 protein P11309 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser253 APRRRAVsMDNSNKY 9606 18593906 t tpavlidou "Pim-mediated phosphorylation and inactivation of forkhead transcription factors, foxo1a and foxo3a, was involved in the transcriptional repression of the p27(kip1) gene." SIGNOR-179304 PIM1 protein P11309 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates activity" phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 18593906 t fspada "Pim1s expression induced the phosphorylation of foxo3a (fig. 5a and b) and inactivated its transcriptional activity (fig. 5c). A previous report showed that phosphorylation at t32, s253, and s315 residues in foxo3a induced 14-3-3 binding, nuclear export, and proteasomemediated degradation (42)." SIGNOR-179308 PIM1 protein P11309 UNIPROT MARK3 protein P27448 UNIPROT down-regulates phosphorylation Thr95 DKTQLNPtSLQKLFR 9606 15319445 t gcesareni "Here we show that the protein kinase cdc25 c-associated kinase 1 (c-tak1) is a binding partner and a substrate of pim-1." SIGNOR-128268 PIM1 protein P11309 UNIPROT FLT3 protein P36888 UNIPROT "up-regulates quantity" phosphorylation Tyr591 SSDNEYFyVDFREYE 9606 BTO:0005720 24040307 t "Pim-1 Kinase Phosphorylates and Stabilizes 130 kDa FLT3 and Promotes Aberrant STAT5 Signaling in Acute Myeloid Leukemia with FLT3 Internal Tandem Duplication[...]Pim-1 inhibition also decreased phosphorylation of FLT3 at tyrosine 591 and of STAT5, and expression of Pim-1 itself, consistent with inhibition of the FLT3-ITD-STAT5 signaling pathway." SIGNOR-259927 PIM1 protein P11309 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr145 QGRKRRQtSMTDFYH 9606 20307683 t lperfetto "Pim-2 phosphorylation of p21(cip1/waf1) enhances its stability and inhibits cell proliferation in hct116 cellshere we demonstrate that like pim-1, pim-2 also phosphorylates the cell cycle inhibitor p21(cip1/waf1) (p21) on thr145 in vitro and in vivo" SIGNOR-164642 PIM1 protein P11309 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser146 GRKRRQTsMTDFYHS 9606 31575057 t gcesareni "Pim-1, PKC, and Akt1 kinases phosphorylate Thr-145 and Ser-146 sites on p21 protein. Phosphorylation at Thr-145 promotes cytoplasmic translocation and stability of p21. Ser-146 phosphorylation mediated by Akt1 enhances p21 stabilization and promotes cell survival." SIGNOR-262961 PIM1 protein P11309 UNIPROT RPS19 protein P39019 UNIPROT up-regulates phosphorylation 9606 BTO:0000007 16266891 t gcesareni "The pim-1/rps19 interaction was demonstrated both in vitro and in living cells and led to phosphorylation of rps19 in an in vitro kinase assay." SIGNOR-141411 PIM1 protein P11309 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Thr157 GIRKRPAtDDSSTQN 9606 18593906 t gcesareni "We show, herein, that all the pim family members (pim1, pim2, and pim3) bind to and directly phosphorylate the cyclin-dependent kinase inhibitor p27(kip1) at threonine-157 and threonine-198 residues in cells and in vitro." SIGNOR-179296 PIM1 protein P11309 UNIPROT CDKN1B protein P46527 UNIPROT "down-regulates activity" phosphorylation Thr198 PGLRRRQt 9606 18593906 t gcesareni "We show, herein, that all the pim family members (pim1, pim2, and pim3) bind to and directly phosphorylate the cyclin-dependent kinase inhibitor p27(kip1) at threonine-157 and threonine-198 residues in cells and in vitro.|Pim kinases promote cell cycle progression and tumorigenesis by down-regulating p27(Kip1) expression at both transcriptional and posttranslational levels." SIGNOR-179300 PIM1 protein P11309 UNIPROT H3C1 protein P68431 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 17643117 t gcesareni "Pim1-dependent phosphorylation of histone h3 at serine 10 is required for myc-dependent transcriptional activation and oncogenic transformation." SIGNOR-156946 PIM1 protein P11309 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates phosphorylation Ser186 RQRKRHKsDSISLSF 9606 BTO:0000785 18467333 t gcesareni "Additionally, the pim kinases phosphorylate mdm2 in vitro and in cultured cells at ser166 and ser186, two previously identified targets of other signaling pathways, including akt." SIGNOR-178619 PIM1 protein P11309 UNIPROT MDM2 protein Q00987 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser166 SSRRRAIsETEENSD 9606 18467333 t gcesareni "Additionally, the pim kinases phosphorylate mdm2 in vitro and in cultured cells at ser166 and ser186, two previously identified targets of other signaling pathways, including akt." SIGNOR-178615 PIM1 protein P11309 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser276 SMQLRRPsDRELSEP 9606 19911008 t llicata "In this study we show that phosphorylation of rela/p65 at ser276 prevents its degradation by ubiquitin-mediated proteolysis. importantly, we identify pim-1 as a further kinase responsible for the phosphorylation of rela/p65 at ser276." SIGNOR-189125 PIM1 protein P11309 UNIPROT SKP2 protein Q13309 UNIPROT "up-regulates activity" phosphorylation Ser64 SNLGHPEsPPRKRLK 9606 BTO:0000567 20663873 t miannu "We found that expression of Pim-1 increases the level of Skp2 through direct binding and phosphorylation of multiple sites on this protein. Along with known Skp2 phosphorylation sites including Ser(64) and Ser(72), we have identified Thr(417) as a unique Pim-1 phosphorylation target. Phosphorylation of Thr(417) controls the stability of Skp2 and its ability to degrade p27." SIGNOR-259818 PIM1 protein P11309 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000007 16403219 t miannu "Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL. pim kinases are constitutively active when expressed in HEK-293 cells and are able to phosphorylate the Bcl-2 family member Bad on three residues, Ser112, Ser136 and Ser155 in vitro and in cells." SIGNOR-250392 PIM1 protein P11309 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates phosphorylation Ser83 ATRGRGSsVGGGSRR 9606 BTO:0002552 19749799 t lperfetto "Pim1 phosphorylates and negatively regulates ask1-mediated apoptosispim1 phosphorylation of ask1 on ser83 inhibited ask1-mediated c-jun n-terminal kinase phosphorylation" SIGNOR-187905 PIM1 protein P11309 UNIPROT FZR1 protein Q9UM11 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000567 20663873 t miannu "Pim-1 phosphorylates Cdh1 and impairs binding of this protein to another APC/C complex member, CDC27. These modifications inhibit Skp2 from degradation.Pim-1 Impairs Cdh1 and CDC27 Interaction and Phosphorylates Cdh1." SIGNOR-259820 PIM1 protein P11309 UNIPROT ABCG2 protein Q9UNQ0 UNIPROT "up-regulates activity" phosphorylation Thr362 GEKKKKItVFKEISY 9606 BTO:0001130 18056989 t lperfetto "Pim-1 kinase phosphorylates BCRP/ABCG2 and thereby promotes its multimerization and drug-resistant activity in human prostate cancer cells|This is further corroborated by our finding that the plasma membrane localization and drug-resistant activity of BCRP were compromised by T362A mutation." SIGNOR-264420 PIM1 protein P11309 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser253 APRRRAVsMDNSNKY 9606 18593906 t tpavlidou "Pim-mediated phosphorylation and inactivation of forkhead transcription factors, foxo1a and foxo3a, was involved in the transcriptional repression of the p27(kip1) gene." SIGNOR-252966 PIM1 protein P11309 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 18593906 t fspada "Pim1s expression induced the phosphorylation of foxo3a (fig. 5a and b) and inactivated its transcriptional activity (fig. 5c). A previous report showed that phosphorylation at t32, s253, and s315 residues in foxo3a induced 14-3-3 binding, nuclear export, and proteasomemediated degradation (42)." SIGNOR-252967 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr605 KDLVSCAyQVARGME 9606 12601080 t lperfetto "Fgfr signaling is under the control of tyrosine phosphorylation to elicit activation of cellular signaling cascades. Ligand binding induces receptor dimerization and transphosphorylation. Fgfr1 contains eleven tyrosine residues (tyr154, tyr280, tyr307, tyr463, tyr585, tyr605, tyr653, tyr654, tyr730 and tyr766), some of which are directly involved regulating the activity of the receptor and others bind to activate substrates leading to the activation of various transduction pathways." SIGNOR-98634 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr463 MLAGVSEyELPEDPR 10116 BTO:0003293 19224897 t lperfetto "This second-stage autophosphorylation occurs on Y583, in the kinase insert region (a noncatalytic sequence within the kinase domain), followed by autophosphorylation of Y463 in the juxtamembrane region, Y766 in the C-terminal tail, and Y585 in the kinase insert region" SIGNOR-235762 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr583 RRPPGLEyCYNPSHN 10116 BTO:0003293 19224897 t lperfetto "Autophosphorylation of Y653 is followed by the ordered autophosphorylation of several key tyrosine residues within binding sites for the SH2 or PTB domains of signaling proteins that bind to and are phosphorylated by activated FGFR1. This second-stage autophosphorylation occurs on Y583, in the kinase insert region (a noncatalytic sequence within the kinase domain), followed by autophosphorylation of Y463 in the juxtamembrane region, Y766 in the C-terminal tail, and Y585 in the kinase insert region" SIGNOR-235906 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr154 NRMPVAPyWTSPEKM 9606 8443592 t lperfetto "Tyrosine residues 154 and 307, which are in the extracellular domain of transmembrane receptor isoforms and are in an unusual sequence context for tyrosine phosphorylation, were also phosphorylated." SIGNOR-98622 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr307 IGPDNLPyVQILKTA 9606 8443592 t lperfetto "Tyrosine residues 154 and 307, which are in the extracellular domain of transmembrane receptor isoforms and are in an unusual sequence context for tyrosine phosphorylation, were also phosphorylated." SIGNOR-98630 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr463 MLAGVSEyELPEDPR 10116 BTO:0002809;BTO:0001009 8622701 t lperfetto "In this report, we describe the identification of six additional autophosphorylation sites (y-463, y-583, y-585, y-653, y-654 and y-730) on fgfr1.We have proposed that the role of the third stage of autophosphorylation is to enable the efficient tyrosine phosphorylation of substrate proteins that are physically bound to the receptor molecule by a maximally activated fgfr1" SIGNOR-236179 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr583 RRPPGLEyCYNPSHN 10116 BTO:0002809;BTO:0001009 8622701 t lperfetto "In this report, we describe the identification of six additional autophosphorylation sites (y-463, y-583, y-585, y-653, y-654 and y-730) on fgfr1.We have proposed that the role of the third stage of autophosphorylation is to enable the efficient tyrosine phosphorylation of substrate proteins that are physically bound to the receptor molecule by a maximally activated fgfr1" SIGNOR-236183 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr585 PPGLEYCyNPSHNPE 10116 BTO:0002809;BTO:0001009 8622701 t lperfetto "In this report, we describe the identification of six additional autophosphorylation sites (y-463, y-583, y-585, y-653, y-654 and y-730) on fgfr1.We have proposed that the role of the third stage of autophosphorylation is to enable the efficient tyrosine phosphorylation of substrate proteins that are physically bound to the receptor molecule by a maximally activated fgfr1" SIGNOR-236187 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr653 RDIHHIDyYKKTTNG 10116 BTO:0002809;BTO:0001009 8622701 t lperfetto "In this report, we describe the identification of six additional autophosphorylation sites (y-463, y-583, y-585, y-653, y-654 and y-730) on fgfr1. We demonstrate that autophosphorylation on tyrosines 653 and 654 is important for activation of tyrosine kinase activity of fgfr1 and is therefore essential for fgfr1-mediated biological responses." SIGNOR-236195 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr654 DIHHIDYyKKTTNGR 10116 BTO:0002809;BTO:0001009 8622701 t lperfetto "In this report, we describe the identification of six additional autophosphorylation sites (y-463, y-583, y-585, y-653, y-654 and y-730) on fgfr1. We demonstrate that autophosphorylation on tyrosines 653 and 654 is important for activation of tyrosine kinase activity of fgfr1 and is therefore essential for fgfr1-mediated biological responses." SIGNOR-236199 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr730 SNCTNELyMMMRDCW 10116 BTO:0002809;BTO:0001009 8622701 t lperfetto "In this report, we describe the identification of six additional autophosphorylation sites (y-463, y-583, y-585, y-653, y-654 and y-730) on fgfr1.We have proposed that the role of the third stage of autophosphorylation is to enable the efficient tyrosine phosphorylation of substrate proteins that are physically bound to the receptor molecule by a maximally activated fgfr1" SIGNOR-235686 FGFR1 protein P11362 UNIPROT ACAT1 protein P24752 UNIPROT "up-regulates activity" phosphorylation Tyr407 HALKQGEyGLASICN 9606 BTO:0002552 27867011 t lperfetto "Treatment with the FGFR1 inhibitor TKI258 in FGFR1-expressing H1299 cells led to decreased Y407 phosphorylation of ACAT1 in the mitochondrial fraction, where both ACAT1 and a fraction of FGFR1 were detected|Inhibition of tetrameric ACAT1 by abolishing Y407 phosphorylation or AH treatment results in decreased ACAT1 activity," SIGNOR-264423 FGFR1 protein P11362 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates phosphorylation Tyr327 PLLREETyDVPPAFA 9606 12601080 t lperfetto "Five tyrosine phosphorylation sites were identified in p130cas on tyr-128, tyr-249, tyr-306, tyr-327, and tyr-410. These tyrosine residues are all located in the substrate domain of p130cas that mediates binding to the sh2 domain of the adaptor molecule crk. Fgf-1-transduced fibroblasts demonstrated a > 10-fold increase in migration, an observation correlated with increased tyrosine phosphorylation of p125fak and p130cas." SIGNOR-98500 FGFR1 protein P11362 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates phosphorylation Tyr410 GVVDSGVyAVPPPAE 9606 12601080 t lperfetto "Five tyrosine phosphorylation sites were identified in p130cas on tyr-128, tyr-249, tyr-306, tyr-327, and tyr-410. These tyrosine residues are all located in the substrate domain of p130cas that mediates binding to the sh2 domain of the adaptor molecule crk. Fgf-1-transduced fibroblasts demonstrated a > 10-fold increase in migration, an observation correlated with increased tyrosine phosphorylation of p125fak and p130cas." SIGNOR-98569 FGFR1 protein P11362 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates 9606 12270934 f lperfetto " Fibroblast growth factor-2 (FGF-2), in the presence of dexamethasone, isobutylmethylxanthine, and insulin, induces a prolonged activation of the MEK/ERK signaling pathway, which lasts for at least 12 h post-induction, and this activity is less sensitive to the MEK inhibitors" SIGNOR-218010 FGFR1 protein P11362 UNIPROT CTTN protein Q14247 UNIPROT down-regulates phosphorylation Tyr446 GTEPEPVySMEAADY 9606 12601080 t lperfetto "Cortactin, which is an actin-binding protein that also plays a role in actin cytoskeleton dynamics (45), was phosphorylated on tyr-446 in our assay (by fgfr1).Phosphorylation of these residues attenuates the f-actin cross-linking activity" SIGNOR-98618 FGFR1 protein P11362 UNIPROT PDK1 protein Q15118 UNIPROT up-regulates phosphorylation Tyr136 AEDAKAIyDFTDTVI 9606 22195962 t llicata "Mitochondrial pdhk1 is tyrosine phosphorylated and activated by fgfr1 in cancer cells further mass spectrometric analysis identified three tyrosine residues of pdhk1, including y136, y243 and y244, that are phosphorylated by fgfr1" SIGNOR-191719 FGFR1 protein P11362 UNIPROT FRS2 protein Q8WU20 UNIPROT "up-regulates activity" phosphorylation 10116 BTO:0002809 9182757 t fspada "In this report, we demonstrate that FGF stimulation induces tyrosine phosphorylation of a novel lipid anchored docking protein, termed FRS2, that forms a complex with Grb2/Sos, thus linking FGF-receptor activation to the Ras/MAPK signaling pathway." SIGNOR-236944 G6PD protein P11413 UNIPROT 6-O-phosphono-D-glucono-1,5-lactone smallmolecule CHEBI:16938 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 24769394 t miannu "G6PD catalyzes the oxidation of glucose-6-phosphate to 6-phosphogluconate and concomitantly reduces NADP+ to NADPH, which is the rate-limiting and primary control step of the NADPH-generating portion in the PPP. Thus, G6PD acts as a guardian of cellular redox potential during oxidative stress" SIGNOR-267051 G6PD protein P11413 UNIPROT NADPH(4-) smallmolecule CHEBI:57783 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 24769394 t miannu "The major NADPH-producing enzymes in the cell are glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) in the pentose phosphate pathway (PPP), malic enzyme (ME) in the pyruvate cycling pathway, and isocitrate dehydrogenase (IDH) in the tricarboxylic acid (TCA) cycle" SIGNOR-267052 G6PD protein P11413 UNIPROT "alpha-D-glucose 6-phosphate(2-)" smallmolecule CHEBI:58225 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 24769394 t miannu "G6PD catalyzes the oxidation of glucose-6-phosphate to 6-phosphogluconate and concomitantly reduces NADP+ to NADPH, which is the rate-limiting and primary control step of the NADPH-generating portion in the PPP. Thus, G6PD acts as a guardian of cellular redox potential during oxidative stress" SIGNOR-267050 VDR protein P11473 UNIPROT CYP24A1 protein Q07973 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000067 9687155 f miannu "Repression of basal transcription of a 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) responsive 25-hydroxyvitamin D3-24-hydroxylase (CYP24) promoter construct as observed in kidney cells in the absence of ligand and this repression was dependent on a functional vitamin D response element (VDRE). Basal repression was also seen with a construct where a consensus DR-3-type VDRE was fused to the thymidine kinase promoter. Expression of a dominant negative vitamin D receptor (VDR) isoform that strongly bound to the VDRE motif in the CYP24 promoter ablated basal repression." SIGNOR-255599 ESRRA protein P11474 UNIPROT SNAI2 protein O43623 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000150 15955695 f miannu "In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro." SIGNOR-253790 ESRRA protein P11474 UNIPROT SNAI1 protein O95863 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000159 15955695 f miannu "In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro." SIGNOR-253799 ESRRA protein P11474 UNIPROT NR2F6 protein P10588 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000156 15955695 f miannu "In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro." SIGNOR-253796 ESRRA protein P11474 UNIPROT NR2F1 protein P10589 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000155 15955695 f miannu "In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro." SIGNOR-253795 ESRRA protein P11474 UNIPROT CYP19A1 protein P11511 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000154 15955695 f miannu "In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro." SIGNOR-253794 PC protein P11498 UNIPROT pyruvate smallmolecule CHEBI:15361 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 24363178 t miannu "As an alternative to decarboxylation by PDH, the second major fate of mitochondrial pyruvate is the irreversible, ATP-dependent carboxylation of pyruvate to oxaloacetate by pyruvate carboxylase (PC). Oxaloacetate is a critical intermediate in metabolism, linking carbohydrate, lipid, amino acid, and nucleotide metabolism (Fig. 2)" SIGNOR-266554 PC protein P11498 UNIPROT "oxaloacetic acid" smallmolecule CHEBI:30744 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 24363178 t miannu "As an alternative to decarboxylation by PDH, the second major fate of mitochondrial pyruvate is the irreversible, ATP-dependent carboxylation of pyruvate to oxaloacetate by pyruvate carboxylase (PC). Oxaloacetate is a critical intermediate in metabolism, linking carbohydrate, lipid, amino acid, and nucleotide metabolism (Fig. 2)" SIGNOR-266552 CYP19A1 protein P11511 UNIPROT 17beta-estradiol smallmolecule CHEBI:16469 ChEBI "up-regulates quantity" "small molecule catalysis" 395188 t lperfetto "Studies show that aromatization (a reaction sequence unique in steroid biosynthesis) of androgens to estrogens is not limited to the female reproductive organs but also occurs in extragonadal tissue. Aromatization involves the loss of the angular C-19 methyl group and cis elimination of the 1beta and 2beta hydrogens from the androgen precursors, androstenedione and testosterone, to yield estrone and estradiol, respectively. In men, the production of estrone is 18 ug/day and is mainly extraglandular. Aromatase activity has also been shown in a variety of tissues in mammalian and other species." SIGNOR-251528 DMD protein P11532 UNIPROT DGC complex SIGNOR-C217 SIGNOR "form complex" binding 9606 15117830 t apalma "The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink)." SIGNOR-255998 EPX protein P11678 UNIPROT RNASE2 protein P10153 UNIPROT "up-regulates activity" "post translational modification" 9606 BTO:0000399 18694936 t miannu "Human eosinophils are bone marrow-derived, non-dividing granulocytes of the innate immune system, which store the highly cationic proteins eosinophil peroxidase (EPO), major basic protein (MBP), eosinophil-derived neurotoxin (EDN), and eosinophil cationic protein (ECP) in secondary granules. we demonstrated that Tyr nitration of the eosinophil granule proteins is exclusively mediated by EPO, in the presence of functional NADPH oxidase and minute amounts of NOx. EPO appears to nitrate itself via an autocatalytic mechanism." SIGNOR-261704 EPX protein P11678 UNIPROT EPX protein P11678 UNIPROT "up-regulates activity" "post translational modification" 9606 BTO:0000399 18694936 t miannu "Human eosinophils are bone marrow-derived, non-dividing granulocytes of the innate immune system, which store the highly cationic proteins eosinophil peroxidase (EPO), major basic protein (MBP), eosinophil-derived neurotoxin (EDN), and eosinophil cationic protein (ECP) in secondary granules. we demonstrated that Tyr nitration of the eosinophil granule proteins is exclusively mediated by EPO, in the presence of functional NADPH oxidase and minute amounts of NOx. EPO appears to nitrate itself via an autocatalytic mechanism." SIGNOR-261706 EPX protein P11678 UNIPROT RNASE3 protein P12724 UNIPROT "up-regulates activity" "post translational modification" 9606 BTO:0000399 18694936 t miannu "Human eosinophils are bone marrow-derived, non-dividing granulocytes of the innate immune system, which store the highly cationic proteins eosinophil peroxidase (EPO), major basic protein (MBP), eosinophil-derived neurotoxin (EDN), and eosinophil cationic protein (ECP) in secondary granules. we demonstrated that Tyr nitration of the eosinophil granule proteins is exclusively mediated by EPO, in the presence of functional NADPH oxidase and minute amounts of NOx. EPO appears to nitrate itself via an autocatalytic mechanism." SIGNOR-261705 EPX protein P11678 UNIPROT PRG2 protein P13727 UNIPROT "up-regulates activity" "post translational modification" 9606 BTO:0000399 18694936 t miannu "Human eosinophils are bone marrow-derived, non-dividing granulocytes of the innate immune system, which store the highly cationic proteins eosinophil peroxidase (EPO), major basic protein (MBP), eosinophil-derived neurotoxin (EDN), and eosinophil cationic protein (ECP) in secondary granules. we demonstrated that Tyr nitration of the eosinophil granule proteins is exclusively mediated by EPO, in the presence of functional NADPH oxidase and minute amounts of NOx. EPO appears to nitrate itself via an autocatalytic mechanism." SIGNOR-261703 CDK4 protein P11802 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser249 AVIPINGsPRTPRRG 9606 15809340 t gcesareni "Phosphorylated by cdk6 and cdk4, and subsequently by cdk2 at ser-567 in g1, thereby releasing e2f1 which is then able to activate cell growth. Here we show that although these cdks phosphorylate multiple residues in prb, they do so with different residue selectivities in vitro;thr821 and thr826 are preferentially phosphorylated by cdk6 and cdk4, respectively." SIGNOR-135181 CDK4 protein P11802 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser811 IYISPLKsPYKISEG 9606 15809340 t gcesareni "Phosphorylated by cdk6 and cdk4, and subsequently by cdk2 at ser-567 in g1, thereby releasing e2f1 which is then able to activate cell growth. Here we show that although these cdks phosphorylate multiple residues in prb, they do so with different residue selectivities in vitro;thr821 and thr826 are preferentially phosphorylated by cdk6 and cdk4, respectively." SIGNOR-135185 CDK4 protein P11802 UNIPROT RBL1 protein P28749 UNIPROT "up-regulates activity" phosphorylation Thr369 KRSFAPStPLTGRRY 9606 BTO:0001938 12006580 t llicata "Here we assessed the effects of alanine substitution at the individual or combined Cdk4(6)-specific sites in p130, compared with homologous sites in p107 (Thr(369)/Ser(650)/Ser(964)). In U-2-OS cells, the triple p107(DeltaCdk4)* mutant strongly inhibited E2F-4 activity and imposed a G(1) arrest resistant to cyclin D1 coexpression. " SIGNOR-250765 CDK4 protein P11802 UNIPROT BRCA1 protein P38398 UNIPROT down-regulates phosphorylation Ser632 LVVSRNLsPPNCTEL 9606 BTO:0000150 SIGNOR-C18 17334399 t lperfetto "In particular, we have identified ser 632 of brca1 as a cyclin d1/cdk4 phosphorylation site in vitro. Using chromatin immunoprecipitation assays, we observed that the inhibition of cyclin d1/cdk4 activity resulted in increased brca1 dna binding at particular promoters in vivo." SIGNOR-153450 CDK4 protein P11802 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Thr8 MSSILPFtPPIVKRL 9606 19114991 t lpetrilli "In the nucleus cdk2/4-mediated phosphorylation of smad3 occurs mostly at thr8, thr179, and ser213. Cdk-dependent phosphorylation of smad3 inhibits its transcriptional activity" SIGNOR-182983 CDK4 protein P11802 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 15241418 t lperfetto "We have mapped CDK4 and CDK2 phosphorylation sites to Thr 8, Thr 178 and Ser 212 in Smad3. Mutation of the CDK phosphorylation sites increases Smad3 transcriptional activity" SIGNOR-232142 CDK4 protein P11802 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" phosphorylation Thr179 PQSNIPEtPPPGYLS 9606 15241418 t lperfetto "We have mapped CDK4 and CDK2 phosphorylation sites to Thr 8, Thr 178 and Ser 212 in Smad3. Mutation of the CDK phosphorylation sites increases Smad3 transcriptional activity" SIGNOR-232146 CDK4 protein P11802 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" phosphorylation Thr8 MSSILPFtPPIVKRL 9606 15241418 t lperfetto "We have mapped CDK4 and CDK2 phosphorylation sites to Thr 8, Thr 178 and Ser 212 in Smad3. Mutation of the CDK phosphorylation sites increases Smad3 transcriptional activity" SIGNOR-232138 CDK4 protein P11802 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" phosphorylation Thr179 PQSNIPEtPPPGYLS 9606 19114991 t lpetrilli "In the nucleus cdk2/4-mediated phosphorylation of smad3 occurs mostly at thr8, thr179, and ser213. Cdk-dependent phosphorylation of smad3 inhibits its transcriptional activity" SIGNOR-182822 CDK4 protein P11802 UNIPROT SMAD3 protein P84022 UNIPROT unknown phosphorylation Ser204 NHSMDAGsPNLSPNP -1 15241418 t llicata "Thus, we have shown that Smad3 is phosphorylated by CDK4 and CDK2. Mutation of its CDK phosphorylation sites increases its transcriptional activity and antiproliferative function. | Thr 8 and the four sites in the linker (Thr 178, Ser 203, Ser 207 and Ser 212). Each of the five sites was phosphorylated by both CDK4 and CDK2 in vitro, and only Thr 8, Thr 178 and Ser 212 were phosphorylated by CDK4 and CDK2 in vivo phosphorylated by both CDK4 and CDK2 in vitro, and only Thr 8, Thr 178 and Ser 212 were phosphorylated by CDK4 and CDK2 in vivo." SIGNOR-250766 CDK4 protein P11802 UNIPROT SMAD3 protein P84022 UNIPROT unknown phosphorylation Ser208 DAGSPNLsPNPMSPA -1 15241418 t llicata "Thus, we have shown that Smad3 is phosphorylated by CDK4 and CDK2. Mutation of its CDK phosphorylation sites increases its transcriptional activity and antiproliferative function. | Thr 8 and the four sites in the linker (Thr 178, Ser 203, Ser 207 and Ser 212). Each of the five sites was phosphorylated by both CDK4 and CDK2 in vitro, and only Thr 8, Thr 178 and Ser 212 were phosphorylated by CDK4 and CDK2 in vivo phosphorylated by both CDK4 and CDK2 in vitro, and only Thr 8, Thr 178 and Ser 212 were phosphorylated by CDK4 and CDK2 in vivo." SIGNOR-250767 CDK4 protein P11802 UNIPROT PRDX1 protein Q06830 UNIPROT down-regulates phosphorylation Thr90 CHLAWVNtPKKQGGL 9606 BTO:0000567 11986303 t lperfetto "Peroxiredoxin (prx) i is a member of the peroxiredoxin family of peroxidases and contains a consensus site (thr(90)-pro-lys-lys) for phosphorylation by cyclin-dependent kinases (cdks). This protein has now been shown to be phosphorylated specifically on thr(90) by several cdks, including cdc2, in vitro. Phosphorylation of prx i on thr(90) reduced the peroxidase activity of this protein by 80%.Prx i was also phosphorylated, with an efficiency similar to that observed with cdc2, when incubated in vitro with cdk2, cdk4, or cdk6 that had been immunoprecipitated from hela cell lysates with specific antibodies (data not shown)." SIGNOR-87105 CDK4 protein P11802 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Thr611 ETLPISStPSKSVLP 9606 22094256 t lperfetto "We identified the forkhead box m1 (foxm1) transcription factor as a common critical phosphorylation target. Cdk4/6 stabilize and activate foxm1these data identify five overlapping in vivo and in vitro cdk4/6 target sites in foxm1 (s4, s35, t611, t620 and t627)" SIGNOR-177255 CDK4 protein P11802 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Thr620 SKSVLPRtPESWRLT 9606 22094256 t lperfetto "We identified the forkhead box m1 (foxm1) transcription factor as a common critical phosphorylation target. Cdk4/6 stabilize and activate foxm1these data identify five overlapping in vivo and in vitro cdk4/6 target sites in foxm1 (s4, s35, t611, t620 and t627)" SIGNOR-177259 CDK4 protein P11802 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Thr627 TPESWRLtPPAKVGG 9606 22094256 t lperfetto "We identified the forkhead box m1 (foxm1) transcription factor as a common critical phosphorylation target. Cdk4/6 stabilize and activate foxm1these data identify five overlapping in vivo and in vitro cdk4/6 target sites in foxm1 (s4, s35, t611, t620 and t627)" SIGNOR-177263 CDK4 protein P11802 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation 9606 22094256 t tpavlidou "We identified the forkhead box m1 (foxm1) transcription factor as a common critical phosphorylation target. Cdk4/6 stabilize and activate foxm1, thereby maintain expression of g1/s phase genes, suppress the levels of reactive oxygen species (ros), and protect cancer cells from senescence." SIGNOR-177266 CDK4 protein P11802 UNIPROT MEF2D protein Q14814 UNIPROT down-regulates binding 9606 SIGNOR-C18 21902831 t gcesareni "In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms." SIGNOR-176524 CDK4 protein P11802 UNIPROT PELP1 protein Q8IZL8 UNIPROT up-regulates phosphorylation Ser477 ADALKLRsPRGSPDG 9606 BTO:0000150 20807815 t llicata "Using site-directed mutagenesis and in vitro kinase assays, we identified ser(477) and ser(991) of pelp1 as cdk phosphorylation sites. we identified pelp1 as a novel substrate of cdks and found that cdk phosphorylation is important for the proper function of pelp1 in modulating hormone-driven cell cycle progression and also for optimal e2f transactivation function." SIGNOR-167770 F5 protein P12259 UNIPROT "Factor Va-Xa" complex SIGNOR-C318 SIGNOR "form complex" binding -1 2026608 t lperfetto "The binding of factor Xa to factor Va in the presence of Ca2+ ions and phospholipid is fundamental for the activation of prothrombin to thrombin. |Regardless of which protein was labeled, a factor Xa-Va complex (s20,w = 9.8) was formed. The interaction is specific and reversible. I" SIGNOR-263558 CDK4 protein P11802 UNIPROT PELP1 protein Q8IZL8 UNIPROT up-regulates phosphorylation Ser991 PALPPPEsPPKVQPE 9606 BTO:0000150 20807815 t llicata "Using site-directed mutagenesis and in vitro kinase assays, we identified ser(477) and ser(991) of pelp1 as cdk phosphorylation sites. we identified pelp1 as a novel substrate of cdks and found that cdk phosphorylation is important for the proper function of pelp1 in modulating hormone-driven cell cycle progression and also for optimal e2f transactivation function." SIGNOR-167774 SRF protein P11831 UNIPROT PLAU protein P00749 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000161 15514113 f miannu "We previously demonstrated that serum response factor (SRF), a critical smooth muscle transcription factor, is highly expressed in LAM cells. Here we show that a high SRF level alters the plasminogen (Plg) system. Specifically, overexpression of SRF in human lung fibroblasts upregulated urokinase-type plasminogen activator (uPA) and its substrate Plg, whereas it downregulated plasminogen activator inhibitor (PAI)-1." SIGNOR-255227 SRF protein P11831 UNIPROT SERPINE1 protein P05121 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000161 15514113 f miannu "We previously demonstrated that serum response factor (SRF), a critical smooth muscle transcription factor, is highly expressed in LAM cells. Here we show that a high SRF level alters the plasminogen (Plg) system. Specifically, overexpression of SRF in human lung fibroblasts upregulated urokinase-type plasminogen activator (uPA) and its substrate Plg, whereas it downregulated plasminogen activator inhibitor (PAI)-1." SIGNOR-255228 SRF protein P11831 UNIPROT PTGS2 protein P35354 UNIPROT up-regulates 9606 22225874 t 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 SRF protein P11831 UNIPROT CNN1 protein P51911 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887;BTO:0001260 21673106 f gcesareni "In particular, high expression of vsmc-specific genes, such as smooth muscle -actin (sma), calponin1 (cnn), and sm22 (sm22) are associated with the contractile vsmc phenotype. Transcription of contractile genes is regulated by srf through a dna sequence motif known as the carg box (cc(a/t)6gg), which is present in the promoters of vsmc-specific genes." SIGNOR-174358 SRF protein P11831 UNIPROT ACTA2 protein P62736 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887;BTO:0001260 15269336 f gcesareni "The primary goal of the present study was to directly assess the role of the degeneracy of sm ?-Actin cargs in the regulation of smc-selective gene expression in vivo. in addition, our present studies address the possible role of this carg degeneracy, and the smc-selective srf coactivator myocardin, in regulating differential expression of carg-dependent smc genes and growth regulatory genes." SIGNOR-126923 SRF protein P11831 UNIPROT TAGLN protein Q01995 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887;BTO:0001260 21673106 f gcesareni "The contractile phenotype of smooth muscle (sm) cells is controlled by serum response factor (srf), which drives the expression of sm-specific genes including sm alpha-actin, sm22, and others." SIGNOR-174393 SRF protein P11831 UNIPROT NKX3-1/SRF complex SIGNOR-C25 SIGNOR "form complex" binding 9606 BTO:0000887;BTO:0001260 10993896 t lperfetto "A novel complex element containing a juxtaposed nkx-binding site (nke) and an srf-binding element (sre) in the proximal promoter region was found to be necessary for the nkx3-1/srf coactivation of smga transcription." SIGNOR-82090 PRPS2 protein P11908 UNIPROT "5-O-phosphonato-alpha-D-ribofuranosyl diphosphate(5-)" smallmolecule CHEBI:58017 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 16939420 t miannu "PRPP (phosphoribosylpyrophosphate) is an important metabolite essential for nucleotide synthesis and PRS (PRPP synthetase) catalyses synthesis of PRPP from R5P (ribose 5-phosphate) and ATP." SIGNOR-267082 PRPS2 protein P11908 UNIPROT "D-ribofuranose 5-phosphate(2-)" smallmolecule CHEBI:78346 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 16939420 t miannu "PRPP (phosphoribosylpyrophosphate) is an important metabolite essential for nucleotide synthesis and PRS (PRPP synthetase) catalyses synthesis of PRPP from R5P (ribose 5-phosphate) and ATP." SIGNOR-267081 CD79A protein P11912 UNIPROT BCL2L1 protein Q07817 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000776 12324477 f gcesareni "Bcr ligation activated mitochondrial apoptotic pathways including down-regulation of bcl-x(l)." SIGNOR-93481 ODC1 protein P11926 UNIPROT L-ornithine smallmolecule CHEBI:15729 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 BTO:0000452 BTO:0001103 14617280 t 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 PABPC1 protein P11940 UNIPROT EIF4E protein P06730 UNIPROT "up-regulates activity" binding 9606 30209168 t miannu "The binding of PABP to mRNA poly(A) tails is followed by interactions with eukaryotic initiation factor (eIF4G) and other translation factors, including eIF4E, to constitute a translation initiation complex, which mediates cellular mRNA circularization and enhances cap-dependent translation by facilitating ribosome recycling" SIGNOR-260968 PABPC1 protein P11940 UNIPROT NFX1 protein Q12986 UNIPROT "up-regulates activity" binding 9606 BTO:0000009 17267499 t Simone "We identifiednew protein partners of NFX1-123, including several cytoplasmic poly(A) binding proteins (PABPCs) thatinteracted with NFX1-123 through its N-terminal PAM2 motif. Central to our findings were our observations that PABPCs copurify with NFX1-123, that a PAM2 motif is present in NFX1, and this motif and the PABPCs are important in the enhancement of hTERT activity by NFX1-123." SIGNOR-261052 PABPC1 protein P11940 UNIPROT eIF4F_complex complex SIGNOR-C44 SIGNOR "up-regulates activity" binding 9606 30209168 t miannu "The binding of PABP to mRNA poly(A) tails is followed by interactions with eukaryotic initiation factor (eIF4G) and other translation factors, including eIF4E, to constitute a translation initiation complex, which mediates cellular mRNA circularization and enhances cap-dependent translation by facilitating ribosome recycling" SIGNOR-260943 PCNA protein P12004 UNIPROT "DNA polymerase epsilon" complex SIGNOR-C377 SIGNOR "up-regulates activity" binding 9534 BTO:0004055 12930972 t lperfetto "Processive DNA synthesis by DNA polymerases delta and epsilon requires the cellular replication factor C (RF‐C) and proliferating cell nuclear antigen (PCNA)." SIGNOR-265512 FGF5 protein P12034 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates binding 9606 8386828 t gcesareni "Fgf-5 can bind and induce autophosphorylation of human fgf receptors (fgfr) 1 and 2." SIGNOR-38704 FGF5 protein P12034 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates binding 9606 8386828 t gcesareni "Fgf-5 can bind and induce autophosphorylation of human fgf receptors (fgfr) 1 and 2" SIGNOR-38995 NEFH protein P12036 UNIPROT "Neurofilament L/H" complex SIGNOR-C208 SIGNOR "form complex" binding 9606 BTO:0000938 19468066 t miannu "Neurofilaments are obligate heteropolymers that are minimally comprised of the low molecular neurofilament protein L (NFL) plus the medium and/or high molecular weight proteins neurofilament protein M (NFM) and neurofilament protein H" SIGNOR-255273 IMPDH2 protein P12268 UNIPROT CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 30518405 f miannu "We further demonstrated that IMPDH2 overexpression accelerated G1/S phase cell cycle transition by inducing increased expression of cyclin D1 and Ki-67 and downregulation of p21Cip1 and p27Kip1. More importantly, G1/S phase cell cycle transition was triggered by IMPDH2 through activation of AKT activity, downregulation of mTOR and FOXO1 transcriptional activity." SIGNOR-260957 IMPDH2 protein P12268 UNIPROT CDKN1A protein P38936 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 30518405 f miannu "We further demonstrated that IMPDH2 overexpression accelerated G1/S phase cell cycle transition by inducing increased expression of cyclin D1 and Ki-67 and downregulation of p21Cip1 and p27Kip1. More importantly, G1/S phase cell cycle transition was triggered by IMPDH2 through activation of AKT activity, downregulation of mTOR and FOXO1 transcriptional activity." SIGNOR-260959 IMPDH2 protein P12268 UNIPROT MKI67 protein P46013 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 30518405 f miannu "We further demonstrated that IMPDH2 overexpression accelerated G1/S phase cell cycle transition by inducing increased expression of cyclin D1 and Ki-67 and downregulation of p21Cip1 and p27Kip1. More importantly, G1/S phase cell cycle transition was triggered by IMPDH2 through activation of AKT activity, downregulation of mTOR and FOXO1 transcriptional activity." SIGNOR-260958 IMPDH2 protein P12268 UNIPROT CDKN1B protein P46527 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 30518405 f miannu "We further demonstrated that IMPDH2 overexpression accelerated G1/S phase cell cycle transition by inducing increased expression of cyclin D1 and Ki-67 and downregulation of p21Cip1 and p27Kip1. More importantly, G1/S phase cell cycle transition was triggered by IMPDH2 through activation of AKT activity, downregulation of mTOR and FOXO1 transcriptional activity." SIGNOR-260960 IMPDH2 protein P12268 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" binding 9606 BTO:0001616 30518405 t miannu "We further demonstrated that IMPDH2 overexpression accelerated G1/S phase cell cycle transition by inducing increased expression of cyclin D1 and Ki-67 and downregulation of p21Cip1 and p27Kip1. More importantly, G1/S phase cell cycle transition was triggered by IMPDH2 through activation of AKT activity, downregulation of mTOR and FOXO1 transcriptional activity. There is evidence that IMPDH2 interacts with the pleckstrin homology domain of PKB/AKT in the regulation of GTP biosynthesis." SIGNOR-260961 TPR protein P12270 UNIPROT MAD1L1 protein Q9Y6D9 UNIPROT up-regulates binding 9606 BTO:0000567 18981471 t miannu "Tpr directly binds to mad1 and mad2. / depletion of tpr decreases the levels of mad1 at kinetochores during prometaphase, correlating with the inability of mad1 to activate mad2, which is required for inhibiting apc(cdc20)." SIGNOR-181918 TPR protein P12270 UNIPROT NPC complex SIGNOR-C263 SIGNOR "form complex" binding 27016207 t lperfetto "The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2)." SIGNOR-262070 CKB protein P12277 UNIPROT N-phosphocreatine smallmolecule CHEBI:17287 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 18502307 t miannu "Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool." SIGNOR-265787 CKB protein P12277 UNIPROT ACTB protein P60709 UNIPROT "up-regulates quantity" relocalization 9606 BTO:0000099 19333390 t miannu "In summary, data presented here strongly suggest that locally generated ATP is an important regulator for actin-based cytoskeletal dynamics involved in cell extension and motility and that CK-B is a controlling enzyme in the compartmentalization of ATP availability. CK-B co-localizes with cortical actin and facilitates spreading of astrocytes" SIGNOR-265791 FCER1A protein P12319 UNIPROT FCER1 complex SIGNOR-C200 SIGNOR "form complex" binding 9606 BTO:0000830 16470226 t "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 ANXA3 protein P12429 UNIPROT NFKBIA protein P25963 UNIPROT "up-regulates activity" 9606 BTO:0000018 27995049 f miannu "We also investigated the potential regulation of cancer-associated signaling pathways by Anxa3 through screening for the altered expression of some common signaling molecules after Anxa3 downregulation. Decreased phosphorylation of MEK1/2, ERK1/2, Akt, and IκBα was detected after downregulating Anxa3 expression in A549 cells." SIGNOR-262213 ANXA3 protein P12429 UNIPROT CASP3 protein P42574 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001109;BTO:0000038 30998268 f miannu "ANXA3 depletion promoted cell apoptosis and upregulated c‐caspase 3 expression in HCT116/Ox and SW480/Ox cells with or without Ox, which is consistent with findings from a preliminary study by Yan et al" SIGNOR-262209 ANXA3 protein P12429 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "up-regulates activity" 9606 BTO:0000018 27995049 f miannu "We also investigated the potential regulation of cancer-associated signaling pathways by Anxa3 through screening for the altered expression of some common signaling molecules after Anxa3 downregulation. Decreased phosphorylation of MEK1/2, ERK1/2, Akt, and IκBα was detected after downregulating Anxa3 expression in A549 cells." SIGNOR-262211 BMP2 protein P12643 UNIPROT BMP2 protein P12643 UNIPROT up-regulates binding 9606 BTO:0000887 11178121 t 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 BMP2 protein P12643 UNIPROT BMPR1A protein P36894 UNIPROT up-regulates binding 26330344 t fferrentino "BMP interacts with specific receptors on the cell surface, BMP receptor types 1 and 2 (BMPr1 and BMPr2)." SIGNOR-253547 BMP2 protein P12643 UNIPROT BMPR1A protein P36894 UNIPROT "up-regulates activity" binding -1 18937504 t 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 BMP2 protein P12643 UNIPROT BMPR2 protein Q13873 UNIPROT up-regulates binding 9606 SIGNOR-C29 7791754 t 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-33425 BMP2 protein P12643 UNIPROT BMPR2 protein Q13873 UNIPROT "up-regulates activity" binding 9534 SIGNOR-C29 7791754 t 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 BMP2 protein P12643 UNIPROT SHH protein Q15465 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 19855020 f gcesareni "On the other hand, bmp activity negatively regulates shh transcription and a bmp-shh nega-tive-feedback loop serves to confine shh expression during limb development." SIGNOR-188853 BMP2 protein P12643 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates 9606 21793042 f gcesareni "Upon bmp binding to the bmpr-ii, bmpr-i is recruited to form an activated quaternary complex, which then phosphorylates and activates intracellular smad proteins. Receptor smads bind to a co-smad and translocate to the nucleus to serve as transcription factors." SIGNOR-175273 BMP2 protein P12643 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates 9606 22298955 f lperfetto "Neogenin, a transmembranous protein, was reported to regulate bmp receptor association with lipid raft, where bmp induces canonical smad1/5/8 phosphorylation." SIGNOR-195561 BMP2 protein P12643 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 12589053 f fspada "Specific inhibitors for p38 kinase inhibited bmp2-induced adipocytic differentiation and transcriptional activation of ppargamma, whereas overexpression of smad6 had no effect on transcriptional activity of ppargamma." SIGNOR-98369 BMP2 protein P12643 UNIPROT SMAD5 protein Q99717 UNIPROT up-regulates 9606 22298955 f gcesareni "Neogenin, a transmembranous protein, was re-ported to regulate bmp receptor association with lipid raft, where bmp induces canonical smad1/5/8 phosphorylation" SIGNOR-195564 BMP2 protein P12643 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates binding 10090 BTO:0001957 11714695 t lperfetto "For this, bmp-2 binds first to the high affinity receptor bri and then recruits brii into the signaling complex." SIGNOR-237000 BMP4 protein P12644 UNIPROT MRTFA protein Q969V6 UNIPROT up-regulates 9606 21673106 f gcesareni "These results demonstrate that mrtf-a is essential for the bmp4-mediated induction of pri-mir-143/145 and mature mir-143/145, whereas tgf- -mediated induction of mir-143/145 requires myocd. Mrtf-a is primarily localized in the cytoplasm in unstimulated cells;upon stimulation with bmp4, mrtf-a translocates into the nucleus to promote changes in gene expression." SIGNOR-174124 BMP4 protein P12644 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates binding 9606 BTO:0001253 7673243 t lperfetto "We have isolated a cdna encoding a novel transmembrane serine/threonine kinase from human skin fibroblasts which we demonstrate here to be a type ii receptor that binds bmp-4. This receptor (brk-3) is distantly related to other known type ii receptors and is distinguished from them by an extremely long carboxyl-terminal sequence following the intracellular kinase domain." SIGNOR-217535 SKI protein P12755 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" binding 9606 10575014 t lperfetto "Smad2/3 interacts with c-ski through its c-terminal mh2 domain in a tgf-beta-dependent mannerc-ski is incorporated in the smad dna binding complex, interferes with the interaction of smad3 with a transcriptional co-activator, p300, and in turn recruits hdac. c-ski is thus a transcriptional co-repressor that links smads to hdac in tgf-beta signaling." SIGNOR-232123 SKI protein P12755 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" binding 9606 BTO:0000848 12793438 t lperfetto "The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway" SIGNOR-236077 SKI protein P12755 UNIPROT EP300 protein Q09472 UNIPROT down-regulates binding 9606 SIGNOR-C6 10575014 t gcesareni "Smad2/3 interacts with c-ski through its c-terminal mh2 domain in a tgf-beta-dependent mannerc-ski is incorporated in the smad dna binding complex, interferes with the interaction of smad3 with a transcriptional co-activator, p300, and in turn recruits hdac. c-ski is thus a transcriptional co-repressor that links smads to hdac in tgf-beta signaling." SIGNOR-72664 SKI protein P12755 UNIPROT SMAD4 protein Q13485 UNIPROT "down-regulates activity" binding 9606 BTO:0000848 12793438 t lperfetto "The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway" SIGNOR-236074 SKI protein P12755 UNIPROT SMAD2 protein Q15796 UNIPROT "down-regulates activity" binding 9606 10575014 t lperfetto "Smad2/3 interacts with c-ski through its c-terminal mh2 domain in a tgf-beta-dependent mannerc-ski is incorporated in the smad dna binding complex, interferes with the interaction of smad3 with a transcriptional co-activator, p300, and in turn recruits hdac. c-ski is thus a transcriptional co-repressor that links smads to hdac in tgf-beta signaling." SIGNOR-217658 SKI protein P12755 UNIPROT SMAD2 protein Q15796 UNIPROT "down-regulates activity" binding 9606 BTO:0000848 12793438 t lperfetto "The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway" SIGNOR-236155 SKI protein P12755 UNIPROT SMAD5 protein Q99717 UNIPROT down-regulates binding 9606 12419246 t gcesareni "Ski also represses bmp signaling through interactions with smad4 and bmp-specific r-smads, smad1 or smad6" SIGNOR-95468 SKI protein P12755 UNIPROT SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR "down-regulates activity" binding 9606 BTO:0000848 12793438 t lperfetto "The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway" SIGNOR-253300 SKI protein P12755 UNIPROT SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR "down-regulates activity" binding 9606 BTO:0000848 12793438 t lperfetto "The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway" SIGNOR-253301 SKIL protein P12757 UNIPROT SMAD5 protein Q99717 UNIPROT down-regulates binding 9606 SIGNOR-C85 12419246 t gcesareni "Ski also represses bmp signaling through interactions with smad4 and bmp-specific r-smads, smad1 or smad8." SIGNOR-95474 SKIL protein P12757 UNIPROT SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR "down-regulates activity" binding 9606 BTO:0000848 12793438 t lperfetto "The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway" SIGNOR-253302 SKIL protein P12757 UNIPROT SMAD1/4 complex SIGNOR-C85 SIGNOR down-regulates binding 9606 12419246 t lperfetto "Ski also represses bmp signaling through interactions with smad4 and bmp-specific r-smads, smad1 or smad7" SIGNOR-217703 SKIL protein P12757 UNIPROT SMAD1/4 complex SIGNOR-C85 SIGNOR down-regulates binding 9606 22298955 t lperfetto "Ski also represses bmp signaling through interactions with smad4 and bmp-specific r-smads, smad1 or smad7" SIGNOR-217709 SKIL protein P12757 UNIPROT SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR "down-regulates activity" binding 9606 BTO:0000848 12793438 t lperfetto "The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway" SIGNOR-253303 ACTN1 protein P12814 UNIPROT PTK2 protein Q05397 UNIPROT "down-regulates activity" binding 9534 16291744 t lperfetto "Consistent with the results obtained with COS-7 cells, coexpression of wild-type Œ±-actinin with PTP 1B in PTP 1B-null cells resulted in Src/Œ±-actinin binding and limited the interaction between FAK and Src" SIGNOR-261799 ACE protein P12821 UNIPROT bradykinin smallmolecule CHEBI:3165 ChEBI "down-regulates quantity by destabilization" binding 9606 16219810 t "The angiotensin-converting enzyme (ACE) is a membrane-bound peptidyl dipeptidase known to act on a variety of peptide substrates in the extracellular space. Its most notable functions are the formation of angiotensin II and the degradation of bradykinin." SIGNOR-253341 ACE protein P12821 UNIPROT AGT protein P01019 UNIPROT "up-regulates activity" cleavage 9606 11076943 t gcesareni "Angiotensin I-converting enzyme is a zinc metallopeptidase that plays an important role in blood pressure regulation by cleaving the inactive decapeptide angiotensin I to angiotensin II, a potent vasopressor octapeptide." SIGNOR-253326 ACE protein P12821 UNIPROT Angiotensin-2 protein P01019_PRO_0000032458 UNIPROT "up-regulates quantity" cleavage 9606 32201502 t MIANNU "Ang I is subsequently converted into the major RAS effector peptide Ang II or Ang (1–8), through activity of the zinc-dependent protease ACE, which hydrolyzes two amino acids from the carboxy terminus of Ang I" SIGNOR-260236 CDH1 protein P12830 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 20940130 t gcesareni "P12Beta-catenin_ also associates to the_ wnt_ co-receptor lrp5/6, an interaction mediated by e-cadherin." SIGNOR-168464 CDH1 protein P12830 UNIPROT CTNNA1 protein P35221 UNIPROT up-regulates binding 9606 24336504 t milica "Additionally, the E-cadherin associated protein _-catenin regulates YAP directly by sequestering YAP/14-3-3 complexes in the cytoplasm." SIGNOR-203468 CDH1 protein P12830 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" binding 9606 21255999 t miannu "At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin" SIGNOR-265863 CDH1 protein P12830 UNIPROT "AE/b7 integrin" complex SIGNOR-C186 SIGNOR up-regulates binding 9606 BTO:0000782 7969453 t gcesareni "Here we show that heterotypic adhesive interactions between epithelial cells and intraepithelial lymphocytes in vitro are mediated by e-cadherin and the alpha e beta 7 integrin." SIGNOR-35210 CDH1 protein P12830 UNIPROT α-Catenin proteinfamily SIGNOR-PF72 SIGNOR "up-regulates activity" binding 9606 24336504 t miannu "Additionally, the E-cadherin associated protein _-catenin regulates YAP directly by sequestering YAP/14-3-3 complexes in the cytoplasm." SIGNOR-265821 SRC protein P12931 UNIPROT SH3PXD2B protein A1X283 UNIPROT "up-regulates activity" phosphorylation Tyr508 DMSASAGyEEISDPD 9606 BTO:0000007;BTO:0000182 20943948 t lperfetto "C-Src-mediated phosphorylation of NoxA1 and Tks4 induces the reactive oxygen species (ROS)-dependent formation of functional invadopodia in human colon cancer cells|Here, we show that the interaction of noxa1 and tks proteins is dependent on src activity. Interestingly, the abolishment of src-mediated phosphorylation of tyr110 on noxa1 and of tyr508 on tks4 blocks their binding and decreases nox1-dependent ros generation." SIGNOR-264705 SRC protein P12931 UNIPROT IKBKB protein O14920 UNIPROT up-regulates phosphorylation Tyr188 SFVGTLQyLAPELLE 9606 SIGNOR-C14 12645577 t gcesareni "These results indicate that c-src can associate with ikkbeta and phosphorylate its tyrosine residues after tnf-alfa or tpa stimulation." SIGNOR-99314 SRC protein P12931 UNIPROT INPPL1 protein O15357 UNIPROT up-regulates phosphorylation Tyr986 NSFNNPAyYVLEGVP 9606 12235291 t lperfetto "Ship2 could be phosphorylated in vitro by recombinant src kinase and tyrosines 986-987 in the npxy motif of ship2 appear to be the major sites of phosphorylation for src both in vitro and in vivo." SIGNOR-92931 SRC protein P12931 UNIPROT INPPL1 protein O15357 UNIPROT up-regulates phosphorylation Tyr987 SFNNPAYyVLEGVPH 9606 12235291 t lperfetto "Ship2 could be phosphorylated in vitro by recombinant src kinase and tyrosines 986-987 in the npxy motif of ship2 appear to be the major sites of phosphorylation for src both in vitro and in vivo." SIGNOR-92935 SRC protein P12931 UNIPROT RGS16 protein O15492 UNIPROT up-regulates phosphorylation Tyr168 TLMEKDSyPRFLKSP 9606 12588871 t miannu "Src-mediated rgs16 tyrosine phosphorylation promotes rgs16 stability. / this result suggests src phosphorylates native rgs16 at residue tyr177 in vitro." SIGNOR-98271 SRC protein P12931 UNIPROT RGS16 protein O15492 UNIPROT up-regulates phosphorylation Tyr177 RFLKSPAyRDLAAQA 9606 12588871 t lperfetto "Src-mediated rgs16 tyrosine phosphorylation promotes rgs16 stability. hosphorylation on tyr(168) was mediated by the epidermal growth factor receptor (egfr)." SIGNOR-98275 SRC protein P12931 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates phosphorylation Tyr373 SEDDEDCyGNYDNLL 9606 BTO:0000887;BTO:0001260 20643654 t miannu "Src-dependent pdk1 tyr373/376 tyrosine phosphorylation. / optimal activation of pdk1 requires phosphorylation of tyr373/376" SIGNOR-166718 SRC protein P12931 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates phosphorylation Tyr376 DEDCYGNyDNLLSQF 9606 BTO:0000887;BTO:0001260 20643654 t miannu "Src-dependent pdk1 tyr373/376 tyrosine phosphorylation. / optimal activation of pdk1 requires phosphorylation of tyr373/376" SIGNOR-166722 SRC protein P12931 UNIPROT PDPK1 protein O15530 UNIPROT "up-regulates activity" phosphorylation Tyr9 ARTTSQLyDAVPIQS 9606 BTO:0000007 11481331 t lperfetto "Using site-directed mutants, we show that, although phosphorylation on tyr-373/376 is important for pdk1 activity, phosphorylation on tyr-9 has no effect on the activity of the kinase. Both of these residues can be phosphorylated by v-src tyrosine kinase in vitro, and co-expression of v-src leads to tyrosine phosphorylation and activation of pdk1." SIGNOR-109533 SRC protein P12931 UNIPROT PROM1 protein O43490 UNIPROT unknown phosphorylation Tyr828 RMDSEDVyDDVETIP 9606 19296573 t llicata "Cd133 (prominin-1) is phosphorylated on cytoplasmic tyrosine-828 and tyrosine-852 by src" SIGNOR-184772 SRC protein P12931 UNIPROT PROM1 protein O43490 UNIPROT unknown phosphorylation Tyr852 GYHKDHVyGIHNPVM 9606 19296573 t llicata "Cd133 (prominin-1) is phosphorylated on cytoplasmic tyrosine-828 and tyrosine-852 by src" SIGNOR-184776 SRC protein P12931 UNIPROT CTNND1 protein O60716 UNIPROT "up-regulates activity" phosphorylation Tyr257 APSRQDVyGPQPQVR -1 11382764 t lperfetto "Identification of Src phosphorylation sites in the catenin p120ctn.Using selected tyrosine to phenylalanine p120 mutants as dominant negative reagents, it may now be possible to selectively block events postulated to be dependent on p120 tyrosine phosphorylation.combinations of Tyr _ Phe mutations at residues 96, 112, 228, 257, 280, 291, 296, and 302" SIGNOR-246488 SRC protein P12931 UNIPROT CTNND1 protein O60716 UNIPROT "up-regulates activity" phosphorylation Tyr280 HRFHPEPyGLEDDQR -1 11382764 t lperfetto "Identification of Src phosphorylation sites in the catenin p120ctn.Using selected tyrosine to phenylalanine p120 mutants as dominant negative reagents, it may now be possible to selectively block events postulated to be dependent on p120 tyrosine phosphorylation.combinations of Tyr _ Phe mutations at residues 96, 112, 228, 257, 280, 291, 296, and 302" SIGNOR-246492 SRC protein P12931 UNIPROT EMD protein P50402 UNIPROT down-regulates phosphorylation Tyr74 TRGDADMyDLPKKED 9606 BTO:0000567 BTO:0000887 19789182 t llicata "Src phosphorylated emerin specifically at y59, y74 and y95; interestingly y-to-f substitutions at identified src sites reduced recombinant emerin binding to endogenous baf" SIGNOR-188312 SRC protein P12931 UNIPROT CTNND1 protein O60716 UNIPROT "up-regulates activity" phosphorylation Tyr291 DDQRSMGyDDLDYGM -1 11382764 t lperfetto "Identification of Src phosphorylation sites in the catenin p120ctn.Using selected tyrosine to phenylalanine p120 mutants as dominant negative reagents, it may now be possible to selectively block events postulated to be dependent on p120 tyrosine phosphorylation.combinations of Tyr _ Phe mutations at residues 96, 112, 228, 257, 280, 291, 296, and 302" SIGNOR-246496 SRC protein P12931 UNIPROT CTNND1 protein O60716 UNIPROT "up-regulates activity" phosphorylation Tyr296 MGYDDLDyGMMSDYG -1 11382764 t lperfetto "Identification of Src phosphorylation sites in the catenin p120ctn.Using selected tyrosine to phenylalanine p120 mutants as dominant negative reagents, it may now be possible to selectively block events postulated to be dependent on p120 tyrosine phosphorylation.combinations of Tyr _ Phe mutations at residues 96, 112, 228, 257, 280, 291, 296, and 302" SIGNOR-246500 SRC protein P12931 UNIPROT DAB1 protein O75553 UNIPROT "up-regulates activity" phosphorylation Tyr185 KQCEQAVyQTILEED 10090 BTO:0000938 11279201 t lperfetto "Dab1 is rapidly phosphorylated when neurons isolated from embryonic brains are stimulated with Reelin, and several tyrosines have been implicated in this response. Mice with phenylalanine substitutions of all five tyrosines (Tyr(185), Tyr(198), Tyr(200), Tyr(220), and Tyr(232)) exhibit a reeler phenotype, implying that tyrosine phosphorylation is critical for Dab1 function. Here we report that, although Src can phosphorylate all five tyrosines in vitro, Tyr(198) and Tyr(220) represent the major sites of Reelin-induced Dab1 phosphorylation in embryonic neurons." SIGNOR-247072 SRC protein P12931 UNIPROT DAB1 protein O75553 UNIPROT "up-regulates activity" phosphorylation Tyr198 EDVEDPVyQYIVFEA 10090 BTO:0000938 11279201 t lperfetto "Dab1 is rapidly phosphorylated when neurons isolated from embryonic brains are stimulated with Reelin, and several tyrosines have been implicated in this response. Mice with phenylalanine substitutions of all five tyrosines (Tyr(185), Tyr(198), Tyr(200), Tyr(220), and Tyr(232)) exhibit a reeler phenotype, implying that tyrosine phosphorylation is critical for Dab1 function. Here we report that, although Src can phosphorylate all five tyrosines in vitro, Tyr(198) and Tyr(220) represent the major sites of Reelin-induced Dab1 phosphorylation in embryonic neurons." SIGNOR-247076 SRC protein P12931 UNIPROT DAB1 protein O75553 UNIPROT "up-regulates activity" phosphorylation Tyr232 SQKKEGVyDVPKSQP 10090 BTO:0000938 11279201 t lperfetto "Dab1 is rapidly phosphorylated when neurons isolated from embryonic brains are stimulated with Reelin, and several tyrosines have been implicated in this response. Mice with phenylalanine substitutions of all five tyrosines (Tyr(185), Tyr(198), Tyr(200), Tyr(220), and Tyr(232)) exhibit a reeler phenotype, implying that tyrosine phosphorylation is critical for Dab1 function. Here we report that, although Src can phosphorylate all five tyrosines in vitro, Tyr(198) and Tyr(220) represent the major sites of Reelin-induced Dab1 phosphorylation in embryonic neurons." SIGNOR-247084 SRC protein P12931 UNIPROT MPZL1 protein O95297 UNIPROT up-regulates phosphorylation Tyr241 SHQGPVIyAQLDHSG 9606 11751924 t lperfetto "Indeed, our studies indicated that cross-linking of pzr by cona lead to activation of c-src, which may be responsible for phosphorylation of pzr and possibly other proteins. Phosphorylation of pzr in turn recruits shp-2, which by itself is an essential signal transducertyrosine residues 241 and 263 embedded in the itims are responsible for the tyrosine phosphorylation of pzr" SIGNOR-113406 SRC protein P12931 UNIPROT MPZL1 protein O95297 UNIPROT up-regulates phosphorylation Tyr263 NKSESVVyADIRKN 9606 11751924 t lperfetto "Indeed, our studies indicated that cross-linking of pzr by cona lead to activation of c-src, which may be responsible for phosphorylation of pzr and possibly other proteins. Phosphorylation of pzr in turn recruits shp-2, which by itself is an essential signal transducertyrosine residues 241 and 263 embedded in the itims are responsible for the tyrosine phosphorylation of pzr" SIGNOR-113410 SRC protein P12931 UNIPROT ABL1 protein P00519 UNIPROT "up-regulates activity" phosphorylation Tyr226 KRNKPTVyGVSPNYD 9606 11847100 t lperfetto "c-Src-induced c-Abl activation involves phosphorylation of Y245 and Y412, two residues required for c-Abl mitogenic function." SIGNOR-246307 SRC protein P12931 UNIPROT ABL1 protein P00519 UNIPROT "up-regulates activity" phosphorylation Tyr393 RLMTGDTyTAHAGAK 9606 11847100 t lperfetto "c-Src-induced c-Abl activation involves phosphorylation of Y245 and Y412, two residues required for c-Abl mitogenic function." SIGNOR-246311 SRC protein P12931 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr869 LGAEEKEyHAEGGKV 9606 BTO:0000452 11983694 t lperfetto "In summary, this study describes a novel mechanism for metal-induced egfr transactivation, which is likely to be mediated by src through the phosphorylation site of tyr-845 on egfr. emanating from a variety of growth factor receptors, including egfry845 (e-e-k-e-y845-h-a-e)" SIGNOR-235921 SRC protein P12931 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr1016 DVVDADEyLIPQQGF 9606 8845374 t lperfetto "The c-terminal autophosphorylation domain of egfr was extensively phosphorylated by c-src./These studies revealed that y1086 was phosphorylated to a significantly higher extent by c-src than by egfr. Additionally, y1101 was identified as a unique c-src phosphorylation site" SIGNOR-44239 SRC protein P12931 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr1110 GSVQNPVyHNQPLNP 9606 8845374 t lperfetto "The c-terminal autophosphorylation domain of egfr was extensively phosphorylated by c-src./These studies revealed that y1086 was phosphorylated to a significantly higher extent by c-src than by egfr. Additionally, y1101 was identified as a unique c-src phosphorylation site." SIGNOR-44243 SRC protein P12931 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr1172 ISLDNPDyQQDFFPK 9606 8845374 t lperfetto "Revealed that peptides derived from egfr residues y992, y1086, y1101, and y1148 bound directly to the sh2 domain of c-src (figure 8c). These experiments demonstrate that a specific subset of egfr receptor c-src phosphorylation sites are also ligands for the sh2 domain of c-src.Cellular src functions as a co-transducer of transmembrane signals emanating from a variety of growth factor receptors, including egfr" SIGNOR-44251 SRC protein P12931 UNIPROT KRAS protein P01116 UNIPROT up-regulates phosphorylation 9606 9096340 t gcesareni "Expression of v-src, a transforming nonreceptor tyrosine kinase, results in ras activation, and ras function in nih 3t3 cells suppresses transformation by v-src, indicating that in these cells ras-dependent signaling pathways are required for v-src to exert its biological effects." SIGNOR-47152 SRC protein P12931 UNIPROT EMD protein P50402 UNIPROT down-regulates phosphorylation Tyr95 KGYNDDYyEESYFTT 9606 BTO:0000567 BTO:0000887 19789182 t llicata "Src phosphorylated emerin specifically at y59, y74 and y95; interestingly y-to-f substitutions at identified src sites reduced recombinant emerin binding to endogenous baf" SIGNOR-188316 SRC protein P12931 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Tyr537 CKNVVPLyDLLLEML 9606 BTO:0000150;BTO:0000567 9500442 t tpavlidou "Although the molecular mechanisms underlying ligand-independent activation of era are not completely understood, phosphorylation of a serine residue in af1 has been implicated in the response to epidermal growth factor. Era is also a target for tyrosine phosphorylation, anda single tyrosine residue located immediately adjacent to af2 has been identified as a substrate for src-family tyrosine kinases." SIGNOR-55857 SRC protein P12931 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Tyr340 RGQRDSSyYWEIEAS 9606 7692235 t gcesareni "We also show that phosphorylation of raf-1 on serine 338 by pak1 and tyrosines 340 and 341 by src relieves autoinhibition and that this occurs through a specific decrease in the binding of the raf-1 regulatory domain to its catalytic domain." SIGNOR-32081 SRC protein P12931 UNIPROT ANXA1 protein P04083 UNIPROT up-regulates phosphorylation Tyr21 IENEEQEyVQTVKSS 9606 24103589 t lperfetto "The authors identified several phosphorylated residues by a combination of peptide mapping and sequence analysis and showed that recombinant pp60c-src phosphorylates annexin a1 near its amino terminus, at tyrosine 21 (tyr21). Also polyoma virus middle t/pp60c-src complex, recombinant pp50v-abl, and the egf receptor/kinase phosphorylated the same tyrosine residue. It was also shown that serine 27 residue of anxa1 is the primary site phosphorylated by protein kinase c (pkc). In the same study, the threonine 41 residue has been identified as a pkc substrate as well. The adenosine cyclic 3_,5_-phosphate dependent protein kinase a (pka) phosphorylates anxa1 in its carboxyl-terminal core at the threonine 216 residue (thr216) [2].Finally in 2013 caron et al. showed the relevance of y21 phosphorylation for the anxa1 stability. In fact the authors demonstrated that the tyrosine 21 phosphorylation is crucial for anxa1 sumoylation induced by egf" SIGNOR-202796 SRC protein P12931 UNIPROT ITGB3 protein P05106 UNIPROT "down-regulates activity" phosphorylation Tyr773 DTANNPLyKEATSTF 9606 BTO:0003904 11723131 t lperfetto "The phosphorylation level of beta(3) integrin was modulated using a temperature-sensitive v-Src kinase. Increased beta(3) phosphorylation abolished alpha(v)beta(3)- but not alpha(5)beta(1)-mediated adhesion to fibronectin. Thus, phosphorylation of the cytoplasmic domain of beta(3) is a negative regulator of alpha(v)beta(3)-fibronectin binding strength." SIGNOR-247202 SRC protein P12931 UNIPROT ITGB2 protein P05107 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000876 25624455 t miannu "PTKs of the JAK and SRC families have a regulatory role in LFA-1 affinity triggering, with JAKs showing a positive role (3), whereas SRCs possibly have a negative role." SIGNOR-254740 SRC protein P12931 UNIPROT GSN protein P06396 UNIPROT unknown phosphorylation Tyr409 TDGLGLSyLSSHIAN -1 10210201 t llicata "Gelsolin phosphorylation by c-Src in the presence of lysophosphatidic acid also revealed Tyr438 as the most prominent site. Additional minor sites were found using the anti-phosphotyrosine bead immunoprecipitation method followed by MALDI-MS and PSD analysis. These sites, representing approximately 5% of the total phosphate incorporation, were identified as Tyr59, Tyr382, Tyr576, and Tyr624." SIGNOR-250780 SRC protein P12931 UNIPROT GSN protein P06396 UNIPROT unknown phosphorylation Tyr465 VPVPTNLyGDFFTGD -1 10210201 t llicata "Gelsolin phosphorylation by c-Src in the presence of lysophosphatidic acid also revealed Tyr438 as the most prominent site. Additional minor sites were found using the anti-phosphotyrosine bead immunoprecipitation method followed by MALDI-MS and PSD analysis. These sites, representing approximately 5% of the total phosphate incorporation, were identified as Tyr59, Tyr382, Tyr576, and Tyr624." SIGNOR-250784 SRC protein P12931 UNIPROT GSN protein P06396 UNIPROT unknown phosphorylation Tyr603 LKTPSAAyLWVGTGA -1 10210201 t llicata "Gelsolin phosphorylation by c-Src in the presence of lysophosphatidic acid also revealed Tyr438 as the most prominent site. Additional minor sites were found using the anti-phosphotyrosine bead immunoprecipitation method followed by MALDI-MS and PSD analysis. These sites, representing approximately 5% of the total phosphate incorporation, were identified as Tyr59, Tyr382, Tyr576, and Tyr624." SIGNOR-250782 SRC protein P12931 UNIPROT GSN protein P06396 UNIPROT unknown phosphorylation Tyr651 ALGGKAAyRTSPRLK -1 10210201 t llicata "Gelsolin phosphorylation by c-Src in the presence of lysophosphatidic acid also revealed Tyr438 as the most prominent site. Additional minor sites were found using the anti-phosphotyrosine bead immunoprecipitation method followed by MALDI-MS and PSD analysis. These sites, representing approximately 5% of the total phosphate incorporation, were identified as Tyr59, Tyr382, Tyr576, and Tyr624." SIGNOR-250783 SRC protein P12931 UNIPROT GSN protein P06396 UNIPROT up-regulates phosphorylation Tyr465 VPVDPATyGQFYGGD 9606 10210201 t lperfetto "Identification of tyr438 as the major in vitro c-src phosphorylation site in human gelsolin recently" SIGNOR-67014 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT up-regulates phosphorylation Tyr1166 DIYETDYyRKGGKGL 9606 8940173 t lperfetto "Src phosphorylates the insulin-like growth factor type i receptor on the autophosphorylation sites. Requirement for transformation by srcsrc kinase can substitute for the receptor kinase in phosphorylating and activating the igf-i receptor" SIGNOR-45130 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT "up-regulates activity" phosphorylation Tyr1161 FGMTRDIyETDYYRK -1 7493944 t 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 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-246272 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT "up-regulates activity" phosphorylation Tyr1166 DIYETDYyRKGGKGL -1 7493944 t 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 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-246268 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT "up-regulates activity" phosphorylation Tyr1346 SFDERQPyAHMNGGR -1 7493944 t 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 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-246276 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT "up-regulates activity" phosphorylation Tyr973 RLGNGVLyASVNPEY -1 8940173 t 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 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-247193 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT "up-regulates activity" phosphorylation Tyr980 YASVNPEyFSAADVY -1 8940173 t 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 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-247197 SRC protein P12931 UNIPROT HSP90AB1 protein P08238 UNIPROT up-regulates phosphorylation Tyr301 DDITQEEyGEFYKSL 9606 17855507 t lperfetto "C-src directly phosphorylates hsp90 on tyrosine 300 residue and that this event is essential for vegf-stimulated enos association to hsp90 and thus no release from endothelial cells." SIGNOR-157781 SRC protein P12931 UNIPROT VIL1 protein P09327 UNIPROT "up-regulates activity" phosphorylation Tyr60 KTASSLSyDIHYWIG 9606 BTO:0000567 15342783 t lperfetto "These data suggest that phosphorylation of villin by c-src is involved in the actin cytoskeleton remodeling necessary for cell migration.To further investigate the role of tyrosine phosphorylated villin in cell migration, we used phosphorylation site mutants (tyrosine to phenylalanine or tyrosine to glutamic acid) in HeLa cells. We determined that tyrosine phosphorylation at residues 60, 81, and 256 of human villin played an essential role in cell migration as well as in the reorganization of the actin cytoskeleton" SIGNOR-247437 SRC protein P12931 UNIPROT VIL1 protein P09327 UNIPROT "up-regulates activity" phosphorylation Tyr81 EQGAAAIyTTQMDDF 9606 BTO:0000567 15342783 t lperfetto "These data suggest that phosphorylation of villin by c-src is involved in the actin cytoskeleton remodeling necessary for cell migration.To further investigate the role of tyrosine phosphorylated villin in cell migration, we used phosphorylation site mutants (tyrosine to phenylalanine or tyrosine to glutamic acid) in HeLa cells. We determined that tyrosine phosphorylation at residues 60, 81, and 256 of human villin played an essential role in cell migration as well as in the reorganization of the actin cytoskeleton" SIGNOR-247441 SRC protein P12931 UNIPROT RRAS protein P10301 UNIPROT "down-regulates activity" phosphorylation Tyr66 DPTIEDSyTKICSVD 9606 BTO:0000007 11682467 t lperfetto "The small gtpase, r-ras, affects cell adhesion by maintaining integrin activity. Activated src oncogene phosphorylates r-ras and suppresses integrin activity. the src phosphorylation site in r-ras was tyrosine 66" SIGNOR-111189 SRC protein P12931 UNIPROT ARAF protein P10398 UNIPROT up-regulates phosphorylation Tyr301 LGYRDSGyYWEVPPS 9534 BTO:0004055 9020159 t lperfetto "A-raf behaves like raf-1, being weakly activated by oncogenic ras more strongly activated by oncogenic src, and these signals synergize to give maximal activation. Activation of Raf-1 and A-Raf by Src requires tyrosine phosphorylation at residues 340 and 341 in Raf-1 and 301 and 302 in A-Raf." SIGNOR-236037 SRC protein P12931 UNIPROT CYP19A1 protein P11511 UNIPROT up-regulates phosphorylation Tyr361 KVMENFIyESMRYQP 9606 BTO:0000150 19556341 t amattioni "Phosphorylation of the 361-tyrosine residue is crucial in the up-regulation of aromatase activity. c-src protein directly phosphorylates aromatase on tyrosine 361." SIGNOR-186284 SRC protein P12931 UNIPROT SRC protein P12931 UNIPROT "down-regulates activity" phosphorylation Tyr530 FTSTEPQyQPGENL 9606 8755732 t lperfetto "Rapid digestion of pp60c-src tyrosine kinase (src TK) in combination with electrospray ionization mass spectrometry enabled the determination of the time course for autophosphorylation of three tyrosine sites (Y338, Y419, and Y530) and a correlation with src TK activity. Here, conditions were identified which promoted essentially complete autophosphorylation of y530. Phosphorylation of y530 was directly correlated to a decrease in tyrosine kinase activity" SIGNOR-43315 SRC protein P12931 UNIPROT SRC protein P12931 UNIPROT up-regulates phosphorylation Tyr419 RLIEDNEyTARQGAK 9606 7578094 t lperfetto "These data are consistent with autophosphorylation on y-419 as predicted. Intermolecular autophosphorylation is consistent with the ability of srctk to dimerize, which is analogous to activation of receptor tyrosine kinases such as the egf receptor kinase in response to growth factors." SIGNOR-29369 SRC protein P12931 UNIPROT CEACAM1 protein P13688 UNIPROT "up-regulates activity" phosphorylation Tyr493 NKMNEVTySTLNFEA 9606 BTO:0000007 9867848 t lperfetto "Recent reports have also suggested that Bgp1 behaves as a signal transduction molecule. Several physiological events promote the Tyr phosphorylation of Bgp1 on one or two Tyr residues within its cytoplasmic domain (Tyr-488 and Tyr-515). BGP becomes Tyr-phosphorylated by Src-like Tyr kinases in activated neutrophils (24) and in human colon carcinoma cellsWe have recently shown that Tyr phosphorylation of the mouse Bgp1 cytoplasmic domain in CT51 mouse colonic carcinoma cells led to its binding to the protein-Tyr phosphatase SHP-1 and that this event required the presence of both Tyr-488 and Tyr-515" SIGNOR-246471 SRC protein P12931 UNIPROT CEACAM1 protein P13688 UNIPROT "up-regulates activity" phosphorylation Tyr520 LTATEIIySEVKKQ 9606 BTO:0000007 9867848 t lperfetto "Recent reports have also suggested that Bgp1 behaves as a signal transduction molecule. Several physiological events promote the Tyr phosphorylation of Bgp1 on one or two Tyr residues within its cytoplasmic domain (Tyr-488 and Tyr-515). BGP becomes Tyr-phosphorylated by Src-like Tyr kinases in activated neutrophils (24) and in human colon carcinoma cellsWe have recently shown that Tyr phosphorylation of the mouse Bgp1 cytoplasmic domain in CT51 mouse colonic carcinoma cells led to its binding to the protein-Tyr phosphatase SHP-1 and that this event required the presence of both Tyr-488 and Tyr-515" SIGNOR-246475 SRC protein P12931 UNIPROT VCL protein P18206 UNIPROT "down-regulates activity" phosphorylation Tyr1133 WVRKTPWyQ 9534 15229287 t lperfetto "The phosphorylation of vinculin on tyrosine residues 100 and 1065, mediated by SRC kinases, affects cell spreadingWhen phosphorylated, the vinculin tail exhibited significantly less binding to the vinculin head domain than the unphosphorylated tail." SIGNOR-247428 SRC protein P12931 UNIPROT CDH2 protein P19022 UNIPROT down-regulates phosphorylation Tyr860 DSLLVFDyEGSGSTA 9606 BTO:0000848 16371504 t lperfetto "Src-mediated phosphorylation of the n-cadherin cytoplasmic domain results in a significant reduction in beta-catenin bindingbeta-catenin dissociates from n-cadherin and redistributes to the nucleus of transmigrating melanoma cells to activate gene transcription.Because there were only four tyrosine residues (y852, y860, y884, and y886) in this peptide, all of them were phosphorylated." SIGNOR-143238 SRC protein P12931 UNIPROT CDH2 protein P19022 UNIPROT down-regulates phosphorylation Tyr884 SSGGEQDyDYLNDWG 9606 BTO:0000848 16371504 t lperfetto "Src-mediated phosphorylation of the n-cadherin cytoplasmic domain results in a significant reduction in beta-catenin bindingbeta-catenin dissociates from n-cadherin and redistributes to the nucleus of transmigrating melanoma cells to activate gene transcription.Because there were only four tyrosine residues (y852, y860, y884, and y886) in this peptide, all of them were phosphorylated." SIGNOR-143242 SRC protein P12931 UNIPROT CDH2 protein P19022 UNIPROT down-regulates phosphorylation Tyr886 GGEQDYDyLNDWGPR 9606 BTO:0000848 16371504 t lperfetto "Src-mediated phosphorylation of the n-cadherin cytoplasmic domain results in a significant reduction in beta-catenin bindingbeta-catenin dissociates from n-cadherin and redistributes to the nucleus of transmigrating melanoma cells to activate gene transcription.Because there were only four tyrosine residues (y852, y860, y884, and y886) in this peptide, all of them were phosphorylated." SIGNOR-143246 SRC protein P12931 UNIPROT PLCG1 protein P19174 UNIPROT "up-regulates activity" phosphorylation Tyr783 EGRNPGFyVEANPMP -1 7682059 t lperfetto "The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors." SIGNOR-247316 SRC protein P12931 UNIPROT GRK2 protein P25098 UNIPROT "up-regulates activity" phosphorylation Tyr13 AVLADVSyLMAMEKS 9606 BTO:0000007 16725308 t miannu "Here, we demonstrate that c-Src kinase activity increases the interaction between GRK2 and Galphaq. Tyrosine phosphorylation of GRK2 appears to be critically involved in the modulation of this interaction since the stimulatory effect of c-Src is not observed with a GRK2 mutant with impaired tyrosine phosphorylation (GRK2 Y13,86,92F), whereas a mutant that mimics GRK2 tyrosine phosphorylation in these residues displays an increased interaction with Galphaq. " SIGNOR-266307 SRC protein P12931 UNIPROT GRK2 protein P25098 UNIPROT "up-regulates activity" phosphorylation Tyr86 ARPLVEFyEEIKKYE 9606 BTO:0000007 16725308 t miannu "Here, we demonstrate that c-Src kinase activity increases the interaction between GRK2 and Galphaq. Tyrosine phosphorylation of GRK2 appears to be critically involved in the modulation of this interaction since the stimulatory effect of c-Src is not observed with a GRK2 mutant with impaired tyrosine phosphorylation (GRK2 Y13,86,92F), whereas a mutant that mimics GRK2 tyrosine phosphorylation in these residues displays an increased interaction with Galphaq. " SIGNOR-266306 SRC protein P12931 UNIPROT GRK2 protein P25098 UNIPROT "up-regulates activity" phosphorylation Tyr92 FYEEIKKyEKLETEE 9606 BTO:0000007 16725308 t miannu "Here, we demonstrate that c-Src kinase activity increases the interaction between GRK2 and Galphaq. Tyrosine phosphorylation of GRK2 appears to be critically involved in the modulation of this interaction since the stimulatory effect of c-Src is not observed with a GRK2 mutant with impaired tyrosine phosphorylation (GRK2 Y13,86,92F), whereas a mutant that mimics GRK2 tyrosine phosphorylation in these residues displays an increased interaction with Galphaq. " SIGNOR-266305 SRC protein P12931 UNIPROT SHC1 protein P29353 UNIPROT "up-regulates activity" phosphorylation Tyr350 EPPDHQYyNDFPGKE 9606 8939605 t lperfetto "Here, we report the identification of two major and novel Shc tyrosine phosphorylation sites, Y239 and Y240. Y239/240 are co-ordinately phosphorylated by the src protein-tyrosine kinase in vitro, and in response to epidermal growth factor stimulation or in v-src-transformed cells in vivo. phosphorylation of y317 has been implicated in grb2 binding and activation of the ras pathway." SIGNOR-44870 SRC protein P12931 UNIPROT BDKRB2 protein P30411 UNIPROT up-regulates phosphorylation Tyr177 GVRWAKLySLVIWGC 9606 16226010 t lperfetto "Here we demonstrate that egf is capable of inducing src-mediated phosphorylation of the tyrosine residues 177 and 347 of bkr. Their replacement by phenylalanine led to bkr mutants which are unable to activate the camp pathway." SIGNOR-141103 SRC protein P12931 UNIPROT BDKRB2 protein P30411 UNIPROT up-regulates phosphorylation Tyr347 RKKSWEVyQGVCQKG 9606 16226010 t lperfetto "Here we demonstrate that egf is capable of inducing src-mediated phosphorylation of the tyrosine residues 177 and 347 of bkr. Their replacement by phenylalanine led to bkr mutants which are unable to activate the camp pathway." SIGNOR-141107 SRC protein P12931 UNIPROT HLA-A protein P30443 UNIPROT unknown phosphorylation Tyr344 SDRKGGSyTQAASSD 9606 6304688 t lperfetto "Hla-a2 and hla-b7 antigens are phosphorylated in vitro by rous sarcoma virus kinase (pp60v-src) at a tyrosine residue encoded in a highly conserved exon of the intracellular domain." SIGNOR-25566 SRC protein P12931 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation Tyr326 EVLEDNDyGRAVDWW 9534 BTO:0004055 11445557 t lperfetto "Regulation of Akt/PKB Activation by Tyrosine PhosphorylationAs shown in Fig. 2 d, while mutation of Tyr340 has little effect on either tyrosine phosphorylation or kinase activity of Akt induced by Src527F, substitution of Tyr315 or Tyr326 with a phenylalanine, respectively, dramatically reduces both the tyrosine phosphorylation and kinase activity of Akt. The combination of these two mutations abolishes Src-induced tyrosine phosphorylation of Akt as well as its kinase activity." SIGNOR-252623 SRC protein P12931 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation Tyr315 TFCGTPEyLAPEVLE 9606 BTO:0000007 12600984 t lperfetto "We also showed that phosphorylation of Tyr-315 in Akt induced by Src or EGF is dependent on the integrity of this proline-rich motif. Furthermore, the Akt mutant lacking this proline motif fails to block the transcription activity of Forkhead in 293 cells and poorly stimulates the proliferation of Madin-Darby canine kidney cells. Taken together, our data suggest that the interaction between the SH3 domain of Src family kinases and the proline-rich motif in the C-terminal regulatory region of Akt is required for tyrosine phosphorylation of Akt and its subsequent activation." SIGNOR-252621 SRC protein P12931 UNIPROT CDH5 protein P33151 UNIPROT "down-regulates activity" phosphorylation Tyr658 GEMDTTSyDVSVLNS 10029 BTO:0000246 16027153 t lperfetto "cadherins also act to prevent epithelial cell motilityCadherin-cytoskeletal interactions occur through a number of adaptor proteins that interact with the C-terminal portion of the cadherin cytoplasmic tail, including the _-, _-, and _-catenin (6, 10). Additionally, VE-cadherin stability at the plasma membrane may be regulated by the binding of p120-catenin to the juxtamembrane region of the cytoplasmic tailWe show here that tyrosine phosphorylation of the adherens junction protein VE-cadherin at two critical tyrosines, Tyr-658 and Tyr-731, via tyrosine kinase activation or phosphatase inactivation was sufficient to prevent the binding of p120- and beta-catenin, respectively, to the cytoplasmic tail of VE-cadherinVE-cadherin becomes phosphorylated on Tyr-658 and/or Tyr-731 in response to Src kinase activity." SIGNOR-246462 SRC protein P12931 UNIPROT MAPK7 protein Q13164 UNIPROT up-regulates 9606 BTO:0000142 11782488 f gcesareni "C-src was suggested to be involved in bmk1 activation from the experiments with herbimycin a and pp2, specific inhibitors of src family kinases." SIGNOR-113779 SRC protein P12931 UNIPROT CDH5 protein P33151 UNIPROT "down-regulates activity" phosphorylation Tyr731 PYDTLHIyGYEGSES 10029 BTO:0000246 16027153 t lperfetto "cadherins also act to prevent epithelial cell motilityCadherin-cytoskeletal interactions occur through a number of adaptor proteins that interact with the C-terminal portion of the cadherin cytoplasmic tail, including the _-, _-, and _-catenin (6, 10). Additionally, VE-cadherin stability at the plasma membrane may be regulated by the binding of p120-catenin to the juxtamembrane region of the cytoplasmic tailWe show here that tyrosine phosphorylation of the adherens junction protein VE-cadherin at two critical tyrosines, Tyr-658 and Tyr-731, via tyrosine kinase activation or phosphatase inactivation was sufficient to prevent the binding of p120- and beta-catenin, respectively, to the cytoplasmic tail of VE-cadherinVE-cadherin becomes phosphorylated on Tyr-658 and/or Tyr-731 in response to Src kinase activity." SIGNOR-246466 SRC protein P12931 UNIPROT CDH5 protein P33151 UNIPROT up-regulates phosphorylation Tyr685 LDARPSLyAQVQKPP 9606 BTO:0000975 16909109 t llicata "In vitro src assay, the ve-cadherin cytoplasmic domain is directly phosphorylated by purified src as well as the tyrosine residue 685 (tyr)685-containing peptide finally, we found that in a vegf-induced wound-healing assay, cadherin adhesive activity was impaired by src kinase inhibitors.RPSLY(685)aqvq." SIGNOR-148818 SRC protein P12931 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Tyr86 VADIDGQyAMTRAQR 9606 BTO:0000038 11279024 t lperfetto "beta-catenin is a good substrate of pp60c- srctyrosine kinase in vitro;this kinase modifies specifically tyr-86 and tyr-654although consistently detected, this negative effect of tyr-86 phosphorylation on tbp binding was clearly less important than the positive effect observed after tyr-654 phosphorylation." SIGNOR-106458 SRC protein P12931 UNIPROT CHKA protein P35790 UNIPROT "up-regulates activity" phosphorylation Tyr197 RSLGPKLyGIFPQGR 9606 BTO:0000093 21822308 t miannu "We find that CHKA forms a complex with EGFR in a c-Src-dependent manner. Endogenous CHKA and EGFR co-immunoprecipitated from a variety of breast cancer cell lines and immortalized mammary epithelial cells. CHKA interacted with the EGFR kinase domain upon c-Src co-overexpression and was phosphorylated in a c-Src-dependent manner on Y197 and Y333." SIGNOR-266351 SRC protein P12931 UNIPROT CHKA protein P35790 UNIPROT "up-regulates activity" phosphorylation Tyr333 LMLIDFEySSYNYRG 9606 BTO:0000093 21822308 t miannu "We find that CHKA forms a complex with EGFR in a c-Src-dependent manner. Endogenous CHKA and EGFR co-immunoprecipitated from a variety of breast cancer cell lines and immortalized mammary epithelial cells. CHKA interacted with the EGFR kinase domain upon c-Src co-overexpression and was phosphorylated in a c-Src-dependent manner on Y197 and Y333." SIGNOR-266350 SRC protein P12931 UNIPROT FLT4 protein P35916 UNIPROT up-regulates phosphorylation Tyr1063 FGLARDIyKDPDYVR 9606 20431062 t lperfetto "Vegfr-3 is a direct c-src target and mass spectrometry analysis identified the sites phosphorylated by c-src as tyrosine 830, 833, 853, 1063, 1333, and 1337 vegfr-3 phosphorylation activates the recruitment to the receptor of the adaptor proteins crki/ii and shc inducing activation of jnk." SIGNOR-165035 SRC protein P12931 UNIPROT FLT4 protein P35916 UNIPROT up-regulates phosphorylation Tyr1333 ARGGQVFyNSEYGEL 9606 20431062 t lperfetto "Vegfr-3 is a direct c-src target and mass spectrometry analysis identified the sites phosphorylated by c-src as tyrosine 830, 833, 853, 1063, 1333, and 1337, demonstrating that integrin-mediated receptor phosphorylation induces a phosphorylation pattern that is distinct from that induced by growth factors. Furthermore, pull-down assays show that integrin-mediated vegfr-3 phosphorylation activates the recruitment to the receptor of the adaptor proteins crki/ii and shc inducing activation of jnk." SIGNOR-165039 SRC protein P12931 UNIPROT FLT4 protein P35916 UNIPROT up-regulates phosphorylation Tyr1337 QVFYNSEyGELSEPS 9606 20431062 t lperfetto "Vegfr-3 is a direct c-src target and mass spectrometry analysis identified the sites phosphorylated by c-src as tyrosine 830, 833, 853, 1063, 1333, and 1337, demonstrating that integrin-mediated receptor phosphorylation induces a phosphorylation pattern that is distinct from that induced by growth factors. Furthermore, pull-down assays show that integrin-mediated vegfr-3 phosphorylation activates the recruitment to the receptor of the adaptor proteins crki/ii and shc inducing activation of jnk." SIGNOR-165043 SRC protein P12931 UNIPROT FLT4 protein P35916 UNIPROT up-regulates phosphorylation Tyr830 PLEEQCEyLSYDASQ 9606 20431062 t lperfetto "Vegfr-3 is a direct c-src target and mass spectrometry analysis identified the sites phosphorylated by c-src as tyrosine 830, 833, 853, 1063, 1333, and 1337 vegfr-3 phosphorylation activates the recruitment to the receptor of the adaptor proteins crki/ii and shc inducing activation of jnk." SIGNOR-165047 SRC protein P12931 UNIPROT FLT4 protein P35916 UNIPROT up-regulates phosphorylation Tyr833 EQCEYLSyDASQWEF 9606 20431062 t lperfetto "Vegfr-3 is a direct c-src target and mass spectrometry analysis identified the sites phosphorylated by c-src as tyrosine 830, 833, 853, 1063, 1333, and 1337, demonstrating that integrin-mediated receptor phosphorylation induces a phosphorylation pattern that is distinct from that induced by growth factors. Furthermore, pull-down assays show that integrin-mediated vegfr-3 phosphorylation activates the recruitment to the receptor of the adaptor proteins crki/ii and shc inducing activation of jnk." SIGNOR-165051 SRC protein P12931 UNIPROT FLT4 protein P35916 UNIPROT up-regulates phosphorylation Tyr853 HLGRVLGyGAFGKVV 9606 20431062 t lperfetto "Vegfr-3 is a direct c-src target and mass spectrometry analysis identified the sites phosphorylated by c-src as tyrosine 830, 833, 853, 1063, 1333, and 1337 vegfr-3 phosphorylation activates the recruitment to the receptor of the adaptor proteins crki/ii and shc inducing activation of jnk." SIGNOR-165055 SRC protein P12931 UNIPROT CHRNA7 protein P36544 UNIPROT down-regulates phosphorylation Tyr442 KILEEVRyIANRFRC 9606 BTO:0000938 16251431 t lperfetto "Alpha7 neuronal nicotinic acetylcholine receptors are negatively regulated by tyrosine phosphorylation and src-family kinasesmutant alpha7 nachrs lacking cytoplasmic loop tyrosine residues because of alanine replacement of tyr-386 and tyr-442 were more active than wild-type receptorsexpression of active src reduced _7 nachr activity" SIGNOR-141311 SRC protein P12931 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000007 14551213 t lperfetto "In the present study, we have delineated the mechanism by which Galpha16 stimulates STAT3 in human embryonic kidney 293 cells. A constitutively active Galpha16 mutant, Galpha16QL, stimulated STAT3-dependent luciferase activity as well as the phosphorylation of STAT3 at both Tyr705 and Ser727.The involvement of tyrosine kinases such as c-Src and Janus kinase 2 and 3 (JAK2 and JAK3) in Galpha16QL-induced activation of STAT3 was illustrated by the combined use of selective inhibitors and dominant negative mutants." SIGNOR-247341 SRC protein P12931 UNIPROT PPP2CA protein P67775 UNIPROT down-regulates phosphorylation Tyr307 VTRRTPDyFL 9606 BTO:0000938 23796501 t llicata "We found that ?-Syn gene overexpression in sk-n-sh cells and primary neurons led to pp2a/c phosphorylation at y307, a known target of src kinase, and consequent phosphatase inhibition." SIGNOR-202192 SRC protein P12931 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0000944 9566874 t lperfetto "Previous studies have demonstrated that one STAT family member, Stat3, possesses constitutively elevated tyrosine phosphorylation and DNA-binding activity in fibroblasts stably transformed by the Src oncoprotein.We conclude that Stat3 activation by the Src oncoprotein leads to specific gene regulation and that Stat3 is one of the critical signaling pathways involved in Src oncogenesis." SIGNOR-235445 SRC protein P12931 UNIPROT HNF4A protein P41235 UNIPROT down-regulates phosphorylation Tyr23 SAALDPAyTTLEFEN 9606 22308320 t lperfetto "Here we show that c-src phosphorylates human hnf4_ on three tyrosines phosphomimetic mutants in the lbd decrease p1-hnf4_ protein stability, nuclear localization and transactivation function." SIGNOR-195883 SRC protein P12931 UNIPROT HNF4A protein P41235 UNIPROT down-regulates phosphorylation Tyr286 LQIDDNEyAYLKAII 9606 22308320 t lperfetto "Here we show that c-src phosphorylates human hnf4_ on three tyrosines phosphomimetic mutants in the lbd decrease p1-hnf4_ protein stability, nuclear localization and transactivation function." SIGNOR-195896 SRC protein P12931 UNIPROT HNF4A protein P41235 UNIPROT down-regulates phosphorylation Tyr288 IDDNEYAyLKAIIFF 9606 22308320 t lperfetto "Here we show that c-src phosphorylates human hnf4_ on three tyrosines phosphomimetic mutants in the lbd decrease p1-hnf4_ protein stability, nuclear localization and transactivation function." SIGNOR-195900 SRC protein P12931 UNIPROT PRKCI protein P41743 UNIPROT up-regulates phosphorylation Tyr265 RVIGRGSyAKVLLVR 9606 11713277 t llicata "Nerve growth factor stimulates multisite tyrosine phosphorylation and activation of the atypical protein kinase c's via a src kinase pathway. tyrosine 256, 271, and 325 were identified as major sites phosphorylated by src in the catalytic domain." SIGNOR-111920 SRC protein P12931 UNIPROT PRKCI protein P41743 UNIPROT up-regulates phosphorylation Tyr280 LKKTDRIyAMKVVKK 9606 11713277 t llicata "Nerve growth factor stimulates multisite tyrosine phosphorylation and activation of the atypical protein kinase c's via a src kinase pathway. tyrosine 256, 271, and 325 were identified as major sites phosphorylated by src in the catalytic domain." SIGNOR-111924 SRC protein P12931 UNIPROT STAT1 protein P42224 UNIPROT "up-regulates activity" phosphorylation Tyr701 DGPKGTGyIKTELIS 9606 BTO:0000763 14978237 t lperfetto "The tyr701 phosphorylation of signal transducer and activator of transcription 1 (stat1) induced by interferon-gamma (ifn-gamma) and 12-o-tetradecanoylphorbol 13-acetate (tpa) was inhibited by the protein kinase c (pkc) inhibitor staurosporine, the tyrosine kinase inhibitor herbimycin, or the src kinase inhibitor pp2. An association between c-src and stat1 was increased by ifn-gamma and tpa, indicating the direct phosphorylation of stat1 by pkc-dependent c-src activation." SIGNOR-235696 SRC protein P12931 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Tyr88 KGSLPEFyYRPPRPP 9606 BTO:0000150 17254967 t lperfetto "Src regulates p27 stability through phosphorylation of p27 at tyrosine 74 and tyrosine 88. Our data indicate that phosphorylation by src impairs the cdk2 inhibitory action of p27" SIGNOR-152835 SRC protein P12931 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Tyr89 GSLPEFYyRPPRPPK 9606 BTO:0000150 17254967 t lperfetto "Src regulates p27 stability through phosphorylation of p27 at tyrosine 74 and tyrosine 88. Our data indicate that phosphorylation by src impairs the cdk2 inhibitory action of p27" SIGNOR-152839 SRC protein P12931 UNIPROT KCNJ1 protein P48048 UNIPROT down-regulates phosphorylation Tyr337 SKTKEGKyRVDFHNF 9606 12217858 t gcesareni "Addition of active c-src and [32p]atp to the purified romk1 protein resulted in the phosphorylation of the romk1 protein. However, c-src did not phosphorylate r1y337a in which tyrosine residue 337 was mutated to alanine. Furthermore, phosphopeptide mapping identified two phosphopeptides from the trypsin-digested romk1 protein." SIGNOR-92513 SRC protein P12931 UNIPROT KCNJ1 protein P48048 UNIPROT down-regulates phosphorylation Tyr337 SKTKEGKyRVDFHNF 9606 12556363 t flangone "Inhibition of c-src with herbimycin a significantly decreased the tyrosine phosphorylation level of romk1... tyrosine dephosphorylation enhances the exocytosis of romk1" SIGNOR-97803 SRC protein P12931 UNIPROT GLRB protein P48167 UNIPROT up-regulates phosphorylation Tyr435 RDFELSNyDCYGKPI 9606 BTO:0000938 BTO:0000142;BTO:0000671 11882681 t gcesareni "These findings indicate that glyr function is upregulated by ptks and this modulation is dependent on the tyrosine-413 residue of the beta subunit." SIGNOR-115705 SRC protein P12931 UNIPROT PXN protein P49023 UNIPROT "up-regulates activity" phosphorylation Tyr88 PQSSSPVyGSSAKTS 9606 BTO:0000182 27447856 t lperfetto "Here, we demonstrate that Src kinase directly phosphorylates Y88 paxillin|In this study, we also show how pY88 paxillin transduces a signal to activate Akt" SIGNOR-263977 SRC protein P12931 UNIPROT ARRB1 protein P49407 UNIPROT down-regulates phosphorylation Tyr54 YLKERRVyVTLTCAF 9606 17456551 t lperfetto "Using fluorescently tagged proteins combined with resonance energy transfer and image cross-correlation spectroscopy approaches, we show in live cells that beta2-adaptin phosphorylation is an important regulatory process for the dissociation of beta-arrestin-AP-2 complexes in CCPs. Finally, we show that beta2-adaptin phosphorylation is involved in the early steps of receptor internalization. Our findings not only unveil beta2-adaptin as a new Src target during AT1R internalization, but also support the role of receptor-mediated signaling in the control of clathrin-dependent endocytosis of receptors." SIGNOR-154564 SRC protein P12931 UNIPROT FHIT protein P49789 UNIPROT "up-regulates activity" phosphorylation Tyr114 FHRNDSIyEELQKHD -1 15835917 t lperfetto "The human tumor suppressor Fhit is a homodimeric histidine triad (HIT) protein of 147 amino acids which has Ap3A hydrolase activity. We have recently discovered that Fhit is phosphorylated in vivo and is phosphorylated in vitro by Src kinaseMALDI-TOF and HPLC-ESI tandem mass spectrometry of intact Fhit and proteolytic peptides of Fhit demonstrated that Fhit is phosphorylated on Y114 on either one or both subunitsThe decreases in the values of Km and kcat for the phosphorylated forms in comparison to those of unphosphorylated Fhit favor the formation and lifetime of the Fhit_Ap3A complex, which may enhance the tumor suppressor activity of Fhit." SIGNOR-247134 SRC protein P12931 UNIPROT MMP14 protein P50281 UNIPROT unknown phosphorylation Tyr573 GTPRRLLyCQRSLLD 9606 17389600 t llicata "We show that mt1-mmp is phosphorylated on the unique tyrosine residue located within this cytoplasmic sequence (tyr(573)) and that this phosphorylation requires the kinase src. accordingly, overexpression of a nonphosphorylable mt1-mmp mutant (y573f) blocked sphingosine-1-phosphate-induced migration of human umbilical vein endothelial cells and ht-1080 (human fibrosarcoma) cells and failed to stimulate migration of cells lacking the enzyme (bovine aortic endothelial cells)." SIGNOR-154006 SRC protein P12931 UNIPROT EMD protein P50402 UNIPROT down-regulates phosphorylation Tyr59 SSSAASSySFSDLNS 9606 BTO:0000567 BTO:0000887 19789182 t llicata "Src phosphorylated emerin specifically at y59, y74 and y95; interestingly y-to-f substitutions at identified src sites reduced recombinant emerin binding to endogenous baf" SIGNOR-188308 SRC protein P12931 UNIPROT STAT5B protein P51692 UNIPROT up-regulates phosphorylation Tyr679 DRPKDEVySKYYTPV 9606 12621061 t llicata "Stat5 is activated by a broad spectrum of cytokines, as well as non-receptor tyrosine kinases, such as src. these conformational differences may in part be due to differential effects of prl and src on stat5b tyrosine phosphorylation, since src induced several additional sites of tyrosine phosphorylation of stat5b at residues other than tyr-699, including tyr-724 and tyr-679." SIGNOR-99002 SRC protein P12931 UNIPROT RPS6KA3 protein P51812 UNIPROT unknown phosphorylation Tyr488 DVYDDGKyVYVVTEL 9606 BTO:0000007 18156174 t llicata "The results showed that tyr-488 is a major site of src but mutations at tyr-529 or tyr-707 did not significantly decrease src-dependent tyrosine phosphorylation of rsk2 (fig. 4c). However, we have previously characterized the tyr-488 site that is also phosphorylated by fgfr3 (14), and substitution of tyr-488 did not affect rsk2 activation." SIGNOR-160056 SRC protein P12931 UNIPROT RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation Tyr529 TITKTVEyLHAQGVV 9606 BTO:0000007 18156174 t llicata "Together, our findings suggest that src-dependent phosphorylation at tyr-529 facilitates inactive erk binding to rsk2, which might be a general requirement for rsk2 activation by egf through the mek/erk pathway." SIGNOR-160052 SRC protein P12931 UNIPROT BMX protein P51813 UNIPROT up-regulates phosphorylation Tyr566 RYVLDDQyVSSVGTK 9606 10688651 t lperfetto "Coexpression of v-src and etk led to a transphosphorylation on tyrosine 566 of etk and subsequent autophosphorylation. These events correlated with a substantial increase in the kinase activity of etk." SIGNOR-75330 SRC protein P12931 UNIPROT ARHGDIA protein P52565 UNIPROT down-regulates phosphorylation Tyr156 YGPRAEEyEFLTPVE 9606 16943322 t llicata "We show here that src kinase binds and phosphorylates rhogdi both in vitro and in vivo at tyr156. analysis of rho gtpase-rhogdi complexes using in vitro assays of complexation and in vivo by coimmunoprecipitation analysis indicates that src-mediated phosphorylation of tyr156 causes a dramatic decrease in the ability of rhogdi to form a complex with rhoa, rac1, or cdc42." SIGNOR-149282 SRC protein P12931 UNIPROT ARHGDIB protein P52566 UNIPROT unknown phosphorylation Tyr153 YGPRPEEyEFLTPVE 9606 19321744 t llicata "Studies confirmed that activated src kinase binds and phosphorylates rhogdi2 in vitro and vivo. Mutagenesis revealed that tyr-153 and, to a lesser degree, tyr-24 were the primary src phosphorylation sites. Phosphorylation decreased the amount of rac1 in rhogdi2 complexes and increased rhogdi2 association with cell membranes." SIGNOR-184908 SRC protein P12931 UNIPROT ARHGDIB protein P52566 UNIPROT unknown phosphorylation Tyr24 ELDSKLNyKPPPQKS 9606 19321744 t llicata "Studies confirmed that activated src kinase binds and phosphorylates rhogdi2 in vitro and vivo. Mutagenesis revealed that tyr-153 and, to a lesser degree, tyr-24 were the primary src phosphorylation sites. Phosphorylation decreased the amount of rac1 in rhogdi2 complexes and increased rhogdi2 association with cell membranes." SIGNOR-184912 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT "up-regulates activity" phosphorylation Tyr115 QPQPDSVyLVPTPSK 10090 12972425 t lperfetto "Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs" SIGNOR-246381 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT "up-regulates activity" phosphorylation Tyr165 PSPATDLyQVPPGPG 10090 12972425 t lperfetto "Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs" SIGNOR-246385 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT "up-regulates activity" phosphorylation Tyr192 AGMGHDIyQVPPSMD 10090 12972425 t lperfetto "Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs" SIGNOR-246393 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT "up-regulates activity" phosphorylation Tyr234 AQPEQDEyDIPRHLL 10090 12972425 t lperfetto "Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs" SIGNOR-246397 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT "up-regulates activity" phosphorylation Tyr249 APGPQDIyDVPPVRG 9606 12972425 t lperfetto "We tested synthetic peptides modeled on cas phosphorylation sites, and found that the sequence containing tyrosine 253 was phosphorylated by src most efficiently. Using cells derived from cas-deficient mice, we confirmed that cas greatly enhanced the ability of src to transform cells." SIGNOR-100363 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT "up-regulates activity" phosphorylation Tyr287 RDPLLEVyDVPPSVE 10090 12972425 t lperfetto "Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs" SIGNOR-246405 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT "up-regulates activity" phosphorylation Tyr362 SPPAEDVyDVPPPAP 10090 12972425 t lperfetto "Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs" SIGNOR-246409 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT "up-regulates activity" phosphorylation Tyr387 RPGPGTLyDVPRERV 10090 12972425 t lperfetto "Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs" SIGNOR-246413 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT "up-regulates activity" phosphorylation Tyr653 QDSPDGQyENSEGGW 10090 12972425 t lperfetto "Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs" SIGNOR-246417 SRC protein P12931 UNIPROT PTEN protein P60484 UNIPROT down-regulates phosphorylation 9606 BTO:0000150 12869565 t gcesareni "Activated src reduces the ability of pten to dephosphorylate phosphatidylinositols in micelles and promotes akt translocation to cellular plasma membranes but does not alter pten activity toward water-soluble phosphatidylinositols." SIGNOR-103721 SRC protein P12931 UNIPROT CDC42 protein P60953 UNIPROT up-regulates phosphorylation Tyr64 DTAGQEDyDRLRPLS 9606 14506284 t gcesareni "Epidermal growth factor-dependent regulation of cdc42 is mediated by the src tyrosine kinaseegf signaling through src appears to have dual regulatory effects on cdc42: 1). it leads to the activation of cdc42 as mediated by the vav2 guanine nucleotide exchange factor, and 2). it results in the phosphorylation of cdc42, which stimulates the binding of rhogdi, perhaps to direct the movement of cdc42 to a specific cellular site to trigger a signaling response, because cdc42-rhogdi interactions are essential for cdc42-induced cellular transformation." SIGNOR-118206 SRC protein P12931 UNIPROT HNRNPK protein P61978 UNIPROT down-regulates phosphorylation Tyr225 IKGRAQPyDPNFYDE 9606 12052863 t lperfetto "We show that hnrnp k and the c-src kinase specifically interact with each other, leading to c-src activation and tyrosine phosphorylation of hnrnp k in vivo and in vitro. c-src-mediated phosphorylation reversibly inhibits the binding of hnrnp k to the differentiation control element (dice) of the lox mrna 3' untranslated region in vitro and specifically derepresses the translation of dice-bearing mrnas in vivo.We confirmed that tyr 230, 234, 236, and 380 are phosphorylated and identified two additional targets of c-src, tyr 72 and tyr 225 (data not shown)." SIGNOR-88899 SRC protein P12931 UNIPROT HNRNPK protein P61978 UNIPROT down-regulates phosphorylation Tyr230 QPYDPNFyDETYDYG 9606 12052863 t lperfetto "We show that hnrnp k and the c-src kinase specifically interact with each other, leading to c-src activation and tyrosine phosphorylation of hnrnp k in vivo and in vitro. c-src-mediated phosphorylation reversibly inhibits the binding of hnrnp k to the differentiation control element (dice) of the lox mrna 3' untranslated region in vitro and specifically derepresses the translation of dice-bearing mrnas in vivo.We confirmed that tyr 230, 234, 236, and 380 are phosphorylated and identified two additional targets of c-src, tyr 72 and tyr 225 (data not shown)." SIGNOR-88903 SRC protein P12931 UNIPROT HNRNPK protein P61978 UNIPROT down-regulates phosphorylation Tyr234 PNFYDETyDYGGFTM 9606 12052863 t lperfetto "We show that hnrnp k and the c-src kinase specifically interact with each other, leading to c-src activation and tyrosine phosphorylation of hnrnp k in vivo and in vitro. c-src-mediated phosphorylation reversibly inhibits the binding of hnrnp k to the differentiation control element (dice) of the lox mrna 3' untranslated region in vitro and specifically derepresses the translation of dice-bearing mrnas in vivo.We confirmed that tyr 230, 234, 236, and 380 are phosphorylated and identified two additional targets of c-src, tyr 72 and tyr 225 (data not shown)." SIGNOR-88907 SRC protein P12931 UNIPROT GRB2 protein P62993 UNIPROT unknown phosphorylation Tyr160 QVPQQPTyVQALFDF 9606 BTO:0000007 20554525 t lperfetto "In our work we show that, in contrast to BCR-ABL and prolactin, NPM-ALK phosphorylates Grb2 mainly in Tyr160)Previous reports suggested an inhibitory role of Grb2 Tyr7, Tyr37, Tyr52, and Tyr209 phosphorylation in receptor tyrosine kinase signaling (16) (43). Instead, in our system Grb2 Tyr160 mutation was not show to have a role in ALCL proliferation." SIGNOR-247138 SRC protein P12931 UNIPROT RAC1 protein P63000 UNIPROT up-regulates phosphorylation 9606 17991704 t gcesareni "N attractive hypothesis consistent with our present data is that the gef responsible for rac activation in mce cells may be activated by src family kinase tyrosine phosphorylationour results present a novel mechanism by which the pi3k and src signaling cascades cooperate to activate rac and promote intestinal epithelial cell migration downstream of egfr." SIGNOR-158954 SRC protein P12931 UNIPROT RACK1 protein P63244 UNIPROT up-regulates phosphorylation Tyr228 LNEGKHLyTLDGGDI 9606 12400005 t gcesareni "We found that rack1 is a src substrate. Moreover, src activity is necessary for both the tyrosine phosphorylation of rack1 and the binding of rack1 to src's sh2 domain that occur following pkc activation. To identify the tyrosine(s) on rack1 that is phosphorylated by src, we generated and tested a series of rack1 mutants. We found that src phosphorylates rack1 on tyr 228 and/or tyr 246" SIGNOR-94796 SRC protein P12931 UNIPROT RACK1 protein P63244 UNIPROT up-regulates phosphorylation Tyr246 LCFSPNRyWLCAATG 9606 12400005 t gcesareni "We found that rack1 is a src substrate. Moreover, src activity is necessary for both the tyrosine phosphorylation of rack1 and the binding of rack1 to src's sh2 domain that occur following pkc activation. To identify the tyrosine(s) on rack1 that is phosphorylated by src, we generated and tested a series of rack1 mutants. We found that src phosphorylates rack1 on tyr 228 and/or tyr 246" SIGNOR-94800 SRC protein P12931 UNIPROT GTF2I protein P78347 UNIPROT "up-regulates activity" phosphorylation Tyr248 EESEDPDyYQYNIQA 9534 BTO:0004055 11934902 t lperfetto "c-Src-dependent transcriptional activation of TFII-ITFII-I is a multifunctional transcription factor that is also involved in signal transduction. Here we show that TFII-I undergoes a c-Src-dependent tyrosine phosphorylation on tyrosine residues 248 and 611 and translocates to the nucleus in response to growth factor signaling" SIGNOR-247185 SRC protein P12931 UNIPROT DNM1 protein Q05193 UNIPROT "up-regulates activity" phosphorylation Tyr597 NTEQRNVyKDYRQLE 9534 BTO:0004055 12011079 t lperfetto "Endocytosis of ligand-activated receptors requires dynamin-mediated GTP hydrolysis, which is regulated by dynamin self-assembly. Here, we demonstrate that phosphorylation of dynamin I by c-Src induces its self-assembly and increases its GTPase activity. Electron microscopic analyses reveal that tyrosine-phosphorylated dynamin I spontaneously self-assembles into large stacks of rings. Tyrosine 597 was identified as being phosphorylated both in vitro and in cultured cells following epidermal growth factor receptor stimulation." SIGNOR-247129 SRC protein P12931 UNIPROT DNM1 protein Q05193 UNIPROT "up-regulates activity" phosphorylation Tyr231 LLPLRRGyIGVVNRS 9606 BTO:0000007 9880482 t lperfetto "Src-mediated tyrosine phosphorylation of dynamin is required for beta2-adrenergic receptor internalization and mitogen-activated protein kinase signalingHere we demonstrate that activation of beta2-adrenergic receptors (beta2-ARs) leads to c-Src-mediated tyrosine phosphorylation of dynamin, which is required for receptor internalization. Two tyrosine residues, Tyr231 and Tyr597, are identified as the major phosphorylation sites" SIGNOR-247124 SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr397 SVSETDDyAEIIDEE 9606 15735019 t miannu "Surprisingly, we found that expression of SrcMF or Src251 resulted in increased tyrosine phosphorylation of FAK on Tyr(407), Tyr(576), Tyr(577), and Tyr(861), which are considered to be Src kinase substrates" SIGNOR-150476 SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr407 IIDEEDTyTMPSTRD 9606 15735019 t miannu "Surprisingly, we found that expression of SrcMF or Src251 resulted in increased tyrosine phosphorylation of FAK on Tyr(407), Tyr(576), Tyr(577), and Tyr(861), which are considered to be Src kinase substrates" SIGNOR-150480 SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr576 RYMEDSTyYKASKGK 9606 15735019 t miannu "Surprisingly, we found that expression of SrcMF or Src251 resulted in increased tyrosine phosphorylation of FAK on Tyr(407), Tyr(576), Tyr(577), and Tyr(861), which are considered to be Src kinase substrates" SIGNOR-150484 SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr577 YMEDSTYyKASKGKL 9606 15735019 t miannu "Surprisingly, we found that expression of SrcMF or Src251 resulted in increased tyrosine phosphorylation of FAK on Tyr(407), Tyr(576), Tyr(577), and Tyr(861), which are considered to be Src kinase substrates" SIGNOR-134212 SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr861 PIGNQHIyQPVGKPD 9606 15735019 t miannu "Surprisingly, we found that expression of SrcMF or Src251 resulted in increased tyrosine phosphorylation of FAK on Tyr(407), Tyr(576), Tyr(577), and Tyr(861), which are considered to be Src kinase substrates" SIGNOR-150492 SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr742 HMVQTNHyQVSGYPG 9606 BTO:0000195 17289681 t "The effect has been demonstrated using P34152-3" gcesareni "We propose that fak/c-src bipartite enzyme is a sensor of cytoplasmic shrinkage, and that the phosphorylation on fak tyr-861 by src and subsequent reorganization of f-actin can initiate an anti-apoptotic signaling pathway that protects cells from hyperosmotic stress." SIGNOR-152967 SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr861 PIGNQHIyQPVGKPD 9606 BTO:0000195 17289681 t "The effect has been demonstrated using P34152-3" gcesareni "We propose that fak/c-src bipartite enzyme is a sensor of cytoplasmic shrinkage, and that the phosphorylation on fak tyr-861 by src and subsequent reorganization of f-actin can initiate an anti-apoptotic signaling pathway that protects cells from hyperosmotic stress." SIGNOR-152971 SRC protein P12931 UNIPROT LRP1 protein Q07954 UNIPROT "up-regulates activity" phosphorylation Tyr4507 TNFTNPVyATLYMGG 9606 BTO:0000007 12789267 t lperfetto "We recently observed that the ldl receptor-related protein 1 (lrp-1) is tyrosine phosphorylated in v-src-transformed cells.Of the four tyrosine residues present in the cytoplasmic domain of lrp-1, only tyr 63 is phosphorylated by v-src in vivo or in vitro. Using fibroblasts deficient in src, yes and fyn, we were able to show that there are multiple kinases present in the cell that can phosphorylate lrp-1. Tyrosine-phosphorylated lrp-1 associates with shc, a ptb and sh2 domain containing signaling protein that is involved in the activation of ras" SIGNOR-101535 SRC protein P12931 UNIPROT GRIN2A protein Q12879 UNIPROT up-regulates phosphorylation Tyr1325 RLLEGNFyGSLFSVP 9606 19834457 t lperfetto "The nr2a subunit of the nmda receptor is tyrosine-phosphorylated, with tyr 1325 as its one of the major phosphorylation sitewe also show that the tyr 1325 phosphorylation site is required for src-induced potentiation of the nmda receptor channel in the striatum." SIGNOR-188531 SRC protein P12931 UNIPROT GRIN2A protein Q12879 UNIPROT "up-regulates activity" phosphorylation Tyr1105 CSEVERTyLKTKSSS -1 10195142 t lperfetto "To gain further insight into the roles of Src and Fyn in the phosphorylation and regulation of the NMDA receptor, we have characterized the tyrosine phosphorylation of NR2A and NR2B by exogenous Src and FynIn the case of NR2A, three potential tyrosine phosphorylation sites have been proposed: Tyr1105, Tyr1267 and Tyr1387 (Zheng et al. 1998; Bi et al. 2000), all of which are similarly located in the C-terminal, cytoplasmic domain." SIGNOR-247163 SRC protein P12931 UNIPROT GRIN2A protein Q12879 UNIPROT "up-regulates activity" phosphorylation Tyr1267 PATGEQVyQQDWAQN -1 10195142 t lperfetto "To gain further insight into the roles of Src and Fyn in the phosphorylation and regulation of the NMDA receptor, we have characterized the tyrosine phosphorylation of NR2A and NR2B by exogenous Src and FynIn the case of NR2A, three potential tyrosine phosphorylation sites have been proposed: Tyr1105, Tyr1267 and Tyr1387 (Zheng et al. 1998; Bi et al. 2000), all of which are similarly located in the C-terminal, cytoplasmic domain." SIGNOR-247167 SRC protein P12931 UNIPROT GRIN2A protein Q12879 UNIPROT "up-regulates activity" phosphorylation Tyr1387 GRCPSDPyKHSLPSQ -1 10195142 t lperfetto "To gain further insight into the roles of Src and Fyn in the phosphorylation and regulation of the NMDA receptor, we have characterized the tyrosine phosphorylation of NR2A and NR2B by exogenous Src and FynIn the case of NR2A, three potential tyrosine phosphorylation sites have been proposed: Tyr1105, Tyr1267 and Tyr1387 (Zheng et al. 1998; Bi et al. 2000), all of which are similarly located in the C-terminal, cytoplasmic domain." SIGNOR-247171 SRC protein P12931 UNIPROT TIAM1 protein Q13009 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 12810717 t gcesareni "Tiam1 cooperated with src to induce activation of rac1 in vivo and the formation of membrane ruffles." SIGNOR-102354 SRC protein P12931 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates phosphorylation Tyr130 VLDVLKFyDSNTVKQ 9606 12215529 t llicata "Pak2 became tyrosine phosphorylated in its n-terminal regulatory domain, where y130 was identified as the major phosphoacceptor site. Tyrosine phosphorylation-mediated superactivation of pak2 could be induced by overexpression of different src kinases or by inhibiting cellular tyrosine phosphatases with pervanadate and could be blocked by the src kinase inhibitor pp1 or by mutating the y130 residue." SIGNOR-92460 SRC protein P12931 UNIPROT GRIN2B protein Q13224 UNIPROT "up-regulates activity" phosphorylation Tyr1474 GSSNGHVyEKLSSIE -1 11483655 t lperfetto "We have investigated the tyrosine phosphorylation of NMDA receptor subunits NR2A and NR2B by exogenous Src Phosphorylation-site specific antibodies identified NR2B Tyr1472 as a phosphorylation site for intrinsic PSD tyrosine kinases" SIGNOR-247180 SRC protein P12931 UNIPROT GRB10 protein Q13322 UNIPROT down-regulates phosphorylation Tyr67 NASLESLySACSMQS 9606 10871840 t lperfetto "Grb10 tyrosine phosphorylation was stimulated by expression of constitutively active src or fyn in cells and by incubation with purified src or fyn in vitro. The insulin stimulated or src/fyn-mediated tyrosine phosphorylation in vivo was significantly reduced when grb10 tyrosine 67 was changed to glycine. This mutant form of grb10 bound with higher affinity to the ir in cells than that of the wild-type protein, suggesting that tyrosine phosphorylation of grb10 may normally negatively regulate its binding to the ir." SIGNOR-78706 SRC protein P12931 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr259 ASVDSSLyNLPRSYS 9606 BTO:0000007 19881549 t lperfetto "Using both mutagenesis and mass spectrometry approaches, y242, y259, y317, y373 and y627 of gab1 were identified to be phosphorylated by c-src a gab1 mutant with substitutions of the src phosphorylation sites failed to promote hgf-induced dna synthesis" SIGNOR-236310 SRC protein P12931 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr317 PPTPGNTyQIPRTFP 9606 BTO:0000007 19881549 t lperfetto "Using both mutagenesis and mass spectrometry approaches, y242, y259, y317, y373 and y627 of gab1 were identified to be phosphorylated by c-src a gab1 mutant with substitutions of the src phosphorylation sites failed to promote hgf-induced dna synthesis" SIGNOR-236306 SRC protein P12931 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr627 KGDKQVEyLDLDLDS 9606 BTO:0000007 19881549 t lperfetto "Using both mutagenesis and mass spectrometry approaches, y242, y259, y317, y373 and y627 of gab1 were identified to be phosphorylated by c-src a gab1 mutant with substitutions of the src phosphorylation sites failed to promote hgf-induced dna synthesis" SIGNOR-236302 SRC protein P12931 UNIPROT RAPGEF1 protein Q13905 UNIPROT up-regulates phosphorylation Tyr504 APIPSVPyAPFAAIL 9606 15320955 t llicata "C3g is activated upon phosphorylation at tyrosine 504 c3g is phosphorylated in vivo on y504 upon coexpression with src or hck, two members of the src family tyrosine kinases." SIGNOR-128273 SRC protein P12931 UNIPROT DAG1 protein Q14118 UNIPROT down-regulates phosphorylation Tyr892 PYRSPPPyVPP 9606 BTO:0000887;BTO:0001103 12795607 t lperfetto "Tyrosine 892 is now thought to be the principal site for recognition by the c-src tyrosine kinase;. We show that upon tyrosine phosphorylation, beta-dystroglycan undergoes a profound change in its sub-cellular localization (e.g., from the plasma membrane to an internal membrane compartment). One possibility is that the net negative charge at position 892 causes the redistribution of beta-dystroglycan to this intracellular vesicular location" SIGNOR-101655 SRC protein P12931 UNIPROT CTTN protein Q14247 UNIPROT down-regulates phosphorylation Tyr446 GTEPEPVySMEAADY 9606 12601080 t lperfetto "Cortactin was first identified as a substrate of v-src (46) that mediates in vitro phosphorylation of residues tyr-421, tyr-466, and tyr-482 at the c terminus of the murine ortholog (47). Phosphorylation of these residues attenuates the f-actin cross-linking activity" SIGNOR-98712 SRC protein P12931 UNIPROT CTTN protein Q14247 UNIPROT down-regulates phosphorylation Tyr470 AYATEAVyESAEAPG 9606 12601080 t lperfetto "Cortactin was first identified as a substrate of v-src (46) that mediates in vitro phosphorylation of residues tyr-421, tyr-466, and tyr-482 at the c terminus of the murine ortholog (47). Phosphorylation of these residues attenuates the f-actin cross-linking activity" SIGNOR-98716 SRC protein P12931 UNIPROT CTTN protein Q14247 UNIPROT down-regulates phosphorylation Tyr486 YPAEDSTyDEYENDL 9606 12601080 t lperfetto "Cortactin was first identified as a substrate of v-src (46) that mediates in vitro phosphorylation of residues tyr-421, tyr-466, and tyr-482 at the c terminus of the murine ortholog (47). Phosphorylation of these residues attenuates the f-actin cross-linking activity" SIGNOR-98720 SRC protein P12931 UNIPROT CTTN protein Q14247 UNIPROT "down-regulates activity" phosphorylation Tyr421 RLPSSPVyEDAASFK -1 15169891 t lperfetto "Erk phosphorylation and a mimicking S405,418D double mutation enhanced cortactin binding and activation of N-WASP. In contrast, Src phosphorylation inhibited the ability of cortactin previously phosphorylated by Erk, and that of S405,418D double mutant cortactin, to bind and activate N-WASP. Furthermore, Y-->D mutation of three tyrosine residues targeted by Src (Y421, Y466, and Y482) inhibited the ability of S405,418D cortactin to activate N-WASP." SIGNOR-246513 SRC protein P12931 UNIPROT PTK2B protein Q14289 UNIPROT up-regulates phosphorylation Tyr402 CSIESDIyAEIPDET 9606 15695828 t llicata "These data indicate that pyk2 activation via phosphorylation at tyr-402 requires ?V?3 Ligation and src activity." SIGNOR-133870 SRC protein P12931 UNIPROT KCNB1 protein Q14721 UNIPROT up-regulates phosphorylation Tyr128 YWGIDEIyLESCCQA 9606 BTO:0000938 19622611 t flangone "In the present study we show that an n-terminal tyrosine of kv2.1 (y124), which is a known target of src kinase, is critical for the apoptotic current surge..Kv2.1-mediated k+ currents are also enhanced during non-injurious conditions through direct phosphorylation of intracellular n-terminal residue tyrosine 124 (y124) by src kinase" SIGNOR-187201 SRC protein P12931 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates phosphorylation Tyr380 TDSEEQPyLEMDLSS 9606 16619028 t lperfetto "Src kinase phosphorylates caspase-8 on tyr380: a novel mechanism of apoptosis suppressionwe identified caspase-8 as a new substrate for src kinase. Phosphorylation occurs on tyr380, situated in the linker region between the large and the small subunits of human procaspase-8, and results in downregulation of caspase-8 proapoptotic function" SIGNOR-146127 SRC protein P12931 UNIPROT PRKD1 protein Q15139 UNIPROT "up-regulates activity" phosphorylation Tyr432 KEGWMVHyTSKDTLR 9606 BTO:0000567 12637538 t lperfetto "Here we report that PKD is tyrosine-phosphorylated within the PH domain, leading to activation. This phosphorylation is mediated by a pathway that consists of the Src and Abl tyrosine kinases and occurs in response to stimulation with pervanadate and oxidative stress. Mutational analysis revealed three tyrosine phosphorylation sites (Tyr(432), Tyr(463), and Tyr(502)), which are regulated by the Src-Abl pathway, and phosphorylation of only one of these (Tyr(463)) leads to PKD activation." SIGNOR-247320 SRC protein P12931 UNIPROT TNS3 protein Q68CZ2 UNIPROT up-regulates phosphorylation Tyr1173 QDTSKFWyKADISRE 9606 BTO:0000150;BTO:0000551;BTO:0000848 19732724 t llicata "Tyrosines in the sh2 domain contribute to the biological activity of tensin-3, and phosphorylation of these tyrosines can regulate ligand binding. tensin-3 is a src substrate" SIGNOR-187843 SRC protein P12931 UNIPROT TNS3 protein Q68CZ2 UNIPROT up-regulates phosphorylation Tyr1206 SHSFRGAyGLAMKVA 9606 BTO:0000150;BTO:0000551;BTO:0000848 19732724 t llicata "Tyrosines in the sh2 domain contribute to the biological activity of tensin-3, and phosphorylation of these tyrosines can regulate ligand binding. tensin-3 is a src substrate" SIGNOR-187847 SRC protein P12931 UNIPROT TNS3 protein Q68CZ2 UNIPROT up-regulates phosphorylation Tyr1256 KGCSNEPyFGSLTAL 9606 BTO:0000150;BTO:0000551;BTO:0000848 19732724 t llicata "Tyrosines in the sh2 domain contribute to the biological activity of tensin-3, and phosphorylation of these tyrosines can regulate ligand binding. tensin-3 is a src substrate" SIGNOR-187851 SRC protein P12931 UNIPROT TNS3 protein Q68CZ2 UNIPROT up-regulates phosphorylation 9606 BTO:0000150;BTO:0000551;BTO:0000848 19732724 t gcesareni "Although sh2 domains have not been reported previously to be phosphorylated, the tensin-3 sh2 domain is a physiologic substrate for src. Tyrosines in the sh2 domain contribute to the biological activity of tensin-3, and phosphorylation of these tyrosines can regulate ligand binding." SIGNOR-187854 SRC protein P12931 UNIPROT RHOU protein Q7L0Q8 UNIPROT "down-regulates activity" phosphorylation Tyr254 SKSWWKKyCCFV 9606 BTO:0002552 20547754 t miannu "Regulation of the Rho family small GTPase Wrch-1/RhoU by C-terminal tyrosine phosphorylation requires Src. Phosphorylation at Y254 negatively regulates Wrch-1-mediated biological functions.Serum-stimulated tyrosine phosphorylation and relocalization of Wrch-1 decreases its activation of downstream effectors in a Y254-dependent manner." SIGNOR-259814 SRC protein P12931 UNIPROT NOXA1 protein Q86UR1 UNIPROT up-regulates phosphorylation Tyr110 RGHAAIDyTQLGLRF 9606 20943948 t llicata "Here, we show that the interaction of noxa1 and tks proteins is dependent on src activity. Interestingly, the abolishment of src-mediated phosphorylation of tyr110 on noxa1 and of tyr508 on tks4 blocks their binding and decreases nox1-dependent ros generation." SIGNOR-168545 SRC protein P12931 UNIPROT SIRT2 protein Q8IXJ6 UNIPROT "down-regulates quantity by destabilization" phosphorylation Tyr104 RSPSTGLyDNLEKYH 9606 BTO:0000007 24996174 t miannu "In this study, we investigated the potential regulation of SIRT2 function by c-Src. We found that the protein levels of SIRT2 were decreased by c-Src, and subsequently rescued by the addition of a Src specific inhibitor, SU6656, or by siRNA-mediated knockdown of c-Src. The c-Src interacts with and phosphorylates SIRT2 at Tyr104." SIGNOR-263104 SRC protein P12931 UNIPROT AFAP1 protein Q8N556 UNIPROT unknown phosphorylation Tyr451 TDPEALHyDYIDVEM 9534 BTO:0004055 9655255 t lperfetto "In this report, site-directed mutagenesis and a transient expression system that permits co-expression of activated pp60c-src (Src527F) and AFAP-110 in Cos-1 cells were used to identify the SH2-binding motif in AFAP-110. Four tyrosine residues, two in the amino terminus (Y93 and Y94) and two in the carboxy terminus (Y451 and Y453), were mutated to phenylalanine, significantly reducing overall steady-state levels of tyrosine phosphorylation and preventing Src527F from forming a stable complex with AFAP-110." SIGNOR-246351 SRC protein P12931 UNIPROT NECTIN2 protein Q92692 UNIPROT unknown phosphorylation Tyr505 EGEEEEEyLDKINPI -1 10962558 t miannu "An inhibitor specific for Src family kinase or expression of Csk reduced tyrosine phosphorylation of nectin-2delta. In addition, Src kinase tyrosine phosphorylates the recombinant cytoplasmic region of nectin-2delta in vitro. The major tyrosine phosphorylation site of nectin-2delta was Tyr505 in the cytoplasmic region" SIGNOR-263200 SRC protein P12931 UNIPROT FERMT2 protein Q96AC1 UNIPROT "up-regulates activity" phosphorylation Tyr193 SKTMTPTyDAHDGSP 9606 BTO:0000007 26037143 t miannu "Here we report that Src binds to and phosphorylates Kindlin-2 at Y193. Reciprocally, Kindlin-2-Y193 phosphorylation activates and maintains Src kinase activity. Kindlin-2-Y193 phosphorylation is also involved in its binding capacity with Migfilin and the recruitment of Migfilin to the focal adhesions. Functionally, we demonstrate that Kindlin-2-Y193 phosphorylation regulates Kindlin-2-mediated cell spreading and migration." SIGNOR-266100 SRC protein P12931 UNIPROT SH3GL1 protein Q99961 UNIPROT down-regulates phosphorylation Tyr315 QPSCKALyDFEPEND 9606 16054026 t lperfetto "Further, we identified an interaction between fak's second pro-rich motif and endophilin a2's sh3 domain. This interaction served as an autophosphorylation-dependent scaffold to allow src phosphorylation of endophilin a2 at tyr315. Tyr315 phosphorylation inhibited endophilin/dynamin interactions, and blockade of tyr315 phosphorylation promoted endocytosis of mt1-mmp. Together, these results suggest a regulatory mechanism of cell invasion whereby fak promotes cell-surface presentation of mt1-mmp by inhibiting endophilin a2-dependent endocytosis." SIGNOR-139150 SRC protein P12931 UNIPROT SRCIN1 protein Q9C0H9 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007 8647432 t miannu "Phosphorylation of multiple tyrosine-containing motifs found on Sin correlated with c-Crk and cellular phosphoprotein binding to Sin as well as increased c-Src activity. These data suggest that (1) SH2 and SH3 ligand sites on Sin cooperatively activate the signaling potential of c-Src, (2) Sin acts as both an activator and a substrate for c-Src, and (3) phosphorylated Sin may serve as a signaling effector molecule for Src by binding to multiple cellular proteins." SIGNOR-263196 SRC protein P12931 UNIPROT ARHGEF4 protein Q9NR80 UNIPROT up-regulates phosphorylation Tyr165 VGSEEDLyDDLHSSS 9606 BTO:0000017 18653540 t llicata "This observation strongly argues for the positive role of tyr94 phosphorylation in egf-induced asef activation following the activation of rac1." SIGNOR-179601 SRC protein P12931 UNIPROT ARHGAP35 protein Q9NRY4 UNIPROT up-regulates phosphorylation Tyr1105 RNEEENIySVPHDST 9606 9819392 t lperfetto "Phosphorylation of y1105, but not the minor site, was modulated in vivo to a greater extent by overexpression of c-src than by the egf receptor and was efficiently catalyzed by c-src in vitro. Mutation of y1105 from tyr to phe resulted in complete loss of p-tyr-dependent complex formation, indicating that p-y1105 was the sole p-tyr residue mediating binding to p120" SIGNOR-61670 SRC protein P12931 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT unknown phosphorylation Tyr45 GLEPVGHyEEVELTE 9606 16640565 t llicata "Src kinase phosphorylates s6k in the n-terminus. tyrosine y39/45 in s6k1/2 is a substrate for src kinase in vitro. tyrosine y39/45 in s6k1/2 is a substrate for src kinase in vivo." SIGNOR-146292 SRC protein P12931 UNIPROT BAIAP2L1 protein Q9UHR4 UNIPROT "up-regulates activity" phosphorylation Tyr274 SNVVRKDyDTLSKCS -1 21840312 t miannu "Here, we report that overexpression of IRTKS increases the speed of wound closure of HT1080 cells in a Src-dependent manner. Active Src phosphorylates IRTKS in vivo and in vitro. Deletion mapping and mutation analysis revealed that six tyrosine residues (Y37, Y156, Y163, Y274, Y293 and Y439) were Src-stimulated phosphorylation sites on IRTKS. Disruption of Src-stimulated IRTKS phosphorylation abolished the effect of IRTKS on wound closure. Collectively, these data suggest Src-stimulated IRTKS phosphorylation is essential for its function in cell motility." SIGNOR-263039 SRC protein P12931 UNIPROT BAIAP2L1 protein Q9UHR4 UNIPROT "up-regulates activity" phosphorylation Tyr293 PAPSGRAyTSPLIDM -1 21840312 t miannu "Here, we report that overexpression of IRTKS increases the speed of wound closure of HT1080 cells in a Src-dependent manner. Active Src phosphorylates IRTKS in vivo and in vitro. Deletion mapping and mutation analysis revealed that six tyrosine residues (Y37, Y156, Y163, Y274, Y293 and Y439) were Src-stimulated phosphorylation sites on IRTKS. Disruption of Src-stimulated IRTKS phosphorylation abolished the effect of IRTKS on wound closure. Collectively, these data suggest Src-stimulated IRTKS phosphorylation is essential for its function in cell motility." SIGNOR-263040 SRC protein P12931 UNIPROT BAIAP2L1 protein Q9UHR4 UNIPROT "up-regulates activity" phosphorylation Tyr37 LINLGKNyEKAVNAM -1 21840312 t miannu "Here, we report that overexpression of IRTKS increases the speed of wound closure of HT1080 cells in a Src-dependent manner. Active Src phosphorylates IRTKS in vivo and in vitro. Deletion mapping and mutation analysis revealed that six tyrosine residues (Y37, Y156, Y163, Y274, Y293 and Y439) were Src-stimulated phosphorylation sites on IRTKS. Disruption of Src-stimulated IRTKS phosphorylation abolished the effect of IRTKS on wound closure. Collectively, these data suggest Src-stimulated IRTKS phosphorylation is essential for its function in cell motility." SIGNOR-263041 SRC protein P12931 UNIPROT BAIAP2L1 protein Q9UHR4 UNIPROT "up-regulates activity" phosphorylation Tyr439 VVIPPPDyLECLSMG -1 21840312 t miannu "Here, we report that overexpression of IRTKS increases the speed of wound closure of HT1080 cells in a Src-dependent manner. Active Src phosphorylates IRTKS in vivo and in vitro. Deletion mapping and mutation analysis revealed that six tyrosine residues (Y37, Y156, Y163, Y274, Y293 and Y439) were Src-stimulated phosphorylation sites on IRTKS. Disruption of Src-stimulated IRTKS phosphorylation abolished the effect of IRTKS on wound closure. Collectively, these data suggest Src-stimulated IRTKS phosphorylation is essential for its function in cell motility." SIGNOR-263042 SRC protein P12931 UNIPROT VAV3 protein Q9UKW4 UNIPROT up-regulates phosphorylation Tyr173 EDEGGEVyEDLMKAE 9606 BTO:0000785 17998938 t gcesareni "Activation of rac1 and the exchange factor vav3 are involved in npm-alk signaling in anaplastic large cell lymphomas." SIGNOR-159240 SRC protein P12931 UNIPROT HCN2 protein Q9UL51 UNIPROT "up-regulates activity" phosphorylation Tyr476 LDSSRRQyQEKYKQV 9606 BTO:0000007 26280531 t miannu "We identified a highly conserved tyrosine residue in the C-linker of HCN channels (Tyr476 in HCN2) that confers modulation by Src. Replacement of this tyrosine by phenylalanine in HCN2 or HCN4 abolished sensitivity to Src inhibitors. Mass spectrometry confirmed that Tyr476 is phosphorylated by Src. Our results have functional implications for HCN channel gating. Furthermore, they indicate that tyrosine phosphorylation contributes in vivo to the fine tuning of HCN channel activity." SIGNOR-263199 SRC protein P12931 UNIPROT DAPP1 protein Q9UN19 UNIPROT "up-regulates activity" phosphorylation Tyr139 KVEEPSIyESVRVHT 9606 BTO:0000776 10880360 t lperfetto "Src family kinases mediate receptor-stimulated, phosphoinositide 3-kinase-dependent, tyrosine phosphorylation of dual adaptor for phosphotyrosine and 3-phosphoinositides-1 in endothelial and B cell linesyrosine phosphorylation of DAPP-1 appears important for appropriate intracellular targeting and creates a potential binding site for Src homology 2 domain-containing proteins." SIGNOR-247119 SRC protein P12931 UNIPROT HCN4 protein Q9Y3Q4 UNIPROT up-regulates phosphorylation Tyr531 RRQYQEKyKQVEQYM 9606 17977941 t fspada "These results demonstrate that src tyrosine kinase enhances hcn4 currents by shifting their activation to more positive potentials and increasing the whole cell channel conductance as well as speeding the channel kinetics. The tyrosine residue that mediates most of src s actions on hcn4 channels is tyr531." SIGNOR-158707 SRC protein P12931 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 12645577 t lperfetto "These results indicate that c-src can associate with ikkbeta and phosphorylate its tyrosine residues after tnf-alfa or tpa stimulation." SIGNOR-217439 SRC protein P12931 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 12707358 t lperfetto "These results indicate that c-src can associate with ikkbeta and phosphorylate its tyrosine residues after tnf-alfa or tpa stimulation." SIGNOR-217442 SRC protein P12931 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Tyr315 TFCGTPEyLAPEVLE 9534 BTO:0004055 11445557 t lperfetto "Regulation of Akt/PKB Activation by Tyrosine PhosphorylationAs shown in Fig. 2 d, while mutation of Tyr340 has little effect on either tyrosine phosphorylation or kinase activity of Akt induced by Src527F, substitution of Tyr315 or Tyr326 with a phenylalanine, respectively, dramatically reduces both the tyrosine phosphorylation and kinase activity of Akt. The combination of these two mutations abolishes Src-induced tyrosine phosphorylation of Akt as well as its kinase activity." SIGNOR-246368 SRC protein P12931 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Tyr326 EVLEDNDyGRAVDWW 9534 BTO:0004055 11445557 t lperfetto "Regulation of Akt/PKB Activation by Tyrosine PhosphorylationAs shown in Fig. 2 d, while mutation of Tyr340 has little effect on either tyrosine phosphorylation or kinase activity of Akt induced by Src527F, substitution of Tyr315 or Tyr326 with a phenylalanine, respectively, dramatically reduces both the tyrosine phosphorylation and kinase activity of Akt. The combination of these two mutations abolishes Src-induced tyrosine phosphorylation of Akt as well as its kinase activity." SIGNOR-246377 SRC protein P12931 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Tyr315 TFCGTPEyLAPEVLE 9606 BTO:0000007 12600984 t lperfetto "We also showed that phosphorylation of Tyr-315 in Akt induced by Src or EGF is dependent on the integrity of this proline-rich motif. Furthermore, the Akt mutant lacking this proline motif fails to block the transcription activity of Forkhead in 293 cells and poorly stimulates the proliferation of Madin-Darby canine kidney cells. Taken together, our data suggest that the interaction between the SH3 domain of Src family kinases and the proline-rich motif in the C-terminal regulatory region of Akt is required for tyrosine phosphorylation of Akt and its subsequent activation." SIGNOR-246373 SRC protein P12931 UNIPROT LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR "down-regulates activity" phosphorylation 9606 30889378 t miannu "SRC can directly phosphorylate and inhibit LATS" SIGNOR-259056 XRCC6 protein P12956 UNIPROT PRKDC protein P78527 UNIPROT up-regulates relocalization 9606 19133841 t gcesareni "Ku and dna-pkcs only interact in the presence of dna and recruitment of dna-pkcs to sites of dna damage in vivo is ku-dependent. Inward translocation of ku allows dna-pkcs to interact with the extreme termini of the dna, allowing two dna-pkcs molecules to interact across the dsb in a so-called synaptic complex . This interaction stimulates the kinase activity of dna-pkcs, promoting phosphorylation in trans across the dsb (discussed in more detail below). Once assembled at the dna ends, the dna-pkcs-ku-dsb complex serves to tether the ends of the dsb together and protects the dna ends from nuclease attack." SIGNOR-183276 XRCC6 protein P12956 UNIPROT UBE2S protein Q16763 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000007 27593939 t lperfetto "As shown in Figure 4, we found that Ku70 (Figure 4b) and Ku80 (Figure 4c) co-immunoprecipitated with UBE2S.>Taken together, these results demonstrate that ETO enhances the UBE2S–Ku70 interaction, and UBE2S can be recruited to the same sites of DSBs with Ku70 upon ETO treatment." SIGNOR-265079 XRCC6 protein P12956 UNIPROT Ku70/Ku80/DNA-PK complex SIGNOR-C107 SIGNOR "form complex" binding 9606 BTO:0002419 17308091 t miannu "complexes formed by interactions between Ku70, Ku80, and DNA-PKcs were well-established" SIGNOR-226023 XRCC5 protein P13010 UNIPROT PDX1 protein P52945 UNIPROT "down-regulates quantity by destabilization" binding 10090 BTO:0002284 16166097 t miannu "The interaction of PDX-1 with Ku subunits and its phosphorylation on threonine 11 by the DNA-PK appear to be implicated in its degradation by the proteosome." SIGNOR-225537 XRCC5 protein P13010 UNIPROT Ku70/Ku80/DNA-PK complex SIGNOR-C107 SIGNOR "form complex" binding 9606 BTO:0002419 17308091 t miannu "complexes formed by interactions between Ku70, Ku80, and DNA-PKcs were well-established" SIGNOR-226019 GP1BB protein P13224 UNIPROT "GPIb-IX-V complex" complex SIGNOR-C270 SIGNOR "form complex" binding 9606 BTO:0000132 16293600 t lperfetto "The GPIb-V-IX receptor consists of 4 transmembrane subunits: GPIbα, disulfide-linked to GPIbβ, and the noncovalently associated GPIX and GPV components, in ratios of 2:2:2:1." SIGNOR-261850 IL7 protein P13232 UNIPROT IL7R protein P16871 UNIPROT up-regulates binding 9606 BTO:0002314 BTO:0000887;BTO:0001103;BTO:0001760 20089933 t milica "This receptor (il-7r) is a heterodimer consisting of the il-7r chain and the common cytokine ? -chain." SIGNOR-163548 IL7 protein P13232 UNIPROT IL7R protein P16871 UNIPROT up-regulates binding 9606 BTO:0000782 8204885 t fspada "Antibody r34.34 was further found to be directed against an epitope interfering with binding of interleukin-7 (il-7) to pre-alp cells. Expression cloning from a pre-alp cdna library showed that r34.34 antigen is cdw127, the 75- to 80-kd il-7 receptor. Proliferation of the b-lineage all cell lines reh and mieliki was inhibited by il-7, and this effect was specifically reverted by moab r34.34. In addition, antibody r34.34 specifically inhibited il-7-dependent proliferation of normal bcp, pre-alp cells, and peripheral t cells. These results imply that both inhibitory and proliferative effects of il-7 can be mediated through the same receptor on various lineages." SIGNOR-37012 IL7 protein P13232 UNIPROT IL2RG protein P31785 UNIPROT up-regulates binding 9606 BTO:0002314 BTO:0000887;BTO:0001103;BTO:0001760 20089933 t milica "This receptor (il-7r) is a heterodimer consisting of the il-7r chain and the common cytokine ? -chain." SIGNOR-163545 CCL4 protein P13236 UNIPROT CCR5 protein P51681 UNIPROT "up-regulates activity" binding 10090 20219869 t 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 BGLF4 protein P13288 UNIPROT IRF3 protein Q14653 UNIPROT "down-regulates activity" phosphorylation Ser123 DFSQPDTsPDTNGGG 9606 BTO:0002181 19052084 t scontino "BGLF4 kinase interacts physically with and phosphorylates IRF3, which is the initial activator of transcription in the innate immune response. BGLF4 suppresses IRF3-dependent transcriptional activation. Data here suggest that Ser123, Ser173, and Thr180 contribute additively to the BGLF4-mediated repression of the IRF3 transactivation activity." SIGNOR-266647 BGLF4 protein P13288 UNIPROT IRF3 protein Q14653 UNIPROT "down-regulates activity" phosphorylation Ser173 PCPQPLRsPSLDNPT 9606 BTO:0002181 19052084 t scontino "BGLF4 kinase interacts physically with and phosphorylates IRF3, which is the initial activator of transcription in the innate immune response. BGLF4 suppresses IRF3-dependent transcriptional activation. Data here suggest that Ser123, Ser173, and Thr180 contribute additively to the BGLF4-mediated repression of the IRF3 transactivation activity." SIGNOR-266648 BGLF4 protein P13288 UNIPROT IRF3 protein Q14653 UNIPROT "down-regulates activity" phosphorylation Thr180 SPSLDNPtPFPNLGP 9606 BTO:0002181 19052084 t scontino "BGLF4 kinase interacts physically with and phosphorylates IRF3, which is the initial activator of transcription in the innate immune response. BGLF4 suppresses IRF3-dependent transcriptional activation. Data here suggest that Ser123, Ser173, and Thr180 contribute additively to the BGLF4-mediated repression of the IRF3 transactivation activity." SIGNOR-266649 MYF5 protein P13349 UNIPROT DES protein P17661 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165 8382796 t lperfetto "Desmin, the muscle specific intermediate filament (IF) protein, is expressed at low levels in myoblasts and at the onset of differentiation its expression increases several fold. In an effort to explore the mechanism involved in the tissue-specific and developmentally regulated expression of desmin, we have isolated the mouse desmin gene.Co-transfection of myoD, myogenin, MRF4 and Myf5, with the desmin-CAT construct into 10T-1/2 cells demonstrated that all these factors could transactivate desmin gene expression" SIGNOR-241494 TDGF1 protein P13385 UNIPROT ACVR2A protein P27037 UNIPROT down-regulates binding 9606 BTO:0000007 12682303 t acerquone "Here we show that cripto can form a complex with activin and actrii/iib cripto inhibited crosslinking of activin to alk4 and the association of alk4 with actrii/iib." SIGNOR-100052 TDGF1 protein P13385 UNIPROT ACVR1B protein P36896 UNIPROT "up-regulates activity" binding 9606 19874624 t Regulation miannu "Nodal effects are dependent upon interactions with Cripto, a small cysteine-rich extracellular protein that is attached to the plasma membrane through a glycosyl phosphatidyl inositol linkage. Cripto interacts with Nodal and ALK4, independently, and promotes the formation of a stable high affinity complex with activin type II receptors." SIGNOR-251938 TDGF1 protein P13385 UNIPROT NODAL protein Q96S42 UNIPROT "up-regulates activity" binding 9606 19874624 t Regulation miannu "Nodal effects are dependent upon interactions with Cripto, a small cysteine-rich extracellular protein that is attached to the plasma membrane through a glycosyl phosphatidyl inositol linkage. Cripto interacts with Nodal and ALK4, independently, and promotes the formation of a stable high affinity complex with activin type II receptors." SIGNOR-251937 BMP1 protein P13497 UNIPROT COL1A1 protein P02452 UNIPROT "up-regulates activity" cleavage 9534 BTO:0000298 11283002 t miannu "BMP-1myc Expressed in COS-7 Cells Exhibits Procollagen C-proteinase Activity. Bone morphogenetic protein (BMP)-1, which belongs to the tolloid subgroup of astacin-like zinc metalloproteinases, cleaves the C-propeptides of procollagen at the physiologic site and is, therefore, a procollagen C-proteinase (PCP). Cleavage occurs between a specific alanine or glycine residue (depending on the procollagen chain) and an invariant aspartic acid residue in each of the three chains of procollagen." SIGNOR-256342 BMP1 protein P13497 UNIPROT COL5A2 protein P05997 UNIPROT "up-regulates activity" cleavage Glu1253 SEVKMDAeFRHDSGY 9606 BTO:0002974 11741999 t miannu "BMP-1 Can Efficiently Cleave Pro-α1(V) N-propeptides and Pro-α2(V) C-propeptides and Less Efficiently Cleave Pro-α1(V) C-propeptides in Vitro. BMP-1 efficiently cleaves pro-α2(V) C-propeptides at a single site between residues 1250 (Glu) and 1251 (Asp)." SIGNOR-256343 BMP1 protein P13497 UNIPROT COL5A1 protein P20908 UNIPROT "up-regulates activity" cleavage Asp1549 IKTEEISeVKMDAEF 9606 BTO:0002974 11741999 t miannu "BMP-1 Can Efficiently Cleave Pro-α1(V) N-propeptides and Pro-α2(V) C-propeptides and Less Efficiently Cleave Pro-α1(V) C-propeptides in Vitro.NH2-terminal sequencing of an ∼35-kDa band in the BMP-1-treated material (N-α1(V), Fig. 3 B,lanes 2 and 3) showed it to correspond to the NH2-terminal portion of the pro-α1(V) N-propeptide previously shown to be cleaved in pro-α1(V)3 homotrimers by BMP-1 (39), whereas NH2-terminal sequencing of an ∼38-kDa band (C-α1(V)BMP-1, Fig. 3 B,lanes 2 and 3) showed it to correspond to pro-α1(V) C-propeptides cleaved between Asp-1594 and Asp-1595." SIGNOR-256344 BMP1 protein P13497 UNIPROT COL7A1 protein Q02388 UNIPROT "up-regulates quantity" cleavage Ala2821 RPLPSYAaDTAGSQL 9606 BTO:0000667 11986329 t miannu " We show that bone morphogenetic protein-1 (BMP-1), which exhibits procollagen C-proteinase activity, cleaves the C-terminal propeptide from human procollagen VII. The cleavage occurs at the BMP-1 consensus cleavage site SYAA/DTAG within the NC-2 domain. Proteinases of the bone morphogenetic protein-1 family convert procollagen VII to mature anchoring fibril collagen." SIGNOR-256338 CCL2 protein P13500 UNIPROT CCR2 protein P41597 UNIPROT "up-regulates activity" binding 9606 20219869 t 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 CCL5 protein P13501 UNIPROT CCR1 protein P32246 UNIPROT up-regulates binding 9606 10734056 t "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 CCL5 protein P13501 UNIPROT CCR3 protein P51677 UNIPROT up-regulates binding 9606 10734056 t "In addition to the CCR1 receptor, RANTES activates several members of the CC subfamily of chemokine receptors including CCR3, CCR4, and CCR5" SIGNOR-254370 RARG protein P13631 UNIPROT RXRA protein P19793 UNIPROT up-regulates binding 9606 1310351 t gcesareni "Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins." SIGNOR-16659 RARG protein P13631 UNIPROT RXRB protein P28702 UNIPROT up-regulates binding 9606 1310351 t gcesareni "Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins." SIGNOR-16662 ATP1A3 protein P13637 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000938 22797008 t miannu "The sodium/potassium transporting ATPase subunit alpha-3 (AT1A3; syn.: sodium pump subunit alpha-3; E.C. 3.6.3.9; UniProtKB ID: Q6PIC6) belongs to the cation transport ATPase (P-type) 3.A.3 family catalyzing hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane. This action generates the electrochemical gradient of sodium and potassium ions thus providing energy for active transport of various nutrients. Three sodium/potassium transporting ATPase isoforms are expressed in the brain but AT1A3 is detectable in neurons exclusively." SIGNOR-265793 C6 protein P13671 UNIPROT "Membrane attack complex" complex SIGNOR-C313 SIGNOR "form complex" binding -1 30552328 t lperfetto "The human MAC pore was formed on liposomes from individual complement proteins. |The maps were further subdivided into three components: an asymmetric region (C5b, C6, C7, and C8), a hinge region (C7, C8, and two C9 molecules), and a C9 oligomer" SIGNOR-263442 OSM protein P13725 UNIPROT AHR protein P35869 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24127753 f gcesareni "The il-6-type cytokine oncostatin m induces ahr expression in a stat3-ependent manner in human hepg2 hepatoma cells." SIGNOR-202963 OSM protein P13725 UNIPROT IL6ST protein P40189 UNIPROT up-regulates binding 9606 BTO:0001271 9143707 t gcesareni "Stimulation of cells with the interleukin-6 family of cytokines triggers homo- or hetero-dimerization of gp130. The dimerization of gp130 leads to activation of associated cytoplasmic tyrosine kinases and subsequent modification of transcription factors. Some of these biological activities of il-6 are also often exerted by other cytokines, i.e. Il-11, lif, osm, cntf, and ct-2." SIGNOR-48114 OSM protein P13725 UNIPROT LIFR protein P42702 UNIPROT up-regulates binding 9606 BTO:0000801;BTO:0001271 1536831 t gcesareni "Oncostatin m binds the high-affinity leukemia inhibitory factor receptor" SIGNOR-19873 F3 protein P13726 UNIPROT "Factor FVIIa:TF" complex SIGNOR-C319 SIGNOR "form complex" binding 9606 BTO:0000131 32665005 t lperfetto "During vascular injury, TF is exposed to the blood, where it functions as a cofactor for the circulating zymogen factor VII (FVII). This TF:FVIIa complex can then bind and activate either factor IX (FIX) or factor X (FX), triggering a cascade that generates fibrin and activates platelets, resulting in a hemostatic plug at the site of injury." SIGNOR-263556 PRKAR2A protein P13861 UNIPROT PRKACA protein P17612 UNIPROT "down-regulates activity" binding 9606 26687711 t "Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets" SIGNOR-258752 ENO3 protein P13929 UNIPROT 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 29767008 t miannu "Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: α-enolase (ENO1) is present in almost all mature tissues; β-enolase (ENO3) exists primarily in muscle tissues; and γ-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits." SIGNOR-266530 ENO3 protein P13929 UNIPROT phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 29767008 t miannu "Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: α-enolase (ENO1) is present in almost all mature tissues; β-enolase (ENO3) exists primarily in muscle tissues; and γ-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits." SIGNOR-266526 GTF2F2 protein P13984 UNIPROT POLR2E protein P19388 UNIPROT "up-regulates activity" binding 9534 11278533 t miannu "Direct Interaction Between the Subunit RAP30 of Transcription Factor IIF (TFIIF) and RNA Polymerase Subunit 5, Which Contributes to the Association Between TFIIF and RNA Polymerase II. we showed that RPB5 binds RAP30 but not RAP74 and associates to TFIIF through the binding to RAP30." SIGNOR-261179 GTF2F2 protein P13984 UNIPROT GTF2F1 protein P35269 UNIPROT "up-regulates activity" binding 9534 11278533 t miannu "Direct Interaction Between the Subunit RAP30 of Transcription Factor IIF (TFIIF) and RNA Polymerase Subunit 5, Which Contributes to the Association Between TFIIF and RNA Polymerase II. we showed that RPB5 binds RAP30 but not RAP74 and associates to TFIIF through the binding to RAP30." SIGNOR-261180 GTF2F2 protein P13984 UNIPROT TFIIF complex SIGNOR-C394 SIGNOR "form complex" binding -1 18218714 t lperfetto "Human general transcription factor IIF (TFIIF), a component of the transcription pre-initiation complex (PIC) associated with RNA polymerase II (Pol II), was characterized by size-exclusion chromatography (SEC), electrospray ionization mass spectrometry (ESI-MS), and chemical cross-linking. Recombinant TFIIF, composed of an equimolar ratio of alpha and beta subunits, was bacterially expressed, purified to homogeneity, and found to have a transcription activity similar to a natural one in the human in vitro transcription system." SIGNOR-266195 CTSE protein P14091 UNIPROT A2M protein P01023 UNIPROT "down-regulates quantity by destabilization" cleavage Phe834 QLEASPAfLAVPVEK -1 12631277 t lperfetto "Disruption of structural and functional integrity of alpha 2-macroglobulin by cathepsin E|Analysis of the N-terminal amino-acid sequences of these proteins revealed that alpha 2M was selectively cleaved at the Phe811-Leu812 bond in about 100mer downstream of the bait region." SIGNOR-266977 EDN3 protein P14138 UNIPROT EDNRB protein P24530 UNIPROT up-regulates binding 9606 BTO:0000975 8086489 t gcesareni "These results demonstrate that lys-161 of the receptor is important for high affinity binding with et-3 which, in part, confers the non-selective binding characteristics of the etb receptor for et isopeptides." SIGNOR-36017 MIF protein P14174 UNIPROT SOD1 protein P00441 UNIPROT "down-regulates quantity by destabilization" relocalization 10090 BTO:0004488 29371591 t "P00441:p.Gly94Ala (mutation causing interaction)" "Here, we show that MIF inhibits mutant SOD1 nuclear clearance when overexpressed in motor neuron-like NSC-34 cells|SOD1WT is evenly distributed between the cytoplasm and the nucleus while mutant SOD1G93A shows predominantly cytoplasmic distribution (Fig. 1a, b). Expression of MIF in cells expressing SOD1WT had no effect on the distribution of the SOD1WT–EGFP protein. However, expression of MIF together with the mutant SOD1G93A–EGFP, inhibited the nuclear clearance of misfolded SOD1 resulting in a more wild-type-like distribution of the mutant SOD1 protein" SIGNOR-262797 MIF protein P14174 UNIPROT CXCR4 protein P61073 UNIPROT "up-regulates activity" binding 10090 BTO:0000876 17435771 t gcesareni "We identify the chemokine receptors CXCR2 and CXCR4 as functional receptors for MIF [] By activating both CXCR2 and CXCR4, MIF displays chemokine-like functions and acts as a major regulator of inflammatory cell recruitment and atherogenesis." SIGNOR-252062 MIF protein P14174 UNIPROT HBA1 protein P69905 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000664 16636133 f "Regulation of expression" miannu "MIF inhibits cytodifferentiation and hemoglobin synthesis of MEL cells." SIGNOR-251832 HGF protein P14210 UNIPROT MET protein P08581 UNIPROT up-regulates binding 9606 8380735 t gcesareni "Hgf is the ligand for p190met, the receptor tyrosine kinase encoded by the met proto-oncogene." SIGNOR-38429 TRIM27 protein P14373 UNIPROT MAPK13 protein O15264 UNIPROT up-regulates 9606 BTO:0000671 12807881 f miannu "We found rfp-mediated activation of both exogenous and endogenous forms of the other stress-activated mapk, p38." SIGNOR-102028 TRIM27 protein P14373 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates 9606 BTO:0000671 12807881 f miannu "Rfp expression in hek 293 cells activated jnk1" SIGNOR-102034 TRIM27 protein P14373 UNIPROT MAPK12 protein P53778 UNIPROT up-regulates 9606 BTO:0000671 12807881 f miannu "We found rfp-mediated activation of both exogenous and endogenous forms of the other stress-activated mapk, p38." SIGNOR-102025 TRIM27 protein P14373 UNIPROT MAPK11 protein Q15759 UNIPROT up-regulates 9606 BTO:0000671 12807881 f miannu "We found rfp-mediated activation of both exogenous and endogenous forms of the other stress-activated mapk, p38." SIGNOR-102022 TRIM27 protein P14373 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 BTO:0000671 12807881 f miannu "We found rfp-mediated activation of both exogenous and endogenous forms of the other stress-activated mapk, p38." SIGNOR-102031 CPM protein P14384 UNIPROT HBA1 protein P69905 UNIPROT "down-regulates activity" cleavage Tyr141 STVLTSKyR -1 8635221 t miannu "Both human plasma carboxypeptidase N (CPN) and membrane-bound carboxypeptidase M (CPM) released the C-terminal arginine (alpha-Arg141) of the alpha chain of human adult hemoglobin. Thus, the hydrolysis of hemoglobin by CPM and CPN demonstrated the contribution of the alpha-Arg141 residue to sustaining the tetrameric structure of hemoglobin and its normal oxygen affinity and vasoactivity." SIGNOR-256507 DRD2 protein P14416 UNIPROT GNB5 protein O14775 UNIPROT "up-regulates activity" binding 9606 BTO:0004032 21303898 t miannu "The D2-class dopamine receptors (D2, D3, and D4) couple to the Gi/o family of G proteins and thus induce inhibition of AC" SIGNOR-264993 DRD2 protein P14416 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256844 DRD2 protein P14416 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256980 ETS1 protein P14921 UNIPROT ATP2A3 protein Q93084 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000255 12119294 t Luana "Ets-1 was able to transactivate the SERCA3 promoter in MoBr 204 as cotransfection of an Ets-1 expression vector increased the activity of the −97/+301-Luc construct by 6-fold." SIGNOR-261601 PRKCA protein P17252 UNIPROT LMNA protein P02545 UNIPROT unknown phosphorylation Ser525 NTWGCGNsLRTALIN -1 8477740 t lperfetto "An interphase-specific phosphorylation at Ser525 matching the PKC consensus sequence and of peptides phosphorylated by unknown kinases was determined." SIGNOR-248935 DRD2 protein P14416 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257096 PKM protein P14618 UNIPROT pyruvate smallmolecule CHEBI:15361 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 15996096 t miannu "Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A)." SIGNOR-266536 PKM protein P14618 UNIPROT phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 15996096 t miannu "Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A)." SIGNOR-266534 CCNB1 protein P14635 UNIPROT CyclinB/CDK1 complex SIGNOR-C17 SIGNOR "form complex" binding 9606 25603287 t lperfetto "The central mitotic kinase, cyclin-dependent kinase-1 (human cdk1 is present through all stages of the cell cycle, but its activity is cell-cycle regulated by phosphorylation/dephosphorylation and cyclin binding.Cdk1-cyclin b phosphorylates ser/thr residues directly preceding pro; thus, it is classified as a proline-directed kinase." SIGNOR-205590 HOXB3 protein P14651 UNIPROT OTX2 protein P32243 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000946 9556594 t Luana "Transactivation of the mouse OTX2 Luc constructs by the human HOXB1, HOXB2, and HOXB3 proteins. | Likewise, the construct pOTX2LucΔ−710 showed an 8-, 12-, and 6-fold increase in transcriptional activity if co-transfected with pSG-HOXB1, -HOXB2, and -HOXB3, respectively" SIGNOR-261635 HOXB2 protein P14652 UNIPROT OTX2 protein P32243 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000946 9556594 t Luana "Transactivation of the mouse OTX2 Luc constructs by the human HOXB1, HOXB2, and HOXB3 proteins. | Likewise, the construct pOTX2LucΔ−710 showed an 8-, 12-, and 6-fold increase in transcriptional activity if co-transfected with pSG-HOXB1, -HOXB2, and -HOXB3, respectively" SIGNOR-261634 HOXB1 protein P14653 UNIPROT OTX2 protein P32243 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000946 9556594 t Luana "Transactivation of the mouse OTX2 Luc constructs by the human HOXB1, HOXB2, and HOXB3 proteins. | Likewise, the construct pOTX2LucΔ−710 showed an 8-, 12-, and 6-fold increase in transcriptional activity if co-transfected with pSG-HOXB1, -HOXB2, and -HOXB3, respectively" SIGNOR-261633 IL1R1 protein P14778 UNIPROT MAPK8 protein P45983 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000801 9625767 t 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-249513 IL1R1 protein P14778 UNIPROT MAPK9 protein P45984 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000801 9625767 t 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-249514 IL1R1 protein P14778 UNIPROT IRAK1 protein P51617 UNIPROT "up-regulates activity" 9606 BTO:0000007 14625308 f lperfetto "Formation of the signaling il-1 receptor complex results in the activation and hyperphosphorylation of irak-1." SIGNOR-119208 IL1R1 protein P14778 UNIPROT MAPK10 protein P53779 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000801 9625767 t 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-249515 IL1R1 protein P14778 UNIPROT MYD88 protein Q99836 UNIPROT "up-regulates activity" binding 9606 BTO:0003432 10217414 t 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 IL1R1 protein P14778 UNIPROT IL1RAP protein Q9NPH3 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 10854325 t 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 IL1R1 protein P14778 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "up-regulates activity" 9606 9625767 f 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 MMP9 protein P14780 UNIPROT HAPLN1 protein P10915 UNIPROT "down-regulates quantity by destabilization" cleavage His31 LDHDRAIhIQAENGP -1 7694569 t miannu "Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix." SIGNOR-256328 IL9 protein P15248 UNIPROT IL2RG protein P31785 UNIPROT up-regulates binding 9606 11418623 t gcesareni "The common gamma-chain (gamma(c)) is an indispensable subunit of the functional receptor complexes for il-4, il-7, il-9, and il-15 as well as il-2. Here we show that the gamma(c) is also shared with the il-21r complex" SIGNOR-108867 MMP9 protein P14780 UNIPROT PZP protein P20742 UNIPROT "down-regulates quantity by destabilization" cleavage Leu778 WKAGAFClSEDAGLG -1 9344465 t lperfetto "The complex formation was confirmed by the use of 125I-labeled matrix metalloproteinase-2. The cleavage sites in the ""bait"" regions following formation of high-molecular-weight complexes of matrix metalloproteinases with the alpha-macroglobulins were determined by protein sequence analysis. Pregnancy zone protein was cleaved at Thr693-Tyr694 and alpha2-macroglobulin at Gly679-Leu680 and Arg696-Leu697 by matrix metalloproteinase-2. Matrix metalloproteinase-9 cleaved alpha2-macroglobulin at the same site as matrix metalloproteinase-2, but cleavage of pregnancy zone protein was at Leu753-Ser754.|MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP." SIGNOR-261785 IL2RB protein P14784 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271;BTO:0000785 24737791 t milica "In lymphocytes, binding of il-15 to the il-2/15rbg heterodimer induces jak1 activation that subsequently phosphorylates stat3 via the b-chain and jak3/stat5 activation via its g-chain" SIGNOR-204972 IL2RB protein P14784 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271;BTO:0000785 24737791 t milica "The signaling mechanism utilizes an adaptor protein, shc, which binds to a phosphotyrosine residue on the il-2/15r?, Resulting in activation of grb2 and onto akt via the shc-grb2-gab2-pi3k-akt signaling pathway to increase cell proliferation and/or survival" SIGNOR-204975 POU2F1 protein P14859 UNIPROT SNAI2 protein O43623 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001939 23836662 f miannu "This PER2-OCT1 interaction effectively converted OCT1 sites, which normally activate expression, into repressor sites by recruitment of a polycomb repressor complex including EZH2 and SUZ12, as well as HDAC2. We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes." SIGNOR-254149 POU2F1 protein P14859 UNIPROT IL4 protein P05112 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000782 11781715 f "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 POU2F1 protein P14859 UNIPROT MYH1 protein P12882 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001103 15728583 t lperfetto "Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation" SIGNOR-238760 POU2F1 protein P14859 UNIPROT TWIST1 protein Q15672 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001939 23836662 f miannu "This PER2-OCT1 interaction effectively converted OCT1 sites, which normally activate expression, into repressor sites by recruitment of a polycomb repressor complex including EZH2 and SUZ12, as well as HDAC2. We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes." SIGNOR-254152 POU2F1 protein P14859 UNIPROT GFI1B protein Q5VTD9 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19965638 f miannu "HMGB2 binds to the GFI1B promoter in vivo and up-regulates its trans-activation most likely by enhancing the binding of Oct-1 and, to a lesser extent, of GATA-1 and NF-Y to the GFI1B promoter." SIGNOR-254432 POU2F1 protein P14859 UNIPROT MYH2 protein Q9UKX2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001103 15728583 t lperfetto "Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation" SIGNOR-238757 GABRA1 protein P14867 UNIPROT "GABA-A (a1-b1-g2) receptor" complex SIGNOR-C330 SIGNOR "form complex" binding 9606 BTO:0000227 18790874 t "brain, See table 3 for identified complexes" lperfetto "The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon." SIGNOR-263750 ETS1 protein P14921 UNIPROT FOS protein P01100 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 1722028 t "Furthermore, the possible involvement of an Ets protein in the control of c-fos has interesting implications for proto-oncogene cooperation in cellular growth control." SIGNOR-256495 ETS1 protein P14921 UNIPROT TBXAS1 protein P24557 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 14586398 f miannu "We demonstrate that p53 and ets-1 coregulate TXSA in an antagonistic and inter-related manner, with ets-1 being a potent transcriptional activator and p53 inhibiting ets-1-dependent transcription." SIGNOR-254088 ETS1 protein P14921 UNIPROT SLC26A3 protein P40879 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000776 7935445 f miannu "Ets-1 activates the DRA promoter in B cells." SIGNOR-254085 ETS1 protein P14921 UNIPROT ECE1 protein P42892 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000396 9595399 f miannu "Endothelial expression of endothelin-converting enzyme-1 beta mRNA is regulated by the transcription factor Ets-1. We conclude that Ets-1 is involved in transcriptional upregulation of ECE-1 beta mRNA in E.A. hy 926 cells induced by phorbol ester." SIGNOR-254080 ETS1 protein P14921 UNIPROT MMP13 protein P45452 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000948 22270366 f miannu "VEGF-induced MMP-9 and MMP-13 promoter activities were down-regulated in ETS-1 siRNA-transfected cells. it is hypothesized that the activation of PI3K/AKT and p38 MAPK by VEGF results in ETS-1 gene expression, which activates MMP-9 and MMP-13, leading to the invasion and scattering of SKOV-3 cells." SIGNOR-254084 ETS1 protein P14921 UNIPROT BAX protein Q07812 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002181 17213822 f miannu "Our results suggest that the interaction between ETS1 and GFI1 facilitates their binding to specific sites on the Bax promoter and represses Bax expression in vivo." SIGNOR-254204 ETS1 protein P14921 UNIPROT MUC4 protein Q99102 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001861 19757157 t lperfetto "Through promoter screening, overexpressing methods and luciferase reporter studies, we found that transcription factors CREB, Ets-1, Elk-1 and STAT1 can positively regulate MUC4 expression at the promoter and mRNA level." SIGNOR-254098 ETS1 protein P14921 UNIPROT GFI1 protein Q99684 UNIPROT "down-regulates activity" binding 9606 BTO:0002181 17213822 t miannu "Co-immunoprecipitation analyses and glutathione-S-transferase pull-down assays revealed that ETS1 bound directly to GFI1 via its Ets domain, and GFI1 bound to ETS1 via its zinc-finger domain. Luciferase (Luc) assays using artificial reporters showed that GFI1 repressed ETS1-mediated transcriptional activation and ETS1 repressed GFI1-mediated transcriptional activation, in a dose-dependent manner." SIGNOR-254202 ETS1 protein P14921 UNIPROT GP6 protein Q9HCN6 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12377757 f miannu "We have determined that the GP6 sequence -191 to -39 represents the core promoter and that transcription is driven largely by GATA-1 (-176) and c-Ets-1 (-45) sites within this segment." SIGNOR-254082 ETS1 protein P14921 UNIPROT ITGA11 protein Q9UKX5 UNIPROT "up-regulates quantity by expression" 9606 BTO:0001282 16300938 t lperfetto "We speculate that the ""mesenchymal signature"" of alpha11 integrin gene expression is controlled by the activity of Sp1/Sp3, fibroblast-specific combinations of Ets family members and yet unidentified enhancer-binding transcription factors." SIGNOR-253352 LIF protein P15018 UNIPROT LIFR protein P42702 UNIPROT up-regulates binding 9606 24710148 t 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-204847 ETS2 protein P15036 UNIPROT BGLAP protein P02818 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 11175361 t miannu "Ets2 is expressed at high levels during the differentiation and matrix mineralization phases of MC3T3-E1 culture. In addition, several extracellular matrix (ECM) associated gene products are targets of Ets2. Some of these matrix associated genes include: bone sialoprotein, osteonectin, osteocalcin and osteopontin" SIGNOR-259875 ETS2 protein P15036 UNIPROT SPARC protein P09486 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 11175361 t miannu "Ets2 is expressed at high levels during the differentiation and matrix mineralization phases of MC3T3-E1 culture. In addition, several extracellular matrix (ECM) associated gene products are targets of Ets2. Some of these matrix associated genes include: bone sialoprotein, osteonectin, osteocalcin and osteopontin" SIGNOR-259874 ETS2 protein P15036 UNIPROT SPP1 protein P10451 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 11175361 t miannu "We demonstrated that Ets2 is capable of binding to and transactivating the OPN promoter using gel shift and transient transfection assays" SIGNOR-259872 ETS2 protein P15036 UNIPROT IBSP protein P21815 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 11175361 t miannu "Ets2 is expressed at high levels during the differentiation and matrix mineralization phases of MC3T3-E1 culture. In addition, several extracellular matrix (ECM) associated gene products are targets of Ets2. Some of these matrix associated genes include: bone sialoprotein, osteonectin, osteocalcin and osteopontin" SIGNOR-259873 BRAF protein P15056 UNIPROT TGFB1 protein P01137 UNIPROT "up-regulates quantity" relocalization 9606 19861538 f miannu "The BRAFV600E oncogene induces transforming growth factor beta secretion leading to sodium iodide symporter repression and increased malignancy in thyroid cancer. BRAF induces TGFβ secretion leading to NIS repression in a MEK-ERK–independent manner but cooperating with the MEK-ERK pathway to induce strong tumor invasion, two major traits acquired during PTC progression." SIGNOR-251987 BRAF protein P15056 UNIPROT MAP2K2 protein P36507 UNIPROT up-regulates phosphorylation Ser222 VSGQLIDsMANSFVG 9606 BTO:0000142 8668348 t gcesareni "We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l." SIGNOR-42664 BRAF protein P15056 UNIPROT MAP2K2 protein P36507 UNIPROT up-regulates phosphorylation Ser226 LIDSMANsFVGTRSY 9606 BTO:0000142 8668348 t gcesareni "We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l." SIGNOR-42668 BRAF protein P15056 UNIPROT MAP2K1 protein Q02750 UNIPROT "up-regulates activity" phosphorylation Ser218 VSGQLIDsMANSFVG 10090 BTO:0000944 8131746 t lperfetto "Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf." SIGNOR-235475 BRAF protein P15056 UNIPROT MAP2K1 protein Q02750 UNIPROT "up-regulates activity" phosphorylation Ser222 LIDSMANsFVGTRSY -1 8413257 t lperfetto "Raf-1 phosphorylation of MEK activated it, as judged by its ability to stimulate the phosphorylation of myelin basic protein by glutathione S-transferase-ERK1." SIGNOR-39054 BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "up-regulates activity" phosphorylation 9606 21900390 t miannu "BRAFV600E has been shown to initiate thyroid follicular cell transformation. The BRAFV600E mutation disrupts the hydrophobic interaction, enabling the BRAF kinase to fold into a catalytically active formation, resulting in an almost 500-fold increase in kinase activity. Mutant BRAF can dimerize and activate MEK without Ras activation." SIGNOR-251988 BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "up-regulates activity" phosphorylation -1 8413257 t lperfetto "Raf-1 phosphorylation of MEK activated it, as judged by its ability to stimulate the phosphorylation of myelin basic protein by glutathione S-transferase-ERK1." SIGNOR-244831 PVR protein P15151 UNIPROT CD226 protein Q15762 UNIPROT "up-regulates activity" binding 9606 BTO:0000914 30591568 t lperfetto "We focused on receptor-ligand interactions between CAFs and NK cell and found that cell-surface poliovirus receptor (PVR/CD155), a ligand of activating NK receptor DNAM-1, was downregulated in the CAFs compared with NEFs. |Poliovirus receptor (PVR/CD155) is a ligand of the paired NK receptors, DNAM-1 (activating) and TIGIT (inhibiting). NK cells can kill cancer cells expressing PVR via the DNAM-1-mediated activating signaling (11,12)." SIGNOR-261424 IL9 protein P15248 UNIPROT IL9R protein Q01113 UNIPROT up-regulates binding 9606 10642536 t fspada "Interleukin 9 (il-9) exerts its pleiotropic effects through the il-9 receptor (il-9r) complex, which consists of the il-9r alpha-chain, which determines the cytokine specificity, and the il-2 receptor gamma-chain" SIGNOR-73601 MYOD1 protein P15172 UNIPROT MYH7 protein P12883 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165 17111365 f Regulation miannu "Transient transfection assays demonstrated that the calcineurin/NFATc1 signaling pathway is essential for MyHCbeta promoter activation during transformation of C2C12 myotubes but is not sufficient for complete fast MyHCIId/x promoter inhibition. Along with NFATc1, myocyte enhancer factor-2D (MEF-2D) and the myogenic transcription factor MyoD transactivated the MyHCbeta promoter in calcium-ionophore-treated myotubes in a calcineurin-dependent manner." SIGNOR-251958 MYOD1 protein P15172 UNIPROT MYOG protein P15173 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" BTO:0001103 12694204 t "Simone Vumbaca" "We conclude that MyoD is the major MRF that binds to the E-box from the myogenin promoter during differentiation." SIGNOR-255640 MYOD1 protein P15172 UNIPROT MYOG protein P15173 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887 15870273 f 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 MYOD1 protein P15172 UNIPROT MYOG protein P15173 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18676376 f 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 MYOD1 protein P15172 UNIPROT VEGFA protein P15692 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001103 18094043 t lperfetto "We further demonstrate that the myogenic transcription factor, MyoD, and its heterodimeric binding proteins E12 and E47, up-regulate the expression of endogenous VEGF through direct interaction with the VEGF promoter." SIGNOR-257598 MYOD1 protein P15172 UNIPROT DES protein P17661 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000222 25653159 t lperfetto "MyoD and HDAC2 repress myogenic late genes at early times of differentiation.A time course of Ckm, Des and Acta1 gene expression demonstrated that these genes were prematurely expressed when differentiation was driven by myogenin and Mef2D1b (Figure _(Figure6A).6A). Since MyoD is not expressed under these conditions, it cannot bind to these genes; ChIP assays demonstrated that HDAC2 also was not present on the Ckm, Des and Acta1 regulatory sequences under these conditions (Figure _(Figure6B).6B). Therefore the presence of MyoD and HDAC2 prior to gene expression functions to repress late gene expression at early times of differentiation." SIGNOR-241762 MYOD1 protein P15172 UNIPROT FST protein P19883 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165 15130492 f lperfetto "MyoD, CREB, and NFAT Mediate the Transcriptional Activation of the Follistatin Promoter Induced by TSA" SIGNOR-251727 MYOD1 protein P15172 UNIPROT CDKN1A protein P38936 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 25211658 t "P21 is regulated by MyoD and myogenin in normal muscle cells and the inactivation of these factors in RMS cells contributes to the silencing of p21 in RMS cells" SIGNOR-251574 MYOD1 protein P15172 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165 10373569 t gcesareni "Here we report that, at the onset of differentiation, activation by MyoD of the Rb, p21, and cyclin D3 genes occurs in the absence of new protein synthesis and with the requirement of the p300 transcriptional coactivator." SIGNOR-238529 MYOD1 protein P15172 UNIPROT MYOD/E12E47 complex SIGNOR-C127 SIGNOR "form complex" binding 10090 BTO:0001103 18094043 t lperfetto "MyoD omodimers or heterodimers of MyoD plus E12 or E47 serve as transcription factor complexes that bind to CANNTG consensus sites in the promoter regions of genes, performing major functions in specification and differentiation of skeletl muscle precursor cells." SIGNOR-241548 MYOD1 protein P15172 UNIPROT MYOD/E2-2 complex SIGNOR-C129 SIGNOR "form complex" binding 9606 16847330 t 2 miannu "The MyoD family of basic helix-loop-helix transcription factors function as heterodimers with members of the E-protein family to induce myogenic gene activation." SIGNOR-241100 MYOD1 protein P15172 UNIPROT "SWI/SNF complex" complex SIGNOR-C92 SIGNOR up-regulates binding 9606 BTO:0001103 17194702 t lperfetto "Myod targets brg1 to the myogenin promoter during the initiation of myogenesis in tissue culture models for skeletal muscle differentiation /initiation of myogenin transcription is dependent upon myod, the pbx homeodomain factor, and swi/snf chromatin-remodeling enzymes" SIGNOR-217737 MYOD1 protein P15172 UNIPROT "MYOD1/SWI/SNF complex" complex SIGNOR-C93 SIGNOR "form complex" binding 9606 BTO:0001103 17194702 t miannu "Myod targets brg1 to the myogenin promoter during the initiation of myogenesis in tissue culture models for skeletal muscle differentiation /initiation of myogenin transcription is dependent upon myod, the pbx homeodomain factor, and swi/snf chromatin-remodeling enzymes" SIGNOR-151682 MYOG protein P15173 UNIPROT MYOG protein P15173 UNIPROT up-regulates "transcriptional regulation" 9606 SIGNOR-C92 17194702 t miannu "Upon the expression of myogenin, myogenin, mef2d, and brg1 localize to the myogenin promoter to maintain myogenin expression./ Swi/snf chromatin-remodeling activity is required for myogenin expression in differentiated skeletal muscle" SIGNOR-151694 MYOG protein P15173 UNIPROT DES protein P17661 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165 25653159 f lperfetto "Ectopic expression of myogenin and a specific Mef2 isoform induced myogenic differentiation without activating endogenous MyoD expression. Under these conditions, the regulatory sequences of late gene loci were not in close proximity, and these genes were prematurely activated." SIGNOR-241501 MYOG protein P15173 UNIPROT MYF6 protein P23409 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" BTO:0001103 7739551 t "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 MYOG protein P15173 UNIPROT CDKN1A protein P38936 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 25211658 t "P21 is regulated by MyoD and myogenin in normal muscle cells and the inactivation of these factors in RMS cells contributes to the silencing of p21 in RMS cells" SIGNOR-251575 MYOG protein P15173 UNIPROT "SWI/SNF complex" complex SIGNOR-C92 SIGNOR up-regulates binding 9606 BTO:0001103 17194702 t lperfetto "Upon the expression of myogenin, myogenin, mef2d, and brg1 localize to the myogenin promoter to maintain myogenin expression./ Swi/snf chromatin-remodeling activity is required for myogenin expression in differentiated skeletal muscle" SIGNOR-217740 MYOG protein P15173 UNIPROT "Myog/SWI/SNF complex" complex SIGNOR-C94 SIGNOR "form complex" binding 9606 BTO:0001103 17194702 t miannu "Upon the expression of myogenin, myogenin, mef2d, and brg1 localize to the myogenin promoter to maintain myogenin expression./ Swi/snf chromatin-remodeling activity is required for myogenin expression in differentiated skeletal muscle" SIGNOR-151691 PGAM2 protein P15259 UNIPROT 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 24786789 t miannu "Phosphoglycerate mutase (PGAM) is a glycolytic enzyme that catalyzes the reversible conversion of 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG; ref. 4). Human genome contains two PGAM genes, PGAM1 (also known as PGAM-B), which is expressed in brain and most other tissues, and PGAM2 (also known as PGAM-M), which is highly expressed in muscle." SIGNOR-266512 PGAM2 protein P15259 UNIPROT 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 24786789 t miannu "Phosphoglycerate mutase (PGAM) is a glycolytic enzyme that catalyzes the reversible conversion of 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG; ref. 4). Human genome contains two PGAM genes, PGAM1 (also known as PGAM-B), which is expressed in brain and most other tissues, and PGAM2 (also known as PGAM-M), which is highly expressed in muscle." SIGNOR-266515 IFNGR1 protein P15260 UNIPROT IFNGR2/INFGR1 complex SIGNOR-C142 SIGNOR "form complex" binding 9606 BTO:0000801 19041276 t 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 ARSA protein P15289 UNIPROT HBB protein P68871 UNIPROT "up-regulates activity" acetylation 9606 237937 t Regulation miannu "ASA acetylates hemoglobin. Purified acetylated hemoglobin had a slightly increased oxygen affinity and decreased heme-heme interaction." SIGNOR-251772 EZR protein P15311 UNIPROT FES protein P07332 UNIPROT up-regulates relocalization 9606 18046454 t miannu "The recruitment and the activation of fes to the cell-cell contacts in confluent cells depend on its interaction with ezrin." SIGNOR-159496 ATF2 protein P15336 UNIPROT PLAT protein P00750 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567 8647095 f lperfetto "We suggest that the mechanism for the transcriptional down-regulation of t-PA by PMA in HT-1080 cells requires CREB-1 binding to the t-PACRE while ATF-2, by associating with the same site, plays a role in PMA-mediated induction of t-PA in HeLa cells." SIGNOR-253724 ATF2 protein P15336 UNIPROT IL6 protein P05231 UNIPROT up-regulates "transcriptional regulation" 9606 BTO:0000801 20086235 f "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-254512 ATF2 protein P15336 UNIPROT POLB protein P06746 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001025 10518804 f miannu "We identified the heterodimeric transcription factor ATF2/CREB as constitutively binding to the essential cAMP response element (CRE) site within the Ca2+-regulated DNA polymerase beta promoter and contributing to the activation of this promoter." SIGNOR-253744 ATF2 protein P15336 UNIPROT GCH1 protein P30793 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16149046 f miannu "Constitutively active mutants of activating transcription factor 2 (ATF2) and c-Jun additionally stimulated GTP cyclohydrolase I promoter activity, but to a lesser extent than the constitutively active CREB mutant. Enzymatic reactions that require tetrahydrobiopterin as cofactor are therefore indirectly controlled by signaling cascades involving the signal-responsive transcription factors CREB, c-Jun, and ATF2." SIGNOR-252226 ATF2 protein P15336 UNIPROT FGF21 protein Q9NSA1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0005787 25055037 f miannu "The increased production of reactive oxygen species, subsequent induction of p38 MAPK (mitogen-activated protein kinase) and activation of an ATF2 (activating transcription factor 2)-binding site at the proximal promoter region of the FGF21 gene was found to be a major mechanism linking mitochondrial dysfunction with enhanced FGF21 gene transcription in myogenic cells." SIGNOR-253743 ATF2 protein P15336 UNIPROT ST3GAL5 protein Q9UNP4 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002335 21699754 f miannu "Our results identified the core promoter region in the hST3Gal V promoter and for the first time demonstrated that ATF2 binding to the CREB/ATF binding site at -143 is essential for transcriptional activation of hST3Gal V in VPA-induced ARPE-19 cells." SIGNOR-253745 CD19 protein P15391 UNIPROT LYN protein P07948 UNIPROT "up-regulates activity" binding 10090 BTO:0000776 25673924 t lperfetto "CD19 has an extracellular region containing two C2-type Ig-like domains and a cytoplasmic region of ~240 amino acids with 9 conserved tyrosine residues24. Lyn, a Src-family protein tyrosine kinase member, is the dominant kinase that phosphorylates CD19 upon stimulation. Once tyrosyl-phosphorylated, CD19 serves as a membrane-bound adaptor protein for Src homology 2-containing signaling molecules such as Lyn, Vav, and phosphatidylinositol 3-kinase, which further mediate downstream activation cascades." SIGNOR-242894 CD19 protein P15391 UNIPROT MAPK1 protein P28482 UNIPROT "up-regulates activity" 9606 10706702 f lperfetto "CD19 is a coreceptor on B cells that enhances the increase in cytoplasmic calcium and ERK2 activation when coligated with the B cell Ag receptor." SIGNOR-249609 CD19 protein P15391 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" binding 10090 BTO:0000899 10201980 t lperfetto "Phosphorylation of CD19 Y484 and Y515, and linked activation of phosphatidylinositol 3-kinase, are required for B cell antigen receptor-mediated activation of Bruton's tyrosine kinase." SIGNOR-252669 CD19 protein P15391 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" binding 10090 BTO:0000776 25673924 t lperfetto "CD19 has an extracellular region containing two C2-type Ig-like domains and a cytoplasmic region of ~240 amino acids with 9 conserved tyrosine residues24. Lyn, a Src-family protein tyrosine kinase member, is the dominant kinase that phosphorylates CD19 upon stimulation. Once tyrosyl-phosphorylated, CD19 serves as a membrane-bound adaptor protein for Src homology 2-containing signaling molecules such as Lyn, Vav, and phosphatidylinositol 3-kinase, which further mediate downstream activation cascades." SIGNOR-252670 FOSL2 protein P15408 UNIPROT FOSL1 protein P15407 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004603 13679379 t Luana "Members of the AP1 family distinctly regulated the fra-1 promoter. In particular, coexpression of c-Jun, Jun-D, and Fra-2 up-regulated fra-1 transcription. " SIGNOR-261602 VAV1 protein P15498 UNIPROT SYK protein P43405 UNIPROT up-regulates binding 9606 11331248 t lperfetto "Vav interacts with the tyrosine kinase syk" SIGNOR-107049 CREB1 protein P16220 UNIPROT SNAI2 protein O43623 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000151 15955695 f miannu "In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro." SIGNOR-253791 VAV1 protein P15498 UNIPROT RHOA protein P61586 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260580 VAV1 protein P15498 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 BTO:0001271 9209406 t gcesareni "Recently, we have shown that the proto-oncogene vav product (vav) is also tyrosine-phosphorylated by treatment with gm-csf and epo and is constitutively associated with the sh3 domain of grb2/ash in ut-7." SIGNOR-49362 VAV1 protein P15498 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 7227 23525006 t "We identify the GTP exchange factor (GEF) Vav as a key regulator of Rac activity downstream of RTKs in a developmentally regulated cell migration event" SIGNOR-259081 VAV1 protein P15498 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260581 VAV1 protein P15498 UNIPROT PRKCQ protein Q04759 UNIPROT up-regulates 9606 BTO:0000782 10725744 f lperfetto "Vav synergizes with protein kinase c theta to mediate il-4 gene expression in response to cd28 costimulation in t cells" SIGNOR-75827 VAV1 protein P15498 UNIPROT GRAP protein Q13588 UNIPROT up-regulates binding 9606 7809090 t gcesareni "Here we report that both in cell extracts and within intact mammalian cells vav binds to grb2 (sem-5/ash/drk), an adaptor molecule which plays a key role in ras activation." SIGNOR-33840 AREG protein P15514 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 10085134 t "Amphiregulin is an autocrine growth factor" gcesareni "The epidermal growth factor receptor (EGFR) mediates the actions of a family of bioactive peptides that include epidermal growth factor (EGF) and amphiregulin (AR)" SIGNOR-65576 AREG protein P15514 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 BTO:0001253 20513444 t "Amphiregulin is an autocrine growth factor" lperfetto "Remarkably, three members of the epidermal growth factor (egf) family (ereg, areg, and epgn) showed increased expression that was associated with elevated epidermal activation of the egf receptor (egfr) and stat3, a downstream effector of egfr signaling." SIGNOR-236356 AREG protein P15514 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" binding 9606 10209155 t "Amphiregulin is an autocrine growth factor" lperfetto "ErbB ligands include: EGF, transforming growth factor (TGF)_, and amphiregulin which only bind ErbB1" SIGNOR-67000 NME1 protein P15531 UNIPROT MMP2 protein P08253 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001567 17671192 f miannu "To elucidate the molecular mechanism of Nm23-H1 motility suppression, expression microarray analysis of an MDA-MB-435 cancer cell line overexpressing wild-type Nm23-H1 was done and cross-compared with expression profiles from lines expressing the P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF, and EDG2, were down-regulated by wild-type but not by mutant Nm23-H1 expression." SIGNOR-255165 NME1 protein P15531 UNIPROT MET protein P08581 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001567 17671192 f miannu "To elucidate the molecular mechanism of Nm23-H1 motility suppression, expression microarray analysis of an MDA-MB-435 cancer cell line overexpressing wild-type Nm23-H1 was done and cross-compared with expression profiles from lines expressing the P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF, and EDG2, were down-regulated by wild-type but not by mutant Nm23-H1 expression." SIGNOR-255164 NME1 protein P15531 UNIPROT NME1 protein P15531 UNIPROT unknown phosphorylation Ser125 HGSDSVEsAEKEIGL -1 8810265 t miannu "For autophosphorylated rNm23-H1, phosphorylation was observed at serine 44 and on a fragment containing serines 120, 122, and 125.The biochemical function of Nm23 serine phosphorylation is unknown." SIGNOR-250198 NME1 protein P15531 UNIPROT NME1 protein P15531 UNIPROT up-regulates phosphorylation His118 QVGRNIIhGSDSVES 9606 BTO:0000763 22869372 t llicata "Ndpk catalytic function requires autophosphorylation at the catalytic his-118 residue. the simplest interpretation of these data is that ampk does not directly phosphorylate ndpk-a at ser-120 or ser-122 (or at any other site) but rather enhances ndpk-a autophosphorylation at his-118." SIGNOR-198667 NME1 protein P15531 UNIPROT NME1 protein P15531 UNIPROT "up-regulates activity" phosphorylation Ser44 GLKFMQAsEDLLKEH 9606 BTO:0000093 8245015 t miannu "An acid-stable (nonhistidine) phosphorylation was identified on autophosphorylated purified recombinant Nm23 proteins and [32P]orthophosphate-labeled human breast carcinoma and murine melanoma Nm23. Phosphoamino acid analysis identified serine as the acid-stable phosphorylation and serine 44 as the major site of phosphorylation. The biological relevance of the novel phosphorylation identified herein is suggested by the direct correlation of in vivo Nm23 acid-stable phosphorylation levels, but not Nm23 NDPK activity, with suppression of tumor metastatic potential among control and nm23-1 transfected murine melanoma cells." SIGNOR-250303 NME1 protein P15531 UNIPROT PTN protein P21246 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001567 17671192 f miannu "To elucidate the molecular mechanism of Nm23-H1 motility suppression, expression microarray analysis of an MDA-MB-435 cancer cell line overexpressing wild-type Nm23-H1 was done and cross-compared with expression profiles from lines expressing the P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF, and EDG2, were down-regulated by wild-type but not by mutant Nm23-H1 expression." SIGNOR-255167 NME1 protein P15531 UNIPROT KSR1 protein Q8IVT5 UNIPROT unknown phosphorylation Ser406 TRLRRTEsVPSDINN -1 12105213 t miannu "Mutation of Ser392 to alanine consistently reduced Nm23-H1 phosphorylation, confirming it as a site of Nm23-H1 kinase activity The unique phosphorylation pattern of KSR by Nm23-H1 will be the subject of further investigation to determine its effects on KSR protein binding, subcellular localization, response to various signals, etc." SIGNOR-250299 ITGB4 protein P16144 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates binding 9606 9428518 t gcesareni "Stable expression of alpha6beta4 increased carcinoma invasion in a pi3k-dependent manner, and transient expression of a constitutively active pi3k increased invasion in the absence of alpha6beta4. Ligation of alpha6beta4 stimulated significantly more pi3k activity than ligation of beta1 integrins, establishing specificity among integrins for pi3k activation." SIGNOR-54615 NME1 protein P15531 UNIPROT LPAR1 protein Q92633 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001567 17671192 f miannu "To elucidate the molecular mechanism of Nm23-H1 motility suppression, expression microarray analysis of an MDA-MB-435 cancer cell line overexpressing wild-type Nm23-H1 was done and cross-compared with expression profiles from lines expressing the P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF, and EDG2, were down-regulated by wild-type but not by mutant Nm23-H1 expression." SIGNOR-255163 NME1 protein P15531 UNIPROT SMO protein Q99835 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001567 17671192 f miannu "To elucidate the molecular mechanism of Nm23-H1 motility suppression, expression microarray analysis of an MDA-MB-435 cancer cell line overexpressing wild-type Nm23-H1 was done and cross-compared with expression profiles from lines expressing the P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF, and EDG2, were down-regulated by wild-type but not by mutant Nm23-H1 expression." SIGNOR-255168 NME1 protein P15531 UNIPROT FZD1 protein Q9UP38 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001567 17671192 f miannu "To elucidate the molecular mechanism of Nm23-H1 motility suppression, expression microarray analysis of an MDA-MB-435 cancer cell line overexpressing wild-type Nm23-H1 was done and cross-compared with expression profiles from lines expressing the P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF, and EDG2, were down-regulated by wild-type but not by mutant Nm23-H1 expression." SIGNOR-255162 VEGFA protein P15692 UNIPROT FLT1 protein P17948 UNIPROT up-regulates binding 9606 BTO:0004980 14704231 t gcesareni "Vegf exerts its action by binding to vegfr-1 and vegfr-2." SIGNOR-121132 VEGFA protein P15692 UNIPROT KDR protein P35968 UNIPROT up-regulates binding 9606 BTO:0000801;BTO:0000876 17658244 t gcesareni "Binding of vegf to the receptor induces dimerisation and autophosphorylation of specific intracellular tyrosine residues. Activation of intracellular cascades results in proliferation, migration, survival and increased permeability." SIGNOR-157100 VEGFA protein P15692 UNIPROT DLL4 protein Q9NR61 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22426001 f gcesareni "Activation triggered by vegf-a (also known as vegf) has been shown to induce expression of thenotchligand dll4 in angiogenic vessels." SIGNOR-196736 PAX1 protein P15863 UNIPROT MEOX1 protein P50221 UNIPROT "up-regulates activity" binding -1 11423130 t miannu "We show that Mox1 and Mox2 proteins are capable of interacting with Pax1 and Pax3. We propose that the Mox family of homeodomain proteins participates in the molecular signaling network regulating the diverse events of somite development through the physical interaction with the Pax1 and Pax3 members of the Pax family." SIGNOR-222193 PAX1 protein P15863 UNIPROT MEOX2 protein P50222 UNIPROT "up-regulates activity" binding -1 11423130 t miannu "We show that Mox1 and Mox2 proteins are capable of interacting with Pax1 and Pax3. We propose that the Mox family of homeodomain proteins participates in the molecular signaling network regulating the diverse events of somite development through the physical interaction with the Pax1 and Pax3 members of the Pax family." SIGNOR-222232 TCF4 protein P15884 UNIPROT ABCB1 protein P08183 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20459685 f miannu "Cd2+ reduced the interaction of beta-catenin with AJ components (E-cadherin, alpha-catenin) and increased binding to the transcription factor TCF4 of the Wnt pathway, which was upregulated and translocated to the nucleus. While Wnt target genes (c-Myc, cyclin D1 and ABCB1) were up-regulated by Cd2+, electromobility shift assays showed increased TCF4 binding to cyclin D1 and ABCB1 promoter sequences with Cd2+. Overexpression of wild-type and mutant TCF4 confirmed Cd2+-induced Wnt signaling." SIGNOR-255389 TCF4 protein P15884 UNIPROT CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20459685 f miannu "Cd2+ reduced the interaction of beta-catenin with AJ components (E-cadherin, alpha-catenin) and increased binding to the transcription factor TCF4 of the Wnt pathway, which was upregulated and translocated to the nucleus. While Wnt target genes (c-Myc, cyclin D1 and ABCB1) were up-regulated by Cd2+, electromobility shift assays showed increased TCF4 binding to cyclin D1 and ABCB1 promoter sequences with Cd2+. Overexpression of wild-type and mutant TCF4 confirmed Cd2+-induced Wnt signaling." SIGNOR-255388 TCF4 protein P15884 UNIPROT SSTR2 protein P30874 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001976 10207097 t Luana "Activation of somatostatin receptor II expression by transcription factors MIBP1 and SEF-2 in the murine brain." SIGNOR-261618 TCF4 protein P15884 UNIPROT SOX9 protein P48436 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15240568 f "The β-catenin–TCF4 complex activity is required for SOX9 expression." SIGNOR-253323 TCF4 protein P15884 UNIPROT CNTNAP2 protein Q9UHC6 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22777675 f miannu "we show that TCF4 can transactivate the NRXN1β and CNTNAP2 promoters in luciferase assays." SIGNOR-255390 TCF4 protein P15884 UNIPROT NRXN1 protein Q9ULB1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22777675 f miannu "we show that TCF4 can transactivate the NRXN1β and CNTNAP2 promoters in luciferase assays." SIGNOR-255391 TCF4 protein P15884 UNIPROT MYOD/E2-2 complex SIGNOR-C129 SIGNOR "form complex" binding 9606 16847330 t 2 miannu "The MyoD family of basic helix-loop-helix transcription factors function as heterodimers with members of the E-protein family to induce myogenic gene activation." SIGNOR-241382 ST6GAL1 protein P15907 UNIPROT CD22 protein Q32M46 UNIPROT "down-regulates activity" glycosylation Asn101 FLGDKNKnCTLSIHP -1 8702538 t lperfetto "CD22-ligand interaction is regulated by the activity of a b-galactoside a2,6- sialyltransferase that can inactivate CD22-mediated binding by sialylating the CD22 receptor itself. These observations suggest that N-linked glycosylation sites on the CD22 molecule may play a role in the regulation of CD22-mediated adhesion." SIGNOR-261741 TCF3 protein P15923 UNIPROT MYOD1 protein P15172 UNIPROT "up-regulates activity" binding 9606 BTO:0000887 1649701 t "E12/E47-like proteins interact in vivo with the myogenic HLH proteins MyoD and myogenin" lperfetto "In addition we demonstrate that myod, in conjunction with e12/e47-like proteins, is functioning as a regulatory nodal point for activation of several other downstream muscle regulators." SIGNOR-20540 ANK1 protein P16157 UNIPROT SLN protein O00631 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 28487373 t lperfetto "These results suggest that sAnk1 interacts with SLN both directly and in complex with SERCA1 and reduces SLN's inhibitory effect on SERCA1 activity." SIGNOR-265930 ANK1 protein P16157 UNIPROT ATP2A1 protein O14983 UNIPROT "down-regulates activity" binding 9986 BTO:0001103 28487373 t lperfetto "We recently reported that small ankyrin 1 (sAnk1) interacts with the sarco(endo)plasmic reticulum Ca2+-ATPase in skeletal muscle (SERCA1) to inhibit its activity." SIGNOR-265927 TCF3 protein P15923 UNIPROT CR2 protein P20023 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 11739509 f miannu "We have previously described the presence of an intronic element that is required for both cell- and stage-specific expression of CR2. In this study, we report the identification of a cell type-specific repressor element within the proximal promoter. By supershift analysis this element binds members of the basic helix-loop-helix family of proteins, in particular E2A gene products. Mutational analysis demonstrates that binding of E2A proteins is critical for functioning of this repressor. Thus, E2A activity is key not only for early B cell development, but also for controlling CR2 expression, a gene expressed only during later stages of ontogeny." SIGNOR-255387 TCF3 protein P15923 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 23684607 f miannu "The transcription factor TCF3, also known as E2A, drives p21 expression while repressing PUMA across cancer cell types of multiple origins." SIGNOR-255385 TCF3 protein P15923 UNIPROT NOTCH1 protein P46531 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 22577461 f miannu "E2a positively regulates notch1 expression, which induces the expression of hebalt, bcl11b, and il7r." SIGNOR-197523 TCF3 protein P15923 UNIPROT BBC3 protein Q96PG8 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 23684607 f miannu "The transcription factor TCF3, also known as E2A, drives p21 expression while repressing PUMA across cancer cell types of multiple origins." SIGNOR-255386 TCF3 protein P15923 UNIPROT MYOD/E12E47 complex SIGNOR-C127 SIGNOR "form complex" binding 10090 BTO:0001103 18094043 t lperfetto "MyoD omodimers or heterodimers of MyoD plus E12 or E47 serve as transcription factor complexes that bind to CANNTG consensus sites in the promoter regions of genes, performing major functions in specification and differentiation of skeletl muscle precursor cells." SIGNOR-241551 GATA1 protein P15976 UNIPROT CYBB protein P04839 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 10734088 t "These results suggest that GATA-1 is an activator and that GATA-2 is a relative competitive inhibitor of GATA-1 in the expression of the gp91(phox) gene in human eosinophils." SIGNOR-259947 GATA1 protein P15976 UNIPROT GP1BA protein P07359 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17725493 f miannu "We and others have previously shown that RUNX1 and GATA-1 physically interact and cooperate in the activation of megakaryocytic promoters such as alpha IIb integrin and glycoprotein Ibalpha." SIGNOR-254191 GATA1 protein P15976 UNIPROT ITGA2B protein P08514 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17725493 f miannu "We and others have previously shown that RUNX1 and GATA-1 physically interact and cooperate in the activation of megakaryocytic promoters such as alpha IIb integrin and glycoprotein Ibalpha." SIGNOR-254192 GATA1 protein P15976 UNIPROT KIT protein P10721 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 27858941 f miannu "DAB2IP suppresses transcription of stem cell factor receptor CD117, by interacting with GATA-1 on a silencer element on its gene" SIGNOR-254771 GATA1 protein P15976 UNIPROT FCER1A protein P12319 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000732 11971001 f "Transcriptional regulation of the gene-encoding human Fc epsilon RI alpha-chain was analyzed in detail. EMSA revealed that either YY1 or PU.1 bound to the region close to that recognized by Elf-1. The alpha-chain promoter activity was up-regulated approximately 2-fold by exogenously expressed YY1 or PU.1 and approximately 7-fold by GATA-1, respectively, in KU812 cells" SIGNOR-254288 GATA1 protein P15976 UNIPROT GP9 protein P14770 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002581 15466856 f miannu "Both Fli-1 and GATA-1 are required for formation of an active transcriptional complex on the C-MPL and GPIX promoters in vivo." SIGNOR-254161 GATA1 protein P15976 UNIPROT GATA1 protein P15976 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12432220 f irozzo "Furthermore, GATA-1 has been shown to auto-regulate its own gene expression." SIGNOR-256057 GATA1 protein P15976 UNIPROT TAL1 protein P17542 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 7632958 f irozzo "Moreover, GATA-1 but not GATA-2 or GATA-3 was able to transactivate SCL promoter 1a in a T-cell environment. These results suggest that inactivity of SCL promoter 1a in T cells reflected the absence of GATA-1 rather than the presence of trans-dominant negative regulators." SIGNOR-256047 GATA1 protein P15976 UNIPROT SPI1 protein P17947 UNIPROT "down-regulates activity" binding 9606 BTO:0004826 10753833 t irozzo "GATA-1 represses PU.1 activity.We have in this report found that the GATA-1 transcription factor is capable of functionally interfering with the PU.1 protein and have provided evidence that this interference is mediated through interaction between the PU.1 ETS domain and the GATA-1 C-finger region." SIGNOR-256050 GATA1 protein P15976 UNIPROT GATA2 protein P23769 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 12432220 f irozzo "Closer examination revealed a cross-regulatory mechanism by which GATA-1 can control the expression of GATA-2 and vice versa, possibly via essential GATA binding sites in their cis-acting elements.In this model, GATA-2 activates GATA-1 gene expression, while GATA-1 represses GATA-2 gene expression." SIGNOR-256058 GATA1 protein P15976 UNIPROT CEBPA protein P49715 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0004475 19825991 f miannu "Gene expression arrays identified components of the PU.1-dependent transcriptome negatively regulated by GATA-1 in MEL cells, including CCAAT/enhancer binding protein alpha (Cebpa) and core-binding factor, beta subunit (Cbfb), which encode two key hematopoietic transcription factors." SIGNOR-254189 GATA1 protein P15976 UNIPROT HBG1 protein P69891 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004911 20395365 f Regulation miannu "BCL11A and SOX6 co-occupy the human beta-globin cluster along with GATA1, and cooperate in silencing gamma-globin transcription in adult human erythroid progenitors." SIGNOR-251806 GATA1 protein P15976 UNIPROT HBG2 protein P69892 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004911 20395365 f Regulation miannu "BCL11A and SOX6 co-occupy the human beta-globin cluster along with GATA1, and cooperate in silencing gamma-globin transcription in adult human erythroid progenitors." SIGNOR-251804 ANK1 protein P16157 UNIPROT "Ankyrin complex" complex SIGNOR-C383 SIGNOR "form complex" binding 9606 BTO:0000424 22465511 t lperfetto "The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB)) " SIGNOR-266013 PPP3CB protein P16298 UNIPROT TFEB protein P19484 UNIPROT "up-regulates activity" dephosphorylation Ser211 LVGVTSSsCPADLTQ 9606 BTO:0000007 26000950 t "Lysosomal Ca2+ release via mucolipin 1 (MCOLN1) activates calcineurin, which binds and de-phosphorylates TFEB, thus promoting its nuclear translocation." SIGNOR-255306 GATA1 protein P15976 UNIPROT RUNX1 protein Q01196 UNIPROT "up-regulates activity" binding 9606 17725493 t miannu "We and others have previously shown that RUNX1 and GATA-1 physically interact and cooperate in the activation of megakaryocytic promoters such as alpha IIb integrin and glycoprotein Ibalpha. In particular, we will elaborate on recent data which suggest that GATA-1 targets RUNX1 for modification, in particular phosphorylation by cyclin-dependent kinases. Furthermore, targeting of RUNX1 by GATA-1 for phosphorylation may convert RUNX1 from a repressor to an activator. This is a potential mechanism of transcriptional cooperation and may be an essential step in megakaryocytic differentiation." SIGNOR-254194 GATA1 protein P15976 UNIPROT FLI1 protein Q01543 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10523830 f irozzo "Our results suggest that Spi-1 and GATA-1 might play a key role in the regulation of Fli-1. Most notably, we observed that the GATA/EBS dual element near the Fli-1 CAP sites had an enhancer activity in HEL cells. Spi-1 and GATA-1 were both found to bind to this sequence and hence both factors could represent potential regulators of Fli-1 expression." SIGNOR-256053 GATA1 protein P15976 UNIPROT RUNX1T1 protein Q06455 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002731 20487545 f Regulation miannu "GATA-1 transcription factor binds and transactivates the ETO proximal promoter in an erythroid/megakaryocytic-specific manner. Thus, trans-acting factors that are essential in erythroid/megakaryocytic differentiation govern ETO expression." SIGNOR-251929 GATA1 protein P15976 UNIPROT KLF1 protein Q13351 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 8195185 f irozzo "Regulation of the Erythroid Kruppel-like Factor (EKLF) Gene Promoter by the Erythroid Transcription Factor GATA-l.Accordingly,we have also demonstrated that GATA-2, like GATA-1, is able to activate the EKLF promoter in NIH3T3." SIGNOR-256051 GATA1 protein P15976 UNIPROT CBFB protein Q13951 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0004475 19825991 f miannu "Gene expression arrays identified components of the PU.1-dependent transcriptome negatively regulated by GATA-1 in MEL cells, including CCAAT/enhancer binding protein alpha (Cebpa) and core-binding factor, beta subunit (Cbfb), which encode two key hematopoietic transcription factors." SIGNOR-254190 GATA1 protein P15976 UNIPROT ZNF268 protein Q14587 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001271 22235304 f miannu "Here we found that gata-1, a master regulator of erythropoiesis, repressed the promoter activity and transcription of znf268" SIGNOR-195410 GATA1 protein P15976 UNIPROT GFI1B protein Q5VTD9 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19965638 f miannu "HMGB2 binds to the GFI1B promoter in vivo and up-regulates its trans-activation most likely by enhancing the binding of Oct-1 and, to a lesser extent, of GATA-1 and NF-Y to the GFI1B promoter." SIGNOR-254430 GATA1 protein P15976 UNIPROT NBEAL2 protein Q6ZNJ1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000132 28082341 f lperfetto "In conclusion, we herein show a long-distance regulatory region with GATA1 binding sites as being a strong enhancer for NBEAL2 expression." SIGNOR-261881 GATA1 protein P15976 UNIPROT ZFPM1 protein Q8IX07 UNIPROT "up-regulates activity" binding 9606 21853041 t miannu "GATA-2 induces the expression of GATA-1, which first activates its cofactor FOG-1, and then downregulates GATA-2 cooperatively with FOG-1." SIGNOR-256059 GATA1 protein P15976 UNIPROT GP6 protein Q9HCN6 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12377757 f miannu "We have determined that the GP6 sequence -191 to -39 represents the core promoter and that transcription is driven largely by GATA-1 (-176) and c-Ets-1 (-45) sites within this segment." SIGNOR-254081 TIMP2 protein P16035 UNIPROT LRP2 protein P98164 UNIPROT "up-regulates quantity" binding 10116 BTO:0001860 28659595 t miannu "We show that megalin/LRP-2 acts as an endocytic receptor for proMMP-2:TIMP-2 complex. We found that RAP, an antagonist of the LDL receptor family18, competed with binding of proMMP-2:TIMP-2 complex onto rat BN16 epithelial cells." SIGNOR-265254 ALOX15 protein P16050 UNIPROT 15(S)-HETE smallmolecule CHEBI:15558 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 BTO:0000018 12517954 t lperfetto "In A549 cells activation of 15-LOX by IL-4 required the coactivation of histone acetyltransferases CREB-binding protein/p300 and led to a sizable production of 15(S)-HETE" SIGNOR-254094 H2AX protein P16104 UNIPROT NBN protein O60934 UNIPROT up-regulates binding 9606 15635255 t esanto "Nbs1 physically interacts with ?-H2ax to form nuclear foci at dna damage sites. The inhibition of this interaction by introduction of anti-?-H2ax antibody into cells abolishes nbs1 foci formation in response to dna damage." SIGNOR-133020 H2AX protein P16104 UNIPROT MDC1 protein Q14676 UNIPROT up-regulates binding 9606 16377563 t fstefani "Here, we demonstrate that mammalian mdc1/nfbd1 directly binds to phospho-h2ax (gammah2ax) by specifically interacting with the phosphoepitope at the gammah2ax carboxyl terminus." SIGNOR-143377 SELP protein P16109 UNIPROT "GPIb-IX-V complex" complex SIGNOR-C270 SIGNOR "up-regulates activity" binding 9606 BTO:0000132 25297919 t lperfetto "Besides VWF as a main ligand, GPIbα also binds multiple ligands such as thrombospondin, Factor XII, Factor XI, thrombin, High Molecular Weight kininogen, P-selectin and Mac-1." SIGNOR-261860 ACAN protein P16112 UNIPROT "A5/b1 integrin" complex SIGNOR-C163 SIGNOR "up-regulates activity" binding 9606 BTO:0003858 16051604 t lperfetto "Cartilage Oligomeric Matrix Protein/Thrombospondin 5 Supports Chondrocyte Attachment through Interaction with Integrins|We show that COMP/TSP5 can support chondrocyte attachment and that the RGD sequence in COMP/TSP5 and the integrin receptors alpha5beta1 and alphaVbeta3 on the chondrocytes are involved in mediating this attachment. The interactions of COMP/TSP5 with the integrins are dependent on COMP/TSP5 conformation." SIGNOR-266988 ACAN protein P16112 UNIPROT "Av/b3 integrin" complex SIGNOR-C177 SIGNOR "up-regulates activity" binding 9606 BTO:0003858 16051604 t lperfetto "Cartilage Oligomeric Matrix Protein/Thrombospondin 5 Supports Chondrocyte Attachment through Interaction with Integrins|We show that COMP/TSP5 can support chondrocyte attachment and that the RGD sequence in COMP/TSP5 and the integrin receptors alpha5beta1 and alphaVbeta3 on the chondrocytes are involved in mediating this attachment. The interactions of COMP/TSP5 with the integrins are dependent on COMP/TSP5 conformation." SIGNOR-266987 ITGB4 protein P16144 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 9428518 t gcesareni "Stable expression of alpha6beta4 increased carcinoma invasion in a pi3k-dependent manner, and transient expression of a constitutively active pi3k increased invasion in the absence of alpha6beta4. Ligation of alpha6beta4 stimulated significantly more pi3k activity than ligation of beta1 integrins, establishing specificity among integrins for pi3k activation." SIGNOR-54530 SELE protein P16581 UNIPROT ITGAL protein P20701 UNIPROT up-regulates 9606 BTO:0000130 23994464 f 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 CREB1 protein P16220 UNIPROT MITF protein O75030 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10841026 t lperfetto "Therefore, the molecular steps linking cAMPto melanogenesis up-regulation appear currently better elucidated. cAMP activates PKA, and PKA phosphorylates and activates CREB which, when activated, binds to the CRE domain present in the microphthalmia promoter,thereby up-regulating its transcription." SIGNOR-249619 CREB1 protein P16220 UNIPROT SNAI1 protein O95863 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000157 15955695 f miannu "In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro." SIGNOR-253797 CREB1 protein P16220 UNIPROT PLAT protein P00750 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001282 8647095 f lperfetto "We suggest that the mechanism for the transcriptional down-regulation of t-PA by PMA in HT-1080 cells requires CREB-1 binding to the t-PACRE while ATF-2, by associating with the same site, plays a role in PMA-mediated induction of t-PA in HeLa cells." SIGNOR-253732 CREB1 protein P16220 UNIPROT FOS protein P01100 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 17668895 f gcesareni "Phosphorylation of creb by msk has been linked to the of nur77, nor1 and c-fos downstream of mapkin various cell types" SIGNOR-157151 CREB1 protein P16220 UNIPROT BCL2 protein P10415 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0001009 10753867 f lperfetto "Creb activity by akt signaling leads to increased bcl-2 promoter activity and cell survival." SIGNOR-76558 CREB1 protein P16220 UNIPROT BCL2 protein P10415 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000776;BTO:0003076 8816467 f lperfetto "Induction of bcl-2 expression by phosphorylated CREB proteins during B-cell activation and rescue from apoptosis" SIGNOR-43927 CREB1 protein P16220 UNIPROT NR2F1 protein P10589 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000152 15955695 f miannu "In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro." SIGNOR-253792 CREB1 protein P16220 UNIPROT CHGA protein P10645 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001007 12456801 t "Recently, binding of specific protein 1 (Sp1) and cAMP response element binding protein (CREB) to a GC-rich element at -92/-62 has been identified as a critical step in gastrin-dependent regulation of the chromogranin A (CgA) gene in gastric epithelial cells. Here we demonstrate that binding of early growth response protein 1 (Egr-1) to the distal part of the -92/-62 site is also required for gastrin-dependent CgA transactivation." SIGNOR-254276 CREB1 protein P16220 UNIPROT CYP19A1 protein P11511 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000158 15955695 f miannu "In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro." SIGNOR-253798 CREB1 protein P16220 UNIPROT MYF5 protein P13349 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001103 21902831 f 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-176533 CREB1 protein P16220 UNIPROT PKM protein P14618 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16308421 f gcesareni "In fasted mammals, glucose homeostasis is maintained through induction of the camp response element-binding protein (creb) coactivator transducer of regulated creb activity 2 (torc2), which stimulates the gluconeogenic program in concert with the forkhead factor foxo1" SIGNOR-142103 CREB1 protein P16220 UNIPROT PKM protein P14618 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20577053 f gcesareni "In fasted mammals, glucose homeostasis is maintained through induction of the camp response element-binding protein (creb) coactivator transducer of regulated creb activity 2 (torc2), which stimulates the gluconeogenic program in concert with the forkhead factor foxo1" SIGNOR-166346 CREB1 protein P16220 UNIPROT MYOD1 protein P15172 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001103 21902831 f 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 CREB1 protein P16220 UNIPROT CEBPB protein P17676 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0002572 14593102 f 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 CREB1 protein P16220 UNIPROT FST protein P19883 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165 15130492 f lperfetto "MyoD, CREB, and NFAT Mediate the Transcriptional Activation of the Follistatin Promoter Induced by TSA" SIGNOR-251714 CREB1 protein P16220 UNIPROT IL10 protein P22301 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000876 10540320 f mianu "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 CREB1 protein P16220 UNIPROT BDNF protein P23560 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 BTO:0000142 32603820 t miannu "Brain-derived neurotrophic factor (BDNF) is a critical molecule for learning and memory. Brain BDNF levels correlate with cognitive status. Activation of CREB facilitates the transcription of crucial proteins for activity-dependent plasticity particularly BDNF." SIGNOR-265062 CREB1 protein P16220 UNIPROT PAX3 protein P23760 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001103 21902831 f 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-176539 CREB1 protein P16220 UNIPROT PCSK1 protein P29120 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 8999965 f miannu "both CREB-1 and ATF-1 transactivate the human PC1 promoter in transient transfection experiments." SIGNOR-253789 FER protein P16591 UNIPROT AR protein P10275 UNIPROT up-regulates phosphorylation Tyr225 PTSSKDNyLGGTSTI 9606 BTO:0001130 23906537 t lperfetto "Fer is required for il-6 mediated ar activation by phosphorylating ar tyrosine 223 and binding via its sh2 domain." SIGNOR-194749 CREB1 protein P16220 UNIPROT G6PC1 protein P35575 UNIPROT "up-regulates quantity" "transcriptional regulation" 9600 BTO:0000567 26652733 t "Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB" SIGNOR-256105 CREB1 protein P16220 UNIPROT BCL2L1 protein Q07817 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16205321 f gcesareni "The results showed that the nuclear pkcalpha was significantly decreased in the liver during sepsis, which was accompanied by decreases in phospho-creb content, dna-binding activity of creb, and bcl-xl expression." SIGNOR-140911 CREB1 protein P16220 UNIPROT HES1 protein Q14469 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000759 14614508 f "HES-1 is a direct CREB target in vivo." SIGNOR-254742 CREB1 protein P16220 UNIPROT NR4A3 protein Q92570 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 17668895 f gcesareni "Phosphorylation of creb by msk has been linked to the transcription of nur77, nor1 and c-fos downstream of mapk signalling in various cell types." SIGNOR-157154 CREB1 protein P16220 UNIPROT SLC5A5 protein Q92911 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001379 34751390 t scontino "CREB recognized and bound to the promoter of SLC5A5 to facilitate its transcription." SIGNOR-267137 CREB1 protein P16220 UNIPROT MUC4 protein Q99102 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001861 19757157 f lperfetto "Through promoter screening, overexpressing methods and luciferase reporter studies, we found that transcription factors CREB, Ets-1, Elk-1 and STAT1 can positively regulate MUC4 expression at the promoter and mRNA level." SIGNOR-254091 CREB1 protein P16220 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 11557984 t "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 CREB1 protein P16220 UNIPROT UXT protein Q9UBK9 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001033 17761951 f lperfetto "The DNA response elements that control the induction of ART-27 gene expression were also characterized. The major cis-acting element corresponds to a consensus cAMP-responsive element (CRE) and binds the CRE-binding protein (CREB) as shown by EMSA and chromatin immunoprecipitation assays. Furthermore, ART-27 promoter activity is induced upon CREB overexpression. Epidermal growth factor, which activates CREB via phosphorylation, also induces ART-27 expression, whereas a reduction in CREB phosphorylation or expression blocks this induction in prostate cells." SIGNOR-254092 PDGFRA protein P16234 UNIPROT PDGFRA protein P16234 UNIPROT "up-regulates activity" phosphorylation Tyr1018 RLSADSGyIIPLPDI 9823 BTO:0004007 7535778 t 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 PDGFRA protein P16234 UNIPROT PDGFRA protein P16234 UNIPROT "up-regulates activity" phosphorylation Tyr988 RVDSDNAyIGVTYKN 9823 BTO:0004007 7535778 t 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 PDGFRA protein P16234 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates phosphorylation 9606 7535778 t miannu "Tyrosine phosphorylation has been shown to increase the enzymatic activity of plc-? / we show that the human pdgf ?- And ?-Receptors differ quantitatively in their abilities to associate with and phosphorylate plc-? And to stimulate inositol phosphate production." SIGNOR-28176 PDGFRA protein P16234 UNIPROT AKT1 protein P31749 UNIPROT up-regulates 9606 24743741 f "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 PDGFRA protein P16234 UNIPROT CRK protein P46108 UNIPROT up-regulates binding 9606 10733900 t amattioni "Crk could bind to both pdgf alpha- and beta-receptors in vivo." SIGNOR-75881 PDGFRA protein P16234 UNIPROT CRK protein P46108 UNIPROT up-regulates binding 9606 19426560 t amattioni "Crk can interact directly with tyrosine kinase receptors (for example pdgfr?) And can transmit signals downstream" SIGNOR-185664 PDGFRA protein P16234 UNIPROT PTK2 protein Q05397 UNIPROT "up-regulates activity" phosphorylation Tyr194 ALEKKSNyEVLEKDV 9606 BTO:0000567 20802513 t miannu "Focal adhesion kinase (FAK) has a crucial role in integration of signals from integrins and growth factor receptors. In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor Met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate FAK on Tyr194 in the FERM domain (band 4.1 and ezrin/radixin/moesin homology domain). Upon binding to Met or phosphoinositides, FAK may undergo conformational changes, which renders Tyr194 accessible for phosphorylation. Substitution of Tyr194 with Phe significantly suppresses the activation of FAK by Met." SIGNOR-259400 PDGFRA protein P16234 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 24743741 f "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 PPP3CB protein P16298 UNIPROT DNM1L protein O00429 UNIPROT "up-regulates activity" dephosphorylation Ser637 VPVARKLsAREQRDC 9606 18838687 t "When mitochondrial depolarization is associated with sustained cytosolic Ca(2+) rise, it activates the cytosolic phosphatase calcineurin that normally interacts with Drp1. Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria as substantiated by site directed mutagenesis." SIGNOR-248361 PPP3CB protein P16298 UNIPROT IL6 protein P05231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 18177723 f lperfetto "Interestingly, since IL-6 production by nerve-mediated skeletal muscle contraction has recently been shown to be partly dependent on the activation of the calcineurin pathway |The fact that IL-6 is produced not only by proliferating satellite cells but also by growing myofibers during hypertrophy" SIGNOR-251734 PPP3CB protein P16298 UNIPROT FLNA protein P21333 UNIPROT "down-regulates quantity by destabilization" dephosphorylation Ser2152 TRRRRAPsVANVGSH 9606 16442073 t "Filamin is a phosphoprotein that organizes actin filaments into networks. We report that a purified C-terminal recombinant region of filamin is a suitable substrate for calcineurin |Mutagenesis analysis showed that a dephosphorylation step occurred in Ser 2152, which was previously shown to provide resistance to calpain cleavage when endogenous PKA is activated. In contrast, phosphorylation of Ser 2152 was recently reported to be necessary for membrane dynamic changes. In this regard, we found that CsA protects filamin in platelets from calpain degradation." SIGNOR-248362 PPP3CB protein P16298 UNIPROT DNM2 protein P50570 UNIPROT unknown dephosphorylation Ser764 LQSASSHsPTPQRRP 10116 20496096 t "CaN is activated, targeting a set of proteins for dephosphorylation, including dynamin II |We have recently discovered that the ubiquitously expressed dynamin isoform, dynII, is phosphorylated at S764 specifically during mitosis (unpublished data). We now show that S764 is phosphorylated throughout mitosis and is dephosphorylated at the time of cytokinesis(dynII)." SIGNOR-248363 PPP3CB protein P16298 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates 9606 BTO:0001103 11062529 f 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-84044 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates dephosphorylation 9606 18676376 t lperfetto "Calcineurin dephosphorylates members of the nuclear factor of activated T cells (NFAT)2 transcription factor family, allowing NFAT to translocate to the nucleus where it cooperates with other transcription factors to induce transcription of target genes." SIGNOR-233438 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates relocalization 9606 BTO:0001103 11062529 t 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-84050 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser168 YREPLCLsPASSGSS 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248364 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser171 PLCLSPAsSGSSASF 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248365 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser174 LSPASSGsSASFISD 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248367 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser175 SPASSGSsASFISDT 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248368 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser177 ASSGSSAsFISDTFS 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248369 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser180 GSSASFIsDTFSPYT 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248370 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser213 QNIPAHYsPRTSPIM 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248371 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser217 AHYSPRTsPIMSPRT 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248372 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser221 PRTSPIMsPRTSLAE 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248373 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser268 VALPPGAsPQRSRSP 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248374 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser274 ASPQRSRsPSPQPSS 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248375 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser276 PQRSRSPsPQPSSHV 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248376 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser280 RSPSPQPsSHVAPQD 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248377 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser326 PPKMWKTsPDPSPVS 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248378 PPP3CB protein P16298 UNIPROT PPP1R1A protein Q13522 UNIPROT unknown dephosphorylation Ser67 LKSTLAMsPRQRKKM 10116 11278334 t "In vitro and in vivo studies indicated that phospho-Ser-67 inhibitor-1 was dephosphorylated by protein phosphatases-2A and -2B. | However, inhibitor-1 phosphorylated at Ser-67 was a less efficient substrate for cAMP-dependent protein kinase. These results demonstrate regulation of a Cdk5-dependent phosphorylation site in inhibitor-1 and suggest a role for this site in modulating the amplitude of signal transduction events that involve cAMP-dependent protein kinase activation." SIGNOR-248379 PPP3CB protein P16298 UNIPROT KSR2 protein Q6VAB6 UNIPROT "up-regulates activity" dephosphorylation Ser198 IRTHLSQsPRVPSKC 10090 19560418 t "These findings indicate that calcineurin modulates the phosphorylation state of KSR2, but not KSR1, and identifies S198, T287, and the S310 14-3-3 binding site as the KSR2 residues targeted by calcineurin.|the negative regulators 14-3-3" SIGNOR-248380 PPP3CB protein P16298 UNIPROT KSR2 protein Q6VAB6 UNIPROT "up-regulates activity" dephosphorylation Ser313 TALHRSKsHEFQLGH 10090 19560418 t "These findings indicate that calcineurin modulates the phosphorylation state of KSR2, but not KSR1, and identifies S198, T287, and the S310 14-3-3 binding site as the KSR2 residues targeted by calcineurin.|the negative regulators 14-3-3" SIGNOR-248382 PPP3CB protein P16298 UNIPROT KSR2 protein Q6VAB6 UNIPROT "up-regulates activity" dephosphorylation Thr290 NKLKPPGtPPPSSRK 10090 19560418 t "These findings indicate that calcineurin modulates the phosphorylation state of KSR2, but not KSR1, and identifies S198, T287, and the S310 14-3-3 binding site as the KSR2 residues targeted by calcineurin.|the negative regulators 14-3-3" SIGNOR-248381 PPP3CB protein P16298 UNIPROT BAD protein Q92934 UNIPROT "up-regulates activity" dephosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000007 10195903 t "Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis." SIGNOR-248383 PPP3CB protein P16298 UNIPROT BAD protein Q92934 UNIPROT "up-regulates activity" dephosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000007 10195903 t "Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis." SIGNOR-248384 NCK1 protein P16333 UNIPROT ABL1 protein P00519 UNIPROT "down-regulates activity" binding 9606 11494134 t lperfetto "We also show that overexpression of nck could repress the phosphorylation of cbl by abl in vivo. Studies with nck mutants suggested that the nck sh2 domain is responsible for inhibiting the activity of abl toward both cbl and nck itself, most likely by competing with the abl sh2 for tyrosine-phosphorylated binding sites" SIGNOR-109672 NCK1 protein P16333 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates binding 10029 BTO:0000246 7862111 t lperfetto "We also found that nck binds directly to the guanine nucleotide exchange factor sos. / by binding to sos, nckmay bring sos to cell membrane where the ras protein is located." SIGNOR-236321 NCK1 protein P16333 UNIPROT PAK1 protein Q13153 UNIPROT "up-regulates activity" binding 10090 BTO:0002572 10026169 t lperfetto "Both nck and grb4 proteins could associate with receptor tyrosine kinases and the sh3-binding proteins pak, sos1, and prk2, and they synergized with v-abl and sos to induce gene expression via the transcription factor elk-1. Association of nck with pak1 may serve to link this important regulatory kinase to cell activation by growth factor receptors." SIGNOR-236512 EPB42 protein P16452 UNIPROT "Ankyrin complex" complex SIGNOR-C383 SIGNOR "form complex" binding 9606 BTO:0000424 22465511 t lperfetto "The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB)) " SIGNOR-266014 TSHR protein P16473 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0001379 32698392 t scontino "Activation of TSHR and the linked signaling cascades through binding of circulating TSH plays a pivotal role in controlling thyrocyte growth and in regulating thyroid hormone production/secretion. This is executed through switching on different subtypes of G proteins and signaling pathways. Among them, the Gαs- and Gαq-induced cascades are of the greatest importance, as they have been tightly linked to specific intracellular signal transductions downstream of TSHR in response to stimulations" SIGNOR-267138 GNB3 protein P16520 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates binding 9606 23074268 t gcesareni "Furthermore, this work suggested that the g subunits released upon gi activation activated phospholipase c (plc- ) to produce inositol 3-phosphate (ip3), which would subsequently increase intracellular ca2+ abundance." SIGNOR-199135 GNB3 protein P16520 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 14668344 t gcesareni "Expression of the g__ sequestrant, _-transducin, inhibits both ras activation and membrane translocation of _-arrestin1, suggesting that g__ dimers from g_i2 and g_q activate different effectors to coordinately regulate the pi 3-kinase/akt pathway. , these data indicate that _-thrombin stimulates rapid pi 3-kinase activity and akt phosphorylation by the g__ dimers released from a ptx-sensitive g protein." SIGNOR-120264 GNB3 protein P16520 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 14668344 t gcesareni "Expression of the g__ sequestrant, _-transducin, inhibits both ras activation and membrane translocation of _-arrestin1, suggesting that g__ dimers from g_i2 and g_q activate different effectors to coordinately regulate the pi 3-kinase/akt pathway. , these data indicate that _-thrombin stimulates rapid pi 3-kinase activity and akt phosphorylation by the g__ dimers released from a ptx-sensitive g protein." SIGNOR-252680 FER protein P16591 UNIPROT JUP protein P14923 UNIPROT "down-regulates activity" phosphorylation Tyr550 AAGTQQPyTDGVRME 10116 BTO:0004604 14517306 t "The tyrosine kinase Fer, which modifies beta-catenin Tyr142, lessening its association with alpha-catenin, phosphorylates plakoglobin Tyr549 and exerts the contrary effect: it raises the binding of plakoglobin to alpha-catenin. Fer stimulation, through modification of Tyr549, causes diminished binding of plakoglobin to components of desmosomes (desmoplakin) and increased interaction with adherens junction proteins (α-catenin)" SIGNOR-251135 FER protein P16591 UNIPROT JUP protein P14923 UNIPROT "up-regulates activity" phosphorylation Tyr550 AAGTQQPyTDGVRME 10116 BTO:0004604 14517306 t "The tyrosine kinase Fer, which modifies beta-catenin Tyr142, lessening its association with alpha-catenin, phosphorylates plakoglobin Tyr549 and exerts the contrary effect: it raises the binding of plakoglobin to alpha-catenin. Fer stimulation, through modification of Tyr549, causes diminished binding of plakoglobin to components of desmosomes (desmoplakin) and increased interaction with adherens junction proteins (α-catenin)" SIGNOR-251134 FER protein P16591 UNIPROT PECAM1 protein P16284 UNIPROT "up-regulates activity" phosphorylation Tyr690 PLNSDVQyTEVQVSS 9606 BTO:0000007 12972546 t miannu "PECAM-1 Is Phosphorylated by Fer and, To a Lesser Extent, by Fes. These results suggest that Fer not only functions as a tyrosine kinase for PECAM-1 but also that Fer modulates the downstream signaling of PECAM-1 by inducing phosphorylation of SHP-2 and Gab1." SIGNOR-262865 FER protein P16591 UNIPROT PECAM1 protein P16284 UNIPROT "up-regulates activity" phosphorylation Tyr713 KKDTETVySEVRKAV 9606 BTO:0000007 12972546 t miannu "PECAM-1 Is Phosphorylated by Fer and, To a Lesser Extent, by Fes. These results suggest that Fer not only functions as a tyrosine kinase for PECAM-1 but also that Fer modulates the downstream signaling of PECAM-1 by inducing phosphorylation of SHP-2 and Gab1." SIGNOR-262866 ATP2A2 protein P16615 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000199 16402920 t lperfetto "In the present study, we have analysed the expression and functional characteristics of SERCA2c relative to SERCA2a and SERCA2b isoforms upon their stable heterologous expression in HEK-293 cells (human embryonic kidney 293 cells). All SERCA2 proteins induced an increased Ca2+ content in the ER of intact transfected cells." SIGNOR-262050 IL7R protein P16871 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 BTO:0000776 18445337 t milica "For instance, jak1 is associated with the ? Subunits of ?c Cytokines such as il-7r? And IL-4R. jak3 is associated with the ?c20,21. Cytokine binding mediates the trans-phosphorylation of receptor associated jak kinases, which in turn phosphorylate tyrosine residues on the receptors themselves. The receptor phosphotyrosines serve as docking sites for sh2 domain proteins including the stat family of transcription factors which are activated by jak-mediated phosphorylation." SIGNOR-178494 PLCG2 protein P16885 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser146 GRKRRQTsMTDFYHS 9606 31575057 t gcesareni "Phosphorylation at Ser-146 by PKCδ increases p21 stability" SIGNOR-262963 RHOQ protein P17081 UNIPROT SLC2A4 protein P14672 UNIPROT up-regulates 9606 12242347 f gcesareni "Tc10 is activated afte rinsulin stimulation, and its activation is required for insulin-stimulated glucose uptake and glut4 translocation" SIGNOR-93117 RHOQ protein P17081 UNIPROT EXOC7 protein Q9UPT5 UNIPROT up-regulates binding 9606 12687004 t gcesareni "Here we show that tc10 interacts with one of the components of the exocyst complex, exo70." SIGNOR-100486 HMGA1 protein P17096 UNIPROT SLC2A3 protein P11169 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22706202 f miannu "CAV1 was shown to stimulate GLUT3 transcription via an HMGA1-binding site within the GLUT3 promoter. HMGA1 was found to interact with and activate the GLUT3 promoter and CAV1 increased the HMGA1 activity by enhancing its nuclear localization." SIGNOR-254427 HMGA1 protein P17096 UNIPROT KITLG protein P21583 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000093 15378028 f miannu "Human KIT ligand promoter is positively regulated by HMGA1 in breast and ovarian cancer cells." SIGNOR-254426 HMGA1 protein P17096 UNIPROT POU3F1 protein Q03052 UNIPROT "up-regulates activity" binding 9606 BTO:0002127 7791781 t 2 miannu "Direct contacts were identified between the POU domain of Tst-1/Oct-6 and a short stretch of 10 amino acids in the central portion of HMG-I/Y. In the presence of HMG-I/Y, Tst-1/Oct-6 exhibited an increased affinity for this AT-rich element." SIGNOR-240155 IFNAR1 protein P17181 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" phosphorylation 9606 21631354 t miannu "These results indicate that NF-κB activation by IFN via the PI3K pathway is distinct from the ISRE-driven mechanism in regulating gene expression. Activation of PI3K/AKT by IFN has also been described through the insulin receptor substrate 1 (Uddin and others 1997) and through the direct interaction of PI3K with IFNAR1, which also leads to induction of NF-κB activity" SIGNOR-260435 PRKCA protein P17252 UNIPROT SNAP23 protein O00161 UNIPROT unknown phosphorylation Ser161 ENLTQVGsILGNLKD 9606 BTO:0000132 12930825 t lperfetto "Ion trap mass spectrometry revealed that platelet SNAP-23 was phosphorylated at Ser23/Thr24 and Ser161, after cell activation by thrombin; these sites were also identified in PKC-phosphorylated r-SNAP-23. SNAP-23 mutants that mimic phosphorylation at Ser23/Thr24 inhibited syntaxin 4 interactions, whereas a phosphorylation mutant of Ser161 had only minor effects. | Because mutants that mimic SNAP-23 phosphorylation affect syntaxin 4 interactions, we hypothesize that SNAP-23 phosphorylation may be important for modulating SNARE-complex interactions during membrane trafficking and fusion." SIGNOR-249227 PRKCA protein P17252 UNIPROT SNAP23 protein O00161 UNIPROT unknown phosphorylation Ser23 ITDESLEsTRRILGL 9606 BTO:0000132 12930825 t lperfetto "Ion trap mass spectrometry revealed that platelet SNAP-23 was phosphorylated at Ser23/Thr24 and Ser161, after cell activation by thrombin; these sites were also identified in PKC-phosphorylated r-SNAP-23. SNAP-23 mutants that mimic phosphorylation at Ser23/Thr24 inhibited syntaxin 4 interactions, whereas a phosphorylation mutant of Ser161 had only minor effects. | Because mutants that mimic SNAP-23 phosphorylation affect syntaxin 4 interactions, we hypothesize that SNAP-23 phosphorylation may be important for modulating SNARE-complex interactions during membrane trafficking and fusion." SIGNOR-249228 PRKCA protein P17252 UNIPROT SNAP23 protein O00161 UNIPROT unknown phosphorylation Thr24 TDESLEStRRILGLA 9606 BTO:0000132 12930825 t lperfetto "Ion trap mass spectrometry revealed that platelet SNAP-23 was phosphorylated at Ser23/Thr24 and Ser161, after cell activation by thrombin; these sites were also identified in PKC-phosphorylated r-SNAP-23. SNAP-23 mutants that mimic phosphorylation at Ser23/Thr24 inhibited syntaxin 4 interactions, whereas a phosphorylation mutant of Ser161 had only minor effects. | Because mutants that mimic SNAP-23 phosphorylation affect syntaxin 4 interactions, we hypothesize that SNAP-23 phosphorylation may be important for modulating SNARE-complex interactions during membrane trafficking and fusion." SIGNOR-249229 PRKCA protein P17252 UNIPROT PLD2 protein O14939 UNIPROT up-regulates phosphorylation Ser243 RWLVVKDsFLLYMCL 9606 15979581 t miannu "The phosphorylation sites in phospholipase d2 (pld2) induced by activation of protein kinase calpha (pkcalpha) in cos 7 cells were analyzed by mass spectrometry. Ser134, 146, and 243, and thr72, 99/100, and 252 were identified. These sites were mutated to ala and the double mutation of ser243 and thr252 eliminated the phosphorylation. / the s243/t252a mutant showed a partial decrease in pld2 activity" SIGNOR-138351 PRKCA protein P17252 UNIPROT PLD2 protein O14939 UNIPROT up-regulates phosphorylation Thr252 LLYMCLEtGAISFVQ 9606 15979581 t miannu "The phosphorylation sites in phospholipase d2 (pld2) induced by activation of protein kinase calpha (pkcalpha) in cos 7 cells were analyzed by mass spectrometry. Ser134, 146, and 243, and thr72, 99/100, and 252 were identified. These sites were mutated to ala and the double mutation of ser243 and thr252 eliminated the phosphorylation. / the s243/t252a mutant showed a partial decrease in pld2 activity" SIGNOR-138355 PRKCA protein P17252 UNIPROT PIP5K1B protein O14986 UNIPROT down-regulates phosphorylation Ser413 PSKKRCNsIAALKAT 9606 23909401 t lperfetto "Collaboration of ampk and pkc to induce phosphorylation of ser413 on pip5k1b resulting in decreased kinase activity and reduced ptdins(4,5)p2 synthesis in response to oxidative stress and energy restriction. we demonstrate that pkc can directly phosphorylate ser413 in vitro" SIGNOR-194820 PRKCA protein P17252 UNIPROT KCNQ2 protein O43526 UNIPROT "up-regulates activity" phosphorylation Ser551 CVMRFLVsKRKFKES 10029 BTO:0000246 12754513 t lperfetto "Phosphorylation of KCNQ2 channels was increased by muscarinic stimulation; this was prevented either by coexpression with AKAP(DeltaA) or pretreatment with PKC inhibitors that compete with diacylglycerol. These inhibitors also reduced muscarinic inhibition of M-current. | These results suggest that Ser534 and 541 are key sites for PKC phosphorylation, although we have not ruled out the possibility that other PKC sites are involved in this process." SIGNOR-249209 PRKCA protein P17252 UNIPROT KCNQ2 protein O43526 UNIPROT "up-regulates quantity" phosphorylation Ser558 SKRKFKEsLRPYDVM 10029 BTO:0000246 12754513 t lperfetto "Phosphorylation of KCNQ2 channels was increased by muscarinic stimulation; this was prevented either by coexpression with AKAP(DeltaA) or pretreatment with PKC inhibitors that compete with diacylglycerol. These inhibitors also reduced muscarinic inhibition of M-current. | These results suggest that Ser534 and 541 are key sites for PKC phosphorylation, although we have not ruled out the possibility that other PKC sites are involved in this process." SIGNOR-249210 PRKCA protein P17252 UNIPROT NPHS1 protein O60500 UNIPROT "up-regulates activity" phosphorylation Thr1120 EYEESQWtGERDTQS 9606 BTO:0000007 21321125 t llicata "Binding of _-arrestin2 to the nephrin intracellular domain depended on phosphorylation of nephrin threonine residues 1120 and 1125 by pkc_." SIGNOR-178695 PRKCA protein P17252 UNIPROT NPHS1 protein O60500 UNIPROT "up-regulates activity" phosphorylation Thr1125 QWTGERDtQSSTVST 9606 BTO:0000007 21321125 t llicata "Binding of _-arrestin2 to the nephrin intracellular domain depended on phosphorylation of nephrin threonine residues 1120 and 1125 by pkc_." SIGNOR-172056 PRKCA protein P17252 UNIPROT PFKFB2 protein O60825 UNIPROT "up-regulates activity" phosphorylation Thr475 TPLSSSNtIRRPRNY -1 1322130 t lperfetto "The phosphorylation sites for both cAMP-dependent protein kinase and protein kinase C were located in a single peptide whose sequence was Arg-Arg-Asn-Ser-(P)-Phe-Thr-Pro-Leu-Ser-Ser-Ser-Asn-Thr(P)-Ile-Arg-Arg-Pro. The seryl residue nearest the N terminus was the residue specifically phosphorylated by cAMP-dependent protein kinase, whereas the threonine residue nearest the C terminus was phosphorylated by protein kinase C. | Phosphorylation of bovine heart Fru-6-P,B-kinase by either protein kinase C or CAMP-dependent protein kinase results in activation of the enzyme." SIGNOR-248844 PRKCA protein P17252 UNIPROT EDF1 protein O60869 UNIPROT "down-regulates activity" phosphorylation Thr91 GRQSKGLtQKDLATK 9606 BTO:0001949 10816571 t lperfetto "EDF-1 was phosphorylated in vitro by PKC in the presence of Ca2+ and phospholipids | This results shows that introduction of a single negative charge by phosphorylation at Thr-91 inhibited CaM-EDF-1 interactions." SIGNOR-249041 PRKCA protein P17252 UNIPROT KCNJ13 protein O60928 UNIPROT down-regulates phosphorylation Ser201 TRPSPLTsVRVSAVL 9606 18976636 t gcesareni "After pharmacological pkc activation, kir7.1 currents were strongly inhibited. Co-application of pkc inhibitors attenuated this effect. Inactivation of pkc consensus sites also strongly attenuated the effect with a single site ((201)s) being essential for almost the total pkc sensitivity." SIGNOR-181863 PRKCA protein P17252 UNIPROT ADAP1 protein O75689 UNIPROT unknown phosphorylation Ser87 AARARFEsKVPSFYY -1 12893243 t lperfetto "The sites of phosphorylation by PKCalpha on centaurin-alpha1‚ were identified as S87 (peptide ARFEK) and T276 (peptide WFMDDRR) (‚ Fig. 5).‚ " SIGNOR-249223 PRKCA protein P17252 UNIPROT ADAP1 protein O75689 UNIPROT unknown phosphorylation Thr276 GFRKRWFtMDDRRLM -1 12893243 t lperfetto "The sites of phosphorylation by PKCalpha on centaurin-alpha1‚ were identified as S87 (peptide ARFEK) and T276 (peptide WFMDDRR) (‚ Fig. 5)." SIGNOR-249225 PRKCA protein P17252 UNIPROT HAND1 protein O96004 UNIPROT unknown phosphorylation Thr107 PKKERRRtESINSAF 9606 BTO:0000007 14636580 t lperfetto "In vitro and in vivo phosphorylation studies show that both PKA and PKC can phosphorylate HAND1 and -2. In addition, phosphopeptide mapping analysis of wild-type and mutant forms of HAND1 shows that three of these conserved residues, T107; S109 within helix I and S98 within the basic domain, are the phosphorylated residues. " SIGNOR-249244 PRKCA protein P17252 UNIPROT EGFR protein P00533 UNIPROT "down-regulates activity" phosphorylation Thr678 RHIVRKRtLRRLLQE 9606 10816576 t lperfetto "Biochemical and morphological analyses indicate that threonine-phosphorylated EGFR molecules undergo normal internalization, but instead of sorting to lysosomal degradation, they recycle back to the cell surfaceThe inhibitory effects of pkc are mediated by a single threonine residue (threonine 654) of egfr" SIGNOR-77421 PRKCA protein P17252 UNIPROT IL2RA protein P01589 UNIPROT unknown phosphorylation Ser268 WQRRQRKsRRTI 9606 BTO:0000782 2303462 t lperfetto "The interleukin-2 (il-2) receptor, the leukocyte-specific membrane glycoprotein, t200, and the class i major histocompatibility antigens (hla) have been identified as substrates for protein kinase c from these studies, it was concluded that ser-247 is the major site of phosphorylation in the il-2 receptor and that thr-250 is a minor site." SIGNOR-22984 PRKCA protein P17252 UNIPROT IL2RA protein P01589 UNIPROT unknown phosphorylation Thr271 RQRKSRRtI 9606 BTO:0000782 2303462 t lperfetto "The interleukin-2 (il-2) receptor, the leukocyte-specific membrane glycoprotein, t200, and the class i major histocompatibility antigens (hla) have been identified as substrates for protein kinase c from these studies, it was concluded that ser-247 is the major site of phosphorylation in the il-2 receptor and that thr-250 is a minor site." SIGNOR-22988 PRKCA protein P17252 UNIPROT LMNA protein P02545 UNIPROT "up-regulates activity" phosphorylation Ser403 QRSRGRAsSHSSQTQ -1 7925482 t lperfetto "Mutation of both Ser-403/Ser-404 within a PKC motif flanking the nuclear localization signal inhibits transport of mutant lamin A to the nucleus in 64% of the cells. It is proposed that phosphorylation of the motif in vivo positively regulates nuclear localization together with the nuclear localization sequence." SIGNOR-248903 PRKCA protein P17252 UNIPROT LMNA protein P02545 UNIPROT "up-regulates activity" phosphorylation Ser404 RSRGRASsHSSQTQG -1 7925482 t lperfetto "Mutation of both Ser-403/Ser-404 within a PKC motif flanking the nuclear localization signal inhibits transport of mutant lamin A to the nucleus in 64% of the cells. It is proposed that phosphorylation of the motif in vivo positively regulates nuclear localization together with the nuclear localization sequence." SIGNOR-248904 PRKCA protein P17252 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser141 MASQKRPsQRHGSKY -1 2413024 t lperfetto "MBP was phosphorylated by either protein kinase A or C | Subsequent amino acid analysis and/or sequential Edman degradation of the purified phosphopeptides, together with the known primary sequence of this protein, revealed that Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-161 at various reaction velocities." SIGNOR-248869 PRKCA protein P17252 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser249 GLSLSRFsWGAEGQR -1 2413024 t lperfetto "MBP was phosphorylated by either protein kinase A or C | Subsequent amino acid analysis and/or sequential Edman degradation of the purified phosphopeptides, together with the known primary sequence of this protein, revealed that Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-161 at various reaction velocities." SIGNOR-248872 PRKCA protein P17252 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser266 FGYGGRAsDYKSAHK -1 2413024 t lperfetto "MBP was phosphorylated by either protein kinase A or C | Subsequent amino acid analysis and/or sequential Edman degradation of the purified phosphopeptides, together with the known primary sequence of this protein, revealed that Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-161 at various reaction velocities." SIGNOR-248873 PRKCA protein P17252 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser285 VDAQGTLsKIFKLGG -1 2413024 t lperfetto "MBP was phosphorylated by either protein kinase A or C | Subsequent amino acid analysis and/or sequential Edman degradation of the purified phosphopeptides, together with the known primary sequence of this protein, revealed that Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-161 at various reaction velocities." SIGNOR-248874 PRKCA protein P17252 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser295 FKLGGRDsRSGSPMA -1 2413024 t lperfetto "MBP was phosphorylated by either protein kinase A or C | Subsequent amino acid analysis and/or sequential Edman degradation of the purified phosphopeptides, together with the known primary sequence of this protein, revealed that Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-161 at various reaction velocities." SIGNOR-248875 PRKCA protein P17252 UNIPROT VTN protein P04004 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser381 RNRKGYRsQRGHSRG -1 9030777 t lperfetto "Phosphorylation of vitronectin on Ser362 by protein kinase C attenuates its cleavage by plasmin." SIGNOR-248962 PRKCA protein P17252 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser43 FGYQRRAsDDGKLTD 9606 7935389 t gcesareni "Pka can inhibit raf-1 function directly via phosphorylation of the raf-1 kinase domain" SIGNOR-34761 PRKCA protein P17252 UNIPROT RAF1 protein P04049 UNIPROT unknown phosphorylation Ser233 VSSQHRYsTPHAFTF 9606 12551925 t gcesareni "For example, PKCα phosphorylates Raf-1 at serine 499 (13), but mutation of this residue did not impede activation of Raf-1 by the physiological stimulators Ras and Lck. Similarly, both v-Src and phorbol esters were able to activate Raf-1 even though the PKC phosphorylation sites at serine 497 and serine 499 were mutated to alanine (14). Thus, although some PKC phosphorylation sites on Raf-1 have been identified, these sites do not appear to be required for activation of Raf-1." SIGNOR-37466 PRKCA protein P17252 UNIPROT RAF1 protein P04049 UNIPROT unknown phosphorylation Ser497 ATVKSRWsGSQQVEQ 9606 12551925 t gcesareni "For example, PKCα phosphorylates Raf-1 at serine 499 (13), but mutation of this residue did not impede activation of Raf-1 by the physiological stimulators Ras and Lck. Similarly, both v-Src and phorbol esters were able to activate Raf-1 even though the PKC phosphorylation sites at serine 497 and serine 499 were mutated to alanine (14). Thus, although some PKC phosphorylation sites on Raf-1 have been identified, these sites do not appear to be required for activation of Raf-1." SIGNOR-37844 PRKCA protein P17252 UNIPROT RAF1 protein P04049 UNIPROT unknown phosphorylation Ser499 VKSRWSGsQQVEQPT 9606 12551925 t gcesareni "For example, PKCα phosphorylates Raf-1 at serine 499 (13), but mutation of this residue did not impede activation of Raf-1 by the physiological stimulators Ras and Lck. Similarly, both v-Src and phorbol esters were able to activate Raf-1 even though the PKC phosphorylation sites at serine 497 and serine 499 were mutated to alanine (14). Thus, although some PKC phosphorylation sites on Raf-1 have been identified, these sites do not appear to be required for activation of Raf-1." SIGNOR-97644 PRKCA protein P17252 UNIPROT ANXA1 protein P04083 UNIPROT up-regulates phosphorylation Ser27 EYVQTVKsSKGGPGS 9606 24103589 t lperfetto "The authors identified several phosphorylated residues by a combination of peptide mapping and sequence analysis and showed that recombinant pp60c-src phosphorylates annexin a1 near its amino terminus, at tyrosine 21 (tyr21). Also polyoma virus middle t/pp60c-src complex, recombinant pp50v-abl, and the egf receptor/kinase phosphorylated the same tyrosine residue. It was also shown that serine 27 residue of anxa1 is the primary site phosphorylated by protein kinase c (pkc). In the same study, the threonine 41 residue has been identified as a pkc substrate as well. The adenosine cyclic 3_,5_-phosphate dependent protein kinase a (pka) phosphorylates anxa1 in its carboxyl-terminal core at the threonine 216 residue (thr216) [2].The phosphorylation of serine 27 is essential for annexin a1 membrane localization." SIGNOR-202780 PRKCA protein P17252 UNIPROT ATP1A1 protein P05023 UNIPROT "down-regulates activity" phosphorylation Ser16 KYEPAAVsEQGDKKG 1792 BTO:0003069 14976217 t miannu "Parathyroid hormone (PTH) inhibits Na+,K+-ATPase activity through protein kinase C- (PKC) and extracellular signal-regulated kinase- (ERK) dependent pathways and increases serine phosphorylation of the α1-subunit. These results suggest that PTH regulates Na(+),K(+)-ATPase by PKC and ERK-dependent alpha(1)-subunit phosphorylation and that the phosphorylation requires the expression of a serine at the 11 position of the Na(+),K(+)-ATPase alpha(1)-subunit." SIGNOR-262941 PRKCA protein P17252 UNIPROT ITGB2 protein P05107 UNIPROT unknown phosphorylation Thr758 NPLFKSAtTTVMNPK 9606 BTO:0000751 11700305 t lperfetto "Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. |" SIGNOR-249121 PRKCA protein P17252 UNIPROT ITGB2 protein P05107 UNIPROT unknown phosphorylation Thr760 LFKSATTtVMNPKFA 9606 BTO:0000751 11700305 t lperfetto "Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. |" SIGNOR-249125 PRKCA protein P17252 UNIPROT HMGN1 protein P05114 UNIPROT down-regulates phosphorylation Ser21 KEEPKRRsARLSAKP 9606 10739259 t lperfetto "Protein kinases that phosphorylate hmg-14 17 at the major sites have been implicated from previous in vitro studies. Protein kinase c and a similar calcium phospholipid-dependent kinase have been reported to phosphorylate both proteins in vitro, where the phosphorylation of hmg-17 occurs predominantly at ser24 and to a lesser degree at ser28. Phosphorylation of hmg-14 at ser6 by camp- or cgmp-dependent kinases has also been reported. Thus, other kinases may contribute to phosphorylation at ser6 in response to oa. Ser88 and ser98 on hmg-14 are also phosphorylated by casein kinase ii in vitro. we conclude that the correlation we observe reflects a causal relationship, in which phosphorylation somehow facilitates the redistribution of hmg-14 and -17 toward non-nuclear pools." SIGNOR-76282 PRKCA protein P17252 UNIPROT HMGN1 protein P05114 UNIPROT down-regulates phosphorylation Ser25 KRRSARLsAKPPAKV 9606 10739259 t lperfetto "Protein kinases that phosphorylate hmg-14 17 at the major sites have been implicated from previous in vitro studies. Protein kinase c and a similar calcium phospholipid-dependent kinase have been reported to phosphorylate both proteins in vitro, where the phosphorylation of hmg-17 occurs predominantly at ser24 and to a lesser degree at ser28. Phosphorylation of hmg-14 at ser6 by camp- or cgmp-dependent kinases has also been reported. Thus, other kinases may contribute to phosphorylation at ser6 in response to oa. Ser88 and ser98 on hmg-14 are also phosphorylated by casein kinase ii in vitro. we conclude that the correlation we observe reflects a causal relationship, in which phosphorylation somehow facilitates the redistribution of hmg-14 and -17 toward non-nuclear pools." SIGNOR-76286 PRKCA protein P17252 UNIPROT HMGN2 protein P05204 UNIPROT down-regulates phosphorylation Ser25 KDEPQRRsARLSAKP 9606 10739259 t lperfetto "Protein kinases that phosphorylate hmg-14 17 at the major sites have been implicated from previous in vitro studies. Protein kinase c and a similar calcium phospholipid-dependent kinase have been reported to phosphorylate both proteins in vitro, where the phosphorylation of hmg-17 occurs predominantly at ser24 and to a lesser degree at ser28. Phosphorylation of hmg-14 at ser6 by camp- or cgmp-dependent kinases has also been reported. Thus, other kinases may contribute to phosphorylation at ser6 in response to oa. Ser88 and ser98 on hmg-14 are also phosphorylated by casein kinase ii in vitro. we conclude that the correlation we observe reflects a causal relationship, in which phosphorylation somehow facilitates the redistribution of hmg-14 and -17 toward non-nuclear pools." SIGNOR-76320 PRKCA protein P17252 UNIPROT CD5 protein P06127 UNIPROT unknown phosphorylation Thr436 FHRNHTAtVRSHAEN 9606 BTO:0000661 11123317 t lperfetto "Here, we present a selective mutagenesis analysis of two conserved threonine residues (T410 and T412) located at the membrane-proximal cytoplasmic region of CD5. These residues are contained within consensus phosphorylation motifs for protein kinase C and are shown here to be critical for in vivo protein kinase C-mediated phosphorylation of CD5. " SIGNOR-249071 PRKCA protein P17252 UNIPROT INSR protein P06213 UNIPROT unknown phosphorylation Ser1062 AVKTVNEsASLRERI -1 7926007 t lperfetto "Identification of serines-1035/1037 in the kinase domain of the insulin receptor as protein kinase C alpha mediated phosphorylation sites." SIGNOR-248905 PRKCA protein P17252 UNIPROT INSR protein P06213 UNIPROT unknown phosphorylation Ser1064 KTVNESAsLRERIEF -1 7926007 t lperfetto "Identification of serines-1035/1037 in the kinase domain of the insulin receptor as protein kinase C alpha mediated phosphorylation sites." SIGNOR-248906 PRKCA protein P17252 UNIPROT INSR protein P06213 UNIPROT unknown phosphorylation Thr1362 YEEHIPYtHMNGGKK -1 8463287 t lperfetto "Therefore, the present study directly identifies threonine 1336 in the HIR as a phosphorylation site for insulin and PMA." SIGNOR-248933 PRKCA protein P17252 UNIPROT LCK protein P06239 UNIPROT unknown phosphorylation Ser42 TLLIRNGsEVRDPLV -1 8506364 t lperfetto "In vitro kinase assays show that Ser-59 can be uniquely phosphorylated by mitogen-activated protein kinase and that Ser-42 can be phosphorylated by either protein kinase A or protein kinase C." SIGNOR-248936 PRKCA protein P17252 UNIPROT EIF4E protein P06730 UNIPROT unknown phosphorylation Ser209 DTATKSGsTTKNRFV 10090 BTO:0000944 8662663 t lperfetto "Phosphorylation of eIF-4E on serine 209 by protein kinase C is inhibited by the translational repressors, 4E-binding proteins." SIGNOR-248945 PRKCA protein P17252 UNIPROT ANXA2 protein P07355 UNIPROT unknown phosphorylation Ser26 TPPSAYGsVKAYTNF 9606 BTO:0000452 2946940 t lperfetto "The protein-tyrosine kinase substrate p36 is also a substrate for protein kinase C in vitro and in vivo. | We present evidence suggesting that protein kinase C mediates phosphorylation of serine 25." SIGNOR-248892 PRKCA protein P17252 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Thr567 QGRDKYKtLRQIRQG 9606 BTO:0000017 15647376 t lperfetto "Phosphorylation of ezrin is required for both conformational activation and for signaling to downstream events. The activating c-terminal threonine phosphorylation on t567 was first described to be downstream of the rho pathway (matsui et al., 1998). Additional studies have implicated protein kinase c (pkc)  in the phosphorylation of ezrin t567." SIGNOR-133223 PRKCA protein P17252 UNIPROT GJB1 protein P08034 UNIPROT "up-regulates activity" phosphorylation Ser229 QRRSNPPsRKGSGFG -1 8390988 t lperfetto "Phosphorylation of connexin-32 by protein kinase C prevents its proteolysis by mu-calpain and m-calpain. |In agreement with other authors (see Saez et al., 1990b), we have found that phosphorylation of connexin-32 by protein kinase A and protein kinase C occurs in serine residues, although we have detected trace amounts of phosphothreonine in connexin-32 phosphorylated by protein kinase C (results not shown). Indeed, Se233 has been shown to be the major phosphorylation site catalyzed by protein kinase A. However, Ser233, Ser239, and perhaps other serines are phosphorylated by protein kinase C (Saez et al., 1990b)." SIGNOR-248919 PRKCA protein P17252 UNIPROT GJB1 protein P08034 UNIPROT "up-regulates activity" phosphorylation Ser233 NPPSRKGsGFGHRLS 8390988 t lperfetto "Phosphorylation of connexin-32 by protein kinase C prevents its proteolysis by mu-calpain and m-calpain. |In agreement with other authors (see Saez et al., 1990b), we have found that phosphorylation of connexin-32 by protein kinase A and protein kinase C occurs in serine residues, although we have detected trace amounts of phosphothreonine in connexin-32 phosphorylated by protein kinase C (results not shown). Indeed, Se233 has been shown to be the major phosphorylation site catalyzed by protein kinase A. However, Ser233, Ser239, and perhaps other serines are phosphorylated by protein kinase C (Saez et al., 1990b)." SIGNOR-248920 PRKCA protein P17252 UNIPROT PLEK protein P08567 UNIPROT up-regulates phosphorylation Ser117 ARKSTRRsIRLPETI 9606 7559487 t gcesareni "To determine the role of pkc-dependent phosphorylation in pleckstrin function, we mapped the phosphorylation sites in vivo of wild-type and site-directed mutants of pleckstrin expressed in cos cells. Phosphorylation was found to occur almost exclusively on ser-113 and ser-117. Replacing all these sites with glycine decreased phosphorylation by > 90% and reduced pleckstrin's ability to inhibit phosphoinositide hydrolysis by as much as 80%." SIGNOR-28884 PRKCA protein P17252 UNIPROT PLEK protein P08567 UNIPROT up-regulates phosphorylation Ser117 ARKSTRRsIRLPETI 9606 8615792 t gcesareni "To determine the role of pkc-dependent phosphorylation in pleckstrin function, we mapped the phosphorylation sites in vivo of wild-type and site-directed mutants of pleckstrin expressed in cos cells. Phosphorylation was found to occur almost exclusively on ser-113 and ser-117. Replacing all these sites with glycine decreased phosphorylation by > 90% and reduced pleckstrin's ability to inhibit phosphoinositide hydrolysis by as much as 80%." SIGNOR-40048 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT "down-regulates activity" phosphorylation Ser39 TTSTRTYsLGSALRP 2500966 t lperfetto "We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65." SIGNOR-248885 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser10 TRSVSSSsYRRMFGG -1 2500966 t lperfetto "We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65." SIGNOR-248877 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser26 GTASRPSsSRSYVTT -1 2500966 t lperfetto "We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65." SIGNOR-248882 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser27 TASRPSSsRSYVTTS -1 2500966 t lperfetto "We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65." SIGNOR-248879 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser34 SRSYVTTsTRTYSLG -1 2500966 t lperfetto "We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65." SIGNOR-248880 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser42 TRTYSLGsALRPSTS -1 2500966 t lperfetto "We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65." SIGNOR-248881 RXRA protein P19793 UNIPROT RARB protein P10826 UNIPROT up-regulates binding 9606 1310351 t gcesareni "Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins" SIGNOR-16668 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser51 LRPSTSRsLYASSPG -1 2500966 t lperfetto "We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65." SIGNOR-248883 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser66 GVYATRSsAVRLRSS -1 2500966 t lperfetto "We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65." SIGNOR-248884 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser7 sSSSYRRM -1 2500966 t lperfetto "We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65." SIGNOR-248886 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser9 STRSVSSsSYRRMFG -1 2500966 t lperfetto "We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65." SIGNOR-248876 PRKCA protein P17252 UNIPROT HNRNPA1 protein P09651 UNIPROT down-regulates phosphorylation Ser95 RAVSREDsQRPGAHL 9606 7727389 t gcesareni "A survey of seven protein kinases showed that a1 was heavily phosphorylated by protein kinase c (pkc) and also was phosphorylated by casein kinase iiamino acid sequencing revealed that these sites were ser95, ser192, and ser199;phosphorylation at ser192 was more abundant than at ser95 and ser199. Phosphorylation by pkc inhibited the strand annealing activity of a1." SIGNOR-32291 PRKCA protein P17252 UNIPROT BCL2 protein P10415 UNIPROT up-regulates phosphorylation Ser70 RDPVARTsPLQTPAA 9606 BTO:0001271 9738012 t gcesareni "Purified pkca can efficiently and directly phosphorylate bcl2 at serine 70" SIGNOR-60120 PRKCA protein P17252 UNIPROT KIT protein P10721 UNIPROT down-regulates phosphorylation Ser741 TKADKRRsVRIGSYI 9606 7539802 t miannu "Phosphorylation of kit/scfr by pkc-_ in vitro: identification of ser-741 and ser-746 as the major phosphorylation sites for pkc / pkc, which acts in an scf-stimulated feedback loop, that negatively controls kit/scfr kinase activity" SIGNOR-28601 PRKCA protein P17252 UNIPROT KIT protein P10721 UNIPROT down-regulates phosphorylation Ser746 RRSVRIGsYIERDVT 9606 7539802 t miannu "Phosphorylation of kit/scfr by pkc-_ in vitro: identification of ser-741 and ser-746 as the major phosphorylation sites for pkc / pkc, which acts in an scf-stimulated feedback loop, that negatively controls kit/scfr kinase activity" SIGNOR-28605 PRKCA protein P17252 UNIPROT KIT protein P10721 UNIPROT "down-regulates activity" phosphorylation Ser741 TKADKRRsVRIGSYI 9823 BTO:0004007 7539802 t lperfetto "We present here the identification of the major phosphorylation sites for PKC in Kit/SCFR. Two serine residues in the kinase insert, Ser-741 and Ser-746, are PKC-dependent phosphorylation sites in vivo and account for all phosphorylation by PKC in vitro. | Two additional serine residues, Ser-821 close to the major tyrosine autophosphorylation site in the kinase domain and Ser-959 in the carboxyl terminus are SCF-stimulated PKC-dependent phosphorylation sites. | Furthermore, the kinase activity of Kit/SCFR(S741A/S746A) toward an exogenous substrate was increased, which was reflected as a decreased Km and an increased Vmax, in accordance with the negative regulatory role of PKC on Kit/SCFR signaling." SIGNOR-248898 PRKCA protein P17252 UNIPROT KIT protein P10721 UNIPROT "down-regulates activity" phosphorylation Ser959 DHSVRINsVGSTASS 9823 BTO:0004007 7539802 t lperfetto "We present here the identification of the major phosphorylation sites for PKC in Kit/SCFR. Two serine residues in the kinase insert, Ser-741 and Ser-746, are PKC-dependent phosphorylation sites in vivo and account for all phosphorylation by PKC in vitro. | Two additional serine residues, Ser-821 close to the major tyrosine autophosphorylation site in the kinase domain and Ser-959 in the carboxyl terminus are SCF-stimulated PKC-dependent phosphorylation sites. | Furthermore, the kinase activity of Kit/SCFR(S741A/S746A) toward an exogenous substrate was increased, which was reflected as a decreased Km and an increased Vmax, in accordance with the negative regulatory role of PKC on Kit/SCFR signaling." SIGNOR-248900 PRKCA protein P17252 UNIPROT SRF protein P11831 UNIPROT down-regulates phosphorylation Ser162 LRRYTTFsKRKTGIM 10090 16537394 t lperfetto "Mimicking phosphorylation of serine-162, a target of protein kinase c-alpha, with an aspartic acid substitution (srf-s162d) completely inhibited srf-dna binding and blocked alpha-actin gene transcription pkc? Highly phosphorylated serine-162." SIGNOR-234461 PRKCA protein P17252 UNIPROT SRF protein P11831 UNIPROT up-regulates phosphorylation Thr159 DNKLRRYtTFSKRKT 10090 12809504 t llicata "Myotonic dystrophy protein kinase (DMPK), a muscle- and neuron-restricted kinase, enhanced SRF-mediated promoter activity of the skeletal and cardiac alpha-actin genes in C2C12 myoblasts as well as in nonmyogenic cells. | Threonine 159 in the MADS box alphaI coil was a specific phosphorylation target in vitro as well as in vivo of both DMPK and protein kinase C-alpha. " SIGNOR-188181 PRKCA protein P17252 UNIPROT ADRA1B protein P35368 UNIPROT "down-regulates activity" phosphorylation Ser406 RSQSRKDsLDDSGSC 9534 BTO:0000298 9353340 t lperfetto " Phorbol ester-induced phosphorylation of the Ser394 and Ser400 as well as GRK2-mediated phosphorylation of the Ser404, Ser408, and Ser410, resulted in the desensitization of alpha1BAR-mediated inositol phosphate response. " SIGNOR-248987 PRKCA protein P17252 UNIPROT SRC protein P12931 UNIPROT unknown phosphorylation Ser12 KSKPKDAsQRRRSLE -1 2996780 t lperfetto "We propose that protein kinase C is responsible for this modification based on the following evidence. First, the tumor promoters, 12-O-tetradecanoylphorbol-13-acetate and teleocidin, and synthetic diacylglycerol, known activators of protein kinase C in vivo, cause nearly complete phosphorylation of pp60src at serine 12. Second, among five purified serine/threonine-specific protein kinases tested, only protein kinase C phosphorylates pp60c-src and pp60v-src in vitro at serine 12. Third, purified protein kinase C phosphorylates a synthetic peptide corresponding to the N-terminal 20 amino acids of pp60c-src at serine 12. The physiological significance of this novel phosphorylation is discussed." SIGNOR-248893 PRKCA protein P17252 UNIPROT CYBA protein P13498 UNIPROT up-regulates phosphorylation Thr147 ERPQIGGtIKQPPSN -1 19948736 t Manara "Phosphorylation of p22phox on threonine 147 enhances NADPH oxidase activity by promoting p47phox binding. | Threonine 147 of p22phox Is Phosphorylated by PKC-α and PKC-δ in Vitro" SIGNOR-260891 PRKCA protein P17252 UNIPROT GFAP protein P14136 UNIPROT "down-regulates activity" phosphorylation Ser13 ITSAARRsYVSSGEM -1 2155236 t lperfetto "Glial fibrillary acidic protein (GFAP), the intermediate filament component of astroglial cells, can serve as an excellent substrate for both cAMP-dependent protein kinase and protein kinase C, in vitro. GFAP phosphorylated by each protein kinase does not polymerize, and the filaments that do polymerize tend to depolymerize after phosphorylation. Dephosphorylation of phospho-GFAP by phosphatase led to a recovery of the polymerization competence of GFAP. Most of the phosphorylation sites for cAMP-dependent protein kinase and protein kinase C on GFAP are the same, Ser-8, Ser-13, and Ser-34. cAMP-dependent protein kinase has one additional phosphorylation site, Thr-7." SIGNOR-248860 PRKCA protein P17252 UNIPROT GFAP protein P14136 UNIPROT "down-regulates activity" phosphorylation Ser38 LGPGTRLsLARMPPP -1 2155236 t lperfetto "Glial fibrillary acidic protein (GFAP), the intermediate filament component of astroglial cells, can serve as an excellent substrate for both cAMP-dependent protein kinase and protein kinase C, in vitro. GFAP phosphorylated by each protein kinase does not polymerize, and the filaments that do polymerize tend to depolymerize after phosphorylation. Dephosphorylation of phospho-GFAP by phosphatase led to a recovery of the polymerization competence of GFAP. Most of the phosphorylation sites for cAMP-dependent protein kinase and protein kinase C on GFAP are the same, Ser-8, Ser-13, and Ser-34. cAMP-dependent protein kinase has one additional phosphorylation site, Thr-7." SIGNOR-248862 PRKCA protein P17252 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser303 RGAPPRRsSIRNAHS 9606 BTO:0000130 12056906 t lperfetto "Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation." SIGNOR-89150 PRKCA protein P17252 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser304 GAPPRRSsIRNAHSI 9606 BTO:0000130 12056906 t lperfetto "Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation." SIGNOR-89154 PRKCA protein P17252 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser315 AHSIHQRsRKRLSQD 9606 BTO:0000130 12056906 t lperfetto "Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation." SIGNOR-89158 PRKCA protein P17252 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser320 QRSRKRLsQDAYRRN 9606 BTO:0000130 12056906 t lperfetto "Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation." SIGNOR-89162 PRKCA protein P17252 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser359 EERQTQRsKPQPAVP 9606 BTO:0000130 12056906 t lperfetto "Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation." SIGNOR-89170 PRKCA protein P17252 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser370 PAVPPRPsADLILNR 9606 BTO:0000130 12056906 t lperfetto "Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation." SIGNOR-89174 PRKCA protein P17252 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser379 DLILNRCsESTKRKL 9606 BTO:0000130 12056906 t lperfetto "Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation." SIGNOR-89178 PRKCA protein P17252 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser656 RAEFLNKsVQKSSGV 9606 BTO:0000887;BTO:0001260 8182108 t gcesareni "Phosphorylation of both intact caldesmon and of its c-terminal fragment (658c), containing residues 658-756, significantly decreased their ability to inhibit acto-heavy meromyosin atpase." SIGNOR-36792 PRKCA protein P17252 UNIPROT KCNE1 protein P15382 UNIPROT "down-regulates activity" phosphorylation Ser102 VQARVLEsYRSCYVV -1 1553557 t lperfetto "Inhibition of the current was not seen in channels in which Ser103 was replaced by Ala, although other properties of the current were unchanged. These results indicate that inhibition of the potassium current results from direct phosphorylation of the channel subunit protein at Ser103." SIGNOR-248852 PRKCA protein P17252 UNIPROT ITGB4 protein P16144 UNIPROT down-regulates phosphorylation Ser1360 VLRSPSGsQRPSVSD 9606 15121854 t lperfetto "Egf stimulates a pkc-?-Dependent pathway that results in the phosphorylation of the ?4 Integrin subunit on serine residues and its redistribution to actin-rich structures together, these results highlight the importance of serine phosphorylation in regulating type ii hemidesmosome disassembly, implicate a cluster of serine residues within the connecting segment of ?4, and argue for a key role for pkc-? In regulating these structures" SIGNOR-124494 PRKCA protein P17252 UNIPROT ITGB4 protein P16144 UNIPROT down-regulates phosphorylation Ser1494 TLTRDYNsLTRSEHS 9606 15121854 t lperfetto "Egf stimulates a pkc-?-Dependent pathway that results in the phosphorylation of the ?4 Integrin subunit on serine residues and its redistribution to actin-rich structures together, these results highlight the importance of serine phosphorylation in regulating type ii hemidesmosome disassembly, implicate a cluster of serine residues within the connecting segment of ?4, and argue for a key role for pkc-? In regulating these structures" SIGNOR-124498 PRKCA protein P17252 UNIPROT CTPS1 protein P17812 UNIPROT up-regulates phosphorylation Ser462 TLFQTKNsVMRKLYG 9606 17463002 t llicata "These data indicated that protein kinase c phosphorylation at ser(462) stimulates human ctp synthetase 1 activity, whereas phosphorylation at thr(455) inhibits activity." SIGNOR-154617 PRKCA protein P17252 UNIPROT DDX5 protein P17844 UNIPROT "down-regulates activity" phosphorylation Ser557 VSAGIQTsFRTGNPT -1 7525583 t lperfetto "We report that p68 is phosphorylated by protein kinase C in vitro and binds calmodulin in a Ca(2+)-dependent manner. Both phosphorylation and calmodulin binding inhibited p68 ATPase activity | In addition, a 20-amino acid peptide corresponding to residues 549-568 of p68 was phosphorylated in a Ca- and phospholipid-dependent manner hy PKC" SIGNOR-248896 PRKCA protein P17252 UNIPROT VCL protein P18206 UNIPROT unknown phosphorylation Ser1101 NAQNLMQsVKETVRE -1 11741957 t lperfetto "PKC Phosphorylates Serines 1033 and 1045 in Helix H5" SIGNOR-249128 PRKCA protein P17252 UNIPROT VCL protein P18206 UNIPROT unknown phosphorylation Ser1113 VREAEAAsIKIRTDA -1 11741957 t lperfetto "PKC Phosphorylates Serines 1033 and 1045 in Helix H5" SIGNOR-249129 PRKCA protein P17252 UNIPROT GNAZ protein P19086 UNIPROT up-regulates phosphorylation Ser16 EKEAARRsRRIDRHL 9606 BTO:0000671 9166747 t gcesareni "Functional role of amino-terminal serine16 and serine27 of g alphaz in receptor and effector coupling." SIGNOR-48677 PRKCA protein P17252 UNIPROT GNAZ protein P19086 UNIPROT up-regulates phosphorylation Ser27 DRHLRSEsQRQRREI 9606 BTO:0000671 9166747 t gcesareni "Functional role of amino-terminal serine16 and serine27 of g alphaz in receptor and effector coupling." SIGNOR-48681 PRKCA protein P17252 UNIPROT PLCG1 protein P19174 UNIPROT down-regulates phosphorylation Ser1248 HGRAREGsFESRYQQ 9606 BTO:0000782;BTO:0000661 1370476 t llicata "The observation that pka also phosphorylates plc-yl on serine 1248 suggests that phosphorylation of this residue may be a common mechanism by which pkc and pka inhibit plc-yl." SIGNOR-17905 PRKCA protein P17252 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates phosphorylation Ser42 AKKKSKIsASRKLQL 9606 BTO:0000887 15769444 t lperfetto "Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction." SIGNOR-134613 PRKCA protein P17252 UNIPROT TNNI3 protein P19429 UNIPROT "down-regulates activity" phosphorylation Ser39 EPHAKKKsKISASRK -1 11121119 t lperfetto "In addition to the established phosphorylation sites (S22 and S23) we found that S38 and S165 were the other two main sites of phosphorylation. | Overphosphorylation of troponin I reduced its affinity for troponin C, as measured by isothermal titration microcalorimetry. Phosphorylation of S22/23A also decreased its affinity for troponin C indicating that phosphorylation of S38 and/or S165 impedes binding of troponin I to troponin C. Formation of a troponin I/troponin C complex prior to cAMP-dependent protein kinase treatment did not prevent overphosphorylation." SIGNOR-249068 PRKCA protein P17252 UNIPROT TNNI3 protein P19429 UNIPROT unknown phosphorylation Ser77 GEKGRALsTRCQPLE -1 2584239 t lperfetto "We have now determined that PKC phosphorylated serine 43 (and/or serine 45), serine 78, and threonine 144 in the free Tn-I subunit" SIGNOR-248890 PRKCA protein P17252 UNIPROT TNNI3 protein P19429 UNIPROT "up-regulates activity" phosphorylation Ser23 PAPIRRRsSNYRAYA -1 11121119 t lperfetto "In addition to the established phosphorylation sites (S22 and S23) we found that S38 and S165 were the other two main sites of phosphorylation. | Phosphorylation of S22/23A also decreased its affinity for troponin C indicating that phosphorylation of S38 and/or S165 impedes binding of troponin I to troponin C. Formation of a troponin I/troponin C complex prior to cAMP-dependent protein kinase treatment did not prevent overphosphorylation." SIGNOR-249066 PRKCA protein P17252 UNIPROT TNNI3 protein P19429 UNIPROT "up-regulates activity" phosphorylation Ser24 APIRRRSsNYRAYAT -1 11121119 t lperfetto "In addition to the established phosphorylation sites (S22 and S23) we found that S38 and S165 were the other two main sites of phosphorylation. | Phosphorylation of S22/23A also decreased its affinity for troponin C indicating that phosphorylation of S38 and/or S165 impedes binding of troponin I to troponin C. Formation of a troponin I/troponin C complex prior to cAMP-dependent protein kinase treatment did not prevent overphosphorylation." SIGNOR-249067 PRKCA protein P17252 UNIPROT ACO1 protein P21399 UNIPROT down-regulates phosphorylation Ser711 REFNSYGsRRGNDAV 9606 BTO:0000671 15636585 t gcesareni "Irp1 ser-711 is a phosphorylation site, critical for regulation of rna-binding and aconitase activities." SIGNOR-133188 PRKCA protein P17252 UNIPROT CBL protein P22681 UNIPROT "down-regulates quantity" phosphorylation Ser619 RELTNRHsLPFSLPS 9606 BTO:0000782 11024037 t lperfetto "However, under normal conditions, PKC activation resulting from CD43 engagement was required to activate the MAPK pathway, suggesting that phosphorylation of Cbl on serine residues by PKC and its association with 14-3-3 molecules may play a role in preventing the Cbl inhibitory effect on the Ras-MAPK pathway. " SIGNOR-249054 PRKCA protein P17252 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser677 AIVSKIDsRLEQYTS 9606 BTO:0000887;BTO:0001260 8182108 t gcesareni "Phosphorylation of both intact caldesmon and of its c-terminal fragment (658c), containing residues 658-756, significantly decreased their ability to inhibit acto-heavy meromyosin atpase." SIGNOR-36796 PRKCA protein P17252 UNIPROT CBL protein P22681 UNIPROT "down-regulates quantity" phosphorylation Ser623 NRHSLPFsLPSQMEP 9606 BTO:0000782 11024037 t lperfetto "However, under normal conditions, PKC activation resulting from CD43 engagement was required to activate the MAPK pathway, suggesting that phosphorylation of Cbl on serine residues by PKC and its association with 14-3-3 molecules may play a role in preventing the Cbl inhibitory effect on the Ras-MAPK pathway. " SIGNOR-249055 PRKCA protein P17252 UNIPROT CBL protein P22681 UNIPROT "down-regulates quantity" phosphorylation Ser639 PDVPRLGsTFSLDTS 9606 BTO:0000782 11024037 t lperfetto "However, under normal conditions, PKC activation resulting from CD43 engagement was required to activate the MAPK pathway, suggesting that phosphorylation of Cbl on serine residues by PKC and its association with 14-3-3 molecules may play a role in preventing the Cbl inhibitory effect on the Ras-MAPK pathway. " SIGNOR-249056 PRKCA protein P17252 UNIPROT CBL protein P22681 UNIPROT "down-regulates quantity" phosphorylation Ser642 PRLGSTFsLDTSMSM 9606 BTO:0000782 11024037 t lperfetto "However, under normal conditions, PKC activation resulting from CD43 engagement was required to activate the MAPK pathway, suggesting that phosphorylation of Cbl on serine residues by PKC and its association with 14-3-3 molecules may play a role in preventing the Cbl inhibitory effect on the Ras-MAPK pathway. " SIGNOR-249057 PRKCA protein P17252 UNIPROT CFL1 protein P23528 UNIPROT down-regulates phosphorylation Ser23 NDMKVRKsSTPEEVK 9606 BTO:0001271 22855535 t lperfetto "Pkc_ phosphorylates cofilin at ser-23 and/or ser-24 during degranulationthese results indicate that a novel pkc_-mediated phosphorylation event regulates cofilin by inhibiting its ability to depolymerize f-actin and bind to 14-3-3_, thereby promoting f-actin polymerization" SIGNOR-198478 PRKCA protein P17252 UNIPROT CFL1 protein P23528 UNIPROT down-regulates phosphorylation Ser24 DMKVRKSsTPEEVKK 9606 BTO:0001271 22855535 t lperfetto "Pkc_ phosphorylates cofilin at ser-23 and/or ser-24 during degranulationthese results indicate that a novel pkc_-mediated phosphorylation event regulates cofilin by inhibiting its ability to depolymerize f-actin and bind to 14-3-3_, thereby promoting f-actin polymerization" SIGNOR-198482 PRKCA protein P17252 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Ser440 RSSPQRKsQRSSYVS -1 12175859 t miannu "Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). The PKC family contains 12 identified mammalian isoenzymes that are universally expressed in all cells and tissues and generally have a cytosolic distributionExamination of two groups of serine and threonine mutations (Fig. 3A, lanes 2 and 3) enabled us to localize the phosphorylation to four specific residues at positions 419, 422, 423, and 426. Fig. 3B shows the levels of phosphorylation with different combinations of the four mutations. Elimination of all four serines completely eliminated phosphorylation (Fig. 3B, lane 1).An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation" SIGNOR-262753 PRKCA protein P17252 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Ser443 PQRKSQRsSYVSMRI -1 12175859 t miannu "Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). The PKC family contains 12 identified mammalian isoenzymes that are universally expressed in all cells and tissues and generally have a cytosolic distributionExamination of two groups of serine and threonine mutations (Fig. 3A, lanes 2 and 3) enabled us to localize the phosphorylation to four specific residues at positions 419, 422, 423, and 426. Fig. 3B shows the levels of phosphorylation with different combinations of the four mutations. Elimination of all four serines completely eliminated phosphorylation (Fig. 3B, lane 1).An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation" SIGNOR-262752 PRKCA protein P17252 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Ser444 QRKSQRSsYVSMRID -1 12175859 t miannu "Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). The PKC family contains 12 identified mammalian isoenzymes that are universally expressed in all cells and tissues and generally have a cytosolic distributionExamination of two groups of serine and threonine mutations (Fig. 3A, lanes 2 and 3) enabled us to localize the phosphorylation to four specific residues at positions 419, 422, 423, and 426. Fig. 3B shows the levels of phosphorylation with different combinations of the four mutations. Elimination of all four serines completely eliminated phosphorylation (Fig. 3B, lane 1).An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation" SIGNOR-262755 PRKCA protein P17252 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Ser447 SQRSSYVsMRIDTHA -1 12175859 t miannu "Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). The PKC family contains 12 identified mammalian isoenzymes that are universally expressed in all cells and tissues and generally have a cytosolic distributionExamination of two groups of serine and threonine mutations (Fig. 3A, lanes 2 and 3) enabled us to localize the phosphorylation to four specific residues at positions 419, 422, 423, and 426. Fig. 3B shows the levels of phosphorylation with different combinations of the four mutations. Elimination of all four serines completely eliminated phosphorylation (Fig. 3B, lane 1).An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation" SIGNOR-262754 PRKCA protein P17252 UNIPROT MYL9 protein P24844 UNIPROT down-regulates phosphorylation Ser2 sSKRAKAK 9606 22136066 t lperfetto "Rlc can also be phosphorylated at ser1/ser2/thr9 by protein kinase c (pkc). Biophysical studies show that phosphorylation at these sites leads to an increase in the km of myosin light chain kinase (mlck) for rlc, thereby indirectly inhibiting myosin ii activity." SIGNOR-177940 PRKCA protein P17252 UNIPROT MYL9 protein P24844 UNIPROT down-regulates phosphorylation Ser3 sKRAKAKT 9606 22136066 t lperfetto "Rlc can also be phosphorylated at ser1/ser2/thr9 by protein kinase c (pkc). Biophysical studies show that phosphorylation at these sites leads to an increase in the km of myosin light chain kinase (mlck) for rlc, thereby indirectly inhibiting myosin ii activity" SIGNOR-192792 PRKCA protein P17252 UNIPROT GRK2 protein P25098 UNIPROT "up-regulates activity" phosphorylation Ser29 ATPAARAsKKILLPE 9606 BTO:0000007 11042191 t lperfetto "Phosphorylation of GRK2 by protein kinase C abolishes its inhibition by calmodulin. In vitro, GRK2 was preferentially phosphorylated by PKC isoforms alpha, gamma, and delta. Two-dimensional peptide mapping of PKCalpha-phosphorylated GRK2 showed a single site of phosphorylation, which was identified as serine 29 by HPLC-MS. A S29A mutant of GRK2 was not phosphorylated by PKC in vitro and showed no phorbol ester-stimulated phosphorylation when transfected into human embryonic kidney (HEK)293 cells." SIGNOR-249058 PRKCA protein P17252 UNIPROT RPL10 protein P27635 UNIPROT unknown -1 9016777 t lperfetto "QM is phosphorylated by PKC and the extent of phosphorylation by PKC is correlated with the extent of inhibition of binding of QM to c-Jun." SIGNOR-248957 PRKCA protein P17252 UNIPROT ITPKB protein P27987 UNIPROT "down-regulates activity" -1 9374536 t lperfetto "However, when assayed in the presence of calcium/calmodulin, the activity of the B isoform was decreased following phosphorylation by either protein kinase." SIGNOR-248990 PRKCA protein P17252 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser464 LLKHVTQsSRKLIRA 9606 BTO:0000938 15381704 t "The effect has been demonstrated using P28329-3" gcesareni "We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation." SIGNOR-129260 PRKCA protein P17252 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser465 LKHVTQSsRKLIRAD 9606 BTO:0000938 15381704 t "The effect has been demonstrated using P28329-3" gcesareni "We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation." SIGNOR-129264 PRKCA protein P17252 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser558 VPTYESAsIRRFQEG 9606 BTO:0000938 15381704 t "The effect has been demonstrated using P28329-3" gcesareni "We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation." SIGNOR-129268 PRKCA protein P17252 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser594 HKAAVPAsEKLLLLK 9606 BTO:0000938 15381704 t "The effect has been demonstrated using P28329-3" gcesareni "We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation." SIGNOR-129272 PRKCA protein P17252 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Thr373 TVLVKDStNRDSLDM 9606 BTO:0000938 15381704 t "The effect has been demonstrated using P28329-3" gcesareni "We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation." SIGNOR-129276 PRKCA protein P17252 UNIPROT PTPN6 protein P29350 UNIPROT down-regulates phosphorylation Ser591 DKEKSKGsLKRK 9606 15269224 t llicata "Protein kinase calpha therefore critically and negatively regulates shp-1 function, forming part of a mechanism to retain shp-1 in a basal active state through interaction with its sh2 domains, and phosphorylating its c-terminal ser591 upon cellular activation" SIGNOR-126876 PRKCA protein P17252 UNIPROT SHC1 protein P29353 UNIPROT "up-regulates activity" phosphorylation Ser139 EEWTRHGsFVNKPTR 10090 BTO:0000944 12052829 t lperfetto "Among them, Ser(29) in p52(Shc) (equivalent to Ser(138) in p66(Shc)) was phosphorylated only after TPA stimulation. Phosphorylation of this site together with the intact phosphotyrosine-binding domain was essential for ShcA binding to the protein-tyrosine phosphatase PTP-PEST. TPA-induced ShcA phosphorylation at this site (and hence, its association with PTP-PEST) was inhibited by a protein kinase C-specific inhibitor and was induced by overexpression of constitutively active mutants of protein kinase Calpha, -epsilon, and -delta isoforms." SIGNOR-263047 PRKCA protein P17252 UNIPROT NOS3 protein P29474 UNIPROT "down-regulates activity" phosphorylation Thr495 TGITRKKtFKEVANA 9606 BTO:0001853 24379783 t lperfetto "The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites" SIGNOR-251620 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT "down-regulates activity" phosphorylation Ser159 KKKKKRFsFKKSFKL -1 1560845 t gcesareni "Here we report that MARCKS is a filamentous (F) actin crosslinking protein, with activity that is inhibited by PKC-mediated phosphorylation and by binding to calcium-calmodulin" SIGNOR-243192 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT "down-regulates activity" phosphorylation Ser163 KRFSFKKsFKLSGFS -1 1560845 t gcesareni "Here we report that MARCKS is a filamentous (F) actin crosslinking protein, with activity that is inhibited by PKC-mediated phosphorylation and by binding to calcium-calmodulin" SIGNOR-249650 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT "down-regulates activity" phosphorylation Ser170 SFKLSGFsFKKNKKE -1 1560845 t gcesareni "Here we report that MARCKS is a filamentous (F) actin crosslinking protein, with activity that is inhibited by PKC-mediated phosphorylation and by binding to calcium-calmodulin" SIGNOR-249670 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser159 KKKKKRFsFKKSFKL 9606 16116087 t llicata "The present experiments demonstrate that ptn stimulates phosphorylation of serines 713 and 726 in the marcks domain of _-adducin (and serine 724 in _-adducin) and serines 152 and 156 in the marcks protein itself through the activation of either pkc _ or _ and perhaps other pkc(s) isoforms." SIGNOR-139906 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser163 KRFSFKKsFKLSGFS 9606 16116087 t llicata "The present experiments demonstrate that ptn stimulates phosphorylation of serines 713 and 726 in the marcks domain of _-adducin (and serine 724 in _-adducin) and serines 152 and 156 in the marcks protein itself through the activation of either pkc _ or _ and perhaps other pkc(s) isoforms." SIGNOR-139910 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser101 AAPEAGAsPVEKEAP -1 8034575 t lperfetto "Of the 7 phosphorylated serine residues identified by Edman degradation, only 1 was within the known phosphorylation domain by protein kinase C. All the other phosphorylated serine residues originated from the N-terminal half of the molecule and were immediately followed by proline. | The other phosphorylated peptides were subjected to the same analysis, and Ser45 (peptide K5), Sel-80(peptide K7), and Ser99 (peptide K8) were confirmed to be the phosphorylation sites." SIGNOR-248909 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser118 GEAAEPGsPTAAEGE -1 8034575 t lperfetto "Of the 7 phosphorylated serine residues identified by Edman degradation, only 1 was within the known phosphorylation domain by protein kinase C. All the other phosphorylated serine residues originated from the N-terminal half of the molecule and were immediately followed by proline. | We conclude that the primary phosphorylation site is Ser116 |" SIGNOR-248907 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser46 VKVNGDAsPAAAESG -1 8034575 t lperfetto "Of the 7 phosphorylated serine residues identified by Edman degradation, only 1 was within the known phosphorylation domain by protein kinase C. All the other phosphorylated serine residues originated from the N-terminal half of the molecule and were immediately followed by proline. | The other phosphorylated peptides were subjected to the same analysis, and Ser45 (peptide K5), Sel-80(peptide K7), and Ser99 (peptide K8) were confirmed to be the phosphorylation sites." SIGNOR-248908 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser81 AAGSGAAsPSAAEKG -1 8034575 t lperfetto "Of the 7 phosphorylated serine residues identified by Edman degradation, only 1 was within the known phosphorylation domain by protein kinase C. All the other phosphorylated serine residues originated from the N-terminal half of the molecule and were immediately followed by proline. | The other phosphorylated peptides were subjected to the same analysis, and Ser45 (peptide K5), Sel-80(peptide K7), and Ser99 (peptide K8) were confirmed to be the phosphorylation sites." SIGNOR-248910 PRKCA protein P17252 UNIPROT AQP1 protein P29972 UNIPROT up-regulates phosphorylation Thr157 VLCVLATtDRRRRDL 9606 BTO:0000671 17522053 t llicata "Activation of protein kinase c (pkc) by 1-oleoyl-2-acetyl-sn-glycerol (oag) induced a marked increase of aqp1-dependent water permeability. This regulation was abolished in mutated aqp1 channels lacking both consensus pkc phosphorylation sites thr(157) and thr(239) (termed aqp1 deltapkc)." SIGNOR-155102 PRKCA protein P17252 UNIPROT AQP1 protein P29972 UNIPROT up-regulates phosphorylation Thr239 APRSSDLtDRVKVWT 9606 BTO:0000671 17522053 t llicata "Activation of protein kinase c (pkc) by 1-oleoyl-2-acetyl-sn-glycerol (oag) induced a marked increase of aqp1-dependent water permeability. This regulation was abolished in mutated aqp1 channels lacking both consensus pkc phosphorylation sites thr(157) and thr(239) (termed aqp1 deltapkc)." SIGNOR-155106 PRKCA protein P17252 UNIPROT CLIP1 protein P30622 UNIPROT down-regulates phosphorylation Ser312 ASLKRSPsASSLSSM 9606 20519438 t lperfetto "Furthermore, by using phosphoproteomic analysis, we determined that s309 and s311 of clip-170 are phosphorylated in cells and mapped s311 as a protein kinase a (pka) phosphorylation site.phosphorylation of s311 may be critical for establishing the ?folded Back? Conformation of clip-170clip-170 open and folded back conformations represent active and inactive modes of the protein, respectively" SIGNOR-165857 PRKCA protein P17252 UNIPROT SDC4 protein P31431 UNIPROT "up-regulates activity" phosphorylation Ser179 MKKKDEGsYDLGKKP 10116 BTO:0001176 11916978 t lperfetto "The phosphorylation state of Ser(183) in the cytoplasmic tail of syndecan-4 determines the binding affinity of the cytoplasmic tail to phosphatidylinositol 4,5-bisphosphate (PIP(2)), the capacity of the tail to multimerize, and its ability to activate protein kinase C (PKC) alpha. We sought to identify the kinase responsible for this phosphorylation and to determine its downstream effects on PKCalpha activity and on endothelial cell function. Among several PKC isoenzymes tested, only PKCalpha and -delta were able to specifically phosphorylate Ser(183) in vitro. However, studies in cultured endothelial cells showed that the phosphorylation level of syndecan-4 was significantly reduced in endothelial cells expressing a dominant negative (DN) PKCdelta but not a DN PKCalpha mutant." SIGNOR-249149 PRKCA protein P17252 UNIPROT SDC2 protein P34741 UNIPROT unknown phosphorylation Ser187 DLGERKPsSAAYQKA -1 9244383 t lperfetto "We investigated phosphorylation of syndecan-2 cytoplasmic domain by PKC | Peptide mapping and substitution studies showed that both serines were phosphoacceptors, but each had slightly different affinity, with that of serine-197 being higher than serine-198." SIGNOR-248973 PRKCA protein P17252 UNIPROT HRH1 protein P35367 UNIPROT down-regulates phosphorylation Ser398 WKRLRSHsRQYVSGL 9606 BTO:0000975 10101032 t "Translocation from Endosome to Lysosome" fspada "In this study, we demonstrated that ser396 and ser398 are phosphorylated by pkc and, that phosphorylation of ser398 is particularly involved in pmainduced desensitization of the h1r." SIGNOR-66015 PRKCA protein P17252 UNIPROT HRH1 protein P35367 UNIPROT down-regulates phosphorylation Ser398 WKRLRSHsRQYVSGL 9606 BTO:0000975 15107581 t "Translocation from Endosome to Lysosome" fspada "The peptide p9-s396a/s398a (both ser396 and ser398 to alanines) was phosphorylated only slightly or not phosphorylated by these kinases. Thus both ser396 and ser398 can be phosphorylated by camk ii and pkc" SIGNOR-124352 PRKCA protein P17252 UNIPROT HRH1 protein P35367 UNIPROT down-regulates phosphorylation Thr478 CNENFKKtFKRILHI 9606 BTO:0000975 15107581 t "Translocation from Endosome to Lysosome" fspada "The peptide p10-t478a (thr478 to alanine) was not phosphorylated by pkc, indicating that thr478 can be phosphorylated by pkc." SIGNOR-124356 PRKCA protein P17252 UNIPROT ADRA1B protein P35368 UNIPROT "down-regulates activity" phosphorylation Ser396 RPWTRGGsLERSQSR 9534 BTO:0000298 9353340 t lperfetto " Phorbol ester-induced phosphorylation of the Ser394 and Ser400 as well as GRK2-mediated phosphorylation of the Ser404, Ser408, and Ser410, resulted in the desensitization of alpha1BAR-mediated inositol phosphate response. " SIGNOR-248985 PRKCA protein P17252 UNIPROT ADRA1B protein P35368 UNIPROT "down-regulates activity" phosphorylation Ser402 GSLERSQsRKDSLDD 9534 BTO:0000298 9353340 t lperfetto " Phorbol ester-induced phosphorylation of the Ser394 and Ser400 as well as GRK2-mediated phosphorylation of the Ser404, Ser408, and Ser410, resulted in the desensitization of alpha1BAR-mediated inositol phosphate response. " SIGNOR-248986 AKT1 protein P31749 UNIPROT PTPN1 protein P18031 UNIPROT "down-regulates activity" phosphorylation Ser50 RNRYRDVsPFDHSRI 10090 BTO:0000944 11579209 t lperfetto "Phosphorylation of ptp1b at ser(50) by akt impairs its ability to dephosphorylate the insulin receptor." SIGNOR-252542 PRKCA protein P17252 UNIPROT ADRA1B protein P35368 UNIPROT "down-regulates activity" phosphorylation Ser410 RKDSLDDsGSCLSGS 9534 BTO:0000298 9353340 t lperfetto " Phorbol ester-induced phosphorylation of the Ser394 and Ser400 as well as GRK2-mediated phosphorylation of the Ser404, Ser408, and Ser410, resulted in the desensitization of alpha1BAR-mediated inositol phosphate response. " SIGNOR-248988 PRKCA protein P17252 UNIPROT ADRA1B protein P35368 UNIPROT "down-regulates activity" phosphorylation Ser412 DSLDDSGsCLSGSQR 9534 BTO:0000298 9353340 t lperfetto " Phorbol ester-induced phosphorylation of the Ser394 and Ser400 as well as GRK2-mediated phosphorylation of the Ser404, Ser408, and Ser410, resulted in the desensitization of alpha1BAR-mediated inositol phosphate response. " SIGNOR-248989 PRKCA protein P17252 UNIPROT RORA protein P35398 UNIPROT unknown phosphorylation Ser35 ETPLNQEsARKSEPP 9606 20122401 t llicata "Wnt5a/pkcalpha-dependent phosphorylation on serine residue 35 of roralpha is crucial to link roralpha to wnt/beta-catenin signaling, which exerts inhibitory function of the expression of wnt/beta-catenin target genes." SIGNOR-163702 PRKCA protein P17252 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser24 GYLRKPKsMHKRFFV 9606 16574739 t flangone "We show that pkcalpha is likely to be directly involved in ser24 phosphorylation...These observations are entirely consistent with a recent independent study demonstrating that the IRS1-S24D mutant shows impaired insulin-stimulated IR-IRS-1 interactions, tyrosine phosphorylation of IRS-1, recruitment/activation of PI 3-Kinase, and insulin-stimulated Glut4 translocation" SIGNOR-145398 PRKCA protein P17252 UNIPROT ADD1 protein P35611 UNIPROT up-regulates phosphorylation Ser726 KKKFRTPsFLKKSKK 9606 8810272 t gcesareni "These data demonstrate that adducin is a significant in vivo substrate for pkc or other pma-activated kinases in a variety of cells, and that phosphorylation of adducin occurs in dendritic spines that are believed to respond to external signals by changes in morphology and reorganization of cytoskeletal structures. Ser-726 and ser-713 in the c-terminal marcks-related domains of alpha- and beta-adducin, respectively, were identified as the major phosphorylation sites common for pka and pkc." SIGNOR-43744 PRKCA protein P17252 UNIPROT ADD1 protein P35611 UNIPROT up-regulates phosphorylation Ser726 KKKFRTPsFLKKSKK 9606 BTO:0000938 BTO:0000671 9679146 t gcesareni "These data demonstrate that adducin is a significant in vivo substrate for pkc or other pma-activated kinases in a variety of cells, and that phosphorylation of adducin occurs in dendritic spines that are believed to respond to external signals by changes in morphology and reorganization of cytoskeletal structures. Ser-726 and ser-713 in the c-terminal marcks-related domains of alpha- and beta-adducin, respectively, were identified as the major phosphorylation sites common for pka and pkc." SIGNOR-59229 PRKCA protein P17252 UNIPROT ADD2 protein P35612 UNIPROT down-regulates phosphorylation Ser713 KKKFRTPsFLKKSKK 9606 16116087 t gcesareni "We now demonstrate that ptn stimulates the phosphorylation of serines 713 and 726 in the myristoylated alanine-rich protein kinase (pk) c substrate domain of beta-adducin through activation of either pkc alpha or beta." SIGNOR-139870 PRKCA protein P17252 UNIPROT OPRD1 protein P41143 UNIPROT unknown phosphorylation Ser344 CGRPDPSsFSRAREA 9606 BTO:0000007 11085981 t lperfetto "In the current study, we identified a PKC-mediated phosphorylation site in the delta-opioid receptor (DOR) and demonstrated that activation of PKC by stimulation of other types of GPCR or increase in intracellular Ca2+concentration in HEK 293 cells induces heterologous phosphorylation of DOR. Our results further established that DOR phosphorylation at Ser-344 by PKC results in internalization of DOR in HEK 293 cells through a beta-arrestin- and clathrin-mediated mechanism." SIGNOR-249062 PRKCA protein P17252 UNIPROT CASR protein P41180 UNIPROT down-regulates phosphorylation Thr888 FKVAARAtLRRSNVS 9606 21135065 t llicata "Casr(t888) is a protein kinase c (pkc) phosphorylation site in the receptor's intracellular domain that has previously been identified as a critical negative regulator of casr downstream signaling in vitro, thus, casr(t888) represents a functionally important, inhibitory phosphorylation site that contributes to the control of pth secretion." SIGNOR-170334 PRKCA protein P17252 UNIPROT GRM5 protein P41594 UNIPROT "up-regulates activity" phosphorylation Ser840 VRSAFTTsTVVRMHV -1 15894802 t lperfetto "Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839." SIGNOR-249278 PRKCA protein P17252 UNIPROT GRM5 protein P41594 UNIPROT "up-regulates activity" phosphorylation Thr841 RSAFTTStVVRMHVG -1 15894802 t lperfetto "Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839." SIGNOR-249285 PRKCA protein P17252 UNIPROT GRIA2 protein P42262 UNIPROT unknown phosphorylation Ser880 YNVYGIEsVKI 9606 BTO:0000007 10501226 t lperfetto "Here, we show that the C terminus of GluR2 of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor is phosphorylated by protein kinase C and that serine-880 is the major phosphorylation site. This phosphorylation also occurs in human embryonic kidney (HEK) cells by addition of 12-O-tetradecanoylphorbol 13-acetate." SIGNOR-249022 PRKCA protein P17252 UNIPROT GRIA2 protein P42262 UNIPROT unknown phosphorylation Ser683 TKEFFRRsKIAVFDK -1 8848293 t lperfetto "Only two peptides containing Ser-662 and Ser-696 were found to be efficiently phosphorylated by protein kinase C (PKC). The peptide including Ser-696 was also phosphorylated by protein kinase G (PKG)." SIGNOR-248954 PRKCA protein P17252 UNIPROT GRIA2 protein P42262 UNIPROT unknown phosphorylation Ser717 GVARVRKsKGKYAYL -1 8848293 t lperfetto "Only two peptides containing Ser-662 and Ser-696 were found to be efficiently phosphorylated by protein kinase C (PKC). The peptide including Ser-696 was also phosphorylated by protein kinase G (PKG)." SIGNOR-248955 PRKCA protein P17252 UNIPROT PTGIR protein P43119 UNIPROT unknown phosphorylation Ser328 TPLSQLAsGRRDPRA 9606 BTO:0000007 9722557 t lperfetto "These results indicate that PKC-dependent phosphorylation is of critical importance to homologous regulation of hIP. Ser-328 is a primary site for PKC phosphorylation of hIP." SIGNOR-249011 PRKCA protein P17252 UNIPROT IQGAP1 protein P46940 UNIPROT up-regulates phosphorylation Ser1443 DKMKKSKsVKEDSNL 9606 BTO:0000150;BTO:0000938 15695813 t gcesareni "Using a mass spectrometry-based assay, we show that egf induces phosphorylation of iqgap1 ser(1443), a residue known to be phosphorylated by pkcthe nonphosphorylatable iqgap1 s1441a/s1443a had no effect. In contrast, the s1441e/s1443d mutation markedly enhanced the ability of iqgap1 to induce neurite outgrowth." SIGNOR-133861 PRKCA protein P17252 UNIPROT GFPT1 protein Q06210 UNIPROT "down-regulates activity" phosphorylation Ser205 AVGTRRGsPLLIGVR -1 10806197 t lperfetto "Phosphorylation of human glutamine:fructose-6-phosphate amidotransferase by cAMP-dependent protein kinase at serine 205 blocks the enzyme activity." SIGNOR-249040 PRKCA protein P17252 UNIPROT IQGAP1 protein P46940 UNIPROT up-regulates phosphorylation Ser1443 DKMKKSKsVKEDSNL 9606 21349850 t gcesareni "Using a mass spectrometry-based assay, we show that egf induces phosphorylation of iqgap1 ser(1443), a residue known to be phosphorylated by pkcthe nonphosphorylatable iqgap1 s1441a/s1443a had no effect. In contrast, the s1441e/s1443d mutation markedly enhanced the ability of iqgap1 to induce neurite outgrowth." SIGNOR-172235 PRKCA protein P17252 UNIPROT GRIA4 protein P48058 UNIPROT unknown phosphorylation Thr850 EAKRMKLtFSEAIRN -1 10366608 t lperfetto "In addition, we identified threonine 830 as a potential PKC phosphorylation site." SIGNOR-249017 PRKCA protein P17252 UNIPROT GRIA4 protein P48058 UNIPROT up-regulates phosphorylation Ser862 IRNKARLsITGSVGE 9606 12536214 t gcesareni "Receptor internalization, altered;intracellular localization" SIGNOR-97554 PRKCA protein P17252 UNIPROT SLC6A9 protein P48067-2 UNIPROT "down-regulates activity" phosphorylation Ser239 LIRGVKSsGKVVYFT 9823 21864610 t miannu "We demonstrated that the isoforms GlyT1a, GlyT1b, and GlyT1c were constitutively phosphorylated, and that phosphorylation was dramatically enhanced, in a time dependent fashion, after PKC activation by phorbol ester. The phosphorylation was PKC-dependent, since pre-incubation of the cells with bisindolylmaleimide I, a selective PKC inhibitor, abolished the phorbol ester-induced phosphorylation. Blotting with specific anti-phospho-tyrosine antibodies did not yield any signal that could correspond to GlyT1 tyrosine phosphorylation, suggesting that the phosphorylation occurs at serine and/or threonine residues. These results together suggest that conventional PKCα and/or β are responsible for the downregulation of glycine transport. We further analyzed the effect of more specific inhibitors to PKCα and PKCβ on the GlyT1 activity. As shown in Fig. 4, panels C-F, incubation of the cells with varying concentrations of the PKCβ inhibitors (referred as PKCβ inhibitor and LY333531) or the PKCα/γ (HDBBE) inhibitors did not prevent the reduction of glycine uptake triggered by PMA, suggesting that PKCα and PKCβ together regulate GlyT1 activity." SIGNOR-262918 PRKCA protein P17252 UNIPROT SLC6A9 protein P48067-2 UNIPROT "down-regulates activity" phosphorylation Ser625 PIVGSNGsSRLQDSR 9823 21864610 t miannu "We demonstrated that the isoforms GlyT1a, GlyT1b, and GlyT1c were constitutively phosphorylated, and that phosphorylation was dramatically enhanced, in a time dependent fashion, after PKC activation by phorbol ester. The phosphorylation was PKC-dependent, since pre-incubation of the cells with bisindolylmaleimide I, a selective PKC inhibitor, abolished the phorbol ester-induced phosphorylation. Blotting with specific anti-phospho-tyrosine antibodies did not yield any signal that could correspond to GlyT1 tyrosine phosphorylation, suggesting that the phosphorylation occurs at serine and/or threonine residues. These results together suggest that conventional PKCα and/or β are responsible for the downregulation of glycine transport. We further analyzed the effect of more specific inhibitors to PKCα and PKCβ on the GlyT1 activity. As shown in Fig. 4, panels C-F, incubation of the cells with varying concentrations of the PKCβ inhibitors (referred as PKCβ inhibitor and LY333531) or the PKCα/γ (HDBBE) inhibitors did not prevent the reduction of glycine uptake triggered by PMA, suggesting that PKCα and PKCβ together regulate GlyT1 activity." SIGNOR-262923 PRKCA protein P17252 UNIPROT SLC6A9 protein P48067-2 UNIPROT "down-regulates activity" phosphorylation Thr276 DGIMYYLtPQWDKIL 9823 21864610 t miannu "We demonstrated that the isoforms GlyT1a, GlyT1b, and GlyT1c were constitutively phosphorylated, and that phosphorylation was dramatically enhanced, in a time dependent fashion, after PKC activation by phorbol ester. The phosphorylation was PKC-dependent, since pre-incubation of the cells with bisindolylmaleimide I, a selective PKC inhibitor, abolished the phorbol ester-induced phosphorylation. Blotting with specific anti-phospho-tyrosine antibodies did not yield any signal that could correspond to GlyT1 tyrosine phosphorylation, suggesting that the phosphorylation occurs at serine and/or threonine residues. These results together suggest that conventional PKCα and/or β are responsible for the downregulation of glycine transport. We further analyzed the effect of more specific inhibitors to PKCα and PKCβ on the GlyT1 activity. As shown in Fig. 4, panels C-F, incubation of the cells with varying concentrations of the PKCβ inhibitors (referred as PKCβ inhibitor and LY333531) or the PKCα/γ (HDBBE) inhibitors did not prevent the reduction of glycine uptake triggered by PMA, suggesting that PKCα and PKCβ together regulate GlyT1 activity." SIGNOR-262920 PRKCA protein P17252 UNIPROT SLC6A9 protein P48067-2 UNIPROT "down-regulates activity" phosphorylation Thr590 PALLEHRtGRYAPTI 9823 21864610 t miannu "We demonstrated that the isoforms GlyT1a, GlyT1b, and GlyT1c were constitutively phosphorylated, and that phosphorylation was dramatically enhanced, in a time dependent fashion, after PKC activation by phorbol ester. The phosphorylation was PKC-dependent, since pre-incubation of the cells with bisindolylmaleimide I, a selective PKC inhibitor, abolished the phorbol ester-induced phosphorylation. Blotting with specific anti-phospho-tyrosine antibodies did not yield any signal that could correspond to GlyT1 tyrosine phosphorylation, suggesting that the phosphorylation occurs at serine and/or threonine residues. These results together suggest that conventional PKCα and/or β are responsible for the downregulation of glycine transport. We further analyzed the effect of more specific inhibitors to PKCα and PKCβ on the GlyT1 activity. As shown in Fig. 4, panels C-F, incubation of the cells with varying concentrations of the PKCβ inhibitors (referred as PKCβ inhibitor and LY333531) or the PKCα/γ (HDBBE) inhibitors did not prevent the reduction of glycine uptake triggered by PMA, suggesting that PKCα and PKCβ together regulate GlyT1 activity." SIGNOR-262921 PRKCA protein P17252 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000782 19836308 t lperfetto "Gsk3 is different from most kinases in that it is constitutively partially active and the most common regulatory mechanism is inhibition by phosphorylation of ser21 in gsk3_ or ser9 in gsk3_. This inhibitory phosphorylation can be mediated by several kinases, such as akt/protein kinase b (pkb), protein kinase c (pkc) and protein kinase a (pka)." SIGNOR-188581 PRKCA protein P17252 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser214 LVRSREVsVDEGRAC -1 9677319 t lperfetto "Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases." SIGNOR-249000 PRKCA protein P17252 UNIPROT APLP2 protein Q06481 UNIPROT unknown phosphorylation Thr723 LRKRQYGtISHGIVE -1 9109675 t lperfetto "We report here that a cytoplasmic domain peptide from APLP1 is phosphorylated in vitro by protein kinase C and that a cytoplasmic domain peptide from APLP2 is phosphorylated in vitro by protein kinase C and cdc2 kinase." SIGNOR-248970 PRKCA protein P17252 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser257 QIRLRRDsKEANARR -1 BTO:0002320 9677319 t lperfetto "Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases." SIGNOR-249002 PRKCA protein P17252 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser273 AGTRRREsLGKKAKR -1 9677319 t lperfetto "Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases." SIGNOR-249004 PRKCA protein P17252 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser290 GRIVARNsRKMAFRA -1 9677319 t lperfetto "Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases." SIGNOR-249006 PRKCA protein P17252 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser299 KMAFRAKsKSCHDLS -1 9677319 t lperfetto "Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases." SIGNOR-249008 PRKCA protein P17252 UNIPROT SNAP25 protein P60880 UNIPROT up-regulates phosphorylation Ser187 RIMEKADsNKTRIDE 9606 BTO:0000938 18171919 t llicata "Phosphorylation of snap-25 at ser187 mediates enhancement of exocytosis by a phorbol ester in ins-1 cells." SIGNOR-160313 PRKCA protein P17252 UNIPROT GMFB protein P60983 UNIPROT unknown phosphorylation Ser53 DEELEGIsPDELKDE -1 9030586 t lperfetto "Using synthetic peptide fragments containing putative phosphorylation sites of GMF, we demonstrate that PKA is capable of phosphorylating threonine 26 and serine 82, whereas PKC, p90 ribosomal S6 kinase, and casein kinase II, can phosphorylate serine 71, threonine 26, and serine 52, respectively." SIGNOR-248960 PRKCA protein P17252 UNIPROT GMFB protein P60983 UNIPROT unknown phosphorylation Ser72 QPRFIVYsYKYQHDD -1 9030586 t lperfetto "Using synthetic peptide fragments containing putative phosphorylation sites of GMF, we demonstrate that PKA is capable of phosphorylating threonine 26 and serine 82, whereas PKC, p90 ribosomal S6 kinase, and casein kinase II, can phosphorylate serine 71, threonine 26, and serine 52, respectively." SIGNOR-248959 PRKCA protein P17252 UNIPROT GMFB protein P60983 UNIPROT unknown phosphorylation Thr27 KFRFRKEtNNAAIIM -1 9030586 t lperfetto "Using synthetic peptide fragments containing putative phosphorylation sites of GMF, we demonstrate that PKA is capable of phosphorylating threonine 26 and serine 82, whereas PKC, p90 ribosomal S6 kinase, and casein kinase II, can phosphorylate serine 71, threonine 26, and serine 52, respectively." SIGNOR-248961 PRKCA protein P17252 UNIPROT STXBP1 protein P61764 UNIPROT unknown phosphorylation Ser306 VSQEVTRsLKDFSSS -1 12519779 t lperfetto "Munc18a is essential for neurotransmitter release by exocytosis and can be phosphorylated by PKC in vitro on Ser-306 and Ser-313. We demonstrate that it is phosphorylated on Ser-313 in response to phorbol ester treatment in adrenal chromaffin cells. Mutation of both phosphorylation sites to glutamate reduces its affinity for syntaxin and so acts as a phosphomimetic mutation." SIGNOR-249182 PRKCA protein P17252 UNIPROT RAB11A protein P62491 UNIPROT unknown phosphorylation Ser177 TEIYRIVsQKQMSDR -1 22188018 t miannu "This report shows for the first time that Rab11 is differentially phosphorylated by distinct PKC isoenzymes and that this post-translational modification might be a regulatory mechanism of intracellular trafficking.Our results demonstrate that classical PKC (PKCα and PKCβII but not PKCβI) directly phosphorylate Rab11 in vitro. In addition, novel PKCε and PKCη but not PKCδ isoenzymes also phosphorylate Rab11. Mass spectrometry analysis revealed that Ser 177 is the Rab11 residue to be phosphorylated in vitro by either PKCβII or PKCε." SIGNOR-263168 PRKCA protein P17252 UNIPROT EWSR1 protein Q01844 UNIPROT "down-regulates activity" phosphorylation Ser266 SSYGQQSsFRQDHPS 9606 9341188 t miannu "Here we report thatews, a nuclearrna-bindingprooncoprotein, contains an iq domain, is phosphorylated byproteinkinase c, and interacts with calmodulin. Interestingly, pkc phosphorylation of ews inhibits its binding to rna homopolymers, and conversely,rna binding to ews interferes with pkc phosphorylation./ these data indicate that ews contains an iq domain with ser266 acting as the primary site for pkc phosphorylation." SIGNOR-52850 PRKCA protein P17252 UNIPROT PLCB3 protein Q01970 UNIPROT down-regulates phosphorylation Ser1105 LDRKRHNsISEAKMR 9606 9660757 t gcesareni "These data establish that direct phosphorylation by pka of ser1105 in the putative g-box of plcbeta3 inhibits galphaq-stimulated plcbeta3 activity." SIGNOR-58859 PRKCA protein P17252 UNIPROT DNM1 protein Q05193 UNIPROT unknown phosphorylation Ser795 VPPARPGsRGPAPGP -1 10766777 t lperfetto "Phosphorylation of dynamin I on Ser-795 by protein kinase C blocks its association with phospholipids." SIGNOR-249039 PRKCA protein P17252 UNIPROT GRIN1 protein Q05586 UNIPROT "up-regulates activity" phosphorylation Ser896 SSFKRRRsSKDTSTG 10116 BTO:0000938 15936117 t miannu "Serines 890 and 896 of the NMDA receptor subunit NR1 are differentially phosphorylated by protein kinase C isoforms. The results show that PKC alpha phosphorylates preferentially S896 and PKC gamma preferentially S890." SIGNOR-263177 PRKCA protein P17252 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser643 CFTPKGSsLKIEERA 9606 BTO:0000887;BTO:0001260 8182108 t gcesareni "Phosphorylation of both intact caldesmon and of its c-terminal fragment (658c), containing residues 658-756, significantly decreased their ability to inhibit acto-heavy meromyosin atpase." SIGNOR-36788 PRKCA protein P17252 UNIPROT SPAG1 protein Q07617 UNIPROT unknown phosphorylation Ser326 VERDLKNsEAASETQ -1 11517287 t lperfetto "In-vitro incubation with [_-32P]ATP showed that HSD-3.8 protein can be phosphorylated by PKC. The phosphate is probably linked to the serine residue presenting the sequence X LysXX SerX." SIGNOR-249109 PRKCA protein P17252 UNIPROT LRP1 protein Q07954 UNIPROT up-regulates phosphorylation Ser4517 LYMGGHGsRHSLAST 9606 15272003 t lperfetto "Serine and threonine phosphorylation of the low density lipoprotein receptor-related protein by protein kinase calpha regulates endocytosis and association with adaptor moleculesthese results indicate that elimination of serine and threonine phosphorylation sites in the lrp cytoplasmic domain reduces the extent of tyr63 phosphorylation and leads to impaired association with the adaptor protein shc." SIGNOR-126958 PRKCA protein P17252 UNIPROT LRP1 protein Q07954 UNIPROT up-regulates phosphorylation Ser4520 GGHGSRHsLASTDEK 9606 15272003 t lperfetto "Serine and threonine phosphorylation of the low density lipoprotein receptor-related protein by protein kinase calpha regulates endocytosis and association with adaptor moleculesthese results indicate that elimination of serine and threonine phosphorylation sites in the lrp cytoplasmic domain reduces the extent of tyr63 phosphorylation and leads to impaired association with the adaptor protein shc." SIGNOR-127207 PRKCA protein P17252 UNIPROT LRP1 protein Q07954 UNIPROT up-regulates phosphorylation Ser4523 GSRHSLAsTDEKREL 9606 15272003 t lperfetto "Serine and threonine phosphorylation of the low density lipoprotein receptor-related protein by protein kinase calpha regulates endocytosis and association with adaptor moleculesthese results indicate that elimination of serine and threonine phosphorylation sites in the lrp cytoplasmic domain reduces the extent of tyr63 phosphorylation and leads to impaired association with the adaptor protein shc." SIGNOR-127211 PRKCA protein P17252 UNIPROT LRP1 protein Q07954 UNIPROT up-regulates phosphorylation Thr4460 GFQHQRMtNGAMNVE 9606 15272003 t lperfetto "Serine and threonine phosphorylation of the low density lipoprotein receptor-related protein by protein kinase calpha regulates endocytosis and association with adaptor moleculesthese results indicate that elimination of serine and threonine phosphorylation sites in the lrp cytoplasmic domain reduces the extent of tyr63 phosphorylation and leads to impaired association with the adaptor protein shc." SIGNOR-127215 PRKCA protein P17252 UNIPROT PLD1 protein Q13393 UNIPROT up-regulates phosphorylation Thr147 PIPTRRHtFRRQNVR 9606 BTO:0000142 10441128 t gcesareni "Serine 2, threonine 147, and serine 561 were identified as phosphorylation sites of pld1 by pkcalpha in the cells." SIGNOR-69938 PRKCA protein P17252 UNIPROT TRPC3 protein Q13507 UNIPROT down-regulates phosphorylation Ser703 SLVPSPKsFVYFIMR 9606 BTO:0000671 15533987 t gcesareni "There are two known phosphorylation-mediated inactivation mechanisms for trpc3 channels. Protein kinase g (pkg) inactivates trpc3 by direct phosphorylation on thr-11 and ser-263 of the trpc3 proteins, and protein kinase c (pkc) inactivates trpc3 by phosphorylation on ser-712." SIGNOR-130269 PRKCA protein P17252 UNIPROT TRPC3 protein Q13507 UNIPROT down-regulates phosphorylation Ser703 SLVPSPKsFVYFIMR 9606 16331690 t gcesareni "There are two known phosphorylation-mediated inactivation mechanisms for trpc3 channels. Protein kinase g (pkg) inactivates trpc3 by direct phosphorylation on thr-11 and ser-263 of the trpc3 proteins, and protein kinase c (pkc) inactivates trpc3 by phosphorylation on ser-712." SIGNOR-142945 PRKCA protein P17252 UNIPROT DGKZ protein Q13574 UNIPROT unknown phosphorylation Ser265 SKKKKRAsFKRKSSK 9716136 t lperfetto "Two isoforms of protein kinase C, but not others, regulate the localization of DGK-zeta. |The PSD in MARCKS is phosphorylated by PKC, which suggested that DGK-zeta may also be a substrate for PKC, and that this couldregulate its intracellular location." SIGNOR-249010 PRKCA protein P17252 UNIPROT THOC5 protein Q13769 UNIPROT up-regulates phosphorylation Ser5 sSKKRKPK 9606 BTO:0000801;BTO:0000876 15221008 t llicata "We conclude m-csf-mediated activation of pkcalpha can potentiate fmip action to initiate survival/differentiation signaling." SIGNOR-126568 PRKCA protein P17252 UNIPROT THOC5 protein Q13769 UNIPROT up-regulates phosphorylation Ser6 sKKRKPKV 9606 BTO:0000801;BTO:0000876 15221008 t llicata "We conclude m-csf-mediated activation of pkcalpha can potentiate fmip action to initiate survival/differentiation signaling." SIGNOR-126572 PRKCA protein P17252 UNIPROT PRKG1 protein Q13976 UNIPROT up-regulates phosphorylation Thr59 THIGPRTtRAQGISA 9606 12609995 t gcesareni "Antibodies generated against phosphorylated threonine 58 were used to demonstrate phosphorylation in response to pma treatment of the cells with kinetics similar to vasodilator-stimulated phosphoprotein phosphorylation. A phospho-mimetic mutation at this site (t58e) generated a partially activated pkg that was more sensitive to cgmp levels. A phospho- mutation (t58a) revealed that this residue is important but not sufficient for pkg activation by pkc." SIGNOR-98803 PRKCA protein P17252 UNIPROT FLNC protein Q14315 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser2236 ERLGSFGsITRQQEG 10090 BTO:0000165 32444788 t miannu "We identified the extended basophilic phosphosite motif RxRxxp[S/T]xxp[S/T] in various proteins including filamin-C (FLNc). Importantly, this extended motif, located in a unique insert in Ig-like domain 20 of FLNc, is doubly phosphorylated. The protein kinases responsible for this dual-site phosphorylation are Akt and PKCα. Proximity proteomics and interaction analysis identified filamin A-interacting protein 1 (FILIP1) as direct FLNc binding partner. FILIP1 binding induces filamin degradation, thereby negatively regulating its function. Here, dual-site phosphorylation of FLNc not only reduces FILIP1 binding, providing a mechanism to shield FLNc from FILIP1-mediated degradation, but also enables fast dynamics of FLNc necessary for its function as signaling adaptor in cross-striated muscle cells. In vitro kinase assays combined with LC-MS confirmed hFLNc-S2233 as a substrate of Akt, whereas PKCα preferentially targeted S2236." SIGNOR-262617 PRKCA protein P17252 UNIPROT PDE3A protein Q14432 UNIPROT up-regulates phosphorylation Ser438 PGLLRRVsSTWTTTT 9606 19261611 t llicata "Protein kinase c-mediated phosphorylation and activation of pde3a regulate camp levels in human platelets. together, these results demonstrate that platelet activation stimulates pkc-dependent phosphorylation of pde3a on ser(312), ser(428), ser(438), ser(465), and ser(492) leading to a subsequent increase in camp hydrolysis and 14-3-3 binding." SIGNOR-184456 PRKCA protein P17252 UNIPROT PDE3A protein Q14432 UNIPROT up-regulates phosphorylation Ser465 VRRDRSTsIKLQEAP 9606 19261611 t llicata "Protein kinase c-mediated phosphorylation and activation of pde3a regulate camp levels in human platelets. together, these results demonstrate that platelet activation stimulates pkc-dependent phosphorylation of pde3a on ser(312), ser(428), ser(438), ser(465), and ser(492) leading to a subsequent increase in camp hydrolysis and 14-3-3 binding." SIGNOR-184460 PRKACA protein P17612 UNIPROT SRC protein P12931 UNIPROT "up-regulates activity" phosphorylation Ser17 DASQRRRsLEPAENV 9606 11804588 t gcesareni "PKA activated Src both in vitro and in vivo by phosphorylating Src on serine 17 within its amino terminus" SIGNOR-247988 PRKCA protein P17252 UNIPROT PDE3A protein Q14432 UNIPROT up-regulates phosphorylation Ser492 MTLTKSRsFTSSYAI 9606 19261611 t llicata "Protein kinase c-mediated phosphorylation and activation of pde3a regulate camp levels in human platelets. together, these results demonstrate that platelet activation stimulates pkc-dependent phosphorylation of pde3a on ser(312), ser(428), ser(438), ser(465), and ser(492) leading to a subsequent increase in camp hydrolysis and 14-3-3 binding." SIGNOR-184464 PRKCA protein P17252 UNIPROT HES1 protein Q14469 UNIPROT "down-regulates activity" phosphorylation Ser37 TASEHRKsSKPIMEK -1 9389649 t lperfetto "Endogenous HES-1 DNA-binding activity is post-translationally inhibited during NGF signaling in vivo, and phosphorylation of PKC consensus sites in the HES-1 DNA-binding domain inhibits DNA binding by purified HES-1 in vitro." SIGNOR-248992 PRKCA protein P17252 UNIPROT HES1 protein Q14469 UNIPROT "down-regulates activity" phosphorylation Ser38 ASEHRKSsKPIMEKR -1 9389649 t lperfetto "Endogenous HES-1 DNA-binding activity is post-translationally inhibited during NGF signaling in vivo, and phosphorylation of PKC consensus sites in the HES-1 DNA-binding domain inhibits DNA binding by purified HES-1 in vitro." SIGNOR-248993 PRKCA protein P17252 UNIPROT PEA15 protein Q15121 UNIPROT down-regulates phosphorylation Ser104 TKLTRIPsAKKYKDI 9606 BTO:0000149 15917297 t miannu "Pea-15 is phosphorylated on two ser residues, ser104 and ser116. Protein kinase c (pkc) phosphorylates ser104 / we report that phosphorylation of pea-15 blocks its interaction with erk1/2 in vitro and in vivo and that phosphorylation of both ser104 and ser116 is required for this effect." SIGNOR-137841 PRKCA protein P17252 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Ser738 ARIIGEKsFRRSVVG 9606 10197446 t llicata "These results provide direct evidence that pkd becomes activated in vivo as a consequence of pkc-mediated phosphorylation of serines 744 and 748." SIGNOR-66666 PRKCA protein P17252 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Ser742 GEKSFRRsVVGTPAY 9606 10197446 t llicata "These results provide direct evidence that pkd becomes activated in vivo as a consequence of pkc-mediated phosphorylation of serines 744 and 748." SIGNOR-66670 PRKCA protein P17252 UNIPROT RALBP1 protein Q15311 UNIPROT "up-regulates activity" phosphorylation Thr297 ACGRTTEtEKVQEFQ -1 16087181 t miannu "In deletion mutant analyses of potential phosphorylation sites in RLIP76, we identified T297 and S509 as targets for phosphorylation by PKCalpha. Phosphorylation at T297 increased doxorubicin (DOX)-transport activity approximately 2-fold for RLIP76 purified from recombinant source" SIGNOR-263164 PRKCA protein P17252 UNIPROT NFE2L2 protein Q16236 UNIPROT up-regulates phosphorylation Ser40 SREVFDFsQRRKEYE 9606 12198130 t miannu "Phosphorylation of nrf2 at ser-40 by protein kinase c regulates antioxidant response element-mediated transcription / recently we reported evidence for the involvement of protein kinase c (pkc) in phosphorylating nrf2 and triggering its nuclear translocation in response to oxidative stress" SIGNOR-91826 PRKCA protein P17252 UNIPROT MEP1B protein Q16820 UNIPROT "down-regulates quantity" phosphorylation Ser687 KKYRERMsSNRPNLT 9534 BTO:0001538 12941954 t miannu "These findings suggest that activation of a protein kinase, presumably PKC, mediates PMA-induced hmeprinβ shedding. By labeling COS-1 cells transfected with mutant constructs lacking the potential phosphorylation sites, we identified Ser687 as the main 32P-acceptor. These data provide evidence that the cytoplasmic domain of hmeprinβ can function as a PKC substrate." SIGNOR-263172 PRKCA protein P17252 UNIPROT HABP4 protein Q5JVS0 UNIPROT "down-regulates activity" phosphorylation Thr354 RKPANDItSQLEINF 9606 BTO:0004974 14699138 t lperfetto "We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation" SIGNOR-249246 PRKCA protein P17252 UNIPROT HABP4 protein Q5JVS0 UNIPROT "down-regulates activity" phosphorylation Thr375 GRGARGGtRGGRGRI 9606 BTO:0004974 14699138 t lperfetto "We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation" SIGNOR-249252 PRKCA protein P17252 UNIPROT CSPG4 protein Q6UVK1 UNIPROT "up-regulates activity" phosphorylation Thr2252 YLRKRNKtGKHDVQV 9606 BTO:0002035 15504744 t miannu "Protein kinase C (PKC)-alpha phosphorylation of recombinant NG2 cytoplasmic domain and phorbol ester-induced PKC-dependent phosphorylation of full-length NG2 expressed in U251 cells are both blocked by mutation of Thr(2256), identifying this residue as a primary phosphorylation site. PKC-alpha-mediated NG2 phosphorylation at Thr(2256) is therefore a key step for initiating cell polarization and motility." SIGNOR-263162 PRKCA protein P17252 UNIPROT NOXA1 protein Q86UR1 UNIPROT down-regulates phosphorylation Ser172 DQVQRRGsLPPRQVP 9606 BTO:0000007 20110267 t llicata "Phosphorylation of nadph oxidase activator 1 (noxa1) on serine 282 by map kinases and on serine 172 by protein kinase c and protein kinase a prevents nox1 hyperactivation." SIGNOR-163667 PRKCA protein P17252 UNIPROT FERMT3 protein Q86UX7 UNIPROT "up-regulates activity" phosphorylation Ser484 LSLQRTGsGGPGNHP 9606 BTO:0000565 25609252 t miannu " PKC-induced phosphorylation events, as we have shown kindlin-3 to be a PKC phosphorylation target (Fig. 6C), are often followed by rapid activation of phosphatases (38). " SIGNOR-266415 PRKCA protein P17252 UNIPROT CD163 protein Q86VB7 UNIPROT unknown phosphorylation Ser1084 QRQRLAVsSRGENLV 9606 BTO:0000801 11298324 t lperfetto "Furthermore, we demonstrated that the cytoplasmic domains of CD163 variants are phosphorylated by PKC-alpha in vitro. Inhibition studies using specific kinase inhibitors reveal that both CKII and PKC are involved in the CD163 signaling mechanism resulting in the secretion of proinflammatory cytokines." SIGNOR-249082 PRKCA protein P17252 UNIPROT NOXO1 protein Q8NFA2 UNIPROT up-regulates phosphorylation Thr346 AIQSRCCtVTRRALE 9606 23957209 t llicata "Phosphorylation of thr341 allows noxo1 to sufficiently interact with noxa1, an interaction that participates in nox1 activation." SIGNOR-202482 PRKCA protein P17252 UNIPROT TRPM4 protein Q8TD43 UNIPROT up-regulates phosphorylation Ser1145 RDKRESDsERLKRTS 9606 15590641 t gcesareni "Phorbol ester-induced activation of protein kinase c (pkc) increased the ca(2+) sensitivity of wild-type trpm4 but not of two mutants mutated at putative pkc phosphorylation sites." SIGNOR-132243 PRKACA protein P17612 UNIPROT CREB1 protein P16220 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0000742 15568017 t 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 PRKCA protein P17252 UNIPROT TRPM4 protein Q8TD43 UNIPROT up-regulates phosphorylation Ser1152 SERLKRTsQKVDLAL 9606 15590641 t gcesareni "Phorbol ester-induced activation of protein kinase c (pkc) increased the ca(2+) sensitivity of wild-type trpm4 but not of two mutants mutated at putative pkc phosphorylation sites." SIGNOR-132247 PRKCA protein P17252 UNIPROT EGLN2 protein Q96KS0 UNIPROT down-regulates phosphorylation Ser234 QRAIPPRsIRGDQIA 9606 18710826 t tpavlidou "Thus, recombinant phd1 was examined for in vitro phosphorylation using protein kinase a, protein kinase calpha, casein kinase i and ii and erk2. The protein was most strongly phosphorylated by protein kinase calpha, and the phosphorylation sites were found to be ser-132, ser-226 and ser-234.Mutation Of ser-132 or ser-234 to asp or glu diminished the enzymatic activity to 25-60%, while mutation of ser-226 scarcely influenced the activity." SIGNOR-180203 PRKCA protein P17252 UNIPROT NOX5 protein Q96PH1 UNIPROT up-regulates phosphorylation Ser536 GRGSKRLsRSVTMRK 9606 24505490 t llicata "A constitutively active form of pkc? Robustly increased basal and pma-stimulated nox5 activity and promoted the phosphorylation of nox5 on ser490, thr494, and ser498." SIGNOR-204546 PRKCA protein P17252 UNIPROT NOX5 protein Q96PH1 UNIPROT up-regulates phosphorylation Ser544 RSVTMRKsQRSSKGS 9606 24505490 t llicata "A constitutively active form of pkc? Robustly increased basal and pma-stimulated nox5 activity and promoted the phosphorylation of nox5 on ser490, thr494, and ser498." SIGNOR-204550 PRKCA protein P17252 UNIPROT NOX5 protein Q96PH1 UNIPROT up-regulates phosphorylation Thr540 KRLSRSVtMRKSQRS 9606 24505490 t llicata "A constitutively active form of pkc? Robustly increased basal and pma-stimulated nox5 activity and promoted the phosphorylation of nox5 on ser490, thr494, and ser498." SIGNOR-204554 PRKCA protein P17252 UNIPROT NR1H4 protein Q96RI1 UNIPROT up-regulates phosphorylation Ser145 VVCGDRAsGYHYNAL 9606 18755856 t llicata "Phosphorylation of farnesoid x receptor by protein kinase c promotes its transcriptional activity. pkcalpha phosphorylates in vitro fxr in its dna-binding domain on s135 and s154." SIGNOR-180537 PRKCA protein P17252 UNIPROT NR1H4 protein Q96RI1 UNIPROT up-regulates phosphorylation Ser164 CKGFFRRsITKNAVY 9606 18755856 t llicata "Phosphorylation of farnesoid x receptor by protein kinase c promotes its transcriptional activity. pkcalpha phosphorylates in vitro fxr in its dna-binding domain on s135 and s154." SIGNOR-180541 PRKCA protein P17252 UNIPROT NKX3-1 protein Q99801 UNIPROT up-regulates phosphorylation Ser48 RQGGRTSsQRQRDPE 9606 BTO:0001130 11980664 t llicata "Phosphorylation of wild-type nkx3.1 decreased the apparent binding affinity of the protein for the consensus sequence by 3-fold relative to the nonphosphorylated protein (fig. 3) _ ." SIGNOR-86723 PRKCA protein P17252 UNIPROT CORO1B protein Q9BR76 UNIPROT down-regulates phosphorylation Ser2 sFRKVVRQ 9606 16027158 t lperfetto "We have identified serine 2 (ser-2) on coronin 1b as the major residue phosphorylated by pkc in vivo.In this work, we show that coronin 1b interacts in vivo with the arp2/3 complex and that this interaction is inhibited by pkc phosphorylation." SIGNOR-138733 PRKCA protein P17252 UNIPROT CDC42EP4 protein Q9H3Q1 UNIPROT "down-regulates activity" phosphorylation Ser18 SVHSKRRsRADLTAE 9606 BTO:0001939 25086031 t miannu "Cdc42 effector protein-4 (CEP4) was recently identified by our laboratory to be a substrate of multiple PKC isoforms in non-transformed MCF-10A human breast cells. MS/MS analysis verified that Ser(18) and Ser(80) were directly phosphorylated by PKCα in vitro. Phosphorylation of CEP4 severely diminished its affinity for Cdc42 while promoting Rac activation and formation of filopodia (microspikes)." SIGNOR-263160 PRKCA protein P17252 UNIPROT CDC42EP4 protein Q9H3Q1 UNIPROT "down-regulates activity" phosphorylation Ser80 SSKRSLLsRKFRGSK 9606 BTO:0001939 25086031 t miannu "Cdc42 effector protein-4 (CEP4) was recently identified by our laboratory to be a substrate of multiple PKC isoforms in non-transformed MCF-10A human breast cells. MS/MS analysis verified that Ser(18) and Ser(80) were directly phosphorylated by PKCα in vitro. Phosphorylation of CEP4 severely diminished its affinity for Cdc42 while promoting Rac activation and formation of filopodia (microspikes)." SIGNOR-263161 PRKCA protein P17252 UNIPROT TRPV4 protein Q9HBA0 UNIPROT "up-regulates activity" phosphorylation Ser162 FDIVSRGsTADLDGL 9606 19661060 t Manara "We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4." SIGNOR-260886 PRKCA protein P17252 UNIPROT TRPV4 protein Q9HBA0 UNIPROT "up-regulates activity" phosphorylation Ser189 DEEFREPsTGKTCLP 9606 19661060 t Manara "We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4." SIGNOR-260884 PRKCA protein P17252 UNIPROT TRPV4 protein Q9HBA0 UNIPROT "up-regulates activity" phosphorylation Thr175 GLLPFLLtHKKRLTD 9606 19661060 t Manara "We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4." SIGNOR-260882 PRKCA protein P17252 UNIPROT PLCB1 protein Q9NQ66 UNIPROT unknown phosphorylation Ser887 HSQPAPGsVKAPAKT 10090 BTO:0005065 11278470 t lperfetto ". Two-dimensional phosphopeptide mapping and site-directed mutagenesis demonstrated that PKC promoted phosphorylation of PLC beta1 at serine 887 in the nucleus of IGF-I-treated cells. Overexpression of either a PLC beta1 mutant in which the PKC phosphorylation site Ser(887) was replaced by alanine, or a dominant-negative PKC alpha, resulted in a sustained activation of nuclear PLC following IGF-I stimulation." SIGNOR-249081 PRKCA protein P17252 UNIPROT TRPV5 protein Q9NQA5 UNIPROT "up-regulates activity" phosphorylation Ser299 FLELVVSsDKREARQ 9606 17006539 t gcesareni "A cell permeable analog of DAG increased TRPV5 activity within 30 min via protein kinase C activation of the channel since mutation of TRPV5 at the putative PKC phosphorylation sites S299 and S654 prevented the stimulatory effect of TK." SIGNOR-149948 PRKCA protein P17252 UNIPROT TRPV5 protein Q9NQA5 UNIPROT "up-regulates activity" phosphorylation Ser654 YVEVFKNsDKEDDQE 9606 17006539 t gcesareni "A cell permeable analog of DAG increased TRPV5 activity within 30 min via protein kinase C activation of the channel since mutation of TRPV5 at the putative PKC phosphorylation sites S299 and S654 prevented the stimulatory effect of TK." SIGNOR-149952 PRKCA protein P17252 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT unknown phosphorylation Ser473 PPSGTKKsKRGRGRP 9606 12529391 t llicata "Pkc-mediated phosphorylation at s486 does not affect s6k activity but eliminates the function of its nuclear localization signal and causes retention of an activated form of the kinase in the cytoplasm." SIGNOR-97279 PRKACA protein P17612 UNIPROT CREB1 protein P16220 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0001103 21902831 t 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 PRKCA protein P17252 UNIPROT ADD3 protein Q9UEY8 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser693 KKKFRTPsFLKKNKK -1 11895774 t lperfetto "Results of in vitro experiments with recombinant alpha adducin demonstrated that PKC-phosphorylated adducin was proteolyzed by calpain more quickly than unphosphorylated adducin. | Phosphorylation of adducin by PKC may be a common mechanism for regulating adducin proteolysis by several proteases. | The antibody used in panel B is specific for the PKC-phosphorylated form of adducin. This antibody was raised against the phosphopeptide CKKFRTP[pS]FLKKNK, corresponding to amino acids 656-668 of human gamma adducin" SIGNOR-249143 PRKCA protein P17252 UNIPROT HSPB8 protein Q9UJY1 UNIPROT up-regulates phosphorylation Ser14 PFSCHYPsRLRRDPF 9606 22721717 t lperfetto "Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation" SIGNOR-197940 PRKCA protein P17252 UNIPROT HSPB8 protein Q9UJY1 UNIPROT up-regulates phosphorylation Thr63 LSSAWPGtLRSGMVP 9606 22721717 t lperfetto "Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation" SIGNOR-197949 PRKCA protein P17252 UNIPROT HSPB8 protein Q9UJY1 UNIPROT "up-regulates activity" phosphorylation Ser14 PFSCHYPsRLRRDPF 9606 BTO:0000887 11342557 t lperfetto "Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation" SIGNOR-107684 PRKCA protein P17252 UNIPROT HSPB8 protein Q9UJY1 UNIPROT "up-regulates activity" phosphorylation Thr63 LSSAWPGtLRSGMVP 9606 BTO:0000887 11342557 t lperfetto "Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation" SIGNOR-107688 PRKCA protein P17252 UNIPROT PA2G4 protein Q9UQ80 UNIPROT unknown phosphorylation Thr366 QSSASRKtQKKKKKK 9606 BTO:0004737 11325528 t lperfetto "We found that Ebp1 was basally phosphorylated in AU565 breast cancer cells on serine/threonine residues and that this phosphorylation was enhanced by heregulin treatment. Both serine and threonine residues of a GST-Ebp1 fusion protein were phosphorylated by PKC in vitro. In vivo, we demonstrated that basal Ebp1 phosphorylation was dependent upon PKC." SIGNOR-249092 PRKCA protein P17252 UNIPROT HDAC5 protein Q9UQL6 UNIPROT "down-regulates activity" phosphorylation Ser259 FPLRKTAsEPNLKVR 10116 BTO:0002320 15367659 t lperfetto "We also demonstrate that protein kinase D (PKD), a downstream effector of PKC, directly phosphorylates HDAC5 and stimulates its nuclear export. | Finally, we assessed the ability of PKD to phosphorylate HDAC5 in cells by employing an antibody that specifically recognizes HDAC5 that has been phosphorylated at serine 259. HDAC5 was basally phosphorylated at serine 259, and phosphorylation at this site was dramatically increased by coexpression of constitutively active PKD S/E" SIGNOR-249268 PRKCA protein P17252 UNIPROT HDAC5 protein Q9UQL6 UNIPROT "down-regulates activity" phosphorylation Ser498 RPLSRTQsSPLPQSP 10116 BTO:0002320 15367659 t lperfetto "We also demonstrate that protein kinase D (PKD), a downstream effector of PKC, directly phosphorylates HDAC5 and stimulates its nuclear export. | Finally, we assessed the ability of PKD to phosphorylate HDAC5 in cells by employing an antibody that specifically recognizes HDAC5 that has been phosphorylated at serine 259. HDAC5 was basally phosphorylated at serine 259, and phosphorylation at this site was dramatically increased by coexpression of constitutively active PKD S/E" SIGNOR-249269 PRKCA protein P17252 UNIPROT F11R protein Q9Y624 UNIPROT unknown phosphorylation Ser284 KVIYSQPsARSEGEF 9606 BTO:0000130;BTO:0000876 11027562 t gcesareni "We also demonstrated phosphorylation of ser 284, a putative pkc phosphorylation site, by immunoblotting with anti-phosphoserine-jam antibody in thrombin-stimulated platelets." SIGNOR-83037 PRKCA protein P17252 UNIPROT F11R protein Q9Y624 UNIPROT unknown phosphorylation Thr92 DRVTFLPtGITFKSV -1 7646439 t lperfetto "Internal amino acid sequence analysis of the F11 antigen provided information concerning 68 amino acids and suggested two consensus phosphorylation sites for protein kinase C (PKC). The phosphorylation by PKC of the isolated F11 antigen was observed following stimulation by phorbol 12-myristate 13-acetate." SIGNOR-248901 JUNB protein P17275 UNIPROT IL4 protein P05112 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 21799768 f "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 JUNB protein P17275 UNIPROT LORICRIN protein P23490 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000667 12200429 f miannu "Loricrin expression is suppressed by Jun B, Sp3, and KSR-1 proteins." SIGNOR-254535 HOXB8 protein P17481 UNIPROT PBX1 protein P40424 UNIPROT "up-regulates activity" binding 9606 BTO:0001545 11571641 t miannu "the ability of HoxB8 to heterodimerizes with endogenous Pbx proteins on DNA alters gene transcription in a manner that prevents progression through an intrinsic genetic differentiation program. In conjunction with Pbx, HoxB8 could alter transcription of Pbx target genes by direct or indirect mechanisms." SIGNOR-223153 HOXB8 protein P17481 UNIPROT PBX3 protein P40426 UNIPROT "up-regulates activity" binding 9606 BTO:0001545 11571641 t miannu "the ability of HoxB8 to heterodimerizes with endogenous Pbx proteins on DNA alters gene transcription in a manner that prevents progression through an intrinsic genetic differentiation program. In conjunction with Pbx, HoxB8 could alter transcription of Pbx target genes by direct or indirect mechanisms." SIGNOR-223149 HOXB8 protein P17481 UNIPROT ACTA2 protein P62736 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10116 BTO:0002196 15886193 t Luana "Results from these experiments demonstrated that in 10T1/2 cells Hoxa10-1 increased the activity of the telokin promoter 3-fold without affecting the activity of the other promoters analyzed (Fig. 2A). Similar results were also observed in A10 SMC (data not shown). In contrast, Hoxb8 significantly repressed the activity of the telokin, smooth muscle α-actin, and SM22α promoters by 70, 50, and 70%, respectively" SIGNOR-261641 HOXB8 protein P17481 UNIPROT TAGLN protein Q01995 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10116 BTO:0002196 15886193 t Luana "Results from these experiments demonstrated that in 10T1/2 cells Hoxa10-1 increased the activity of the telokin promoter 3-fold without affecting the activity of the other promoters analyzed (Fig. 2A). Similar results were also observed in A10 SMC (data not shown). In contrast, Hoxb8 significantly repressed the activity of the telokin, smooth muscle α-actin, and SM22α promoters by 70, 50, and 70%, respectively" SIGNOR-261642 HOXB8 protein P17481 UNIPROT MYLK protein Q15746 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10116 BTO:0002196 15886193 t Luana "Results from these experiments demonstrated that in 10T1/2 cells Hoxa10-1 increased the activity of the telokin promoter 3-fold without affecting the activity of the other promoters analyzed (Fig. 2A). Similar results were also observed in A10 SMC (data not shown). In contrast, Hoxb8 significantly repressed the activity of the telokin, smooth muscle α-actin, and SM22α promoters by 70, 50, and 70%, respectively" SIGNOR-261640 HOXB6 protein P17509 UNIPROT HBG1 protein P69891 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000664 15269212 t Luana "HOXB6 protein represses globin transcript levels in stably transfected K562 cells in a DNA-binding dependent fashion." SIGNOR-261638 HOXB6 protein P17509 UNIPROT HBA1 protein P69905 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000664 15269212 t Luana "HOXB6 protein represses globin transcript levels in stably transfected K562 cells in a DNA-binding dependent fashion." SIGNOR-261637 TAL1 protein P17542 UNIPROT ANGPT2 protein O15123 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000574 22792348 f miannu "Here, we identified angiopoietin-2 (ang-2), which encodes a major regulator of angiogenesis, as a direct transcriptional target of tal1,lyl1and lmo2. Knockdown of any of the three transcription factors in human blood and lymphatic endothelial cells caused ang-2 mrna and protein down-regulation." SIGNOR-198279 TAL1 protein P17542 UNIPROT ERG protein P11308 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001106 21536859 f miannu "We further demonstrate that ERG expression in primary human T-ALL cells is mediated by the binding of other T-cell oncogenes SCL/TAL1, LMO2, and LYL1 in concert with ERG, FLI1, and GATA3 to the ERG +85 enhancer." SIGNOR-253924 TAL1 protein P17542 UNIPROT MEF2C protein Q06413 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000661 21261500 f miannu "TAL1 and LYL1 are two leukemic members of the bHLH family of transcription factors. TAL1 and LYL1 activate expression of MEF2C" SIGNOR-254209 TAL1 protein P17542 UNIPROT FUBP1 protein Q96AE4 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 30653565 t irozzo "TAL1 directly activates the FUBP1 promoter, leading to increased FUBP1 expression during erythroid differentiation." SIGNOR-259131 NDUFB7 protein P17568 UNIPROT "Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND5-module corresponds to the distal part of the membrane arm and it is composed of MT-ND5, NDUFB2, NDUFB3, NDUFB7, NDUFB8, NDUFB9 and NDUFAB1" SIGNOR-262170 PRKACA protein P17612 UNIPROT FXYD1 protein O00168 UNIPROT unknown phosphorylation Ser88 RSSIRRLsTRRR 9606 21220422 t llicata "We conclude that phosphorylation of plm increases its oligomerization into tetramers, decreases its binding to nka, and alters the structures of both the tetramer and nka regulatory complex." SIGNOR-171188 PRKACA protein P17612 UNIPROT FXYD1 protein O00168 UNIPROT "up-regulates activity" phosphorylation Ser83 EEGTFRSsIRRLSTR -1 15621037 t miannu "PKA-dependent, alpha 1-specific NKA activation may be mediated through phosphorylation of the accessory protein PLM, rather than direct alpha1 subunit phosphorylation. we propose that phosphorylation of the small accessory protein phospholemman (PLM) by PKA at serine 68 is responsible for the observed isoform-specific activation of NKA." SIGNOR-263117 PRKACA protein P17612 UNIPROT EEF2K protein O00418 UNIPROT "up-regulates activity" phosphorylation Ser366 SPQVRTLsGSRPPLL -1 11171059 t miannu "EEF-2K can be phosphorylated in vitro by cAMP-dependent protein kinase (PKA) and that this induces significant Ca(2+)/calmodulin (CaM)-independent eEF-2K activity. sites of phosphorylation were Ser-365 and Ser-499" SIGNOR-250354 PRKACA protein P17612 UNIPROT EEF2K protein O00418 UNIPROT "up-regulates activity" phosphorylation Ser500 RLHLPRAsAVALEVQ -1 11171059 t miannu "EEF-2K can be phosphorylated in vitro by cAMP-dependent protein kinase (PKA) and that this induces significant Ca(2+)/calmodulin (CaM)-independent eEF-2K activity. sites of phosphorylation were Ser-365 and Ser-499" SIGNOR-250444 PRKACA protein P17612 UNIPROT HSPB6 protein O14558 UNIPROT down-regulates phosphorylation Ser16 PSWLRRAsAPLPGLS 9606 BTO:0000887;BTO:0001260 10196226 t llicata "Hosphorylation of hsp20 at ser16 is not only associated with cyclic nucleotide-dependent vasorelaxation but also inhibits agonist-induced contractile responses." SIGNOR-66493 PRKACA protein P17612 UNIPROT KCNK3 protein O14649 UNIPROT "up-regulates activity" phosphorylation Ser393 GLMKRRSsV 9606 21357689 t lperfetto "Mutation of the ser393 to alanine, which can neither be phosphorylated nor mimic a phosphorylated residue, resulted in the channel failing to pass current all of our findings support the conclusion that camp-dependent protein kinase is responsible for the phosphorylation of the terminal serine in both k2p3.1 and k2p9.1." SIGNOR-172430 PRKACA protein P17612 UNIPROT PHOX2A protein O14813 UNIPROT down-regulates phosphorylation Ser153 RKQERAAsAKGAAGA 9606 BTO:0000938 19564421 t llicata "Phox2a becomes phosphorylated by protein kinase a (pka) on ser153, which prevents association of phox2a with dna and terminates p27(kip1) transcription." SIGNOR-186462 PRKACA protein P17612 UNIPROT AURKA protein O14965 UNIPROT "up-regulates activity" phosphorylation Thr288 APSSRRTtLCGTLDY -1 11039908 t miannu "Aurora2 is regulated by phosphorylation. phosphorylation occurs on a conserved residue, Threonine 288, within the activation loop of the catalytic domain of the kinase and results in a significant increase in the enzymatic activity. Threonine 288 resides within a consensus motif for the cAMP dependent kinase and can be phosphorylated by PKA in vitro." SIGNOR-250337 PRKACA protein P17612 UNIPROT CLDN3 protein O15551 UNIPROT unknown phosphorylation Thr192 PPREKKYtATKVVYS 9606 BTO:0001023 15905176 t llicata "Our results suggest that claudin-3 phosphorylation by pka, a kinase frequently activated in ovarian cancer, may provide a mechanism for the disruption of tjs in this cancer." SIGNOR-137291 PRKACA protein P17612 UNIPROT RGS14 protein O43566 UNIPROT "up-regulates activity" phosphorylation Ser260 NAALRREsQGSLNSS -1 12534294 t miannu "RGS14 is phosphorylated in vitro at Ser258 and Thr494 by PKA. cAMP-induced phosphorylation as an important modulator of RGS14 function since phosphorylation could enhance RGS14 binding to Galpha(i)-GDP" SIGNOR-250045 PRKACA protein P17612 UNIPROT PPARG protein P37231 UNIPROT "up-regulates activity" 10090 BTO:0000011 20638365 f "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 PRKACA protein P17612 UNIPROT RGS14 protein O43566 UNIPROT "up-regulates activity" phosphorylation Thr495 SATGKRQtCDIEGLV -1 12534294 t miannu "RGS14 is phosphorylated in vitro at Ser258 and Thr494 by PKA. cAMP-induced phosphorylation as an important modulator of RGS14 function since phosphorylation could enhance RGS14 binding to Galpha(i)-GDP" SIGNOR-250046 PRKACA protein P17612 UNIPROT RGS10 protein O43665 UNIPROT "down-regulates activity" phosphorylation Ser176 QTAAKRAsRIYNT 9606 BTO:0000007 11443111 t lperfetto "We report in this study the acute functional regulation of rgs10 thru the specific and inducible phosphorylation of rgs10 protein at serine 168 by camp-dependent kinase a. This phosphorylation nullifies the rgs10 activity at the plasma membrane, which controls the g protein-dependent activation of the inwardly rectifying potassium channel." SIGNOR-109173 PRKACA protein P17612 UNIPROT PLIN1 protein O60240 UNIPROT "down-regulates activity" phosphorylation Ser220 KAKPSLLsRVGALTN 10090 11751901 t miannu "PKA increased lipolysis in cells expressing Peri A because it abrogated the inhibitory actions of Peri A on lipolysis.‚  amino-terminal PKA sites (Ser-81, Ser-222, and Ser-276)" SIGNOR-250028 PRKACA protein P17612 UNIPROT PLIN1 protein O60240 UNIPROT "down-regulates activity" phosphorylation Ser277 QAVSRRRsEVRVPWL 10090 11751901 t miannu "PKA increased lipolysis in cells expressing Peri A because it abrogated the inhibitory actions of Peri A on lipolysis.‚  amino-terminal PKA sites (Ser-81, Ser-222, and Ser-276)" SIGNOR-250029 PRKACA protein P17612 UNIPROT PLIN1 protein O60240 UNIPROT "down-regulates activity" phosphorylation Ser81 EPVVRRLsTQFTAAN 10090 BTO:0000944 11751901 t miannu "PKA increased lipolysis in cells expressing Peri A because it abrogated the inhibitory actions of Peri A on lipolysis.  amino-terminal PKA sites (Ser-81, Ser-222, and Ser-276)" SIGNOR-250492 PRKACA protein P17612 UNIPROT CTNND1 protein O60716 UNIPROT down-regulates phosphorylation Ser879 LIDRNQKsDKKPDRE 9606 BTO:0000763 22798526 t lperfetto "We showed that pkc_ phosphorylation of p120 at serine (s)879 in response to thrombin or lipopolysaccharide challenge reduced p120 binding affinity for ve-cadherin and mediated aj disassembly secondary to ve-cadherin internalization" SIGNOR-198288 PRKACA protein P17612 UNIPROT PFKFB2 protein O60825 UNIPROT "up-regulates activity" phosphorylation Ser466 PVRMRRNsFTPLSSS -1 12853467 t miannu "PFK-2 that was phosphorylated on Ser466, but not Ser483, by PKA did not bind to 14-3-3s‚ " SIGNOR-250025 PRKACA protein P17612 UNIPROT LRP6 protein O75581 UNIPROT "up-regulates activity" phosphorylation 10116 BTO:0001593 18981475 t gcesareni "These results suggest that camppka activation is involved in activation of lrp6(...) our results demonstrate that lrp6 can be directly phosphorylated by pka catalytic subunit." SIGNOR-181979 PRKACA protein P17612 UNIPROT GABBR2 protein O75899 UNIPROT "down-regulates activity" phosphorylation Ser893 EHIQRRLsLQLPILH 9534 BTO:0001538 11976702 t miannu "Here we show that the functional coupling of GABA(B)R1/GABA(B)R2 receptors to inwardly rectifying K(+) channels rapidly desensitizes. This effect is alleviated after direct phosphorylation of a single serine residue (Ser892) in the cytoplasmic tail of GABA(B)R2 by cyclic AMP (cAMP)-dependent protein kinase (PKA)." SIGNOR-263150 PRKACA protein P17612 UNIPROT ABCA1 protein O95477 UNIPROT "up-regulates activity" phosphorylation Ser1042 GGMQRKLsVALAFVG 10090 BTO:0000801 12196520 t miannu "Ser-1042 and Ser-2054, located in the nucleotide binding domains of ABCA1, are major phosphorylation sites for PKA. ABCA1 phosphorylation may affect ApoA-I-dependent phospholipid efflux by either altering the conformation of the protein to a more active state or by affecting the interaction between ABCA1 and its partner proteins." SIGNOR-250326 PRKACA protein P17612 UNIPROT ABCA1 protein O95477 UNIPROT "up-regulates activity" phosphorylation Ser2054 GGNKRKLsTAMALIG 10090 BTO:0000801 12196520 t miannu "Ser-1042 and Ser-2054, located in the nucleotide binding domains of ABCA1, are major phosphorylation sites for PKA. ABCA1 phosphorylation may affect ApoA-I-dependent phospholipid efflux by either altering the conformation of the protein to a more active state or by affecting the interaction between ABCA1 and its partner proteins." SIGNOR-250327 PRKACA protein P17612 UNIPROT NFATC1 protein O95644 UNIPROT down-regulates phosphorylation Ser245 PSTSPRAsVTEESWL 9606 12351631 t lperfetto "Here we show that overexpression of pka causes phosphorylation and cytoplasmic accumulation of nf-atc1 in direct opposition to calcineurin by phosphorylating ser-245, ser-269, and ser-294 in the conserved serine-proline repeat domainwe further show that a complete block of nf-atc1 nuclear localization by pka requires a second kinase activity that can be supplied by glycogen synthase kinase-3 (gsk-3)" SIGNOR-93531 PRKACA protein P17612 UNIPROT HAND1 protein O96004 UNIPROT "down-regulates activity" phosphorylation Ser109 KERRRTEsINSAFAE 10116 BTO:0001556 14636580 t miannu "In vitro and in vivo phosphorylation studies show that both PKA and PKC can phosphorylate HAND1 and -2. T107; S109 within helix I and S98 within the basic domain, are the phosphorylated residues. We determined that modification of HAND1 at residues 107 and 109 affects dimerization affinities with E-proteins, thus changing the bHLH dimer equilibrium within the cell. These modifications also affect HAND1 function." SIGNOR-249989 PRKACA protein P17612 UNIPROT HAND1 protein O96004 UNIPROT "down-regulates activity" phosphorylation Thr107 PKKERRRtESINSAF 10116 BTO:0001556 14636580 t miannu "In vitro and in vivo phosphorylation studies show that both PKA and PKC can phosphorylate HAND1 and -2. T107; S109 within helix I and S98 within the basic domain, are the phosphorylated residues. We determined that modification of HAND1 at residues 107 and 109 affects dimerization affinities with E-proteins, thus changing the bHLH dimer equilibrium within the cell. These modifications also affect HAND1 function." SIGNOR-249991 PRKACA protein P17612 UNIPROT HAND1 protein O96004 UNIPROT unknown phosphorylation Ser98 RLGRRKGsGPKKERR 10116 BTO:0001556 14636580 t miannu "In vitro and in vivo phosphorylation studies show that both PKA and PKC can phosphorylate HAND1 and -2. T107; S109 within helix I and S98 within the basic domain, are the phosphorylated residues. We determined that modification of HAND1 at residues 107 and 109 affects dimerization affinities with E-proteins, thus changing the bHLH dimer equilibrium within the cell. These modifications also affect HAND1 function." SIGNOR-249990 PRKACA protein P17612 UNIPROT FOS protein P01100 UNIPROT "up-regulates activity" phosphorylation Ser362 AAAHRKGsSSNEPSS 9534 1545828 t miannu "Human c-Fos protein is phosphorylated in vitro by PKA. phosphorylation of Fos occurs at serine residue 362. Modification of the Fos protein by phosphorylation with PKA then allows it to act as a regulator of its own synthesis by downregulating fos gene expression at a transcriptional level" SIGNOR-250356 PRKACA protein P17612 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser141 MASQKRPsQRHGSKY -1 2413024 t miannu "Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-161" SIGNOR-250010 PRKACA protein P17612 UNIPROT NOLC1 protein Q14978 UNIPROT "up-regulates activity" phosphorylation Ser622 KKGEKRAsSPFRRVR -1 12167624 t miannu "PKA-dependent Nopp140 phosphorylation is important for its role in agp gene activation. both Ser627 and Ser628 are phosphorylated by PKA." SIGNOR-250019 PRKACA protein P17612 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser146 RPSQRHGsKYLATAS -1 2413024 t miannu "Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-161" SIGNOR-250011 PRKACA protein P17612 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser190 RGAPKRGsGKDSHHP -1 2413024 t miannu "Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-162" SIGNOR-250012 PRKACA protein P17612 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser266 FGYGGRAsDYKSAHK -1 2413024 t miannu "Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-163" SIGNOR-250013 PRKACA protein P17612 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser295 FKLGGRDsRSGSPMA -1 2413024 t miannu "Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-164" SIGNOR-250014 PRKACA protein P17612 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Thr169 FLPRHRDtGILDSIG -1 2413024 t miannu "Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-165" SIGNOR-250015 PRKACA protein P17612 UNIPROT RAF1 protein P04049 UNIPROT "down-regulates activity" phosphorylation Ser259 SQRQRSTsTPNVHMV 9534 BTO:0004055 12801936 t miannu "Protein kinase A blocks Raf-1 activity by stimulating 14-3-3 binding and blocking Raf-1 interaction with Ras. Cyclic AMP (cAMP) blocks Raf-1 activation by stimulating its phosphorylation on serine 43 (Ser43), serine 233 (Ser233), and serine 259 (Ser259)." SIGNOR-250041 PRKACA protein P17612 UNIPROT RAF1 protein P04049 UNIPROT "down-regulates activity" phosphorylation Ser43 FGYQRRAsDDGKLTD 9534 BTO:0004055 12801936 t miannu "Protein kinase A blocks Raf-1 activity by stimulating 14-3-3 binding and blocking Raf-1 interaction with Ras. Cyclic AMP (cAMP) blocks Raf-1 activation by stimulating its phosphorylation on serine 43 (Ser43), serine 233 (Ser233), and serine 259 (Ser259)." SIGNOR-250039 PRKACA protein P17612 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser621 PKINRSAsEPSLHRA 9606 11971957 t gcesareni "We have mapped all camp-induced phosphorylation sites in raf-1, showing that serines 43, 259, and 621 are phosphorylated by pka in vitro and induced by camp in vivo" SIGNOR-86137 PRKACA protein P17612 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates phosphorylation Thr686 QQKIRKYtMRRLLQE 9606 18799465 t lperfetto "Pka directly phosphorylated erbb2 on thr-686, a highly conserved intracellular regulatory site that was required for the pka-mediated synergistic enhancement of neuregulin-induced erbb2-erbb3 activation and proliferation in scs." SIGNOR-181191 PRKACA protein P17612 UNIPROT NEFL protein P07196 UNIPROT "down-regulates activity" phosphorylation 9606 8019002 t miannu "Phosphorylation of neurofilament-L protein (NF-L) by the catalytic subunit of cAMP-dependent protein kinase (A-kinase) inhibits the reassembly of NF-L and disassembles filamentous NF-L." SIGNOR-252401 PRKACA protein P17612 UNIPROT RET protein P07949 UNIPROT down-regulates phosphorylation Ser696 SSGARRPsLDSMENQ 9606 BTO:0000938 20682772 t llicata "Furthermore, we find that activation of protein kinase a (pka) by forskolin reduces the recruitment of shp2 to ret and negatively affects ligand-mediated neurite outgrowth. In agreement with this, mutation of ser(696), a known pka phosphorylation site in ret, enhances shp2 binding to the receptor and eliminates the effect of forskolin on ligand-induced outgrowth." SIGNOR-167349 PRKACA protein P17612 UNIPROT GJB1 protein P08034 UNIPROT unknown phosphorylation Ser233 NPPSRKGsGFGHRLS -1 8390988 t miannu "connexin- 32 is proteolyzed by pcalpain and mcalpain. phosphorylation of connexin-32 by protein kinase C, but not by protein kinase A, efficiently prevents its proteolysis by both calpain isoforms. major phosphorylation sites: Ser233(for protein kinase A). Phosphorylation of connexin-32 by protein kinase C,but not by protein kinase A, prevents the proteolytic attack of p-calpain and m-calpain. Phosphorylation of connexin-32 by protein kinase A and protein kinase C does not prevent its proteolysis by papain, a-chymotrypsin, proteinase K, and trypsin" SIGNOR-249715 PRKACA protein P17612 UNIPROT GLI1 protein P08151 UNIPROT down-regulates phosphorylation 16293631 t "We report that activation of PKA retains Gli1 in the cytoplasm. Conversely, inhibition of PKA activity promotes nuclear accumulation of Gli1.We provide direct evidence to support that the cAMP/PKA signaling axis regulates Gli1 protein localization primarily through a site at Thr374. .These data suggest that Thr374 is an important PKA site responsible for PKA phosphorylation and for the transcriptional activity of Gli1." SIGNOR-253539 PRKACA protein P17612 UNIPROT VIM protein P08670 UNIPROT "down-regulates activity" phosphorylation Ser25 PGTASRPsSSRSYVT -1 2500966 t miannu "Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. Domain- and sequence-specific phosphorylation of vimentin induces disassembly of the filament structure." SIGNOR-250066 PRKACA protein P17612 UNIPROT VIM protein P08670 UNIPROT "down-regulates activity" phosphorylation Ser39 TTSTRTYsLGSALRP -1 2500966 t miannu "Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. Domain- and sequence-specific phosphorylation of vimentin induces disassembly of the filament structure." SIGNOR-250067 PRKACA protein P17612 UNIPROT VIM protein P08670 UNIPROT "down-regulates activity" phosphorylation Ser47 LGSALRPsTSRSLYA -1 2500966 t miannu "Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. Domain- and sequence-specific phosphorylation of vimentin induces disassembly of the filament structure." SIGNOR-250070 PRKACA protein P17612 UNIPROT GLI2 protein P10070 UNIPROT down-regulates phosphorylation 9606 17419683 t gcesareni "In the absence of hh ligands, cubitus interruptus (in drosophila) and gli2 and gli3 (in vertebrates) are phosphorylated by protein kinase a and glycogen synthase kinase-3beta and are proteolytically processed in vertebrates, pka-mediated phosphorylation of gli2 and gli3 initiates a phosphorylation cascade that leads to processing into repressors of transcription or frank degradation" SIGNOR-154273 PRKACA protein P17612 UNIPROT GLI3 protein P10071 UNIPROT down-regulates phosphorylation 9606 17419683 t gcesareni "In vertebrates,pka-mediated phosphorylation of gli2 and gli3 initiates a phosphorylation cascade that leads to processing into repressors of transcription or frank degradation" SIGNOR-154276 PRKACA protein P17612 UNIPROT GLI3 protein P10071 UNIPROT "down-regulates quantity" phosphorylation Ser1006 GHGVRRAsDPVRTGS 9606 10693759 t lperfetto "Ci/gli zinc finger proteins mediate the transcriptional effects of hedgehog protein signals. In drosophila, ci action as transcriptional repressor or activator is contingent upon hedgehog-regulated, pka-dependent proteolytic processingall six pka phosphorylation sites are required for processing of gli3." SIGNOR-75339 PRKACA protein P17612 UNIPROT GLI3 protein P10071 UNIPROT "down-regulates quantity" phosphorylation Ser849 NMLNRRDsSASTISS 9606 10693759 t lperfetto "Ci/gli zinc finger proteins mediate the transcriptional effects of hedgehog protein signals. In drosophila, ci action as transcriptional repressor or activator is contingent upon hedgehog-regulated, pka-dependent proteolytic processingall six pka phosphorylation sites are required for processing of gli3." SIGNOR-75343 PRKACA protein P17612 UNIPROT GLI3 protein P10071 UNIPROT "down-regulates quantity" phosphorylation Ser865 YLSSRRSsGISPCFS 9606 10693759 t lperfetto "Ci/gli zinc finger proteins mediate the transcriptional effects of hedgehog protein signals. In drosophila, ci action as transcriptional repressor or activator is contingent upon hedgehog-regulated, pka-dependent proteolytic processingall six pka phosphorylation sites are required for processing of gli3." SIGNOR-75347 PRKACA protein P17612 UNIPROT GLI3 protein P10071 UNIPROT "down-regulates quantity" phosphorylation Ser877 CFSSRRSsEASQAEG 9606 10693759 t lperfetto "Ci/gli zinc finger proteins mediate the transcriptional effects of hedgehog protein signals. In drosophila, ci action as transcriptional repressor or activator is contingent upon hedgehog-regulated, pka-dependent proteolytic processingall six pka phosphorylation sites are required for processing of gli3." SIGNOR-75351 PRKACA protein P17612 UNIPROT GLI3 protein P10071 UNIPROT "down-regulates quantity" phosphorylation Ser980 VHAPRRCsDGGAHGY 9606 10693759 t lperfetto "Ci/gli zinc finger proteins mediate the transcriptional effects of hedgehog protein signals. In drosophila, ci action as transcriptional repressor or activator is contingent upon hedgehog-regulated, pka-dependent proteolytic processingall six pka phosphorylation sites are required for processing of gli3." SIGNOR-75359 PRKACA protein P17612 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser579 NVKSKIGsTENLKHQ 9606 BTO:0000938 9771888 t "The effect has been demonstrated using P10636-8" gcesareni "Tau is phosphorylated by gsk-3 at several sites found in alzheimer disease and its biological activity markedly inhibited only after it is prephosphorylated by a-kinase." SIGNOR-60659 PRKACA protein P17612 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser579 NVKSKIGsTENLKHQ -1 12435421 t miannu "Ser214, Ser262, Ser356, and Ser409 of tau441‚ were phosphorylated by PKA. tau in PHF is abnormally hyperphosphorylated and lacks its normal activity to bind to microtubules and to stimulate their assembly" SIGNOR-250008 PRKACA protein P17612 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser673 RVQSKIGsLDNITHV -1 12435421 t miannu "Ser214, Ser262, Ser356, and Ser409 of tau441‚ were phosphorylated by PKA. tau in PHF is abnormally hyperphosphorylated and lacks its normal activity to bind to microtubules and to stimulate their assembly" SIGNOR-250007 PRKACA protein P17612 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser726 DTSPRHLsNVSSTGS -1 12435421 t miannu "Ser214, Ser262, Ser356, and Ser409 of tau441‚ were phosphorylated by PKA. tau in PHF is abnormally hyperphosphorylated and lacks its normal activity to bind to microtubules and to stimulate their assembly" SIGNOR-250009 PRKACA protein P17612 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser531 GSRSRTPsLPTPPTR -1 9614189 t miannu "S214 can be rapidly and selectively phosphorylated in vitro by PKA, and this single site strongly affects tau's ability to bind and stabilize microtubules." SIGNOR-250006 PRKACA protein P17612 UNIPROT MAP2 protein P11137 UNIPROT "down-regulates activity" phosphorylation Ser1679 NVKSKIGsTDNIKYQ 9606 BTO:0000567 11029056 t miannu "CAMP-dependent protein kinase activity disrupts the MAP2-microtubule interaction in living HeLa cells. S319, S350, and S382 were thus identified as preferred targets of PKA" SIGNOR-250001 PRKACA protein P17612 UNIPROT MAP2 protein P11137 UNIPROT "down-regulates activity" phosphorylation Ser1710 HVTSKCGsLKNIRHR 9606 BTO:0000567 11029056 t miannu "CAMP-dependent protein kinase activity disrupts the MAP2-microtubule interaction in living HeLa cells. S319, S350, and S382 were thus identified as preferred targets of PKA" SIGNOR-250002 PRKACA protein P17612 UNIPROT MAP2 protein P11137 UNIPROT "down-regulates activity" phosphorylation Ser1742 KAQAKVGsLDNAHHV 9606 BTO:0000567 11029056 t miannu "CAMP-dependent protein kinase activity disrupts the MAP2-microtubule interaction in living HeLa cells. S319, S350, and S382 were thus identified as preferred targets of PKA" SIGNOR-250003 PRKACA protein P17612 UNIPROT MAP2 protein P11137 UNIPROT up-regulates phosphorylation Ser1782 GAEIITQsPGRSSVA 9606 BTO:0000567;BTO:0000938 BTO:0000142 11029056 t gcesareni "Specific phosphorylation states may enhance the interaction of map2 with the actin cytoskeleton, thereby providing a regulated mechanism for map2 function within distinct cytoskeletal domains" SIGNOR-83100 PRKACA protein P17612 UNIPROT SLC2A2 protein P11168 UNIPROT "down-regulates activity" phosphorylation Ser503 AAEFQKKsGSAHRPK 9534 BTO:0004055 8626492 t miannu "GLUT2 is rapidly phosphorylated by protein kinase A following activation of adenylyl cyclase by forskolin. serines 489 and 501/503 and threonine 510 in the carboxyl-terminal tail of the transporter are the in vitro and in vivo sites of phosphorylation. Stimulation of GLUT2 phosphorylation in beta cells reduces the initial rate of 3-O-methyl glucose uptake by approximately 48% but does not change the Michaelis constant. a consequence of GLUT2 phosphorylation is a reduction of its catalytic activity." SIGNOR-250050 PRKACA protein P17612 UNIPROT SLC2A2 protein P11168 UNIPROT "down-regulates activity" phosphorylation Ser505 EFQKKSGsAHRPKAA 9534 BTO:0004055 8626492 t miannu "GLUT2 is rapidly phosphorylated by protein kinase A following activation of adenylyl cyclase by forskolin. serines 489 and 501/503 and threonine 510 in the carboxyl-terminal tail of the transporter are the in vitro and in vivo sites of phosphorylation. Stimulation of GLUT2 phosphorylation in beta cells reduces the initial rate of 3-O-methyl glucose uptake by approximately 48% but does not change the Michaelis constant. a consequence of GLUT2 phosphorylation is a reduction of its catalytic activity." SIGNOR-250051 PRKACA protein P17612 UNIPROT SRF protein P11831 UNIPROT up-regulates phosphorylation Thr159 DNKLRRYtTFSKRKT 10090 12809504 t llicata "Myotonic dystrophy protein kinase (DMPK), a muscle- and neuron-restricted kinase, enhanced SRF-mediated promoter activity of the skeletal and cardiac alpha-actin genes in C2C12 myoblasts as well as in nonmyogenic cells. | Threonine 159 in the MADS box alphaI coil was a specific phosphorylation target in vitro as well as in vivo of both DMPK and protein kinase C-alpha. " SIGNOR-188177 PRKACA protein P17612 UNIPROT SRC protein P12931 UNIPROT up-regulates phosphorylation Ser17 DASQRRRsLEPAENV 9606 11804588 t llicata "Pka activated src both in vitro and in vivo by phosphorylating src on serine 17" SIGNOR-114277 PRKACA protein P17612 UNIPROT GP1BB protein P13224 UNIPROT "down-regulates activity" phosphorylation Ser191 ARAAARLsLTDPLVA -1 2504723 t miannu "Platelet glycoprotein Ib beta is phosphorylated on serine 166 by cyclic AMP-dependent protein kinase. phosphorylation of this residue may contribute to the inhibitory actions of cyclic AMP by inhibiting collagen-induced polymerization of actin." SIGNOR-249986 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT "down-regulates activity" phosphorylation Ser737 EPLERRLsLVPDSEQ 9606 19095655 t Luana "AMPK phosphorylates CFTR in vitro at two essential serines (Ser737and Ser768) in the R domain, formerly identified as ""inhibitory"" PKA sites." SIGNOR-21316 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser813 DIYSRRLsQETGLEI 9606 1716180 t lperfetto "Cftr, the protein associated with cystic fibrosis, is phosphorylated on serine residues in response to camp agonists. Serines 660, 737, 795, and 813 were identified as in vivo targets for phosphorylation by protein kinase a.mutagenesis of all four sites abolished the response." SIGNOR-21324 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT "up-regulates activity" phosphorylation Ser660 FSAERRNsILTETLH -1 1377674 t miannu "CFTR is phosphorylated directly by PKA and PKC in vivo. phosphorylation by PKA is necessary to allow ATP hydrolysis by CFTR and that ATP hydrolysis is necessary for channel opening. CF-2 was phosphorylated by PKA in vitro on serines 660,700, 737, 813 and most likely on both serines 768 and 795." SIGNOR-250349 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT "up-regulates activity" phosphorylation Ser700 FGEKRKNsILNPINS -1 1377674 t miannu "CFTR is phosphorylated directly by PKA and PKC in vivo. phosphorylation by PKA is necessary to allow ATP hydrolysis by CFTR and that ATP hydrolysis is necessary for channel opening. CF-2 was phosphorylated by PKA in vitro on serines 660,700, 737, 813 and most likely on both serines 768 and 795." SIGNOR-250348 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT "up-regulates activity" phosphorylation Ser813 DIYSRRLsQETGLEI -1 1377674 t miannu "CFTR is phosphorylated directly by PKA and PKC in vivo. phosphorylation by PKA is necessary to allow ATP hydrolysis by CFTR and that ATP hydrolysis is necessary for channel opening. CF-2 was phosphorylated by PKA in vitro on serines 660,700, 737, 813 and most likely on both serines 768 and 795." SIGNOR-250351 PRKACA protein P17612 UNIPROT ITGA4 protein P13612 UNIPROT "up-regulates activity" phosphorylation Ser1021 QEENRRDsWSYINSK 9606 BTO:0000782 11533025 t lperfetto "PKA phosphorylationin vitro blocks the binding of the alpha4 tail to paxillin. A mutation that mimics alpha4 phosphorylation disrupts paxillin binding and promotes cell spreading" SIGNOR-110119 PRKACA protein P17612 UNIPROT LCP1 protein P13796 UNIPROT up-regulates phosphorylation Ser5 sVSDEEMM 9606 BTO:0000007 16636079 t gcesareni "Phosphorylation on ser5 increases the f-actin-binding activity of l-plastin and promotes its targeting to sites of actin assembly in cells. L-plastin phosphorylation require protein kinase a." SIGNOR-146287 PRKACA protein P17612 UNIPROT GYS1 protein P13807 UNIPROT "down-regulates activity" phosphorylation Ser698 PEWPRRAsCTSSTSG -1 196939 t "The results presented in this paper show that the phosphorylation of glycogen synthetase a by cyclic AMP-dependent protein kinase results in the phosphorylation of two distinct serines termed site-l and site-2, which account for 90% of the total phosphorylation" SIGNOR-253009 PRKACA protein P17612 UNIPROT GYS1 protein P13807 UNIPROT unknown phosphorylation Ser8 MPLNRTLsMSSLPGL -1 2117608 t miannu "Phosphorylation of rabbit muscle glycogen synthase by cyclic AMP-dependent protein kinase has been shown to enhance subsequent phosphorylation by casein kinase I . phosphorylation at Ser7 is required for modification of Ser10 by casein kinase I." SIGNOR-249988 PRKACA protein P17612 UNIPROT GFAP protein P14136 UNIPROT "down-regulates activity" phosphorylation Ser13 ITSAARRsYVSSGEM -1 2155236 t miannu "GFAP can serve as a substrate for phosphorylation by CAMP-dependent protein kinase. CAMP-dependent protein kinase or protein kinase C phosphorylated Ser-8, Ser-13, and Ser-34.each phosphorylation was shown to induce disassembly of the glial filaments." SIGNOR-249711 PRKACA protein P17612 UNIPROT GFAP protein P14136 UNIPROT "down-regulates activity" phosphorylation Ser38 LGPGTRLsLARMPPP -1 2155236 t miannu "GFAP can serve as a substrate for phosphorylation by CAMP-dependent protein kinase. CAMP-dependent protein kinase or protein kinase C phosphorylated Ser-8, Ser-13, and Ser-34.each phosphorylation was shown to induce disassembly of the glial filaments." SIGNOR-249713 PRKACA protein P17612 UNIPROT GFAP protein P14136 UNIPROT "down-regulates activity" phosphorylation Thr7 tSAARRSY -1 2155236 t miannu "GFAP can serve as a substrate for phosphorylation by CAMP-dependent protein kinase. CAMP-dependent protein kinase or protein kinase C phosphorylated Ser-8, Ser-13, and Ser-34.each phosphorylation was shown to induce disassembly of the glial filaments." SIGNOR-249712 PRKACA protein P17612 UNIPROT BRAF protein P15056 UNIPROT "down-regulates activity" phosphorylation Ser429 PQRERKSsSSSEDRN 10116 BTO:0001009 11510412 t "The in vitro phosphorylation of a site unique to B-Raf (Ser429) has been proposed to be responsible for the negative regulation of the isoenzyme by Akt. Using phosphopetide mapping and site-directed mutagenesis we showed that Ser429 is phosphorylated upon cAMP elevation in PC12 cells and proposed that PKA is a major kinase phosphorylating the B-Raf-specific site in vivo" SIGNOR-259922 PRKACA protein P17612 UNIPROT DSP protein P15924 UNIPROT "down-regulates activity" phosphorylation Ser2849 RSGSRRGsFDATGNS 9606 BTO:0000567 7525582 t miannu "HeLa cells treated with forskolin indicated that stimulation of protein kinase A in transfected cells could decrease the interaction of DP.AN.SerC23 with keratin IF networks. phosphorylation of Ser-C23 could destabilize interactions that occur either directly through this 20 residue sequence or that are dependent on its correct conformation" SIGNOR-250353 PRKACA protein P17612 UNIPROT CD44 protein P16070 UNIPROT up-regulates phosphorylation Ser697 AVEDRKPsGLNGEAS 9606 16785995 t lperfetto "Pka can phosphorylate ser316 directly cd44 s291a and s316a mutants may disrupt downstream signalling events by displacing endogenous cd44 from plasma membrane microdomains." SIGNOR-147208 PRKACA protein P17612 UNIPROT ITGB4 protein P16144 UNIPROT down-regulates phosphorylation Ser1364 PSGSQRPsVSDDTGC 9606 17615294 t lperfetto "Additionally, we show that s1360 and s1364 of beta4 are the only residues phosphorylated by pkc and pka in cells, respectivelywe have defined three regions on beta4 that together harbor all the serine and threonine phosphorylation sites and show that three serines (s1356, s1360, and s1364), previously implicated in hd regulation, prevent the interaction of beta4 with the plectin actin-binding domain when phosphorylated" SIGNOR-156873 PRKACA protein P17612 UNIPROT CREB1 protein P16220 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0000669 15568017 t 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 PRKACA protein P17612 UNIPROT CREB1 protein P16220 UNIPROT "up-regulates activity" phosphorylation Ser119 EILSRRPsYRKILND 10116 BTO:0001009 8336722 t 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 PRKACA protein P17612 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser16 KELEKRAsGQAFELI 9606 BTO:0000782;BTO:0001271 8125092 t gcesareni "Phosphorylation of either serine 16 or 63 is sufficient to inhibit stathmin in vitro. Phosphorylation at ser-63 reduces tubulin binding 10-fold and suppresses the mt polymerization inhibition activity." SIGNOR-36370 PRKACA protein P17612 UNIPROT SYN1 protein P17600 UNIPROT "down-regulates activity" phosphorylation Ser9 NYLRRRLsDSNFMAN -1 10571231 t miannu "Synapsin phosphorylation in the A domain, at the only phosphorylation site shared by all synapsins, dissociates synapsins from synaptic vesicles.This site is located in the N-terminal A domain and is a substrate for both PKA and CaM Kinase I" SIGNOR-250058 PRKACA protein P17612 UNIPROT CAPN2 protein P17655 UNIPROT down-regulates phosphorylation Thr370 GNWRRGStAGGCRNY 9606 11909964 t llicata "Activation of m-calpain (calpain ii) by epidermal growth factor is limited by protein kinase a phosphorylation of m-calpain.These Data point to a novel mechanism of negative control of calpain activation, direct phosphorylation by pka." SIGNOR-116248 PRKACA protein P17612 UNIPROT ATF1 protein P18846 UNIPROT "up-regulates activity" phosphorylation Ser63 GILARRPsYRKILKD -1 9016641 t miannu "PKA catalytic subunit phosphorylates ATF-1 at Ser63 and that phosphorylation is essential for efficient DNA binding by ATF-1." SIGNOR-250336 PRKACA protein P17612 UNIPROT PLCG1 protein P19174 UNIPROT down-regulates phosphorylation Ser1248 HGRAREGsFESRYQQ 9606 BTO:0000782;BTO:0000661 1370476 t llicata "The observation that pka also phosphorylates plc-yl on serine 1248 suggests that phosphorylation of this residue may be a common mechanism by which pkc and pka inhibit plc-yl." SIGNOR-17901 PRKACA protein P17612 UNIPROT TNNI3 protein P19429 UNIPROT "up-regulates activity" phosphorylation Ser23 PAPIRRRsSNYRAYA 9606 15769444 t lperfetto "Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction." SIGNOR-134605 PRKACA protein P17612 UNIPROT TNNI3 protein P19429 UNIPROT "up-regulates activity" phosphorylation Ser24 APIRRRSsNYRAYAT 9606 15769444 t lperfetto "Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction." SIGNOR-134609 PRKACA protein P17612 UNIPROT RXRA protein P19793 UNIPROT down-regulates phosphorylation Ser27 TSPTGRGsMAAPSLH 9606 11162439 t llicata "Serine 27, a human retinoid x receptor alpha residue, phosphorylated by protein kinase a is essential for cyclicamp-mediated downregulation of rxralpha function." SIGNOR-104954 PRKACA protein P17612 UNIPROT NFKB1 protein P19838 UNIPROT up-regulates phosphorylation Ser337 FVQLRRKsDLETSEP 9606 SIGNOR-C13 17959673 t llicata "In this study, we demonstrate that the phosphorylation of p50 and p65 by the catalytic subunit of protein kinase a (pkac) is essential for nf-kappab dna binding and transactivation activity. treatment with h89 and knockdown of pkac in cells led to the inhibition of phosphorylation at p50 ser(337) and p65 ser(276) and loss of dna binding by nf-kappab." SIGNOR-158595 PRKACA protein P17612 UNIPROT NFKB1 protein P19838 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser937 ETSFRKLsFTESLTS 19531803 t lperfetto "Ser940 of p105 was phosphorylated by PKA to a similar extent, whereas no phosphorylation of the same sequence occurred when Ser940 was substituted by Ala|Mechanistically, phosphorylation of p105 at Ser940 by PKA appeared to attenuate the extent of IKK-dependent phosphorylation of p105 at Ser935, which could in turn influence the rate of activation of NF-kappaB" SIGNOR-260327 PRKACA protein P17612 UNIPROT ATP2B1 protein P20020 UNIPROT "up-regulates activity" phosphorylation Ser1178 APTKRNSsPPPSPNK -1 2548572 t miannu "The ATPase is phosphorylated only at this site by the cAMP-dependent protein kinase, and the phosphorylation is inhibited by calmodulin. The effect of the phosphorylation is to decrease the Km for Ca2+ of the purified ATPase from about 10 microM to about 1.4 microM and to increase the Vmax of ATP hydrolysis about 2-fold." SIGNOR-262694 PRKACA protein P17612 UNIPROT FLNA protein P21333 UNIPROT up-regulates phosphorylation Ser2152 TRRRRAPsVANVGSH 9606 15228085 t gcesareni "Site-directed mutagenesis analysis indicated that serine 2152 is the unique substrate in the c-terminal region of abp for endogenously activated pka." SIGNOR-126659 PRKACA protein P17612 UNIPROT RYR1 protein P21817 UNIPROT "up-regulates activity" phosphorylation Ser2843 KKKTRKIsQSAQTYD -1 14532276 t miannu "PKA-mediated hyperphosphorylation of a conserved serine, Ser-2843 in skeletal RyR and Ser-2809 in cardiac RyR, results in an aberrant SR function during heart failure. hyperphosphorylated RyRs are leaky and therefore lead to a reduced SR Ca2+ load and impaired contractile function in heart failure" SIGNOR-250078 PRKACA protein P17612 UNIPROT ITPKA protein P23677 UNIPROT "up-regulates activity" phosphorylation Ser121 LQQPRRLsTSSVSST -1 9374536 t miannu "Two isoforms of the inositol 1,4,5-trisphosphate 3-kinase have been identified, the A form and the B form. phosphorylation of isoform A by the cyclic AMP-dependent protein kinase increased activity 1.5-fold, whereas phosphorylation of isoform B decreased activity by 45%. major phosphorylation sites in the protein are Ser119 for PKA. Ser119 in the A isoform is conserved in the B isoform as Ser328" SIGNOR-249994 PRKACA protein P17612 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Ser443 PQRKSQRsSYVSMRI -1 12175859 t miannu "Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). These data, indicate that S422 and/or S423 are the major sites of PKA-mediated phosphorylation of the 1 GABA receptor.An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation" SIGNOR-262751 PRKACA protein P17612 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Ser444 QRKSQRSsYVSMRID -1 12175859 t miannu "Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). These data, indicate that S422 and/or S423 are the major sites of PKA-mediated phosphorylation of the 1 GABA receptor.An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation" SIGNOR-262750 PRKACA protein P17612 UNIPROT CCND1 protein P24385 UNIPROT unknown phosphorylation Ser234 YRLTRFLsRVIKCDP -1 8058338 t miannu "PKA phosphorylates three distinct serine residues in cyclin D1 at positions 90, 197 and 234." SIGNOR-250346 PRKACA protein P17612 UNIPROT CCND1 protein P24385 UNIPROT unknown phosphorylation Ser90 NYLDRFLsLEPVKKS -1 8058338 t miannu "PKA phosphorylates three distinct serine residues in cyclin D1 at positions 90, 197 and 234." SIGNOR-250347 PRKACA protein P17612 UNIPROT KDELR1 protein P24390 UNIPROT up-regulates phosphorylation Ser209 VLKGKKLsLPA 9606 14517323 t llicata "We conclude that pka phosphorylation of serine 209 is required for the retrograde transport of the kdel receptor from the golgi complex to the er from which the retrieval of proteins bearing the kdel signal depends." SIGNOR-118257 PRKACA protein P17612 UNIPROT CAD protein P27708 UNIPROT down-regulates phosphorylation Ser1406 GAGGRRLsSFVTKGY 9606 17206380 t gcesareni "Protein kinase a phosphorylation at thr456 of the multifunctional protein cad antagonizes activation by the map kinase cascade." SIGNOR-151816 PRKACA protein P17612 UNIPROT CAD protein P27708 UNIPROT "down-regulates activity" phosphorylation Ser1406 GAGGRRLsSFVTKGY 11986331 t miannu "CAD is down-regulated as the cells emerge from S phase by protein kinase A (PKA) phosphorylation. PKA phosphorylates Ser1406 and Ser1859, although only Ser1406 is involved in regulation." SIGNOR-250344 PRKACA protein P17612 UNIPROT CAD protein P27708 UNIPROT unknown phosphorylation Ser1859 PPRIHRAsDPGLPAE 11986331 t miannu "CAD is down-regulated as the cells emerge from S phase by protein kinase A (PKA) phosphorylation. PKA phosphorylates Ser1406 and Ser1859, although only Ser1406 is involved in regulation." SIGNOR-250343 PRKACA protein P17612 UNIPROT ITPKB protein P27987 UNIPROT "down-regulates activity" phosphorylation -1 9374536 t miannu "Two isoforms of the inositol 1,4,5-trisphosphate 3-kinase have been identified, the A form and the B form. phosphorylation of isoform A by the cyclic AMP-dependent protein kinase increased activity 1.5-fold, whereas phosphorylation of isoform B decreased activity by 45%. major phosphorylation sites in the protein are Ser119 for PKA. Ser119 in the A isoform is conserved in the B isoform as Ser328" SIGNOR-249995 PRKACA protein P17612 UNIPROT NOS3 protein P29474 UNIPROT up-regulates phosphorylation Ser1177 TSRIRTQsFSLQERQ 9606 11729179 t gcesareni "Recently many investigators have shown that protein phosphorylation of enos by several serine/threonine kinases is a critical control step for no production by endothelial cells. Phosphorylation by amp kinase, akt (or protein kinase b), or protein kinase aon serine 1179 (bovine) or serine 1177 (human) of enos leads to enhanced activity of the enzyme and, thus, augmented production of no." SIGNOR-112371 PRKACA protein P17612 UNIPROT NOS3 protein P29474 UNIPROT "up-regulates activity" phosphorylation Ser615 SYKIRFNsISCSDPL 9606 BTO:0001853 24379783 t lperfetto "The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites" SIGNOR-251617 PRKACA protein P17612 UNIPROT NOS3 protein P29474 UNIPROT "up-regulates activity" phosphorylation Ser633 WRRKRKEsSNTDSAG 9606 BTO:0001853 24379783 t lperfetto "The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites" SIGNOR-251616 PRKACA protein P17612 UNIPROT NOS1 protein P29475 UNIPROT unknown phosphorylation -1 1375933 t miannu "NOS is stoichiometrically phosphorylated by PKA, PKC, and CaMK, with each enzyme predominantly phosphorylating a distinct serine. CPT-CAMP has no effect on NOS activity" SIGNOR-250021 PRKACA protein P17612 UNIPROT MIP protein P30301 UNIPROT "down-regulates activity" phosphorylation Ser229 LLFPRLKsISERLSV -1 2176601 t miannu "Phosphorylation at one of these sites (serine 243) could be increased by A kinase in vitro. phosphorylation of MIP reconstituted into single bilayers increased the voltage dependence and long-term closures of the channels observed." SIGNOR-250018 PRKACA protein P17612 UNIPROT PRKAR2B protein P31323 UNIPROT "up-regulates activity" phosphorylation Ser114 NRFTRRAsVCAEAYN 9606 15187164 t gcesareni "Serine 114 phosphorylation is required for both nuclear localization and down-regulation of il-2 production by riibeta." SIGNOR-125545 PRKACA protein P17612 UNIPROT MC4R protein P32245 UNIPROT "down-regulates activity" phosphorylation Thr312 RSQELRKtFKEIICC 9606 12639913 t miannu "Activation of MC4R by agonist is associated with protein kinase A (PKA) and GRK phosphorylation of serine/threonine residues in the C-terminal tail of MC4R, followed by -arrestin and dynamin-dependent internalization of the receptor. Thr312 and Ser329/330 in the C-terminal tail of MC4R are potential sites for PKA" SIGNOR-250017 PRKACA protein P17612 UNIPROT CIITA protein P33076 UNIPROT "down-regulates activity" phosphorylation Ser1050 AASLLRLsLYNNCIC 9606 BTO:0000984 11416140 t lperfetto "Downregulation of ciita function by protein kinase a (pka)-mediated phosphorylation phosphorylation at ciita serines 834 and 1050 accounts for the inhibitory effects of pka on ciita-driven class ii mhc transcription." SIGNOR-108569 PRKACA protein P17612 UNIPROT CIITA protein P33076 UNIPROT "down-regulates activity" phosphorylation Ser834 QELPGRLsFLGTRLT 9606 BTO:0000984 11416140 t lperfetto "Downregulation of ciita function by protein kinase a (pka)-mediated phosphorylationphosphorylation at ciita serines 834 and 1050 accounts for the inhibitory effects of pka on ciita-driven class ii mhc transcription." SIGNOR-108573 PRKACA protein P17612 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007 16199882 t gcesareni "Although pka did not affect the formation of a complex between glycogen synthase kinase 3beta (gsk-3beta), beta-catenin, and axin, phosphorylation of beta-catenin by pka inhibited ubiquitination of beta-catenin in intact cells and in vitro." SIGNOR-140902 PRKACA protein P17612 UNIPROT NOLC1 protein Q14978 UNIPROT up-regulates phosphorylation Ser623 KGEKRASsPFRRVRE 9606 12167624 t gcesareni "Here we demonstrate that protein kinase a (pka)-dependent phosphorylation of nopp140 at ser 627, together with c/ebpbeta, induces agp gene expression synergistically." SIGNOR-91186 PRKACA protein P17612 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" phosphorylation Ser552 QDTQRRTsMGGTQQQ 9606 16476742 t lperfetto "In the present study, we have shown that (i) beta-catenin can be phosphorylated by protein kinase a (pka) in vitro and in intact cells at two novel sites, ser-552 and ser-675;(ii) phosphorylation by pka promotes the transcriptional activity (tcf/lef transactivation) of beta-catenin" SIGNOR-144478 PRKACA protein P17612 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" phosphorylation Ser675 QDYKKRLsVELTSSL 9606 BTO:0000007 16476742 t lperfetto "In the present study, we have shown that (i) beta-catenin can be phosphorylated by protein kinase a (pka) in vitro and in intact cells at two novel sites, ser-552 and ser-675;(ii) phosphorylation by pka promotes the transcriptional activity (tcf/lef transactivation) of beta-catenin" SIGNOR-144482 PRKACA protein P17612 UNIPROT PTPN7 protein P35236 UNIPROT down-regulates phosphorylation Ser44 RLQERRGsNVALMLD 9606 10559944 t llicata "Here we show that cyclic-amp-dependent protein kinase (pka) phosphorylates serine residue 23 in the kim of heptp in vitro and in intact cells. This modification reduces binding of map kinases to the kim, an effect that is prevented by mutation of serine 23 to alanine." SIGNOR-72147 PRKACA protein P17612 UNIPROT NF2 protein P35240 UNIPROT down-regulates phosphorylation Ser518 DTDMKRLsMEIEKEK 9606 18071304 t lperfetto "Merlin localizes to the cell membrane where it links the actin cytoskeleton to membrane proteins.we identify a novel pka phosphorylation site, serine 10, in the n terminus of merlin. s10a reduces the amount of cellular f-actin and merlin s10d stabilizes f-actin filaments." SIGNOR-159844 PRKACA protein P17612 UNIPROT NF2 protein P35240 UNIPROT up-regulates phosphorylation Ser10 GAIASRMsFSSLKRK 9606 18071304 t lperfetto "Merlin contains a c-terminal serine 518, which is phosphorylated both by p21-activated kinase (pak) and protein kinase a (pka) (shaw et al., 2001;kissil et al., 2002;xiao et al., 2002;alfthan et al., 2004). Phosphorylation at this site is predicted to result in a more open conformation incapable of inhibiting cell growth," SIGNOR-159840 PRKACA protein P17612 UNIPROT HRH1 protein P35367 UNIPROT down-regulates phosphorylation Ser396 FTWKRLRsHSRQYVS 9606 15328002 t gcesareni "Two amino acid residues (ser396, ser398) on hr1 were determined to be pkc phosphorylation sites by in vitro phosphorylation studies.Site-directed mutagenesis studies suggests that the ser398 residue was primarily involved in pkc-mediated desensitization. Possibly, phosphorylation of the residues is required for receptor transport from endosomes to lysosomes." SIGNOR-128411 PRKACA protein P17612 UNIPROT HRH1 protein P35367 UNIPROT down-regulates phosphorylation Ser398 WKRLRSHsRQYVSGL 9606 15328002 t gcesareni "Two amino acid residues (ser396, ser398) on hr1 were determined to be pkc phosphorylation sites by in vitro phosphorylation studies.Site-directed mutagenesis studies suggests that the ser398 residue was primarily involved in pkc-mediated desensitization. Possibly, phosphorylation of the residues is required for receptor transport from endosomes to lysosomes." SIGNOR-128415 PRKACA protein P17612 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser1222 ESSSTRRsSEDLSAY 9606 BTO:0000975 17360977 t lperfetto "Tyrosine phosphorylation of IRS-1 initiates insulin signaling, whereas serine/threonine phosphorylation alters the ability of IRS-1 to transduce the insulin signalInsulin increased the phosphorylation of Ser312, Ser616, Ser636, Ser892, Ser1101, and Ser1223" SIGNOR-236729 PRKACA protein P17612 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser1223 SSSTRRSsEDLSAYA 9606 BTO:0000975 17360977 t lperfetto "Tyrosine phosphorylation of IRS-1 initiates insulin signaling, whereas serine/threonine phosphorylation alters the ability of IRS-1 to transduce the insulin signalInsulin increased the phosphorylation of Ser312, Ser616, Ser636, Ser892, Ser1101, and Ser1223" SIGNOR-236603 PRKACA protein P17612 UNIPROT ADD1 protein P35611 UNIPROT "down-regulates activity" phosphorylation Ser408 REKSKKYsDVEVPAS -1 8810272 t miannu "Protein kinase A phosphorylates -adducin at three sites in the neck domain (Ser-408, ’436, and ’481) in addition to the MARCKS-related domain of both subunits. Phosphorylation by PKA, in contrast to PKC, reduced affinity of erythrocyte adducin for spectrin-F-actin complexes as well as activity of adducin in promoting binding of spectrin to F-actin." SIGNOR-250329 PRKACA protein P17612 UNIPROT ADD1 protein P35611 UNIPROT "down-regulates activity" phosphorylation Ser436 TCSPLRHsFQKQQRE -1 8810272 t miannu "Protein kinase A phosphorylates -adducin at three sites in the neck domain (Ser-408, ’436, and ’481) in addition to the MARCKS-related domain of both subunits. Phosphorylation by PKA, in contrast to PKC, reduced affinity of erythrocyte adducin for spectrin-F-actin complexes as well as activity of adducin in promoting binding of spectrin to F-actin." SIGNOR-250330 PRKACA protein P17612 UNIPROT ADD1 protein P35611 UNIPROT "down-regulates activity" phosphorylation Ser481 KEDGHRTsTSAVPNL -1 8810272 t miannu "Protein kinase A phosphorylates -adducin at three sites in the neck domain (Ser-408, ’436, and ’481) in addition to the MARCKS-related domain of both subunits. Phosphorylation by PKA, in contrast to PKC, reduced affinity of erythrocyte adducin for spectrin-F-actin complexes as well as activity of adducin in promoting binding of spectrin to F-actin." SIGNOR-250331 PRKACA protein P17612 UNIPROT ADD2 protein P35612 UNIPROT "down-regulates activity" phosphorylation Ser713 KKKFRTPsFLKKSKK -1 8810272 t miannu "Ser-726 and Ser-713 in the C-terminal MARCKS-related domains of - and -adducin, respectively, were identified as the major phosphorylation sites common for PKA and PKC. Phosphorylation by PKA, but not PKC, reduced the affinity of adducin for spectrin-F-actin complexes as well as the activity of adducin in promoting binding of spectrin to F-actin." SIGNOR-250332 PRKACA protein P17612 UNIPROT ADD2 protein P35612 UNIPROT "down-regulates activity" phosphorylation Ser726 KKKEKVEs -1 8810272 t miannu "Ser-726 and Ser-713 in the C-terminal MARCKS-related domains of - and -adducin, respectively, were identified as the major phosphorylation sites common for PKA and PKC. Phosphorylation by PKA, but not PKC, reduced the affinity of adducin for spectrin-F-actin complexes as well as the activity of adducin in promoting binding of spectrin to F-actin." SIGNOR-250333 PRKACA protein P17612 UNIPROT GJA5 protein P36382 UNIPROT "up-regulates activity" phosphorylation Ser120 RAKEVRGsGSYEYPV 9606 BTO:0003477 10728420 t miannu "Gap junction channels formed of Cx40 are modulated by protein-kinase-A-mediated phosphorylation. Macroscopic conductance and permeability of Cx40 gap junctions is strongly increased by cAMP. two serine residues that can be phosphorylated by PKA, S120 and S345" SIGNOR-250357 PRKACA protein P17612 UNIPROT GJA5 protein P36382 UNIPROT "up-regulates activity" phosphorylation Ser345 HSDKRRLsKASSKAR 9606 BTO:0003477 10728420 t miannu "Gap junction channels formed of Cx40 are modulated by protein-kinase-A-mediated phosphorylation. Macroscopic conductance and permeability of Cx40 gap junctions is strongly increased by cAMP. two serine residues that can be phosphorylated by PKA, S120 and S345" SIGNOR-249982 PRKACA protein P17612 UNIPROT ETV5 protein P41161 UNIPROT "up-regulates activity" phosphorylation Ser367 PPYQRRGsLQLWQFL 9606 BTO:0002909 11682477 t lperfetto "We further show that the increase in erm transcriptional activity after pka phosphorylation is closely correlated with a drastic reduction in the dna binding of the transcription factor. These results indicate that the phosphorylation of erm by pka is involved in erm-mediated transcription and suggest that the activation of erm is probably related to conformational changes." SIGNOR-111239 PRKACA protein P17612 UNIPROT CSK protein P41240 UNIPROT "up-regulates activity" phosphorylation Ser364 ALREKKFsTKSDVWS 9606 BTO:0000782 11181701 t lperfetto "Activation of the cooh-terminal src kinase (csk) by camp-dependent protein kinase inhibits signaling through the t cell receptor.Pka phosphorylates csk at s364 in vitro and in vivo leading to a two- to fourfold increase in csk activity that is necessary for camp-mediated inhibition of tcr-induced interleukin 2 secretion." SIGNOR-105229 PRKACA protein P17612 UNIPROT PHKA1 protein P46020 UNIPROT "up-regulates activity" phosphorylation Ser1018 QVEFRRLsISAESQS 10487978 t miannu "Phosphorylation of the alpha and beta subunits by the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the enzyme. Ser1018 within this multiphosphorylation domain is phosphorylated by PKA and is a major site of regulatory phosphorylation in vivo" SIGNOR-250026 PRKACA protein P17612 UNIPROT RAP1GAP protein P47736 UNIPROT unknown phosphorylation Ser490 KSPTRKKsGPFGSRR -1 1406653 t miannu "We have localized two of the sites of phosphorylation in vitro by cAMP-dependent kinase to serine residues 490 and 499. raplGAP undergoes phosphorylation at specific sites in vivo, the effects of phosphorylation on raplGAP have remained elusive." SIGNOR-250043 PRKACA protein P17612 UNIPROT RAP1GAP protein P47736 UNIPROT unknown phosphorylation Ser499 PFGSRRSsAIGIENI -1 1406653 t miannu "We have localized two of the sites of phosphorylation in vitro by cAMP-dependent kinase to serine residues 490 and 499. raplGAP undergoes phosphorylation at specific sites in vivo, the effects of phosphorylation on raplGAP have remained elusive." SIGNOR-250044 PRKACA protein P17612 UNIPROT GRIA4 protein P48058 UNIPROT up-regulates phosphorylation Ser862 IRNKARLsITGSVGE 9606 12536214 t gcesareni "We found that pka phosphorylation of the ampa receptor subunits glur4 and glur1 directly controlled the synaptic incorporation of ampa receptors in organotypic slices from rat hippocampus." SIGNOR-97550 PRKACA protein P17612 UNIPROT SOX9 protein P48436 UNIPROT up-regulates phosphorylation Ser181 YQPRRRKsVKNGQAE 9606 15889150 t llicata "We find that activation of camp-dependent protein kinase a (pka) induces phosphorylation of sox9 on its two s64 and s181 pka sites, and its nuclear localization by enhancing sox9 binding to the nucleocytoplasmic transport protein importin beta." SIGNOR-137085 PRKACA protein P17612 UNIPROT SOX9 protein P48436 UNIPROT up-regulates phosphorylation Ser64 EPDLKKEsEEDKFPV 9606 15889150 t llicata "We find that activation of camp-dependent protein kinase a (pka) induces phosphorylation of sox9 on its two s64 and s181 pka sites, and its nuclear localization by enhancing sox9 binding to the nucleocytoplasmic transport protein importin beta." SIGNOR-137089 PRKACA protein P17612 UNIPROT KCNJ3 protein P48549 UNIPROT unknown phosphorylation Ser385 NSKERHNsVECLDGL 9606 19151997 t llicata "Using this approach, we identified s385 as an in vitro phosphorylation site. Mutation of this residue to alanine resulted in a reduced sensitivity of kir3.1* currents to h89 and forskolin, confirming an in vivo role for this novel site of the kir3.1 channel subunit in its regulation by pka." SIGNOR-183475 PRKACA protein P17612 UNIPROT ACADVL protein P49748 UNIPROT "up-regulates activity" phosphorylation Ser586 VVVLSRAsRSLSEGH -1 19889959 t lperfetto "As shown in Fig. 2C, an in vitro kinase assay carried out using PKA and a GST fusion protein containing the COOH-terminal 258 amino acids showed the protein to be efficiently phosphorylated in a time-dependent manner. |Furthermore, a phosphorylation-negative mutant (S586A) VLCAD shows reduced electron transfer activity and a strong dominant-negative effect on fatty acid beta-oxidation." SIGNOR-264422 PRKACA protein P17612 UNIPROT PSEN1 protein P49768 UNIPROT unknown phosphorylation Ser310 PEAQRRVsKNSKYNA -1 14576165 t miannu "PKA-mediated phosphorylation of PS1 is completely inhibited by mutation of Ser310.phosphorylation of Ser310 does not inhibit the caspase-mediated cleavage of PS1, and the biological function of this phosphorylation event remains to be determined in further experiments." SIGNOR-250036 PRKACA protein P17612 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation Ser21 SGRARTSsFAEPGGG 9606 11035810 t gcesareni "Phosphorylation of ser21 and inactivation of glycogen synthase kinase 3 by protein kinase a." SIGNOR-83221 PRKACA protein P17612 UNIPROT GSK3B protein P49841 UNIPROT "down-regulates activity" phosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000782 19836308 t lperfetto "Gsk3 is different from most kinases in that it is constitutively partially active and the most common regulatory mechanism is inhibition by phosphorylation of ser21 in gsk3alpha or ser9 in gsk3beta. This inhibitory phosphorylation can be mediated by several kinases, such as akt/protein kinase b (pkb), protein kinase c (pkc) and protein kinase a (pka)." SIGNOR-188577 PRKACA protein P17612 UNIPROT VASP protein P50552 UNIPROT unknown phosphorylation Ser239 GAKLRKVsKQEEASG 9606 12576312 t miannu "Three phosphorylation sites have been identified in VASP: Ser157, Ser239, and Thr278, all of which can be phosphorylated by either PKA or PKG in vitro" SIGNOR-250063 PRKACA protein P17612 UNIPROT VASP protein P50552 UNIPROT unknown phosphorylation Ser157 EHIERRVsNAGGPPA 9606 16197368 t llicata "We show that, in human platelets, vasp is phosphorylated by pkc on ser157, but not ser239, in response to phorbol ester stimulation, in a manner blocked by the pkc inhibitor bim i (bisindolylmaleimide i)." SIGNOR-140841 PRKACA protein P17612 UNIPROT VASP protein P50552 UNIPROT unknown phosphorylation Thr278 LARRRKAtQVGEKTP -1 8182057 t miannu "The vasodilator-stimulated phosphoprotein (VASP) is a major substrate for cAMP-dependent- (cAK) and cGMP-dependent protein kinase (cGK) in human platelets and other cardiovascular cells.‚  three VASP phosphorylation sites are phosphorylated by cAK and cGK. Thr, Ser I, and Ser 2 correspond to Thr278, Ser157, Ser239 of the VASP protein, respectively" SIGNOR-250065 PRKACA protein P17612 UNIPROT ARHGDIA protein P52565 UNIPROT down-regulates phosphorylation Ser174 KGMLARGsYSIKSRF 9606 18768928 t llicata "The results indicate that phosphorylation of gdi_ at ser174 by pka suppresses rhoa activity, providing a potential protective signaling mechanism for inflammatory injury." SIGNOR-180576 PRKACA protein P17612 UNIPROT THOP1 protein P52888 UNIPROT "up-regulates activity" phosphorylation Ser643 KVGMDYRsCILRPGG -1 10969067 t miannu "PKA phosphorylation is suggested to play a regulatory role in EP24.15 enzyme activity. Mutation analysis of each putative PKA site, in vitro phosphorylation, and phosphopeptide mapping indicated serine 644 as the phosphorylation site. The most dramatic change upon PKA phosphorylation was a substrate-specific, 7-fold increase in both K(m) and k(cat) for GnRH." SIGNOR-250060 PRKACA protein P17612 UNIPROT ACLY protein P53396 UNIPROT "up-regulates activity" phosphorylation Ser455 PAPSRTAsFSESRAD -1 10653665 t miannu "Phosphorylation of Recombinant Human ATP:Citrate Lyase by cAMP-Dependent Protein Kinase Abolishes Homotropic Allosteric Regulation of the Enzyme by Citrate and Increases the Enzyme Activity. Ser 454, which is phosphorylated by the catalytic subunit of cAMP-dependent protein kinase (PKA)" SIGNOR-250328 PRKACA protein P17612 UNIPROT MYOM2 protein P54296 UNIPROT down-regulates phosphorylation Ser76 RVCAKRVsTQEDEEQ 9606 BTO:0000887 9529381 t llicata "This binding is regulated in vitro by phosphorylation of a single serine residue (ser76) in the immediately adjacent amino-terminal domain mp1. M-protein phosphorylation by camp-dependent kinase a inhibits binding to myosin lmm." SIGNOR-56395 PRKACA protein P17612 UNIPROT PRKAA2 protein P54646 UNIPROT down-regulates phosphorylation Ser173 DGEFLRTsCGSPNYA 9606 19942859 t gcesareni "Pka associates with and phosphorylates ampk?1 At ser-173 to impede threonine thr-172 phosphorylation and thus activation of ampk1 by lkb1 in response to lipolytic signals" SIGNOR-161860 PRKACA protein P17612 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser273 AGTRRREsLGKKAKR -1 9677319 t miannu "Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII). Incubation of Rad with PKA decreases GTP binding by 60-70%, but this effect seems to be independent of phosphorylation, as it is observed with the Ser273-->Ala mutant of Rad containing a mutation at the site of PKA phosphorylation." SIGNOR-250048 PRKACA protein P17612 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Ser183 GLRTRTGsNIDCEKL 9606 15703181 t lperfetto "We show that protein kinase a inhibits activation of caspase-9 and caspase-3 downstream of cytochrome c in xenopus egg extracts and in a human cell-free system. Protein kinase a directly phosphorylates human caspase-9 at serines 99, 183, and 195." SIGNOR-133880 PRKACA protein P17612 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Ser195 EKLRRRFsSLHFMVE 9606 15703181 t lperfetto "We show that protein kinase a inhibits activation of caspase-9 and caspase-3 downstream of cytochrome c in xenopus egg extracts and in a human cell-free system. Protein kinase a directly phosphorylates human caspase-9 at serines 99, 183, and 195." SIGNOR-133884 PRKACA protein P17612 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Ser99 NRQAAKLsKPTLENL 9606 15703181 t lperfetto "We show that protein kinase a inhibits activation of caspase-9 and caspase-3 downstream of cytochrome c in xenopus egg extracts and in a human cell-free system. Protein kinase a directly phosphorylates human caspase-9 at serines 99, 183, and 195." SIGNOR-133888 PRKACA protein P17612 UNIPROT SNAP25 protein P60880 UNIPROT unknown phosphorylation Thr138 GGFIRRVtNDARENE 10116 BTO:0001009 12459461 t miannu "Thr138 as the exclusive site of SNAP-25 phosphorylation by protein kinase A in vivo. PMA or forskolin treatment alone resulted in dramatic phosphorylation of SNAP-25 Ser187 and/or Thr138 without appreciable neurotransmitter release." SIGNOR-250052 PRKACA protein P17612 UNIPROT ASIC1 protein P78348 UNIPROT unknown phosphorylation Ser479 QKEAKRSsADKGVAL 9606 BTO:0000142 12578970 t llicata "We found that protein kinase a phosphorylation of ser-479 in the asic1 c terminus interfered with pick1 binding." SIGNOR-98196 PRKACA protein P17612 UNIPROT H3-3A protein P84243 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 10464286 t gcesareni "Identification of a novel phosphorylation site on histone h3 coupled with mitotic chromosome condensation." SIGNOR-70424 PRKACA protein P17612 UNIPROT TFAM protein Q00059 UNIPROT up-regulates phosphorylation Ser55 SCPKKPVsSYLRFSK 9606 23201127 t llicata "Here, we demonstrate that tfam is phosphorylated within its hmg box 1 (hmg1) by camp-dependent protein kinase in mitochondria. Hmg1 phosphorylation impairs the ability of tfam to bind dna and to activate transcription." SIGNOR-199934 PRKACA protein P17612 UNIPROT CDK16 protein Q00536 UNIPROT down-regulates phosphorylation Ser153 SRRLRRVsLSEIGFG 9606 BTO:0000142 22184064 t llicata "Here, we report that cdk16 is activated by membrane-associated cyclin y (ccny). Treatment of transfected human cells with the protein kinase a (pka) activator forskolin blocked, while kinase inhibition promoted, ccny-dependent targeting of cdk16-green fluorescent protein (gfp) to the cell membrane. Ccny binding to cdk16 required a region upstream of the kinase domain and was found to be inhibited by phosphorylation of serine 153, a potential pka phosphorylation site." SIGNOR-191623 PRKACA protein P17612 UNIPROT HSF1 protein Q00613 UNIPROT up-regulates phosphorylation Ser320 ASPGRPSsVDTLLSP 9606 21085490 t lperfetto "Protein kinase a binds and activates heat shock factor 1hsf1 binds avidly to the catalytic subunit of pka, (pkac_) and becomes phosphorylated on a novel serine phosphorylation site within its central regulatory domain (serine 320 or s320), both in vitro and in vivo. Intracellular pkac_ levels and phosphorylation of hsf1 at s320 were both required for hsf1 to be localized to the nucleus, bind to response elements in the promoter of an hsf1 target gene" SIGNOR-169853 PRKACA protein P17612 UNIPROT CACNA1D protein Q01668 UNIPROT "up-regulates activity" phosphorylation Ser1700 VNSDRRDsLQQTNTT -1 19074150 t miannu "We recently demonstrated that PKA activation led to increased alpha(1D) Ca(2+) channel activity in tsA201 cells by phosphorylation of the channel protein. Western blotting showed that the N terminus and C terminus were phosphorylated. Serines 1743 and 1816, two PKA consensus sites, were phosphorylated by PKA and identified by mass spectrometry." SIGNOR-263108 PRKACA protein P17612 UNIPROT CACNA1D protein Q01668 UNIPROT "up-regulates activity" phosphorylation Ser1773 AAHGKRPsIGNLEHV -1 19074150 t miannu "We recently demonstrated that PKA activation led to increased alpha(1D) Ca(2+) channel activity in tsA201 cells by phosphorylation of the channel protein. Western blotting showed that the N terminus and C terminus were phosphorylated. Serines 1743 and 1816, two PKA consensus sites, were phosphorylated by PKA and identified by mass spectrometry." SIGNOR-263109 PRKACA protein P17612 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser276 SMQLRRPsDRELSEP 9606 SIGNOR-C13 9660950 t llicata "The transcriptional activity of nf-kappa b is stimulated upon phosphorylation of its p65 subunit on serine 276 by protein kinase a (pka)." SIGNOR-58972 PRKACA protein P17612 UNIPROT UBE3A protein Q05086 UNIPROT "down-regulates activity" phosphorylation Thr508 MYSERRItVLYSLVQ 10090 BTO:0000142 26255772 t gcesareni "These data suggest that PKA phosphorylation at T485 inhibits UBE3A ubiquitin ligase activity in cells." SIGNOR-236899 PRKACA protein P17612 UNIPROT LIPE protein Q05469 UNIPROT down-regulates phosphorylation Ser855 EPMRRSVsEAALAQP 9606 9636039 t gcesareni "Phosphorylation of bovine hormone-sensitive lipase by the amp-activated protein kinase." SIGNOR-58259 PRKACA protein P17612 UNIPROT PRKAA1 protein Q13131 UNIPROT "down-regulates activity" phosphorylation Ser486 DDEITEAKsGTATPQRS 10116 BTO:0002135 17023420 t "These agents also enhanced phosphorylation of alpha-Ser(485/491) by the cAMP-dependent protein kinase. AMPK alpha-Ser(485/491) phosphorylation was necessary but not sufficient for inhibition of AMPK activity in response to forskolin/isobutylmethylxanthine." SIGNOR-256110 PRKACA protein P17612 UNIPROT LIPE protein Q05469 UNIPROT "up-regulates activity" phosphorylation Ser853 IAEPMRRsVSEAALA 10090 BTO:0000944 11581251 t lperfetto "HSL activity is known to be regulated by phosphorylation (3). PKA increases HSL activity via phosphorylation at Ser563, Ser659, and Ser660 (14,15), although phosphorylation at Ser565 by glycogen synthase kinase, AMP-dependent protein kinase, or Ca2+/calmodulin-dependent protein kinase II has been reported to prevent activation of the enzyme" SIGNOR-249202 PRKACA protein P17612 UNIPROT LIPE protein Q05469 UNIPROT "up-regulates activity" phosphorylation Ser950 EGFHPRRsSQGATQM 10090 BTO:0000944 11581251 t lperfetto "HSL activity is known to be regulated by phosphorylation (3). PKA increases HSL activity via phosphorylation at Ser563, Ser659, and Ser660 (14,15), although phosphorylation at Ser565 by glycogen synthase kinase, AMP-dependent protein kinase, or Ca2+/calmodulin-dependent protein kinase II has been reported to prevent activation of the enzyme" SIGNOR-249203 PRKACA protein P17612 UNIPROT LIPE protein Q05469 UNIPROT "up-regulates activity" phosphorylation Ser951 GFHPRRSsQGATQMP 10090 BTO:0000944 11581251 t lperfetto "HSL activity is known to be regulated by phosphorylation (3). PKA increases HSL activity via phosphorylation at Ser563, Ser659, and Ser660 (14,15), although phosphorylation at Ser565 by glycogen synthase kinase, AMP-dependent protein kinase, or Ca2+/calmodulin-dependent protein kinase II has been reported to prevent activation of the enzyme" SIGNOR-249204 PRKACA protein P17612 UNIPROT CDK18 protein Q07002 UNIPROT "up-regulates activity" phosphorylation Ser14 KNFKRRFsLSVPRTE 28361970 t lperfetto "We previously revealed that PCTK3 is activated by two pathways: interaction with cytoplasmic cyclin A and phosphorylation at Ser-12 by protein kinase A (PKA)12. Activated PCTK3 phosphorylates retinoblastoma protein (Rb) in vitro. " SIGNOR-264560 PRKACA protein P17612 UNIPROT PDE4B protein Q07343 UNIPROT "up-regulates activity" phosphorylation Ser56 NLQLPPLsQRQSERA 9534 BTO:0000298 12441002 t miannu "PKA-mediated phosphorylation of Ser-56 in UCR1 of PDE4B4 leads to activation of this long isoform" SIGNOR-250024 PRKACA protein P17612 UNIPROT CACNB2 protein Q08289 UNIPROT "up-regulates activity" phosphorylation Ser514 SAPIRSAsQAEEEPS 10441130 t miannu "Voltage-dependent L-type calcium (Ca) channels are heteromultimeric proteins that are regulated through phosphorylation by cAMP-dependent protein kinase (PKA) Mutagenesis of a single residue at Ser459 resulted in the loss of one site of phosphorylation by PKA, and mutagenesis of two residues at Ser478/479 resulted in the loss of approximately two sites of PKA-mediated phosphorylation" SIGNOR-249714 PRKACA protein P17612 UNIPROT CACNB2 protein Q08289 UNIPROT "up-regulates activity" phosphorylation Ser533 KKSQHRSsSSAPHHN 10441130 t miannu "Voltage-dependent L-type calcium (Ca) channels are heteromultimeric proteins that are regulated through phosphorylation by cAMP-dependent protein kinase (PKA) Mutagenesis of a single residue at Ser459 resulted in the loss of one site of phosphorylation by PKA, and mutagenesis of two residues at Ser478/479 resulted in the loss of approximately two sites of PKA-mediated phosphorylation" SIGNOR-250340 PRKACA protein P17612 UNIPROT CACNB2 protein Q08289 UNIPROT "up-regulates activity" phosphorylation Ser534 KSQHRSSsSAPHHNH 10441130 t miannu "Voltage-dependent L-type calcium (Ca) channels are heteromultimeric proteins that are regulated through phosphorylation by cAMP-dependent protein kinase (PKA) Mutagenesis of a single residue at Ser459 resulted in the loss of one site of phosphorylation by PKA, and mutagenesis of two residues at Ser478/479 resulted in the loss of approximately two sites of PKA-mediated phosphorylation" SIGNOR-250341 PRKACA protein P17612 UNIPROT AKAP13 protein Q12802 UNIPROT down-regulates phosphorylation Ser1565 LSPFRRHsWGPGKNA 9606 15229649 t llicata "Elevation of the cellular concentration of camp activates the pka holoenzyme anchored to akap-lbc, which phosphorylates the anchoring protein on the serine 1565. This phosphorylation event induces the recruitment of 14-3-3, which inhibits the rho-gef activity of akap-lbc." SIGNOR-126723 PRKACA protein P17612 UNIPROT AKAP13 protein Q12802 UNIPROT up-regulates phosphorylation Ser2733 SVSPKRNsISRTHKD 9606 15383279 t llicata "Using a combination of biochemical, enzymatic, and immunofluorescence techniques, we show that the anchoring protein contributes to pkd activation in two ways: it recruits an upstream kinase pkceta and coordinates pka phosphorylation events that release activated protein kinase d. Thus, akap-lbc synchronizes pka and pkc activities in a manner that leads to the activation of a third kinase." SIGNOR-129345 PRKACA protein P17612 UNIPROT KCNH2 protein Q12809 UNIPROT up-regulates phosphorylation Ser1137 EGPTRRLsLPGQLGA 9606 10488078 t lperfetto "Deletion of protein kinase a phosphorylation sites in the herg potassium channel inhibits activation shift by protein kinase afour consensus pka phosphorylation sites (s283a, s890a, t895a, s1137a)" SIGNOR-70718 PRKACA protein P17612 UNIPROT KCNH2 protein Q12809 UNIPROT up-regulates phosphorylation Ser283 CASVRRAsSADDIEA 9606 10488078 t lperfetto "Deletion of protein kinase a phosphorylation sites in the herg potassium channel inhibits activation shift by protein kinase afour consensus pka phosphorylation sites (s283a, s890a, t895a, s1137a)" SIGNOR-70722 PRKACA protein P17612 UNIPROT KCNH2 protein Q12809 UNIPROT up-regulates phosphorylation Ser890 RQRKRKLsFRRRTDK 9606 10488078 t lperfetto "Deletion of protein kinase a phosphorylation sites in the herg potassium channel inhibits activation shift by protein kinase afour consensus pka phosphorylation sites (s283a, s890a, t895a, s1137a)" SIGNOR-70726 PRKACA protein P17612 UNIPROT KCNH2 protein Q12809 UNIPROT up-regulates phosphorylation Thr895 KLSFRRRtDKDTEQP 9606 10488078 t lperfetto "Deletion of protein kinase a phosphorylation sites in the herg potassium channel inhibits activation shift by protein kinase afour consensus pka phosphorylation sites (s283a, s890a, t895a, s1137a)" SIGNOR-70730 PRKACA protein P17612 UNIPROT PPP1R8 protein Q12972 UNIPROT "down-regulates activity" phosphorylation Ser178 TAHNKRIsTLTIEEG -1 9407077 t miannu "NIPP-1 is the RNA-binding subunit of a major species of protein phosphatase-1 in the nucleus. The purified recombinant protein was a potent (Ki = 9.9 +/- 0.3 pM) and specific inhibitor of protein phosphatase-1 and was stoichiometrically phosphorylated by protein kinases A and CK2. At physiological ionic strength, phosphorylation by these protein kinases drastically decreased the inhibitory potency of free NIPP-1. Sequencing and phosphoamino acid analysis of tryptic phosphopeptides enabled us to identify Ser178 and Ser199 as the phosphorylation sites of protein kinase A" SIGNOR-250032 PRKACA protein P17612 UNIPROT GRIK2 protein Q13002 UNIPROT "up-regulates activity" phosphorylation Ser715 FMSSRRQsVLVKSNE 9606 BTO:0000007 8094892 t miannu "GluR6 glutamate receptor, transiently expressed in mammalian cells, is directly phosphorylated by PKA, and that intracellularly applied PKA increases the amplitude of the glutamate response. Site-specific mutagenesis of the serine residue (Ser 684) representing a PKA consensus site completely eliminates PKA-mediated phosphorylation of this site as well as the potentiation of the glutamate response." SIGNOR-250315 PRKACA protein P17612 UNIPROT PRKAA1 protein Q13131 UNIPROT "down-regulates activity" phosphorylation Ser491 SSTPQRSCsAAGLHRPR 10116 BTO:0002135 17023420 t "These agents also enhanced phosphorylation of alpha-Ser(485/491) by the cAMP-dependent protein kinase. AMPK alpha-Ser(485/491) phosphorylation was necessary but not sufficient for inhibition of AMPK activity in response to forskolin/isobutylmethylxanthine." SIGNOR-256112 PRKACA protein P17612 UNIPROT PRKAA1 protein Q13131 UNIPROT "down-regulates activity" phosphorylation Ser496 ATPQRSGsVSNYRSC 9606 27784766 t Luana "These data indicate a novel regulatory role of PKC to inhibit AMPKα1 in human cells. As PKC activation is associated with insulin resistance and obesity, PKC may underlie the reduced Protein kinase C phosphorylates AMP-activated protein kinase α1 Ser487. | AMPK activity reported in response to overnutrition in insulin-resistant metabolic and vascular tissues." SIGNOR-259865 PRKACA protein P17612 UNIPROT PIN1 protein Q13526 UNIPROT "down-regulates activity" phosphorylation Ser16 PGWEKRMsRSSGRVY 9606 11723108 t llicata "Pka and pkc readily phosphorylated pin1 and its ww domain in summary, we have demonstrated that phosphorylation of the pin1 ww domain on ser16 regulates its ability to function as a pser/thr-binding module. |To examine the importance of Ser16 of Pin1, it was mutated to Glu to mimic pSer, and the mutant Pin1S16E failed to bind mitotic phosphoproteins" SIGNOR-112164 PRKACA protein P17612 UNIPROT CACNA1S protein Q13698 UNIPROT "up-regulates activity" phosphorylation Ser1575 PEICRTVsGDLAAEE -1 20937870 t miannu "To identify the regulatory sites of phosphorylation under physiologically relevant conditions, Ca(V)1.1 channels were purified from skeletal muscle and sites of phosphorylation on the α1 subunit were identified by mass spectrometry. Two phosphorylation sites were identified in the proximal C-terminal domain, serine 1575 (S1575) and threonine 1579 (T1579), which are conserved in cardiac Ca(V)1.2 channels (S1700 and T1704, respectively). In vitro phosphorylation revealed that Ca(V)1.1-S1575 is a substrate for both cAMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase II, whereas Ca(V)1.1-T1579 is a substrate for casein kinase 2." SIGNOR-263112 PRKACA protein P17612 UNIPROT CACNA1C protein Q13936 UNIPROT "up-regulates activity" phosphorylation Ser1897 LLRKANPsRCHSRES 10090 BTO:0000087 28119464 t "These findings reveal an essential role for _1C phosphorylation at Ser1928 in stimulating CaV1.2 channel activity and vasoconstriction by AKAP-targeted PKA upon exposure to increased glucose and in diabetes" SIGNOR-251709 PRKACA protein P17612 UNIPROT RASGRF1 protein Q13972 UNIPROT up-regulates phosphorylation Ser927 KEKYRRMsLASAGFP 9606 BTO:0000938 10601308 t llicata "Phosphorylation of serine 916 of ras-grf1 contributes to the activation of exchange factor activity by muscarinic receptors." SIGNOR-73202 PRKACA protein P17612 UNIPROT HNRNPD protein Q14103 UNIPROT up-regulates phosphorylation Ser87 SNSSPRHsEAATAQR 9606 11903055 t gcesareni "Protein kinase a enhances, whereas glycogen synthase kinase-3 beta inhibits, the activity of the exon 2-encoded transactivator domain of heterogeneous nuclear ribonucleoprotein d in a hierarchical fashion." SIGNOR-116144 PRKACA protein P17612 UNIPROT SCRIB protein Q14160 UNIPROT unknown phosphorylation Ser1445 PSPTSRQsPASPPPL 9606 BTO:0000007 20622900 t miannu "HScrib is a substrate of ERK and PKA. Under normal growth conditions, hScrib is phosphorylated at S853, most likely by ERK, and at S1445 by PKA. Interestingly, stimulation of MAPK by osmotic stress results in a marked loss of phosphorylation at the PKA site S1445, but a concomitant increase in phosphorylation at S1448, presumably also by ERK. At present, we have no information as to what are the functional consequences of ERK or PKA phosphorylation of hScrib. However, we can speculate that this will most likely affect the ability of hScrib to interact with some of its cellular partners, and studies are currently in progress to investigate these aspects further." SIGNOR-263066 PRKACA protein P17612 UNIPROT GNA13 protein Q14344 UNIPROT "down-regulates activity" phosphorylation Thr203 ILLARRPtKGIHEYD 9534 BTO:0000298 12399457 t miannu "PKA directly phosphorylates Galpha(13). Galpha(13)-T203A mutant (in COS-7 cells) could not be phosphorylated by PKA. PKA blocks Rho activation by phosphorylation of Galpha(13) Thr(203)." SIGNOR-249985 PRKACA protein P17612 UNIPROT LASP1 protein Q14847 UNIPROT "down-regulates activity" phosphorylation Ser146 MEPERRDsQDGSSYR -1 12432067 t miannu "Lasp-1 binds to non-muscle filamentous (F) actin in vitro in a phosphorylation-dependent manner. Phosphorylation of recombinant lasp-1 with recombinant PKA increased the Kd and decreased the Bmax for lasp-1 binding to F-actin. PKA-dependent phosphorylation sites in rabbit lasp-1 to S99 and S146" SIGNOR-250074 PRKACA protein P17612 UNIPROT LASP1 protein Q14847 UNIPROT "down-regulates activity" phosphorylation Ser146 MEPERRDsQDGSSYR 9606 12571245 t lperfetto "Actin binding of human lim and sh3 protein is regulated by cgmp- and camp-dependent protein kinase phosphorylation on serine 146. Phosphorylation of lasp at ser-146 leads to a redistribution of the actin-bound protein from the tips of the cell membrane to the cytosol, accompanied with a reduced cell migration" SIGNOR-97938 PRKACA protein P17612 UNIPROT LASP1 protein Q14847 UNIPROT "down-regulates activity" phosphorylation Ser146 MEPERRDsQDGSSYR 9606 22665060 t llicata "Phosphorylation of lasp-1 by pka at serine 146 induces translocation of the lasp-1/zo-2 complex from the cytoplasm to the nucleus. Interaction occurs within the carboxyterminal proline-rich motif of zo-2 and the sh3 domain in lasp-1." SIGNOR-197720 PRKACA protein P17612 UNIPROT LASP1 protein Q14847 UNIPROT "up-regulates activity" phosphorylation Ser99 KNKGKGFsVVADTPE -1 12432067 t miannu "Lasp-1 binds to non-muscle filamentous (F) actin in vitro in a phosphorylation-dependent manner. Phosphorylation of recombinant lasp-1 with recombinant PKA increased the Kd and decreased the Bmax for lasp-1 binding to F-actin. PKA-dependent phosphorylation sites in rabbit lasp-1 to S99 and S146" SIGNOR-250075 PRKACA protein P17612 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser275 LSAFRRTsLAGGGRR 9606 BTO:0000887 20151718 t miannu "Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human)." SIGNOR-163752 PRKACA protein P17612 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser311 SFRTPRDsKLEAPAE 9606 BTO:0000887 20151718 t miannu "Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human)." SIGNOR-163764 PRKACA protein P17612 UNIPROT SYN2 protein Q92777 UNIPROT "down-regulates activity" phosphorylation Ser10 NFLRRRLsDSSFIAN -1 10571231 t miannu "Synapsin phosphorylation in the A domain, at the only phosphorylation site shared by all synapsins, dissociates synapsins from synaptic vesicles.This site is located in the N-terminal A domain and is a substrate for both PKA and CaM Kinase I" SIGNOR-250059 PRKACA protein P17612 UNIPROT FRAT1 protein Q92837 UNIPROT down-regulates phosphorylation Ser188 RLQQRRGsQPETRTG 9606 16982607 t lperfetto "Phosphorylation of ser188 by pka inhibited the ability of frat1 to activate beta-catenin-dependent transcription." SIGNOR-149689 PRKACA protein P17612 UNIPROT GPKOW protein Q92917 UNIPROT "up-regulates activity" phosphorylation Ser27 SFGFTRTsARRRLAD -1 21880142 t miannu "PKA phosphorylates GPKOW at S27 and T316 in vitro. GPKOWs ability to bind RNA is sensitive to mutations of its PKA phosphorylation sites." SIGNOR-266309 PRKACA protein P17612 UNIPROT GPKOW protein Q92917 UNIPROT "up-regulates activity" phosphorylation Thr316 GTASSRKtLWNQELY -1 21880142 t miannu "PKA phosphorylates GPKOW at S27 and T316 in vitro. GPKOWs ability to bind RNA is sensitive to mutations of its PKA phosphorylation sites." SIGNOR-266308 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 10230394 t gcesareni "Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo." SIGNOR-67379 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 10230394 t gcesareni "Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo." SIGNOR-67387 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 10949026 t gcesareni "Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo." SIGNOR-81129 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 10949026 t gcesareni "Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo." SIGNOR-81137 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser118 GRELRRMsDEFVDSF 9534 BTO:0000298 10880354 t miannu "Ser(155) is phosphorylated preferentially by PKA in vitro and is the only residue in BAD that becomes phosphorylated when cells are exposed to cAMP-elevating agents. The phosphorylation of BAD at Ser(155) prevents it from binding to Bcl-X(L) and promotes its interaction with 14-3-3 proteins." SIGNOR-250338 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser99 PFRGRSRsAPPNLWA -1 10949026 t gcesareni "Survival factors, acting through kinases such as Akt and PKA, induce endogenous BAD phosphorylation at two evolutionarily conserved sites, Ser-112 and Ser-136, which leads to the translocation of BAD from the mitochondria to the cytoplasm and the inhibition of BAD-dependent death" SIGNOR-180780 PRKACA protein P17612 UNIPROT CUL5 protein Q93034 UNIPROT "up-regulates activity" phosphorylation Ser730 MKMRKKIsNAQLQTE 9534 BTO:0000298 10898738 t miannu "Elimination of the S730 but not the T325 PKA phosphorylation site of VACM-1 resulted in a complete inhibition of the VACM-1 activity, thus suggesting a direct effect of PKA on the VACM-1 receptor." SIGNOR-250352 PRKACA protein P17612 UNIPROT STMN2 protein Q93045 UNIPROT "down-regulates activity" phosphorylation Ser50 KQINKRAsGQAFELI 9534 BTO:0000298 9525956 t miannu "Using in vitro phosphorylated recombinant protein, four phosphorylation sites were identified in the SCG10 sequence. Ser-50 and Ser-97 were the target sites for protein kinase A. phosphorylation negatively regulates the microtubule-depolymerizing activity of SCG10 and that all four sites participate in this regulation" SIGNOR-250056 PRKACA protein P17612 UNIPROT STMN2 protein Q93045 UNIPROT "down-regulates activity" phosphorylation Ser97 AAEERRKsQEAQVLK 9534 BTO:0000298 9525956 t miannu "Using in vitro phosphorylated recombinant protein, four phosphorylation sites were identified in the SCG10 sequence. Ser-50 and Ser-97 were the target sites for protein kinase A. phosphorylation negatively regulates the microtubule-depolymerizing activity of SCG10 and that all four sites participate in this regulation" SIGNOR-250057 PRKACA protein P17612 UNIPROT NEDD4L protein Q96PU5 UNIPROT down-regulates phosphorylation Ser448 IRRPRSLsSPTVTLS 9606 15328345 t gcesareni "Nedd4-2 was a substrate for phosphorylation by pka in vitro and in cells;three nedd4-2 residues were phosphorylated by pka and were required for camp to inhibit nedd4-2 (relative functional importance ser-327 > ser-221 > thr-246)." SIGNOR-128429 PRKACA protein P17612 UNIPROT PPP1R9B protein Q96SB3 UNIPROT "down-regulates activity" phosphorylation Ser94 SERGVRLsLPRASSL 9606 BTO:0000007 12417592 t miannu "Spinophilin is phosphorylated in vitro by protein kinase A (PKA). two major sites of phosphorylation, Ser-94 and Ser-177, that are located within the actin-binding domain of spinophilin. Phosphorylation of spinophilin by PKA modulated the association between spinophilin and the actin cytoskeleton. phosphorylation of spinophilin reduced the stoichiometry of the spinophilin-actin interaction. In contrast, the ability of spinophilin to bind to PP1 remained unchanged." SIGNOR-250035 PRKACA protein P17612 UNIPROT HDAC8 protein Q9BY41 UNIPROT down-regulates phosphorylation Ser39 AKIPKRAsMVHSLIE 9606 14701748 t lperfetto "Negative regulation of histone deacetylase 8 activity by cyclic amp-dependent protein kinase athe pka phosphoacceptor site of hdac8 is ser(39)" SIGNOR-120643 PRKACA protein P17612 UNIPROT GLIS2 protein Q9BZE0 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000938 16537363 t lperfetto "Protein kinase a (pka) and glycogen synthase kinase 3beta sequentially phosphorylate gli2 at multiple sites, identified by mutagenesis, thus resulting in a reduction of its transcriptional activity" SIGNOR-145131 PRKACA protein P17612 UNIPROT MCOLN1 protein Q9GZU1 UNIPROT down-regulates phosphorylation Ser557 SGKFRRGsGSACSLL 9606 17988215 t llicata "The stimulatory effect of h89 on mcoln1 function was not observed when ser(557) and ser(559) were mutated to alanine residues, indicating that these two residues are essential for pka-mediated negative regulation of mcoln1." SIGNOR-158946 PRKACA protein P17612 UNIPROT MCOLN1 protein Q9GZU1 UNIPROT down-regulates phosphorylation Ser559 KFRRGSGsACSLLCC 9606 17988215 t llicata "The stimulatory effect of h89 on mcoln1 function was not observed when ser(557) and ser(559) were mutated to alanine residues, indicating that these two residues are essential for pka-mediated negative regulation of mcoln1." SIGNOR-158950 PRKACA protein P17612 UNIPROT AICDA protein Q9GZX7 UNIPROT unknown phosphorylation Ser38 YVVKRRDsATSFSLD 9606 BTO:0000776 18417471 t llicata "We have found using sf9 insect cells to overexpress human gst-aid that a small fraction of the enzyme is phosphorylated at ser38 and thr27 and at two residues not reported previously, ser41 and ser43" SIGNOR-178244 PRKACA protein P17612 UNIPROT KCNN2 protein Q9H2S1 UNIPROT down-regulates phosphorylation Ser567 SSSRRRRsSSTAPPT 9606 16513649 t llicata "Mutagenesis and mass spectrometry studies identified four pka phosphorylation sites: ser465 (minor site) and three amino acid residues ser568, ser569, and ser570 (major sites) within the carboxyl-terminal region. pka activation decreased sk2 surface localization" SIGNOR-145032 PRKACA protein P17612 UNIPROT KCNN2 protein Q9H2S1 UNIPROT down-regulates phosphorylation Ser568 SSRRRRSsSTAPPTS 9606 16513649 t llicata "Mutagenesis and mass spectrometry studies identified four pka phosphorylation sites: ser465 (minor site) and three amino acid residues ser568, ser569, and ser570 (major sites) within the carboxyl-terminal region. pka activation decreased sk2 surface localization" SIGNOR-145040 PRKACA protein P17612 UNIPROT KCNN2 protein Q9H2S1 UNIPROT down-regulates phosphorylation Ser569 SRRRRSSsTAPPTSS 9606 16513649 t llicata "Mutagenesis and mass spectrometry studies identified four pka phosphorylation sites: ser465 (minor site) and three amino acid residues ser568, ser569, and ser570 (major sites) within the carboxyl-terminal region. pka activation decreased sk2 surface localization" SIGNOR-145044 PRKACA protein P17612 UNIPROT DNAJC5 protein Q9H3Z4 UNIPROT unknown phosphorylation Ser10 DQRQRSLsTSGESLY 9606 BTO:0000938 18951872 t gcesareni "Csp is phosphorylated in vivo on a single residue, ser10, and this phosphorylation regulates its cellular functions,[...]PKA Phosphorylation of full-length csp protein stimulated 14-3-3 binding, and this was abolished in a ser10-ala mutant csp, confirming the binding site as phospho-ser10" SIGNOR-181788 PRKACA protein P17612 UNIPROT APOBEC3G protein Q9HC16 UNIPROT up-regulates phosphorylation Thr32 PILSRRNtVWLCYEV 9606 18836454 t llicata "Here we show that pka binds and specifically phosphorylates a3g at thr32 in vitro and in vivo. This phosphorylation event reduces the binding of a3g to vif and its subsequent ubiquitination and degradation, and thus promotes a3g antiviral activity." SIGNOR-181526 PRKACA protein P17612 UNIPROT KCNK9 protein Q9NPC2 UNIPROT up-regulates phosphorylation Ser373 RLMKRRKsV 9606 BTO:0000007 21357689 t llicata "Patch clamp analysis, flow cytometry, and immunocytochemistry studies of hek293 transfected with wt hk2p3.1 and cultured in the presence of pka activators or inhibitors all confirm that activation of pka resulted in an increase in hk2p3.1 current expression (figs. 4_4?6) and demonstrate the dynamic regulatory effect of pka activity on k2p3.1 channel expression." SIGNOR-172466 PRKACA protein P17612 UNIPROT KCNQ5 protein Q9NR82 UNIPROT "up-regulates activity" phosphorylation Ser88 GKQGARMsLLGKPLS 9606 BTO:0001660 30061510 t miannu "We conclude that phosphorylation of S53 on the amino terminus of Kv7.5 is essential for PKA-dependent enhancement of channel activity in response to βAR activation in vascular and airway smooth muscle cells." SIGNOR-265980 PRKACA protein P17612 UNIPROT DUOX1 protein Q9NRD9 UNIPROT up-regulates phosphorylation Ser1217 SHHFRRRsFRGFWLT 9606 19144650 t llicata "We analyzed the duox1 phosphorylation state with an anti-rxx(ps/pt) antibody that could potentially recognize phosphorylation on ser955 and ser1217 but not on thr1007. duox1 but not duox2 activity is stimulated by forskolin (ec50 = 0.1 _m) via protein kinase a-mediated duox1 phosphorylation on serine 955. duox1 is positively regulated by the camp-dependent protein kinase a (pka)6 cascade" SIGNOR-183445 PRKACA protein P17612 UNIPROT DUOX1 protein Q9NRD9 UNIPROT up-regulates phosphorylation Ser955 KDLCRRAsYISQDMI 9606 19144650 t llicata "We analyzed the duox1 phosphorylation state with an anti-rxx(ps/pt) antibody that could potentially recognize phosphorylation on ser955 and ser1217 but not on thr1007. duox1 but not duox2 activity is stimulated by forskolin (ec50 = 0.1 _m) via protein kinase a-mediated duox1 phosphorylation on serine 955. duox1 is positively regulated by the camp-dependent protein kinase a (pka)6 cascade" SIGNOR-183449 PRKACA protein P17612 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation 10090 BTO:0000944 23644383 t milica "Here, we show that cyclic amp (camp)-dependent protein kinase (pka) phosphorylates lats and thereby enhances its activity sufficiently to phosphorylate yap on ser381." SIGNOR-236994 PRKACA protein P17612 UNIPROT CHCHD3 protein Q9NX63 UNIPROT unknown phosphorylation Thr11 TTSTRRVtFEADENE -1 17242405 t miannu "Identification of ChChd3 as a novel substrate of the cAMP-dependent protein kinase (PKA) using an analog-sensitive catalytic subunit. we used the recombinant GST-ChChd3 for an in vitro kinase assays to determine whether in vitro phosphorylation by PKA was direct. Fig. 6 demonstrates that PKA directly phosphorylates recombinant Chchd3 with a stoichiometry of 0.3 mol of phosphate incorporated per mol of ChChd3. Although three potential PKA phosphorylation sites exist in ChChd3, Thr10 represents the most likely site to be phosphorylated." SIGNOR-263116 PRKACA protein P17612 UNIPROT NDE1 protein Q9NXR1 UNIPROT up-regulates phosphorylation Thr131 LERAKRAtIMSLEDF 9606 BTO:0000142 21677187 t lperfetto "Here, we demonstrate that disc1 and pde4 modulate nde1 phosphorylation by camp-dependent protein kinase a (pka) and identify a novel pka substrate site on nde1 at threonine-131 (t131).Since phosphorylated t131 is detectable at multiple subcellular locations (centrosome, nucleus, postsynaptic density, proximal axon), there is potential for disc1/pde4 to influence several important brain processes that critically depend on the nde1/ndel1/lis1 comple" SIGNOR-174410 PRKACA protein P17612 UNIPROT SUFU protein Q9UMX1 UNIPROT up-regulates phosphorylation Ser346 RAPSRKDsLESDSST 9606 23337587 t gcesareni "Interestingly, sufu stability is regulated via dual phosphorylation at ser342/ser346 by pka and gsk3, and blocking sufu phosphorylation either by mutating ser346 to ala or by treating cultured cells with pka inhibitors attenuates sufu ciliary accumulation, whereas phospho-mimetic forms of sufu exhibits increased ciliary localization" SIGNOR-119099 PRKACA protein P17612 UNIPROT SUFU protein Q9UMX1 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser342 LAHDRAPsRKDSLES 9606 21317289 t gcesareni "We report that Sufu is phosphorylated at Ser-342 and Ser-346 by GSK3? and cAMP-dependent protein kinase A (PKA), respectively, and phosphorylation at this dual site stabilizes Sufu against Shh signaling-induced degradation." SIGNOR-171999 PRKACA protein P17612 UNIPROT SUFU protein Q9UMX1 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser346 RAPSRKDsLESDSST 9606 21317289 t gcesareni "We report that Sufu is phosphorylated at Ser-342 and Ser-346 by GSK3? and cAMP-dependent protein kinase A (PKA), respectively, and phosphorylation at this dual site stabilizes Sufu against Shh signaling-induced degradation" SIGNOR-172003 PRKACA protein P17612 UNIPROT HDAC5 protein Q9UQL6 UNIPROT "up-regulates activity" phosphorylation Ser279 KVAERRSsPLLRRKD 9606 22865920 t lperfetto "PKA/Cdk5-mediated phosphorylation of HDAC5 at Ser279 within the NLS promotes nuclear localization of HDAC5 and interaction with the nuclear corepressor complex" SIGNOR-198658 PRKACA protein P17612 UNIPROT PDE10A protein Q9Y233 UNIPROT unknown phosphorylation Thr15 SQHLTGLtDEKVKAY 9606 BTO:0000007 20610737 t llicata "When coexpressed with the catalytic subunit of pka in transfected hek293 cells, wild-type (wt) pde10a2 (pde10a2wt) was phosphorylated at thr-16 these data confirm the previously reported findings that pka phosphorylation of pde10a2 on thr-16 results in a cytosolic localization" SIGNOR-166559 PRKACA protein P17612 UNIPROT STK24 protein Q9Y6E0 UNIPROT unknown phosphorylation Thr18 ALNKRRAtLPHPGGS 9606 BTO:0000007 BTO:0000142;BTO:0000671 10644707 t llicata "Further experiments demonstrated that mst3b, but not mst3, was effectively phosphorylated by activation of cyclic amp-dependent protein kinase (pka) in both in vivo and in vitro assays. The mutation of thr-18 into ala in mst3b (t18a), a putative pka phosphorylation site that is absent in mst3, abolished its phosphorylation by pka." SIGNOR-74284 PRKACA protein P17612 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates phosphorylation Ser857 PPYNRAVsLDSPVSV 9606 15383283 t gcesareni "Herein, we report the successful identification of six functional in vivo src-3 phosphorylation sites." SIGNOR-129349 PRKACA protein P17612 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 9660950 t lperfetto "The transcriptional activity of nf-kappa b is stimulated upon phosphorylation of its p65 subunit on serine 276 by protein kinase a (pka)." SIGNOR-217364 PRKACA protein P17612 UNIPROT AMPK complex SIGNOR-C15 SIGNOR "down-regulates activity" phosphorylation 10116 BTO:0002135 17023420 t "These agents also enhanced phosphorylation of alpha-Ser(485/491) by the cAMP-dependent protein kinase. AMPK alpha-Ser(485/491) phosphorylation was necessary but not sufficient for inhibition of AMPK activity in response to forskolin/isobutylmethylxanthine." SIGNOR-256111 PRKACA protein P17612 UNIPROT PIM proteinfamily SIGNOR-PF34 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000007 30017192 t miannu "In this study, we found that PKCα stabilized and activated PIM-1L by phosphorylation at Ser65. The PIM-1L phosphorylation suppressed sotrastaurin-induced apoptosis. These findings suggest that PKCα promotes cell survival and proliferation by upregulating PIM-1L in acute myeloid leukemia." SIGNOR-259413 CAPN2 protein P17655 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" cleavage 9606 BTO:0000590 25969760 t lperfetto "Besides tau phosphorylation, calpain activation might play a role in tau-mediated neurodegeneration by inducing tau cleavage. In vitro studies have shown that both fetal and adult tau isoforms are rapidly proteolyzed by calpains" SIGNOR-251611 CAPN2 protein P17655 UNIPROT GSK3A protein P49840 UNIPROT "up-regulates activity" cleavage 9606 BTO:0000590 25969760 t lperfetto "Thus, it has been shown that calpain cleaves the inhibitory domain of GSK3 generating two fragments of 40 and 30 kDa. This cleavage enhanced activity of the kinase" SIGNOR-251612 CAPN2 protein P17655 UNIPROT GSK3B protein P49841 UNIPROT "up-regulates activity" cleavage 9606 BTO:0000590 25969760 t lperfetto "Thus, it has been shown that calpain cleaves the inhibitory domain of GSK3 generating two fragments of 40 and 30 kDa. This cleavage enhanced activity of the kinase" SIGNOR-251613 CAPN2 protein P17655 UNIPROT F2RL1 protein P55085 UNIPROT "down-regulates activity" cleavage Gly71 FSASVLTgKLTTVFL -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3" SIGNOR-263581 CAPN2 protein P17655 UNIPROT F2RL1 protein P55085 UNIPROT "down-regulates activity" cleavage Thr45 LIGKVDGtSHVTGKG -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3" SIGNOR-263582 CAPN2 protein P17655 UNIPROT CDK5R1 protein Q15078 UNIPROT "up-regulates activity" cleavage 9606 BTO:0000590 25969760 t lperfetto "Calpains also modulate the activity of CDK5. Physiologically, CDK 5 is activated by p35 and its cleaved product p25. The latter has a longer half life than p35 and therefore it is a more potent activator of CDK5. The cleavage of p35 to p25 is mediated by calpain" SIGNOR-251610 CAPN2 protein P17655 UNIPROT CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR "up-regulates activity" cleavage 9606 BTO:0000590 25969760 t lperfetto "Calpains also modulate the activity of CDK5. Physiologically, CDK 5 is activated by p35 and its cleaved product p25. The latter has a longer half life than p35 and therefore it is a more potent activator of CDK5. The cleavage of p35 to p25 is mediated by calpain" SIGNOR-251608 CEBPB protein P17676 UNIPROT C3 protein P01024 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 25617152 t Gianni "CCAAT/enhancer binding protein β directly regulates the expression of the complement component 3 gene in neural cells: implications for the pro-inflammatory effects of this transcription factor" SIGNOR-261927 CEBPB protein P17676 UNIPROT S100A9 protein P06702 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001370 9706399 t "Among several known transcription factor binding motifs, nuclear protein(s) of VD3-treated HL-60 cells and THP-1 cells bound to the CCAAT/enhancer binding protein (C/EBP)-binding motif that was located in the upstream region of the MRP14 gene (-81), as evidenced by the competitive gel mobility-shift assay.|Thus, it was concluded that C/EBP alpha and -beta were able to bind to the C/EBP motif, and that C/EBP alpha bound to the motif in THP-1 cells and C/EBP beta bound to that in the VD3-treated HL-60 cells." SIGNOR-254044 CEBPB protein P17676 UNIPROT ABCB1 protein P08183 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000093 15044620 f miannu "C/EBPbeta activates the endogenous MDR1 gene of MCF-7 cells, and this activation was associated with a novel C/EBPbeta interaction region within the proximal MDR1 promoter (-128 to -75)." SIGNOR-253771 CEBPB protein P17676 UNIPROT GOT1 protein P17174 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 8454627 t "Tumor necrosis factor (TNF)-stimulated gene 6 (TSG-6) encodes a protein expressed during inflammation. We have previously shown that transcription factors of the NF-IL6 and AP-1 families cooperatively modulate activation of the TSG-6 gene by TNF or interleukin 1 (IL-1) through a promoter region that contains an NF-IL6 site (-106 to -114) and an AP-1 element" SIGNOR-254051 CEBPB protein P17676 UNIPROT CSRP1 protein P21291 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000972 14522018 t "We conclude that c-Rel regulates CRP expression without the requirement of binding to a kappaB site, and binds directly to C/EBPbeta to facilitate the binding of C/EBPbeta to the CRP promoter" SIGNOR-254049 CEBPB protein P17676 UNIPROT IL10 protein P22301 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000738;BTO:0001370 12493739 f mianu "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 CEBPB protein P17676 UNIPROT SFTPD protein P35247 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001910 11912209 t "Cotransfection of C/EBPalpha, C/EBPbeta, or C/EBPdelta cDNA in H441 lung adenocarcinoma cells significantly increased the luciferase activity of a wild-type SP-D promoter construct containing 698 bp of upstream sequence (SS698). Transfection of C/EBP also increased the level of endogenous SP-D mRNA in H441 cells| Thus, interactions among C/EBP elements in the near-distal promoter can modulate the promoter activity of SP-D." SIGNOR-254045 CEBPB protein P17676 UNIPROT ADM protein P35318 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9480831 t "These findings suggest that NF-IL6 and AP-2 sites in the promoter region are the functional elements in the transcriptional regulation of human AM gene in vascular endothelial cells." SIGNOR-254047 CEBPB protein P17676 UNIPROT STAR protein P49675 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003697 18583320 t "Electrophoretic mobility shift assay demonstrated that this region of the StAR promoter was bound by C/EBPalpha, C/EBPbeta, and CREB. Forced expression of either C/EBPalpha or C/EBPbeta alone was sufficient to up-regulate StAR promoter activity whereas PGE(2) was needed to induce StAR promoter activity in CREB-overexpressed cells." SIGNOR-254046 CEBPB protein P17676 UNIPROT GFER protein P55789 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000599 20690902 f miannu "In the present study, we investigated transcription of hHSS triggered by EGF (epidermal growth factor) and the role of C/EBPβ (CCAAT/enhancer-binding protein β) as a potential core factor responsible for hHSS transcription in HepG2 cells. The results show that EGF suppresses hHSS mRNA expression at early time points. Using a promoter deletion assay, we identified a proximal region (-358/-212) that is required for EGF suppression. Overexpression of C/EBPβ enhances EGF suppression of hHSS, and mutation of the C/EBPβ-binding site at -292/-279 or siRNA (short interfering RNA) interference abolishes EGF suppression." SIGNOR-253772 CEBPB protein P17676 UNIPROT KLF5 protein Q13887 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 16054042 f 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 CEBPB protein P17676 UNIPROT PCK2 protein Q16822 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000608 8093246 f miannu "C/EBP beta can regulate PEPCK gene transcription by acting through the CRE and that C/EBP beta, together with CREB, may contribute to the cAMP responsiveness of the PEPCK promoter." SIGNOR-253773 CEBPB protein P17676 UNIPROT SLC5A8 protein Q8N695 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20082847 t "Luciferase reporter assays of deletion mutants of SLC5A8 promoter demonstrated that a 295-bp region is essential for the basal promoter activity of the SLC5A8 gene. Further analysis indicated that the CCAAT boxes and GC boxes were involved in positive regulation of SLC5A8 promoter. Overexpression of two transcription factors, CCAAT/enhancer binding protein beta (C/EBPbeta) and specific transcription factor 1 (Sp1), upregulated the activities of the human SLC5A8 promoter and protein expression, suggesting that both C/EBPbeta and Sp1 transcription factors might have functions in SLC5A8 transcription." SIGNOR-254054 CEBPB protein P17676 UNIPROT GDF15 protein Q99988 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 24086573 t "Promoter analysis and chromatin immunoprecipitation analysis revealed that CEBPB could contribute to K7174-mediated transcriptional activation of GDF15." SIGNOR-254050 HLA-G protein P17693 UNIPROT LILRB1 protein Q8NHL6 UNIPROT up-regulates binding 9606 15718280 t gcesareni "Hla-g binds a limited repertoire of peptides and interacts with the inhibitory leukocyte ig-like receptors lir-1 and lir-2" SIGNOR-134180 HLA-G protein P17693 UNIPROT KIR2DL4 protein Q99706 UNIPROT up-regulates binding 9606 10190900 t gcesareni "Recombinant soluble kir2dl4 binds to cells expressing hla-g but not to cells expressing other hla class i molecules." SIGNOR-66132 PTPN2 protein P17706 UNIPROT WASL protein O00401 UNIPROT down-regulates dephosphorylation Tyr256 RETSKVIyDFIEKTG 9606 BTO:0000782 16293614 t gcesareni "Similarly, the t cell phosphatase has a 30-fold lower kcat/km toward autoinhibited p-n-wasp than toward the isolated p-gbd, and again this effect is largely reversed by that cdc42" SIGNOR-141652 PTPN2 protein P17706 UNIPROT EGFR protein P00533 UNIPROT down-regulates dephosphorylation 9606 BTO:0000527 11514572 t gcesareni "Tc45 dephosphorylated delta egfr in u87mg glioblastoma cells and inhibited mitogen-activated protein kinase erk2 and phosphatidylinositol 3-kinase signaling. In contrast, the substrate-trapping tc45-d182a mutant, which is capable of forming stable complexes with tc45 substrates, suppressed the activation of erk2 but not phosphatidylinositol 3-kinase. The activation results in reduced egfr phosphorylation after egf stimulation. Introduction of the alpha(1) cytoplasmic domain peptide into cells induces phosphatase activation and inhibits egf-induced cell proliferation and anchorage-independent growth of malignant cells." SIGNOR-109804 PTPN2 protein P17706 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 10734133 t flangone "Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1." SIGNOR-75910 PTPN2 protein P17706 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 10734133 t flangone "Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1." SIGNOR-75914 PTPN2 protein P17706 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 10734133 t flangone "Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1." SIGNOR-75918 PTPN2 protein P17706 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 10734133 t flangone "Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1." SIGNOR-75922 PTPN2 protein P17706 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 1373652 t gcesareni "The question of whether protein tyrosine phosphatases (ptpases) dephosphorylate a multiply phosphorylated peptide in a random or ordered manner was investigated using the synthetic triphosphotyrosyl peptide trdiy(p)etdy(p)y(p)rk, corresponding to the major sites of autophosphorylation of the insulin receptor, as a substrate for four purified ptpases." SIGNOR-18018 PTPN2 protein P17706 UNIPROT INSR protein P06213 UNIPROT "down-regulates activity" dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 BTO:0000007 12612081 t "In this study, we investigated the downregulation of insulin receptor (IR) signaling by TCPTP. In response to insulin stimulation, the TC48-D182A and TC45-D182A substrate-trapping mutants formed stable complexes with the endogenous tyrosine-phosphorylated IR beta-subunit in 293 cells.|IR β-subunit phosphorylated on tyrosine and specifically on tyrosines 1162 and 1163 could be coimmunoprecipitated with the TC48-D182A and TC45-D182A mutants but not the wild-type TC48 or TC45 in response to insulin" SIGNOR-248385 PTPN2 protein P17706 UNIPROT FYN protein P06241 UNIPROT down-regulates dephosphorylation Tyr420 RLIEDNEyTARQGAK 9606 BTO:0000782 22080863 t lperfetto "Previously, we reported that sfks can serve as bona fide substrates for tcptp and that tcptp dephosphorylates the y418 activation loop autophosphorylation site (corresponding to y394 in lck and y417 in fyn) to inactivate sfks" SIGNOR-177113 PTPN2 protein P17706 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1234 RDMYDKEyYSVHNKT 9606 18819921 t gcesareni "We have identified ptp1b and tcptp as negative regulators of the hepatocyte growth factor receptor, the met receptor-tyrosine kinase. In vivo, loss of ptp1b or tcptp enhances hepatocyte growth factor-mediated phosphorylation of met." SIGNOR-181331 PTPN2 protein P17706 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1235 DMYDKEYySVHNKTG 9606 18819921 t gcesareni "We have identified ptp1b and tcptp as negative regulators of the hepatocyte growth factor receptor, the met receptor-tyrosine kinase. In vivo, loss of ptp1b or tcptp enhances hepatocyte growth factor-mediated phosphorylation of met." SIGNOR-181335 PTPN2 protein P17706 UNIPROT MET protein P08581 UNIPROT "down-regulates activity" dephosphorylation Tyr1234 RDMYDKEyYSVHNKT 9606 18819921 t "Using substrate trapping mutants of PTP1B or TCPTP, we have demonstrated that both phosphatases interact with Met and that these interactions require phosphorylation of twin tyrosines (Tyr-1234/1235) in the activation loop of the Met kinase domain.|Using small interfering RNA against PTP1B and TCPTP, we demonstrate that phosphorylation of Tyr-1234/1235 in the activation loop of the Met receptor is elevated in the absence of either PTP1B or TCPTP and further elevated upon loss of both phosphatases." SIGNOR-248387 PTPN2 protein P17706 UNIPROT MET protein P08581 UNIPROT "down-regulates activity" dephosphorylation Tyr1235 DMYDKEYySVHNKTG 9606 18819921 t "Using substrate trapping mutants of PTP1B or TCPTP, we have demonstrated that both phosphatases interact with Met and that these interactions require phosphorylation of twin tyrosines (Tyr-1234/1235) in the activation loop of the Met kinase domain.|Using small interfering RNA against PTP1B and TCPTP, we demonstrate that phosphorylation of Tyr-1234/1235 in the activation loop of the Met receptor is elevated in the absence of either PTP1B or TCPTP and further elevated upon loss of both phosphatases." SIGNOR-248388 PTPN2 protein P17706 UNIPROT PDGFRB protein P09619 UNIPROT "down-regulates activity" dephosphorylation Tyr1021 PNEGDNDyIIPLPDP 10090 BTO:0002572 14966296 t "The PDGF beta receptor is negatively regulated by protein tyrosine phosphatases (PTPs).|In summary, our findings identify TC-PTP as a previously unrecognized negative regulator of PDGF beta receptor signaling and support the general notion that PTPs display site selectivity in their action on tyrosine kinase receptors.The fact that two of the investigated PDGF β receptor sites, Y1021 and Y771, displayed a larger increase in phosphorylation than Y579 and Y751 in TC-PTP ko MEFs indicated that these two sites are preferred substrates for TC-PTP." SIGNOR-248390 PTPN2 protein P17706 UNIPROT PDGFRB protein P09619 UNIPROT "down-regulates activity" dephosphorylation Tyr771 ADIESSNyMAPYDNY 10090 BTO:0002572 14966296 t "The PDGF beta receptor is negatively regulated by protein tyrosine phosphatases (PTPs).|In summary, our findings identify TC-PTP as a previously unrecognized negative regulator of PDGF beta receptor signaling and support the general notion that PTPs display site selectivity in their action on tyrosine kinase receptors.The fact that two of the investigated PDGF β receptor sites, Y1021 and Y771, displayed a larger increase in phosphorylation than Y579 and Y751 in TC-PTP ko MEFs indicated that these two sites are preferred substrates for TC-PTP." SIGNOR-248389 PTPN2 protein P17706 UNIPROT GHR protein P10912 UNIPROT "down-regulates activity" dephosphorylation Tyr332 ILAIHDSyKPEFHSD 10029 BTO:0000246 12907755 t "PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates" SIGNOR-248391 PTPN2 protein P17706 UNIPROT GHR protein P10912 UNIPROT "down-regulates activity" dephosphorylation Tyr487 SLSNIDFyAQVSDIT 10029 BTO:0000246 12907755 t "PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates" SIGNOR-248392 PTPN2 protein P17706 UNIPROT GHR protein P10912 UNIPROT "down-regulates activity" dephosphorylation Tyr534 NFLMDNAyFCEADAK 10029 BTO:0000246 12907755 t "PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates" SIGNOR-248393 POU3F2 protein P20265 UNIPROT MITF protein O75030 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 18628967 t lperfetto "We further demonstrate that BRN2 induces MITF transcription through a binding site located at ˆ’50/ˆ’36 of the MITF promoter" SIGNOR-249616 PTPN2 protein P17706 UNIPROT GHR protein P10912 UNIPROT "down-regulates activity" dephosphorylation Tyr566 SLNQEDIyITTESLT 10029 BTO:0000246 12907755 t "PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates" SIGNOR-248394 PTPN2 protein P17706 UNIPROT GJA1 protein P17302 UNIPROT up-regulates dephosphorylation Tyr247 VKGKSDPyHATSGAL 9606 BTO:0000671 24849651 t lperfetto "Tc-ptp dephosphorylates cx43 residues y247 and y265, dephosphorylation maintained cx43 gap junctions at the plaque and partially reversed the channel closure caused by v-src-mediated phosphorylation of cx43." SIGNOR-205097 PTPN2 protein P17706 UNIPROT GJA1 protein P17302 UNIPROT up-regulates dephosphorylation Tyr265 KDCGSQKyAYFNGCS 9606 BTO:0000671 24849651 t lperfetto "Tc-ptp dephosphorylates cx43 residues y247 and y265, dephosphorylation maintained cx43 gap junctions at the plaque and partially reversed the channel closure caused by v-src-mediated phosphorylation of cx43." SIGNOR-205101 PTPN2 protein P17706 UNIPROT JAK1 protein P23458 UNIPROT "down-regulates activity" dephosphorylation Tyr1034 AIETDKEyYTVKDDR 10090 11909529 t "The T cell protein tyrosine phosphatase is a negative regulator of janus family kinases 1 and 3|We have identified JAK1 and JAK3 as physiological substrates of TCPTP.| Using a site-specific antibody directed against the activation loop phosphotyrosines in JAK1 (pY1022/pY1023), we found that these sites were in fact dephosphorylated by TCPTP" SIGNOR-248395 PTPN2 protein P17706 UNIPROT JAK1 protein P23458 UNIPROT "down-regulates activity" dephosphorylation 9606 15780598 t lperfetto "Upon ligand binding, IL-2R , IL-6R or LeptinR , IFN-_R , IFN-_R and PRLR or growth hormone (GH) receptor associated JAKs become activated. These JAKs mediate phosphorylation of specific tyrosine residues and recruit STATs. Activated STATs are released from the receptor and translocate to the nucleus. PTP1B dephosphorylates JAK2, TYK2 and STAT5 . The 45-kDa form of TC-PTP was shown to dephosphorylate JAK1 and JAK3 as well as STAT1, STAT3 and STAT5." SIGNOR-134620 PTPN2 protein P17706 UNIPROT SHC1 protein P29353 UNIPROT "down-regulates activity" dephosphorylation Tyr349 EEPPDHQyYNDFPGK 9606 9488479 t llicata "However, TC45 inhibited the EGF-induced association of p52Shc with Grb2, which was attributed to the ability of the PTP to recognize specifically p52Shc phosphorylated on Y239. These results indicate that TC45 recognizes not only selected substrates in a cellular context but also specific sites within substrates and thus may regulate discrete signaling events." SIGNOR-248397 PTPN2 protein P17706 UNIPROT AKT1 protein P31749 UNIPROT down-regulates 9606 12612081 f acerquone "We found that insulin-induced ir tyrosine phosphorylation and pkb/akt sig- naling were enhanced in tcptp- cells and suppressed upon tcptp reconstitution, providing persuasive evidence that tcptp can regulate ir activation and signaling." SIGNOR-252640 PTPN2 protein P17706 UNIPROT KDR protein P35968 UNIPROT down-regulates dephosphorylation Tyr996 EEAPEDLyKDFLTLE 9606 BTO:0000782 18840653 t gcesareni "Vegfr2 contains several critical tyrosine residues that are autophosphorylated following activation. Our phosphorylation assays showed that tcptp was able to target specific tyrosines in vegfr2. The autophosphorylation sites tyr1054/1059 and tyr1214 were dephosphorylated by tcptp. Tyr996 was a tcptp target as well." SIGNOR-181550 PTPN2 protein P17706 UNIPROT KDR protein P35968 UNIPROT "down-regulates activity" dephosphorylation Tyr1054 FGLARDIyKDPDYVR 9606 BTO:0000007 18840653 t "We show that a TCPTP substrate-trapping mutant interacts with VEGFR2. Moreover, TCPTP dephosphorylates VEGFR2 in a phosphosite-specific manner, inhibits its kinase activity and prevents its internalization from the cell surface. |The autophosphorylation sites Tyr1054/1059 and Tyr1214 were dephosphorylated by TCPTP (Fig. 4B). Tyr996, the functional significance of which is currently uncertain (Olsson et al., 2006), was a TCPTP target as well." SIGNOR-248399 PTPN2 protein P17706 UNIPROT KDR protein P35968 UNIPROT "down-regulates activity" dephosphorylation Tyr1059 DIYKDPDyVRKGDAR 9606 BTO:0000007 18840653 t "We show that a TCPTP substrate-trapping mutant interacts with VEGFR2. Moreover, TCPTP dephosphorylates VEGFR2 in a phosphosite-specific manner, inhibits its kinase activity and prevents its internalization from the cell surface. |The autophosphorylation sites Tyr1054/1059 and Tyr1214 were dephosphorylated by TCPTP (Fig. 4B). Tyr996, the functional significance of which is currently uncertain (Olsson et al., 2006), was a TCPTP target as well." SIGNOR-248400 PTPN2 protein P17706 UNIPROT KDR protein P35968 UNIPROT "down-regulates activity" dephosphorylation Tyr1214 VCDPKFHyDNTAGIS 9606 BTO:0000007 18840653 t "We show that a TCPTP substrate-trapping mutant interacts with VEGFR2. Moreover, TCPTP dephosphorylates VEGFR2 in a phosphosite-specific manner, inhibits its kinase activity and prevents its internalization from the cell surface. |The autophosphorylation sites Tyr1054/1059 and Tyr1214 were dephosphorylated by TCPTP (Fig. 4B). Tyr996, the functional significance of which is currently uncertain (Olsson et al., 2006), was a TCPTP target as well." SIGNOR-248401 PTPN2 protein P17706 UNIPROT KDR protein P35968 UNIPROT unknown dephosphorylation Tyr996 EEAPEDLyKDFLTLE 9606 BTO:0000007 18840653 t "We show that a TCPTP substrate-trapping mutant interacts with VEGFR2. Moreover, TCPTP dephosphorylates VEGFR2 in a phosphosite-specific manner, inhibits its kinase activity and prevents its internalization from the cell surface. |The autophosphorylation sites Tyr1054/1059 and Tyr1214 were dephosphorylated by TCPTP (Fig. 4B). Tyr996, the functional significance of which is currently uncertain (Olsson et al., 2006), was a TCPTP target as well." SIGNOR-248398 PTPN2 protein P17706 UNIPROT STAT1 protein P42224 UNIPROT "down-regulates activity" dephosphorylation Tyr701 DGPKGTGyIKTELIS 9606 12138178 t "Upon interferon (IFN) stimulation, Stat1 becomes tyrosine phosphorylated and translocates into the nucleus, where it binds to DNA to activate transcription. The activity of Stat1 is dependent on tyrosine phosphorylation, and its inactivation in the nucleus is accomplished by a previously unknown protein tyrosine phosphatase (PTP). We have now purified a Stat1 PTP activity from HeLa cell nuclear extract and identified it as TC45, the nuclear isoform of the T-cell PTP (TC-PTP)." SIGNOR-248402 PTPN2 protein P17706 UNIPROT STAT1 protein P42224 UNIPROT "down-regulates activity" dephosphorylation 9606 15780598 t lperfetto "Upon ligand binding, IL-2R , IL-6R or LeptinR , IFN-_R , IFN-_R and PRLR or growth hormone (GH) receptor associated JAKs become activated. These JAKs mediate phosphorylation of specific tyrosine residues and recruit STATs. Activated STATs are released from the receptor and translocate to the nucleus. PTP1B dephosphorylates JAK2, TYK2 and STAT5 . The 45-kDa form of TC-PTP was shown to dephosphorylate JAK1 and JAK3 as well as STAT1, STAT3 and STAT5." SIGNOR-133279 EGR1 protein P18146 UNIPROT COL10A1 protein Q03692 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21931594 f Regulation miannu "Egr-1 induced a time-dependent ECM gene expression program, with the number of ECM genes increasing >2.5-fold (from 16 to 41) between 24 and 48 h. Genes in this group include those coding for multiple collagens (COL4A1, COL4A2, COL11A1, COL7A1, COL10A1)" SIGNOR-251921 PTPN2 protein P17706 UNIPROT STAT5A protein P42229 UNIPROT "down-regulates activity" dephosphorylation 9606 15780598 t lperfetto "Upon ligand binding, IL-2R , IL-6R or LeptinR , IFN-_R , IFN-_R and PRLR or growth hormone (GH) receptor associated JAKs become activated. These JAKs mediate phosphorylation of specific tyrosine residues and recruit STATs. Activated STATs are released from the receptor and translocate to the nucleus. PTP1B dephosphorylates JAK2, TYK2 and STAT5 . The 45-kDa form of TC-PTP was shown to dephosphorylate JAK1 and JAK3 as well as STAT1, STAT3 and STAT5." SIGNOR-133547 PTPN2 protein P17706 UNIPROT JAK3 protein P52333 UNIPROT "down-regulates activity" dephosphorylation 9606 15780598 t lperfetto "Upon ligand binding, IL-2R , IL-6R or LeptinR , IFN-_R , IFN-_R and PRLR or growth hormone (GH) receptor associated JAKs become activated. These JAKs mediate phosphorylation of specific tyrosine residues and recruit STATs. Activated STATs are released from the receptor and translocate to the nucleus. PTP1B dephosphorylates JAK2, TYK2 and STAT5 . The 45-kDa form of TC-PTP was shown to dephosphorylate JAK1 and JAK3 as well as STAT1, STAT3 and STAT5." SIGNOR-133078 PTPN2 protein P17706 UNIPROT FKBP4 protein Q02790 UNIPROT down-regulates dephosphorylation 9606 BTO:0000567 12552015 t tpavlidou "We have documented that a cellular protein that binds the immunosuppressant drug fk506, termed the fk506-binding protein (fkbp52), interacts with the single-stranded d sequence within the aav inverted terminal repeats, inhibits viral second-strand dna synthesis, and consequently limits high-efficiency transgene expression. Deliberate overexpression of the murine wild-type (wt) tc-ptp gene, but not that of a cysteine-to-serine (c-s) mutant, caused tyrosine dephosphorylation of fkbp52, leading to efficient viral second-strand dna synthesis and resulting in a significant increase in aav-mediated transduction efficiency in hela cells in vitro." SIGNOR-97794 PTPN2 protein P17706 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates 9606 12612081 f acerquone "We found that insulin-induced ir tyrosine phosphorylation and pkb/akt sig- naling were enhanced in tcptp- cells and suppressed upon tcptp reconstitution, providing persuasive evidence that tcptp can regulate ir activation and signaling." SIGNOR-98811 TPH1 protein P17752 UNIPROT 5-hydroxy-L-tryptophan smallmolecule CHEBI:17780 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 BTO:0006205 31024440 t brain lperfetto "In serotonergic neurons Trp serves as the precursor for 5-HT. The 5-HT metabolic pathway is initiated by Trp being hydroxylated to the intermediate 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated to become 5-HT|Thus, the rate limiting step in the biosynthesis of 5-HT is the hydroxylation of Trp which is catalyzed by the enzyme tryptophan hydroxylase (TPH) (Figure 1). This enzyme is specific for 5-HT producing cells, however, it is present in two different isoforms, TPH1 and TPH2 [reviewed in (22, 23)]." SIGNOR-264010 TPH1 protein P17752 UNIPROT tryptophan smallmolecule CHEBI:27897 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 31024440 t brain lperfetto "In serotonergic neurons Trp serves as the precursor for 5-HT. The 5-HT metabolic pathway is initiated by Trp being hydroxylated to the intermediate 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated to become 5-HT|Thus, the rate limiting step in the biosynthesis of 5-HT is the hydroxylation of Trp which is catalyzed by the enzyme tryptophan hydroxylase (TPH) (Figure 1). This enzyme is specific for 5-HT producing cells, however, it is present in two different isoforms, TPH1 and TPH2 [reviewed in (22, 23)]." SIGNOR-264009 DDX5 protein P17844 UNIPROT TP53 protein P04637 UNIPROT up-regulates binding 9606 15660129 t miannu "The dead box protein p68: a novel transcriptional coactivator of the p53 tumour suppressor" SIGNOR-133341 DDX5 protein P17844 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates binding 9606 17369852 t miannu "Wt p68 co-immunoprecipitates efficiently with hdac1, the k53r p68 does not / sumoylation is important for the interaction of p68 with hdac1 and for transcriptional repression by p68" SIGNOR-153715 DDX5 protein P17844 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates binding 10090 BTO:0000165 17960593 t miannu "P68 (ddx5) interacts with runx2 and regulates osteoblast differentiation. / p68 is a novel co-activator for runx2" SIGNOR-236974 DDX5 protein P17844 UNIPROT "RNA helicases p68/p72" complex SIGNOR-C34 SIGNOR "form complex" binding 9606 BTO:0000887;BTO:0001103 17011493 t lperfetto "We have found that the rna helicases p68/p72 are myod-associated proteins and that the noncoding rna sra also immunoprecipitates with myod. In vitro and in vivo experiments indicated that both p68/p72 and sra are coactivators of myod." SIGNOR-149964 PFKL protein P17858 UNIPROT "beta-D-fructofuranose 1,6-bisphosphate(4-)" smallmolecule CHEBI:32966 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 16051738 t miannu "Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35." SIGNOR-266472 PFKL protein P17858 UNIPROT "beta-D-fructofuranose 6-phosphate(2-)" smallmolecule CHEBI:57634 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 16051738 t miannu "Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35." SIGNOR-266468 LGALS3 protein P17931 UNIPROT BCL2L1 protein Q07817 UNIPROT "up-regulates quantity by stabilization" 9606 BTO:0000664 21821001 f miannu "Our study also showed that a number of K562 cells survived despite the apoptotic stimuli. Within these surviving cells, galectin-3 was upregulated through newly synthesized protein. Notably, inducible galectin-3, which stabilized the pro-survival Bcl-2 family proteins Mcl-1, Bcl-xL, and Bcl-2, was essential for anti-apoptosis. Unpredictably, GSK-3β was critical for inducible galectin-3 expression as well as for cell survival. As summarized in Fig. 4C, we not only found inducible galectin-3 has an anti-apoptotic effect, but we also identified a GSK-3β-regulated mechanism for apoptotic resistance in K562 cells." SIGNOR-261906 LGALS3 protein P17931 UNIPROT MCL1 protein Q07820 UNIPROT "up-regulates quantity by stabilization" 9606 BTO:0000664 21821001 f miannu "Our study also showed that a number of K562 cells survived despite the apoptotic stimuli. Within these surviving cells, galectin-3 was upregulated through newly synthesized protein. Notably, inducible galectin-3, which stabilized the pro-survival Bcl-2 family proteins Mcl-1, Bcl-xL, and Bcl-2, was essential for anti-apoptosis. Unpredictably, GSK-3β was critical for inducible galectin-3 expression as well as for cell survival. As summarized in Fig. 4C, we not only found inducible galectin-3 has an anti-apoptotic effect, but we also identified a GSK-3β-regulated mechanism for apoptotic resistance in K562 cells." SIGNOR-261905 FLT1 protein P17948 UNIPROT FLT1 protein P17948 UNIPROT up-regulates phosphorylation Tyr1327 CCSPPPDyNSVVLYS 9606 9722576 t lperfetto "Receptor tyrosine phosphorylation is crucial for signal transduction by creating high affinity binding sites for src homology 2 domain-containing molecules. By expressing the intracellular domain of flt-1/vascular endothelial growth factor receptor-1 in the baculosystem, we identified two major tyrosine phosphorylation sites at tyr-1213 and tyr-1242 and two minor tyrosine phosphorylation sites at tyr-1327 and tyr-1333 in this receptor." SIGNOR-59758 LGALS3 protein P17931 UNIPROT BAD protein Q92934 UNIPROT "up-regulates quantity by stabilization" 9606 BTO:0000664 21821001 f miannu "Our study also showed that a number of K562 cells survived despite the apoptotic stimuli. Within these surviving cells, galectin-3 was upregulated through newly synthesized protein. Notably, inducible galectin-3, which stabilized the pro-survival Bcl-2 family proteins Mcl-1, Bcl-xL, and Bcl-2, was essential for anti-apoptosis. Unpredictably, GSK-3β was critical for inducible galectin-3 expression as well as for cell survival. As summarized in Fig. 4C, we not only found inducible galectin-3 has an anti-apoptotic effect, but we also identified a GSK-3β-regulated mechanism for apoptotic resistance in K562 cells." SIGNOR-261907 SPI1 protein P17947 UNIPROT MEIS1 protein O00470 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 26622774 f miannu "In the present study, PU.1 siRNA was demonstrated to efficiently inhibit the transcription level of oncogene MEIS1 in the human acute myeloid non-MLL leukemia U937 cell line. In addition, PU.1, as a positive regulator of MEIS1, performed a crucial role in maintaining cell proliferation." SIGNOR-256002 SPI1 protein P17947 UNIPROT ANXA1 protein P04083 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 19428102 f miannu "Identification of annexin 1 as a PU.1 target gene in leukemia cells. PU.1 is a master regulator, and critical for the developmen tof a common progenitor for lymphoid-myeloid cell lineages in the hematopoietic system. From microarray analysis, we found that several genes including annexin 1 were markedly induced in K562PU.1KD cells. Annexin 1 is a calcium- and phospholipid-binding protein and increased expression leads to the constitutive activation of extracellular signal-regulated kinase (ERK)" SIGNOR-261688 SPI1 protein P17947 UNIPROT JUN protein P05412 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 17041602 f miannu "Knockdown of the transcription factor PU.1 (encoded by Sfpi1) leads to acute myeloid leukemia (AML) in mice. We examined the transcriptome of preleukemic hematopoietic stem cells (HSCs) in which PU.1 was knocked down (referred to as 'PU.1-knockdown HSCs') to identify transcriptional changes preceding malignant transformation. Transcription factors c-Jun and JunB were among the top-downregulated targets." SIGNOR-256065 SPI1 protein P17947 UNIPROT CD14 protein P08571 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12393465 f apalma "In patients with t(8;21), expression of the cell surface markers CD11b, CD14, and CD64 was less in comparison to patients without t(8;21) (Figure 5B). CD14 and CD64 promoters have putative PU.1 binding sites but not AML1-, C/EBPα-, or MEF-binding sites suggesting that down-regulation of the function of PU.1 by AML1-ETO could possibly be an important step in progression toward leukemia." SIGNOR-255696 SPI1 protein P17947 UNIPROT ITGAM protein P11215 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12393465 f apalma "CD11b is regulated by PU.1 and its promoter contains putative binding sites of AML1. In this case AML1-ETO interaction and down-regulation of important myeloid transcription factors like PU.1 and AML1 could explain the lower CD11b expression" SIGNOR-255661 SPI1 protein P17947 UNIPROT FCGR1A protein P12314 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12393465 f apalma "In patients with t(8;21), expression of the cell surface markers CD11b, CD14, and CD64 was less in comparison to patients without t(8;21) (Figure 5B). CD14 and CD64 promoters have putative PU.1 binding sites but not AML1-, C/EBPŒ±-, or MEF-binding sites suggesting that down-regulation of the function of PU.1 by AML1-ETO could possibly be an important step in progression toward leukemia." SIGNOR-255697 SPI1 protein P17947 UNIPROT TAL1 protein P17542 UNIPROT "down-regulates activity" binding 9606 BTO:0000567 16298389 t irozzo "PU.1/Spi-1 binds to the human TAL-1 silencer to mediate its activity.By expressing a mutant protein containing only the ETS domain of PU.1 in human erythroleukemic HEL cells, we demonstrated that PU.1 mediates the transcriptional repression activity of the silencer. Our data clearly demonstrate that PU.1 mediates TAL-1 silencer activity" SIGNOR-256048 SPI1 protein P17947 UNIPROT SPI1 protein P17947 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15767686 f irozzo "These data suggest that a potential positive autoregulatory loop mediated through an upstream regulatory element is essential for proper PU.1 gene expression.These data demonstrate that PU.1 protein is in a complex binding to a site within the kb −14 URE, suggesting that autoregulation through this region might be important for expression of PU.1." SIGNOR-256070 SPI1 protein P17947 UNIPROT GATA2 protein P23769 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 12433372 f irozzo "Using these progenitors and a conditionally activatable PU.1 protein, we show that PU.1 can negatively regulate expression of the GATA-2 gene.The above experiments suggested that PU.1 may physiologically downregulate the expression of the GATA-2 gene during the differentiation of myeloid progenitors into macrophages." SIGNOR-256069 SPI1 protein P17947 UNIPROT CD68 protein P34810 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000801 12676954 f "However, our data show that PU.1/IRF-4 and IRF-8 heterocomplexes down-regulate CD68 promoter activity in macrophages and repression is dependent on the integrity of both the IRF and PU.1 half-sites of this composite element." SIGNOR-254286 SPI1 protein P17947 UNIPROT FLI1 protein Q01543 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10523830 f irozzo "Our results suggest that Spi-1 and GATA-1 might play a key role in the regulation of Fli-1. Most notably, we observed that the GATA/EBS dual element near the Fli-1 CAP sites had an enhancer activity in HEL cells. Spi-1 and GATA-1 were both found to bind to this sequence and hence both factors could represent potential regulators of Fli-1 expression." SIGNOR-256054 SPI1 protein P17947 UNIPROT IRF8 protein Q02556 UNIPROT "up-regulates activity" binding 9606 BTO:0001413 11483597 t miannu "We found that tyrosine phosphorylated ICSBP activates CYBB and NCF2 transcription, during late myeloid differentiation, by interacting with PU.1, IRF1 and CBP." SIGNOR-222880 FLT1 protein P17948 UNIPROT FLT1 protein P17948 UNIPROT up-regulates phosphorylation Tyr1213 GSSDDVRyVNAFKFM 9606 9722576 t tpavlidou "By expressing the intracellular domain of flt-1/vascular endothelial growth factor receptor-1 in the baculosystem, we identified two major tyrosine phosphorylation sites at tyr-1213 and tyr-1242 and two minor tyrosine phosphorylation sites at tyr-1327 and tyr-1333 in this receptor." SIGNOR-59750 FLT1 protein P17948 UNIPROT FLT1 protein P17948 UNIPROT up-regulates phosphorylation Tyr1242 ATSMFDDyQGDSSTL 9606 9722576 t lperfetto "Receptor tyrosine phosphorylation is crucial for signal transduction by creating high affinity binding sites for src homology 2 domain-containing molecules. By expressing the intracellular domain of flt-1/vascular endothelial growth factor receptor-1 in the baculosystem, we identified two major tyrosine phosphorylation sites at tyr-1213 and tyr-1242 and two minor tyrosine phosphorylation sites at tyr-1327 and tyr-1333 in this receptor." SIGNOR-59754 FLT1 protein P17948 UNIPROT FLT1 protein P17948 UNIPROT up-regulates phosphorylation Tyr1333 DYNSVVLySTPPI 9606 9722576 t lperfetto "Receptor tyrosine phosphorylation is crucial for signal transduction by creating high affinity binding sites for src homology 2 domain-containing molecules. By expressing the intracellular domain of flt-1/vascular endothelial growth factor receptor-1 in the baculosystem, we identified two major tyrosine phosphorylation sites at tyr-1213 and tyr-1242 and two minor tyrosine phosphorylation sites at tyr-1327 and tyr-1333 in this receptor." SIGNOR-59762 FLT1 protein P17948 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates binding 9606 9398617 t gcesareni "We conclude that both flt-1 and kdr have the potential to signal through plc gamma via phosphotyrosine residues located in juxta-membrane and carboxyl tail regions" SIGNOR-53743 FLT1 protein P17948 UNIPROT PHACTR1 protein Q9C0D0 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21939755 f miannu "Recently, we identified a new Vascular Endothelial Growth Factor (VEGF)-A(165)-induced gene Phactr-1, (Phosphatase Actin Regulator-1). We found that neuropilin-1 (NRP-1) and VEGF-R1 depletion inhibited Phactr-1 mRNA expression while NRP-2 and VEGF-R2 depletion had no effect." SIGNOR-260060 PSMC3 protein P17980 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "form complex" binding 9606 BTO:0000007 29636472 t lperfetto "Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line" SIGNOR-263369 PTPN1 protein P18031 UNIPROT LAT protein O43561 UNIPROT "down-regulates activity" dephosphorylation 9606 12857726 t "Using a pharmacological inhibitor, we provide evidence that PTP1B activation and LAT dephosphorylation processes were required for irreversible platelet aggregation.|In collagen-stimulated platelets, the signaling complexes recruited by tyrosine-phosphorylated LAT are essential for PLCgamma2 activation" SIGNOR-248403 PTPN1 protein P18031 UNIPROT JAK2 protein O60674 UNIPROT down-regulates dephosphorylation Tyr1008 LPQDKEYyKVKEPGE 9606 15780598 t lperfetto "JAK2 and STAT3 are dephosphorylated by PTP1B in vitro" SIGNOR-133852 PTPN1 protein P18031 UNIPROT JAK2 protein O60674 UNIPROT down-regulates dephosphorylation Tyr1007 VLPQDKEyYKVKEPG 9606 15821101 t gcesareni "Ptp1b has been shown to regulate the activation of cytokine receptors through the dephosphorylation of specific members of the jak family, namely jak2 and tyk2" SIGNOR-134955 PTPN1 protein P18031 UNIPROT JAK2 protein O60674 UNIPROT down-regulates dephosphorylation 9606 15821101 t gcesareni "Ptp1b has been shown to regulate the activation of cytokine receptors through the dephosphorylation of specific members of the jak family, namely jak2 and tyk2" SIGNOR-135207 PTPN1 protein P18031 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates activity" dephosphorylation Tyr1007 VLPQDKEyYKVKEPG 9606 BTO:0000007 11970898 t "Immunoblots with phospho-specific antibodies confirmed that PTP1B suppresses phosphorylation of the Jak2 activation site tyrosines (Y1007/Y1008) and Stat3 in a dose-dependent manner" SIGNOR-248404 PTPN1 protein P18031 UNIPROT ABL1 protein P00519 UNIPROT down-regulates dephosphorylation 9606 9566916 t gcesareni "These results illustrate selectivity in the effects of ptps in a cellular context and suggest that ptp1b may function as a specific, negative regulator of p210 bcr-abl signalling in vivo." SIGNOR-56815 PTPN1 protein P18031 UNIPROT EGFR protein P00533 UNIPROT "down-regulates activity" dephosphorylation Tyr1016 DVVDADEyLIPQQGF -1 8621392 t "We have shown previously that amino acid residues flanking the phosphotyrosine are important for efficient PTP1 catalysis (Table 1 and Refs. 9, 10, and 17). For example, the kcat/Km value for the undecapeptide, EGFR988-989 (epidermal growth factor autophosphorylation site Tyr992, residues 988-998) (Asp-Ala-Asp-Glu-pTyr-Leu-Ile-Pro-Gln-Gln-Gly) is 3220-fold higher than that of phosphotyrosine (Table 1). We further demonstrated that a minimum of six amino acid residues are required for the most efficient PTP1 binding and catalysis." SIGNOR-248407 PTPN1 protein P18031 UNIPROT KRT8 protein P05787 UNIPROT "down-regulates activity" dephosphorylation Tyr267 IAEVKAQyEDIANRS 9606 BTO:0000182 24003221 t lperfetto "Keratin 8 phospho-Tyr-267 is dephosphorylated by PTP1B and promotes insolubility and filament organization, as does the paralogous GFAP tyrosine." SIGNOR-265495 PTPN1 protein P18031 UNIPROT INSR protein P06213 UNIPROT "down-regulates activity" dephosphorylation Tyr1185 FGMTRDIyETDYYRK 10090 BTO:0000944 11579209 t lperfetto "Ptp1b is a protein tyrosine phosphatase that negatively regulates insulin sensitivity by dephosphorylating the insulin receptor." SIGNOR-235495 PTPN1 protein P18031 UNIPROT INSR protein P06213 UNIPROT "down-regulates activity" dephosphorylation Tyr1189 RDIYETDyYRKGGKG 10090 BTO:0000944 11579209 t lperfetto "Ptp1b is a protein tyrosine phosphatase that negatively regulates insulin sensitivity by dephosphorylating the insulin receptor." SIGNOR-235499 PTPN1 protein P18031 UNIPROT INSR protein P06213 UNIPROT "down-regulates activity" dephosphorylation Tyr1190 DIYETDYyRKGGKGL 10090 BTO:0000944 11579209 t lperfetto "Ptp1b is a protein tyrosine phosphatase that negatively regulates insulin sensitivity by dephosphorylating the insulin receptor." SIGNOR-235503 PTPN1 protein P18031 UNIPROT INSR protein P06213 UNIPROT "down-regulates activity" dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 BTO:0000007 16582879 t "Binding of insulin to the IR results in autophosphorylation of each beta‐subunit on at least six different tyrosines. This autophosphorylation occurs first on three tyrosines located in the activation loop of the kinase domain (Y1158, 1162 and 1163), resulting in the stabilization of the kinase in an active conformation.|Termination of the signal involves inactivation of the IR by dephosphorylation of the three tyrosines of the kinase domain (Tonks, 2003). PTP1B is a protein tyrosine phosphatase located in the endoplasmic reticulum that has an important role in the dephosphorylation of these tyrosines after internalization of the IR" SIGNOR-248408 PTPN1 protein P18031 UNIPROT INSR protein P06213 UNIPROT "down-regulates activity" dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 BTO:0000007 16582879 t "Binding of insulin to the IR results in autophosphorylation of each beta‐subunit on at least six different tyrosines. This autophosphorylation occurs first on three tyrosines located in the activation loop of the kinase domain (Y1158, 1162 and 1163), resulting in the stabilization of the kinase in an active conformation.|Termination of the signal involves inactivation of the IR by dephosphorylation of the three tyrosines of the kinase domain (Tonks, 2003). PTP1B is a protein tyrosine phosphatase located in the endoplasmic reticulum that has an important role in the dephosphorylation of these tyrosines after internalization of the IR" SIGNOR-248409 PTPN1 protein P18031 UNIPROT BCR protein P11274 UNIPROT down-regulates dephosphorylation 9606 9566916 t "The effect has been demonstrated using P11274-1" gcesareni "These results illustrate selectivity in the effects of ptps in a cellular context and suggest that ptp1b may function as a specific, negative regulator of p210 bcr-abl signalling in vivo." SIGNOR-56818 PTPN1 protein P18031 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1234 RDMYDKEyYSVHNKT 9606 16537444 t gcesareni "Using substrate trapping mutants of ptp1b or tcptp, we have demonstrated that both phosphatases interact with met and that these interactions require phosphorylation of twin tyrosines (tyr-1234/1235) in the activation loop of the met kinase domain. We demonstrate that phosphorylation of tyr-1234/1235 in the activation loop of the met receptor is elevated in the absence of either ptp1b or tcptp and further elevated upon loss of both phosphatases. This enhanced phosphorylation of met corresponds to enhanced biological activity and cellular invasion." SIGNOR-145141 PTPN1 protein P18031 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1235 DMYDKEYySVHNKTG 9606 16537444 t gcesareni "Using substrate trapping mutants of ptp1b or tcptp, we have demonstrated that both phosphatases interact with met and that these interactions require phosphorylation of twin tyrosines (tyr-1234/1235) in the activation loop of the met kinase domain. We demonstrate that phosphorylation of tyr-1234/1235 in the activation loop of the met receptor is elevated in the absence of either ptp1b or tcptp and further elevated upon loss of both phosphatases. This enhanced phosphorylation of met corresponds to enhanced biological activity and cellular invasion." SIGNOR-145145 PTPN1 protein P18031 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1234 RDMYDKEyYSVHNKT 9606 18819921 t gcesareni "Using substrate trapping mutants of ptp1b or tcptp, we have demonstrated that both phosphatases interact with met and that these interactions require phosphorylation of twin tyrosines (tyr-1234/1235) in the activation loop of the met kinase domain. We demonstrate that phosphorylation of tyr-1234/1235 in the activation loop of the met receptor is elevated in the absence of either ptp1b or tcptp and further elevated upon loss of both phosphatases. This enhanced phosphorylation of met corresponds to enhanced biological activity and cellular invasion." SIGNOR-181323 PTPN1 protein P18031 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1235 DMYDKEYySVHNKTG 9606 18819921 t gcesareni "Using substrate trapping mutants of ptp1b or tcptp, we have demonstrated that both phosphatases interact with met and that these interactions require phosphorylation of twin tyrosines (tyr-1234/1235) in the activation loop of the met kinase domain. We demonstrate that phosphorylation of tyr-1234/1235 in the activation loop of the met receptor is elevated in the absence of either ptp1b or tcptp and further elevated upon loss of both phosphatases. This enhanced phosphorylation of met corresponds to enhanced biological activity and cellular invasion." SIGNOR-181327 PTPN1 protein P18031 UNIPROT MET protein P08581 UNIPROT "down-regulates activity" dephosphorylation Tyr1235 DMYDKEYySVHNKTG 9606 18819921 t "Using substrate trapping mutants of PTP1B or TCPTP, we have demonstrated that both phosphatases interact with Met and that these interactions require phosphorylation of twin tyrosines (Tyr-1234/1235) in the activation loop of the Met kinase domain.|Using small interfering RNA against PTP1B and TCPTP, we demonstrate that phosphorylation of Tyr-1234/1235 in the activation loop of the Met receptor is elevated in the absence of either PTP1B or TCPTP and further elevated upon loss of both phosphatases." SIGNOR-248412 PTPN1 protein P18031 UNIPROT ROS1 protein P08922 UNIPROT down-regulates dephosphorylation Tyr2115 DIYKNDYyRKRGEGL 9606 17416557 t gcesareni "In an approach to gain insight into the sequence-dependent dephosphorylation of multiple phosphotyrosyl-containing peptides by the phosphatases shp-1 and ptp1b, we applied a chromatographic technique for the analysis of the dephosphorylation products." SIGNOR-154207 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates dephosphorylation Tyr751 SKDESVDyVPMLDMK 9606 18567737 t gcesareni "Ptp1b blocked pdgf-induced tyr716 and tyr751 phosphorylation of the pdgfr." SIGNOR-179076 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates dephosphorylation Tyr771 ADIESSNyMAPYDNY 9606 18567737 t gcesareni "Ptp1b blocked pdgf-induced tyr716 and tyr751 phosphorylation of the pdgfr." SIGNOR-179080 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT "down-regulates activity" dephosphorylation Tyr1021 PNEGDNDyIIPLPDP -1 7545675 t "Upon activation, the βPDGFR is phosphorylated at multiple tyrosine residues and thereby becomes a docking site for SH2-domain-containing signal transduction proteins.|While all phosphotyrosine sites on the βPDGFR are equally good targets for rPTP1B, maps of the βPDGFR dephosphorylated by rSyp showed that rSyp had a distinct preference for certain sites (Fig. 4 D-F). The low dose of rSyp primarily dephosphorylated spots 1, 6, 7, 9, and to a lesser extent 8a|Spot 1 corresponds to tyrosine 751; spot 3 corresponds to tyrosine 1009; spot 6 corresponds to tyrosine 740; spot 8b corresponds to tyrosine 1021; spot 9 corresponds to tyrosine 771, and spots 2, 7, and 8a are as yet unidentified phosphopeptides" SIGNOR-248417 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT "down-regulates activity" dephosphorylation Tyr740 TGESDGGyMDMSKDE -1 7545675 t "Upon activation, the βPDGFR is phosphorylated at multiple tyrosine residues and thereby becomes a docking site for SH2-domain-containing signal transduction proteins.|While all phosphotyrosine sites on the βPDGFR are equally good targets for rPTP1B, maps of the βPDGFR dephosphorylated by rSyp showed that rSyp had a distinct preference for certain sites (Fig. 4 D-F). The low dose of rSyp primarily dephosphorylated spots 1, 6, 7, 9, and to a lesser extent 8a|Spot 1 corresponds to tyrosine 751; spot 3 corresponds to tyrosine 1009; spot 6 corresponds to tyrosine 740; spot 8b corresponds to tyrosine 1021; spot 9 corresponds to tyrosine 771, and spots 2, 7, and 8a are as yet unidentified phosphopeptides" SIGNOR-248413 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT "down-regulates activity" dephosphorylation Tyr751 SKDESVDyVPMLDMK -1 7545675 t "Upon activation, the βPDGFR is phosphorylated at multiple tyrosine residues and thereby becomes a docking site for SH2-domain-containing signal transduction proteins.|While all phosphotyrosine sites on the βPDGFR are equally good targets for rPTP1B, maps of the βPDGFR dephosphorylated by rSyp showed that rSyp had a distinct preference for certain sites (Fig. 4 D-F). The low dose of rSyp primarily dephosphorylated spots 1, 6, 7, 9, and to a lesser extent 8a|Spot 1 corresponds to tyrosine 751; spot 3 corresponds to tyrosine 1009; spot 6 corresponds to tyrosine 740; spot 8b corresponds to tyrosine 1021; spot 9 corresponds to tyrosine 771, and spots 2, 7, and 8a are as yet unidentified phosphopeptides" SIGNOR-248414 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT "down-regulates activity" dephosphorylation Tyr771 ADIESSNyMAPYDNY -1 7545675 t "Upon activation, the βPDGFR is phosphorylated at multiple tyrosine residues and thereby becomes a docking site for SH2-domain-containing signal transduction proteins.|While all phosphotyrosine sites on the βPDGFR are equally good targets for rPTP1B, maps of the βPDGFR dephosphorylated by rSyp showed that rSyp had a distinct preference for certain sites (Fig. 4 D-F). The low dose of rSyp primarily dephosphorylated spots 1, 6, 7, 9, and to a lesser extent 8a|Spot 1 corresponds to tyrosine 751; spot 3 corresponds to tyrosine 1009; spot 6 corresponds to tyrosine 740; spot 8b corresponds to tyrosine 1021; spot 9 corresponds to tyrosine 771, and spots 2, 7, and 8a are as yet unidentified phosphopeptides" SIGNOR-248415 PTPN1 protein P18031 UNIPROT SRC protein P12931 UNIPROT "up-regulates activity" dephosphorylation Tyr419 RLIEDNEyTARQGAK 9606 BTO:0000007 11007774 t gcesareni "Incubation of the inactivated c-Src with PTP1B results in a dose-dependent reactivation of c-Src tyrosine kinase activity. Incubation of c-Src with 2 or 10 g of PTP1B results in partial or full restoration of c-Src kinase activity, respectively. The activation is accompanied by dephosphorylation of c-Src, both of Tyr-419 and of Tyr-530" SIGNOR-245299 PTPN1 protein P18031 UNIPROT PTPN1 protein P18031 UNIPROT "down-regulates activity" dephosphorylation Tyr152 ISEDIKSyYTVRQLE -1 11506178 t "Tyrosine residues 66, 152 and/or 153 of PTP1B are phosphorylated by the activated insulin receptor and are also necessary for formation of the PTP1B:insulin receptor complex| Furthermore, tyrosine phosphorylation of PTP1B by the insulin receptor tyrosine kinase increases the catalytic activity of PTP1B|These results suggest that PTP1B can dephosphorylate itself under in vitro conditions." SIGNOR-248424 PTPN1 protein P18031 UNIPROT PTPN1 protein P18031 UNIPROT "down-regulates activity" dephosphorylation Tyr153 SEDIKSYyTVRQLEL -1 11506178 t "Tyrosine residues 66, 152 and/or 153 of PTP1B are phosphorylated by the activated insulin receptor and are also necessary for formation of the PTP1B:insulin receptor complex| Furthermore, tyrosine phosphorylation of PTP1B by the insulin receptor tyrosine kinase increases the catalytic activity of PTP1B|These results suggest that PTP1B can dephosphorylate itself under in vitro conditions." SIGNOR-248425 PTPN1 protein P18031 UNIPROT PTPN1 protein P18031 UNIPROT "down-regulates activity" dephosphorylation Tyr66 LHQEDNDyINASLIK -1 11506178 t "Tyrosine residues 66, 152 and/or 153 of PTP1B are phosphorylated by the activated insulin receptor and are also necessary for formation of the PTP1B:insulin receptor complex| Furthermore, tyrosine phosphorylation of PTP1B by the insulin receptor tyrosine kinase increases the catalytic activity of PTP1B|These results suggest that PTP1B can dephosphorylate itself under in vitro conditions." SIGNOR-248423 PTPN1 protein P18031 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates dephosphorylation Tyr42 DSMKDEEyEQMVKEL 9606 8940099 t gcesareni "Ptp1b is able to dephosphorylate phosphorylated-tyr-42 on ikappabalpha" SIGNOR-45004 PTPN1 protein P18031 UNIPROT TYK2 protein P29597 UNIPROT "down-regulates activity" dephosphorylation 9606 15780598 t lperfetto "Upon ligand binding, IL-2R , IL-6R or LeptinR , IFN-_R , IFN-_R and PRLR or growth hormone (GH) receptor associated JAKs become activated. These JAKs mediate phosphorylation of specific tyrosine residues and recruit STATs. Activated STATs are released from the receptor and translocate to the nucleus. PTP1B dephosphorylates JAK2, TYK2 and STAT5 . The 45-kDa form of TC-PTP was shown to dephosphorylate JAK1 and JAK3 as well as STAT1, STAT3 and STAT5." SIGNOR-134564 PTPN1 protein P18031 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation 9606 15632081 t gcesareni "Whereas insulin-induced phosphatidylinositol 3-kinase/akt signaling was prolonged in both tcptp-/- and ptp1b-/- immortalized mouse embryo fibroblasts (mefs), mitogen-activated protein kinase erk1/2 signaling was elevated only in ptp1b- mefs" SIGNOR-252639 PTPN1 protein P18031 UNIPROT IRS1 protein P35568 UNIPROT down-regulates dephosphorylation -1 10660596 t lperfetto "Tyrosine dephosphorylation and deactivation of insulin receptor substrate-1 by protein-tyrosine phosphatase 1B. Possible facilitation by the formation of a ternary complex with the Grb2 adaptor protein." SIGNOR-74852 PTPN1 protein P18031 UNIPROT STAT5B protein P51692 UNIPROT down-regulates dephosphorylation Tyr699 TAKAVDGyVKPQIKQ 9606 BTO:0000149 10993888 t gcesareni "A cytosolic protein-tyrosine phosphatase ptp1b specifically dephosphorylates and deactivates prolactin-activated stat5a and stat5b." SIGNOR-82042 PTPN1 protein P18031 UNIPROT STAT5B protein P51692 UNIPROT "down-regulates activity" dephosphorylation Tyr699 TAKAVDGyVKPQIKQ 9534 BTO:0004055 10993888 t "A Cytosolic Protein-tyrosine Phosphatase PTP1B Specifically Dephosphorylates and Deactivates Prolactin-activated STAT5a and STAT5b" SIGNOR-248429 PTPN1 protein P18031 UNIPROT CAV1 protein Q03135 UNIPROT unknown dephosphorylation Tyr14 VDSEGHLyTVPIREQ -1 16388599 t "The scaffolding protein caveolin-1 is also a participant in these pathways and is specifically phosphorylated on tyrosine 14, when these pathways are activated. Here, we provide evidence that PTP1B can efficiently catalyze the removal of the phosphoryl group from phosphocaveolin-1." SIGNOR-248430 PTPN1 protein P18031 UNIPROT PTK2 protein Q05397 UNIPROT "down-regulates activity" dephosphorylation Tyr397 SVSETDDyAEIIDEE 9534 BTO:0004055 16291744 t "The focal adhesion kinase (FAK) is a key regulator of cell migration. Phosphorylation at Tyr-397 activates FAK |The dephosphorylation at Tyr-397 in FAK triggered by wild-type alpha-actinin and PTP 1B caused a significant increase in cell migration." SIGNOR-248431 PTPN1 protein P18031 UNIPROT PRKCD protein Q05655 UNIPROT down-regulates dephosphorylation 9606 11350745 t gcesareni "Dephosphorylation of tyrosine residues by ptp1b, a protein tyrosine phosphatase, reduced the enhanced pkcdelta activity." SIGNOR-107754 PTPN1 protein P18031 UNIPROT CTTN protein Q14247 UNIPROT "up-regulates activity" dephosphorylation Tyr446 GTEPEPVySMEAADY 9534 BTO:0004055 18387954 t "Here, we have identified cortactin, a central regulator of actin cytoskeletal dynamics, as a substrate of PTP1B. A trapping mutant of PTP1B binds cortactin at the phosphorylation site Tyr446, |Cortactin exerts its effects on the actin cytoskeleton by interacting directly with the Arp2/3 complex , F-actin |Src phosphorylates murine cortactin predominantly at three key sites in vitro, Tyr421, Tyr466, and Tyr482 (corresponding to Tyr421, Tyr470, and Try486 in human cortactin), resulting in decreased actin cross-linking activity" SIGNOR-248432 PTPN1 protein P18031 UNIPROT NTRK2 protein Q16620 UNIPROT "down-regulates activity" dephosphorylation Tyr706 RDVYSTDyYRVGGHT 9606 BTO:0000793 26214522 t Luana "Collectively, these data establish a direct enzyme-substrate interaction between PTP1B and phosphorylated Y705/706 (p-Y705/706) TRKB, the critical autophosphorylation sites that mediate BDNF-induced signaling.| Therefore, the data are consistent with a role of PTP1B as an inhibitor of BDNF/TRKB signaling" SIGNOR-264554 PTPN1 protein P18031 UNIPROT NTRK2 protein Q16620 UNIPROT "down-regulates activity" dephosphorylation Tyr707 DVYSTDYyRVGGHTM 9606 26214522 t Luana "Collectively, these data establish a direct enzyme-substrate interaction between PTP1B and phosphorylated Y705/706 (p-Y705/706) TRKB, the critical autophosphorylation sites that mediate BDNF-induced signaling.| Therefore, the data are consistent with a role of PTP1B as an inhibitor of BDNF/TRKB signaling" SIGNOR-264553 PTPN1 protein P18031 UNIPROT MAPK15 protein Q8TD08 UNIPROT down-regulates dephosphorylation Tyr177 EDQAVTEyVATRWYR 9606 16336213 t lperfetto "Erk8 (extracellular-signal-regulated protein kinase 8) expressed in escherichia coli or insect cells was catalytically active and phosphorylated at both residues of the thr-glu-tyr motif. Dephosphorylation of the threonine residue by pp2a (protein serine/threonine phosphatase 2a) decreased erk8 activity by over 95% in vitro, whereas complete dephosphorylation of the tyrosine residue by ptp1b (protein tyrosine phosphatase 1b) decreased activity by only 15-20%" SIGNOR-142981 PTPN1 protein P18031 UNIPROT TRPV6 protein Q9H1D0 UNIPROT down-regulates dephosphorylation 9606 BTO:0000007 17197020 t gcesareni "We conclude that phosphorylation/dephosphorylation of tyrosines in position 161 and 162 is essential for regulation of ca2+ influx through trpv6 ca2+ channels in hek293 cells. Co-transfection with src led to tyrosine phosphorylation of trpv6 which could be dephosphorylated by ptp1b. y161/162 are essential for tyrosine phosphorylation-dependent modulation of trpv6-mediated ca2+ entry." SIGNOR-151711 PTPN1 protein P18031 UNIPROT TRPV6 protein Q9H1D0 UNIPROT "down-regulates activity" dephosphorylation 9606 BTO:0000007 17197020 t llicata "In HEK293 cells, transfected with the Ca2+ channel protein TRPV6, Ca2+ influx is increased and TRPV6 is tyrosine phosphorylated following addition of the tyrosine phosphatase inhibitor|PTP1B interacts with the N-terminal domain of TRPV6 within a region of amino acids 1-191 as shown by co-immunoprecipitation, bimolecular fluorescence complementation and the yeast 2-hybrid system. Point mutation of both tyrosines 161 and 162 in the TRPV6 protein abolishes the DMHV-effect on Ca2+ influx and tyrosine phosphorylation by Src. Single mutations of Y161 or Y162 shows that each of both tyrosines alone is sufficient for the DMHV-effect. We conclude that phosphorylation/dephosphorylation of tyrosines in position 161 and 162 is essential for regulation of Ca2+ influx through TRPV6 Ca2+ channels in HEK293 cells." SIGNOR-248433 PTPN1 protein P18031 UNIPROT BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR down-regulates dephosphorylation 9606 phosphorylation:Tyr177 9566916 t gcesareni "We have observed association and dephosphorylation of p210 bcr-abl, but not v-abl, by ptp1b in vivo." SIGNOR-56822 PTPN1 protein P18031 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates dephosphorylation 9606 15632081 t gcesareni "Whereas insulin-induced phosphatidylinositol 3-kinase/akt signaling was prolonged in both tcptp-/- and ptp1b-/- immortalized mouse embryo fibroblasts (mefs), mitogen-activated protein kinase erk1/2 signaling was elevated only in ptp1b- mefs" SIGNOR-132959 ERCC2 protein P18074 UNIPROT ERCC3 protein P19447 UNIPROT up-regulates binding 9606 10024882 t miannu "Xpd helps xpb in promoter opening and as such participates in the transcription reaction." SIGNOR-64672 BMP7 protein P18075 UNIPROT BMP7 protein P18075 UNIPROT up-regulates binding 9606 BTO:0000887 11178121 t lperfetto "Bmps are dimeric proteins with a single inter-chain disulfide bond. The dimeric conformation is an absolute requirement for the biological action and interac- tion with receptors" SIGNOR-236172 BMP7 protein P18075 UNIPROT UCP1 protein P25874 UNIPROT up-regulates "transcriptional regulation" 9606 18719589 f fspada "Bmp7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate prdm16 (pr-domain-containing 16; ref. 4) and pgc-1alpha (peroxisome proliferator-activated receptor-gamma (ppargamma) coactivator-1alpha; ref. 5), increased expression of the brown-fat-defining marker uncoupling protein 1 (ucp1) and adipogenic transcription factors ppargamma and ccaat/enhancer-binding proteins (c/ebps), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (map) kinase-(also known as mapk14) and pgc-1-dependent pathways" SIGNOR-210059 BMP7 protein P18075 UNIPROT UCP1 protein P25874 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18719589 f fspada "Bmp7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate prdm16 (pr-domain-containing 16;ref. 4) and pgc-1alpha (peroxisome proliferator-activated receptor-gamma (ppargamma) coactivator-1alpha;ref. 5), increased expression of the brown-fat-defining marker uncoupling protein 1 (ucp1) and adipogenic transcription factors ppargamma and ccaat/enhancer-binding proteins (c/ebps), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (map) kinase-(also known as mapk14) and pgc-1-dependent pathways" SIGNOR-180354 BMP7 protein P18075 UNIPROT ACVR2A protein P27037 UNIPROT up-regulates binding 9606 9748228 t fspada "We show that bmp7 and activin bind to the same type ii receptors, actrii and iib, but recruit distinct type i receptors into heteromeric receptor complexes" SIGNOR-60237 BMP7 protein P18075 UNIPROT PPARG protein P37231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 18719589 f lperfetto "Bmp7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate prdm16 (pr-domain-containing 16;ref. 4) and pgc-1alpha (peroxisome proliferator-activated receptor-gamma (ppargamma) coactivator-1alpha;ref. 5), increased expression of the brown-fat-defining marker uncoupling protein 1 (ucp1) and adipogenic transcription factors ppargamma and ccaat/enhancer-binding proteins (c/ebps), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (map) kinase-(also known as mapk14) and pgc-1-dependent pathways" SIGNOR-180311 BMP7 protein P18075 UNIPROT MMP13 protein P45452 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0003858 12734180 f miannu "In the present study we investigated the inhibitory effects of IGF-1 and OP-1 on MMP-13 expression in human chondrocytes. We found that the suppressive effect of IGF-1 and OP-1 on the MMP-13 promoter activity was dose-dependent at the transcriptional level with a corresponding decrease in the level of MMP-13 protein." SIGNOR-254801 BMP7 protein P18075 UNIPROT ACTR2 protein P61160 UNIPROT up-regulates binding 9606 16446785 t acerquone "The two ligands induce the formation of two ligand-receptor complexes, cbmp7 (blue) and ctgf-b (red), that share the type i receptor alk2" SIGNOR-144144 BMP7 protein P18075 UNIPROT DLK1 protein P80370 UNIPROT down-regulates "transcriptional regulation" 9606 20584981 f fspada "Bmp7 could directly suppress pref-1 expression, thereby allowing the initiation of the adipogenic program. " SIGNOR-210074 BMP7 protein P18075 UNIPROT DLK1 protein P80370 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 20584981 f fspada "Bmp7 could directly suppress pref-1 expression, thereby allowing the initiation of the adipogenic program." SIGNOR-166426 BMP7 protein P18075 UNIPROT ACVR1 protein Q04771 UNIPROT up-regulates binding 10090 BTO:0000165 SIGNOR-C30 11282024 t gcesareni "Bmp-4 and gdf-5 are known to bind to activin receptor-like kinase 3 (alk-3) and/or alk-6 (also termed bmp type ia and type ib receptors, respectively), whereas bmp-6 and bmp-7 preferentially bind to alk-2" SIGNOR-236913 BMP7 protein P18075 UNIPROT ACVR2B protein Q13705 UNIPROT up-regulates binding 9606 9748228 t acerquone "We show that bmp7 and activin bind to the same type ii receptors, actrii and iib, but recruit distinct type i receptors into heteromeric receptor complexes." SIGNOR-60240 BMP7 protein P18075 UNIPROT BMPR2 protein Q13873 UNIPROT up-regulates binding 9606 SIGNOR-C29 7644468 t acerquone "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-30512 BMP7 protein P18075 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 18719589 f "induction of mitochondrial biogenesis" fspada "Bmp7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate prdm16 (pr-domain-containing 16;ref. 4) and pgc-1alpha (peroxisome proliferator-activated receptor-gamma (ppargamma) coactivator-1alpha;ref. 5), increased expression of the brown-fat-defining marker uncoupling protein 1 (ucp1) and adipogenic transcription factors ppargamma and ccaat/enhancer-binding proteins (c/ebps), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (map) kinase-(also known as mapk14) and pgc-1-dependent pathways" SIGNOR-180308 BMP7 protein P18075 UNIPROT PRDM16 protein Q9HAZ2 UNIPROT up-regulates "transcriptional regulation" 9606 18719589 f fspada "Bmp7 activates a full program of€š brown€š adipogenesis€š including induction of early regulators of€š brown€š fat fate prdm16 (pr-domain-containing 16; ref. 4) and pgc-1alpha (peroxisome proliferator-activated receptor-gamma (ppargamma) coactivator-1alpha; ref. 5), increased expression of the€š brown-fat-defining marker uncoupling protein 1 (ucp1) and adipogenic transcription factors ppargamma and ccaat/enhancer-binding proteins (c/ebps), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (map) kinase-(also known as mapk14) and pgc-1-dependent pathways" SIGNOR-210053 BMP7 protein P18075 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates "transcriptional regulation" 9606 18719589 f "Induction of mitochondrial biogenesis" fspada "Bmp7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate prdm16 (pr-domain-containing 16; ref. 4) and pgc-1alpha (peroxisome proliferator-activated receptor-gamma (ppargamma) coactivator-1alpha; ref. 5), increased expression of the brown-fat-defining marker uncoupling protein 1 (ucp1) and adipogenic transcription factors ppargamma and ccaat/enhancer-binding proteins (c/ebps), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (map) kinase-(also known as mapk14) and pgc-1-dependent pathways" SIGNOR-210056 BMP7 protein P18075 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18719589 f "induction of mitochondrial biogenesis" fspada "Bmp7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate prdm16 (pr-domain-containing 16;ref. 4) and pgc-1alpha (peroxisome proliferator-activated receptor-gamma (ppargamma) coactivator-1alpha;ref. 5), increased expression of the brown-fat-defining marker uncoupling protein 1 (ucp1) and adipogenic transcription factors ppargamma and ccaat/enhancer-binding proteins (c/ebps), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (map) kinase-(also known as mapk14) and pgc-1-dependent pathways" SIGNOR-180314 BMP7 protein P18075 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates binding 9606 7644468 t 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 BMP7 protein P18075 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR "up-regulates activity" binding 9606 7791754 t 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-232216 BMP7 protein P18075 UNIPROT ACVR1/BMPR2 complex SIGNOR-C30 SIGNOR up-regulates binding 10090 BTO:0000165 11282024 t lperfetto "Bmp-4 and gdf-5 are known to bind to activin receptor-like kinase 3 (alk-3) and/or alk-6 (also termed bmp type ia and type ib receptors, respectively), whereas bmp-6 and bmp-7 preferentially bind to alk-2" SIGNOR-235364 RPL35A protein P18077 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262465 ITGB5 protein P18084 UNIPROT PTK2 protein Q05397 UNIPROT "up-regulates activity" 9606 15688067 f miannu "Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin." SIGNOR-257722 ADRA2B protein P18089 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256993 ADRA2B protein P18089 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257109 TNFRSF1A protein P19438 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" 20887952 f "These results indicate that TNF-a-activated p38 pathway negatively controls the expansion of PAX7-positive SCs" SIGNOR-253602 TRIM21 protein P19474 UNIPROT GMPS protein P49915 UNIPROT down-regulates ubiquitination 9606 24462112 t miannu "Cytoplasmic sequestration of gmps requires ubiquitylation by trim21, a ubiquitin ligase associated with autoimmune disease." SIGNOR-204478 ADRA2B protein P18089 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256714 ADRA2B protein P18089 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257201 EGR1 protein P18146 UNIPROT SLC4A2 protein P04920 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000269 22228178 f "Cellular and molecular experiments indicated that AE2 expression promoted proliferation of colon cancer cells. In addition, we found that transcription factor EGR1 underlies AE2 upregulation and the AE2 sequester p16INK4a (P16) in the cytoplasm of colon cancer cells" SIGNOR-254250 EGR1 protein P18146 UNIPROT FCER2 protein P06734 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0003076 9300687 f "Thus, Egr-1 seems to control the expression of downstream target genes not only as a transcriptional activator, but also as a repressor molecule. In B cells, Egr-1 therefore plays a critical role in integrating the short-lived signal delivered by triggering of the Ag receptor into phenotypic changes, including repression of CD95 and CD23 transcription." SIGNOR-254277 EGR1 protein P18146 UNIPROT ABCB1 protein P08183 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000574 7565762 f miannu "TPA induced EGR1 binding to the -69/+20 promoter sequences over a time course which correlated with increased MDR1 promoter activity and increased steady-state MDR1 RNA levels. These data suggest a role for EGR1 in modulating MDR1 promoter activity in hematopoietic cells." SIGNOR-253871 EGR1 protein P18146 UNIPROT COL4A2 protein P08572 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21931594 f Regulation miannu "Egr-1 induced a time-dependent ECM gene expression program, with the number of ECM genes increasing >2.5-fold (from 16 to 41) between 24 and 48 h. Genes in this group include those coding for multiple collagens (COL4A1, COL4A2, COL11A1, COL7A1, COL10A1)" SIGNOR-251918 EGR1 protein P18146 UNIPROT CHGA protein P10645 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001007 12456801 t "Recently, binding of specific protein 1 (Sp1) and cAMP response element binding protein (CREB) to a GC-rich element at -92/-62 has been identified as a critical step in gastrin-dependent regulation of the chromogranin A (CgA) gene in gastric epithelial cells. Here we demonstrate that binding of early growth response protein 1 (Egr-1) to the distal part of the -92/-62 site is also required for gastrin-dependent CgA transactivation." SIGNOR-254265 EGR1 protein P18146 UNIPROT COL11A1 protein P12107 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21931594 f Regulation miannu "Egr-1 induced a time-dependent ECM gene expression program, with the number of ECM genes increasing >2.5-fold (from 16 to 41) between 24 and 48 h. Genes in this group include those coding for multiple collagens (COL4A1, COL4A2, COL11A1, COL7A1, COL10A1)" SIGNOR-251919 EGR1 protein P18146 UNIPROT PCSK2 protein P16519 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9359835 f miannu "we show that the transcription factor EGR-1 interacts with two distinct elements within the proximal human PC2 promoter region. Transfection experiments also demonstrate that EGR-1 is able to enhance PC2 promoter activity." SIGNOR-253896 EGR1 protein P18146 UNIPROT PPARG protein P37231 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0003336 29212876 t miannu "Previous studies have reported that the PPARγ proximal promoter contains an overlapping binding site for Egr-1, which is involved in the down-regulation of PPARγ. In the present study, we have provided direct evidence that leptin causes PPARγ reduction in primary cultured PASMC; this effect is coupled to leptin-induced ERK1/2 activation and subsequent induction of Egr-1, which further down-regulates PPARγ expression and results in PASMC proliferation. The present study confirmed that ERK1/2 signaling cascade mediated leptin-induced PPARγ reduction by up-regulation of Egr-1 in PASMC." SIGNOR-263508 EGR1 protein P18146 UNIPROT SLC9A3 protein P48764 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 7227 BTO:0001677 16464174 f "Transcriptional stimulation of the human NHE3 promoter activity by PMA: PKC independence and involvement of the transcription factor EGR-1|Co-transfection of Sp1 or Sp3 into SL2 cells activated the NHE3-reporter constructs, suggesting that Sp1 and Sp3 act as positive regulators of the NHE3 expression. In addition, overexpression of EGR-1 was sufficient to transactivate the NHE3-reporter gene activity" SIGNOR-254269 EGR1 protein P18146 UNIPROT BCAR1 protein P56945 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000093 22431919 f miannu "Overexpression or short interfering RNA (siRNA)-mediated down-regulation of EGR1 or NAB2, and chromatin immunoprecipitations indicated that EGR1 and NAB2 act in concert to positively regulate p130(Cas)/BCAR1 expression in breast cancer cells." SIGNOR-253890 EGR1 protein P18146 UNIPROT HSD11B2 protein P80365 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15659537 f miannu "Overexpression of p50 inhibited HSD11B2 promoter activity and overexpression of Egr-1 inhibited transactivation of the HSD11B2 promoter by p65/p50." SIGNOR-253876 EGR1 protein P18146 UNIPROT COL7A1 protein Q02388 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21931594 f Regulation miannu "Egr-1 induced a time-dependent ECM gene expression program, with the number of ECM genes increasing >2.5-fold (from 16 to 41) between 24 and 48 h. Genes in this group include those coding for multiple collagens (COL4A1, COL4A2, COL11A1, COL7A1, COL10A1)" SIGNOR-251920 CSNK2A2 protein P19784 UNIPROT PTPN1 protein P18031 UNIPROT unknown phosphorylation -1 9600099 t llicata "In this study, we demonstrate that HPTP1B are multiple phosphorylated on threonine and tyrosine as well as serine near its N-terminus by CKII and p60c-src in vitro." SIGNOR-251028 EGR1 protein P18146 UNIPROT HYAL1 protein Q12794 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004796 18718911 f miannu "In 253J-Lung and HT1376 bladder cancer cell lines, which show high HYAL-1 expression, transcription factors Egr-1, AP-2, and NFκB bind the HYAL-1 promoter. Because both SP1 and Egr-1 have two overlapping binding sites within the promoter (Fig. 5), it appears that although SP1 binding to the methylated HYAL-1 promoter turns off transcription, binding of Erg-1 (and also AP-2) to the unmethylated promoter turns on transcription." SIGNOR-253878 EGR1 protein P18146 UNIPROT FAP protein Q12884 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567 20515787 f "Down-regulation of EGR1 resulted in a significant reduction in endogenous FAP mRNA expression. These findings identify the basal transcriptional requirements of FAP gene expression and show EGR1 is an important regulator of FAP expression." SIGNOR-254248 EGR1 protein P18146 UNIPROT NAB2 protein Q15742 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000848 20506119 f miannu "In melanoma and carcinoma cells EGR1 activates NAB2 expression. we investigated the influence of EGR2 and EGR3 on NAB2 expression in melanoma and carcinoma cells. Here, we show that like EGR1, EGR2 and EGR3 induced NAB2 expression in these cells. EGR1 and EGR3 act in concert on the NAB2 promoter and are more potent activators of NAB2 transcription than EGR2." SIGNOR-253881 EGR1 protein P18146 UNIPROT GDF15 protein Q99988 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000018 17715378 f "Isochaihulactone treatment increased the luciferase activity of NAG-1 in A549 cells transfected with the NAG-1 promoter construct. This induction increased expression of NAG-1 that was p53-independent and Sp1-dependent. Our findings suggest that NAG-1 expression is up-regulated by isochaihulactone through an ERK-dependent pathway involving the activation of EGR-1." SIGNOR-254266 EGR1 protein P18146 UNIPROT PDGFC protein Q9NRA1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0001685 15247255 f "The PDGF family of ligands is comprised of A, B, C, and D chains. Here, we provide the first functional characterization of the PDGF-C promoter. We examined 797 bp of the human PDGF-C promoter and identified several putative recognition elements for Sp1, Ets Egr-1, and Smad.|These findings thus demonstrate that PDGF-C transcription, activated by FGF-2, is mediated by Egr-1 and its upstream kinase ERK.|Egr-1 and Sp1 specifically bind the PDGF-C promoter" SIGNOR-254268 EGR1 protein P18146 UNIPROT HPSE protein Q9Y251 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001671;BTO:0001345 16007175 t "Promoter CpG hypomethylation and transcription factor EGR1 hyperactivate heparanase expression in bladder cancer." SIGNOR-254267 SRD5A1 protein P18405 UNIPROT 17beta-hydroxy-5alpha-androstan-3-one smallmolecule CHEBI:16330 ChEBI "up-regulates activity" "small molecule catalysis" 9606 15861399 t miannu "Testosterone is the predominant circulating androgen in mammals and is converted to dihydrotestosterone (DHT) by 5α-reductase in certain tissues of the male urogenital tract, skin, and other target cells. DHT binds with highest affinity to AR and together with testosterone promotes AR transcriptional activity thereby ensuring the development and maintenance of male reproductive functions." SIGNOR-251534 PTPRA protein P18433 UNIPROT FYN protein P06241 UNIPROT "up-regulates activity" dephosphorylation Tyr531 FTATEPQyQPGENL 10090 BTO:0000255 9535845 t "In a coexpression system, PTPalpha effected a dose-dependent tyrosine dephosphorylation and activation of p59(fyn), where maximal dephosphorylation correlated with a 5-fold increase in kinase activity.|the increased p59fyn catalytic activity and SH2 availability for binding are consistent with a PTPα-mediated dephosphorylation of the C-terminal Tyr-531 of p59fyn." SIGNOR-248435 PTPRA protein P18433 UNIPROT LYN protein P07948 UNIPROT "down-regulates activity" dephosphorylation Tyr397 RVIEDNEyTAREGAK 10116 15537644 t "We found that PTPα and SHP-1 both dephosphorylate Lyn exclusively at Tyr-397|Lyn expressed in CHO cells has a substantially higher specific activity than Lyn in RBL cells because of high levels of phosphorylation at its active site Tyr-397 (Fig. 1). Enhanced Lyn kinase activity in the CHO cells leads to spontaneous phosphorylation of multiple cellular proteins, including FcϵRI" SIGNOR-248436 PTPRA protein P18433 UNIPROT SRC protein P12931 UNIPROT up-regulates dephosphorylation Tyr530 FTSTEPQyQPGENL 9606 BTO:0000938 7691597 t gcesareni "Endogenous pp60c-src kinase activity is enhanced in the rptp alpha-transfected cells, which may be due to direct dephosphorylation of the regulatory tyr residue at position 527 in pp60c-src by rptp alpha." SIGNOR-32014 PTPRA protein P18433 UNIPROT SRC protein P12931 UNIPROT "up-regulates activity" dephosphorylation Tyr530 FTSTEPQyQPGENL 10090 BTO:0000944 10698938 t "Protein tyrosine phosphatase alpha (PTPalpha) is believed to dephosphorylate physiologically the Src proto-oncogene at phosphotyrosine (pTyr)527, a critical negative-regulatory residue. It thereby activates Src, and PTPalpha overexpression neoplastically transforms NIH 3T3 cells." SIGNOR-248438 PTPRA protein P18433 UNIPROT SRC protein P12931 UNIPROT "up-regulates activity" dephosphorylation Tyr530 FTSTEPQyQPGENL 9606 17974954 t "Several protein tyrosine phosphatases are capable of activating Src by dephosphorylating Y530 (reviewed in ref. 9). These include PTP-α, PTP-λ, SHP-1, SHP-2, and PTP1B" SIGNOR-248437 PTPRA protein P18433 UNIPROT PTPRA protein P18433 UNIPROT "down-regulates activity" dephosphorylation Tyr798 YIDAFSDyANFK 9606 7518772 t "Transient overexpression of c-Src together with RPTP alpha in human embryonic kidney 293 cells increased phosphorylation of Tyr789, suggesting that c-Src may phosphorylate RPTP alpha in vivo. RPTP alpha had autodephosphorylation activity in vitro. When expressed in 293 cells the level of Tyr789 phosphorylation was higher in a non-functional mutant of RPTP alpha than in wild type RPTP alpha, indicating that RPTP alpha may have autodephosphorylation activity in vivo as well.|We show that RPTP alpha, but not a mutant of RPTP alpha with a Tyr-->Phe mutation at position 789, bound to GRB2 in vitro." SIGNOR-248439 GABRB1 protein P18505 UNIPROT "GABA-A (a1-b1-g2) receptor" complex SIGNOR-C330 SIGNOR "form complex" binding 9606 BTO:0000227 18790874 t "brain, See table 3 for identified complexes" lperfetto "The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon." SIGNOR-263751 GABRB1 protein P18505 UNIPROT "GABA-A (a2-b1-g2) receptor" complex SIGNOR-C331 SIGNOR "form complex" binding 9606 BTO:0000227 18790874 t "brain, See table 3 for identified complexes" lperfetto "The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon." SIGNOR-263754 GABRB1 protein P18505 UNIPROT "GABA-A (a3-b1-g2) receptor" complex SIGNOR-C332 SIGNOR "form complex" binding 9606 BTO:0000227 18790874 t "brain, See table 3 for identified complexes" lperfetto "The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon." SIGNOR-263757 GABRG2 protein P18507 UNIPROT "GABA-A (a1-b1-g2) receptor" complex SIGNOR-C330 SIGNOR "form complex" binding 9606 BTO:0000227 18790874 t "brain, See table 3 for identified complexes" lperfetto "The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon." SIGNOR-263752 GABRG2 protein P18507 UNIPROT "GABA-A (a2-b1-g2) receptor" complex SIGNOR-C331 SIGNOR "form complex" binding 9606 BTO:0000227 18790874 t "brain, See table 3 for identified complexes" lperfetto "The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon." SIGNOR-263755 GABRG2 protein P18507 UNIPROT "GABA-A (a3-b1-g2) receptor" complex SIGNOR-C332 SIGNOR "form complex" binding 9606 BTO:0000227 18790874 t "brain, See table 3 for identified complexes" lperfetto "The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon." SIGNOR-263758 GABRG2 protein P18507 UNIPROT "GABA-A (a4-b1-g2) receptor" complex SIGNOR-C333 SIGNOR "form complex" binding 9606 BTO:0000227 18790874 t "brain, See table 3 for identified complexes" lperfetto "The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon." SIGNOR-263761 GABRG2 protein P18507 UNIPROT "GABA-A (a6-b1-g2) receptor" complex SIGNOR-C334 SIGNOR "form complex" binding 9606 BTO:0000227 18790874 t "brain, See table 3 for identified complexes" lperfetto "The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon." SIGNOR-263764 GABRG2 protein P18507 UNIPROT "GABA-A (a5-b1-g2) receptor" complex SIGNOR-C335 SIGNOR "form complex" binding 9606 BTO:0000227 18790874 t "brain, See table 3 for identified complexes" lperfetto "The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon." SIGNOR-263767 ADCYAP1 protein P18509 UNIPROT VIPR1 protein P32241 UNIPROT up-regulates binding 9606 11897681 t gcesareni "Pacap binds to a pacap-specific receptor (pac1) and to vpac receptors (vpac1 and vpac2), which share high affinity for vasoactive intestinal polypeptide (vip)." SIGNOR-116066 ADCYAP1 protein P18509 UNIPROT ADCYAP1R1 protein P41586 UNIPROT up-regulates binding 9606 8703026 t gcesareni "Type i pacap receptors bind pacap-27 and -38. the potencies of the two forms of pacap are similar for adenylate cyclase stimulation, whereas pacap-38 is more potent than pacap-27 in phospholipase c activation." SIGNOR-43225 IL1RN protein P18510 UNIPROT IL1R1 protein P14778 UNIPROT "down-regulates activity" binding 9606 2876877 t Gianni "Homozygous truncating mutations result in lack of secreted interleukin-1–receptor antagonist protein, which inhibits the proinflammatory cytokines interleukin-1α and interleukin-1β" SIGNOR-262302 RHCE protein P18577 UNIPROT "Ankyrin complex" complex SIGNOR-C383 SIGNOR "form complex" binding 9606 BTO:0000424 22465511 t lperfetto "The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB)) " SIGNOR-266022 RPL17 protein P18621 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262482 PGAM1 protein P18669 UNIPROT 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 24786789 t miannu "Phosphoglycerate mutase (PGAM) is a glycolytic enzyme that catalyzes the reversible conversion of 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG; ref. 4). Human genome contains two PGAM genes, PGAM1 (also known as PGAM-B), which is expressed in brain and most other tissues, and PGAM2 (also known as PGAM-M), which is highly expressed in muscle." SIGNOR-266511 PGAM1 protein P18669 UNIPROT 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 24786789 t miannu "Phosphoglycerate mutase (PGAM) is a glycolytic enzyme that catalyzes the reversible conversion of 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG; ref. 4). Human genome contains two PGAM genes, PGAM1 (also known as PGAM-B), which is expressed in brain and most other tissues, and PGAM2 (also known as PGAM-M), which is highly expressed in muscle." SIGNOR-266514 ADRA2C protein P18825 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256842 ADRA2C protein P18825 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256978 ADRA2C protein P18825 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257094 ADRA2C protein P18825 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256699 ATF4 protein P18848 UNIPROT NUPR1 protein O60356 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567 19946894 f lperfetto "Nuclear protein 1 induced by ATF4 in response to various stressors acts as a positive regulator on the transcriptional activation of ATF4." SIGNOR-253730 ATF4 protein P18848 UNIPROT PPP1R15A protein O75807 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 31226023 t miannu "ATF4 also induces another bZIP protein C/EBP-homologous protein (CHOP), which is responsible for triggering apoptosis in cells under prolonged ER stress. ATF4 and CHOP further induce growth arrest and DNA damage–inducible protein 34 (GADD34),a regulatory subunit of protein phosphatase 1 (PP1) that dephosphorylates eIF2α. This negative feedback mechanism enables protein synthesis to resume after resolution of ER stress." SIGNOR-260172 ATF4 protein P18848 UNIPROT FGF19 protein O95750 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000195 23205607 t lperfetto "Reporter gene analyses using the 5'-promoter region of FGF19 revealed that a functional AARE (amino-acid-response element) was localized in this region, and this site was responsible for inducing its transcription through ATF4 (activating transcription factor 4), which is activated in response to ER stress" SIGNOR-253727 ATF4 protein P18848 UNIPROT ASNS protein P08243 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002182 18940792 f miannu "C/EBP homology protein (CHOP) interacts with activating transcription factor 4 (ATF4) and negatively regulates the stress-dependent induction of the asparagine synthetase gene." SIGNOR-253838 ATF4 protein P18848 UNIPROT ASNS protein P08243 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11960987 f miannu "Transcription from the asparagine synthetase (A.S.) gene is increased in response to either amino acid (amino acid response) or glucose (endoplasmic reticulum stress response) deprivation. the results provide both in vitro and in vivo evidence for a role of ATF4 in the transcriptional activation of the A.S. gene in response to nutrient deprivation." SIGNOR-253747 ATF4 protein P18848 UNIPROT HSPA5 protein P11021 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 16205636 f miannu "Suppression of ATF4 expression by small interfering RNA (siRNA) partially inhibited the celecoxib-dependent upregulation of GRP78." SIGNOR-253749 ATF4 protein P18848 UNIPROT "NLRP1 inflammasome" complex SIGNOR-C224 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 26086088 t miannu "Transcription Factor ATF4 Induces NLRP1 Inflammasome Expression During Endoplasmic Reticulum Stress. Here we report that expression of NLRP1, a core inflammasome component, is specifically up-regulated during severe ER stress conditions in human cell lines. Both IRE1α and PERK, but not the ATF6 pathway, modulate NLRP1 gene expression. Furthermore, using mutagenesis, chromatin immunoprecipitation and CRISPR-Cas9-mediated genome editing technology, we demonstrate that ATF4 transcription factor directly binds to NLRP1 promoter during ER stress." SIGNOR-260354 ATF6 protein P18850 UNIPROT HSPA5 protein P11021 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567 14973138 t Luana " Accordingly, N-terminal fragments of each ATF6 isoform (N-ATF6α and N-ATF6β) were overexpressed in HeLa cells and the effects on GRP78 induction were assessed. When expressed at similar levels, N-ATF6α conferred ∼200-fold greater GRP78 promoter activation than N-ATF6β. " SIGNOR-261565 ATF6 protein P18850 UNIPROT XBP-1S protein P17861_P17861-2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 31226023 t miannu "Apart from ER protein chaperones, ATF6 also induces the expression of CHOP and XBP1, thereby connecting the three UPR branches into an integrated signaling network" SIGNOR-260184 ATF6 protein P18850 UNIPROT ATF6 protein P18850 UNIPROT "up-regulates activity" binding -1 12805554 t miannu "E4BP4, ATF-6, OASIS, and XBP-1 all formed strong homodimeric associations on the array Transcription factor dimerization can increase the selectivity of protein-DNA interactions and generate a large amount of DNA binding diversity from a relatively small number of proteins" SIGNOR-224202 ATF6 protein P18850 UNIPROT DDIT3 protein P35638 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 31226023 t miannu "Apart from ER protein chaperones, ATF6 also induces the expression of CHOP and XBP1, thereby connecting the three UPR branches into an integrated signaling network" SIGNOR-260180 ATF6 protein P18850 UNIPROT NUCB1 protein Q02818 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17686766 f miannu "we identified nucleobindin 1 (NUCB1) as a novel repressor of the S1P-mediated ATF6 activation. NUCB1 is an ER stress-inducible gene with the promoter region having functional cis-elements for transcriptional activation by ATF6." SIGNOR-253753 ATF6 protein P18850 UNIPROT HYOU1 protein Q9Y4L1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001088 20861013 f miannu "We recently found that in cultured gastric cells, expression of endoplasmic reticulum (ER) chaperones (such as 150-kDa oxygen-regulated protein (ORP150) and glucose-regulated protein 78 (GRP78)) is induced by NSAIDs and confers protection against NSAID-induced apoptosis, which is important in the development of NSAID-induced gastric lesions. In this study we have found that co-culture of gastric cells with H. pylori suppresses the expression of ER chaperones. This suppression was regulated at the level of transcription and accompanied by a reduction in the level of activating transcription factor 6 (ATF6), one of the transcription factors for ER chaperone genes." SIGNOR-253752 PLCG1 protein P19174 UNIPROT ITPRIPL1 protein Q6GPH6 UNIPROT up-regulates 9606 BTO:0000938 21368195 f gcesareni "Recruitment of g protein also can activate phospholipase c (plc) that in turn increases inositol triphosphate (ip3) levels and induces ca2+ release from internal stores" SIGNOR-172500 NCL protein P19338 UNIPROT MYB protein P10242 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 10660576 t miannu "We identify nucleolin as one of the nuclear polypeptides that interact specifically with the A-Myb and c-Myb. We show that the interaction of nucleolin with Myb is functional because co-transfection of nucleolin down-regulates Myb transcriptional activity." SIGNOR-221236 NCL protein P19338 UNIPROT MYBL1 protein P10243 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 10660576 t miannu "We identify nucleolin as one of the nuclear polypeptides that interact specifically with the A-Myb and c-Myb. We show that the interaction of nucleolin with Myb is functional because co-transfection of nucleolin down-regulates Myb transcriptional activity." SIGNOR-221233 POLR2C protein P19387 UNIPROT "RNA Polymerase II" complex SIGNOR-C391 SIGNOR "form complex" binding 9606 BTO:0000567 9852112 t lperfetto "Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II" SIGNOR-266163 POLR2E protein P19388 UNIPROT "RNA Polymerase III" complex SIGNOR-C389 SIGNOR "form complex" binding 9606 BTO:0000567 12391170 t lperfetto "In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights." SIGNOR-266138 POLR2E protein P19388 UNIPROT "RNA Polymerase I" complex SIGNOR-C390 SIGNOR "form complex" binding 22260999 t lperfetto "In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1). " SIGNOR-266147 POLR2E protein P19388 UNIPROT "RNA Polymerase II" complex SIGNOR-C391 SIGNOR "form complex" binding 9606 BTO:0000567 9852112 t lperfetto "Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II" SIGNOR-266167 NDUFV2 protein P19404 UNIPROT "Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24]." SIGNOR-262184 ELK1 protein P19419 UNIPROT MUC4 protein Q99102 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001861 19757157 t lperfetto "Through promoter screening, overexpressing methods and luciferase reporter studies, we found that transcription factors CREB, Ets-1, Elk-1 and STAT1 can positively regulate MUC4 expression at the promoter and mRNA level." SIGNOR-254096 TNFRSF1A protein P19438 UNIPROT NFKBIA protein P25963 UNIPROT "down-regulates quantity by destabilization" 10090 BTO:0002572;BTO:0000801 21232017 f lperfetto "Tnfr1-induced phosforylation and degradarionn of ikb are almost completely abolished in tradd-deficient mefs,these hallmarks of classical nf-kn signaling are only attenuated in tradd-deficient macrophage." SIGNOR-235789 TNFRSF1A protein P19438 UNIPROT TRADD protein Q15628 UNIPROT "up-regulates activity" binding 9606 11502070 t lperfetto "The death domain of tnfrsf1a provides a novel molecular interface that interacts specifically with the death domain of tradd." SIGNOR-109719 TNFRSF1A protein P19438 UNIPROT TRADD protein Q15628 UNIPROT "up-regulates activity" binding 10090 BTO:0002572;BTO:0000801 21232017 t 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 TNFRSF1A protein P19438 UNIPROT TRADD protein Q15628 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 7758105 t 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 TNFRSF1A protein P19438 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 BTO:0000567 11672426 f 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 TNFRSF1A protein P19438 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 10090 BTO:0000165 17151142 f lperfetto "These results indicate that TNF-alpha regulates myogenesis and muscle regeneration as a key activator of p38." SIGNOR-235370 TNFRSF1A protein P19438 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" 17151142 f "[...] TNF-alpha is critical for p38 activation during the early stages of myoblast differentiation" SIGNOR-253600 EIF2AK2 protein P19525 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser392 FKTEGPDsD 9606 10348343 t gcesareni "The double-stranded rna activated protein kinase pkr physically associates with the tumor suppressor p53 protein and phosphorylates human p53 on serine 392 in vitro." SIGNOR-68033 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Ser242 NQRKAKRsLAPRFDL 9606 11152499 t tpavlidou "We previously identified four autophosphorylated amino acids and elucidated their participation in pkr activation.Replacement Of all four of these residues in pkr with alanines did not dramatically affect kinase activity in vitro or in yeast saccharomyces cerevisiae.However, when coupled with mutations of serine 242 and threonines 255 and 258 in the central region, these mutations increased pkr protein expression in mammalian cells, consistent with diminished kinase activity." SIGNOR-85765 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Ser83 NKEKKAVsPLLLTTT 9606 11152499 t tpavlidou "Taken together, these results show that pkr is autophosphorylated on serine 83 and threonines 88, 89, and 90, that this autophosphorylation may enhance kinase activation, and that the inhibition of pkr by hcv e2 is not solely due to duplication of and competition with these autophosphorylation sites." SIGNOR-85769 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Thr255 DLPDMKEtKYTVDKR 9606 11152499 t tpavlidou "We previously identified four autophosphorylated amino acids and elucidated their participation in pkr activation.Replacement Of all four of these residues in pkr with alanines did not dramatically affect kinase activity in vitro or in yeast saccharomyces cerevisiae.However, when coupled with mutations of serine 242 and threonines 255 and 258 in the central region, these mutations increased pkr protein expression in mammalian cells, consistent with diminished kinase activity." SIGNOR-85773 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Thr258 DMKETKYtVDKRFGM 9606 11152499 t tpavlidou "We previously identified four autophosphorylated amino acids and elucidated their participation in pkr activation.Replacement Of all four of these residues in pkr with alanines did not dramatically affect kinase activity in vitro or in yeast saccharomyces cerevisiae.However, when coupled with mutations of serine 242 and threonines 255 and 258 in the central region, these mutations increased pkr protein expression in mammalian cells, consistent with diminished kinase activity." SIGNOR-85777 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Thr88 AVSPLLLtTTNSSEG 9606 11152499 t tpavlidou "Taken together, these results show that pkr is autophosphorylated on serine 83 and threonines 88, 89, and 90, that this autophosphorylation may enhance kinase activation, and that the inhibition of pkr by hcv e2 is not solely due to duplication of and competition with these autophosphorylation sites." SIGNOR-85781 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Thr89 VSPLLLTtTNSSEGL 9606 11152499 t tpavlidou "Taken together, these results show that pkr is autophosphorylated on serine 83 and threonines 88, 89, and 90, that this autophosphorylation may enhance kinase activation, and that the inhibition of pkr by hcv e2 is not solely due to duplication of and competition with these autophosphorylation sites." SIGNOR-85785 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Thr90 SPLLLTTtNSSEGLS 9606 11152499 t tpavlidou "Taken together, these results show that pkr is autophosphorylated on serine 83 and threonines 88, 89, and 90, that this autophosphorylation may enhance kinase activation, and that the inhibition of pkr by hcv e2 is not solely due to duplication of and competition with these autophosphorylation sites." SIGNOR-85789 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT "up-regulates activity" phosphorylation Thr446 LKNDGKRtRSKGTLR 4932 11337501 t "Trans-autophosphorylation of Thr-446 and Thr-451 by the two kinase moieties in a PKR dimer. autophosphorylation in the activation loop would promote proper alignment of key catalytic residues, or the correct orientation of the two lobes of the PKR kinase domain, required for substrate binding or phosphoryl transfer" SIGNOR-251110 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT "up-regulates activity" phosphorylation Thr451 KRTRSKGtLRYMSPE 9606 BTO:0000567 11337501 t lperfetto "Taken together, our findings support the idea that binding of pkr to dsrna increases autophosphorylation in the activation loop of the kinase domain (fig. 9). Because dsrna binding promotes dimerization, this would facilitate trans-autophosphorylation of thr-446 and thr-451 by the two kinase moieties in a pkr dimer" SIGNOR-107511 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT "up-regulates activity" phosphorylation Tyr101 EGLSMGNyIGLINRI -1 16373505 t Manara "PKR autophosphorylates on Y101, Y162, and Y293 in vitro. Site-specific tyrosine phosphorylation is essential for efficient dsRNA-binding, dimerization, kinase activation and eIF2alpha phosphorylation of PKR." SIGNOR-260782 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT "up-regulates activity" phosphorylation Tyr101 EGLSMGNyIGLINRI 9606 BTO:0001282 16373505 t "PKR autophosphorylates on Y101, Y162, and Y293. unctional characterization of Y101F and Y162F mutants revealed that phosphorylation at these sites is needed for efficient dsRNA binding and kinase dimerization and activation." SIGNOR-251112 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT "up-regulates activity" phosphorylation Tyr162 QLAAKLAyLQILSEE 9606 BTO:0001282 16373505 t "PKR autophosphorylates on Y101, Y162, and Y293. unctional characterization of Y101F and Y162F mutants revealed that phosphorylation at these sites is needed for efficient dsRNA binding and kinase dimerization and activation." SIGNOR-251113 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT "up-regulates activity" phosphorylation Tyr162 QLAAKLAyLQILSEE -1 16373505 t Manara "PKR autophosphorylates on Y101, Y162, and Y293 in vitro. Site-specific tyrosine phosphorylation is essential for efficient dsRNA-binding, dimerization, kinase activation and eIF2alpha phosphorylation of PKR." SIGNOR-260783 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT "up-regulates activity" phosphorylation Tyr293 HRIDGKTyVIKRVKY -1 16373505 t Manara "PKR autophosphorylates on Y101, Y162, and Y293 in vitro. Site-specific tyrosine phosphorylation is essential for efficient dsRNA-binding, dimerization, kinase activation and eIF2alpha phosphorylation of PKR." SIGNOR-260784 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT "up-regulates activity" phosphorylation Tyr293 HRIDGKTyVIKRVKY 9606 BTO:0001282 16373505 t "PKR autophosphorylates on Y101, Y162, and Y293. The introduction of the Y293F mutation causes significant defects in PKR autophosphorylation and eIF2α phosphorylation, providing evidence for a critical function of this phosphorylated residue." SIGNOR-251114 EIF2AK2 protein P19525 UNIPROT NFKBIA protein P25963 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser32 LLDDRHDsGLDSMKD 10723127 t lperfetto "As described for other stimuli, following pIC treatment, PKR phosphorylates the NF-kappa B inhibitor I kappa B alpha at serine 32 before degradation." SIGNOR-249335 EIF2AK2 protein P19525 UNIPROT PPP2R5A protein Q15172 UNIPROT up-regulates phosphorylation Ser28 VDGFTRKsVRKAQRQ 9606 BTO:0001271 18957415 t llicata "Phosphorylation of serine 28 by pkr promotes mitochondrial localization of b56alpha, because wild-type but not mutant s28a b56alpha promoted mitochondrial pp2a activity." SIGNOR-181793 EIF2AK2 protein P19525 UNIPROT "AIM2 inflammasome" complex SIGNOR-C222 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 22801494 t miannu "Here we identify a role for double-stranded RNA-dependent protein kinase (PKR, also known as EIF2AK2) in inflammasome activation. PKR physically interacts with several inflammasome components, including NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3), NLRP1, NLR family CARD domain-containing protein 4 (NLRC4), absent in melanoma 2 (AIM2), and broadly regulates inflammasome activation." SIGNOR-263120 EIF2AK2 protein P19525 UNIPROT "NLRC4 inflammasome" complex SIGNOR-C223 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 22801494 t miannu "Here we identify a role for double-stranded RNA-dependent protein kinase (PKR, also known as EIF2AK2) in inflammasome activation. PKR physically interacts with several inflammasome components, including NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3), NLRP1, NLR family CARD domain-containing protein 4 (NLRC4), absent in melanoma 2 (AIM2), and broadly regulates inflammasome activation." SIGNOR-263121 EIF2AK2 protein P19525 UNIPROT "NLRP1 inflammasome" complex SIGNOR-C224 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 22801494 t miannu "Here we identify a role for double-stranded RNA-dependent protein kinase (PKR, also known as EIF2AK2) in inflammasome activation. PKR physically interacts with several inflammasome components, including NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3), NLRP1, NLR family CARD domain-containing protein 4 (NLRC4), absent in melanoma 2 (AIM2), and broadly regulates inflammasome activation." SIGNOR-263118 EIF2AK2 protein P19525 UNIPROT "NLRP3 inflammasome" complex SIGNOR-C225 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 22801494 t miannu "Here we identify a role for double-stranded RNA-dependent protein kinase (PKR, also known as EIF2AK2) in inflammasome activation. PKR physically interacts with several inflammasome components, including NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3), NLRP1, NLR family CARD domain-containing protein 4 (NLRC4), absent in melanoma 2 (AIM2), and broadly regulates inflammasome activation." SIGNOR-263119 TFE3 protein P19532 UNIPROT MYH9 protein P35579 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567 11467950 f miannu "we have focused on element F of the NMHC-A gene. We have identified and characterized the factors which are capable of binding to element F. The basic helix_loop_helix leucine zipper (bHLH-LZ) proteins, TFEC-l and -s, which are alternatively spliced isoforms, TFE3, USF1, and USF2 have all been found to bind to element F with different binding activities and with different transcriptional activation potencies." SIGNOR-222504 WT1 protein P19544 UNIPROT PODXL protein O00592 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000671 11719225 t "Binding of WT1 to conserved elements within the Podocalyxin gene promoter results in potent transcriptional activation, and the specific expression pattern of Podocalyxin in the developing kidney mirrors that of WT1 itself." SIGNOR-252300 WT1 protein P19544 UNIPROT REN protein P00797 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000007 18496514 t "Here, we show that a splice variant of the Wilms' tumor protein lacking three amino acids WT1(-KTS) suppresses renin gene transcription" SIGNOR-252296 WT1 protein P19544 UNIPROT PAX2 protein Q02962 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000671 7720589 t "A marked increase in WT1 protein levels coincided precisely with down-regulation of the Pax-2 gene in the individual precursor cells of the visceral glomerular epithelium, suggesting a direct effect of the WT1 repressor protein on Pax-2 regulatory elements. To examine whether WT1 could directly repress Pax-2 transcription, binding of WT1 to three high affinity sites in the 5' untranslated Pax-2 leader sequence was demonstrated by DNAseI footprinting analysis" SIGNOR-252298 WT1 protein P19544 UNIPROT SRY protein Q05066 UNIPROT up-regulates binding 9606 12970737 t miannu "Here we report that wt1 binds to and acts synergistically with sry to activate transcription from a promoter containing sry-binding sites" SIGNOR-100345 WT1 protein P19544 UNIPROT RBM4 protein Q9BWF3 UNIPROT down-regulates binding 9606 16934801 t miannu "Wilm's tumor protein 1 (wt1), a protein implicated in various cancers and developmental disorders, consists of two major isoforms: wt1(-kts), a transcription factor, and wt1(+kts), a post-transcriptional regulator that binds to rna and can interact with splicing components. Here we show that wt1 interacts with the novel splicing regulator rbm4. / we conclude that the (+kts) form of wt1 is able to inhibit the effect of rbm4 on alternative splicing." SIGNOR-149166 EN2 protein P19622 UNIPROT FGF8 protein P55075 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0003560 10026229 t miannu "Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression." SIGNOR-265775 EN2 protein P19622 UNIPROT FGF8 protein P55075 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0003560 10026229 t miannu "Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression." SIGNOR-265801 CSNK2A2 protein P19784 UNIPROT SPIB protein Q01892 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser146 PALEVSDsESDEALV 9606 BTO:0000567 10618498 t llicata "Phosphorylation of the Spi-B transcription factor reduces its intrinsic stability. | Serine residues 37 in the transactivation domain and 129, 144 and 146 in the PEST domain of Spi-B are phosphorylated by CKII in vitro | The CKII phosphorylation sites mapped in vitro are phosphorylated in vivo" SIGNOR-251041 CSNK2A2 protein P19784 UNIPROT CASQ2 protein O14958 UNIPROT unknown phosphorylation Ser385 DDDDDDNsDEEDNDD -1 1985907 t llicata "Both cardiac and skeletal muscle calsequestrins were phosphorylated by casein kinase II, but cardiac calsequestrin was phosphorylated to a higher stoichiometry and at least 50 times more rapidly. The site of rapid phosphorylation of cardiac calsequestrin was localized to the distinct COOH terminus, where a cluster of three closely spaced serine residues are found (S378DEESN-DDSDDDDE-COOH)." SIGNOR-250980 CSNK2A2 protein P19784 UNIPROT MYCN protein P04198 UNIPROT unknown phosphorylation Ser263 GEDTLSDsDDEDDEE -1 1425701 t llicata "Analysis of phosphorylation sites in synthetic peptides of this acidic region identified the major sites phosphorylated by CKII as Ser261 and Ser263." SIGNOR-251015 CSNK2A2 protein P19784 UNIPROT HNRNPC protein P07910 UNIPROT unknown phosphorylation Ser260 SEGGADDsAEEGDLL -1 12564933 t llicata "Protein kinase CK2 phosphorylates hnRNP-C1/C2 at S247" SIGNOR-251007 CSNK2A2 protein P19784 UNIPROT PTPRC protein P08575 UNIPROT "up-regulates activity" phosphorylation Ser1001 SKESEHDsDESSDDD 9606 BTO:0000661 10066810 t llicata "Mutational analysis of CK2 consensus sites showed that the target for CK2 was in an acidic insert of 19 amino acids in the D2 domain, and Ser to Ala mutations at amino acids 965, 968, 969, and 973 abrogated CK2 phosphorylation of CD45. CK2 phosphorylation increased CD45 activity 3-fold toward phosphorylated myelin basic protein, and this increase was reversible by PP2A treatment. " SIGNOR-251032 CSNK2A2 protein P19784 UNIPROT PTPRC protein P08575 UNIPROT "up-regulates activity" phosphorylation Ser1004 SEHDSDEsSDDDSDS 9606 BTO:0000661 10066810 t llicata "Mutational analysis of CK2 consensus sites showed that the target for CK2 was in an acidic insert of 19 amino acids in the D2 domain, and Ser to Ala mutations at amino acids 965, 968, 969, and 973 abrogated CK2 phosphorylation of CD45. CK2 phosphorylation increased CD45 activity 3-fold toward phosphorylated myelin basic protein, and this increase was reversible by PP2A treatment. " SIGNOR-251029 CSNK2A2 protein P19784 UNIPROT PTPRC protein P08575 UNIPROT "up-regulates activity" phosphorylation Ser1005 EHDSDESsDDDSDSE 9606 BTO:0000661 10066810 t llicata "Mutational analysis of CK2 consensus sites showed that the target for CK2 was in an acidic insert of 19 amino acids in the D2 domain, and Ser to Ala mutations at amino acids 965, 968, 969, and 973 abrogated CK2 phosphorylation of CD45. CK2 phosphorylation increased CD45 activity 3-fold toward phosphorylated myelin basic protein, and this increase was reversible by PP2A treatment. " SIGNOR-251030 CSNK2A2 protein P19784 UNIPROT PTPRC protein P08575 UNIPROT "up-regulates activity" phosphorylation Ser1009 DESSDDDsDSEEPSK 9606 BTO:0000661 10066810 t llicata "Mutational analysis of CK2 consensus sites showed that the target for CK2 was in an acidic insert of 19 amino acids in the D2 domain, and Ser to Ala mutations at amino acids 965, 968, 969, and 973 abrogated CK2 phosphorylation of CD45. CK2 phosphorylation increased CD45 activity 3-fold toward phosphorylated myelin basic protein, and this increase was reversible by PP2A treatment. " SIGNOR-251031 CSNK2A2 protein P19784 UNIPROT CLTB protein P09497 UNIPROT unknown phosphorylation Ser13 GFFSSSEsGAPEAAE -1 3128543 t llicata "To date, the only evidence for a functional distinction of LCa and LCb is the preferential phosphorylation of LCb, which takes place at serine residues and is mediated by coated vesicle-associated casein kinase II. As a first step toward determining the function of light chain diversity, we have mapped the in vitro phosphorylation sites on LCb. We use [32P]ATP to phosphorylate LCb within coated vesicles, followed by sequencing of 32P-labeled chymotryptic peptides thereof, to identify serine residues at positions 11 and 13 as the phosphorylation sites." SIGNOR-250984 CSNK2A2 protein P19784 UNIPROT MS4A1 protein P11836 UNIPROT unknown phosphorylation Ser231 KSNIVLLsAEEKKEQ 9606 BTO:0000776 7678037 t llicata "These data suggest taht CKII can phosphorylate more than one site on CD20 molecule. | Taken together, this data shown that insulin can increase serine/ threonine phosphorylation and may stimulate CKII activity in B cells." SIGNOR-251011 CSNK2A2 protein P19784 UNIPROT MS4A1 protein P11836 UNIPROT unknown phosphorylation Ser289 PPQDQESsPIENDSS 9606 BTO:0000776 7678037 t llicata "These data suggest taht CKII can phosphorylate more than one site on CD20 molecule. | Taken together, this data shown that insulin can increase serine/ threonine phosphorylation and may stimulate CKII activity in B cells." SIGNOR-251012 CSNK2A2 protein P19784 UNIPROT MS4A1 protein P11836 UNIPROT unknown phosphorylation Thr250 KEEVVGLtETSSQPK 9606 BTO:0000776 7678037 t llicata "These data suggest taht CKII can phosphorylate more than one site on CD20 molecule. | Taken together, this data shown that insulin can increase serine/ threonine phosphorylation and may stimulate CKII activity in B cells." SIGNOR-251013 CSNK2A2 protein P19784 UNIPROT MYF5 protein P13349 UNIPROT "up-regulates activity" phosphorylation Ser133 NAIRYIEsLQELLRE -1 9461343 t llicata "Here, we report that Myf-5 protein constitutes a substrate for phosphorylation in vitro by protein kinase CK2. We identified two potential phosphorylation sites at serine49 and serine133, both of which seem to be necessary for Myf-5 activity. " SIGNOR-251016 CSNK2A2 protein P19784 UNIPROT MYF5 protein P13349 UNIPROT "up-regulates activity" phosphorylation Ser49 HKAELQGsDEDEHVR -1 9461343 t llicata "Here, we report that Myf-5 protein constitutes a substrate for phosphorylation in vitro by protein kinase CK2. We identified two potential phosphorylation sites at serine49 and serine133, both of which seem to be necessary for Myf-5 activity. " SIGNOR-251017 CSNK2A2 protein P19784 UNIPROT HMGA1 protein P17096 UNIPROT unknown phosphorylation Ser102 EEGISQEsSEEEQ -1 2806554 t llicata "Sequence analysis of the native peptide (90-107) after treatment, which specifically converts phosphoserine residues to S-ethylcysteine, revealed that 70-80% of serine residues 102 and 103 were phosphorylated in vivo. Both residues were fully phosphorylated in vitro by incubation with casein kinase II. These results suggest that casein kinase II is involved in the regulation of HMG-I function in the cells." SIGNOR-251004 CSNK2A2 protein P19784 UNIPROT HMGA1 protein P17096 UNIPROT unknown phosphorylation Ser103 EGISQESsEEEQ -1 2806554 t llicata "Sequence analysis of the native peptide (90-107) after treatment, which specifically converts phosphoserine residues to S-ethylcysteine, revealed that 70-80% of serine residues 102 and 103 were phosphorylated in vivo. Both residues were fully phosphorylated in vitro by incubation with casein kinase II. These results suggest that casein kinase II is involved in the regulation of HMG-I function in the cells." SIGNOR-251005 CSNK2A2 protein P19784 UNIPROT HMGA1 protein P17096 UNIPROT unknown phosphorylation Ser99 KEEEEGIsQESSEEE -1 2806554 t llicata "Sequence analysis of the native peptide (90-107) after treatment, which specifically converts phosphoserine residues to S-ethylcysteine, revealed that 70-80% of serine residues 102 and 103 were phosphorylated in vivo. Both residues were fully phosphorylated in vitro by incubation with casein kinase II. These results suggest that casein kinase II is involved in the regulation of HMG-I function in the cells. | After an 80 min incubation with CK-II, both serines were fully phosphorylated to 1 mol/mol and serine-99 to 0.3 mol/mol." SIGNOR-251006 CSNK2A2 protein P19784 UNIPROT XRCC1 protein P18887 UNIPROT "up-regulates activity" phosphorylation Ser518 GEDPYAGsTDENTDS 9606 BTO:0000567 15367657 t llicata "XRCC1 is phosphorylated in vivo and in vitro by CK2, and CK2 phosphorylation of XRCC1 on S518, T519, and T523 largely determines aprataxin binding to XRCC1 though its FHA domain | In addition, we present data to show that the acute loss of aprataxin by small interfering RNA (siRNA) renders HeLa cells sensitive to MMS through a mechanism that destabilizes XRCC1." SIGNOR-251050 CSNK2A2 protein P19784 UNIPROT XRCC1 protein P18887 UNIPROT "up-regulates activity" phosphorylation Thr519 EDPYAGStDENTDSE 9606 BTO:0000567 15367657 t llicata "XRCC1 is phosphorylated in vivo and in vitro by CK2, and CK2 phosphorylation of XRCC1 on S518, T519, and T523 largely determines aprataxin binding to XRCC1 though its FHA domain | In addition, we present data to show that the acute loss of aprataxin by small interfering RNA (siRNA) renders HeLa cells sensitive to MMS through a mechanism that destabilizes XRCC1." SIGNOR-251051 CSNK2A2 protein P19784 UNIPROT XRCC1 protein P18887 UNIPROT "up-regulates activity" phosphorylation Thr523 AGSTDENtDSEEHQE 9606 BTO:0000567 15367657 t llicata "XRCC1 is phosphorylated in vivo and in vitro by CK2, and CK2 phosphorylation of XRCC1 on S518, T519, and T523 largely determines aprataxin binding to XRCC1 though its FHA domain | In addition, we present data to show that the acute loss of aprataxin by small interfering RNA (siRNA) renders HeLa cells sensitive to MMS through a mechanism that destabilizes XRCC1." SIGNOR-251052 CSNK2A2 protein P19784 UNIPROT SAT1 protein P21673 UNIPROT unknown phosphorylation Ser146 FYKRRGAsDLSSEEG -1 8954982 t llicata "Casein kinase 2 phosphorylates recombinant human spermidine/spermine N1-acetyltransferase on both serine and threonine residues. | suggesting that the Ser-phosphorylated residues are located in the C-terminus of the protein, probably Ser 146 and 149." SIGNOR-251034 CSNK2A2 protein P19784 UNIPROT SAT1 protein P21673 UNIPROT unknown phosphorylation -1 8954982 t llicata "Casein kinase 2 phosphorylates recombinant human spermidine/spermine N1-acetyltransferase on both serine and threonine residues. | suggesting that the Ser-phosphorylated residues are located in the C-terminus of the protein, probably Ser 146 and 149." SIGNOR-251036 CSNK2A2 protein P19784 UNIPROT EEF1B2 protein P24534 UNIPROT unknown phosphorylation Ser106 DDIDLFGsDDEEESE -1 8547318 t llicata "EF-1 beta was highly phosphorylated by casein kinase II, with up to 1.3 mol of phosphate incorporated per mol protein. From microsequence analysis and manual Edman degradation, the majority of the phosphate was shown to be present in serine 106 in the peptide DLFGS106DDEEES112EEA. Serine 112 was also phosphorylated by casein kinase II, but to a lesser extent." SIGNOR-250987 CSNK2A2 protein P19784 UNIPROT EEF1B2 protein P24534 UNIPROT unknown phosphorylation Ser112 GSDDEEEsEEAKRLR -1 8547318 t llicata "EF-1 beta was highly phosphorylated by casein kinase II, with up to 1.3 mol of phosphate incorporated per mol protein. From microsequence analysis and manual Edman degradation, the majority of the phosphate was shown to be present in serine 106 in the peptide DLFGS106DDEEES112EEA. Serine 112 was also phosphorylated by casein kinase II, but to a lesser extent." SIGNOR-250988 CSNK2A2 protein P19784 UNIPROT ARRB2 protein P32121 UNIPROT unknown phosphorylation Thr382 EFDTNYAtDDDIVFE -1 11877451 t llicata "We found that arrestin-3 is constitutively phosphorylated at Thr-382 and becomes dephosphorylated upon beta(2)-adrenergic receptor activation in COS-1 cells. Casein kinase II (CKII) appears to be the major kinase mediating arrestin-3 phosphorylation, since 1) Thr-382 is contained within a canonical consensus sequence for CKII phosphorylation and 2) wild type arrestin-3 but not a T382A mutant is phosphorylated by CKII in vitro. | However, additional analysis reveals that arrestin-3 phosphorylation may regulate formation of a large arrestin-3-containing protein complex." SIGNOR-250977 CSNK2A2 protein P19784 UNIPROT PPP1R2 protein P41236 UNIPROT "up-regulates activity" phosphorylation Ser121 YRIQEQEsSGEEDSD -1 8288648 t llicata "Recombinant wild-type I-2 and the Ala-120/121 mutant were phosphorylated synergistically by GSK-3 and casein kinase II. The Thr-72 and Ser-86 mutants, however, did not undergo this synergistic phosphorylation. Our studies indicate that Thr-72 is the only GSK-3 site and that Ser-86 is the casein kinase II site required for the potentiation of GSK-3 action." SIGNOR-251020 CSNK2A2 protein P19784 UNIPROT PPP1R2 protein P41236 UNIPROT "up-regulates activity" phosphorylation Ser122 RIQEQESsGEEDSDL -1 8288648 t llicata "Recombinant wild-type I-2 and the Ala-120/121 mutant were phosphorylated synergistically by GSK-3 and casein kinase II. The Thr-72 and Ser-86 mutants, however, did not undergo this synergistic phosphorylation. Our studies indicate that Thr-72 is the only GSK-3 site and that Ser-86 is the casein kinase II site required for the potentiation of GSK-3 action." SIGNOR-251021 CSNK2A2 protein P19784 UNIPROT PPP1R2 protein P41236 UNIPROT "up-regulates activity" phosphorylation Ser87 GDDEDACsDTEATEA -1 8288648 t llicata "Recombinant wild-type I-2 and the Ala-120/121 mutant were phosphorylated synergistically by GSK-3 and casein kinase II. The Thr-72 and Ser-86 mutants, however, did not undergo this synergistic phosphorylation. Our studies indicate that Thr-72 is the only GSK-3 site and that Ser-86 is the casein kinase II site required for the potentiation of GSK-3 action." SIGNOR-251022 CSNK2A2 protein P19784 UNIPROT WAS protein P42768 UNIPROT "up-regulates activity" phosphorylation Ser484 RSRAIHSsDEGEDQA 9606 BTO:0001412 12769847 t llicata "We identify two phosphorylation sites in the VCA domain of WASP at serines 483 and 484. S483 and S484 are substrates for casein kinase 2 in vitro and in vivo. Phosphorylation of these residues increases the affinity of the VCA domain for the Arp2/3 complex 7-fold and is required for efficient in vitro actin polymerization by the full-length WASP molecule. " SIGNOR-251049 CSNK2A2 protein P19784 UNIPROT RGS19 protein P49795 UNIPROT unknown phosphorylation Ser24 ADRPPSMsSHDTASP -1 10760275 t llicata "Phosphorylation was Mn(2+)-dependent, using both purified CK2 and CCVs. Ser-24 was identified as one of the phosphorylation sites. Our results establish that GAIP is phosphorylated and that only the membrane pool is phosphorylated, suggesting that GAIP can be regulated by phosphorylation events taking place at the level of clathrin-coated pits and vesicles." SIGNOR-251033 CSNK2A2 protein P19784 UNIPROT GTF2A1 protein P52655 UNIPROT "up-regulates activity" phosphorylation Ser280 VDGTGDTsSEEDEDE -1 11278496 t llicata "We now show that human TFIIA is phosphorylated in vivo on serine residues that are partially conserved between yeast and human TFIIA large subunits. Alanine substitution mutation of serine residues 316 and 321 in TFIIA alphabeta reduced TFIIA phosphorylation significantly in vivo. Additional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels. Mutation of all four serine residues reduced the ability of TFIIA to stimulate transcription in transient transfection assays with various activators and promoters, indicating that TFIIA phosphorylation is required globally for optimal function." SIGNOR-250995 POU3F2 protein P20265 UNIPROT GNRH1 protein P01148 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11875100 f miannu "Functional studies demonstrated that Brn-2 increased promoter activity of the human and mouse GnRH genes." SIGNOR-254928 CSNK2A2 protein P19784 UNIPROT GTF2A1 protein P52655 UNIPROT "up-regulates activity" phosphorylation Ser281 DGTGDTSsEEDEDEE -1 11278496 t llicata "We now show that human TFIIA is phosphorylated in vivo on serine residues that are partially conserved between yeast and human TFIIA large subunits. Alanine substitution mutation of serine residues 316 and 321 in TFIIA alphabeta reduced TFIIA phosphorylation significantly in vivo. Additional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels. Mutation of all four serine residues reduced the ability of TFIIA to stimulate transcription in transient transfection assays with various activators and promoters, indicating that TFIIA phosphorylation is required globally for optimal function." SIGNOR-250996 CSNK2A2 protein P19784 UNIPROT GTF2A1 protein P52655 UNIPROT "up-regulates activity" phosphorylation Ser316 VEEEPLNsEDDVSDE -1 11278496 t llicata "We now show that human TFIIA is phosphorylated in vivo on serine residues that are partially conserved between yeast and human TFIIA large subunits. Alanine substitution mutation of serine residues 316 and 321 in TFIIA alphabeta reduced TFIIA phosphorylation significantly in vivo. Additional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels. Mutation of all four serine residues reduced the ability of TFIIA to stimulate transcription in transient transfection assays with various activators and promoters, indicating that TFIIA phosphorylation is required globally for optimal function." SIGNOR-250997 CSNK2A2 protein P19784 UNIPROT GTF2A1 protein P52655 UNIPROT "up-regulates activity" phosphorylation Ser321 LNSEDDVsDEEGQEL -1 11278496 t llicata "We now show that human TFIIA is phosphorylated in vivo on serine residues that are partially conserved between yeast and human TFIIA large subunits. Alanine substitution mutation of serine residues 316 and 321 in TFIIA alphabeta reduced TFIIA phosphorylation significantly in vivo. Additional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels. Mutation of all four serine residues reduced the ability of TFIIA to stimulate transcription in transient transfection assays with various activators and promoters, indicating that TFIIA phosphorylation is required globally for optimal function." SIGNOR-250998 CSNK2A2 protein P19784 UNIPROT AQP4 protein P55087 UNIPROT "down-regulates activity" phosphorylation Ser276 AAQQTKGsYMEVEDN 9615 BTO:0000837 11742978 t llicata "We found that the stress-induced kinase casein kinase (CK)II phosphorylates the Ser276 immediately preceding the tyrosine motif, increasing AQP4-mu 3A interaction and enhancing AQP4-lysosomal targeting and degradation. | To determine whether Ser276 is an actual CKII substrate, we used GST–AQP4‐Cter proteins in which only one out of the three C‐terminal CKII consensus sites was sequentially conserved (Ser276, Ser285 and Ser315, respectively). Figure 7B (right panel) shows that the three serine residues, including Ser276, were indeed efficiently phosphorylated by CKII." SIGNOR-250974 CSNK2A2 protein P19784 UNIPROT AQP4 protein P55087 UNIPROT "down-regulates activity" phosphorylation Ser285 MEVEDNRsQVETDDL 9615 BTO:0000837 11742978 t llicata "We found that the stress-induced kinase casein kinase (CK)II phosphorylates the Ser276 immediately preceding the tyrosine motif, increasing AQP4-mu 3A interaction and enhancing AQP4-lysosomal targeting and degradation. | To determine whether Ser276 is an actual CKII substrate, we used GST–AQP4‐Cter proteins in which only one out of the three C‐terminal CKII consensus sites was sequentially conserved (Ser276, Ser285 and Ser315, respectively). Figure 7B (right panel) shows that the three serine residues, including Ser276, were indeed efficiently phosphorylated by CKII." SIGNOR-250975 CSNK2A2 protein P19784 UNIPROT BID protein P55957 UNIPROT "up-regulates activity" phosphorylation Thr59 EGYDELQtDGNRSSH 9606 BTO:0000567 11583622 t llicata "Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid." SIGNOR-250979 CSNK2A2 protein P19784 UNIPROT PTEN protein P60484 UNIPROT "down-regulates activity" phosphorylation Ser370 TSVTPDVsDNEPDHY -1 12297295 t llicata "We used mass spectrometric methods to identify Ser(370) and Ser(385) as in vivo phosphorylation sites of PTEN. These sites also are phosphorylated by CK2 in vitro, and phosphorylation inhibits PTEN activity towards its substrate, PIP3. We also identify a novel in vivo phosphorylation site, Thr(366). " SIGNOR-251025 CSNK2A2 protein P19784 UNIPROT PTEN protein P60484 UNIPROT "down-regulates activity" phosphorylation Ser385 RYSDTTDsDPENEPF -1 12297295 t llicata "We used mass spectrometric methods to identify Ser(370) and Ser(385) as in vivo phosphorylation sites of PTEN. These sites also are phosphorylated by CK2 in vitro, and phosphorylation inhibits PTEN activity towards its substrate, PIP3. We also identify a novel in vivo phosphorylation site, Thr(366). " SIGNOR-251027 CSNK2A2 protein P19784 UNIPROT PTEN protein P60484 UNIPROT "down-regulates activity" phosphorylation Thr366 ASSSTSVtPDVSDNE -1 12297295 t llicata "We used mass spectrometric methods to identify Ser(370) and Ser(385) as in vivo phosphorylation sites of PTEN. These sites also are phosphorylated by CK2 in vitro, and phosphorylation inhibits PTEN activity towards its substrate, PIP3. We also identify a novel in vivo phosphorylation site, Thr(366). " SIGNOR-251026 CSNK2A2 protein P19784 UNIPROT HSF1 protein Q00613 UNIPROT up-regulates phosphorylation Thr142 DSVTKLLtDVQLMKG 9606 12659875 t lperfetto "Transcriptional activity and dna binding of heat shock factor-1 involve phosphorylation on threonine 142 by ck2.As hsf1 is activated by heat shock simultaneously with the nuclear translocation of the protein kinase ck2, we have investigated the role of ck2 in hsf1 activatio" SIGNOR-99606 CSNK2A2 protein P19784 UNIPROT SET protein Q01105-2 UNIPROT down-regulates phosphorylation Ser9 SAPAAKVsKKELNSN 9606 BTO:0000938 BTO:0000142 23374587 t "The effect has been demonstrated using Q01105-2" miannu "Ckii-mediated phosphorylation at ser9 hinders nuclear import of set" SIGNOR-200802 CSNK2A2 protein P19784 UNIPROT SPIB protein Q01892 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser129 PYPSPVLsEEEDLPL 9606 BTO:0000567 10618498 t llicata "Phosphorylation of the Spi-B transcription factor reduces its intrinsic stability. | Serine residues 37 in the transactivation domain and 129, 144 and 146 in the PEST domain of Spi-B are phosphorylated by CKII in vitro | The CKII phosphorylation sites mapped in vitro are phosphorylated in vivo" SIGNOR-251039 CSNK2A2 protein P19784 UNIPROT SPIB protein Q01892 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser144 DSPALEVsDSESDEA 9606 BTO:0000567 10618498 t llicata "Phosphorylation of the Spi-B transcription factor reduces its intrinsic stability. | Serine residues 37 in the transactivation domain and 129, 144 and 146 in the PEST domain of Spi-B are phosphorylated by CKII in vitro | The CKII phosphorylation sites mapped in vitro are phosphorylated in vivo" SIGNOR-251040 TNFRSF1B protein P20333 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" 17151142 f "[...] TNF-alpha is critical for p38 activation during the early stages of myoblast differentiation" SIGNOR-253601 CSNK2A2 protein P19784 UNIPROT SPIB protein Q01892 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser37 KHSSYPDsEGAPDSL 9606 BTO:0000567 10618498 t llicata "Phosphorylation of the Spi-B transcription factor reduces its intrinsic stability. | Serine residues 37 in the transactivation domain and 129, 144 and 146 in the PEST domain of Spi-B are phosphorylated by CKII in vitro | The CKII phosphorylation sites mapped in vitro are phosphorylated in vivo" SIGNOR-251042 CSNK2A2 protein P19784 UNIPROT SLC18A2 protein Q05940 UNIPROT unknown phosphorylation Ser511 PIGEDEEsESD -1 9045708 t llicata "Purified CKI and CKII phosphorylate the wild-type carboxyl terminus of VMAT2, but not a double mutant with both serines 512 and 514 replaced by alanine. The protein kinase inhibitor CKI-7 and unlabeled GTP both block in vitro phosphorylation by cell homogenates, indicating a role for CKII and possibly CKI in vivo. Both kinases phosphorylate the VMAT2 fusion protein to a much greater extent than a similar fusion protein containing the carboxyl terminus of VMAT1, consistent with differential phosphorylation of the two transporters observed in intact cells. " SIGNOR-251038 CSNK2A2 protein P19784 UNIPROT SLC18A2 protein Q05940 UNIPROT unknown phosphorylation Ser513 GEDEESEsD -1 9045708 t llicata "Purified CKI and CKII phosphorylate the wild-type carboxyl terminus of VMAT2, but not a double mutant with both serines 512 and 514 replaced by alanine. The protein kinase inhibitor CKI-7 and unlabeled GTP both block in vitro phosphorylation by cell homogenates, indicating a role for CKII and possibly CKI in vivo. Both kinases phosphorylate the VMAT2 fusion protein to a much greater extent than a similar fusion protein containing the carboxyl terminus of VMAT1, consistent with differential phosphorylation of the two transporters observed in intact cells. " SIGNOR-251037 CSNK2A2 protein P19784 UNIPROT PPP1R8 protein Q12972 UNIPROT "up-regulates activity" phosphorylation Ser204 KNSRVTFsEDDEIIN -1 9407077 t llicata "Phosphorylation of NIPP-1 in a heterodimeric complex with the catalytic subunit of protein phosphatase-1 resulted in an activation of the holoenzyme without a release of NIPP-1. Sequencing and phosphoamino acid analysis of tryptic phosphopeptides enabled us to identify Ser178 and Ser199 as the phosphorylation sites of protein kinase A, whereas Thr161 and Ser204 were phosphorylated by protein kinase CK2." SIGNOR-251023 CSNK2A2 protein P19784 UNIPROT PPP1R8 protein Q12972 UNIPROT "up-regulates activity" phosphorylation Thr161 LGLPEEEtELDNLTE -1 9407077 t llicata "Phosphorylation of NIPP-1 in a heterodimeric complex with the catalytic subunit of protein phosphatase-1 resulted in an activation of the holoenzyme without a release of NIPP-1. Sequencing and phosphoamino acid analysis of tryptic phosphopeptides enabled us to identify Ser178 and Ser199 as the phosphorylation sites of protein kinase A, whereas Thr161 and Ser204 were phosphorylated by protein kinase CK2." SIGNOR-251024 CSNK2A2 protein P19784 UNIPROT ACACA protein Q13085 UNIPROT unknown phosphorylation Ser29 GSVSEDNsEDEISNL -1 2900140 t llicata "Phosphorylation at site 6 by casein kinase-2 is in good agreement with previous studies on the specificity of this kinase, which is known to phosphorylate serine residues followed by an acidic cluster" SIGNOR-250973 CSNK2A2 protein P19784 UNIPROT EIF2B5 protein Q13144 UNIPROT "up-regulates activity" phosphorylation Ser717 LKEAEEEsSEDD 9606 BTO:0000007 11500362 t llicata "Two conserved sites (Ser712/713) are phosphorylated by casein kinase 2. They lie at the extreme C-terminus and are required for the interaction of eIF2Bepsilon with its substrate, eIF2, in vivo and for eIF2B activity in vitro. " SIGNOR-250989 CSNK2A2 protein P19784 UNIPROT EIF2B5 protein Q13144 UNIPROT "up-regulates activity" phosphorylation Ser718 KEAEEESsEDD 9606 BTO:0000007 11500362 t llicata "Two conserved sites (Ser712/713) are phosphorylated by casein kinase 2. They lie at the extreme C-terminus and are required for the interaction of eIF2Bepsilon with its substrate, eIF2, in vivo and for eIF2B activity in vitro. " SIGNOR-250990 CSNK2A2 protein P19784 UNIPROT KLF1 protein Q13351 UNIPROT "up-regulates activity" phosphorylation Thr23 ALGPFPDtQDDFLKW 10090 BTO:0004475 9722526 t 2 miannu "Regulation of erythroid Krppel-like factor (EKLF) transcriptional activity by phosphorylation of a protein kinase casein kinase II site within its interaction domain. the transactivation capability of EKLF is augmented by co-transfection of CKIIalpha. in vitro assays demonstrate that CKIIalpha interacts with EKLF, and that the EKLF interaction domain is phosphorylated by CKII only at Thr-41" SIGNOR-241365 CSNK2A2 protein P19784 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Ser112 KRAGGEEsQFEMDI 9606 BTO:0000007 9806882 t lperfetto "The kinase is quite distinct from casein kinase 2, which also phosphorylates Ser-111 of 4E-BP1. The possible importance of these kinases in the phosphorylation of 4E-BP1 in fat cells is discussed. It is suggested that the phosphorylation of Ser-111 might be a priming event that facilitates the subsequent phosphorylation of Thr-36, Thr-45, Ser-64 and Thr69 by a rapamycin-sensitive process that initiates the dissociation of 4E-BP1 from eIF4E and hence the formation of the eIF4F complex." SIGNOR-249334 CSNK2A2 protein P19784 UNIPROT HDAC1 protein Q13547 UNIPROT "up-regulates activity" phosphorylation Ser421 IACEEEFsDSEEEGE 9606 BTO:0000661 11602581 t llicata "Human HDAC1 protein was analyzed by ion trap mass spectrometry, and two phosphorylated serine residues, Ser(421) and Ser(423), were unambiguously identified. Loss of phosphorylation at Ser(421) and Ser(423) due to mutation to alanine or disruption of the casein kinase 2 consensus sequence directing phosphorylation reduced the enzymatic activity and complex formation of HDAC1." SIGNOR-250999 CSNK2A2 protein P19784 UNIPROT HDAC1 protein Q13547 UNIPROT "up-regulates activity" phosphorylation Ser423 CEEEFSDsEEEGEGG 9606 BTO:0000661 11602581 t llicata "Human HDAC1 protein was analyzed by ion trap mass spectrometry, and two phosphorylated serine residues, Ser(421) and Ser(423), were unambiguously identified. Loss of phosphorylation at Ser(421) and Ser(423) due to mutation to alanine or disruption of the casein kinase 2 consensus sequence directing phosphorylation reduced the enzymatic activity and complex formation of HDAC1." SIGNOR-251000 CSNK2A2 protein P19784 UNIPROT STX1A protein Q16623 UNIPROT unknown phosphorylation Ser14 ELRTAKDsDDDDDVA 10116 BTO:0000142 10844023 t llicata "We generated an antibody that specifically recognizes a casein kinase II-mediated phosphorylation on serine-14 of syntaxin 1. In this report we show that this phosphorylation occurs in vivo and is developmentally regulated in the rat brain | Phosphorylated syntaxin is preferentially associated with SNAP-25 and localizes to discrete domains of the axonal plasma membrane that do not colocalize with pools of synaptic vesicles." SIGNOR-251043 CSNK2A2 protein P19784 UNIPROT CTDP1 protein Q9Y5B0 UNIPROT "down-regulates activity" phosphorylation Ser740 TKAQRENsPAAFPDR 9606 BTO:0000567 12591939 t llicata "We found that only phosphorylated FCP1 can physically interact with TFIIF. We set out to purify an FCP1 kinase from HeLa cells and identified casein kinase 2, which, surprisingly, displayed a negative effect on FCP1-associated activities.| Phosphorylation of FCP1 by CK2 Inhibits the Transcription Elongation Activity of FCP1. | Two in vivo phosphorylation sites within the C terminus of FCP1 at Ser-575 and Ser-740 were identified" SIGNOR-250986 CSNK2A2 protein P19784 UNIPROT UBE2R2 protein Q712K3 UNIPROT "up-regulates activity" phosphorylation Ser233 DCYDDDDsGNEES 9606 12037680 t llicata "UBC3B is specifically phosphorylated by CK2 in vitro and in vivo. We mapped by deletions and site directed mutagenesis the phosphorylation site to a serine residue within the C-terminal domain in position 233 of UBC3B and in the corresponding serine residue of UBC3. | Following CK2-dependent phosphorylation both UBC3B and UBC3 bind to the F-box protein beta-TrCP, the substrate recognition subunit of an SCF (Skp1, Cul1, F-box) ubiquitin ligase. Furthermore, we observed that co-transfection of CK2alpha' together with UBC3B, but not with UBC3DeltaC, enhances the degradation of beta-catenin." SIGNOR-251047 CSNK2A2 protein P19784 UNIPROT HSPH1 protein Q92598 UNIPROT "down-regulates activity" phosphorylation Ser509 PTEENEMsSEADMEC -1 12558502 t llicata "Protein kinase CK2 phosphorylates Hsp105 alpha at Ser509 and modulates its function. | the phosphorylation of Hsp105 alpha at Ser(509) abolished the inhibitory activity of Hsp105 alpha in vitro." SIGNOR-251008 CSNK2A2 protein P19784 UNIPROT HDAC2 protein Q92769 UNIPROT "up-regulates activity" phosphorylation Ser394 EDAVHEDsGDEDGED 9606 BTO:0000567 12082111 t llicata "HDAC2 is phosphorylated uniquely by protein kinase CK2 in vitro. Studies using unfractionated cell extracts with CK2 inhibitors suggest that protein kinase CK2 is the major source of HDAC2 kinase. Finally, and perhaps most interesting, HDAC2 phosphorylation promotes enzymatic activity, selectively regulates complex formation, but has no effect on transcriptional repression. | Since our data suggest that protein kinase CK2 is the major kinase responsible for HDAC2 phosphorylation, and because Ser422 and Ser424, but not Ser411, lie within CK2 recognition sequences, we believe that Ser394, Ser422, and Ser424 constitute the three phosphorylated residues in HDAC2." SIGNOR-251001 CSNK2A2 protein P19784 UNIPROT HDAC2 protein Q92769 UNIPROT "up-regulates activity" phosphorylation Ser422 IACDEEFsDSEDEGE 9606 BTO:0000567 12082111 t llicata "HDAC2 is phosphorylated uniquely by protein kinase CK2 in vitro. Studies using unfractionated cell extracts with CK2 inhibitors suggest that protein kinase CK2 is the major source of HDAC2 kinase. Finally, and perhaps most interesting, HDAC2 phosphorylation promotes enzymatic activity, selectively regulates complex formation, but has no effect on transcriptional repression. | Since our data suggest that protein kinase CK2 is the major kinase responsible for HDAC2 phosphorylation, and because Ser422 and Ser424, but not Ser411, lie within CK2 recognition sequences, we believe that Ser394, Ser422, and Ser424 constitute the three phosphorylated residues in HDAC2." SIGNOR-251002 CSNK2A2 protein P19784 UNIPROT HDAC2 protein Q92769 UNIPROT "up-regulates activity" phosphorylation Ser424 CDEEFSDsEDEGEGG 9606 BTO:0000567 12082111 t llicata "HDAC2 is phosphorylated uniquely by protein kinase CK2 in vitro. Studies using unfractionated cell extracts with CK2 inhibitors suggest that protein kinase CK2 is the major source of HDAC2 kinase. Finally, and perhaps most interesting, HDAC2 phosphorylation promotes enzymatic activity, selectively regulates complex formation, but has no effect on transcriptional repression. | Since our data suggest that protein kinase CK2 is the major kinase responsible for HDAC2 phosphorylation, and because Ser422 and Ser424, but not Ser411, lie within CK2 recognition sequences, we believe that Ser394, Ser422, and Ser424 constitute the three phosphorylated residues in HDAC2." SIGNOR-251003 CSNK2A2 protein P19784 UNIPROT NKX3-1 protein Q99801 UNIPROT up-regulates phosphorylation Thr89 AAPEEAEtLAETEPE 9606 BTO:0001130 16581776 t llicata "In vitro kinase assays followed by mass spectrometric analyses demonstrated that ck2 phosphorylated recombinant nkx3.1 on thr89 and thr93. We have also determined that nkx3.1 is degraded primarily through a proteasomal pathway, suggesting that phosphorylation by ck2 protects nkx3.1 from degradation." SIGNOR-145501 CSNK2A2 protein P19784 UNIPROT NKX3-1 protein Q99801 UNIPROT up-regulates phosphorylation Thr93 EAETLAEtEPERHLG 9606 BTO:0001130 16581776 t llicata "In vitro kinase assays followed by mass spectrometric analyses demonstrated that ck2 phosphorylated recombinant nkx3.1 on thr89 and thr93. We have also determined that nkx3.1 is degraded primarily through a proteasomal pathway, suggesting that phosphorylation by ck2 protects nkx3.1 from degradation." SIGNOR-145505 CSNK2A2 protein P19784 UNIPROT PPP1R1B protein Q9UD71 UNIPROT "up-regulates activity" phosphorylation Ser45 LFRLSEHsSPEEEAS -1 2557337 t llicata "Study of [Plphosphate release during manual Edman degradation confirmed that the phosphorylated residues in rat DARPP-32 were Ser45 and Ser102. | Phosphorylation by casein kinase II did not affect the potency of DARPP-32 as an inhibitor of protein phosphatase-1, which depended only on phosphorylation of Thr34 by cAMP-dependent protein kinase. However, phosphorylation of DARPP-32 by casein kinase II facilitated phosphorylation of Thr34 by cAMP-dependent protein kinase" SIGNOR-251019 CSNK2A2 protein P19784 UNIPROT GTF2A1L protein Q9UNN4 UNIPROT "up-regulates activity" phosphorylation Ser356 VDGSGDTsSNEEIGS -1 12107178 t llicata "ALF was able to stabilize the binding of TBP to DNA, but it could not stabilize TBP mutants A184E, N189E, E191R, and R205E nor could it facilitate binding of the TBP-like factor TRF2/TLF to a consensus TATA element. However, phosphorylation of ALF with casein kinase II resulted in the partial restoration of complex formation using mutant TBPs. | Because the residues involved (Ser-280, Ser-281, Ser-316, and Ser-321) are conserved in ALF (Ser-356, Ser-357, Ser-418, and Ser-423), we tested whether its activity might also be affected by this modification. We first showed that ALF and TFIIAα/β polypeptides incubated with casein kinase II and [γ-32P]ATP could be labeled." SIGNOR-250991 CSNK2A2 protein P19784 UNIPROT GTF2A1L protein Q9UNN4 UNIPROT "up-regulates activity" phosphorylation Ser357 DGSGDTSsNEEIGST -1 12107178 t llicata "ALF was able to stabilize the binding of TBP to DNA, but it could not stabilize TBP mutants A184E, N189E, E191R, and R205E nor could it facilitate binding of the TBP-like factor TRF2/TLF to a consensus TATA element. However, phosphorylation of ALF with casein kinase II resulted in the partial restoration of complex formation using mutant TBPs. | Because the residues involved (Ser-280, Ser-281, Ser-316, and Ser-321) are conserved in ALF (Ser-356, Ser-357, Ser-418, and Ser-423), we tested whether its activity might also be affected by this modification. We first showed that ALF and TFIIAα/β polypeptides incubated with casein kinase II and [γ-32P]ATP could be labeled." SIGNOR-250992 CSNK2A2 protein P19784 UNIPROT CTDP1 protein Q9Y5B0 UNIPROT "down-regulates activity" phosphorylation Ser575 AGESLDQsMEEEEEE 9606 BTO:0000567 12591939 t llicata "We found that only phosphorylated FCP1 can physically interact with TFIIF. We set out to purify an FCP1 kinase from HeLa cells and identified casein kinase 2, which, surprisingly, displayed a negative effect on FCP1-associated activities.| Phosphorylation of FCP1 by CK2 Inhibits the Transcription Elongation Activity of FCP1. | Two in vivo phosphorylation sites within the C terminus of FCP1 at Ser-575 and Ser-740 were identified" SIGNOR-250985 RXRA protein P19793 UNIPROT RARA protein P10276 UNIPROT up-regulates binding 9606 1310351 t gcesareni "Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins" SIGNOR-16665 RXRA protein P19793 UNIPROT THRA protein P10827 UNIPROT up-regulates binding 9606 10976919 t gcesareni "Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr)." SIGNOR-81446 RXRA protein P19793 UNIPROT THRB protein P10828 UNIPROT up-regulates binding 9606 10976919 t gcesareni "Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr" SIGNOR-81449 RXRA protein P19793 UNIPROT RARG protein P13631 UNIPROT up-regulates binding 9606 1310351 t gcesareni "Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins" SIGNOR-16671 RXRA protein P19793 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 12771132 t gcesareni "Rxr agonists still inactivated endogenous beta-catenin via rxr alpha." SIGNOR-101293 RXRA protein P19793 UNIPROT PPARG protein P37231 UNIPROT up-regulates binding 9606 11237216 t 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 NFKB1 protein P19838 UNIPROT IEX-1L protein O75353 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9703517 f gcesareni "Transcription factors of the nuclear factor-kappab/rel (nf-kappab) family may be important in cell survival by regulating unidentified, anti-apoptotic genes. One such gene that protects cells from apoptosis induced by fas or tumor necrosis factor type alpha (tnf), iex-1l, is described here. Its transcription induced by tnf was decreased in cells with defective nf-kappab activation, rendering them sensitive to tnf-induced apoptosis, which was abolished by transfection with iex-1l." SIGNOR-59539 NFKB1 protein P19838 UNIPROT KLK3 protein P07288 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001321 11909978 t "NF-kappa B activates prostate-specific antigen expression and is upregulated in androgen-independent prostate cancer." SIGNOR-253668 NFKB1 protein P19838 UNIPROT BMP4 protein P12644 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000018 17350185 t Luana " The effect of TNF-alpha on the Bmp4 promoter is mediated through NF-kB." SIGNOR-266086 NFKB1 protein P19838 UNIPROT NPPB protein P16860 UNIPROT unknown "transcriptional regulation" 15837525 f "In comparison to the ANF gene, less is known about BNP promoter consensus elements that regulate gene expression by mechanical or neurohumoral agonists. A number of cis-acting elements for GATA, Nkx2.5, NF-kappaB and TEF transcription factors have recently been identified within the BNP promoter that regulate BNP expression in response to specific agonists. This review focuses on the information available regarding cis-acting determinants responsible for inducible BNP transcription." SIGNOR-253648 NFKB1 protein P19838 UNIPROT CD80 protein P33681 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000776 12860928 f "Upon CD40 signaling, transcription of the CD80 gene is induced by the nuclear factor (NF)-kappaB transcription factor. Our results show that BCL6 prevents CD40-induced expression of CD80 by binding its promoter region in vivo and suppressing its transcriptional activation by NF-kappaB. Consistent with a physiologic role for BCL6 in suppressing CD80, the expression of these two genes is mutually exclusive in B cells, and BCL6-defective mice show increased expression of CD80 in B cells." SIGNOR-253934 FST protein P19883 UNIPROT INHBA protein P08476 UNIPROT "down-regulates activity" binding 10090 BTO:0005787 24627466 t 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 CR2 protein P20023 UNIPROT CD19 protein P15391 UNIPROT "up-regulates activity" binding 9606 BTO:0000776 31732528 t scontino "Complement receptor type 2 (CR2)/CD21 plays a key role in the development of high-affinity Abs and long-lasting memory to foreign Ags. When CR2 is bound by its primary C3 activation fragment–derived ligand, designated C3d, it coassociates with CD19 on B cells to amplify BCR signaling." SIGNOR-266642 EIF2S2 protein P20042 UNIPROT EGLN1 protein Q9GZT9 UNIPROT "up-regulates quantity" "translation regulation" 9606 BTO:0000007 29530922 t miannu "DAP5 is involved in PHD2 translation. Distinct responses to DAP5 depletion (under hypoxia) of primary MEFs versus malignant glioma cells suggest that DAP5-mediated control of PHD2 may have special significance in cancer. Neoplastic cells may exploit DAP5 for managing chronic oxygen deprivation, possibly contributing to their adaptation to growth/proliferation under hypoxia." SIGNOR-266386 KLK2 protein P20151 UNIPROT NCOA4 protein Q13772 UNIPROT up-regulates 9606 BTO:0001130 24122203 f miannu "Klk2may cooperate with the ar coregulator, ara70, to enhance ar transactivation" SIGNOR-202885 TBP protein P20226 UNIPROT LIN28B protein Q6ZN17 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000093 23494474 f miannu "We conclude that the oncoprotein HBXIP as a co-activator of TF II D transactivates Lin28B promoter via directly binding to TBP to upregulate the expression of Lin28B in promotion of proliferation of breast cancer cells, in which Lin28B maintains the high level of HBXIP through suppressing miR-520b in a feedback manner." SIGNOR-255252 TBP protein P20226 UNIPROT TFIID complex SIGNOR-C343 SIGNOR "form complex" binding 9606 27096372 t miannu "The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences." SIGNOR-263933 TBP protein P20226 UNIPROT TFIIIB complex SIGNOR-C393 SIGNOR "form complex" binding 29378333 t lperfetto "Both in yeast and mammalian cells, TFIIIB consists of three subunits: TFIIB-related Brf1, TATA-box binding protein (TBP), common also for the other two RNA polymerases, and Pol III-specific subunit, Bdp1 (Table 1)." SIGNOR-266192 CCNA2 protein P20248 UNIPROT CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR "form complex" binding 9606 19056339 t lperfetto "We therefore compared human cyclin a1- and cyclin a2-containing cdk complexes in vitro by determining kinetic constants and by examining the complexes for their ability to phosphorylate prb and p53. Differences in biochemical activity were observed in cdk2 but not cdk1 when complexed with cyclin a1 versus cyclin a2. Further, cdk1/cyclin a1 is a better kinase complex for phosphorylating potentially physiologically relevant substrates prb and p53 than cdk2/cyclin a2." SIGNOR-182566 BTF3 protein P20290 UNIPROT EPHB2 protein P29323 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000584 17312387 f "In contrast, BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others. In conclusion, BTF3 is overexpressed in PDAC, where it acts as a transcriptional regulator rather than a direct modulator of apoptosis." SIGNOR-253949 BTF3 protein P20290 UNIPROT ABL2 protein P42684 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000584 17312387 f "In contrast, BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others. In conclusion, BTF3 is overexpressed in PDAC, where it acts as a transcriptional regulator rather than a direct modulator of apoptosis." SIGNOR-253947 BTF3 protein P20290 UNIPROT RRAS2 protein P62070 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0003081 17312387 f miannu "BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others." SIGNOR-253766 BTF3 protein P20290 UNIPROT ATM protein Q13315 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000584 17312387 f "In contrast, BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others. In conclusion, BTF3 is overexpressed in PDAC, where it acts as a transcriptional regulator rather than a direct modulator of apoptosis." SIGNOR-253948 BTF3 protein P20290 UNIPROT MADCAM1 protein Q13477 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000584 17312387 f "In contrast, BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others. In conclusion, BTF3 is overexpressed in PDAC, where it acts as a transcriptional regulator rather than a direct modulator of apoptosis." SIGNOR-253945 BTF3 protein P20290 UNIPROT SSPN protein Q14714 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000584 17312387 f "In contrast, BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others. In conclusion, BTF3 is overexpressed in PDAC, where it acts as a transcriptional regulator rather than a direct modulator of apoptosis." SIGNOR-253951 BTF3 protein P20290 UNIPROT HPSE2 protein Q8WWQ2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003081 17312387 f miannu "BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others." SIGNOR-253765 BTF3 protein P20290 UNIPROT IRAG1 protein Q9Y6F6 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000584 17312387 f "In contrast, BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others. In conclusion, BTF3 is overexpressed in PDAC, where it acts as a transcriptional regulator rather than a direct modulator of apoptosis." SIGNOR-253946 CHRM3 protein P20309 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257134 CHRM3 protein P20309 UNIPROT GNA15 protein P30679 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257224 CHRM3 protein P20309 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257018 CHRM3 protein P20309 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256739 TNFRSF1B protein P20333 UNIPROT TRAF2 protein Q12933 UNIPROT "up-regulates activity" binding 9606 8069916 t lperfetto "Our analysis indicates that traf1 and traf2 are associated with the cytoplasmic domain of tnf-r2 in a heterodimeric complex in which traf2 contacts the receptor directly." SIGNOR-34645 TNFRSF1B protein P20333 UNIPROT TRAF1 protein Q13077 UNIPROT up-regulates 9606 8069916 f gcesareni "Traf1 interacts with tnf-r2 indirectly through heterodimer formation with traf2." SIGNOR-33843 RAB5A protein P20339 UNIPROT "Early Endosome" complex SIGNOR-C246 SIGNOR "form complex" binding 9606 19924646 t lperfetto "The Rab proteins primarily localized to the EE include Rab5 and Rab4, which regulate distinct early endocytic events. In addition to these two Rab proteins, some of the other less well-characterized Rabs at the EE include Rab10 , Rab14 , Rab21 and Rab22" SIGNOR-260616 RAB6A protein P20340 UNIPROT VPS13B protein Q7Z7G8 UNIPROT "up-regulates activity" binding 10116 BTO:0003102 25492866 t miannu "Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. We show that COH1 forms a physical and functional complex with RAB6. Our results point to a role of COH1 as a RAB6 effector protein. Depletion of COH1 leads to decreased neurite outgrowth in cultured primary hippocampal neurons. These results establish a critical role for RAB6-dependent function of COH1 in neuritogenesis by regulating Golgi complex organization." SIGNOR-266869 PMCH protein P20382 UNIPROT MCHR2 protein Q969V1 UNIPROT up-regulates binding 9606 BTO:0000142 10471841 t gcesareni "Upon several purification steps, followed by mass spectrometric analysis and peptide sequencing, the ligand was identified as melanin concentrating hormone (mch), revealing that the orphan slc-1 is the mch receptor." SIGNOR-70520 PMCH protein P20382 UNIPROT MCHR1 protein Q99705 UNIPROT up-regulates binding 9606 BTO:0000007 10421367 t gcesareni "Here we show that the 353-amino-acid human orphan g-protein-coupled receptor slc-1 expressed in hek293 cells binds mch with sub-nanomolar affinity, and is stimulated by mch to mobilize intracellular ca2+ and reduce forskolin-elevated cyclic amp levels." SIGNOR-69517 NR1D1 protein P20393 UNIPROT ARNTL protein O00327 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001103 21881539 f lperfetto "Concomitant attenuation of NR1D1 downregulation (-2.4-fold compared with -4.1-fold in placebo; P=0.04), a transcriptional repressor of ARNTL, supported the view that ramipril might modulate glucose homeostasis pathways involving the NR1D1 ARNTL axis." SIGNOR-253719 NR1D1 protein P20393 UNIPROT NR2E3 protein Q9Y5X4 UNIPROT up-regulates 9606 15190009 f gcesareni "Our results show that nr1d1 (rev-erb?) Also functions as a transcriptional activator of rod genes in the presence of nr2e3" SIGNOR-125658 PSMB1 protein P20618 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "form complex" binding 9606 BTO:0000007 29636472 t lperfetto "Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line" SIGNOR-263356 ITGAL protein P20701 UNIPROT ICAM1 protein P05362 UNIPROT up-regulates binding 9606 BTO:0000130 23994464 t 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 ITGAL protein P20701 UNIPROT AKAP9 protein Q99996 UNIPROT "up-regulates activity" binding 9606 BTO:0001945 16339516 t Giulio "However, association of CG-NAP/AKAP450 was signifi-cantly enhanced at 37°C in LFA-1-activated cells triggered toundergo motility. Taken together, our findings provide the first definitiveevidence that the protein CG-NAP/AKAP450 is a key scaffoldingcomponent of the multimolecular complex assembled in T cellsupon LFA cross-linking and is functionally indispensable for cellpolarity and migration induced by this integrin." SIGNOR-260304 ITGAL protein P20701 UNIPROT "AL/b2 integrin" complex SIGNOR-C169 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253189 ITGAX protein P20702 UNIPROT "AX/b2 integrin" complex SIGNOR-C171 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253193 DDC protein P20711 UNIPROT tyramine smallmolecule CHEBI:15760 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 BTO:0004032 NBK536726 t brain lperfetto "Under specific conditions, dopamine can also be synthesized by a minor pathway, in which L-tyrosine is converted into p-tyramine (mediated by AADC), with subsequent hydroxylation to dopamine by the enzyme CYP2D6 (Cytochrome P450 2D6) which is found in the substantia nigra of human brain " SIGNOR-263994 PZP protein P20742 UNIPROT MMP9 protein P14780 UNIPROT "down-regulates activity" binding -1 9344465 t lperfetto "Both PZP and a2M collagenase complexes incubated with gelatin demonstrated a significant inhibition of the catalytic activity| MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP." SIGNOR-261802 BCL3 protein P20749 UNIPROT HDAC3 protein O15379 UNIPROT up-regulates binding 9606 15469820 t gcesareni "We show that bcl-3 is a substrate for the protein kinase gsk3 and that gsk3-mediated bcl-3 phosphorylation, which is inhibited by akt activation, targets its degradation through the proteasome pathway. This phosphorylation modulates its association with hdac1, 3 and 6." SIGNOR-129804 BCL3 protein P20749 UNIPROT NFKB1 protein P19838 UNIPROT "up-regulates activity" binding 9606 BTO:0004298 21912613 t miannu "In the present study, we report that regulation of CTCF by extracellular stress signals is dependent upon activations of an oxidative stress-regulated protein Bcl-3. We found that activated Bcl-3 was able to bind to the κB sites identified in the CTCF promoter region. Bcl-3 was activated by UV irradiation to interact with NF-κB p50 by forming a Bcl-3/p50 heterodimer complex. The Bcl-3/p50 complex suppressed CTCF promoter activity to down-regulate CTCF transcription." SIGNOR-254789 BCL3 protein P20749 UNIPROT CTCF protein P49711 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004298 21912613 f miannu "In the present study, we report that regulation of CTCF by extracellular stress signals is dependent upon activations of an oxidative stress-regulated protein Bcl-3. We found that activated Bcl-3 was able to bind to the κB sites identified in the CTCF promoter region. Bcl-3 was activated by UV irradiation to interact with NF-κB p50 by forming a Bcl-3/p50 heterodimer complex. The Bcl-3/p50 complex suppressed CTCF promoter activity to down-regulate CTCF transcription." SIGNOR-253757 CAST protein P20810 UNIPROT CAPN1 protein P07384 UNIPROT "down-regulates activity" binding 9606 BTO:0000590 25969760 t lperfetto "In addition to Ca2+, calpastatin has a key role in the regulation of calpain. Calpastatin, a heat-stable protein ranging from ~70 to ~140 kDa of apparent molecular weight depending on the cell type, is considered a specific endogenous inhibitor of calpains|The calpastatin molecule contains four inhibitory units [75–77]. Each of these units binds to one calpain molecule [75–77]. Therefore, the ratio calpain/calpastatin plays a key role in the regulation of calpain activity [78–80]. The inhibitory effect of calpastatin requires Ca2+-dependent high-affinity binding to three sites of calpain" SIGNOR-251582 CAST protein P20810 UNIPROT CAPN2 protein P17655 UNIPROT "down-regulates activity" binding 9606 BTO:0000590 25969760 t lperfetto "In addition to Ca2+, calpastatin has a key role in the regulation of calpain. Calpastatin, a heat-stable protein ranging from ~70 to ~140 kDa of apparent molecular weight depending on the cell type, is considered a specific endogenous inhibitor of calpains|The calpastatin molecule contains four inhibitory units [75–77]. Each of these units binds to one calpain molecule [75–77]. Therefore, the ratio calpain/calpastatin plays a key role in the regulation of calpain activity [78–80]. The inhibitory effect of calpastatin requires Ca2+-dependent high-affinity binding to three sites of calpain" SIGNOR-251609 CAST protein P20810 UNIPROT CAPN3 protein P20807 UNIPROT "down-regulates activity" binding 9606 BTO:0000590 25969760 t lperfetto "In addition to Ca2+, calpastatin has a key role in the regulation of calpain. Calpastatin, a heat-stable protein ranging from ~70 to ~140 kDa of apparent molecular weight depending on the cell type, is considered a specific endogenous inhibitor of calpains|The calpastatin molecule contains four inhibitory units [75–77]. Each of these units binds to one calpain molecule [75–77]. Therefore, the ratio calpain/calpastatin plays a key role in the regulation of calpain activity [78–80]. The inhibitory effect of calpastatin requires Ca2+-dependent high-affinity binding to three sites of calpain" SIGNOR-251603 HNF1A protein P20823 UNIPROT UGT1A9 protein O60656 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000195 15044625 t "Using gel shift and functional assays, HNF1alpha was demonstrated to bind to and activate the UGT1A8, -1A9, and -1A10 promoters. In contrast, Cdx2 bound to and activated the UGT1A8 and -1A10 promoters but could not activate the UGT1A9 promoter." SIGNOR-253973 HNF1A protein P20823 UNIPROT AFP protein P02771 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11314020 f miannu "We investigated AFP gene regulation in AFP-GC by an active transcription factor, HNF1 (hepatocyte nuclear factor 1) and a repressive transcription factor, ATBF1 (AT motif binding factor 1). CAT assays showed the direct inhibition of AFP gene expression by ATBF1." SIGNOR-254435 HNF1A protein P20823 UNIPROT AFP protein P02771 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 7549116 f miannu "HNF-1 beta was found to be more potent than HNF-1 alpha in activating the AFP promoter in the HepG2 cells." SIGNOR-254637 HNF1A protein P20823 UNIPROT AFP protein P02771 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000972 9792724 f miannu "AFP promoter-chloramphenicol acetyltransferase transient transfection assays demonstrated that the level of HNF1 had a direct impact on basal transcription as well as RA-mediated down-regulation of the AFP gene, and that co-transfection of HNF1 and HNF4, but not transfection of either factor alone, reversed the RA-mediated inhibition. Taken together these data point to an interaction among the RA, HNF1, and HNF4 signals, which is reflected in decreased expression of AFP." SIGNOR-254447 HNF1A protein P20823 UNIPROT CDH17 protein Q12864 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000972;BTO:0004168 20568120 t "The present study aims to identify the transcription factors which interact and regulate CDH17 promoter activity that might contribute to the up-regulation of CDH17 gene in human HCC|we identified hepatic nuclear factor 1α (HNF1α) and caudal-related homeobox 2 (CDX2) binding sites at the proximal promoter region which modulate the CDH17 promoter activities in two HCC cell lines (Hep3B and MHCC97L)" SIGNOR-253970 HNF1A protein P20823 UNIPROT UGT1A10 protein Q9HAW8 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000195 15044625 t "Using gel shift and functional assays, HNF1alpha was demonstrated to bind to and activate the UGT1A8, -1A9, and -1A10 promoters. In contrast, Cdx2 bound to and activated the UGT1A8 and -1A10 promoters but could not activate the UGT1A9 promoter." SIGNOR-253971 HNF1A protein P20823 UNIPROT UGT1A8 protein Q9HAW9 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000195 15044625 t "Using gel shift and functional assays, HNF1alpha was demonstrated to bind to and activate the UGT1A8, -1A9, and -1A10 promoters. In contrast, Cdx2 bound to and activated the UGT1A8 and -1A10 promoters but could not activate the UGT1A9 promoter." SIGNOR-253972 EFNA1 protein P20827 UNIPROT EPHA1 protein P21709 UNIPROT up-regulates binding 9606 9576626 t tpavlidou "Ephrin-a1 binds and activates the tyrosine kinase activity of eph-a2, and has a dissociation constant of 20_30 nm. ephrin-a1 interacts with all the other epha subclass receptors as well, although with different affinity" SIGNOR-56898 EFNA1 protein P20827 UNIPROT EPHA2 protein P29317 UNIPROT up-regulates binding 9606 9330863 t tpavlidou "Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor" SIGNOR-51939 EFNA1 protein P20827 UNIPROT EPHA2 protein P29317 UNIPROT up-regulates binding 9606 9576626 t tpavlidou "Ephrin-a1 binds and activates the tyrosine kinase activity of eph-a2, and has a dissociation constant of 20_30 nm" SIGNOR-56901 EFNA1 protein P20827 UNIPROT EPHA3 protein P29320 UNIPROT up-regulates binding 9606 9330863 t gcesareni "Transmembrane ligands for eph receptors also exhibit properties of signal transducing molecules, suggesting that bidirectional signaling occurs when receptor-expressing cells contact ligand-expressing cells." SIGNOR-52005 EFNA1 protein P20827 UNIPROT EPHA3 protein P29320 UNIPROT up-regulates binding 9606 9576626 t tpavlidou "Ephrin-a1 binds and activates the tyrosine kinase activity of eph-a2, and has a dissociation constant of 20_30 nm. ephrin-a1 interacts with all the other epha subclass receptors as well, although with different affinity" SIGNOR-56904 EFNA1 protein P20827 UNIPROT EPHA8 protein P29322 UNIPROT up-regulates binding 9606 17420126 t gcesareni "Ephrins are cell-surface tethered guidance cues that bind to eph receptor tyrosine kinases in trans on opposing cells." SIGNOR-154298 BMI1 protein P35226 UNIPROT BMI1 protein P35226 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000093 23239878 t gcesareni "Here, we report that BMI1 autoactivates its own promoter via an E-box present in its promoter." SIGNOR-245344 NEB protein P20929 UNIPROT WASL protein O00401 UNIPROT up-regulates binding 9606 21798082 t gcesareni "Igf1-akt signaling, by inhibiting gsk3b, allows the interaction of n-wasp with the unphosphorylated nebulin;the consequent recruitment of n-wasp to the z-disk promotes actin nucleation and elongation of actin filaments." SIGNOR-175671 RASA1 protein P20936 UNIPROT HRAS protein P01112 UNIPROT down-regulates binding 9606 10394594 t lperfetto "The Ras protein sits at the center of a many-tiered cascade of molecular interactions. Most of the proteins along this cascade are activated by phosphorylation, but Ras uses a bound guanine nucleotide to toggle between its “on” and “off” states. Ras hydrolyzes GTP to GDP fairly quickly, turning itself “off,” and a collection of GTPase-activating proteins (GAPs) speed up the processthe complex between human h-ras bound to guanosine diphosphate and the guanosine triphosphatase (gtpase)-activating domain of the human gtpase-activating protein p120gap (gap-334) in the presence of aluminum fluoride was solved." SIGNOR-68990 RASA1 protein P20936 UNIPROT HRAS protein P01112 UNIPROT down-regulates binding 9606 9219684 t gcesareni "The three-dimensional structure of the complex between human h-ras bound to guanosine diphosphate and the guanosine triphosphatase (gtpase)-activating domain of the human gtpase-activating protein p120gap (gap-334) in the presence of aluminum fluoride was solved at a resolution of 2.5 angstroms." SIGNOR-49477 CD247 protein P20963 UNIPROT TCR complex SIGNOR-C153 SIGNOR "form complex" binding 9606 12507424 t miannu "The T cell receptor-CD3 complex (TCR-CD3) serves a critical role in the differentiation, survival, and function of T cells, and receptor triggering elicits a complex set of biological responses that serve to protect the organism from infectious agents. The receptor is composed of six different chains that form the TCR heterodimer responsible for ligand recognition, as well as the CD3γε, CD3δε, and ζζ signaling modules.the TCRα-CD3δε and TCRβ-CD3γε interactions are similar since both require a lysine in the TM region of the respective TCR chain and both acidic TM residues in the relevant CD3 heterodimer. Nevertheless, formation of fully assembled αβ TCR-CD3 complexes containing the ζ-chain strictly required both CD3γ and δ" SIGNOR-255290 CDK11B protein P21127 UNIPROT EIF3F protein O00303 UNIPROT down-regulates phosphorylation Ser46 PAAAPASsSDPAAAA 9606 12446680 t lperfetto "The interaction between cdk11p46 and eif3 p47 occurs in vitro and in vivo. In addition, cdk11 protein kinase isolated from cells undergoing apoptosis can phosphorylate eif3 p47in vitro, and serine phosphorylation of eif3 p47 occurs in cells during apoptosis.Purified recombinant cdk11p46 inhibited translation of a reporter gene in vitro in a dose-dependent manner.These data suggest that the function of the caspase-processed cdk11p110 isoform may be to inhibit translation during apoptosis. However, whether or not this inhibition of protein translation occurs in an eif3 p47-dependent or -independent manner remains to be clarified." SIGNOR-95762 CDK11B protein P21127 UNIPROT EIF3F protein O00303 UNIPROT unknown phosphorylation Thr119 GAARVIGtLLGTVDK 9606 19245811 t lperfetto "Here, we identified a second eif3f phosphorylation site (thr119) by cdk11p46 during apoptosis.Thr119 is located in the mov34 domain of eif3f which is important for both the translational inhibitory function of eif3ffurther studies of how eif3f phosphorylation regulates its function will refine insights into the mechanism and regulation of translation initiation, apoptotic signaling, and tumorigenesis." SIGNOR-184185 FLNA protein P21333 UNIPROT MAP2K7 protein O14733 UNIPROT "up-regulates activity" binding 9606 20156194 t miannu "We used Filamin-A-deficient cells to show that Filamin A enhances MKK7 activation and is important for synergistic stress-induced JNK activation in vivo. Thus Filamin A is a novel member of the group of scaffold proteins whose function is to link two MAPKKs together and promote JNK activation. The present study provides evidence that Filamin A is one of the ‘binder’ molecules presumed to directly and closely connect MKK4 and MKK7 so that they can mediate this tyrosine/threonine phosphorylation. We showed that Filamin A (as well as Filamin B and C) associate with MKK7 and MKK4, but not with JNK1 itself" SIGNOR-260628 FLNA protein P21333 UNIPROT MAPK8 protein P45983 UNIPROT "up-regulates activity" 9606 18667433 f areggio "Additionally, the association of Ror2 with the actin-binding protein filamin A is required for Wnt5a-induced JNK activation and polarized cell migration. " SIGNOR-258973 FLNA protein P21333 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates binding 9606 BTO:0000848 9006895 t gcesareni "Sek-1 binds directly and specifically to the actin-binding protein abp-280. As a consequence, active sek-1 is capable of phosphorylating and activating in vitro added bacterial recombinant sapk." SIGNOR-45887 FLNA protein P21333 UNIPROT MAP2K4 protein P45985 UNIPROT "up-regulates activity" binding 9606 20156194 t miannu "We used Filamin-A-deficient cells to show that Filamin A enhances MKK7 activation and is important for synergistic stress-induced JNK activation in vivo. Thus Filamin A is a novel member of the group of scaffold proteins whose function is to link two MAPKKs together and promote JNK activation. The present study provides evidence that Filamin A is one of the ‘binder’ molecules presumed to directly and closely connect MKK4 and MKK7 so that they can mediate this tyrosine/threonine phosphorylation. We showed that Filamin A (as well as Filamin B and C) associate with MKK7 and MKK4, but not with JNK1 itself" SIGNOR-260629 NF1 protein P21359 UNIPROT ADCY3 protein O60266 UNIPROT up-regulates 9606 BTO:0000938 24431436 f miannu "Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation" SIGNOR-204034 NF1 protein P21359 UNIPROT ADCY5 protein O95622 UNIPROT up-regulates 9606 BTO:0000938 24431436 f miannu "Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation" SIGNOR-204140 NF1 protein P21359 UNIPROT HRAS protein P01112 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000938 24431436 t miannu "Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation" SIGNOR-204357 NF1 protein P21359 UNIPROT AFP protein P02771 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000599 7549116 f miannu "Our results pointed to a key role that NF1 might play in the functioning of the AFP promoter. Indeed, overexpression of NF1 induced a specific decrease in the activity of the AFP promoter. Competition between NF1 and HNF-1 for binding to their overlapping binding sites on the AFP promoter would be critical for modulating its activity." SIGNOR-254636 NF1 protein P21359 UNIPROT ADCY8 protein P40145 UNIPROT up-regulates 9606 BTO:0000938 24431436 f miannu "Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation" SIGNOR-204289 NF1 protein P21359 UNIPROT ADCY7 protein P51828 UNIPROT up-regulates 9606 BTO:0000938 24431436 f miannu "Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation" SIGNOR-204246 TACR2 protein P21452 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257015 TACR2 protein P21452 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256736 S1PR1 protein P21453 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256992 S1PR1 protein P21453 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257108 FPR1 protein P21462 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256825 FPR1 protein P21462 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256682 CNR1 protein P21554 UNIPROT HCRTR1 protein O43613 UNIPROT "up-regulates activity" binding 9606 BTO:0000142 29751001 t miannu "Another example is the heteromer between CB1 and orexin 1 receptor (OX1R). The CB1 activation potentiated the OX1R signaling (218), suggesting the interaction of these two receptors. Interaction of their surface distribution was also reported. " SIGNOR-264269 CNR1 protein P21554 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257211 CNR1 protein P21554 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257003 CNR1 protein P21554 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" 9606 BTO:0002036 25012566 f lperfetto "We subsequently analyzed whether Gαo modulates the cellular activities of Necdin. Notably, expression of Gαo significantly augmented Necdin-mediated cellular responses, such as proliferation and differentiation. Moreover, activation of type 1 cannabinoid receptor (CB1R), a Gi/oα-coupled receptor, augmented cell growth suppression, which was mediated by Gαo and Necdin in U87MG cells containing CB1R, Gαo, and Necdin as normal components." SIGNOR-253389 CNR1 protein P21554 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257119 CNR1 protein P21554 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256724 CNR1 protein P21554 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257285 CNR1 protein P21554 UNIPROT GNA13 protein Q14344 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257346 SYT1 protein P21579 UNIPROT SNAP25 protein P60880 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 SIGNOR-C346 16679567 t miannu "Because synaptotagmins bind SNAP-25 and Ca2+, SNAP-25 has also been linked to the Ca2+ dependence of exocytosis (42). One model suggests that synaptotagmin blocks full SNARE fusion pore formation by binding to t-SNAREs.This interaction prevents fusion from occurring in the absence of calcium. When Ca2+ is present, synaptotagmin releases the t-SNAREs so they can fully zipper with the v-SNARE, leading to fusion" SIGNOR-263975 KITLG protein P21583 UNIPROT KIT protein P10721 UNIPROT up-regulates binding 9606 1698556 t gcesareni "We have also provided biological and physical evidence that scf is a ligand for the c-kit receptor." SIGNOR-21193 DRD1 protein P21728 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257391 DRD1 protein P21728 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257181 DRD1 protein P21728 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257269 DRD1 protein P21728 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257335 DRD1 protein P21728 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257068 DRD1 protein P21728 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256796 C5AR1 protein P21730 UNIPROT ITGAM protein P11215 UNIPROT "up-regulates quantity by expression" 1847994 f lperfetto "The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils." SIGNOR-263464 C5AR1 protein P21730 UNIPROT SELL protein P14151 UNIPROT "down-regulates quantity by repression" 1847994 f lperfetto "The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils." SIGNOR-263468 C5AR1 protein P21730 UNIPROT CR1 protein P17927 UNIPROT "up-regulates quantity by expression" 1847994 f lperfetto "The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils." SIGNOR-263466 TBXA2R protein P21731 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257023 FGFR2 protein P21802 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates 10090 BTO:0000011 12270934 f lperfetto " Fibroblast growth factor-2 (FGF-2), in the presence of dexamethasone, isobutylmethylxanthine, and insulin, induces a prolonged activation of the MEK/ERK signaling pathway, which lasts for at least 12 h post-induction, and this activity is less sensitive to the MEK inhibitors" SIGNOR-235337 FGFR2 protein P21802 UNIPROT FRS2 protein Q8WU20 UNIPROT "up-regulates activity" phosphorylation 10116 BTO:0002809 9182757 t fspada "In this report, we demonstrate that FGF stimulation induces tyrosine phosphorylation of a novel lipid anchored docking protein, termed FRS2, that forms a complex with Grb2/Sos, thus linking FGF-receptor activation to the Ras/MAPK signaling pathway." SIGNOR-236950 FGFR2 protein P21802 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates 10090 BTO:0000011 12270934 f lperfetto "Fibroblast growth factor-2 (FGF-2), in the presence of dexamethasone, isobutylmethylxanthine, and insulin, induces a prolonged activation of the MEK/ERK signaling pathway, which lasts for at least 12 h post-induction, and this activity is less sensitive to the MEK inhibitors" SIGNOR-244868 ERBB3 protein P21860 UNIPROT PIK3CD protein O00329 UNIPROT up-regulates binding 9606 16729043 t gcesareni "Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4." SIGNOR-146867 ERBB3 protein P21860 UNIPROT AR protein P10275 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001130 15542423 f gcesareni "Suspected erbb receptor involvement in prostate cancer originates partly from the realization that these proteins are capable of promoting the transcriptional activity of the androgen receptor (ar), her2/her3 effects on ar included effects on protein stability and stimulation of dna binding to ar target genes." SIGNOR-130443 ERBB3 protein P21860 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 16729043 t gcesareni "Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4." SIGNOR-146861 ERBB3 protein P21860 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates binding 9606 16729043 t gcesareni "Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4." SIGNOR-146864 ERBB3 protein P21860 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 16729043 t gcesareni "Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4." SIGNOR-146870 SDHB protein P21912 UNIPROT "Mitochondrial respiratory chain complex II" complex SIGNOR-C278 SIGNOR "form complex" binding 30030361 t lperfetto "Complex II (EC 1.3.5.1) or succinate dehydrogenase (quinone) is shared between the TCA cycle and the ETC and has no proton pumping activity. It is composed of four nDNA-encoded subunits. The two hydrophilic catalytic subunits are SDHA/SDH1 and SDHB/SDH2. Hydrophobic subunits SDHC/SDH3 and SDHD/SDH4 constitute the cII membrane anchor, containing a haem b group and two CoQ binding sites" SIGNOR-262189 SDHB protein P21912 UNIPROT SDH complex SIGNOR-C400 SIGNOR "form complex" binding 9606 16143825 t miannu "Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. Four nuclear genes encode the four subunits, SDHA (15 exons), SDHB (8 exons), SDHC (6 exons) and SDHD (4 exons), mapping on to chromosomes 5p15, 1p35-p36.1, 1q21 and 11q23, respectively." SIGNOR-266272 DRD4 protein P21917 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256846 DRD4 protein P21917 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256982 DRD4 protein P21917 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257098 DRD4 protein P21917 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256703 DRD5 protein P21918 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257418 DRD5 protein P21918 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257311 DRD5 protein P21918 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256914 DRD5 protein P21918 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257369 DRD5 protein P21918 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257043 DRD5 protein P21918 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256771 IL10 protein P22301 UNIPROT IL10RB protein Q08334 UNIPROT up-regulates binding 9606 BTO:0000801;BTO:0000776 10347215 t 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-68007 IL10 protein P22301 UNIPROT IL10RB protein Q08334 UNIPROT up-regulates binding 9606 BTO:0000671 11035029 t fspada "The il-10r2 chain is ubiquitously expressed, whereas the il-10 activity is restricted mainly to cells of hematopoietic origin (35, 36). This raised the question of why the second chain of the il-10 receptor complex is widely expressed when its function was required only in limited cellular subsets. One hypothesis is that the il-10r2 chain is shared by receptors for ligands other than il-10" SIGNOR-83191 IL10 protein P22301 UNIPROT IL10RA protein Q13651 UNIPROT up-regulates binding 9606 BTO:0000801;BTO:0000776 10347215 t 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 IL10 protein P22301 UNIPROT IL10RA protein Q13651 UNIPROT "up-regulates activity" binding 9606 BTO:0000801 26260587 t 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 IL10 protein P22301 UNIPROT SCN5A protein Q14524 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10116 BTO:0000938 BTO:0001264 23357618 f miannu "Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons. Consistent with the electrophysiological results, real-time PCR and western blot revealed that IL-10 (200 pg/ml) down-regulated VGSCs in both mRNA and protein levels and reversed the up-regulation of VGSCs by TNF-α." SIGNOR-253496 IL10 protein P22301 UNIPROT SCN8A protein Q9UQD0 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10116 BTO:0000938 BTO:0001264 23357618 f miannu "Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons. Consistent with the electrophysiological results, real-time PCR and western blot revealed that IL-10 (200 pg/ml) down-regulated VGSCs in both mRNA and protein levels and reversed the up-regulation of VGSCs by TNF-α." SIGNOR-253501 IL10 protein P22301 UNIPROT SCN10A protein Q9Y5Y9 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10116 BTO:0000938 BTO:0001264 23357618 f miannu "Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons. Consistent with the electrophysiological results, real-time PCR and western blot revealed that IL-10 (200 pg/ml) down-regulated VGSCs in both mRNA and protein levels and reversed the up-regulation of VGSCs by TNF-α." SIGNOR-253503 ACHE protein P22303 UNIPROT acetylcholine smallmolecule CHEBI:15355 ChEBI "down-regulates quantity" "small molecule catalysis" 15841900 t "Acetylcholinesterase (AChE) is one of the most crucial enzymes for nerve response and function. AChE catalyzes the hydrolysis of acylcholine esters with a relative specificity for acetylcholine.|The intracellular effects of acetylcholine are mediated by the activation of nicotinic and muscarinic acetylcholine receptors (AChRs). AChE terminates transmission of neuronal impulses by rapid hydrolysis of acetylcholine." SIGNOR-253983 CCL1 protein P22362 UNIPROT CCR8 protein P51685 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000785 12645948 t gcesareni "Ccl1 activates the mapk pathway in ccr8-transfected cho cells." SIGNOR-99401 NME2 protein P22392 UNIPROT KCNN4 protein O15554 UNIPROT up-regulates phosphorylation His358 FRQVRLKhRKLREQV 9606 BTO:0000782 17157250 t lperfetto "Ndpk-b directly binds and activates kca3.1 by phosphorylating histidine 358 in the carboxyl terminus of kca3.1" SIGNOR-151130 NME2 protein P22392 UNIPROT KCNN4 protein O15554 UNIPROT up-regulates phosphorylation His358 FRQVRLKhRKLREQV 9606 BTO:0000782 18796614 t gcesareni "We previously showed that nucleoside diphosphate kinase beta (ndpk-b), a mammalian histidine kinase, is required for kca3.1 channel activation in human cd4 t lymphocytes." SIGNOR-181083 NME2 protein P22392 UNIPROT NME2 protein P22392 UNIPROT "up-regulates activity" phosphorylation His118 QVGRNIIhGSDSVKS -1 8132589 t miannu "Using site-directed mutagenesis of the cDNA encoding NM23-H2, we have created a mutant substituting for the amino acid histidine 118, the presumed site of phosphorylation in the formation of the phosphoenzyme intermediate, the nonphosphorylatable amino acid phenylalanine. The H118F mutant protein is shown to be catalytically inactive" SIGNOR-250304 NME2 protein P22392 UNIPROT NME2 protein P22392 UNIPROT "up-regulates activity" phosphorylation Ser44 AMKFLRAsEEHLKQH 9606 BTO:0000093 8245015 t miannu "An acid-stable (nonhistidine) phosphorylation was identified on autophosphorylated purified recombinant Nm23 proteins and [32P]orthophosphate-labeled human breast carcinoma and murine melanoma Nm23. Phosphoamino acid analysis identified serine as the acid-stable phosphorylation and serine 44 as the major site of phosphorylation. The biological relevance of the novel phosphorylation identified herein is suggested by the direct correlation of in vivo Nm23 acid-stable phosphorylation levels, but not Nm23 NDPK activity, with suppression of tumor metastatic potential among control and nm23-1 transfected murine melanoma cells." SIGNOR-250201 ENPP1 protein P22413 UNIPROT "3',5'-cyclic AMP" smallmolecule CHEBI:17489 ChEBI "down-regulates quantity" "small molecule catalysis" 20923972 t "Phosphodiesterases Catalyze Hydrolysis of cAMP-bound to Regulatory Subunit of Protein Kinase A and Mediate Signal Termination" SIGNOR-253018 USF1 protein P22415 UNIPROT S100A6 protein P06703 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11118618 f miannu "The results indicate that USF1 binds to an E-box sequence of the calcyclin gene promoter and enhances its transcription activity." SIGNOR-255598 PTPRG protein P23470 UNIPROT PXN protein P49023 UNIPROT "up-regulates activity" dephosphorylation -1 25624455 t miannu "a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254722 USF1 protein P22415 UNIPROT CTSD protein P07339 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000093 9731700 f miannu "Overexpression of cathepsin D (CD), a ubiquitous lysosomal protease, is closely associated with a poor clinical outcome for patients with breast cancer. Estrogen greatly induces transcription of the CD gene in estrogen receptor (ER)-positive breast cancer cells. These experiments suggest a model for ER stimulation of the CD promoter in which recruitment of USF-1/2 to the promoter is required for activation of transcription." SIGNOR-255595 USF1 protein P22415 UNIPROT CBS protein P35520 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12427542 f miannu "We previously described essential transactivating roles for specificity protein 1 (Sp1), Sp3, nuclear factor Y (NF-Y), and USF-1 in the regulation of the CBS-1b promoter." SIGNOR-254814 USF1 protein P22415 UNIPROT MYH9 protein P35579 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567 11467950 f miannu "we have focused on element F of the NMHC-A gene. We have identified and characterized the factors which are capable of binding to element F. The basic helix_loop_helix leucine zipper (bHLH-LZ) proteins, TFEC-l and -s, which are alternatively spliced isoforms, TFE3, USF1, and USF2 have all been found to bind to element F with different binding activities and with different transcriptional activation potencies." SIGNOR-222554 USF1 protein P22415 UNIPROT CEBPA protein P49715 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 7862113 f irozzo "Our studies show that the human C/EBPa protein stimulates USF to bind to a USF consensus element within C/EBPa promoter and activates it by two- to threefold.The mechanism by which C/EBPa enhances USF binding and transactivation is currently under study." SIGNOR-255702 USF1 protein P22415 UNIPROT B2M protein P61769 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12480693 f miannu "Here we show that upstream stimulatory factor 1 (USF1) and USF2 bind to the E box and regulate beta(2)m transactivation." SIGNOR-254655 USF1 protein P22415 UNIPROT FMR1 protein Q06787 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 "BTO:0001363; BTO:0000142" 11058604 f miannu "We have also shown that USF1, USF2, and alpha-Pal/Nrf-1 are the major transcription factors that bind the promoter in brain and testis extracts and suggest that elevated levels of these factors account in part for elevated FMR1 expression in these organs." SIGNOR-254882 USF1 protein P22415 UNIPROT JMJD1C protein Q15652 UNIPROT "up-regulates activity" binding 9606 BTO:0000759 32034158 t miannu "We show that, by direct interaction with USF-1, JMJD1C is recruited to lipogenic promoters. We also show that JMJD1C is phosphorylated at T505 by mammalian target of rapamyci (mTOR) to be recruited to lipogenic genes in response to insulin/feeding." SIGNOR-265167 FGFR4 protein P22455 UNIPROT FGFR4 protein P22455 UNIPROT up-regulates phosphorylation Tyr642 RGVHHIDyYKKTSNG 9606 BTO:0001130 18670643 t lperfetto "Binding of fgf to fgf receptors leads to receptor dimerization and subsequent tyrosine autophosphorylation and phosphorylation of target substrates. Autophosphorylation on tyrosine is considered to have at least two functions. One such function is the stimulation of the intrinsic protein tyrosine kinase activity by an allosteric mechanismthis antibody specifically recognizes tyr642/643 in fgfr-4." SIGNOR-179776 FGFR4 protein P22455 UNIPROT FGFR4 protein P22455 UNIPROT up-regulates phosphorylation Tyr643 GVHHIDYyKKTSNGR 9606 BTO:0001130 18670643 t lperfetto "Binding of fgf to fgf receptors leads to receptor dimerization and subsequent tyrosine autophosphorylation and phosphorylation of target substrates. Autophosphorylation on tyrosine is considered to have at least two functions. One such function is the stimulation of the intrinsic protein tyrosine kinase activity by an allosteric mechanismthis antibody specifically recognizes tyr642/643 in fgfr-4." SIGNOR-179780 FGFR4 protein P22455 UNIPROT FGFR4 protein P22455 UNIPROT "up-regulates activity" phosphorylation Tyr754 LLAVSEEyLDLRLTF -1 8576110 t "Analysis of the major autophosphorylation site Y754F mutant of FGFR-4 showed that binding of p85 and its serine phosphorylation were independent of receptor autophosphorylation at this site." SIGNOR-251140 FGFR4 protein P22455 UNIPROT STAT1 protein P42224 UNIPROT "up-regulates activity" phosphorylation Tyr701 DGPKGTGyIKTELIS 9606 BTO:0000007 10918587 t "Activation of Stat1 and Stat3 by FGFR derivatives. Lysates of 293T cells transfected as indicated were analysed by Western blotting using Phospho-Stat1 (Y701) antisera (top) or Stat1 antisera (bottom). (b) The same lysates in (a) were re-examined for phosphorylated Stat3 by Western blotting with Phospho-Stat3 (Y705) (top). all three FGFR family members examined here are able to lead to Stat activation. Expression of the 'TDII-like' derivatives of FGFR1, FGFR3, and FGFR4, as well as myrR1-WT, led to phosphorylation of both Stat1 and Stat3." SIGNOR-251141 FGFR3 protein P22607 UNIPROT FGFR3 protein P22607 UNIPROT "down-regulates activity" phosphorylation Tyr770 LSAPFEQySPGGQDT 9606 BTO:0000007 11294897 t lperfetto "Ligand stimulation leads to autophosphorylation of fgfr3these results suggest that y770 may negatively regulate the activation of pi 3-kinase by constitutively activated fgfr3" SIGNOR-106746 FGFR3 protein P22607 UNIPROT FGFR3 protein P22607 UNIPROT "up-regulates activity" phosphorylation Tyr577 RRPPGLDySFDTCKP 9606 BTO:0000007 11294897 t lperfetto "Ligand stimulation leads to autophosphorylation of fgfr3 the absence of y577 (3y-577f) or y760 (3y-760f) resulted in a modest decrease in activity." SIGNOR-106726 FGFR3 protein P22607 UNIPROT FGFR3 protein P22607 UNIPROT "up-regulates activity" phosphorylation Tyr647 RDVHNLDyYKKTTNG 9606 BTO:0000007 11294897 t lperfetto "Ligand stimulation leads to autophosphorylation of fgfr3 the two tyrosine residues in the YYKK Motif of the activation loop of fgfrs are required for kinase activity of fgfr1 and fgfr3." SIGNOR-106730 FGFR3 protein P22607 UNIPROT FGFR3 protein P22607 UNIPROT "up-regulates activity" phosphorylation Tyr648 DVHNLDYyKKTTNGR 9606 BTO:0000007 11294897 t lperfetto "Ligand stimulation leads to autophosphorylation of fgfr3the two tyrosine residues in the YYKK Motif of the activation loop of fgfrs are required for kinase activity of fgfr1 and fgfr3." SIGNOR-106734 FGFR3 protein P22607 UNIPROT FGFR3 protein P22607 UNIPROT "up-regulates activity" phosphorylation Tyr724 ANCTHDLyMIMRECW 9606 BTO:0000007 11294897 t lperfetto "Ligand stimulation leads to autophosphorylation of fgfr3taken together, these results clearly implicate y724 in the activation of stat proteins by constitutively activated mutants of fgfr3 and suggest that both y724 and y760 are required for maximal stat activation." SIGNOR-106738 FGFR3 protein P22607 UNIPROT FGFR3 protein P22607 UNIPROT "up-regulates activity" phosphorylation Tyr760 TVTSTDEyLDLSAPF 9606 BTO:0000007 11294897 t lperfetto "Ligand stimulation leads to autophosphorylation of fgfr3taken together, these results clearly implicate y724 in the activation of stat proteins by constitutively activated mutants of fgfr3 and suggest that both y724 and y760 are required for maximal stat activation." SIGNOR-106742 MAPK3 protein P27361 UNIPROT UBTF protein P17480 UNIPROT down-regulates phosphorylation Thr201 DIPEKPKtPQQLWYT 9606 11741541 t lperfetto "Erk1/2 was found to phosphorylate the architectural transcription factor ubf at amino acids 117 and 201 within hmg boxes 1 and 2, preventing their interaction with dna" SIGNOR-112817 FGFR3 protein P22607 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000007 10918587 t "Activation of Stat1 and Stat3 by FGFR derivatives. Lysates of 293T cells transfected as indicated were analysed by Western blotting using Phospho-Stat1 (Y701) antisera (top) or Stat1 antisera (bottom). (b) The same lysates in (a) were re-examined for phosphorylated Stat3 by Western blotting with Phospho-Stat3 (Y705) (top). all three FGFR family members examined here are able to lead to Stat activation. Expression of the 'TDII-like' derivatives of FGFR1, FGFR3, and FGFR4, as well as myrR1-WT, led to phosphorylation of both Stat1 and Stat3." SIGNOR-251139 FGFR3 protein P22607 UNIPROT STAT1 protein P42224 UNIPROT "up-regulates activity" phosphorylation Tyr701 DGPKGTGyIKTELIS 9606 BTO:0000007 10918587 t "Activation of Stat1 and Stat3 by FGFR derivatives. Lysates of 293T cells transfected as indicated were analysed by Western blotting using Phospho-Stat1 (Y701) antisera (top) or Stat1 antisera (bottom). (b) The same lysates in (a) were re-examined for phosphorylated Stat3 by Western blotting with Phospho-Stat3 (Y705) (top). all three FGFR family members examined here are able to lead to Stat activation. Expression of the 'TDII-like' derivatives of FGFR1, FGFR3, and FGFR4, as well as myrR1-WT, led to phosphorylation of both Stat1 and Stat3." SIGNOR-251138 FGFR3 protein P22607 UNIPROT PTEN protein P60484 UNIPROT unknown phosphorylation Tyr240 RREDKFMyFEFPQPL 9606 BTO:0000527 22891331 t llicata "Fgfrs phosphorylate pten at tyrosine 240" SIGNOR-191797 PRKACG protein P22612 UNIPROT NOS3 protein P29474 UNIPROT up-regulates phosphorylation Ser1177 TSRIRTQsFSLQERQ 9606 11729179 t gcesareni "Recently many investigators have shown that protein phosphorylation of enos by several serine/threonine kinases is a critical control step for no production by endothelial cells. Phosphorylation by amp kinase, akt (or protein kinase b), or protein kinase a on serine 1179 (bovine) or serine 1177 (human) of enos leads to enhanced activity of the enzyme and, thus, augmented production of no." SIGNOR-112375 PRKACG protein P22612 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser275 LSAFRRTsLAGGGRR 9606 BTO:0000887 20151718 t miannu "Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human)." SIGNOR-163784 PRKACG protein P22612 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser284 AGGGRRIsDSHEDTG 9606 BTO:0000887 20151718 t miannu "Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human)." SIGNOR-163788 PRKACG protein P22612 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser304 SLLKKRDsFRTPRDS 9606 BTO:0000887 20151718 t miannu "Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human)." SIGNOR-163792 PRKACG protein P22612 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser311 SFRTPRDsKLEAPAE 9606 BTO:0000887 20151718 t miannu "Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human)." SIGNOR-163796 PRKACG protein P22612 UNIPROT TENT2 protein Q6PIY7 UNIPROT "down-regulates activity" phosphorylation Ser116 LSGERRYsMPPLFHT 9606 BTO:0000007 31057087 t miannu "We found that Gld2 activity is regulated by site-specific phosphorylation in its disordered N-terminal domain. We identified two phosphorylation sites (S62, S110) where phosphomimetic substitutions increased Gld2 activity and one site (S116) that markedly reduced activity. Using mass spectrometry, we confirmed that HEK 293 cells readily phosphorylate the N-terminus of Gld2. We identified protein kinase A (PKA) and protein kinase B (Akt1) as the kinases that site-specifically phosphorylate Gld2 at S116, abolishing Gld2-mediated nucleotide addition." SIGNOR-259404 PRKACG protein P22612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 10230396 t gcesareni "Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo." SIGNOR-67392 PRKACG protein P22612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 10230396 t gcesareni "Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo." SIGNOR-67396 PRKACG protein P22612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 10949026 t gcesareni "Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo." SIGNOR-81153 RFX1 protein P22670 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 12032779 f miannu "Several different transcription factors have been implicated in the down-regulation of c-myc expression during differentiation, including C/EBPalpha, CTCF, BLIMP-1, and RFX1." SIGNOR-253829 RFX1 protein P22670 UNIPROT HLA-DOB protein P13765 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000776 11823510 f "Class II transactivator is required for maximal expression of HLA-DOB in B cells|HLA-DO, encoded by the HLA-DOA and HLA-DOB genes, has been shown to function as a modulator of Ag presentation. DNA microarray comparisons between B cells wild-type and mutant for the master regulator of MHC class II transcription, class II transactivator (CIITA), identified HLA-DOA and HLA-DOB as being up-regulated by CIITA." SIGNOR-254022 CBL protein P22681 UNIPROT PIK3R2 protein O00459 UNIPROT down-regulates ubiquitination 9606 BTO:0000782 11526404 t lperfetto "Cbl-b, a ring-type e3 ubiquitin protein ligase, is implicated in setting the threshold of t lymphocyte activation. The p85 regulatory subunit of phosphatidylinositol 3 kinase (pi3k) was identified as a substrate for cbl-b. We have shown that cbl-b negatively regulated p85 in a proteolysis-independent manner." SIGNOR-110063 CBL protein P22681 UNIPROT CFLAR protein O15519 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 phosphorylation:Ser2;Tyr182 sAEVIHQV;VQGAGTSyRNVLQAA 19597496 t "CFLAR has to be phosphorylated on Tyr211 and Ser4 by c-Abl and p38, respectively. This phosphorylation facilitated specific interaction between FLIPS and the ubiquitin E3 ligase c-Cbl" gcesareni "We therefore conclude that c-cbl is a e3 ubiquitin ligase for flips and that the interaction of flips with c-cbl requires phosphorylation of both ser4 and tyr211 of flips.This interaction triggered proteasomal degradation of FLIP(S), which promoted activation of caspase-8 and apoptosis." SIGNOR-186998 CBL protein P22681 UNIPROT SORBS2 protein O94875 UNIPROT down-regulates ubiquitination 9606 12475393 t gcesareni "Cbl-argbp2 complex mediates ubiquitination and degradation of c-abl" SIGNOR-96325 CBL protein P22681 UNIPROT ABL1 protein P00519 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0001271 20675402 t lperfetto "We found that while c-cbl e3 ligase induced ubiquitin-dependent degradation of mature and phosphorylated bcr-abl proteins" SIGNOR-167194 CBL protein P22681 UNIPROT EGFR protein P00533 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 20332299 t lperfetto "Ligand binding to EGFR also leads to rapid internalization and proteosomal/lysosomal degradation of the receptors. This process results in a dramatic downregulation of both total and cell surface receptors. EGF-induced degradation of EGFR is thought to be initiated by phosphorylation of tyrosine 1045 of the receptor followed by binding of Cbl adaptor proteins and ubiquitination of the receptor. Internalized EGFR is transported to early endosomes where receptor-ligand complexes are sorted for either degradation or recycling to the cell surface." SIGNOR-65642 CBL protein P22681 UNIPROT KIT protein P10721 UNIPROT "down-regulates activity" ubiquitination 9606 15315962 t miannu "KIT binds to and induces the phosphorylation of Cbl proteins, which in turn act as E3 ligases, mediating the ubiquitination and degradation of KIT and themselves. Tyrosine kinase binding and RING finger domains of Cbl are essential for Cbl-mediated ubiquitination and degradation of KIT." SIGNOR-260104 CBL protein P22681 UNIPROT PDGFRA protein P16234 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 10347229 t lperfetto "Cbl overexpression in nih3t3 cells enhanced the ubiquitination and degradation of the platelet-derived growth factor receptor-alpha (pdgfralpha)" SIGNOR-68024 CBL protein P22681 UNIPROT PIK3R1 protein P27986 UNIPROT down-regulates ubiquitination 9606 BTO:0000782 11526404 t lperfetto "Cbl-b, a ring-type e3 ubiquitin protein ligase, is implicated in setting the threshold of t lymphocyte activation. The p85 regulatory subunit of phosphatidylinositol 3 kinase (pi3k) was identified as a substrate for cbl-b. We have shown that cbl-b negatively regulated p85 in a proteolysis-independent manner." SIGNOR-110060 CBL protein P22681 UNIPROT FLT3 protein P36888 UNIPROT "down-regulates activity" binding 10090 BTO:0001516 19276253 t "Functionally, CBL negatively regulated FMS-like tyrosine kinase 3 (FLT3) activity and interacted with human FLT3 via the autophosphorylation sites Y589 and Y599 and colocalized in vivo." SIGNOR-255739 CBL protein P22681 UNIPROT FRS2 protein Q8WU20 UNIPROT down-regulates ubiquitination 9606 11997436 t lperfetto "The experiments presented in this report illustrate that in response to fgf stimulation, cbl is recruited by grb2 binding to the frs2_ multiprotein complex, resulting in ubiquitination of frs2_ and fgfr. grb2 functions as a link between frs2_ and cbl;grb2 is bound to tyrosine-phosphorylated frs2_ by means of its sh2 domain and to a proline-rich region in the c terminus of cbl by means of its sh3 domains." SIGNOR-87166 CBL protein P22681 UNIPROT LRIG1 protein Q96JA1 UNIPROT down-regulates ubiquitination 9606 BTO:0001253 15282549 t gcesareni "We report upregulation of lrig1 transcript and protein upon egf stimulation, and physical association of the encoded protein with the four egfr orthologs of mammals. Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation." SIGNOR-127289 CBL protein P22681 UNIPROT PI3K complex SIGNOR-C156 SIGNOR down-regulates ubiquitination 9606 BTO:0000782 11526404 t lperfetto "Cbl-b, a ring-type e3 ubiquitin protein ligase, is implicated in setting the threshold of t lymphocyte activation. The p85 regulatory subunit of phosphatidylinositol 3 kinase (pi3k) was identified as a substrate for cbl-b. We have shown that cbl-b negatively regulated p85 in a proteolysis-independent manner." SIGNOR-252668 PRKACB protein P22694 UNIPROT NGFR protein P08138 UNIPROT up-regulates phosphorylation Ser303 PEGEKLHsDSGISVD 9606 BTO:0000938 12682012 t llicata "Pka phosphorylates the p75 receptor and regulates its localization to lipid rafts. activation of camp?PKA Is required for translocation of p75ntr to lipid rafts, and for biochemical and biological activities of p75ntr, such as inactivation of rho and the neurite outgrowth." SIGNOR-99755 PRKACB protein P22694 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser275 LSAFRRTsLAGGGRR 9606 BTO:0000887 20151718 t miannu "Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human)." SIGNOR-163768 PRKACB protein P22694 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser284 AGGGRRIsDSHEDTG 9606 BTO:0000887 20151718 t miannu "Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human)." SIGNOR-163772 PRKACB protein P22694 UNIPROT GPKOW protein Q92917 UNIPROT "up-regulates activity" phosphorylation Ser27 SFGFTRTsARRRLAD -1 21880142 t miannu "Using yeast two-hybrid screening with the PKA Cβ2 subunit as bait we identified GPKOW, also known as MOS2 homolog or T54 protein, as an interaction partner for Cβ2. PKA phosphorylates GPKOW at S27 and T316 in vitro. GPKOWs ability to bind RNA is sensitive to mutations of its PKA phosphorylation sites." SIGNOR-266311 PRKACB protein P22694 UNIPROT GPKOW protein Q92917 UNIPROT "up-regulates activity" phosphorylation Thr316 GTASSRKtLWNQELY -1 21880142 t miannu "Using yeast two-hybrid screening with the PKA Cβ2 subunit as bait we identified GPKOW, also known as MOS2 homolog or T54 protein, as an interaction partner for Cβ2.PKA phosphorylates GPKOW at S27 and T316 in vitro. GPKOWs ability to bind RNA is sensitive to mutations of its PKA phosphorylation sites." SIGNOR-266310 PRKACB protein P22694 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 10949026 t gcesareni "Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136." SIGNOR-81141 PRKACB protein P22694 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 10949026 t gcesareni "Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136." SIGNOR-81145 PRKACB protein P22694 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 10949026 t gcesareni "Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136." SIGNOR-81149 UQCRC2 protein P22695 UNIPROT "Mitochondrial respiratory chain complex III" complex SIGNOR-C279 SIGNOR "form complex" binding 30030361 t lperfetto "Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits" SIGNOR-262191 NR4A1 protein P22736 UNIPROT NR3C1 protein P04150 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15591535 f gcesareni "Our data suggest a mechanism for transrepression between two nuclear receptors, gr and ngfi-b." SIGNOR-132312 NR4A1 protein P22736 UNIPROT HSD3B2 protein P26439 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0005761 15666793 f miannu "Herein we discuss the evidence that suggests a role for NURR1 (NR4A2) in the expression of CYP11B2 in the glomerulosa as well as in the dysregulation of CYP11B2 gene expression as is seen in aldosterone-producing adenoma (APA), a major cause of endocrine hypertension. NURR1 appears to be important for CYP11B2 transcription and is found at higher levels in glomerulosa and in APA." SIGNOR-254866 MMP8 protein P22894 UNIPROT FGA protein P02671 UNIPROT "down-regulates quantity by destabilization" cleavage Ala20 VVGTAWTaDSGEGDF -1 10930399 t lperfetto "Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system. |Fibrinogen was subjected to MMP-cleavage, and the resulting fragments were isolated. The amino acid sequences were determined by automated Edman degradation.|MMP-8 20ADSGEGD a-chain | 442LRTGKEKV a-chain" SIGNOR-263625 ITGA6 protein P23229 UNIPROT "A6/b4 integrin" complex SIGNOR-C174 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253199 KEL protein P23276 UNIPROT EDN3 protein P14138 UNIPROT "up-regulates activity" cleavage Trp117 YCHLDIIwINTPEQT -1 10438732 t miannu "These data demonstrate that the Kell blood group protein is a proteolytic enzyme that processes big ET-3, generating ET-3, a potent bioactive peptide with multiple biological roles." SIGNOR-256354 ME2 protein P23368 UNIPROT NADPH(4-) smallmolecule CHEBI:57783 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 24769394 t miannu "The major NADPH-producing enzymes in the cell are glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) in the pentose phosphate pathway (PPP), malic enzyme (ME) in the pyruvate cycling pathway, and isocitrate dehydrogenase (IDH) in the tricarboxylic acid (TCA) cycle" SIGNOR-267054 RPS3 protein P23396 UNIPROT "40S cytosolic small ribosomal subunit" complex SIGNOR-C286 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262421 RPS6KB1 protein P23443 UNIPROT PFKFB2 protein O60825 UNIPROT "up-regulates activity" phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000562 9211863 t gcesareni "Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b." SIGNOR-49371 RPS6KB1 protein P23443 UNIPROT URI1 protein O94763 UNIPROT "down-regulates activity" phosphorylation Ser372 AKRKRKNsTGSGHSA 9606 BTO:0000567 17936702 t miannu "Here we report that the prefoldin chaperone URI represents a mitochondrial substrate of S6K1. In growth factor-deprived or rapamycin-treated cells, URI forms stable complexes with protein phosphatase (PP)1gamma at mitochondria, thereby inhibiting the activity of the bound enzyme. Growth factor stimulation induces disassembly of URI/PP1gamma complexes through S6K1-mediated phosphorylation of URI at serine 371." SIGNOR-262943 RPS6KB1 protein P23443 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser15 FSLLRGPsWDPFRDW 9606 19593530 t "10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro." lperfetto "Ser-15, ser-78, and ser-82 in hsp27 (ser-15 and ser-86 in hsp25) are part of the rxxs motif, a known recognition site for p70rsk." SIGNOR-186951 RPS6KB1 protein P23443 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser78 PAYSRALsRQLSSGV 9606 19593530 t "10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro." lperfetto "Ser-15, ser-78, and ser-82 in hsp27 (ser-15 and ser-86 in hsp25) are part of the rxxs motif, a known recognition site for p70rsk." SIGNOR-186955 RPS6KB1 protein P23443 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser82 RALSRQLsSGVSEIR 9606 19593530 t "10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro." lperfetto "Ser-15, ser-78, and ser-82 in hsp27 (ser-15 and ser-86 in hsp25) are part of the rxxs motif, a known recognition site for p70rsk." SIGNOR-186959 RPS6KB1 protein P23443 UNIPROT GLI1 protein P08151 UNIPROT up-regulates phosphorylation Ser84 LTKKRALsISPLSDA 9606 22439934 t gcesareni "In this study, we found that an activated mtor/s6k1 pathway promotes gli1 transcriptional activity and oncogenic function through s6k1-mediated gli1 phosphorylation at ser84, which releases gli1 from its endogenous inhibitor, sufu." SIGNOR-196756 RPS6KB1 protein P23443 UNIPROT EIF4B protein P23588 UNIPROT up-regulates phosphorylation Ser422 RERSRTGsESSQTGT 9606 15071500 t gcesareni "S6k1/s6k2 specifically phosphorylate ser422 in vitro. Substitution of ser422 with ala results in a loss of activity in an in vivo translation assay, indicating that phosphorylation of this site plays an important role in eif4b function." SIGNOR-123997 RPS6KB1 protein P23443 UNIPROT CAD protein P27708 UNIPROT up-regulates phosphorylation Ser1859 PPRIHRAsDPGLPAE 9606 23429703 t lperfetto "Mtorc1 signaling posttranslationally regulated this metabolic pathway via its downstream target ribosomal protein s6 kinase 1 (s6k1), which directly phosphorylates s1859 on cad, the enzyme that catalyzes the first three steps of de novo pyrimidine synthesis. Growth signaling through mtorc1 thus stimulates the production of new nucleotides to accommodate an increase in rna and dna synthesis." SIGNOR-201117 RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser1101 GCRRRHSsETFSSTP 10090 15306821 t lperfetto "Nevertheless, s6k1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from s6k1 to insulin receptor substrate 1 (irs1), which blunts s307 and s636/s639 phosphorylation; thus under conditions of nutrient satiation s6k1 negatively regulates insulin." SIGNOR-127904 RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser639 YMPMSPKsVSAPQQI 10090 15306821 t lperfetto "Nevertheless, s6k1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from s6k1 to insulin receptor substrate 1 (irs1), which blunts s307 and s636/s639 phosphorylation; thus under conditions of nutrient satiation s6k1 negatively regulatesinsulin." SIGNOR-127203 RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser527 RFRKRTHsAGTSPTI 9606 BTO:0000007 16914728 t lperfetto "Turnover of the active fraction of irs1 involves raptor-mtor- and s6k1-dependent serine phosphorylation in cell culture models of tuberous sclerosiss6k1 phosphorylates irs1 in vitro on multiple residues showing strong preference for rxrxxs/t over s/t,p sites." SIGNOR-148903 RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser270 EFRPRSKsQSSSNCS 9606 BTO:0000975;BTO:0001760;BTO:0000142 9312143 t lperfetto "Turnover of the active fraction of irs1 involves raptor-mtor- and s6k1-dependent serine phosphorylation in cell culture models of tuberous sclerosiss6k1 phosphorylates irs1 in vitro on multiple residues showing strong preference for rxrxxs/t over s/t,p sites." SIGNOR-51216 RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser527 RFRKRTHsAGTSPTI 10090 BTO:0002572 18498745 t lperfetto "In this report, we identified insulin receptor substrate 1 (IRS-1), a critical mediator of the insulin/insulin-like growth factor 1 signaling, as a proteolytic target of the CUL7 E3 ligase in a manner that depends on mammalian target of rapamycin and the p70 S6 kinase activities.Elimination of phosphorylation at S307/S312/S527/S636/S639 renders V5-IRS-1 partially resistant to degradation by Fbw8" SIGNOR-236595 RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser639 YMPMSPKsVSAPQQI 10090 BTO:0002572 18498745 t lperfetto "In this report, we identified insulin receptor substrate 1 (IRS-1), a critical mediator of the insulin/insulin-like growth factor 1 signaling, as a proteolytic target of the CUL7 E3 ligase in a manner that depends on mammalian target of rapamycin and the p70 S6 kinase activities.Elimination of phosphorylation at S307/S312/S527/S636/S639 renders V5-IRS-1 partially resistant to degradation by Fbw8" SIGNOR-236599 RPS6KB1 protein P23443 UNIPROT SREBF1 protein P36956 UNIPROT up-regulates 10090 BTO:0002572 20670887 f lperfetto "We find that srebp1 and 2 promote proliferation downstream of mtorc1, and the activation of these transcription factors is mediated by s6k1." SIGNOR-167190 RPS6KB1 protein P23443 UNIPROT MTOR protein P42345 UNIPROT "down-regulates activity" phosphorylation Thr2446 NKRSRTRtDSYSAGQ 9606 15905173 t lperfetto "Importantly, phosphorylation of mTOR by S6K1 occurs at threonine 2446/serine 2448. This region has been shown previously to be part of a regulatory repressor domain. These sites are also constitutively phosphorylated in the breast cancer cell line MCF7 carrying an amplification of the S6K1 geneit has been proposed that other inputs, in addition to phosphorylation of Thr-2446/Ser-2448 by S6K1, are part of the mechanism involved in inhibiting this repressor domain" SIGNOR-102051 RPS6KB1 protein P23443 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates 9606 17181399 f gcesareni "Finally, downregulation of p70 s6 kinase by sirna significantly enhanced the fgf-2-stimulated vegf release and phosphorylation of sapk/jnk." SIGNOR-149367 RPS6KB1 protein P23443 UNIPROT MRE11 protein P49959 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr597 SQRGRADtGLETSTR -1 28967905 t miannu "MRE11 is highly unstable in PTEN-deficient cells but stability can be significantly restored by inhibiting mTORC1 or p70S6 kinase (p70S6K), downstream kinases whose activities are stimulated by AKT, or by mutating a residue in MRE11 that we show is phosphorylated by p70S6K in vitro." SIGNOR-265944 RPS6KB1 protein P23443 UNIPROT RPS6 protein P62753 UNIPROT "up-regulates activity" phosphorylation Ser235 IAKRRRLsSLRASTS 10090 15809305 t lperfetto "A knockin mouse carrying mutations at all phosphorylation sites in the primary s6k substrate, ribosomal protein s6 (rps6), has provided insight into the physiological role of this protein phosphorylation event. Of the many known substrates of s6k1, it is rps6 that has been shown to be directly involved, via its phosphorylation, in controlling cell size." SIGNOR-135172 RPS6KB1 protein P23443 UNIPROT RPS6 protein P62753 UNIPROT "up-regulates activity" phosphorylation Ser236 AKRRRLSsLRASTSK 10090 15809305 t lperfetto "A knockin mouse carrying mutations at all phosphorylation sites in the primary s6k substrate, ribosomal protein s6 (rps6), has provided insight into the physiological role of this protein phosphorylation event. Of the many known substrates of s6k1, it is rps6 that has been shown to be directly involved, via its phosphorylation, in controlling cell size." SIGNOR-135176 RPS6KB1 protein P23443 UNIPROT MXD1 protein Q05195 UNIPROT down-regulates phosphorylation Ser145 IERIRMDsIGSTVSS 9606 18451027 t llicata "Both rsk and s6k phosphorylate serine 145 of mad1 upon serum or insulin stimulation. Ser-145 phosphorylation of mad1 accelerates the ubiquitination and degradation of mad1 through the 26s proteasome pathway, which in turn promotes the transcriptional activity of myc." SIGNOR-178590 RPS6KB1 protein P23443 UNIPROT PDCD4 protein Q53EL6 UNIPROT down-regulates phosphorylation Ser67 KRRLRKNsSRDSGRG 9606 17053147 t gcesareni "Both akt and p70(s6k) phosphorylate pdcd4, allowing for binding of the e3-ubiquitin ligase beta-trcp and consequently ubiquitylation." SIGNOR-150144 RPS6KB1 protein P23443 UNIPROT PDCD4 protein Q53EL6 UNIPROT down-regulates phosphorylation Ser67 KRRLRKNsSRDSGRG 9606 BTO:0000007 BTO:0001253 18296647 t gcesareni "Both akt and p70(s6k) phosphorylate pdcd4, allowing for binding of the e3-ubiquitin ligase beta-trcp and consequently ubiquitylation." SIGNOR-160989 RPS6KB1 protein P23443 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates phosphorylation Thr491 PQQRNALtPTTIPDG 9606 18769144 t lperfetto "Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively" SIGNOR-180784 JAK1 protein P23458 UNIPROT IL2RB protein P14784 UNIPROT "up-regulates activity" phosphorylation Tyr418 LSGEDDAyCTFPSRD 9534 BTO:0000298 8700888 t "In COS-7 cells, overexpression of Jak1 augmented phosphorylation of Y338 as well as Y392 and Y510. Y392 and Y510 were critical for IL-2-induced activation of signal transducers and activators of transcription (STAT proteins), Y338 was required for Shc-IL-2Rbeta association and for IL-2-induced tyrosine phosphorylation of Shc." SIGNOR-251340 JAK1 protein P23458 UNIPROT IL2RB protein P14784 UNIPROT "up-regulates activity" phosphorylation Tyr536 LPLNTDAyLSLQELQ 9534 BTO:0000298 8700888 t "In COS-7 cells, overexpression of Jak1 augmented phosphorylation of Y338 as well as Y392 and Y510. Y392 and Y510 were critical for IL-2-induced activation of signal transducers and activators of transcription (STAT proteins), Y338 was required for Shc-IL-2Rbeta association and for IL-2-induced tyrosine phosphorylation of Shc." SIGNOR-251341 JAK1 protein P23458 UNIPROT IFNGR1 protein P15260 UNIPROT up-regulates phosphorylation Tyr457 KAPTSFGyDKPHVLV 9606 7615558 t 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 JAK1 protein P23458 UNIPROT IFNGR1 protein P15260 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000801 19041276 t 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 JAK1 protein P23458 UNIPROT TYK2 protein P29597 UNIPROT up-regulates phosphorylation Tyr1054 AVPEGHEyYRVREDG 9606 BTO:0000667 30029643 t "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-256221 JAK1 protein P23458 UNIPROT TYK2 protein P29597 UNIPROT up-regulates phosphorylation Tyr1054 AVPEGHEyYRVREDG 9606 8702790 t llicata "These results indicate that tyk2 is activated by phosphorylation on tyr-1054 and/or tyr-1055 and that this phosphorylation requires another kinase, most likely jak1." SIGNOR-43080 JAK1 protein P23458 UNIPROT TYK2 protein P29597 UNIPROT up-regulates phosphorylation Tyr1055 VPEGHEYyRVREDGD 9606 8702790 t llicata "These results indicate that tyk2 is activated by phosphorylation on tyr-1054 and/or tyr-1055 and that this phosphorylation requires another kinase, most likely jak1." SIGNOR-43084 JAK1 protein P23458 UNIPROT IRS1 protein P35568 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0002882 9305869 t "Janus kinase-dependent activation of insulin receptor substrate 1" SIGNOR-251343 JAK1 protein P23458 UNIPROT STAT1 protein P42224 UNIPROT "up-regulates activity" phosphorylation Tyr701 DGPKGTGyIKTELIS 9606 BTO:0000567 11823427 t 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 JAK1 protein P23458 UNIPROT STAT1 protein P42224 UNIPROT "up-regulates activity" phosphorylation Tyr701 DGPKGTGyIKTELIS -1 7657660 t 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 JAK1 protein P23458 UNIPROT STAT1 protein P42224 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007 9020188 t 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 JAK1 protein P23458 UNIPROT STAT6 protein P42226 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000801 23124025 t lperfetto "IL-4-stimulated Stat6 activation is mediated by Jak1 whereas Tyk2 is required for Stat6 activation in IL-13-treated monocytes" SIGNOR-249531 JAK1 protein P23458 UNIPROT STAT6 protein P42226 UNIPROT "up-regulates activity" phosphorylation 9606 9852261 t gcesareni "Stat6 activation is mediated through jak1 and jak2 tyrosine kinases" SIGNOR-62582 JAK1 protein P23458 UNIPROT JAK3 protein P52333 UNIPROT up-regulates phosphorylation 9606 BTO:0000782 17259970 t milica "Il-7r signalling is initiated when il-7 crosslinks the extracellular domains of il-7ralpha and gammac, bringing together jak1 and jak3, which mutually phosphorylate each other, increasing their kinase activity." SIGNOR-152914 PTPRG protein P23470 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates activity" dephosphorylation Tyr1008 LPQDKEYyKVKEPGE 9606 BTO:0000876 25624455 t miannu "Deeper examination shows that JAKs are critically involved in integrin-mediated monocyte adhesion and that PTPRG activation leads to JAK2 dephosphorylation on the critical 1007–1008 phosphotyrosine residues, implying JAK2 inhibition and thus explaining the antiadhesive role of PTPRG." SIGNOR-254690 JAK1 protein P23458 UNIPROT IL10RA protein Q13651 UNIPROT "up-regulates activity" phosphorylation Tyr496 PPALAKGyLKQDPLE 10433356 t "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 JAK1 protein P23458 UNIPROT "ISGF3 complex" complex SIGNOR-C124 SIGNOR "up-regulates activity" phosphorylation 9606 15120645 t miannu "Despite signaling through distinct receptor complexes, type I IFNs and IFN-lambda activate similar signaling events and biological activities, consistent with their common ability to mediate an antiviral state in cells (Fig. 6). In both cases, receptor engagement leads via the activation of the Jak kinases Jak1 and Tyk2 to the activation of the IFN-stimulated gene factor 3 (ISGF3) transcription complex, composed of latent transcriptional factors of the Signal Transducers and Activators of Transcription (STAT) family, Stat1 and Stat2, and of the interferon regulatory factor (IRF) IRF9 (ISGF3g or p48)." SIGNOR-260149 JAK1 protein P23458 UNIPROT IFNGR2/INFGR1 complex SIGNOR-C142 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000801 19041276 t 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 PTPRB protein P23467 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 10734133 t gcesareni "Identification of tyrosine phosphatases that dephosphorylate the insulin receptor." SIGNOR-75989 PTPRB protein P23467 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 10734133 t gcesareni "Identification of tyrosine phosphatases that dephosphorylate the insulin receptor." SIGNOR-75993 PTPRB protein P23467 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 10734133 t gcesareni "Identification of tyrosine phosphatases that dephosphorylate the insulin receptor." SIGNOR-75997 PTPRB protein P23467 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates dephosphorylation 9606 12840032 t gcesareni "When cells are stimulated with various ligands such as growth factors, hormones, neurotransmitters, or tumor promoters, erk1/2 is activated through dualphosphorylation at the -ptepy-motif. Subsequently, p-erk1/2 translocates into the nucleus and phosphorylates elk-1, thereby acting as a transcription factor for cell proliferationthese data indicate that sa-p-erk1/2 might not only be regulated by mkp such as rvhr, but also by pp1 and ptp as well" SIGNOR-103165 PTPRB protein P23467 UNIPROT KDR protein P35968 UNIPROT "down-regulates activity" dephosphorylation Tyr1175 AQQDGKDyIVLPISE 9606 19136612 t "VE-PTP/VEGFR2 complex formation resumes with time, leading to dephosphorylation and deactivation of VEGFR2 (right). B) In VE-PTP-deficient cells, such as after siRNA treatment, VEGFR2 activation (middle) is exaggerated, leading to increased phosphorylation at the Y951 and Y1175 phosphorylation sites" SIGNOR-248441 PTPRD protein P23468 UNIPROT STAT3 protein P40763 UNIPROT down-regulates dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000551;BTO:0000527 BTO:0000142 19478061 t miannu "Transfection of wild-type ptprd resulted in the specific dephosphorylation of stat3 at tyrosine 705, a residue that must be phosphorylated for stat3 to be active" SIGNOR-185933 PTPRD protein P23468 UNIPROT STAT3 protein P40763 UNIPROT "down-regulates activity" dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000007 19478061 t "Transfection of wild-type PTPRD resulted in the specific dephosphorylation of STAT3 at tyrosine 705, a residue that must be phosphorylated for STAT3 to be active" SIGNOR-248442 PTPRE protein P23469 UNIPROT INSR protein P06213 UNIPROT "down-regulates activity" dephosphorylation Tyr1185 FGMTRDIyETDYYRK 10116 BTO:0000575 15738637 t "In this study, we showed that receptor-type PTPepsilon (PTP epsilonM) dephosphorylated IR in rat primary hepatocytes and tyrosines 972, 1158, 1162 and 1163| These results suggest that PTPepsilonM is a negative regulator of IR signaling and involved in insulin-induced glucose metabolism mainly through direct dephosphorylation and inactivation of IR in hepatocytes and liver." SIGNOR-248444 PTPRE protein P23469 UNIPROT INSR protein P06213 UNIPROT "down-regulates activity" dephosphorylation Tyr1189 RDIYETDyYRKGGKG 10116 BTO:0000575 15738637 t "In this study, we showed that receptor-type PTPepsilon (PTP epsilonM) dephosphorylated IR in rat primary hepatocytes and tyrosines 972, 1158, 1162 and 1163| These results suggest that PTPepsilonM is a negative regulator of IR signaling and involved in insulin-induced glucose metabolism mainly through direct dephosphorylation and inactivation of IR in hepatocytes and liver." SIGNOR-248445 PTPRE protein P23469 UNIPROT INSR protein P06213 UNIPROT "down-regulates activity" dephosphorylation Tyr1190 DIYETDYyRKGGKGL 10116 BTO:0000575 15738637 t "In this study, we showed that receptor-type PTPepsilon (PTP epsilonM) dephosphorylated IR in rat primary hepatocytes and tyrosines 972, 1158, 1162 and 1163| These results suggest that PTPepsilonM is a negative regulator of IR signaling and involved in insulin-induced glucose metabolism mainly through direct dephosphorylation and inactivation of IR in hepatocytes and liver." SIGNOR-248446 PTPRE protein P23469 UNIPROT KCNB1 protein Q14721 UNIPROT "down-regulates activity" dephosphorylation Tyr128 YWGIDEIyLESCCQA 9606 BTO:0000007 10921884 t "Hypomyelination and increased activity of voltage-gated K(+) channels in mice lacking protein tyrosine phosphatase epsilon" SIGNOR-248450 PTPRG protein P23470 UNIPROT DOK2 protein O60496 UNIPROT "up-regulates activity" dephosphorylation Tyr139 CMEENELySSAVTVG -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254698 PTPRG protein P23470 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates activity" dephosphorylation Tyr1007 VLPQDKEyYKVKEPG 9606 BTO:0000876 25624455 t miannu "Deeper examination shows that JAKs are critically involved in integrin-mediated monocyte adhesion and that PTPRG activation leads to JAK2 dephosphorylation on the critical 1007–1008 phosphotyrosine residues, implying JAK2 inhibition and thus explaining the antiadhesive role of PTPRG." SIGNOR-254689 PTPRG protein P23470 UNIPROT DAB1 protein O75553 UNIPROT "down-regulates activity" dephosphorylation Tyr198 EDVEDPVyQYIVFEA -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254697 PTPRG protein P23470 UNIPROT ABL1 protein P00519 UNIPROT "down-regulates activity" dephosphorylation Tyr413 TAPESLAyNKFSIKS -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254691 PTPRG protein P23470 UNIPROT EGFR protein P00533 UNIPROT "down-regulates activity" dephosphorylation Tyr1069 EDSFLQRySSDPTGA -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254699 PTPRG protein P23470 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" dephosphorylation Tyr1172 ISLDNPDyQQDFFPK -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254700 PTPRG protein P23470 UNIPROT ERBB2 protein P04626 UNIPROT "up-regulates activity" dephosphorylation Tyr1248 PTAENPEyLGLDVPV -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254701 PTPRG protein P23470 UNIPROT ITGB2 protein P05107 UNIPROT "down-regulates activity" 9606 25624455 f miannu "PTPRG activation inhibits chemoattractant induced LFA-1 affinity triggering and mediated adhesion in human primary monocytes.we show that PTPRG is a novel negative regulator of LFA-1 high-affinity-state triggering and mediated arrest by chemoattractants in human primary monocytes. Notably, PTKs of the JAK and SRC families have a regulatory role in LFA-1 affinity triggering, with JAKs showing a positive role (3), whereas SRCs possibly have a negative role (37). In our context, SRC appears inhibited by PTPRG activation (Table I), thus making it unlikely that the antiadhesive effect of PTPRG is mediated by SRC activation." SIGNOR-254735 PTPRG protein P23470 UNIPROT ITGB1 protein P05556 UNIPROT "down-regulates activity" dephosphorylation Tyr783 DTGENPIyKSAVTTV -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254706 PTPRG protein P23470 UNIPROT INSR protein P06213 UNIPROT "up-regulates activity" dephosphorylation Tyr1189 RDIYETDyYRKGGKG -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254704 PTPRG protein P23470 UNIPROT INSR protein P06213 UNIPROT "up-regulates activity" dephosphorylation Tyr999 YASSNPEyLSASDVF -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254703 PTPRG protein P23470 UNIPROT MET protein P08581 UNIPROT "down-regulates activity" dephosphorylation Tyr1003 VSNESVDyRATFPED -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254712 PTPRG protein P23470 UNIPROT KIT protein P10721 UNIPROT "down-regulates activity" dephosphorylation Tyr730 DMKPGVSyVVPTKAD -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254710 PTPRG protein P23470 UNIPROT SRC protein P12931 UNIPROT "down-regulates activity" dephosphorylation Tyr419 RLIEDNEyTARQGAK -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254725 PTPRG protein P23470 UNIPROT SRC protein P12931 UNIPROT "down-regulates activity" dephosphorylation Tyr530 FTSTEPQyQPGENL -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254726 PTPRG protein P23470 UNIPROT PDGFRA protein P16234 UNIPROT "up-regulates activity" dephosphorylation Tyr754 ERKEVSKySDIQRSL -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254714 PTPRG protein P23470 UNIPROT VCL protein P18206 UNIPROT "down-regulates activity" dephosphorylation Tyr822 KSFLDSGyRILGAVA -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254731 PTPRG protein P23470 UNIPROT ITGAL protein P20701 UNIPROT "down-regulates activity" 9606 25624455 f miannu "PTPRG activation inhibits chemoattractantinduced LFA-1 affinity triggering and mediated adhesion in human primary monocytes. we show that PTPRG is a novel negative regulator of LFA-1 high-affinity-state triggering and mediated arrest by chemoattractants in human primary monocytes. Notably, PTKs of the JAK and SRC families have a regulatory role in LFA-1 affinity triggering, with JAKs showing a positive role (3), whereas SRCs possibly have a negative role (37). In our context, SRC appears inhibited by PTPRG activation (Table I), thus making it unlikely that the antiadhesive effect of PTPRG is mediated by SRC activation." SIGNOR-254736 PTPRG protein P23470 UNIPROT CDK2 protein P24941 UNIPROT "down-regulates activity" dephosphorylation Tyr15 EKIGEGTyGVVYKAR -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254695 PTPRG protein P23470 UNIPROT SHC1 protein P29353 UNIPROT "down-regulates activity" dephosphorylation Tyr349 EEPPDHQyYNDFPGK -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254723 PTPRG protein P23470 UNIPROT KDR protein P35968 UNIPROT "down-regulates activity" dephosphorylation Tyr1059 DIYKDPDyVRKGDAR -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254708 PTPRG protein P23470 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" dephosphorylation Tyr705 DPGSAAPyLKTKFIC -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254729 PTPRG protein P23470 UNIPROT STAT5A protein P42229 UNIPROT "up-regulates activity" dephosphorylation Tyr694 LAKAVDGyVKPQIKQ -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254730 PTPRG protein P23470 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" dephosphorylation Tyr315 MPMDTSVyESPYSDP -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254733 PTPRG protein P23470 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" dephosphorylation Tyr319 TSVYESPySDPEELK -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254734 PTPRG protein P23470 UNIPROT PXN protein P49023 UNIPROT "up-regulates activity" dephosphorylation Tyr118 VGEEEHVySFPNKQK -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254721 PTPRG protein P23470 UNIPROT BMX protein P51813 UNIPROT "down-regulates activity" dephosphorylation Tyr40 LTKTNLSyYEYDKMK -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254693 PTPRG protein P23470 UNIPROT STAT2 protein P52630 UNIPROT "up-regulates activity" dephosphorylation Tyr690 NLQERRKyLKHRLIV -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254728 PTPRG protein P23470 UNIPROT PTK2 protein Q05397 UNIPROT "down-regulates activity" dephosphorylation Tyr577 YMEDSTYyKASKGKL -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254718 PTPRG protein P23470 UNIPROT PTK2 protein Q05397 UNIPROT "down-regulates activity" dephosphorylation Tyr861 PIGNQHIyQPVGKPD -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254720 PTPRG protein P23470 UNIPROT PTK2 protein Q05397 UNIPROT "up-regulates activity" dephosphorylation Tyr397 SVSETDDyAEIIDEE -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254717 PTPRG protein P23470 UNIPROT PTK2 protein Q05397 UNIPROT "up-regulates activity" dephosphorylation Tyr576 RYMEDSTyYKASKGK -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254719 PTPRG protein P23470 UNIPROT BTK protein Q06187 UNIPROT "down-regulates activity" dephosphorylation Tyr223 LKKVVALyDYMPMNA -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254694 PTPRG protein P23470 UNIPROT GRIN2B protein Q13224 UNIPROT "up-regulates activity" dephosphorylation Tyr1474 GSSNGHVyEKLSSIE -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254702 PTPRG protein P23470 UNIPROT CTTN protein Q14247 UNIPROT "down-regulates activity" dephosphorylation Tyr470 AYATEAVyESAEAPG -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254696 PTPRG protein P23470 UNIPROT BLNK protein Q8WV28 UNIPROT "up-regulates activity" dephosphorylation Tyr84 EHSDSEMyVMPAEEN -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254692 PTPRZ1 protein P23471 UNIPROT ARHGAP35 protein Q9NRY4 UNIPROT "down-regulates activity" dephosphorylation Tyr1105 RNEEENIySVPHDST 10090 BTO:0000601 16513268 t "Protein tyrosine phosphatase receptor type Z is involved in hippocampus-dependent memory formation through dephosphorylation at Y1105 on p190 RhoGAP| Furthermore, Ptprz selectively dephosphorylated pY1105 of p190 RhoGAP in vitro, and the tyrosine phosphorylation at Y1105 controls p190 RhoGAP activity in vivo." SIGNOR-248451 PTPRZ1 protein P23471 UNIPROT ALK protein Q9UM73 UNIPROT down-regulates dephosphorylation 9606 BTO:0000785 17681947 t gcesareni "Rptpbeta/zeta dephosphorylates alk at the site(s) in alk that is undergoing autophosphorylation through autoactivation." SIGNOR-157227 TNFSF4 protein P23510 UNIPROT TNFRSF4 protein P43489 UNIPROT up-regulates binding 9606 BTO:0000007 9488716 t gcesareni "Activation of nf-kappab in ox40-transfected hsb-2 cells was detected by electrophoretic mobility shift assay within 30 min after the binding of the ligand gp34." SIGNOR-54927 NFYA protein P23511 UNIPROT OGG1 protein O15527 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 14688259 f miannu "these results demonstrate that MMS can up-regulate hOGG1 expression through the induction of the transcription factor, NF-YA, and increased transcription level of the hOGG1 gene correlates with an increase in enzyme activity providing functional protection from MMS." SIGNOR-254817 NFYA protein P23511 UNIPROT SP1 protein P08047 UNIPROT "up-regulates activity" binding 9606 12427542 t miannu "Our results further confirm the important transactivating role for NF-Y for the CBS-1b promoter, via its synergism with Sp1. While differential phosphorylation of Sp1 likely contributes to binding to multiple GC-/GT-boxes in the CBS-1b and promoter activation [16], NF-Y is clearly necessary for a maximal activation response." SIGNOR-254816 NFYA protein P23511 UNIPROT GCH1 protein P30793 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15496512 f miannu "Coactivator RNF4 is involved in the GCH gene expression. Through serial deletion and mutagenesis studies of the GCH promoter, we defined the RNF4-responsive element on GCH proximal promoter as a CCAAT box. RNF4 did not possess specific DNA binding activity toward this CCAAT box, which suggests that RNF4 may be a coactivator of the CCAAT boxbinding protein nuclear factor Y (NF-Y). RNF4 is a coactivator for nuclear factor Y on GTP cyclohydrolase I proximal promoter." SIGNOR-252232 NFYA protein P23511 UNIPROT CBS protein P35520 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12427542 f miannu "Our results further confirm the important transactivating role for NF-Y for the CBS-1b promoter, via its synergism with Sp1. While differential phosphorylation of Sp1 likely contributes to binding to multiple GC-/GT-boxes in the CBS-1b and promoter activation [16], NF-Y is clearly necessary for a maximal activation response." SIGNOR-254815 NFYA protein P23511 UNIPROT SOX18 protein P35713 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567 18496767 f miannu "co-transfection experiments revealed that over-expression of Sp3 and ZBP-89 down-regulate, while over-expression of NF-Y up-regulates SOX18 promoter activity in HeLa cells" SIGNOR-254818 OMG protein P23515 UNIPROT LINGO1 protein Q96FE5 UNIPROT up-regulates binding 9606 BTO:0000938 15694321 t flangone "Nogo-a, myelin-associated glycoprotein (mag), and oligodendrocyte myelin glycoprotein (omgp)...signal through a common receptor complex in neurons, which includes the ligand binding nogo-66 receptor (ngr), and two signal-transducing binding partners, p75 and lingo-1..." SIGNOR-133640 EIF4B protein P23588 UNIPROT EIF4A1 protein P60842 UNIPROT "up-regulates activity" binding -1 11418588 t "Either eIF4B or eIF4H stimulated the initial rate and amplitude of eIF4A-dependent duplex unwinding, and the magnitude of stimulation is dependent on duplex stability" SIGNOR-261293 PAX7 protein P23759 UNIPROT KMT2D protein O14686 UNIPROT up-regulates binding 9606 BTO:0002314 BTO:0000887;BTO:0001103 SIGNOR-C88 22863532 t miannu "Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5." SIGNOR-198629 PAX7 protein P23759 UNIPROT "MLL2 complex" complex SIGNOR-C88 SIGNOR up-regulates binding 9606 BTO:0002314 BTO:0000887;BTO:0001103 22863532 t lperfetto "Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5." SIGNOR-217712 PAX7 protein P23759 UNIPROT "PAX7/MLL2 complex" complex SIGNOR-C91 SIGNOR "form complex" binding 9606 BTO:0002314 BTO:0000887;BTO:0001103 22863532 t miannu "Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5." SIGNOR-198635 PAX3 protein P23760 UNIPROT MYF5 protein P13349 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887 23384562 f gcesareni "Direct molecular regulation of the myogenic determination gene myf5 by pax3, with modulation by six1/4 factors, is exemplified by the -111 kb-myf5 enhancer." SIGNOR-200862 PAX3 protein P23760 UNIPROT MYOD1 protein P15172 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000222 18854138 f 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-181621 PAX3 protein P23760 UNIPROT FGFR4 protein P22455 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25211658 t "FGFR4 is a transcriptional target of PAX3 and the PAX3-FOXO1 fusion protein found in ARMS." SIGNOR-251572 PAX3 protein P23760 UNIPROT MEOX1 protein P50221 UNIPROT "up-regulates activity" binding -1 11423130 t miannu "We show that Mox1 and Mox2 proteins are capable of interacting with Pax1 and Pax3. We propose that the Mox family of homeodomain proteins participates in the molecular signaling network regulating the diverse events of somite development through the physical interaction with the Pax1 and Pax3 members of the Pax family." SIGNOR-222235 PAX3 protein P23760 UNIPROT MEOX2 protein P50222 UNIPROT "up-regulates activity" binding -1 11423130 t miannu "We show that Mox1 and Mox2 proteins are capable of interacting with Pax1 and Pax3. We propose that the Mox family of homeodomain proteins participates in the molecular signaling network regulating the diverse events of somite development through the physical interaction with the Pax1 and Pax3 members of the Pax family." SIGNOR-222238 PAX3 protein P23760 UNIPROT TBX2 protein Q13207 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002267 25211658 t lperfetto "We have recently found that a T-box gene family member, TBX2, is highly overexpressed in both ERMS and ARMS cells (Zhu et al, 2014). The regulation of TBX2 is uncharacterised in RMS cells, but is likely to link TBX2 expression to the known deregulation of signalling pathways in RMS. In melanoma cells, TBX2 is regulated by PAX3" SIGNOR-249596 GATA2 protein P23769 UNIPROT SPI1 protein P17947 UNIPROT "down-regulates activity" binding 9606 BTO:0000664 10411939 t irozzo "Here we demonstrate that a region of the PU.1 Ets domain (the winged helix–turn–helix wing) interacts with the conserved carboxyl-terminal zinc finger of GATA-1 and GATA-2 and that GATA proteins inhibit PU.1 transactivation of critical myeloid target genes." SIGNOR-256071 GATA2 protein P23769 UNIPROT SPI1 protein P17947 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 24583263 f irozzo "We also identify Spi1 as a common downstream target gene of Etv2 and Gata2. We provide evidence that Etv2 and Gata2 bind to the Spi1 promoter in vitro and in vivo. Etv2 and Gata2 synergistically transactivate Spi1 gene expression." SIGNOR-256007 GATA2 protein P23769 UNIPROT PPARG protein P37231 UNIPROT "down-regulates activity" 9606 20510530 t fferrentino "GATA2 interacts directly with PPARG and C/EBP a , which may deplete PPARG involved in the promotion of adipogenesis" SIGNOR-132949 GATA2 protein P23769 UNIPROT PPARG protein P37231 UNIPROT "down-regulates quantity" "transcriptional regulation" 9606 19772889 t "These findings indicate that fatty marrow replacement in AA patients can be explained by downregulation of GATA-2 and overexpression of PPARgamma in MSCs. Decreased expression of GATA-2 might be responsible for the pathogenesis and development of the clinical features of the disease." SIGNOR-259949 GATA2 protein P23769 UNIPROT KLF1 protein Q13351 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 8195185 f irozzo "Regulation of the Erythroid Kruppel-like Factor (EKLF) Gene Promoter by the Erythroid Transcription Factor GATA-l.Accordingly,we have also demonstrated that GATA-2, like GATA-1, is able to activate the EKLF promoter in NIH3T3." SIGNOR-256052 GATA3 protein P23771 UNIPROT CD8A protein P01732 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 8413295 f miannu "Taken together, these results suggest that the human CD8 alpha gene is regulated by the interaction of multiple T-cell nuclear proteins with a transcriptional enhancer located in the last intron of the gene. Site-directed mutation of the Ets-1 and GATA-3 sites dramatically reduced enhancer activity." SIGNOR-254079 GATA3 protein P23771 UNIPROT IL4 protein P05112 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 12876556 f "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 GATA3 protein P23771 UNIPROT TBX21 protein Q9UL17 UNIPROT down-regulates 9606 16386358 f "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 RRM1 protein P23921 UNIPROT "Ribonucleotide reductase" complex SIGNOR-C233 SIGNOR "form complex" binding 9606 14583450 t miannu "Ribonucleotide reductase (RR) is responsible for the de novo conversion of the ribonucleoside diphosphates to deoxyribonucleoside diphosphates, which are essential for DNA synthesis and repair.RR consists of two subunits, hRRM1 and hRRM2." SIGNOR-259363 CMA1 protein P23946 UNIPROT EDN1 protein P05305 UNIPROT "up-regulates activity" cleavage Tyr83 TPEHVVPyGLGSPRS 9606 BTO:0000830 9257865 t miannu "Chymase from human mast cells selectively cleaved big endothelins (ETs) at the Tyr31-Gly32 bond and produced novel trachea-constricting 31-amino acid-length endothelins, ETs(1-31), without any further degradation products." SIGNOR-256356 CMA1 protein P23946 UNIPROT EDN3 protein P14138 UNIPROT "up-regulates activity" cleavage Tyr127 TPEQTVPyGLSNYRG 9606 BTO:0000830 9257865 t miannu "Chymase from human mast cells selectively cleaved big endothelins (ETs) at the Tyr31-Gly32 bond and produced novel trachea-constricting 31-amino acid-length endothelins, ETs(1-31), without any further degradation products." SIGNOR-256355 PRTN3 protein P24158 UNIPROT F2R protein P25116 UNIPROT "down-regulates activity" cleavage Pro54 NPNDKYEpFWEDEEK -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site." SIGNOR-263578 CCND1 protein P24385 UNIPROT CDK4 protein P11802 UNIPROT up-regulates binding 9606 7736585 t gcesareni "D-type cyclins (cyclin d1, d2, or d3) and their associated cyclin-dependent kinases (cdk4, cdk6) connect signals from cytokines to the cell cycle machinery, and they propel cells through the g1 restriction point and into the s phase when activated by cyclin d1, cdk4 is able to phosphorylate prb," SIGNOR-32295 3a protein P59632 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" 9606 BTO:0001950 18632968 f Luana "Severe Acute Respiratory Syndrome Coronavirus 3a Protein Activates the Mitochondrial Death Pathway Through p38 MAP Kinase Activation" SIGNOR-260444 PRTN3 protein P24158 UNIPROT F2R protein P25116 UNIPROT "down-regulates activity" cleavage Val72 GLTEYRLvSINKSSP -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site." SIGNOR-263579 PRTN3 protein P24158 UNIPROT F2R protein P25116 UNIPROT "up-regulates activity" cleavage Ala36 PESKATNaTLDPRSF -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus" SIGNOR-263575 PRTN3 protein P24158 UNIPROT F2RL1 protein P55085 UNIPROT "down-regulates activity" cleavage Asp62 VETVFSVdEFSASVL -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3" SIGNOR-263593 PRTN3 protein P24158 UNIPROT F2RL1 protein P55085 UNIPROT "down-regulates activity" cleavage Lys72 SASVLTGkLTTVFLP -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3" SIGNOR-263594 PRTN3 protein P24158 UNIPROT F2RL1 protein P55085 UNIPROT "down-regulates activity" cleavage Thr57 GKGVTVEtVFSVDEF -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3" SIGNOR-263595 PRTN3 protein P24158 UNIPROT F2RL1 protein P55085 UNIPROT "down-regulates activity" cleavage Thr74 SVLTGKLtTVFLPIV -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3" SIGNOR-263596 PRTN3 protein P24158 UNIPROT F2RL1 protein P55085 UNIPROT "down-regulates activity" cleavage Thr75 VLTGKLTtVFLPIVY -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3" SIGNOR-263597 PRTN3 protein P24158 UNIPROT F2RL1 protein P55085 UNIPROT "down-regulates activity" cleavage Val76 LTGKLTTvFLPIVYT -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3" SIGNOR-263601 CCND1 protein P24385 UNIPROT HDAC3 protein O15379 UNIPROT up-regulates binding 9606 15713663 t gcesareni "Collectively, these studies suggest an important role of cyclin d1 in regulation of ppargamma-mediated adipocyte differentiation through recruitment of hdacs to regulate ppar response element local chromatin structure and ppargamma function." SIGNOR-134056 CCND1 protein P24385 UNIPROT MSI1 protein O43347 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150 BTO:0000149 20443831 f gcesareni "We hypothesized that cyclin d1 may induce notch1 activity either by repressing numb or by inducing musashi 1 expression" SIGNOR-165186 CCND1 protein P24385 UNIPROT CDK4 protein P11802 UNIPROT up-regulates binding 9606 BTO:0000150 23562856 t gcesareni "D-type cyclins (cyclin d1, d2, or d3) and their associated cyclin-dependent kinases (cdk4, cdk6) connect signals from cytokines to the cell cycle machinery, and they propel cells through the g1 restriction point and into the s phase when activated by cyclin d1, cdk4 is able to phosphorylate prb," SIGNOR-201666 MAPK3 protein P27361 UNIPROT SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1193 QPTSKAYsPRYSISD 9606 8816480 t gcesareni "In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1" SIGNOR-43951 CCND1 protein P24385 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates 9606 BTO:0000150 BTO:0000149 20443831 f gcesareni "The mechanism by which cyclin d1 enhances notch1 activity in different cell types remains to be determined;the current studies demonstrate for the first time that notch1 activity is induced by cyclin d1. The expression of cyclin d1 sirna reduced notch1 activity." SIGNOR-165189 CCND1 protein P24385 UNIPROT HDAC2 protein Q92769 UNIPROT up-regulates binding 9606 15713663 t gcesareni "Cyclin d1 bound hdac in vivo and preferentially physically associated with hdac1, hdac2, hdac3, and hdac5." SIGNOR-134053 CHM protein P24386 UNIPROT RABGGTA protein Q92696 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 18532927 t miannu "Prenylation (or geranylgeranylation) of Rab GTPases is catalysed by RGGT (Rab geranylgeranyl transferase) and requires REP (Rab escort protein). In the classical pathway, REP associates first with unprenylated Rab, which is then prenylated by RGGT. In the alternative pathway, REP associates first with RGGT; this complex then binds and prenylates Rab proteins." SIGNOR-265570 IL4R protein P24394 UNIPROT JAK2 protein O60674 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000801 18852293 t 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 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 t 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 IL4R protein P24394 UNIPROT JAK1 protein P23458 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000801 23124025 t 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 IL4R protein P24394 UNIPROT IL2RG protein P31785 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000801;BTO:0000876 BTO:0000887;BTO:0000763;BTO:0001260 12704343 t milica "The type i il-4 receptors result from association of IL-4R With the common ? Chain (?c), which is also a component of the receptors for il-2, il-7, il-9, and il-15." SIGNOR-100765 IL4R protein P24394 UNIPROT IL2RG protein P31785 UNIPROT up-regulates binding 9606 8266078 t gcesareni "Il-2r gamma was demonstrated to be a component of the il-4 receptor on the basis of chemical cross-linking data, the ability of il-2r gamma to augment il-4 binding affinity, and the requirement for il-2r gamma in il-4-mediated phosphorylation of insulin receptor substrate-1." SIGNOR-37362 IL4R protein P24394 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation 9606 BTO:0000782;BTO:0000801;BTO:0000876 BTO:0000887;BTO:0000763;BTO:0001260 12704343 t milica "Irs-1 and a homologous protein, irs-2 (also known as 4-phosphotyrosine substrate), are recruited to phosphorylated y497 of IL-4R After ligand binding, leading to phosphorylation and activation of irs-1 and irs-2." SIGNOR-100768 IL4R protein P24394 UNIPROT STAT5A protein P42229 UNIPROT up-regulates 9606 20824124 t "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 IL4R protein P24394 UNIPROT JAK3 protein P52333 UNIPROT up-regulates 9606 BTO:0000776 7538655 f gcesareni "The overlapping and distinct protein tyrosine phosphorylation and activation of the same jak1 kinase in t lymphocytes strongly suggests that il-4 and il-9 share the common signal transduction pathways." SIGNOR-28399 IL4R protein P24394 UNIPROT IRS2 protein Q9Y4H2 UNIPROT up-regulates phosphorylation 9606 BTO:0000782;BTO:0000801;BTO:0000876 BTO:0000887;BTO:0000763;BTO:0001260 12704343 t milica "Irs-1 and a homologous protein, irs-2 (also known as 4-phosphotyrosine substrate), are recruited to phosphorylated y497 of IL-4R After ligand binding, leading to phosphorylation and activation of irs-1 and irs-2." SIGNOR-100771 NR2F2 protein P24468 UNIPROT NR3C1 protein P04150 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 14739255 f gcesareni "Gralpha, but not grbeta, enhanced coup-tfii-induced transactivation of the simple coup-tfii-responsive 7alpha-hydroxylase promoter through the transcriptional activity of its activation function-1 domain, whereas coup-tfii repressed gralpha-induced transactivation of the glucocorticoid-responsive promoter by attracting the silencing mediator for retinoid and thyroid hormone receptors." SIGNOR-121419 NR2F2 protein P24468 UNIPROT NR2F1 protein P10589 UNIPROT up-regulates binding 9606 10900149 t gcesareni "Arp-1/rxr, coup-tfi/rxr, and arp-1/coup-tfi heterodimers bound the fp330-3' site." SIGNOR-79443 NR2F2 protein P24468 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates binding 9606 9826778 t gcesareni "The orphan nuclear receptor, coup-tf ii, inactivates myogenesis by post-transcriptional regulation of myod function: coup-tf ii directly interacts with p300 and myod." SIGNOR-62248 NR2F2 protein P24468 UNIPROT RXRA protein P19793 UNIPROT up-regulates binding 9606 10900149 t lperfetto "Arp-1/rxr, coup-tfi/rxr, and arp-1/coup-tfi heterodimers bound the fp330-3' site" SIGNOR-79446 GADD45A protein P24522 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates binding 9606 BTO:0000782 15735649 t gcesareni "Both phosphorylation of p38 ty323 and the activity of this phosphorylated species are inhibited by binding gadd45alpha, thus preventing these low-treshold signals from activating p38" SIGNOR-134333 EDNRB protein P24530 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257166 EDNRB protein P24530 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257254 EDNRB protein P24530 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257321 EDNRB protein P24530 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256924 EDNRB protein P24530 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257379 AKAP5 protein P24588 UNIPROT PRKACA protein P17612 UNIPROT "up-regulates activity" relocalization 10116 10939335 t "In this report, we demonstrate that glutamate receptors and PKA are recruited into a macromolecular signaling complex through direct interaction between the MAGUK proteins, PSD-95 and SAP97, and AKAP79/150" SIGNOR-261292 AKAP5 protein P24588 UNIPROT PPP3CC protein P48454 UNIPROT "up-regulates activity" relocalization 10116 BTO:0004553 20694001 t "Using a viral-mediated molecular replacement strategy in rat hippocampal slices, we found that AKAP is required for NMDA receptor-dependent long-term depression solely because of its interaction with calcineurin" SIGNOR-261291 ACP1 protein P24666 UNIPROT PDGFRB protein P09619 UNIPROT "down-regulates activity" dephosphorylation Tyr857 DIMRDSNyISKGSTF 9606 12149261 t "Insight into the role of low molecular weight phosphotyrosine phosphatase (LMW-PTP) on platelet-derived growth factor receptor (PDGF-r) signaling. LMW-PTP controls PDGF-r kinase activity through TYR-857 dephosphorylation|On the basis of these results, we propose a key role for LMW-PTP in PDGF-r down-regulation through the dephosphorylation of the activation loop Tyr-857, thus determining a general negative regulation of all downstream signals, with the exception of those elicited by internalized receptors." SIGNOR-248452 ACP1 protein P24666 UNIPROT SRC protein P12931 UNIPROT "down-regulates activity" dephosphorylation Tyr419 RLIEDNEyTARQGAK 10090 "phosphorylation: tyr530" FTSTEPQyQPGENL 19088431 t "LMWPTP dephosphorylated pY(527)-Src and pY(416)-Src in vitro, with greater specificity for pY(527)Src. Activation of LMWPTP produced strong activation of Src mediated by fast dephosphorylation of pY(527)-Src, followed by slower deactivation of this kinase via dephosphorylation of pY(416)Src." SIGNOR-248453 ACP1 protein P24666 UNIPROT SRC protein P12931 UNIPROT "up-regulates activity" dephosphorylation Tyr530 FTSTEPQyQPGENL 10090 19088431 t "LMWPTP dephosphorylated pY(527)-Src and pY(416)-Src in vitro, with greater specificity for pY(527)Src. Activation of LMWPTP produced strong activation of Src mediated by fast dephosphorylation of pY(527)-Src, followed by slower deactivation of this kinase via dephosphorylation of pY(416)Src." SIGNOR-248454 ACP1 protein P24666 UNIPROT EPHA2 protein P29317 UNIPROT "down-regulates activity" dephosphorylation Tyr575 RQSPEDVyFSKSEQL -1 21538645 t gcesareni "The SAM domain tyrosine Y960 which has been implicated in downstream PI3K signaling is dephosphorylated exclusively by HCPTP-B. The activation loop tyrosine (Y772) which directly controls kinase activity is dephosphorylated about six times faster by HCPTP-A. In contrast, the juxtamembrane tyrosines (Y575, Y588 and Y594) which are implicated in both control of kinase activity and downstream signaling are dephosphorylated by both variants with similar rates" SIGNOR-246031 ACP1 protein P24666 UNIPROT EPHA2 protein P29317 UNIPROT "down-regulates activity" dephosphorylation Tyr588 QLKPLKTyVDPHTYE -1 21538645 t gcesareni "The SAM domain tyrosine Y960 which has been implicated in downstream PI3K signaling is dephosphorylated exclusively by HCPTP-B. The activation loop tyrosine (Y772) which directly controls kinase activity is dephosphorylated about six times faster by HCPTP-A. In contrast, the juxtamembrane tyrosines (Y575, Y588 and Y594) which are implicated in both control of kinase activity and downstream signaling are dephosphorylated by both variants with similar rates" SIGNOR-246035 ACP1 protein P24666 UNIPROT EPHA2 protein P29317 UNIPROT "down-regulates activity" dephosphorylation Tyr594 TYVDPHTyEDPNQAV -1 21538645 t gcesareni "The SAM domain tyrosine Y960 which has been implicated in downstream PI3K signaling is dephosphorylated exclusively by HCPTP-B. The activation loop tyrosine (Y772) which directly controls kinase activity is dephosphorylated about six times faster by HCPTP-A. In contrast, the juxtamembrane tyrosines (Y575, Y588 and Y594) which are implicated in both control of kinase activity and downstream signaling are dephosphorylated by both variants with similar rates" SIGNOR-246039 ACP1 protein P24666 UNIPROT EPHA2 protein P29317 UNIPROT "down-regulates activity" dephosphorylation Tyr960 GHQKRIAySLLGLKD -1 21538645 t gcesareni "The SAM domain tyrosine Y960 which has been implicated in downstream PI3K signaling is dephosphorylated exclusively by HCPTP-B. The activation loop tyrosine (Y772) which directly controls kinase activity is dephosphorylated about six times faster by HCPTP-A. In contrast, the juxtamembrane tyrosines (Y575, Y588 and Y594) which are implicated in both control of kinase activity and downstream signaling are dephosphorylated by both variants with similar rates" SIGNOR-246023 CCNE1 protein P24864 UNIPROT CDK2 protein P24941 UNIPROT up-regulates binding 9606 23437375 t gcesareni "Our results suggest that ad-induced cyclin e activates cdk2 that targets the transcriptional repressor prb/cyclin e activates the cdk2 kinase necessary for the actual initiation of dna replication" SIGNOR-201506 ACP1 protein P24666 UNIPROT AKT2 protein P31751 UNIPROT "down-regulates activity" dephosphorylation Ser474 RTHFPQFsYSASIRE 10090 17353188 t "Reduction in the levels of both LMW-PTP isoforms in vitro and in vivo increased tyrosine phosphorylation of IR and AktSer473 and increased IRS-1- and IRS-2-associated PI3-K activities in both liver and fat.|Activated PI3-K stimulates Akt (or protein kinase B) that in turn phosphorylates and inactivates glycogen synthase kinase-3" SIGNOR-248456 ACP1 protein P24666 UNIPROT AKT3 protein Q9Y243 UNIPROT "down-regulates activity" dephosphorylation Ser472 RPHFPQFsYSASGRE 10090 17353188 t "Reduction in the levels of both LMW-PTP isoforms in vitro and in vivo increased tyrosine phosphorylation of IR and AktSer473 and increased IRS-1- and IRS-2-associated PI3-K activities in both liver and fat.|Activated PI3-K stimulates Akt (or protein kinase B) that in turn phosphorylates and inactivates glycogen synthase kinase-3" SIGNOR-248457 ACP1 protein P24666 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" dephosphorylation 10090 17353188 t "Reduction in the levels of both LMW-PTP isoforms in vitro and in vivo increased tyrosine phosphorylation of IR and AktSer473 and increased IRS-1- and IRS-2-associated PI3-K activities in both liver and fat.|Activated PI3-K stimulates Akt (or protein kinase B) that in turn phosphorylates and inactivates glycogen synthase kinase-3" SIGNOR-248458 PRKCH protein P24723 UNIPROT ANXA1 protein P04083 UNIPROT up-regulates phosphorylation Ser27 EYVQTVKsSKGGPGS 9606 24103589 t lperfetto "The authors identified several phosphorylated residues by a combination of peptide mapping and sequence analysis and showed that recombinant pp60c-src phosphorylates annexin a1 near its amino terminus, at tyrosine 21 (tyr21). Also polyoma virus middle t/pp60c-src complex, recombinant pp50v-abl, and the egf receptor/kinase phosphorylated the same tyrosine residue. It was also shown that serine 27 residue of anxa1 is the primary site phosphorylated by protein kinase c (pkc). In the same study, the threonine 41 residue has been identified as a pkc substrate as well. The adenosine cyclic 3_,5_-phosphate dependent protein kinase a (pka) phosphorylates anxa1 in its carboxyl-terminal core at the threonine 216 residue (thr216) [2].The phosphorylation of serine 27 is essential for annexin a1 membrane localization." SIGNOR-202792 PRKCH protein P24723 UNIPROT ITGB2 protein P05107 UNIPROT unknown phosphorylation Ser745 FEKEKLKsQWNNDNP 9606 BTO:0000751 11700305 t lperfetto "Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. |" SIGNOR-249118 PRKCH protein P24723 UNIPROT ITGB2 protein P05107 UNIPROT unknown phosphorylation Thr758 NPLFKSAtTTVMNPK 9606 BTO:0000751 11700305 t lperfetto "Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. |" SIGNOR-249123 PRKCH protein P24723 UNIPROT MAPK1 protein P28482 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000093 28939105 t miannu "Protein kinase C-eta regulates Mcl-1 level via ERK1. knockdown of PKCη but not PKCα, -δ or -ε caused a significant decrease in ERK (extracellular signal-regulated kinase) phosphorylation. Knockdown of ERK1 but not ERK2 decreased Mcl-1 level, and the decrease in Mcl-1 caused by PKCη knockdown was restored by ERK1 overexpression. These results suggest that PKCη utilizes the ERK signaling pathway to protect against ubiquitin-mediated proteasomal degradation of Mcl-1." SIGNOR-261910 PRKCH protein P24723 UNIPROT NOS3 protein P29474 UNIPROT "down-regulates activity" phosphorylation Thr495 TGITRKKtFKEVANA 9606 BTO:0001853 24379783 t lperfetto "The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites" SIGNOR-251634 PRKCH protein P24723 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates phosphorylation Ser876 QGLAERIsVL 9606 12058027 t gcesareni "Thus, pkd2 is likely to be a novel downstream target of specific pkcs upon the stimulation of ags-b cells with gastrin. Our data suggest a two-step mechanism of activation of pkd2 via endogenously produced diacylglycerol and the activation of pkcs." SIGNOR-89431 TNC protein P24821 UNIPROT "A8/b1 integrin" complex SIGNOR-C165 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 7559467 t lperfetto "The human integrin alpha 8 beta 1 functions as a receptor for tenascin, fibronectin, and vitronectin." SIGNOR-253306 TNC protein P24821 UNIPROT "A9/b1 integrin" complex SIGNOR-C166 SIGNOR "up-regulates activity" binding 9606 BTO:0000801;BTO:0001336 24241034 t 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 CCNC protein P24863 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates phosphorylation 9606 15546612 t "Leads to a following ubiquitination and degradation" gcesareni "Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo." SIGNOR-130592 CCNC protein P24863 UNIPROT HES1 protein Q14469 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15546612 f gcesareni "Cycc:cdk8 and cyct1:cdk9/p-tefb are recruited with notch and associated coactivators (mam, skip) to the hes1 promoter in signaling cells." SIGNOR-130589 CCNC protein P24863 UNIPROT "CKM complex" complex SIGNOR-C406 SIGNOR "form complex" binding 9606 23563140 t miannu "The CDK8 kinase module (CKM) is a conserved, dissociable Mediator subcomplex whose component subunits were genetically linked to the RNA polymerase II (RNAPII) C-terminal domain (CTD) and individually recognized as transcriptional repressors before Mediator was identified as a pre-eminent complex in eukaryotic transcription regulation." SIGNOR-266685 CCNC protein P24863 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates phosphorylation 9606 15546612 t "Leads to a following ubiquitination and degradation" gcesareni "Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo." SIGNOR-254309 3b protein P59633 UNIPROT MAP2K4 protein P45985 UNIPROT "up-regulates activity" 9606 21561061 f Luana "An enhanced phosphorylation of JNK and MEK4 was observed in cells expressing 3b ascompared to control cells expressing GFP" SIGNOR-260761 POLR2A protein P24928 UNIPROT "RNA Polymerase II" complex SIGNOR-C391 SIGNOR "form complex" binding 9606 BTO:0000567 9852112 t lperfetto "Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II" SIGNOR-266160 CDK2 protein P24941 UNIPROT TP73 protein O15350 UNIPROT "down-regulates activity" phosphorylation Thr86 AASASPYtPEHAASV 9606 SIGNOR-C16 12676926 t gcesareni "Cyclin-dependent kinases phosphorylate p73 at threonine 86 in a cell cycle-dependent manner and negatively regulate p73.Furthermore, cyclin a/cdk1/2, cyclin b/cdk1/2, and cyclin e/cdk2 complexes can phosphorylate multiple p73 isoforms in vitro at threonine 86." SIGNOR-99746 CDK2 protein P24941 UNIPROT CCP110 protein O43303 UNIPROT "down-regulates activity" phosphorylation Ser170 RDSEGFNsPKQCDSS -1 12361598 t miannu "GST-tagged recombinant CP110 (GST-wt) was robustly phosphorylated by cyclin E/CDK2 (Figure 2A). Expression of a mutant derivative of CP110 refractory to CDK phosphorylation provokes marked polyploidy. We localized the majority (nine of ten) of potential CDK2 phosphorylation sites in CP110 to an amino-terminal fragment (GST-ΔN1; Figure 1B)" SIGNOR-265958 CDK2 protein P24941 UNIPROT CCP110 protein O43303 UNIPROT "down-regulates activity" phosphorylation Ser400 PINACELsPKGKEQA -1 12361598 t miannu "GST-tagged recombinant CP110 (GST-wt) was robustly phosphorylated by cyclin E/CDK2 (Figure 2A). Expression of a mutant derivative of CP110 refractory to CDK phosphorylation provokes marked polyploidy. We localized the majority (nine of ten) of potential CDK2 phosphorylation sites in CP110 to an amino-terminal fragment (GST-ΔN1; Figure 1B)" SIGNOR-265956 CDK2 protein P24941 UNIPROT CCP110 protein O43303 UNIPROT "down-regulates activity" phosphorylation Ser45 FHGVAILsPLLNIEK -1 12361598 t miannu "GST-tagged recombinant CP110 (GST-wt) was robustly phosphorylated by cyclin E/CDK2 (Figure 2A). Expression of a mutant derivative of CP110 refractory to CDK phosphorylation provokes marked polyploidy. We localized the majority (nine of ten) of potential CDK2 phosphorylation sites in CP110 to an amino-terminal fragment (GST-ΔN1; Figure 1B)" SIGNOR-265957 CDK2 protein P24941 UNIPROT CCP110 protein O43303 UNIPROT "down-regulates activity" phosphorylation Thr566 NTRQQMDtPMVSCGN -1 12361598 t miannu "GST-tagged recombinant CP110 (GST-wt) was robustly phosphorylated by cyclin E/CDK2 (Figure 2A). Expression of a mutant derivative of CP110 refractory to CDK phosphorylation provokes marked polyploidy. We localized the majority (nine of ten) of potential CDK2 phosphorylation sites in CP110 to an amino-terminal fragment (GST-ΔN1; Figure 1B)" SIGNOR-265959 CDK2 protein P24941 UNIPROT MCM3AP protein O60318 UNIPROT "up-regulates activity" phosphorylation Ser508 FWHRKKIsPNKKPFS 10090 BTO:0000776 11526238 t miannu "To study the inducible regulation of GANP DNA-primase during cell activation, we examined phosphorylation induced by various kinds of kinases.We observed that the cell cycle-associated kinase Cdks induced phosphorylation of GANP in vitro. Examination of immunoprecipitates of Cdk2 from B cells revealed phosphorylation of GANP-PD at a consensus sequence of Cdk phosphorylation at Ser502 (S/T-P-X-K/R) (Fig. ​(Fig.1C1C Left; ref. 22)." SIGNOR-262734 CDK2 protein P24941 UNIPROT SF3B1 protein O75533 UNIPROT up-regulates phosphorylation Thr248 GSETPGAtPGSKIWD 9606 SIGNOR-C16 12105215 t gcesareni "To map the set of phosphorylation sites in sap155-(223-322) that determine its interaction with nipp1, we have identified phosphorylation sites of cyclin e-cdk2 by the sequencing of proteolytically derived phosphopeptides. Three phosphorylation sites were identified as thr244, thr248, and thr313" SIGNOR-90438 CDK2 protein P24941 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser104 FPPLNSVsPSPLMLL 9606 SIGNOR-C83 10428798 t gcesareni "Within er af-1, serines 104, 106, and 118 represent potential cdk phosphorylation sites, and in this current study, we ascertain their importance in mediating cyclin a-cdk2-dependent enhancement of er transcriptional activity." SIGNOR-69710 CDK2 protein P24941 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser106 PLNSVSPsPLMLLHP 9606 SIGNOR-C83 10428798 t gcesareni "Within er af-1, serines 104, 106, and 118 represent potential cdk phosphorylation sites, and in this current study, we ascertain their importance in mediating cyclin a-cdk2-dependent enhancement of er transcriptional activity." SIGNOR-69714 CDK2 protein P24941 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 SIGNOR-C83 10428798 t gcesareni "Within er af-1, serines 104, 106, and 118 represent potential cdk phosphorylation sites, and in this current study, we ascertain their importance in mediating cyclin a-cdk2-dependent enhancement of er transcriptional activity." SIGNOR-69718 CDK2 protein P24941 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser294 RAANLWPsPLMIKRS 9606 BTO:0000150 23390529 t lperfetto "The pi3k/akt pathway is necessary to activate cdk2, which phosphorylates eralphaser294, and mediates the binding between pin1 and eralpha" SIGNOR-200867 CDK2 protein P24941 UNIPROT NR3C1 protein P04150 UNIPROT "up-regulates activity" phosphorylation Ser203 DLEFSSGsPGKETNE -1 9199329 t lperfetto "Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232.|MAPKs and CDKs exert opposite effects on receptor transcriptional enhancement. From our results, we speculate that activators of the MAPK pathway, such as growth factors, insulin, and certain oncoproteins, or inhibitors of CDK function, such as tumor growth factor beta (TGF_), p21, and p27, might attenuate receptor-induced transcrip- tional responses. In contrast, negative regulators of MAPK, such as pKA, as well as activators of CDK, such as the cyclins or CAKs, should potentiate receptor action." SIGNOR-249426 CDK2 protein P24941 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" phosphorylation Ser315 LPNNTSSsPQPKKKP 9606 SIGNOR-C83 24173284 t lperfetto "The N-terminus of E2F1 can interact directly with a region towards the C-terminus of p53, resulting in increased nuclear retention of p53 and p53-mediated transcription and apoptosis. This is inhibited by competition between p53 and cyclin A at the binding site within E2F19,10. The interaction between p53 and E2F1 is enhanced by phosphorylation of p53 on Ser315, a residue within the E2F1 binding region that is phosphorylated by cell cycle kinases such as cdk1, cdk2, cdk9 and Aurora kinase A" SIGNOR-119379 CDK2 protein P24941 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C16 21902831 t gcesareni "Cycline/cdk2 blocks myod-induced gene expression through the phosphorylation of rb, preventing rb from binding and transactivating myod, and triggering s phase entry instead of differentiation." SIGNOR-176512 CDK2 protein P24941 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Thr821 KISEGLPtPTKMTPR 9606 SIGNOR-C83 9139732 t miannu "We demonstrate that phosphorylation by either cdk2-cyclin a, which phosphorylates t821, or cdk4-cyclin d1, which phosphorylates threonine 826, can disable prb for subsequent binding of an lxcxe protein." SIGNOR-47895 CDK2 protein P24941 UNIPROT PGR protein P06401 UNIPROT down-regulates phosphorylation Ser294 APMAPGRsPLATTVM 9606 BTO:0000150 10655479 t miannu "Phosphorylation of human progesterone receptors at serine-294 by mitogen-activated protein kinase signals their degradation by the 26s proteasome" SIGNOR-74708 CDK2 protein P24941 UNIPROT PGR protein P06401 UNIPROT unknown phosphorylation Ser20 HVAGGPPsPEVGSPL 9606 11110801 t llicata "In vitro phosphorylation of pr with cdk2 has revealed five additional in vitro cdk2 phosphorylation sites: ser(25), ser(213), thr(430), ser(554), and ser(676)." SIGNOR-84980 CDK2 protein P24941 UNIPROT PGR protein P06401 UNIPROT unknown phosphorylation Ser213 SGAPVKPsPQAAAVE 9606 11110801 t llicata "In vitro phosphorylation of pr with cdk2 has revealed five additional in vitro cdk2 phosphorylation sites: ser(25), ser(213), thr(430), ser(554), and ser(676)." SIGNOR-84984 CDK2 protein P24941 UNIPROT PGR protein P06401 UNIPROT unknown phosphorylation Ser25 PPSPEVGsPLLCRPA 9606 11110801 t llicata "In vitro phosphorylation of pr with cdk2 has revealed five additional in vitro cdk2 phosphorylation sites: ser(25), ser(213), thr(430), ser(554), and ser(676)." SIGNOR-84988 CDK2 protein P24941 UNIPROT PGR protein P06401 UNIPROT unknown phosphorylation Ser554 PDSEASQsPQYSFES 9606 11110801 t llicata "In vitro phosphorylation of pr with cdk2 has revealed five additional in vitro cdk2 phosphorylation sites: ser(25), ser(213), thr(430), ser(554), and ser(676)." SIGNOR-84992 CDK2 protein P24941 UNIPROT PGR protein P06401 UNIPROT unknown phosphorylation Ser676 LSQRFTFsPGQDIQL 9606 11110801 t llicata "In vitro phosphorylation of pr with cdk2 has revealed five additional in vitro cdk2 phosphorylation sites: ser(25), ser(213), thr(430), ser(554), and ser(676)." SIGNOR-84996 CDK2 protein P24941 UNIPROT PGR protein P06401 UNIPROT unknown phosphorylation Thr430 PPLPPRAtPSRPGEA 9606 11110801 t llicata "In vitro phosphorylation of pr with cdk2 has revealed five additional in vitro cdk2 phosphorylation sites: ser(25), ser(213), thr(430), ser(554), and ser(676)." SIGNOR-85000 CDK2 protein P24941 UNIPROT NPM1 protein P06748 UNIPROT "down-regulates activity" phosphorylation Thr234 SFKKQEKtPKTPKGP 9606 SIGNOR-C16 12058066 t gcesareni "Both subtypes of B23 proteins were phosphorylated during mitosis by cyclin B/cdc2. The RNA binding activity of B23.1 was repressed through cyclin B/cdc2-mediated phosphorylation at specific sites in B23. Thus, the RNA binding activity of B23.1 is stringently modulated by its phosphorylation and subtype association." SIGNOR-89609 CDK2 protein P24941 UNIPROT NPM1 protein P06748 UNIPROT unknown phosphorylation Ser70 EAMNYEGsPIKVTLA 9606 BTO:0001271 19933706 t gcesareni "Simultaneous inactivation of two cdk phosphorylation sites at ser10 and ser70 (npm-aa) induced g(2)/m cell cycle arrest, phosphorylation of cdk1 at tyr15 (cdc2(tyr15)) and increased cytoplasmic accumulation of cdc25c." SIGNOR-161805 CDK2 protein P24941 UNIPROT SP1 protein P08047 UNIPROT "up-regulates activity" phosphorylation Ser59 GGQESQPsPLALLAA 10090 BTO:0000944 11598016 t gcesareni "Mutation of Sp1 Ser59 abrogates the cyclin A€“CDK augmentation of Sp1-dependent transcriptional transactivation" SIGNOR-248232 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates phosphorylation Ser577 RKPGLRRsPIKKVRK 9606 SIGNOR-C83 9840932 t lperfetto "The cell-cycle regulated transcription factor b-myb is phosphorylated by cyclin a/cdk2 at sites that enhance its transactivation properties. we show that b-myb is phosphorylated at thr447, thr490, thr497 and ser581 by cyclin a/cdk5" SIGNOR-62353 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates phosphorylation Thr444 NSLTPKStPVKTLPF 9606 SIGNOR-C83 9840932 t lperfetto "The cell-cycle regulated transcription factor b-myb is phosphorylated by cyclin a/cdk2 at sites that enhance its transactivation properties. we show that b-myb is phosphorylated at thr447, thr490, thr497 and ser581 by cyclin a/cdk3" SIGNOR-62357 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates phosphorylation Thr487 SQKVVVTtPLHRDKT 9606 SIGNOR-C83 9840932 t lperfetto "The cell-cycle regulated transcription factor b-myb is phosphorylated by cyclin a/cdk2 at sites that enhance its transactivation properties. we show that b-myb is phosphorylated at thr447, thr490, thr497 and ser581 by cyclin a/cdk2" SIGNOR-62361 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates phosphorylation Thr494 TPLHRDKtPLHQKHA 9606 SIGNOR-C83 9840932 t lperfetto "The cell-cycle regulated transcription factor b-myb is phosphorylated by cyclin a/cdk2 at sites that enhance its transactivation properties. we show that b-myb is phosphorylated at thr447, thr490, thr497 and ser581 by cyclin a/cdk4" SIGNOR-62365 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT "up-regulates activity" phosphorylation Ser393 RGELIPIsPSTEVGG BTO:0000007 10593981 t llicata "Ten phosphorylation sites carboxyl-terminal to the DNA-binding domain were identified by this method: threonines at positions 267, 408, 497, 519, 522, and 524 and serines at positions 283, 396, 455, and 581. | Our results indicate that B-Myb can be phosphorylated in a cell-free system by both cyclin A-Cdk2 and cyclin E-Cdk2 complexes. | These data suggest that B-Myb is a target for phosphorylation by cyclin-Cdk2 and that phosphorylation of B-Myb regulates its transcriptional activity." SIGNOR-250734 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT "up-regulates activity" phosphorylation Ser452 PVKTLPFsPSQFLNF BTO:0000007 10593981 t llicata "Ten phosphorylation sites carboxyl-terminal to the DNA-binding domain were identified by this method: threonines at positions 267, 408, 497, 519, 522, and 524 and serines at positions 283, 396, 455, and 581. | Our results indicate that B-Myb can be phosphorylated in a cell-free system by both cyclin A-Cdk2 and cyclin E-Cdk2 complexes. | These data suggest that B-Myb is a target for phosphorylation by cyclin-Cdk2 and that phosphorylation of B-Myb regulates its transcriptional activity." SIGNOR-250735 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT "up-regulates activity" phosphorylation Thr266 TDLDAVRtPEPLEEF BTO:0000007 10593981 t llicata "Ten phosphorylation sites carboxyl-terminal to the DNA-binding domain were identified by this method: threonines at positions 267, 408, 497, 519, 522, and 524 and serines at positions 283, 396, 455, and 581. | Our results indicate that B-Myb can be phosphorylated in a cell-free system by both cyclin A-Cdk2 and cyclin E-Cdk2 complexes. | These data suggest that B-Myb is a target for phosphorylation by cyclin-Cdk2 and that phosphorylation of B-Myb regulates its transcriptional activity." SIGNOR-250736 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT down-regulates phosphorylation Ser1112 LLEDGSEsPAKRICP 9606 BTO:0001938 12006580 t gcesareni "When expressed in u2os cells, the phosphorylation-deficient mutant p130(delta)(cdk4), in which the cdk4 specific sites were mutated to alanine residues, imposed a more sustained g1 arrest than a constitutively active prb(delta)(cdk), known to repress all cellular e2f activity" SIGNOR-87492 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT "up-regulates activity" phosphorylation Thr405 VGGSGIGtPPSVLKR BTO:0000007 10593981 t llicata "Ten phosphorylation sites carboxyl-terminal to the DNA-binding domain were identified by this method: threonines at positions 267, 408, 497, 519, 522, and 524 and serines at positions 283, 396, 455, and 581. | Our results indicate that B-Myb can be phosphorylated in a cell-free system by both cyclin A-Cdk2 and cyclin E-Cdk2 complexes. | These data suggest that B-Myb is a target for phosphorylation by cyclin-Cdk2 and that phosphorylation of B-Myb regulates its transcriptional activity." SIGNOR-250737 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT "up-regulates activity" phosphorylation Thr515 QKYSMDNtPHTPTPF BTO:0000007 10593981 t llicata "Ten phosphorylation sites carboxyl-terminal to the DNA-binding domain were identified by this method: threonines at positions 267, 408, 497, 519, 522, and 524 and serines at positions 283, 396, 455, and 581. | Our results indicate that B-Myb can be phosphorylated in a cell-free system by both cyclin A-Cdk2 and cyclin E-Cdk2 complexes. | These data suggest that B-Myb is a target for phosphorylation by cyclin-Cdk2 and that phosphorylation of B-Myb regulates its transcriptional activity." SIGNOR-250739 CDK2 protein P24941 UNIPROT PTHLH protein P12272 UNIPROT down-regulates phosphorylation Thr121 YKEQPLKtPGKKKKG 9606 10373465 t llicata "Phosphorylation at the cyclin-dependent kinases site (thr85) of parathyroid hormone-related protein negatively regulates its nuclear localization" SIGNOR-68548 CDK2 protein P24941 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates phosphorylation Ser200 YSGDSDAsSPRSNCS 9606 SIGNOR-C16 21902831 t gcesareni "Cyclin e/cdk2 can phosphorylate myod at serine 200, which causes ubiquitination and degradation of this transcription factor during g1, preventing its accumulation and a commitment to differentiation." SIGNOR-176509 CDK2 protein P24941 UNIPROT HMGA1 protein P17096 UNIPROT down-regulates phosphorylation Ser36 PRKQPPVsPGTALVG 9606 17960875 t gcesareni "Here, we found that hipk2 phosphorylates hmga1a at ser-35, thr-52, and thr-77, and hmga1b at thr-41 and thr-66. In addition, we demonstrated that cdc2, which is known to phosphorylate hmga1 proteins, could induce the phosphorylation of hmga1 proteins at the same ser/thr sites. we found that the hipk2-phosphorylated hmga1a reduced the binding affinity of hmga1a to human germ line promoter, and the drop in binding affinity induced by hipk2 phosphorylation was lower than that introduced by cdc2 phosphorylation." SIGNOR-158612 CDK2 protein P24941 UNIPROT UBTF protein P17480 UNIPROT "up-regulates activity" phosphorylation Ser389 INKKQATsPASKKPA 10090 BTO:0000944 SIGNOR-C16 11698641 t lperfetto "Phosphorylation of ubf at serine 388 is required for interaction with rna polymerase i and activation of rdna transcription. After g(1) progression ubf is phosphorylated at serine 388 by cdk2/cyclin e and cdk2/cyclin a. Conversion of serine 388 to glycine abolishes ubf activity" SIGNOR-235419 CDK2 protein P24941 UNIPROT CEBPB protein P17676 UNIPROT up-regulates phosphorylation Thr235 SSSSPPGtPSPADAK 9606 SIGNOR-C83 17601773 t fspada "Mass spectrometric analysis revealed that cdk2/cyclina phosphorylates c/ebpbeta on thr(188) and is required for phosphorylation (on ser(184) or thr(179)) of c/ebpbeta by gsk3beta and maintenance of dna binding activity." SIGNOR-156509 CDK2 protein P24941 UNIPROT CEBPB protein P17676 UNIPROT up-regulates phosphorylation Thr235 SSSSPPGtPSPADAK 9606 SIGNOR-C83 22369944 t fspada "Mass spectrometric analysis revealed that cdk2/cyclina phosphorylates c/ebpbeta on thr(188) and is required for phosphorylation (on ser(184) or thr(179)) of c/ebpbeta by gsk3beta and maintenance of dna binding activity." SIGNOR-196372 CDK2 protein P24941 UNIPROT PTPN2 protein P17706 UNIPROT unknown phosphorylation Ser304 LSPAFDHsPNKIMTE 9606 15030318 t llicata "Our studies identify ser-304 as a major phosphorylation site in human tcptp, and the tc45 variant as a novel mitotic cdk substrate." SIGNOR-123471 CDK2 protein P24941 UNIPROT LIG1 protein P18858 UNIPROT "up-regulates activity" phosphorylation Ser51 GVVSESDsPVKRPGR 9606 BTO:0000567 12851383 t lperfetto "Thus, phosphorylation of serine 51 on hligi plays a critical role in regulating the interaction between hligi and rfc, which is required for efficient dna replication and repair." SIGNOR-103246 CDK2 protein P24941 UNIPROT LIG1 protein P18858 UNIPROT "up-regulates activity" phosphorylation Ser76 EEEDEALsPAKGQKP 9606 BTO:0000567 12851383 t lperfetto "We show that three residues (ser51, ser76, and ser91), which are part of cyclin-dependent kinase sites, are phosphorylated in a cell cycle-dependent manner." SIGNOR-103250 CDK2 protein P24941 UNIPROT LIG1 protein P18858 UNIPROT "up-regulates activity" phosphorylation Ser91 ALDCSQVsPPRPATS 9606 BTO:0000567 12851383 t lperfetto "We show that three residues (ser51, ser76, and ser91), which are part of cyclin-dependent kinase sites, are phosphorylated in a cell cycle-dependent manner." SIGNOR-103254 CDK2 protein P24941 UNIPROT CCNA2 protein P20248 UNIPROT up-regulates phosphorylation Ser154 PMDGSFEsPHTMDMS 9606 10652300 t lperfetto "Here we present evidence from in vitro and in vivo assay systems that the degradation of human cyclin a can be inhibited by kinase-inactive mutants of cdk2 and cdc2cdk2 can phosphorylate cyclin a on ser-154" SIGNOR-74466 CDK2 protein P24941 UNIPROT CDK2 protein P24941 UNIPROT up-regulates phosphorylation Thr160 GVPVRTYtHEVVTLW 9606 17361108 t gcesareni "Our results demonstrate that cdk2 is capable of autophosphorylation at thr160." SIGNOR-153636 CDK2 protein P24941 UNIPROT GRK2 protein P25098 UNIPROT down-regulates phosphorylation Ser670 KMKNKPRsPVVELSK 9606 20080565 t gcesareni "We report that grk2 protein levels are transiently down-regulated during the g2/m transition by a mechanism involving cdk2-mediated phosphorylation of grk2 at serine670, which triggers binding to the prolyl-isomerase pin1 and subsequent degradation." SIGNOR-163279 CDK2 protein P24941 UNIPROT MCM3 protein P25205 UNIPROT up-regulates phosphorylation Thr722 EEMPQVHtPKTADSQ 9606 SIGNOR-C16 21965652 t gcesareni "In this study, we demonstrate that mcm3 is a substrate of cyclin e/cdk2 and can be phosphorylated by cyclin e/cdk2 at thr-722." SIGNOR-176656 CDK2 protein P24941 UNIPROT DNMT1 protein P26358 UNIPROT up-regulates phosphorylation Ser154 AKPEPSPsPRITRKS 9606 21565170 t gcesareni "We report that cyclin-dependent kinases (cdks) 1, 2 and 5 can phosphorylate ser154 of human dnmt1 in vitro. Further evidence of phosphorylation of endogenous dnmt1 at position 154 by cdks is also found in 293 cells treated with roscovitine, a specific inhibitor of cdk1, 2 and 5" SIGNOR-173681 CDK2 protein P24941 UNIPROT MCM4 protein P33991 UNIPROT "down-regulates activity" phosphorylation Ser32 RSEDARSsPSQRRRG 9606 BTO:0000567 SIGNOR-C83 12714602 t lperfetto "We reported that the dna helicase activity of the human and mouse mcm4-6-7 complex, a sub-complex of the mcm2-7 heterohexamer, is inhibited by the phosphorylation by cdk2-cyclin a we identified six sites, including ser-32, ser-53, and thr-109, in the amino-terminal region of mouse mcm4 that are required for the phosphorylation with cdk2-cyclin a." SIGNOR-100881 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser434 SFEPKIRsPRRFIGS 9606 21035469 t gcesareni "Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase" SIGNOR-169150 CDK2 protein P24941 UNIPROT MCM4 protein P33991 UNIPROT "down-regulates activity" phosphorylation Thr110 PRSGVRGtPVRQRPD 9606 BTO:0000567 SIGNOR-C83 12714602 t lperfetto "We reported that the dna helicase activity of the human and mouse mcm4-6-7 complex, a sub-complex of the mcm2-7 heterohexamer, is inhibited by the phosphorylation by cdk2-cyclin a we identified six sites, including ser-32, ser-53, and thr-109, in the amino-terminal region of mouse mcm4 that are required for the phosphorylation with cdk2-cyclin a." SIGNOR-100889 CDK2 protein P24941 UNIPROT MCM4 protein P33991 UNIPROT "down-regulates activity" phosphorylation Thr19 GSRRGRAtPAQTPRS 9606 BTO:0000567 12714602 t lperfetto "We report here that human mcm4, a subunit of the putative dna replicative helicase, is extensively phosphorylated in hela cells when they are incubated in the presence of inhibitors of dna synthesis or are exposed to uv irradiation. The data presented here indicate that the consecutive actions of atr-chk1 and cdk2 kinases are involved in this phosphorylation in the presence of hydroxyurea. Phosphorylation of t19 correlates with lowered level of dna helicase activity of the purified mcm4,6,7 complex." SIGNOR-100893 CDK2 protein P24941 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1497 EPGVERSsPSKCPSL 9606 BTO:0000551 19683496 t gcesareni "However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci." SIGNOR-187607 CDK2 protein P24941 UNIPROT CDKN1A protein P38936 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser130 SGEQAEGsPGGPGDS 9606 15964852 t lperfetto "Cdk2 destabilizes p21 via the cy2 cyclin-binding motif and p21 phosphorylation at ser-130." SIGNOR-149416 CDK2 protein P24941 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Thr187 NAGSVEQtPKKPGLR 9606 17409098 t gcesareni "Ubiquitination and subsequent degradation play a critical role in regulating the levels of p27 during cell cycle progression. Here we provide evidence suggesting that both cdk2/e and phosphorylation of thr(187) on p27 are essential for the recognition of p27 by the scf(skp2/cks1) complex, the ubiquitin-protein isopeptide ligase (e3)." SIGNOR-154188 CDK2 protein P24941 UNIPROT UBE2A protein P49459 UNIPROT up-regulates phosphorylation Ser120 LDEPNPNsPANSQAA 9606 11953320 t llicata "Hhr6a is phosphorylated in vitro by cdk-1 and -2 on ser120, a residue conserved in all hhr6a homologues, resulting in a 4-fold increase in its ubiquitin-conjugating activity." SIGNOR-116508 CDK2 protein P24941 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser13 ESFTMASsPAQRRRG 9606 16446360 t gcesareni "In this work, by in vitro kinase reactions and mass spectrometry analysis of the products, we have mapped phosphorylation sites in the n terminus of mcm2 by cdc7, cdk2, cdk1, and ck2" SIGNOR-144000 CDK2 protein P24941 UNIPROT LIG3 protein P49916 UNIPROT down-regulates phosphorylation Ser210 TTTGQVTsPVKGASF 9606 17040896 t llicata "Dna ligase iii_ is specifically phosphorylated in replicating cells by the cell cycle kinase cdk2. However, in response to oxidative dna damage, dna ligase iii_ is dephosphorylated in a pathway that is dependent upon the dna damage-activated, phosphatidylinositol 3-phosphate (pi3)1-related kinase atm." SIGNOR-150121 CDK2 protein P24941 UNIPROT CDK7 protein P50613 UNIPROT unknown phosphorylation Ser164 GLAKSFGsPNRAYTH 9606 11113184 t amattioni "Cdk2 phosphorylates serine-164 in the cdk7 t loop." SIGNOR-84832 CDK2 protein P24941 UNIPROT CDK7 protein P50613 UNIPROT up-regulates phosphorylation Thr170 GSPNRAYtHQVVTRW 9606 11113184 t amattioni "Threonine-170 of cdk7 is phosphorylated in vitro by cdk2. Full activation of cdk7 requires phorylation of a conserved threonine residue at position 170 in its own t loop." SIGNOR-85013 CDK2 protein P24941 UNIPROT HIRA protein P54198 UNIPROT "up-regulates activity" phosphorylation Thr555 LSPSVLTtPSKIEPM 9606 BTO:0001938 SIGNOR-C16 11238922 t lperfetto "Hira bound to and was phosphorylated by cyclin a- and e-cdk2 in vitrohira became phosphorylated on threonine 555 in s phase when cyclin-cdk2 kinases are active.ectopic expression of hira in cells caused arrest in s phase and this is consistent with the notion that it is a cyclin-cdk2 substrate that has a role in control of the cell cycle." SIGNOR-105548 CDK2 protein P24941 UNIPROT CDKN2D protein P55273 UNIPROT up-regulates phosphorylation Ser76 VQDTSGTsPVHDAAR 9606 22558186 t lperfetto "Cdk2 and pka were found to participate in p19ink4d phosphorylation process and that they would mediate serine 76 and threonine 141 modifications respectively. Nuclear translocation of p19ink4d induced by dna damage was shown to be dependent on serine 76 phosphorylation." SIGNOR-197270 CDK2 protein P24941 UNIPROT CDKN2D protein P55273 UNIPROT up-regulates phosphorylation Thr141 RRDARGLtPLELALQ 9606 22558186 t lperfetto "Cdk2 and pka were found to participate in p19ink4d phosphorylation process and that they would mediate serine 76 and threonine 141 modifications respectively.we propose a sequential phosphorylation model for p19 in which modification at s76 would enable a second phosphorylation event at t141. The phosphorylation-induced structural changes could have functional implicancies for p19 in the dna damage response" SIGNOR-197274 CDK2 protein P24941 UNIPROT PPP1CA protein P62136 UNIPROT "down-regulates activity" phosphorylation Thr320 NPGGRPItPPRNSAK 9606 12202491 t gcesareni "Both of these pp1 isoforms contain an arg-pro-ile/val-thr-pro-pro-arg sequence near the c terminus, a known site of phosphorylation by cdc/cdk kinases, and phosphorylation attenuates phosphatase activity" SIGNOR-92265 CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 15241418 t gcesareni "We have mapped cdk4 and cdk2 phosphorylation sites to thr 8, thr 178 and ser 212 in smad3. taken together, these findings indicate that cdk phosphorylation of smad3 inhibits its transcriptional activity and antiproliferative function" SIGNOR-126732 CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" phosphorylation Thr8 MSSILPFtPPIVKRL 9606 15241418 t lperfetto "We have mapped CDK4 and CDK2 phosphorylation sites to Thr 8, Thr 178 and Ser 212 in Smad3. Mutation of the CDK phosphorylation sites increases Smad3 transcriptional activity," SIGNOR-217734 CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" phosphorylation Thr179 PQSNIPEtPPPGYLS 9606 19114991 t lpetrilli "In the nucleus cdk2/4-mediated phosphorylation of smad3 occurs mostly at thr8, thr179, and ser213. Cdk-dependent phosphorylation of smad3 inhibits its transcriptional activity" SIGNOR-182971 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser662 GLGRSITsPTTLYDR 9606 BTO:0001938 11157749 t llicata "We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130." SIGNOR-104683 CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT unknown phosphorylation Ser204 NHSMDAGsPNLSPNP -1 15241418 t llicata "Thus, we have shown that Smad3 is phosphorylated by CDK4 and CDK2. Mutation of its CDK phosphorylation sites increases its transcriptional activity and antiproliferative function. | Thr 8 and the four sites in the linker (Thr 178, Ser 203, Ser 207 and Ser 212). Each of the five sites was phosphorylated by both CDK4 and CDK2 in vitro, and only Thr 8, Thr 178 and Ser 212 were phosphorylated by CDK4 and CDK2 in vivo phosphorylated by both CDK4 and CDK2 in vitro, and only Thr 8, Thr 178 and Ser 212 were phosphorylated by CDK4 and CDK2 in vivo." SIGNOR-250749 CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT unknown phosphorylation Ser208 DAGSPNLsPNPMSPA -1 15241418 t llicata "Thus, we have shown that Smad3 is phosphorylated by CDK4 and CDK2. Mutation of its CDK phosphorylation sites increases its transcriptional activity and antiproliferative function. We propose that under physiological conditions, phosphorylation of Smad3 by CDK inhibits its transcriptional activity, contributing to a decreased level of p15 and an increased level of c-Myc, thus facilitating cell cycle progression from G1 to S phase." SIGNOR-250750 CDK2 protein P24941 UNIPROT FOXK2 protein Q01167 UNIPROT up-regulates phosphorylation Ser373 SSRSAPAsPNHAGVL 9606 20810654 t gcesareni "We have mapped two cdk phosphorylation sites, serines 368 and 423, which play a role in defining foxk2 function through regulating its stability and its activity as a transcriptional repressor protein. These two cdk sites appear vital for foxk2 function because expression of a mutant lacking these sites cannot be tolerated and causes apoptosis." SIGNOR-167830 CDK2 protein P24941 UNIPROT FOXK2 protein Q01167 UNIPROT up-regulates phosphorylation Ser428 FAQSAPGsPLSSQPV 9606 20810654 t gcesareni "We have mapped two cdk phosphorylation sites, serines 368 and 423, which play a role in defining foxk2 function through regulating its stability and its activity as a transcriptional repressor protein. These two cdk sites appear vital for foxk2 function because expression of a mutant lacking these sites cannot be tolerated and causes apoptosis." SIGNOR-167834 CDK2 protein P24941 UNIPROT RUNX1 protein Q01196 UNIPROT "down-regulates activity" phosphorylation Ser276 VHPATPIsPGRASGM 9606 SIGNOR-C83 17015473 t "The effect has been demonstrated using Q01196-8" gcesareni "Previous studies have shown that phosphorylation of aml1, particularly at serines 276 and 303, affects its transcriptional activation. Here, we report that phosphorylation of aml1 serines 276 and 303 can be blocked in vivo by inhibitors of the cyclin-dependent kinases (cdks) cdk1 and cdk2. Furthermore, these residues can be phosphorylated in vitro by purified cdk1/cyclin b and cdk2/cyclin a." SIGNOR-149976 CDK2 protein P24941 UNIPROT RUNX1 protein Q01196 UNIPROT "up-regulates activity" phosphorylation Ser276 VHPATPIsPGRASGM 9606 16046550 t "The effect has been demonstrated using Q01196-8" gcesareni "We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein." SIGNOR-138936 CDK2 protein P24941 UNIPROT RUNX1 protein Q01196 UNIPROT "up-regulates activity" phosphorylation Thr273 SPSVHPAtPISPGRA 9606 BTO:0002181 16046550 t "The effect has been demonstrated using Q01196-8" gcesareni "We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein." SIGNOR-138940 CDK2 protein P24941 UNIPROT ID2 protein Q02363 UNIPROT down-regulates phosphorylation Ser5 sPVRSVRK 9606 SIGNOR-C16 9029153 t lperfetto "Id2 acts by forming heterodimers that are unable to bind to specific (e-box) dna sequences. Here we show that this activity can be overcome by phosphorylation of a serine residue within a consensus target site for cyclin-dependent kinases (cdks). In vitro, id2 can be phosphorylated by either cyclin e-cdk2 or cyclin a-cdk2_" SIGNOR-46397 CDK2 protein P24941 UNIPROT ID3 protein Q02535 UNIPROT down-regulates phosphorylation Ser5 sPVRGCYE 9606 9372912 t lperfetto "We now show that an analogous cell-cycle-regulated phosphorylation of id3 alters the specificity of id3 for abrogating both e-box-dependent bhlh homo- or heterodimer complex formation in vitro and e-box-dependent reporter gene function in vivo._" SIGNOR-53306 CDK2 protein P24941 UNIPROT ZBTB16 protein Q05516 UNIPROT down-regulates phosphorylation Ser197 SFGLSAMsPTKAAVD 9606 BTO:0001271 18246121 t llicata "Here we show that the main cyclin-dependent kinase involved at the g(1) to s transition (cdk2) phosphorylates plzf at two consensus sites found within pest domains present in the hinge region of the protein. This phosphorylation triggers the ubiquitination and subsequent degradation of plzf, which impairs plzf transcriptional repression ability and antagonizes its growth inhibitory effects." SIGNOR-160626 CDK2 protein P24941 UNIPROT ZBTB16 protein Q05516 UNIPROT down-regulates phosphorylation Thr282 RGKEGPGtPTRSSVI 9606 BTO:0001271 18246121 t llicata "Here we show that the main cyclin-dependent kinase involved at the g(1) to s transition (cdk2) phosphorylates plzf at two consensus sites found within pest domains present in the hinge region of the protein. This phosphorylation triggers the ubiquitination and subsequent degradation of plzf, which impairs plzf transcriptional repression ability and antagonizes its growth inhibitory effects." SIGNOR-160630 CDK2 protein P24941 UNIPROT PRDX1 protein Q06830 UNIPROT down-regulates phosphorylation Thr90 CHLAWVNtPKKQGGL 9606 BTO:0000567 11986303 t lperfetto "Peroxiredoxin (prx) i is a member of the peroxiredoxin family of peroxidases and contains a consensus site (thr(90)-pro-lys-lys) for phosphorylation by cyclin-dependent kinases (cdks). This protein has now been shown to be phosphorylated specifically on thr(90) by several cdks, including cdc2, in vitro. Phosphorylation of prx i on thr(90) reduced the peroxidase activity of this protein by 80%.Prx i was also phosphorylated, with an efficiency similar to that observed with cdc2, when incubated in vitro with cdk2, cdk4, or cdk6 that had been immunoprecipitated from hela cell lysates with specific antibodies (data not shown)." SIGNOR-87101 CDK2 protein P24941 UNIPROT FOXM1 protein Q08050 UNIPROT "up-regulates activity" phosphorylation Thr611 ETLPISStPSKSVLP BTO:0001938 15024056 t llicata "We demonstrated that FoxM1B transcriptional activity requires binding of either S-phase or M-phase Cdk-cyclin complexes to mediate efficient Cdk phosphorylation of the FoxM1B Thr 596 residue, which is essential for recruitment of p300/CBP coactivator proteins." SIGNOR-250731 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT down-regulates phosphorylation Ser1112 LLEDGSEsPAKRICP 9606 BTO:0001938 11157749 t gcesareni "When expressed in u2os cells, the phosphorylation-deficient mutant p130(delta)(cdk4), in which the cdk4 specific sites were mutated to alanine residues, imposed a more sustained g1 arrest than a constitutively active prb(delta)(cdk), known to repress all cellular e2f activity" SIGNOR-104656 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser688 RLFVENDsPSDGGTP 9606 BTO:0001938 11157749 t llicata "We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130." SIGNOR-104687 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser952 DSRSHQNsPTELNKD 9606 BTO:0001938 11157749 t llicata "We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130." SIGNOR-104691 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Thr1097 SMIRTGEtPTKKRGI 9606 BTO:0001938 11157749 t llicata "We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130." SIGNOR-104695 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Thr417 KENSPCVtPVSTATH 9606 BTO:0001938 11157749 t llicata "We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130." SIGNOR-104699 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Thr642 CIAGSPLtPRRVTEV 9606 BTO:0001938 11157749 t llicata "We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130." SIGNOR-104703 CDK2 protein P24941 UNIPROT SKP2 protein Q13309 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser64 SNLGHPEsPPRKRLK 18239684 t lperfetto "The activity of SCF(Skp2) is regulated by the Cyclin-dependent kinase (CDK)2-mediated phosphorylation of Skp2 on Ser64 allows its expression in mid-G1 phase, even in the presence of active APC(Cdh1). Reciprocally, dephosphorylation of Skp2 by the mitotic phosphatase Cdc14B at the M --> G1 transition promotes its degradation by APC(Cdh1)." SIGNOR-249173 CDK2 protein P24941 UNIPROT ORC2 protein Q13416 UNIPROT up-regulates phosphorylation Thr116 LASELAKtPQKSVSF 9606 SIGNOR-C83 11931757 t lperfetto "We also found that horc2p is phosphorylated in vitro by cyclin a/cdk2, specifically at residues thr116 and thr226. These data combined strongly suggest that skp2 promotes horc1p turnover and that the n-terminal domain of horc1p, containing most of the phosphorylation sites and overlapping with one of the skp2-interacting domains, is a regulatory element for horc1p stability." SIGNOR-116364 CDK2 protein P24941 UNIPROT ORC2 protein Q13416 UNIPROT up-regulates phosphorylation Thr226 SAPVGKEtPSKRMKR 9606 SIGNOR-C83 11931757 t lperfetto "We also found that horc2p is phosphorylated in vitro by cyclin a/cdk2, specifically at residues thr116 and thr226. These data combined strongly suggest that skp2 promotes horc1p turnover and that the n-terminal domain of horc1p, containing most of the phosphorylation sites and overlapping with one of the skp2-interacting domains, is a regulatory element for horc1p stability." SIGNOR-116476 CDK2 protein P24941 UNIPROT ORC2 protein Q13416 UNIPROT up-regulates phosphorylation Thr226 SAPVGKEtPSKRMKR 9606 22334659 t gcesareni "Phosphorylation at thr-116 and thr-226 of orc2 occurs by cyclin-dependent kinase during the s phase and is maintained until the m phase. Phosphorylation of orc2 at thr-116 and thr-226 dissociated the orc2-5 from chromatin." SIGNOR-196048 CDK2 protein P24941 UNIPROT NPAT protein Q14207 UNIPROT up-regulates phosphorylation Thr1270 SDLPVPRtPGSGAGE 9606 10995387 t llicata "Importantly, mutation of cdk2 phosphorylation sites to alanine abrogates the ability of p220 to activate the histone h2b promoter." SIGNOR-82137 CDK2 protein P24941 UNIPROT NPAT protein Q14207 UNIPROT up-regulates phosphorylation Thr1350 ISRTTSAtPLKDNTQ 9606 10995387 t llicata "Importantly, mutation of cdk2 phosphorylation sites to alanine abrogates the ability of p220 to activate the histone h2b promoter." SIGNOR-82141 CDK2 protein P24941 UNIPROT EZH2 protein Q15910 UNIPROT "up-regulates activity" phosphorylation Thr416 EANSRCQtPIKMKPN 9606 BTO:0000007 23241245 t "Here, we demonstrate that the phosphorylation of EZH2 by cyclin-dependent kinases at Thr416 creates a docking site for the ForkHead-associated domain of NIPP1." SIGNOR-255656 CDK2 protein P24941 UNIPROT CDX2 protein Q99626 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser283 RSVPEPLsPVSSLQA 9606 16027724 t llicata "Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation|We found that cyclin-dependent kinase 2 phosphorylated Cdx2 in vitro and in vivo." SIGNOR-138825 CDK2 protein P24941 UNIPROT CDX2 protein Q99626 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser287 EPLSPVSsLQASVPG 9606 16027724 t llicata "Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation|We found that cyclin-dependent kinase 2 phosphorylated Cdx2 in vitro and in vivo." SIGNOR-250728 CDK2 protein P24941 UNIPROT CDX2 protein Q99626 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser291 PVSSLQAsVPGSVPG 9606 16027724 t llicata "Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation|We found that cyclin-dependent kinase 2 phosphorylated Cdx2 in vitro and in vivo." SIGNOR-250729 CDK2 protein P24941 UNIPROT CDX2 protein Q99626 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser295 LQASVPGsVPGVLGP 9606 16027724 t llicata "Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation|We found that cyclin-dependent kinase 2 phosphorylated Cdx2 in vitro and in vivo." SIGNOR-250730 CDK2 protein P24941 UNIPROT RAD9A protein Q99638 UNIPROT unknown phosphorylation Ser328 VLPSISLsPGPQPPK 9606 SIGNOR-C83 23028682 t llicata "The forced activation of cyclin a-cdk2 in these cells by the overexpression of cyclin a,triggered rad9 phosphorylation at serine 328 and thereby promoted the interaction of rad9 with bcl-xl and the subsequent initiation of the apoptotic program." SIGNOR-199020 CDK2 protein P24941 UNIPROT RBBP8 protein Q99708 UNIPROT up-regulates phosphorylation Thr847 FRYIPPNtPENFWEV 9606 19202191 t llicata "Collectively, these findings thereby provided strong support for ctip thr-847 indeed being a cdk target. it is established that both cdk-dependent and checkpoint-dependent phosphorylations are required for activation of sae2/ctip in vivo" SIGNOR-183840 MAOB protein P27338 UNIPROT dopamine smallmolecule CHEBI:18243 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 BTO:0004032;BTO:0002606 NBK536726 t brain lperfetto "Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells |dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO." SIGNOR-264002 CDK2 protein P24941 UNIPROT CDC6 protein Q99741 UNIPROT "down-regulates activity" phosphorylation Ser74 TPHLPPCsPPKQGKK 9606 SIGNOR-C83 10339564 t lperfetto "Hscdc6 is an excellent substrate for cdk2 in vitro and is phosphorylated in vivo at three sites (ser-54, ser-74, and ser-106)|An HsCdc6A1A2A3 mutant, which mimics unphosphorylated HsCdc6, is exclusively nuclear, and its expression inhibits initiation of DNA replication. An HsCdc6E1E2E3 mutant, which mimics phosphorylated HsCdc6, is exclusively cytoplasmic and is not associated with the chromatin/nuclear matrix fraction." SIGNOR-67548 CDK2 protein P24941 UNIPROT CDC6 protein Q99741 UNIPROT "down-regulates activity" phosphorylation Ser54 RVKALPLsPRKRLGD 9606 SIGNOR-C83 9889196 t lperfetto "Phosphorylation of mammalian cdc6 by cyclin a/cdk2 regulates its subcellular localization/based on our data we suggest that the phosphorylation of cdc6 by cyclin a/cdk2 is a negative regulatory event that could be implicated in preventing re-replication during s phase and g2." SIGNOR-63891 CDK2 protein P24941 UNIPROT CDC6 protein Q99741 UNIPROT "down-regulates activity" phosphorylation Ser74 TPHLPPCsPPKQGKK 9606 SIGNOR-C83 9889196 t lperfetto "Phosphorylation of mammalian cdc6 by cyclin a/cdk2 regulates its subcellular localization/based on our data we suggest that the phosphorylation of cdc6 by cyclin a/cdk2 is a negative regulatory event that could be implicated in preventing re-replication during s phase and g2." SIGNOR-63895 CDK2 protein P24941 UNIPROT CDC6 protein Q99741 UNIPROT up-regulates phosphorylation Ser106 DNQLTIKsPSKRELA 9606 SIGNOR-C83 10339564 t lperfetto "Based on these results, we propose that phosphorylation of hscdc6 by cdks regulates dna replication of at least two steps: first, by promoting initiation of dna replication and, second, through nuclear exclusion preventing dna rereplication. hscdc6 is an excellent substrate for cdk2 in vitro and is phosphorylated in vivo at three sites (ser-54, ser-74, and ser-106)" SIGNOR-67540 CDK2 protein P24941 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates phosphorylation Ser477 NSMNKLPsVSQLINP 9606 18769144 t lperfetto "Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively" SIGNOR-180759 CDK2 protein P24941 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates phosphorylation Ser560 LARLGCSsCLDYFTT 9606 18769144 t lperfetto "Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively" SIGNOR-180763 CDK2 protein P24941 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates phosphorylation Thr491 PQQRNALtPTTIPDG 9606 18769144 t lperfetto "Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively" SIGNOR-180767 CDK2 protein P24941 UNIPROT TPX2 protein Q9ULW0 UNIPROT "down-regulates activity" phosphorylation Thr72 NLQQAIVtPLKPVDN -1 25688093 t lperfetto "In this study, we characterize the phosphorylation of threonine 72 (Thr(72)) in human TPX2, a residue highly conserved across species. We find that Cdk1/2 phosphorylate TPX2 in vitro and in vivo. |Endogenous TPX2 phosphorylated at Thr(72) does not associate with the mitotic spindle. Furthermore, ectopic GFP-TPX2 T72A preferentially concentrates on the spindle" SIGNOR-265099 CDK2 protein P24941 UNIPROT FZR1 protein Q9UM11 UNIPROT "down-regulates activity" phosphorylation Ser151 DVSPYSLsPVSNKSQ BTO:0000007 12560341 t llicata " A nuclear localization signal conserved in various species was identified in CDH1, and it sufficiently targets green fluorescent protein to the nucleus. Interestingly, a CDH1-4D mutant mimicking the hyperphosphorylated form was constitutively found in the cytoplasm. In further support of the notion that phosphorylation inhibits nuclear import, the nuclear localization signal of CDH1 with two phospho-accepting serine/threonine residues changed into aspartates was unable to drive heterologous protein into the nucleus. " SIGNOR-250732 CDK2 protein P24941 UNIPROT CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR "form complex" binding 9606 19056339 t lperfetto "We therefore compared human cyclin a1- and cyclin a2-containing cdk complexes in vitro by determining kinetic constants and by examining the complexes for their ability to phosphorylate prb and p53. Differences in biochemical activity were observed in cdk2 but not cdk1 when complexed with cyclin a1 versus cyclin a2. Further, cdk1/cyclin a1 is a better kinase complex for phosphorylating potentially physiologically relevant substrates prb and p53 than cdk2/cyclin a2." SIGNOR-182569 CDK2 protein P24941 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser249 EGGKSGKsPRRRAAS 9606 17038621 t lperfetto "Cdk2 specifically phosphorylated foxo1 at serine-249 (ser249) in vitro and in vivo. Phosphorylation of ser249 resulted in cytoplasmic localization and inhibition of foxo1." SIGNOR-252892 CDK2 protein P24941 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni "Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity" SIGNOR-252891 CDK2 protein P24941 UNIPROT PP1 proteinfamily SIGNOR-PF54 SIGNOR "down-regulates activity" phosphorylation 9606 12202491 t lperfetto "Both of these pp1 isoforms contain an arg-pro-ile/val-thr-pro-pro-arg sequence near the c terminus, a known site of phosphorylation by cdc/cdk kinases, and phosphorylation attenuates phosphatase activity" SIGNOR-264650 HRH2 protein P25021 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257424 HRH2 protein P25021 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257162 HRH2 protein P25021 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257250 HRH2 protein P25021 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257317 HRH2 protein P25021 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256777 APC protein P25054 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates quantity" binding 9606 22083140 t amattioni "Apc binds to both b-catenin and axin, and could shuttle b-catenin from the plasma membrane and nucleus to the cytoplasmic axin complex. APC cooperates with Axin to promote the phosphorylation of _-catenin by GSK3 [which requires priming phosphorylation by casein kinase 1, _-isoform (CK1_)]." SIGNOR-177230 APC protein P25054 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "form complex" binding 9606 BTO:0000586 9734785 t lperfetto "Axin, an inhibitor of the wnt pathway, interacts with beta-catenin, gsk-3beta and apc and reduces the beta-catenin level." SIGNOR-227296 FPR2 protein P25090 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256888 GRK2 protein P25098 UNIPROT ADRA2A protein P08913 UNIPROT "down-regulates activity" phosphorylation Ser311 DALDLEEsSSSDHAE 10029 BTO:0000246 7876239 t "The alpha 2A-adrenergic receptor (alpha 2AAR) undergoes rapid functional desensitization caused by phosphorylation of the receptor by the beta-adrenergic receptor kinase (beta ARK). beta ARK-mediated phosphorylation of alpha 2C10 occurs at Ser-296-299 in the third intracellular loop, and this represents the critical step in rapid agonist-promoted desensitization." SIGNOR-251440 GRK2 protein P25098 UNIPROT ADRA2A protein P08913 UNIPROT "down-regulates activity" phosphorylation Ser312 ALDLEESsSSDHAER 10029 BTO:0000246 7876239 t "The alpha 2A-adrenergic receptor (alpha 2AAR) undergoes rapid functional desensitization caused by phosphorylation of the receptor by the beta-adrenergic receptor kinase (beta ARK). beta ARK-mediated phosphorylation of alpha 2C10 occurs at Ser-296-299 in the third intracellular loop, and this represents the critical step in rapid agonist-promoted desensitization." SIGNOR-251441 GRK2 protein P25098 UNIPROT ADRA2A protein P08913 UNIPROT "down-regulates activity" phosphorylation Ser313 LDLEESSsSDHAERP 10029 BTO:0000246 7876239 t "The alpha 2A-adrenergic receptor (alpha 2AAR) undergoes rapid functional desensitization caused by phosphorylation of the receptor by the beta-adrenergic receptor kinase (beta ARK). beta ARK-mediated phosphorylation of alpha 2C10 occurs at Ser-296-299 in the third intracellular loop, and this represents the critical step in rapid agonist-promoted desensitization." SIGNOR-251442 GRK2 protein P25098 UNIPROT ADRA2A protein P08913 UNIPROT "down-regulates activity" phosphorylation Ser314 DLEESSSsDHAERPP 10029 BTO:0000246 7876239 t "The alpha 2A-adrenergic receptor (alpha 2AAR) undergoes rapid functional desensitization caused by phosphorylation of the receptor by the beta-adrenergic receptor kinase (beta ARK). beta ARK-mediated phosphorylation of alpha 2C10 occurs at Ser-296-299 in the third intracellular loop, and this represents the critical step in rapid agonist-promoted desensitization." SIGNOR-251443 GRK2 protein P25098 UNIPROT CLTB protein P09497 UNIPROT unknown phosphorylation Ser205 LCDFNPKsSKQCKDV 9606 22704991 t llicata "Moreover, we demonstrate that phosphorylation of ser204 in clcb is required for efficient endocytosis of a subset of gpcrs and identify g protein-coupled receptor kinase 2 (grk2) as a kinase that can phosphorylate clcb on ser204. Overexpression of clcb(s204a) specifically inhibits the endocytosis of those gpcrs whose endocytosis is grk2-dependent." SIGNOR-197873 GRK2 protein P25098 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Thr567 QGRDKYKtLRQIRQG 9606 15843435 t llicata "Grk2 phosphorylates glutathione s-transferase (gst)-ezrin, but not an ezrin fusion protein lacking threonine 567 (t567), in vitro. These results suggest that t567, the regulatory phosphorylation site responsible for maintaining ezrin in its active conformation, represents the principle site of grk2-mediated phosphorylation." SIGNOR-135622 GRK2 protein P25098 UNIPROT PDE6G protein P18545 UNIPROT "up-regulates activity" phosphorylation Thr62 PGMEGLGtDITVICP 9606 BTO:0000007 11502744 t "Rod PDEγ is predominantly phosphorylated by GRK2 at the Thr-62. GRK2 is required for the stimulatory effect of rod PDEγ on both the EGF- and thrombin-dependent activation of p42/p44 MAPK" SIGNOR-251459 GRK2 protein P25098 UNIPROT PDE6G protein P18545 UNIPROT "up-regulates activity" phosphorylation Thr62 PGMEGLGtDITVICP 9606 BTO:0000007 12624098 t gcesareni "Mutation of Thr-62 (to Ala) in PDEgamma produced a GRK2 phosphorylation-resistant mutant that was less effective in associating with GRK2 in response to epidermal growth factor and did not potentiate the stimulation of p42/p44 mitogen-activated protein kinase by this growth factor." SIGNOR-247823 GRK2 protein P25098 UNIPROT FPR1 protein P21462 UNIPROT "down-regulates activity" phosphorylation Ser328 ERALTEDsTQTSDTA -1 7836371 t gcesareni "Kinetic studies demonstrated that GRK2 has a Km for the carboxyl-terminal domain of the FPR of approximately 1.5 microM and that denaturation of the substrate results in an almost complete loss of phosphorylation [€] simultaneous substitution of the upstream Ser328, Thr329, Thr331, and Ser332 or merely the Ser328 and Thr329 residues resulted in an approximately 80% reduction in phosphorylation." SIGNOR-247763 GRK2 protein P25098 UNIPROT FPR1 protein P21462 UNIPROT "down-regulates activity" phosphorylation Ser332 TEDSTQTsDTATNST -1 7836371 t gcesareni "Kinetic studies demonstrated that GRK2 has a Km for the carboxyl-terminal domain of the FPR of approximately 1.5 microM and that denaturation of the substrate results in an almost complete loss of phosphorylation [€] simultaneous substitution of the upstream Ser328, Thr329, Thr331, and Ser332 or merely the Ser328 and Thr329 residues resulted in an approximately 80% reduction in phosphorylation." SIGNOR-249680 GRK2 protein P25098 UNIPROT FPR1 protein P21462 UNIPROT "down-regulates activity" phosphorylation Thr336 TQTSDTAtNSTLPSA -1 7836371 t gcesareni "Kinetic studies demonstrated that GRK2 has a Km for the carboxyl-terminal domain of the FPR of approximately 1.5 microM and that denaturation of the substrate results in an almost complete loss of phosphorylation [€] simultaneous substitution of the upstream Ser328, Thr329, Thr331, and Ser332 or merely the Ser328 and Thr329 residues resulted in an approximately 80% reduction in phosphorylation." SIGNOR-249686 GRK2 protein P25098 UNIPROT FPR1 protein P21462 UNIPROT "down-regulates activity" phosphorylation Thr339 SDTATNStLPSAEVE -1 7836371 t "Phosphorylation of the FPR carboxyl terminus by GRK2 is the result of a high affinity interaction and proceeds in a hierarchical manner. sequential mechanism of phosphorylation beginning with residues 328 and/or 329, followed by residues 331 and/or 332, and finally residues 334 through 339. Attenuation of receptor-mediated signal amplification in response to external stimuli, an essential step in the balance of cellular activation, may be mediated by receptor phosphorylation." SIGNOR-251452 GRK2 protein P25098 UNIPROT CXCR2 protein P25025 UNIPROT "down-regulates activity" phosphorylation 10090 BTO:0000763 22634615 t miannu "Upon activation, GRK2 phosphorylates CXCR2 and causes receptor desensitization and internalization, leading to down-regulation of neutrophil chemotaxis" SIGNOR-260647 GRK2 protein P25098 UNIPROT BDKRB2 protein P30411 UNIPROT "down-regulates activity" phosphorylation Ser366 EPIQMENsMGTLRTS 9606 BTO:0000007 11517230 t "Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration." SIGNOR-251444 GRK2 protein P25098 UNIPROT BDKRB2 protein P30411 UNIPROT "down-regulates activity" phosphorylation Ser373 SMGTLRTsISVERQI 9606 BTO:0000007 11517230 t "Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration." SIGNOR-251445 GRK2 protein P25098 UNIPROT BDKRB2 protein P30411 UNIPROT "down-regulates activity" phosphorylation Ser375 GTLRTSIsVERQIHK 9606 BTO:0000007 11517230 t "Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration." SIGNOR-251446 GRK2 protein P25098 UNIPROT OPRM1 protein P35372 UNIPROT "down-regulates activity" phosphorylation Ser358 EFCIPTSsNIEQQNS 9606 BTO:0000007 12123746 t gcesareni "These results suggest that two C-terminal amino acids, Ser(355) and Thr(357), are required for short-term homologous desensitization and agonist-induced phosphorylation of mu-opioid receptors expressed in HEK 293 cells" SIGNOR-249661 GRK2 protein P25098 UNIPROT OPRM1 protein P35372 UNIPROT "down-regulates activity" phosphorylation Thr356 FREFCIPtSSNIEQQ 9606 BTO:0000007 12123746 t gcesareni "These results suggest that two C-terminal amino acids, Ser(355) and Thr(357), are required for short-term homologous desensitization and agonist-induced phosphorylation of mu-opioid receptors expressed in HEK 293 cells" SIGNOR-247782 GRK2 protein P25098 UNIPROT SNCA protein P37840 UNIPROT "down-regulates activity" phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 10852916 t llicata "We found that grk-mediated phosphorylation inhibits synuclein's interaction with both phospholipids and pld2. These findings suggest that gpcrs may be able to indirectly stimulate pld2 activity via their ability to regulate grk-promoted phosphorylation of synuclein." SIGNOR-78333 GRK2 protein P25098 UNIPROT OPRD1 protein P41143 UNIPROT "down-regulates activity" phosphorylation Ser363 RVTACTPsDGPGGGA 9606 BTO:0000007 11040053 t gcesareni "Taken together, we have demonstrated that agonist-induced opioid receptor phosphorylation occurs exclusively at two phosphate acceptor sites (T358 and S363) of GRK2 at the DOR carboxyl terminus." SIGNOR-249660 GRK2 protein P25098 UNIPROT OPRD1 protein P41143 UNIPROT "down-regulates activity" phosphorylation Thr358 ATARERVtACTPSDG 9606 BTO:0000007 11040053 t "GRK2 strongly enhanced agonist-stimulated phosphorylation of the wild-type DOR (WT), but Delta15 or mutant DOR (T358A/T361A/S363G) failed to show any detectable phosphorylation under these conditions. agonist-induced opioid receptor phosphorylation occurs exclusively at two phosphate acceptor sites (T358 and S363) of GRK2 at the DOR carboxyl terminus. GRKs are important mediators in agonist-induced opioid receptor phosphorylation and desensitization." SIGNOR-251457 GRK2 protein P25098 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates phosphorylation Thr123 IVKCQKLtDDHVQFL 9606 BTO:0000801 17055984 t lperfetto "Phosphorylation of p38 by grk2 at the docking groove unveils a novel mechanism for inactivating p38mapk p38 associates with grk2 endogenously and is phosphorylated by grk2 at thr-123, a residue located at its docking groove. Mimicking phosphorylation at this site impairs the binding and activation of p38 by mkk6 and diminishes the capacity of p38 to bind and phosphorylate its substrates" SIGNOR-150152 GRK2 protein P25098 UNIPROT SMO protein Q99835 UNIPROT up-regulates phosphorylation 9606 15618519 t gcesareni "We find that two molecules interact with mammalian smo in an activation-dependent manner: g protein-coupled receptor kinase 2 (grk2) leads to phosphorylation of smo, and beta-arrestin 2 fused to green fluorescent protein interacts with smo. Ck1a, grk2, and another still-unidentified protein kinase phosphorylate the c-tail of mammalian smo in the presence of hh proteins" SIGNOR-132669 GRK2 protein P25098 UNIPROT SMO protein Q99835 UNIPROT up-regulates phosphorylation 9606 21695114 t gcesareni "We find that two molecules interact with mammalian smo in an activation-dependent manner: g protein-coupled receptor kinase 2 (grk2) leads to phosphorylation of smo, and beta-arrestin 2 fused to green fluorescent protein interacts with smo. Ck1a, grk2, and another still-unidentified protein kinase phosphorylate the c-tail of mammalian smo in the presence of hh proteins" SIGNOR-174539 ADRA1D protein P25100 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256951 ADRA1D protein P25100 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257080 ADRA1D protein P25100 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256808 EDNRA protein P25101 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257427 EDNRA protein P25101 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257165 EDNRA protein P25101 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256923 EDNRA protein P25101 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001260 15475516 t gcesareni "The response to endothelin-1 (et-1) consisted of two phases in both cell types. The initial, transient phase of contraction and phosphorylation of 20-kda myosin light chain (mlc20) was mediated additively by eta and etb receptors and initiated by galphaq-, ca2+/calmodulin-dependent activation of mlc kinase." SIGNOR-129817 EDNRA protein P25101 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257378 EDNRA protein P25101 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257052 EDNRA protein P25101 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 BTO:0000671 10199825 t gcesareni "We studied the ability of et receptors to activate galfa13 using an assay for g protein alfa-chain activation that is based on the fact that an activated (gtp-bound) alfa-chain is resistant to trypsinization compared with an inactive (gdp-bound) alfa-chain." SIGNOR-66856 EDNRA protein P25101 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256780 TACR1 protein P25103 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257316 TACR1 protein P25103 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256919 PTAFR protein P25105 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257174 PTAFR protein P25105 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257262 PTAFR protein P25105 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257329 CTSS protein P25774 UNIPROT BGLAP protein P02818 UNIPROT "down-regulates quantity by destabilization" cleavage Gly58 RYLYQWLgAPVPYPD -1 9076588 t miannu "This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42." SIGNOR-256323 PTAFR protein P25105 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256789 F2R protein P25116 UNIPROT LATS1 protein O95835 UNIPROT down-regulates 9606 BTO:0000007 22972936 f "Here we report that stimulation of protease-activated receptors (PARs) activates YAP/TAZ by decreasing phosphorylation and increasing nuclear localization." milica "Par1 acts through g12/13 and rho gtpase to inhibit the lats1/2 kinase." SIGNOR-192045 F2R protein P25116 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257293 F2R protein P25116 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257127 F2R protein P25116 UNIPROT GNA15 protein P30679 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257353 F2R protein P25116 UNIPROT SDC4 protein P31431 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007 21072196 f miannu "Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer." SIGNOR-254852 F2R protein P25116 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 9606 22972936 t milica "Par1 acts through g12/13 and rho gtpase to inhibit the lats1/2 kinase." SIGNOR-199010 F2R protein P25116 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257403 F2R protein P25116 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 22318735 t milica "The protease-activated receptors (PAR)2 are a class of G protein-coupled receptors (GPCR) that are activated by the proteolysis of the N-terminal exodomain. Upon proteolysis, the newly formed n terminus acts as a tethered ligand that activates the receptor and initiates signaling cascades through multiple g proteins (galfaq, galfai, and galfa12/13)." SIGNOR-196006 F2R protein P25116 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates 9606 BTO:0000007 22972936 t milica "Par1 acts through g12/13 and rho gtpase to inhibit the lats1/2 kinase." SIGNOR-192042 F2R protein P25116 UNIPROT KLF6 protein Q99612 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007 21072196 f miannu "Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer." SIGNOR-254849 F2R protein P25116 UNIPROT TNFRSF12A protein Q9NP84 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007 21072196 f miannu "Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer." SIGNOR-254846 F2R protein P25116 UNIPROT LATS2 protein Q9NRM7 UNIPROT down-regulates 9606 BTO:0000007 22972936 f milica "Par1 acts through g12/13 and rho gtpase to inhibit the lats1/2 kinase." SIGNOR-192048 F2R protein P25116 UNIPROT CORO1C protein Q9ULV4 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007 21072196 f miannu "Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer." SIGNOR-254847 NFYB protein P25208 UNIPROT PHGDH protein O43175 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18378410 f miannu "Positive regulation of promoter activity of human 3-phosphoglycerate dehydrogenase (PHGDH) gene is mediated by transcription factors Sp1 and NF-Y." SIGNOR-255210 PAX6 protein P26367 UNIPROT PCSK1 protein P29120 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 19034419 f miannu "PAX6 can bind to the promoter and directly upregulate production of prohormone convertase (PC)1/3, an enzyme essential for conversion of proinsulin to insulin." SIGNOR-254900 NFYB protein P25208 UNIPROT GCH1 protein P30793 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15496512 f miannu "Coactivator RNF4 is involved in the GCH gene expression. Through serial deletion and mutagenesis studies of the GCH promoter, we defined the RNF4-responsive element on GCH proximal promoter as a CCAAT box. RNF4 did not possess specific DNA binding activity toward this CCAAT box, which suggests that RNF4 may be a coactivator of the CCAAT boxbinding protein nuclear factor Y (NF-Y). RNF4 is a coactivator for nuclear factor Y on GTP cyclohydrolase I proximal promoter." SIGNOR-252233 NFYB protein P25208 UNIPROT SOX18 protein P35713 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567 18496767 f miannu "co-transfection experiments revealed that over-expression of Sp3 and ZBP-89 down-regulate, while over-expression of NF-Y up-regulates SOX18 promoter activity in HeLa cells" SIGNOR-254819 NFYB protein P25208 UNIPROT GFI1B protein Q5VTD9 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19965638 f miannu "HMGB2 binds to the GFI1B promoter in vivo and up-regulates its trans-activation most likely by enhancing the binding of Oct-1 and, to a lesser extent, of GATA-1 and NF-Y to the GFI1B promoter." SIGNOR-254431 BRD2 protein P25440 UNIPROT TP53BP1 protein Q12888 UNIPROT "up-regulates activity" relocalization 9606 BTO:0001938 29018219 t lperfetto "BRD2 is required to recruit 53BP1 to DSBs.|When BRD2 recruitment was blocked with shRNA or JQ1 (Fig. 3a and Supplementary Figure 3c) or a panel of BRD2 siRNAs (Supplementary Figure 3a), the recruitment of 53BP1 to DSBs was significantly delayed." SIGNOR-262035 BRD2 protein P25440 UNIPROT ZMYND8 protein Q9ULU4 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000007 29018219 t lperfetto "ZMYND8 and BRD2 therefore work together to protect H4Ac domains from HDAC activity.|Further, when BRD2 was depleted, ZMYND8 accumulation was lost (Fig. 2e), indicating that either BRD2, or the underlying H4Ac, is required for ZMYND8 loading." SIGNOR-262036 FAS protein P25445 UNIPROT FAS protein P25445 UNIPROT "up-regulates activity" binding 9606 14585074 t lperfetto "The fas receptor, upon binding to the fasl, trimerizes" SIGNOR-85991 FAS protein P25445 UNIPROT FAS protein P25445 UNIPROT "up-regulates activity" binding 9606 BTO:0000776 19305384 t lperfetto "Fas/FasL, TRAIL/DR4, TRAIL/DR5 and TNF-alpha/TNFR1 are ligand/receptor pairs of the tumor necrosis factor/nerve growth factor family, which are able to induce apoptosis by trimerization of the receptor by its corresponding ligand." SIGNOR-217809 FAS protein P25445 UNIPROT FADD protein Q13158 UNIPROT "up-regulates activity" binding 9606 21959933 t lperfetto "Aggregation-induced conformational changes in fas lead to the formation of the death-inducing signalling complex (disc) which involves recruitment of the adaptor protein fadd/mort1 through a homotypic interaction of death domains, present in both the intracellular region of fas and the c-terminus of fadd." SIGNOR-176651 FAS protein P25445 UNIPROT RIPK1 protein Q13546 UNIPROT "up-regulates activity" binding 10090 BTO:0000944 7538908 t lperfetto "Fas associates with rip. Rip is a novel form of apoptosis-inducing protein" SIGNOR-235430 FAS protein P25445 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates binding 9606 11495919 t amattioni "Ask1 binds fas" SIGNOR-109676 FAS protein P25445 UNIPROT RASSF1 protein Q9NS23 UNIPROT up-regulates 9606 22830020 f gcesareni "It was also shown that the fas active receptor induces rassf1a to compete with raf1 in binding to mst2, thus promoting the formation of a lats1 complex." SIGNOR-198435 FAS protein P25445 UNIPROT DAXX protein Q9UER7 UNIPROT up-regulates 9606 9743501 f gcesareni "Fas activation induced daxx to interact with ask1" SIGNOR-60167 YY1 protein P25490 UNIPROT FCER1A protein P12319 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000732 11971001 f "Transcriptional regulation of the gene-encoding human Fc epsilon RI alpha-chain was analyzed in detail. EMSA revealed that either YY1 or PU.1 bound to the region close to that recognized by Elf-1. The alpha-chain promoter activity was up-regulated approximately 2-fold by exogenously expressed YY1 or PU.1 and approximately 7-fold by GATA-1, respectively, in KU812 cells" SIGNOR-254290 YY1 protein P25490 UNIPROT COX7C protein P15954 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9092564 f miannu "Mutation of both YY1 sites eliminates most of the promoter activity. Mutation at the upstream YY1 site significantly reduces the efficiency of transcript initiation at the major start site and thus plays the dominant role in COX7C regulation." SIGNOR-255617 YY1 protein P25490 UNIPROT HSD3B2 protein P26439 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15291746 f miannu "These results designate YY1 as the factor responsible for the intron 1-mediated boost of the HSD3B2 gene basal promoter activity." SIGNOR-255619 YY1 protein P25490 UNIPROT ATP6V1A protein P38606 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 28592880 t Giorgia "We investigated the relationship between transcription factor YY1 and ATP6V1A, and found that mRNA expression of YY1 had significant correlation with that of ATP6V1A. To validate that YY1 transcriptionally regulates ATP6V1A, we discovered that the ATP6V1A core promoter region contains three YY1 binding sites. Moreover, RNAi-mediated knockdown of YY1 in GC cells significantly decreased ATP6V1A mRNA and protein expression, while YY1 overexpression increased ATP6V1A expression level." SIGNOR-260635 YY1 protein P25490 UNIPROT NOTCH1 protein P46531 UNIPROT "down-regulates activity" binding 9606 BTO:0000664 12913000 t "Taken together, these results indicate that transcription factor YY1 may modulate Notch signaling via association with the high molecular weight Notch complex [..] both YY1 and N1IC were present in a large complex of the nucleus to suppress the luciferase reporter activity transactivated by Notch signaling." SIGNOR-251654 YY1 protein P25490 UNIPROT POSTN protein Q15063 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 21839814 f miannu "In this study we demonstrate that the ability of the human POSTN promoter to drive transcription mostly depends on the activity of YingYang-1 (YY1) zinc finger transcription factor. YY1, whose regulatory role in biology includes, besides transcriptional control, also chromatin remodeling, DNA damage repair and tumorigenesis, acts as a strong negative modulator of the POSTN expression." SIGNOR-255621 YY1 protein P25490 UNIPROT HOXB13 protein Q92826 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001130 19013255 f miannu "Recruitment of HDAC4 by transcription factor YY1 represses HOXB13 to affect cell growth in AR-negative prostate cancers." SIGNOR-254233 YY1 protein P25490 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR "down-regulates activity" binding 9606 BTO:0000664 12913000 t "Taken together, these results indicate that transcription factor YY1 may modulate Notch signaling via association with the high molecular weight Notch complex [..] both YY1 and N1IC were present in a large complex of the nucleus to suppress the luciferase reporter activity transactivated by Notch signaling." SIGNOR-254305 PSMA1 protein P25786 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "form complex" binding 9606 BTO:0000007 29636472 t lperfetto "Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line" SIGNOR-263363 PSMA2 protein P25787 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "form complex" binding 9606 BTO:0000007 29636472 t lperfetto "Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line" SIGNOR-263367 PSMA3 protein P25788 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "form complex" binding 9606 BTO:0000007 29636472 t lperfetto "Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line" SIGNOR-263362 PSMA4 protein P25789 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "form complex" binding 9606 BTO:0000007 29636472 t lperfetto "Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line" SIGNOR-263366 LMO2 protein P25791 UNIPROT ANGPT2 protein O15123 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000574 22792348 f miannu "Here, we identified angiopoietin-2 (ang-2), which encodes a major regulator of angiogenesis, as a direct transcriptional target of tal1,lyl1and lmo2. Knockdown of any of the three transcription factors in human blood and lymphatic endothelial cells caused ang-2 mrna and protein down-regulation." SIGNOR-198249 LMO2 protein P25791 UNIPROT ERG protein P11308 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001106 21536859 f miannu "We further demonstrate that ERG expression in primary human T-ALL cells is mediated by the binding of other T-cell oncogenes SCL/TAL1, LMO2, and LYL1 in concert with ERG, FLI1, and GATA3 to the ERG +85 enhancer." SIGNOR-253922 LMO2 protein P25791 UNIPROT TAL1 protein P17542 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271 9020185 t miannu "Transcriptional activity of tal1 in t cell acute lymphoblastic leukemia (t-all) requires rbtn1 or -2" SIGNOR-46161 CD40 protein P25942 UNIPROT BCL2L1 protein Q07817 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000776 12324477 f gcesareni "Cd40 ligation up-regulated bcl-2 and bcl-xl as much as 9.7- (p < 0.01) and 6.8-fold (p < 0.01), respectively (fig. 2, b and c). Under similar conditions, cd27 ligation also up-regulated bcl-2 and bcl-xl as much as 5.0- (p < 0.01) and 3.9-fold (p < 0.01), respectively." SIGNOR-93387 CD40 protein P25942 UNIPROT TRAF2 protein Q12933 UNIPROT "up-regulates activity" binding 9606 BTO:0000776 18635759 t lperfetto "Cd40, a tumor necrosis factor receptor (tnfr) family member, forms a complex containing adaptor molecules traf2 and traf3." SIGNOR-179473 CD40 protein P25942 UNIPROT BIK protein Q13323 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000776 12324477 f gcesareni "Bik expression was weakly but significantly down-regulated by cd27 but up-regulated by cd40." SIGNOR-93390 NFKBIA protein P25963 UNIPROT S100A6 protein P06703 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000599 12859951 f miannu "Transient expression of NF-kappaB (p65) increased S100A6 promoter activity and expression of inhibitor of NF-kappaB (IkappaBalpha) decreased TNFalpha-induced S100A6 promoter activity. " SIGNOR-254804 NFKBIA protein P25963 UNIPROT NFKB1 protein P19838 UNIPROT "down-regulates activity" binding 9606 SIGNOR-C13 1340770 t 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-17688 NFKBIA protein P25963 UNIPROT RELA protein Q04206 UNIPROT "up-regulates activity" binding 9606 SIGNOR-C13 1340770 t 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-17691 NFKBIA protein P25963 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "down-regulates activity" binding 9606 1340770 t 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 ITGA3 protein P26006 UNIPROT "A3/b1 integrin" complex SIGNOR-C161 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253173 ITGB7 protein P26010 UNIPROT PTK2 protein Q05397 UNIPROT "up-regulates activity" 9606 15688067 f miannu "Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin." SIGNOR-257726 ITGB7 protein P26010 UNIPROT "AE/b7 integrin" complex SIGNOR-C186 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253292 ITGB7 protein P26010 UNIPROT "A4/b7 integrin" complex SIGNOR-C187 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253294 ITGB8 protein P26012 UNIPROT TGFB1 protein P01137 UNIPROT up-regulates 9606 BTO:0000142 11970960 f lperfetto "Integrin _v_8-mediated tgf_ activation is also required to regulate neurovascular homeostasis in the adult brain" SIGNOR-117386 ITGB8 protein P26012 UNIPROT PTK2 protein Q05397 UNIPROT "up-regulates activity" 9606 15688067 f miannu "Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin." SIGNOR-257729 PTPN3 protein P26045 UNIPROT VCP protein P55072 UNIPROT "down-regulates activity" dephosphorylation Tyr796 GGTGGSVyTEDNDDD 9606 BTO:0000007 10364224 t "Identification of VCP as a substrate of PTPH1in vivo.|The tyrosines (Tyr796 and Tyr805) at the C terminus of VCP have been reported to be the major sites of phosphorylation, with Tyr805 accounting for more than 90% of the tyrosine phosphorylation on the protein |The Y796F/Y805F VCP mutant was not associated with any of the PTPH1 constructs." SIGNOR-248460 PTPN3 protein P26045 UNIPROT VCP protein P55072 UNIPROT "down-regulates activity" dephosphorylation Tyr805 EDNDDDLyG 9606 BTO:0000007 10364224 t "Identification of VCP as a substrate of PTPH1in vivo.|The tyrosines (Tyr796 and Tyr805) at the C terminus of VCP have been reported to be the major sites of phosphorylation, with Tyr805 accounting for more than 90% of the tyrosine phosphorylation on the protein |The Y796F/Y805F VCP mutant was not associated with any of the PTPH1 constructs." SIGNOR-248461 DNMT1 protein P26358 UNIPROT BAG4 protein O95429 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001109 18413740 f lperfetto "In contrast, an increase in BAG-1, BAG-3, and BAG-4 gene expression was observed in HCT116 cells overexpressing either DNMT1 (DNMT1+) or DNMT3B (DNMT3B+)" SIGNOR-254112 DNMT1 protein P26358 UNIPROT BAG3 protein O95817 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001109 18413740 f lperfetto "In contrast, an increase in BAG-1, BAG-3, and BAG-4 gene expression was observed in HCT116 cells overexpressing either DNMT1 (DNMT1+) or DNMT3B (DNMT3B+)" SIGNOR-254110 DNMT1 protein P26358 UNIPROT ESR1 protein P03372 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001570 23242655 f "Our previous studies demonstrated that mutant p53 along with repression complex proteins including DNMT1, HDAC1 and MeCP2 is associated with ER-negative promoter in MDA-MB-468 cells." SIGNOR-254027 DNMT1 protein P26358 UNIPROT IL32 protein P24001 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000018 20889550 f lperfetto "A virus or dsRNA in human PBMCs from healthy volunteers. We demonstrate that the NF-κB and CREB pathways play key roles in the activation of IL-32 production in response to influenza virus infection in A549 human lung epithelial cells.|Overexpression assays combined with RNA interference show that DNA methyltransferases DNMT1 and DNMT3b are critical for IL32 promoter methylation and gene silencing before viral infection." SIGNOR-254126 DNMT1 protein P26358 UNIPROT MBD2 protein Q9UBB5 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000815 15618232 f lperfetto "We then examined the levels of DNMT1 and methylated DNA-binding protein 2 (MBD2) expressions in these cells to determine whether this reduction in uPA expression is associated with changes in the DNA methylation machinery. Our results showed that ectopic expression of RAS induced DNMT1 expression and activity and inhibited MBD2 expression." SIGNOR-254128 DNMT1 protein P26358 UNIPROT DNMT1/DNMT3A complex SIGNOR-C42 SIGNOR "form complex" binding 9606 12145218 t miannu "We show that the human de novo enzymes hdnmt3a and hdnmt3b form complexes with the major maintenance enzyme hdnmt1 /in vivo co-expression of hdnmt1 and hdnmt3a or hdnmt3b leads to methylation spreading in the genome, suggesting co-operation between de novo and maintenance enzymes during dna methylation" SIGNOR-90836 DNMT1 protein P26358 UNIPROT DNMT1/DNMT3B complex SIGNOR-C43 SIGNOR "form complex" binding 9606 12145218 t miannu "We show that the human de novo enzymes hdnmt3a and hdnmt3b form complexes with the major maintenance enzyme hdnmt1 /in vivo co-expression of hdnmt1 and hdnmt3a or hdnmt3b leads to methylation spreading in the genome, suggesting co-operation between de novo and maintenance enzymes during dna methylation" SIGNOR-90839 PAX6 protein P26367 UNIPROT GCG protein P01275 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000120 12783165 f miannu "In the heterologous cell line BHK-21, Pdx1 inhibited by 60 to 80% the activation of the alpha-cell specific element G1 conferred by Pax-6 and/or Cdx-2/3. Although Pdx1 could bind three AT-rich motifs within G1, two of which are binding sites for Pax-6 and Cdx-2/3, the affinity of Pdx1 for G1 was much lower as compared to Pax-6. In addition, Pdx1 inhibited Pax-6 mediated activation through G3, to which Pdx1 was unable to bind. Moreover, a mutation impairing DNA binding of Pdx1 had no effect on its inhibition on Cdx-2/3. Since Pdx1 interacts directly with Pax-6 and Cdx-2/3 forming heterodimers, we suggest that Pdx1 inhibits glucagon gene transcription through protein to protein interactions with Pax-6 and Cdx-2/3." SIGNOR-254905 PAX6 protein P26367 UNIPROT PAX6 protein P26367 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001874 17251190 f Regulation miannu "Pax6-stimulated activity of the Pax6 promoter is repressed by TGFβ signalling. TGFβ receptor activation represses Pax6 promoter activity by releasing Pax6 from autoregulating its own promoter." SIGNOR-251873 PAX6 protein P26367 UNIPROT CTNND2 protein Q9UQB3 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 16973151 f "Indirect:regulation of expression" miannu "In Pax6 mutant embryos, delta-catenin expression was severely reduced in the optic vesicle neural ectoderm, in the ventricular zone of the neocortex and in the external granule layer of the cerebellum. We identified a Pax6 binding site in delta-catenin promoter that is conserved between mice and humans and which is effectively bound by Pax6 in vitro. Our results suggest that Pax6 regulates delta-catenin expression during CNS development in mice." SIGNOR-251878 PAX6 protein P26367 UNIPROT CDX2/PAX6/P300 complex SIGNOR-C33 SIGNOR "form complex" binding 9606 10506141 t lperfetto "In the present study, we investigated the interaction of cdx-2 and pax-6 with p300, a co-activator coupled to the basal transcription machinery. In transient transfection-expression experiments, we found that the transactivating effects of cdx-2 and pax-6 on the glucagon gene were greatly enhanced by the additional expression of p300." SIGNOR-70963 U2AF2 protein P26368 UNIPROT ZRSR2/U2AF2 complex SIGNOR-C81 SIGNOR "form complex" binding 9606 9237760 t miannu "Recognition of a functional 3' splice site in pre-mrna splicing requires a heterodimer of the proteins u2af65/u2af35." SIGNOR-50173 ELAVL4 protein P26378 UNIPROT ADAM10 protein O14672 UNIPROT "up-regulates quantity" "post transcriptional regulation" 9606 BTO:0000793 19221430 t miannu "Neuronal ELAV (nELAV) proteins are RNA-binding proteins which play a physiological role in controlling gene expression in memory formation, and their alteration may contribute to cognitive impairment associated with neurodegenerative pathologies such as Alzheimer's disease (AD). The experiments show for the first time that ADAM10mRNA represents a nELAV target and that these RNA-binding proteins can play a role in the post-transcriptional regulation of ADAM10 expression. nELAV proteins specifically bind the ADAM10 mRNA and this binding is disrupted following Aβ exposure" SIGNOR-266865 HMGB2 protein P26583 UNIPROT POU2F1 protein P14859 UNIPROT "up-regulates activity" binding 10090 BTO:0002910 7720710 t 2 miannu "HMG2 and Oct2 interact via their HMG domains and POU homeodomains, respectively. This interaction is not restricted to Oct2, as other members of the octamer transcription factor family like Oct1 and Oct6 also interact with HMG2. The interaction with HMG2 results in a marked increase in the sequence-specific DNA binding activity of the Oct proteins" SIGNOR-240151 HMGB2 protein P26583 UNIPROT POU3F1 protein Q03052 UNIPROT "up-regulates activity" binding 10090 BTO:0002910 7720710 t 2 miannu "HMG2 and Oct2 interact via their HMG domains and POU homeodomains, respectively. This interaction is not restricted to Oct2, as other members of the octamer transcription factor family like Oct1 and Oct6 also interact with HMG2. The interaction with HMG2 results in a marked increase in the sequence-specific DNA binding activity of the Oct proteins" SIGNOR-240148 CD27 protein P26842 UNIPROT BCL2L1 protein Q07817 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000776 12324477 f gcesareni "Cd40 ligation up-regulated bcl-2 and bcl-xl as much as 9.7- (p < 0.01) and 6.8-fold (p < 0.01), respectively (fig. 2, b and c). Under similar conditions, cd27 ligation also up-regulated bcl-2 and bcl-xl as much as 5.0- (p < 0.01) and 3.9-fold (p < 0.01), respectively." SIGNOR-93320 MST1 protein P26927 UNIPROT H2BC3 protein P33778 UNIPROT up-regulates phosphorylation Ser15 APAPKKGsKKAITKA 9606 21212262 t lperfetto "The mst1 is a serine/threonine kinase that is activated upon apoptotic stimulation, which in turn activates its downstream targets, jnk/p38, histone h2b and foxo. Mst1 induces apoptosis by phosphorylating histone h2b on a relatively conserved site, ser-14 in mammalian cells" SIGNOR-171005 MST1 protein P26927 UNIPROT STK4 protein Q13043 UNIPROT up-regulates phosphorylation Thr183 DTMAKRNtVIGTPFW 9606 11805089 t llicata "We directly show that okadaic acid induces phosphorylation in the activation loop of mst, and, once phosphorylated, mst is rapidly translocated to the nucleus. when thr183 in mst1 was mutated to ala, no band could be detected by oa treatment,2 indicating that thr183 was the site of phosphorylation." SIGNOR-114289 IL3RA protein P26951 UNIPROT JAK2 protein O60674 UNIPROT up-regulates binding 9606 15795318 t gcesareni "Indeed, only upon fibronectin adhesion is janus kinase 2 (jak2) recruited to the beta1 integrin-il-3r complex and triggers il-3r beta common phosphorylation, leading to the formation of docking sites for activated stat5a." SIGNOR-134859 IL3RA protein P26951 UNIPROT STAT5A protein P42229 UNIPROT up-regulates 9606 15795318 f gcesareni "We previously demonstrated that integrin-dependent adhesion activates stat5a, a well known target of il-3-mediated signaling" SIGNOR-134862 CNTFR protein P26992 UNIPROT STAT3 protein P40763 UNIPROT up-regulates 9606 10582086 f gcesareni "Clc/clf activates stat1 and stat3." SIGNOR-72774 CNTFR protein P26992 UNIPROT STAT1 protein P42224 UNIPROT up-regulates 9606 10582086 f gcesareni "Signal transduction by cntf requires that it bind first to cntfr alpha, permitting the recruitment of gp130 and lifr beta, forming a tripartite receptor complex. Cntf-induced heterodimerization of the beta receptor subunits leads to tyrosine phosphorylation (through constitutively associated jaks), and the activated receptor provides docking sites for sh2-containing signaling molecules, such as stat proteins." SIGNOR-72771 ACVR2A protein P27037 UNIPROT ACVR1B protein P36896 UNIPROT up-regulates phosphorylation 9606 BTO:0000007 12682303 t acerquone "In this complex, the actrii??/Iib kinase phosphorylates alk4 within a glycine- and serine-rich region called the gs domain, and this phosphorylation event activates the alk4 kinase" SIGNOR-99995 ACVR2A protein P27037 UNIPROT ACVR1 protein Q04771 UNIPROT up-regulates binding 9606 9748228 t fspada "The major bmp7 type i receptor observed was alk2," SIGNOR-60234 STOM protein P27105 UNIPROT SLC2A1 protein P11166 UNIPROT "down-regulates activity" binding 9606 10562431 t Giulio "Similar to the results obtained in the RBC, Glut1 and stomatin immunoprecipitated with each other in lysates of Clone 9 cells. The above results suggest that stomatin is closely associated with Glut1 in the plasma membrane and that overexpression of stomatin results in a depression in the basal rate of glucose transport." SIGNOR-261278 STOM protein P27105 UNIPROT "4.1 complex" complex SIGNOR-C386 SIGNOR "form complex" binding 9606 BTO:0000424 33187473 t lperfetto "The cytoskeleton plays a key role in maintaining the morphology and function of erythrocyte membranes. Many proteins, such as ankyrin, spectrin alpha- and beta-chains, proteins 4.1, or 4.1R and actin, cover the inner surface of the erythrocyte membrane to form two protein complexes, the ankyrin and protein 4.1 complex| the latter consists of Band 3 dimers binding Adducins alpha and beta, Glycophorin C, GLUT1 and Stomatin [15, 16]" SIGNOR-266040 MAOB protein P27338 UNIPROT 3-methoxytyramine smallmolecule CHEBI:1582 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 BTO:0004032;BTO:0002606 NBK536726 t brain lperfetto "Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells |dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO." SIGNOR-264000 MAPK3 protein P27361 UNIPROT APBB1 protein O00213 UNIPROT unknown phosphorylation Ser175 EEEEDLSsPPGLPEP 9606 14697653 t lperfetto "Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved." SIGNOR-120467 MAPK3 protein P27361 UNIPROT APBB1 protein O00213 UNIPROT unknown phosphorylation Ser287 WEPPGRAsPSQGSSP 9606 14697653 t lperfetto "Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved." SIGNOR-120475 MAPK3 protein P27361 UNIPROT APBB1 protein O00213 UNIPROT unknown phosphorylation Ser347 TFPAQSLsPEPLPQE 9606 14697653 t lperfetto "Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved." SIGNOR-120479 MAPK3 protein P27361 UNIPROT APBB1 protein O00213 UNIPROT unknown phosphorylation Thr709 PKRLGAHtP 9606 14697653 t lperfetto "Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved." SIGNOR-120483 MAPK3 protein P27361 UNIPROT SYN3 protein O14994 UNIPROT up-regulates phosphorylation Ser470 PQGQQPLsPQSGSPQ 9606 BTO:0000938 14732590 t lperfetto "A rare, missense polymorphism, s470n, was identified in the synapsin iii gene and appeared more frequently in individuals with schizophrenia than in controls. Ser470, was determined to be a substrate for mitogen-activated protein kinase, a downstream effector of neurotrophin action." SIGNOR-121402 MAPK3 protein P27361 UNIPROT BCL2L11 protein O43521 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser69 GPLAPPAsPGPFATR 9606 15486195 t lperfetto "In vitro, bimel was phosphorylated by extracellular signal-regulated kinase on ser(69), which resides in the bimel-specific insert region. Using phosphospecific antibody against this site, we show that this residue is actually phosphorylated in cells. We also show that phosphorylation of ser(69) promotes ubiquitination of bimel. We conclude that mek inhibitors sensitize mda-mb231 and hbc4 cells to anoikis by blocking phosphorylation and hence degradation of bimel" SIGNOR-129878 MAPK3 protein P27361 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser294 QLSKWPGsPTSRSSD 9606 19282669 t lperfetto "Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway" SIGNOR-184569 MAPK3 protein P27361 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser344 QDDDAPLsPMLYSSS 9606 19282669 t lperfetto "Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway" SIGNOR-184573 MAPK3 protein P27361 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser425 TKGSGLGsPTSSFNS 9606 19282669 t lperfetto "Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway" SIGNOR-184577 MAPK3 protein P27361 UNIPROT MITF protein O75030 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser180 PGSSAPNsPMAMLTL 10841026 t lperfetto "More interestingly, ERK-dependent phosphorylation of MITF at Ser 73 is essential for MITF ubiquitinilation and degradation (87). Putting together all these findings, it can be proposed that MAPK activation inhibits melanogenesis due to an increased MITF degradation which is dependent on the MAPK-induced MITF phosphorylation and ubiquitinilation. In summary, although the phosphorylation of MITF at Ser73 increases its intrinsic transcriptional activity, this phosphorylation also targets MITF to the proteasome for its degradation. Consequently, the decrease in MITF levels leads to a down-regulation of melanogenic enzymes expression and to an inhibition of melanogenesis." SIGNOR-249620 MAPK3 protein P27361 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Ser360 TEMDPTYsPAALPQS 9606 15568999 t gcesareni "In the present study, we show that, in addition to being phosphorylated on thr-581 and ser-360 by erk1/2 or p38, msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758." SIGNOR-131379 MAPK3 protein P27361 UNIPROT RPS6KA5 protein O75582 UNIPROT "up-regulates activity" phosphorylation Ser376 EKLFQGYsFVAPSIL 15568999 t lperfetto "In the present study, we show that, in addition to being phosphorylated on Thr-581 and Ser-360 by ERK1/2 or p38, MSK1 can autophosphorylate on at least six sites: Ser-212, Ser-376, Ser-381, Ser-750, Ser-752 and Ser-758. Of these sites, the N-terminal T-loop residue Ser-212 and the 'hydrophobic motif' Ser-376 are phosphorylated by the C-terminal kinase domain of MSK1, and their phosphorylation is essential for the catalytic activity of the N-terminal kinase domain of MSK1" SIGNOR-249479 MAPK3 protein P27361 UNIPROT RPS6KA4 protein O75676 UNIPROT up-regulates phosphorylation 9606 9792677 t lperfetto "Rsk-b is a p38alphamapk substrate, and activated by p38alphamapk and, more weakly, by erk1" SIGNOR-60998 MAPK3 protein P27361 UNIPROT NFATC1 protein O95644 UNIPROT down-regulates phosphorylation Ser172 YRDPSCLsPASSLSS 9606 10652349 t "Translocation from Nucleus to Cytoplasm" esanto "We show that jnk, erk, and p38 physically associate with the nfatc n-terminal regulatory domain and can directly phosphorylate functionally important residues involved in regulating nfatc subcellular localization, namely ser(172) and the conserved nfatc ser-pro repeats." SIGNOR-74564 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1717 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120200 MAPK3 protein P27361 UNIPROT EGFR protein P00533 UNIPROT down-regulates phosphorylation Thr693 RELVEPLtPSGEAPN 9606 1651322 t lperfetto "It is likely that the map2 and ert kinases account for the phosphorylation of the egf receptor at thr669 (egf receptor (krel veplt669psgeapnqallr)) observed in cultured cells.Phosphorylation at ser-695 is partial and occurs only if thr-693 is phosphorylated. Phosphorylation at thr-678 and thr-693 by prkd1 inhibits egf-induced mapk8/jnk1 activation." SIGNOR-20549 MAPK3 protein P27361 UNIPROT FOS protein P01100 UNIPROT up-regulates phosphorylation Thr232 GGLPEVAtPESEEAF 9606 7816602 t lperfetto "Phosphorylation of the c-fos and c-jun hob1 motif stimulates its activation capacity here we show that the hob1-containing activation domain of c-fos is stimulated by ha-ras in vivo and phosphorylated by a map kinase family member in vitro and that mutating t232 to ala abolishes both functions." SIGNOR-33909 MAPK3 protein P27361 UNIPROT FOS protein P01100 UNIPROT "up-regulates activity" phosphorylation Ser374 PSSDSLSsPTLLAL 9606 12972619 t lperfetto "In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity." SIGNOR-118023 MAPK3 protein P27361 UNIPROT FOS protein P01100 UNIPROT "up-regulates activity" phosphorylation Thr325 TELEPLCtPVVTCTP 9606 12972619 t lperfetto "In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity." SIGNOR-118027 MAPK3 protein P27361 UNIPROT FOS protein P01100 UNIPROT "up-regulates activity" phosphorylation Thr325 TELEPLCtPVVTCTP phosphorylation:Ser374;Ser362 PSSDSLSsPTLLAL;AAAHRKGsSSNEPSS 16055710 t lperfetto "Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos" SIGNOR-263012 MAPK3 protein P27361 UNIPROT FOS protein P01100 UNIPROT "up-regulates activity" phosphorylation Thr331 CTPVVTCtPSCTAYT phosphorylation:Ser374;Ser362 PSSDSLSsPTLLAL;AAAHRKGsSSNEPSS 16055710 t lperfetto "Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos" SIGNOR-263008 MAPK3 protein P27361 UNIPROT MBP protein P02686 UNIPROT down-regulates phosphorylation Thr232 KNIVTPRtPPPSQGK 9606 BTO:0000142 16401070 t lperfetto "Phosphorylation decreased the ability of mbp to polymerize actin and to bundle actin filaments but had no effect on the dissociation constant of the mbp-actin complex or on the ability of ca2+-calmodulin to dissociate the complex. The most significant effect of phosphorylation on the mbp-actin complex was a dramatic reduction in its ability to bind to negatively charged lipid bilayers. The identification of myelin basic protein (phosphorylation at -pro-arg-thr-pro-) as a substrate for the erk kinases (fig. 1) demonstrates that there are other determinants important for substrate recognition than those present in the originally identified consensus sequence." SIGNOR-143481 MAPK3 protein P27361 UNIPROT MBP protein P02686 UNIPROT down-regulates phosphorylation Thr232 KNIVTPRtPPPSQGK 9606 1939237 t lperfetto "Phosphorylation decreased the ability of mbp to polymerize actin and to bundle actin filaments but had no effect on the dissociation constant of the mbp-actin complex or on the ability of ca2+-calmodulin to dissociate the complex. The most significant effect of phosphorylation on the mbp-actin complex was a dramatic reduction in its ability to bind to negatively charged lipid bilayers. The identification of myelin basic protein (phosphorylation at -pro-arg-thr-pro-) as a substrate for the erk kinases (fig. 1) demonstrates that there are other determinants important for substrate recognition than those present in the originally identified consensus sequence." SIGNOR-22424 MAPK3 protein P27361 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser104 FPPLNSVsPSPLMLL 9606 BTO:0000567 17615152 t gcesareni "In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity" SIGNOR-156860 MAPK3 protein P27361 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser106 PLNSVSPsPLMLLHP 9606 BTO:0000567 17615152 t gcesareni "In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity" SIGNOR-156864 MAPK3 protein P27361 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 BTO:0000567 17615152 t gcesareni "In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo." SIGNOR-156868 MAPK3 protein P27361 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser301 SSSPNNLsPTGWSQP 9606 16407412 t gcesareni "Using mass spectrometry, we identified raf-1 phosphorylation on three sp motif sites: s289/s296/s301. These sites were phosphorylated by extracellular signal-regulated kinase (erk)-1 in vitro, and their phosphorylation in vivo was dependent on endogenous erk activity. Functionally, erk-1 expression sustains raf-1 activation in a manner dependent on raf-1 phosphorylation on the identified sites, and s289/296/301a substitution markedly decreases the in vivo activity of raf-1 s259a." SIGNOR-143696 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1724 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120204 MAPK3 protein P27361 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation 9606 9922370 t gcesareni "Mapkerk1/2 is also able to phopshorylate the egf receptor, the ras exchange factor sos, mkkkraf1, and mkkmek1. The phosphorylation of each of these proteins by mapkerk1/2 is believed to reduce their catalytic activity. previous studies have shown that phosphorylation is required for raf-1 activation, and here, we identify six phosphorylation sites that contribute to the downregulation of raf-1 after mitogen stimulation. Five of the identified sites are proline-directed targets of activated erk" SIGNOR-64172 MAPK3 protein P27361 UNIPROT RAF1 protein P04049 UNIPROT "down-regulates activity" phosphorylation Ser289 RSHSESAsPSALSSS 10090 15664191 t lperfetto "Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2" SIGNOR-143688 MAPK3 protein P27361 UNIPROT RAF1 protein P04049 UNIPROT "down-regulates activity" phosphorylation Ser296 SPSALSSsPNNLSPT 10090 15664191 t lperfetto "Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2" SIGNOR-143692 MAPK3 protein P27361 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates phosphorylation Ser226 IDENCLLsPLAGEDD -1 9199329 t lperfetto "Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232.|MAPKs and CDKs exert opposite effects on receptor transcriptional enhancement. From our results, we speculate that activators of the MAPK pathway, such as growth factors, insulin, and certain oncoproteins, or inhibitors of CDK function, such as tumor growth factor beta (TGF_), p21, and p27, might attenuate receptor-induced transcrip- tional responses. In contrast, negative regulators of MAPK, such as pKA, as well as activators of CDK, such as the cyclins or CAKs, should potentiate receptor action." SIGNOR-154409 MAPK3 protein P27361 UNIPROT LCK protein P06239 UNIPROT "up-regulates activity" phosphorylation Ser59 EGSNPPAsPLQDNLV 9606 BTO:0000567 8618896 t lperfetto "Phosphorylation at Ser-59 (or alternatively, its mutation to Glu) reverses the inhibition and allows interaction of the p56lck SH2 domain with p62.|phosphotyrosine-independent binding of p62 to the p56lck SH2 domain appears to provide an alternative pathway for p56lck signaling that is regulated by Ser-59 phosphorylation." SIGNOR-249469 MAPK3 protein P27361 UNIPROT PGR protein P06401 UNIPROT down-regulates phosphorylation Ser294 APMAPGRsPLATTVM 9606 BTO:0000150 10655479 t gcesareni "Specifically, down-regulation of mature prs occurs by a mechanism in which ligand binding activates pr phosphorylation by mapks at a unique serine residue, which then targets the receptors for degradation." SIGNOR-74716 MAPK3 protein P27361 UNIPROT TH protein P07101 UNIPROT up-regulates phosphorylation Ser62 SYTPTPRsPRFIGRR 9606 7901013 t gcesareni "In this paper we have studied the phosphorylation and activation of alternatively spliced forms of human th by mapkap kinase-1 , mapkap kinase-2, map kinase, and cam kinase-11" SIGNOR-34678 MAPK3 protein P27361 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr739 SEGSGTAtPSALITT 9606 11904305 t gcesareni "Here we show that p42/p44 mapk directly phosphorylates sp1 on threonines 453 and 739 both in vitro and in vivo. sa-perk1/2 activates the transcription factor, sp1, via ser59 phosphorylation downstream of pkc_, leading to transcription of p21sdi1 and resulting in replicative senescence of hdf cells." SIGNOR-116174 MAPK3 protein P27361 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr453 SGPIIIRtPTVGPNG 9606 BTO:0000887;BTO:0001260 14593115 t gcesareni "We showed that perifosine activates the mitogen-activated protein/extracellular signal-regulated kinase pathway, and this activation promotes the phosphorylation of sp1 in known mitogen-activated protein kinase residues (threonine 453 and 739), thereby leading to increased sp1 binding and enhanced p21(waf1/cip1) transcription." SIGNOR-248066 MAPK3 protein P27361 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr739 SEGSGTAtPSALITT 9606 BTO:0000887;BTO:0001260 14593115 t gcesareni "We showed that perifosine activates the mitogen-activated protein/extracellular signal-regulated kinase pathway, and this activation promotes the phosphorylation of sp1 in known mitogen-activated protein kinase residues (threonine 453 and 739), thereby leading to increased sp1 binding and enhanced p21(waf1/cip1) transcription." SIGNOR-118936 MAPK3 protein P27361 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr453 SGPIIIRtPTVGPNG 9606 BTO:0000552 14744793 t gcesareni "We showed that perifosine activates the mitogen-activated protein/extracellular signal-regulated kinase pathway, and this activation promotes the phosphorylation of sp1 in known mitogen-activated protein kinase residues (threonine 453 and 739), thereby leading to increased sp1 binding and enhanced p21(waf1/cip1) transcription." SIGNOR-248062 MAPK3 protein P27361 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr739 SEGSGTAtPSALITT 9606 BTO:0000552 14744793 t gcesareni "We showed that perifosine activates the mitogen-activated protein/extracellular signal-regulated kinase pathway, and this activation promotes the phosphorylation of sp1 in known mitogen-activated protein kinase residues (threonine 453 and 739), thereby leading to increased sp1 binding and enhanced p21(waf1/cip1) transcription." SIGNOR-248070 MAPK3 protein P27361 UNIPROT ALOX5 protein P09917 UNIPROT "up-regulates activity" phosphorylation Ser272 CSLERQLsLEQEVQQ 9606 BTO:0000567 12670876 t lperfetto "Intriguingly, a significant difference in the potency of nonredox-type inhibitors (but not of BWA4C) was determined between wild-type 5-LO and the mutant S271A/S663A-5-LO (lacking phosphorylation sites for ERK1/2 and MAPKAPK-2) in HeLa cells. Collectively, our data suggest that compared with Ca2+-mediated 5-LO product formation, enzyme activation involving 5-LO phosphorylation events specifically and strongly alters the susceptibility of 5-LO toward nonredox-type inhibitors in intact cells." SIGNOR-264441 MAPK3 protein P27361 UNIPROT GJA1 protein P17302 UNIPROT "down-regulates activity" phosphorylation Ser282 TAPLSPMsPPGYKLV 9606 BTO:0000567 9535909 t lperfetto "These studies confirm that connexin-43 is a MAP kinase substrate in vivo and that phosphorylation on Ser255, Ser279, and/or Ser282 initiates the down-regulation of gap junctional communication. Studies with connexin-43 mutants suggest that MAP kinase phosphorylation at one or more of the tandem Ser279/Ser282 sites is sufficient to disrupt gap junctional intercellular communication." SIGNOR-249467 MAPK3 protein P27361 UNIPROT ALOX5 protein P09917 UNIPROT "up-regulates activity" phosphorylation Ser664 QLPYYYLsPDRIPNS 9606 BTO:0000567 12670876 t lperfetto "Intriguingly, a significant difference in the potency of nonredox-type inhibitors (but not of BWA4C) was determined between wild-type 5-LO and the mutant S271A/S663A-5-LO (lacking phosphorylation sites for ERK1/2 and MAPKAPK-2) in HeLa cells. Collectively, our data suggest that compared with Ca2+-mediated 5-LO product formation, enzyme activation involving 5-LO phosphorylation events specifically and strongly alters the susceptibility of 5-LO toward nonredox-type inhibitors in intact cells." SIGNOR-264440 MAPK3 protein P27361 UNIPROT MYB protein P10242 UNIPROT down-regulates phosphorylation Ser532 KIKQEVEsPTDKSGN 9606 8798443 t llicata "Here we describe that human c-myb can be phosphorylated by mitogen-activated protein kinases (mapk's) at serine 532 of the carboxy (c-) terminal regulatory domain in vitro. expression of a constitutively active form of ras together with c-myb in transient transfection experiments had no effect on the transcriptional activity of c-myb, while expression of a polypeptide containing the c-myb c-terminal domain stimulated c-myb activity. This effect is reduced upon mapk-dependent phosphorylation of serine 532." SIGNOR-43558 MAPK3 protein P27361 UNIPROT MYB protein P10242 UNIPROT down-regulates phosphorylation Ser532 KIKQEVEsPTDKSGN 9606 BTO:0000661 8960373 t lperfetto "Functional analysis of phosphorylation at serine 532 of human c-myb by map kinase. expression of a polypeptide containing the c-myb c-terminal domain stimulated c-myb activity. This effect is reduced upon mapk-dependent phosphorylation of serine 532. Our data suggest that the mapk-dependent state of phosphorylation modifies the cellular function of c-myb by modulating its interaction with a putative inhibitory factor" SIGNOR-45348 MAPK3 protein P27361 UNIPROT BCL2 protein P10415 UNIPROT up-regulates phosphorylation Ser70 RDPVARTsPLQTPAA 9606 10669763 t gcesareni "Erk1 and erk2 directly phosphorylate bcl2 exclusively at ser-70 p44mapk/extracellular signal-regulated kinase 1 (erk1) and p42 mapk/erk2 are activated by il-3, colocalize with mitochondrial bcl2, and can directly phosphorylate bcl2 on ser-70 in a stauro-resistant manner both in vitro and in vivo molecular association." SIGNOR-74935 MAPK3 protein P27361 UNIPROT BCL2 protein P10415 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr56 FSSQPGHtPHPAASR 9606 10669763 t gcesareni "Phosphorylation of the map kinase sites in bcl-2, thr56, thr74, and ser87, is sufficient to inhibit tnf--induced degradation. p44mapk/extracellular signal-regulated kinase 1 (erk1) and p42 mapk/erk2 are activated by il-3, colocalize with mitochondrial bcl2, and can directly phosphorylate bcl2 on ser-70 in a stauro-resistant manner both_ in vitro_ and_ in vivo." SIGNOR-74939 MAPK3 protein P27361 UNIPROT THRB protein P10828 UNIPROT "down-regulates activity" phosphorylation Ser142 IQKNLHPsYSCKYEG 9606 12809513 t llicata "We concluded that serine 142 of the tr dbd is the likely site of phosphorylation by t(4)-activated mapk and that the docking site on tr for activated mapk includes residues 128-133 (kgffrr), a basic amino acid-enriched motif novel for mapk substrates. Tr mutations in the proposed mapk docking domain and at residue 142 modulated t(4)-conditioned shedding of co-repressor and recruitment of co-activator proteins by the receptor, and they altered transcriptional activity of tr in a thyroid hormone response element-luciferase reporter assay." SIGNOR-102224 MAPK3 protein P27361 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser345 QARPGPQsPGSPLEE 9606 BTO:0000130 16778989 t gcesareni "Inhibitors of the erk1/2 pathway abrogated gm-csf-induced phosphorylation of ser345, while p38 mapk inhibitor abrogated tnf-alpha-induced phosphorylation of ser345.These results show that the ala-mutated p47phox acts as a dominant-negative inhibitor of endogenous p47phox and clearly indicate that phosphorylation of ser345 is required for the priming of nadph oxidase activity in neutrophil-like cells." SIGNOR-147174 MAPK3 protein P27361 UNIPROT ETS1 protein P14921 UNIPROT up-regulates phosphorylation Thr38 CADVPLLtPSSKEMM 9606 11948414 t gcesareni "We found that hgf/sf activates the erk1 map kinase, leading to the phosphorylation of the threonine 38 residue of ets1" SIGNOR-116494 MAPK3 protein P27361 UNIPROT BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr753 YACASPKtPIQAGGY 9606 16508002 t gcesareni "Erk-induced phosphorylation of b-raf on t753 promoted the disassembly of raf heterodimers, and the mutation of t753 prolonged growth factor-induced heterodimerization. The b-raf t753a mutant enhanced differentiation of pc12 cells, which was previously shown to be dependent on sustained erk signaling. Site is critical for v-src dependent modulation of slk kinase activity." SIGNOR-144827 MAPK3 protein P27361 UNIPROT BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr753 YACASPKtPIQAGGY 9606 19933846 t gcesareni "Erk-induced phosphorylation of b-raf on t753 promoted the disassembly of raf heterodimers, and the mutation of t753 prolonged growth factor-induced heterodimerization. The b-raf t753a mutant enhanced differentiation of pc12 cells, which was previously shown to be dependent on sustained erk signaling. Site is critical for v-src dependent modulation of slk kinase activity." SIGNOR-161819 MAPK3 protein P27361 UNIPROT BRAF protein P15056 UNIPROT "down-regulates activity" phosphorylation Ser151 VARSNPKsPQKPIVR 9606 BTO:0000848 21478863 t "We show that overactivation of the MAPK pathway, induced by the oncogenic Ras in melanoma, induces constitutive phosphorylation of BRAF on Ser151 by ERK, which inhibits NRAS-BRAF interaction" SIGNOR-259921 MAPK3 protein P27361 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 12110590 t gcesareni "Here, we show that in fibroblasts, insulin, epidermal growth factor (egf) and serum activate atf2 via a so far unknown two-step mechanism involving two distinct ras effector pathways: the raf-mek-erk pathway induces phosphorylation of atf2 thr71, whereas subsequent atf2 thr69 phosphorylation requires the ral-ralgds-src-p38 pathway." SIGNOR-90529 MAPK3 protein P27361 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 12110590 t gcesareni "Here, we show that in fibroblasts, insulin, epidermal growth factor (egf) and serum activate atf2 via a so far unknown two-step mechanism involving two distinct ras effector pathways: the raf-mek-erk pathway induces phosphorylation of atf2 thr71, whereas subsequent atf2 thr69 phosphorylation requires the ral-ralgds-src-p38 pathway." SIGNOR-90533 MAPK3 protein P27361 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 20068231 t gcesareni "Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity." SIGNOR-163254 MAPK3 protein P27361 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 20068231 t gcesareni "Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity." SIGNOR-163258 MAPK3 protein P27361 UNIPROT JUND protein P17535 UNIPROT up-regulates phosphorylation Ser100 LGLLKLAsPELERLI 9606 22327296 t gcesareni "Menin binds the jun family transcription factor jund and inhibits its transcriptional activity. The menin-jund interaction blocks jun n-terminal kinase (jnk)-mediated jund phosphorylation and suppresses jund-induced transcription. We found a role for phosphorylation of the ser100 residue of jund;jund phosphorylation were prevented by inhibitors of calcium, calmodulin, or erk1/2 kinase." SIGNOR-196034 MAPK3 protein P27361 UNIPROT TAL1 protein P17542 UNIPROT down-regulates phosphorylation Ser122 DGRMVQLsPPALAAP 9606 11904294 t gcesareni "We report here that the important proangiogenic stimulus hypoxia stimulates phosphorylation, ubiquitination, and proteasomal breakdown of tal1 in endothelial cells. A specific serine in the putative transactivation domain of the protein, ser122, is preferentially phosphorylated by mapk in vitro." SIGNOR-116153 MAPK3 protein P27361 UNIPROT CAPN2 protein P17655 UNIPROT up-regulates phosphorylation Ser50 GTLFQDPsFPAIPSA 9606 14993287 t lperfetto "Epidermal growth factor activates m-calpain (calpain ii), at least in part, by extracellular signal-regulated kinase-mediated phosphorylation.We now show that erk directly phosphorylates and activates m-calpain both in vitro and in vivo. We identified serine 50 as required for epidermal growth factor (egf)-induced calpain activation in vitro and in vivo." SIGNOR-123083 MAPK3 protein P27361 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser422 LSTPVVLsPGPQKP 9606 7889942 t gcesareni "Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency." SIGNOR-34665 MAPK3 protein P27361 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Thr336 GGPGPERtPGSGSGS 9606 7889942 t gcesareni "Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency." SIGNOR-34669 MAPK3 protein P27361 UNIPROT RXRA protein P19793 UNIPROT "down-regulates activity" phosphorylation Ser260 NMGLNPSsPNDPVTN 9606 17604322 t lperfetto "In colon cancer cells, the Ras/mitogen‐activated protein kinase (MAPK) pathway phosphorylates RXRalpha, which impairs its function as a heterodimeric partner for PPARgamma|A point‐mutated RXRalpha T82A/S260A, which mimics the unphosphorylated form of RXRalpha, can form a heterodimer with PPARgamma and thereby activate target gene expression by binding to the PPRE" SIGNOR-88662 MAPK3 protein P27361 UNIPROT RXRA protein P19793 UNIPROT "down-regulates activity" phosphorylation Thr82 HSMSVPTtPTLGFST 9606 17604322 t lperfetto "In colon cancer cells, the Ras/mitogen‐activated protein kinase (MAPK) pathway phosphorylates RXRalpha, which impairs its function as a heterodimeric partner for PPARgamma|A point‐mutated RXRalpha T82A/S260A, which mimics the unphosphorylated form of RXRalpha, can form a heterodimer with PPARgamma and thereby activate target gene expression by binding to the PPRE" SIGNOR-262959 MAPK3 protein P27361 UNIPROT RPS3 protein P23396 UNIPROT unknown phosphorylation Thr42 SGVEVRVtPTRTEII 9606 15950189 t llicata "Erk phosphorylates threonine 42 residue of ribosomal protein s3." SIGNOR-137959 MAPK3 protein P27361 UNIPROT RPS3 protein P23396 UNIPROT up-regulates phosphorylation Thr42 SGVEVRVtPTRTEII 9606 15950189 t lperfetto "Erk phosphorylates threonine 42 residue of ribosomal protein s3." SIGNOR-137175 MAPK3 protein P27361 UNIPROT RPS6KB1 protein P23443 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000176 14967450 t lperfetto "Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase" SIGNOR-121997 MAPK3 protein P27361 UNIPROT RPS6KB1 protein P23443 UNIPROT "up-regulates activity" phosphorylation Ser441 SPRRFIGsPRTPVSP 10116 15774499 t lperfetto "Thr 421/Ser 424 have been reported to be targeted by ERK1, 2 (39), JNK or p38 MAPKs (36). Interestingly, with a comparable kinetics, FSH represses ERK1, 2 constitutive phosphorylation in Sertoli cells isolated from 19-d-old rats" SIGNOR-111515 MAPK3 protein P27361 UNIPROT RPS6KB1 protein P23443 UNIPROT "up-regulates activity" phosphorylation Thr444 RFIGSPRtPVSPVKF 10116 15774499 t lperfetto "Thr 421/Ser 424 have been reported to be targeted by ERK1, 2 (39), JNK or p38 MAPKs (36). Interestingly, with a comparable kinetics, FSH represses ERK1, 2 constitutive phosphorylation in Sertoli cells isolated from 19-d-old rats" SIGNOR-134662 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1619 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120172 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1626 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120176 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1647 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120180 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1668 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120188 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1675 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120192 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1696 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120196 MAPK3 protein P27361 UNIPROT PML protein P29590 UNIPROT up-regulates phosphorylation Ser530 DGPPSPRsPVIGSEV 9606 BTO:0001271 15093545 t "The effect has been demonstrated using P29590-4" gcesareni "Phosphorylation of pml by mitogen-activated protein kinases plays a key role in arsenic trioxide-mediated apoptosis." SIGNOR-124317 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1738 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120208 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1766 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120212 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1787 SPNYSPTsPSYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120216 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1864 SPKYSPTsPKYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120220 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1871 SPKYSPTsPKYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120224 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1882 SPTSPTYsPTTPKYS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120228 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1892 TPKYSPTsPTYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120232 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1899 SPTYSPTsPVYTPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120236 MAPK3 protein P27361 UNIPROT GRK2 protein P25098 UNIPROT down-regulates phosphorylation Ser670 KMKNKPRsPVVELSK 9606 BTO:0000007 10574913 t gcesareni "Erk1 phosphorylates grk2 at ser(670). Inhibition of erk activity in hek293 cells potentiates grk2 activity, whereas, conversely, erk activation inhibits grk2 activity." SIGNOR-72582 MAPK3 protein P27361 UNIPROT MAPK3 protein P27361 UNIPROT "up-regulates activity" phosphorylation Thr202 HDHTGFLtEYVATRW 1712480 t lperfetto "Microtubule-associated protein 2 kinases, ERK1 and ERK2, undergo autophosphorylation on both tyrosine and threonine residues: implications for their mechanism of activation.|" SIGNOR-249471 MAPK3 protein P27361 UNIPROT MAPK3 protein P27361 UNIPROT "up-regulates activity" phosphorylation Tyr204 HTGFLTEyVATRWYR 1712480 t lperfetto "Microtubule-associated protein 2 kinases, ERK1 and ERK2, undergo autophosphorylation on both tyrosine and threonine residues: implications for their mechanism of activation.|" SIGNOR-249472 MAPK3 protein P27361 UNIPROT MAPK3 protein P27361 UNIPROT "up-regulates activity" phosphorylation Thr207 FLTEYVAtRWYRAPE 9606 BTO:0000562 19060905 t lperfetto "Here we show that autophosphorylation of erk1/2 on thr188 directs erk1/2 to phosphorylate nuclear targets known to cause cardiac hypertrophy." SIGNOR-182628 MAPK3 protein P27361 UNIPROT CAD protein P27708 UNIPROT up-regulates phosphorylation Thr456 KVYFLPItPHYVTQV 9606 15890648 t lperfetto "Cad is a multifunctional protein that initiates and regulates mammalian de novo pyrimidine biosynthesis. The activation of the pathway required for cell proliferation is a consequence of the phosphorylation of cad thr-456 by mitogen-activated protein (map) kinase.Activated map kinase (erk1/2), the enzyme responsible for the phosphorylation of thr-456, was also present in larger amounts in the nucleus than the cytosol" SIGNOR-137179 MAPK3 protein P27361 UNIPROT DUSP1 protein P28562 UNIPROT down-regulates phosphorylation Ser296 KQRRSIIsPNFSFMG 9606 16286470 t lperfetto "The dual-specificity mapk phosphatase mkp-1/cl100/dusp1 is an inducible nuclear protein controlled by p44/42 mapk (erk1/2) in a negative feedback mechanism to inhibit kinase activity. Here, we report on the molecular basis for a novel positive feedback mechanism to sustain erk activation by triggering mkp-1 proteolysis. Active erk2 docking to the def motif (fxfp, residues 339-342) of n-terminally truncated mkp-1 in vitro initiated phosphorylation at the ser(296)/ser(323) domain" SIGNOR-141605 MAPK3 protein P27361 UNIPROT DUSP1 protein P28562 UNIPROT down-regulates phosphorylation Ser323 HCSAEAGsPAMAVLD 9606 16286470 t lperfetto "The dual-specificity mapk phosphatase mkp-1/cl100/dusp1 is an inducible nuclear protein controlled by p44/42 mapk (erk1/2) in a negative feedback mechanism to inhibit kinase activity. Here, we report on the molecular basis for a novel positive feedback mechanism to sustain erk activation by triggering mkp-1 proteolysis. Active erk2 docking to the def motif (fxfp, residues 339-342) of n-terminally truncated mkp-1 in vitro initiated phosphorylation at the ser(296)/ser(323) domain" SIGNOR-141609 MAPK3 protein P27361 UNIPROT DUSP1 protein P28562 UNIPROT up-regulates phosphorylation Ser359 SALSYLQsPITTSPS 9606 10617468 t lperfetto "Mkp-1 was a target in vivo and in vitro for p42(mapk) or p44(mapk), which phosphorylates mkp-1 on two carboxyl-terminal serine residues, serine 359 and serine 364. This phosphorylation did not modify mkp-1's intrinsic ability to dephosphorylate p44(mapk) but led to stabilization of the protein." SIGNOR-73629 MAPK3 protein P27361 UNIPROT DUSP1 protein P28562 UNIPROT up-regulates phosphorylation Ser364 LQSPITTsPSC 9606 10617468 t lperfetto "Mkp-1 was a target in vivo and in vitro for p42(mapk) or p44(mapk), which phosphorylates mkp-1 on two carboxyl-terminal serine residues, serine 359 and serine 364. This phosphorylation did not modify mkp-1's intrinsic ability to dephosphorylate p44(mapk) but led to stabilization of the protein." SIGNOR-73633 MAPK3 protein P27361 UNIPROT CIITA protein P33076 UNIPROT down-regulates phosphorylation Ser288 PDRPGSTsPFAPSAT 9606 18245089 t gcesareni "In this study we show that the extracellular signal-regulated kinases 1 and 2 (erk1/2) interact directly with ciita, targeting serine residues in the amino terminus of the protein, including serine 288. These data suggest a model whereby erk1/2-mediated phosphorylation of ciita down-regulates ciita activity by priming it for nuclear export, thus providing a means for cells to tightly regulate the extent of antigen presentation." SIGNOR-160617 MAPK3 protein P27361 UNIPROT CIITA protein P33076 UNIPROT up-regulates phosphorylation Ser280 TVHGLPTsPDRPGST 9606 BTO:0000782;BTO:0000801 17095509 t gcesareni "We found that in these cells, lipopolysaccharide stimulates the expression of mhc ii genes via the activation of erk1/2, which is mediated by toll-like receptor 4. Erk1/2 then phosphorylates the serine at position 357, which is located in a degron of ciita isoform 1 that leads to its monoubiquitylation." SIGNOR-150545 MAPK3 protein P27361 UNIPROT NOS2 protein P35228 UNIPROT up-regulates phosphorylation Ser745 KSRQNLQsPTSSRAT 9606 BTO:0000007 17804409 t esanto "Erk phosphorylated inos on ser745. Mutation of ser745 to ala did not affect basal inos activity but eliminated inos phosphorylation and activation in response to b1r agonist." SIGNOR-157711 MAPK3 protein P27361 UNIPROT PTPN7 protein P35236 UNIPROT "up-regulates activity" phosphorylation Thr66 EPICSVNtPREVTLH -1 16226275 t lperfetto "First, Erk phosphorylates HePTP at residues Thr45 and Ser72. Second, HePTP dephosphorylates Erk at PTyr185.|" SIGNOR-249476 MAPK3 protein P27361 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser636 SGDYMPMsPKSVSAP 9606 12510059 t gcesareni "Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1." SIGNOR-249409 MAPK3 protein P27361 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser616 DDGYMPMsPGVAPVP 9606 15001544 t lperfetto "Rin beta-cells exposed to high glucose exhibited increased c-jun n-terminal kinase (jnk) and erk1/2 activity, which was associated with increased irs-1 phosphorylation at serine (ser)(307) and ser(612), respectively, that inhibits coupling of irs-1 to the insulin receptor and is upstream of the inhibition of irs-1 tyrosine phosphorylation." SIGNOR-123177 MAPK3 protein P27361 UNIPROT SREBF1 protein P36956 UNIPROT "up-regulates activity" phosphorylation Ser117 YPSMPAFsPGPGIKE 9606 BTO:0000599 10915800 t lperfetto "Map kinases erk1/2 phosphorylate sterol regulatory element-binding protein (srebp)-1a at serine 117 in vitro. mutation of serine 117 to alanine abolished erk2-mediated phosphorylation in vitro and the map kinase-related transcriptional activation of srebp-1a by insulin and platelet-derived growth factor in vivo." SIGNOR-80096 MAPK3 protein P27361 UNIPROT PPARG protein P37231 UNIPROT "down-regulates activity" relocalization 9606 18596912 t lperfetto "The genomic activity of ppargamma is modulated, in addition to ligand binding, by phosphorylation of a serine residue by mapks, such as extracellular signal-regulated protein kinases-1/2 (erk-1/2), or by nucleocytoplasmic compartmentalization through the erk activators mapk kinases-1/2 (mek-1/2). These mapks phosphorylate (in humans) ser 84 in the ppargamma1 and ser 114 in ppargamma2 isoform" SIGNOR-179407 MAPK3 protein P27361 UNIPROT PPARG protein P37231 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser112 AIKVEPAsPPYYSEK 9606 11733495 t gcesareni "Moreover, the inhibition of erks 1 and 2 with a mek inhibitor, u1026, lead to an inhibition in the decay of ppargamma proteins, indicating that serine phosphorylation influences the degradation of ppargamma in fat cells." SIGNOR-179404 MAPK3 protein P27361 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 BTO:0001271 BTO:0000671 14551213 t gcesareni "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,92 src,5 janus-activated kinases (jak), and extracellular signal-regulated kinase (erk)a constitutively active galpha16 mutant, galpha16ql, stimulated stat3-dependent luciferase activity as well as the phosphorylation of stat3 at both tyr705 and ser727. Galpha16ql-induced stat3 activation was enhanced by overexpression of extracellular signal-regulated kinase 1 (erk1" SIGNOR-118596 MAPK3 protein P27361 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0001271 BTO:0000671 14551213 t gcesareni "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,92 src,5 janus-activated kinases (jak), and extracellular signal-regulated kinase (erk)a constitutively active galpha16 mutant, galpha16ql, stimulated stat3-dependent luciferase activity as well as the phosphorylation of stat3 at both tyr705 and ser727. Galpha16ql-induced stat3 activation was enhanced by overexpression of extracellular signal-regulated kinase 1 (erk1" SIGNOR-118600 MAPK3 protein P27361 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 19723038 t gcesareni "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,92 src,5 janus-activated kinases (jak), and extracellular signal-regulated kinase (erk)a constitutively active galpha16 mutant, galpha16ql, stimulated stat3-dependent luciferase activity as well as the phosphorylation of stat3 at both tyr705 and ser727. Galpha16ql-induced stat3 activation was enhanced by overexpression of extracellular signal-regulated kinase 1 (erk1" SIGNOR-187779 MAPK3 protein P27361 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 19723038 t gcesareni "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,92 src,5 janus-activated kinases (jak), and extracellular signal-regulated kinase (erk)a constitutively active galpha16 mutant, galpha16ql, stimulated stat3-dependent luciferase activity as well as the phosphorylation of stat3 at both tyr705 and ser727. Galpha16ql-induced stat3 activation was enhanced by overexpression of extracellular signal-regulated kinase 1 (erk1" SIGNOR-187787 MAPK3 protein P27361 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 BTO:0000007 14551213 t lperfetto "The hematopoietic-specific Galpha16 protein has recently been shown to mediate receptor-induced activation of the signal transducer and activator of transcription 3 (STAT3). In the present study, we have delineated the mechanism by which Galpha16 stimulates STAT3 in human embryonic kidney 293 cells. A constitutively active Galpha16 mutant, Galpha16QL, stimulated STAT3-dependent luciferase activity as well as the phosphorylation of STAT3 at both Tyr705 and Ser727. Galpha16QL-induced STAT3 activation was enhanced by overexpression of extracellular signal-regulated kinase 1 (ERK1)," SIGNOR-249450 MAPK3 protein P27361 UNIPROT BCL6 protein P41182 UNIPROT down-regulates phosphorylation Ser333 KGLVSPQsPQKSDCQ 9606 BTO:0000782;BTO:0000785 9649500 t gcesareni "Here we show that antigen receptor activation leads to bcl-6 phosphorylation by mitogen-activated protein kinase (mapk). Phosphorylation, in turn, targets bcl-6 for rapid degradation by the ubiquitin/proteasome pathway." SIGNOR-58489 MAPK3 protein P27361 UNIPROT BCL6 protein P41182 UNIPROT down-regulates phosphorylation Ser343 KSDCQPNsPTESCSS 9606 BTO:0000782;BTO:0000785 9649500 t gcesareni "Here we show that antigen receptor activation leads to bcl-6 phosphorylation by mitogen-activated protein kinase (mapk). Phosphorylation, in turn, targets bcl-6 for rapid degradation by the ubiquitin/proteasome pathway." SIGNOR-58493 MAPK3 protein P27361 UNIPROT ETV6 protein P41212 UNIPROT down-regulates phosphorylation Ser213 DNMIRRLsPAERAQG 10090 15060146 t miannu "Tel became phosphorylated by erk on two serine residues, ser213 and ser257, in the internal domain between the hlh and ets domains. Tel lost its abilities to repress transcription through the phosphorylation." SIGNOR-123656 MAPK3 protein P27361 UNIPROT ETV6 protein P41212 UNIPROT down-regulates phosphorylation Ser257 ESHPKPSsPRQESTR 10090 BTO:0000944 15060146 t miannu "Tel became phosphorylated by erk on two serine residues, ser213 and ser257, in the internal domain between the hlh and ets domains. Tel lost its abilities to repress transcription through the phosphorylation." SIGNOR-260085 MAPK3 protein P27361 UNIPROT STAT5A protein P42229 UNIPROT up-regulates phosphorylation Ser780 DSLDSRLsPPAGLFT 9606 BTO:0000975 10194762 t gcesareni "Serine 780 is the only substrate in full-length stat5a for active erk" SIGNOR-66247 MAPK3 protein P27361 UNIPROT LIFR protein P42702 UNIPROT down-regulates phosphorylation Ser1044 WNLVSPDsPRSIDSN 9606 7777512 t gcesareni "Thus, our results identify the human lifr as a substrate for mapk and suggest a mechanism of heterologous receptor regulation of lifr signaling occurring at ser-1044." SIGNOR-32757 MAPK3 protein P27361 UNIPROT MAGEA11 protein P43364 UNIPROT up-regulates phosphorylation Ser174 ESPSPPQsPQEESFS 9606 BTO:0000848 19828458 t llicata "Mage-11 ser-174 appears to be a post-translational regulatory site phosphorylated by erk1, based on the inhibitory effect of the s174a mutation in the context of shorter ar nh2-terminal fragments (19), and the greater transcriptional activity of gal-mage-11 fusion proteins containing the s174d phosphomimetic." SIGNOR-188466 MAPK3 protein P27361 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Thr187 NAGSVEQtPKKPGLR 9606 BTO:0000150 10931950 t gcesareni "These data suggest that increased signaling by erbb receptors up-regulates mapk activity, which, in turn, phosphorylates and destabilizes p27, thus contributing to dysregulated cell cycle progression." SIGNOR-80234 MAPK3 protein P27361 UNIPROT PLA2G4A protein P47712 UNIPROT up-regulates phosphorylation Ser505 LNTSYPLsPLSDFAT 9606 8381049 t gcesareni "Activated map kinase phosphorylates cpla2 at ser-505, causing increased enzymatic activity of cpla2, which is only realized upon translocation of cpla2 to the membrane." SIGNOR-38434 MAPK3 protein P27361 UNIPROT SOX9 protein P48436 UNIPROT up-regulates "transcriptional regulation" 9606 20457810 f fspada "Soluble pref-1 inhibits adipocyte differentiation through the activation of extracellular signal-regulated kinase/mitogen-activated protein kinase (erk/mapk) and the subsequent upregulation of sox9 expression." SIGNOR-209965 MAPK3 protein P27361 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates phosphorylation 9606 14967450 t gcesareni "Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase" SIGNOR-121994 MAPK3 protein P27361 UNIPROT ARRB1 protein P49407 UNIPROT down-regulates phosphorylation Ser412 EEEDGTGsPQLNNR 9606 10347142 t gcesareni "Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation" SIGNOR-67634 MAPK3 protein P27361 UNIPROT ARRB1 protein P49407 UNIPROT down-regulates phosphorylation Ser412 EEEDGTGsPQLNNR 9606 19153083 t gcesareni "Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation" SIGNOR-183484 MAPK3 protein P27361 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Ser295 PARPRSPsQTRKGPP 9606 BTO:0000142 15262992 t lperfetto "Thus, we propose that mapk phosphorylation of amphiphysin1 controls ngf receptor/trka-mediated endocytosis by terminating the amphiphysin1-ap-2 interaction.Our results indicate that phosphorylation of amphiphysin 1 at ser-285 and/or ser-293 affects the function of amphiphysin1.Mapk phosphorylation of ser-285 and ser-293 could modulate the interaction between prd and ap-2, resulting in the dissociation of amphiphysin1 from ap-2." SIGNOR-126871 MAPK3 protein P27361 UNIPROT AMPH protein P49418 UNIPROT "down-regulates activity" phosphorylation Ser293 PAPARPRsPSQTRKG 9606 15262992 t lperfetto "Thus, we propose that mapk phosphorylation of amphiphysin1 controls ngf receptor/trka-mediated endocytosis by terminating the amphiphysin1-ap-2 interaction.Our results indicate that phosphorylation of amphiphysin 1 at ser-285 and/or ser-293 affects the function of amphiphysin1.Mapk phosphorylation of ser-285 and ser-293 could modulate the interaction between prd and ap-2, resulting in the dissociation of amphiphysin1 from ap-2." SIGNOR-126867 MAPK3 protein P27361 UNIPROT PCYT1A protein P49585 UNIPROT down-regulates phosphorylation Ser315 GRMLQAIsPKQSPSS 9606 BTO:0000763 15788406 t gcesareni "Oxysterols inhibit phosphatidylcholine synthesis via erk docking and phosphorylation of ctp:phosphocholine cytidylyltransferase. Mutagenesis of ser315 within cctalpha was both required and sufficient to confer significant resistance to 22-hc/9-cis-ra inhibition of ptdcho synthesis." SIGNOR-134841 MAPK3 protein P27361 UNIPROT CEBPA protein P49715 UNIPROT down-regulates phosphorylation Ser21 PMSSHLQsPPHAPSS 9606 BTO:0000876 14701740 t lperfetto "Ccaat/enhancer-binding protein alpha (c/ebpalpha) is one of the key transcription factors that mediate lineage specification and differentiation of multipotent myeloid progenitors into mature granulocytes.Here we report that inducers of monocyte differentiation inhibit the alternate cell fate choice, that of granulopoiesis, through inhibition of c/ebpalpha. This inhibition is mediated by extracellular signal-regulated kinases 1 and/or 2 (erk1/2), which interact with c/ebpalpha through an fxfp docking site and phosphorylate serine 21." SIGNOR-120570 MAPK3 protein P27361 UNIPROT NUP153 protein P49790 UNIPROT unknown phosphorylation Ser529 SPMFKFSsPIVKSTE 9606 19767751 t llicata "These results indicate that phosphorylation of nup153 and nup214 by erk strongly reduces their affinity for importin-. nup153 depletion caused a strong inhibition of nuclear accumulation of gfp?importin-beta in both erk-inhibited and erk-activated cells (fig. 8b,c), indicating that nup153 is essential for the efficient importin-beta transport." SIGNOR-188143 MAPK3 protein P27361 UNIPROT TSC2 protein P49815 UNIPROT "down-regulates activity" phosphorylation Ser664 KKTSGPLsPPTGPPG 10090 BTO:0000944 15851026 t lperfetto "Here, we show that Erk may play a critical role in TSC progression through posttranslational inactivation of TSC2. Erk-dependent phosphorylation leads to TSC1-TSC2 dissociation and markedly impairs TSC2 ability to inhibit mTOR signaling, cell proliferation, and oncogenic transformation. |Serine to alanine substitution at S664 or double S664A/S540A mutagenesis resulted in a marked reduction in TSC2 phosphorylation to a similar extent. In contrast, S540A substitution only moderately impaired TSC2 phosphorylation (Figure 3D), corroborating the notion that in vivo S664 is the most relevant residue for Erk-mediated phosphorylation." SIGNOR-249457 MAPK3 protein P27361 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Thr43 KVTTVVAtPGQGPDR 9606 BTO:0000150;BTO:0000680 16039586 t lperfetto "Erk, which is activated by hbx, associates with gsk-3beta through a docking motif ((291)fkfp) of gsk-3beta and phosphorylates gsk-3beta at the (43)thr residue, which primes gsk-3beta for its subsequent phosphorylation at ser9 by p90rsk, resulting in inactivation of gsk-3beta and upregulation of beta-catenin." SIGNOR-138898 MAPK3 protein P27361 UNIPROT GSK3B protein P49841 UNIPROT "down-regulates activity" phosphorylation Ser9 SGRPRTTsFAESCKP 10090 BTO:0002572 28646232 t Gianni "We demonstrate that insulin-mediated activation of ERK1/2 results in phosphorylation of GSK3β at S9 independently of Akt/mTORC1 activity in Tsc2 null mouse embryonic fibroblasts. In addition, we show that inhibition of ERK1/2 rescues GSK3β activity and restores protein synthesis in Tsc2 −/− MEFs to normal levels" SIGNOR-262523 MAPK3 protein P27361 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser154 SSVSSSPsPPFGHSA 9606 12050114 t gcesareni "Tob is rapidly phosphorylated at Ser 152, Ser 154, and Ser 164 by Erk1 and Erk2 upon growth-factor stimulation." SIGNOR-88732 MAPK3 protein P27361 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser164 FGHSAAVsPTFMPRS 9606 12050114 t gcesareni "Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro. Erk catalyzes the phosphorylation more efficiently than jnk" SIGNOR-88736 MAPK3 protein P27361 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser154 SSVSSSPsPPFGHSA 9606 BTO:0000782 12151396 t gcesareni "Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro. Erk catalyzes the phosphorylation more efficiently than jnk" SIGNOR-91059 MAPK3 protein P27361 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser164 FGHSAAVsPTFMPRS 9606 BTO:0000782 12151396 t gcesareni "Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro. Erk catalyzes the phosphorylation more efficiently than jnk" SIGNOR-91063 MAPK3 protein P27361 UNIPROT SCNN1B protein P51168 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr615 QALPIPGtPPPNYDS -1 11805112 t lperfetto "Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4." SIGNOR-249447 MAPK3 protein P27361 UNIPROT RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation Thr577 AENGLLMtPCYTANF 9606 10980595 t llicata "We have generated two monoclonal antibodies that recognize two phosphorylated sites, p-ser227 and p-thr577, in the n- and c-terminal kinase domains of rsk2, respectively. phosphorylation and activation of rsk2 by uv light involves the erk pathway" SIGNOR-81464 MAPK3 protein P27361 UNIPROT RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation 9606 19282669 t gcesareni "Erk-activates the rsk family of serine/threonine kinases,rsk1, rsk2, and rsk3." SIGNOR-184583 MAPK3 protein P27361 UNIPROT RCAN1 protein P53805 UNIPROT "up-regulates activity" phosphorylation Ser167 FLISPPAsPPVGWKQ 10090 BTO:0000165 12063245 t lperfetto "Consensus phosphorylation sites for p42/44 MAPK and GSK-3 are present in the SP repeat of MCIP1 at serine 112 and serine 108, respectively |Several endogenous proteins are capable of inhibiting the catalytic activity of calcineurin. Modulatory calcineurin interacting protein 1 (MCIP1) is unique among these proteins on the basis of its pattern of expression and its function in a negative feedback loop to regulate calcineurin activity. Here we show that MCIP1 can be phosphorylated by MAPK and glycogen synthase kinase-3 and that phosphorylated MCIP1 is a substrate for calcineurin." SIGNOR-249478 MAPK3 protein P27361 UNIPROT CASP9 protein P55211 UNIPROT "down-regulates activity" phosphorylation Thr125 PEVLRPEtPRPVDIG 9606 12792650 t lperfetto "Inhibition of caspase-9 through phosphorylation at thr 125 by erk mapk" SIGNOR-101548 MAPK3 protein P27361 UNIPROT MAZ protein P56270 UNIPROT up-regulates phosphorylation Thr72 AAPAPPPtPQAPAAE 9606 11809795 t lperfetto "Together, these results show that activation of saf-1 in response to il-1 and -6 is mediated via map kinase-regulated phosphorylation." SIGNOR-114475 MAPK3 protein P27361 UNIPROT HNRNPK protein P61978 UNIPROT down-regulates phosphorylation Ser284 RRDYDDMsPRRGPPP 9606 16564677 t gcesareni "Erk phosphorylation drives cytoplasmic accumulation of hnrnp-k and inhibition of mrna translation mitogen-activated protein kinase/extracellular-signal-regulated kinase (mapk/erk) efficiently phosphorylates hnrnp-k both in vitro and in vivo at serines 284 and 353." SIGNOR-145375 MAPK3 protein P27361 UNIPROT HNRNPK protein P61978 UNIPROT "down-regulates activity" phosphorylation Ser284 RRDYDDMsPRRGPPP 9606 11231586 t lperfetto "Erk phosphorylation drives cytoplasmic accumulation of hnrnp-k and inhibition of mrna translation mitogen-activated protein kinase/extracellular-signal-regulated kinase (mapk/erk) efficiently phosphorylates hnrnp-k both in vitro and in vivo at serines 284 and 353." SIGNOR-105238 MAPK3 protein P27361 UNIPROT GTF2I protein P78347 UNIPROT up-regulates phosphorylation Ser668 INTKALQsPKRPRSP 9606 10648599 t lperfetto "Tfii-i can be phosphorylated in vitro by erk and mutation of consensus map kinase substrate sites at serines 627 and 633 impairs the phosphorylation of tfii-i by erk and its activity on the c-fos promoter. These results suggest that erk regulates the activity of tfii-i by direct phosphorylation." SIGNOR-74304 MAPK3 protein P27361 UNIPROT GTF2I protein P78347 UNIPROT up-regulates phosphorylation Ser674 QSPKRPRsPGSNSKV 9606 10648599 t lperfetto "Tfii-i can be phosphorylated in vitro by erk and mutation of consensus map kinase substrate sites at serines 627 and 633 impairs the phosphorylation of tfii-i by erk and its activity on the c-fos promoter. These results suggest that erk regulates the activity of tfii-i by direct phosphorylation." SIGNOR-74308 MAPK3 protein P27361 UNIPROT SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1178 IMSKHLDsPPAIPPR 9606 8816480 t gcesareni "In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1" SIGNOR-43947 MAPK3 protein P27361 UNIPROT ADAM17 protein P78536 UNIPROT up-regulates phosphorylation Thr735 KPFPAPQtPGRLQPA 9606 12058067 t gcesareni "Extracellular signal-regulated kinase phosphorylates tumor necrosis factor alpha-converting enzyme at threonine 735: a potential role in regulated sheddingwe show that extracellular signal-regulated kinase (erk) acts as an intermediate in protein kinase c-regulated trka cleavage. We report that the cytosolic tail of the tumor necrosis factor alpha-converting enzyme (tace) is phosphorylated by erk at threonine 735. In addition, we show that erk and tace associate. This association is favored by erk activation and by the presence of threonine 735. In contrast to the erk route, the p38 mapk was able to stimulate trka cleavage in cells devoid of tace activity, indicating that other proteases are also involved in trka shedding." SIGNOR-89625 MAPK3 protein P27361 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation 9606 BTO:0000763;BTO:0000149 10197981 t gcesareni "These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3." SIGNOR-66781 MAPK3 protein P27361 UNIPROT H3-3A protein P84243 UNIPROT up-regulates phosphorylation Ser29 ATKAARKsAPSTGGV 9606 15994958 t gcesareni "Phosphorylation of histone h3 at serine 10 is indispensable for neoplastic cell transformation. When h3 wt was overexpressed, egf induction of c-fos and c-jun promoter activity was significantly increased compared with control cells but not in the h3 mutant s10a or s28a cells." SIGNOR-138455 MAPK3 protein P27361 UNIPROT HSF1 protein Q00613 UNIPROT down-regulates phosphorylation Ser307 EPPSPPQsPRVEEAS 9606 8940068 t gcesareni "Sequential phosphorylation of hsf1 by mitogen-activated protein kinase and glycogen synthase kinase 3 at ser-303 and ser-307 represses transcriptional activation by heat shock factor-1." SIGNOR-44999 MAPK3 protein P27361 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates phosphorylation 9606 14967450 t gcesareni "Erk also undergoes rapid translocation into the nucleus, where it phosphorylates and activates a variety of transcription factor targets, including sp1, e2f, elk-1, and ap1" SIGNOR-121991 MAPK3 protein P27361 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 22802261 t gcesareni "Erk also undergoes rapid translocation into the nucleus, where it phosphorylates and activates a variety of transcription factor targets, including sp1, e2f, elk-1, and ap1" SIGNOR-198292 MAPK3 protein P27361 UNIPROT EWSR1 protein Q01844 UNIPROT unknown phosphorylation Thr79 QPPTGYTtPTAPQAY 9606 19076070 t lperfetto "Here we report that ews and ews-fli1 become phosphorylated at thr79 in the n-terminal domain in response to mitogens or dna damage. Mitogen-induced phosphorylation of ews and ews-fli1 was weak and catalysed by erk1 (extracellular signal-regulated kinase 1) and erk2." SIGNOR-182782 MAPK3 protein P27361 UNIPROT SP3 protein Q02447 UNIPROT up-regulates phosphorylation Ser73 CSKIGPPsPGDDEEE 9606 17685427 t gcesareni "Here, we show that sp3, which, as sp1, belongs to the gc-rich binding transcription factor family, is also phosphorylated by erk in vitro on serine 73." SIGNOR-157276 MAPK3 protein P27361 UNIPROT LIPE protein Q05469 UNIPROT "up-regulates activity" phosphorylation Thr891 NSETSSDtPEMSLSA 10090 BTO:0000944 11581251 t lperfetto "Thus, activation of the ERK pathway appears to be able to regulate adipocyte lipolysis by phosphorylating HSL on Ser(600) and increasing the activity of HSL." SIGNOR-249470 MAPK3 protein P27361 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser759 KTPDGNKsPAPKPSD 9606 BTO:0001260 10514499 t lperfetto "Extracellular signal-regulated kinases (erks) phosphorylate the high molecular mass isoform of the actin-binding protein caldesmon (h-cad) at two sites (ser(759) and ser(789)) during smooth muscle stimulation. Nmr spectroscopy shows that the actin binding properties of the minimal inhibitory region of caldesmon, residues 750-779, alter upon map kinase phosphorylation of ser-759, a residue not involved in actin binding. This phosphorylation leads to markedly diminished actin affinity as a result of the loss of interaction at one of the two sites that bind to f-actin." SIGNOR-71041 MAPK3 protein P27361 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser789 QSVDKVTsPTKV 9606 BTO:0001260 10514499 t lperfetto "Extracellular signal-regulated kinases (erks) phosphorylate the high molecular mass isoform of the actin-binding protein caldesmon (h-cad) at two sites (ser(759) and ser(789)) during smooth muscle stimulation. Nmr spectroscopy shows that the actin binding properties of the minimal inhibitory region of caldesmon, residues 750-779, alter upon map kinase phosphorylation of ser-759, a residue not involved in actin binding. This phosphorylation leads to markedly diminished actin affinity as a result of the loss of interaction at one of the two sites that bind to f-actin." SIGNOR-71045 MAPK3 protein P27361 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser759 KTPDGNKsPAPKPSD 9606 BTO:0000887;BTO:0001260 11983427 t amattioni "The actin binding properties of the minimal inhibitory region of caldesmon, residues 750-779, alter upon map kinase phosphorylation of ser-759. This phosphorylation leads to markedly diminished actin affinity." SIGNOR-86741 MAPK3 protein P27361 UNIPROT MCL1 protein Q07820 UNIPROT up-regulates phosphorylation Thr163 TDGSLPStPPPAEEE 9606 BTO:0000150 18676833 t fstefani "We then showed that erk could phosphorylate mcl-1 at two consensus residues, thr 92 and 163, which is required for the association of mcl-1 and pin1, resulting in stabilization of mcl-1." SIGNOR-179812 MAPK3 protein P27361 UNIPROT KLC1 protein Q07866 UNIPROT down-regulates phosphorylation Ser460 YKACKVDsPTVTTTL 9606 21385839 t gcesareni "Phosphorylation of kinesin light chain 1 at serine 460 modulates binding and trafficking of calsyntenin-1mutation of klc1ser460 to an alanine residue, to preclude phosphorylation, increased the binding of calsyntenin-1, whereas mutation to an aspartate residueklc1ser460 is a predicted mitogen-activated protein kinase (mapk) target site, and we show that extracellular-signal-regulated kinase (erk) phosphorylates this residue in vitro." SIGNOR-172642 MAPK3 protein P27361 UNIPROT PPARA protein Q07869 UNIPROT "up-regulates activity" phosphorylation Ser21 LEAGDLEsPLSEEFL 9606 BTO:0000599 10187842 t lperfetto "We now demonstrate that amino acids 1-92 of hPPARalpha contain an activation function (AF)-1-like domain, which is further activated by insulin through a pathway involving the mitogen-activated protein kinases p42 and p44. Further analysis of the amino-terminal region of PPARalpha revealed that the insulin-induced trans-activation occurs through the phosphorylation of two mitogen-activated protein kinase sites at positions 12 and 21, both of which are conserved across evolution." SIGNOR-249474 MAPK3 protein P27361 UNIPROT SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1132 TLPHGPRsASVSSIS 9606 8816480 t lperfetto "In this report, we describe the identification of five MAP kinase sites (S-1137, S-1167, S-1178, S-1193, and S-1197) on hSos1.Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1" SIGNOR-43939 MAPK3 protein P27361 UNIPROT SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1167 ESAPAESsPSKIMSK 9606 8816480 t gcesareni "In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1" SIGNOR-43943 MAPK3 protein P27361 UNIPROT PDE4D protein Q08499 UNIPROT down-regulates phosphorylation Ser715 YQSTIPQsPSPAPDD 9606 10828059 t "The effect has been demonstrated using Q08499-2" gcesareni "These straddle the target residue, ser(579), for erk2 phosphorylation of pde4d3. Mutation of either or both of these docking sites prevented erk2 from being co-immunoprecipitated with pde4d3, ablated the ability of epidermal growth factor to inhibit pde4d3 through erk2 action in transfected cos cells, and attenuated the ability of erk2 to phosphorylate pde4d3 in vitro." SIGNOR-77578 MAPK3 protein P27361 UNIPROT SREBF2 protein Q12772 UNIPROT up-regulates phosphorylation Ser432 NQNVLLMsPPASDSG 9606 14988395 t lperfetto "Insulin-activated erk-mitogen-activated protein kinases phosphorylate sterol regulatory element-binding protein-2 at serine residues 432 and 455 in vivo.Further characterization by electrophoretic mobility shift assay and promoter reporter gene analyses revealed that phosphorylation does not influence protein/dna interaction, but enhances trans-activity." SIGNOR-123049 MAPK3 protein P27361 UNIPROT SREBF2 protein Q12772 UNIPROT up-regulates phosphorylation Ser455 SIDSEPGsPLLDDAK 9606 14988395 t lperfetto "Insulin-activated erk-mitogen-activated protein kinases phosphorylate sterol regulatory element-binding protein-2 at serine residues 432 and 455 in vivo.Further characterization by electrophoretic mobility shift assay and promoter reporter gene analyses revealed that phosphorylation does not influence protein/dna interaction, but enhances trans-activity." SIGNOR-123053 MAPK3 protein P27361 UNIPROT TFCP2 protein Q12800 UNIPROT down-regulates phosphorylation Ser291 TYVNNSPsPGFNSSH 9606 19237534 t lperfetto "We previously established that phosphorylation of lsf in early g1 at ser-291 and ser-309 inhibits its transcriptional activity and that dephosphorylation later in g1 is required for its reactivation. At the peak activities of erk and cyclin c/cdk2 in early g1, lsf is efficiently phosphorylated on ser-291 and ser-309." SIGNOR-184176 MAPK3 protein P27361 UNIPROT EPS8 protein Q12929 UNIPROT "down-regulates activity" phosphorylation Ser625 ADTPPAPsPPPTPAP -1 19564905 t miannu "We further show that the actin barbed-end capping activity of Eps8 is inhibited by brain-derived neurotrophic factor (BDNF) treatment through MAPK-dependent phosphorylation of Eps8 residues S624 and T628. Additionally, an Eps8 mutant, impaired in the MAPK target sites (S624A/T628A), displays increased association to actin-rich structures, is resistant to BDNF-mediated release from microfilaments, and inhibits BDNF-induced filopodia. The opposite is observed for a phosphomimetic Eps8 (S624E/T628E) mutant. Thus, collectively, our data identify Eps8 as a critical capping protein in the regulation of axonal filopodia and delineate a molecular pathway by which BDNF, through MAPK-dependent phosphorylation of Eps8, stimulates axonal filopodia formation, a process with crucial impacts on neuronal development and synapse formation." SIGNOR-263058 MAPK3 protein P27361 UNIPROT GRB10 protein Q13322 UNIPROT up-regulates phosphorylation Ser150 PELCGPGsPPVLTPG 9606 15952796 t lperfetto "Phosphorylation of grb10 by mitogen-activated protein kinase: identification of ser150 and ser476 of human grb10zeta as major phosphorylation sitesreplacing ser(150) and ser(476) with alanines reduced the inhibitory effect of human grb10zeta on insulin-stimulated irs1 tyrosine phosphorylation" SIGNOR-138171 MAPK3 protein P27361 UNIPROT GRB10 protein Q13322 UNIPROT up-regulates phosphorylation Ser476 MNILGSQsPLHPSTL 9606 15952796 t lperfetto "Phosphorylation of grb10 by mitogen-activated protein kinase: identification of ser150 and ser476 of human grb10zeta as major phosphorylation sitesreplacing ser(150) and ser(476) with alanines reduced the inhibitory effect of human grb10zeta on insulin-stimulated irs1 tyrosine phosphorylation" SIGNOR-138175 MAPK3 protein P27361 UNIPROT PPP2R5C protein Q13362 UNIPROT down-regulates phosphorylation Ser337 QLAKCVSsPHFQVAE 9606 16456541 t gcesareni "Iex-1 binds to b56 subunits and perk independently, enhances b56 phosphorylation by erk at a conserved ser/pro site in this complex and triggers dissociation from the catalytic subunit." SIGNOR-144317 MAPK3 protein P27361 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Ser381 CIPTAGMsPSRSNTI 10029 BTO:0000246 15379552 t lperfetto "Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal" SIGNOR-249459 MAPK3 protein P27361 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Ser454 YVPMNPNsPPRQHSS 10029 BTO:0000246 15379552 t lperfetto "Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal" SIGNOR-249460 MAPK3 protein P27361 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Ser551 ELQAPVRsPITRSFA 10029 BTO:0000246 15379552 t lperfetto "Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal" SIGNOR-249461 MAPK3 protein P27361 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Ser567 DSSRFPMsPRPDSVH 10029 BTO:0000246 15379552 t lperfetto "Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal" SIGNOR-249462 MAPK3 protein P27361 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Thr312 ISYDIPPtPGNTYQI 10029 BTO:0000246 15379552 t lperfetto "Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal" SIGNOR-249463 MAPK3 protein P27361 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Thr476 EANYVPMtPGTFDFS 10029 BTO:0000246 15379552 t lperfetto "Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal" SIGNOR-249464 MAPK3 protein P27361 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates phosphorylation Thr277 GSRTAPYtPNLPHHQ 9606 12801888 t llicata "Our results suggest that map kinase can phosphorylate thr276 of smad4 and that phosphorylation can lead to enhanced tgf-beta-induced nuclear accumulation and, as a consequence, enhanced transcriptional activity of smad4." SIGNOR-101664 MAPK3 protein P27361 UNIPROT MKNK1 protein Q9BUB5 UNIPROT up-regulates phosphorylation Thr385 APEKGLPtPQVLQRN 9606 BTO:0000567 9155018 t lperfetto "Mnk1 was phosphorylated and activated in vitro by erk1 and p38 map kinasespreliminary results showed that thr344 at least was one of the major sites phosphorylated by erk1" SIGNOR-48360 MAPK3 protein P27361 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser405 KTQTPPVsPAPQPTE 9606 BTO:0000938 20444238 t gcesareni "Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement." SIGNOR-165208 MAPK3 protein P27361 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser418 TEERLPSsPVYEDAA 9606 BTO:0000938 20444238 t gcesareni "Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement." SIGNOR-165212 MAPK3 protein P27361 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser405 KTQTPPVsPAPQPTE 9606 BTO:0000938 21079800 t gcesareni "Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement." SIGNOR-169682 MAPK3 protein P27361 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser418 TEERLPSsPVYEDAA 9606 BTO:0000938 21079800 t gcesareni "Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement." SIGNOR-169686 MAPK3 protein P27361 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates phosphorylation Ser387 YLEMDLSsPQTRYIP 9606 BTO:0000149 24342355 t lperfetto "We demonstrate that perk 1/2 can phosphorylate pro-caspase-8 at s387 by knocking-down the endogenous pro-caspase-8 using rnai and replacing it with its non-phosphorylatable counterpart (s387a), a significant increase in caspase-8 activity" SIGNOR-203480 MAPK3 protein P27361 UNIPROT NFATC4 protein Q14934 UNIPROT up-regulates phosphorylation Ser676 SNGRRKRsPTQSFRF 9606 15657420 t lperfetto "The formation of rsk-nfatc4-dna transcription complex is also apparent upon adipogenesis. Bound rsk phosphorylates ser(676) and potentiates nfatc4 dna binding by escalating nfat-dna association. Ser(676) is also targeted by the erk map kinase, which interacts with nfat at a distinct region than rsk. Thus, integration of the erk/rsk signaling pathway provides a mechanism to modulate nfatc4 transcription activity." SIGNOR-133276 MAPK3 protein P27361 UNIPROT KARS1 protein Q15046 UNIPROT up-regulates phosphorylation Ser207 PYEITLLsPCLHMLP 9606 19524539 t gcesareni "Lysrs serves as a key signaling molecule in the immune response by regulating gene expression. Lysrs was phosphorylated on serine 207 in a mapk-dependent manner, released from the multisynthetase complex, and translocated into the nucleus." SIGNOR-186125 MAPK3 protein P27361 UNIPROT PTPRR protein Q15256 UNIPROT "up-regulates activity" phosphorylation Thr361 EPFVSIPtPREKVAM 11493009 t lperfetto "Specifically, the complex formation between PTP-SL and ERK2 involves an unusual interaction leading to the phosphorylation of PTP-SL by ERK2 at Thr253 and the inactivating dephosphorylation of ERK2 by PTP-SL." SIGNOR-249477 MAPK3 protein P27361 UNIPROT RPS6KA2 protein Q15349 UNIPROT up-regulates phosphorylation 9606 8939914 t gcesareni "Several lines of investigation have suggested that rsk is phosphorylated and activated by erk1/2 mapk isoforms" SIGNOR-44949 MAPK3 protein P27361 UNIPROT PCBP2 protein Q15366 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser173 MLETLSQsPPKGVTI 9606 BTO:0000664 17475908 t miannu "We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B)." SIGNOR-262914 MAPK3 protein P27361 UNIPROT PCBP2 protein Q15366 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr213 SASFPHTtPSMCLNP 9606 BTO:0000664 17475908 t miannu "We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B)." SIGNOR-262917 MAPK3 protein P27361 UNIPROT RPS6KA1 protein Q15418 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0000938 8387505 t lperfetto "The pp90rsk phosphothreonine content paralleled the ERK1 activity more closely than the phosphoserine level. These results provide compelling evidence that in fibroblasts and PC12 cells ERK1 plays a direct role in the phosphorylation of pp90rsk and that pp90rsk represents a physiologically relevant substrate of extracellular-regulated kinases" SIGNOR-38999 MAPK3 protein P27361 UNIPROT RPS6KA1 protein Q15418 UNIPROT "up-regulates activity" phosphorylation Ser221 DHEKKAYsFCGTVEY 9534 BTO:0001538 9430688 t lperfetto "Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733." SIGNOR-219332 MAPK3 protein P27361 UNIPROT MKNK1 protein Q9BUB5 UNIPROT "up-regulates activity" phosphorylation -1 9155018 t "These results indicate that MNK1 is a novel class of protein kinase that is activated through both the ERK and p38 MAP kinase signaling pathways" SIGNOR-253012 MAPK3 protein P27361 UNIPROT RPS6KA1 protein Q15418 UNIPROT "up-regulates activity" phosphorylation Ser363 TSRTPKDsPGIPPSA 9534 BTO:0001538 9430688 t lperfetto "Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733." SIGNOR-219337 MAPK3 protein P27361 UNIPROT RPS6KA1 protein Q15418 UNIPROT "up-regulates activity" phosphorylation Thr573 AENGLLMtPCYTANF 9534 BTO:0001538 9430688 t lperfetto "Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733." SIGNOR-219353 MAPK3 protein P27361 UNIPROT MED1 protein Q15648 UNIPROT up-regulates phosphorylation Thr1457 HSKSPAYtPQNLDSE 9606 12356758 t lperfetto "Phosphorylation of transcriptional coactivator peroxisome proliferator-activated receptor (ppar)-binding protein (pbp). Stimulation of transcriptional regulation by mitogen-activated protein kinase" SIGNOR-93993 MAPK3 protein P27361 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation Ser68 GGGDEPGsPAQGKRG 9606 BTO:0000150 21502402 t llicata "Phosphorylation of serine 68 of twist1 by mapks stabilizes twist1 protein and promotes breast cancer cell invasiveness. this ser 68 is phosphorylated by p38, c-jun n-terminal kinases (jnk), and extracellular signal-regulated kinases1/2 in vitro" SIGNOR-173413 MAPK3 protein P27361 UNIPROT NCOA1 protein Q15788 UNIPROT up-regulates phosphorylation Ser1185 GTPPASTsPFSQLAA 9606 BTO:0001130 12163482 t lperfetto "Mapk also directly phosphorylates src-1 at thr1179 and ser1185. Phosphorylation of src-1 by mitogen-activated protein kinase (mapk) is required for optimal progesterone receptor-dependent transcription and for functional cooperation with camp response element-binding protein-binding protein" SIGNOR-91139 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser245 NQSMDTGsPAELSPT 9606 BTO:0000763;BTO:0000149 10197981 t gcesareni "These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity" SIGNOR-66759 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser250 TGSPAELsPTTLSPV 9606 BTO:0000763;BTO:0000149 10197981 t gcesareni "These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity" SIGNOR-66763 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser255 ELSPTTLsPVNHSLD 9606 BTO:0000763;BTO:0000149 10197981 t gcesareni "These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity" SIGNOR-66767 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Thr220 QSNYIPEtPPPGYIS 9606 BTO:0000763;BTO:0000149 10197981 t gcesareni "These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity" SIGNOR-66771 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Thr8 MSSILPFtPPVVKRL 9606 BTO:0000763;BTO:0000149 10197981 t gcesareni "These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity" SIGNOR-66775 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser245 NQSMDTGsPAELSPT 9606 BTO:0000763 12193595 t gcesareni "These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity" SIGNOR-91730 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser250 TGSPAELsPTTLSPV 9606 BTO:0000763 12193595 t gcesareni "These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity" SIGNOR-91734 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser255 ELSPTTLsPVNHSLD 9606 BTO:0000763 12193595 t gcesareni "These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity" SIGNOR-91738 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Thr8 MSSILPFtPPVVKRL 9606 BTO:0000763 12193595 t gcesareni "These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity" SIGNOR-91746 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser245 NQSMDTGsPAELSPT 9606 19115199 t gcesareni "These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity" SIGNOR-182988 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser250 TGSPAELsPTTLSPV 9606 19115199 t gcesareni "These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity" SIGNOR-182992 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser255 ELSPTTLsPVNHSLD 9606 19115199 t gcesareni "These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity" SIGNOR-182996 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Thr220 QSNYIPEtPPPGYIS 9606 19115199 t gcesareni "These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity" SIGNOR-183000 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Thr8 MSSILPFtPPVVKRL 9606 19115199 t gcesareni "These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity" SIGNOR-183004 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000763;BTO:0000149 10197981 t lperfetto "These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity" SIGNOR-236067 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT "up-regulates activity" phosphorylation Thr8 MSSILPFtPPVVKRL 9606 12193595 t lperfetto "We show that phosphorylation of Smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (ERK1) increases the amount of Smad2 protein and leads to enhanced transcriptional activity.[] A site of ERK-dependent phosphorylation on Smad2 was located to Thr8" SIGNOR-227514 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT "up-regulates activity" phosphorylation 9606 19115199 t lperfetto "These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity" SIGNOR-217613 MAPK3 protein P27361 UNIPROT STK11 protein Q15831 UNIPROT "down-regulates activity" phosphorylation Ser428 SSKIRRLsACKQQ 9606 25846811 t lperfetto "Directly and/or through the activation of p90RSK, ERK phosphorylates LKB-1 at Ser325 and Ser428. The phosphorylation of LKB-1 causes the dissociation of LKB-1 from AMPK, resulting in the impaired activation of AMPK." SIGNOR-209880 MAPK3 protein P27361 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates phosphorylation Ser641 DIKILIAsPSPTHIH 9606 BTO:0000567 18519666 t lperfetto "We show that at least two different nuclear protein kinases, one of them identified as p42/p44 mapk, can modify hif-1_. Analysis of in vitro phosphorylated hif-1_ by mass spectroscopy revealed residues ser-641 and ser-643 as possible mapk phosphorylation sites these data suggest that phosphorylation of ser-641/643 by mapk promotes the nuclear accumulation and transcriptional activity of hif-1_" SIGNOR-178731 MAPK3 protein P27361 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates phosphorylation Ser643 KILIASPsPTHIHKE 9606 BTO:0000567 18519666 t lperfetto "We show that at least two different nuclear protein kinases, one of them identified as p42/p44 mapk, can modify hif-1_. Analysis of in vitro phosphorylated hif-1_ by mass spectroscopy revealed residues ser-641 and ser-643 as possible mapk phosphorylation sites these data suggest that phosphorylation of ser-641/643 by mapk promotes the nuclear accumulation and transcriptional activity of hif-1_" SIGNOR-178735 MAPK3 protein P27361 UNIPROT DUSP6 protein Q16828 UNIPROT down-regulates phosphorylation Ser159 DGSCSSSsPPLPVLG 9606 15632084 t amattioni "Phosphorylation of serines 159 and 197 by erk1/2 enhances proteasomal degradation of mkp-3" SIGNOR-132975 MAPK3 protein P27361 UNIPROT DUSP6 protein Q16828 UNIPROT down-regulates phosphorylation Ser197 SATDSDGsPLSNSQP 9606 15632084 t amattioni "Phosphorylation of serines 159 and 197 by erk1/2 enhances proteasomal degradation of mkp-3" SIGNOR-132979 MAPK3 protein P27361 UNIPROT METTL3 protein Q86U44 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser43 RNPEAALsPTFRSDS 9606 BTO:0000007 33217317 t miannu "Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex." SIGNOR-265949 MAPK3 protein P27361 UNIPROT METTL3 protein Q86U44 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser50 SPTFRSDsPVPTAPT 9606 BTO:0000007 33217317 t miannu "Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex." SIGNOR-265945 MAPK3 protein P27361 UNIPROT IRX2 protein Q9BZI1 UNIPROT "up-regulates activity" phosphorylation Ser317 TPQGSRTsPGAPPPA -1 15133517 t miannu "To identify the phosphorylated residue, we introduced a serine-to-alanine substitution at residues 294 and 326 and a threonine-to-alanine substitution at residue 331 in Irx2(291–356). Erk1 phosphorylated S294A and T331A, but not S326A (Fig. 4b), indicating that Ser326 is the bona fide MAP kinase target." SIGNOR-263060 MAPK3 protein P27361 UNIPROT METTL3 protein Q86U44 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser525 YGMIERLsPGTRKIE 9606 BTO:0000007 33217317 t miannu "Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex." SIGNOR-265947 MAPK3 protein P27361 UNIPROT NOXA1 protein Q86UR1 UNIPROT down-regulates phosphorylation Ser282 VGKQAPLsPGLPAMG 9606 20230789 t lperfetto "Accumulating evidence indicates that protein phosphorylation regulates nox activity. In this report, we show that serine282 residue of nox activator 1 (noxa1) is phosphorylated by erk in response to egf resulting in desensitization of nox1 activity" SIGNOR-164231 MAPK3 protein P27361 UNIPROT WWC1 protein Q8IX03 UNIPROT unknown phosphorylation Ser548 SSPSPPCsPLMADPL 9606 BTO:0000149 24269383 t llicata "We demonstrated that erk1/2 phosphorylate kibra at ser(548) in cells as well as in vitro." SIGNOR-203290 MAPK3 protein P27361 UNIPROT ABI1 protein Q8IZP0 UNIPROT up-regulates phosphorylation Ser225 ARLGSQHsPGRTASL 9606 21419341 t gcesareni "We show that erk colocalizes with the wrc at lamellipodial leading edges and directly phosphorylates two wrc components: wave2 and abi1." SIGNOR-172881 MAPK3 protein P27361 UNIPROT RPTOR protein Q8N122 UNIPROT "up-regulates activity" phosphorylation Ser696 EKNYALPsPATTEGG 9606 BTO:0000007 SIGNOR-C3 21071439 t lperfetto "We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1." SIGNOR-169526 MAPK3 protein P27361 UNIPROT RPTOR protein Q8N122 UNIPROT "up-regulates activity" phosphorylation Ser8 MESEMLQsPLLGLGE 9606 BTO:0000007 SIGNOR-C3 21071439 t lperfetto "We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1." SIGNOR-169530 MAPK3 protein P27361 UNIPROT RPTOR protein Q8N122 UNIPROT "up-regulates activity" phosphorylation Ser863 LTQSAPAsPTNKGVH 9606 SIGNOR-C3 21071439 t lperfetto "We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1." SIGNOR-169534 MAPK3 protein P27361 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation 9606 BTO:0000567 19777442 t gcesareni "Erk-1 map kinase prevents tnf-induced apoptosis through bad phosphorylation and inhibition of bax translocation in hela cells." SIGNOR-188172 MAPK3 protein P27361 UNIPROT ARHGEF2 protein Q92974 UNIPROT up-regulates phosphorylation Thr679 PGVELLLtPREPALP 9606 BTO:0000567 18211802 t gcesareni "Activates rhoa and as a result regulates actin assembly." SIGNOR-160420 MAPK3 protein P27361 UNIPROT STMN2 protein Q93045 UNIPROT "down-regulates activity" phosphorylation Ser62 ELILKPPsPISEAPR 10116 BTO:0000142 9525956 t lperfetto "SCG10, a growth cone-enriched MT-destabilizing protein, has been recently characterized as an in vitro substrate for various serine/threonine kinases including PKA, MAP kinase, and CDK (19). We have found that SCG10 is phosphorylated in vivo in developing rat brain.| The sites for MAP kinase phosphorylation were identified as Ser-62 and Ser-73 of SCG10|By expressing a series of phosphorylation site mutants, we showed that the MT-destabilizing effect of SCG10 could be modulated. While the nonphosphorylatable mutant showed higher activity than the wild-type protein, the activity of the mutant in which phosphorylation on all four sites was mimicked by an aspartate residue was greatly reduced. These data suggest that the nonphosphorylated state of SCG10 represents the most active form of the protein." SIGNOR-249115 MAPK3 protein P27361 UNIPROT STMN2 protein Q93045 UNIPROT "down-regulates activity" phosphorylation Ser73 EAPRTLAsPKKKDLS 10116 BTO:0000142 9525956 t lperfetto "SCG10, a growth cone-enriched MT-destabilizing protein, has been recently characterized as an in vitro substrate for various serine/threonine kinases including PKA, MAP kinase, and CDK (19). We have found that SCG10 is phosphorylated in vivo in developing rat brain.| The sites for MAP kinase phosphorylation were identified as Ser-62 and Ser-73 of SCG10|By expressing a series of phosphorylation site mutants, we showed that the MT-destabilizing effect of SCG10 could be modulated. While the nonphosphorylatable mutant showed higher activity than the wild-type protein, the activity of the mutant in which phosphorylation on all four sites was mimicked by an aspartate residue was greatly reduced. These data suggest that the nonphosphorylated state of SCG10 represents the most active form of the protein." SIGNOR-249116 MAPK3 protein P27361 UNIPROT MRTFA protein Q969V6 UNIPROT down-regulates phosphorylation Ser454 TGSTPPVsPTPSERS 9606 18694962 t "Translocation from Nuleus to Cytoplasm" gcesareni "Serum induces rhoa-dependent translocation of mkl1 from the cytoplasm to the nucleus and also causes a rapid increase in mkl1 phosphorylation. Serum-induced phosphorylation of the serum response factor coactivator mkl1 by the extracellular signal-regulated kinase 1/2 pathway inhibits its nuclear localization." SIGNOR-179963 MAPK3 protein P27361 UNIPROT MRTFA protein Q969V6 UNIPROT down-regulates phosphorylation Ser454 TGSTPPVsPTPSERS 9606 BTO:0000150;BTO:0000551 22139079 t "Translocation from Nuleus to Cytoplasm" gcesareni "Serum induces rhoa-dependent translocation of mkl1 from the cytoplasm to the nucleus and also causes a rapid increase in mkl1 phosphorylation. Serum-induced phosphorylation of the serum response factor coactivator mkl1 by the extracellular signal-regulated kinase 1/2 pathway inhibits its nuclear localization." SIGNOR-195157 MAPK3 protein P27361 UNIPROT CIC protein Q96RK0 UNIPROT down-regulates phosphorylation Ser1409 SAPEDPTsPKRKMRR 9606 BTO:0000848 21087211 t gcesareni "Specifically, 14-3-3 binds to p90(rsk)-phosphorylated ser?_??_ Of capic?_A thereby modulating dna binding to its hmg (high-mobility group) box, whereas erk phosphorylations prevent binding of a c-terminal nls (nuclear localization sequence) to importin ?4 (kpna3)[...] These results suggest that erk phosphorylation of ser1382 and ser1409 masks the nls and prevents its binding to kpna3" SIGNOR-169879 MAPK3 protein P27361 UNIPROT SULT4A1 protein Q9BR01 UNIPROT down-regulates phosphorylation Thr11 SEAETPStPGEFESK 9606 BTO:0000938 BTO:0000142 20920535 t gcesareni "The phosphorylation of sult4a1 allows interaction with pin1, which then promotes degradation of the sulfotransferase." SIGNOR-168248 MAPK3 protein P27361 UNIPROT MKNK1 protein Q9BUB5 UNIPROT up-regulates phosphorylation 9606 9155017 t gcesareni "We have identified a new subfamily of murine serine/threonine kinases, whose members, map kinase-interacting kinase 1 (mnk1) and mnk2, bind tightly to the growth factor-regulated map kinases, erk1 and erk2." SIGNOR-48352 MAPK3 protein P27361 UNIPROT IRX2 protein Q9BZI1 UNIPROT "up-regulates activity" phosphorylation Ser325 PGAPPPAsKPKLWSL -1 15133517 t miannu "To identify the phosphorylated residue, we introduced a serine-to-alanine substitution at residues 294 and 326 and a threonine-to-alanine substitution at residue 331 in Irx2(291–356). Erk1 phosphorylated S294A and T331A, but not S326A (Fig. 4b), indicating that Ser326 is the bona fide MAP kinase target." SIGNOR-263061 MAPK3 protein P27361 UNIPROT XPO5 protein Q9HAV4 UNIPROT "down-regulates activity" phosphorylation Ser416 GFPSKTDsPSCEYSR 9606 BTO:0000007 27846390 t lperfetto "Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading. " SIGNOR-262979 MAPK3 protein P27361 UNIPROT XPO5 protein Q9HAV4 UNIPROT "down-regulates activity" phosphorylation Thr345 GADSDVEtPSNFGKY 9606 BTO:0000007 27846390 t lperfetto "Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading. " SIGNOR-262985 MAPK3 protein P27361 UNIPROT MKNK2 protein Q9HBH9 UNIPROT up-regulates phosphorylation 9606 9155017 t gcesareni "Erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity." SIGNOR-48355 MAPK3 protein P27361 UNIPROT PLCB1 protein Q9NQ66 UNIPROT "up-regulates activity" phosphorylation Ser982 KKKSEPSsPDHGSST -1 11287604 t lperfetto "Plc beta1 could be efficiently phosphorylated by activated mitogen-activated protein kinase but not by pka. The erk phosphorylation site was mapped to serine 982" SIGNOR-106565 MAPK3 protein P27361 UNIPROT SPHK2 protein Q9NRA0 UNIPROT up-regulates phosphorylation Ser387 PATVEPAsPTPAHSL 9606 BTO:0000150 17311928 t llicata "Sphingosine kinase type 2 activation by erk-mediated phosphorylation. site-directed mutagenesis indicated that hsphk2 is phosphorylated on ser-351 and thr-578 by erk1" SIGNOR-153387 MAPK3 protein P27361 UNIPROT SPHK2 protein Q9NRA0 UNIPROT up-regulates phosphorylation Thr614 AFRLEPLtPRGVLTV 9606 BTO:0000150 17311928 t llicata "Sphingosine kinase type 2 activation by erk-mediated phosphorylation. site-directed mutagenesis indicated that hsphk2 is phosphorylated on ser-351 and thr-578 by erk1" SIGNOR-153391 MAPK3 protein P27361 UNIPROT SPHK1 protein Q9NYA1 UNIPROT up-regulates phosphorylation Ser225 VGSKTPAsPVVVQQG 9606 14532121 t gcesareni "Activation of sphingosine kinase 1 by erk1/2-mediated phosphorylation." SIGNOR-118550 MAPK3 protein P27361 UNIPROT RRN3 protein Q9NYV6 UNIPROT up-regulates phosphorylation Ser633 SFDTHFRsPSSSVGS 9606 12620228 t llicata "Erk-dependent phosphorylation of the transcription initiation factor tif-ia is required for rna polymerase i transcription and cell growth. phosphopeptide mapping and mutational analysis reveals two serine residues (s633 and s649) that are phosphorylated by erk and rsk kinases. Replacement of s649 by alanine inactivates tif-ia, inhibits pre-rrna synthesis, and retards cell growth." SIGNOR-98980 MAPK3 protein P27361 UNIPROT RRN3 protein Q9NYV6 UNIPROT up-regulates phosphorylation Ser649 PVLYMQPsPL 9606 12620228 t llicata "Erk-dependent phosphorylation of the transcription initiation factor tif-ia is required for rna polymerase i transcription and cell growth. phosphopeptide mapping and mutational analysis reveals two serine residues (s633 and s649) that are phosphorylated by erk and rsk kinases. Replacement of s649 by alanine inactivates tif-ia, inhibits pre-rrna synthesis, and retards cell growth." SIGNOR-98984 MAPK3 protein P27361 UNIPROT NCKIPSD protein Q9NZQ3 UNIPROT up-regulates phosphorylation 9606 14559906 t gcesareni "Spin90 was phosphorylated by erk1, which was, itself, activated by cell adhesion and platelet-derived growth factor. Such phosphorylation of spin90 likely promotes the interaction of the spin90.betapix.wasp complex and nck" SIGNOR-118747 MAPK3 protein P27361 UNIPROT HDAC6 protein Q9UBN7 UNIPROT up-regulates phosphorylation Ser1035 DHQTPPTsPVQGTTP 9606 24089523 t lperfetto "Histone deacetylase 6 (hdac6) is well known for its ability to promote cell migrationextracellular signal-regulated kinase (erk) phosphorylates histone deacetylase 6 (hdac6) at serine 1035 to stimulate cell migrationwe have identified two novel erk-mediated phosphorylation sites: threonine 1031 and serine 1035 in hdac6. Both sites were phosphorylated by erk1" SIGNOR-202698 MAPK3 protein P27361 UNIPROT HDAC6 protein Q9UBN7 UNIPROT up-regulates phosphorylation Thr1031 ASSTDHQtPPTSPVQ 9606 24089523 t lperfetto "Histone deacetylase 6 (hdac6) is well known for its ability to promote cell migrationextracellular signal-regulated kinase (erk) phosphorylates histone deacetylase 6 (hdac6) at serine 1035 to stimulate cell migrationwe have identified two novel erk-mediated phosphorylation sites: threonine 1031 and serine 1035 in hdac6. Both sites were phosphorylated by erk1" SIGNOR-202702 MAPK3 protein P27361 UNIPROT BAZ1B protein Q9UIG0 UNIPROT up-regulates phosphorylation Ser158 KSDGACDsPSSDKEN 9606 19776015 t gcesareni "Wstf, a specific component of two chromatin remodeling complexes (swi/snf-type winac and iswi-type wich), was phosphorylated by the stimulation of mapk cascades in vitro and in vivo. Ser-158 residue in the wac (wstf/acf1/cbpq46) domain, located close to the n terminus of wstf, was identified as a major phosphorylation target" SIGNOR-188164 MAPK3 protein P27361 UNIPROT HSPB8 protein Q9UJY1 UNIPROT up-regulates phosphorylation Ser27 PFRDSPLsSRLLDDG 9606 22721717 t lperfetto "Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation" SIGNOR-197932 MAPK3 protein P27361 UNIPROT HSPB8 protein Q9UJY1 UNIPROT up-regulates phosphorylation Thr87 GVPAEGRtPPPFPGE 9606 22721717 t lperfetto "Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation" SIGNOR-197936 MAPK3 protein P27361 UNIPROT HSPB8 protein Q9UJY1 UNIPROT "up-regulates activity" phosphorylation Ser27 PFRDSPLsSRLLDDG 9606 BTO:0000887 11342557 t lperfetto "Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation" SIGNOR-107676 GNG2 protein P59768 UNIPROT GNB/GNG complex SIGNOR-C202 SIGNOR "form complex" binding 9606 23994464 t apalma "Instead, our current understanding is that the majority of GPCR signal transduction in neutrophils occurs through the GŒ≤Œ≥ subunit" SIGNOR-255005 MAPK3 protein P27361 UNIPROT HSPB8 protein Q9UJY1 UNIPROT "up-regulates activity" phosphorylation Thr87 GVPAEGRtPPPFPGE 9606 BTO:0000887 11342557 t lperfetto "Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation" SIGNOR-107680 MAPK3 protein P27361 UNIPROT NUP50 protein Q9UKX7 UNIPROT down-regulates phosphorylation Ser221 KVAAETQsPSLFGST 9606 19767751 t gcesareni "Erk phosphorylates nup50 at ser221 and ser315 erk phosphorylation of the fg repeat region of nup50 reduced its affinity for importin-beta family proteins, importin-beta and transportin." SIGNOR-188151 MAPK3 protein P27361 UNIPROT ARHGAP26 protein Q9UNA1 UNIPROT unknown phosphorylation Ser685 PMFSAPSsPMPTSST -1 9525907 t miannu "In vitro, purified mitogen-activated protein (MAP) kinase catalyzed the phosphorylation of Graf on serine 510, suggesting that Graf phosphorylation may be mediated through MAP kinase signaling." SIGNOR-262945 MAPK3 protein P27361 UNIPROT GAB2 protein Q9UQC2 UNIPROT up-regulates phosphorylation Ser623 ALDFQPSsPSPHRKP 9606 15356145 t lperfetto "Phosphorylation of grb2-associated binder 2 on serine 623 by erk mapk regulates its association with the phosphatase shp-2 and decreases stat5 activation.We and others have demonstrated that il-2-induced tyrosine phosphorylation of gab2 and its interaction with its sh2 domain-containing partners, shp-2, p85 pi3k, and crkl (5, 26, 27). we report that pretreatment of kit 225 cells with the mek inhibitor u0126, strongly decreased the characteristic shift of gab2 in response to il-2 and increased gab2/shp-2 association, an effect that could be ascribed to erk phosphorylation of serine 623." SIGNOR-128731 MAPK3 protein P27361 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "down-regulates activity" phosphorylation 10090 BTO:0002572 28646232 t Gianni "We demonstrate that insulin-mediated activation of ERK1/2 results in phosphorylation of GSK3β at S9 independently of Akt/mTORC1 activity in Tsc2 null mouse embryonic fibroblasts. In addition, we show that inhibition of ERK1/2 rescues GSK3β activity and restores protein synthesis in Tsc2 −/− MEFs to normal levels" SIGNOR-262520 MAPK3 protein P27361 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR unknown phosphorylation 9606 21071439 t lperfetto "We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1." SIGNOR-217577 MAPK3 protein P27361 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates phosphorylation 9606 19346248 t lperfetto "The phosphorylation of raptor is stimulated by insulin and inhibited by rapamycin. Importantly, the site-directed mutation of raptor at one phosphorylation site, Ser(863), reduced mTORC1 activity both in vitro and in vivo." SIGNOR-217556 MAPK3 protein P27361 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates phosphorylation 9606 19864431 t lperfetto "Here we focus primarily although not exclusively on raptor Ser(863) phosphorylation. We report that insulin promotes mTORC1-associated phosphorylation of raptor Ser(863) via the canonical PI3K/TSC/Rheb pathway in a rapamycin-sensitive manner. mTORC1 activation by other stimuli (e.g. amino acids, epidermal growth factor/MAPK signaling, and cellular energy) also promote raptor Ser(863) phosphorylation." SIGNOR-217559 MAPK3 protein P27361 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates phosphorylation 9606 21757713 t lperfetto "The phosphorylation of Raptor on these sites enhances mTORC1 activity, and contributes largely to arsenite-induced mTORC1 activation." SIGNOR-217544 MAPK3 protein P27361 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR "up-regulates activity" phosphorylation 9606 19143636 t lperfetto "Activation of mTORC1 in two steps: Rheb-GTP activation of catalytic function and increased binding of substrates to raptor." SIGNOR-209859 MAPK3 protein P27361 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000007 12832467 t lperfetto "Phosphorylation of p90 ribosomal S6 kinase (RSK) regulates extracellular signal-regulated kinase docking and RSK activity.Erk-activates the rsk family of serine/threonine kinases,rsk1, rsk2, and rsk3." SIGNOR-252760 MAPK3 protein P27361 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR "up-regulates activity" phosphorylation Ser363 TSRTPKDsPGIPPSA 9534 BTO:0001538 9430688 t lperfetto "Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733." SIGNOR-252759 MAPK3 protein P27361 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR "up-regulates activity" phosphorylation Ser380 HQLFRGFsFVATGLM 9534 BTO:0001538 9430688 t lperfetto "Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733." SIGNOR-252756 MAPK3 protein P27361 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR "up-regulates activity" phosphorylation Ser732 RRVRKLPsTTL 9534 BTO:0001538 9430688 t lperfetto "Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733." SIGNOR-252761 CAD protein P27708 UNIPROT CAD protein P27708 UNIPROT "up-regulates activity" phosphorylation Thr1037 QQCRVLGtSPEAIDS -1 11986331 t llicata "Autophosphorylation resulted in a 2-fold increase in CPSase activity, an increased sensitivity to the feedback inhibitor UTP, and decreased allosteric activation by 5-phosphoribosyl-1-pyrophosphate" SIGNOR-250610 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser447 GSPRTPVsPVKFSPG 9606 21035469 t gcesareni "Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase" SIGNOR-169154 MAPK3 protein P27361 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR "up-regulates activity" phosphorylation Thr359 DTEFTSRtPKDSPGI 9534 BTO:0001538 9430688 t lperfetto "Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733." SIGNOR-252755 MAPK3 protein P27361 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR "up-regulates activity" phosphorylation Thr573 AENGLLMtPCYTANF 9534 BTO:0001538 9430688 t lperfetto "Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733." SIGNOR-252757 MAPK3 protein P27361 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates quantity by destabilization" phosphorylation Ser344 QDDDAPLsPMLYSSS 9606 19282669 t lperfetto "Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway" SIGNOR-252962 MAPK3 protein P27361 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates quantity by destabilization" phosphorylation Ser425 TKGSGLGsPTSSFNS 9606 19282669 t lperfetto "Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway" SIGNOR-252963 ARNT protein P27540 UNIPROT JUN protein P05412 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000599 21544813 f lperfetto "Screening by quantitative reverse-transcription PCR and PCR arrays revealed that cyclin E1, CDK2, Fos and Jun were negatively regulated by ARNT, whereas CDKN1C, CNKN2A, CDKN2B, MAPK11 and MAPK14 were positively regulated in HCC" SIGNOR-253697 ARNT protein P27540 UNIPROT TH protein P07101 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0003945 17457889 f lperfetto "Overexpression and siRNA experiments revealed that NPAS1, in concert with ARNT, negatively regulates the expression of TH and that this regulation is mediated by a direct binding of NPAS1 on the TH promoter." SIGNOR-253701 ARNT protein P27540 UNIPROT CCNE1 protein P24864 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000599 21544813 f lperfetto "Screening by quantitative reverse-transcription PCR and PCR arrays revealed that cyclin E1, CDK2, Fos and Jun were negatively regulated by ARNT, whereas CDKN1C, CNKN2A, CDKN2B, MAPK11 and MAPK14 were positively regulated in HCC" SIGNOR-253692 ARNT protein P27540 UNIPROT CDK2 protein P24941 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000599 21544813 f lperfetto "Screening by quantitative reverse-transcription PCR and PCR arrays revealed that cyclin E1, CDK2, Fos and Jun were negatively regulated by ARNT, whereas CDKN1C, CNKN2A, CDKN2B, MAPK11 and MAPK14 were positively regulated in HCC" SIGNOR-253693 ARNT protein P27540 UNIPROT HIF1A protein Q16665 UNIPROT "up-regulates activity" binding 14764593 t lperfetto "The functional transcription factor exists as a heterodimeric complex consisting of HIF-1alpha and the aryl hydrocarbon receptor nuclear translocator (ARNT). Association of HIF-1 with ARNT is required for its activity; however, no other role has been ascribed to this interaction." SIGNOR-253720 ARNT protein P27540 UNIPROT CYP1B1 protein Q16678 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001033 16115918 f miannu "Expressions of CYP1B1 mRNA and protein were increased in prostate cancer. The aryl hydrocarbon receptor (AhR)/AhR nuclear translocator (ARNT) heterodimer complex activates gene transcription by binding to the DREs of CYP1B1." SIGNOR-253740 ARNT protein P27540 UNIPROT CA9 protein Q16790 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599;BTO:0001950 22387692 f lperfetto "The miR-24-dependent down-regulation of ARNT decreased the expression of its downstream genes such as CYP1A1 and carbonic anhydrase IX." SIGNOR-253706 ARNT protein P27540 UNIPROT AHR-ARNT complex SIGNOR-C125 SIGNOR "form complex" binding -1 9020169 t 2 miannu "SIM1 and SIM2, and the mammalian aryl hydrocarbon receptor (AHR) and aryl hydrocarbon receptor nuclear translocator (ARNT) proteins are members of the basic-helix-loop-helix·PAS family of transcription factors. In the yeast two-hybrid system, we demonstrate strong constitutive interaction of ARNT with SIM1 and SIM2 and fully ligand-dependent interaction of ARNT with AHR. SIM1 inhibits binding of the AHR·ARNT dimer to the xenobiotic response element in vitro Introduction of SIM1 into hepatoma cells inhibits transcriptional transactivation by the endogenous AHR·ARNT dimer." SIGNOR-240814 RPL10 protein P27635 UNIPROT JUN protein P05412 UNIPROT down-regulates binding 9606 12138090 t miannu "The qm gene encodes a 24.5 kda ribosomal protein l10 known to be highly homologous to a jun-binding protein (jif-1), which inhibits the formation of jun-jun dimers." SIGNOR-90750 RPL10 protein P27635 UNIPROT YES1 protein P07947 UNIPROT down-regulates binding 9606 12138090 t miannu "Several c-yes kinase activity assays indicated that the qm protein reduced c-yes kinase activity by 70%" SIGNOR-90805 RPA1 protein P27694 UNIPROT POLA1 protein P09884 UNIPROT "up-regulates activity" binding -1 9214288 t Federica "In our studies, we have shown that T antigen, DNA polymerase R, and the activation domain of VP16 all interact with overlapping regions of the 70-kDa subunit of RPA.| In the latter, both the direct protein-protein interaction and ssDNA-binding activities of RPA were needed for RPA to modulate polymerase processivity. We also found that SV40 T antigen inhibited the ability of RPA to increase processivity of DNA polymerase alpha, suggesting that this activity of RPA may be important for elongation but not during the initiation of DNA replication." SIGNOR-261272 APEX1 protein P27695 UNIPROT CYP11B2 protein P19099 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 22652909 f miannu "We conclude that APEX1 is a novel transcriptional repressor of CYP11B2 and that differential APEX1 binding at -1651 of CYP11B2 results in altered gene expression." SIGNOR-253736 APEX1 protein P27695 UNIPROT SLC5A5 protein Q92911 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567 14630715 t Luana "These data demonstrate a role for APE/Ref-1 protein in the transcriptional regulation of NIS gene expression by itself and in cooperation with PAX8. " SIGNOR-261564 PIK3R1 protein P27986 UNIPROT "1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate" smallmolecule CHEBI:16618 ChEBI "up-regulates quantity" 10116 21798082 f 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-175678 PIK3R1 protein P27986 UNIPROT PIK3CD protein O00329 UNIPROT "up-regulates activity" binding 9534 BTO:0004055 14665640 t lperfetto "Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival" SIGNOR-242643 PIK3R1 protein P27986 UNIPROT PIK3CA protein P42336 UNIPROT "up-regulates activity" binding 9534 BTO:0004055 14665640 t lperfetto "Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival" SIGNOR-242637 PIK3R1 protein P27986 UNIPROT PIK3CB protein P42338 UNIPROT "up-regulates activity" binding 9534 BTO:0004055 14665640 t lperfetto "Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival" SIGNOR-242640 PIK3R1 protein P27986 UNIPROT PIK3CG protein P48736 UNIPROT "up-regulates activity" binding 9534 BTO:0004055 14665640 t lperfetto "Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival" SIGNOR-242646 PIK3R1 protein P27986 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "form complex" binding 9606 19805105 t miannu "Phosphoinositol 3- kinase alpha (PI3Kα) is a heterodimeric enzyme formed by a catalytic subunit (p110α, encoded by PIK3CA) and one of several regulatory subunits (a major one being p85α, encoded by PI3KR1)." SIGNOR-255300 PSMB8 protein P28062 UNIPROT MCL1 protein Q07820 UNIPROT "down-regulates quantity by destabilization" 9606 BTO:0003445 19443843 t Gianni "Surprisingly, siRNA knockdown of PSMB8 (LMP7), an ‘immunoproteasome’ component, reversed IFNγ-induced sensitivity to Fas ligation and prevented Fas/IFNγ-induced degradation of Mcl-1, but did not protect p-Bcl-2 or p-Bcl-XL. Proteasome inhibition markedly increased Mcl-1, p-Bcl-2, and p-Bcl-XL levels after IFNγ treatment" SIGNOR-261974 PSMA5 protein P28066 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "form complex" binding 9606 BTO:0000007 29636472 t lperfetto "Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line" SIGNOR-263364 POU1F1 protein P28069 UNIPROT GH1 protein P01241 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15998782 f miannu "Such findings are consistent with the existence, in humans, of an LHX4-driven pathway leading to the expression of GH through transcriptional activation of POU1F1." SIGNOR-254559 HTR1D protein P28221 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256864 HTR1D protein P28221 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257000 HTR1D protein P28221 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257116 HTR1B protein P28222 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257207 MAPK1 protein P28482 UNIPROT MCRIP1 protein C9JLW8 UNIPROT "down-regulates activity" phosphorylation Thr30 PSSSEIFtPAHEENV 9606 BTO:0000007 25728771 t lperfetto "When phosphorylated by ERK, MCRIP1 dissociates from CtBP, allowing CtBP to interact with ZEB1. In this manner, the CtBP co-repressor complex is recruited to, and silences, the E-cadherin promoter by inducing chromatin modifications.| While substitution of S4 or S18 with Ala did not affect the phosphorylation of MCRIP1 by ERK, substitution of either S21 or T30 significantly reduced MCRIP1 phosphorylation" SIGNOR-264774 HTR1B protein P28222 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256863 HTR1B protein P28222 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256999 HTR1B protein P28222 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257115 HTR1B protein P28222 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256720 HTR2A protein P28223 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257227 HTR2A protein P28223 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257137 HTR2A protein P28223 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256742 LOX protein P28300 UNIPROT EFEMP2 protein O95967 UNIPROT "up-regulates activity" binding 9606 19570982 t miannu "Fibulin-4 directly binds LOX, and this interaction enhances fibulin-4 binding to tropoelastin, thus forming a ternary complex that may be critical for elastin cross-linking." SIGNOR-252135 ELK4 protein P28324 UNIPROT INSIG2 protein Q9Y5U4 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 20145255 t Luana "Under these conditions, a significant reduction in INSIG2 expression was only observed when SAP1a siRNA was used. These observations provide supporting evidence that SAP1a may be one of the transactivators of the human INSIG2 promoter." SIGNOR-261592 PEX2 protein P28328 UNIPROT PEX5 protein P50542 UNIPROT "down-regulates quantity by destabilization" ubiquitination -1 19687296 t miannu "Here we report on the identification of the protein-ubiquitin ligases that are responsible for the ubiquitination of the peroxisomal protein import receptor Pex5. It is demonstrated that each of the three RING peroxins Pex2, Pex10, and Pex12 exhibits ubiquitin-protein isopeptide ligase activity. Our results show that Pex2 mediates the Ubc4-dependent polyubiquitination whereas Pex12 facilitates the Pex4-dependent monoubiquitination of Pex5.While polyubiquitinated Pex5 is degraded by the proteasome, monoubiquitinated Pex5 is destined for a new round of the receptor cycle." SIGNOR-253021 MAPK1 protein P28482 UNIPROT PARP1 protein P09874 UNIPROT up-regulates phosphorylation Thr373 AATPPPStASAPAAV 9606 BTO:0000938 BTO:0000142 16627622 t esanto "Parp1 phosphorylation by erk1/2 is required for maximal parp-1 activation after dna damage. S372a and t373a mutations impaired parp-1 activation." SIGNOR-146224 HTR2C protein P28335 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257295 HTR2C protein P28335 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256877 HTR2C protein P28335 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257013 HTR2C protein P28335 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257129 HTR2C protein P28335 UNIPROT GNA15 protein P30679 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257355 NMBR protein P28336 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257422 NMBR protein P28336 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257160 NMBR protein P28336 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257315 NMBR protein P28336 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257047 NMBR protein P28336 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 9606 BTO:0001130;BTO:0000551 11313903 t gcesareni "These neuropeptides, including gastrin-releasing peptide, neuromedin b, neurotensin, gastrin, cholecystokinin and arginine vasopressin bind seven transmembrane-spanning receptors that couple to heterotrimeric g proteins. Studies with human small cell lung cancer (sclc) cells support a requirement for balanced signaling through g(q) and g(12/13) proteins leading to intracellular ca2+ mobilization, pkc activation and regulation of the erk and jnk map kinase pathways." SIGNOR-107025 NMBR protein P28336 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 BTO:0001130;BTO:0000551 11313903 t gcesareni "These neuropeptides, including gastrin-releasing peptide, neuromedin b, neurotensin, gastrin, cholecystokinin and arginine vasopressin bind seven transmembrane-spanning receptors that couple to heterotrimeric g proteins. Studies with human small cell lung cancer (sclc) cells support a requirement for balanced signaling through g(q) and g(12/13) proteins leading to intracellular ca2+ mobilization, pkc activation and regulation of the erk and jnk map kinase pathways." SIGNOR-107028 NMBR protein P28336 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256775 TEAD1 protein P28347 UNIPROT MYF5 protein P13349 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887 21527258 f gcesareni "We found that the expression of myf5 and cyclind1 remained significantly elevated upon induction of differentiation in cells that were overexpressing hyap1 s127a compared to cells transfected with wildtype hyap and empty vector;yap directly induced the transcription of ccnd1 and foxm1, in cooperation with tead transcription factor." SIGNOR-173445 TEAD1 protein P28347 UNIPROT CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103;BTO:0001760 20153295 f lperfetto "We found that the expression of myf5 and cyclind1 remained significantly elevated upon induction of differentiation in cells that were overexpressing hyap1 s127a compared to cells transfected with wildtype hyap and empty vector;yap directly induced the transcription of ccnd1 and foxm1, in cooperation with tead transcription factor." SIGNOR-235849 TEAD1 protein P28347 UNIPROT CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22286761 f gcesareni "Yap directly induced the transcription of ccnd1 and foxm1, in cooperation with tead transcription factor." SIGNOR-195534 TEAD1 protein P28347 UNIPROT FOXM1 protein Q08050 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22286761 f gcesareni "Yap directly induced the transcription of ccnd1 and foxm1, in cooperation with tead transcription factor." SIGNOR-194371 HOXD9 protein P28356 UNIPROT MEIS1 protein O00470 UNIPROT "up-regulates activity" binding 9606 10523646 t miannu "We find that DNA binding by MEIS1A is absolutely required for the formation of a cooperative complex with HOXD9" SIGNOR-220721 HOXD10 protein P28358 UNIPROT MEIS1 protein O00470 UNIPROT "up-regulates activity" binding -1 9343407 t 2 miannu "We now show that the Hoxa-9 protein physically interacts with Meis1 proteins. Hox proteins from the other AbdB-like paralogs, Hoxa-10, Hoxa-11, Hoxd-12, and Hoxb-13, also form DNA binding complexes with Meis1b. DNA binding complexes formed by Meis1 with Hox proteins dissociate much more slowly than DNA complexes with Meis1 alone, suggesting that Hox proteins stabilize the interactions of Meis1 proteins with their DNA targets." SIGNOR-241226 MSX1 protein P28360 UNIPROT MYOD1 protein P15172 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001103 15192231 f gcesareni "We found that msx1 and h1b bind to a key regulatory element of myod, a central regulator of skeletal muscle differentiation, where they induce repressed chromatin." SIGNOR-125765 MSX1 protein P28360 UNIPROT TBP protein P20226 UNIPROT "down-regulates activity" binding -1 8700832 t 2 miannu "Msx-1 is a potent transcriptional repressor and that this activity is independent of its DNA binding function. Here we show that Msx-1 interacts directly with the TATA binding protein (TBP) but not with several other general transcription factors. This interaction is mediated by the Msx-1 homeodomain, specifically through residues in the N-terminal arm. These same N-terminal arm residues are required for repression by Msx-1, suggesting a functional relationship between TBP association and transcriptional repression." SIGNOR-240401 MSX1 protein P28360 UNIPROT LHX2 protein P50458 UNIPROT "down-regulates activity" binding -1 9697309 t 2 miannu "Protein complex formation between Msx1 and Lhx2 homeoproteins is incompatible with DNA binding activity" SIGNOR-241330 MSX1 protein P28360 UNIPROT DLX5 protein P56178 UNIPROT "down-regulates activity" binding 10090 BTO:0000946 9111364 t 2 miannu "We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities." SIGNOR-240987 MSX1 protein P28360 UNIPROT DLX2 protein Q07687 UNIPROT "down-regulates activity" binding 10090 BTO:0000944 9111364 t 2 miannu "We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities." SIGNOR-240929 MAPK1 protein P28482 UNIPROT MCRIP1 protein C9JLW8 UNIPROT "down-regulates activity" phosphorylation Ser21 KRTSSPRsPPSSSEI 9606 BTO:0000007 25728771 t lperfetto "When phosphorylated by ERK, MCRIP1 dissociates from CtBP, allowing CtBP to interact with ZEB1. In this manner, the CtBP co-repressor complex is recruited to, and silences, the E-cadherin promoter by inducing chromatin modifications.| While substitution of S4 or S18 with Ala did not affect the phosphorylation of MCRIP1 by ERK, substitution of either S21 or T30 significantly reduced MCRIP1 phosphorylation" SIGNOR-264775 MAPK1 protein P28482 UNIPROT APBB1 protein O00213 UNIPROT unknown phosphorylation Ser175 EEEEDLSsPPGLPEP 9606 14697653 t lperfetto "Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved." SIGNOR-120451 MAPK1 protein P28482 UNIPROT APBB1 protein O00213 UNIPROT unknown phosphorylation Ser287 WEPPGRAsPSQGSSP 9606 14697653 t lperfetto "Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved." SIGNOR-120455 MAPK1 protein P28482 UNIPROT APBB1 protein O00213 UNIPROT unknown phosphorylation Ser347 TFPAQSLsPEPLPQE 9606 14697653 t lperfetto "Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved." SIGNOR-120459 MAPK1 protein P28482 UNIPROT APBB1 protein O00213 UNIPROT unknown phosphorylation Thr709 PKRLGAHtP 9606 14697653 t lperfetto "Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved." SIGNOR-120463 MAPK1 protein P28482 UNIPROT PITPNM1 protein O00562 UNIPROT up-regulates phosphorylation Thr1223 AEREGPGtPPTTLAR 9606 15125835 t lperfetto "Both cdk1 and erk2 induced phosphorylation of the wild-type nir2. Substitution of t794 by alanine reduced the phosphorylation by erk2, whereas the double mutations t794/1223a completely abolished it. The requirement of multiple nir2 phosphorylation sites for plk1 binding may provide a mechanism that sets a threshold for the nir2-plk1 interaction during mitosis." SIGNOR-124646 MAPK1 protein P28482 UNIPROT PITPNM1 protein O00562 UNIPROT up-regulates phosphorylation Thr794 LEMLVPStPTSTSGA 9606 15125835 t lperfetto "Both cdk1 and erk2 induced phosphorylation of the wild-type nir2. Substitution of t794 by alanine reduced the phosphorylation by erk2, whereas the double mutations t794/1223a completely abolished it. The requirement of multiple nir2 phosphorylation sites for plk1 binding may provide a mechanism that sets a threshold for the nir2-plk1 interaction during mitosis." SIGNOR-124650 MAPK1 protein P28482 UNIPROT CDC42EP2 protein O14613 UNIPROT unknown phosphorylation Ser101 RELPDGPsPLLKNAI 10090 BTO:0000944 22028470 t miannu "We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)" SIGNOR-262770 MAPK1 protein P28482 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser344 QDDDAPLsPMLYSSS 9606 BTO:0000007 18204439 t lperfetto "Here, we show that erk downregulates forkhead box o 3a (foxo3a) by directly interacting with and phosphorylating foxo3a at ser 294, ser 344 and ser 425, which consequently promotes cell proliferation and tumorigenesisMDM2 is required for ERk-mediated FOXO3a degradation." SIGNOR-160411 MAPK1 protein P28482 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser425 TKGSGLGsPTSSFNS 9606 BTO:0000007 18204439 t lperfetto "Here, we show that erk downregulates forkhead box o 3a (foxo3a) by directly interacting with and phosphorylating foxo3a at ser 294, ser 344 and ser 425, which consequently promotes cell proliferation and tumorigenesisMDM2 is required for ERk-mediated FOXO3a degradation." SIGNOR-160415 MAPK1 protein P28482 UNIPROT SORBS3 protein O60504 UNIPROT unknown phosphorylation 9606 15184391 t "The effect has been demonstrated using O60504-2" llicata "Vinexin was directly phosphorylated by erk2 upon stimulation with egf at the serine 189 of vinexin _." SIGNOR-125224 MAPK1 protein P28482 UNIPROT JAK2 protein O60674 UNIPROT down-regulates phosphorylation Ser523 GVSDVPTsPTLQRPT 9534 BTO:0004055 16705159 t "16705160:the phosphorylation of Jak2 on Ser523 inhibits Jak2 activity and represents a novel mechanism for the regulation of Jak2-dependent cytokine signaling." lperfetto "We hypothesize that phosphorylation of ser523 in jak2 by erks 1 and/or 2 or other as-yet-unidentified kinases acts in a negative feedback manner" SIGNOR-236331 MAPK1 protein P28482 UNIPROT MITF protein O75030 UNIPROT down-regulates phosphorylation Ser180 PGSSAPNsPMAMLTL 9606 10673502 t "The effect has been demonstrated using O75030-9" gcesareni "The current study reveals that c-kit signaling triggers two phosphorylation events on mi, which up-regulate transactivation potential yet simultaneously target mi for ubiquitin-dependent proteolysis. The specific activation/degradation signals derive from mapk/erk targeting of serine 73the results suggested that s1p reduced melanin synthesis via s1p(3) receptor-mediated erk and rsk-1 activation, and subsequent mitf dual phosphorylation and degradation." SIGNOR-75030 MAPK1 protein P28482 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation 9606 20974802 t gcesareni "We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. External stimuli, which control the activity of mapks, such as phorbol esters and fibroblast growth factor 2 (fgf2) control the choice of the lrp6-ppps/tp kinase and regulate the amplitude of lrp6 phosphorylation and wnt/beta-catenin-dependent transcription." SIGNOR-169001 MAPK1 protein P28482 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Ser360 TEMDPTYsPAALPQS 9606 BTO:0000887 11940578 t gcesareni "Together, our in vivo and in vitro studies indicate that the pkc/c-raf/mek/erk pathway plays a major role in the s6k1 activation in hypertrophic cardiac growth." SIGNOR-116485 MAPK1 protein P28482 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Thr581 PDNQPLKtPCFTLHY 9606 BTO:0000887 11940578 t gcesareni "Together, our in vivo and in vitro studies indicate that the pkc/c-raf/mek/erk pathway plays a major role in the s6k1 activation in hypertrophic cardiac growth." SIGNOR-116489 MAPK1 protein P28482 UNIPROT EGFR protein P00533 UNIPROT "down-regulates activity" phosphorylation Thr693 RELVEPLtPSGEAPN -1 1651322 t lperfetto "A growth factor-stimulated protein kinase activity that phosphorylates the epidermal growth factor (EGF) receptor at Thr669 has been described Anion-exchange chromatography demonstrated that this protein kinase activity was accounted for by two enzymes. The first peak of activity eluted from the column corresponded to the microtubule-associated protein 2 (MAP2) kinase" SIGNOR-20545 MAPK1 protein P28482 UNIPROT FOS protein P01100 UNIPROT "up-regulates activity" phosphorylation Ser374 PSSDSLSsPTLLAL 9606 12972619 t lperfetto "We have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. ERK2 phosphorylated c-Fos TADs that included Thr- 325, Thr-331, or Ser-374 as unique phospho-acceptor sites, thus indicating that these residues can serve as in vitro targets for the enzymatic activity of ERK2." SIGNOR-235671 MAPK1 protein P28482 UNIPROT FOS protein P01100 UNIPROT "up-regulates activity" phosphorylation Thr325 TELEPLCtPVVTCTP 9606 12972619 t lperfetto "We have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. ERK2 phosphorylated c-Fos TADs that included Thr- 325, Thr-331, or Ser-374 as unique phospho-acceptor sites, thus indicating that these residues can serve as in vitro targets for the enzymatic activity of ERK2." SIGNOR-236010 MAPK1 protein P28482 UNIPROT FOS protein P01100 UNIPROT "up-regulates activity" phosphorylation Thr331 CTPVVTCtPSCTAYT phosphorylation:Ser374;Ser362 PSSDSLSsPTLLAL;AAAHRKGsSSNEPSS 16055710 t lperfetto "Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos" SIGNOR-263007 MAPK1 protein P28482 UNIPROT FOS protein P01100 UNIPROT "up-regulates activity" phosphorylation Thr232 GGLPEVAtPESEEAF 9606 BTO:0004971 7816602 t lperfetto "Phosphorylation of the c-fos and c-jun hob1 motif stimulates its activation capacity here we show that the hob1-containing activation domain of c-fos is stimulated by ha-ras in vivo and phosphorylated by a map kinase family member in vitro and that mutating t232 to ala abolishes both functions." SIGNOR-235877 MAPK1 protein P28482 UNIPROT MYC protein P01106 UNIPROT "up-regulates activity" phosphorylation Ser62 LLPTPPLsPSRRSGL 9534 BTO:0004055 8386367 t lperfetto "Transactivation of gene expression by myc is inhibited by mutation at the phosphorylation sites thr-58 and ser-62." SIGNOR-235700 MAPK1 protein P28482 UNIPROT MBP protein P02686 UNIPROT down-regulates phosphorylation Thr232 KNIVTPRtPPPSQGK 9606 BTO:0000142 16401070 t lperfetto "Phosphorylation decreased the ability of mbp to polymerize actin and to bundle actin filaments but had no effect on the dissociation constant of the mbp-actin complex or on the ability of ca2+-calmodulin to dissociate the complex. The most significant effect of phosphorylation on the mbp-actin complex was a dramatic reduction in its ability to bind to negatively charged lipid bilayers. The identification of myelin basic protein (phosphorylation at -pro-arg-thr-pro-) as a substrate for the erk kinases (fig. 1) demonstrates that there are other determinants important for substrate recognition than those present in the originally identified consensus sequence." SIGNOR-143477 MAPK1 protein P28482 UNIPROT MBP protein P02686 UNIPROT down-regulates phosphorylation Thr232 KNIVTPRtPPPSQGK 9606 1939237 t lperfetto "Phosphorylation decreased the ability of mbp to polymerize actin and to bundle actin filaments but had no effect on the dissociation constant of the mbp-actin complex or on the ability of ca2+-calmodulin to dissociate the complex. The most significant effect of phosphorylation on the mbp-actin complex was a dramatic reduction in its ability to bind to negatively charged lipid bilayers. The identification of myelin basic protein (phosphorylation at -pro-arg-thr-pro-) as a substrate for the erk kinases (fig. 1) demonstrates that there are other determinants important for substrate recognition than those present in the originally identified consensus sequence." SIGNOR-22420 MAPK1 protein P28482 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Thr229 HFFKNIVtPRTPPPS 9606 BTO:0000661 12760422 t lperfetto "Thr94 in bovine myelin basic protein is a second phosphorylation site for 42-kDa mitogen-activated protein kinase (ERK2)." SIGNOR-249419 MAPK1 protein P28482 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser104 FPPLNSVsPSPLMLL 9606 BTO:0000567 17615152 t gcesareni "In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity" SIGNOR-156848 MAPK1 protein P28482 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser106 PLNSVSPsPLMLLHP 9606 BTO:0000567 17615152 t gcesareni "In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity" SIGNOR-156852 MAPK1 protein P28482 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser104 FPPLNSVsPSPLMLL 9606 BTO:0000150 18372406 t gcesareni "In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity" SIGNOR-178133 MAPK1 protein P28482 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser106 PLNSVSPsPLMLLHP 9606 BTO:0000150 18372406 t gcesareni "In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity" SIGNOR-178137 MAPK1 protein P28482 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation 9606 9922370 t gcesareni "Mapkerk1/2 is also able to phopshorylate the egf receptor, the ras exchange factor sos, mkkkraf1, and mkkmek1. The phosphorylation of each of these proteins by mapkerk1/2 is believed to reduce their catalytic activity" SIGNOR-64169 MAPK1 protein P28482 UNIPROT RAF1 protein P04049 UNIPROT "down-regulates activity" phosphorylation Ser289 RSHSESAsPSALSSS 10090 15664191 t lperfetto "Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2" SIGNOR-249440 MAPK1 protein P28482 UNIPROT RAF1 protein P04049 UNIPROT "down-regulates activity" phosphorylation Ser29 FDGSSCIsPTIVQQF 10090 BTO:0000944 15664191 t lperfetto "Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2" SIGNOR-249441 MAPK1 protein P28482 UNIPROT RAF1 protein P04049 UNIPROT "down-regulates activity" phosphorylation Ser301 SSSPNNLsPTGWSQP 10090 BTO:0000944 15664191 t lperfetto "Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2" SIGNOR-249443 MAPK1 protein P28482 UNIPROT RAF1 protein P04049 UNIPROT "down-regulates activity" phosphorylation Ser43 FGYQRRAsDDGKLTD 10090 BTO:0000944 15664191 t lperfetto "Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2" SIGNOR-249439 MAPK1 protein P28482 UNIPROT RAF1 protein P04049 UNIPROT "down-regulates activity" phosphorylation Ser642 NACTLTTsPRLPVF 10090 BTO:0000944 15664191 t lperfetto "Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2" SIGNOR-249444 MAPK1 protein P28482 UNIPROT NR3C1 protein P04150 UNIPROT "down-regulates activity" phosphorylation Ser226 IDENCLLsPLAGEDD -1 9199329 t lperfetto "Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232.|MAPKs and CDKs exert opposite effects on receptor transcriptional enhancement. From our results, we speculate that activators of the MAPK pathway, such as growth factors, insulin, and certain oncoproteins, or inhibitors of CDK function, such as tumor growth factor beta (TGF_), p21, and p27, might attenuate receptor-induced transcrip- tional responses. In contrast, negative regulators of MAPK, such as pKA, as well as activators of CDK, such as the cyclins or CAKs, should potentiate receptor action." SIGNOR-249428 MAPK1 protein P28482 UNIPROT ATP1A1 protein P05023 UNIPROT "down-regulates activity" phosphorylation Ser16 KYEPAAVsEQGDKKG 1792 BTO:0003069 14976217 t miannu "Parathyroid hormone (PTH) inhibits Na+,K+-ATPase activity through protein kinase C- (PKC) and extracellular signal-regulated kinase- (ERK) dependent pathways and increases serine phosphorylation of the α1-subunit. These results suggest that PTH regulates Na(+),K(+)-ATPase by PKC and ERK-dependent alpha(1)-subunit phosphorylation and that the phosphorylation requires the expression of a serine at the 11 position of the Na(+),K(+)-ATPase alpha(1)-subunit." SIGNOR-262940 MAPK1 protein P28482 UNIPROT KRT8 protein P05787 UNIPROT unknown phosphorylation Ser432 SAYGGLTsPGLSYSL 16554440 t lperfetto "Also, several probable in vivo K8 kinases have been identified including Erk1/2 for K8 Ser431 (Ku and Omary, 1997), and p38 and Jun kinases for K8 Ser73 (Ku et al., 2002a; He et al., 2002)." SIGNOR-249411 MAPK1 protein P28482 UNIPROT LCK protein P06239 UNIPROT down-regulates phosphorylation Ser42 TLLIRNGsEVRDPLV 9606 BTO:0000782 8226850 t lperfetto "Phosphorylation of serine-59 on p56lck in vivo, which correlated with the shift to p60lck. We also demonstrated that the same serine residue could be phosphorylated in vitro with mitogen-activated protein kinases and that this event was capable of reducing p56lck activity in vitro." SIGNOR-37017 MAPK1 protein P28482 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr453 SGPIIIRtPTVGPNG 9606 11904305 t gcesareni "Here we show that p42/p44 mapk directly phosphorylates sp1 on threonines 453 and 739 both in vitro and in vivo. Mutation of these sites to alanines decreases by half the mapk-dependent transcriptional activity of sp1. Phosphorylated extracellular signal-regulated protein kinases 1 and 2 phosphorylate sp1 on serine 59 and regulate cellular senescence via transcription of p21sdi1/cip1/waf1." SIGNOR-116162 MAPK1 protein P28482 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr739 SEGSGTAtPSALITT 9606 11904305 t gcesareni "Here we show that p42/p44 mapk directly phosphorylates sp1 on threonines 453 and 739 both in vitro and in vivo. Mutation of these sites to alanines decreases by half the mapk-dependent transcriptional activity of sp1. Phosphorylated extracellular signal-regulated protein kinases 1 and 2 phosphorylate sp1 on serine 59 and regulate cellular senescence via transcription of p21sdi1/cip1/waf1." SIGNOR-116166 MAPK1 protein P28482 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Ser59 GGQESQPsPLALLAA 9606 BTO:0000452 19318349 t gcesareni "PKCalpha, which was activated in senescent cells by ROS strongly activated Erk1/2, and the SA-pErk1/2 in turn phosphorylated Sp1 on Ser(59). Sp1-enhanced transcription of p21(Sdi1) resulted in regulation of cellular senescence in primary human diploid fibroblast cells." SIGNOR-248075 MAPK1 protein P28482 UNIPROT PARP1 protein P09874 UNIPROT up-regulates phosphorylation Ser372 VAATPPPsTASAPAA 9606 BTO:0000938 BTO:0000142 16627622 t esanto "Parp1 phosphorylation by erk1/2 is required for maximal parp-1 activation after dna damage. S372a and t373a mutations impaired parp-1 activation." SIGNOR-146220 MAPK1 protein P28482 UNIPROT ALOX5 protein P09917 UNIPROT "up-regulates activity" phosphorylation Ser272 CSLERQLsLEQEVQQ 9606 BTO:0000567 12670876 t lperfetto "Intriguingly, a significant difference in the potency of nonredox-type inhibitors (but not of BWA4C) was determined between wild-type 5-LO and the mutant S271A/S663A-5-LO (lacking phosphorylation sites for ERK1/2 and MAPKAPK-2) in HeLa cells. Collectively, our data suggest that compared with Ca2+-mediated 5-LO product formation, enzyme activation involving 5-LO phosphorylation events specifically and strongly alters the susceptibility of 5-LO toward nonredox-type inhibitors in intact cells." SIGNOR-264439 MAPK1 protein P28482 UNIPROT ALOX5 protein P09917 UNIPROT "up-regulates activity" phosphorylation Ser664 QLPYYYLsPDRIPNS 9606 BTO:0000567 12670876 t lperfetto "Intriguingly, a significant difference in the potency of nonredox-type inhibitors (but not of BWA4C) was determined between wild-type 5-LO and the mutant S271A/S663A-5-LO (lacking phosphorylation sites for ERK1/2 and MAPKAPK-2) in HeLa cells. Collectively, our data suggest that compared with Ca2+-mediated 5-LO product formation, enzyme activation involving 5-LO phosphorylation events specifically and strongly alters the susceptibility of 5-LO toward nonredox-type inhibitors in intact cells." SIGNOR-264409 MAPK1 protein P28482 UNIPROT MYB protein P10242 UNIPROT unknown phosphorylation Ser532 KIKQEVEsPTDKSGN -1 8960373 t lperfetto "Functional analysis of phosphorylation at serine 532 of human c-Myb by MAP kinase| Expression of a constitutively active form of Ras together with c-Myb in transient transfection experiments had no effect on the transcriptional activity of c-Myb, while expression of a polypeptide containing the c-Myb C-terminal domain stimulated c-Myb activity. This effect is reduced upon MAPK-dependent phosphorylation of serine 532." SIGNOR-249420 MAPK1 protein P28482 UNIPROT AR protein P10275 UNIPROT down-regulates phosphorylation Ser516 VSRVPYPsPTCVKSE 9606 BTO:0001130 18511414 t gcesareni "Map kinase-dependent phosphorylation at ar ser-515 was supported by the decrease in intensity of the slower migrating 23-kda band after treatment with both egf and increasing concentrations of the map kinase inhibitor, u0126" SIGNOR-178718 MAPK1 protein P28482 UNIPROT BCL2 protein P10415 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser70 RDPVARTsPLQTPAA 9606 BTO:0000567 10669763 t lperfetto "Phosphorylation of the map kinase sites in bcl-2, thr56, thr74, and ser87, is sufficient to inhibit tnf--induced degradation. p44mapk/extracellular signal-regulated kinase 1 (erk1) and p42 mapk/erk2 are activated by il-3, colocalize with mitochondrial bcl2, and can directly phosphorylate bcl2 on ser-70 in a stauro-resistant manner both_ in vitro_ and_ in vivo." SIGNOR-74919 MAPK1 protein P28482 UNIPROT BCL2 protein P10415 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser87 AAAGPALsPVPPVVH 9606 BTO:0000567 10669763 t lperfetto "Phosphorylation of the map kinase sites in bcl-2, thr56, thr74, and ser87, is sufficient to inhibit tnf--induced degradation." SIGNOR-74931 MAPK1 protein P28482 UNIPROT BCL2 protein P10415 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr56 FSSQPGHtPHPAASR 9606 10669763 t lperfetto "Phosphorylation of the map kinase sites in bcl-2, thr56, thr74, and ser87, is sufficient to inhibit tnf--induced degradation. p44mapk/extracellular signal-regulated kinase 1 (erk1) and p42 mapk/erk2 are activated by il-3, colocalize with mitochondrial bcl2, and can directly phosphorylate bcl2 on ser-70 in a stauro-resistant manner both_ in vitro_ and_ in vivo." SIGNOR-74923 MAPK1 protein P28482 UNIPROT BCL2 protein P10415 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr74 ARTSPLQtPAAPGAA 9606 BTO:0000567 10669763 t lperfetto "In endothelial cells, tumor necrosis factor alpha (tnf-alpha) induces dephosphorylation and subsequent ubiquitin-dependent degradation of the antiapoptotic protein bcl-2. Here, we investigate the role of different putative phosphorylation sites to facilitate bcl-2 degradation" SIGNOR-74927 MAPK1 protein P28482 UNIPROT BCL2 protein P10415 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser70 RDPVARTsPLQTPAA 9534 BTO:0004055 10677502 t lperfetto "Erk1 and erk2 directly phosphorylate bcl2 exclusively at ser-70." SIGNOR-219217 MAPK1 protein P28482 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser519 SGYSSPGsPGTPGSR 9606 BTO:0000590 10737616 t lperfetto "Using nanoelectrospray mass spectrometry, we have undertaken an extensive comparison of phosphorylation in vitro by several candidate tau kinases, namely, JNK, p38, ERK2, and glycogen synthase kinase 3beta (GSK3beta). Between 10 and 15 sites were identified for each kinase. The three MAP kinases phosphorylated Ser202 and Thr205 but not detectably Ser199, whereas conversely GSK3beta phosphorylated Ser199 but not detectably Ser202 or Thr205. Phosphorylated Ser404 was found with all of these kinases except JNK. The MAP kinases may not be strictly proline specific: p38 phosphorylated the nonproline sites Ser185, Thr245, Ser305, and Ser356, whereas ERK2 was the most strict. All of the sites detected except Thr245 and Ser305 are known or suspected phosphorylation sites in paired helical filament-tau extracted from Alzheimer brains. Thus, the three MAP kinases and GSK3beta are importantly all strong candidates as tau kinases that may be involved in the pathogenic hyperphosphorylation of tau in Alzheimer's disease." SIGNOR-249416 MAPK1 protein P28482 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser721 PVVSGDTsPRHLSNV 9606 BTO:0000590 10737616 t lperfetto "Using nanoelectrospray mass spectrometry, we have undertaken an extensive comparison of phosphorylation in vitro by several candidate tau kinases, namely, JNK, p38, ERK2, and glycogen synthase kinase 3beta (GSK3beta). Between 10 and 15 sites were identified for each kinase. The three MAP kinases phosphorylated Ser202 and Thr205 but not detectably Ser199, whereas conversely GSK3beta phosphorylated Ser199 but not detectably Ser202 or Thr205. Phosphorylated Ser404 was found with all of these kinases except JNK. The MAP kinases may not be strictly proline specific: p38 phosphorylated the nonproline sites Ser185, Thr245, Ser305, and Ser356, whereas ERK2 was the most strict. All of the sites detected except Thr245 and Ser305 are known or suspected phosphorylation sites in paired helical filament-tau extracted from Alzheimer brains. Thus, the three MAP kinases and GSK3beta are importantly all strong candidates as tau kinases that may be involved in the pathogenic hyperphosphorylation of tau in Alzheimer's disease." SIGNOR-249418 MAPK1 protein P28482 UNIPROT NEFH protein P12036 UNIPROT "up-regulates activity" phosphorylation Ser518 SPEKEAKsPVKEEAK 10116 BTO:0000938 9592082 t lperfetto "The fraction containing Erk2, as well as bacterially expressed Erk1 and Erk2, phosphorylated all types of KSP motifs in peptides (KSPXK, KSPXXK, KSPXXXK, and KSPXXXXK) derived from NF-M and NF-H. They also phosphorylated an expressed 24 KSPXXXK repeat NF-H polypeptide, an expressed NF-H as well as dephosphorylated native rat NF-H, and NF-M proteins with accompanying decreases in their respective electrophoretic mobilities. |Our data on primary hippocampal cells also showed an inhibition of neurite outgrowth by the drug that was accompanied by inhibition of MAP, NF-H, and NF-M phosphorylation." SIGNOR-249423 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser447 GSPRTPVsPVKFSPG 9606 BTO:0000150 19085255 t gcesareni "Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase." SIGNOR-182808 MAPK1 protein P28482 UNIPROT NEFH protein P12036 UNIPROT "up-regulates activity" phosphorylation Ser526 PVKEEAKsPAEAKSP 10116 BTO:0000938 9592082 t lperfetto "The fraction containing Erk2, as well as bacterially expressed Erk1 and Erk2, phosphorylated all types of KSP motifs in peptides (KSPXK, KSPXXK, KSPXXXK, and KSPXXXXK) derived from NF-M and NF-H. They also phosphorylated an expressed 24 KSPXXXK repeat NF-H polypeptide, an expressed NF-H as well as dephosphorylated native rat NF-H, and NF-M proteins with accompanying decreases in their respective electrophoretic mobilities. |Our data on primary hippocampal cells also showed an inhibition of neurite outgrowth by the drug that was accompanied by inhibition of MAP, NF-H, and NF-M phosphorylation." SIGNOR-249424 MAPK1 protein P28482 UNIPROT TPR protein P12270 UNIPROT up-regulates phosphorylation Ser2155 GFAEAIHsPQVAGVP 9606 18794356 t miannu "Tpr is phosphorylated by erk2 at four different sites. / because phosphorylation of tpr by activated erk stabilizes their interaction, we hypothesize that this phosphorylation is not part of a signal amplification cascade but rather positions activated erk to perform a continuing function in the nuclear pore." SIGNOR-181014 MAPK1 protein P28482 UNIPROT TPR protein P12270 UNIPROT up-regulates phosphorylation Thr2116 VGRGLQLtPGIGGMQ 9606 18794356 t miannu "Tpr is phosphorylated by erk2 at four different sites. / because phosphorylation of tpr by activated erk stabilizes their interaction, we hypothesize that this phosphorylation is not part of a signal amplification cascade but rather positions activated erk to perform a continuing function in the nuclear pore." SIGNOR-181018 MAPK1 protein P28482 UNIPROT TPR protein P12270 UNIPROT up-regulates phosphorylation Thr2137 EDRTVPStPTLVVPH 9606 18794356 t miannu "Tpr is phosphorylated by erk2 at four different sites. / because phosphorylation of tpr by activated erk stabilizes their interaction, we hypothesize that this phosphorylation is not part of a signal amplification cascade but rather positions activated erk to perform a continuing function in the nuclear pore." SIGNOR-181022 MAPK1 protein P28482 UNIPROT TPR protein P12270 UNIPROT up-regulates phosphorylation Thr2214 GGRSVPTtPLQVAAP 9606 18794356 t miannu "Tpr is phosphorylated by erk2 at four different sites. / because phosphorylation of tpr by activated erk stabilizes their interaction, we hypothesize that this phosphorylation is not part of a signal amplification cascade but rather positions activated erk to perform a continuing function in the nuclear pore." SIGNOR-181026 MAPK1 protein P28482 UNIPROT NID1 protein P14543 UNIPROT unknown phosphorylation Ser333 YSVPSVLsPRRAATE 10090 BTO:0000944 22028470 t miannu "We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)" SIGNOR-262771 MAPK1 protein P28482 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser345 QARPGPQsPGSPLEE 9606 BTO:0000130 16778989 t gcesareni "Erk1/2 are the kinases involved in p47phox_ phosphorylation on ser345 in gm-csfprimed human neutrophils._ Phosphorylation of ser345 is required for the priming of nadph oxidase activity in neutrophil-like cells" SIGNOR-147170 MAPK1 protein P28482 UNIPROT SLC2A4 protein P14672 UNIPROT up-regulates 9606 20231899 f gcesareni "An erk pharmacological inhibitor, pd98059, and the pld inhibitor, 1-btoh, both attenuate (14)c-glucose uptake in muscle cells. Finally, the extracellular stresses caused by glucose deprivation or aminoimidazole carboxamide ribonucleotide (aicar;ampk activator) regulate (14)c-glucose uptake and cell surface glucose transport (glut) 4 through erk stimulation by ampk-mediated pld1 activation." SIGNOR-164286 MAPK1 protein P28482 UNIPROT BRAF protein P15056 UNIPROT "down-regulates activity" phosphorylation Thr753 YACASPKtPIQAGGY 10116 BTO:0001009 16508002 t lperfetto "Erk-induced phosphorylation of b-raf on t753 promoted the disassembly of raf heterodimers, and the mutation of t753 prolonged growth factor-induced heterodimerization. The b-raf t753a mutant enhanced differentiation of pc12 cells, which was previously shown to be dependent on sustained erk signaling. Site is critical for v-src dependent modulation of slk kinase activity." SIGNOR-236388 MAPK1 protein P28482 UNIPROT BRAF protein P15056 UNIPROT "down-regulates activity" phosphorylation Ser151 VARSNPKsPQKPIVR 9606 BTO:0000848 21478863 t "We show that overactivation of the MAPK pathway, induced by the oncogenic Ras in melanoma, induces constitutive phosphorylation of BRAF on Ser151 by ERK, which inhibits NRAS-BRAF interaction" SIGNOR-259920 MAPK1 protein P28482 UNIPROT GJA1 protein P17302 UNIPROT "down-regulates activity" phosphorylation Ser255 HATSGALsPAKDCGS 9606 BTO:0000567 9535909 t lperfetto "These studies confirm that connexin-43 is a MAP kinase substrate in vivo and that phosphorylation on Ser255, Ser279, and/or Ser282 initiates the down-regulation of gap junctional communication. Studies with connexin-43 mutants suggest that MAP kinase phosphorylation at one or more of the tandem Ser279/Ser282 sites is sufficient to disrupt gap junctional intercellular communication." SIGNOR-249401 MAPK1 protein P28482 UNIPROT GJA1 protein P17302 UNIPROT "down-regulates activity" phosphorylation Ser279 SSPTAPLsPMSPPGY 9606 BTO:0000567 9535909 t lperfetto "These studies confirm that connexin-43 is a MAP kinase substrate in vivo and that phosphorylation on Ser255, Ser279, and/or Ser282 initiates the down-regulation of gap junctional communication. Studies with connexin-43 mutants suggest that MAP kinase phosphorylation at one or more of the tandem Ser279/Ser282 sites is sufficient to disrupt gap junctional intercellular communication." SIGNOR-249402 MAPK1 protein P28482 UNIPROT GJA1 protein P17302 UNIPROT "down-regulates activity" phosphorylation Ser282 TAPLSPMsPPGYKLV 9606 BTO:0000567 9535909 t lperfetto "These studies confirm that connexin-43 is a MAP kinase substrate in vivo and that phosphorylation on Ser255, Ser279, and/or Ser282 initiates the down-regulation of gap junctional communication. Studies with connexin-43 mutants suggest that MAP kinase phosphorylation at one or more of the tandem Ser279/Ser282 sites is sufficient to disrupt gap junctional intercellular communication." SIGNOR-249403 MAPK1 protein P28482 UNIPROT UBTF protein P17480 UNIPROT down-regulates phosphorylation Thr201 DIPEKPKtPQQLWYT 9606 11741541 t lperfetto "Erk1/2 was found to phosphorylate the architectural transcription factor ubf at amino acids 117 and 201 within hmg boxes 1 and 2, preventing their interaction with dna" SIGNOR-112809 MAPK1 protein P28482 UNIPROT JUND protein P17535 UNIPROT up-regulates phosphorylation Ser100 LGLLKLAsPELERLI 9606 22327296 t gcesareni "Menin binds the jun family transcription factor jund and inhibits its transcriptional activity. The menin-jund interaction blocks jun n-terminal kinase (jnk)-mediated jund phosphorylation and suppresses jund-induced transcription. We found a role for phosphorylation of the ser100 residue of jund;jund phosphorylation were prevented by inhibitors of calcium, calmodulin, or erk1/2 kinase." SIGNOR-196030 MAPK1 protein P28482 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Thr336 GGPGPERtPGSGSGS 10090 BTO:0000944 7889942 t lperfetto "We demonstrate that elk-1, a protein closely related to p62tcf in function, is a nuclear target of two members of the map kinase family, erk1 and erk2, erki phosphorylates five c-terminal sites in elk-i (s324,t336, s383, s389 and s422) with varying degrees of efficiency." SIGNOR-235467 MAPK1 protein P28482 UNIPROT ELK1 protein P19419 UNIPROT "up-regulates activity" phosphorylation Ser324 RDLELPLsPSLLGGP 10090 BTO:0000944 7889942 t lperfetto "We demonstrate that elk-1, a protein closely related to p62tcf in function, is a nuclear target of two members of the map kinase family, erk1 and erk2, erk1 phosphorylates five c-terminal sites in elk-1 (s324,t336, s383, s389 and s422) with varying degrees of efficiency." SIGNOR-235459 MAPK1 protein P28482 UNIPROT ELK1 protein P19419 UNIPROT "up-regulates activity" phosphorylation Ser383 IHFWSTLsPIAPRSP 10090 BTO:0000944 7889942 t lperfetto "We demonstrate that elk-1, a protein closely related to p62tcf in function, is a nuclear target of two members of the map kinase family, erk1 and erk2, erk1 phosphorylates five c-terminal sites in elk-1 (s324,t336, s383, s389 and s422) with varying degrees of efficiency." SIGNOR-235455 MAPK1 protein P28482 UNIPROT ELK1 protein P19419 UNIPROT "up-regulates activity" phosphorylation Ser389 LSPIAPRsPAKLSFQ 10090 BTO:0000944 7889942 t lperfetto "We demonstrate that elk-1, a protein closely related to p62tcf in function, is a nuclear target of two members of the map kinase family, erk1 and erk2, erki phosphorylates five c-terminal sites in elk-i (s324,t336, s383, s389 and s422) with varying degrees of efficiency." SIGNOR-235471 MAPK1 protein P28482 UNIPROT ELK1 protein P19419 UNIPROT "up-regulates activity" phosphorylation Ser422 LSTPVVLsPGPQKP 10090 BTO:0000944 7889942 t lperfetto "We demonstrate that elk-1, a protein closely related to p62tcf in function, is a nuclear target of two members of the map kinase family, erk1 and erk2, erki phosphorylates five c-terminal sites in elk-i (s324,t336, s383, s389 and s422) with varying degrees of efficiency." SIGNOR-235463 MAPK1 protein P28482 UNIPROT TNFRSF1A protein P19438 UNIPROT "down-regulates activity" phosphorylation Ser274 LAPNPSFsPTPGFTP -1 11606045 t lperfetto "Phosphorylation of murine CD120a by p42(mapk/erk2) has been shown to inhibit its ability to initiate apoptosis while preserving signaling events such as NF-kappaB activation.|Additionally, we demonstrated that (i) the p42(mapk/erk2)-dependent phosphorylation of CD120a and DR3 occurred on Ser and Thr residues, (ii) p42(mapk/erk2) phosphorylated residues located in the membrane proximal regions but not the death domains of CD120a and DR3, (iii) Ser 253 is a preferred site of phosphorylation on CD120a" SIGNOR-249452 MAPK1 protein P28482 UNIPROT TNFRSF1A protein P19438 UNIPROT "down-regulates activity" phosphorylation Thr280 FSPTPGFtPTLGFSP -1 11606045 t lperfetto "Phosphorylation of murine CD120a by p42(mapk/erk2) has been shown to inhibit its ability to initiate apoptosis while preserving signaling events such as NF-kappaB activation.|Additionally, we demonstrated that (i) the p42(mapk/erk2)-dependent phosphorylation of CD120a and DR3 occurred on Ser and Thr residues, (ii) p42(mapk/erk2) phosphorylated residues located in the membrane proximal regions but not the death domains of CD120a and DR3, (iii) Ser 253 is a preferred site of phosphorylation on CD120a" SIGNOR-249453 MAPK1 protein P28482 UNIPROT TFEB protein P19484 UNIPROT "down-regulates activity" phosphorylation Ser142 AGNSAPNsPMAMLHI 9606 BTO:0000567 21617040 t gcesareni "Evidence for ERK2-mediated TFEB phosphorylation came from ERK2-TFEB coimmuno-precipitation (fig. S12C) in normal but not in starved medium and from a peptide-based kinase assay showing that mutation of Ser142 to alanine abolished ERK2-mediated phosphorylation (" SIGNOR-248279 MAPK1 protein P28482 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Thr451 KRTRSKGtLRYMSPE 9606 9528799 t gcesareni "Our results provide strong evidence that dsrna binding is required for dimerization of full-length pkr molecules in vivo, leading to autophosphorylation in the activation loop and stimulation of the eif2alpha kinase function of pkr." SIGNOR-56337 MAPK1 protein P28482 UNIPROT SLC9A1 protein P19634 UNIPROT up-regulates phosphorylation Ser770 MMRSKETsSPGTDDV 9606 17209041 t miannu "We have demonstrated that the map kinases extracellular signal-regulated kinases 1 and 2 (erk1/2) are implicated in growth factor activation of nhe1. / our results suggest that amino acids ser770 and ser771 mediate erk-dependent activation of the na+/h+ exchanger in vivo." SIGNOR-151925 MAPK1 protein P28482 UNIPROT RXRA protein P19793 UNIPROT "down-regulates activity" phosphorylation Ser260 NMGLNPSsPNDPVTN 9606 17604322 t lperfetto "In colon cancer cells, the Ras/mitogen‐activated protein kinase (MAPK) pathway phosphorylates RXRalpha, which impairs its function as a heterodimeric partner for PPARgamma|A point‐mutated RXRalpha T82A/S260A, which mimics the unphosphorylated form of RXRalpha, can form a heterodimer with PPARgamma and thereby activate target gene expression by binding to the PPRE" SIGNOR-88658 MAPK1 protein P28482 UNIPROT RXRA protein P19793 UNIPROT "down-regulates activity" phosphorylation Thr82 HSMSVPTtPTLGFST 9606 17604322 t lperfetto "In colon cancer cells, the Ras/mitogen‐activated protein kinase (MAPK) pathway phosphorylates RXRalpha, which impairs its function as a heterodimeric partner for PPARgamma|A point‐mutated RXRalpha T82A/S260A, which mimics the unphosphorylated form of RXRalpha, can form a heterodimer with PPARgamma and thereby activate target gene expression by binding to the PPRE" SIGNOR-262958 MAPK1 protein P28482 UNIPROT NR4A1 protein P22736 UNIPROT "up-regulates activity" phosphorylation Thr143 CSAPSPStPSFQPPQ 10116 BTO:0001009 11883936 t lperfetto "NGFI-B is an inducible orphan nuclear receptor that initiates apoptosis. Growth factors such as EGF activate the MAP kinase ERK, whose activity may determine if a cell survives or undergoes apoptosis. EGF stimulation of cells leads to phosphorylation of threonine in NGFI-B. Thr-142 of NGFI-B is comprised in a consensus MAP kinase site and was identified as a preferred substrate for ERK2 (but not ERK1) in vitro." SIGNOR-249430 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr444 RFIGSPRtPVSPVKF 9606 BTO:0000887;BTO:0001103 11705993 t gcesareni "The principal target of rapamycin-induced p70s6k inactivation is a novel phosphorylation site within a conserved hydrophobic domain." SIGNOR-111511 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser434 SFEPKIRsPRRFIGS 9606 14967450 t gcesareni "Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase" SIGNOR-121984 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser447 GSPRTPVsPVKFSPG 9606 14967450 t gcesareni "Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase" SIGNOR-121988 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser434 SFEPKIRsPRRFIGS 9606 BTO:0000150 19085255 t gcesareni "Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase." SIGNOR-182804 MAPK1 protein P28482 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Ser434 LTLASERsSPQRKSQ -1 12175859 t miannu "Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). From these data we conclude that T373 is the predominant site of phosphorylation, with a low level of phosphorylation at S413 and/or S414.An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation" SIGNOR-262748 MAPK1 protein P28482 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Ser435 TLASERSsPQRKSQR -1 12175859 t miannu "Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). From these data we conclude that T373 is the predominant site of phosphorylation, with a low level of phosphorylation at S413 and/or S414. An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation" SIGNOR-262747 MAPK1 protein P28482 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Thr394 SGLPPPRtAMLDGNY -1 12175859 t miannu "Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). From these data we conclude that T373 is the predominant site of phosphorylation, with a low level of phosphorylation at S413 and/or S414.An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation" SIGNOR-262749 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1619 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120084 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1626 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120088 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1647 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120092 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1654 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-119366 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1668 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120096 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1675 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120100 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1696 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120104 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1717 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120108 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1724 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120112 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1738 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120116 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1766 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120120 MAPK1 protein P28482 UNIPROT PTPN7 protein P35236 UNIPROT "up-regulates activity" phosphorylation Thr66 EPICSVNtPREVTLH -1 16226275 t lperfetto "First, Erk phosphorylates HePTP at residues Thr45 and Ser72. Second, HePTP dephosphorylates Erk at PTyr185.|" SIGNOR-249437 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1787 SPNYSPTsPSYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120124 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1864 SPKYSPTsPKYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120128 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1871 SPKYSPTsPKYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120132 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1882 SPTSPTYsPTTPKYS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120136 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1892 TPKYSPTsPTYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120140 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1899 SPTYSPTsPVYTPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120144 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1913 SPKYSPTsPTYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120148 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1920 SPTYSPTsPKYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120152 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1927 SPKYSPTsPTYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120156 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1934 SPTYSPTsPKGSTYS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120160 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1944 GSTYSPTsPGYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120164 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1951 SPGYSPTsPTYSLTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120168 MAPK1 protein P28482 UNIPROT CDK2 protein P24941 UNIPROT up-regulates phosphorylation Thr160 GVPVRTYtHEVVTLW 9606 SIGNOR-C16 12359725 t gcesareni "In addition to its role in stimulating cyclin d1 expression and nuclear translocation of cdk2, erk regulates thr-160 phosphorylation of cdk2-cyclin e." SIGNOR-94003 MAPK1 protein P28482 UNIPROT ZFP36 protein P26651 UNIPROT unknown phosphorylation Ser228 PPGDLPLsPSAFSAA 10090 BTO:0000944 7768935 t lperfetto "By a combination of protease digestion experiments and site-directed mutagenesis strategies, we found that serine 220 was phosphorylated by p42 MAP kinase in vitro. Expression of mutant TTP in fibroblasts confirmed that serine 220 was one of the major, mitogen-stimulated phosphorylation sites on the protein in intact cells. |It is not obvious how phosphorylation of TTP at serine 220 would alter DNA binding, since this residue lies well outside of the putative zinc finger region, which is between amino acids 95 to 159 in the mouse protein" SIGNOR-249456 MAPK1 protein P28482 UNIPROT CAD protein P27708 UNIPROT up-regulates phosphorylation Thr456 KVYFLPItPHYVTQV 9606 15890648 t lperfetto "Cad is a multifunctional protein that initiates and regulates mammalian de novo pyrimidine biosynthesis. The activation of the pathway required for cell proliferation is a consequence of the phosphorylation of cad thr-456 by mitogen-activated protein (map) kinase.Activated map kinase (erk1/2), the enzyme responsible for the phosphorylation of thr-456, was also present in larger amounts in the nucleus than the cytosol" SIGNOR-137171 MAPK1 protein P28482 UNIPROT MAPK1 protein P28482 UNIPROT "up-regulates activity" phosphorylation Thr185 HDHTGFLtEYVATRW 1712480 t lperfetto "Microtubule-associated protein 2 kinases, ERK1 and ERK2, undergo autophosphorylation on both tyrosine and threonine residues: implications for their mechanism of activation.|" SIGNOR-249414 MAPK1 protein P28482 UNIPROT MAPK1 protein P28482 UNIPROT "up-regulates activity" phosphorylation Tyr187 HTGFLTEyVATRWYR 1712480 t lperfetto "Microtubule-associated protein 2 kinases, ERK1 and ERK2, undergo autophosphorylation on both tyrosine and threonine residues: implications for their mechanism of activation.|" SIGNOR-249415 MAPK1 protein P28482 UNIPROT DUSP1 protein P28562 UNIPROT down-regulates phosphorylation Ser296 KQRRSIIsPNFSFMG 9606 16286470 t lperfetto "The dual-specificity mapk phosphatase mkp-1/cl100/dusp1 is an inducible nuclear protein controlled by p44/42 mapk (erk1/2) in a negative feedback mechanism to inhibit kinase activity. Here, we report on the molecular basis for a novel positive feedback mechanism to sustain erk activation by triggering mkp-1 proteolysis. Active erk2 docking to the def motif (fxfp, residues 339-342) of n-terminally truncated mkp-1 in vitro initiated phosphorylation at the ser(296)/ser(323) domain" SIGNOR-141593 MAPK1 protein P28482 UNIPROT DUSP1 protein P28562 UNIPROT down-regulates phosphorylation Ser323 HCSAEAGsPAMAVLD 9606 16286470 t lperfetto "The dual-specificity mapk phosphatase mkp-1/cl100/dusp1 is an inducible nuclear protein controlled by p44/42 mapk (erk1/2) in a negative feedback mechanism to inhibit kinase activity. Here, we report on the molecular basis for a novel positive feedback mechanism to sustain erk activation by triggering mkp-1 proteolysis. Active erk2 docking to the def motif (fxfp, residues 339-342) of n-terminally truncated mkp-1 in vitro initiated phosphorylation at the ser(296)/ser(323) domain" SIGNOR-141601 MAPK1 protein P28482 UNIPROT DUSP1 protein P28562 UNIPROT up-regulates phosphorylation Ser359 SALSYLQsPITTSPS 9606 10617468 t lperfetto "Mkp-1 was a target in vivo and in vitro for p42(mapk) or p44(mapk), which phosphorylates mkp-1 on two carboxyl-terminal serine residues, serine 359 and serine 364. This phosphorylation did not modify mkp-1's intrinsic ability to dephosphorylate p44(mapk) but led to stabilization of the protein." SIGNOR-73621 MAPK1 protein P28482 UNIPROT DUSP1 protein P28562 UNIPROT up-regulates phosphorylation Ser364 LQSPITTsPSC 9606 10617468 t lperfetto "Mkp-1 was a target in vivo and in vitro for p42(mapk) or p44(mapk), which phosphorylates mkp-1 on two carboxyl-terminal serine residues, serine 359 and serine 364. This phosphorylation did not modify mkp-1's intrinsic ability to dephosphorylate p44(mapk) but led to stabilization of the protein." SIGNOR-73625 MAPK1 protein P28482 UNIPROT PML protein P29590 UNIPROT up-regulates phosphorylation Ser36 PSEGRQPsPSPSPTE 9606 BTO:0001271 15093545 t "The effect has been demonstrated using P29590-4" gcesareni "We conclude that phosphorylation by map kinase cascades potentiates the antiproliferative functions of pml and helps mediate the proapoptotic effects of as(2)o(3)." SIGNOR-124240 MAPK1 protein P28482 UNIPROT PML protein P29590 UNIPROT up-regulates phosphorylation Ser38 EGRQPSPsPSPTERA 9606 BTO:0001271 15093545 t "The effect has been demonstrated using P29590-4" gcesareni "We conclude that phosphorylation by map kinase cascades potentiates the antiproliferative functions of pml and helps mediate the proapoptotic effects of as(2)o(3)." SIGNOR-124244 MAPK1 protein P28482 UNIPROT PML protein P29590 UNIPROT up-regulates phosphorylation Ser40 RQPSPSPsPTERAPA 9606 BTO:0001271 15093545 t llicata "We report here that as(2)o(3) treatment induces phosphorylation of the pml protein through a mitogen-activated protein (map) kinase pathway. Increased pml phosphorylation is associated with increased sumoylation of pml and increased pml-mediated apoptosis." SIGNOR-124248 MAPK1 protein P28482 UNIPROT PML protein P29590 UNIPROT up-regulates phosphorylation Ser527 PHLDGPPsPRSPVIG 9606 BTO:0001271 15093545 t "The effect has been demonstrated using P29590-4" gcesareni "We conclude that phosphorylation by map kinase cascades potentiates the antiproliferative functions of pml and helps mediate the proapoptotic effects of as(2)o(3)." SIGNOR-124252 MAPK1 protein P28482 UNIPROT PML protein P29590 UNIPROT up-regulates phosphorylation Ser530 DGPPSPRsPVIGSEV 9606 BTO:0001271 15093545 t "The effect has been demonstrated using P29590-4" gcesareni "We conclude that phosphorylation by map kinase cascades potentiates the antiproliferative functions of pml and helps mediate the proapoptotic effects of as(2)o(3)." SIGNOR-124056 MAPK1 protein P28482 UNIPROT PRDX6 protein P30041 UNIPROT up-regulates phosphorylation Thr177 TAEKRVAtPVDWKDG 9606 BTO:0000763 19140803 t miannu "These results show that the mapks can mediate phosphorylation of prdx6 at thr-177 with a consequent marked increase in its aipla(2) activity." SIGNOR-183379 MAPK1 protein P28482 UNIPROT HNRNPH1 protein P31943 UNIPROT unknown phosphorylation Ser104 LKHTGPNsPDTANDG 10090 BTO:0000944 22028470 t miannu "We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)" SIGNOR-262776 MAPK1 protein P28482 UNIPROT CIITA protein P33076 UNIPROT down-regulates phosphorylation Ser288 PDRPGSTsPFAPSAT 9606 15210796 t gcesareni "Erk1/2-mediated phosphorylation of ciita down-regulates ciita activity by priming it for nuclear export, thus providing a means for cells to tightly regulate the extent of antigen presentation." SIGNOR-126254 MAPK1 protein P28482 UNIPROT CIITA protein P33076 UNIPROT down-regulates phosphorylation Ser288 PDRPGSTsPFAPSAT 9606 18245089 t gcesareni "Novel phosphorylation sites were determined to be located within a region that contains serine residues 286, 288, and 293. ... Erk1/2-mediated phosphorylation of ciita down-regulates ciita activity by priming it for nuclear export, thus providing a means for cells to tightly regulate the extent of antigen presentation." SIGNOR-160613 MAPK1 protein P28482 UNIPROT CIITA protein P33076 UNIPROT up-regulates phosphorylation Ser280 TVHGLPTsPDRPGST 9606 15210796 t gcesareni "We show in this study that the nuclear localized form of ciita is a predominantly phosphorylated form of the protein, whereas cytoplasmic ciita is predominantly unphosphorylated. Novel phosphorylation sites were determined to be located within a region that contains serine residues 286, 288, and 293. Double mutations of these residues increased nuclear ciita, indicating that these sites are not required for nuclear import. Erk1/2-mediated phosphorylation of ciita down-regulates ciita activity by priming it for nuclear export, thus providing a means for cells to tightly regulate the extent of antigen presentation." SIGNOR-126250 MAPK1 protein P28482 UNIPROT CIITA protein P33076 UNIPROT up-regulates phosphorylation Ser280 TVHGLPTsPDRPGST 9606 18245089 t gcesareni "We show in this study that the nuclear localized form of ciita is a predominantly phosphorylated form of the protein, whereas cytoplasmic ciita is predominantly unphosphorylated. Novel phosphorylation sites were determined to be located within a region that contains serine residues 286, 288, and 293. Double mutations of these residues increased nuclear ciita, indicating that these sites are not required for nuclear import. Erk1/2-mediated phosphorylation of ciita down-regulates ciita activity by priming it for nuclear export, thus providing a means for cells to tightly regulate the extent of antigen presentation." SIGNOR-160609 MAPK1 protein P28482 UNIPROT PTPN7 protein P35236 UNIPROT "up-regulates activity" phosphorylation Ser93 ALQRQPPsPKQLEEE -1 16226275 t lperfetto "First, Erk phosphorylates HePTP at residues Thr45 and Ser72. Second, HePTP dephosphorylates Erk at PTyr185.|" SIGNOR-249436 MAPK1 protein P28482 UNIPROT RORA protein P35398 UNIPROT down-regulates phosphorylation Thr183 PGEAEPLtPTYNISA 9606 17512500 t "The effect has been demonstrated using P35398-4" gcesareni "We identified the extracellular signal-regulated kinase 2 (erk-2) as roralpha4 phosphorylating kinase in vitro. The primary sequence of roralpha4 contains an erk-2 recognition motif (p-l-t(128)-p) within the hinge domain, and mutation of thr-128 to ala prevents roralpha4 phosphorylation by erk. The roralpha4-t128a mutant exhibits an increased dna-binding affinity, an increased transcriptional activity" SIGNOR-154914 MAPK1 protein P28482 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser312 TESITATsPASMVGG 9606 BTO:0004980 17242212 t gcesareni "Our data suggest that il-6 impairs the vasodilator effects of insulin that are mediated by the irs-1/pi3-kinase/akt/enos pathway through activation of jnk and erk1/2." SIGNOR-152418 MAPK1 protein P28482 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser636 SGDYMPMsPKSVSAP 9606 12510059 t gcesareni "Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1." SIGNOR-249407 MAPK1 protein P28482 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser616 DDGYMPMsPGVAPVP 9606 15001544 t lperfetto "Rin beta-cells exposed to high glucose exhibited increased c-jun n-terminal kinase (jnk) and erk1/2 activity, which was associated with increased irs-1 phosphorylation at serine (ser)(307) and ser(612), respectively, that inhibits coupling of irs-1 to the insulin receptor and is upstream of the inhibition of irs-1 tyrosine phosphorylation." SIGNOR-123173 MAPK1 protein P28482 UNIPROT SREBF1 protein P36956 UNIPROT up-regulates phosphorylation Ser117 YPSMPAFsPGPGIKE 9606 10915800 t llicata "Map kinases erk1/2 phosphorylate sterol regulatory element-binding protein (srebp)-1a at serine 117 in vitro. mutation of serine 117 to alanine abolished erk2-mediated phosphorylation in vitro and the map kinase-related transcriptional activation of srebp-1a by insulin and platelet-derived growth factor in vivo." SIGNOR-80092 MAPK1 protein P28482 UNIPROT PPARG protein P37231 UNIPROT down-regulates phosphorylation 9606 18596912 t lbriganti "The genomic activity of ppargamma is modulated, in addition to ligand binding, by phosphorylation of a serine residue by mapks, such as extracellular signal-regulated protein kinases-1/2 (erk-1/2), or by nucleocytoplasmic compartmentalization through the erk activators mapk kinases-1/2 (mek-1/2). These mapks phosphorylate (in humans) ser 84 in the ppargamma1 and ser 114 in ppargamma2 isoform" SIGNOR-210182 MAPK1 protein P28482 UNIPROT PPARG protein P37231 UNIPROT down-regulates relocalization 9606 18596912 t fspada "The genomic activity of ppargamma is modulated, in addition to ligand binding, by phosphorylation of a serine residue by mapks, such as extracellular signal-regulated protein kinases-1/2 (erk-1/2), or by nucleocytoplasmic compartmentalization through the erk activators mapk kinases-1/2 (mek-1/2). These mapks phosphorylate (in humans) ser 84 in the ppargamma1 and ser 114 in ppargamma2 isoform" SIGNOR-179400 MAPK1 protein P28482 UNIPROT PPARG protein P37231 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser112 AIKVEPAsPPYYSEK 9606 11733495 t gcesareni "Moreover, the inhibition of erks 1 and 2 with a mek inhibitor, u1026, lead to an inhibition in the decay of ppargamma proteins, indicating that serine phosphorylation influences the degradation of ppargamma in fat cells." SIGNOR-112544 MAPK1 protein P28482 UNIPROT TAGLN2 protein P37802 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser145 ARDDGLFsGDPNWFP 9606 BTO:0003491 30041673 t lperfetto "ERK2 interacted with 29-31 amino acids of transgelin-2 and subsequently phosphorylated the S145 residue of transgelin-2. S145 phosphorylation of transgelin-2 played important roles in cell proliferation and tumorigenesis of PDAC.| We found that the protein stability of transgelin-2 was regulated by KRAS. ERK-mediated phosphorylation resulted in accumulation of transgelin-2 protein." SIGNOR-265221 MAPK1 protein P28482 UNIPROT CDKN1A protein P38936 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser130 SGEQAEGsPGGPGDS 9606 19364816 t gcesareni "Extracellular signal-regulated kinase 2-dependent phosphorylation induces cytoplasmic localization and degradation of p21cip1.|Phosphopeptide analysis of in vitro ERK2-phosphorylated p21(Cip1) revealed two phosphorylation sites, Thr57 and Ser130." SIGNOR-185215 MAPK1 protein P28482 UNIPROT BCL6 protein P41182 UNIPROT down-regulates phosphorylation Ser333 KGLVSPQsPQKSDCQ 9606 BTO:0000782;BTO:0000785 9649500 t gcesareni "Here we show that antigen receptor activation leads to bcl-6 phosphorylation by mitogen-activated protein kinase (mapk). Phosphorylation, in turn, targets bcl-6 for rapid degradation by the ubiquitin/proteasome pathway." SIGNOR-58481 MAPK1 protein P28482 UNIPROT BCL6 protein P41182 UNIPROT down-regulates phosphorylation Ser343 KSDCQPNsPTESCSS 9606 BTO:0000782;BTO:0000785 9649500 t gcesareni "Here we show that antigen receptor activation leads to bcl-6 phosphorylation by mitogen-activated protein kinase (mapk). Phosphorylation, in turn, targets bcl-6 for rapid degradation by the ubiquitin/proteasome pathway." SIGNOR-58485 MAPK1 protein P28482 UNIPROT ETV6 protein P41212 UNIPROT down-regulates phosphorylation Ser213 DNMIRRLsPAERAQG 10090 BTO:0000944 15060146 t miannu "Tel became phosphorylated by erk on two serine residues, ser213 and ser257, in the internal domain between the hlh and ets domains. Tel lost its abilities to repress transcription through the phosphorylation." SIGNOR-260086 MAPK1 protein P28482 UNIPROT ETV6 protein P41212 UNIPROT down-regulates phosphorylation Ser257 ESHPKPSsPRQESTR 10090 BTO:0000944 15060146 t miannu "Tel became phosphorylated by erk on two serine residues, ser213 and ser257, in the internal domain between the hlh and ets domains. Tel lost its abilities to repress transcription through the phosphorylation." SIGNOR-260087 MAPK1 protein P28482 UNIPROT STAT5A protein P42229 UNIPROT up-regulates phosphorylation Ser780 DSLDSRLsPPAGLFT 9606 BTO:0000975 10194762 t lperfetto "Gh treatment of chinese hamster ovary cells stably transfected with the gh receptor (choa cells) led to rapid and transient activation of both stat5a and erk1 and erk2. these observations show, for the first time, direct physical interaction between erk and stat5a and also clearly identify serine 780 as a target for erk." SIGNOR-66239 MAPK1 protein P28482 UNIPROT LIFR protein P42702 UNIPROT down-regulates phosphorylation Ser1044 WNLVSPDsPRSIDSN 9606 7777512 t gcesareni "Indeed, phosphorylation of the cytoplasmic domain of the low-affinity lif receptor alpha-subunit (lifr) in mono q-fractionated, lif-stimulated 3t3-l1 extracts occurred only in those fractions containing activated mapk;ser-1044 served as the major phosphorylation site in the human lifr for mapk both in agonist-stimulated 3t3-l1 lysates and by recombinant extracellular signal-regulated kinase 2 in vitro" SIGNOR-32753 MAPK1 protein P28482 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser154 SSVSSSPsPPFGHSA 9606 12050114 t gcesareni "Tob is rapidly phosphorylated at ser 152, ser 154, and ser 164 by erk1 and erk2 upon growth-factor stimulation." SIGNOR-88720 MAPK1 protein P28482 UNIPROT NR4A2 protein P43354 UNIPROT up-regulates phosphorylation Ser126 SVYYKPSsPPTPTTP 9606 BTO:0000938 BTO:0000142 17681692 t llicata "We have shown that erk2 is a kinase to phosphorylate nurr1 on multiple sites. S126 and t132, which are located near af1 core of nurr1, are dominant sites phosphorylated by erk2. reporter gene assays show that nurr1delta124-133/t185a, an erk2 phospho-site mutant form, could not further increase its transcriptional activity on th promoter, suggesting that nurr1 phosphorylation by erk2 may regulate its transcriptional activity on th promoter." SIGNOR-157167 MAPK1 protein P28482 UNIPROT NR4A2 protein P43354 UNIPROT up-regulates phosphorylation Thr132 SSPPTPTtPGFQVQH 9606 BTO:0000938 BTO:0000142 17681692 t llicata "We have shown that erk2 is a kinase to phosphorylate nurr1 on multiple sites. S126 and t132, which are located near af1 core of nurr1, are dominant sites phosphorylated by erk2. reporter gene assays show that nurr1delta124-133/t185a, an erk2 phospho-site mutant form, could not further increase its transcriptional activity on th promoter, suggesting that nurr1 phosphorylation by erk2 may regulate its transcriptional activity on th promoter." SIGNOR-157171 MAPK1 protein P28482 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates phosphorylation Ser10 NVRVSNGsPSLERMD 9606 10831586 t gcesareni "Phosphorylation on ser-10 of kip1 is the major site of phosphorylation in resting cells, takes place at the g(0)-g1 phase and leads to protein stability." SIGNOR-77651 MAPK1 protein P28482 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates phosphorylation Ser178 EENVSDGsPNAGSVE 9606 10831586 t lperfetto "Indeed, p27kip1 was phosphorylated by p42 mapk (erk2) in vitrothese results suggest that ser(10) is the major site of phosphorylation of p27(kip1) and that phosphorylation at this site, like that at thr(187), contributes to regulation of p27(kip1) stability." SIGNOR-77655 MAPK1 protein P28482 UNIPROT IER3 protein P46695 UNIPROT up-regulates phosphorylation Thr18 MTILQAPtPAPSTIP 9606 12356731 t lperfetto "Upon phosphorylation by erks, iex-1 acquires the ability to inhibit cell death induced by various stimuli. In turn, iex-1 potentiates erk activation in response to various growth factors." SIGNOR-93740 MAPK1 protein P28482 UNIPROT PLA2G4A protein P47712 UNIPROT unknown phosphorylation Ser505 LNTSYPLsPLSDFAT 9606 BTO:0000567 9468497 t llicata "The inhibitor of the 38-kda stress-activated protein kinase (p38(mapk)), sb 203580, reduced phosphorylation of both ser-505 and ser-727 by 50 and 60%, respectively, in thrombin-stimulated platelets." SIGNOR-55706 MAPK1 protein P28482 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates phosphorylation Ser272 SNHGLAIsPGMKTRI 9606 8846784 t fstefani "Using novel methodology we demonstrate that activation of mapkap kinase-2 requires the phosphorylation of any two of the three residues thr222, ser272 and thr334. gst-mapkap kinase-2 lacking the n-terminal domain was inactive, but activated fully when phosphorylated at thr222, ser272 and thr334 by p42 mapk or rk." SIGNOR-44339 MAPK1 protein P28482 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates phosphorylation Thr222 TSHNSLTtPCYTPYY 9606 8846784 t fstefani "Using novel methodology we demonstrate that activation of mapkap kinase-2 requires the phosphorylation of any two of the three residues thr222, ser272 and thr334. gst-mapkap kinase-2 lacking the n-terminal domain was inactive, but activated fully when phosphorylated at thr222, ser272 and thr334 by p42 mapk or rk." SIGNOR-44343 MAPK1 protein P28482 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates phosphorylation Thr334 QSTKVPQtPLHTSRV 9606 8846784 t fstefani "Using novel methodology we demonstrate that activation of mapkap kinase-2 requires the phosphorylation of any two of the three residues thr222, ser272 and thr334. gst-mapkap kinase-2 lacking the n-terminal domain was inactive, but activated fully when phosphorylated at thr222, ser272 and thr334 by p42 mapk or rk." SIGNOR-44347 MAPK1 protein P28482 UNIPROT ARRB1 protein P49407 UNIPROT down-regulates phosphorylation Ser412 EEEDGTGsPQLNNR 9606 10347142 t gcesareni "Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation" SIGNOR-67630 MAPK1 protein P28482 UNIPROT ARRB1 protein P49407 UNIPROT down-regulates phosphorylation Ser412 EEEDGTGsPQLNNR 9606 15456867 t gcesareni "Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation" SIGNOR-129585 MAPK1 protein P28482 UNIPROT ARRB1 protein P49407 UNIPROT down-regulates phosphorylation Ser412 EEEDGTGsPQLNNR 9606 19153083 t gcesareni "Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation" SIGNOR-183480 MAPK1 protein P28482 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Ser295 PARPRSPsQTRKGPP 9606 BTO:0000142 15262992 t lperfetto "Thus, we propose that mapk phosphorylation of amphiphysin1 controls ngf receptor/trka-mediated endocytosis by terminating the amphiphysin1-ap-2 interaction.Our results indicate that phosphorylation of amphiphysin 1 at ser-285 and/or ser-293 affects the function of amphiphysin1.Mapk phosphorylation of ser-285 and ser-293 could modulate the interaction between prd and ap-2, resulting in the dissociation of amphiphysin1 from ap-2." SIGNOR-126863 MAPK1 protein P28482 UNIPROT AMPH protein P49418 UNIPROT "down-regulates activity" phosphorylation Ser293 PAPARPRsPSQTRKG 9606 15262992 t lperfetto "Thus, we propose that mapk phosphorylation of amphiphysin1 controls ngf receptor/trka-mediated endocytosis by terminating the amphiphysin1-ap-2 interaction.Our results indicate that phosphorylation of amphiphysin 1 at ser-285 and/or ser-293 affects the function of amphiphysin1.Mapk phosphorylation of ser-285 and ser-293 could modulate the interaction between prd and ap-2, resulting in the dissociation of amphiphysin1 from ap-2." SIGNOR-126859 MAPK1 protein P28482 UNIPROT PCYT1A protein P49585 UNIPROT down-regulates phosphorylation Ser315 GRMLQAIsPKQSPSS 9606 BTO:0000763 15788406 t gcesareni "Oxysterols inhibit phosphatidylcholine synthesis via erk docking and phosphorylation of ctp:phosphocholine cytidylyltransferase. Mutagenesis of ser315 within cctalpha was both required and sufficient to confer significant resistance to 22-hc/9-cis-ra inhibition of ptdcho synthesis." SIGNOR-134837 MAPK1 protein P28482 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser164 FGHSAAVsPTFMPRS 9606 12050114 t gcesareni "Tob is rapidly phosphorylated at ser 152, ser 154, and ser 164 by erk1 and erk2 upon growth-factor stimulation." SIGNOR-88724 MAPK1 protein P28482 UNIPROT CEBPA protein P49715 UNIPROT down-regulates phosphorylation Ser21 PMSSHLQsPPHAPSS 9606 BTO:0000876 14701740 t lperfetto "Ccaat/enhancer-binding protein alpha (c/ebpalpha) is one of the key transcription factors that mediate lineage specification and differentiation of multipotent myeloid progenitors into mature granulocytes.Here we report that inducers of monocyte differentiation inhibit the alternate cell fate choice, that of granulopoiesis, through inhibition of c/ebpalpha. This inhibition is mediated by extracellular signal-regulated kinases 1 and/or 2 (erk1/2), which interact with c/ebpalpha through an fxfp docking site and phosphorylate serine 21." SIGNOR-120566 MAPK1 protein P28482 UNIPROT NUP153 protein P49790 UNIPROT unknown phosphorylation Ser529 SPMFKFSsPIVKSTE 9606 19767751 t llicata "These results indicate that phosphorylation of nup153 and nup214 by erk strongly reduces their affinity for importin-. nup153 depletion caused a strong inhibition of nuclear accumulation of gfp?importin-beta in both erk-inhibited and erk-activated cells (fig. 8b,c), indicating that nup153 is essential for the efficient importin-beta transport." SIGNOR-188123 MAPK1 protein P28482 UNIPROT NUP153 protein P49790 UNIPROT unknown phosphorylation Thr388 VYFKPSLtPSGEFRK 9606 19767751 t llicata "These results indicate that phosphorylation of nup153 and nup214 by erk strongly reduces their affinity for importin-. nup153 depletion caused a strong inhibition of nuclear accumulation of gfp?importin-beta in both erk-inhibited and erk-activated cells (fig. 8b,c), indicating that nup153 is essential for the efficient importin-beta transport." SIGNOR-188127 MAPK1 protein P28482 UNIPROT RGS19 protein P49795 UNIPROT up-regulates phosphorylation Ser151 EDYVSILsPKEVSLD 9606 10993892 t gcesareni "Phosphorylation of gaip by erk2 were abrogated when serine at position 151 in the rgs domain was substituted by an alanine residue using site-directed mutagenesis. Furthermore, the lysosomal-autophagic pathway was not stimulated in s151a-gaip mutant-expressing cells when compared with wild-type gaip-expressing cells. These results demonstrate that the gtpase-activating protein activity of gaip is stimulated by erk2 phosphorylation." SIGNOR-82083 MAPK1 protein P28482 UNIPROT RGS19 protein P49795 UNIPROT up-regulates phosphorylation Ser151 EDYVSILsPKEVSLD 9606 15488168 t gcesareni "Phosphorylation of gaip by erk2 were abrogated when serine at position 151 in the rgs domain was substituted by an alanine residue using site-directed mutagenesis. Furthermore, the lysosomal-autophagic pathway was not stimulated in s151a-gaip mutant-expressing cells when compared with wild-type gaip-expressing cells. These results demonstrate that the gtpase-activating protein activity of gaip is stimulated by erk2 phosphorylation." SIGNOR-129883 MAPK1 protein P28482 UNIPROT TSC2 protein P49815 UNIPROT down-regulates phosphorylation Ser664 KKTSGPLsPPTGPPG 9606 15851026 t llicata "Here, we show that erk may play a critical role in tsc progression through posttranslational inactivation of tsc2. s664 is the primary erk phosphorylation site on tsc2 in vitro and in vivo" SIGNOR-135696 MAPK1 protein P28482 UNIPROT TSC2 protein P49815 UNIPROT "down-regulates activity" phosphorylation Ser540 KVMARSLsPPPELEE 10090 BTO:0000944 15851026 t lperfetto "Here, we show that Erk may play a critical role in TSC progression through posttranslational inactivation of TSC2. Erk-dependent phosphorylation leads to TSC1-TSC2 dissociation and markedly impairs TSC2 ability to inhibit mTOR signaling, cell proliferation, and oncogenic transformation. |Serine to alanine substitution at S664 or double S664A/S540A mutagenesis resulted in a marked reduction in TSC2 phosphorylation to a similar extent. In contrast, S540A substitution only moderately impaired TSC2 phosphorylation (Figure 3D), corroborating the notion that in vivo S664 is the most relevant residue for Erk-mediated phosphorylation." SIGNOR-249454 MAPK1 protein P28482 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Thr43 KVTTVVAtPGQGPDR 9606 BTO:0000150;BTO:0000680 16039586 t lperfetto "Erk, which is activated by hbx, associates with gsk-3beta through a docking motif ((291)fkfp) of gsk-3beta and phosphorylates gsk-3beta at the (43)thr residue, which primes gsk-3beta for its subsequent phosphorylation at ser9 by p90rsk, resulting in inactivation of gsk-3beta and upregulation of beta-catenin." SIGNOR-138894 MAPK1 protein P28482 UNIPROT GSK3B protein P49841 UNIPROT "down-regulates activity" phosphorylation Ser9 SGRPRTTsFAESCKP 10090 BTO:0002572 28646232 t Gianni "We demonstrate that insulin-mediated activation of ERK1/2 results in phosphorylation of GSK3β at S9 independently of Akt/mTORC1 activity in Tsc2 null mouse embryonic fibroblasts. In addition, we show that inhibition of ERK1/2 rescues GSK3β activity and restores protein synthesis in Tsc2 −/− MEFs to normal levels" SIGNOR-262524 MAPK1 protein P28482 UNIPROT GSK3B protein P49841 UNIPROT up-regulates phosphorylation 9606 18045539 t fspada "In vitro phosphorylations were performed in two stages, and it was found that gsk3b caused the incorporation of [g-32p]atp by smad1 linker protein, but only after prephosphorylation by erk/mapk" SIGNOR-159487 MAPK1 protein P28482 UNIPROT ERF protein P50548 UNIPROT down-regulates phosphorylation Thr526 GEAGGPLtPRRVSSD 9606 7588608 t lperfetto "Consistent with the in vivo phosphorylation and inactivation by ras, erf is efficiently phosphorylated in vitro by erk2 and cdc2/cyclin b kinases, at sites similar to those detected in vivo. Furthermore, a single mutation at position 526 results in the loss of a specific phosphopeptide both in in vivo and in vitro (by erk2) labeling. Substitution of thr526 for glutamic acid also decreases the repression ability of erf" SIGNOR-29505 MAPK1 protein P28482 UNIPROT ERF protein P50548 UNIPROT up-regulates phosphorylation Ser161 SPTEDPRsPPACSSS 9606 10330152 t lperfetto "The experiments presented here indicate that erf is regulated during nuclear import and/or export and that this process depends on its phosphorylation by erks our analysis indicates that in addition to t526 (position 7), s161 (position 2), s246 (position 3), and s251 (position 4) are also phosphorylated in vitro by erk2 and in vivo after mitogenic stimulation (fig. 3a)." SIGNOR-67520 MAPK1 protein P28482 UNIPROT ERF protein P50548 UNIPROT up-regulates phosphorylation Ser246 RGGPEPLsPFPVSPL 9606 10330152 t lperfetto "The experiments presented here indicate that erf is regulated during nuclear import and/or export and that this process depends on its phosphorylation by erks our analysis indicates that in addition to t526 (position 7), s161 (position 2), s246 (position 3), and s251 (position 4) are also phosphorylated in vitro by erk2 and in vivo after mitogenic stimulation (fig. 3a)." SIGNOR-67524 MAPK1 protein P28482 UNIPROT ERF protein P50548 UNIPROT up-regulates phosphorylation Ser251 PLSPFPVsPLAGPGS 9606 10330152 t lperfetto "The experiments presented here indicate that erf is regulated during nuclear import and/or export and that this process depends on its phosphorylation by erks our analysis indicates that in addition to t526 (position 7), s161 (position 2), s246 (position 3), and s251 (position 4) are also phosphorylated in vitro by erk2 and in vivo after mitogenic stimulation (fig. 3a)." SIGNOR-67528 MAPK1 protein P28482 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser152 PASSVSSsPSPPFGH 9606 12050114 t gcesareni "Tob is rapidly phosphorylated at ser 152, ser 154, and ser 164 by erk1 and erk2 upon growth-factor stimulation." SIGNOR-88716 MAPK1 protein P28482 UNIPROT SCNN1B protein P51168 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr615 QALPIPGtPPPNYDS -1 11805112 t lperfetto "Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4." SIGNOR-249446 MAPK1 protein P28482 UNIPROT RCAN1 protein P53805 UNIPROT "up-regulates activity" phosphorylation Ser167 FLISPPAsPPVGWKQ 10090 BTO:0000165 12063245 t lperfetto "Consensus phosphorylation sites for p42/44 MAPK and GSK-3 are present in the SP repeat of MCIP1 at serine 112 and serine 108, respectively |Several endogenous proteins are capable of inhibiting the catalytic activity of calcineurin. Modulatory calcineurin interacting protein 1 (MCIP1) is unique among these proteins on the basis of its pattern of expression and its function in a negative feedback loop to regulate calcineurin activity. Here we show that MCIP1 can be phosphorylated by MAPK and glycogen synthase kinase-3 and that phosphorylated MCIP1 is a substrate for calcineurin." SIGNOR-249198 MAPK1 protein P28482 UNIPROT CASP9 protein P55211 UNIPROT "down-regulates activity" phosphorylation Thr125 PEVLRPEtPRPVDIG 9606 12792650 t lperfetto "Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK" SIGNOR-101544 MAPK1 protein P28482 UNIPROT CASP9 protein P55211 UNIPROT "down-regulates activity" phosphorylation Thr125 PEVLRPEtPRPVDIG 10090 BTO:0000782 16888006 t lperfetto "ERK/MAPK phosphorylates caspase-9 at Thr(125), and this phosphorylation is crucial for caspase-9 inhibition" SIGNOR-148616 MAPK1 protein P28482 UNIPROT CSNK2A1 protein P68400 UNIPROT up-regulates phosphorylation Ser362 ISSVPTPsPLGPLAG 9606 BTO:0000527 19941816 t lperfetto "Erk2, which is activated by egfr signaling, directly binds to ck2alpha via the erk2 docking groove and phosphorylates ck2alpha primarily at t360/s362, subsequently enhancing ck2alpha activity" SIGNOR-161851 MAPK1 protein P28482 UNIPROT CSNK2A1 protein P68400 UNIPROT up-regulates phosphorylation Thr360 SGISSVPtPSPLGPL 9606 BTO:0000527 19941816 t lperfetto "Erk2, which is activated by egfr signaling, directly binds to ck2alpha via the erk2 docking groove and phosphorylates ck2alpha primarily at t360/s362, subsequently enhancing ck2alpha activity" SIGNOR-161855 MAPK1 protein P28482 UNIPROT GTF2I protein P78347 UNIPROT up-regulates phosphorylation Ser668 INTKALQsPKRPRSP 9606 10648599 t lperfetto "Tfii-i can be phosphorylated in vitro by erk and mutation of consensus map kinase substrate sites at serines 627 and 633 impairs the phosphorylation of tfii-i by erk and its activity on the c-fos promoter. These results suggest that erk regulates the activity of tfii-i by direct phosphorylation." SIGNOR-74296 MAPK1 protein P28482 UNIPROT GTF2I protein P78347 UNIPROT up-regulates phosphorylation Ser674 QSPKRPRsPGSNSKV 9606 10648599 t lperfetto "Tfii-i can be phosphorylated in vitro by erk and mutation of consensus map kinase substrate sites at serines 627 and 633 impairs the phosphorylation of tfii-i by erk and its activity on the c-fos promoter. These results suggest that erk regulates the activity of tfii-i by direct phosphorylation." SIGNOR-74300 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 BTO:0000763;BTO:0000149 10197981 t llicata "Oncogenically activated ras inhibits the tgfbeta-induced nuclear accumulation of smad2 and smad3 and smad-dependent transcription. Ras acting via erk map kinases causes phosphorylation of smad2 and smad3 at specific sites in the region linking the dna-binding domain and the transcriptional activation domain." SIGNOR-66742 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation 9606 BTO:0000763;BTO:0000149 10197981 t lperfetto "These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3" SIGNOR-66749 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 19914161 t lpetrilli "Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3" SIGNOR-161617 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 19914168 t lpetrilli "Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3" SIGNOR-161706 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" phosphorylation Ser208 DAGSPNLsPNPMSPA 9606 19914161 t lpetrilli "Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3" SIGNOR-161613 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT unknown phosphorylation Ser204 NHSMDAGsPNLSPNP 9606 SIGNOR-C9 15241418 t llicata "We found that ser 203 and ser 207 were phosphorylated by map kinase and that thr 178 was phosphorylated mostly by cdk and to a lesser extent by map kinase" SIGNOR-126744 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT unknown phosphorylation Ser208 DAGSPNLsPNPMSPA 9606 SIGNOR-C9 15241418 t llicata "We found that ser 203 and ser 207 were phosphorylated by map kinase and that thr 178 was phosphorylated mostly by cdk and to a lesser extent by map kinase" SIGNOR-126748 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT unknown phosphorylation Ser204 NHSMDAGsPNLSPNP 9606 19914168 t lpetrilli "In contrast, ERK2 phosphorylated all four Smad1 residues almost evenly, while showing a preference for S204 over S208 and S213 in Smad3" SIGNOR-161698 MAPK1 protein P28482 UNIPROT H3-3A protein P84243 UNIPROT up-regulates phosphorylation Ser29 ATKAARKsAPSTGGV 9606 15994958 t gcesareni "Phosphorylation of histone h3 at serine 10 is indispensable for neoplastic cell transformation. When h3 wt was overexpressed, egf induction of c-fos and c-jun promoter activity was significantly increased compared with control cells but not in the h3 mutant s10a or s28a cells." SIGNOR-138451 MAPK1 protein P28482 UNIPROT KHDRBS1 protein Q07666 UNIPROT up-regulates phosphorylation Thr84 TVGGPAPtPLLPPSA 9606 12478298 t lperfetto "In support of this assumption, purified gst_sam68 protein was phosphorylated by recombinant erk2we found that sam68 mutated in ser 58, thr 71 and thr 84 showed the same extent of impairment in induced exon inclusion as did sam68 mutated in all s/tp sites" SIGNOR-96418 MAPK1 protein P28482 UNIPROT CDC42EP1 protein Q00587 UNIPROT unknown phosphorylation Ser113 SPAPPAIsPIIKNAI 10090 BTO:0000944 22028470 t miannu "We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)" SIGNOR-262765 MAPK1 protein P28482 UNIPROT CDC42EP1 protein Q00587 UNIPROT unknown phosphorylation Ser195 RRSDSLLsFRLDLDL 10090 BTO:0000944 22028470 t miannu "We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)" SIGNOR-262766 MAPK1 protein P28482 UNIPROT RUNX1 protein Q01196 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser276 VHPATPIsPGRASGM 9606 16046550 t "The effect has been demonstrated using Q01196-8" gcesareni "Mutation of the four phosphorylation sites necessary for transcriptional regulation (serine 276, serine 293, serine 303, and threonine 300) mimics the effects of the proteasome inhibitor, increasing the levels of ubiquitinated, matrix-bound aml1c. Thus, phosphorylation of aml1c on specific serine/threonine residues controls both transcriptional activity and rate of degradation." SIGNOR-138985 MAPK1 protein P28482 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser249 DTRQIQPsPPWSYDQ 9606 BTO:0002181 16046550 t "The effect has been demonstrated using Q01196-8" gcesareni "We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein." SIGNOR-138969 MAPK1 protein P28482 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser266 QYLGSIAsPSVHPAT 9606 BTO:0002181 16046550 t "The effect has been demonstrated using Q01196-8" gcesareni "We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein." SIGNOR-138973 MAPK1 protein P28482 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Thr273 SPSVHPAtPISPGRA 9606 BTO:0002181 16046550 t "The effect has been demonstrated using Q01196-8" gcesareni "We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein." SIGNOR-138981 MAPK1 protein P28482 UNIPROT POU5F1 protein Q01860 UNIPROT down-regulates phosphorylation Ser111 ESNSDGAsPEPCTVT 9606 23024368 t miannu "We demonstrate that oct4a interacts with erk1/2 by using both in vitro gst pulldown and in vivo co-immunoprecipitation assays. Ms analysis identified phosphorylation of oct4a at ser-111. / serine 111 phosphorylation regulates oct4a protein subcellular distribution and degradation." SIGNOR-192097 MAPK1 protein P28482 UNIPROT SP3 protein Q02447 UNIPROT up-regulates phosphorylation Ser73 CSKIGPPsPGDDEEE 9606 17685427 t llicata "Here, we show that sp3, which, as sp1, belongs to the gc-rich binding transcription factor family, is also phosphorylated by erk in vitro on serine 73. in the inducible cell lines, expression of wild-type form of sp3 increases vegf production whereas the s73a form has a reduced potential reflecting its lower transcriptional activity." SIGNOR-157272 MAPK1 protein P28482 UNIPROT MAP2K1 protein Q02750 UNIPROT "down-regulates activity" phosphorylation Thr292 ETPPRPRtPGRPLSS 9534 BTO:0004055 14993270 t lperfetto "We propose that activation of erk during adhesion creates a feedback system in which erk phosphorylates mek1 on t292, and this in turn blocks additional s298 phosphorylation in response to integrin signaling." SIGNOR-236335 MAPK1 protein P28482 UNIPROT LIPE protein Q05469 UNIPROT "up-regulates activity" phosphorylation Thr891 NSETSSDtPEMSLSA 10090 BTO:0000944 11581251 t lperfetto "Thus, activation of the ERK pathway appears to be able to regulate adipocyte lipolysis by phosphorylating HSL on Ser(600) and increasing the activity of HSL." SIGNOR-249413 MAPK1 protein P28482 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser759 KTPDGNKsPAPKPSD 9606 BTO:0001260 10514499 t lperfetto "Extracellular signal-regulated kinases (erks) phosphorylate the high molecular mass isoform of the actin-binding protein caldesmon (h-cad) at two sites (ser(759) and ser(789)) during smooth muscle stimulation. Nmr spectroscopy shows that the actin binding properties of the minimal inhibitory region of caldesmon, residues 750-779, alter upon map kinase phosphorylation of ser-759, a residue not involved in actin binding. This phosphorylation leads to markedly diminished actin affinity as a result of the loss of interaction at one of the two sites that bind to f-actin." SIGNOR-71033 MAPK1 protein P28482 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser789 QSVDKVTsPTKV 9606 BTO:0001260 10514499 t lperfetto "Extracellular signal-regulated kinases (erks) phosphorylate the high molecular mass isoform of the actin-binding protein caldesmon (h-cad) at two sites (ser(759) and ser(789)) during smooth muscle stimulation. Nmr spectroscopy shows that the actin binding properties of the minimal inhibitory region of caldesmon, residues 750-779, alter upon map kinase phosphorylation of ser-759, a residue not involved in actin binding. This phosphorylation leads to markedly diminished actin affinity as a result of the loss of interaction at one of the two sites that bind to f-actin." SIGNOR-71037 MAPK1 protein P28482 UNIPROT KHDRBS1 protein Q07666 UNIPROT up-regulates phosphorylation Ser58 SRGGARAsPATQPPP 9606 12478298 t lperfetto "In support of this assumption, purified gst_sam68 protein was phosphorylated by recombinant erk2we found that sam68 mutated in ser 58, thr 71 and thr 84 showed the same extent of impairment in induced exon inclusion as did sam68 mutated in all s/tp sites" SIGNOR-96410 MAPK1 protein P28482 UNIPROT KHDRBS1 protein Q07666 UNIPROT up-regulates phosphorylation Thr72 PLLPPSAtGPDATVG 9606 12478298 t lperfetto "In support of this assumption, purified gst_sam68 protein was phosphorylated by recombinant erk2we found that sam68 mutated in ser 58, thr 71 and thr 84 showed the same extent of impairment in induced exon inclusion as did sam68 mutated in all s/tp sites" SIGNOR-96414 MAPK1 protein P28482 UNIPROT MCL1 protein Q07820 UNIPROT up-regulates phosphorylation Thr163 TDGSLPStPPPAEEE 9606 12223490 t gcesareni "We found that jnk phosphorylated ser-121 and thr-163 of mcl-1 in response to stimulation with h(2)o(2) and that transfection of unphosphorylatable mcl-1 resulted in an enhanced anti-apoptotic activity in response to stimulation with h(2)o(2). Jnk-dependent phosphorylation and thus inactivation of mcl-1 may be one of the mechanisms through which oxidative stress induces cellular damage." SIGNOR-92593 MAPK1 protein P28482 UNIPROT PPARA protein Q07869 UNIPROT "up-regulates activity" phosphorylation Ser12 ESPLCPLsPLEAGDL 9606 BTO:0000599 10187842 t lperfetto "We now demonstrate that amino acids 1-92 of hPPARalpha contain an activation function (AF)-1-like domain, which is further activated by insulin through a pathway involving the mitogen-activated protein kinases p42 and p44. Further analysis of the amino-terminal region of PPARalpha revealed that the insulin-induced trans-activation occurs through the phosphorylation of two mitogen-activated protein kinase sites at positions 12 and 21, both of which are conserved across evolution." SIGNOR-249433 MAPK1 protein P28482 UNIPROT PPARA protein Q07869 UNIPROT "up-regulates activity" phosphorylation Ser21 LEAGDLEsPLSEEFL 9606 BTO:0000599 10187842 t lperfetto "We now demonstrate that amino acids 1-92 of hPPARalpha contain an activation function (AF)-1-like domain, which is further activated by insulin through a pathway involving the mitogen-activated protein kinases p42 and p44. Further analysis of the amino-terminal region of PPARalpha revealed that the insulin-induced trans-activation occurs through the phosphorylation of two mitogen-activated protein kinase sites at positions 12 and 21, both of which are conserved across evolution." SIGNOR-249434 MAPK1 protein P28482 UNIPROT SOS1 protein Q07889 UNIPROT "down-regulates activity" phosphorylation Ser1132 TLPHGPRsASVSSIS 9534 BTO:0004055 8816480 t lperfetto "In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1" SIGNOR-235742 MAPK1 protein P28482 UNIPROT SOS1 protein Q07889 UNIPROT "down-regulates activity" phosphorylation Ser1167 ESAPAESsPSKIMSK 9534 BTO:0004055 8816480 t lperfetto "In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1" SIGNOR-235933 MAPK1 protein P28482 UNIPROT SOS1 protein Q07889 UNIPROT "down-regulates activity" phosphorylation Ser1178 IMSKHLDsPPAIPPR 9534 BTO:0004055 8816480 t lperfetto "In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1" SIGNOR-235925 MAPK1 protein P28482 UNIPROT SOS1 protein Q07889 UNIPROT "down-regulates activity" phosphorylation Ser1193 QPTSKAYsPRYSISD 9534 BTO:0004055 8816480 t lperfetto "In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1" SIGNOR-236440 MAPK1 protein P28482 UNIPROT SOS1 protein Q07889 UNIPROT "down-regulates activity" phosphorylation Ser1197 KAYSPRYsISDRTSI 9534 BTO:0004055 8816480 t lperfetto "In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1" SIGNOR-235929 MAPK1 protein P28482 UNIPROT PDE4C protein Q08493 UNIPROT down-regulates phosphorylation Ser641 YQSKIPRsPSDLTNP 9606 11030732 t "The effect has been demonstrated using Q08493-2" gcesareni "The short-form pde4b2 isoenzyme was activated by erk2 phosphorylation. sub-family selective actions in the ability of erk2 map kinase to phosphorylate and regulate the activity of pde4 cyclic amp-specific phosphodiesterases" SIGNOR-83187 MAPK1 protein P28482 UNIPROT PDE4D protein Q08499 UNIPROT down-regulates phosphorylation Ser715 YQSTIPQsPSPAPDD 9606 BTO:0000007 10022832 t "The effect has been demonstrated using Q08499-2" gcesareni "These straddle the target residue, ser(579), for erk2 phosphorylation of pde4d3. Mutation of either or both of these docking sites prevented erk2 from being co-immunoprecipitated with pde4d3, ablated the ability of epidermal growth factor to inhibit pde4d3 through erk2 action in transfected cos cells, and attenuated the ability of erk2 to phosphorylate pde4d3 in vitro." SIGNOR-64326 MAPK1 protein P28482 UNIPROT PDE4D protein Q08499 UNIPROT down-regulates phosphorylation Ser715 YQSTIPQsPSPAPDD 9606 BTO:0000801 16973330 t "The effect has been demonstrated using Q08499-2" gcesareni "These straddle the target residue, ser(579), for erk2 phosphorylation of pde4d3. Mutation of either or both of these docking sites prevented erk2 from being co-immunoprecipitated with pde4d3, ablated the ability of epidermal growth factor to inhibit pde4d3 through erk2 action in transfected cos cells, and attenuated the ability of erk2 to phosphorylate pde4d3 in vitro." SIGNOR-149570 MAPK1 protein P28482 UNIPROT EP300 protein Q09472 UNIPROT up-regulates phosphorylation Ser2279 PVQPNPMsPQQHMLP 9606 17623675 t lperfetto "Serine residues (ser-2279, ser-2315, and ser-2366) on the c terminus of p300 were the major signaling targets of egf. Furthermore, the c-terminal serine phosphorylation of p300 stimulated its histone acetyltransferase activity these results also constituted the first report identifying the unique p300 phosphorylation sites induced by erk2 in vivo." SIGNOR-156887 MAPK1 protein P28482 UNIPROT EP300 protein Q09472 UNIPROT up-regulates phosphorylation Ser2315 RSPQPVPsPRPQSQP 9606 17623675 t gcesareni "Erk2-mediated c-terminal serine phosphorylation of p300 (ser-2279, ser-2315, and ser-2366) is vital to the regulation of epidermal growth factor-induced keratin 16 gene expression." SIGNOR-156891 MAPK1 protein P28482 UNIPROT EP300 protein Q09472 UNIPROT up-regulates phosphorylation Ser2366 MEQGHFAsPDQNSML 9606 17623675 t lperfetto "Serine residues (ser-2279, ser-2315, and ser-2366) on the c terminus of p300 were the major signaling targets of egf. Furthermore, the c-terminal serine phosphorylation of p300 stimulated its histone acetyltransferase activity these results also constituted the first report identifying the unique p300 phosphorylation sites induced by erk2 in vivo." SIGNOR-156895 MAPK1 protein P28482 UNIPROT AHNAK protein Q09666 UNIPROT unknown phosphorylation Ser216 PSGSGAAsPTGSAVD 10090 BTO:0000944 22028470 t miannu "We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)" SIGNOR-262762 MAPK1 protein P28482 UNIPROT AHNAK protein Q09666 UNIPROT unknown phosphorylation Ser5099 DVEFDIKsPKFKAEA 10090 BTO:0000944 22028470 t miannu "We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)" SIGNOR-262763 MAPK1 protein P28482 UNIPROT AHNAK protein Q09666 UNIPROT unknown phosphorylation Ser5110 KAEAPLPsPKLEGEL 10090 BTO:0000944 22028470 t miannu "We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)" SIGNOR-262764 MAPK1 protein P28482 UNIPROT AHNAK protein Q09666 UNIPROT unknown phosphorylation Thr5794 REFSGPStPTGTLEF 10090 BTO:0000944 22028470 t miannu "We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)" SIGNOR-262767 MAPK1 protein P28482 UNIPROT TFCP2 protein Q12800 UNIPROT down-regulates phosphorylation Ser309 SLGEGNGsPNHQPEP 9606 19237534 t lperfetto "We previously established that phosphorylation of lsf in early g1 at ser-291 and ser-309 inhibits its transcriptional activity and that dephosphorylation later in g1 is required for its reactivation. At the peak activities of erk and cyclin c/cdk2 in early g1, lsf is efficiently phosphorylated on ser-291 and ser-309." SIGNOR-184172 MAPK1 protein P28482 UNIPROT PAK1 protein Q13153 UNIPROT "down-regulates activity" phosphorylation Thr212 VIEPLPVtPTRDVAT 10116 BTO:0001260 15542607 t lperfetto "We also show that ERK2 phosphorylates PAK1 on Thr(212) in vitro and that Thr(212) is phosphorylated in smooth muscle cells following PDGF-BB treatment in an adhesion- and MEK/ERK-dependent fashion. Expression of a phosphomimic variant, PAK-T212E, does not alter ERK association, but markedly attenuates downstream ERK signaling. Taken together, these data suggest that PAK1 may facilitate ERK signaling by serving as a scaffold to recruit Raf, MEK, and ERK to adhesion complexes, and that subsequent growth factor-stimulated phosphorylation of PAK-Thr(212) by ERK may serve to provide a negative feedback signal" SIGNOR-249432 MAPK1 protein P28482 UNIPROT NR5A1 protein Q13285 UNIPROT "up-regulates activity" phosphorylation Ser203 EYPEPYAsPPQPGLP 9534 BTO:0004055 10230405 t lperfetto "Here we show that maximal SF-1-mediated transcription and interaction with general nuclear receptor cofactors depends on phosphorylation of a single serine residue (Ser-203) located in a major activation domain (AF-1) of the protein. Moreover, phosphorylation-dependent SF-1 activation is likely mediated by the mitogen-activated protein kinase (MAPK) signaling pathway." SIGNOR-249431 MAPK1 protein P28482 UNIPROT GRB10 protein Q13322 UNIPROT unknown phosphorylation Ser418 QQRKALLsPFSTPVR -1 15952796 t lperfetto "We identified Ser150, Ser418, and Ser476 of human Grb10 as MAPK-mediated in vitro phosphorylation sites." SIGNOR-249405 MAPK1 protein P28482 UNIPROT GRB10 protein Q13322 UNIPROT up-regulates phosphorylation Ser150 PELCGPGsPPVLTPG 9606 15952796 t lperfetto "We show that grb10 is a direct substrate of the p42/44 mitogen-activated protein kinase (mapk)we identified ser(150), ser(418), and ser(476) of human grb10zeta as mapk-mediated in vitro phosphorylation sites. Replacing ser(150) and ser(476) with alanines reduced the inhibitory effect of human grb10zeta on insulin-stimulated irs1 tyrosine phosphorylation. Taken together, our findings suggest that phosphorylation of the adaptor protein may provide a feedback inhibitory mechanism by which grb10 regulates insulin signaling." SIGNOR-138163 MAPK1 protein P28482 UNIPROT MYO9B protein Q13459 UNIPROT unknown phosphorylation Thr1346 RATGAALtPTEERRT 10090 BTO:0000944 22028470 t miannu "We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)" SIGNOR-262777 MAPK1 protein P28482 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Ser381 CIPTAGMsPSRSNTI 10029 BTO:0000246 15379552 t lperfetto "Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal" SIGNOR-249395 MAPK1 protein P28482 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Ser551 ELQAPVRsPITRSFA 10029 BTO:0000246 15379552 t lperfetto "Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal" SIGNOR-249397 MAPK1 protein P28482 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Ser567 DSSRFPMsPRPDSVH 10029 BTO:0000246 15379552 t lperfetto "Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal" SIGNOR-249398 MAPK1 protein P28482 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Thr312 ISYDIPPtPGNTYQI 10029 BTO:0000246 15379552 t lperfetto "Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal" SIGNOR-249399 MAPK1 protein P28482 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Thr476 EANYVPMtPGTFDFS 10029 BTO:0000246 15379552 t lperfetto "Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal" SIGNOR-249400 MAPK1 protein P28482 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates phosphorylation Thr277 GSRTAPYtPNLPHHQ 9606 12801888 t lpetrilli "Phosphorylation of thr276 is shown to be important for tgf-?-Induced nuclear accumulation and, as a consequence, transcriptional activity of smad4. these results suggest that smad4 can be phosphorylated by erk2 at thr276." SIGNOR-101660 MAPK1 protein P28482 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Ser65 FLMECRNsPVTKTPP 9606 BTO:0000007 11691836 t lperfetto "The 4E-BPs inhibit translation in a reversible manner. Hypophosphorylated 4E-BPs interact avidly with eIF4E, whereas 4E-BP hyperphosphorylation, elicited by stimulation of cells with hormones, cytokines, or growth factors, results in an abrogation of eIF4E-binding activity.|These results are at variance with reports that have characterized the 4E-BP1/eIF4E interaction utilizing recombinant 4E-BP1 proteins phosphorylated in vitro with ERK, and harboring alanine substitutions at Thr 37, Thr 46, Thr 70, and Ser 83 |phosphorylation of either Thr 46 or Ser 65 was reported to result in a decrease in eIF4E binding" SIGNOR-249390 MAPK1 protein P28482 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Ser83 PTIPGVTsPSSDEPP 9606 BTO:0000007 11691836 t lperfetto "The 4E-BPs inhibit translation in a reversible manner. Hypophosphorylated 4E-BPs interact avidly with eIF4E, whereas 4E-BP hyperphosphorylation, elicited by stimulation of cells with hormones, cytokines, or growth factors, results in an abrogation of eIF4E-binding activity.|These results are at variance with reports that have characterized the 4E-BP1/eIF4E interaction utilizing recombinant 4E-BP1 proteins phosphorylated in vitro with ERK, and harboring alanine substitutions at Thr 37, Thr 46, Thr 70, and Ser 83 |phosphorylation of either Thr 46 or Ser 65 was reported to result in a decrease in eIF4E binding" SIGNOR-249391 MAPK1 protein P28482 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr37 PPGDYSTtPGGTLFS 9606 BTO:0000007 11691836 t lperfetto "The 4E-BPs inhibit translation in a reversible manner. Hypophosphorylated 4E-BPs interact avidly with eIF4E, whereas 4E-BP hyperphosphorylation, elicited by stimulation of cells with hormones, cytokines, or growth factors, results in an abrogation of eIF4E-binding activity.|These results are at variance with reports that have characterized the 4E-BP1/eIF4E interaction utilizing recombinant 4E-BP1 proteins phosphorylated in vitro with ERK, and harboring alanine substitutions at Thr 37, Thr 46, Thr 70, and Ser 83 |phosphorylation of either Thr 46 or Ser 65 was reported to result in a decrease in eIF4E binding" SIGNOR-249392 MAPK1 protein P28482 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr46 GGTLFSTtPGGTRII 9606 BTO:0000007 11691836 t lperfetto "The 4E-BPs inhibit translation in a reversible manner. Hypophosphorylated 4E-BPs interact avidly with eIF4E, whereas 4E-BP hyperphosphorylation, elicited by stimulation of cells with hormones, cytokines, or growth factors, results in an abrogation of eIF4E-binding activity.|These results are at variance with reports that have characterized the 4E-BP1/eIF4E interaction utilizing recombinant 4E-BP1 proteins phosphorylated in vitro with ERK, and harboring alanine substitutions at Thr 37, Thr 46, Thr 70, and Ser 83 |phosphorylation of either Thr 46 or Ser 65 was reported to result in a decrease in eIF4E binding" SIGNOR-249393 MAPK1 protein P28482 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr70 RNSPVTKtPPRDLPT 9606 BTO:0000007 11691836 t lperfetto "The 4E-BPs inhibit translation in a reversible manner. Hypophosphorylated 4E-BPs interact avidly with eIF4E, whereas 4E-BP hyperphosphorylation, elicited by stimulation of cells with hormones, cytokines, or growth factors, results in an abrogation of eIF4E-binding activity.|These results are at variance with reports that have characterized the 4E-BP1/eIF4E interaction utilizing recombinant 4E-BP1 proteins phosphorylated in vitro with ERK, and harboring alanine substitutions at Thr 37, Thr 46, Thr 70, and Ser 83 |phosphorylation of either Thr 46 or Ser 65 was reported to result in a decrease in eIF4E binding" SIGNOR-249394 MAPK1 protein P28482 UNIPROT STIM1 protein Q13586 UNIPROT up-regulates phosphorylation Ser575 LVEKLPDsPALAKKA 9606 BTO:0000222 22298426 t gcesareni "The netrin-2-mediated nfatc3 activation was coincident with robust interactions between cdo and stim1 in myoblasts and the erk-mediated stim1 phosphorylation at serine 575" SIGNOR-192788 MAPK1 protein P28482 UNIPROT TP53BP2 protein Q13625 UNIPROT "up-regulates activity" phosphorylation Ser827 NSDMPAPsPGLDYEP -1 24312625 t lperfetto "Hence ASPP2 can be phosphorylated at serine 827 by MAPK1 in vitro.|Phosphorylation of ASPP2 by MAPK is required for RAS-induced increased binding to p53 and increased transactivation of pro-apoptotic genes." SIGNOR-264414 MAPK1 protein P28482 UNIPROT DOCK1 protein Q14185 UNIPROT unknown phosphorylation Thr1772 QQTPPPVtPRAKLSF 10090 BTO:0000944 22028470 t miannu "We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)" SIGNOR-262769 MAPK1 protein P28482 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser405 KTQTPPVsPAPQPTE 9606 BTO:0000938 20444238 t gcesareni "Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement." SIGNOR-165200 MAPK1 protein P28482 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser418 TEERLPSsPVYEDAA 9606 BTO:0000938 20444238 t gcesareni "Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement." SIGNOR-165204 MAPK1 protein P28482 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser405 KTQTPPVsPAPQPTE 9606 BTO:0000938 21079800 t gcesareni "Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement." SIGNOR-169674 MAPK1 protein P28482 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "down-regulates activity" phosphorylation 9606 BTO:0000007 10567369 t lperfetto "An ERK2-binding site at the N terminus of MEK1 was reported to mediate their stable association. We examined the importance of this binding site in the feedback phosphorylation of mek1 on thr(292) and thr(386) by erk2" SIGNOR-244912 MAPK1 protein P28482 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser418 TEERLPSsPVYEDAA 9606 BTO:0000938 21079800 t gcesareni "Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement." SIGNOR-169678 MAPK1 protein P28482 UNIPROT ESPL1 protein Q14674 UNIPROT down-regulates phosphorylation Ser1126 IAPSTNSsPVLKTKP 9606 11747808 t lperfetto "Both cdc2/cyclinb1 and mapk (erk2) efficiently phosphorylate separase at its major inhibitory site in vitro" SIGNOR-113130 MAPK1 protein P28482 UNIPROT NCOA6 protein Q14686 UNIPROT "up-regulates activity" phosphorylation Ser884 NKDVTLTsPLLVNLL -1 11773444 t miannu "In vitro phosphorylation studies with His-tagged TRBP (795–931) suggested that S884 can be phosphorylated by MAPK (ERK2) in vitro (Fig. 10A).Analysis of in vitro and in vivo receptor interactions with TRBP suggested that S884 allowed selective interactions for ERβ, TR, and RXR vs. ERα." SIGNOR-265882 MAPK1 protein P28482 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates phosphorylation Ser387 YLEMDLSsPQTRYIP 9606 BTO:0000149 24342355 t lperfetto "We demonstrate that perk 1/2 can phosphorylate pro-caspase-8 at s387 by knocking-down the endogenous pro-caspase-8 using rnai and replacing it with its non-phosphorylatable counterpart (s387a), a significant increase in caspase-8 activity" SIGNOR-203473 MAPK1 protein P28482 UNIPROT NFATC4 protein Q14934 UNIPROT up-regulates phosphorylation Ser676 SNGRRKRsPTQSFRF 9606 15657420 t esanto "We demonstrate that p90 ribosomal s6 kinase (rsk) is recruited to the nfat-dna transcription complex upon activation.Bound Rsk phosphorylates ser(676) and potentiates nfatc4 dna binding. Ser(676) is also targeted by the erk map kinase." SIGNOR-133272 MAPK1 protein P28482 UNIPROT PTPRR protein Q15256 UNIPROT "up-regulates activity" phosphorylation Thr361 EPFVSIPtPREKVAM 11493009 t lperfetto "Specifically, the complex formation between PTP-SL and ERK2 involves an unusual interaction leading to the phosphorylation of PTP-SL by ERK2 at Thr253 and the inactivating dephosphorylation of ERK2 by PTP-SL." SIGNOR-249438 MAPK1 protein P28482 UNIPROT PCBP2 protein Q15366 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser189 YRPKPSSsPVIFAGG 9606 BTO:0000664 17475908 t miannu "We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B)." SIGNOR-262911 MAPK1 protein P28482 UNIPROT PCBP2 protein Q15366 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser272 FSGIESSsPEVKGYW 9606 BTO:0000664 17475908 t miannu "We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B)." SIGNOR-262912 MAPK1 protein P28482 UNIPROT PCBP2 protein Q15366 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr213 SASFPHTtPSMCLNP 9606 BTO:0000664 17475908 t miannu "We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B)." SIGNOR-262913 MAPK1 protein P28482 UNIPROT RPS6KA1 protein Q15418 UNIPROT "up-regulates activity" phosphorylation Ser221 DHEKKAYsFCGTVEY 9534 BTO:0004055 9430688 t lperfetto "Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733." SIGNOR-219308 MAPK1 protein P28482 UNIPROT RPS6KA1 protein Q15418 UNIPROT "up-regulates activity" phosphorylation Ser363 TSRTPKDsPGIPPSA 9534 BTO:0004055 9430688 t lperfetto "Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733." SIGNOR-219312 MAPK1 protein P28482 UNIPROT RPS6KA1 protein Q15418 UNIPROT "up-regulates activity" phosphorylation Ser380 HQLFRGFsFVATGLM 9534 BTO:0004055 9430688 t lperfetto "Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733." SIGNOR-219316 AKT1 protein P31749 UNIPROT FOXO4 protein P98177 UNIPROT "down-regulates activity" phosphorylation Ser197 APRRRAAsMDSSSKL 10090 BTO:0004245 10217147 t "Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf -16 (refs 5, 6, 9), both in vitro and in vivo." SIGNOR-252568 MAPK1 protein P28482 UNIPROT RPS6KA1 protein Q15418 UNIPROT "up-regulates activity" phosphorylation Thr359 DTEFTSRtPKDSPGI 9534 BTO:0004055 9430688 t lperfetto "Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733." SIGNOR-219324 MAPK1 protein P28482 UNIPROT RPS6KA1 protein Q15418 UNIPROT "up-regulates activity" phosphorylation Thr573 AENGLLMtPCYTANF 9534 BTO:0004055 9430688 t lperfetto "Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733." SIGNOR-219328 MAPK1 protein P28482 UNIPROT RPS6KA1 protein Q15418 UNIPROT "up-regulates activity" phosphorylation Thr573 AENGLLMtPCYTANF 9606 BTO:0000567 9687510 t lperfetto "Thus, MAPK1/ERK1 and MAPK2/ERK2 activate three closely related protein kinases known as MAPK_activated protein kinases_1a, _1b and _1c (MAPKAP_K1a/b/c; also known as RSK1/2/3)" SIGNOR-59363 MAPK1 protein P28482 UNIPROT MED1 protein Q15648 UNIPROT up-regulates phosphorylation Thr1032 SSSNRPFtPPTSTGG 9606 16314496 t fstefani "We demonstrate that erk phosphorylates trap220/med1 in vivo at two specific sites: threonine 1032 and threonine 1457. importantly, we found that erk phosphorylation significantly increases the stability and half-life of trap220/med1 in vivo and correlates with increased thyroid hormone receptor-dependent transcription." SIGNOR-142458 MAPK1 protein P28482 UNIPROT MED1 protein Q15648 UNIPROT up-regulates phosphorylation Thr1457 HSKSPAYtPQNLDSE 9606 16314496 t fstefani "We demonstrate that erk phosphorylates trap220/med1 in vivo at two specific sites: threonine 1032 and threonine 1457. importantly, we found that erk phosphorylation significantly increases the stability and half-life of trap220/med1 in vivo and correlates with increased thyroid hormone receptor-dependent transcription." SIGNOR-142462 MAPK1 protein P28482 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation Ser68 GGGDEPGsPAQGKRG 9606 BTO:0000007;BTO:0000150 21502402 t gcesareni "We identified the serine 68 (s68) as a major phosphorylation site of twist1 by mass spectrometry and with specific antibodies. This s68 is phosphorylated by p38, jnk and erk1/2 in vitro, and its phosphorylation levels positively correlate with twist1 protein levels in hek293 and breast cancer cells." SIGNOR-173401 MAPK1 protein P28482 UNIPROT NCOA1 protein Q15788 UNIPROT up-regulates phosphorylation Ser1185 GTPPASTsPFSQLAA 9606 10660621 t lperfetto "Furthermore, erk-2 phosphorylated threonine 1179 and serine 1185 (and to a lesser extent, serine 395) in vitro, suggesting the importance of this pathway for src-1 regulation. Treatment of cells expressing src-1 with epidermal growth factor enhanced the ligand-dependent, progesterone receptor-mediated activation of a target reporter gene." SIGNOR-74872 MAPK1 protein P28482 UNIPROT NCOA1 protein Q15788 UNIPROT up-regulates phosphorylation Ser395 PSVNPSIsPAHGVAR 9606 10660621 t lperfetto "Furthermore, erk-2 phosphorylated threonine 1179 and serine 1185 (and to a lesser extent, serine 395) in vitro, suggesting the importance of this pathway for src-1 regulation. Treatment of cells expressing src-1 with epidermal growth factor enhanced the ligand-dependent, progesterone receptor-mediated activation of a target reporter gene." SIGNOR-74876 MAPK1 protein P28482 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser245 NQSMDTGsPAELSPT 9606 BTO:0000763 12193595 t gcesareni "We show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity." SIGNOR-91714 MAPK1 protein P28482 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser250 TGSPAELsPTTLSPV 9606 BTO:0000763 12193595 t miannu "Phosphorylation of smad2 by erk increases its transcriptional activity /thr220 and ser245, ser250, and ser255 were possible phosphorylation sites. The phosphorylation of peak a peptide by erk1 is consistent with that prediction." SIGNOR-91718 MAPK1 protein P28482 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser255 ELSPTTLsPVNHSLD 9606 BTO:0000763 12193595 t miannu "Phosphorylation of smad2 by erk increases its transcriptional activity /thr220 and ser245, ser250, and ser255 were possible phosphorylation sites. The phosphorylation of peak a peptide by erk1 is consistent with that prediction." SIGNOR-91722 MAPK1 protein P28482 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Thr220 QSNYIPEtPPPGYIS 9606 BTO:0000763 12193595 t miannu "Phosphorylation of smad2 by erk increases its transcriptional activity /thr220 and ser245, ser250, and ser255 were possible phosphorylation sites. The phosphorylation of peak a peptide by erk1 is consistent with that prediction." SIGNOR-91726 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser187 NSHPFPHsPNSSYPN 9606 19914161 t lpetrilli "Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3" SIGNOR-161593 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser195 PNSSYPNsPGSSSST 9606 19914161 t lpetrilli "Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3" SIGNOR-161597 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser214 PTSSDPGsPFQMPAD 9606 19914161 t lpetrilli "Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3" SIGNOR-161605 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser195 PNSSYPNsPGSSSST 9606 19914168 t lpetrilli "Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3" SIGNOR-161686 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser214 PTSSDPGsPFQMPAD 9606 19914168 t lpetrilli "Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3" SIGNOR-161694 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser187 NSHPFPHsPNSSYPN 9606 9335504 t llicata "In contrast to the bmp-stimulated phosphorylation of smad1, which affects carboxy-terminal serines and induces nuclear accumulation of smad1, erk-mediated phosphorylation specifically inhibits the nuclear accumulation of smad1. phosphorylation occurs at specific serines within the region linking the inhibitory and effector domains of smad1" SIGNOR-52674 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser195 PNSSYPNsPGSSSST 9606 9335504 t llicata "In contrast to the bmp-stimulated phosphorylation of smad1, which affects carboxy-terminal serines and induces nuclear accumulation of smad1, erk-mediated phosphorylation specifically inhibits the nuclear accumulation of smad1. phosphorylation occurs at specific serines within the region linking the inhibitory and effector domains of smad1" SIGNOR-52678 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT "down-regulates activity" phosphorylation Ser206 SSSTYPHsPTSSDPG 9606 9335504 t llicata "In contrast to the bmp-stimulated phosphorylation of smad1, which affects carboxy-terminal serines and induces nuclear accumulation of smad1, erk-mediated phosphorylation specifically inhibits the nuclear accumulation of smad1. phosphorylation occurs at specific serines within the region linking the inhibitory and effector domains of smad1" SIGNOR-52687 MAPK1 protein P28482 UNIPROT STK11 protein Q15831 UNIPROT "down-regulates activity" phosphorylation Ser428 SSKIRRLsACKQQ 9606 25846811 t lperfetto "Directly and/or through the activation of p90RSK, ERK phosphorylates LKB-1 at Ser325 and Ser428. The phosphorylation of LKB-1 causes the dissociation of LKB-1 from AMPK, resulting in the impaired activation of AMPK." SIGNOR-209876 MAPK1 protein P28482 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates 9606 BTO:0000801 11842088 f gcesareni "In addition, immunoblot and immunostaining analysis revealed that phosphorylation of erk was increased by treatment with sb203580;whereas pd98059 increased the phosphorylation of p38, which implies a seesaw-like balance between erk and p38 phosphorylation." SIGNOR-114771 MAPK1 protein P28482 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates 9606 18481201 f gcesareni "In addition, immunoblot and immunostaining analysis revealed that phosphorylation of erk was increased by treatment with sb203580;whereas pd98059 increased the phosphorylation of p38, which implies a seesaw-like balance between erk and p38 phosphorylation." SIGNOR-178639 MAPK1 protein P28482 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates phosphorylation Ser641 DIKILIAsPSPTHIH 9606 BTO:0000567 18519666 t lperfetto "We show that at least two different nuclear protein kinases, one of them identified as p42/p44 mapk, can modify hif-1_. Analysis of in vitro phosphorylated hif-1_ by mass spectroscopy revealed residues ser-641 and ser-643 as possible mapk phosphorylation sites these data suggest that phosphorylation of ser-641/643 by mapk promotes the nuclear accumulation and transcriptional activity of hif-1_" SIGNOR-178723 MAPK1 protein P28482 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates phosphorylation Ser643 KILIASPsPTHIHKE 9606 BTO:0000567 18519666 t lperfetto "We show that at least two different nuclear protein kinases, one of them identified as p42/p44 mapk, can modify hif-1_. Analysis of in vitro phosphorylated hif-1_ by mass spectroscopy revealed residues ser-641 and ser-643 as possible mapk phosphorylation sites these data suggest that phosphorylation of ser-641/643 by mapk promotes the nuclear accumulation and transcriptional activity of hif-1_" SIGNOR-178727 MAPK1 protein P28482 UNIPROT DUSP6 protein Q16828 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser159 DGSCSSSsPPLPVLG 9606 15632084 t gcesareni "In vitro phosphorylation assays using glutathione S-transferase (GST)-MKP-3 fusion proteins indicated that ERK2 could phosphorylate MKP-3 on serines 159 and 197Double serine mutants of MKP-3 or MKP-3-GFP were more efficiently protected from degradation than single mutants or wild-type MKP-3, indicating that phosphorylation of either serine by ERK1/2 enhances proteasomal degradation of MKP-3." SIGNOR-132967 MAPK1 protein P28482 UNIPROT DUSP6 protein Q16828 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser197 SATDSDGsPLSNSQP 9606 15632084 t gcesareni "In vitro phosphorylation assays using glutathione S-transferase (GST)-MKP-3 fusion proteins indicated that ERK2 could phosphorylate MKP-3 on serines 159 and 197Double serine mutants of MKP-3 or MKP-3-GFP were more efficiently protected from degradation than single mutants or wild-type MKP-3, indicating that phosphorylation of either serine by ERK1/2 enhances proteasomal degradation of MKP-3." SIGNOR-132971 MAPK1 protein P28482 UNIPROT CEP55 protein Q53EZ4 UNIPROT down-regulates phosphorylation Ser425 NREKVAAsPKSPTAA 9606 16198290 t lperfetto "Upon mitotic entry, centrosome dissociation of cep55 is triggered by erk2/cdk1-dependent phosphorylation at s425 and s428. S425/428 phosphorylation is required for interaction with plk1, enabling phosphorylation of cep55 at s436. enabling it to relocate to the midbody to function in mitotic exit and cytokinesis." SIGNOR-140890 MAPK1 protein P28482 UNIPROT CEP55 protein Q53EZ4 UNIPROT down-regulates phosphorylation Ser428 KVAASPKsPTAALNE 9606 16198290 t lperfetto "Upon mitotic entry, centrosome dissociation of cep55 is triggered by erk2/cdk1-dependent phosphorylation at s425 and s428. S425/428 phosphorylation is required for interaction with plk1, enabling phosphorylation of cep55 at s436. enabling it to relocate to the midbody to function in mitotic exit and cytokinesis." SIGNOR-140894 MAPK1 protein P28482 UNIPROT PDXDC1 protein Q6P996 UNIPROT unknown phosphorylation Thr691 AGVTLPPtPSGSRTK 10090 BTO:0000944 22028470 t miannu "We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)" SIGNOR-262759 MAPK1 protein P28482 UNIPROT METTL3 protein Q86U44 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser43 RNPEAALsPTFRSDS 9606 BTO:0000007 33217317 t miannu "Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex." SIGNOR-265950 MAPK1 protein P28482 UNIPROT METTL3 protein Q86U44 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser50 SPTFRSDsPVPTAPT 9606 BTO:0000007 33217317 t miannu "Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex." SIGNOR-265946 MAPK1 protein P28482 UNIPROT METTL3 protein Q86U44 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser525 YGMIERLsPGTRKIE 9606 BTO:0000007 33217317 t miannu "Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex." SIGNOR-265948 MAPK1 protein P28482 UNIPROT NOXA1 protein Q86UR1 UNIPROT down-regulates phosphorylation Ser282 VGKQAPLsPGLPAMG 9606 BTO:0000007 20110267 t llicata "These results demonstrated a critical role of noxa1 phosphorylation on ser-282 and ser-172 in preventing nox1 hyperactivation through the decrease of noxa1 interaction to nox1 and rac1." SIGNOR-163659 MAPK1 protein P28482 UNIPROT NOXA1 protein Q86UR1 UNIPROT down-regulates phosphorylation Ser282 VGKQAPLsPGLPAMG 9606 20230789 t lperfetto "Accumulating evidence indicates that protein phosphorylation regulates nox activity. In this report, we show that serine282 residue of nox activator 1 (noxa1) is phosphorylated by erk in response to egf resulting in desensitization of nox1 activity" SIGNOR-164227 MAPK1 protein P28482 UNIPROT AEBP1 protein Q8IUX7 UNIPROT "up-regulates activity" phosphorylation Thr621 GEPEFRYtAGIHGNE 10090 BTO:0000944 15654748 t miannu "We show that DNA binding by AEBP1 requires both the N- and C-terminal domains of AEBP1, and MAPK interaction with AEBP1 (through its N terminus) results in enhanced DNA binding. A threonine at position 623 within the C-terminal domain of AEBP1 plays an important role in DNA binding by AEBP1, because the mutation results in decreased DNA binding by AEBP1, which leads to a decrease in the transcriptional repression ability of AEBP1. We also show that in vitro phosphorylation of AEBP1 by MAPK is greatly reduced upon mutation of T623. These results suggest that MAPK regulates the transcriptional activity of AEBP1 by a novel dual mechanism, in which MAPK interaction enhances and subsequent phosphorylation decreases the DNA-binding ability of AEBP1." SIGNOR-262897 MAPK1 protein P28482 UNIPROT MAPKAPK5 protein Q8IW41 UNIPROT up-regulates phosphorylation Thr182 IDQGDLMtPQFTPYY 9606 BTO:0000567 9628874 t gcesareni "Activated following phosphorylation at thr-182 by p38-alpha/mapk14, p38-beta/mapk11, erk2/mapk1, erk3/mapk6, and erk4/mapk4." SIGNOR-58127 MAPK1 protein P28482 UNIPROT WWC1 protein Q8IX03 UNIPROT unknown phosphorylation Ser548 SSPSPPCsPLMADPL 9606 BTO:0000149 24269383 t llicata "We demonstrated that erk1/2 phosphorylate kibra at ser(548) in cells as well as in vitro." SIGNOR-203286 MAPK1 protein P28482 UNIPROT ABI1 protein Q8IZP0 UNIPROT up-regulates phosphorylation Ser183 PPTQKPPsPPMSGRG 9606 21419341 t lperfetto "Our mass spectrometry also identified abi1 s183 and s225 on abi1 (numbering corresponds to abi1 isoform 1) as sites phosphorylated on endogenous protein and in the wildtype erk-dependent in vitro phosphorylated sample. these data indicate erk phosphorylation of abi1 is required for basal and egf-induced wrc interaction with the wrp2/3 complex." SIGNOR-172869 MAPK1 protein P28482 UNIPROT ABI1 protein Q8IZP0 UNIPROT up-regulates phosphorylation Ser222 TSPARLGsQHSPGRT 9606 21419341 t lperfetto "Our mass spectrometry also identified abi1 s183 and s225 on abi1 (numbering corresponds to abi1 isoform 1) as sites phosphorylated on endogenous protein and in the wildtype erk-dependent in vitro phosphorylated sample. these data indicate erk phosphorylation of abi1 is required for basal and egf-induced wrc interaction with the wrp2/3 complex." SIGNOR-172873 MAPK1 protein P28482 UNIPROT RPTOR protein Q8N122 UNIPROT unknown phosphorylation Ser8 MESEMLQsPLLGLGE 9606 SIGNOR-C3 21071439 t llicata "We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1." SIGNOR-169518 MAPK1 protein P28482 UNIPROT RPTOR protein Q8N122 UNIPROT "up-regulates activity" phosphorylation Ser863 LTQSAPAsPTNKGVH 9606 SIGNOR-C3 21071439 t lperfetto "We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1." SIGNOR-188916 MAPK1 protein P28482 UNIPROT DDHD1 protein Q8NEL9 UNIPROT unknown phosphorylation Ser727 TIPSPVTsPVLSRRH -1 11328814 t miannu "Here we incubated a recombinant preparation of the phospholipase in vitro with several enzymes including protein kinase CK2 (CK2), extracellular signal-regulated kinase 2 (ERK2), and protein phosphatase 2A (PP2A) to identify effects that might be of regulatory importance in vivo.Major findings were that 1) CK2 phosphorylated the phospholipase on serines 93, 105, and 716; 2) ERK2 phosphorylated the enzyme on serine 730; 3) there was cross-antagonism between the reactions that phosphorylated serines 716 and 730; 4) PP2A selectively hydrolyzed phosphate groups that were esterified to serines 716 and 730. The results of two independent experiments with each type of assay indicated that the incubation caused a 50% loss of phospholipase activity (TableV). These results differed from those of corresponding incubation experiments with PA-PLA1α plus ERK2 and MgATP (see “Experimental Procedures”), which provided no evidence for complex formation or phosphorylation-dependent loss of phospholipase activity" SIGNOR-262972 MAPK1 protein P28482 UNIPROT MAFA protein Q8NHW3 UNIPROT "up-regulates activity" phosphorylation Ser14 MGAELPSsPLAIEYV 9606 BTO:0000567 11416124 t lperfetto "These residues are phosphorylated by erk2 but not by p38, jnk, and erk5 in vitro. However, the contribution of the mek/erk pathway to mafa phosphorylation in vivo appears to be moderate, implicating another kinase. The integrity of serine 14 and serine 65 residues is required for transcriptional activity, since their mutation into alanine severely impairs mafa capacity to activate transcription." SIGNOR-108560 ARPC4 protein P59998 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR "form complex" binding 9606 12479800 t "The subunits in mammalian cells are named Arp3, Arp2, p41-Arc, p34-Arc, p21-Arc, p20-Arc and p16-Arc" SIGNOR-251517 MAPK1 protein P28482 UNIPROT MAFA protein Q8NHW3 UNIPROT "up-regulates activity" phosphorylation Ser65 PCSSVPSsPSFCAPS 9606 BTO:0000567 11416124 t lperfetto "These residues are phosphorylated by erk2 but not by p38, jnk, and erk5 in vitro. However, the contribution of the mek/erk pathway to mafa phosphorylation in vivo appears to be moderate, implicating another kinase. The integrity of serine 14 and serine 65 residues is required for transcriptional activity, since their mutation into alanine severely impairs mafa capacity to activate transcription." SIGNOR-108564 MAPK1 protein P28482 UNIPROT TSC1 protein Q92574 UNIPROT down-regulates phosphorylation 9606 15851026 t gcesareni "Here, we show that erk may play a critical role in tsc progression through posttranslational inactivation of tsc2. Erk-dependent phosphorylation leads to tsc1-tsc2 dissociation and markedly impairs tsc2 ability to inhibit mtor signalin." SIGNOR-135692 MAPK1 protein P28482 UNIPROT TSC1 protein Q92574 UNIPROT down-regulates phosphorylation 9606 BTO:0000150;BTO:0001573 17671177 t gcesareni "Here, we show that erk may play a critical role in tsc progression through posttranslational inactivation of tsc2. Erk-dependent phosphorylation leads to tsc1-tsc2 dissociation and markedly impairs tsc2 ability to inhibit mtor signalin." SIGNOR-157162 MAPK1 protein P28482 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation -1 8929531 t lperfetto "The rapid phosphorylation of bad following il-3 connects a proximal survival signal with the bcl-2 family, modulating this checkpoint for apoptosis.phosphorylatedBAD is bound to 14-3-3 within the cytosol, while only nonphosphorylated BAD is heterodimerized with membrane-bound BCL-XL." SIGNOR-44858 MAPK1 protein P28482 UNIPROT ARHGEF2 protein Q92974 UNIPROT up-regulates phosphorylation Thr679 PGVELLLtPREPALP 9606 BTO:0000671 19261619 t gcesareni "Importantly tnf-alpha enhanced the erk pathway-dependent phosphorylation of thr-678 of gef-h1 that was key for activation." SIGNOR-184469 MAPK1 protein P28482 UNIPROT MRTFA protein Q969V6 UNIPROT down-regulates phosphorylation Ser454 TGSTPPVsPTPSERS 9606 18694962 t "Translocation from Nuleus to Cytoplasm" gcesareni "Serum induces rhoa-dependent translocation of mkl1 from the cytoplasm to the nucleus and also causes a rapid increase in mkl1 phosphorylation. Serum-induced phosphorylation of the serum response factor coactivator mkl1 by the extracellular signal-regulated kinase 1/2 pathway inhibits its nuclear localization." SIGNOR-179959 MAPK1 protein P28482 UNIPROT DAZAP1 protein Q96EP5 UNIPROT "down-regulates activity" phosphorylation Thr269 FTSYIVStPPGGFPP 9606 BTO:0000007 16848763 t miannu "Further experiments showed that DAZAP1 was phosphorylated stoichiometrically in vitro by ERK2 (extracellular-signal-regulated protein kinase 2) at two Thr-Pro sequences (Thr269 and Thr315), and that both sites became phosphorylated in HEK-293 (human embryonic kidney 293) cells in response to PMA or EGF (epidermal growth factor), or RAW 264.7 macrophages in response to LPS. Phosphorylation of the ARE-binding protein DAZAP1 by ERK2 induces its dissociation from DAZ" SIGNOR-262970 MAPK1 protein P28482 UNIPROT DAZAP1 protein Q96EP5 UNIPROT "down-regulates activity" phosphorylation Thr315 GVPPPPAtPGAAPLA 9606 BTO:0000007 16848763 t miannu "Further experiments showed that DAZAP1 was phosphorylated stoichiometrically in vitro by ERK2 (extracellular-signal-regulated protein kinase 2) at two Thr-Pro sequences (Thr269 and Thr315), and that both sites became phosphorylated in HEK-293 (human embryonic kidney 293) cells in response to PMA or EGF (epidermal growth factor), or RAW 264.7 macrophages in response to LPS. Phosphorylation of the ARE-binding protein DAZAP1 by ERK2 induces its dissociation from DAZ" SIGNOR-262971 MAPK1 protein P28482 UNIPROT BMF protein Q96LC9 UNIPROT up-regulates phosphorylation Ser74 DKATQTLsPASPSQG 9606 BTO:0000785 22258404 t llicata "Phosphomimetic mutation of this site (s74d) moderately enhanced bmf apoptotic activity in vivo.22 here, we demonstrate a previously unrecognized mode of regulation of bmf. We show that b-raf-mek-erk2 signaling regulates bmf phosphorylation at serine 74 and serine 77. Phosphorylation of serine 77 downregulates the pro-apoptotic activity of bmf." SIGNOR-195471 MAPK1 protein P28482 UNIPROT BMF protein Q96LC9 UNIPROT up-regulates phosphorylation Ser77 TQTLSPAsPSQGVML 9606 BTO:0000785 22258404 t llicata "Phosphomimetic mutation of this site (s74d) moderately enhanced bmf apoptotic activity in vivo.22 here, we demonstrate a previously unrecognized mode of regulation of bmf. We show that b-raf-mek-erk2 signaling regulates bmf phosphorylation at serine 74 and serine 77. Phosphorylation of serine 77 downregulates the pro-apoptotic activity of bmf." SIGNOR-195475 MAPK1 protein P28482 UNIPROT NOX5 protein Q96PH1 UNIPROT up-regulates phosphorylation Ser544 RSVTMRKsQRSSKGS 9606 21297032 t "The effect has been demonstrated using Q96PH1-4" gcesareni "These results suggest that the mek/erk1/2 pathway is necessary but not sufficient to regulate the pma-dependent activation of nox5." SIGNOR-171847 MAPK1 protein P28482 UNIPROT CIC protein Q96RK0 UNIPROT down-regulates phosphorylation Ser1409 SAPEDPTsPKRKMRR 9606 BTO:0000848 21087211 t gcesareni "Specifically, 14-3-3 binds to p90(rsk)-phosphorylated ser?_??_ Of capic?_A thereby modulating dna binding to its hmg (high-mobility group) box, whereas erk phosphorylations prevent binding of a c-terminal nls (nuclear localization sequence) to importin ?4 (kpna3))[...] These results suggest that erk phosphorylation of ser1382 and ser1409 masks the nls and prevents its binding to kpna3" SIGNOR-169875 MAPK1 protein P28482 UNIPROT PPP1R9B protein Q96SB3 UNIPROT unknown phosphorylation Ser15 GPGGPLRsASPHRSA 9606 BTO:0000007 15728359 t lperfetto "We have identified three sites phosphorylated by ERK2 (Ser-15 and Ser-205) and cyclin-dependent PK 5 (Cdk5) (Ser-17), within the actin-binding domain of spinophilin." SIGNOR-249435 MAPK1 protein P28482 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates 9606 BTO:0000130 16709866 f gcesareni "The role of members of the arrestin family to mediate kinase activation is also a well-established phenomenon, including activation of members of the src family, erk1/2, and jnk3. Activation often includes the recruitment and interaction of arrestins with upstream mapks (ask1, mek3, mkk3, and mek kinase-2)." SIGNOR-146751 MAPK1 protein P28482 UNIPROT GORASP1 protein Q9BQQ3 UNIPROT "down-regulates activity" phosphorylation Ser274 DPLPGPGsPSHSAPD 10116 BTO:0000951 15834132 t miannu "Here we show that GRASP65 is phosphorylated on serine 277 in interphase cells, and this is strongly enhanced in response to the addition of serum or epidermal growth factor. This is directly mediated by ERK suggesting that GRASP65 has some role in growth factor signal transduction. These results argue against Ser-277 phosphorylation alone causing the dissolution of GRASP65 oligomers and cisternal unstacking, although it may make a significant contribution to these events." SIGNOR-262841 MAPK1 protein P28482 UNIPROT MKNK1 protein Q9BUB5 UNIPROT up-regulates phosphorylation 9606 9155017 t gcesareni "We have identified a new subfamily of murine serine/threonine kinases, whose members, map kinase-interacting kinase 1 (mnk1) and mnk2, bind tightly to the growth factor-regulated map kinases, erk1 and erk2erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity toward a substrate, eukaryotic initiation factor-4e (eif-4e)." SIGNOR-48298 MAPK1 protein P28482 UNIPROT IRX2 protein Q9BZI1 UNIPROT "up-regulates activity" phosphorylation Ser46 SASGSAFsPYPGSAA -1 15133517 t miannu "We tested the transcriptional properties of Irx2 by dividing it into amino- and carboxy terminal parts and found that Mek1-mediated phosphorylation activates and derepresses the amino and carboxyl parts, respectively. When Ser46 and Ser65 were mutated to alanine (S46A and S65A), phosphorylation was reduced, whereas substitution of Ser83 and Ser103 (S83A and S103A) did not affect phosphorylation." SIGNOR-263052 MAPK1 protein P28482 UNIPROT IRX2 protein Q9BZI1 UNIPROT "up-regulates activity" phosphorylation Ser64 QAATGFGsPLQYSAD -1 15133517 t miannu "We tested the transcriptional properties of Irx2 by dividing it into amino- and carboxy terminal parts and found that Mek1-mediated phosphorylation activates and derepresses the amino and carboxyl parts, respectively. When Ser46 and Ser65 were mutated to alanine (S46A and S65A), phosphorylation was reduced, whereas substitution of Ser83 and Ser103 (S83A and S103A) did not affect phosphorylation." SIGNOR-263053 MAPK1 protein P28482 UNIPROT TNKS1BP1 protein Q9C0C2 UNIPROT unknown phosphorylation Thr1032 GGLFSPStAHVPDGA 10090 BTO:0000944 22028470 t miannu "We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)" SIGNOR-262781 MAPK1 protein P28482 UNIPROT TNKS1BP1 protein Q9C0C2 UNIPROT unknown phosphorylation Thr131 KEEPPPLtPPARCAA 10090 BTO:0000944 22028470 t miannu "We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)" SIGNOR-262782 MAPK1 protein P28482 UNIPROT GORASP2 protein Q9H8Y8 UNIPROT unknown phosphorylation Thr225 QMAGTPItPLKDGFT 9606 BTO:0000567 11408587 t lperfetto "Furthermore, ERK2 directly phosphorylated GRASP55 on the same residues that generated the MPM2 phospho-epitope.|The obvious next challenge is to demonstrate the precise role of these phosphorylation events." SIGNOR-249404 MAPK1 protein P28482 UNIPROT XPO5 protein Q9HAV4 UNIPROT "down-regulates activity" phosphorylation Ser416 GFPSKTDsPSCEYSR 9606 BTO:0000007 27846390 t lperfetto "Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading. " SIGNOR-262978 MAPK1 protein P28482 UNIPROT XPO5 protein Q9HAV4 UNIPROT "down-regulates activity" phosphorylation Ser497 GSLCSVFsPSFVQWE 9606 BTO:0000007 27846390 t lperfetto "Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading. " SIGNOR-262981 MAPK1 protein P28482 UNIPROT XPO5 protein Q9HAV4 UNIPROT "down-regulates activity" phosphorylation Thr345 GADSDVEtPSNFGKY 9606 BTO:0000007 27846390 t lperfetto "Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading. " SIGNOR-262984 MAPK1 protein P28482 UNIPROT MKNK2 protein Q9HBH9 UNIPROT up-regulates phosphorylation 9606 9155017 t gcesareni "We have identified a new subfamily of murine serine/threonine kinases, whose members, map kinase-interacting kinase 1 (mnk1) and mnk2, bind tightly to the growth factor-regulated map kinases, erk1 and erk2erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity" SIGNOR-48338 MAPK1 protein P28482 UNIPROT PLCB1 protein Q9NQ66 UNIPROT "up-regulates activity" phosphorylation Ser982 KKKSEPSsPDHGSST -1 11287604 t lperfetto "coimmunoprecipitation detected a specific association between the activated erk and plc beta1 within the nucleus. In vitro studies revealed that recombinant plc beta1 could be efficiently phosphorylated by activated mitogen-activated protein kinase but not by pka. The erk phosphorylation site was mapped to serine 982 this result suggests that erk-evoked phosphorylation of plc beta1 at serine 982 plays a critical role in the activation of the nuclear pi cycle and is also crucial to the mitogenic action of igf-i." SIGNOR-106561 MAPK1 protein P28482 UNIPROT PARVA protein Q9NVD7 UNIPROT "up-regulates activity" phosphorylation Ser8 MATSPQKsPSVPKSP 9606 BTO:0001938 22955285 t lperfetto "Actopaxin (alpha-parvin) is a paxillin, integrin-linked kinase, and F-actin binding focal adhesion protein with several serine phosphorylation sites in the amino terminus that contribute to the regulation of cell spreading and migration.|Actopaxin phosphorylation of Ser4/8 enhances cell migration whereas a nonphosphorylatable (Quint) mutant suppresses migration in U2OS osteosarcoma cells (7)." SIGNOR-265759 MAPK1 protein P28482 UNIPROT NDE1 protein Q9NXR1 UNIPROT "up-regulates activity" phosphorylation Ser239 FRRGLDDsTGGTPLT 9606 BTO:0000007 12556484 t lperfetto "Moreover, both proteins were phosphorylated by Cdc2 and Erk2 in vitro. In the case of Nudel, the phosphorylation sites were also located in the S/TP motifs. Detailed mutagenesis study indicated that T219, S242, and T245 were phosphorylated by Cdc2, while T219 and T245 were phosphorylated by Erk2.|Phosphorylation of Nudel in M phase appears to positively modulate dynein motor activity. Both phosphorylated and unphosphorylated forms of Nudel were transported by dynein (Fig. 7 and 9 and data not shown), indicating that neither of them inactivated the dynein motor. On the other hand, both phospho-Nudel and Nudelpmt5 bound Lis1 more strongly than Nudel or Nudelmt5 did" SIGNOR-249421 MAPK1 protein P28482 UNIPROT NDE1 protein Q9NXR1 UNIPROT "up-regulates activity" phosphorylation Thr215 ATGSVPStPIAHRGP 9606 BTO:0000007 12556484 t lperfetto "Moreover, both proteins were phosphorylated by Cdc2 and Erk2 in vitro. In the case of Nudel, the phosphorylation sites were also located in the S/TP motifs. Detailed mutagenesis study indicated that T219, S242, and T245 were phosphorylated by Cdc2, while T219 and T245 were phosphorylated by Erk2.|Phosphorylation of Nudel in M phase appears to positively modulate dynein motor activity. Both phosphorylated and unphosphorylated forms of Nudel were transported by dynein (Fig. 7 and 9 and data not shown), indicating that neither of them inactivated the dynein motor. On the other hand, both phospho-Nudel and Nudelpmt5 bound Lis1 more strongly than Nudel or Nudelmt5 did" SIGNOR-249422 MAPK1 protein P28482 UNIPROT SPHK1 protein Q9NYA1 UNIPROT up-regulates phosphorylation Ser225 VGSKTPAsPVVVQQG 9606 14532121 t gcesareni "Activation of sphingosine kinase 1 by erk1/2-mediated phosphorylation." SIGNOR-118546 MAPK1 protein P28482 UNIPROT STMN3 protein Q9NZ72 UNIPROT unknown phosphorylation Ser68 PSDLSPEsPMLSSPP -1 22577147 t lperfetto "Altogether, these results indicate that CDK5 phosphorylates similarly serines 68 and 73, whereas ERK2 targets mostly serine 68 and GSK-3beta mostly serine 60.|This observation may support the hypothesis of a specific localization of stathmin 3 depending on its phosphorylation by GSK-3beta" SIGNOR-264895 MAPK1 protein P28482 UNIPROT KCND2 protein Q9NZV8 UNIPROT "up-regulates activity" phosphorylation Ser616 EGDDRPEsPEYSGGN 10116 BTO:0000601 11080179 t miannu "We determined that the Kv4.2 C-terminal cytoplasmic domain is an effective ERK2 substrate, and that it is phosphorylated at three sites: Thr(602), Thr(607), and Ser(616). Phosphorylation of the Kv4.2 channel by ERK during LTP induction may lead to increased excitability and membrane depolarization of neurons, which would increase the magnitude of the calcium influx and the probability of triggering LTP." SIGNOR-262934 MAPK1 protein P28482 UNIPROT KCND2 protein Q9NZV8 UNIPROT "up-regulates activity" phosphorylation Thr602 TAIISIPtPPVTTPE 10116 BTO:0000601 11080179 t miannu "We determined that the Kv4.2 C-terminal cytoplasmic domain is an effective ERK2 substrate, and that it is phosphorylated at three sites: Thr(602), Thr(607), and Ser(616). Phosphorylation of the Kv4.2 channel by ERK during LTP induction may lead to increased excitability and membrane depolarization of neurons, which would increase the magnitude of the calcium influx and the probability of triggering LTP." SIGNOR-262935 MAPK1 protein P28482 UNIPROT KCND2 protein Q9NZV8 UNIPROT "up-regulates activity" phosphorylation Thr607 IPTPPVTtPEGDDRP 10116 BTO:0000601 11080179 t miannu "We determined that the Kv4.2 C-terminal cytoplasmic domain is an effective ERK2 substrate, and that it is phosphorylated at three sites: Thr(602), Thr(607), and Ser(616). Phosphorylation of the Kv4.2 channel by ERK during LTP induction may lead to increased excitability and membrane depolarization of neurons, which would increase the magnitude of the calcium influx and the probability of triggering LTP." SIGNOR-262936 MAPK1 protein P28482 UNIPROT RAI14 protein Q9P0K7 UNIPROT unknown phosphorylation Thr249 SQDADLKtPTKPKQH 10090 BTO:0000944 22028470 t miannu "We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)" SIGNOR-262760 MAPK1 protein P28482 UNIPROT LIMA1 protein Q9UHB6 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser362 PVHPKPLsPDSRASS 9606 BTO:0001033 23188829 t miannu "Mechanistic study revealed that EGF could activate the phosphorylation, ubiquitination, and degradation of EPLIN through an extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent signaling cascade. Pharmacological inhibition of the ERK1/2 pathway effectively antagonized EGF-induced EPLIN degradation. Two serine residues, i.e. serine 362 and serine 604, were identified as putative ERK1/2 phosphorylation sites in human EPLIN, whose point mutation rendered resistance to EGF-induced protein turnover." SIGNOR-263054 MAPK1 protein P28482 UNIPROT NUP50 protein Q9UKX7 UNIPROT "down-regulates activity" phosphorylation Ser221 KVAAETQsPSLFGST 9606 19767751 t gcesareni "Erk phosphorylates nup50 at ser221 and ser315 erk phosphorylation of the fg repeat region of nup50 reduced its affinity for importin-beta family proteins, importin-beta and transportin." SIGNOR-188139 MAPK1 protein P28482 UNIPROT NUP50 protein Q9UKX7 UNIPROT "down-regulates activity" phosphorylation Ser315 TQSKPVSsPFPTKPL 9606 19767751 t llicata "Erk phosphorylates nup50 at ser221 and ser315 erk phosphorylation of the fg repeat region of nup50 reduced its affinity for importin-beta family proteins, importin-beta and transportin." SIGNOR-188135 MAPK1 protein P28482 UNIPROT ARHGAP26 protein Q9UNA1 UNIPROT unknown phosphorylation Ser685 PMFSAPSsPMPTSST -1 9525907 t miannu "In vitro, purified mitogen-activated protein (MAP) kinase catalyzed the phosphorylation of Graf on serine 510, suggesting that Graf phosphorylation may be mediated through MAP kinase signaling." SIGNOR-262944 MAPK1 protein P28482 UNIPROT EXOC7 protein Q9UPT5 UNIPROT up-regulates phosphorylation Ser250 SSSGVPYsPAIPNKR 9606 22595671 t lperfetto "Erk1/2 phosphorylation enhances the binding of exo70 to other exocyst components and promotes the assembly of the exocyst complex in response to epidermal growth factor (egf) signaling." SIGNOR-197543 MAPK1 protein P28482 UNIPROT GAB2 protein Q9UQC2 UNIPROT up-regulates phosphorylation Ser623 ALDFQPSsPSPHRKP 9606 15356145 t lperfetto "Phosphorylation of grb2-associated binder 2 on serine 623 by erk mapk regulates its association with the phosphatase shp-2 and decreases stat5 activation.We and others have demonstrated that il-2-induced tyrosine phosphorylation of gab2 and its interaction with its sh2 domain-containing partners, shp-2, p85 pi3k, and crkl (5, 26, 27). we report that pretreatment of kit 225 cells with the mek inhibitor u0126, strongly decreased the characteristic shift of gab2 in response to il-2 and increased gab2/shp-2 association, an effect that could be ascribed to erk phosphorylation of serine 623." SIGNOR-128727 MAPK1 protein P28482 UNIPROT DYNC1LI1 protein Q9Y6G9 UNIPROT unknown phosphorylation Ser516 VSPTTPTsPTEGEAS 10090 BTO:0000944 22028470 t miannu "We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)" SIGNOR-262773 MAPK1 protein P28482 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "down-regulates activity" phosphorylation 10090 BTO:0002572 28646232 t Gianni "We demonstrate that insulin-mediated activation of ERK1/2 results in phosphorylation of GSK3β at S9 independently of Akt/mTORC1 activity in Tsc2 null mouse embryonic fibroblasts. In addition, we show that inhibition of ERK1/2 rescues GSK3β activity and restores protein synthesis in Tsc2 −/− MEFs to normal levels" SIGNOR-262521 MAPK1 protein P28482 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR up-regulates phosphorylation 9606 12359725 t lperfetto "In addition to its role in stimulating cyclin d1 expression and nuclear translocation of cdk2, erk regulates thr-160 phosphorylation of cdk2-cyclin e." SIGNOR-217499 MAPK1 protein P28482 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR unknown phosphorylation 9606 21071439 t lperfetto "We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1." SIGNOR-217574 MAPK1 protein P28482 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "down-regulates activity" phosphorylation 9534 BTO:0004055 14993270 t lperfetto "We propose that activation of erk during adhesion creates a feedback system in which erk phosphorylates mek1 on t292, and this in turn blocks additional s298 phosphorylation in response to integrin signaling." SIGNOR-244916 MAPK1 protein P28482 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000007 12832467 t lperfetto "Efficient rsk activation by erk requires its interaction through a docking site located near the c terminus of rsk" SIGNOR-252749 MAPK1 protein P28482 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR "up-regulates activity" phosphorylation Ser363 TSRTPKDsPGIPPSA 9534 BTO:0004055 9430688 t lperfetto "Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733." SIGNOR-252754 MAPK1 protein P28482 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR "up-regulates activity" phosphorylation Ser380 HQLFRGFsFVATGLM 9534 BTO:0004055 9430688 t lperfetto "Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733." SIGNOR-252748 MAPK1 protein P28482 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR "up-regulates activity" phosphorylation Ser732 RRVRKLPsTTL 9534 BTO:0004055 9430688 t lperfetto "Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733." SIGNOR-252747 MAPK1 protein P28482 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR "up-regulates activity" phosphorylation Thr359 DTEFTSRtPKDSPGI 9534 BTO:0004055 9430688 t lperfetto "Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733." SIGNOR-252751 MAPK1 protein P28482 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates quantity by destabilization" phosphorylation Ser344 QDDDAPLsPMLYSSS 9606 BTO:0000007 18204439 t lperfetto "Here, we show that erk downregulates forkhead box o 3a (foxo3a) by directly interacting with and phosphorylating foxo3a at ser 294, ser 344 and ser 425, which consequently promotes cell proliferation and tumorigenesisMDM2 is required for ERk-mediated FOXO3a degradation." SIGNOR-252958 MAPK1 protein P28482 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates quantity by destabilization" phosphorylation Ser425 TKGSGLGsPTSSFNS 9606 BTO:0000007 18204439 t lperfetto "Here, we show that erk downregulates forkhead box o 3a (foxo3a) by directly interacting with and phosphorylating foxo3a at ser 294, ser 344 and ser 425, which consequently promotes cell proliferation and tumorigenesisMDM2 is required for ERk-mediated FOXO3a degradation." SIGNOR-252959 DUSP1 protein P28562 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates dephosphorylation 9606 10617468 t gcesareni "The mitogen-activated protein (map) kinase cascade is inactivated at the level of map kinase by members of the map kinase phosphatase (mkp) family, including mkp-1." SIGNOR-73617 DUSP1 protein P28562 UNIPROT MAPK3 protein P27361 UNIPROT "down-regulates activity" dephosphorylation Thr202 HDHTGFLtEYVATRW 10116 7535768 t "We demonstrate that ERK, JNK, and p38 are activated by distinct combinations of stimuli in T cells that simulate full or partial activation through the T cell receptor. These kinases are regulated by reversible phosphorylation on Tyr and Thr, and the dual specific phosphatases PAC1 and MKP-1 previously have been implicated in the in vivo inactivation of ERK or of ERK and JNK, respectively" SIGNOR-248462 DUSP1 protein P28562 UNIPROT MAPK3 protein P27361 UNIPROT "down-regulates activity" dephosphorylation Tyr204 HTGFLTEyVATRWYR 10116 7535768 t "We demonstrate that ERK, JNK, and p38 are activated by distinct combinations of stimuli in T cells that simulate full or partial activation through the T cell receptor. These kinases are regulated by reversible phosphorylation on Tyr and Thr, and the dual specific phosphatases PAC1 and MKP-1 previously have been implicated in the in vivo inactivation of ERK or of ERK and JNK, respectively" SIGNOR-248463 DUSP1 protein P28562 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 10617468 t lperfetto "The mitogen-activated protein (map) kinase cascade is inactivated at the level of map kinase by members of the map kinase phosphatase (mkp) family, including mkp-1" SIGNOR-73614 DUSP1 protein P28562 UNIPROT MAPK1 protein P28482 UNIPROT "down-regulates activity" dephosphorylation Thr185 HDHTGFLtEYVATRW 10116 7535768 t "We demonstrate that ERK, JNK, and p38 are activated by distinct combinations of stimuli in T cells that simulate full or partial activation through the T cell receptor. These kinases are regulated by reversible phosphorylation on Tyr and Thr, and the dual specific phosphatases PAC1 and MKP-1 previously have been implicated in the in vivo inactivation of ERK or of ERK and JNK, respectively" SIGNOR-248464 DUSP1 protein P28562 UNIPROT MAPK1 protein P28482 UNIPROT "down-regulates activity" dephosphorylation Tyr187 HTGFLTEyVATRWYR 10116 7535768 t "We demonstrate that ERK, JNK, and p38 are activated by distinct combinations of stimuli in T cells that simulate full or partial activation through the T cell receptor. These kinases are regulated by reversible phosphorylation on Tyr and Thr, and the dual specific phosphatases PAC1 and MKP-1 previously have been implicated in the in vivo inactivation of ERK or of ERK and JNK, respectively" SIGNOR-248465 DUSP1 protein P28562 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates dephosphorylation 9606 9020184 t gcesareni "Jnk1 phosphorylation and activation was inhibited by expression of both mkp1 and mkp2." SIGNOR-46079 DUSP1 protein P28562 UNIPROT MAPK9 protein P45984 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 8626452 t fstefani "We assayed the relative ability of mkp-2, pac1, and mkp-1 to dephosphorylate erk2 and the other related map kinases, jnk2 and p38. the dual specific phosphatases pac1 and mkp-1 previously have been implicated in the in vivo inactivation of erk or of erk and jnk, respectively." SIGNOR-40879 DUSP1 protein P28562 UNIPROT MAPK14 protein Q16539 UNIPROT "down-regulates activity" dephosphorylation 9606 BTO:0000567 12356755 t 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 DUSP1 protein P28562 UNIPROT MAPK14 protein Q16539 UNIPROT "down-regulates activity" dephosphorylation 10090 17158101 t 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 DUSP1 protein P28562 UNIPROT MAPK14 protein Q16539 UNIPROT "down-regulates activity" dephosphorylation 9606 20626350 t 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 HTR1E protein P28566 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256848 HTR1E protein P28566 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256984 HTR1E protein P28566 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257100 HTR1E protein P28566 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256705 MZF1 protein P28698 UNIPROT PRKCA protein P17252 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16297876 f irozzo "We demonstrated that both Elk-1 and MZF-1 were highly expressed in human poor differentiated HCC cells and involved in the up-regulation of PKCa, which was essential for cell migration and invasion. Over-expression assay confirmed that the PKCa expression may be modulated by these two factors at the transcriptional level." SIGNOR-256283 MZF1 protein P28698 UNIPROT PRKCA protein P17252 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 26010542 t irozzo "The luciferase reporter assay results revealed that the presence of both MZF-1 and Elk-1 significantly contributed to the upregulation of PKCα gene transcription activity." SIGNOR-256337 MZF1 protein P28698 UNIPROT CCN2 protein P29279 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25899830 f miannu "we report the regulation of the CTGF and NOV genes by Myeloid Zinc Finger-1 (MZF-1), a hematopoietic transcription factor. We show the interaction of MZF-1 with the CTGF and NOV promoters in several cell types. Up-regulation of MZF-1 via calcitriol and vitamin A induces expression of CTGF and NOV, implicating a role for these vitamins in the functions of these two genes. Lastly, knockdown of MZF1 reduces levels of CTGF and NOV." SIGNOR-226307 MZF1 protein P28698 UNIPROT CCN3 protein P48745 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25899830 f miannu "we report the regulation of the CTGF and NOV genes by Myeloid Zinc Finger-1 (MZF-1), a hematopoietic transcription factor. We show the interaction of MZF-1 with the CTGF and NOV promoters in several cell types. Up-regulation of MZF-1 via calcitriol and vitamin A induces expression of CTGF and NOV, implicating a role for these vitamins in the functions of these two genes. Lastly, knockdown of MZF1 reduces levels of CTGF and NOV." SIGNOR-226356 RXRB protein P28702 UNIPROT RARA protein P10276 UNIPROT up-regulates binding 9606 1310351 t gcesareni "Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins" SIGNOR-16674 RXRB protein P28702 UNIPROT RARB protein P10826 UNIPROT up-regulates binding 9606 1310351 t gcesareni "Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins." SIGNOR-16677 RXRB protein P28702 UNIPROT RARB protein P10826 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 1310351 f gcesareni "Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins" SIGNOR-16680 RXRB protein P28702 UNIPROT THRA protein P10827 UNIPROT up-regulates binding 9606 10976919 t gcesareni "Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr" SIGNOR-81452 RXRB protein P28702 UNIPROT THRB protein P10828 UNIPROT up-regulates binding 9606 10976919 t gcesareni "Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr" SIGNOR-81455 RXRB protein P28702 UNIPROT RARG protein P13631 UNIPROT up-regulates binding 9606 1310351 t gcesareni "Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins." SIGNOR-16683 RXRB protein P28702 UNIPROT PPARG protein P37231 UNIPROT up-regulates binding 9606 11237216 t 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 RXRB protein P28702 UNIPROT NR4A2 protein P43354 UNIPROT up-regulates binding 9606 BTO:0000938 9636132 t lperfetto "The recent discovery that the nuclear transcription factor, nurr1, in heterodimeric tandem with rxr, is unequivocally necessary for the expression of dopaminergic neurons" SIGNOR-58309 RXRB protein P28702 UNIPROT NRIP1 protein P48552 UNIPROT up-regulates binding 9606 12403842 t gcesareni "Receptor interacting protein 140 (rip140) is a coregulator for a large number of transcription factors. Rip140 interacts with retinoic acid receptor (rar) and retinoid x receptor (rxr) with or without ligands" SIGNOR-95160 RXRB protein P28702 UNIPROT PPARD protein Q03181 UNIPROT up-regulates binding 9606 11237216 t 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-105451 RXRB protein P28702 UNIPROT PPARA protein Q07869 UNIPROT up-regulates binding 9606 11237216 t 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-105448 ERCC5 protein P28715 UNIPROT ERCC2 protein P18074 UNIPROT "up-regulates quantity by stabilization" binding 9606 20840796 t "Regulation of binding" "The NER protein XPG was also found to associate with the TFIIH complex by interacting directly with XPD stabilizing the interaction between TFIIH and the CAK-XPD complex" SIGNOR-251974 GRN protein P28799 UNIPROT TNFRSF1A protein P19438 UNIPROT down-regulates binding 9606 21393509 t gcesareni "Collectively, these findings demonstrate that pgrn is a ligand of tnfr, an antagonist of tnf signaling, and plays a critical role in the pathogenesis of inflammatory arthritis in mice." SIGNOR-172684 CD38 protein P28907 UNIPROT NMN(+) smallmolecule CHEBI:14648 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 18626062 t miannu "CD38 is also able to catalyze the degradation of the NAD precursor nicotinamide mono-nucleotide (NMN) into nicotinamide" SIGNOR-264252 CD38 protein P28907 UNIPROT NAD(+) smallmolecule CHEBI:15846 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 18626062 t miannu "The membrane proteins CD38 and CD157 belong to an evolutionarily conserved family of enzymes that play crucial roles in human physiology. Expressed in distinct patterns in most tissues, CD38 (and CD157) cleaves NAD(+) and NADP(+), generating cyclic ADP ribose (cADPR), NAADP, and ADPR." SIGNOR-264246 CD38 protein P28907 UNIPROT nicotinamide smallmolecule CHEBI:17154 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 18626062 t miannu "CD38 is also able to catalyze the degradation of the NAD precursor nicotinamide mono-nucleotide (NMN) into nicotinamide" SIGNOR-264253 CD38 protein P28907 UNIPROT NADP(+) smallmolecule CHEBI:18009 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 18626062 t miannu "The membrane proteins CD38 and CD157 belong to an evolutionarily conserved family of enzymes that play crucial roles in human physiology. Expressed in distinct patterns in most tissues, CD38 (and CD157) cleaves NAD(+) and NADP(+), generating cyclic ADP ribose (cADPR), NAADP, and ADPR." SIGNOR-264247 CD38 protein P28907 UNIPROT "cyclic ADP-ribose" smallmolecule CHEBI:31445 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 18626062 t miannu "The membrane proteins CD38 and CD157 belong to an evolutionarily conserved family of enzymes that play crucial roles in human physiology. Expressed in distinct patterns in most tissues, CD38 (and CD157) cleaves NAD(+) and NADP(+), generating cyclic ADP ribose (cADPR), NAADP, and ADPR." SIGNOR-264244 CD38 protein P28907 UNIPROT "nicotinic acid-adenine dinucleotide phosphate" smallmolecule CHEBI:76072 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 18626062 t miannu "The membrane proteins CD38 and CD157 belong to an evolutionarily conserved family of enzymes that play crucial roles in human physiology. Expressed in distinct patterns in most tissues, CD38 (and CD157) cleaves NAD(+) and NADP(+), generating cyclic ADP ribose (cADPR), NAADP, and ADPR." SIGNOR-264245 PCSK1 protein P29120 UNIPROT IAPP protein P10997 UNIPROT "up-regulates activity" cleavage Lys72 VGSNTYGkRNAVEVL -1 10931181 t lperfetto "The processing of proinsulin to insulin occurs in the secretory granules at the C-terminal end of pairs of basic amino acids, Arg31-Arg32 and Lys64-Arg65 [9,10]. Following cleavage, by the prohormone convertases, PC3 (also known as PC1) and PC2, the pair of basic amino acids are removed rapidly by carboxypeptidase E (CPE) to produce the mature insulin molecule" SIGNOR-261782 PCSK6 protein P29122 UNIPROT INSR protein P06213 UNIPROT "up-regulates activity" cleavage 9606 BTO:0000666 25527501 t Giorgia "Here we demonstrate that the two IR isoforms are similarly cleaved by furin, but when this furin-dependent maturation is inefficient, IR proforms move to the cell surface where the proprotein convertase PACE4 selectively supports IRB maturation." SIGNOR-260366 ADORA2A protein P29274 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257413 ADORA2A protein P29274 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257151 ADORA2A protein P29274 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257239 ADORA2A protein P29274 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257306 ADORA2A protein P29274 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256909 ADORA2A protein P29274 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256766 ADORA2B protein P29275 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257414 ADORA2B protein P29275 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257152 ADORA2B protein P29275 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257240 ADORA2B protein P29275 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257307 ADORA2B protein P29275 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257039 ADORA2B protein P29275 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256767 EPHA2 protein P29317 UNIPROT CLDN4 protein O14493 UNIPROT "down-regulates activity" phosphorylation Tyr208 RSAAASNyV 9534 BTO:0001538 16236711 t miannu "EphA2 associates with claudin-4 via their extracellular domains. This association, in turn, leads to phosphorylation of the cytoplasmic carboxyl terminus of claudin-4 at Tyr-208. The tyrosine phosphorylation of claudin-4 attenuates association of claudin-4 with ZO-1, decreasing integration of claudin-4 into sites of cell-cell contact and enhancing paracellular permeability. These results indicate that EphA2 moderates the function of tight junctions via phosphorylation of claudin-4." SIGNOR-262859 EPHA2 protein P29317 UNIPROT EPHA2 protein P29317 UNIPROT up-regulates phosphorylation Tyr588 QLKPLKTyVDPHTYE 9606 18387945 t lperfetto "The binding of ephrin ligands to eph receptors induces the transphosphorylation of the cytoplasmic domains and initiates kinase activity.Taken together, these results suggest that tyr587, tyr593, tyr771, and tyr734 are likely to be autophospho-rylated in vascular endothelial cells." SIGNOR-178169 EPHA2 protein P29317 UNIPROT EPHA2 protein P29317 UNIPROT up-regulates phosphorylation Tyr735 KYLANMNyVHRDLAA 9606 18387945 t lperfetto "The binding of ephrin ligands to eph receptors induces the transphosphorylation of the cytoplasmic domains and initiates kinase activity.Taken together, these results suggest that tyr587, tyr593, tyr771, and tyr734 are likely to be autophospho-rylated in vascular endothelial cells." SIGNOR-178177 EPHA3 protein P29320 UNIPROT SRC protein P12931 UNIPROT up-regulates binding 9606 BTO:0000938 9632142 t gcesareni "We propose src kinase as a downstream effector that mediates the neuron's response to eph receptor activation." SIGNOR-58139 EPHA3 protein P29320 UNIPROT CRK protein P46108 UNIPROT up-regulates binding 9606 BTO:0000007 11870224 t lperfetto "Our results suggest that recruitment of crkii and activation of rho signalling are responsible for epha3-mediated cell rounding, blebbing and de-adhesion, and that ephrin-a5-mediated receptor clustering and epha3 tyrosine kinase activity are essential for this response" SIGNOR-115335 EPHA8 protein P29322 UNIPROT EPHA8 protein P29322 UNIPROT "up-regulates activity" phosphorylation Tyr616 FYAEPHTyEEPGRAG 9606 BTO:0000007 10498895 t "Tyr-615 and Tyr-838 are major autophosphorylation sites of the EphA8 receptor. phosphorylation of Tyr-615 is critical for determining the association with Fyn whereas the integrity of Tyr-838 phosphorylation is required for efficient phosphorylation at Tyr-615 as well as other major sites." SIGNOR-251120 EPHA8 protein P29322 UNIPROT EPHA8 protein P29322 UNIPROT "up-regulates activity" phosphorylation Tyr839 LAYGERPyWNMTNRD 9606 BTO:0000007 10498895 t "Tyr-615 and Tyr-838 are major autophosphorylation sites of the EphA8 receptor. phosphorylation of Tyr-615 is critical for determining the association with Fyn whereas the integrity of Tyr-838 phosphorylation is required for efficient phosphorylation at Tyr-615 as well as other major sites." SIGNOR-251121 EPHB2 protein P29323 UNIPROT ARHGEF15 protein O94989 UNIPROT "down-regulates quantity by destabilization" phosphorylation Tyr353 PLQDEPLyQTYRAAV 9606 BTO:0000007 21029865 t miannu "We have identified a RhoA guanine nucleotide exchange factor, Ephexin5, which negatively regulates excitatory synapse development until EphrinB binding to the EphB receptor tyrosine kinase triggers Ephexin5 phosphorylation, ubiquitination, and degradation. EphB2 mediates phosphorylation of Ephexin5 at tyrosine-361" SIGNOR-262864 EPHB2 protein P29323 UNIPROT RRAS protein P10301 UNIPROT "down-regulates activity" phosphorylation Tyr66 DPTIEDSyTKICSVD 9606 10570155 t "Tyrosine 66 of R-Ras is phosphorylated by EphB2|. R-Ras, a small intracellular GTPase, regulates the binding of integrins to their ligands outside the cell. |Cells in which EphB2 is activated become poorly adherent to substrates coated with integrin ligands, and a tyrosine residue in the R-Ras effector domain is phosphorylated." SIGNOR-251125 EPHB2 protein P29323 UNIPROT NRCAM protein Q92823 UNIPROT "up-regulates activity" phosphorylation Tyr1276 DGSFIGQySGKKEKE 9606 BTO:0000007 24023801 t miannu "EphB receptors were found to induce phosphorylation of NrCAM on the tyrosine residue within the FIGQY ankyrin binding motif, inhibiting ankyrin recruitment. Furthermore, NrCAM phospho-FIGQY levels in the SC were decreased in EphB1/3 and EphB1/2/3 null mice and increased in mutant mice overexpressing constitutively active EphB2 kinase. " SIGNOR-262863 PTPN6 protein P29350 UNIPROT SOCS1 protein O15524 UNIPROT up-regulates binding 9606 14551136 t gcesareni "All together, our results indicate that shp-1 inhibits prlr and epor signaling by recruitment and targeting of socs-1 to jak2, highlighting a new mechanism of shp-1 regulation of cytokine-receptor signaling." SIGNOR-118572 PTPN6 protein P29350 UNIPROT NFAT5 protein O94916 UNIPROT "down-regulates activity" dephosphorylation Tyr143 PKRHTVLyISPPPED 9606 BTO:0000007 20351292 t "We confirmed that SHP-1 is inhibitory by overexpressing it, which reduces TonEBP/OREBP transcriptional activity at 500 mosmol/kg. SHP-1 dephosphorylates TonEBP/OREBP at a known regulatory site, Y143, both in vivo and in vitro. It inhibits TonEBP/OREBP by both reducing TonEBP/OREBP nuclear localization, which is Y143 dependent, and by lowering high NaCl-induced TonEBP/OREBP transactivating activity" SIGNOR-248467 PTPN6 protein P29350 UNIPROT EGFR protein P00533 UNIPROT down-regulates dephosphorylation Tyr1197 STAENAEyLRVAPQS 9606 9733788 t tpavlidou "The sh2-domain ptpase shp-1 binds to and dephosphorylates autophosphorylated egfr and may participate in modulation of egfr signaling in epithelial cells. Reduced shp-1 binding to the egfr y1173f mutant resulted in a reduced receptor dephosphorylation by coexpressed shp-1 and less interference with egf-dependent mitogen-activated protein kinase stimulation." SIGNOR-59965 PTPN6 protein P29350 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 10734133 t flangone "Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1." SIGNOR-75926 PTPN6 protein P29350 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 10734133 t flangone "Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1." SIGNOR-75930 PTPN6 protein P29350 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 10734133 t flangone "Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1." SIGNOR-75934 PTPN6 protein P29350 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 10734133 t flangone "Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1." SIGNOR-75938 PTPN6 protein P29350 UNIPROT SRC protein P12931 UNIPROT "down-regulates activity" dephosphorylation Tyr419 RLIEDNEyTARQGAK 9606 9261115 t "To determine whether the COOH-terminal or other phosphotyrosine residues within Src are subject to dephosphorylation by SHP-1, the effects of this phosphatase on Src tyrosine phosphorylation were initially examined using CNBr cleavage analysis. As illustrated in Fig.1 A, CNBr treatment of32P-labeled human Src has been shown previously to yield phosphorylated cleavage fragments of about 31, 9.7, and 4.7 kDa, which, respectively, contain the Src NH2-terminal region encompassing the major sites for serine phosphorylation on Src, Ser-12 and Ser-17 (31-kDa fragment), the inhibitory tyrosine phosphorylation site, Tyr-530 (4.7-kDa fragment), and a key site for autophosphorylation on activated Src, Tyr-419" SIGNOR-248473 PTPN6 protein P29350 UNIPROT IL2RB protein P14784 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 9520455 t gcesareni "We have found that il-2 induces association of shp-1 with the il-2 receptor complex, and that once shp-1 is recruited to the activated receptor it is able to decrease tyrosine phosphorylation of il-2rbeta and the associated tyrosine kinases jak1 and jak3." SIGNOR-55989 PTPN6 protein P29350 UNIPROT CD72 protein P21854 UNIPROT down-regulates dephosphorylation 9606 BTO:0000776 9740800 t gcesareni "Our work clearly identifies cd72 as both an shp-1 binding protein (figure 1,figure 2) and a direct substrate for shp-1 in vivo (figure 3). As tyrosine phosphorylation of cd72 strongly correlates with the ability of the bcr to deliver growth-inhibitory/apoptosis-inducing signals (figure 4), our results suggest that shp-1-catalyzed dephosphorylation of cd72 may antagonize these signals." SIGNOR-60155 PTPN6 protein P29350 UNIPROT JAK1 protein P23458 UNIPROT down-regulates dephosphorylation 9606 BTO:0000150;BTO:0001271;BTO:0000785;BTO:0000661;BTO:0003076 14624462 t gcesareni "We find, for the first time, that shp-1 down-regulates the level of tyk2 kinase in h9 cells and of jak1 kinase in htb26 cells, by accelerating their degradation." SIGNOR-119197 PTPN6 protein P29350 UNIPROT TYK2 protein P29597 UNIPROT down-regulates 9606 BTO:0000150;BTO:0001271;BTO:0000785;BTO:0000661;BTO:0003076 14624462 f lperfetto "We find, for the first time, that shp-1 down-regulates the level of tyk2 kinase in h9 cells and of jak1 kinase in htb26 cells, by accelerating their degradation" SIGNOR-119200 PTPN6 protein P29350 UNIPROT KDR protein P35968 UNIPROT unknown dephosphorylation Tyr996 EEAPEDLyKDFLTLE 9606 BTO:0000007 18840653 t "Src homology 2 (SH2) domain containing protein tyrosine phosphatase-1 (SHP-1) dephosphorylates VEGF Receptor-2 and attenuates endothelial DNA synthesis, but not migration|Knockdown of SHP-1 by siRNA or inhibition of c-Src by an inhibitor, results in augmented DNA synthesis perhaps due to increased phosphorylation of at least three tyrosine residues of KDR 996, 1059 and 1175" SIGNOR-248476 PTPN6 protein P29350 UNIPROT STAT3 protein P40763 UNIPROT down-regulates dephosphorylation 9606 18508557 t gcesareni "Stat3 may also be a substrate of shp1" SIGNOR-178699 PTPN6 protein P29350 UNIPROT STAT6 protein P42226 UNIPROT down-regulates 9606 BTO:0000801 9852037 f gcesareni "Expression of an shp-1 transgene in nih 3t3 cells markedly reduces both il-4-dependent stat6 activation and stat6-mediated transcription of il-4-responsive genes" SIGNOR-62578 PTPN6 protein P29350 UNIPROT ZAP70 protein P43403 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 10458769 t miannu "We propose that shp1 can dephosphorylate sites in zap-70 and syk that are involved in coupling these kinases to downstream signaling cascades, including erk2 and elements of the il-2 gene." SIGNOR-70237 PTPN6 protein P29350 UNIPROT SYK protein P43405 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 10458769 t miannu "We propose that shp1 can dephosphorylate sites in zap-70 and syk that are involved in coupling these kinases to downstream signaling cascades, including erk2 and elements of the il-2 gene." SIGNOR-70234 PTPN6 protein P29350 UNIPROT ACTG1 protein P63261 UNIPROT down-regulates dephosphorylation Tyr218 DIKEKLCyVALDFEQ 9606 BTO:0000776 12646642 t gcesareni "Our data suggest that shp-1 plays a pivotal role in reorganization of cytoskeletal architecture inducing actin dephosphorylation. These results clearly demonstrate the direct interaction of shp-1 with actin" SIGNOR-99565 PTPN6 protein P29350 UNIPROT KCNH2 protein Q12809 UNIPROT down-regulates dephosphorylation 9606 BTO:0000142 12361947 t gcesareni "Our results show that erg-1 is a shp-1 substrate constituting the first report that an ion current is regulated by shp-1." SIGNOR-94007 PTPN6 protein P29350 UNIPROT CASP8 protein Q14790 UNIPROT "up-regulates activity" dephosphorylation Tyr380 TDSEEQPyLEMDLSS 9606 18086677 t "Caspase-8 is tyrosine-phosphorylated in freshly isolated neutrophils but spontaneously dephosphorylates in culture, in association with the progression of constitutive apoptosis. Phosphorylation of caspase-8 on Tyr-310 facilitates its interaction with the Src-homology domain 2 containing tyrosine phosphatase-1 (SHP-1) and enables SHP-1 to dephosphorylate caspase-8, permitting apoptosis to proceed. The non-receptor tyrosine kinase, Lyn, can phosphorylate caspase-8 on Tyr-397 and Tyr-465, rendering it resistant to activational cleavage and inhibiting apoptosis. Exposure to lipopolysaccharide reduces SHP-1 activity and binding to caspase-8, caspase-8 activity, and rates of spontaneous apoptosis." SIGNOR-248477 PTPN6 protein P29350 UNIPROT CASP8 protein Q14790 UNIPROT "up-regulates activity" dephosphorylation Tyr448 TILTEVNyEVSNKDD 9606 18086677 t "Caspase-8 is tyrosine-phosphorylated in freshly isolated neutrophils but spontaneously dephosphorylates in culture, in association with the progression of constitutive apoptosis. Phosphorylation of caspase-8 on Tyr-310 facilitates its interaction with the Src-homology domain 2 containing tyrosine phosphatase-1 (SHP-1) and enables SHP-1 to dephosphorylate caspase-8, permitting apoptosis to proceed. The non-receptor tyrosine kinase, Lyn, can phosphorylate caspase-8 on Tyr-397 and Tyr-465, rendering it resistant to activational cleavage and inhibiting apoptosis. Exposure to lipopolysaccharide reduces SHP-1 activity and binding to caspase-8, caspase-8 activity, and rates of spontaneous apoptosis." SIGNOR-248478 SHC1 protein P29353 UNIPROT MAPK3 protein P27361 UNIPROT "up-regulates activity" 10090 BTO:0000944 17673906 f lperfetto "We report that upon TGF__ stimulation, the activated TGF__ type I receptor (T_RI) recruits and directly phosphorylates ShcA proteins on tyrosine and serine. This dual phosphorylation results from an intrinsic T_RI tyrosine kinase activity that complements its well_defined serine_threonine kinase function. TGF___induced ShcA phosphorylation induces ShcA association with Grb2 and Sos, thereby initiating the well_characterised pathway linking receptor tyrosine kinases with Erk MAP kinases." SIGNOR-242625 SHC1 protein P29353 UNIPROT MAPK1 protein P28482 UNIPROT "up-regulates activity" 10090 BTO:0000944 17673906 f lperfetto "We report that upon TGF__ stimulation, the activated TGF__ type I receptor (T_RI) recruits and directly phosphorylates ShcA proteins on tyrosine and serine. This dual phosphorylation results from an intrinsic T_RI tyrosine kinase activity that complements its well_defined serine_threonine kinase function. TGF___induced ShcA phosphorylation induces ShcA association with Grb2 and Sos, thereby initiating the well_characterised pathway linking receptor tyrosine kinases with Erk MAP kinases." SIGNOR-242622 SHC1 protein P29353 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 BTO:0000776 10207047 t lperfetto "The results indicate that ship, shc, and grb2 form a ternary complex in stimulated b cells, with grb2 stabilizing the interaction between shc and ship. The interactions between shc, grb2, and ship are therefore analogous to the interactions between shc, grb2, and sos. Shc and grb2 may help to localize ship to the cell membrane, regulating ship's inhibitory function following bcr stimulation." SIGNOR-235881 SHC1 protein P29353 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9823 BTO:0004007 10523831 t lperfetto "Phosphorylation of the adapter protein shc by growth factor receptors provides association sites for grb2-sos, thereby activating the ras/map kinase pathway." SIGNOR-235615 SHC1 protein P29353 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 10090 BTO:0005065 17673906 t lperfetto "TGF-beta-induced ShcA phosphorylation induces ShcA association with Grb2 and Sos, thereby initiating the well-characterised pathway linking receptor tyrosine kinases with Erk MAP kinases." SIGNOR-236366 SHC1 protein P29353 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271;BTO:0000785 24737791 t lperfetto "The signaling mechanism utilizes an adaptor protein, shc, which binds to a phosphotyrosine residue on the il-2/15r?, Resulting in activation of grb2 and onto akt via the shc-grb2-gab2-pi3k-akt signaling pathway to increase cell proliferation and/or survival" SIGNOR-236236 SHC1 protein P29353 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates binding 10090 BTO:0005065 17673906 t lperfetto "TGF-beta-induced ShcA phosphorylation induces ShcA association with Grb2 and Sos, thereby initiating the well-characterised pathway linking receptor tyrosine kinases with Erk MAP kinases." SIGNOR-236363 SHC1 protein P29353 UNIPROT GRAP protein Q13588 UNIPROT up-regulates binding 9606 BTO:0000782 8995379 t gcesareni "T cell activation effects an increase in grap association with p36/38, shc, sos, and dynamin." SIGNOR-45528 SHC1 protein P29353 UNIPROT INPP5D protein Q92835 UNIPROT up-regulates binding 9606 BTO:0000776 10207047 t gcesareni "The results indicate that ship, shc, and grb2 form a ternary complex in stimulated b cells, with grb2 stabilizing the interaction between shc and ship. The interactions between shc, grb2, and ship are therefore analogous to the interactions between shc, grb2, and sos. Shc and grb2 may help to localize ship to the cell membrane, regulating ship's inhibitory function following bcr stimulation." SIGNOR-66949 SHC1 protein P29353 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "up-regulates activity" 10090 BTO:0000944 17673906 f lperfetto "We report that upon TGF__ stimulation, the activated TGF__ type I receptor (T_RI) recruits and directly phosphorylates ShcA proteins on tyrosine and serine. This dual phosphorylation results from an intrinsic T_RI tyrosine kinase activity that complements its well_defined serine_threonine kinase function. TGF___induced ShcA phosphorylation induces ShcA association with Grb2 and Sos, thereby initiating the well_characterised pathway linking receptor tyrosine kinases with Erk MAP kinases." SIGNOR-242628 TACR3 protein P29371 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257333 TACR3 protein P29371 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257179 LTK protein P29376 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation 9606 BTO:0000938 9223670 t gcesareni "Recently, we demonstrated that ltk utilizes shc and irs-1 as two major substrates and while both equally activate the ras pathway, only irs-1 suppresses apoptosis of hematopoietic cells." SIGNOR-49625 LTK protein P29376 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation 9606 BTO:0000938 9223670 t gcesareni "Recently, we demonstrated that ltk utilizes shc and irs-1 as two major substrates and while both equally activate the ras pathway, only irs-1 suppresses apoptosis of hematopoietic cells." SIGNOR-49531 TACR3 protein P29371 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256937 TACR3 protein P29371 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257267 TACR3 protein P29371 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257066 TACR3 protein P29371 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257389 TACR3 protein P29371 UNIPROT GNA13 protein Q14344 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257438 TACR3 protein P29371 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256794 KDM5A protein P29375 UNIPROT PTEN protein P60484 UNIPROT "down-regulates quantity by destabilization" "transcriptional regulation" 9606 31374292 t miannu "The retinoblastoma binding protein 2 (RBP2) belongs to the KDM5 family, and is also known as JARID1A or KDM5A. We found that histone H3 lysine 4 (H3K4) demethylase RBP2 expression is negatively correlated with BCR-ABL expression, which suggests a regulatory link between these two genes. We also discovered that RBP2 mediates the dephosphorylation of BCR-ABL by directly downregulating PTEN expression, depending on histone demethylase activity, while PTEN targets protein phosphatase activity of BCR-ABL, a phosphatase which directly dephosphorylates BCR-ABL." SIGNOR-260079 KDM5A protein P29375 UNIPROT H3C1 protein P68431 UNIPROT "up-regulates activity" demethylation Lys5 kQTARKST 9606 30246379 t miannu "KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing." SIGNOR-264299 KDM5A protein P29375 UNIPROT H3-3A protein P84243 UNIPROT "up-regulates activity" demethylation Lys5 kQTARKST 9606 30246379 t miannu "KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing." SIGNOR-264301 KDM5A protein P29375 UNIPROT H3-4 protein Q16695 UNIPROT "up-regulates activity" demethylation Lys5 kQTARKST 9606 30246379 t miannu "KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing." SIGNOR-264300 KDM5A protein P29375 UNIPROT RBPJ/NOTCH complex SIGNOR-C97 SIGNOR down-regulates binding 7227 BTO:0000782 20231316 t lperfetto "In this study, we show that the histone demethylase kdm5a associated with rbp-j protein and is essential for notch/rbp-j target gene silencing in vitro." SIGNOR-219250 LTK protein P29376 UNIPROT CBL protein P22681 UNIPROT up-regulates phosphorylation 9606 BTO:0000938 9223670 t gcesareni "Although c-cbl is found to be phosphorylated by ltk and therefore is a second candidate linking ltk with the pi3-kinase pathway along with irs-1, we found that the p85 subunit of pi3 kinase directly binds to tyrosine 753 of ltk, which is located within a yxxm motif, a consensus binding amino acid sequence for the sh2 domain of p85." SIGNOR-49528 LTK protein P29376 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 BTO:0000938 9223670 t gcesareni "Although c-cbl is found to be phosphorylated by ltk and therefore is a second candidate linking ltk with the pi3-kinase pathway along with irs-1, we found that the p85 subunit of pi3 kinase directly binds to tyrosine 753 of ltk, which is located within a yxxm motif, a consensus binding amino acid sequence for the sh2 domain of p85" SIGNOR-49622 TKT protein P29401 UNIPROT "sedoheptulose 7-phosphate" smallmolecule CHEBI:15721 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 24929114 t miannu "Transketolase (TK, EC 2.2.1.1) is the key rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway of carbohydrate transformation. TKs (with the exception of the enzymes of mammalian origin) are characterized by broad substrate specificity. Xylulose 5-phosphate (X5P), fructose 6-phosphate (F6P), erythrulose 4-phosphate, and sedoheptulose 7-phosphate are typical donor substrates of TK; ribose 5-phosphate (R5P), glyceraldehyde 3-phosphate (G3P), and erythrose 4-phosphate are typical acceptor substrates." SIGNOR-267087 TKT protein P29401 UNIPROT "D-glyceraldehyde 3-phosphate(2-)" smallmolecule CHEBI:59776 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 24929114 t miannu "Transketolase (TK, EC 2.2.1.1) is the key rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway of carbohydrate transformation. TKs (with the exception of the enzymes of mammalian origin) are characterized by broad substrate specificity. Xylulose 5-phosphate (X5P), fructose 6-phosphate (F6P), erythrulose 4-phosphate, and sedoheptulose 7-phosphate are typical donor substrates of TK; ribose 5-phosphate (R5P), glyceraldehyde 3-phosphate (G3P), and erythrose 4-phosphate are typical acceptor substrates." SIGNOR-267088 IL12A protein P29459 UNIPROT IFNG protein P01579 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10653850 f miannu "IL-18, originally described as IFN-γ-inducing factor, is secreted from activated macrophages and Kupffer cells (1–3). The major activity associated with this cytokine is induction of IFN-γ production from CD4+ Th1 cells, T cells, B cells and NK cells, especially in collaboration with IL-12" SIGNOR-260859 IL12A protein P29459 UNIPROT IFNG protein P01579 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10653850 f miannu "IL-18, originally described as IFN-γ-inducing factor, is secreted from activated macrophages and Kupffer cells (1–3). The major activity associated with this cytokine is induction of IFN-γ production from CD4+ Th1 cells, T cells, B cells and NK cells, especially in collaboration with IL-12" SIGNOR-260861 IL12A protein P29459 UNIPROT IL12B protein P29460 UNIPROT up-regulates binding 9606 7527811 t fspada "However, a proper conformation required for high affinity binding is achieved only when p40 is associated with a p35 subunit or another p40 subunit. When p40 is associated with a p35 subunit, the heterodimer acts as an agonist mediating biologic activity. However, when p40 associates with another p40, the homodimer behaves as an antagonist in vitro" SIGNOR-27619 IL12A protein P29459 UNIPROT IL12RB1 protein P42701 UNIPROT up-regulates binding 9606 BTO:0000782 12023369 t gcesareni "Like il-12, il-23 binds to the il-12r subunit il-12rbeta1." SIGNOR-87677 IL12A protein P29459 UNIPROT IL12RB2 protein Q99665 UNIPROT up-regulates binding 9606 11086056 t gcesareni "Il-12r beta 2 plays an essential role in mediating the biological functions of il-12 in mice." SIGNOR-84361 IL12B protein P29460 UNIPROT IL12RB1 protein P42701 UNIPROT up-regulates binding 9606 7527811 t fspada "Characterization of the p40 proteins for binding and bioactivity showed that both the p40 monomer and dimer inhibited 125i-labeled il-12 binding to il-12r, but the 80-kda species, having a 50% inhibitory concentration (ic50) of 20 to 70 ng/ml, was at least 20-fold more effective than the monomer. The results suggest that the il-12 p40 subunit contains the essential epitopes for receptor binding." SIGNOR-27690 CASP1 protein P29466 UNIPROT PSEN1 protein P49768 UNIPROT "up-regulates activity" cleavage Asp345 EEWEAQRdSHLGPHR -1 10069390 t lperfetto "Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis." SIGNOR-261755 CASP1 protein P29466 UNIPROT PSEN2 protein P49810 UNIPROT "up-regulates activity" cleavage Asp326 YDPEMEEdSYDSFGE -1 10069390 t lperfetto "In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329." SIGNOR-261747 CASP1 protein P29466 UNIPROT "AIM2 inflammasome" complex SIGNOR-C222 SIGNOR "form complex" binding 30288079 t lperfetto "Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin." SIGNOR-256400 CASP1 protein P29466 UNIPROT "NLRC4 inflammasome" complex SIGNOR-C223 SIGNOR "form complex" binding 30288079 t lperfetto "Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin." SIGNOR-256402 CASP1 protein P29466 UNIPROT "NLRP1 inflammasome" complex SIGNOR-C224 SIGNOR "form complex" binding 30288079 t lperfetto "Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin." SIGNOR-256406 CASP1 protein P29466 UNIPROT "NLRP3 inflammasome" complex SIGNOR-C225 SIGNOR "form complex" binding 30288079 t lperfetto "Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin." SIGNOR-256409 TYK2 protein P29597 UNIPROT STAT1 protein P42224 UNIPROT "up-regulates activity" phosphorylation Tyr701 DGPKGTGyIKTELIS -1 7657660 t lperfetto "Co-expression of Stat1 with Tyk2, Jak1, or Jak2 resulted in the specific tyrosine phosphorylation of Stat1 at Tyr701Phosphorylation of purified Stat1 was necessary and sufficient for the acquisition of DNA binding activity." SIGNOR-246943 CASP1 protein P29466 UNIPROT "Pyrin inflammasome" complex SIGNOR-C226 SIGNOR "form complex" binding 30288079 t lperfetto "Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin." SIGNOR-256412 NOS1 protein P29475 UNIPROT "nitric oxide" smallmolecule CHEBI:16480 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 21890489 t gcesareni "Nitric oxide (NO), the smallest signalling molecule known, is produced by three isoforms of NO synthase (NOS; EC 1.14.13.39). They all utilize l-arginine and molecular oxygen as substrates" SIGNOR-243957 NOS1 protein P29475 UNIPROT HDAC2 protein Q92769 UNIPROT "down-regulates activity" s-nitrosylation 10090 BTO:0001103 19047631 t gcesareni "we found that restoration of NO signaling in vivo, by adenoviral-mediated expression of a constitutively active endothelial NOS mutant in MDX muscles, and in vitro, by exposing MDX-derived satellite cells to NO donors, resulted in HDAC2 blockade by cysteine S-nitrosylation" SIGNOR-236919 NOS1 protein P29475 UNIPROT DGC complex SIGNOR-C217 SIGNOR "form complex" binding 9606 15117830 t apalma "The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink)." SIGNOR-255996 PML protein P29590 UNIPROT ZFYVE9 protein O95405 UNIPROT up-regulates binding 9606 15356634 t gcesareni "Cytoplasmic pml physically interacts with smad2/3 and sara (smad anchor for receptor activation) and is required for association of smad2/3 with sara and for the accumulation of sara and tgf-beta receptor in the early endosome." SIGNOR-128744 PML protein P29590 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates binding 9606 15356634 t gcesareni "Cytoplasmic pml physically interacts with smad2/3 and sara (smad anchor for receptor activation) and is required for association of smad2/3 with sara and for the accumulation of sara and tgf-beta receptor in the early endosome." SIGNOR-128741 PML protein P29590 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" binding 9606 15356634 t lperfetto "Cytoplasmic pml physically interacts with smad2/3 and sara (smad anchor for receptor activation) and is required for association of smad2/3 with sara and for the accumulation of sara and tgf-beta receptor in the early endosome." SIGNOR-232090 PML protein P29590 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates binding 9606 15356634 t gcesareni "Cytoplasmic pml physically interacts with smad2/3 and sara (smad anchor for receptor activation) and is required for association of smad2/3 with sara and for the accumulation of sara and tgf-beta receptor in the early endosome." SIGNOR-128735 PML protein P29590 UNIPROT SMAD2 protein Q15796 UNIPROT "up-regulates activity" binding 9606 15356634 t lperfetto "Cytoplasmic pml physically interacts with smad2/3 and sara (smad anchor for receptor activation) and is required for association of smad2/3 with sara and for the accumulation of sara and tgf-beta receptor in the early endosome." SIGNOR-128738 PML protein P29590 UNIPROT KAT6A/PML complex SIGNOR-C55 SIGNOR "form complex" binding 9606 BTO:0001271 23431171 t miannu "We show here that moz is an acetyltransferase of p53 at k120 and k382 and colocalizes with p53 in promyelocytic leukemia (pml) nuclear bodies following cellular stress. The moz-pml-p53 interaction enhances moz-mediated acetylation of p53, and this ternary complex enhances p53-dependent p21 expression" SIGNOR-201489 TYK2 protein P29597 UNIPROT IFNAR1 protein P17181 UNIPROT "up-regulates activity" phosphorylation Tyr481 PSSSIDEyFSEQPLK 9606 7526154 t lperfetto "In this report, we demonstrate that the alpha subunit of the type I IFN receptor (IFN-R) corresponds to the product of a previously cloned receptor subunit cDNA and, further, that the p135tyk2 tyrosine kinase directly binds and tyrosine phosphorylates this receptor subunit.These data support the hypothesis that the Tyk2 protein functions as part of a receptor complex to initiate intracellular signaling in response to type I IFNs" SIGNOR-246939 TYK2 protein P29597 UNIPROT IFNAR1 protein P17181 UNIPROT "up-regulates activity" phosphorylation Tyr466 VFLRCINyVFFPSLK -1 8605876 t lperfetto "We demonstrate that, in vitro, p135tyk2 phosphorylates two tyrosines on IFNaR1. A phosphopeptide corresponding to the major phosphorylation site (Tyr466) binds STAT2, but not STAT1, in an SH-2-dependent manner. Furthermore, only latent, non-phosphorylated STAT2 interacts with this phosphopeptide. When this phosphopeptide is introduced into permeabilized cells, the IFN alpha-dependent tyrosine phosphorylation of both STATs is blocked. Finally, mutant versions of IFNaR1, in which Tyr466 is changed to phenylalanine, can act in a dominant negative manner to inhibit phosphorylation of STAT2." SIGNOR-246934 TYK2 protein P29597 UNIPROT TYK2 protein P29597 UNIPROT "up-regulates activity" phosphorylation Tyr1054 AVPEGHEyYRVREDG 9606 BTO:0000452 8702790 t lperfetto "These results indicate that tyk2 is activated by phosphorylation on tyr-1054 and/or tyr-1055The K930R mutant, bearing a mutation in the ATP binding site, is catalytically inactive (Fig. 3B, lanes 5 and 6). This protein is not basally phosphorylated, while the wt and the Y1054F/Y1055F proteins are (Fig. 3A), suggesting that autophosphorylation is responsible for the basal level of phosphorylation." SIGNOR-43088 TYK2 protein P29597 UNIPROT TYK2 protein P29597 UNIPROT "up-regulates activity" phosphorylation Tyr1055 VPEGHEYyRVREDGD 9606 BTO:0000452 8702790 t lperfetto "These results indicate that tyk2 is activated by phosphorylation on tyr-1054 and/or tyr-1055The K930R mutant, bearing a mutation in the ATP binding site, is catalytically inactive (Fig. 3B, lanes 5 and 6). This protein is not basally phosphorylated, while the wt and the Y1054F/Y1055F proteins are (Fig. 3A), suggesting that autophosphorylation is responsible for the basal level of phosphorylation." SIGNOR-43092 TYK2 protein P29597 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation 9606 10542297 t lperfetto "Stat3 activation requires kinase function of tyk2." SIGNOR-71781 TYK2 protein P29597 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation 9606 30029643 t "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 TYK2 protein P29597 UNIPROT DUSP3 protein P51452 UNIPROT up-regulates phosphorylation Tyr138 SPTLVIAyLMMRQKM 9606 17785772 t lperfetto "Phosphorylation of vhr at tyr(138) was required for its phosphatase activity toward stat5. In addition, the src homology 2 domain of stat5 was required for the effective dephosphorylation of stat5 by vhr. The tyrosine kinase tyk2, which mediates the phosphorylation of stat5, was also responsible for the phosphorylation of vhr at tyr(138)." SIGNOR-157655 TYK2 protein P29597 UNIPROT "ISGF3 complex" complex SIGNOR-C124 SIGNOR "up-regulates activity" phosphorylation 9606 15120645 t miannu "Despite signaling through distinct receptor complexes, type I IFNs and IFN-lambda activate similar signaling events and biological activities, consistent with their common ability to mediate an antiviral state in cells (Fig. 6). In both cases, receptor engagement leads via the activation of the Jak kinases Jak1 and Tyk2 to the activation of the IFN-stimulated gene factor 3 (ISGF3) transcription complex, composed of latent transcriptional factors of the Signal Transducers and Activators of Transcription (STAT) family, Stat1 and Stat2, and of the interferon regulatory factor (IRF) IRF9 (ISGF3g or p48)." SIGNOR-260148 EEF1D protein P29692 UNIPROT ITGA7 protein Q13683 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000165 16129691 t lperfetto "alpha7 Integrin Expression Is Negatively Regulated by deltaEF1 during Skeletal Myogenesis" SIGNOR-241773 CD40LG protein P29965 UNIPROT IGSF6 protein O95976 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 9809579 f miannu "CD40L activation of dendritic cells down-regulates DORA, a novel member of the immunoglobulin superfamily" SIGNOR-261727 CD40LG protein P29965 UNIPROT CD40 protein P25942 UNIPROT "up-regulates activity" binding 9606 BTO:0000776 12324477 t lperfetto "Ramos cells were mixed with increasing numbers of transfected cells that expressed cd70 (cd27l) or cd154 (cd40l), both of which are expressed by activated T cells, in the presence of anti-igm ab. Cd27 ligation as well as cd40 ligation inhibited bcr-mediated apoptosis in a dose-dependent manner. cd40 binds its ligand cd40l." SIGNOR-93432 CD40LG protein P29965 UNIPROT CD40 protein P25942 UNIPROT "up-regulates activity" binding 9606 BTO:0000782;BTO:0003076 19426221 t lperfetto "Ramos cells were mixed with increasing numbers of transfected cells that expressed cd70 (cd27l) or cd154 (cd40l), both of which are expressed by activated t cells, in the presence of anti-igm ab. Cd27 ligation as well as cd40 ligation inhibited bcr-mediated apoptosis in a dose-dependent manner .cd40 binds its ligand cd40l." SIGNOR-185660 CD40LG protein P29965 UNIPROT PTPN7 protein P35236 UNIPROT down-regulates 9606 BTO:0000776 19047375 f gcesareni "Coimmunoprecipitation and western blot analysis showed that heptp was phosphorylated in a pka-dependent manner, which inactivated heptp and allowed for increased free p38 mapk to be phosphorylated by the mapk cascade that was activated by cd40l" SIGNOR-182519 GCHFR protein P30047 UNIPROT GCH1 protein P30793 UNIPROT "down-regulates activity" binding 9606 11361142 t miannu "The enzyme activity of GTP cyclohydrolase I is controlled by a regulatory protein for this enzyme, GFRP, which is a pentamer of identical subunits. GFRP mediates feedback inhibition of GTP cyclohydrolase I activity by BH4, and the inhibition by BH4 is reversed by phenylalanine" SIGNOR-252203 RPL12 protein P30050 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262487 PPP2R1A protein P30153 UNIPROT PPP2CB protein P62714 UNIPROT up-regulates binding 9606 16039140 t miannu "Pr65/a acts as a scaffold protein for binding pp2ac and regulatory b subunits in a heterotrimeric holoenzyme" SIGNOR-138886 PPP2R1A protein P30153 UNIPROT PPP2CA protein P67775 UNIPROT up-regulates binding 9606 16039140 t miannu "Pr65/a acts as a scaffold protein for binding pp2ac and regulatory b subunits in a heterotrimeric holoenzyme" SIGNOR-138883 PPP2R1A protein P30153 UNIPROT SGO1 protein Q5FBB7 UNIPROT up-regulates binding 9606 BTO:0000567 16580887 t miannu "Identification of subunits of protein phosphatase 2a (pp2a) as sgo1 binding proteins / pp2a is required for proper chromosome segregation and centromeric localization of sgo1 in hela cells" SIGNOR-145486 PPP2R1A protein P30153 UNIPROT PP2CA_R1A_R2A complex SIGNOR-C132 SIGNOR "form complex" binding 9606 23454242 t gcesareni "[PP2A] ... is multifarious as it is composed of catalytic, scaffold and regulatory subunits. The catalytic and scaffold subunits have two isoforms and the regulatory subunit has four different families containing different isoforms. The regulatory subunit is the most diverse with temporal and spatial specificity." SIGNOR-243427 PPP2R1A protein P30153 UNIPROT PP2Ca_R1A_Bd complex SIGNOR-C133 SIGNOR "form complex" binding 9606 23454242 t gcesareni "[PP2A] ... is multifarious as it is composed of catalytic, scaffold and regulatory subunits. The catalytic and scaffold subunits have two isoforms and the regulatory subunit has four different families containing different isoforms. The regulatory subunit is the most diverse with temporal and spatial specificity." SIGNOR-243445 PPP2R1A protein P30153 UNIPROT PP2Ca_R1A_Bd complex SIGNOR-C134 SIGNOR "form complex" binding 9606 23454242 t gcesareni "[PP2A] ... is multifarious as it is composed of catalytic, scaffold and regulatory subunits. The catalytic and scaffold subunits have two isoforms and the regulatory subunit has four different families containing different isoforms. The regulatory subunit is the most diverse with temporal and spatial specificity." SIGNOR-243436 PPP2R1B protein P30154 UNIPROT PPP2CA protein P67775 UNIPROT "up-regulates activity" binding 9606 19114990 t lperfetto "Since B_ suppresses the association of the catalytic C and regulatory A subunits of protein phosphatase 2A [94], the B_ interaction with the receptor is expected to result in enhanced protein phosphatase 2A activity" SIGNOR-217872 CDC27 protein P30260 UNIPROT APC-c complex SIGNOR-C150 SIGNOR "form complex" binding 16896351 t lperfetto "The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex." SIGNOR-252003 WEE1 protein P30291 UNIPROT CDK1 protein P06493 UNIPROT down-regulates phosphorylation Tyr15 EKIGEGTyGVVYKGR 9606 16096060 t gcesareni "The wee1 kinase phosphorylates and inhibits cyclin-dependent kinase 1 (cdk1), thereby delaying entry into mitosis until appropriate conditions have been met" SIGNOR-139491 WEE1 protein P30291 UNIPROT CDK2 protein P24941 UNIPROT down-regulates phosphorylation Tyr15 EKIGEGTyGVVYKAR 9606 BTO:0000567 11029659 t gcesareni "Identification and characterization of human wee1b, a new member of the wee1 family of cdk-inhibitory kinases." SIGNOR-83139 CDC25A protein P30304 UNIPROT RAF1 protein P04049 UNIPROT down-regulates dephosphorylation 9606 7744247 t gcesareni "Cdc25a can act on substrates other than cdks, since it dephosphorylates the homeodomain transcription factor cut and interacts with and dephosphorylates the proto-oncogene raf-1, resulting in a significant decrease in raf-1 kinase activity" SIGNOR-32548 CDC25A protein P30304 UNIPROT CDK1 protein P06493 UNIPROT "up-regulates activity" dephosphorylation Thr14 IEKIGEGtYGVVYKG 9606 10454565 t "Phosphatase activity of Cdc25A is critical for its activating capacity (data not shown). In this context, it should also be mentioned that Cdc25A is able to activate cyclin B-Cdk1 in vitro" SIGNOR-248479 CDC25A protein P30304 UNIPROT CDK1 protein P06493 UNIPROT "up-regulates activity" dephosphorylation Tyr15 EKIGEGTyGVVYKGR 9606 10454565 t "Phosphatase activity of Cdc25A is critical for its activating capacity (data not shown). In this context, it should also be mentioned that Cdc25A is able to activate cyclin B-Cdk1 in vitro" SIGNOR-248480 CDC25A protein P30304 UNIPROT CDK2 protein P24941 UNIPROT up-regulates dephosphorylation Thr14 VEKIGEGtYGVVYKA 9606 12411508 t gcesareni "Cell division cycle 25 a (cdc25a), a dual-specificity protein phosphatase, is one of the most crucial cell cycle regulators, which removes the inhibitory phosphorylation in cyclin-dependent kinases (cdks), such as cdk2, cdk4, and cdk6, and positively regulates the activities of cdks that lead to cell cycle progression." SIGNOR-95252 CDC25A protein P30304 UNIPROT CDK2 protein P24941 UNIPROT up-regulates dephosphorylation Thr14 VEKIGEGtYGVVYKA 9606 22263797 t gcesareni "Cell division cycle 25 a (cdc25a), a dual-specificity protein phosphatase, is one of the most crucial cell cycle regulators, which removes the inhibitory phosphorylation in cyclin-dependent kinases (cdks), such as cdk2, cdk4, and cdk6, and positively regulates the activities of cdks that lead to cell cycle progression." SIGNOR-195521 CDC25A protein P30304 UNIPROT CDK2 protein P24941 UNIPROT "up-regulates activity" dephosphorylation Thr14 VEKIGEGtYGVVYKA 9606 10454565 t "The phosphatase activity of Cdc25A is necessary for Cdk2 activation, most likely due to dephosphorylation on Tyr-15 and Thr-14 of Cdk2." SIGNOR-248481 CDC25A protein P30304 UNIPROT CDK2 protein P24941 UNIPROT "up-regulates activity" dephosphorylation Tyr15 EKIGEGTyGVVYKAR 9606 10454565 t "The phosphatase activity of Cdc25A is necessary for Cdk2 activation, most likely due to dephosphorylation on Tyr-15 and Thr-14 of Cdk2." SIGNOR-248482 CDC25A protein P30304 UNIPROT CDK2 protein P24941 UNIPROT "up-regulates activity" dephosphorylation 9606 BTO:0000093 11154267 t lperfetto "Expression of Cdc25A mRNA and protein was induced by E(2) in control and p16(INK4a)-expressing MCF-7 cells; however, functional activity of Cdc25A was inhibited in cells expressing p16(INK4a). Inhibition of Cdc25A activity in p16(INK4a)-expressing cells was associated with depressed Cdk2 activity" SIGNOR-245449 CDC25A protein P30304 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates dephosphorylation 9606 BTO:0000093 15672448 t gcesareni "We found that cdc25a physically interacted with and de-phosphorylated phospho-erk both in vitro and in cell culture." SIGNOR-133392 CDC25A protein P30304 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR "up-regulates activity" dephosphorylation 9606 BTO:0000093 11154267 t lperfetto "Cyclin E-Cdk2 complexes from p16INK4a-expressing MCF-7 cells are activated in vitro and in vivo by Cdc25A" SIGNOR-245452 CDC25A protein P30304 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR "up-regulates activity" dephosphorylation 9606 BTO:0000007 23429262 t lperfetto "We show that the miRNA-induced silencing of CDC25A increases the tyrosine phosphorylation status of CDK4/6 cyclin-dependent kinases which, in turn, abolishes CDK4/6 capacity to associate with D-type cyclins. This prevents CDK4/6 kinases’ activation, impairs downstream events such as cyclin E stimulation and sequesters cells in early G1." SIGNOR-245456 CDC25B protein P30305 UNIPROT CDK1 protein P06493 UNIPROT up-regulates dephosphorylation 9606 SIGNOR-C17 7880537 t gcesareni "Cdc25 dephosphorylates cdc2/cdk1 within the activation loop of the kinase domain to achieve full activity of the cyclin-cdk complex" SIGNOR-34541 CDC25B protein P30305 UNIPROT CyclinB/CDK1 complex SIGNOR-C17 SIGNOR up-regulates dephosphorylation 9606 7880537 t lperfetto "Cdc25 dephosphorylates cdc2/cdk1 within the activation loop of the kinase domain to achieve full activity of the cyclin-cdk complex" SIGNOR-217511 CDC25C protein P30307 UNIPROT CDK1 protein P06493 UNIPROT up-regulates dephosphorylation Tyr15 EKIGEGTyGVVYKGR 9606 19574738 t gcesareni "Cdk1/cdc2 activation involves tyr15/thr14 dephosphorylation by cdc25c" SIGNOR-186621 CDC25C protein P30307 UNIPROT CyclinB/CDK1 complex SIGNOR-C17 SIGNOR "up-regulates activity" dephosphorylation Thr14 IEKIGEGtYGVVYKG 9606 BTO:0001938 10913154 t lperfetto "Cyclin B-Cdc2 complexes are maintained in an inactive state until the end of G2 by phosphorylation of the Thr14/Tyr15 residues. Around the time of nuclear translocation of the complex, these residues are dephosphorylated, resulting in the formation of an active cyclin B-Cdc2 complex (2). As mentioned, this dephosphorylation occurs by a Cdc25 protein phosphatase. Three Cdc25 family members have been identified to date, A, B and C, the last one being the active one at the onset of mitosis. The activity of Cdc25C itself can be enhanced through phosphorylation by cyclin B-Cdc2 (9, 10). Therefore, activation of cyclin B-Cdc2 has been proposed to result in an autocatalytic feedback loop to ensure rapid activation of these complexes at the G2/M transition" SIGNOR-251509 CDC25C protein P30307 UNIPROT CyclinB/CDK1 complex SIGNOR-C17 SIGNOR "up-regulates activity" dephosphorylation Tyr15 EKIGEGTyGVVYKGR 9606 BTO:0001938 10913154 t lperfetto "Cyclin B-Cdc2 complexes are maintained in an inactive state until the end of G2 by phosphorylation of the Thr14/Tyr15 residues. Around the time of nuclear translocation of the complex, these residues are dephosphorylated, resulting in the formation of an active cyclin B-Cdc2 complex (2). As mentioned, this dephosphorylation occurs by a Cdc25 protein phosphatase. Three Cdc25 family members have been identified to date, A, B and C, the last one being the active one at the onset of mitosis. The activity of Cdc25C itself can be enhanced through phosphorylation by cyclin B-Cdc2 (9, 10). Therefore, activation of cyclin B-Cdc2 has been proposed to result in an autocatalytic feedback loop to ensure rapid activation of these complexes at the G2/M transition" SIGNOR-255037 PPIF protein P30405 UNIPROT ATP5PO protein P48047 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 32814770 t lperfetto "We here hypothesized that CypD phosphorylation on its residue S191 induces its translocation and binding to the OSCP to favor mPTP opening. " SIGNOR-264881 HOXA10 protein P31260 UNIPROT MYLK protein Q15746 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0002196 15886193 t Luana "Results from these experiments demonstrated that in 10T1/2 cells Hoxa10-1 increased the activity of the telokin promoter 3-fold without affecting the activity of the other promoters analyzed (Fig. 2A). Similar results were also observed in A10 SMC (data not shown). In contrast, Hoxb8 significantly repressed the activity of the telokin, smooth muscle α-actin, and SM22α promoters by 70, 50, and 70%, respectively" SIGNOR-261643 BDKRB2 protein P30411 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257199 BDKRB2 protein P30411 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256838 BDKRB2 protein P30411 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256974 BDKRB2 protein P30411 UNIPROT GNA15 protein P30679 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257281 BDKRB2 protein P30411 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257090 BDKRB2 protein P30411 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256695 BDKRB2 protein P30411 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257344 BDKRB2 protein P30411 UNIPROT GNA13 protein Q14344 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257399 AVPR2 protein P30518 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256897 AVPR2 protein P30518 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256754 HMOX2 protein P30519 UNIPROT heme smallmolecule CHEBI:30413 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 10490932 t Regulation miannu "Heme oxygenase (HO), by catabolizing heme to bile pigments, down-regulates cellular hemoprotein, hemoglobin, and heme" SIGNOR-251912 HMOX2 protein P30519 UNIPROT HBA1 protein P69905 UNIPROT "down-regulates activity" 9606 10490932 t Regulation miannu "Heme oxygenase (HO), by catabolizing heme to bile pigments, down-regulates cellular hemoprotein, hemoglobin, and heme" SIGNOR-251814 AXL protein P30530 UNIPROT AXL protein P30530 UNIPROT "up-regulates activity" phosphorylation Tyr779 ADCLDGLyALMSRCW -1 9178760 t llicata "Our data showed that various receptor substrates are at least associated with the C-terminal tyrosine pY821. Two additional potential autophosphorylation sites (pY866 and pY779) may play a minor role in binding of e€ector proteins" SIGNOR-250591 AXL protein P30530 UNIPROT AXL protein P30530 UNIPROT "up-regulates activity" phosphorylation Tyr821 QEPDEILyVNMDEGG -1 9178760 t llicata "Our data showed that various receptor substrates are at least associated with the C-terminal tyrosine pY821. Two additional potential autophosphorylation sites (pY866 and pY779) may play a minor role in binding of e€ector proteins" SIGNOR-250592 AXL protein P30530 UNIPROT AXL protein P30530 UNIPROT "up-regulates activity" phosphorylation Tyr866 EVHPAGRyVLCPSTT -1 9178760 t llicata "Our data showed that various receptor substrates are at least associated with the C-terminal tyrosine pY821. Two additional potential autophosphorylation sites (pY866 and pY779) may play a minor role in binding of e€ector proteins" SIGNOR-250593 ADORA1 protein P30542 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256840 ADORA1 protein P30542 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256976 ADORA1 protein P30542 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257092 ADORA1 protein P30542 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256697 GRPR protein P30550 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257421 GRPR protein P30550 UNIPROT PLA2G1B protein P04054 UNIPROT up-regulates binding 9606 17251915 t gcesareni "Grpr stimulation activates phospholipase a2 (pla2) and cyclooxygenase 2 (cox2), which leads to prostaglandin e2 (pge2) production and ep receptor stimulation." SIGNOR-152756 HOXA7 protein P31268 UNIPROT IVL protein P07476 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000667 11435435 f miannu "Antisense HOXA7 expression activated transglutaminase 1, involucrin, and keratin 10 message and protein levels, demonstrating that endogenous HOXA7 down-regulates multiple differentiation-specific keratinocyte genes." SIGNOR-254473 GRPR protein P30550 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257159 GRPR protein P30550 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257247 GRPR protein P30550 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257314 GRPR protein P30550 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256917 GRPR protein P30550 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 BTO:0000189 17251915 t gcesareni "Gastrin-releasing peptide receptors (grpr) are coupled primarily to galfaq, and are highly expressed in many cancers, including small-cell lung cancer" SIGNOR-152679 GRPR protein P30550 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257372 GRPR protein P30550 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257046 GRPR protein P30550 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256774 AGTR1 protein P30556 UNIPROT NPHS1 protein O60500 UNIPROT "down-regulates activity" 10116 21982880 f miannu "Ang II-receiving rats displayed diminished phosphorylation of nephrin but enhanced glomerular/podocyte injury and proteinuria when compared to control rats. These findings indicate that Ang II induces nephrin dephosphorylation and podocyte injury through a caveolin-1-dependent mechanism." SIGNOR-253342 AGTR1 protein P30556 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257133 HBA1 protein P69905 UNIPROT CYP2E1 protein P05181 UNIPROT "up-regulates activity" 9606 BTO:0000575 19325051 f Regulation miannu "Hemoglobin dramatically stimulated CYP 2E1 activity but not the protein expression in quercetin- and ethanol-cotreated hepatocytes." SIGNOR-251765 AGTR1 protein P30556 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256881 AGTR1 protein P30556 UNIPROT GNA15 protein P30679 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257223 AGTR1 protein P30556 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257017 AGTR1 protein P30556 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256738 AGTR1 protein P30556 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 21289285 t gcesareni "These results indicate that ang ii increases endothelial arginase activity/expression through galfa12/13 g proteins coupled to at(1) receptors and subsequent activation of rhoa/rock/p38 mapk pathways leading to endothelial dysfunction." SIGNOR-171760 AGTR1 protein P30556 UNIPROT GNG12 protein Q9UBI6 UNIPROT up-regulates binding 9606 21289285 t gcesareni "These results indicate that ang ii increases endothelial arginase activity/expression through galfa12/13 g proteins coupled to at(1) receptors and subsequent activation of rhoa/rock/p38 mapk pathways leading to endothelial dysfunction." SIGNOR-171763 OXTR protein P30559 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257332 OXTR protein P30559 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257178 OXTR protein P30559 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256936 HOXA7 protein P31268 UNIPROT KRT10 protein P13645 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000667 11435435 f miannu "Antisense HOXA7 expression activated transglutaminase 1, involucrin, and keratin 10 message and protein levels, demonstrating that endogenous HOXA7 down-regulates multiple differentiation-specific keratinocyte genes." SIGNOR-254472 OXTR protein P30559 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257266 OXTR protein P30559 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257065 OXTR protein P30559 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256793 ADSL protein P30566 UNIPROT fumarate(2-) smallmolecule CHEBI:29806 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 22812634 t miannu "ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case" SIGNOR-266606 ADSL protein P30566 UNIPROT "adenosine 5'-monophosphate(2-)" smallmolecule CHEBI:456215 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 22812634 t miannu "ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case" SIGNOR-266607 ADSL protein P30566 UNIPROT N(6)-(1,2-dicarboxylatoethyl)-AMP(4-) smallmolecule CHEBI:57567 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 22812634 t miannu "ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case" SIGNOR-266612 ADSL protein P30566 UNIPROT SAICAR(4-) smallmolecule CHEBI:58443 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 22812634 t miannu "ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case" SIGNOR-266611 ADSL protein P30566 UNIPROT 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide(2-) smallmolecule CHEBI:58475 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 22812634 t miannu "ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case" SIGNOR-266608 ADSL protein P30566 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007 31729379 f miannu "An integrated transcriptomics and metabolomics analysis reveals that ADSL activates the oncogenic cMYC pathway by regulating cMYC protein level via a mechanism requiring ADSL proline 24 hydroxylation. ADSL regulates cMYC protein level through adenosine levels" SIGNOR-266614 PKLR protein P30613 UNIPROT pyruvate smallmolecule CHEBI:15361 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 15996096 t miannu "Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A)." SIGNOR-266537 PKLR protein P30613 UNIPROT phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 15996096 t miannu "Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A)." SIGNOR-266535 CLIP1 protein P30622 UNIPROT DCTN1 protein Q14203 UNIPROT "up-regulates activity" binding 9606 15381688 t miannu "MT-unbound CLIP-170 can adopt a folded conformation through an intramolecular interaction of its terminal domains. Binding to MTs correlates with the unfolding of CLIP-170, which allows the interaction of the COOH-terminal domain with its binding partners, such as dynactin, resulting in their recruitment to the MT tip. The NH2 terminus of p150Glued binds directly to the COOH terminus of CLIP-170 through its second metal-binding motif." SIGNOR-252164 SSTR1 protein P30872 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256822 SSTR1 protein P30872 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256679 SSTR1 protein P30872 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256958 SSTR2 protein P30874 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256827 SSTR2 protein P30874 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256684 POLR2B protein P30876 UNIPROT "RNA Polymerase II" complex SIGNOR-C391 SIGNOR "form complex" binding 9606 BTO:0000567 9852112 t lperfetto "Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II" SIGNOR-266162 HTR1F protein P30939 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256816 HTR1F protein P30939 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256673 GNRHR protein P30968 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257331 GNRHR protein P30968 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257177 HIVEP2 protein P31629 UNIPROT SSTR2 protein P30874 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001976 10207097 t Luana "Activation of somatostatin receptor II expression by transcription factors MIBP1 and SEF-2 in the murine brain." SIGNOR-261617 GNRHR protein P30968 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256935 GNRHR protein P30968 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257265 GNRHR protein P30968 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257064 GNRHR protein P30968 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256792 NTS protein P30990 UNIPROT NTSR2 protein O95665 UNIPROT down-regulates binding 9606 BTO:0000975 9851594 t gcesareni "Neurotensin binding to recombinant neurotensin nt2 receptor expressed in cho cells does not elicit a biological response as determined by second messenger measurements." SIGNOR-62519 NTS protein P30990 UNIPROT NTSR1 protein P30989 UNIPROT up-regulates binding 9606 BTO:0000975 1331689 t gcesareni "The rat neurotensin receptor cdna sequence was transfected in chinese hamster ovary cells and cellular clones which stably express the corresponding protein were isolated and characterized. The scatchard analysis of the specific binding of [3h]neurotensin indicated a kd value of 0.45 +/- 0.08 nm and a bmax value of 3.27 +/- 0.29 pmol/mg of protein. ...Neurotensin Stimulated the phosphoinositides hydrolysis" SIGNOR-17369 SDHA protein P31040 UNIPROT "Mitochondrial respiratory chain complex II" complex SIGNOR-C278 SIGNOR "form complex" binding 30030361 t lperfetto "Complex II (EC 1.3.5.1) or succinate dehydrogenase (quinone) is shared between the TCA cycle and the ETC and has no proton pumping activity. It is composed of four nDNA-encoded subunits. The two hydrophilic catalytic subunits are SDHA/SDH1 and SDHB/SDH2. Hydrophobic subunits SDHC/SDH3 and SDHD/SDH4 constitute the cII membrane anchor, containing a haem b group and two CoQ binding sites" SIGNOR-262188 SDHA protein P31040 UNIPROT SDH complex SIGNOR-C400 SIGNOR "form complex" binding 9606 16143825 t miannu "Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. Four nuclear genes encode the four subunits, SDHA (15 exons), SDHB (8 exons), SDHC (6 exons) and SDHD (4 exons), mapping on to chromosomes 5p15, 1p35-p36.1, 1q21 and 11q23, respectively." SIGNOR-266271 HOXD3 protein P31249 UNIPROT "A5/b1 integrin" complex SIGNOR-C163 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002828 14610084 t Luana "The homeobox transcription factor Hox D3 promotes integrin alpha5beta1 expression and function during angiogenesis." SIGNOR-261650 HOXA10 protein P31260 UNIPROT PHGDH protein O43175 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001996 19778996 f miannu "PHGDH is expressed in both endometrial epithelial and stromal cells. HOXA10 represses endometrial PHGDH expression." SIGNOR-254468 HOXA10 protein P31260 UNIPROT MYCN protein P04198 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000661 21261500 f miannu "HOXA9/HOXA10 activated expression of NMYC which in turn mediated MEF2C repression, indicating an indirect mode of regulation via NMYC interactor (NMI) and STAT5." SIGNOR-254215 HOXA10 protein P31260 UNIPROT IGFBP1 protein P08833 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0003697 17350963 f miannu "The functional role of HOXA10 in IGFBP1 expression was further explored using human endometrial stromal cells (HSC). Overexpression of HOXA10 in HSC resulted in a decrease of IGFBP1 mRNA, whereas silencing HOXA10 caused an increase of IGFBP1 mRNA, even in the presence of H + dbcAMP. These data demonstrate that HOXA10 negatively influences IGFBP1 expression in decidualizing cells." SIGNOR-254467 HOXA10 protein P31260 UNIPROT EMX2 protein Q04743 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15494461 f miannu "EMSA demonstrated HOXA10-Pbx2 binding as a heterodimer to an enhancer of the EMX2 gene, a known target of HOXA10 regulation." SIGNOR-254465 HOXA10 protein P31260 UNIPROT MEF2C protein Q06413 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000661 21261500 f miannu "Overexpression of HOXA9 or HOXA10 in JURKAT cells by lentiviral transduction resulted in decreased expression of MEF2C, indicating repression by these homeodomain proteins. HOXA9/10 inhibits expression of MEF2C via NMYC" SIGNOR-254212 HOXA7 protein P31268 UNIPROT TGM1 protein P22735 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000667 11435435 f miannu "Antisense HOXA7 expression activated transglutaminase 1, involucrin, and keratin 10 message and protein levels, demonstrating that endogenous HOXA7 down-regulates multiple differentiation-specific keratinocyte genes." SIGNOR-254474 HOXA9 protein P31269 UNIPROT MEIS1 protein O00470 UNIPROT "up-regulates activity" binding -1 9343407 t 2 miannu "We now show that the Hoxa-9 protein physically interacts with Meis1 proteins. Hox proteins from the other AbdB-like paralogs, Hoxa-10, Hoxa-11, Hoxd-12, and Hoxb-13, also form DNA binding complexes with Meis1b. DNA binding complexes formed by Meis1 with Hox proteins dissociate much more slowly than DNA complexes with Meis1 alone, suggesting that Hox proteins stabilize the interactions of Meis1 proteins with their DNA targets." SIGNOR-241162 HOXA9 protein P31269 UNIPROT MYCN protein P04198 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000661 21261500 f miannu "HOXA9/HOXA10 activated expression of NMYC which in turn mediated MEF2C repression, indicating an indirect mode of regulation via NMYC interactor (NMI) and STAT5." SIGNOR-254213 HOXA9 protein P31269 UNIPROT IGF1 protein P05019 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25252870 f miannu "Hoxa9bound directly to the putative promoter and a dnase-hypersensitive region in the first intron of the igf1 gene. Transcription rates of the igf1 gene paralleledhoxa9activity" SIGNOR-205308 HOXA9 protein P31269 UNIPROT PIM1 protein P11309 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001412 17327400 t Luana "Thus Pim1 appears to be a direct transcriptional target of HOXA9 and a mediator of its antiapoptotic and proproliferative effects in early cells. " SIGNOR-261632 HOXA9 protein P31269 UNIPROT MEF2C protein Q06413 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000661 21261500 f miannu "Overexpression of HOXA9 or HOXA10 in JURKAT cells by lentiviral transduction resulted in decreased expression of MEF2C, indicating repression by these homeodomain proteins. HOXA9/10 inhibits expression of MEF2C via NMYC" SIGNOR-254211 HOXA9 protein P31269 UNIPROT MSI2 protein Q96DH6 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20805843 f gcesareni "Nup98-hoxa9 oncogene binds the putative element at 5.7 kb upstream of transcription start site to trigger the upregulated expression of musashi2 gene (b). The elevated level of musashi2 leads to the downregulation of numb, by binding to the 3' utr of numb mrna to inhibit translation" SIGNOR-167725 HOXA11 protein P31270 UNIPROT HOXA10 protein P31260 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001549 17688409 f miannu "Chromatin immunoprecipitation (ChIP) and chloramphenicol acetyl transferase (CAT) assays confirm that HOXA11 binds to the putative binding site, resulting in repression of HOXA10 expression." SIGNOR-254469 HOXA13 protein P31271 UNIPROT EPHA7 protein Q15375 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16314414 f miannu "We show that hoxd13 andhoxa13activate transcription from the epha7 promoter and that a mutation of thehoxa13/hoxd13 binding site was sufficient to abolish activation." SIGNOR-142428 HOXA13 protein P31271 UNIPROT EPHA7 protein Q15375 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000942 21829694 t Luana "Analysis of normalized luciferase expression confirmed that wt HOXA13 regulates gene expression through the EphA7 cis-regulatory DNA element" SIGNOR-261631 HOXC13 protein P31276 UNIPROT FOXN1 protein O15353 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001253 21191399 f miannu "Hoxc13-dependent activation of foxn1 is part of a regulatory cascade controlling the expression of terminal differentiation markers." SIGNOR-170850 HOXC13 protein P31276 UNIPROT LAMB2 protein P55268 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9534 BTO:0000298 10835276 t Luana "The specificity of binding of these two proteins to the Lamin B2 origin is confirmed by both band-shift and in vitro footprinting assays. In addition, the ability of HOXC10 and HOXC13 to increase the activity of a promoter containing the 74 bp sequence, as assayed by CAT-assay experiments, demonstrates a direct interaction of these homeoproteins with the origin sequence in mammalian cells." SIGNOR-261644 HOXC13 protein P31276 UNIPROT DSG4 protein Q86SJ6 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000552 19683850 f miannu "we studied the transcriptional regulation of DSG4 by transcription factors/pathways that are known regulators of hair keratin or KAP expression. We show that HOXC13, LEF1 and FOXN1 repress DSG4 transcription and provide in vitro and in vivo evidence correlating the Notch pathway with the activation and/or maintenance of DSG4 expression in the hair follicle." SIGNOR-254184 HOXD11 protein P31277 UNIPROT MEIS1 protein O00470 UNIPROT "up-regulates activity" binding -1 9343407 t 2 miannu "We now show that the Hoxa-9 protein physically interacts with Meis1 proteins. Hox proteins from the other AbdB-like paralogs, Hoxa-10, Hoxa-11, Hoxd-12, and Hoxb-13, also form DNA binding complexes with Meis1b. DNA binding complexes formed by Meis1 with Hox proteins dissociate much more slowly than DNA complexes with Meis1 alone, suggesting that Hox proteins stabilize the interactions of Meis1 proteins with their DNA targets." SIGNOR-241229 TLX1 protein P31314 UNIPROT RB1 protein P06400 UNIPROT "down-regulates activity" binding 9606 BTO:0000661 15897879 t 2 miannu "ectopic HOX11 expression resulted in hyperphosphorylation of the retinoblastoma protein (Rb), which correlated with inhibition of the major Rb serine/threonine phosphatase PP1." SIGNOR-240725 TLX1 protein P31314 UNIPROT ETS1 protein P14921 UNIPROT "down-regulates activity" binding 9606 BTO:0002504 22516263 t irozzo "We show that the cortical thymic maturation arrest in T-lineage ALLs that overexpress TLX1 or TLX3 is due to binding of TLX1/TLX3 to ETS1, leading to repression of T cell receptor (TCR) α enhanceosome activity and blocked TCR-Jα rearrangement." SIGNOR-259097 TLX1 protein P31314 UNIPROT PPP2CB protein P62714 UNIPROT "down-regulates activity" binding 9606 BTO:0000661 15897879 t 2 miannu "HOX11 also inhibited PP2A serine/threonine phosphatase activity concomitant with stimulation of the AKT/PKB signaling cascade." SIGNOR-240722 TLX1 protein P31314 UNIPROT PPP2CA protein P67775 UNIPROT "down-regulates activity" binding 9606 BTO:0000661 15897879 t 2 miannu "HOX11 also inhibited PP2A serine/threonine phosphatase activity concomitant with stimulation of the AKT/PKB signaling cascade." SIGNOR-240719 PRKAR1B protein P31321 UNIPROT PRKACA protein P17612 UNIPROT "down-regulates activity" binding 9606 26687711 t "Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets" SIGNOR-258753 HBA1 protein P69905 UNIPROT EDN1 protein P05305 UNIPROT "down-regulates activity" 9606 8573884 f "Regulation of localization" miannu "Hb inhibitory activity toward ET-1 production might be related to Hb mediated endothelial oxidative injury." SIGNOR-251767 PRKAR1B protein P31321 UNIPROT PRKACB protein P22694 UNIPROT "down-regulates activity" binding 9606 26687711 t "Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets" SIGNOR-258756 PRKAR2B protein P31323 UNIPROT PRKACA protein P17612 UNIPROT "down-regulates activity" binding 9606 26687711 t "Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets" SIGNOR-258754 PRKAR2B protein P31323 UNIPROT PRKACB protein P22694 UNIPROT "down-regulates activity" binding 9606 26687711 t "Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets" SIGNOR-258758 PRKAR2B protein P31323 UNIPROT PRKAR2B protein P31323 UNIPROT "up-regulates activity" phosphorylation Ser114 NRFTRRAsVCAEAYN 10090 15822905 t miannu "Ser114 (the autophosphorylation site) of human RII beta. Point mutation of the autophosphorylation site or in the nuclear location signal causes protein kinase A RII beta regulatory subunit to lose its ability to revert transformed fibroblasts." SIGNOR-250076 RRM2 protein P31350 UNIPROT "Ribonucleotide reductase" complex SIGNOR-C233 SIGNOR "form complex" binding 9606 14583450 t miannu "Ribonucleotide reductase (RR) is responsible for the de novo conversion of the ribonucleoside diphosphates to deoxyribonucleoside diphosphates, which are essential for DNA synthesis and repair.RR consists of two subunits, hRRM1 and hRRM2." SIGNOR-259364 FGF9 protein P31371 UNIPROT TGFB1 protein P01137 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15780951 f "FGF-2 and FGF-9 increased expression of other??osteogenic??factors??BMP-2??and TGFbeta-1" gcesareni "Fgf-2 and fgf-9 increased expression of other osteogenic factors bmp-2 and tgf-beta1, and endogenous fgf/fgfr signaling is a positive upstream regulator of the bmp-2 gene in calvarial osteoblasts" SIGNOR-134797 FGF9 protein P31371 UNIPROT TGFB1 protein P01137 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22298955 f "FGF-2 and FGF-9 increased expression of other??osteogenic??factors??BMP-2??and TGFbeta-1" gcesareni "Fgf-2 and fgf-9 increased expression of other osteogenic factors bmp-2 and tgf-beta1, and endogenous fgf/fgfr signaling is a positive upstream regulator of the bmp-2 gene in calvarial osteoblasts" SIGNOR-195594 FGF9 protein P31371 UNIPROT BMP2 protein P12643 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15780951 f "FGF-2 and FGF-9 increased expression of other??osteogenic??factors??BMP-2??and TGFbeta-1." gcesareni "Fgf-2 and fgf-9 increased expression of other osteogenic factors bmp-2 and tgf-beta1, and endogenous fgf/fgfr signaling is a positive upstream regulator of the bmp-2 gene in calvarial osteoblasts." SIGNOR-134794 FGF9 protein P31371 UNIPROT BMP2 protein P12643 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22298955 f "FGF-2 and FGF-9 increased expression of other??osteogenic??factors??BMP-2??and TGFbeta-1." gcesareni "Fgf-2 and fgf-9 increased expression of other osteogenic factors bmp-2 and tgf-beta1, and endogenous fgf/fgfr signaling is a positive upstream regulator of the bmp-2 gene in calvarial osteoblasts." SIGNOR-195591 SSTR4 protein P31391 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256823 SSTR4 protein P31391 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256680 SSTR4 protein P31391 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256959 SDC4 protein P31431 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" binding 9606 BTO:0002314 BTO:0001103 23290138 t 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 SDC4 protein P31431 UNIPROT DVL3 protein Q92997 UNIPROT up-regulates binding 9606 23151663 t gcesareni "Like other wnt co-receptors, syndecan 4 directly interacts with dvl during pcp 1." SIGNOR-199638 SDC4 protein P31431 UNIPROT FN1/SDC4 complex SIGNOR-C210 SIGNOR "form complex" binding 23290138 t apalma "We found that binding of ECM glycoprotein Fibronectin (FN) to Sdc4 stimulates the ability of Wnt7a to induce the symmetric expansion of satellite stem cells" SIGNOR-255286 SDC4 protein P31431 UNIPROT FZD7/SDC4 complex SIGNOR-C216 SIGNOR "form complex" binding 9606 BTO:0002314 BTO:0001103 23290138 t 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 GABRA5 protein P31644 UNIPROT "GABA-A (a5-b1-g2) receptor" complex SIGNOR-C335 SIGNOR "form complex" binding 9606 BTO:0000227 18790874 t "brain, See table 3 for identified complexes" lperfetto "The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon." SIGNOR-263765 AKT1 protein P31749 UNIPROT FOXO6 protein A8MYZ6 UNIPROT down-regulates phosphorylation 9606 18394876 t lperfetto "The phosphorylation of the two remaining akt-dependent sites inhibits foxo6 transcriptional activity" SIGNOR-252582 AKT1 protein P31749 UNIPROT FOXO6 protein A8MYZ6 UNIPROT down-regulates phosphorylation 9606 21798082 t gcesareni "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-175294 AKT1 protein P31749 UNIPROT SH2B2 protein O14492 UNIPROT unknown phosphorylation Ser598 SARSRSNsAERLLEA 10090 BTO:0000944 16141217 t "Serine 588 of APS is a newly identified target for protein kinase B in intact cells and in vitro. The precise function of this PKB-mediated phosphorylation event is not entirely clear but may be responsible for regulating cellular localization and will be the subject of future investigation." SIGNOR-252577 AKT1 protein P31749 UNIPROT SH2B2 protein O14492 UNIPROT "up-regulates activity" phosphorylation Ser598 SARSRSNsAERLLEA 10090 BTO:0000011 16141217 t gcesareni "This study identifies APS as a novel physiological substrate for PKB and the first serine phosphorylation site on APS" SIGNOR-252557 AKT1 protein P31749 UNIPROT TERT protein O14746 UNIPROT up-regulates phosphorylation Ser227 GARRRGGsASRSLPL 9606 BTO:0000848 10224060 t gcesareni "Akt kinase enhances human telomerase activity through phosphorylation of htert subunit as one of its substrate proteins." SIGNOR-67313 AKT1 protein P31749 UNIPROT TERT protein O14746 UNIPROT up-regulates phosphorylation Ser824 AVRIRGKsYVQCQGI 9606 BTO:0000848 10224060 t gcesareni "Akt kinase enhances human telomerase activity through phosphorylation of htert subunit as one of its substrate proteins." SIGNOR-67317 AKT1 protein P31749 UNIPROT CHEK1 protein O14757 UNIPROT down-regulates phosphorylation Ser280 AKRPRVTsGGVSESP 9606 15107605 t gcesareni "The chk1 protein phosphorylated by pkb on serine 280 does not enter into protein complexes after replication arrest. Moreover, chk1 phosphorylated by pkb fails to undergo activating phosphorylation on serine 345 by atm/atr. Phosphorylation by atm/atr and association with other checkpoint proteins are essential steps in activation of chk1." SIGNOR-124365 AKT1 protein P31749 UNIPROT CHUK protein O15111 UNIPROT up-regulates phosphorylation Thr23 EMRERLGtGGFGNVC 9606 BTO:0001454 SIGNOR-C14 19609947 t gcesareni "Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta" SIGNOR-187006 AKT1 protein P31749 UNIPROT MDM4 protein O15151 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser367 PDCRRTIsAPVVRPK 9606 18356162 t lperfetto "We demonstrate that the serine/threonine kinase akt mediates phosphorylation of mdmx at ser367. This phosphorylation leads to stabilization of mdmx and consequent stabilization of mdm2." SIGNOR-252517 AKT1 protein P31749 UNIPROT FANCA protein O15360 UNIPROT unknown phosphorylation Ser1149 CLRSRDPsLMVDFIL -1 11855836 t "FANCA is phosphorylated at Ser1149 by Akt. The biological significance of FANCA phosphorylation and its regulation by Akt remains unclear at this time." SIGNOR-252567 AKT1 protein P31749 UNIPROT CFLAR protein O15519 UNIPROT "down-regulates quantity" phosphorylation Ser273 LLRDTFTsLGYEVQK 9606 BTO:0000801 19339247 t gcesareni "TNFalpha enhanced FLIP(L) serine phosphorylation, which was increased by activated Akt-1. Serine 273, a putative Akt-1 phosphorylation site in FLIP(L), was critical for the activation-induced reduction of FLIP(L). Thus, these observations document a novel mechanism where by TNFalpha facilitates the reduction of FLIP(L) protein, which is dependent on the phosphatidylinositol 3-kinase/Akt signaling." SIGNOR-252548 AKT1 protein P31749 UNIPROT HTRA2 protein O43464 UNIPROT down-regulates phosphorylation Ser212 RVRVRLLsGDTYEAV 9606 17311912 t lperfetto "Akt attenuation of the serine protease activity of htra2/omi through phosphorylation of serine 212" SIGNOR-252500 AKT1 protein P31749 UNIPROT BCL2L11 protein O43521 UNIPROT "down-regulates activity" phosphorylation Ser87 FIFMRRSsLLSRSSS 9606 BTO:0000776 16282323 t lperfetto "Recombinant Akt could directly phosphorylate a GST-Bim(EL) fusion protein and identified the Akt phosphorylation site in the Bim(EL) domain as Ser(87). Further, we demonstrated that cytokine stimulation promotes Bim(EL) binding to 14-3-3 proteins. Finally, we show that mutation of Ser(87) dramatically increases the apoptotic potency of Bim(EL)." SIGNOR-252487 AKT1 protein P31749 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates activity" phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t 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-252522 AKT1 protein P31749 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates activity" phosphorylation Ser315 DFRSRTNsNASTVSG 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t 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-252523 AKT1 protein P31749 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates activity" phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t 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-252524 AKT1 protein P31749 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0001103 21798082 t 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-175288 AKT1 protein P31749 UNIPROT TAL1 protein P17542 UNIPROT down-regulates phosphorylation Thr90 EARHRVPtTELCRPP 9606 BTO:0000782;BTO:0001271 15930267 t miannu "Akt phosphorylates tal1 oncoprotein and inhibits its repressor activity. / our results show that akt specifically phosphorylates thr90 of the tal1 protein within its transactivation domain in vitro and in vivo." SIGNOR-252479 AKT1 protein P31749 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser253 APRRRAVsMDNSNKY 19951971 t 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 AKT1 protein P31749 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser315 DFRSRTNsNASTVSG 19951971 t 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 AKT1 protein P31749 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr32 QSRPRSCtWPLQRPE 19951971 t 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 AKT1 protein P31749 UNIPROT NUAK1 protein O60285 UNIPROT up-regulates phosphorylation Ser600 PARQRIRsCVSAENF 9606 12409306 t esanto "Ser(600) in ark5 was found to be phosphorylated by active akt resulting in the activation of kinase activity." SIGNOR-252591 AKT1 protein P31749 UNIPROT TBC1D4 protein O60343 UNIPROT down-regulates phosphorylation 9606 BTO:0000887 12637568 t gcesareni "Recently, we identified a 160-kda protein in adipocytes, designated as160, that is phosphorylated by the insulin-activated kinase akt" SIGNOR-252594 AKT1 protein P31749 UNIPROT TBC1D4 protein O60343 UNIPROT unknown phosphorylation Thr642 QFRRRAHtFSHPPSS 9606 16880201 t llicata "14-3-3 proteins interact with as160 in an insulin- and akt-dependent manner via an akt phosphorylation site, thr-642." SIGNOR-252494 AKT1 protein P31749 UNIPROT PFKFB2 protein O60825 UNIPROT unknown phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000567 12853467 t "14-3-3s bind directly to cardiac PFK-2 phosphorylated by PKB. PFK-2 was phosphorylated on both Ser466 and Ser483 by PKB. the precise mechanism of fru-2,6-P2 regulation by 14-3-3s is still puzzling." SIGNOR-252574 AKT1 protein P31749 UNIPROT PFKFB2 protein O60825 UNIPROT unknown phosphorylation Ser483 IRRPRNYsVGSRPLK 9606 BTO:0000567 12853467 t "14-3-3s bind directly to cardiac PFK-2 phosphorylated by PKB. PFK-2 was phosphorylated on both Ser466 and Ser483 by PKB. the precise mechanism of fru-2,6-P2 regulation by 14-3-3s is still puzzling." SIGNOR-252575 AKT1 protein P31749 UNIPROT PFKFB2 protein O60825 UNIPROT "up-regulates activity" phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000562 10521487 t gcesareni "Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b." SIGNOR-252584 AKT1 protein P31749 UNIPROT PFKFB2 protein O60825 UNIPROT "up-regulates activity" phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000567 12853467 t gcesareni "These findings suggest that PKB-dependent binding of 14-3-3s to phospho-Ser483 of cardiac PFK-2 mediates the stimulation of glycolysis by growth factor." SIGNOR-252555 AKT1 protein P31749 UNIPROT PFKFB2 protein O60825 UNIPROT "up-regulates activity" phosphorylation Ser483 IRRPRNYsVGSRPLK 9606 BTO:0000567 BTO:0000562 12853467 t lperfetto "These findings suggest that pkb-dependent binding of 14-3-3s to phospho-ser483 of cardiac pfk-2 mediates the stimulation of glycolysis by growth factor." SIGNOR-252464 AKT1 protein P31749 UNIPROT PFKFB2 protein O60825 UNIPROT "up-regulates activity" phosphorylation Ser483 IRRPRNYsVGSRPLK 9606 BTO:0000562 23457334 t lperfetto "Akt-dependent activation of the heart 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (pfkfb2) isoenzyme by amino acids." SIGNOR-252528 AKT1 protein P31749 UNIPROT NCOR1 protein O75376 UNIPROT down-regulates phosphorylation Ser1450 TVRSRHTsVVSSGPS 9606 BTO:0001271 23940660 t llicata "Akt-induced phosphorylation of n-cor at serine 1450 contributes to its misfolded conformational dependent loss (mcdl) in acute myeloid leukemia of the m5 subtype." SIGNOR-198913 AKT1 protein P31749 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser104 FPPLNSVsPSPLMLL 9606 11108261 t lperfetto "Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt." SIGNOR-84963 AKT1 protein P31749 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser106 PLNSVSPsPLMLLHP 9606 11108261 t lperfetto "Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt." SIGNOR-84967 AKT1 protein P31749 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 11108261 t lperfetto "Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt." SIGNOR-84971 AKT1 protein P31749 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser167 GGRERLAsTNDKGSM 9606 11108261 t lperfetto "Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt." SIGNOR-84975 AKT1 protein P31749 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser259 SQRQRSTsTPNVHMV 9606 BTO:0000222 BTO:0000887;BTO:0001760 10576741 t gcesareni "Akt and protein kinase a (pka) phosphorylate s259 on raf-1 and inhibit its activity." SIGNOR-252588 AKT1 protein P31749 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser259 SQRQRSTsTPNVHMV 9606 BTO:0000150;BTO:0001130 16854453 t gcesareni "Akt and protein kinase a (pka) phosphorylate s259 on raf-1 and inhibit its activity." SIGNOR-147963 AKT1 protein P31749 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates phosphorylation Ser134 ANLNRSTsVPENPKS 9606 BTO:0000731 24291004 t lperfetto "Akt1 impairs glucocorticoid-induced gene expression by direct phosphorylation of nr3c1 at position s134 and blocking glucocorticoid-induced nr3c1 translocation to the nucleus" SIGNOR-252543 AKT1 protein P31749 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser82 RALSRQLsSGVSEIR 9606 19593530 t "10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro." lperfetto "First, the akt1, akt2, and akt3 isoforms can bind directly to hsp27 and can be found in a complex with p38 mapk, mk2, and hsp27 [98_100]. Second, rane and colleagues showed that akt could phosphorylate hsp27 at ser-82, but not ser-15 or ser-78, in vitro, while co-expression of an active akt mutant and hsp27 in hek cells resulted in hsp27 phosphorylation at the same residue." SIGNOR-252526 AKT1 protein P31749 UNIPROT ITGB3 protein P05106 UNIPROT "down-regulates activity" phosphorylation Thr779 LYKEATStFTNITYR 9606 BTO:0000132 10896934 t gcesareni "A survey of several protein kinases revealed that Thr-753 was avidly phosphorylated by PDK1 and Akt/PKB in vitro. These observations suggest that activation of PDK1 and/or Akt/PKB in platelets may modulate the binding activity and/or specificity of beta(3) for signaling molecules." SIGNOR-252552 AKT1 protein P31749 UNIPROT ADRB2 protein P07550 UNIPROT down-regulates phosphorylation Ser345 ELLCLRRsSLKAYGN 9606 11809767 t lperfetto "Akt mediates sequestration of the beta(2)-adrenergic receptor in response to insulin. Phosphorylation studies of the c-terminal cytoplasmic domain of the beta(2)-adrenergic receptor by akt in vitro identified ser(345) and ser(346) within a consensus motif for akt phosphorylation." SIGNOR-252469 AKT1 protein P31749 UNIPROT ADRB2 protein P07550 UNIPROT down-regulates phosphorylation Ser346 LLCLRRSsLKAYGNG 9606 11809767 t lperfetto "Akt mediates sequestration of the beta(2)-adrenergic receptor in response to insulin. Phosphorylation studies of the c-terminal cytoplasmic domain of the beta(2)-adrenergic receptor by akt in vitro identified ser(345) and ser(346) within a consensus motif for akt phosphorylation." SIGNOR-252470 AKT1 protein P31749 UNIPROT VIM protein P08670 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser39 TTSTRTYsLGSALRP 9606 20856200 t llicata "The binding of akt (tail region) to vim (head region) results in vim ser39 phosphorylation enhancing the ability of vim to induce motility and invasion while protecting vim from caspase-induced proteolysis." SIGNOR-252511 AKT1 protein P31749 UNIPROT HMOX1 protein P09601 UNIPROT unknown phosphorylation Ser188 LYRSRMNsLEMTPAV 9606 BTO:0000007 15581622 t llicata "We have identified a putative consensus sequence for phosphorylation by akt/pkb of ho-1 at ser188. although the changes in activity are small, this study provides the first evidence for a role of the survival kinase akt in the regulation of ho-1." SIGNOR-252506 AKT1 protein P31749 UNIPROT HNRNPA1 protein P09651 UNIPROT down-regulates phosphorylation Ser199 SQRGRSGsGNFGGGR 9606 18562319 t gcesareni "Our data also suggest that akt negatively regulates hnrnp a1-mediated ires activity via phosphorylation at ser199." SIGNOR-252519 AKT1 protein P31749 UNIPROT AR protein P10275 UNIPROT down-regulates phosphorylation Ser215 SGRAREAsGAPTSSK 9606 BTO:0000938 17470458 t acerquone "The work presented here is the first demonstration that phosphorylation at s215 and s792 by akt regulates ligand binding, and the subcellular distribution of the receptor" SIGNOR-154631 AKT1 protein P31749 UNIPROT AR protein P10275 UNIPROT "down-regulates activity" phosphorylation Ser215 SGRAREAsGAPTSSK 9534 BTO:0001538 11404460 t lperfetto "Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor. Here, we demonstrate that akt phosphorylates the androgen receptor (ar) at ser-210 and ser-790" SIGNOR-108504 AKT1 protein P31749 UNIPROT AR protein P10275 UNIPROT "down-regulates activity" phosphorylation Ser792 CVRMRHLsQEFGWLQ 9534 BTO:0001538 11404460 t lperfetto "Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor. Here, we demonstrate that akt phosphorylates the androgen receptor (ar) at ser-210 and ser-790" SIGNOR-108508 AKT1 protein P31749 UNIPROT RARA protein P10276 UNIPROT down-regulates phosphorylation Ser96 FVCQDKSsGYHYGVS 9606 BTO:0000551 16417524 t miannu "We report that akt, which is constitutively activated in nsclc cells, phosphorylates raralpha and inhibits its transactivation. / mutation of ser96 to alanine abrogated the suppressive effect of akt." SIGNOR-252489 AKT1 protein P31749 UNIPROT SLC2A1 protein P11166 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 8940145 f gcesareni "The constitutively active akt also increased the synthesis of the ubiquitously expressed glucose transporter 1. The increased glucose influx in the 3t3-l1 adipocytes directed lipid but not glycogen synthesis" SIGNOR-252579 AKT1 protein P31749 UNIPROT IMPDH2 protein P12268 UNIPROT "up-regulates activity" phosphorylation 9534 BTO:0004055 10930578 t Federica "Further, we have demonstrated an in vivo association of IMPDH and PKB/Akt by co‐immunoprecipitation from COS cells expressing a constitutively active form of PKB/Akt. Finally, we were able to show that this constitutively active PKB/Akt could phosphorylate IMPDH in vitro. Thus, the interplay between PKB/Akt and IMPDH reported here could suggest that PKB/Akt activation leads to IMPDH type II activation which in turn prepares the cell for entry into S phase." SIGNOR-261262 AKT1 protein P31749 UNIPROT SKI protein P12755 UNIPROT down-regulates phosphorylation Thr458 QPRKRKLtVDTPGAP 9606 19875456 t llicata "The phosphorylation of ski at threonine 458 is induced by akt pathway activators including insulin, insulin-like growth factor-1, and hepatocyte growth factor. The phosphorylation of ski causes its destabilization and reduces ski-mediated inhibition of expression of another negative regulator of tgf-beta, smad7" SIGNOR-252527 AKT1 protein P31749 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser304 GAPPRRSsIRNAHSI 9606 BTO:0000130 10559253 t esanto "Akt phosphorylates p47phox and mediates respiratory burst activity in human neutrophils. A direct interaction between p47(phox) and akt was shown. Active recombinant akt phosphorylated recombinant p47(phox) in vitro. Mutation analysis indicated that 2 aa residues, ser(304) and ser(328), were phosphorylated by akt. Inhibition of akt activity also inhibited fmlp-stimulated neutrophil chemotaxis." SIGNOR-252586 AKT1 protein P31749 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser328 QDAYRRNsVRFLQQR 9606 BTO:0000130 10559253 t esanto "Akt phosphorylates p47phox and mediates respiratory burst activity in human neutrophils. A direct interaction between p47(phox) and akt was shown. Active recombinant akt phosphorylated recombinant p47(phox) in vitro. Mutation analysis indicated that 2 aa residues, ser(304) and ser(328), were phosphorylated by akt. Inhibition of akt activity also inhibited fmlp-stimulated neutrophil chemotaxis." SIGNOR-252587 AKT1 protein P31749 UNIPROT SLC2A4 protein P14672 UNIPROT up-regulates 9606 9415393 f "Translocation from intracellular compartment to cell surface in muscle and adipose tissue" gcesareni "Akt is not only capable of stimulating the translocation of glut4 to the cell surface. Endogenous akt is likely to play a significant physiological role in insulin-stimulated glucose uptake in insulin targets such as muscle and adipose tissue" SIGNOR-252580 AKT1 protein P31749 UNIPROT BRAF protein P15056 UNIPROT "down-regulates activity" phosphorylation Ser429 PQRERKSsSSSEDRN 9606 BTO:0000007 10869359 t "Akt phosphorylates both S364 and S428. Akt downregulates B-Raf activity in vivo" SIGNOR-251472 AKT1 protein P31749 UNIPROT GATA1 protein P15976 UNIPROT up-regulates phosphorylation Ser310 QTRNRKAsGKGKKKR 9606 16107690 t llicata "We found that akt directly phosphorylates the transcription factor gata-1 at serine 310 and that this site-specific phosphorylation is required for the transcriptional activation of the timp-1 promoter." SIGNOR-139782 AKT1 protein P31749 UNIPROT PRKACA protein P17612 UNIPROT up-regulates 9606 BTO:0000938 16537363 f gcesareni "Indicating that akt positively regulates shh signaling by controlling pka-mediated gli inactivation." SIGNOR-252490 AKT1 protein P31749 UNIPROT HK1 protein P19367 UNIPROT up-regulates binding 9606 16892082 t gcesareni "The glucose dependence of the antiapoptotic effects of growth factors and akt plus a strong correlation between akt-regulated mitochondrial hexokinase association and apoptotic susceptibility suggest a major role for hexokinases in these effects." SIGNOR-252495 AKT1 protein P31749 UNIPROT S1PR1 protein P21453 UNIPROT "up-regulates activity" phosphorylation Thr236 RTRSRRLtFRKNISK 9606 BTO:0001949 11583630 t lperfetto "Activated akt binds to edg-1 and phosphorylates the third intracellular loop at the t(236) residue. Transactivation of edg-1 by akt is not required for g(i)-dependent signaling but is indispensable for rac activation, cortical actin assembly, and chemotaxis" SIGNOR-252467 AKT1 protein P31749 UNIPROT RPS3 protein P23396 UNIPROT "up-regulates activity" phosphorylation Thr70 GRRIRELtAVVQKRF 10116 BTO:0003060 20605787 t miannu "Here, we show that human RPS3 is a physiological target of Akt kinase and a novel mediator of neuronal apoptosis. NGF stimulation resulted in phosphorylation of threonine 70 of RPS3 by Akt, and this phosphorylation was required for Akt binding to RPS3.our experiment demonstrated that Akt up-regulates the endonuclease activity of RPS3 via phosphorylation and led us to believe that Akt phosphorylation of RPS3 after DNA damage is an antiapoptotic signal or a molecular switch that extends the life of a cell after DNA damage." SIGNOR-259815 AKT1 protein P31749 UNIPROT EIF4B protein P23588 UNIPROT up-regulates phosphorylation Ser422 RERSRTGsESSQTGT 9606 18836482 t gcesareni "Using an in vitro kinase assay, we found that pkb can directly phosphorylate eif4b on serine 422 (ser422). This was prevented by pretreatment of cells with the phosphatidylinositol 3-kinase (pi3k) inhibitor ly294002 or pharmacological inhibition of pkb. Phosphorylation regultes the activation of eukaryotic translation initiation factor 4b." SIGNOR-252520 AKT1 protein P31749 UNIPROT GATA2 protein P23769 UNIPROT down-regulates phosphorylation Ser401 QTRNRKMsNKSKKSK 9606 BTO:0000876 15837948 t "PI-3K/Akt-dependent manner." fspada "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-135614 AKT1 protein P31749 UNIPROT CDK2 protein P24941 UNIPROT up-regulates phosphorylation Thr39 LKKIRLDtETEGVPS 9606 18354084 t lperfetto "Akt phosphorylates cdk2 at threonine 39 residue both in vitro and in vivo. Although cdk2 threonine 39 phosphorylation mediated by akt enhances cyclin-a binding, it is dispensable for its basal binding and the kinase activity." SIGNOR-178058 AKT1 protein P31749 UNIPROT FAS protein P25445 UNIPROT down-regulates 9606 15004527 f gcesareni "Akt may serve to stimulate certain proteins (e.g., Ikk) involved in the prevention of apoptosis such as nf-kb as well as repress other proteins normally involved in the induction of apoptosis such as the forkhead transcription factors (fkhr, now know as foxo3), creb, glycogen synthetase-3 kinase-beta (gsk-3beta), fas, caspase-9 and cell cycle inhibitors such as p27" SIGNOR-252473 AKT1 protein P31749 UNIPROT DNMT1 protein P26358 UNIPROT up-regulates phosphorylation Ser143 RTPRRSKsDGEAKPE 9606 21151116 t gcesareni "Akt1 kinase colocalizes and directly interacts with dnmt1 and phosphorylates ser143. Phosphorylated dnmt1 peaks during dna synthesis, before dnmt1 methylation. Depletion of akt1 or overexpression of dominant-negative akt1 increases methylated dnmt1, resulting in a decrease in dnmt1 abundance. In mammalian cells, phosphorylated dnmt1 is more stable than methylated dnmt1." SIGNOR-170530 AKT1 protein P31749 UNIPROT PLN protein P26678 UNIPROT "down-regulates activity" phosphorylation Thr17 SAIRRAStIEMPQQA 10090 BTO:0003265 19696029 t "Akt interacts with and phosphorylates PLN at Thr(17), the Ca(2+)-calmodulin-dependent kinase IIdelta site, whereas silencing Akt signaling, through the knock-out of phosphatidylinositol-dependent kinase-1, resulted in reduced phosphorylation of PLN at Thr(17)." SIGNOR-252578 AKT1 protein P31749 UNIPROT TKT protein P29401 UNIPROT "up-regulates activity" phosphorylation Thr382 GCATRNRtVPFCSTF 9606 BTO:0000567 24981175 t lperfetto "Akt phosphorylates TKT on Thr382, markedly enhancing enzyme activity and increasing carbon flow through the nonoxidative PPP, thereby increasing purine synthesis." SIGNOR-265101 AKT1 protein P31749 UNIPROT NOS3 protein P29474 UNIPROT up-regulates phosphorylation Ser1177 TSRIRTQsFSLQERQ 9606 11729179 t gcesareni "Recently many investigators have shown that protein phosphorylation of enos by several serine/threonine kinases is a critical control step for no production by endothelial cells. Phosphorylation by amp kinase, akt (or protein kinase b), or protein kinase a on serine 1179 (bovine) or serine 1177 (human) of enos leads to enhanced activity of the enzyme and, thus, augmented production of no." SIGNOR-112363 AKT1 protein P31749 UNIPROT NOS3 protein P29474 UNIPROT "up-regulates activity" phosphorylation Ser615 SYKIRFNsISCSDPL 9606 BTO:0001853 24379783 t lperfetto "The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites" SIGNOR-251622 AKT1 protein P31749 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Ser552 QDTQRRTsMGGTQQQ 9606 17287208 t lperfetto "Phosphorylation of beta-catenin by akt promotes beta-catenin transcriptional activity|we have demonstrated that akt phosphorylates beta-catenin at ser552 in vitro and in vivo." SIGNOR-252499 AKT1 protein P31749 UNIPROT BMI1 protein P35226 UNIPROT "up-regulates activity" phosphorylation Ser316 ANRPRKSsVNGSSAT 22505453 t lperfetto "The polycomb group silencing protein Bmi1 can be phosphorylated by AKT, which enhances its oncogenic potential in PCa. Overexpression of Bmi1 can act in combination with PTEN haploinsufficiency to induce invasive carcinogenic formation in the prostate" SIGNOR-252559 AKT1 protein P31749 UNIPROT LONP1 protein P36776 UNIPROT "up-regulates activity" phosphorylation Ser173 VFLKRDDsNESDVVE 9606 BTO:0001061 31406245 t lperfetto "In mitochondria, LonP1 is phosphorylated by Akt on Ser173 and Ser181, enhancing its protease activity." SIGNOR-265724 AKT1 protein P31749 UNIPROT LONP1 protein P36776 UNIPROT "up-regulates activity" phosphorylation Ser181 NESDVVEsLDEIYHT 9606 BTO:0001061 31406245 t lperfetto "In mitochondria, LonP1 is phosphorylated by Akt on Ser173 and Ser181, enhancing its protease activity." SIGNOR-265725 AKT1 protein P31749 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Thr509 LKRKRRPtSGLHPED 9606 BTO:0000150 17428466 t lperfetto "Phosphatidylinositol 3-kinase/akt signaling enhances nuclear localization and transcriptional activity of brca1. mutation of threonine 509 in brca1, the site of akt phosphorylation, to an alanine, attenuates the ability of heregulin to induce brca1 nuclear accumulation" SIGNOR-154312 AKT1 protein P31749 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser694 QTSKRHDsDTFPELK 9606 BTO:0000150 20085797 t lperfetto "We identify a novel akt phosphorylation site in brca1 at s694 which is responsive to activation of these signaling pathways. These data suggest akt phosphorylation of brca1 increases total protein expression by preventing proteasomal degradation" SIGNOR-163472 AKT1 protein P31749 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr145 QGRKRRQtSMTDFYH 9606 16982699 t gcesareni "Whereas akt1 phosphorylates p21, inducing its release from cdk2 and cytoplasmic localization as previously described for akt, akt2 binds p21 in the region spanning the t145 site of p21, thus competing with phosphorylation by akt1 and inducing its accumulation in the nucleus. These distinct roles of akt/pkb isoforms in modulating proliferation and p21 have important implications for the development of drugs aimed at inhibiting cancer cell proliferation.[...] We next investigated if phosphorylation of p21-t145 interfered with akt2 binding. As shown in fig. ?Fig.8e8e (right lane), phosphorylation of p21 on t145 effectively prevented akt2 interaction." SIGNOR-149698 AKT1 protein P31749 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser146 GRKRRQTsMTDFYHS 9606 31575057 t gcesareni "Pim-1, PKC, and Akt1 kinases phosphorylate Thr-145 and Ser-146 sites on p21 protein. Phosphorylation at Thr-145 promotes cytoplasmic translocation and stability of p21. Ser-146 phosphorylation mediated by Akt1 enhances p21 stabilization and promotes cell survival." SIGNOR-157790 AKT1 protein P31749 UNIPROT MAP3K8 protein P41279 UNIPROT "up-regulates activity" phosphorylation Ser400 EDQPRCQsLDSALLE 9606 BTO:0000007 12138205 t "Akt-dependent phosphorylation of Cot occurs exclusively on serines 400 and 413. Akt to phosphorylate Cot at two sites in the carboxy-terminal domain, at least one of which may promote binding of substrates or coactivators to Cot, or alternatively may relieve binding of a negative regulator." SIGNOR-252571 AKT1 protein P31749 UNIPROT MAP3K8 protein P41279 UNIPROT "up-regulates activity" phosphorylation Ser413 LERKRLLsRKELELP 9606 BTO:0000007 12138205 t "Akt-dependent phosphorylation of Cot occurs exclusively on serines 400 and 413. Akt to phosphorylate Cot at two sites in the carboxy-terminal domain, at least one of which may promote binding of substrates or coactivators to Cot, or alternatively may relieve binding of a negative regulator." SIGNOR-252572 AKT1 protein P31749 UNIPROT MTOR protein P42345 UNIPROT unknown phosphorylation Ser2448 RSRTRTDsYSAGQSV 9606 BTO:0000007 10910062 t lperfetto "Although AKT phosphorylated mTOR at two COOH-terminal sites (Thr2446 and Ser2448) in vitro, Ser2448 was the major phosphorylation site in insulin-stimulated or -activated AKT-expressing human embryonic kidney cells. Transient transfection assays with mTOR mutants bearing Ala substitutions at Ser2448 and/or Thr2446 indicated that AKT-dependent mTOR phosphorylation was not essential for either PHAS-I phosphorylation or p70S6K activation in HEK cells." SIGNOR-251099 AKT1 protein P31749 UNIPROT MTOR protein P42345 UNIPROT up-regulates phosphorylation 9606 BTO:0001103 15829723 t 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-255107 AKT1 protein P31749 UNIPROT HTT protein P42858 UNIPROT unknown phosphorylation Ser419 GGRSRSGsIVELIAG 9606 BTO:0000938 12062094 t llicata "We demonstrate that huntingtin is a substrate of akt and that phosphorylation of huntingtin by akt is crucial to mediate the neuroprotective effects of igf-1." SIGNOR-252590 AKT1 protein P31749 UNIPROT MAP2K4 protein P45985 UNIPROT down-regulates phosphorylation Ser80 IERLRTHsIESSGKL 9606 BTO:0000007 11707464 t lperfetto "Akt phosphorylated sek1 on serine 78." SIGNOR-236494 AKT1 protein P31749 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates binding 9606 23400686 t gcesareni "Furthermore, akt promotes cell cycle progression through downregulation of the cyclin dependent kinase inhibitor p27kip1." SIGNOR-252534 AKT1 protein P31749 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Thr198 PGLRRRQt 9606 12042314 t miannu "Because Thr198-phosphorylated p27Kip1 was localized only in the cytoplasm, Akt might promote 14-3-3 binding to p27Kip1 by phosphorylation at Thr198, allowing its cytoplasmic localization and degradation." SIGNOR-88294 AKT1 protein P31749 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation 9606 14967450 t gcesareni "Furthermore, akt promotes cell cycle progression through downregulation of the cyclin dependent kinase inhibitor p27kip1." SIGNOR-121944 AKT1 protein P31749 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Thr157 GIRKRPAtDDSSTQN 9606 18570873 t gcesareni "Mtor may promote g1 progression in part through sgk1 activation and deregulate the cell cycle in cancers through both akt- and sgk-mediated p27 t157 phosphorylation and cytoplasmic p27 mislocalization." SIGNOR-179109 AKT1 protein P31749 UNIPROT CDKN1B protein P46527 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 18423396 f fspada "Moreover, expression of p27(kip1), an inhibitor of the cell cycle, was down regulated in an akt1/pkbalpha-specific manner during adipocytedifferentiation." SIGNOR-178269 AKT1 protein P31749 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser127 PQHVRAHsSPASLQL 9606 12535517 t gcesareni "One protein that associates with 14-3-3 in an akt-dependent manner is shown here to be the yes-associated protein (yap), which is phosphorylated by akt at serine 127, leading to binding to 14-3-3. Akt promotes yap localization to the cytoplasm, resulting in loss from the nucleus where it functions as a coactivator of transcription factors including p73." SIGNOR-252593 AKT1 protein P31749 UNIPROT CLK2 protein P49760 UNIPROT up-regulates phosphorylation Ser34 HKRRRSRsWSSSSDR 9606 BTO:0000567 20682768 t lperfetto "Akt directly binds to and phosphorylates clk2 on serine 34 and threonine 127, in vitro and in vivo.Our results suggest that akt activation controls cell survival to ionizing radiation by phosphorylating clk2, revealing an important regulatory mechanism required for promoting cell surviva" SIGNOR-167336 AKT1 protein P31749 UNIPROT FOXO4 protein P98177 UNIPROT "down-regulates activity" phosphorylation Ser262 TFRPRSSsNASSVST 10090 BTO:0004245 10217147 t "Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf -16 (refs 5, 6, 9), both in vitro and in vivo." SIGNOR-252569 AKT1 protein P31749 UNIPROT CLK2 protein P49760 UNIPROT up-regulates phosphorylation Thr127 RRRRRSRtFSRSSSQ 9606 BTO:0000567 20682768 t lperfetto "Akt directly binds to and phosphorylates clk2 on serine 34 and threonine 127, in vitro and in vivo.Our results suggest that akt activation controls cell survival to ionizing radiation by phosphorylating clk2, revealing an important regulatory mechanism required for promoting cell surviva" SIGNOR-167340 AKT1 protein P31749 UNIPROT TSC2 protein P49815 UNIPROT "down-regulates activity" phosphorylation Ser939 SFRARSTsLNERPKS 10090 BTO:0000944 12150915 t lperfetto "We demonstrate that, upon activation of PI3K, tuberin is phosphorylated on consensus recognition sites for PI3K-dependent S/T kinases. Moreover, Akt/PKB can phosphorylate tuberin in vitro and in vivo. We also show that S939 and T1462 of tuberin are PI3K-regulated phosphorylation sites and that T1462 is constitutively phosphorylated in PTEN(-/-) tumor-derived cell lines." SIGNOR-235511 AKT1 protein P31749 UNIPROT TSC2 protein P49815 UNIPROT "down-regulates activity" phosphorylation Thr1462 GLRPRGYtISDSAPS 10090 BTO:0000944 12150915 t lperfetto "We demonstrate that, upon activation of PI3K, tuberin is phosphorylated on consensus recognition sites for PI3K-dependent S/T kinases. Moreover, Akt/PKB can phosphorylate tuberin in vitro and in vivo. We also show that S939 and T1462 of tuberin are PI3K-regulated phosphorylation sites and that T1462 is constitutively phosphorylated in PTEN(-/-) tumor-derived cell lines." SIGNOR-235515 AKT1 protein P31749 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation Ser21 SGRARTSsFAEPGGG 9606 11035810 t gcesareni "In response to insulin, gsk3a inhibited by phosphorylation at ser-21 by pkb/akt1;phosphorylation at this site causes a conformational change, preventing access of substrates to the active site." SIGNOR-252589 AKT1 protein P31749 UNIPROT GSK3B protein P49841 UNIPROT "down-regulates activity" phosphorylation Ser9 SGRPRTTsFAESCKP 9606 23552696 t lperfetto "Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3beta (GSK3B). The AKT-mediated phosphorylation of glycogen synthase kinase 3b on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1" SIGNOR-245416 AKT1 protein P31749 UNIPROT GSK3B protein P49841 UNIPROT "down-regulates activity" phosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000007 9373175 t gcesareni "Evidence that the inhibition of glycogen synthase kinase-3beta by IGF-1 is mediated by PDK1/PKB-induced phosphorylation of Ser-9" SIGNOR-252546 AKT1 protein P31749 UNIPROT GSK3B protein P49841 UNIPROT "down-regulates activity" 9606 BTO:0001103 15829723 t apalma "GSK-3beta activity can be inhibited by Akt phosphorylation (12), which may provide a mechanism for Akt to promote muscle growth through inhibition of the negative regulator GSK-3beta." SIGNOR-255109 AKT1 protein P31749 UNIPROT CDKN1C protein P49918 UNIPROT down-regulates phosphorylation Ser282 FFAKRKRsAPEKSSG 9606 BTO:0000150 23421998 t lperfetto "Cdk inhibitor p57 (kip2) is downregulated by akt during her2-mediated tumorigenicityakt phosphorylates p57 on ser 282 or thr310. Akt activity results in destabilization of p57 by accelerating turnover rate of p57 and enhancing p57 ubiquitination" SIGNOR-252535 AKT1 protein P31749 UNIPROT CDKN1C protein P49918 UNIPROT down-regulates phosphorylation Thr310 GVGSVEQtPRKRLR 9606 BTO:0000150 23421998 t lperfetto "Cdk inhibitor p57 (kip2) is downregulated by akt during her2-mediated tumorigenicityakt phosphorylates p57 on ser 282 or thr310. Akt activity results in destabilization of p57 by accelerating turnover rate of p57 and enhancing p57 ubiquitination" SIGNOR-252536 AKT1 protein P31749 UNIPROT IRAK1 protein P51617 UNIPROT "down-regulates activity" phosphorylation Thr100 LRARDIItAWHPPAP 9606 BTO:0000007 11976320 t gcesareni "CaMKKc and Akt overexpression increases IRAK1 phosphorylation at Thr100, and point mutation of this site abrogates the inhibitory effect of Akt on IRAK1-mediated NF-kappaB activation." SIGNOR-252551 AKT1 protein P31749 UNIPROT HK2 protein P52789 UNIPROT "up-regulates activity" phosphorylation Thr473 QHRARQKtLEHLQLS 9606 BTO:0000192 31435020 t "K63-linked ubiquitination enhances the interaction between Akt and HK2 and eventually increases HK2 phosphorylation on Thr473 and mitochondrial localization" SIGNOR-259984 AKT1 protein P31749 UNIPROT ARFIP2 protein P53365 UNIPROT unknown phosphorylation Ser260 GTRGRLEsAQATFQA 9606 BTO:0000938 15809304 t llicata "Akt phosphorylated arfaptin 2 at ser(260). we have also demonstrated that arfaptin 2 phosphorylation restores proteasome activity that is inhibited by the presence of polyq-huntingtin in cells." SIGNOR-252476 AKT1 protein P31749 UNIPROT ACLY protein P53396 UNIPROT unknown phosphorylation Ser455 PAPSRTAsFSESRAD 10116 BTO:0000443 12107176 t gcesareni "Taken together, these results demonstrate that serine 454 of ATP-citrate lyase is a novel and major in vivo substrate for protein kinase B." SIGNOR-245255 AKT1 protein P31749 UNIPROT TTC3 protein P53804 UNIPROT up-regulates phosphorylation Ser378 AYTPRSLsAPIFTTS 9606 20059950 t llicata "Phosphorylation of ttc3 at ser378 is required for efficient biological function together, these observations support that ttc3 is a phosphorylation target of akt both in an in vitro and in a cellular context" SIGNOR-252508 AKT1 protein P31749 UNIPROT ATXN1 protein P54253 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser775 ATRKRRWsAPESRKL 9606 BTO:0000567 12757707 t "Interaction of Ataxin-1 and 14-3-3 Requires Akt Phosphorylation at S776. 14-3-3 protein, a multifunctional regulatory molecule, mediates the neurotoxicity of ataxin-1 by binding to and stabilizing ataxin-1, thereby slowing its normal degradation." SIGNOR-252561 AKT1 protein P31749 UNIPROT USP14 protein P54578 UNIPROT "up-regulates activity" phosphorylation Ser432 THQGRSSsSGHYVSW 9606 BTO:0000007 26523394 t lperfetto "Phosphorylation and activation of ubiquitin-specific protease-14 by Akt regulates the ubiquitin-proteasome system|These results suggested S432 as a major and S143 as a minor phosphorylation site of Akt." SIGNOR-265056 AKT1 protein P31749 UNIPROT VCP protein P55072 UNIPROT up-regulates phosphorylation Ser352 AATNRPNsIDPALRR 9606 BTO:0000150 16551632 t llicata "Site-directed mutagenesis identified ser-351, ser-745, and ser-747 as akt phosphorylation sites on vcp. however, our study also suggests that other known biological activities of vcp, such as those related to intracellular trafficking, ubiquitin-mediated proteolysis, and activation of transcription (28), might be regulated by akt through the activation of vcp. I" SIGNOR-252491 AKT1 protein P31749 UNIPROT VCP protein P55072 UNIPROT up-regulates phosphorylation Ser746 AMRFARRsVSDNDIR 9606 BTO:0000150 16551632 t llicata "Site-directed mutagenesis identified ser-351, ser-745, and ser-747 as akt phosphorylation sites on vcp. however, our study also suggests that other known biological activities of vcp, such as those related to intracellular trafficking, ubiquitin-mediated proteolysis, and activation of transcription (28), might be regulated by akt through the activation of vcp. I" SIGNOR-252492 AKT1 protein P31749 UNIPROT VCP protein P55072 UNIPROT up-regulates phosphorylation Ser748 RFARRSVsDNDIRKY 9606 BTO:0000150 16551632 t llicata "Site-directed mutagenesis identified ser-351, ser-745, and ser-747 as akt phosphorylation sites on vcp. however, our study also suggests that other known biological activities of vcp, such as those related to intracellular trafficking, ubiquitin-mediated proteolysis, and activation of transcription (28), might be regulated by akt through the activation of vcp. I" SIGNOR-252493 AKT1 protein P31749 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Ser196 KLRRRFSsLHFMVEV 9606 15004527 t gcesareni "Akt phosphorylated recombinant casp9 in vitro on serine-196 and inhibited its protease activity" SIGNOR-252472 AKT1 protein P31749 UNIPROT CASP9 protein P55211 UNIPROT "down-regulates activity" phosphorylation Ser196 KLRRRFSsLHFMVEV 9606 BTO:0000938 10529400 t lperfetto "Akt phosphorylation site found in human caspase-9 is absent in mouse caspase-9BAD phosphorylation by Akt is an essential step for growth factor-mediated inhibition of caspase activation" SIGNOR-252585 AKT1 protein P31749 UNIPROT CASP9 protein P55211 UNIPROT "down-regulates activity" phosphorylation Ser196 KLRRRFSsLHFMVEV -1 9812896 t lperfetto "Akt phosphorylated recombinant casp9 in vitro on serine-196 and inhibited its protease activity" SIGNOR-252581 AKT1 protein P31749 UNIPROT DLX5 protein P56178 UNIPROT up-regulates phosphorylation 9606 21619873 t gcesareni "Akt, a member of the ser-ine/threonine-specific protein kinase, was found to phosphorylate osx and dlx5. akt interacts with and phosphorylates dlx5. In addition, we provide evidences that akt kinase activity is important for akt to enhance the protein stability and transcriptional activity of dlx5." SIGNOR-252513 AKT1 protein P31749 UNIPROT DLX5 protein P56178 UNIPROT up-regulates phosphorylation 9606 22298955 t gcesareni "Akt, a member of the ser-ine/threonine-specific protein kinase, was found to phosphorylate osx and dlx5. akt interacts with and phosphorylates dlx5. In addition, we provide evidences that akt kinase activity is important for akt to enhance the protein stability and transcriptional activity of dlx5." SIGNOR-195546 AKT1 protein P31749 UNIPROT RAC1 protein P63000 UNIPROT "down-regulates activity" phosphorylation Ser71 YDRLRPLsYPQTDVF 9606 BTO:0000848 10617634 t "Akt protein kinase inhibits Rac1-GTP binding through phosphorylation at serine 71 of Rac1" SIGNOR-252576 AKT1 protein P31749 UNIPROT YWHAZ protein P63104 UNIPROT unknown phosphorylation Ser58 VVGARRSsWRVVSSI 9606 BTO:0000007 11956222 t llicata "Ese data indicate that pkb/akt phosphorylates ser-58 on 14-3-3zeta both in vitro and in intact cells. The functional relevance of this phosphorylation remains to be determined." SIGNOR-116587 AKT1 protein P31749 UNIPROT YBX1 protein P67809 UNIPROT up-regulates phosphorylation Ser102 NPRKYLRsVGDGETV 9606 BTO:0000150 15806160 t lperfetto "Phosphorylation of yb-1 at the serine 102 residue is required for transcriptional activation of growth-enhancing genes, such as egfr. Herein, we illustrate that activated akt binds to and phosphorylates the yb-1 cold shock domain at ser102" SIGNOR-252475 AKT1 protein P31749 UNIPROT YBX1 protein P67809 UNIPROT up-regulates phosphorylation Ser102 NPRKYLRsVGDGETV 9606 BTO:0000150 19036157 t lperfetto "Phosphorylation of yb-1 at the serine 102 residue is required for transcriptional activation of growth-enhancing genes, such as egfr. Herein, we illustrate that activated akt binds to and phosphorylates the yb-1 cold shock domain at ser102" SIGNOR-252521 AKT1 protein P31749 UNIPROT SRPK2 protein P78362 UNIPROT up-regulates phosphorylation Thr492 PSHDRSRtVSASSTG 9606 BTO:0000938 BTO:0000142 19592491 t lperfetto "Here we show that srpk2, a protein kinase specific for the serine/arginine (sr) family of splicing factors, triggers cell cycle progression in neurons and induces apoptosis through regulation of nuclear cyclin d1. Akt phosphorylates srpk2 on thr-492 and promotes its nuclear translocation leading to cyclin d1 up-regulation, cell cycle reentry, and neuronal apoptosis." SIGNOR-186760 AKT1 protein P31749 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates binding 9606 15048128 t 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-123606 AKT1 protein P31749 UNIPROT H3-3A protein P84243 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 12588998 t gcesareni "Additionally, active akt1 kinase strongly phosphorylates histone h3 at serine 10 in vitro" SIGNOR-98285 AKT1 protein P31749 UNIPROT XIAP protein P98170 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser87 VGRHRKVsPNCRFIN 9606 BTO:0001023 14645242 t lperfetto "Akt, including akt1 and akt2, interacts with and phosphorylates x-linked inhibitor of apoptosis protein (xiap) at residue serine-87 in vitro and in vivo. Phosphorylation of xiap by akt protects xiap from ubiquitination and degradation in response to cisplatin." SIGNOR-119488 AKT1 protein P31749 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates phosphorylation Ser197 APRRRAAsMDSSSKL 9606 16272144 t lperfetto "Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression" SIGNOR-252484 AKT1 protein P31749 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates phosphorylation Ser262 TFRPRSSsNASSVST 9606 16272144 t lperfetto "Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression" SIGNOR-252485 AKT1 protein P31749 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates phosphorylation Thr32 QSRPRSCtWPLPRPE 9606 16272144 t lperfetto "Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression" SIGNOR-252486 AKT1 protein P31749 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates phosphorylation 9606 21620960 t gcesareni "Akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. In addition, phosphorylation of afx by protein kinase b inhibits its transcriptional activity." SIGNOR-252515 AKT1 protein P31749 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates phosphorylation 9606 21798082 t gcesareni "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-175291 AKT1 protein P31749 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates phosphorylation Ser188 RKRHKSDsISLSFDE 9606 BTO:0000671 15169778 t lperfetto "Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylationhere we show that pkb inhibits mdm2 self-ubiquitination via phosphorylation of mdm2 on ser(166) and ser(188)" SIGNOR-124953 AKT1 protein P31749 UNIPROT MDM2 protein Q00987 UNIPROT "up-regulates activity" phosphorylation Ser186 RQRKRHKsDSISLSF 9606 11504915 t lperfetto "Mitogen-induced activation of phosphatidylinositol 3-kinase (pi3-kinase) and its downstream target, the akt/pkb serine-threonine kinase, results in phosphorylation of mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of mdm2 from the cytoplasm into the nucleus.Both akt expression and serum treatment induced phosphorylation of mdm2 at ser186." SIGNOR-116274 AKT1 protein P31749 UNIPROT MDM2 protein Q00987 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser166 SSRRRAIsETEENSD 9606 11504915 t lperfetto "Mitogen-induced activation of phosphatidylinositol 3-kinase (pi3-kinase) and its downstream target, the akt/pkb serine-threonine kinase, results in phosphorylation of mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of mdm2 from the cytoplasm into the nucleus.Both akt expression and serum treatment induced phosphorylation of mdm2 at ser186." SIGNOR-116270 AKT1 protein P31749 UNIPROT MDM2 protein Q00987 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser166 SSRRRAIsETEENSD 9606 15169778 t gcesareni "Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylation." SIGNOR-124949 AKT1 protein P31749 UNIPROT POU5F1 protein Q01860 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr235 QARKRKRtSIENRVR 9606 BTO:0004180 23041284 t flangone "Here we show that in ECCs, Akt phosphorylated the master pluripotency factor Oct4 at threonine 235, and that the levels of phosphorylated Oct4 in ECCs correlated with resistance to apoptosis and tumorigenic potential. Phosphorylation of Oct4 increased its stability and facilitated its nuclear localization and its interaction with Sox2, which promoted the transcription of the core stemness genes POU5F1 and NANOG." SIGNOR-252545 AKT1 protein P31749 UNIPROT MST1R protein Q04912 UNIPROT up-regulates phosphorylation Ser1394 VRRPRPLsEPPRPT 9606 14505491 t lperfetto "Akt/pkb phosphorylates ron ser-1394, thus providing a docking site for 14-3-3based on these results, we propose a mechanism based on msp-ron-dependent phosphorylation and 14-3-3 association, whereby the function of alpha6beta4 switches from a mechanical adhesive device into a signaling component, and might be critically involved in human epidermal wound healing" SIGNOR-252471 AKT1 protein P31749 UNIPROT MEF2C protein Q06413 UNIPROT "up-regulates activity" 9606 BTO:0000222 BTO:0000887;BTO:0001103 10896679 f 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 AKT1 protein P31749 UNIPROT ZFP36L1 protein Q07352 UNIPROT down-regulates phosphorylation Ser92 RFRDRSFsEGGERLL 9606 15538381 t llicata "Here we report that protein kinase b (pkb/akt) stabilizes are transcripts by phosphorylating brf1 at serine 92 (s92). Recombinant brf1 promoted in vitro decay of are-containing mrna (are-mrna), yet phosphorylation by pkb impaired this activity." SIGNOR-130376 AKT1 protein P31749 UNIPROT BAX protein Q07812 UNIPROT "down-regulates activity" phosphorylation Ser184 VAGVLTAsLTIWKKM 9606 BTO:0003473 14766748 t lperfetto "Phosphorylation of Bax Ser184 by Akt regulates its activity and apoptosis in neutrophilsWe suggest that Bax is regulated by phosphorylation of Ser(184) in an Akt-dependent manner and that phosphorylation inhibits Bax effects on the mitochondria by maintaining the protein in the cytoplasm, heterodimerized with antiapoptotic Bcl-2 family members" SIGNOR-252538 AKT1 protein P31749 UNIPROT EP300 protein Q09472 UNIPROT up-regulates phosphorylation Ser1834 MLRRRMAsMQRTGVV 9606 16926151 t lperfetto "We find that suberoylanilide hydroxamic acid stimulates akt activity, which is required to phosphorylate p300 at ser(1834). Akt-mediated phosphorylation of p300 dramatically increases its acetyltransferase activity" SIGNOR-148983 AKT1 protein P31749 UNIPROT EP300 protein Q09472 UNIPROT up-regulates phosphorylation 9606 BTO:0000887 SIGNOR-C7 17964260 t gcesareni "Akt1 and 2 promote the association of myod with p300 and pcaf acetyltransferases, via direct phosphorylation of p300." SIGNOR-158624 AKT1 protein P31749 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates phosphorylation Ser319 TFRPRTSsNASTISG 9606 11237865 t 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-105459 AKT1 protein P31749 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates phosphorylation 9606 21798082 t 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-175285 AKT1 protein P31749 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates relocalization 10090 BTO:0002572 18423396 t 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-236209 AKT1 protein P31749 UNIPROT FOXO1 protein Q12778 UNIPROT "down-regulates activity" phosphorylation Ser256 SPRRRAAsMDNNSKF -1 BTO:0000318 10377430 t 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 AKT1 protein P31749 UNIPROT FOXO1 protein Q12778 UNIPROT "down-regulates activity" phosphorylation Thr24 LPRPRSCtWPLPRPE -1 BTO:0000318 10377430 t 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 AKT1 protein P31749 UNIPROT FOXO1 protein Q12778 UNIPROT "down-regulates activity" phosphorylation 10090 BTO:0002572 18423396 t lperfetto "Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export ofFoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation." SIGNOR-236206 AKT1 protein P31749 UNIPROT FOXO1 protein Q12778 UNIPROT "down-regulates quantity by destabilization" phosphorylation 9606 21440011 t 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-209647 AKT1 protein P31749 UNIPROT FSTL1 protein Q12841 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001103 18718903 f miannu "Akt1 Overexpression in Skeletal Muscle Increases Capillary Vessel Formation and Up-regulates Fstl1 Expression" SIGNOR-266605 AKT1 protein P31749 UNIPROT ILF3 protein Q12906 UNIPROT "up-regulates activity" phosphorylation Ser647 RGRGRGGsIRGRGRG 9606 20870937 t llicata "Upon T cell activation, NF90 translocates from the nucleus into the cytoplasm, where it binds to the AU-rich element-containing 3' untranslated regions of IL-2 mRNA and stabilizes it.|Our previous work showed that CD28 costimulation of T cells activated AKT to phosphorylate NF90 at Ser647 and caused NF90 to undergo nuclear export and stabilize IL-2 mRNA." SIGNOR-252512 AKT1 protein P31749 UNIPROT STK4 protein Q13043 UNIPROT down-regulates phosphorylation Thr120 IIRLRNKtLTEDEIA 9606 19940129 t llicata "Akt interacts with mst1 and phosphorylates a highly conserved residue threonine 120 of mst1, which leads to inhibition of its kinase activity and nuclear translocation as well as the autophosphorylation of thr(183)." SIGNOR-252507 AKT1 protein P31749 UNIPROT STK4 protein Q13043 UNIPROT down-regulates phosphorylation Thr387 TMKRRDEtMQPAKPS 9606 23431053 t gcesareni "Full activation of mst1 requires an activation cleavage that is prevented by the phosphorylation of thr-387 by akt." SIGNOR-252537 AKT1 protein P31749 UNIPROT PRKAA1 protein Q13131 UNIPROT "down-regulates activity" phosphorylation -1 16340011 t gcesareni "It is proposed that the effect of insulin to antagonize AMP-activated protein kinase activation involves a hierarchical mechanism whereby Ser 485/Ser 491 phosphorylation by protein kinase B reduces subsequent phosphorylation of Thr 172 by LKB1 and the resulting activation of AMP-activated protein kinase." SIGNOR-252739 AKT1 protein P31749 UNIPROT STK3 protein Q13188 UNIPROT down-regulates phosphorylation Thr117 IIRLRNKtLIEDEIA 9606 20086174 t llicata "We determined that mst2 phosphorylation by akt limits mst2 activity in two ways: first, by blocking its binding to rassf1a and by promoting its association into the raf-1 inhibitory complex, and second, by preventing homodimerization of mst2, which is needed for its activation. we identified t117 and t384 as akt phosphorylation sites in mst2." SIGNOR-163533 AKT1 protein P31749 UNIPROT STK3 protein Q13188 UNIPROT down-regulates phosphorylation Thr384 GTMKRNAtSPQVQRP 9606 20086174 t llicata "We determined that mst2 phosphorylation by akt limits mst2 activity in two ways: first, by blocking its binding to rassf1a and by promoting its association into the raf-1 inhibitory complex, and second, by preventing homodimerization of mst2, which is needed for its activation. we identified t117 and t384 as akt phosphorylation sites in mst2." SIGNOR-163537 AKT1 protein P31749 UNIPROT STK3 protein Q13188 UNIPROT down-regulates phosphorylation Thr117 IIRLRNKtLIEDEIA 9606 BTO:0000150 20231902 t gcesareni "Akt phosphorylates mst2 at thr117 in vitro and in vivo, which leads to mst2 cleavage and kinase activity as well as nuclear translocation." SIGNOR-252509 AKT1 protein P31749 UNIPROT PDE3B protein Q13370 UNIPROT up-regulates phosphorylation Ser295 VIRPRRRsSCVSLGE 9606 10454575 t esanto "Pde3b is a physiological substrate of akt and that akt-mediated phosphorylation of pde3b on serine-273 is important for insulin-induced activation of pde3b." SIGNOR-252583 AKT1 protein P31749 UNIPROT PDE3B protein Q13370 UNIPROT "up-regulates activity" phosphorylation Ser295 VIRPRRRsSCVSLGE 10090 BTO:0000944 10454575 t "PDE3B is a physiological substrate of Akt and that Akt-mediated phosphorylation of PDE3B on serine-273 is important for insulin-induced activation of PDE3B" SIGNOR-252573 AKT1 protein P31749 UNIPROT PDE3B protein Q13370 UNIPROT "up-regulates activity" phosphorylation Ser318 CKIFRRPsLPCISRE 10090 BTO:0000011 10454575 t gcesareni "PDE3B is a physiological substrate of Akt and that Akt-mediated phosphorylation of PDE3B on serine-273 is important for insulin-induced activation of PDE3B." SIGNOR-252554 AKT1 protein P31749 UNIPROT MEF2D protein Q14814 UNIPROT up-regulates 9606 BTO:0000222 BTO:0000887;BTO:0001103 10896679 f 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-79338 AKT1 protein P31749 UNIPROT PEA15 protein Q15121 UNIPROT "up-regulates activity" phosphorylation Ser116 KDIIRQPsEEEIIKL 9606 BTO:0000007 12808093 t lperfetto "Protein kinase b/akt binds and phosphorylates ped/pea-15, stabilizing its antiapoptotic action." SIGNOR-102092 AKT1 protein P31749 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation Ser42 GGRKRRSsRRSAGGG 9606 20400976 t llicata "Moreover, phosphorylation of twist-1 at ser42 was shown in vivo in various human cancer tissues, suggesting that this post-translational modification ensures functional activation of twist-1 after promotion of survival during carcinogenesis." SIGNOR-164884 AKT1 protein P31749 UNIPROT EZH2 protein Q15910 UNIPROT "down-regulates activity" phosphorylation Ser21 CWRKRVKsEYMRLRQ 9606 16224021 t lperfetto "Enhancer of zeste homolog 2 (ezh2) is a methyltransferase that plays an important role in many biological processes through its ability to trimethylate lysine 27 in histone h3. Here, we show that akt phosphorylates ezh2 at serine 21 and suppresses its methyltransferase activity by impeding ezh2 binding to histone h3" SIGNOR-141043 AKT1 protein P31749 UNIPROT ZYX protein Q15942 UNIPROT down-regulates phosphorylation Ser142 PQPREKVsSIDLEID 9606 17572661 t llicata "Akt binds and phosphorylates zyxin on serine 142, leading to its association with acinus zyxin is a substrate of caspases, but akt phosphorylation fails to protect its proteolytic degradation" SIGNOR-156122 AKT1 protein P31749 UNIPROT MAP3K11 protein Q16584 UNIPROT down-regulates phosphorylation Ser674 PGRERGEsPTTPPTP 9606 BTO:0000938 12458207 t lperfetto "Negative regulation of mixed lineage kinase 3 by protein kinase b/akt leads to cell survivalthe expression of activated akt1 inhibits mlk3-mediated cell death in a manner dependent on serine 674 phosphorylation." SIGNOR-252592 AKT1 protein P31749 UNIPROT UBE2S protein Q16763 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr152 AARARLLtEIHGGAG 9606 BTO:0000007 27593939 t lperfetto "Mechanistically, Akt1 physically interacted with and phosphorylated UBE2S at Thr 152, enhancing its stability by inhibiting proteasomal degradation." SIGNOR-265078 AKT1 protein P31749 UNIPROT GAB2 protein Q9UQC2 UNIPROT down-regulates phosphorylation Ser159 LLRERKSsAPSHSSQ 9606 11782427 t lperfetto "Pkb constitutively associates with gab2, phosphorylates gab2 on a consensus phosphorylation site, ser159, in vitro and inhibits gab2 tyrosine phosphorylation." SIGNOR-252468 AKT1 protein P31749 UNIPROT PFKFB3 protein Q16875 UNIPROT up-regulates phosphorylation Ser461 NPLMRRNsVTPLASP 9606 15896703 t gcesareni "We also found that AMP activated protein kinase and protein kinases A, B, and C catalyzed the phosphorylation of Ser-460 of HBP1, and that in addition both isoforms are phosphorylated at a second, as yet undetermined site by protein kinase C. However, none of the phosphorylations had any effect on the intrinsic kinetic characteristics of either enzymatic activity, and neither did point mutation (mimicking phosphorylation), deletion, and alternative-splice modification of the HBP1 carboxy-terminal region. Instead, these phosphorylations and mutations decreased the sensitivity of the 6PF2K to a potent allosteric inhibitor, phosphoenolpyruvate, which appears to be the major regulatory mechanism." SIGNOR-252477 AKT1 protein P31749 UNIPROT CCDC88A protein Q3V6T2 UNIPROT unknown phosphorylation Ser1417 INRERQKsLTLTPTR 9606 16139227 t llicata "Akt phosphorylates serine at position 1416 in girdin, and phosphorylated girdin accumulates at the leading edge of migrating cells." SIGNOR-252482 AKT1 protein P31749 UNIPROT PDCD4 protein Q53EL6 UNIPROT down-regulates phosphorylation Ser457 RGRKRFVsEGDGGRL 9606 16357133 t gcesareni "Our results show that akt specifically phosphorylates ser(67) and ser(457) residues of pdcd4 in vitro and in vivo. We further show that phosphorylation of pdcd4 by akt causes nuclear translocation of pdcd4." SIGNOR-252488 AKT1 protein P31749 UNIPROT PDCD4 protein Q53EL6 UNIPROT down-regulates phosphorylation Ser67 KRRLRKNsSRDSGRG 9606 17053147 t gcesareni "Both akt and p70(s6k) phosphorylate pdcd4, allowing for binding of the e3-ubiquitin ligase beta-trcp and consequently ubiquitylation." SIGNOR-252496 AKT1 protein P31749 UNIPROT PDCD4 protein Q53EL6 UNIPROT down-regulates phosphorylation Ser67 KRRLRKNsSRDSGRG 9606 BTO:0000007 BTO:0001253 18296647 t gcesareni "Both akt and p70(s6k) phosphorylate pdcd4, allowing for binding of the e3-ubiquitin ligase beta-trcp and consequently ubiquitylation." SIGNOR-252505 AKT1 protein P31749 UNIPROT DAB2IP protein Q5VWQ8 UNIPROT "down-regulates activity" phosphorylation Ser971 STRLRQQsSSSKGDS 9606 27858941 t miannu "DAB2IP can be phosphorylated by RIP1 on Ser 604 within the PER domain, and by AKT1 on Ser 847 within the proline-rich domain. Although RIP1-mediated phosphorylation is stimulatory,40 a recent study reported that AKT-mediated phosphorylation inhibits DAB2IP functions" SIGNOR-254780 AKT1 protein P31749 UNIPROT TENT2 protein Q6PIY7 UNIPROT "down-regulates activity" phosphorylation Ser116 LSGERRYsMPPLFHT 9606 BTO:0000007 31057087 t miannu "We found that Gld2 activity is regulated by site-specific phosphorylation in its disordered N-terminal domain. We identified two phosphorylation sites (S62, S110) where phosphomimetic substitutions increased Gld2 activity and one site (S116) that markedly reduced activity. Using mass spectrometry, we confirmed that HEK 293 cells readily phosphorylate the N-terminus of Gld2. We identified protein kinase A (PKA) and protein kinase B (Akt1) as the kinases that site-specifically phosphorylate Gld2 at S116, abolishing Gld2-mediated nucleotide addition." SIGNOR-259405 AKT1 protein P31749 UNIPROT LARP1 protein Q6PKG0 UNIPROT "down-regulates activity" phosphorylation Ser1056 EGRKRCPsQSSSRPA 9606 BTO:0002181 28650797 t SARA "LARP1 is a direct substrate of Akt/S6K1 and mTORC1. Akt is a physiologically relevant primary kinase for S770/S979 phosphorylation of LARP1|Importantly, phosphorylation of LARP1 by mTORC1 and Akt/S6K1 dissociates it from 5’UTRs and relieves its inhibitory activity on RP mRNA translation." SIGNOR-260992 AKT1 protein P31749 UNIPROT LARP1 protein Q6PKG0 UNIPROT "down-regulates activity" phosphorylation Ser847 EHRPRTAsISSSPSE 9606 BTO:0002181 28650797 t SARA "LARP1 is a direct substrate of Akt/S6K1 and mTORC1. Akt is a physiologically relevant primary kinase for S770/S979 phosphorylation of LARP1|Importantly, phosphorylation of LARP1 by mTORC1 and Akt/S6K1 dissociates it from 5’UTRs and relieves its inhibitory activity on RP mRNA translation." SIGNOR-260991 AKT1 protein P31749 UNIPROT SH3RF1 protein Q7Z6J0 UNIPROT down-regulates phosphorylation Ser304 KNTKKRHsFTSLTMA 9606 17535800 t miannu "We report here that posh is a direct substrate for phosphorylation by akt in vivo and in vitro, and we identify a major site of akt phosphorylation as serine 304 of posh, which lies within the rac-binding domain. We further show that phosphorylation of posh results in a decreased ability to bind activated rac, as does phosphomimetic s304d and s304e mutation of posh." SIGNOR-252501 AKT1 protein P31749 UNIPROT ALYREF protein Q86V81 UNIPROT up-regulates phosphorylation Thr219 GGGTRRGtRGGARGR 9606 18562279 t llicata "Nuclear akt directly binds aly and phosphorylates it on the t219 residue. gfp-aly t219d displayed comparable activity to gfp control and wild-type aly, indicating that aly phosphorylation by akt is sufficient to enhance mrna export." SIGNOR-252518 AKT1 protein P31749 UNIPROT SP7 protein Q8TDD2 UNIPROT up-regulates phosphorylation 9606 21619873 t gcesareni "Akt, a member of the ser-ine/threonine-specific protein kinase, was found to phosphorylate osx and dlx5" SIGNOR-252514 AKT1 protein P31749 UNIPROT SP7 protein Q8TDD2 UNIPROT up-regulates phosphorylation 9606 21777568 t gcesareni "We found that Akt phosphorylates Osterix and that Akt activation increases protein stability, osteogenic activity and transcriptional activity of Osterix. We also found that BMP-2 increases the protein level of Osterix in an Akt activity-dependent manner." SIGNOR-195549 AKT1 protein P31749 UNIPROT PALLD protein Q8WX93 UNIPROT unknown phosphorylation Ser1118 VRRPRSRsRDSGDEN 9606 BTO:0000150 20471940 t llicata "Akt1, but not akt2, phosphorylates palladin at ser507 in a domain that is critical for f-actin bundling." SIGNOR-252510 AKT1 protein P31749 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser118 GRELRRMsDEFVDSF 9606 BTO:0000938 9346240 t lperfetto "Experiments in this study reveal that akt phosphorylates bad both in vitro and in vivo and that akt-mediated phosphorylation of bad effectively blocks bad induced cell death.[...] In addition, these findings implicate a particular phosphorylation site on bad, serine 136, in the suppression of bad-mediated death by akt.[...]The Phosphorylation of bad may lead to the prevention of cell death via a mechanism that involves the selective association of the phosphorylated forms of bad with 14-3-3 protein isoforms. Akt phosphorylates bad in vitro and in vivo we show that growth factor activation of the pi3'k/akt signaling pathway culminates in the phosphorylation of the bcl-2 family member bad, thereby suppressing apoptosis and promoting cell survival. Akt phosphorylates bad in vitro and in vivo erbb-mediated phosphorylation of bad by akt promotes survival by blocking the interaction of this pro-apoptotic molecule with bcl-2 and bcl-x proteins" SIGNOR-52859 AKT1 protein P31749 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT "down-regulates activity" phosphorylation Ser571 RMRSRSRsFSRHRSC 9606 BTO:0000759 17554339 t lperfetto "Here we describe a mechanism by which insulin, through the intermediary protein kinase akt2/protein kinase b (pkb)-beta, elicits the phosphorylation and inhibition of the transcriptional coactivator peroxisome proliferator-activated receptor-coactivator 1alpha (pgc-1alpha), a global regulator of hepatic metabolism during fasting / phosphorylation of pgc-1alpha At ser570 Is required for akt to inhibit recruitment of pgc-1alpha To chromatin." SIGNOR-252502 AKT1 protein P31749 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000938 9346240 t lperfetto "Experiments in this study reveal that akt phosphorylates bad both in vitro and in vivo and that akt-mediated phosphorylation of bad effectively blocks bad induced cell death.[...] In addition, these findings implicate a particular phosphorylation site on bad, serine 136, in the suppression of bad-mediated death by akt.[...]The Phosphorylation of bad may lead to the prevention of cell death via a mechanism that involves the selective association of the phosphorylated forms of bad with 14-3-3 protein isoforms. Akt phosphorylates bad in vitro and in vivo we show that growth factor activation of the pi3'k/akt signaling pathway culminates in the phosphorylation of the bcl-2 family member bad, thereby suppressing apoptosis and promoting cell survival. Akt phosphorylates bad in vitro and in vivo erbb-mediated phosphorylation of bad by akt promotes survival by blocking the interaction of this pro-apoptotic molecule with bcl-2 and bcl-x proteins" SIGNOR-52863 AKT1 protein P31749 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000007 9381178 t "Active Akt induced a significant increase in BAD phosphorylation. mutant BAD with alanine substitutions at Ser112 and Ser136 was not phosphorylated by active Akt . phosphorylation of BAD by Akt will preclude its binding to membrane-anchored Bcl-xL, leading to increased cell survival." SIGNOR-252562 AKT1 protein P31749 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000007 9381178 t "Active Akt induced a significant increase in BAD phosphorylation. mutant BAD with alanine substitutions at Ser112 and Ser136 was not phosphorylated by active Akt . phosphorylation of BAD by Akt will preclude its binding to membrane-anchored Bcl-xL, leading to increased cell survival." SIGNOR-252563 AKT1 protein P31749 UNIPROT KHSRP protein Q92945 UNIPROT "down-regulates activity" phosphorylation Ser193 GLPERSVsLTGAPES 9606 17177604 t lperfetto "Beta-catenin transcript can be stabilized by either wnt or pi3k-akt signaling activation. Akt phosphorylates ksrp at a unique serine residue akt phosphorylates the mrna decay-promoting factor ksrp at a unique serine residue, induces its association with the multifunctional protein 14-3-3, and prevents ksrp interaction with the exoribonucleolytic complex exosome." SIGNOR-252497 AKT1 protein P31749 UNIPROT AKT1S1 protein Q96B36 UNIPROT "down-regulates activity" phosphorylation Thr246 LPRPRLNtSDFQKLK 9606 BTO:0000007 12524439 t gcesareni "Treatment of these cells with 4-hydroxytamoxifen stimulated the phosphorylation of wt PRAS40 but not the mutant PRAS40 in which Thr-246 was mutated. These results demonstrate that activation of Akt alone is sufficient to induce phosphorylation of PRAS40" SIGNOR-252544 AKT1 protein P31749 UNIPROT SCYL1 protein Q96KG9 UNIPROT "up-regulates activity" phosphorylation Thr469 STRHRVLtSAFSRAT 9606 BTO:0000567 24769208 t lperfetto "In previous work, we demonstrated that TEIF (transcriptional element-interacting factor) distributes in the centrosomes and regulates centrosome status under both physiologic and pathologic conditions.|A consensus motif for Akt phosphorylation (RHRVLT) proved to be involved in centrosomal TEIF localization, and the 469-threonine of this motif may be phosphorylated by Akt both in vitro and in vivo. Elimination of this phosphorylated site on TEIF caused reduced centrosome distribution and centrosome splitting or amplification." SIGNOR-265496 AKT1 protein P31749 UNIPROT DLC1 protein Q96QB1 UNIPROT unknown phosphorylation Ser766 VTRTRSLsACNKRVG 10116 BTO:0000443 16338927 t gcesareni "We have demonstrated that Ser-322 is phosphorylated upon insulin stimulation of intact cells and that this site is directly phosphorylated in vitro by PKB and ribosomal S6 kinase, members of the AGC (protein kinases A, G, and C) family of insulin-stimulated protein kinases" SIGNOR-252550 AKT1 protein P31749 UNIPROT TP53RK protein Q96S44 UNIPROT up-regulates phosphorylation Ser250 RLRGRKRsMVG 9606 17712528 t gcesareni "Here we show that such an activation of prpk is mediated by another kinase, akt/pkb, which phosphorylates prpk at ser250." SIGNOR-252503 AKT1 protein P31749 UNIPROT AGAP2 protein Q99490 UNIPROT up-regulates phosphorylation Ser985 THLSRVRsLDLDDWP 9606 BTO:0001130 19176382 t llicata "In addition, we have found that activated akt can bind and phosphorylate ggap2 at serine 629, which enhances gtp binding by ggap2." SIGNOR-183543 AKT1 protein P31749 UNIPROT PHB2 protein Q99623 UNIPROT down-regulates binding 10090 15173318 t lperfetto "Akt binds prohibitin 2 and relieves its repression of myod and muscle differentiation" SIGNOR-252541 AKT1 protein P31749 UNIPROT MAP3K5 protein Q99683 UNIPROT "down-regulates activity" phosphorylation Ser83 ATRGRGSsVGGGSRR 9606 BTO:0000007 11154276 t lperfetto "Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1 akt decreased ask1 kinase activity stimulated by both oxidative stress and overexpression in 293 cells by phosphorylating a consensus akt site at serine 83 of ask1." SIGNOR-252465 AKT1 protein P31749 UNIPROT PHF20 protein Q9BVI0 UNIPROT down-regulates phosphorylation Ser291 ELRRRKIsKGCEVPL 9606 22334668 t llicata "Akt phosphorylates phf20 at ser(291) in vitro and in vivo, which results in its translocation from the nucleus to the cytoplasm and attenuation of phf20 function." SIGNOR-252529 AKT1 protein P31749 UNIPROT CDCA7 protein Q9BWT1 UNIPROT down-regulates phosphorylation Thr163 SRRPRRRtFPGVASR 9606 23166294 t llicata "The prosurvival kinase akt phosphorylates cdca7 at threonine 163, promoting binding to 14-3-3, dissociation from myc, and sequestration to the cytoplasm. we have mapped the domains of interaction and have discovered that akt phosphorylates cdca7 near this contact region, leading to loss of its association with myc, binding to 14-3-3 proteins, and exclusion from the nucleus." SIGNOR-252533 AKT1 protein P31749 UNIPROT NIBAN1 protein Q9BZQ8 UNIPROT unknown phosphorylation Ser602 ASPARRAsAILPGVL 9606 22510990 t llicata "We demonstrate here that ultraviolet irradiation induces phosphorylation of niban at s602 by akt, which increases the association of niban with nucleophosmin and disassociation of nucleophosmin from the mdm2 complex." SIGNOR-252530 AKT1 protein P31749 UNIPROT WNK1 protein Q9H4A3 UNIPROT up-regulates phosphorylation Thr60 EYRRRRHtMDKDSRG 9606 16081417 t llicata "Phosphorylation of wnk1 on thr-58 contributes to sgk1 activation. these data suggest that activation of sgk1 by wnk1 requires the catalytic activity of akt." SIGNOR-252481 AKT1 protein P31749 UNIPROT RANBP3 protein Q9H6Z4 UNIPROT unknown phosphorylation Ser126 VKRERTSsLTQFPPS 9606 18280241 t llicata "Akt regulates ranbp3 phosphorylation in vitro and in vivo" SIGNOR-252504 AKT1 protein P31749 UNIPROT LTB4R2 protein Q9NPC1 UNIPROT unknown phosphorylation Thr324 GGRSREGtMELRTTP 9606 22044535 t llicata "Blt2 phosphorylation at thr355 by akt is necessary for blt2-mediated chemotaxis." SIGNOR-252516 AKT1 protein P31749 UNIPROT METTL1 protein Q9UBP6 UNIPROT down-regulates phosphorylation Ser27 YYRQRAHsNPMADHT 9606 3627513 t lperfetto "The trna methylase mettl1 is phosphorylated and inactivated by pkb and rsk in vitro and in cells" SIGNOR-24994 AKT1 protein P31749 UNIPROT PIKFYVE protein Q9Y2I7 UNIPROT up-regulates phosphorylation Ser307 PARNRSAsITNLSLD 9606 BTO:0000887 15546921 t gcesareni "Here we report that serine318 on the fyve domain-containing ptdins3p 5-kinase (pikfyve) is a novel substrate for pkb, and show that phosphorylation stimulates the ptdins3p 5-kinase activity of the enzyme." SIGNOR-252474 AKT1 protein P31749 UNIPROT CARHSP1 protein Q9Y2V2 UNIPROT unknown phosphorylation Ser52 TRRTRTFsATVRASQ 9606 BTO:0000671 15910284 t lperfetto "These and other results demonstrate that crhsp24 is phosphorylated at ser52 by pkbalpha in response to igf-1, at ser52 by pkbalpha and rsk in response to egf" SIGNOR-252478 AKT1 protein P31749 UNIPROT RNF11 protein Q9Y3C5 UNIPROT "down-regulates quantity" phosphorylation Thr135 DWLMRSFtCPSCMEP 9606 BTO:0003474 16123141 t gcesareni "Upon inhibition of the AKT pathway or mutation of T135, the phosphorylation at one of these sites is virtually eliminated, suggesting that AKT may phosphorylate RNF11 at T135. Moreover, RNF11 is phosphorylated by AKT in vitro and is recognized by phospho-AKT substrate antibodies. RNF11 shows enhanced binding to 14-3-3 in WM239 cells compared with that seen in the parental WM35 cells which have low AKT activity" SIGNOR-252558 AKT1 protein P31749 UNIPROT TSC1/TSC2 complex SIGNOR-C101 SIGNOR "down-regulates activity" phosphorylation 10090 BTO:0000944 12150915 t lperfetto "We have shown thataktregulates the tsc1-tsc2 complex by directly phosphorylating tsc2. Tsc2 is inactivated by akt-dependent phosphorylation, which destabilizes tsc2 and disrupts its interaction with tsc1. Tsc2 is inactivated by akt-dependent phosphorylation, which destabilizes tsc2 and disrupts its interaction with tsc1akt has been shown to directly phosphorylate two sites on tsc2 (s939 and t1462 on the full-length human protein), which are conserved and phosphorylated in drosophila tsc2, and is likely to phosphorylate two or three additional sites (s981 and s1130/s1132)." SIGNOR-235628 AKT1 protein P31749 UNIPROT TSC1/TSC2 complex SIGNOR-C101 SIGNOR "down-regulates activity" phosphorylation 10090 BTO:0000011 19593385 t 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-235340 AKT1 protein P31749 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 BTO:0001454 19609947 t lperfetto "Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta" SIGNOR-217460 AKT1 protein P31749 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR down-regulates phosphorylation 9606 BTO:0000887;BTO:0001103 17130464 t "Translocation from Cytoplasm to Nucleus" lperfetto "Phosphorylation of pras40-thr246 by pkb/akt, and pras40-ser183 and pras40-ser221 by mtorc1 results in dissociation from mtorc1, and its binding to 14-3-3 proteins." SIGNOR-252540 AKT1 protein P31749 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR down-regulates phosphorylation 9606 BTO:0000887;BTO:0001103;BTO:0001760 20138985 t 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-252539 AKT1 protein P31749 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates phosphorylation 9606 BTO:0001103 15829723 t 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 AKT1 protein P31749 UNIPROT P300/PCAF complex SIGNOR-C7 SIGNOR up-regulates phosphorylation 9606 BTO:0000887 17964260 t lperfetto "Akt1 and 2 promote the association of myod with p300 and pcaf acetyltransferases, via direct phosphorylation of p300." SIGNOR-217670 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser256 SPRRRAAsMDNNSKF -1 BTO:0000318 10377430 t 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-252856 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Thr24 LPRPRSCtWPLPRPE -1 BTO:0000318 10377430 t 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-252857 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser319 TFRPRTSsNASTISG 9606 11237865 t 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-252860 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser197 APRRRAAsMDSSSKL 9606 16272144 t lperfetto "Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression" SIGNOR-252853 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser262 TFRPRSSsNASSVST 9606 16272144 t lperfetto "Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression" SIGNOR-252854 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Thr32 QSRPRSCtWPLPRPE 9606 16272144 t lperfetto "Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression" SIGNOR-252855 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 18394876 t lperfetto "The phosphorylation of the two remaining akt-dependent sites inhibits foxo6 transcriptional activity" SIGNOR-252859 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 21620960 t gcesareni "Akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. In addition, phosphorylation of afx by protein kinase b inhibits its transcriptional activity." SIGNOR-252847 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 21798082 t gcesareni "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-252843 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates relocalization 10090 BTO:0002572 18423396 t lperfetto "Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export ofFoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation." SIGNOR-252852 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Ser197 APRRRAAsMDSSSKL 10090 BTO:0004245 10217147 t "Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf -16 (refs 5, 6, 9), both in vitro and in vivo." SIGNOR-252861 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Ser262 TFRPRSSsNASSVST 10090 BTO:0004245 10217147 t "Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf -16 (refs 5, 6, 9), both in vitro and in vivo." SIGNOR-252862 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation 10090 BTO:0002572 18423396 t lperfetto "Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export ofFoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation." SIGNOR-252851 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t 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-252849 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Ser315 DFRSRTNsNASTVSG 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t 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-252850 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t 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-252848 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation 9606 BTO:0001103 21798082 t 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-252841 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates quantity by destabilization" phosphorylation Ser253 APRRRAVsMDNSNKY 19951971 t 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-252844 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates quantity by destabilization" phosphorylation Ser315 DFRSRTNsNASTVSG 19951971 t 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-252845 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates quantity by destabilization" phosphorylation Thr32 QSRPRSCtWPLQRPE 19951971 t 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-252846 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates quantity by destabilization" phosphorylation 9606 21440011 t 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-252858 AKT2 protein P31751 UNIPROT CHUK protein O15111 UNIPROT up-regulates phosphorylation Thr23 EMRERLGtGGFGNVC 9606 BTO:0001454 SIGNOR-C14 19609947 t gcesareni "Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta" SIGNOR-187010 AKT2 protein P31751 UNIPROT HTRA2 protein O43464 UNIPROT down-regulates phosphorylation Ser212 RVRVRLLsGDTYEAV 9606 17311912 t lperfetto "Akt attenuation of the serine protease activity of htra2/omi through phosphorylation of serine 212" SIGNOR-153327 AKT2 protein P31751 UNIPROT STK3 protein Q13188 UNIPROT down-regulates phosphorylation Thr117 IIRLRNKtLIEDEIA 9606 BTO:0000150 20231902 t gcesareni "Akt phosphorylates mst2 at thr117 in vitro and in vivo, which leads to mst2 cleavage and kinase activity as well as nuclear translocation." SIGNOR-164302 AKT2 protein P31751 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates activity" phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t 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 akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites." SIGNOR-236671 AKT2 protein P31751 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates activity" phosphorylation Ser315 DFRSRTNsNASTVSG 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t 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 akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites." SIGNOR-235960 AKT2 protein P31751 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates activity" phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t 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 akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites." SIGNOR-236675 AKT2 protein P31751 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser253 APRRRAVsMDNSNKY 19951971 t 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-249640 AKT2 protein P31751 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser315 DFRSRTNsNASTVSG 19951971 t 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-249641 AKT2 protein P31751 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr32 QSRPRSCtWPLQRPE 19951971 t 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-249639 AKT2 protein P31751 UNIPROT ESR1 protein P03372 UNIPROT "up-regulates activity" phosphorylation Ser167 GGRERLAsTNDKGSM 9534 BTO:0001538 11139588 t "AKT activate ERalpha in the absence of estrogen. The consensus AKT phosphorylation site Ser-167 of ERalpha is required for phosphorylation and activation by AKT." SIGNOR-251490 AKT2 protein P31751 UNIPROT RAF1 protein P04049 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000150 10576742 t lperfetto "Akt (protein kinase b), a member of a different signaling pathway that also regulates these responses, interacted with raf and phosphorylated this protein at a highly conserved serine residue in its regulatory domain in vivo. This phosphorylation of raf by akt inhibited activation of the raf-mek-erk signaling pathway and shifted the cellular response in a human breast cancer cell line from cell cycle arrest to proliferation." SIGNOR-235678 AKT2 protein P31751 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser82 RALSRQLsSGVSEIR 9606 19593530 t "10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro." lperfetto "First, the akt1, akt2, and akt3 isoforms can bind directly to hsp27 and can be found in a complex with p38 mapk, mk2, and hsp27 [98_100]. Second, rane and colleagues showed that akt could phosphorylate hsp27 at ser-82, but not ser-15 or ser-78, in vitro, while co-expression of an active akt mutant and hsp27 in hek cells resulted in hsp27 phosphorylation at the same residue." SIGNOR-186776 AKT2 protein P31751 UNIPROT BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser364 FGQRDRSsSAPNVHI 9606 10869359 t gcesareni "We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf" SIGNOR-78681 AKT2 protein P31751 UNIPROT BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser428 GPQRERKsSSSSEDR 9606 10869359 t gcesareni "We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf" SIGNOR-78685 AKT2 protein P31751 UNIPROT BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr440 EDRNRMKtLGRRDSS 9606 10869359 t gcesareni "We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf" SIGNOR-78689 AKT2 protein P31751 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Thr567 QGRDKYKtLRQIRQG 9606 15531580 t llicata "Purified akt directly phosphorylates recombinant ezrin at threonine 567 in vitro in an atp-dependent manner. ezrin activation after initiation of na+-glucose cotransport requires akt2 expression" SIGNOR-130260 AKT2 protein P31751 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser119 EILSRRPsYRKILND 9606 9829964 t gcesareni "Creb is a nuclear target for activation via the growth factor-dependent ser/thr kinase akt/pkb. When overexpressed in serum-stimulated cells, akt/pkb potently induced ser-133 phosphorylation of creb and promoted recruitment of cbp." SIGNOR-62253 RELA protein Q04206 UNIPROT REL/RELA complex SIGNOR-C68 SIGNOR "form complex" binding 9606 BTO:0000671 9056676 t miannu "Tnf-alpha induces the formation of a specific kappab binding complex, mainly composed of nf-kappab subunits rela and c-rel." SIGNOR-46948 AKT2 protein P31751 UNIPROT PTPN1 protein P18031 UNIPROT "down-regulates activity" phosphorylation Ser50 RNRYRDVsPFDHSRI 10090 BTO:0000944 11579209 t lperfetto "We conclude that ptp1b is a novel substrate for akt and that phosphorylation of ptp1b by akt at ser(50) may negatively modulate its phosphatase activity creating a positive feedback mechanism forinsulin signaling" SIGNOR-235491 AKT2 protein P31751 UNIPROT NFKB1 protein P19838 UNIPROT up-regulates 9606 17604717 f gcesareni "Several studies have demonstrated that akt signaling can activate the nf-kb transcription factor downstream of a variety of stimuli, such as tumor necrosis factor (tnfalfa)" SIGNOR-156530 AKT2 protein P31751 UNIPROT NOS3 protein P29474 UNIPROT "up-regulates activity" phosphorylation Ser615 SYKIRFNsISCSDPL 9606 BTO:0001853 24379783 t lperfetto "The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites" SIGNOR-251624 AKT2 protein P31751 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Ser552 QDTQRRTsMGGTQQQ 9606 17287208 t lperfetto "Phosphorylation of beta-catenin by akt promotes beta-catenin transcriptional activitywe have demonstrated that akt phosphorylates beta-catenin at ser552 in vitro and in vivo." SIGNOR-152958 AKT2 protein P31751 UNIPROT BMI1 protein P35226 UNIPROT "up-regulates activity" phosphorylation Ser316 ANRPRKSsVNGSSAT 22505453 t lperfetto "the polycomb group silencing protein Bmi1 can be phosphorylated by AKT, which enhances its oncogenic potential in PCa. Overexpression of Bmi1 can act in combination with PTEN haploinsufficiency to induce invasive carcinogenic formation in the prostate" SIGNOR-249582 AKT2 protein P31751 UNIPROT CDKN1A protein P38936 UNIPROT "down-regulates activity" binding 9606 BTO:0000222 16982699 t gcesareni "Whereas akt1 phosphorylates p21, inducing its release from cdk2 and cytoplasmic localization as previously described for akt, akt2 binds p21 in the region spanning the t145 site of p21, thus competing with phosphorylation by akt1 and inducing its accumulation in the nucleus. These distinct roles of akt/pkb isoforms in modulating proliferation and p21 have important implications for the development of drugs aimed at inhibiting cancer cell proliferation." SIGNOR-149705 AKT2 protein P31751 UNIPROT MTOR protein P42345 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 12782654 f gcesareni "It was shown recently that akt activates mtor through direct phosphorylation of tsc2 the serine/threonine kinase akt is an upstream positive regulator of the mammalian target of rapamycin (mtor). However, the mechanism by which akt activates mtor is not fully understood. The known pathway by which akt activates mtor is via direct phosphorylation and tuberous sclerosis complex 2 (tsc2), which is a negative regulator of mtor." SIGNOR-101324 AKT2 protein P31751 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Thr157 GIRKRPAtDDSSTQN 9606 BTO:0000150 12244303 t gcesareni "Akt-induced t157 phosphorylation causes retention of p27(kip1) in the cytoplasm, precluding p27(kip1)-induced g1 arrest.[__]Thus, cytoplasmic relocalization of p27(kip1), secondary to akt-mediated phosphorylation, is a novel mechanism whereby the growth inhibitory properties of p27(kip1) are functionally inactivated and the proliferation of breast cancer cells is sustained." SIGNOR-93122 AKT2 protein P31751 UNIPROT TSC2 protein P49815 UNIPROT down-regulates phosphorylation Ser939 SFRARSTsLNERPKS 9606 12150915 t gcesareni "We demonstrate here that tuberin is phosphorylated on s939 and t1462 in response to pi3k activation. Our results are consistent with akt being the pi3k-depen-dent tuberin kinase. The pi3k-akt-mediated phosphorylation of tuberin would inhibit the function of the tuberin-hamartin complex." SIGNOR-91041 AKT2 protein P31751 UNIPROT TSC2 protein P49815 UNIPROT down-regulates phosphorylation Thr1462 GLRPRGYtISDSAPS 9606 12150915 t gcesareni "We demonstrate here that tuberin is phosphorylated on s939 and t1462 in response to pi3k activation. Our results are consistent with akt being the pi3k-depen-dent tuberin kinase. The pi3k-akt-mediated phosphorylation of tuberin would inhibit the function of the tuberin-hamartin complex." SIGNOR-91045 AKT2 protein P31751 UNIPROT TSC2 protein P49815 UNIPROT down-regulates phosphorylation Ser939 SFRARSTsLNERPKS 9606 12172553 t gcesareni "We demonstrate here that tuberin is phosphorylated on s939 and t1462 in response to pi3k activation. Our results are consistent with akt being the pi3k-depen-dent tuberin kinase. The pi3k-akt-mediated phosphorylation of tuberin would inhibit the function of the tuberin-hamartin complex." SIGNOR-91388 AKT2 protein P31751 UNIPROT TSC2 protein P49815 UNIPROT down-regulates phosphorylation Thr1462 GLRPRGYtISDSAPS 9606 12172553 t gcesareni "We demonstrate here that tuberin is phosphorylated on s939 and t1462 in response to pi3k activation. Our results are consistent with akt being the pi3k-depen-dent tuberin kinase. The pi3k-akt-mediated phosphorylation of tuberin would inhibit the function of the tuberin-hamartin complex." SIGNOR-91392 AKT2 protein P31751 UNIPROT TSC2 protein P49815 UNIPROT down-regulates phosphorylation Ser939 SFRARSTsLNERPKS 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni "We demonstrate here that tuberin is phosphorylated on s939 and t1462 in response to pi3k activation. Our results are consistent with akt being the pi3k-depen-dent tuberin kinase. The pi3k-akt-mediated phosphorylation of tuberin would inhibit the function of the tuberin-hamartin complex." SIGNOR-183636 AKT2 protein P31751 UNIPROT TSC2 protein P49815 UNIPROT down-regulates phosphorylation Thr1462 GLRPRGYtISDSAPS 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni "We demonstrate here that tuberin is phosphorylated on s939 and t1462 in response to pi3k activation. Our results are consistent with akt being the pi3k-depen-dent tuberin kinase. The pi3k-akt-mediated phosphorylation of tuberin would inhibit the function of the tuberin-hamartin complex." SIGNOR-183640 AKT2 protein P31751 UNIPROT FOXO1 protein Q12778 UNIPROT "down-regulates activity" phosphorylation Thr24 LPRPRSCtWPLPRPE 9606 10377430 t lperfetto "Our results demonstrate that pkb/akt directly phosphorylates fkhr1, a member of the closely related fkhr subclass of the forkhead family of transcription factors, on at least two residues (threonine-24 and serine-253). These results indicate that phosphorylation by pkbyakt negatively regulates fkhr1 by promoting export from the nucleus." SIGNOR-68656 AKT2 protein P31751 UNIPROT GSK3B protein P49841 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000586 SIGNOR-C110 16293724 t lperfetto "We show that PGE2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor, EP2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase Akt by free G protein betagamma subunits and the direct association of the G protein alphas subunit with the regulator of G protein signaling (RGS) domain of axin. This leads to the inactivation and release of glycogen synthase kinase 3beta from its complex with axin, thereby relieving the inhibitory phosphorylation of beta-catenin and activating its signaling pathway." SIGNOR-235718 AKT2 protein P31751 UNIPROT GSK3B protein P49841 UNIPROT "down-regulates activity" phosphorylation Ser9 SGRPRTTsFAESCKP 9606 23552696 t lperfetto "Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3_ (GSK3_). The AKT-mediated phosphorylation of glycogen synthase kinase 3_ on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1" SIGNOR-245420 AKT2 protein P31751 UNIPROT ACLY protein P53396 UNIPROT unknown phosphorylation Ser455 PAPSRTAsFSESRAD 10116 BTO:0000443 12107176 t gcesareni "Taken together, these results demonstrate that serine 454 of ATP-citrate lyase is a novel and major in vivo substrate for protein kinase B." SIGNOR-245263 AKT2 protein P31751 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Ser196 KLRRRFSsLHFMVEV 9606 15004527 t gcesareni "Akt phosphorylated recombinant casp9 in vitro on serine-196 and inhibited its protease activity" SIGNOR-123243 AKT2 protein P31751 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Ser196 KLRRRFSsLHFMVEV 9606 9812896 t gcesareni "Akt phosphorylated recombinant casp9 in vitro on serine-196 and inhibited its protease activity" SIGNOR-61561 AKT2 protein P31751 UNIPROT XIAP protein P98170 UNIPROT up-regulates phosphorylation Ser87 VGRHRKVsPNCRFIN 9606 14645242 t llicata "Here, we demonstrate that akt, including akt1 and akt2, interacts with and phosphorylates x-linked inhibitor of apoptosis protein (xiap) at residue serine-87 in vitro and in vivo. Phosphorylation of xiap by akt protects xiap from ubiquitination and degradation in response to cisplatin. Moreover, autoubiquitination of xiap is also inhibited by akt." SIGNOR-119492 AKT2 protein P31751 UNIPROT FOXO4 protein P98177 UNIPROT "down-regulates activity" phosphorylation Thr32 QSRPRSCtWPLPRPE 10090 BTO:0000944 11313479 t "Phosphorylation of AFX by PKB occurs in the nucleus. Phosphorylation of S193 reduces the rate of nuclear import. PKB-mediated phosphorylation of AFX, therefore, attenuates the import of the transcription factor, which shifts the localization of the protein from the nucleus to the cytoplasm and results in the inhibition of AFX transcriptional activity." SIGNOR-251491 AKT2 protein P31751 UNIPROT FOXO4 protein P98177 UNIPROT "down-regulates activity" phosphorylation Thr32 QSRPRSCtWPLPRPE 9606 16272144 t gcesareni "FOXO4 transcription factor, also referred to AFX, contains three putative phosphorylation motif sites for protein kinase B (PKB), Thr32, Ser197, and Ser262, and it is proposed that phosphorylated FOXO4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression.[...]These results indicate that phosphorylation at Thr32 and Ser197 is indispensable, whereas that at Ser262 is not critical, for regulation of the nuclear localization and transcriptional activity of FOXO4" SIGNOR-248055 AKT2 protein P31751 UNIPROT FOXO4 protein P98177 UNIPROT "down-regulates activity" phosphorylation 9606 21620960 t lperfetto "Akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. In addition, phosphorylation of afx by protein kinase b inhibits its transcriptional activity." SIGNOR-233529 AKT2 protein P31751 UNIPROT MDM2 protein Q00987 UNIPROT "up-regulates activity" phosphorylation Ser186 RQRKRHKsDSISLSF 9606 BTO:0000093 11504915 t lperfetto "Mitogen-induced activation of phosphatidylinositol 3-kinase (pi3-kinase) and its downstream target, the akt/pkb serine-threonine kinase, results in phosphorylation of mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of mdm2 from the cytoplasm into the nucleus.. Both akt expression and serum treatment induced phosphorylation of mdm2 at ser186." SIGNOR-109736 AKT2 protein P31751 UNIPROT MDM2 protein Q00987 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser166 SSRRRAIsETEENSD 9606 11504915 t lperfetto "Mitogen-induced activation of phosphatidylinositol 3-kinase (pi3-kinase) and its downstream target, the akt/pkb serine-threonine kinase, results in phosphorylation of mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of mdm2 from the cytoplasm into the nucleus.. Both akt expression and serum treatment induced phosphorylation of mdm2 at ser186." SIGNOR-109732 AKT2 protein P31751 UNIPROT POU5F1 protein Q01860 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr235 QARKRKRtSIENRVR 9606 BTO:0004180 23041284 t flangone "Here we show that in ECCs, Akt phosphorylated the master pluripotency factor Oct4 at threonine 235, and that the levels of phosphorylated Oct4 in ECCs correlated with resistance to apoptosis and tumorigenic potential. Phosphorylation of Oct4 increased its stability and facilitated its nuclear localization and its interaction with Sox2, which promoted the transcription of the core stemness genes POU5F1 and NANOG." SIGNOR-242097 AKT2 protein P31751 UNIPROT EP300 protein Q09472 UNIPROT up-regulates phosphorylation Ser1834 MLRRRMAsMQRTGVV 9606 16926151 t lperfetto "We find that suberoylanilide hydroxamic acid stimulates akt activity, which is required to phosphorylate p300 at ser(1834). Akt-mediated phosphorylation of p300 dramatically increases its acetyltransferase activity" SIGNOR-148987 AKT2 protein P31751 UNIPROT EP300 protein Q09472 UNIPROT up-regulates phosphorylation 9606 BTO:0000887 SIGNOR-C7 17964260 t gcesareni "Akt1 and 2 promote the association of myod with p300 and pcaf acetyltransferases, via direct phosphorylation of p300." SIGNOR-158627 AKT2 protein P31751 UNIPROT FOXO1 protein Q12778 UNIPROT "down-regulates activity" phosphorylation Ser256 SPRRRAAsMDNNSKF 9606 10377430 t lperfetto "Our results demonstrate that pkb/akt directly phosphorylates fkhr1, a member of the closely related fkhr subclass of the forkhead family of transcription factors, on at least two residues (threonine-24 and serine-253). These results indicate that phosphorylation by pkbyakt negatively regulates fkhr1 by promoting export from the nucleus." SIGNOR-68652 AKT2 protein P31751 UNIPROT STK4 protein Q13043 UNIPROT down-regulates phosphorylation Thr387 TMKRRDEtMQPAKPS 9606 23431053 t gcesareni "Full activation of mst1 requires an activation cleavage that is prevented by the phosphorylation of thr-387 by akt." SIGNOR-201125 AKT2 protein P31751 UNIPROT PCBP1 protein Q15365 UNIPROT "down-regulates activity" phosphorylation Ser43 VKRIREEsGARINIS 10090 BTO:0004183 20154680 t miannu "We show that heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1) binds a structural, 33-nucleotide TGF-beta-activated translation (BAT) element in the 3' untranslated region of disabled-2 (Dab2) and interleukin-like EMT inducer (ILEI) transcripts, and represses their translation.TGF-beta activation leads to phosphorylation at Ser 43 of hnRNP E1 by protein kinase Bbeta/Akt2, inducing its release from the BAT element and translational activation of Dab2 and ILEI messenger RNAs." SIGNOR-262625 AKT2 protein P31751 UNIPROT MAPK14 protein Q16539 UNIPROT "down-regulates activity" 9606 BTO:0000150 12697749 f lperfetto "Our data indicate that akt2 inhibits cisplatin-induced jnk/p38 and bax activation through phosphorylation of ask1" SIGNOR-100591 AKT2 protein P31751 UNIPROT STXBP4 protein Q6ZWJ1 UNIPROT "down-regulates activity" phosphorylation Ser99 GAKLRLEsAWEIAFI 10029 BTO:0000246 15753124 t miannu "Akt2 phosphorylates Synip to regulate docking and fusion of GLUT4-containing vesicles. These data demonstrate that insulin activation of Akt2 specifically regulates the docking/fusion step of GLUT4-containing vesicles at the plasma membrane through the regulation of Synip phosphorylation and Synip-Syntaxin4 interaction.Thus, our data demonstrate that insulin-stimulated Akt2-dependent phosphorylation of Synip on serine residue 99 results in reduced binding interactions between Synip and Syntaxin4." SIGNOR-262635 AKT2 protein P31751 UNIPROT SH3RF1 protein Q7Z6J0 UNIPROT down-regulates phosphorylation Ser304 KNTKKRHsFTSLTMA 9606 17535800 t gcesareni "Overexpression of posh induces apoptosis in a variety of cell types, but apoptosis can be prevented by co-expressing the pro-survival protein kinase akt. We report here that posh is a direct substrate for phosphorylation by akt in vivo and in vitro, and we identify a major site of akt phosphorylation as serine 304 of posh, which lies within the rac-binding domain. We further show that phosphorylation of posh results in a decreased ability to bind activated rac" SIGNOR-155233 AKT2 protein P31751 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 10949026 t gcesareni "Ser-136 is the major phosphoacceptor site for akt;akt can weakly phosphorilate ser-155." SIGNOR-81110 AKT2 protein P31751 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 10949026 t gcesareni "Ser-136 is the major phosphoacceptor site for akt;akt can weakly phosphorilate ser-155." SIGNOR-81114 AKT2 protein P31751 UNIPROT AKT1S1 protein Q96B36 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C3 17277771 t gcesareni "Furthermore, pras40 phosphorylation by akt and association with 14-3-3, a cytosolic anchor protein, are crucial for insulin to stimulate mtor. These findings identify pras40 as an important regulator of insulin sensitivity of the akt-mtor pathway and a potential target for the treatment of cancers, insulin resistance and hamartoma syndromes." SIGNOR-152936 AKT2 protein P31751 UNIPROT AKT1S1 protein Q96B36 UNIPROT "down-regulates activity" phosphorylation Thr246 LPRPRLNtSDFQKLK 9606 BTO:0000007 12524439 t gcesareni "1) PRAS40 was phosphorylated in vitro by purified Akt on the same site that was phosphorylated in insulin-treated cells; 2) activation of an inducible Akt was alone sufficient to stimulate the phosphorylation of PRAS40; and 3) cells lacking Akt1 and Akt2 exhibit a diminished ability to phosphorylate this protein" SIGNOR-248046 AKT2 protein P31751 UNIPROT MAP3K5 protein Q99683 UNIPROT "down-regulates activity" phosphorylation Ser83 ATRGRGSsVGGGSRR 9606 BTO:0000150 12697749 t lperfetto "Akt2 interacts with and phosphorylates ask1 at ser-83 resulting in inhibition of its kinase activity" SIGNOR-100588 AKT2 protein P31751 UNIPROT ANKRD2 protein Q9GZV1 UNIPROT up-regulates phosphorylation Ser99 QERVRKTsLDLRREI 10090 BTO:0000165;BTO:0000222 21737686 t llicata "In vitro and in vivo studies confirmed that akt phosphorylates ankrd2 at ser-99. moreover, the forced expression of a phosphorylation-defective mutant form of ankrd2 in c2c12 myoblasts promoted a faster differentiation program, implicating akt-dependent phosphorylation at ser-99 in the negative regulation of myogenesis in response to stress conditions." SIGNOR-236978 AKT2 protein P31751 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT down-regulates phosphorylation Ser571 RMRSRSRsFSRHRSC 9606 17554339 t miannu "Here we describe a mechanism by which insulin, through the intermediary protein kinase akt2/protein kinase b (pkb)-beta, elicits the phosphorylation and inhibition of the transcriptional coactivator peroxisome proliferator-activated receptor-coactivator 1alpha (pgc-1alpha), a global regulator of hepatic metabolism during fasting / phosphorylation of pgc-1? At ser?570 Is required for akt to inhibit recruitment of pgc-1? To chromatin." SIGNOR-155536 AKT2 protein P31751 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT "down-regulates activity" phosphorylation Ser571 RMRSRSRsFSRHRSC 10090 17554339 t miannu "Here we describe a mechanism by which insulin, through the intermediary protein kinase Akt2/protein kinase B (PKB)-beta, elicits the phosphorylation and inhibition of the transcriptional coactivator peroxisome proliferator-activated receptor-coactivator 1alpha (PGC-1alpha), a global regulator of hepatic metabolism during fasting.  Akt phosphorylates PGC-1α at Ser 570." SIGNOR-262626 AKT2 protein P31751 UNIPROT MYO5A protein Q9Y4I1 UNIPROT "up-regulates activity" phosphorylation Thr1650 PTGLRKRtSSIADEG 10090 BTO:0000944 17515613 t miannu "Here we identify an Akt consensus phosphorylation motif in the actin-based motor protein myosin 5a and show that insulin stimulation leads to phosphorylation of myosin 5a at serine 1650. This Akt-mediated phosphorylation event enhances the ability of myosin 5a to interact with the actin cytoskeleton.Taken together, these data indicate that myosin 5a is a newly identified direct substrate of Akt2 and, upon insulin stimulation, phosphorylated myosin 5a facilitates anterograde movement of GLUT4 vesicles along actin to the cell surface." SIGNOR-262632 AKT2 protein P31751 UNIPROT TSC1/TSC2 complex SIGNOR-C101 SIGNOR "down-regulates activity" phosphorylation 10090 BTO:0000011 19593385 t 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-235852 AKT2 protein P31751 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 BTO:0001454 19609947 t lperfetto "Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta" SIGNOR-217463 RYK protein P34925 UNIPROT FZD8 protein Q9H461 UNIPROT up-regulates binding 9606 17035295 t gcesareni "Interaction between ryk and fz has been reported, suggesting that the two proteins may form a multi-receptor complex signalling through the canonical pathway" SIGNOR-150010 AKT2 protein P31751 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR "up-regulates activity" phosphorylation 9606 17277771 t lperfetto "Furthermore, pras40 phosphorylation by akt and association with 14-3-3, a cytosolic anchor protein, are crucial for insulin to stimulate mtor. These findings identify pras40 as an important regulator of insulin sensitivity of the akt-mtor pathway and a potential target for the treatment of cancers, insulin resistance and hamartoma syndromes." SIGNOR-235967 AKT2 protein P31751 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000007 17386266 t lperfetto "Insulin-stimulated phosphorylation of pras40 by akt/pkb suppresses its mtorc1 inhibitory activity." SIGNOR-236705 AKT2 protein P31751 UNIPROT P300/PCAF complex SIGNOR-C7 SIGNOR up-regulates phosphorylation 9606 BTO:0000887 17964260 t lperfetto "Akt1 and 2 promote the association of myod with p300 and pcaf acetyltransferases, via direct phosphorylation of p300." SIGNOR-217673 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Ser256 SPRRRAAsMDNNSKF 9606 10377430 t lperfetto "Our results demonstrate that pkb/akt directly phosphorylates fkhr1, a member of the closely related fkhr subclass of the forkhead family of transcription factors, on at least two residues (threonine-24 and serine-253). These results indicate that phosphorylation by pkbyakt negatively regulates fkhr1 by promoting export from the nucleus." SIGNOR-252871 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Thr24 LPRPRSCtWPLPRPE 9606 10377430 t lperfetto "Our results demonstrate that pkb/akt directly phosphorylates fkhr1, a member of the closely related fkhr subclass of the forkhead family of transcription factors, on at least two residues (threonine-24 and serine-253). These results indicate that phosphorylation by pkbyakt negatively regulates fkhr1 by promoting export from the nucleus." SIGNOR-252872 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Thr32 QSRPRSCtWPLPRPE 10090 BTO:0000944 11313479 t "Phosphorylation of AFX by PKB occurs in the nucleus. Phosphorylation of S193 reduces the rate of nuclear import. PKB-mediated phosphorylation of AFX, therefore, attenuates the import of the transcription factor, which shifts the localization of the protein from the nucleus to the cytoplasm and results in the inhibition of AFX transcriptional activity." SIGNOR-252873 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Thr32 QSRPRSCtWPLPRPE 9606 16272144 t gcesareni "FOXO4 transcription factor, also referred to AFX, contains three putative phosphorylation motif sites for protein kinase B (PKB), Thr32, Ser197, and Ser262, and it is proposed that phosphorylated FOXO4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression.[...]These results indicate that phosphorylation at Thr32 and Ser197 is indispensable, whereas that at Ser262 is not critical, for regulation of the nuclear localization and transcriptional activity of FOXO4" SIGNOR-252870 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t 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 akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites." SIGNOR-252867 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Ser315 DFRSRTNsNASTVSG 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t 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 akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites." SIGNOR-252868 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t 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 akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites." SIGNOR-252869 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation 9606 21620960 t lperfetto "Akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. In addition, phosphorylation of afx by protein kinase b inhibits its transcriptional activity." SIGNOR-252866 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates quantity by destabilization" phosphorylation Ser253 APRRRAVsMDNSNKY 19951971 t 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-252863 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates quantity by destabilization" phosphorylation Ser315 DFRSRTNsNASTVSG 19951971 t 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-252864 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates quantity by destabilization" phosphorylation Thr32 QSRPRSCtWPLQRPE 19951971 t 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-252865 IL2RG protein P31785 UNIPROT JAK3 protein P52333 UNIPROT up-regulates binding 9606 BTO:0000776 18445337 t milica "Jak3 is associated with the ?c20,21. Cytokine binding mediates the trans-phosphorylation of receptor associated jak kinases, which in turn phosphorylate tyrosine residues on the receptors themselves. The receptor phosphotyrosines serve as docking sites for sh2 domain proteins including the stat family of transcription factors which are activated by jak-mediated phosphorylation." SIGNOR-178491 UQCRC1 protein P31930 UNIPROT "Mitochondrial respiratory chain complex III" complex SIGNOR-C279 SIGNOR "form complex" binding 30030361 t lperfetto "Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits" SIGNOR-262198 HNRNPH1 protein P31943 UNIPROT SRC protein P12931 UNIPROT "up-regulates quantity by expression" "post transcriptional regulation" 9606 BTO:0000938 9858532 t lperfetto "HnRNP H is a component of a splicing enhancer complex that activates a c-src alternative exon in neuronal cells." SIGNOR-261273 HNRNPH1 protein P31943 UNIPROT TERF2 protein Q15554 UNIPROT "down-regulates quantity" "post transcriptional regulation" 10116 BTO:0001009 27117401 t miannu "During neuronal differentiation, use of an alternative splice site on the rat telomere repeat-binding factor 2 (TRF2) mRNA generates a short TRF2 protein isoform (TRF2-S) capable of derepressing neuronal genes. However, the RNA-binding proteins (RBPs) controlling this splicing event are unknown. Here, using affinity pull-down analysis, we identified heterogeneous nuclear ribonucleoproteins H1 and H2(HNRNPH) as RBPs specifically capable of interacting with the spliced RNA segment (exon 7) of Trf2 pre-mRNA. HNRNPH proteins prevent the production of the short isoform of Trf2 mRNA, as HNRNPH silencing selectively elevates TRF2-S levels." SIGNOR-266807 YWHAB protein P31946 UNIPROT NEFL protein P07196 UNIPROT "down-regulates activity" binding 9606 23230147 t miannu "These results suggest the important role of 14-3-3 in the dynamic regulation of NF-L assembly, and in the capacity to prevent the formation of NF-L aggregates. all seven isoforms specifically interacted with NF-L, but not NF-M or NF-H. specific interaction of 14-3-3 proteins with phosphorylated NF-L subunits also indicated the role of 14-3-3 and NF-L phosphorylation in the disassembly of neurofilaments. What is more, binding of 14-3-3 to phosphorylated NF-L subunits may prevent the dephosphorylation of these subunits by phosphatases, maintaining the hyperphosphorylation state of the subunits, which facilitates the disassembly of neurofilaments." SIGNOR-252396 YWHAB protein P31946 UNIPROT SRPK2 protein P78362 UNIPROT down-regulates binding 9606 phosphorylation:Thr492 PSHDRSRtVSASSTG 19592491 t lperfetto "14-3-3 interacts with akt-phosphorylated srpk2 and blocks its nuclear translocation. kt phosphorylates SRPK2 on Thr-492 and promotes its nuclear translocation leading to cyclin D1 up-regulation, cell cycle reentry, and neuronal apoptosis. In addition, SRPK2 phosphorylates SC35 and, thus, inactivates p53, resulting in cyclin D1 up-regulation. 14-3-3 binding to SRPK2, regulated by Akt phosphorylation, inhibits these events." SIGNOR-186767 STIP1 protein P31948 UNIPROT HSP90AA1 protein P07900 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 27353360 t miannu "Hsp90 chaperone cycle is tightly regulated by another group of proteins referred to as ‘co-chaperones'. Their stability does not depend on Hsp90 function but they interact with distinct Hsp90 conformational states, providing directionality to the Hsp90 cycle. Furthermore, certain co-chaperones, such as HOP and Cdc37p50 inhibit the Hsp90 chaperone cycle, assisting in delivery of distinct sets of client proteins (steroid hormone receptors and kinases, respectively) to the Hsp90 chaperone machine." SIGNOR-261411 STIP1 protein P31948 UNIPROT HSP90AB1 protein P08238 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 27353360 t miannu "Hsp90 chaperone cycle is tightly regulated by another group of proteins referred to as ‘co-chaperones'. Their stability does not depend on Hsp90 function but they interact with distinct Hsp90 conformational states, providing directionality to the Hsp90 cycle4. Furthermore, certain co-chaperones, such as HOP and Cdc37p50 inhibit the Hsp90 chaperone cycle, assisting in delivery of distinct sets of client proteins (steroid hormone receptors and kinases, respectively) to the Hsp90 chaperone machine." SIGNOR-261412 FCGR2B protein P31994 UNIPROT TLR4 protein O00206 UNIPROT "down-regulates activity" 9606 BTO:0000801 24445665 f lperfetto "Triggering of FcgammaRIIB also subverted the normal activation of DCs by the TLR4 agonist lipopolysaccharide. In addition, triggering of FcgammaRIIB by immune complexes might affect the differentiation of moDCs. When moDCs develop from monocytes invitro in the presence of immune complexes, their differentiation is hampered and they no longer produce IL-12 in response to TLR4 agonists." SIGNOR-249525 ARRB2 protein P32121 UNIPROT ADRB2 protein P07550 UNIPROT "down-regulates activity" binding -1 2163110 t "The protein, termed beta-arrestin, was expressed and partially purified. It inhibited the signaling function of beta ARK-phosphorylated beta-adrenergic receptors by more than 75 percent, but not that of rhodopsin. It is proposed that beta-arrestin in concert with beta ARK effects homologous desensitization of beta-adrenergic receptors" SIGNOR-256501 ARRB2 protein P32121 UNIPROT ADRB1 protein P08588 UNIPROT "down-regulates activity" binding -1 2163110 t "The protein, termed beta-arrestin, was expressed and partially purified. It inhibited the signaling function of beta ARK-phosphorylated beta-adrenergic receptors by more than 75 percent, but not that of rhodopsin. It is proposed that beta-arrestin in concert with beta ARK effects homologous desensitization of beta-adrenergic receptors" SIGNOR-256502 ARRB2 protein P32121 UNIPROT KIF3A protein Q9Y496 UNIPROT up-regulates binding 9606 16908539 t gcesareni "We demonstrate that _-arrestins mediate the activity-dependent interaction of smo and the kinesin motor protein kif3a." SIGNOR-148773 ARRB2 protein P32121 UNIPROT KIF3A protein Q9Y496 UNIPROT up-regulates binding 9606 23074268 t gcesareni "Betaarrestin 2 was subsequentialy shown to bridge smo to the kinestesin motor kif3 to promote ciliary accumulation of smo in mammalian cells" SIGNOR-199107 CCKAR protein P32238 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257361 CIITA protein P33076 UNIPROT HLA-DOA protein P06340 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000776 11823510 f "Class II transactivator is required for maximal expression of HLA-DOB in B cells|HLA-DO, encoded by the HLA-DOA and HLA-DOB genes, has been shown to function as a modulator of Ag presentation. DNA microarray comparisons between B cells wild-type and mutant for the master regulator of MHC class II transcription, class II transactivator (CIITA), identified HLA-DOA and HLA-DOB as being up-regulated by CIITA." SIGNOR-254005 CCKAR protein P32238 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257148 CCKAR protein P32238 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257236 CCKAR protein P32238 UNIPROT GNA15 protein P30679 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257410 CCKAR protein P32238 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256906 CCKAR protein P32238 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 BTO:0001130;BTO:0000551 11313903 t gcesareni "These neuropeptides, including gastrin-releasing peptide, neuromedin b, neurotensin, gastrin, cholecystokinin and arginine vasopressin bind seven transmembrane-spanning receptors that couple to heterotrimeric g proteins. Studies with human small cell lung cancer (sclc) cells support a requirement for balanced signaling through g(q) and g(12/13) proteins leading to intracellular ca2+ mobilization, pkc activation and regulation of the erk and jnk map kinase pathways." SIGNOR-106998 CCKAR protein P32238 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257303 CCKAR protein P32238 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257035 CCKAR protein P32238 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256763 CCKBR protein P32239 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257363 BMI1 protein P35226 UNIPROT PTEN protein P60484 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000785 19884659 f gcesareni "Chromatin immunoprecipitation assays revealed the bmi-1 transcriptionally downregulated expression of the tumor suppressor pten in tumor cells through direct association with the pten locus." SIGNOR-189040 CCKBR protein P32239 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257150 CCKBR protein P32239 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257238 CCKBR protein P32239 UNIPROT GNA15 protein P30679 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257412 CCKBR protein P32239 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256908 CCKBR protein P32239 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257305 CCKBR protein P32239 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257037 CCKBR protein P32239 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256765 OTX1 protein P32242 UNIPROT BEST1 protein O76090 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" -1 18849347 f miannu "Three OTX family proteins - OTX1, OTX2 and CRX - bound to both Sites 1 and 2 in vitro, and all of them increased BEST1 promoter activity." SIGNOR-254887 OTX2 protein P32243 UNIPROT BEST1 protein O76090 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" -1 18849347 f miannu "Three OTX family proteins - OTX1, OTX2 and CRX - bound to both Sites 1 and 2 in vitro, and all of them increased BEST1 promoter activity." SIGNOR-254888 OTX2 protein P32243 UNIPROT BEST1 protein O76090 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 20530484 f miannu "BEST1 promoter activity was increased by SOX9 overexpression and decreased by siRNA-mediated SOX9 knockdown. SOX9 physically interacted with MITF and OTX2 and orchestrated synergistic activation of the BEST1 promoter with the paired SOX site playing essential roles." SIGNOR-255186 OTX2 protein P32243 UNIPROT RBP3 protein P10745 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10354480 f miannu "OTX2, as well as CRX, a homeodomain protein very similar to OTX2, activates the human IRBP promoter in co-transfection experiments." SIGNOR-254889 CIITA protein P33076 UNIPROT HLA-E protein P13747 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000776 11137213 f "HLA-E is inducible by CIITA through the SXY regulatory module. HLA-F is inducible by NF-kappaB through the kappaB1 site of enhancer A, is responsive to IFN-gamma through the ISRE, and is inducible by CIITA" SIGNOR-254019 MC4R protein P32245 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257392 MC4R protein P32245 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257182 MC4R protein P32245 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257270 MC4R protein P32245 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256940 MC4R protein P32245 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257336 MC4R protein P32245 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257069 MC4R protein P32245 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257440 MC4R protein P32245 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256797 CCR1 protein P32246 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "up-regulates activity" phosphorylation 10090 20219869 t 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 CIITA protein P33076 UNIPROT HLA-DRB4 protein P13762 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002417 10886240 f "These results indicate that impaired up-regulation of HLA-DR in response to IFN-gamma results from insufficient induction of CIITA, but not from the signal from IFN-gamma receptor to the nucleus. The abnormal regulation of HLA-DR expression caused by impaired induction of CIITA may affect CD4+ T cell development in thymoma." SIGNOR-254012 GPR183 protein P32249 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256858 GPR183 protein P32249 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256994 GPR183 protein P32249 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257110 GPR183 protein P32249 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256715 GPR183 protein P32249 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257202 GRK4 protein P32298 UNIPROT BDKRB2 protein P30411 UNIPROT "down-regulates activity" phosphorylation Ser366 EPIQMENsMGTLRTS 9606 BTO:0000007 11517230 t gcesareni "...expression of GRK4Ž drastically increased the basal level of32P incorporation into B2R.[€]a clustered phosphorylation around Ser(346) is necessary for desensitization of the B2 receptor-induced phospholipase C activation." SIGNOR-247902 GRK4 protein P32298 UNIPROT BDKRB2 protein P30411 UNIPROT "down-regulates activity" phosphorylation Ser373 SMGTLRTsISVERQI 9606 BTO:0000007 11517230 t "Expression of GRK4α drastically increased the basal level of32P incorporation into B2R. GRK4α elevated the basal phosphorylation of Ser339 and Ser346/Ser348. phosphorylation of specific residues was correlated with the initiation of receptor internalization and the regulation of its desensitization." SIGNOR-251193 GRK4 protein P32298 UNIPROT BDKRB2 protein P30411 UNIPROT "down-regulates activity" phosphorylation Ser375 GTLRTSIsVERQIHK 9606 BTO:0000007 11517230 t gcesareni "...expression of GRK4ƒŽ‚ drastically increased the basal level of32P incorporation into B2R.[ƒ‚€‚]a clustered phosphorylation around Ser(346) is necessary for desensitization of the B2 receptor-induced phospholipase C activation." SIGNOR-249674 ELF1 protein P32519 UNIPROT IL2RA protein P01589 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000661 7862168 f 2 miannu "The interleukin 2 receptor alpha-chain (IL-2R alpha) gene is rapidly and potently induced in T cells in response to mitogenic stimuli. Previously, an inducible enhancer between nucleotides -299 and -228 that contains NF-kappa B and CArG motifs was identified. We now report the characterization of a second essential positive regulatory element located between nucleotides -137 and -64 that binds Elf-1 and HMG-I(Y). Transcription from the IL-2R alpha promoter was inhibited when either the Elf-1 or the HMG-I(Y) binding site was mutated. Coexpression of both proteins activated transcription of the -137 to -64 element in COS-7 cells." SIGNOR-240193 ELF1 protein P32519 UNIPROT FCER1A protein P12319 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000732 11971001 f "Transcriptional regulation of the gene-encoding human Fc epsilon RI alpha-chain was analyzed in detail. EMSA revealed that either YY1 or PU.1 bound to the region close to that recognized by Elf-1|These up-regulating effects of PU.1 and YY1 with GATA-1 were inhibited by overexpression of Elf-1, indicating that Elf-1 serves as a repressor for the alpha-chain gene expression" SIGNOR-254287 ELF1 protein P32519 UNIPROT CD68 protein P34810 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000801 12676954 f "Band shift experiments show that PU.1 associates with the -89 site whereas, Elf-1 preferentially binds the -106 Ets binding site and enhances CD68 activity in vitro." SIGNOR-254282 CIITA protein P33076 UNIPROT HLA-DOB protein P13765 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000776 11823510 f "Class II transactivator is required for maximal expression of HLA-DOB in B cells|HLA-DO, encoded by the HLA-DOA and HLA-DOB genes, has been shown to function as a modulator of Ag presentation. DNA microarray comparisons between B cells wild-type and mutant for the master regulator of MHC class II transcription, class II transactivator (CIITA), identified HLA-DOA and HLA-DOB as being up-regulated by CIITA." SIGNOR-254015 SSTR3 protein P32745 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256820 SSTR3 protein P32745 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256677 GTF2H1 protein P32780 UNIPROT E2F1 protein Q01094 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser403 PEEFISLsPPHEALD -1 10428966 t "TFIIH-mediated phosphorylation of E2F-1 plays a role in triggering E2F-1 degradation during S phase. E2F-1 activation domain interacts with a kinase activity which phosphorylates two sites, Ser403 and Thr433, within the activation domain. We demonstrate that TFIIH is responsible for the E2F-1 phosphorylation observed in cell extracts and that endogenous E2F-1 interacts in vivo with p62, a component of TFIIH, during S phase." SIGNOR-251259 GTF2H1 protein P32780 UNIPROT E2F1 protein Q01094 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr433 DCDFGDLtPLDF -1 10428966 t "TFIIH-mediated phosphorylation of E2F-1 plays a role in triggering E2F-1 degradation during S phase. E2F-1 activation domain interacts with a kinase activity which phosphorylates two sites, Ser403 and Thr433, within the activation domain. We demonstrate that TFIIH is responsible for the E2F-1 phosphorylation observed in cell extracts and that endogenous E2F-1 interacts in vivo with p62, a component of TFIIH, during S phase." SIGNOR-251260 CSF2RB protein P32927 UNIPROT CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR "form complex" binding 9606 BTO:0000876 BTO:0001103 9680354 t 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 ICAM3 protein P32942 UNIPROT "AD/b2 integrin" complex SIGNOR-C172 SIGNOR "up-regulates activity" binding 8777714 t lperfetto "A novel leukointegrin, alpha d beta 2, binds preferentially to ICAM-3." SIGNOR-253371 RPL9 protein P32969 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262452 CD70 protein P32970 UNIPROT CD27 protein P26842 UNIPROT up-regulates binding 9606 BTO:0000776 12324477 t gcesareni "The molecule defining the cd70 ag is identical to the recently defined ligand for cd27. Bioassays demonstrated that the cd70 cdna clone expressed in african green monkey kidney cells would induce the proliferation of pha-costimulated t cells. Ramos cells were mixed with increasing numbers of transfected cells that expressed cd70 (cd27l) or cd154 (cd40l), both of which are expressed by activated t cells, in the presence of anti-igm ab. Cd27 ligation as well as cd40 ligation inhibited bcr-mediated apoptosis in a dose-dependent manner." SIGNOR-93435 CD70 protein P32970 UNIPROT CD27 protein P26842 UNIPROT up-regulates binding 9606 BTO:0001103;BTO:0000142;BTO:0000562;BTO:0000672 8120384 t gcesareni "The molecule defining the cd70 ag is identical to the recently defined ligand for cd27. Bioassays demonstrated that the cd70 cdna clone expressed in african green monkey kidney cells would induce the proliferation of pha-costimulated t cells. Ramos cells were mixed with increasing numbers of transfected cells that expressed cd70 (cd27l) or cd154 (cd40l), both of which are expressed by activated t cells, in the presence of anti-igm ab. Cd27 ligation as well as cd40 ligation inhibited bcr-mediated apoptosis in a dose-dependent manner." SIGNOR-36357 MC5R protein P33032 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257393 MC5R protein P33032 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257183 CIITA protein P33076 UNIPROT MYOG protein P15173 UNIPROT down-regulates binding 9606 BTO:0001103 28163303 t 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 RORA protein P35398 UNIPROT NTRK2 protein Q16620 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 28608249 t lperfetto "Some genes which are directly regulated by RORA such as NLGN1 and NTRK2 have been shown to be associated with increased susceptibility to ASD (Correia et al. 2010; Ylisaukko-oja et al. 2005)." SIGNOR-265137 MC5R protein P33032 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257271 MC5R protein P33032 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256941 MC5R protein P33032 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257337 MC5R protein P33032 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257070 MC5R protein P33032 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257441 MC5R protein P33032 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256798 CIITA protein P33076 UNIPROT HLA-DRA protein P01903 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002417 10886240 f "These results indicate that impaired up-regulation of HLA-DR in response to IFN-gamma results from insufficient induction of CIITA, but not from the signal from IFN-gamma receptor to the nucleus. The abnormal regulation of HLA-DR expression caused by impaired induction of CIITA may affect CD4+ T cell development in thymoma." SIGNOR-254008 CIITA protein P33076 UNIPROT HLA-DRB1 protein P01912 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002417 10886240 f "These results indicate that impaired up-regulation of HLA-DR in response to IFN-gamma results from insufficient induction of CIITA, but not from the signal from IFN-gamma receptor to the nucleus. The abnormal regulation of HLA-DR expression caused by impaired induction of CIITA may affect CD4+ T cell development in thymoma." SIGNOR-253976 CIITA protein P33076 UNIPROT HLA-DQB1 protein P01920 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000776 11332992 f "The class II transactivator (CIITA) regulates expression of the classical and non-classical MHC class II genes, HLA-DR, -DP, -DQ and -DM," SIGNOR-254017 CIITA protein P33076 UNIPROT HLA-C protein P04222 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002269 11053628 f miannu "Transfection of CIITA in JEG-3 cells also upregulated functional HLA-B and HLA-C expression." SIGNOR-253775 CIITA protein P33076 UNIPROT HLA-DPB1 protein P04440 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000776 11889043 f "Promoter-specific functions of CIITA and the MHC class II enhanceosome in transcriptional activation|We compared four genes co-regulated by RFX and CIITA (HLA-DRA, HLA-DPB, HLA-DMB and Ii) and found that the enhanceosome and CIITA make variable, promoter-dependent contributions to histone acetylation and transcription apparatus recruitment." SIGNOR-254006 CIITA protein P33076 UNIPROT IL4 protein P05112 UNIPROT down-regulates "transcriptional regulation" 9606 BTO:0000782 10946277 f "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 CIITA protein P33076 UNIPROT HLA-G protein P17693 UNIPROT unknown "transcriptional regulation" 9606 BTO:0000776 11137218 f "The X1 box is the binding site for the ubiquitous RFX complex consisting of three subunits; the X2 box is bound by the X2BP/ATF/CREB family factors. The basic S-X-Y regulatory module interacts with CIITA, which is expressed constitutively in APCs, but may be inducible in others cell types by IFN-gamma|We propose that the X region in the HLA-G gene promoter might participate to the combination of factors which play a role in HLA-G gene activation" SIGNOR-254021 CIITA protein P33076 UNIPROT S100A4 protein P26447 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 17143014 f miannu "IFN-gamma represses S100A4 promoter activity through induction of the class II transactivator (CIITA)." SIGNOR-253776 CIITA protein P33076 UNIPROT HLA-DMA protein P28067 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9300700 f "The class II transactivator (CIITA) is a highly specific transcription factor that activates only genes known to be involved in the class II MHC processing pathway, including class II MHC, invariant chain, and HLA-DMA/B genes." SIGNOR-254004 CIITA protein P33076 UNIPROT HLA-DMB protein P28068 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000776 11889043 f "Promoter-specific functions of CIITA and the MHC class II enhanceosome in transcriptional activation|We compared four genes co-regulated by RFX and CIITA (HLA-DRA, HLA-DPB, HLA-DMB and Ii) and found that the enhanceosome and CIITA make variable, promoter-dependent contributions to histone acetylation and transcription apparatus recruitment." SIGNOR-254010 CIITA protein P33076 UNIPROT HLA-DMB protein P28068 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000776 9300700 f "The class II transactivator (CIITA) is a highly specific transcription factor that activates only genes known to be involved in the class II MHC processing pathway, including class II MHC, invariant chain, and HLA-DMA/B genes." SIGNOR-254014 CIITA protein P33076 UNIPROT HLA-A protein P30443 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000776 10329350 f "Transfection of CIITA in JEG-3 cells also upregulated functional HLA-B and HLA-C expression." SIGNOR-254020 CIITA protein P33076 UNIPROT HLA-F protein P30511 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000776 11137213 f "HLA-E is inducible by CIITA through the SXY regulatory module. HLA-F is inducible by NF-kappaB through the kappaB1 site of enhancer A, is responsive to IFN-gamma through the ISRE, and is inducible by CIITA" SIGNOR-254018 CIITA protein P33076 UNIPROT RFX5 protein P48382 UNIPROT "up-regulates activity" binding 9606 BTO:0000776 9177217 t 2 miannu "RFX5 can activate transcription only in cooperation with CIITA. RFX5 and CIITA associate to form a complex capable of activating transcription from class II major histocompatibility complex promoters. In this complex, promoter specificity is determined by the DNA binding domain of RFX5 and the general transcription apparatus is recruited by the acidic activation domain of CIITA." SIGNOR-240980 CIITA protein P33076 UNIPROT HLA-DRB5 protein Q30154 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002417 10886240 f "These results indicate that impaired up-regulation of HLA-DR in response to IFN-gamma results from insufficient induction of CIITA, but not from the signal from IFN-gamma receptor to the nucleus. The abnormal regulation of HLA-DR expression caused by impaired induction of CIITA may affect CD4+ T cell development in thymoma." SIGNOR-254013 CDH5 protein P33151 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" binding 9606 21255999 t miannu "At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin" SIGNOR-265867 KIF5B protein P33176 UNIPROT JAKMIP1 protein Q96N16 UNIPROT "up-regulates activity" relocalization 10090 17532644 t SARA "Marlin-1 is associated with kinesin-I and suggest that the movement of Marlin-1 is mediated by plus end microtubuledependent molecular motors" SIGNOR-260989 KIF5B protein P33176 UNIPROT SYBU protein Q9NX95 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000938 15459722 t miannu "Conventional kinesin I heavy chain binds to syntabulin and associates with syntabulin-linked syntaxin vesicles in vivo. These findings suggest that syntabulin functions as a linker molecule that attaches syntaxin-cargo vesicles to kinesin I, enabling the transport of syntaxin-1 to neuronal processes." SIGNOR-264811 KIF5B protein P33176 UNIPROT GABBR1 protein Q9UBS5 UNIPROT "up-regulates activity" relocalization 10090 17532644 t SARA "GABABR1 co-immunoprecipitated with Marlin-1 and kinesin-I, providing evidence for the existence of a complex between these proteins. Kinesin-I modulates GABAB receptor transport." SIGNOR-260990 TTK protein P33981 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates phosphorylation Thr68 SSLETVStQELYSIP 9606 15618221 t lperfetto "Ttk/hmps1 directly phosphorylates chk2 on thr-68 in vitro.ablation of ttk expression using small interfering rna results not only in reduced chk2 thr-68 phosphorylation, but also in impaired growth arrest. Our results are consistent with a model in which ttk functions upstream from chk2 in response to dna damage" SIGNOR-132665 TTK protein P33981 UNIPROT ABL1 protein P00519 UNIPROT down-regulates phosphorylation Thr735 DTEWRSVtLPRDLQS 9606 18794806 t lperfetto "Ttk phosphorylation of thr735 was associated with partial inhibition of nuclear targeting of c-abl." SIGNOR-181064 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT down-regulates phosphorylation Thr675 ANQMQPDtTSVVKDS 9606 18680479 t miannu "We have identified 16 sites of mps1 autophosphorylation in vitro, several of which are required for catalytic activity / mutation of thr675 to alanine increased mps1 catalytic domain activity, and this was reduced to wt levels by mutation to aspartate" SIGNOR-179904 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT down-regulates phosphorylation Thr806 NQMAKGTtEEMKYVL 9606 18680479 t miannu "We have identified 16 sites of mps1 autophosphorylation in vitro, several of which are required for catalytic activity / t806d mps1 was significantly less active than t806a, demonstrating a potential negative correlation between phosphorylation and activity at this site." SIGNOR-179908 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates phosphorylation Ser582 LNKLQQHsDKIIRLY 9606 18680479 t miannu "We have identified 16 sites of mps1 autophosphorylation in vitro, several of which are required for catalytic activity / autophosphorylation outside the activation segment was also important for activity in vitro, since s582a/s582d and y811f mutants exhibited decreased activity" SIGNOR-179896 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates phosphorylation Ser742 QQIINQIsKLHAIID 9606 18680479 t gcesareni "We have identified 16 sites of mps1 autophosphorylation in vitro, several of which are required for catalytic activity after expression in bacteria or in cultured human cells." SIGNOR-179900 RYK protein P34925 UNIPROT DVL3 protein Q92997 UNIPROT up-regulates binding 9606 15454084 t gcesareni "Ryk also binds to dishevelled, through which it activates the canonical wnt, providing a link between wnt and dishevelled" SIGNOR-129574 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates phosphorylation Ser677 QMQPDTTsVVKDSQV 9606 19120698 t llicata "Autophosphorylation appears to be a priming event for kinase activation. We identified mps1 autophosphorylation sites in the activation and the p+1 loops. Whereas activation loop autophosphorylation enhances kinase activity" SIGNOR-183022 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates phosphorylation Thr676 NQMQPDTtSVVKDSQ 9606 19120698 t llicata "Autophosphorylation appears to be a priming event for kinase activation. We identified mps1 autophosphorylation sites in the activation and the p+1 loops. Whereas activation loop autophosphorylation enhances kinase activity" SIGNOR-183026 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates phosphorylation Thr686 VKDSQVGtVNYMPPE 9606 19120698 t llicata "Autophosphorylation appears to be a priming event for kinase activation. We identified mps1 autophosphorylation sites in the activation and the p+1 loops. Whereas activation loop autophosphorylation enhances kinase activity, autophosphorylation at the p+1 loop (t686) is associated with the active kinase." SIGNOR-183030 TTK protein P33981 UNIPROT HSPA9 protein P38646 UNIPROT up-regulates phosphorylation Ser65 IDLGTTNsCVAVMEG 9606 17573779 t lperfetto "Mortalin binds to mps1, and is phosphorylated by mps1 on thr62 and ser65. The phosphorylated mortalin then super-activates mps1 in a feedback manner. Mps1-associated acceleration of centrosome duplication depends on the presence of mortalin and super-activation by the thr62/ser65 phosphorylated mortalin" SIGNOR-156181 TTK protein P33981 UNIPROT HSPA9 protein P38646 UNIPROT up-regulates phosphorylation Thr62 VVGIDLGtTNSCVAV 9606 17573779 t lperfetto "Mortalin binds to mps1, and is phosphorylated by mps1 on thr62 and ser65. The phosphorylated mortalin then super-activates mps1 in a feedback manner. Mps1-associated acceleration of centrosome duplication depends on the presence of mortalin and super-activation by the thr62/ser65 phosphorylated mortalin" SIGNOR-156185 TTK protein P33981 UNIPROT MAD2L1 protein Q13257 UNIPROT "up-regulates activity" phosphorylation 18541701 t lperfetto "Mps1 is an upstream component of the spindle assembly checkpoint, which, in human cells, is required for checkpoint activation in response to spindle damage but not apparently during an unperturbed mitosis. Mps1 also recruits Mad1 and Mad2 to kinetochores.|Thus, in human cells, Mps1 catalytic activity is required for spindle checkpoint function and recruitment of Mad2." SIGNOR-252036 TTK protein P33981 UNIPROT CDCA8 protein Q53HL2 UNIPROT up-regulates phosphorylation 9606 18243099 t amattioni "Direct phosphorylation of the aurora b regulator borealin by mps1 enhances aurora b activity and is essential for chromosome alignment" SIGNOR-160604 TTK protein P33981 UNIPROT CDCA8 protein Q53HL2 UNIPROT up-regulates phosphorylation Thr169 KRSSRANtVTPAVGR 9606 19530738 t lperfetto "First, we confirmed that wild-type borealin is phosphorylated at the previously described sites t88, t94, t169, and t230 when present in complex with survivin borealin might be a substrate for mps1. In the case of wild-type borealin, the fast exchange between the monomeric and dimeric forms may allow mps1 to phosphorylate the monomer. In turn, mps1 may regulate borealin function by unfolding the c-terminal domain and/or shifting the population to the monomeric form." SIGNOR-186143 TTK protein P33981 UNIPROT CDCA8 protein Q53HL2 UNIPROT up-regulates phosphorylation Thr230 DSKEIFLtVPVGGGE 9606 19530738 t lperfetto "We found that substitutions at borealin t230, recently identified as an mps1 phosphorylation site, can modulate the dimerization state of borealin. Mutation of this single residue to alanine or valine impairs aurora b activity during mitosis and causes chromosome segregation defects" SIGNOR-186147 TTK protein P33981 UNIPROT CDCA8 protein Q53HL2 UNIPROT up-regulates phosphorylation Thr88 QALEEAAtADLDITE 9606 19530738 t lperfetto "First, we confirmed that wild-type borealin is phosphorylated at the previously described sites t88, t94, t169, and t230 when present in complex with survivin borealin might be a substrate for mps1. In the case of wild-type borealin, the fast exchange between the monomeric and dimeric forms may allow mps1 to phosphorylate the monomer. In turn, mps1 may regulate borealin function by unfolding the c-terminal domain and/or shifting the population to the monomeric form." SIGNOR-186151 TTK protein P33981 UNIPROT CDCA8 protein Q53HL2 UNIPROT up-regulates phosphorylation Thr94 ATADLDItEINKLTA 9606 19530738 t lperfetto "First, we confirmed that wild-type borealin is phosphorylated at the previously described sites t88, t94, t169, and t230 when present in complex with survivin borealin might be a substrate for mps1. In the case of wild-type borealin, the fast exchange between the monomeric and dimeric forms may allow mps1 to phosphorylate the monomer. In turn, mps1 may regulate borealin function by unfolding the c-terminal domain and/or shifting the population to the monomeric form." SIGNOR-186155 MCM4 protein P33991 UNIPROT MCM complex SIGNOR-C268 SIGNOR "form complex" binding 9606 19946136 t "The Mcm2-7 complex serves as the eukaryotic replicative helicase, the molecular motor that both unwinds duplex DNA and powers fork progression during DNA replication." SIGNOR-261674 MCM5 protein P33992 UNIPROT MCM complex SIGNOR-C268 SIGNOR "form complex" binding 9606 19946136 t "The Mcm2-7 complex serves as the eukaryotic replicative helicase, the molecular motor that both unwinds duplex DNA and powers fork progression during DNA replication." SIGNOR-261675 MCM7 protein P33993 UNIPROT MCM complex SIGNOR-C268 SIGNOR "form complex" binding 9606 19946136 t "The Mcm2-7 complex serves as the eukaryotic replicative helicase, the molecular motor that both unwinds duplex DNA and powers fork progression during DNA replication." SIGNOR-261677 NTF4 protein P34130 UNIPROT NTRK1 protein P04629 UNIPROT up-regulates binding 9606 11114882 t gcesareni "Ngf is the preferred ligand for trka, bdnf and nt4/5 are preferred for trkb, and nt3 for trkc (barbacid 1994). These specificities are not absolute, and nt3 is also a ligand for trka and trkb." SIGNOR-85117 NTF4 protein P34130 UNIPROT NTRK2 protein Q16620 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 7679912 t gcesareni "Its interactions with trkb can be distinguished from those of brain-derived neurotrophic factor (bdnf) with trkb." SIGNOR-31644 GABRA3 protein P34903 UNIPROT "GABA-A (a3-b1-g2) receptor" complex SIGNOR-C332 SIGNOR "form complex" binding 9606 BTO:0000227 18790874 t "brain, See table 3 for identified complexes" lperfetto "The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon." SIGNOR-263756 RYK protein P34925 UNIPROT DVL1 protein O14640 UNIPROT up-regulates binding 9606 15454084 t gcesareni "Ryk also binds to dishevelled, through which it activates the canonical wnt, providing a link between wnt and dishevelled." SIGNOR-129568 RYK protein P34925 UNIPROT DVL2 protein O14641 UNIPROT up-regulates binding 9606 15454084 t gcesareni "Ryk also binds to dishevelled, through which it activates the canonical wnt, providing a link between wnt and dishevelled." SIGNOR-129571 GRK5 protein P34947 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation 9606 2787365 t gcesareni "we found that g protein-coupled receptor kinases 5 and 6 (grk5/6), traditionally known to phosphorylate and desensitize 7tm g protein-coupled receptors, directly phosphorylate the pppsp motifs on single transmembrane lrp6 and regulate wnt/lrp6 signaling" SIGNOR-23330 GRK5 protein P34947 UNIPROT TP53 protein P04637 UNIPROT down-regulates phosphorylation Thr55 DDIEQWFtEDPGPDE 9606 20124405 t llicata "Grk5, but not grk2 or grk6, phosphorylates p53 at thr-55, which promotes the degradation of p53, leading to inhibition of p53-dependent apoptotic response to genotoxic damage." SIGNOR-163707 GRK5 protein P34947 UNIPROT ADRB2 protein P07550 UNIPROT unknown phosphorylation Ser396 GHQGTVPsDNIDSQG -1 8662852 t "we report the identification of the sites of GRK2- and GRK5-mediated beta2AR phosphorylation. six are phosphorylated by GRK5 (Thr-384, Thr-393, Ser-396, Ser-401, Ser-407, and Ser-411)." SIGNOR-251195 GRK5 protein P34947 UNIPROT ADRB2 protein P07550 UNIPROT unknown phosphorylation Ser401 VPSDNIDsQGRNCST -1 8662852 t "we report the identification of the sites of GRK2- and GRK5-mediated beta2AR phosphorylation. six are phosphorylated by GRK5 (Thr-384, Thr-393, Ser-396, Ser-401, Ser-407, and Ser-411)." SIGNOR-251196 GRK5 protein P34947 UNIPROT ADRB2 protein P07550 UNIPROT unknown phosphorylation Ser407 DSQGRNCsTNDSLL -1 8662852 t "we report the identification of the sites of GRK2- and GRK5-mediated beta2AR phosphorylation. six are phosphorylated by GRK5 (Thr-384, Thr-393, Ser-396, Ser-401, Ser-407, and Ser-411)." SIGNOR-251197 GRK5 protein P34947 UNIPROT ADRB2 protein P07550 UNIPROT unknown phosphorylation Ser411 RNCSTNDsLL -1 8662852 t "we report the identification of the sites of GRK2- and GRK5-mediated beta2AR phosphorylation. six are phosphorylated by GRK5 (Thr-384, Thr-393, Ser-396, Ser-401, Ser-407, and Ser-411)." SIGNOR-251198 GRK5 protein P34947 UNIPROT ADRB2 protein P07550 UNIPROT unknown phosphorylation Thr384 LCEDLPGtEDFVGHQ -1 8662852 t "we report the identification of the sites of GRK2- and GRK5-mediated beta2AR phosphorylation. six are phosphorylated by GRK5 (Thr-384, Thr-393, Ser-396, Ser-401, Ser-407, and Ser-411)." SIGNOR-251199 GRK5 protein P34947 UNIPROT ADRB2 protein P07550 UNIPROT unknown phosphorylation Thr393 DFVGHQGtVPSDNID -1 8662852 t "we report the identification of the sites of GRK2- and GRK5-mediated beta2AR phosphorylation. six are phosphorylated by GRK5 (Thr-384, Thr-393, Ser-396, Ser-401, Ser-407, and Ser-411)." SIGNOR-251200 GRK5 protein P34947 UNIPROT BDKRB2 protein P30411 UNIPROT "down-regulates activity" phosphorylation Ser366 EPIQMENsMGTLRTS 9606 BTO:0000007 11517230 t "Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration." SIGNOR-251210 GRK5 protein P34947 UNIPROT BDKRB2 protein P30411 UNIPROT "down-regulates activity" phosphorylation Ser373 SMGTLRTsISVERQI 9606 BTO:0000007 11517230 t "Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration." SIGNOR-251208 GRK5 protein P34947 UNIPROT BDKRB2 protein P30411 UNIPROT "down-regulates activity" phosphorylation Ser375 GTLRTSIsVERQIHK 9606 BTO:0000007 11517230 t "Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration." SIGNOR-251209 GRK5 protein P34947 UNIPROT GRK5 protein P34947 UNIPROT "up-regulates activity" phosphorylation Ser484 VLDIEQFsTVKGVNL -1 8144599 t "Autophosphorylation of GRK5 occurs primarily at residues Ser-484 and Thr-485. Phospholipid-stimulated autophosphorylation activates the G protein-coupled receptor kinase GRK5." SIGNOR-251201 GRK5 protein P34947 UNIPROT GRK5 protein P34947 UNIPROT "up-regulates activity" phosphorylation Thr485 LDIEQFStVKGVNLD -1 8144599 t "Autophosphorylation of GRK5 occurs primarily at residues Ser-484 and Thr-485. Phospholipid-stimulated autophosphorylation activates the G protein-coupled receptor kinase GRK5." SIGNOR-251202 GRK5 protein P34947 UNIPROT SNCA protein P37840 UNIPROT "down-regulates activity" phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 16957079 t llicata "Grk5 phosphorylated ser-129 of alpha-synuclein at the plasma membrane and induced translocation of phosphorylated alpha-synuclein to the perikaryal area. Grk5-catalyzed phosphorylation also promoted the formation of soluble oligomers and aggregates of alpha-synuclein." SIGNOR-149372 GRK5 protein P34947 UNIPROT ST13 protein P50502 UNIPROT "up-regulates activity" phosphorylation Ser346 AQNPANMsKYQSNPK 9606 BTO:0000007 21728385 t miannu "An in vitro screen for novel GRK substrates revealed Hsp70 interacting protein (Hip) as a substrate. GRK5, but not GRK2, bound to and stoichiometrically phosphorylated Hip in vitro. The primary binding domain of GRK5 was mapped to residues 303-319 on Hip, while the major site of phosphorylation was identified to be Ser-346. GRK5 also bound to and phosphorylated Hip on Ser-346 in cells.we found that the phosphorylation of Ser-346 was required for proper agonist-induced internalization of the chemokine receptor CXCR4." SIGNOR-262877 GRK5 protein P34947 UNIPROT SNCB protein Q16143 UNIPROT "down-regulates activity" phosphorylation Ser118 LMEPEGEsYEDPPQE -1 10852916 t "GRK5 prefers alpha-synuclein as a substrate. GRK-mediated phosphorylation inhibits synuclein's interaction with both phospholipids and PLD2. Mutation of Ser118 practically abolishes Œ≤-synuclein phosphorylation by both GRK2 and GRK5" SIGNOR-251203 BTC protein P35070 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 14967450 t gcesareni "Betacellulin is synthesized primarily as a transmembrane precursor, which is then processed to mature molecule by proteolytic events;ten growth factors and their erbb specificities are depicted: egf, amphiregulin((ar), and tgfalfa bind erbb-1, betacellulin, heparin binding egf-like growth factor, and epiregulin bing both erbb-1 and erbb-4." SIGNOR-121953 HTR7 protein P34969 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257430 HTR7 protein P34969 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257168 HTR7 protein P34969 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257256 HTR7 protein P34969 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257323 HTR7 protein P34969 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256926 HTR7 protein P34969 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257381 HTR7 protein P34969 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257055 HTR7 protein P34969 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256783 CNR2 protein P34972 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256843 CNR2 protein P34972 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256979 CNR2 protein P34972 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257095 CNR2 protein P34972 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256700 PTGER1 protein P34995 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257194 PTGER1 protein P34995 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 BTO:0000586 17251915 t gcesareni "Ep1 is a galfaq-coupled receptor that promotes calcium mobilization and pkc activation, whereas ep2 and ep4, which have a more prominent role in colon cancer, are coupled to galfas and stimulate camp accumulation" SIGNOR-152802 PTGER1 protein P34995 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257083 PTGER1 protein P34995 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257278 PTGER1 protein P34995 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256811 PRSS3 protein P35030 UNIPROT F2RL1 protein P55085 UNIPROT "up-regulates activity" cleavage Arg36 TNRSSKGrSLIGKVD -1 10978167 t lperfetto "Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3." SIGNOR-263604 PRSS3 protein P35030 UNIPROT F2RL1 protein P55085 UNIPROT "up-regulates activity" cleavage Lys34 QGTNRSSkGRSLIGK -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3" SIGNOR-263607 IL13 protein P35225 UNIPROT IL13RA1 protein P78552 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000801;BTO:0000876 BTO:0000887;BTO:0000763;BTO:0001260 12704343 t milica "It is now known that this alternate receptor is a heterodimer, the type ii il-4 receptor or the il-13 receptor, which is comprised of IL-4R And IL-13R1." SIGNOR-100750 BTC protein P35070 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 23382875 t gcesareni "Betacellulin is synthesized primarily as a transmembrane precursor, which is then processed to mature molecule by proteolytic events;ten growth factors and their erbb specificities are depicted: egf, amphiregulin((ar), and tgfalfa bind erbb-1, betacellulin, heparin binding egf-like growth factor, and epiregulin bing both erbb-1 and erbb-4." SIGNOR-200813 BTC protein P35070 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 BTO:0000150 9528863 t gcesareni "Betacellulin is synthesized primarily as a transmembrane precursor, which is then processed to mature molecule by proteolytic events;ten growth factors and their erbb specificities are depicted: egf, amphiregulin((ar), and tgfalfa bind erbb-1, betacellulin, heparin binding egf-like growth factor, and epiregulin bing both erbb-1 and erbb-4." SIGNOR-56365 BTC protein P35070 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 10209155 t gcesareni "For example, betacellulin binds to and activates both erbb1 and erbb4, whereas epiregulin binds to erbb1, erbb3 and erbb4" SIGNOR-67006 BTC protein P35070 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 16829981 t gcesareni "For example, betacellulin binds to and activates both erbb1 and erbb4, whereas epiregulin binds to erbb1, erbb3 and erbb4" SIGNOR-147823 BTC protein P35070 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 BTO:0000142 22232668 t gcesareni "For example, betacellulin binds to and activates both erbb1 and erbb4, whereas epiregulin binds to erbb1, erbb3 and erbb4" SIGNOR-195347 USP6 protein P35125 UNIPROT MMP10 protein P09238 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20418905 f miannu "In this study we show that tre17 is sufficient to induce expression of mmp-9 and mmp-10, in a manner requiring its usp activity, but not its ability to bind arf6. Tre17 induces transcription of mmp-9 through activation of nuclear factor-kappab (nf-kappab), mediated in part by the gtpase rhoa and its effector kinase, rock." SIGNOR-164943 USP6 protein P35125 UNIPROT MMP9 protein P14780 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20418905 f miannu "In this study we show that tre17 is sufficient to induce expression of mmp-9 and mmp-10, in a manner requiring its usp activity, but not its ability to bind arf6. Tre17 induces transcription of mmp-9 through activation of nuclear factor-kappab (nf-kappab), mediated in part by the gtpase rhoa and its effector kinase, rock." SIGNOR-164946 USP6 protein P35125 UNIPROT ARF6 protein P62330 UNIPROT up-regulates relocalization 9606 15509780 t miannu "Here we show that tre17 (also called tre-2 and usp6), a founding member of the tbc family, targets the arf family gtpase arf6, which regulates plasma membrane-endosome trafficking. Surprisingly, tre17 does not function as a gap for arf6 but rather promotes its activation in vivo. Forced expression of tre17 promotes the localization of arf6 to the plasma membrane, leading to arf6 activation, presumably due to facilitated access to membrane-associated guanine nucleotide exchange factors (gefs)." SIGNOR-130019 CTNNA1 protein P35221 UNIPROT YAP1 protein P46937 UNIPROT down-regulates binding 9606 23431053 t milica "The trimeric complex of alfa-catenin, 14-3-3, and yap sequesters yap at ajs and prevents yap dephosphorylation/activation." SIGNOR-201173 CTNNB1 protein P35222 UNIPROT KLF4 protein O43474 UNIPROT "up-regulates activity" binding 10090 BTO:0002572 BTO:0002181 24482235 t flangone "The interaction of Beta-catenin with Tcf is important for Beta-catenin s's function in iPSCs induction. In addition, Beta-catenin interacts with Oct4, Sox2, and Klf4, respectively. In the reprogramming process, Beta-catenin further enhances expression of pluripotency-related genes." SIGNOR-242100 CTNNB1 protein P35222 UNIPROT CCN4 protein O95388 UNIPROT "up-regulates quantity" "transcriptional regulation" 10116 BTO:0002409 10716946 t "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 CTNNB1 protein P35222 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16510874 f gcesareni "Beta-cat promotes h3k4 trimethylation at the c-myc gene in vivo. H3k4 trimethylation in vivo requires prior ubiquitination of h2b, and we find that ubiquitin is necessary for transcription initiation on chromatin but not nonchromatin templates in vitro.Chromatin Immunoprecipitation experiments reveal that beta-cat recruits pygopus, bcl-9/legless, and mll/set1-type complexes to the c-myc enhancertogether with the negative wnt regulators, apc, and betatrcp." SIGNOR-19153 CTNNB1 protein P35222 UNIPROT MYOD1 protein P15172 UNIPROT "up-regulates activity" binding 9606 BTO:0000887 18316399 t 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 CTNNB1 protein P35222 UNIPROT TCF4 protein P15884 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 11713476 t amattioni "beta-catenin interacts with the TCF/Lef family transcription factors." SIGNOR-178042 CTNNB1 protein P35222 UNIPROT CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12589056 f gcesareni "The resulting accumulation of beta-catenin leads to its nuclear translocation and binding to tcf/lef transcription factors to induce target genes including cyclin d1." SIGNOR-98379 CTNNB1 protein P35222 UNIPROT CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 15735151 f gcesareni "Activated dvl binds and inhibits the phosphorylation of beta catenin by gsk3beta/alfa, blocking beta catenin degradation (fig 2?2),), 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-134216 CTNNB1 protein P35222 UNIPROT TCF7 protein P36402 UNIPROT up-regulates binding 9606 BTO:0000782 15735151 t gcesareni "Activated dvl binds and inhibits the phosphorylation of beta catenin by gsk3beta/alfa, blocking beta catenin degradation (fig 2?2),), 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-134282 CTNNB1 protein P35222 UNIPROT PPARG protein P37231 UNIPROT down-regulates 9606 BTO:0000222 10937998 f 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 CTNNB1 protein P35222 UNIPROT PPARG protein P37231 UNIPROT "down-regulates activity" binding 10090 BTO:0003346 16847334 t "Oncogenic beta-catenin resists proteasomal degradation by inhibiting PPARgamma activity, which requires its TCF/LEF binding domain" SIGNOR-256072 CTNNB1 protein P35222 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 10090 BTO:0000165 19000719 t "Through Armadillo repeat domain" gcesareni "Beta-catenin can regulate the level and transcriptional activity of the notch1 and notch1 intracellular domain (nicd). The in vivo and in vitro results demonstrate that beta-catenin binds with notch1 and nicd, for which its armadillo repeat domain is essential." SIGNOR-236858 CTNNB1 protein P35222 UNIPROT SOX2 protein P48431 UNIPROT "up-regulates activity" binding 10090 BTO:0002572 BTO:0002181 24482235 t flangone "The interaction of Beta-catenin with Tcf is important for Beta-catenin s's function in iPSCs induction. In addition, Beta-catenin interacts with Oct4, Sox2, and Klf4, respectively. In the reprogramming process, Beta-catenin further enhances expression of pluripotency-related genes." SIGNOR-242087 CTNNB1 protein P35222 UNIPROT CEBPA protein P49715 UNIPROT down-regulates 9606 BTO:0000222 10937998 f 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-80589 CTNNB1 protein P35222 UNIPROT AFF3 protein P51826 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 26214578 f irozzo "We demonstrate that AFF3 is a new target of Wnt/β-catenin pathway involved in ACC, acting on transcription and RNA splicing." SIGNOR-259192 CTNNB1 protein P35222 UNIPROT CLDN2 protein P57739 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0003569 14751232 f lperfetto "Furthermore, claudin-2 promoter activity was found to be enhanced by the TCF-4/beta-catenin transcription complex." SIGNOR-254114 CTNNB1 protein P35222 UNIPROT H3C1 protein P68431 UNIPROT "up-regulates activity" Lys5 kQTARKST 9606 16510874 f Luana "Beta-cat promotes h3k4 trimethylation at the c-myc gene in vivo. H3k4 trimethylation in vivo requires prior ubiquitination of h2b, and we find that ubiquitin is necessary for transcription initiation on chromatin but not nonchromatin templates in vitro. Chromatin immunoprecipitation experiments reveal that beta-cat recruits pygopus, bcl-9/legless, and mll/set1-type complexes to the c-myc enhancertogether with the negative wnt regulators, apc, and betatrcp." SIGNOR-260448 CTNNB1 protein P35222 UNIPROT POU5F1 protein Q01860 UNIPROT "up-regulates activity" binding 10090 BTO:0001086 21295277 t flangone "We provide evidence suggesting that Beta-catenin’s interaction with the pluripotency regulator Oct-4 at least partially underlies its effects on sustaining pluripotency." SIGNOR-241981 CTNNB1 protein P35222 UNIPROT EP300 protein Q09472 UNIPROT up-regulates binding 9606 10775268 t gcesareni "Ctnnb1 forms a ternary complex with lef1 and ep300 that is disrupted by ctnnbip1 binding" SIGNOR-76987 CTNNB1 protein P35222 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates 9606 19175684 f gcesareni "In-teractions between beta-catenin and runx2 play an im-portant role in bmp-9-induced osteogenic differentia-tion of mscs." SIGNOR-183532 CTNNB1 protein P35222 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates 9606 22298955 f gcesareni "In-teractions between beta-catenin and runx2 play an im-portant role in bmp-9-induced osteogenic differentia-tion of mscs." SIGNOR-195570 CTNNB1 protein P35222 UNIPROT SCRIB protein Q14160 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 21255999 t miannu "Cadherins mediate the localization of vesicles to presynaptic compartments through multiple mechanisms. Cadherin-bound β-catenin then recruits scribble (Scrib) which acts as a scaffold for the further recruitment of proteins that mediate the localization of SVs." SIGNOR-265826 CTNNB1 protein P35222 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT "up-regulates activity" binding 9606 20492721 t 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 CTNNB1 protein P35222 UNIPROT LEF1 protein Q9UJU2 UNIPROT "up-regulates activity" binding 9606 BTO:0000782 15735151 t 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 CTNNB1 protein P35222 UNIPROT LEF1 protein Q9UJU2 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 21078818 t 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 CTNNB1 protein P35222 UNIPROT LEF1 protein Q9UJU2 UNIPROT "up-regulates activity" binding 9606 23151663 t 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 CTNNB1 protein P35222 UNIPROT FOXA2 protein Q9Y261 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22945641 f gcesareni "Our study indicates that beta-catenin regulates foxa2 expression, and this interaction is possibly essential to control cell cycle progression during endometrial hyperplasia formation" SIGNOR-198929 CTNNB1 protein P35222 UNIPROT TRRAP protein Q9Y4A5 UNIPROT up-regulates binding 9606 16510874 t gcesareni "The beta-cat c-terminal activation domain associates with trrap/tip60 and mixed-lineage-leukemia (mll1/mll2) set1-type chromatin-modifying complexes in vitro, and we show that beta-cat promotes h3k4 trimethylation at the c-myc gene in vivo." SIGNOR-144966 CTNNB1 protein P35222 UNIPROT α-Catenin proteinfamily SIGNOR-PF72 SIGNOR "up-regulates activity" binding 9606 21255999 t miannu "At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin" SIGNOR-265813 IL13 protein P35225 UNIPROT IL4R protein P24394 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000801;BTO:0000876 BTO:0000887;BTO:0000763;BTO:0001260 12704343 t milica "Both il-4 and il-13 use the IL-4R Chain as a component of their receptors." SIGNOR-100753 IL13 protein P35225 UNIPROT IL4R protein P24394 UNIPROT "up-regulates activity" binding 9606 BTO:0000801 19880493 t lperfetto "IL-4 and IL-13 have overlapping but distinct effects on MFs, dependent on a common IL-4R, with profound changes in the expression of a range of cellular proteins and functions broadly implicated in the regulation of inflammation and repair." SIGNOR-249528 BMI1 protein P35226 UNIPROT CDKN2A protein Q8N726 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 20551323 f gcesareni "One important pathway in which bmi-1 acts to promote the overall growth of mice and cellular proliferation includes cdkn2a;bmi-1 represses the expression of cdkn2a, which encodes two cyclin-dependent kinase inhibitors, p16ink4a (p16) and p19arf" SIGNOR-259359 BMI1 protein P35226 UNIPROT NDN protein Q99608 UNIPROT down-regulates 9606 BTO:0000007 24392140 f lperfetto "In HEK293A cells transfected with luciferase reporter constructs, necdin relieves Bmi1-dependent repression of p16 promoter activity, whereas Bmi1 counteracts necdin-mediated repression of E2F1-dependent Cdk1 promoter activity." SIGNOR-253386 BMI1 protein P35226 UNIPROT PRC1 complex SIGNOR-C408 SIGNOR "form complex" binding 9606 31608994 t miannu "PRC1 has been categorised into canonical and noncanonical/variant PRC1; canonical PRC1 (Morey, Aloia, Cozzuto, Benitah, & Di Croce, 2013) includes chromobox (Cbx) proteins, Ring1, human polyhomeotic homologue protein (Hph) and polycomb ring finger (Pcgf) (Pcgf2/Mel18 and Pcgf4/Bmi1) proteins whereas noncanonical/variant PRC1 involves RING1 and YY1 binding protein (Rybp), Ring1 and Pcgf (Pcgf 1–6) proteins (Wu, Johansen, & Helin, 2013). Figure 3 illustrates the various proteins that form the canonical and noncanonical PRC1. The Ring1 along with Pcgf2/4 forms a core heterodimer which interacts with other accessory components of PRC1 complex through C‐terminal ring finger and WD40 ubiquitin‐like (RAWUL) domains see Figure 4b" SIGNOR-266812 PCGF2 protein P35227 UNIPROT UBE2I protein P63279 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 18211895 t miannu "Based on this finding of interaction between MEL-18 and UBC9, we envisioned a mechanism in which MEL-18 bound to HSF2 inhibits its sumoylation by binding to and inhibiting the activity of UBC9 enzymes that approach HSF2." SIGNOR-226248 PCGF2 protein P35227 UNIPROT HSF2 protein Q03933 UNIPROT "down-regulates activity" sumoylation 9606 BTO:0000007 18211895 t miannu "MEL-18, in contrast to the polycomb protein PC2/CBX4, in which SUMO E3 activity stimulates sumoylation of certain proteins, actually functions like an anti-SUMO E3 protein, interacting with both HSF2 and the SUMO E2 UBC9 but acting to inhibit UBC9 activity and thereby decreasing sumoylation of a target protein, in this case that of HSF2. sumoylation of HSF2 is up-regulated during mitosis and is important for the interaction of this factor with a subunit of the condensin complex during the bookmarking process" SIGNOR-226245 PCGF2 protein P35227 UNIPROT PRC1 complex SIGNOR-C408 SIGNOR "form complex" binding 9606 31608994 t miannu "PRC1 has been categorised into canonical and noncanonical/variant PRC1; canonical PRC1 (Morey, Aloia, Cozzuto, Benitah, & Di Croce, 2013) includes chromobox (Cbx) proteins, Ring1, human polyhomeotic homologue protein (Hph) and polycomb ring finger (Pcgf) (Pcgf2/Mel18 and Pcgf4/Bmi1) proteins whereas noncanonical/variant PRC1 involves RING1 and YY1 binding protein (Rybp), Ring1 and Pcgf (Pcgf 1–6) proteins (Wu, Johansen, & Helin, 2013). Figure 3 illustrates the various proteins that form the canonical and noncanonical PRC1. The Ring1 along with Pcgf2/4 forms a core heterodimer which interacts with other accessory components of PRC1 complex through C‐terminal ring finger and WD40 ubiquitin‐like (RAWUL) domains see Figure 4b" SIGNOR-266813 NOS2 protein P35228 UNIPROT "nitric oxide" smallmolecule CHEBI:16480 ChEBI up-regulates 9606 BTO:0000801 7537672 f 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 NOS2 protein P35228 UNIPROT L-citrulline smallmolecule CID:9750 PUBCHEM up-regulates 9606 BTO:0000801 7537672 f 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 PTPN7 protein P35236 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 BTO:0000007 10415025 t fstefani "Lc-ptp dephosphorylated erk2 in vitro. the complex formation of lc-ptp with erk is the essential mechanism for the suppression. Taken collectively, these results indicate that lc-ptp suppresses mitogen-activated protein kinase directly in vivo." SIGNOR-69448 PTPN7 protein P35236 UNIPROT MAPK1 protein P28482 UNIPROT "down-regulates activity" dephosphorylation Tyr187 HTGFLTEyVATRWYR 9606 10702794 t "HePTP efficiently dephosphorylated active ERK2 on the tyrosine residue in the activation loop in vitro. Together, these data identify ERK2 as a specific and direct target of HePTP and are consistent with a model in which HePTP negatively regulates ERK2 activity as part of a feedback mechanism" SIGNOR-248484 PTPN7 protein P35236 UNIPROT MAPK1 protein P28482 UNIPROT "down-regulates activity" dephosphorylation Tyr187 HTGFLTEyVATRWYR 9606 16226275 t "First, Erk phosphorylates HePTP at residues Thr45 and Ser72. Second, HePTP dephosphorylates Erk at PTyr185" SIGNOR-248483 PTPN7 protein P35236 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates binding 9606 BTO:0000776 19047375 t gcesareni "Thus, beta(2)ar stimulation on a b cell phosphorylates and inactivates heptp in a gs/camp/pka-dependent manner to release bound p38 mapk, making more available for phosphorylation and subsequent ige regulation" SIGNOR-182525 PTPN7 protein P35236 UNIPROT MAPK14 protein Q16539 UNIPROT "down-regulates activity" dephosphorylation Tyr182 TDDEMTGyVATRWYR 9606 BTO:0000661 10206983 t "In Jurkat cells, LC-PTP suppressed the ERK and p38 mitogen-activated protein kinase cascades" SIGNOR-248485 NF2 protein P35240 UNIPROT LATS1 protein O95835 UNIPROT up-regulates binding 9606 24012335 t "The opposite changes in Lats/YAP and Mst1/2 phosphorylation upon loss of NF2 therefore argue against the generally assumed linear model in which NF2 signals through activation of Mst1/3" flangone "As expected, the nf2-/- fc-912 cells were defective in lats1/2 phosphorylation (figure s2e-f). Subcellular fractionation revealed a significant increase of endogenous lats1/2 in the cytoplasmic relative to the membrane fraction in the nf2-/- fc-912 schwann cells compared to the nf2+/+ fh-912 schwann cells (figure 2e). This localization defect was rescued by re-expression of nf2" SIGNOR-202604 NF2 protein P35240 UNIPROT STK4 protein Q13043 UNIPROT "up-regulates activity" binding 10090 BTO:0003324 27402866 t "Hippo pathway" Gianni "NF2 is activated by oxidative stress in cardiomyocytes and mouse myocardium and facilitates apoptosis. NF2 promotes I/R injury through activation of Mst1 and inhibition of Yap, thereby regulating Hippo signaling in the adult heart." SIGNOR-261956 NF2 protein P35240 UNIPROT STK3 protein Q13188 UNIPROT "up-regulates activity" binding 10090 BTO:0003324 27402866 t "Hippo pathway" Gianni "NF2 is activated by oxidative stress in cardiomyocytes and mouse myocardium and facilitates apoptosis. NF2 promotes I/R injury through activation of Mst1 and inhibition of Yap, thereby regulating Hippo signaling in the adult heart." SIGNOR-261955 SOX6 protein P35712 UNIPROT PPARG protein P37231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003298 26893351 f "We found that SOX6 regulates adipogenesis in vertebrate species by activating adipogenic regulators including PPARŒ≥, C/EBPŒ± and MEST" SIGNOR-255822 NF2 protein P35240 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates binding 9606 24012335 t "The opposite changes in Lats/YAP and Mst1/2 phosphorylation upon loss of NF2 therefore argue against the generally assumed linear model in which NF2 signals through activation of Mst1/2" flangone "As expected, the nf2-/- fc-912 cells were defective in lats1/2 phosphorylation (figure s2e-f). Subcellular fractionation revealed a significant increase of endogenous lats1/2 in the cytoplasmic relative to the membrane fraction in the nf2-/- fc-912 schwann cells compared to the nf2+/+ fh-912 schwann cells (figure 2e). This localization defect was rescued by re-expression of nf2" SIGNOR-202607 NF2 protein P35240 UNIPROT LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR "up-regulates activity" binding 9606 33058421 t miannu "The Hippo pathway tumor suppressor Merlin/NF2 is known to be regulated by phosphorylation. Here, the E3 ubiquitin ligase NEDD4L is shown to promote Hippo pathway activation via ubiquitination of Merlin." SIGNOR-263663 RFC4 protein P35249 UNIPROT "RF-C complex" complex SIGNOR-C375 SIGNOR "form complex" binding 12930972 t lperfetto "RF‐C, a complex of five subunits, is conserved in all eukaryotes (reviewed in 5). In yeast, all subunits of RF‐C are essential for viability. The genes encoding all five subunits of mammalian RF‐C (145, 40, 38, 37 and 36 kDa) have been cloned" SIGNOR-265508 RFC2 protein P35250 UNIPROT "RF-C complex" complex SIGNOR-C375 SIGNOR "form complex" binding 12930972 t lperfetto "RF‐C, a complex of five subunits, is conserved in all eukaryotes (reviewed in 5). In yeast, all subunits of RF‐C are essential for viability. The genes encoding all five subunits of mammalian RF‐C (145, 40, 38, 37 and 36 kDa) have been cloned" SIGNOR-265506 RFC1 protein P35251 UNIPROT "RF-C complex" complex SIGNOR-C375 SIGNOR "form complex" binding 12930972 t lperfetto "RF‐C, a complex of five subunits, is conserved in all eukaryotes (reviewed in 5). In yeast, all subunits of RF‐C are essential for viability. The genes encoding all five subunits of mammalian RF‐C (145, 40, 38, 37 and 36 kDa) have been cloned" SIGNOR-265505 RPL22 protein P35268 UNIPROT RPL22L1 protein Q6P5R6 UNIPROT down-regulates 9606 23990801 f miannu "We find that rpl22 directly represses expression of rpl22l1 mrna by binding to an internal hairpin structure." SIGNOR-202600 RPL22 protein P35268 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262499 GTF2F1 protein P35269 UNIPROT GTF2F1 protein P35269 UNIPROT down-regulates phosphorylation Ser385 GGSSRGNsRPGTPSA 9606 10428810 t gcesareni "We show that tfiifalpha possesses a serine/threonine kinase activity, allowing an autophosphorylation of the two residues at position serine 385 and threonine 389. Mutation analysis strongly suggests that autophosphorylation of both sites regulates the transcription elongation process." SIGNOR-69767 GTF2F1 protein P35269 UNIPROT GTF2F1 protein P35269 UNIPROT down-regulates phosphorylation Thr389 RGNSRPGtPSAEGGS 9606 10428810 t gcesareni "We show that tfiifalpha possesses a serine/threonine kinase activity, allowing an autophosphorylation of the two residues at position serine 385 and threonine 389. Mutation analysis strongly suggests that autophosphorylation of both sites regulates the transcription elongation process." SIGNOR-69771 GTF2F1 protein P35269 UNIPROT TFIIF complex SIGNOR-C394 SIGNOR "form complex" binding -1 18218714 t lperfetto "Human general transcription factor IIF (TFIIF), a component of the transcription pre-initiation complex (PIC) associated with RNA polymerase II (Pol II), was characterized by size-exclusion chromatography (SEC), electrospray ionization mass spectrometry (ESI-MS), and chemical cross-linking. Recombinant TFIIF, composed of an equimolar ratio of alpha and beta subunits, was bacterially expressed, purified to homogeneity, and found to have a transcription activity similar to a natural one in the human in vitro transcription system." SIGNOR-266194 SSTR5 protein P35346 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256833 SSTR5 protein P35346 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256969 SSTR5 protein P35346 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256690 RORA protein P35398 UNIPROT SHH protein Q15465 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001011 19381306 t miannu "RORα regulates the expression of several genes in Purkinje cells. RORα becomes highly expressed in postmitotic Purkinje cells. It regulates their maturation, particularly dendritic differentiation. Dendritogenesis and the expression of several genes, including Shh, Itpr1, Pcp4, Calb1, Pcp2, and Slc1a6, normally expressed in mature Purkinje cells, are inhibited in RORα-deficient mice." SIGNOR-266846 ADRA1A protein P35348 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257195 ADRA1A protein P35348 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256955 ADRA1A protein P35348 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257084 ADRA1A protein P35348 UNIPROT GNA13 protein Q14344 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257279 ADRA1A protein P35348 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256812 PTGS2 protein P35354 UNIPROT "prostaglandin F2alpha" smallmolecule CHEBI:15553 ChEBI up-regulates "small molecule catalysis" 9606 11751058 t 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 PTGS2 protein P35354 UNIPROT "prostaglandin F2alpha" smallmolecule CHEBI:15553 ChEBI up-regulates "small molecule catalysis" 9606 BTO:0001103 20219869 t apalma "NSAIDs are strong inhibitors of cycloxygenases (COX), and thereby impair the metabolism of arachidonic acid that is necessary for the synthesis of prostaglandins" SIGNOR-255359 PTGS2 protein P35354 UNIPROT "prostaglandin D2" smallmolecule CHEBI:15555 ChEBI up-regulates "small molecule catalysis" 9606 11751058 t 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-113282 PTGS2 protein P35354 UNIPROT "episterol ester" smallmolecule CHEBI:52393 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 BTO:0000142 19126760 t miannu "After biosynthesis, 2-AG is partially degraded by postsynaptic COX-2, and partly released to the extracellular space. " SIGNOR-264270 PTGS2 protein P35354 UNIPROT Prostacycline smallmolecule CID:159 PUBCHEM up-regulates "small molecule catalysis" 9606 11751058 t 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-113300 PTGS2 protein P35354 UNIPROT IL4 protein P05112 UNIPROT up-regulates 9606 22225874 t FFerrentino "Cox2 Is a Direct Srf Target Gene and Controls Il4 Expression" SIGNOR-255967 PTGS2 protein P35354 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates 9606 BTO:0001103 20219869 t 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 PTGS2 protein P35354 UNIPROT GSK3B protein P49841 UNIPROT down-regulates 9606 BTO:0000586 16293724 f lperfetto "We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein)coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin. This leads to the inactivation and release of glycogen synthase kinase 3b from its complex with axin, thereby relieving the inhibitory phosphorylation of b-catenin and activating its signaling pathway." SIGNOR-141783 HRH1 protein P35367 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257425 HRH1 protein P35367 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257163 HRH1 protein P35367 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257251 HRH1 protein P35367 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257318 HRH1 protein P35367 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256921 HRH1 protein P35367 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257376 HRH1 protein P35367 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257050 HRH1 protein P35367 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256778 ADRA1B protein P35368 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257190 ADRA1B protein P35368 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256950 ADRA1B protein P35368 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257079 ADRA1B protein P35368 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256807 OPRM1 protein P35372 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256854 OPRM1 protein P35372 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256990 OPRM1 protein P35372 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257106 OPRM1 protein P35372 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256711 RORA protein P35398 UNIPROT PCP4 protein P48539 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001011 19381306 t miannu "RORα regulates the expression of several genes in Purkinje cells. RORα becomes highly expressed in postmitotic Purkinje cells. It regulates their maturation, particularly dendritic differentiation. Dendritogenesis and the expression of several genes, including Shh, Itpr1, Pcp4, Calb1, Pcp2, and Slc1a6, normally expressed in mature Purkinje cells, are inhibited in RORα-deficient mice." SIGNOR-266848 RORA protein P35398 UNIPROT SLC1A6 protein P48664 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001011 19381306 t miannu "RORα regulates the expression of several genes in Purkinje cells. RORα becomes highly expressed in postmitotic Purkinje cells. It regulates their maturation, particularly dendritic differentiation. Dendritogenesis and the expression of several genes, including Shh, Itpr1, Pcp4, Calb1, Pcp2, and Slc1a6, normally expressed in mature Purkinje cells, are inhibited in RORα-deficient mice." SIGNOR-266850 RORA protein P35398 UNIPROT ITPR1 protein Q14643 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001011 19381306 t miannu "RORα regulates the expression of several genes in Purkinje cells. RORα becomes highly expressed in postmitotic Purkinje cells. It regulates their maturation, particularly dendritic differentiation. Dendritogenesis and the expression of several genes, including Shh, Itpr1, Pcp4, Calb1, Pcp2, and Slc1a6, normally expressed in mature Purkinje cells, are inhibited in RORα-deficient mice." SIGNOR-266847 RORA protein P35398 UNIPROT PCP2 protein Q8IVA1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001011 19381306 t miannu "RORα regulates the expression of several genes in Purkinje cells. RORα becomes highly expressed in postmitotic Purkinje cells. It regulates their maturation, particularly dendritic differentiation. Dendritogenesis and the expression of several genes, including Shh, Itpr1, Pcp4, Calb1, Pcp2, and Slc1a6, normally expressed in mature Purkinje cells, are inhibited in RORα-deficient mice." SIGNOR-266849 RORA protein P35398 UNIPROT NLGN1 protein Q8N2Q7 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 28608249 t lperfetto "Some genes which are directly regulated by RORA such as NLGN1 and NTRK2 have been shown to be associated with increased susceptibility to ASD (Correia et al. 2010; Ylisaukko-oja et al. 2005)." SIGNOR-265136 RORA protein P35398 UNIPROT CPT1B protein Q92523 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001103 15199055 f "Furthermore, we show that the muscle carnitine palmitoyltransferase-1 and caveolin-3 promoters are directly regulated by ROR and coactivated by p300 and PGC-1. This study implicates RORs in the control of lipid homeostasis in skeletal muscle." SIGNOR-254256 PTGER4 protein P35408 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256903 PTGER4 protein P35408 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257032 PTGER4 protein P35408 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256760 APLNR protein P35414 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256960 APLNR protein P35414 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256824 APLNR protein P35414 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256681 THBS2 protein P35442 UNIPROT CD47 protein Q08722 UNIPROT up-regulates binding 9606 8550562 t gcesareni "We report here that iap is a receptor for the ts1 cbd and its vvm-containing peptides and that a function-blocking anti-iap mab inhibits the chemotactic response to ts1 and its cbd peptides in endothelial cells." SIGNOR-39749 HOXD12 protein P35452 UNIPROT MEIS1 protein O00470 UNIPROT "up-regulates activity" binding -1 9343407 t 2 miannu "We now show that the Hoxa-9 protein physically interacts with Meis1 proteins. Hox proteins from the other AbdB-like paralogs, Hoxa-10, Hoxa-11, Hoxd-12, and Hoxb-13, also form DNA binding complexes with Meis1b. DNA binding complexes formed by Meis1 with Hox proteins dissociate much more slowly than DNA complexes with Meis1 alone, suggesting that Hox proteins stabilize the interactions of Meis1 proteins with their DNA targets." SIGNOR-241232 HOXD12 protein P35452 UNIPROT MAFG protein O15525 UNIPROT "down-regulates activity" binding -1 11036080 t miannu "Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf." SIGNOR-221958 HOXD12 protein P35452 UNIPROT MAFK protein O60675 UNIPROT "down-regulates activity" binding -1 11036080 t miannu "Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf." SIGNOR-221929 HOXD12 protein P35452 UNIPROT MAF protein O75444 UNIPROT "down-regulates activity" binding -1 11036080 t miannu "Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf." SIGNOR-221887 HOXD12 protein P35452 UNIPROT MAFF protein Q9ULX9 UNIPROT "down-regulates activity" binding -1 11036080 t miannu "Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf." SIGNOR-221884 HOXD12 protein P35452 UNIPROT MAFB protein Q9Y5Q3 UNIPROT "down-regulates activity" binding -1 11036080 t miannu "Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf." SIGNOR-221896 HOXD13 protein P35453 UNIPROT MEIS1 protein O00470 UNIPROT "up-regulates activity" binding -1 9343407 t 2 miannu "We now show that the Hoxa-9 protein physically interacts with Meis1 proteins. Hox proteins from the other AbdB-like paralogs, Hoxa-10, Hoxa-11, Hoxd-12, and Hoxb-13, also form DNA binding complexes with Meis1b. DNA binding complexes formed by Meis1 with Hox proteins dissociate much more slowly than DNA complexes with Meis1 alone, suggesting that Hox proteins stabilize the interactions of Meis1 proteins with their DNA targets." SIGNOR-241235 HOXD13 protein P35453 UNIPROT EPHA7 protein Q15375 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16314414 f miannu "We show that hoxd13 andhoxa13activate transcription from the epha7 promoter and that a mutation of thehoxa13/hoxd13 binding site was sufficient to abolish activation." SIGNOR-142453 DRD3 protein P35462 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256845 DRD3 protein P35462 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256981 DRD3 protein P35462 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257097 DRD3 protein P35462 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256702 MSX2 protein P35548 UNIPROT DLX5 protein P56178 UNIPROT "down-regulates activity" binding 10090 BTO:0000947 9111364 t 2 miannu "We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities." SIGNOR-240990 MSX2 protein P35548 UNIPROT DLX2 protein Q07687 UNIPROT "down-regulates activity" binding 10090 BTO:0000945 9111364 t 2 miannu "We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities." SIGNOR-240932 MSX2 protein P35548 UNIPROT SPEN protein Q96T58 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271;BTO:0000661 19835636 t gcesareni "Furthermore, in addition to msx2, both tlx1 and nkx2-5 proteins interacted with notch-pathway repressors, spen/mint/sharp and tle1/grg1, representing a potential mechanism for (de)regulation." SIGNOR-188572 FBN1 protein P35555 UNIPROT TGFB1 protein P01137 UNIPROT "up-regulates quantity" binding 9606 17242066 t "Regulation of localization" miannu "We have discovered that fibrillin-1, which forms extracellular microfibrils, can regulate the bioavailability of transforming growth factor (TGF) beta1, a powerful cytokine that modulates cell survival and phenotype. Altered TGFbeta signaling is a major contributor to the pathology of Marfan syndrome (MFS) and related diseases. In the presence of cell layer extracellular matrix, a fibrillin-1 sequence encoded by exons 44-49 releases endogenous TGFbeta1, thereby stimulating TGFbeta receptor-mediated Smad2 signaling." SIGNOR-251888 FBN1 protein P35555 UNIPROT MMP1 protein P03956 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16442122 f "Regulation of expression" miannu "In this study we show that a fibrillin-1 fragment containing a EGFEPG sequence that conforms to a putative GxxPG elastin-binding protein (EBP) consensus sequence upregulates the expression and production of matrix metalloproteinase (MMP)-1 by up to ninefold in a cell culture system. Mutations in the gene for fibrillin-1 cause Marfan syndrome (MFS), a common hereditary disorder of connective tissue" SIGNOR-251887 FBN1 protein P35555 UNIPROT SMAD2 protein Q15796 UNIPROT "up-regulates activity" 9606 17242066 f Regulation miannu "Fibrillin-1 sequence encoded by exons 44-49 releases endogenous TGFbeta1, thereby stimulating TGFbeta receptor-mediated Smad2 signaling." SIGNOR-251889 FBN1 protein P35555 UNIPROT FBLN5 protein Q9UBX5 UNIPROT "down-regulates activity" binding 9606 19570982 t miannu "Fibulin-4 and -5 are extracellular glycoproteins with essential non-compensatory roles in elastic fiber assembly. We have determined how they interact with tropoelastin, lysyl oxidase, and fibrillin-1, thereby revealing how they differentially regulate assembly. Both fibulins differentially bound N-terminal fibrillin-1, which strongly inhibited their binding to lysyl oxidase and tropoelastin." SIGNOR-252138 IRS1 protein P35568 UNIPROT PIK3R1 protein P27986 UNIPROT "up-regulates activity" binding 10116 BTO:0001103 21798082 t 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-175668 IRS1 protein P35568 UNIPROT PIK3CB protein P42338 UNIPROT "up-regulates activity" binding 10090 BTO:0000944 11416002 t lperfetto "To examine contributions of specific YXXM motifs in human insulin receptor substrate-1 (IRS-1) to mediating the metabolic actions of insulin, we studied IRS-1 mutants containing various substitutions of Phe for Tyr. In transfected NIH-3T3(IR) cells, insulin stimulation caused a 5-fold increase in phosphatidylinositol 3-kinase (PI3K) activity coimmunoprecipitated with wild-type IRS-1" SIGNOR-235487 IRS1 protein P35568 UNIPROT PIK3CB protein P42338 UNIPROT "up-regulates activity" binding 10090 BTO:0000887 14623899 t lperfetto "As shown previously, IRS-1 was required for insulin-stimulated phosphorylation of Akt in 32D cells, which is consistent with the binding and activation of PI3K by IRS-1 during insulin stimulation" SIGNOR-236618 IRS1 protein P35568 UNIPROT GRB2 protein P62993 UNIPROT "up-regulates activity" binding 9606 BTO:0000156 11259577 t lperfetto "Association ofinsulinreceptor substrate 1 (irs-1) y895 with grb-2 mediates theinsulinsignaling involved in irs-1-deficient brown adipocyte mitogenesis." SIGNOR-236614 IRS1 protein P35568 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" binding 9606 BTO:0000551 20966354 t lperfetto "Irs proteins are capable of both regulating and activating pi3k, depending on the cell of origin." SIGNOR-256170 IRS1 protein P35568 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" binding 10116 BTO:0001103 21798082 t 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 G6PC1 protein P35575 UNIPROT alpha-D-glucose smallmolecule CHEBI:17925 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 12093796 t miannu "Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis" SIGNOR-266578 G6PC1 protein P35575 UNIPROT alpha-D-glucose smallmolecule CHEBI:17925 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 12093796 t miannu "Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis" SIGNOR-266564 G6PC1 protein P35575 UNIPROT "alpha-D-glucose 6-phosphate(2-)" smallmolecule CHEBI:58225 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 12093800 t miannu "Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis" SIGNOR-266582 G6PC1 protein P35575 UNIPROT "alpha-D-glucose 6-phosphate(2-)" smallmolecule CHEBI:58225 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 12093800 t miannu "Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis" SIGNOR-266568 SOAT1 protein P35610 UNIPROT "cholesteryl ester" smallmolecule CHEBI:17002 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 BTO:0000759 31848472 t miannu "Excess cholesterol is esterified by acyl coenzyme A:cholesterol acyltransferase (ACAT; also known as SOAT) to cholesteryl esters" SIGNOR-265160 ADD1 protein P35611 UNIPROT "4.1 complex" complex SIGNOR-C386 SIGNOR "form complex" binding 9606 BTO:0000424 33187473 t lperfetto "The cytoskeleton plays a key role in maintaining the morphology and function of erythrocyte membranes. Many proteins, such as ankyrin, spectrin alpha- and beta-chains, proteins 4.1, or 4.1R and actin, cover the inner surface of the erythrocyte membrane to form two protein complexes, the ankyrin and protein 4.1 complex| the latter consists of Band 3 dimers binding Adducins alpha and beta, Glycophorin C, GLUT1 and Stomatin [15, 16]" SIGNOR-266037 ADD2 protein P35612 UNIPROT "4.1 complex" complex SIGNOR-C386 SIGNOR "form complex" binding 9606 BTO:0000424 33187473 t lperfetto "The cytoskeleton plays a key role in maintaining the morphology and function of erythrocyte membranes. Many proteins, such as ankyrin, spectrin alpha- and beta-chains, proteins 4.1, or 4.1R and actin, cover the inner surface of the erythrocyte membrane to form two protein complexes, the ankyrin and protein 4.1 complex| the latter consists of Band 3 dimers binding Adducins alpha and beta, Glycophorin C, GLUT1 and Stomatin [15, 16]" SIGNOR-266039 TIMP3 protein P35625 UNIPROT MMP14 protein P50281 UNIPROT "down-regulates activity" binding 10090 BTO:0005300 28709001 t "FAP cilia regulated the expression of TIMP3, a secreted metalloproteinase inhibitor, that inhibited MMP14 to block adipogenesis." SIGNOR-255908 GRK3 protein P35626 UNIPROT BDKRB2 protein P30411 UNIPROT "down-regulates activity" phosphorylation Ser366 EPIQMENsMGTLRTS 9606 BTO:0000007 11517230 t "Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration." SIGNOR-251460 GRK3 protein P35626 UNIPROT BDKRB2 protein P30411 UNIPROT "down-regulates activity" phosphorylation Ser373 SMGTLRTsISVERQI 9606 BTO:0000007 11517230 t gcesareni "...expression of GRK4Ž drastically increased the basal level of32P incorporation into B2R.[€]a clustered phosphorylation around Ser(346) is necessary for desensitization of the B2 receptor-induced phospholipase C activation." SIGNOR-249658 GRK3 protein P35626 UNIPROT BDKRB2 protein P30411 UNIPROT "down-regulates activity" phosphorylation Ser375 GTLRTSIsVERQIHK 9606 BTO:0000007 11517230 t "Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration." SIGNOR-251462 GRK3 protein P35626 UNIPROT OPRM1 protein P35372 UNIPROT "down-regulates activity" phosphorylation Thr182 VKALDFRtPRNAKII 8355 BTO:0000512 11060299 t gcesareni "These results demonstrate that the T180A mutation probably blocks GRK3- and arr3-mediated desensitization of MOR by preventing a critical agonist-dependent receptor phosphorylation and suggest a novel GRK3 site of regulation not yet described for other G-protein-coupled receptors" SIGNOR-247915 GRK3 protein P35626 UNIPROT CCR5 protein P51681 UNIPROT "down-regulates activity" phosphorylation Ser336 QEAPERAsSVYTRST 9534 BTO:0000298 10085131 t "Serine residues at positions 336, 337, 342, and 349 represent GRK phosphorylation sites on CCR5. CCR5 phosphorylation and desensitization through a GRK-mediated mechanism" SIGNOR-251463 GRK3 protein P35626 UNIPROT CCR5 protein P51681 UNIPROT "down-regulates activity" phosphorylation Ser337 EAPERASsVYTRSTG 9534 BTO:0000298 10085131 t "Serine residues at positions 336, 337, 342, and 349 represent GRK phosphorylation sites on CCR5. CCR5 phosphorylation and desensitization through a GRK-mediated mechanism" SIGNOR-251464 GRK3 protein P35626 UNIPROT CCR5 protein P51681 UNIPROT "down-regulates activity" phosphorylation Ser342 ASSVYTRsTGEQEIS 9534 BTO:0000298 10085131 t gcesareni "Phosphoamino acid analysis revealed that RANTES-induced CCR5 phosphorylation selectively occurs on serine residues. Our findings with receptor mutants indicate that serine residues at positions 336, 337, 342, and 349 represent GRK phosphorylation sites on CCR5." SIGNOR-249675 GRK3 protein P35626 UNIPROT CCR5 protein P51681 UNIPROT "down-regulates activity" phosphorylation Ser349 STGEQEIsVGL 9534 BTO:0000298 10085131 t gcesareni "Phosphoamino acid analysis revealed that RANTES-induced CCR5 phosphorylation selectively occurs on serine residues. Our findings with receptor mutants indicate that serine residues at positions 336, 337, 342, and 349 represent GRK phosphorylation sites on CCR5." SIGNOR-249679 FUS protein P35637 UNIPROT AGRN protein O00468 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 10090 BTO:0001279 28515487 f "This conclusion is also supported by the analysis of alternative splicing events in hFUS+/+; Smn+/− mice. As shown in Fig. 6b, the splicing of Dusp22, Mphosph9, Adarb1, hnRNP A2/B1, Gria4, Vps16, Atxn2 and Agrin, which are significantly affected in hFUS+/+ mice, is not further modified by SMN decrease" SIGNOR-262807 FUS protein P35637 UNIPROT DDX3X protein O00571 UNIPROT "down-regulates activity" relocalization 9606 BTO:0000793 27460707 t "P35637:p.Pro525Leu (mutation causing interaction)" "We found that ALS mutants of FUS co-localized with Caprin-1, DDX3X, and DHX9 in cytoplasmic inclusions that could lead to the mis-regulation of their respective pathways, providing further clues to the mechanism of ALS pathogenesis.|FUS interacting proteins were sequestered into the cytoplasmic mutant FUS inclusions that could lead to their mis-regulation or loss of function, contributing to ALS pathogenesis. | We also demonstrated the co-localization of DHX9, DDX3X and Caprin-1 with cytoplasmic EGFP-P525L mutant FUS inclusions in primary cortical neurons" SIGNOR-262811 FUS protein P35637 UNIPROT CSDE1 protein O75534 UNIPROT "up-regulates quantity by stabilization" "post transcriptional regulation" 9606 BTO:0000551 32808651 t lperfetto "These findings demonstrated that LINC00205 facilitates malignant phenotypes in LC by recruiting FUS to stabilize CSDE1, suggesting LINC00205 as a potential target for LC therapy.|Subsequent RIP assay con- firmed such prediction, as CSDE1 mRNA was evidently precipitated by anti-FUS (Figure 3A)." SIGNOR-262110 FUS protein P35637 UNIPROT SNRNP70 protein P08621 UNIPROT "up-regulates activity" binding 9606 26124092 t "FUS functions in coupling transcription to splicing by mediating an interaction between RNAP II and U1 snRNP" SIGNOR-262823 FUS protein P35637 UNIPROT MATR3 protein P43243 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000007 27731383 t "P35637:p.Pro525Leu (mutation disrupting interaction)" "Moreover, FUS interacts with another nuclear matrix-associated protein Matrin3, which is muted in a subset of familial ALS cases and reportedly interacts with TDP-43. Interestingly, ectopic ALS-linked FUS mutant sequestered endogenous Matrin3 and SAFB1 in the cytoplasmic aggregates." SIGNOR-262822 FUS protein P35637 UNIPROT GRIA4 protein P48058 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 10090 BTO:0001279 28515487 f "This conclusion is also supported by the analysis of alternative splicing events in hFUS+/+; Smn+/− mice. As shown in Fig. 6b, the splicing of Dusp22, Mphosph9, Adarb1, hnRNP A2/B1, Gria4, Vps16, Atxn2 and Agrin, which are significantly affected in hFUS+/+ mice, is not further modified by SMN decrease" SIGNOR-262806 FUS protein P35637 UNIPROT GEMIN4 protein P57678 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000567 23022481 t lperfetto "Here, we report that FUS associates with the SMN complex, mediated by U1 snRNP and by direct interactions between FUS and SMN.|The FUS IP and pulldown revealed that FUS also associates with components of the SMN complex, including SMN and Gemins 4 and 6 |Remarkably, the number of SMN-stained nuclear bodies was dramatically reduced in the FUS knockdown cells" SIGNOR-262105 FUS protein P35637 UNIPROT DLG4 protein P78352 UNIPROT "up-regulates quantity" "post transcriptional regulation" 10090 BTO:0000142 32118033 t lperfetto "These results point toward a novel mechanism by which FUS targets neuronal mRNA and given that these PSD-95 and Shank1 3'-UTR G quadruplex structures are also targeted by the fragile X mental retardation protein (FMRP), they raise the possibility that FUS and FMRP might work together to regulate the translation of these neuronal mRNA targets.|As seen in Figure 7 (top panel), both PSD-95 Q1-Q2 and Shank1a GQ probes pulled down endogenous FUS, whereas their M2 mutants did not, indicating that the GQ structure is sufficient for recognition." SIGNOR-262103 FUS protein P35637 UNIPROT ADARB1 protein P78563 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 10090 BTO:0001279 28515487 f "This conclusion is also supported by the analysis of alternative splicing events in hFUS+/+; Smn+/− mice. As shown in Fig. 6b, the splicing of Dusp22, Mphosph9, Adarb1, hnRNP A2/B1, Gria4, Vps16, Atxn2 and Agrin, which are significantly affected in hFUS+/+ mice, is not further modified by SMN decrease" SIGNOR-262805 FUS protein P35637 UNIPROT DHX9 protein Q08211 UNIPROT "down-regulates activity" relocalization 9606 BTO:0000793 27460707 t "P35637:p.Pro525Leu (mutation causing interaction)" "We found that ALS mutants of FUS co-localized with Caprin-1, DDX3X, and DHX9 in cytoplasmic inclusions that could lead to the mis-regulation of their respective pathways, providing further clues to the mechanism of ALS pathogenesis.|FUS interacting proteins were sequestered into the cytoplasmic mutant FUS inclusions that could lead to their mis-regulation or loss of function, contributing to ALS pathogenesis. | We also demonstrated the co-localization of DHX9, DDX3X and Caprin-1 with cytoplasmic EGFP-P525L mutant FUS inclusions in primary cortical neurons" SIGNOR-262810 FUS protein P35637 UNIPROT SMN1 protein Q16637 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000567 23022481 t lperfetto "Here, we report that FUS associates with the SMN complex, mediated by U1 snRNP and by direct interactions between FUS and SMN.|The FUS IP and pulldown revealed that FUS also associates with components of the SMN complex, including SMN and Gemins 4 and 6 |Remarkably, the number of SMN-stained nuclear bodies was dramatically reduced in the FUS knockdown cells" SIGNOR-262107 FUS protein P35637 UNIPROT GEMIN6 protein Q8WXD5 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000567 23022481 t lperfetto "Here, we report that FUS associates with the SMN complex, mediated by U1 snRNP and by direct interactions between FUS and SMN.|The FUS IP and pulldown revealed that FUS also associates with components of the SMN complex, including SMN and Gemins 4 and 6 |Remarkably, the number of SMN-stained nuclear bodies was dramatically reduced in the FUS knockdown cells" SIGNOR-262106 FUS protein P35637 UNIPROT MPHOSPH9 protein Q99550 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 10090 BTO:0001279 28515487 f "This conclusion is also supported by the analysis of alternative splicing events in hFUS+/+; Smn+/− mice. As shown in Fig. 6b, the splicing of Dusp22, Mphosph9, Adarb1, hnRNP A2/B1, Gria4, Vps16, Atxn2 and Agrin, which are significantly affected in hFUS+/+ mice, is not further modified by SMN decrease" SIGNOR-262804 FUS protein P35637 UNIPROT ATXN2 protein Q99700 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 10090 BTO:0001279 28515487 f "This conclusion is also supported by the analysis of alternative splicing events in hFUS+/+; Smn+/− mice. As shown in Fig. 6b, the splicing of Dusp22, Mphosph9, Adarb1, hnRNP A2/B1, Gria4, Vps16, Atxn2 and Agrin, which are significantly affected in hFUS+/+ mice, is not further modified by SMN decrease" SIGNOR-262809 FUS protein P35637 UNIPROT VPS16 protein Q9H269 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 10090 BTO:0001279 28515487 f "This conclusion is also supported by the analysis of alternative splicing events in hFUS+/+; Smn+/− mice. As shown in Fig. 6b, the splicing of Dusp22, Mphosph9, Adarb1, hnRNP A2/B1, Gria4, Vps16, Atxn2 and Agrin, which are significantly affected in hFUS+/+ mice, is not further modified by SMN decrease" SIGNOR-262808 FUS protein P35637 UNIPROT DUSP22 protein Q9NRW4 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 10090 BTO:0001279 28515487 f "This conclusion is also supported by the analysis of alternative splicing events in hFUS+/+; Smn+/− mice. As shown in Fig. 6b, the splicing of Dusp22, Mphosph9, Adarb1, hnRNP A2/B1, Gria4, Vps16, Atxn2 and Agrin, which are significantly affected in hFUS+/+ mice, is not further modified by SMN decrease" SIGNOR-262803 FUS protein P35637 UNIPROT PA2G4 protein Q9UQ80 UNIPROT "up-regulates activity" sumoylation Lys298 MGVVECAkHELLQPF 9606 BTO:0000007 19946338 t gcesareni "Here, we show that Ebp1 p42 isoform can be sumoylated on both K93 and K298 residues, which mediate its nuclear translocation and are required for its anti-proliferative activity €.. Hence, TLS-mediated sumoylation is required for Ebp1 transcriptional repressive activity." SIGNOR-249657 FUS protein P35637 UNIPROT PA2G4 protein Q9UQ80 UNIPROT "up-regulates activity" sumoylation Lys93 VCHFSPLkSDQDYIL 9606 BTO:0000007 19946338 t gcesareni "Here, we show that Ebp1 p42 isoform can be sumoylated on both K93 and K298 residues, which mediate its nuclear translocation and are required for its anti-proliferative activity €.. Hence, TLS-mediated sumoylation is required for Ebp1 transcriptional repressive activity." SIGNOR-236904 FUS protein P35637 UNIPROT SHANK1 protein Q9Y566 UNIPROT "up-regulates quantity" "post transcriptional regulation" 10090 BTO:0000142 32118033 t lperfetto "These results point toward a novel mechanism by which FUS targets neuronal mRNA and given that these PSD-95 and Shank1 3'-UTR G quadruplex structures are also targeted by the fragile X mental retardation protein (FMRP), they raise the possibility that FUS and FMRP might work together to regulate the translation of these neuronal mRNA targets.|As seen in Figure 7 (top panel), both PSD-95 Q1-Q2 and Shank1a GQ probes pulled down endogenous FUS, whereas their M2 mutants did not, indicating that the GQ structure is sufficient for recognition." SIGNOR-262104 SOX6 protein P35712 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0003298 26893351 t "In adipocytes, in addition to the direct regulation of PPARγ andC/EBP expression, we showed that SOX6 inhibitsWNT signaling by binding to β-catenin, potentially leading to its degradation" SIGNOR-255825 DDIT3 protein P35638 UNIPROT PPP1R15A protein O75807 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 31226023 t miannu "ATF4 also induces another bZIP protein C/EBP-homologous protein (CHOP), which is responsible for triggering apoptosis in cells under prolonged ER stress. ATF4 and CHOP further induce growth arrest and DNA damage–inducible protein 34 (GADD34),a regulatory subunit of protein phosphatase 1 (PP1) that dephosphorylates eIF2α. This negative feedback mechanism enables protein synthesis to resume after resolution of ER stress." SIGNOR-260173 DDIT3 protein P35638 UNIPROT ASNS protein P08243 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002181 18940792 f miannu "C/EBP homology protein (CHOP) interacts with activating transcription factor 4 (ATF4) and negatively regulates the stress-dependent induction of the asparagine synthetase gene." SIGNOR-253837 DDIT3 protein P35638 UNIPROT CEBPB protein P17676 UNIPROT "down-regulates quantity" "transcriptional regulation" 10090 7588595 t "We find that expression of CHOP, a nuclear protein that dimerizes avidly with C/EBP isoforms alpha and beta and directs the resulting heterodimer away from classic C/EBP-binding sites, markedly inhibits this differentiation process." SIGNOR-255914 DDIT3 protein P35638 UNIPROT CEBPA protein P49715 UNIPROT "down-regulates quantity" "transcriptional regulation" 10090 7588595 t "We find that expression of CHOP, a nuclear protein that dimerizes avidly with C/EBP isoforms alpha and beta and directs the resulting heterodimer away from classic C/EBP-binding sites, markedly inhibits this differentiation process." SIGNOR-255913 DDIT3 protein P35638 UNIPROT ANKRD1 protein Q15327 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10116 BTO:0003324 19299913 f lperfetto "Promoter deletion and reporter analysis revealed that hypoxia transcriptionally activates a GADD153 promoter through the AP-1 element in neonatal cardiomyocytes. Ectopic overexpression of GADD153 resulted in the downregulation of CARP expression." SIGNOR-254122 DDIT3 protein P35638 UNIPROT TRIB3 protein Q96RU7 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002183 18940792 f miannu "Exogenous CHOP expression enhanced the TRB3 gene induction by amino acid deprivation." SIGNOR-253839 NUP214 protein P35658 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates binding 9606 SIGNOR-C9 12917407 t gcesareni "We demonstrate that smad3 and smad4 are capable of interaction with the nucleoporin can/nup214, and this interaction is required for nuclear import." SIGNOR-117644 NUP214 protein P35658 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates binding 9606 SIGNOR-C9 12917407 t gcesareni "We demonstrate that smad3 and smad4 are capable of interaction with the nucleoporin can/nup214, and this interaction is required for nuclear import" SIGNOR-117647 NUP214 protein P35658 UNIPROT NPC complex SIGNOR-C263 SIGNOR "form complex" binding 27016207 t lperfetto "The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2)." SIGNOR-262075 NUP214 protein P35658 UNIPROT SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR "up-regulates activity" relocalization 9606 12917407 t lperfetto "We demonstrate that smad3 and smad4 are capable of interaction with the nucleoporin can/nup214, and this interaction is required for nuclear import." SIGNOR-217719 DEK protein P35659 UNIPROT PRDX5 protein P30044 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000567 19229864 f lperfetto "We further demonstrated by ChIP analysis that knock-down of DEK caused hyperacetylation of histones around Prx VI promoter which is upregulated in our profile." SIGNOR-254125 HNF1B protein P35680 UNIPROT ALB protein P02768 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 1673926 f Regulation miannu "VHNF1 transactivated the albumin promoter in transfection experiments" SIGNOR-251930 HNF1B protein P35680 UNIPROT AFP protein P02771 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 7549116 f miannu "HNF-1 beta was found to be more potent than HNF-1 alpha in activating the AFP promoter in the HepG2 cells." SIGNOR-254638 HNF1B protein P35680 UNIPROT CREB1 protein P16220 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 9671480 t 2 miannu "The mammalian two-hybrid system showed that the region aa 393 to 476 of LFB3 is involved in the interaction with CREB or ATF1. The importance of this region for mediating cAMP induction was confirmed in transient transfection assays." SIGNOR-241323 HNF1B protein P35680 UNIPROT AKR1C4 protein P17516 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003846 2044952 f 2 miannu "Hepatocyte nuclear factor (HNF)-4_/_, HNF-1_, and vHNF-1 regulate the cell-specific expression of the human dihydrodiol dehydrogenase (DD)4/AKR1C4 gene.HNF-1_ binds to the target element in the rat DBP gene in the liver, while vHNF-1 recognizes a target element in extrahepatic tissues. The ability of vHNF-1-A to activate the rat DBP gene is much higher than that of vHNF-1-C." SIGNOR-239960 HNF1B protein P35680 UNIPROT ATF1 protein P18846 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 9671480 t 2 miannu "The mammalian two-hybrid system showed that the region aa 393 to 476 of LFB3 is involved in the interaction with CREB or ATF1. The importance of this region for mediating cAMP induction was confirmed in transient transfection assays." SIGNOR-241320 HNF1B protein P35680 UNIPROT FXYD2 protein P54710 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19389850 f Regulation miannu "We analyzed genes associated with hypermagnesuria and detected highly conserved HNF1 recognition sites in FXYD2, a gene that can cause autosomal dominant hypomagnesemia and hypocalciuria when mutated. Using a luciferase reporter assay, we demonstrated HNF1B-mediated transactivation of FXYD2." SIGNOR-251927 HNF1B protein P35680 UNIPROT FXYD2 protein P54710 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000482 24204001 f miannu "Overexpression in a human kidney cell line showed that wild-type PCBD1 binds HNF1B to costimulate the FXYD2 promoter, the activity of which is instrumental in Mg(2+) reabsorption in the DCT." SIGNOR-254909 SOX5 protein P35711 UNIPROT COL2A1 protein P02458 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10980415 f miannu "Since Sox9 also contains a potent transcription activation domain, it is a typical transcription factor. Two other members of the Sox family, L-Sox5 and Sox6, also bind to the 48-bp Col2a1 enhancer and together with Sox9 activate this enhancer as well as the endogenous Col2a1" SIGNOR-251759 SOX6 protein P35712 UNIPROT COL2A1 protein P02458 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10980415 f miannu "Since Sox9 also contains a potent transcription activation domain, it is a typical transcription factor. Two other members of the Sox family, L-Sox5 and Sox6, also bind to the 48-bp Col2a1 enhancer and together with Sox9 activate this enhancer as well as the endogenous Col2a1" SIGNOR-251760 SOX6 protein P35712 UNIPROT HBG1 protein P69891 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004911 20395365 f Regulation miannu "BCL11A and SOX6 co-occupy the human beta-globin cluster along with GATA1, and cooperate in silencing gamma-globin transcription in adult human erythroid progenitors." SIGNOR-251810 SOX6 protein P35712 UNIPROT HBG2 protein P69892 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004911 20395365 f Regulation miannu "BCL11A and SOX6 co-occupy the human beta-globin cluster along with GATA1, and cooperate in silencing gamma-globin transcription in adult human erythroid progenitors." SIGNOR-251808 SOX6 protein P35712 UNIPROT MEST protein Q5EB52 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003298 26893351 f "We found that SOX6 regulates adipogenesis in vertebrate species by activating adipogenic regulators including PPARγ, C/EBPα and MEST." SIGNOR-255823 SOX11 protein P35716 UNIPROT SPAST protein Q9UBP0 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22574173 f miannu "we demonstrate that SPAST transcription is positively regulated by NRF1 and SOX11." SIGNOR-254886 CHKA protein P35790 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" binding 9606 BTO:0000093 21822308 t miannu "We find that CHKA forms a complex with EGFR in a c-Src-dependent manner. Endogenous CHKA and EGFR co-immunoprecipitated from a variety of breast cancer cell lines and immortalized mammary epithelial cells. CHKA interacted with the EGFR kinase domain upon c-Src co-overexpression and was phosphorylated in a c-Src-dependent manner on Y197 and Y333. CHKA is required for maximum EGF-dependent cell growth in mammary epithelium-derived cell lines" SIGNOR-266352 PPM1A protein P35813 UNIPROT IKBKB protein O14920 UNIPROT down-regulates dephosphorylation Ser177 AKELDQGsLCTSFVG 9606 18930133 t lperfetto "Using a functional genomic approach, we have identified two protein serine/threonine phosphatases, ppm1a and ppm1b, as ikkbeta phosphatases. Overexpression of ppm1a or ppm1b results in dephosphorylation of ikkbeta at ser177 and ser181 and termination of ikkbeta-induced nf-kappab activation" SIGNOR-181655 PPM1A protein P35813 UNIPROT IKBKB protein O14920 UNIPROT down-regulates dephosphorylation Ser181 DQGSLCTsFVGTLQY 9606 18930133 t lperfetto "Using a functional genomic approach, we have identified two protein serine/threonine phosphatases, ppm1a and ppm1b, as ikkbeta phosphatases. Overexpression of ppm1a or ppm1b results in dephosphorylation of ikkbeta at ser177 and ser181 and termination of ikkbeta-induced nf-kappab activation" SIGNOR-181659 PPM1A protein P35813 UNIPROT IKBKB protein O14920 UNIPROT "down-regulates activity" dephosphorylation Ser177 AKELDQGsLCTSFVG 9606 BTO:0000007 18930133 t "PPM1A and PPM1B act as IKKbeta phosphatases to terminate TNFalpha-induced IKKbeta-NF-kappaB activation|Overexpression of PPM1A or PPM1B results in dephosphorylation of IKKbeta at Ser177 and Ser181 and termination of IKKbeta-induced NF-kappaB activation." SIGNOR-248486 PPM1A protein P35813 UNIPROT IKBKB protein O14920 UNIPROT "down-regulates activity" dephosphorylation Ser181 DQGSLCTsFVGTLQY 9606 BTO:0000007 18930133 t "PPM1A and PPM1B act as IKKbeta phosphatases to terminate TNFalpha-induced IKKbeta-NF-kappaB activation|Overexpression of PPM1A or PPM1B results in dephosphorylation of IKKbeta at Ser177 and Ser181 and termination of IKKbeta-induced NF-kappaB activation." SIGNOR-248487 PPM1A protein P35813 UNIPROT AXIN1 protein O15169 UNIPROT "down-regulates quantity by destabilization" dephosphorylation 9606 10644691 t "In addition, PP2C expression relieves Axin-mediated repression of LEF-1-dependent transcription. PP2C utilizes Axin as a substrate both in vitro and in vivo and decreases its half-life. These results indicate that PP2C is a positive regulator of Wnt signal transduction and mediates its effects through the dephosphorylation of Axin." SIGNOR-248488 PPM1A protein P35813 UNIPROT PIK3R1 protein P27986 UNIPROT "up-regulates activity" dephosphorylation Ser608 ENTEDQYsLVEDDED 10090 BTO:0000944 15016818 t "Protein phosphatase-2C alpha as a positive regulator of insulin sensitivity through direct activation of phosphatidylinositol 3-kinase in 3T3-L1 adipocytes|PP2Cα dephosphorylates the p85 subunit of PI3K, and dephosphorylation of the p85 subunit of PI3K at Ser608 increases its activity" SIGNOR-248489 PPM1A protein P35813 UNIPROT CDK9 protein P50750 UNIPROT "down-regulates activity" dephosphorylation Thr186 NSQPNRYtNRVVTLW 9606 18829461 t gcesareni "Taken together, our data indicate that PPM1A and to some extent PPM1B are important negative regulators of P-TEFb function" SIGNOR-248490 PPM1A protein P35813 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates dephosphorylation 9606 16751101 t lpetrilli "Ppm1a dephosphorylates and promotes nuclear export of tgfbeta-activated smad2/3. in conclusion, ppm1a is a bona fide phosphatase that directly dephosphorylates the critical sxs motif of r-smads." SIGNOR-146922 PPM1A protein P35813 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" dephosphorylation 9606 16751101 t lperfetto "Ppm1a dephosphorylates and promotes nuclear export of tgfbeta-activated smad2/3; these results suggest that phospho-smad2 is a direct substrate of mg2+-dependent ppm1a. in conclusion, ppm1a is a bona fide phosphatase that directly dephosphorylates the critical sxs motif of r-smads." SIGNOR-232110 PPM1A protein P35813 UNIPROT PAK1 protein Q13153 UNIPROT "down-regulates activity" dephosphorylation Ser199 PRPEHTKsVYTRSVI 10116 18586681 t "Purified PP2Cα protein efficiently dephosphorylated PAK1 in vitro (Fig. 1, D and E). We previously assessed the time course of phospho-PAK1 dephosphorylation assessed using specific antibodies against either Ser(P)198/203 or Thr(P)422 sites in the PAK1 activation loop." SIGNOR-248492 PPM1A protein P35813 UNIPROT PAK1 protein Q13153 UNIPROT "down-regulates activity" dephosphorylation Ser57 KKDRFYRsILPGDKT 10116 18586681 t "Both sites were dephosphorylated with the same kinetics; the anti-Ser(P)198 antibody was subsequently used as it exhibited lower background staining. Direct comparison of PP2Cα with purified PP1 and PP2A lead us to conclude that at the same molar ratio PP2Cα was the most efficient in dephosphorylating PAK1 (Fig. 1D). In this case we monitored two autophosphorylation sites in the Pak1 N-terminal regulatory region (Ser57 and Ser198/203) using phosphospecific antibodies: both sites showed the same kinetics of inactivation." SIGNOR-248493 PPM1A protein P35813 UNIPROT PAK1 protein Q13153 UNIPROT "down-regulates activity" dephosphorylation Thr423 PEQSKRStMVGTPYW 10116 18586681 t "Purified PP2Cα protein efficiently dephosphorylated PAK1 in vitro (Fig. 1, D and E). We previously assessed the time course of phospho-PAK1 dephosphorylation assessed using specific antibodies against either Ser(P)198/203 or Thr(P)422 sites in the PAK1 activation loop." SIGNOR-248491 PPM1A protein P35813 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates dephosphorylation 9606 16751101 t lpetrilli "Ppm1a dephosphorylates and promotes nuclear export of tgfbeta-activated smad2/3; these results suggest that phospho-smad2 is a direct substrate of mg2+-dependent ppm1a. in conclusion, ppm1a is a bona fide phosphatase that directly dephosphorylates the critical sxs motif of r-smads." SIGNOR-146919 PPM1A protein P35813 UNIPROT SMAD2 protein Q15796 UNIPROT "down-regulates activity" dephosphorylation 9606 16751101 t lperfetto "Ppm1a dephosphorylates and promotes nuclear export of tgfbeta-activated smad2/3; these results suggest that phospho-smad2 is a direct substrate of mg2+-dependent ppm1a. in conclusion, ppm1a is a bona fide phosphatase that directly dephosphorylates the critical sxs motif of r-smads." SIGNOR-217628 PPM1A protein P35813 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates dephosphorylation 9606 16931515 t lpetrilli "In this study, we have found that ppm1a, a metal ion-dependent protein serine/threonine phosphatase, physically interacts with and dephosphorylates smad1 both in vitro and in vivo. considering the highly conserved nature of the sxs motif in all r-smads, we reasoned that ppm1a might also recognize the sxs motif in the bmp-activated smad1." SIGNOR-149077 PPM1A protein P35813 UNIPROT MAPK14 protein Q16539 UNIPROT "down-regulates activity" dephosphorylation 9606 9707433 t lperfetto "Moreover, when expressed in mammalian cells, pp2ca inhibited the activation of the p38 and jnk cascades induced by environmental stresses. Both in vivo and in vitro observations indicated that pp2ca dephosphorylated and inactivated mapkks (mkk6 and sek1) and a mapk (p38) in the stress-responsive mapk cascades. Furthermore, a direct interaction of pp2ca and p38 was demonstrated by a co-immunoprecipitation assay" SIGNOR-59618 PPM1A protein P35813 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates dephosphorylation 9606 10644691 t lperfetto "Pp2c utilizes axin as a substrate both in vitro and in vivo and decreases its half-life. These results indicate that pp2c is a positive regulator of wnt signal transduction and mediates its effects through the dephosphorylation of axin." SIGNOR-227955 PPM1A protein P35813 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" dephosphorylation Ser608 ENTEDQYsLVEDDED 10090 BTO:0000944 15016818 t "Protein phosphatase-2C alpha as a positive regulator of insulin sensitivity through direct activation of phosphatidylinositol 3-kinase in 3T3-L1 adipocytes|PP2C_ dephosphorylates the p85 subunit of PI3K, and dephosphorylation of the p85 subunit of PI3K at Ser608 increases its activity" SIGNOR-252724 AHR protein P35869 UNIPROT CYP1A1 protein P04798 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17012224 t miannu "Kaempferol proved to be capable of inhibiting binding of agonist and agonist-induced formation of the AHR/ARNT DNA-binding complex and upregulation of the AHR target gene, CYP1A1." SIGNOR-259909 AHR protein P35869 UNIPROT CYP1A1 protein P04798 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" -1 9865727 t "Resveratrol inhibits transcription of CYP1A1 in vitro by preventing activation of the aryl hydrocarbon receptor|These data demonstrate that resveratrol inhibits CYP1A1 expression in vitro, and that it does this by preventing the binding of the AHR to promoter sequences that regulate CYP1A1 transcription." SIGNOR-253639 AHR protein P35869 UNIPROT UGT1A1 protein P22309 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18172616 f miannu "Human UDP-glucuronosyltransferase (UGT)1A1 is a critical enzyme responsible for detoxification and metabolism of endogenous and exogenous lipophilic compounds, such as potentially neurotoxic bilirubin and the anticancer drug irinotecan SN-38, via conjugation with glucuronic acid. A 290-bp distal enhancer module, phenobarbital-responsive enhancer module of UGT1A1 (gtPBREM), fully accounts for constitutive androstane receptor (CAR)-, pregnane X receptor (PXR)-, glucocorticoid receptor (GR)-, and aryl hydrocarbon receptor (AhR)-mediated activation of the UGT1A1 gene." SIGNOR-253734 AHR protein P35869 UNIPROT CYP1B1 protein Q16678 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001033 16115918 f miannu "Expressions of CYP1B1 mRNA and protein were increased in prostate cancer. The aryl hydrocarbon receptor (AhR)/AhR nuclear translocator (ARNT) heterodimer complex activates gene transcription by binding to the DREs of CYP1B1." SIGNOR-253733 AHR protein P35869 UNIPROT CYP1B1 protein Q16678 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 17012224 t "The formation of the AHR/ARNT dimerization complex converts the AHR into a high affinity DNA-binding form that recognizes specific DNA recognition sites termed DREs. In this manner, the agonist activated AHR upregulates a battery of target genes, including those involved in the metabolism of chemical carcinogens, such as CYP1A1 and CYP1B1 ." SIGNOR-253642 AHR protein P35869 UNIPROT AHR-ARNT complex SIGNOR-C125 SIGNOR "form complex" binding -1 9020169 t 2 miannu "SIM1 and SIM2, and the mammalian aryl hydrocarbon receptor (AHR) and aryl hydrocarbon receptor nuclear translocator (ARNT) proteins are members of the basic-helix-loop-helix·PAS family of transcription factors. In the yeast two-hybrid system, we demonstrate strong constitutive interaction of ARNT with SIM1 and SIM2 and fully ligand-dependent interaction of ARNT with AHR. SIM1 inhibits binding of the AHR·ARNT dimer to the xenobiotic response element in vitro Introduction of SIM1 into hepatoma cells inhibits transcriptional transactivation by the endogenous AHR·ARNT dimer." SIGNOR-240817 FLT4 protein P35916 UNIPROT SHC1 protein P29353 UNIPROT unknown phosphorylation Tyr349 EEPPDHQyYNDFPGK 9606 9927207 t llicata "We have investigated which of the shc tyrosine residues are targeted by the vegfr3/ flt4 kinase and the role of the shc ptb and sh2 domains in this process. Our results show that y239/ y240 and y313 are simultaneously phosphorylated by the kinase, creating grb2 binding sites." SIGNOR-64186 FLT4 protein P35916 UNIPROT SHC1 protein P29353 UNIPROT unknown phosphorylation Tyr350 EPPDHQYyNDFPGKE 9606 9927207 t llicata "We have investigated which of the shc tyrosine residues are targeted by the vegfr3/ flt4 kinase and the role of the shc ptb and sh2 domains in this process. Our results show that y239/ y240 and y313 are simultaneously phosphorylated by the kinase, creating grb2 binding sites." SIGNOR-64076 FLT4 protein P35916 UNIPROT SHC1 protein P29353 UNIPROT unknown phosphorylation Tyr427 ELFDDPSyVNVQNLD 9606 9927207 t llicata "We have investigated which of the shc tyrosine residues are targeted by the vegfr3/ flt4 kinase and the role of the shc ptb and sh2 domains in this process. Our results show that y239/ y240 and y313 are simultaneously phosphorylated by the kinase, creating grb2 binding sites." SIGNOR-64190 FLT4 protein P35916 UNIPROT FLT4 protein P35916 UNIPROT "up-regulates activity" phosphorylation Tyr1230 RHSLAARyYNWVSFP 9606 BTO:0000394 12881528 t lperfetto "Trans-phosphorylation of activated, dimerized receptor tyrosine kinases is known to be critical for the regulation of kinase activity and for receptor interaction with signal transduction molecules. In this study, we have identified five tyrosyl phosphorylation sites in the vegfr-3 carboxyl-terminal tail." SIGNOR-104072 FLT4 protein P35916 UNIPROT FLT4 protein P35916 UNIPROT "up-regulates activity" phosphorylation Tyr1265 FPMTPTTyKGSVDNQ 9606 BTO:0000394 12881528 t lperfetto "Trans-phosphorylation of activated, dimerized receptor tyrosine kinases is known to be critical for the regulation of kinase activity and for receptor interaction with signal transduction molecules. In this study, we have identified five tyrosyl phosphorylation sites in the vegfr-3 carboxyl-terminal tail." SIGNOR-104080 FLT4 protein P35916 UNIPROT FLT4 protein P35916 UNIPROT "up-regulates activity" phosphorylation Tyr1333 ARGGQVFyNSEYGEL 9606 BTO:0000394 12881528 t lperfetto "Trans-phosphorylation of activated, dimerized receptor tyrosine kinases is known to be critical for the regulation of kinase activity and for receptor interaction with signal transduction molecules. In this study, we have identified five tyrosyl phosphorylation sites in the vegfr-3 carboxyl-terminal tail." SIGNOR-104084 FLT4 protein P35916 UNIPROT FLT4 protein P35916 UNIPROT "up-regulates activity" phosphorylation Tyr1337 QVFYNSEyGELSEPS 9606 BTO:0000394 12881528 t lperfetto "Trans-phosphorylation of activated, dimerized receptor tyrosine kinases is known to be critical for the regulation of kinase activity and for receptor interaction with signal transduction molecules. In this study, we have identified five tyrosyl phosphorylation sites in the vegfr-3 carboxyl-terminal tail." SIGNOR-104088 FLT4 protein P35916 UNIPROT FLT4 protein P35916 UNIPROT "up-regulates activity" phosphorylation Tyr1363 TFFTDNSy 9606 BTO:0000394 12881528 t lperfetto "Trans-phosphorylation of activated, dimerized receptor tyrosine kinases is known to be critical for the regulation of kinase activity and for receptor interaction with signal transduction molecules. In this study, we have identified five tyrosyl phosphorylation sites in the vegfr-3 carboxyl-terminal tail." SIGNOR-104092 FLT4 protein P35916 UNIPROT RPS6KA3 protein P51812 UNIPROT down-regulates phosphorylation Tyr707 KGAMAATySALNRNQ 9606 12601080 t llicata "Upon truncation of this c-terminal stretch, or mutation of the tyr-707 residue alone, autoinhibition is attenuated, and the kinase becomes constitutively active. Based on these findings we propose that phosphorylation of the tyr-707 represents a novel alternative regulatory mechanism for p90rsk activation." SIGNOR-98708 KDR protein P35968 UNIPROT PIK3R1 protein P27986 UNIPROT "up-regulates activity" binding 9606 BTO:0001949 11278468 t Gianni SIGNOR-261917 KDR protein P35968 UNIPROT SHC1 protein P29353 UNIPROT "up-regulates activity" relocalization 9825 BTO:0004007 phosphorylation:Tyr1175 AQQDGKDyIVLPISE 9405464 t "VEGF pathway" Gianni "In a similar fashion, KDR associates with Grb2 and Nck in a ligand-dependent fashion, suggesting Shc, Grb2, and Nck as potential candidates involved in the regulation of endothelial function." SIGNOR-261949 KDR protein P35968 UNIPROT KDR protein P35968 UNIPROT up-regulates phosphorylation Tyr996 EEAPEDLyKDFLTLE 9606 10102632 t lperfetto "Autophosphorylation of kdr in the kinase domain is required for maximal vegf-stimulated kinase activity and receptor internalizationthe intensity of vegf-induced autophosphorylation is significantly reduced when using receptor mutated at y996, confirming that this is a major site of autophosphorylation. Second, tyrosines 951 and 996 are the only two tyrosines in the receptor's kinase insert domain, and there is strong evidence from studies using the pdgfr and cfms that autophosphorylation of tyrosines in this domain leads to important signaling events." SIGNOR-66040 KDR protein P35968 UNIPROT KDR protein P35968 UNIPROT up-regulates phosphorylation Tyr1054 FGLARDIyKDPDYVR 9606 BTO:0000801;BTO:0000876 17658244 t gcesareni "Binding of vegf to the receptor induces dimerisation and autophosphorylation of specific intracellular tyrosine residues. Activation of intracellular cascades results in proliferation, migration, survival and increased permeability." SIGNOR-157081 KDR protein P35968 UNIPROT KDR protein P35968 UNIPROT up-regulates phosphorylation Tyr1059 DIYKDPDyVRKGDAR 9606 BTO:0000801;BTO:0000876 17658244 t gcesareni "Binding of vegf to the receptor induces dimerisation and autophosphorylation of specific intracellular tyrosine residues. Activation of intracellular cascades results in proliferation, migration, survival and increased permeability." SIGNOR-157085 KDR protein P35968 UNIPROT KDR protein P35968 UNIPROT up-regulates phosphorylation Tyr1175 AQQDGKDyIVLPISE 9606 BTO:0000801;BTO:0000876 17658244 t gcesareni "Binding of vegf to the receptor induces dimerisation and autophosphorylation of specific intracellular tyrosine residues. Activation of intracellular cascades results in proliferation, migration, survival and increased permeability." SIGNOR-157089 KDR protein P35968 UNIPROT KDR protein P35968 UNIPROT up-regulates phosphorylation Tyr1214 VCDPKFHyDNTAGIS 9606 BTO:0000801;BTO:0000876 17658244 t gcesareni "Binding of vegf to the receptor induces dimerisation and autophosphorylation of specific intracellular tyrosine residues. Activation of intracellular cascades results in proliferation, migration, survival and increased permeability." SIGNOR-157093 KDR protein P35968 UNIPROT KDR protein P35968 UNIPROT up-regulates phosphorylation Tyr951 RFRQGKDyVGAIPVD 9606 BTO:0000801;BTO:0000876 17658244 t gcesareni "Binding of vegf to the receptor induces dimerisation and autophosphorylation of specific intracellular tyrosine residues. Activation of intracellular cascades results in proliferation, migration, survival and increased permeability." SIGNOR-157097 KDR protein P35968 UNIPROT GRB2 protein P62993 UNIPROT "up-regulates activity" relocalization 9825 BTO:0004007 phosphorylation:Tyr1175 AQQDGKDyIVLPISE 9405464 t "VEGF pathway" Gianni "In a similar fashion, KDR associates with Grb2 and Nck in a ligand-dependent fashion, suggesting Shc, Grb2, and Nck as potential candidates involved in the regulation of endothelial function." SIGNOR-261948 KDR protein P35968 UNIPROT PTK2 protein Q05397 UNIPROT "up-regulates activity" 10090 22264731 t "VEGF pathway" Gianni "Here we show that genetic or pharmacological FAK inhibition in ECs prevents VEGF-stimulated permeability downstream of VEGF receptor or Src tyrosine kinase activation in vivo. VEGF promotes tension-independent FAK activation" SIGNOR-261945 KDR protein P35968 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" binding 9606 11278468 t Gianni "These results demonstrate that activation of VEGFR-2 results in activation of PI3K and that activation of PI3K/S6kinase pathway, but not Ras/MAPK, is responsible for VEGFR-2-mediated cell growth." SIGNOR-261916 PSMC2 protein P35998 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "form complex" binding 9606 BTO:0000007 29636472 t lperfetto "Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line" SIGNOR-263374 SLC16A2 protein P36021 UNIPROT L-thyroxine smallmolecule CHEBI:18332 ChEBI "down-regulates quantity" relocalization 9606 BTO:0001379 28153798 t scontino "T4 and T3 are released from the thyroid cell through transporters present at the basolateral plasma membrane of thyrocytes (Fig. 1). The most important transporter known to be responsible for thyroid hormone transport is the SLC16A2 monocarboxylate transporter 8 (MCT8), which can promote both uptake and efflux of TH and is involved in the release of TH from the thyroid gland." SIGNOR-267140 SLC16A2 protein P36021 UNIPROT 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI "down-regulates quantity" relocalization 9606 BTO:0001379 28153798 t scontino "T4 and T3 are released from the thyroid cell through transporters present at the basolateral plasma membrane of thyrocytes (Fig. 1). The most important transporter known to be responsible for thyroid hormone transport is the SLC16A2 monocarboxylate transporter 8 (MCT8), which can promote both uptake and efflux of TH and is involved in the release of TH from the thyroid gland." SIGNOR-267139 TRIM23 protein P36406 UNIPROT TBK1 protein Q9UHD2 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 28871090 t miannu "TRIM23 interacts with TBK1 and p62. TRIM23 GTPase activates TBK1 to phosphorylate p62. Biochemical characterization showed that TRIM23 binds with its C-terminal ARF domain to the N-terminal KD of TBK1, and that GTP hydrolysis activity of the ARF stimulates TBK1-mediated phosphorylation of p62 at S403 in its ubiquitin-associated (UBA) domain, which was shown to promote cargo recruitment and autophagic flux" SIGNOR-266654 TRIM23 protein P36406 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT "up-regulates activity" ubiquitination 9606 BTO:0003682 19176615 t miannu "We show here that the upregulation of NF-kappaB by UL144 is dependent upon cellular tripartite motif 23 (TRIM23) protein. We propose a mechanism by which UL144 activates NF-kappaB through a direct interaction with the cellular protein TRIM23 in a complex containing TRAF6. we propose that TRIM23 mediates TRAF6 autoubiquitination in the presence of UL144, resulting in the virally controlled activation of NF-κB stimulation at early times of HCMV infection." SIGNOR-266655 MAP2K2 protein P36507 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates phosphorylation Tyr204 HTGFLTEyVATRWYR 9606 BTO:0000142 1411546 t gcesareni "The primary structure of mek, a protein kinase that phosphorylates the erk gene product" SIGNOR-19244 MAP2K2 protein P36507 UNIPROT MAPK3 protein P27361 UNIPROT "up-regulates activity" phosphorylation 10090 11730323 t "Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs" SIGNOR-258997 MAP2K2 protein P36507 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates phosphorylation Thr185 HDHTGFLtEYVATRW 9606 11971971 t gcesareni "Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity." SIGNOR-86709 MAP2K2 protein P36507 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates phosphorylation Tyr187 HTGFLTEyVATRWYR 9606 11971971 t gcesareni "Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity." SIGNOR-86713 MAP2K2 protein P36507 UNIPROT MAPK1 protein P28482 UNIPROT "up-regulates activity" phosphorylation 10090 11730323 t "Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs" SIGNOR-258996 MAP2K2 protein P36507 UNIPROT PPARG protein P37231 UNIPROT up-regulates binding 9606 18596912 t gcesareni "The genomic activity of ppargamma is modulated, in addition to ligand binding, by phosphorylation of a serine residue by mapks, such as extracellular signal-regulated protein kinases-1/2 (erk-1/2), or by nucleocytoplasmic compartmentalization through the erk activators mapk kinases-1/2 (mek-1/2). These mapks phosphorylate (in humans) ser 84 in the ppargamma1 and ser 114 in ppargamma2 isoform." SIGNOR-179393 MAP2K2 protein P36507 UNIPROT CASP9 protein P55211 UNIPROT "down-regulates activity" phosphorylation Thr125 PEVLRPEtPRPVDIG 12792650 t lperfetto "Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK|The opposing protein kinase activity is overcome by treatment with the broad-specificity kinase inhibitor staurosporine or with inhibitors of MEK1/2" SIGNOR-249386 MAP2K2 protein P36507 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 11971971 t lperfetto "Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity." SIGNOR-244637 MAP2K2 protein P36507 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "up-regulates activity" phosphorylation 10090 11730323 t "Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs" SIGNOR-258995 CHRNA7 protein P36544 UNIPROT RHOA protein P61586 UNIPROT "up-regulates activity" binding 27167578 t "Here, we demonstrate a role for α7 nAChR/G protein interaction in the activation of the small (monomeric) RhoA GTPase leading to cytoskeletal changes during neurite growth. Treatment of PC12 cells with the α7 nAChR agonist choline or PNU-282987 was associated with an increase in RhoA activity and an inhibition in neurite growth." SIGNOR-253985 RPL4 protein P36578 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262460 LONP1 protein P36776 UNIPROT STAR protein P49675 UNIPROT "down-regulates quantity by destabilization" cleavage 10116 BTO:0000542 17579211 t lperfetto "Turnover of mitochondrial steroidogenic acute regulatory (StAR) protein by Lon protease: the unexpected effect of proteasome inhibitors" SIGNOR-265726 PPP1CC protein P36873 UNIPROT AXIN1 protein O15169 UNIPROT "down-regulates activity" dephosphorylation Ser217 YTRTGSEsPKVCSDQ 9606 17318175 t "The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated" SIGNOR-248496 PPP1CC protein P36873 UNIPROT AXIN1 protein O15169 UNIPROT "down-regulates activity" dephosphorylation Ser469 AHEENPEsILDEHVQ 9606 17318175 t "The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated" SIGNOR-248497 PPP1CC protein P36873 UNIPROT AXIN1 protein O15169 UNIPROT "down-regulates activity" dephosphorylation Ser75 LGYEPEGsASPTPPY 9606 17318175 t "The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated" SIGNOR-248494 TGFBR2 protein P37173 UNIPROT ZFYVE9 protein O95405 UNIPROT "up-regulates activity" binding 9606 9865696 t 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-245093 PPP1CC protein P36873 UNIPROT AXIN1 protein O15169 UNIPROT "down-regulates activity" dephosphorylation Ser77 YEPEGSAsPTPPYLK 9606 17318175 t "The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated" SIGNOR-248495 PPP1CC protein P36873 UNIPROT AHCYL1 protein O43865 UNIPROT unknown dephosphorylation Ser68 RSLSRSIsQSSTDSY 10090 17635105 t "Moreover, IRBIT-associated PP1 specifically dephosphorylated Ser68 of IRBIT. Phosphorylation of Ser68 was required for subsequent phosphorylation of Ser71 and Ser74, but the latter two sites were not targeted by PP1. We found that phosphorylation of Ser71 and Ser74 were sufficient to enable inhibition of IP3 binding to the IP3R|Given the importance of phosphorylation for the function of IRBIT in suppressing IP3R activity [7,10], in the present study, we searched for a protein phosphatase involved in the dephosphorylation and, hence, inactivation of IRBIT. We found that IRBIT contains a specific well-conserved binding site for PP1." SIGNOR-248498 PPP1CC protein P36873 UNIPROT DDX58 protein O95786 UNIPROT "up-regulates activity" dephosphorylation Ser8 MTTEQRRsLQAFQDY 9606 BTO:0000007 23499489 t lperfetto "We identified PP1alpha and PP1gamma as primary phosphatases responsible for MDA5 and RIG-I dephosphorylation, leading to their activation.|endogenous RIG-I and MDA5 that interacted with PP1 exhibited markedly decreased phosphorylation levels at S8 and S88, respectively " SIGNOR-264580 PPP1CC protein P36873 UNIPROT TP53 protein P04637 UNIPROT "down-regulates activity" dephosphorylation Ser15 PSVEPPLsQETFSDL 9606 16501611 t "Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities|In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway." SIGNOR-248499 PPP1CC protein P36873 UNIPROT TP53 protein P04637 UNIPROT "down-regulates activity" dephosphorylation Ser37 NVLSPLPsQAMDDLM 9606 16501611 t "Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities|In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway." SIGNOR-248500 PPP1CC protein P36873 UNIPROT EIF2S1 protein P05198 UNIPROT "up-regulates activity" dephosphorylation 9606 27629041 t miannu "Dephosphorylation of eIF2α is central to ISR signal termination to restore protein synthesis and normal cell functioning. It is mediated by protein phosphatase 1 (PP1) complex that recruits a PP1 catalytic subunit (PP1c) and one of the two regulatory subunits. In mammals, phosphatase activity is regulated by either PPP1R15A (also known as growth arrest and DNA damage‐inducible protein, GADD34), which is induced as part of the ISR. the GADD34–PP1 complex acts as an important negative feedback loop to restore protein synthesis once the ER stress has been resolved, and as such aids in cell survival" SIGNOR-254119 PPP1CC protein P36873 UNIPROT NOS3 protein P29474 UNIPROT "up-regulates activity" dephosphorylation Thr495 TGITRKKtFKEVANA 9606 BTO:0001176 19036824 t "The increase in eNOS activity coincided with specific dephosphorylation of eNOS-Thr495, known to enhance eNOS activity. Inhibition of protein phosphatase 1 (PP1) by calyculin A, tautomycetin, or siRNA against PP1 reversed NF-induced eNOS-Thr495 dephosphorylation" SIGNOR-248501 PPP1CC protein P36873 UNIPROT AKT1 protein P31749 UNIPROT "down-regulates activity" dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0002419 14633703 t "Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells" SIGNOR-252605 PPP1CC protein P36873 UNIPROT TGFBR1 protein P36897 UNIPROT down-regulates dephosphorylation 9606 14718519 t lpetrilli "We found smad7 interacts with growth arrest and dna damage protein, gadd34, a regulatory subunit of the protein phosphatase 1 (pp1) holoenzyme, which subsequently recruits catalytic subunit of pp1 (pp1c) to dephosphorylate t?RI." SIGNOR-121277 PPP1CC protein P36873 UNIPROT CASP2 protein P42575 UNIPROT "up-regulates activity" dephosphorylation Ser164 STDTVEHsLDNKDGP -1 19531356 t llicata "nutrient-replete oocytes inhibit C2 via S135 phosphorylation catalyzed by calcium/calmodulin-dependent protein kinase II. We now show that C2 phosphorylated at S135 binds 14-3-3zeta, thus preventing C2 dephosphorylation. Moreover, we determined that S135 dephosphorylation is catalyzed by protein phosphatase-1 (PP1), which directly binds C2." SIGNOR-248503 PPP1CC protein P36873 UNIPROT CDK9 protein P50750 UNIPROT up-regulates dephosphorylation Ser175 FGLARAFsLAKNSQP 9606 21533037 t gcesareni "Protein phosphatase-1 activates cdk9 by dephosphorylating ser175" SIGNOR-173450 PPP1CC protein P36873 UNIPROT MDM2 protein Q00987 UNIPROT "up-regulates quantity by stabilization" dephosphorylation Ser370 KKTIVNDsRESCVEE 9606 BTO:0001938 23277204 t "Three phosphorylation sites identified are Ser342, Ser367, and Ser403. In the present study, we identify protein phosphatase 1 (PP1) as a negative regulator in the p53 signaling pathway. PP1 directly interacts with Mdmx and specifically dephosphorylates Mdmx at Ser367. The dephosphorylation of Mdmx increases its stability and thereby inhibits p53 activity." SIGNOR-248504 PPP1CC protein P36873 UNIPROT IKZF1 protein Q13422 UNIPROT up-regulates dephosphorylation 9606 BTO:0001271 21750978 t miannu "Ikarosis dephosphorylated by protein phosphatase 1 (pp1) via interaction at a consensus pp1-binding motif/ hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway" SIGNOR-174865 PPP1CC protein P36873 UNIPROT IFIH1 protein Q9BYX4 UNIPROT "up-regulates activity" dephosphorylation Ser88 EALRRTGsPLAARYM 9606 BTO:0000007 23499489 t lperfetto "Exogenous PP1alpha or PP1gamma substantially decreased the S88 phosphorylation of Flag-MDA5|we identified PP1alpha and PP1gamma as primary phosphatases responsible for MDA5 and RIG-I dephosphorylation, leading to their activation." SIGNOR-264579 PPP1CC protein P36873 UNIPROT IFIH1 protein Q9BYX4 UNIPROT "up-regulates activity" dephosphorylation Ser88 EALRRTGsPLAARYM 9606 BTO:0000007 25865883 t lperfetto "A recent study has revealed that PP1alpha and PP1gamma phosphatases are responsible for dephosphorylating MDA5 and are essential for its activation. |PP1gamma mediates dephosphorylation of MDA5 not only at Ser-88 but also at other Ser/Thr residues." SIGNOR-264578 PPP1CC protein P36873 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0002419 14633703 t "Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells" SIGNOR-248502 FLT3 protein P36888 UNIPROT SOCS2 protein O14508 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 12468433 f "We have also found SOCS2 and SOCS3 specifically induced in 32D/Flt3-ITD, both of which are STAT3/5 target genes and known negative regulators of receptor signaling" SIGNOR-261545 FLT3 protein P36888 UNIPROT SOCS3 protein O14543 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 12468433 f "We have also found SOCS2 and SOCS3 specifically induced in 32D/Flt3-ITD, both of which are STAT3/5 target genes and known negative regulators of receptor signaling" SIGNOR-261546 FLT3 protein P36888 UNIPROT BCL2L11 protein O43521 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 14981546 f "FLT3-ITD signaling contributes to transcriptional inhibition of p27Kip1 and Bim gene expression" SIGNOR-261525 FLT3 protein P36888 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates activity" 10090 14981546 f "Immunoblot analysis indicated an increased level of Foxo3a phosphorylation on residue Thr32, as shown by the appearance of additional slower-migrating phospho-species immediately after induction of FLT3-ITD4 expression" SIGNOR-261523 FLT3 protein P36888 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity by expression" 9606 25280219 f "MYC expression was relatively higher (P <0Æ1) in theFLT3/ITD-positive AML samples compared to non-mutant FLT3 AML." SIGNOR-261556 FLT3 protein P36888 UNIPROT PARP1 protein P09874 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 21228325 f "Interestingly, quantitative RT-PCR analysis demonstrated a 2-fold increase in PARP-1 expression. Western blotting analysis of protein nuclear extracts from FLT3/ITD B-cells confirmed that PARP1 was up-regulated, compared with wild-type controls " SIGNOR-261554 FLT3 protein P36888 UNIPROT PIM1 protein P11309 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 15498859 f "Pim-1 is a proto-oncogene and is known to be up-regulated by signal transducer and activator of transcription 5 (STAT5), which itself is a downstream target of FLT3 signaling. constitutively activated FLT3 signaling up-regulates Pim-1 expression in leukemia cells." SIGNOR-261519 FLT3 protein P36888 UNIPROT XRCC5 protein P13010 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 21228325 f fcortellessa "We detected an approximately 5-fold decrease in Ku86 expression in early pro-B cells from FLT3/ITD mice compared with the wild-type controls. These data support the finding that FLT3/ITD mutations exert a suppressive role on Ku86 expression." SIGNOR-261684 FLT3 protein P36888 UNIPROT SPI1 protein P17947 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 14592841 f "This data confirms that PU.1 is a downstream target of activated C/EBPα and is suppressed in FLT3/ITD-expressing cells as a result of C/EBPα suppression." SIGNOR-261530 FLT3 protein P36888 UNIPROT PIK3R1 protein P27986 UNIPROT "up-regulates activity" 10090 BTO:0001516 23246379 f miannu "Grb10 transduces signal from FLT3 by direct interaction with p85 and Ba/F3-FLT3-ITD cells expressing Grb10 exhibits higher STAT5 activation. These results suggest that Grb10 binds to both normal and oncogenic FLT3 and induces PI3K-Akt and STAT5 signaling pathways resulting in an enhanced proliferation, survival and colony formation of hematopoietic cells." SIGNOR-260081 FLT3 protein P36888 UNIPROT PTPN6 protein P29350 UNIPROT "down-regulates quantity" "transcriptional regulation" 9606 BTO:0004760 15574429 f "Furthermore, a small but reproducible growth/survival advantage was observed in both TF-1 and TF-1/ITD cells when SHP-1 expression was knocked down by RNAi. Taken together, these data provide the first evidence that suppression of SHP-1 by FLT3/ITD signaling may be another mechanism contributing to the transformation by FLT3/ITD mutations" SIGNOR-259950 FLT3 protein P36888 UNIPROT PTPN6 protein P29350 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15574429 f "Expression of FLT3/ITD induces down-regulation of SHP-1 expression and activity" SIGNOR-261532 FLT3 protein P36888 UNIPROT SHC1 protein P29353 UNIPROT "up-regulates activity" phosphorylation Tyr349 EEPPDHQyYNDFPGK 9606 10482988 t miannu "Intracellular FLT3 signaling involves tyrosine phosphorylation of several cytoplasmic proteins including SHC. We have found that upon FLT3 activation SHC phosphorylation occurs at tyrosine 239/240 and 313." SIGNOR-251146 FLT3 protein P36888 UNIPROT SHC1 protein P29353 UNIPROT "up-regulates activity" phosphorylation Tyr350 EPPDHQYyNDFPGKE 9606 10482988 t miannu "Intracellular FLT3 signaling involves tyrosine phosphorylation of several cytoplasmic proteins including SHC. We have found that upon FLT3 activation SHC phosphorylation occurs at tyrosine 239/240 and 313." SIGNOR-251147 FLT3 protein P36888 UNIPROT SHC1 protein P29353 UNIPROT "up-regulates activity" phosphorylation Tyr427 ELFDDPSyVNVQNLD 9606 10482988 t miannu "Intracellular FLT3 signaling involves tyrosine phosphorylation of several cytoplasmic proteins including SHC. We have found that upon FLT3 activation SHC phosphorylation occurs at tyrosine 239/240 and 313." SIGNOR-251148 FLT3 protein P36888 UNIPROT SHC1 protein P29353 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0002882 15769897 t "we observed constitutive activation of Erk-1 and Erk-2, Akt, and of Shc by both Flt3-ITD and Flt3-D835Y" SIGNOR-261540 FLT3 protein P36888 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" 9606 16266983 f gcesareni "We show that the presence of Flt3-ITD constitutively activates Akt (PKB), a key serine-threonine kinase within the phosphatidylinositol 3-kinase pathway." SIGNOR-252626 FLT3 protein P36888 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0001545 17851558 t miannu "Endogenous beta-catenin co-immunoprecipitated with endogenous activated FLT3, and recombinant activated FLT3 directly phosphorylated recombinant beta-catenin. Finally, FLT3 inhibitor decreased tyrosine phosphorylation of beta-catenin in leukemia cells obtained from FLT3-ITD-positive AML patients. These data demonstrate that FLT3 activation induces beta-catenin tyrosine phosphorylation and nuclear localization, and thus suggest a mechanism for the association of FLT3 activation and beta-catenin oncogeneic signaling in AML." SIGNOR-260124 FLT3 protein P36888 UNIPROT FLT3 protein P36888 UNIPROT up-regulates phosphorylation Tyr589 TGSSDNEyFYVDFRE 9606 BTO:0001271 11971190 t lperfetto "Previously we reported that flt3 with itd (flt3/itd) formed a homodimer and was autophosphorylated on tyrosine residuewe examined the role of tyr residues (y589, y591, y597 and y599) in the jm domain in the activation of flt3. In wt-flt3, these tyr residues were important for the fl-dependent activation" SIGNOR-117571 FLT3 protein P36888 UNIPROT FLT3 protein P36888 UNIPROT up-regulates phosphorylation Tyr591 SSDNEYFyVDFREYE 9606 BTO:0001271 11971190 t lperfetto "Previously we reported that flt3 with itd (flt3/itd) formed a homodimer and was autophosphorylated on tyrosine residuewe examined the role of tyr residues (y589, y591, y597 and y599) in the jm domain in the activation of flt3. In wt-flt3, these tyr residues were important for the fl-dependent activation" SIGNOR-117575 FLT3 protein P36888 UNIPROT FLT3 protein P36888 UNIPROT up-regulates phosphorylation Tyr597 FYVDFREyEYDLKWE 9606 BTO:0001271 11971190 t lperfetto "Previously we reported that flt3 with itd (flt3/itd) formed a homodimer and was autophosphorylated on tyrosine residuewe examined the role of tyr residues (y589, y591, y597 and y599) in the jm domain in the activation of flt3. In wt-flt3, these tyr residues were important for the fl-dependent activation" SIGNOR-117579 FLT3 protein P36888 UNIPROT FLT3 protein P36888 UNIPROT up-regulates phosphorylation Tyr599 VDFREYEyDLKWEFP 9606 BTO:0001271 11971190 t lperfetto "Previously we reported that flt3 with itd (flt3/itd) formed a homodimer and was autophosphorylated on tyrosine residuewe examined the role of tyr residues (y589, y591, y597 and y599) in the jm domain in the activation of flt3. In wt-flt3, these tyr residues were important for the fl-dependent activation" SIGNOR-117583 FLT3 protein P36888 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 15003515 f "Flt3 Mutation Activates p21WAF1/CIP1 Gene Expression Through the Action of STAT5. Through the Action of STAT5. Co-transfection of p21 promoter-luciferase constructs with Flt3-ITD plasmid into K562 and BaF3 cells results in the induction of p21 promoter activity and a -692/-684 STAT site is important for the induction. STAT5a binds specifically to this element and Flt3-ITD enhances the protein binding to this site." SIGNOR-261520 FLT3 protein P36888 UNIPROT ID1 protein P41134 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 18559972 f apalma "In this study, we used specific tyrosine kinase inhibitors to identify critical target genes that are regulated by oncogenic tyrosine kinases. Using oligonucleotide microarrays, we identified genes that are either up- or down-regulated by selective small molecule inhibitors that target the ABL, PDGFβR, or FLT3 kinases. Genes induced by these inhibitors are presumably repressed by activated tyrosine kinases.Among these genes, we detected a 5- to 50-fold reduction in Id1 expression when the cancer cells were treated with inhibitors." SIGNOR-255698 FLT3 protein P36888 UNIPROT STAT5A protein P42229 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0001516 12796379 t "FLT3-ITDs induced a strong activation of STAT5. FLT3-ITD mutants induce an autophosphorylation of the receptor, interleukin 3-independent growth in Ba/F3 cells, and a strong STAT5 and mitogen-activated protein kinase (MAPK) activation." SIGNOR-261516 FLT3 protein P36888 UNIPROT STAT5A protein P42229 UNIPROT "up-regulates activity" phosphorylation Tyr694 LAKAVDGyVKPQIKQ 10090 BTO:0002882 17356133 t gcesareni "in vitro kinase assays revealed that STAT5 is a direct target of Flt3" SIGNOR-245069 FLT3 protein P36888 UNIPROT CDKN1B protein P46527 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 14981546 f "FLT3-ITD signaling contributes to transcriptional inhibition of p27Kip1 and Bim gene expression" SIGNOR-261524 FLT3 protein P36888 UNIPROT CEBPA protein P49715 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 14592841 f "Thus, induction of C/EBPα and PU.1 expression is inhibited in 32D cells due to the expression of FLT3/ITD" SIGNOR-261529 FLT3 protein P36888 UNIPROT HK2 protein P52789 UNIPROT "up-regulates activity" 9606 BTO:0002144 28194038 f "FLT3/ITD causes a significant increase in aerobic glycolysis through AKT-mediated upregulation of mitochondrial hexokinase (HK2), and renders the leukemia cells highly dependent on glycolysis and sensitive to pharmacological inhibition of glycolytic activity" SIGNOR-261322 FLT3 protein P36888 UNIPROT GRB2 protein P62993 UNIPROT "up-regulates activity" binding 10090 10080542 t gcesareni "FL stimulation induces association of Grb2 with Flt3, SHP-2,and Shc" SIGNOR-245060 FLT3 protein P36888 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" 10090 BTO:0002882 18192505 f "Inhibition of FLT3/ITD leads to a small decrease in RAC1 activity" SIGNOR-261536 FLT3 protein P36888 UNIPROT RUNX1 protein Q01196 UNIPROT "up-regulates activity" 9606 28213513 f "Our finding that RUNX1 protein levels are dependent on FLT3-ITD signaling in AML cells and that, together, they synergize to generate AML. […]Our work demonstrated that Tyr phosphorylation within the ID region of RUNX1 is critical for its oncogenic potential," SIGNOR-256307 FLT3 protein P36888 UNIPROT ZBTB16 protein Q05516 UNIPROT "down-regulates activity" 10090 BTO:0002181 14982881 f "We report here that the Flt3-ITD interferes with the transcriptional and biologic action of the PLZF transcriptional repressor. In the presence of Flt3-ITD, PLZF-SMRT interaction was reduced, transcriptional repression by PLZF was inhibited, and PLZF-mediated growth suppression of leukemia cells was partially blocked. Furthermore, overexpression of Flt3-ITD led to a partial relocalization of SMRT protein from the nucleus to the cytoplasm." SIGNOR-261537 FLT3 protein P36888 UNIPROT PTPN11 protein Q06124 UNIPROT "up-regulates activity" binding 10090 BTO:0002882 phosphorylation:Tyr599 VDFREYEyDLKWEFP 16684964 t gcesareni "Y599 was additionally found to interact with the protein tyrosine phosphatase SHP2 in a phosphorylation-dependent manner. As Y599F-Flt3-32D was unable to associate with and to phosphorylate SHP2 and since silencing of SHP2 in WT-Flt3-expressing cells mimicked the Y599F-Flt3 phenotype, we hypothesize that recruitment of SHP2 to pY599 contributes to FL-mediated Erk activation and proliferation." SIGNOR-245057 FLT3 protein P36888 UNIPROT RAD51 protein Q06609 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 15626738 f "FLT3-ITD-TKD dual mutants induce hyperactivation of STAT5 and up-regulation of its downstream targets Bcl-x(L) and RAD51 in Ba/F3 cells" SIGNOR-261550 FLT3 protein P36888 UNIPROT BCL2L1 protein Q07817 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 15626738 f "FLT3-ITD-TKD dual mutants induce hyperactivation of STAT5 and up-regulation of its downstream targets Bcl-x(L) and RAD51 in Ba/F3 cells" SIGNOR-261549 FLT3 protein P36888 UNIPROT PTPRJ protein Q12913 UNIPROT "down-regulates activity" 10090 22438257 f "Taken together, the described findings supported the notion that FLT3 ITD causes reduced DEP-1 activity compared with cells expressing WT FLT3 rather than alterations in mRNA or protein levels." SIGNOR-261553 FLT3 protein P36888 UNIPROT GRB10 protein Q13322 UNIPROT "up-regulates activity" binding 10090 BTO:0001516 23246379 t "These results suggest that Grb10 binds to both normal and oncogenic FLT3 and induces PI3K–Akt and STAT5 signaling pathways resulting in an enhanced proliferation, survival and colony formation of hematopoietic cells." SIGNOR-255947 FLT3 protein P36888 UNIPROT SIRT1 protein Q96EB6 UNIPROT "up-regulates quantity by stabilization" "post transcriptional regulation" 9606 26049753 f "SIRT1 protein but not mRNA expression is increased in CD34+ cells from FLT3-ITD positive AML patients compared to FLT3 wild-type AML patients" SIGNOR-261555 FLT3 protein P36888 UNIPROT CISH protein Q9NSE2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 15769897 f "The STAT5 target gene CIS, a member of the suppressor of cytokine signaling (SOCS) protein family, was highly induced by Flt3-ITD" SIGNOR-261542 FLT3 protein P36888 UNIPROT PIM2 protein Q9P1W9 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 15769897 f "The serine-threonine kinase Pim-2 is a functionally relevant downstream target of STAT5.24 Here, we observed only a weak induction of Pim-2 by Flt3-D835Y compared to the effects of Flt3-ITD." SIGNOR-261541 FLT3 protein P36888 UNIPROT FZD4 protein Q9ULV1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0002882 15650056 f "AML-typical Flt3 mutations induce the expression of Frizzled-4 on the mRNA and protein level, mimicking the effects of IL-3." SIGNOR-261533 FLT3 protein P36888 UNIPROT FZD4 protein Q9ULV1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 15650056 f "Microarray analyses revealed higher mRNA expression of Frizzled-4, a receptor for Wnt ligands in 32D/Flt3-ITD cells. Findings were verified by quantitative realtime reverse transcription–polymerase chain reaction (RT-PCR) and on the protein level." SIGNOR-260121 FLT3 protein P36888 UNIPROT USP22 protein Q9UPT9 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 26049753 f "USP22 deubiquitinase was overexpressed in FLT3-ITD positive AML CD34+ cells.USP22 expression was regulated by c-MYC and contributed to c-MYC mediated reduction in SIRT1 polyubiquitination and degradation. USP22 directly interacted with and removing polyubiquitin chains from SIRT1 to increase SIRT1 protein stabilization and expression. These results support a role for USP22 in MYC-mediated increase in SIRT1 protein stabilization, and indicate that FLT3-ITD, c-MYC and USP22 form an oncogenic network that enhances SIRT1 expression and activity in leukemic cells." SIGNOR-261559 FLT3 protein P36888 UNIPROT NCOR2 protein Q9Y618 UNIPROT "down-regulates activity" relocalization 10090 14982881 f "We report here that the Flt3-ITD interferes with the transcriptional and biologic action of the PLZF transcriptional repressor. In the presence of Flt3-ITD, PLZF-SMRT interaction was reduced, transcriptional repression by PLZF was inhibited, and PLZF-mediated growth suppression of leukemia cells was partially blocked. Furthermore, overexpression of Flt3-ITD led to a partial relocalization of SMRT protein from the nucleus to the cytoplasm." SIGNOR-261538 FLT3 protein P36888 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" 10090 BTO:0001516 23246379 f miannu "Grb10 transduces signal from FLT3 by direct interaction with p85 and Ba/F3-FLT3-ITD cells expressing Grb10 exhibits higher STAT5 activation. These results suggest that Grb10 binds to both normal and oncogenic FLT3 and induces PI3K-Akt and STAT5 signaling pathways resulting in an enhanced proliferation, survival and colony formation of hematopoietic cells." SIGNOR-260083 FLT3 protein P36888 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "up-regulates activity" phosphorylation 10090 14981546 f "These data confirm previous findings that FLT3 receptors with ITD mutations efficiently trigger the activation of ERK, STAT5 and Akt in the absence of FL stimulation." SIGNOR-261521 FLT3 protein P36888 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "up-regulates activity" 9606 30552988 f miannu "Oncogenic, constitutively active mutants of FLT3 are known to be expressed in acute myeloid leukemia and to correlate with poor prognosis. Activation of the receptor mediates cell survival, cell proliferation and differentiation of cells. Several of the signal transduction pathways downstream of FLT3 have been shown to include various members of the SRC family of kinases (SFKs). They are involved in regulating the activity of RAS/ERK pathways through the scaffolding protein GAB2 and the adaptor protein SHC." SIGNOR-260132 FLT3 protein P36888 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation 10090 BTO:0001516 14981546 t "These data confirm previous findings that FLT3 receptors with ITD mutations efficiently trigger the activation of ERK, STAT5 and Akt in the absence of FL stimulation." SIGNOR-261522 FLT3 protein P36888 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" 9606 16266983 f gcesareni "We show that the presence of Flt3-ITD constitutively activates Akt (PKB), a key serine-threonine kinase within the phosphatidylinositol 3-kinase pathway." SIGNOR-245064 BMPR1A protein P36894 UNIPROT FAM83G protein A6ND36 UNIPROT "up-regulates activity" phosphorylation Ser610 GPGPRRPsVASSVSE 9606 BTO:0000007 24554596 t lperfetto "These results indicate that ALK3 phosphorylates PAWS1 predominantly at Ser610 but can also phosphorylate at Ser614 and Ser616 in vitro. |Here, we report the discovery and characterization of PAWS1/FAM83G as a novel SMAD1 interactor. PAWS1 forms a complex with SMAD1 in a SMAD4-independent manner, and BMP signalling induces the phosphorylation of PAWS1 through BMPR1A. The phosphorylation of PAWS1 in response to BMP is essential for activation of the SMAD4-independent BMP target genes NEDD9 and ASNS. Our findings identify PAWS1 as the first non-SMAD substrate for type I BMP receptor kinases and as a novel player in the BMP pathway." SIGNOR-264765 BMPR1A protein P36894 UNIPROT FAM83G protein A6ND36 UNIPROT "up-regulates activity" phosphorylation Ser614 RRPSVASsVSEEYFE -1 24554596 t lperfetto "These results indicate that ALK3 phosphorylates PAWS1 predominantly at Ser610 but can also phosphorylate at Ser614 and Ser616 in vitro. |Here, we report the discovery and characterization of PAWS1/FAM83G as a novel SMAD1 interactor. PAWS1 forms a complex with SMAD1 in a SMAD4-independent manner, and BMP signalling induces the phosphorylation of PAWS1 through BMPR1A. The phosphorylation of PAWS1 in response to BMP is essential for activation of the SMAD4-independent BMP target genes NEDD9 and ASNS. Our findings identify PAWS1 as the first non-SMAD substrate for type I BMP receptor kinases and as a novel player in the BMP pathway." SIGNOR-264766 BMPR1A protein P36894 UNIPROT FAM83G protein A6ND36 UNIPROT "up-regulates activity" phosphorylation Ser616 PSVASSVsEEYFEVR -1 24554596 t lperfetto "These results indicate that ALK3 phosphorylates PAWS1 predominantly at Ser610 but can also phosphorylate at Ser614 and Ser616 in vitro. |Here, we report the discovery and characterization of PAWS1/FAM83G as a novel SMAD1 interactor. PAWS1 forms a complex with SMAD1 in a SMAD4-independent manner, and BMP signalling induces the phosphorylation of PAWS1 through BMPR1A. The phosphorylation of PAWS1 in response to BMP is essential for activation of the SMAD4-independent BMP target genes NEDD9 and ASNS. Our findings identify PAWS1 as the first non-SMAD substrate for type I BMP receptor kinases and as a novel player in the BMP pathway." SIGNOR-264767 TGFBR1 protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" phosphorylation 9606 19701891 t 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 BMPR1A protein P36894 UNIPROT SMAD9 protein O15198 UNIPROT "up-regulates activity" phosphorylation 9606 19620713 t ggiuliani "To ascertain whether overexpression of BMPr1A can initiate adipocyte lineage commitment in the absence of its BMP ligand, constitutively active (CA)-BMPr1A and CA-BMPr1B were expressed in C3H10T1/2 stem cells using a mouse stem cell virus (MSCV) retroviral system. […]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." SIGNOR-255772 BMPR1A protein P36894 UNIPROT BMPR2 protein Q13873 UNIPROT up-regulates binding 10090 10712517 t gcesareni "Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known bmp type i receptors" SIGNOR-75652 BMPR1A protein P36894 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation 9606 19620713 t gcesareni "Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression." SIGNOR-187181 BMPR1A protein P36894 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation Ser463 SPHNPISsVS 9606 9136927 t fspada "Here, we report that bmp receptors phosphorylate and activate smad1 directly. Phosphorylation of smad1 in vivo involves serines in the carboxy-terminal motif ssxs. These residues are phosphorylated directly by a bmp type i receptor in vitro" SIGNOR-210084 BMPR1A protein P36894 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation Ser465 HNPISSVs 9606 9136927 t fspada "Here, we report that bmp receptors phosphorylate and activate smad1 directly. Phosphorylation of smad1 in vivo involves serines in the carboxy-terminal motif ssxs. These residues are phosphorylated directly by a bmp type i receptor in vitro" SIGNOR-249649 BMPR1A protein P36894 UNIPROT SMAD1 protein Q15797 UNIPROT "up-regulates activity" phosphorylation 9606 19620713 t lperfetto "Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression." SIGNOR-255263 BMPR1A protein P36894 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" 10090 19620713 f 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-255785 BMPR1A protein P36894 UNIPROT SMAD5 protein Q99717 UNIPROT up-regulates phosphorylation 9606 19620713 t gcesareni "Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression." SIGNOR-187184 BMPR1A protein P36894 UNIPROT SMAD5 protein Q99717 UNIPROT up-regulates 10090 BTO:0000165 10564272 f lperfetto "We found that both smad6 and smad7 inhibit the activation of smad1 and smad5 by bmpr-ia/alk-3 and bmpr-ib/alk-6, as well as that by alk-2" SIGNOR-235361 BMPR1A protein P36894 UNIPROT SMAD5 protein Q99717 UNIPROT "up-regulates activity" phosphorylation 9606 19620713 t lperfetto "Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression." SIGNOR-255261 BMPR1A protein P36894 UNIPROT SOST protein Q9BQB4 UNIPROT up-regulates 9606 19874086 f gcesareni "These results demonstrate that bmpria in osteoblasts negatively regulates endogenous bone mass and wnt/beta-catenin signaling and that this regulation may be mediated by the activities of sost and dkk1." SIGNOR-188958 BMPR1A protein P36894 UNIPROT SMAD5/SMAD4 complex SIGNOR-C205 SIGNOR "up-regulates activity" phosphorylation 10090 19620713 t 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-255788 BMPR1A protein P36894 UNIPROT SMAD5/SMAD4 complex SIGNOR-C205 SIGNOR "up-regulates activity" phosphorylation 9606 9442019 t 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-255779 BMPR1A protein P36894 UNIPROT SMAD8/SMAD4 complex SIGNOR-C206 SIGNOR "up-regulates activity" phosphorylation 10090 19620713 t 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-255786 BMPR1A protein P36894 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR "form complex" binding 9606 7791754 t 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 BMPR1A protein P36894 UNIPROT SMAD1/4 complex SIGNOR-C85 SIGNOR "up-regulates activity" phosphorylation 9606 8893010 t ggiuliani "Conversely, Smad1 and DPC4 formed a complex when the cells were stimulated with BMP4 but not with activin of TGF-beta." SIGNOR-255778 TGFBR1 protein P36897 UNIPROT SPTBN1 protein Q01082 UNIPROT up-regulates phosphorylation 9606 12543979 t gcesareni "This suggests that, upon stimulation with tgf-beta1, phosphorylation of elf could induce a conformational change that reduces its affinity for ankyrin and tropomyosin and facilitates an association with smad3 and smad4 instead." SIGNOR-97626 SMAD4 protein Q13485 UNIPROT LEF1 protein Q9UJU2 UNIPROT "up-regulates activity" 9606 BTO:0000599 10890911 f lperfetto "Coexpression of smad2 and smad4, smad3 alone, or smad3 and smad4 resulted in strong enhancement of lef1-dependent transcriptional activity" SIGNOR-229311 BMPR1A protein P36894 UNIPROT SMAD1/4 complex SIGNOR-C85 SIGNOR "up-regulates activity" 10090 19620713 f 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-255787 BMPR1A protein P36894 UNIPROT SMAD1/5/8 proteinfamily SIGNOR-PF35 SIGNOR "up-regulates activity" phosphorylation 10090 BTO:0004058 19620713 t 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 BMPR1A protein P36894 UNIPROT SMAD1/5/8 proteinfamily SIGNOR-PF35 SIGNOR "up-regulates activity" phosphorylation 9606 "BTO:0000165;BTO:0002974; BTO:0002809" 9442019 t 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 ACVR1B protein P36896 UNIPROT TDP2 protein O95551 UNIPROT "up-regulates activity" phosphorylation Thr88 PKTYVDLtNEETTDS 9606 BTO:0000007 18039968 t miannu "ALK4 phosphorylated TTRAP in vitro (Fig. 6A). The band migrating at the position of TTRAP was excised and analyzed by LC-MS/MS. One TTRAP peptide was phosphorylated either on T88 and T92, or on T92 only (Fig. 6B)." SIGNOR-262611 ACVR1B protein P36896 UNIPROT TDP2 protein O95551 UNIPROT "up-regulates activity" phosphorylation Thr92 VDLTNEEtTDSTTSK 9606 BTO:0000007 18039968 t miannu "ALK4 phosphorylated TTRAP in vitro (Fig. 6A). The band migrating at the position of TTRAP was excised and analyzed by LC-MS/MS. One TTRAP peptide was phosphorylated either on T88 and T92, or on T92 only (Fig. 6B).We tested in vivo phosphorylation of Strep-TTRAP by co-expression with mouse Alk4 in HEK293T cells, and affinity-purified TTRAP. In this preparation TTRAP-specific peptides were reproducibly found in both the singly (T92) and doubly phosphorylated form (T88/T92). mutant TTRAPT88A,T92A is not able to rescue the TtrapMO phenotype, suggesting that phosphorylation of Ttrap on Thr88 and Thr92 is essential for Ttrap function." SIGNOR-262612 ACVR1B protein P36896 UNIPROT HBB protein P68871 UNIPROT "up-regulates quantity by stabilization" 9606 2920215 f Regulation miannu "Activin, also named FSH-releasing protein, was previously shown to induce hemoglobin accumulation in K562 cells and potentiate the proliferation and differentiation of CFU-E in human bone marrow cultures." SIGNOR-251768 ACVR1B protein P36896 UNIPROT HBA1 protein P69905 UNIPROT "up-regulates quantity by stabilization" 9606 2920215 f Regulation miannu "Activin, also named FSH-releasing protein, was previously shown to induce hemoglobin accumulation in K562 cells and potentiate the proliferation and differentiation of CFU-E in human bone marrow cultures." SIGNOR-251769 ACVR1B protein P36896 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" phosphorylation 10090 14517293 t 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 ACVR1B protein P36896 UNIPROT SMAD2 protein Q15796 UNIPROT "up-regulates activity" phosphorylation 10090 14517293 t 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 TGFBR1 protein P36897 UNIPROT PIK3R2 protein O00459 UNIPROT up-regulates binding 9606 BTO:0001660 9435577 t lperfetto "These studies revealed that PI 3-kinase is associated in vivo with both TGF-_ receptor subtypes and that TGF-_1 stimulation enhances PI 3-kinase activity associated with type I TGF-_ receptor in hASM cells." SIGNOR-227531 TGFBR1 protein P36897 UNIPROT ZFYVE9 protein O95405 UNIPROT "up-regulates activity" binding 9606 9865696 t 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 TGFBR1 protein P36897 UNIPROT SERPINE1 protein P05121 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 28520219 f miannu "The transforming growth factor-β pathway is the major driver of fibrotic response. Plasminogen activator inhibitor-1 (PAI-1) is a crucial downstream target of this pathway. Transforming growth factor-β positively regulates PAI-1 gene expression via two main pathways including Smad-mediated canonical and non-canonical pathways." SIGNOR-260590 TGFBR1 protein P36897 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates binding 9606 BTO:0001660 9435577 t lperfetto "These studies revealed that PI 3-kinase is associated in vivo with both TGF-_ receptor subtypes and that TGF-_1 stimulation enhances PI 3-kinase activity associated with type I TGF-_ receptor in hASM cells." SIGNOR-227525 TGFBR1 protein P36897 UNIPROT RHOA protein P61586 UNIPROT "up-regulates activity" 9606 19726546 t lperfetto "Thus, TGF-_1 rapidly stimulates activity of both RhoA and Rac1 and this activation requires ALK5/T_RI kinase activity." SIGNOR-227499 TGFBR1 protein P36897 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" 9606 19726546 t lperfetto "Thus, TGF-_1 rapidly stimulates activity of both RhoA and Rac1 and this activation requires ALK5/T_RI kinase activity." SIGNOR-227496 TGFBR1 protein P36897 UNIPROT EEF1A1 protein P68104 UNIPROT down-regulates phosphorylation Ser300 EMHHEALsEALPGDN 9606 20832312 t llicata "Phosphorylation of eEF1A1 at Ser300 by T_R-I results in inhibition of mRNA translation" SIGNOR-167943 TGFBR1 protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" phosphorylation Ser423 SPSIRCSsVS 10090 BTO:0005493;BTO:0000165 19458083 t 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 TGFBR1 protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" phosphorylation Ser425 SIRCSSVs 10090 BTO:0005493;BTO:0000165 19458083 t 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 TGFBR1 protein P36897 UNIPROT SMAD2 protein Q15796 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000801 10973958 t 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 TGFBR1 protein P36897 UNIPROT SMAD2 protein Q15796 UNIPROT "up-regulates activity" phosphorylation Ser465 SPSVRCSsMS 9534 BTO:0001538 9346908 t 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 TGFBR1 protein P36897 UNIPROT TP63 protein Q9H3D4 UNIPROT unknown phosphorylation Ser160 SSTFDALsPSPAIPS 9606 23166821 t llicata "We show that phosphorylation of _np63_ at s66/68 in response to ultraviolet (uv) irradiation is mediated by alk5" SIGNOR-199781 TGFBR1 protein P36897 UNIPROT TP63 protein Q9H3D4 UNIPROT unknown phosphorylation Ser68 FLEQPICsVQPIDLN 9606 23166821 t llicata "We show that phosphorylation of _np63_ at s66/68 in response to ultraviolet (uv) irradiation is mediated by alk5" SIGNOR-199785 TGFBR1 protein P36897 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT "up-regulates activity" binding 9606 BTO:0002181 18758450 t 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 TGFBR1 protein P36897 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 18922473 t 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 TGFBR1 protein P36897 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 26194464 f "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 LTBR protein P36941 UNIPROT TRAF2 protein Q12933 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 12571250 t lperfetto "Endogenous association of traf2, traf3, ciap1, and smac with lymphotoxin beta receptor reveals a novel mechanism of apoptosis." SIGNOR-97950 POLR2I protein P36954 UNIPROT "RNA Polymerase II" complex SIGNOR-C391 SIGNOR "form complex" binding 9606 BTO:0000567 9852112 t lperfetto "Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II" SIGNOR-266166 SREBF1 protein P36956 UNIPROT PPARG protein P37231 UNIPROT "up-regulates activity" 10090 BTO:0000011 9539737 f 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 SREBF1 protein P36956 UNIPROT MTTP protein P55157 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000575 11111091 f miannu "SREBP1 increased the expression of MTP and increased the assembly and secretion of VLDL containing apo B100." SIGNOR-252113 SREBF1 protein P36956 UNIPROT LRP1 protein Q07954 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 20980003 f miannu "In the present study we report that specific silencing of either SREBP-1 or SREBP-2 enhanced LRP1 whereas overexpression of the active SREBP isoforms decreased LRP1 expression." SIGNOR-254462 SREBF1 protein P36956 UNIPROT SND1 protein Q7KZF4 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 29296233 t irozzo "These findings reveal that SREBP-2 and SREBP-1 bind to specific sites in SND1 promoter and regulate SND1 transcription in opposite ways; it is induced by SREBP-2 activating conditions and repressed by SREBP-1 overexpression." SIGNOR-259137 DLST protein P36957 UNIPROT OGDC complex SIGNOR-C397 SIGNOR "form complex" binding 9606 15953811 t miannu "The α-ketoglutarate–dehydrogenase complex is a complex including multiple copies of three proteins: E1k (α-ketoglutarate dehydrogenase), E2k (dihydrolipoyl succinyltransferase), and E3 (dihydrolipoamide dehydrogenase) (Fig. 2). The consecutive action of the three catalytic components of KGDHC results in oxidative decarboxylation of 2-oxoglutarate, preserving the energy in the form of succinylCoA and NADH." SIGNOR-266254 TGFBR2 protein P37173 UNIPROT PIK3R2 protein O00459 UNIPROT up-regulates binding 9606 BTO:0001660 9435577 t lperfetto "These studies revealed that PI 3-kinase is associated in vivo with both TGF-_ receptor subtypes and that TGF-_1 stimulation enhances PI 3-kinase activity associated with type I TGF-_ receptor in hASM cells." SIGNOR-227528 RIPK1 protein Q13546 UNIPROT TAB2 protein Q9NYJ8 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 15327770 t lperfetto "TNF_ induced the polyubiquitination of RIP and the association of polyubiquitinated RIP with TAB2." SIGNOR-128406 TGFBR2 protein P37173 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates binding 9606 BTO:0001660 9435577 t lperfetto "These studies revealed that PI 3-kinase is associated in vivo with both TGF-_ receptor subtypes and that TGF-_1 stimulation enhances PI 3-kinase activity associated with type I TGF-_ receptor in hASM cells." SIGNOR-227521 TGFBR2 protein P37173 UNIPROT PIK3R1 protein P27986 UNIPROT "up-regulates activity" binding 9606 19114990 t lperfetto "in immunoprecipitation esperiments, the TGF _ RII receptor was found to be constitutively associated with p85, the regulatory subunity of PI3K" SIGNOR-217830 TGFBR2 protein P37173 UNIPROT TGFBR1 protein P36897 UNIPROT "up-regulates activity" phosphorylation Thr200 LPLLVQRtIARTIVL 452646 7774578 t 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 TGFBR2 protein P37173 UNIPROT TGFBR1 protein P36897 UNIPROT "up-regulates activity" phosphorylation Thr204 VQRTIARtIVLQESI 452646 7774578 t 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 TGFBR2 protein P37173 UNIPROT TGFBR1 protein P36897 UNIPROT "up-regulates activity" phosphorylation Ser172 SLDRPFIsEGTTLKD 9606 8576253 t lperfetto "Recent studies have revealed that upon TGF-beta binding several serine and threonine residues in the GS domain of TGF-beta type I receptor (T beta R-I) are phosphorylated by TGF-beta type II receptor (T beta R-II) and that the phosphorylation of GS domain is essential for TGF-beta signalingThese observations indicate that serine 172 and threonine 176 of T beta R-I are dispensable for extracellular matrix protein production but essential to the growth inhibition by TGF-beta" SIGNOR-246728 TGFBR2 protein P37173 UNIPROT TGFBR1 protein P36897 UNIPROT "up-regulates activity" phosphorylation Thr176 PFISEGTtLKDLIYD -1 8576253 t "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 TGFBR2 protein P37173 UNIPROT TGFBR2 protein P37173 UNIPROT "down-regulates activity" phosphorylation Ser416 SVDDLANsGQVGTAR 9606 BTO:0000972 phosphorylation:Ser213 TRKLMEFsEHCAIIL 9155023 t lperfetto "Ser213, in the membrane-proximal segment outside the kinase domain, undergoes intra-molecular autophosphorylation which is essential for the activation of TbetaRII kinase activity, activation of TbetaRI and TGF-beta-induced growth inhibition. In contrast, phosphorylation of Ser409 and Ser416, located in a segment corresponding to the substrate recognition T-loop region in a three-dimensional structural model of protein kinases, is enhanced by receptor dimerization and can occur via an intermolecular mechanism. Phosphorylation of Ser409 is essential for TbetaRII kinase signaling, while phosphorylation of Ser416 inhibits receptor function." SIGNOR-246737 TGFBR2 protein P37173 UNIPROT TGFBR2 protein P37173 UNIPROT "down-regulates activity" phosphorylation Ser416 SVDDLANsGQVGTAR 9606 9155023 t lperfetto "Tbetarii kinase is regulated intricately by autophosphorylation on at least three serine residues. Phosphorylation of ser416 inhibits receptor function." SIGNOR-48412 TGFBR2 protein P37173 UNIPROT TGFBR2 protein P37173 UNIPROT "up-regulates activity" phosphorylation Ser213 TRKLMEFsEHCAIIL 9606 BTO:0002181 9155023 t lperfetto "Here we show that TbetaRII kinase is regulated intricately by autophosphorylation on at least three serine residues. Ser213, in the membrane-proximal segment outside the kinase domain, undergoes intra-molecular autophosphorylation which is essential for the activation of TbetaRII kinase activity, activation of TbetaRI and TGF-beta-induced growth inhibition." SIGNOR-236087 TGFBR2 protein P37173 UNIPROT TGFBR2 protein P37173 UNIPROT "up-regulates activity" phosphorylation Ser409 LRLDPTLsVDDLANS 9606 BTO:0000972 phosphorylation:Ser213 TRKLMEFsEHCAIIL 9155023 t lperfetto "Ser213, in the membrane-proximal segment outside the kinase domain, undergoes intra-molecular autophosphorylation which is essential for the activation of TbetaRII kinase activity, activation of TbetaRI and TGF-beta-induced growth inhibition. In contrast, phosphorylation of Ser409 and Ser416, located in a segment corresponding to the substrate recognition T-loop region in a three-dimensional structural model of protein kinases, is enhanced by receptor dimerization and can occur via an intermolecular mechanism. Phosphorylation of Ser409 is essential for TbetaRII kinase signaling, while phosphorylation of Ser416 inhibits receptor function." SIGNOR-246743 TGFBR2 protein P37173 UNIPROT TGFBR2 protein P37173 UNIPROT "up-regulates activity" phosphorylation Tyr259 KGRFAEVyKAKLKQN -1 9169454 t lperfetto "Tryptic mapping and amino acid sequencing of in vitro autophosphorylated type ii receptor cytoplasmic domain allowed the localization of the sites of tyrosine phosphorylation to positions 259, 336, and 424. Replacement of all three tyrosines with phenylalanines strongly inhibited the kinase activity of the receptor, suggesting that tyrosine autophosphorylation may play an autoregulatory role for the kinase activity of this receptor." SIGNOR-48859 TGFBR2 protein P37173 UNIPROT TGFBR2 protein P37173 UNIPROT "up-regulates activity" phosphorylation Tyr336 AKGNLQEyLTRHVIS -1 9169454 t lperfetto "Tryptic mapping and amino acid sequencing of in vitro autophosphorylated type ii receptor cytoplasmic domain allowed the localization of the sites of tyrosine phosphorylation to positions 259, 336, and 424. Replacement of all three tyrosines with phenylalanines strongly inhibited the kinase activity of the receptor, suggesting that tyrosine autophosphorylation may play an autoregulatory role for the kinase activity of this receptor." SIGNOR-48863 TGFBR2 protein P37173 UNIPROT TGFBR2 protein P37173 UNIPROT "up-regulates activity" phosphorylation Tyr424 GQVGTARyMAPEVLE -1 9169454 t lperfetto "Tryptic mapping and amino acid sequencing of in vitro autophosphorylated type ii receptor cytoplasmic domain allowed the localization of the sites of tyrosine phosphorylation to positions 259, 336, and 424. Replacement of all three tyrosines with phenylalanines strongly inhibited the kinase activity of the receptor, suggesting that tyrosine autophosphorylation may play an autoregulatory role for the kinase activity of this receptor." SIGNOR-48867 TGFBR2 protein P37173 UNIPROT VPS39 protein Q96JC1 UNIPROT "up-regulates activity" binding 9534 12941698 t miannu "TLP interacts with TGF-β and activin receptors in vivo. Endogenous TLP associates with both active and kinase-deficient TGF-beta and activin type II receptors, but interacts with the common-mediator Smad4 only in the presence of TGF-beta/activin signaling." SIGNOR-261374 TGFBR2 protein P37173 UNIPROT PARD6A protein Q9NPB6 UNIPROT up-regulates phosphorylation Ser345 RGDGSGFsL 9606 BTO:0004183 15761148 t lperfetto "We demonstrate that Par6, a regulator of epithelial cell polarity and tight-junction assembly, interacts with TGFbeta receptors and is a substrate of the type II receptor, TbetaRII. [...] These data suggest that T_RII phosphorylates Par6 at its penultimate residue, Ser345." SIGNOR-227484 TGFBR2 protein P37173 UNIPROT PARD6A protein Q9NPB6 UNIPROT up-regulates phosphorylation Ser345 RGDGSGFsL 9606 BTO:0000551 23249950 t lpetrilli "Transforming growth factor ? (tgf-?) Has been shown to regulate cell plasticity through the phosphorylation of par6 on a conserved serine residue (s345) by the type ii tgf-? Receptor." SIGNOR-200193 TGFBR2 protein P37173 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0001660 9435577 t lperfetto "These studies revealed that PI 3-kinase is associated in vivo with both TGF-_ receptor subtypes and that TGF-_1 stimulation enhances PI 3-kinase activity associated with type I TGF-_ receptor in hASM cells." SIGNOR-252732 TGFBR2 protein P37173 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" binding 9606 19114990 t lperfetto "In immunoprecipitation esperiments, the TGF _ RII receptor was found to be constitutively associated with p85, the regulatory subunity of PI3K" SIGNOR-252731 NUP62 protein P37198 UNIPROT TUBG1 protein P23258 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 24107630 t Simone "Furthermore, we found interactions and co-localization with γ-tubulin and SAS-6. Our results also point to a potential role of Nup62 in targeting gamma-tubulin and SAS-6 to the centrioles." SIGNOR-261257 NUP62 protein P37198 UNIPROT SASS6 protein Q6UVJ0 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 24107630 t Simone "Furthermore, we found interactions and co-localization with γ-tubulin and SAS-6. Our results also point to a potential role of Nup62 in targeting gamma-tubulin and SAS-6 to the centrioles." SIGNOR-261256 NUP62 protein P37198 UNIPROT p62_complex complex SIGNOR-C259 SIGNOR "form complex" binding 10116 BTO:0000154 2050741 t Simone "Thus, the p62-p58-p54 complex defines a group of proteins with strong protein-protein interactions that form a unit of pore structure essential for pore function." SIGNOR-261258 NUP62 protein P37198 UNIPROT NPC complex SIGNOR-C263 SIGNOR "form complex" binding 27016207 t lperfetto "The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2)." SIGNOR-262079 PPARG protein P37231 UNIPROT JUN protein P05412 UNIPROT "up-regulates activity" 9606 BTO:0000801 17681149 f 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-249558 PPARG protein P37231 UNIPROT ACADM protein P11310 UNIPROT "down-regulates activity" binding 9606 BTO:0001370 28974683 t Federica "This truncated PPARγ translocates to mitochondria, where it directly interacts with medium-chain acyl-CoA dehydrogenase (MCAD). This binding event attenuates MCAD activity and inhibits fatty acid oxidation" SIGNOR-261264 PPARG protein P37231 UNIPROT FABP4 protein P15090 UNIPROT up-regulates "transcriptional regulation" 10116 8943212 f fspada "We report that insulin and a ppargamma ligand (thiazolidinedione (tzd)) stimulate in a synergistic manner the expression of an adipocyte-specific gene (ap2) in rat adipocytes and 3t3-l1 cells" SIGNOR-210149 PPARG protein P37231 UNIPROT FABP4 protein P15090 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000975 8943212 f fspada "We report that insulin and a ppargamma ligand (thiazolidinedione (tzd)) stimulate in a synergistic manner the expression of an adipocyte-specific gene (ap2) in rat adipocytes and 3t3-l1 cells" SIGNOR-45294 PPARG protein P37231 UNIPROT UCP1 protein P25874 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165 32991581 t brain lperfetto "NFIA binds to and activates the brown-fat-specific enhancers even before differentiation and later facilitates the binding of PPARgamma|NFIA has at least three functions on the transcriptional regulation of brown fat [2]. First, NFIA activates adipogenesis per se, through activating the transcription of Pparg, which encodes PPARgamma. Second, NFIA also activates the brown-fat-specific gene expression (such as Ucp1 and Ppargc1a) independent of the degree of adipocyte differentiation, through facilitating the binding of PPARgamma to the brown-fat-specific enhancers. Third, NFIA represses myogenesis through suppression of myogenic transcription factors such as Myod1 as well as Myog," SIGNOR-263985 PPARG protein P37231 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 20303941 f gcesareni "The results from mammalian one-hybrid experiments showed that functional ppar gamma was necessary for ligand-dependent inhibition of beta-catenin transactivation." SIGNOR-164516 PPARG protein P37231 UNIPROT STAT3 protein P40763 UNIPROT down-regulates 9606 BTO:0000801 17681149 f 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 PPARG protein P37231 UNIPROT CEBPA protein P49715 UNIPROT "up-regulates activity" "transcriptional regulation" 10090 BTO:0002572;BTO:0000011;BTO:0005065 16431920 f "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 PPARG protein P37231 UNIPROT PTEN protein P60484 UNIPROT "down-regulates activity" 9606 23128507 t "PAX8-PPARγ fusion protein" miannu "The PAX8-PPARγ rearrangement leads to strong induction of the PPARγ protein and the consequent abrogation of the normal PPARγ function. PPARγ overexpression abolishes the PTEN-inhibitory effect on immunoactive AKT, which in turn induces the PI3K signaling pathway." SIGNOR-251997 PPARG protein P37231 UNIPROT HDAC1 protein Q13547 UNIPROT down-regulates relocalization 9606 16431920 t fspada "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-143961 PPARG protein P37231 UNIPROT CPT1B protein Q92523 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165 15356291 f miannu "Mutation analysis indicated that the MEF2 site contributed to the activation of the CPT1beta promoter by PPAR in C2C12 cells. The reporter construct containing the PPRE and the MEF2C site was synergistically activated by co-expression of PPAR, retinoid X receptor (RXR) and MEF2C in non-muscle cells. Moreover, protein-binding assays demonstrated that MEF2C and PPAR specifically bound to one another in vitro. Also for the synergistic activation of the CPT1beta gene promoter by MEF2C and PPARalpha-RXRalpha, a precise arrangement of its binding sites was essential." SIGNOR-254581 PPARG protein P37231 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165 32991581 t brain lperfetto "NFIA binds to and activates the brown-fat-specific enhancers even before differentiation and later facilitates the binding of PPARgamma|NFIA has at least three functions on the transcriptional regulation of brown fat [2]. First, NFIA activates adipogenesis per se, through activating the transcription of Pparg, which encodes PPARgamma. Second, NFIA also activates the brown-fat-specific gene expression (such as Ucp1 and Ppargc1a) independent of the degree of adipocyte differentiation, through facilitating the binding of PPARgamma to the brown-fat-specific enhancers. Third, NFIA represses myogenesis through suppression of myogenic transcription factors such as Myod1 as well as Myog," SIGNOR-263984 PPARG protein P37231 UNIPROT ABCG2 protein Q9UNQ0 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002042 16785230 f miannu "these results uncovered a mechanism by which up-regulation of functional ABCG2 expression can be achieved via exogenous or endogenous activation of the lipid-activated transcription factor, PPARgamma." SIGNOR-255054 PPARG protein P37231 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "down-regulates quantity by repression" 9606 BTO:0000801 17681149 f 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 ZEB1 protein P37275 UNIPROT CDH1 protein P12830 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15311212 f miannu "known E-cadherin transcriptional repressors, such as SLUG (SNAI2), SIP1 (ZEB2), TWIST1, SNAIL (SNAI1) and ZEB1 (TCF8), but not E12/E47 (TCF3), had a lack of upregulation in cells expressing mutated E-cadherin compared to WT." SIGNOR-255158 ZEB1 protein P37275 UNIPROT EPCAM protein P16422 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000150;BTO:0000584 23667256 f miannu "We found a similar ZEB1-dependent repression of EPCAM expression in human pancreatic and breast cancer cell lines, mediated through direct binding of ZEB1 to the EPCAM promoter." SIGNOR-255622 ZEB1 protein P37275 UNIPROT GRHL2 protein Q6ISB3 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000150 23814079 f miannu "we could further demonstrate that expression of GRHL2 is directly suppressed by the transcription factor zinc finger enhancer-binding protein 1 (ZEB1), which in turn is a direct target for repression by GRHL2, suggesting that the EMT transcription factors GRHL2 and ZEB1 form a double negative regulatory feedback loop in breast cancer cells." SIGNOR-255623 AVPR1A protein P37288 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256948 AVPR1A protein P37288 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257077 AVPR1A protein P37288 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256805 TAGLN2 protein P37802 UNIPROT ACTB protein P60709 UNIPROT "down-regulates activity" binding 21577206 t lperfetto "Taken together, our data propose a novel, oncogene-tumor suppressor interplay, where oncogenic PFTK1 confers HCC cell motility through inactivating the actin-binding motile suppressing function of TAGLN2 via phosphorylation." SIGNOR-265104 TALDO1 protein P37837 UNIPROT "D-erythrose 4-phosphate(2-)" smallmolecule CHEBI:16897 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 19401148 t miannu "Transaldolase (TAL, sedoheptulose 7-phosphate: d-glyceraldehyde 3-phosphate dihydroxyacetone transferase; EC number 2.2.1.2) is a cofactor-less enzyme of the pentose phosphate pathway (PPP) (Fig. 1A and B). It catalyzes the reversible transfer of a three carbon unit (“dihydroxyacetone”) between various sugar phosphates (from 3 to 8 carbon atoms in length). Physiological donor compounds are ketose sugar phosphates as fructose 6-phosphate or sedoheptulose 7-phosphate. Acceptor compounds are aldose sugar phosphates as glyceraldehyde 3-phosphate and erythrose 4-phosphate." SIGNOR-267092 TALDO1 protein P37837 UNIPROT "beta-D-fructofuranose 6-phosphate(2-)" smallmolecule CHEBI:57634 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 19401148 t miannu "Transaldolase (TAL, sedoheptulose 7-phosphate: d-glyceraldehyde 3-phosphate dihydroxyacetone transferase; EC number 2.2.1.2) is a cofactor-less enzyme of the pentose phosphate pathway (PPP) (Fig. 1A and B). It catalyzes the reversible transfer of a three carbon unit (“dihydroxyacetone”) between various sugar phosphates (from 3 to 8 carbon atoms in length). Physiological donor compounds are ketose sugar phosphates as fructose 6-phosphate or sedoheptulose 7-phosphate. Acceptor compounds are aldose sugar phosphates as glyceraldehyde 3-phosphate and erythrose 4-phosphate." SIGNOR-267091 GGCX protein P38435 UNIPROT "Reduced Vitamin K" smallmolecule CHEBI:8784 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 31226734 t lperfetto "GGCX carboxylates the glutamic acid residues of vitamin K-dependent proteins (VKDP) to Gla using reduced vitamin K, while simultaneously oxidizing the reduced form of vitamin K to an epoxide form." SIGNOR-265908 SNCA protein P37840 UNIPROT VAMP2 protein P63027 UNIPROT "down-regulates quantity" binding 9606 BTO:0000938 31110017 t miannu "The normal function of the small presynaptic protein α-synuclein (α-syn) is of exceptional interest, not only in the context of neurodegeneration, but also as a cytosolic regulator of neurotransmission. we show that α-syn-VAMP2 interactions are necessary for α-syn-induced synaptic attenuation. Our data connect divergent views and suggest a unified model of α-syn function. the data indicate that α-syn–VAMP2 binding is essential for α-syn function and advocate an “interlocking model” where α-syn multimers on the SV surface interact with VAMP2 on adjacent SVs, helping to maintain physiologic SV clustering." SIGNOR-264104 BRCA1 protein P38398 UNIPROT ESR1 protein P03372 UNIPROT "down-regulates activity" 9606 BTO:0000356;BTO:0001033 11244506 f "The BRCA1 gene was previously found to inhibit the transcriptional activity of the estrogen receptor [ER-alpha] in human breast and prostate cancer cell lines." SIGNOR-253974 BRCA1 protein P38398 UNIPROT TFF1 protein P04155 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000356;BTO:0001033 11244506 f "In addition, BRCA1 blocked the expression of two endogenous estrogen-regulated gene products in human breast cancer cells: pS2 and cathepsin D." SIGNOR-253937 BRCA1 protein P38398 UNIPROT CTSD protein P07339 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000150 11244506 f miannu "BRCA1 blocked the expression of two endogenous estrogen-regulated gene products in human breast cancer cells: pS2 and cathepsin D." SIGNOR-253759 BRCA1 protein P38398 UNIPROT HSPA5 protein P11021 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000093 18776923 f miannu "We report here that glucose-regulated protein (GRP)-78, a critical regulator of the unfolded protein response (UPR), is a novel downstream target of BRCA1. We showed that overexpression of wild-type BRCA1 suppressed the expression of GRP78, whereas expression of mutant BRCA1 gene or targeted inhibition of endogenous BRCA1 using small-interfering RNA (siRNA) enhanced GRP78 expression." SIGNOR-253761 BRCA1 protein P38398 UNIPROT AKT1 protein P31749 UNIPROT "down-regulates quantity by destabilization" ubiquitination 10090 BTO:0002572 19074868 t gcesareni "The BRCA1-BRCT domains bind to phosphorylated AKT (pAKT) and lead to its ubiquitination toward protein degradation" SIGNOR-252435 BRCA1 protein P38398 UNIPROT CDKN1B protein P46527 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150 16331276 f miannu "We identified a foxa1 binding site within the brca1-responsive element of the p27(kip1) promoter and showed that foxa1 activated the promoter alone and in conjunction with brca1." SIGNOR-142888 BRCA1 protein P38398 UNIPROT RNASEL protein Q05823 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15940267 f miannu "We propose that BRCA1 may be an upstream regulator of RNaseL, acting in concert with IFN-gamma to transcriptionally activate 2,5 OAS, leading to the downstream activation of RNaseL and apoptosis." SIGNOR-253762 BRCA1 protein P38398 UNIPROT ATM protein Q13315 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001130 22832221 f gcesareni "Brca1/e2f1/ctipbinding to atm promoter activates atm transcription." SIGNOR-198467 BRCA1 protein P38398 UNIPROT RBBP8 protein Q99708 UNIPROT up-regulates ubiquitination 9606 16818604 t gcesareni "In conclusion, our data show that ctip is a physiological substrate of the brca1 e3 ligase. Brca1 recruits ctip through its c-terminal brct domains and promotes ctip ubiquitination through its n-terminal ring domain. The ubiquitinated ctip is not targeted for degradation. Instead, ubiquitinated ctip binds to chromatin following dna damage and is likely to be involved in dna damage checkpoint control." SIGNOR-147711 BRCA1 protein P38398 UNIPROT FOXC2 protein Q99958 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000150 22120723 f miannu "We show that the BRCA1-GATA3 interaction is important for the repression of genes associated with triple-negative and basal-like breast cancer (BLBCs) including FOXC1, and that GATA3 interacts with a C-terminal region of BRCA1. We demonstrate that this BRCA1-GATA3 repression complex is not a FOXC1-specific phenomenon as a number of other genes associated with BLBCs such as FOXC2, CXCL1 and p-cadherin were also repressed in a similar manner." SIGNOR-253760 BRCA1 protein P38398 UNIPROT FANCD2 protein Q9BXW9 UNIPROT "up-regulates activity" ubiquitination 9606 BTO:0003323 SIGNOR-C297 12485996 t lperfetto "The major genetic evidence supporting ubiquitin ligase function for BRCA1 in vivo comes from studies on the FANCD2 protein. Whereas in wild‐type cells the FANCD2 protein co‐localizes with BRCA1 in nuclear foci and becomes monoubiquitylated in response to DNA damage, HCC1937 cells, which encode a mutated form of BRCA1, are largely defective for both monoubiquitylation of FANCD2 and foci formation" SIGNOR-263236 BRCA1 protein P38398 UNIPROT MRE11/RAD50/NBS1 complex SIGNOR-C147 SIGNOR "up-regulates activity" binding 10426999 t lperfetto "BRCA1 encodes a tumor suppressor that is mutated in familial breast and ovarian cancers. Here, it is shown that BRCA1 interacts in vitro and in vivo with hRad50, which forms a complex with hMre11 and p95/nibrin. Upon irradiation, BRCA1 was detected in discrete foci in the nucleus, which colocalize with hRad50.| These data suggest that BRCA1 is important for the cellular responses to DNA damage that are mediated by the hRad50-hMre11-p95 complex." SIGNOR-251501 BRCA1 protein P38398 UNIPROT "BRCA1-BARD1 complex" complex SIGNOR-C297 SIGNOR "form complex" binding 25400280 t lperfetto "Intriguingly, another BRCA1 complex, the BRCA1–A complex, which itself contains RAP80 along with MERIT40, BRCC36/45 and Abraxas, has been reported to inhibit DNA end resection, suggesting that, in some contexts, BRCA1 may function to limit and/or prevent over resection of DNA breaks." SIGNOR-263224 BRCA1 protein P38398 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates quantity by destabilization" ubiquitination 10090 BTO:0002572 19074868 t gcesareni "The BRCA1-BRCT domains bind to phosphorylated AKT (pAKT) and lead to its ubiquitination toward protein degradation" SIGNOR-252458 GNAL protein P38405 UNIPROT ADCY5 protein O95622 UNIPROT "up-regulates activity" binding 9606 BTO:0004032 21303898 t miannu "D1-class dopamine receptors (D1 and D5) activate the G s/olf family of G proteins to stimulate cAMP produc tion by AC and are found exclusively postsynaptically on dopamine-receptive cells, such as GABA-ergic medium spiny neurons (MSNs) in the striatum." SIGNOR-264997 GNAL protein P38405 UNIPROT ADCY1 protein Q08828 UNIPROT "up-regulates activity" binding 9606 BTO:0004032 21303898 t miannu "D1-class dopamine receptors (D1 and D5) activate the G s/olf family of G proteins to stimulate cAMP produc tion by AC and are found exclusively postsynaptically on dopamine-receptive cells, such as GABA-ergic medium spiny neurons (MSNs) in the striatum." SIGNOR-264992 GGCX protein P38435 UNIPROT "vitamin K epoxide" smallmolecule CHEBI:28371 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 31226734 t lperfetto "GGCX carboxylates the glutamic acid residues of vitamin K-dependent proteins (VKDP) to Gla using reduced vitamin K, while simultaneously oxidizing the reduced form of vitamin K to an epoxide form." SIGNOR-265909 DYRK1A protein Q13627 UNIPROT DYRK1A protein Q13627 UNIPROT up-regulates phosphorylation Tyr319 CQLGQRIyQYIQSRF 9606 10910078 t lperfetto "Mirk kinase is activated by autophosphorylation on tyrosine at the y271/y273 site" SIGNOR-79760 GGCX protein P38435 UNIPROT SMAD7 protein O15105 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 31539109 f miannu "GGCX can regulate osteoporosis via promoting the TGFβ/smad signaling pathway, facilitating BMSCs osteogenic differentiation, and inhibiting BMSCs adipogenic differentiation. The transfection of pcDNA-GGCX plasmid significantly promoted BMSC cell proliferation, increased calcified nodule formation, inhibited adipogenic differentiation, enhanced ALP activity, elevated RUNX2, and OPN mRNA expressions, and upregulated TGFβ1, Smad2, and Smad7 expressions (p < 0.05)." SIGNOR-261233 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT "up-regulates activity" carboxylation Glu49 RRANTFLeEVRKGNL -1 10556651 t lperfetto "We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood." SIGNOR-263675 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT "up-regulates activity" carboxylation Glu50 RANTFLEeVRKGNLE -1 10556651 t lperfetto "We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood." SIGNOR-263676 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT "up-regulates activity" carboxylation Glu57 EVRKGNLeRECVEET -1 10556651 t lperfetto "We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood." SIGNOR-263677 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT "up-regulates activity" carboxylation Glu59 RKGNLEReCVEETCS -1 10556651 t lperfetto "We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood." SIGNOR-263678 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT "up-regulates activity" carboxylation Glu62 NLERECVeETCSYEE -1 10556651 t lperfetto "We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood." SIGNOR-263679 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT "up-regulates activity" carboxylation Glu63 LERECVEeTCSYEEA -1 10556651 t lperfetto "We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood." SIGNOR-263680 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT "up-regulates activity" carboxylation Glu68 VEETCSYeEAFEALE -1 10556651 t lperfetto "We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood." SIGNOR-263681 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT "up-regulates activity" carboxylation Glu69 EETCSYEeAFEALES -1 10556651 t lperfetto "We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood." SIGNOR-263682 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT "up-regulates activity" carboxylation Glu72 CSYEEAFeALESSTA -1 10556651 t lperfetto "We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood." SIGNOR-263683 DYRK1A protein Q13627 UNIPROT DYRK1A protein Q13627 UNIPROT up-regulates phosphorylation Tyr321 LGQRIYQyIQSRFYR 9606 10910078 t lperfetto "Mirk kinase is activated by autophosphorylation on tyrosine at the y271/y273 site" SIGNOR-79764 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT "up-regulates activity" carboxylation Glu75 EEAFEALeSSTATDV -1 10556651 t lperfetto "We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood." SIGNOR-263684 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT "up-regulates activity" carboxylation 9606 31226734 t lperfetto "Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation." SIGNOR-265918 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT "up-regulates activity" carboxylation Glu53 RYNSGKLeEFVQGNL 10090 BTO:0001103 11133752 t lperfetto "The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing." SIGNOR-263686 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT "up-regulates activity" carboxylation Glu54 YNSGKLEeFVQGNLE 10090 BTO:0001103 11133752 t lperfetto "The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing." SIGNOR-263687 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT "up-regulates activity" carboxylation Glu61 EFVQGNLeRECMEEK 10090 BTO:0001103 11133752 t lperfetto "The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing." SIGNOR-263688 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT "up-regulates activity" carboxylation Glu63 VQGNLEReCMEEKCS 10090 BTO:0001103 11133752 t lperfetto "The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing." SIGNOR-263689 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT "up-regulates activity" carboxylation Glu66 NLERECMeEKCSFEE 10090 BTO:0001103 11133752 t lperfetto "The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing." SIGNOR-263690 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT "up-regulates activity" carboxylation Glu67 LERECMEeKCSFEEA 10090 BTO:0001103 11133752 t lperfetto "The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing." SIGNOR-263691 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT "up-regulates activity" carboxylation Glu72 MEEKCSFeEAREVFE 10090 BTO:0001103 11133752 t lperfetto "The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing." SIGNOR-263692 GDNF protein P39905 UNIPROT NCAM1 protein P13591 UNIPROT "up-regulates activity" binding 10116 BTO:0002881 15212950 t miannu "Recently, NCAM was identified as an alternative receptor for GDNF. These new results may explain the findings that, in several regions, the GDNF receptor (GFRa1) is highly expressed, while RET is undetectable." SIGNOR-252189 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT "up-regulates activity" carboxylation Glu73 EEKCSFEeAREVFEN 10090 BTO:0001103 11133752 t lperfetto "The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing." SIGNOR-263693 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT "up-regulates activity" carboxylation Glu76 CSFEEAReVFENTER 10090 BTO:0001103 11133752 t lperfetto "The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing." SIGNOR-263694 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT "up-regulates activity" carboxylation Glu79 EEAREVFeNTERTTE 10090 BTO:0001103 11133752 t lperfetto "The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing." SIGNOR-263685 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT "up-regulates activity" carboxylation Glu82 REVFENTeRTTEFWK 10090 BTO:0001103 11133752 t lperfetto "The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing." SIGNOR-263695 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT "up-regulates activity" carboxylation Glu86 ENTERTTeFWKQYVD 10090 BTO:0001103 11133752 t lperfetto "The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing." SIGNOR-263696 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT "up-regulates activity" carboxylation 9606 31226734 t lperfetto "Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation." SIGNOR-265920 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT "up-regulates activity" carboxylation Glu46 TRANSFLeEMKKGHL -1 9538022 t lperfetto "This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39)." SIGNOR-263664 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT "up-regulates activity" carboxylation Glu47 RANSFLEeMKKGHLE -1 9538022 t lperfetto "This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39)." SIGNOR-263665 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT "up-regulates activity" carboxylation Glu54 EMKKGHLeRECMEET -1 9538022 t lperfetto "This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39)." SIGNOR-263666 VHL protein P40337 UNIPROT KLF10 protein Q13118 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0003781 18359287 f lperfetto "In this study, we show that both TGFBI and KLF10 are down-regulated by VHL in 786-0 cells, and that KLF10 may serve as a transactivator of the TGFBI promoter." SIGNOR-253213 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT "up-regulates activity" carboxylation Glu56 KKGHLEReCMEETCS -1 9538022 t lperfetto "This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39)." SIGNOR-263667 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT "up-regulates activity" carboxylation Glu59 HLERECMeETCSYEE -1 9538022 t lperfetto "This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39)." SIGNOR-263668 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT "up-regulates activity" carboxylation Glu60 LERECMEeTCSYEEA -1 9538022 t lperfetto "This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39)." SIGNOR-263669 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT "up-regulates activity" carboxylation Glu65 MEETCSYeEAREVFE -1 9538022 t lperfetto "This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39)." SIGNOR-263670 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT "up-regulates activity" carboxylation Glu66 EETCSYEeAREVFED -1 9538022 t lperfetto "This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39)." SIGNOR-263671 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT "up-regulates activity" carboxylation Glu69 CSYEEAReVFEDSDK -1 9538022 t lperfetto "This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39)." SIGNOR-263672 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT "up-regulates activity" carboxylation Glu72 EEAREVFeDSDKTNE -1 9538022 t lperfetto "This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39)." SIGNOR-263673 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT "up-regulates activity" carboxylation Glu79 EDSDKTNeFWNKYKD -1 9538022 t lperfetto "This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39)." SIGNOR-263674 GGCX protein P38435 UNIPROT TGFB1 protein P01137 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 31539109 f miannu "GGCX can regulate osteoporosis via promoting the TGFβ/smad signaling pathway, facilitating BMSCs osteogenic differentiation, and inhibiting BMSCs adipogenic differentiation. The transfection of pcDNA-GGCX plasmid significantly promoted BMSC cell proliferation, increased calcified nodule formation, inhibited adipogenic differentiation, enhanced ALP activity, elevated RUNX2, and OPN mRNA expressions, and upregulated TGFβ1, Smad2, and Smad7 expressions (p < 0.05)." SIGNOR-261231 RPS19 protein P39019 UNIPROT "40S cytosolic small ribosomal subunit" complex SIGNOR-C286 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262432 GGCX protein P38435 UNIPROT F7 protein P08709 UNIPROT "up-regulates activity" carboxylation 9606 31226734 t lperfetto "Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation." SIGNOR-265919 GGCX protein P38435 UNIPROT RUNX2 protein Q13950 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 31539109 f miannu "GGCX can regulate osteoporosis via promoting the TGFβ/smad signaling pathway, facilitating BMSCs osteogenic differentiation, and inhibiting BMSCs adipogenic differentiation. The transfection of pcDNA-GGCX plasmid significantly promoted BMSC cell proliferation, increased calcified nodule formation, inhibited adipogenic differentiation, enhanced ALP activity, elevated RUNX2, and OPN mRNA expressions, and upregulated TGFβ1, Smad2, and Smad7 expressions (p < 0.05)." SIGNOR-261230 GGCX protein P38435 UNIPROT SMAD2 protein Q15796 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 31539109 f miannu "GGCX can regulate osteoporosis via promoting the TGFβ/smad signaling pathway, facilitating BMSCs osteogenic differentiation, and inhibiting BMSCs adipogenic differentiation. The transfection of pcDNA-GGCX plasmid significantly promoted BMSC cell proliferation, increased calcified nodule formation, inhibited adipogenic differentiation, enhanced ALP activity, elevated RUNX2, and OPN mRNA expressions, and upregulated TGFβ1, Smad2, and Smad7 expressions (p < 0.05)." SIGNOR-261232 IFNGR2 protein P38484 UNIPROT JAK2 protein O60674 UNIPROT "up-regulates activity" binding 9606 BTO:0000801 23898330 t 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 IFNGR2 protein P38484 UNIPROT IFNGR2/INFGR1 complex SIGNOR-C142 SIGNOR "form complex" binding 9606 BTO:0000801 19041276 t 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 ITGAE protein P38570 UNIPROT "AE/b7 integrin" complex SIGNOR-C186 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253291 EIF4A3 protein P38919 UNIPROT "Exon junction complex" complex SIGNOR-C369 SIGNOR "form complex" binding -1 16923391 t miannu "The EJC is deposited onto mRNA during splicing and is transported to the cytoplasm where it influences translation, surveillance, and localization of the spliced mRNA. The complex is formed by the association of four proteins (eIF4AIII, Barentsz [Btz], Mago, and Y14), mRNA, and ATP." SIGNOR-265240 CDKN1A protein P38936 UNIPROT RB1 protein P06400 UNIPROT "up-regulates activity" 9606 10439039 f gcesareni "P21 may inhibit cell cycle progression by preventing the phosphorylation of prb." SIGNOR-69925 CDKN1A protein P38936 UNIPROT CDK4 protein P11802 UNIPROT down-regulates binding 9606 7626805 t gcesareni "P21cip1 is a cyclin-dependent kinase (cdk) inhibitor that is transcriptionally activated by p53 in response to dna damage.We Have explored the interaction of p21 with the currently known cdks. p21 effectively inhibits cdk2, cdk3, cdk4, and cdk6 kinases." SIGNOR-29957 CDKN1A protein P38936 UNIPROT PCNA protein P12004 UNIPROT down-regulates binding 9606 22911014 t gcesareni "P21 exerts its effect on the cell cycle not only by inhibiting cyclin/cdk complexes, but also by inhibiting proliferating cell nuclear antigen (pcna)" SIGNOR-191939 CDKN1A protein P38936 UNIPROT CCNB1 protein P14635 UNIPROT down-regulates binding 9606 19158493 t gcesareni "P21-mediated degradation of cyclin b1 in response to dna damage is necessary for the maintenance of g2 cell cycle arrest." SIGNOR-183498 CDKN1A protein P38936 UNIPROT CDK2 protein P24941 UNIPROT down-regulates binding 9606 BTO:0000222 16982699 t gcesareni "Considering that akt1 phosphorylates p21, this dissociation likely results from phosphorylation of p21 and release of cdk2." SIGNOR-149711 CDKN1A protein P38936 UNIPROT CDK3 protein Q00526 UNIPROT down-regulates binding 9606 7626805 t gcesareni "P21cip1 is a cyclin-dependent kinase (cdk) inhibitor that is transcriptionally activated by p53 in response to dna damage. We have explored the interaction of p21 with the currently known cdks. p21 effectively inhibits cdk2, cdk3, cdk4, and cdk6 kinases." SIGNOR-29954 CDKN1A protein P38936 UNIPROT CDK6 protein Q00534 UNIPROT down-regulates binding 9606 7626805 t gcesareni "P21cip1 is a cyclin-dependent kinase (cdk) inhibitor that is transcriptionally activated by p53 in response to dna damage.We Have explored the interaction of p21 with the currently known cdks. p21 effectively inhibits cdk2, cdk3, cdk4, and cdk6 kinases" SIGNOR-30030 CDKN1A protein P38936 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR "down-regulates activity" binding 9606 BTO:0000093 11154267 t lperfetto "Overexpression of p16INK4a in cells with functional pRb results in inhibition of both Cdk4- and Cdk6-associated kinase activity and pRb phosphorylation, with subsequent cell cycle arrest (46, 50). In addition, inhibition of D cyclin-Cdk4 complex formation by p16INK4a prevents sequestration of p21Cip1 and p27Kip1 by these complexes in early G1, leading to suppression of cyclin E-Cdk2 activity" SIGNOR-245462 CDKN1A protein P38936 UNIPROT CyclinB/CDK1 complex SIGNOR-C17 SIGNOR "down-regulates activity" binding 10913154 t lperfetto "P21 Inhibits Thr161 Phosphorylation of Cdc2 to Enforce the G2 DNA Damage Checkpoint|The cyclin-dependent kinase inhibitor p21 is required for a sustained G2 arrest after activation of the DNA damage checkpoint. Here we have addressed the mechanism by which p21 can contribute to this arrest in G2. We show that p21 blocks the activating phosphorylation of Cdc2 on Thr161" SIGNOR-251498 RPL3 protein P39023 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262495 GRIK1 protein P39086 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000938 29953871 t miannu "Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial." SIGNOR-264942 ANP32A protein P39687 UNIPROT CASP9 protein P55211 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 12522243 t "PHAP proteins promoted caspase-9 activation after apoptosome formation, whereas ProT negatively regulated caspase-9 activation by inhibiting apoptosome formation." SIGNOR-259082 CUX1 protein P39880 UNIPROT PIK3IP1 protein Q96FE7 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 24316979 t miannu "We demonstrate that CUX1 deficiency activates phosphoinositide 3-kinase (PI3K) signaling through direct transcriptional downregulation of the PI3K inhibitor PIK3IP1 (phosphoinositide-3-kinase interacting protein 1), leading to increased tumor growth and susceptibility to PI3K-AKT inhibition." SIGNOR-260072 MMP12 protein P39900 UNIPROT F12 protein P00748 UNIPROT "down-regulates quantity by destabilization" cleavage Gly376 SMTRVVGgLVALRGA -1 10930399 t lperfetto "The data presented in this study show for the first time the degradation of Factor XII of the blood clotting system by matrix metalloproteinases. MMP-12, MMP-13, and MMP-14 cleave at Gly376Leu377|However, no activity of Factor XII can be observed after MMPinduced cleavage." SIGNOR-263611 MMP12 protein P39900 UNIPROT FGA protein P02671 UNIPROT "down-regulates quantity by destabilization" cleavage Ala20 VVGTAWTaDSGEGDF -1 10930399 t lperfetto "Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system. |Fibrinogen was subjected to MMP-cleavage, and the resulting fragments were isolated. The amino acid sequences were determined by automated Edman degradation.|MMP-12 20ADSGEGD a-chain| 540FVSETESRG a-chain|433LVTSKGDK a-chain" SIGNOR-263622 MMP12 protein P39900 UNIPROT FGA protein P02671 UNIPROT "down-regulates quantity by destabilization" cleavage Leu433 REYHTEKlVTSKGDK -1 10930399 t lperfetto "Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system. |Fibrinogen was subjected to MMP-cleavage, and the resulting fragments were isolated. The amino acid sequences were determined by automated Edman degradation.|MMP-12 20ADSGEGD a-chain| 540FVSETESRG a-chain|433LVTSKGDK a-chain" SIGNOR-263624 MMP12 protein P39900 UNIPROT FGA protein P02671 UNIPROT "down-regulates quantity by destabilization" cleavage Phe540 FSPMLGEfVSETESR -1 10930399 t lperfetto "Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system. |Fibrinogen was subjected to MMP-cleavage, and the resulting fragments were isolated. The amino acid sequences were determined by automated Edman degradation.|MMP-12 20ADSGEGD a-chain| 540FVSETESRG a-chain|433LVTSKGDK a-chain" SIGNOR-263623 GDNF protein P39905 UNIPROT GFRA2 protein O00451 UNIPROT up-regulates binding 9606 BTO:0000938 9192898 t gcesareni "Gdnf mediates its actions through a multicomponent receptor system composed of a ligand-binding glycosyl-phosphatidylinositol (gpi)-linked protein (designated gdnfr-alpha)." SIGNOR-49184 GDNF protein P39905 UNIPROT BIN1 protein O00499 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0002881 15212950 f miannu "We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression." SIGNOR-252178 GDNF protein P39905 UNIPROT PDPK1 protein O15530 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0002881 15212950 f miannu "We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression." SIGNOR-252186 GDNF protein P39905 UNIPROT DCX protein O43602 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10116 BTO:0002881 15212950 f miannu "We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells. GDNF down-regulates doublecortin, Paf-ah1b (Lis1), dynamin, and a-tubulin, which are involved in neocortical lamination and cytoskeletal reorganization." SIGNOR-252172 GDNF protein P39905 UNIPROT RET protein P07949 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 9182803 t gcesareni "A receptor complex comprised of trnr1 (gdnfr alpha) and ret was recently identified and found to be capable of mediating both gdnf and ntn signaling" SIGNOR-49094 GDNF protein P39905 UNIPROT CLU protein P10909 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0002881 15212950 f miannu "We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression." SIGNOR-252187 GDNF protein P39905 UNIPROT RHOQ protein P17081 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0002881 15212950 f miannu "We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression." SIGNOR-252185 GDNF protein P39905 UNIPROT FST protein P19883 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0002881 15212950 f miannu "We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression." SIGNOR-252188 GDNF protein P39905 UNIPROT GCH1 protein P30793 UNIPROT "up-regulates activity" 9606 12358777 f miannu "GDNF can support the function of primary dopaminergic neurones by triggering activation of GTP-cyclohydrolase I (GTPCH I), a key enzyme in catecholamine biosynthesis. GTPCH I mRNA levels in primary dopaminergic neurones were not altered by GDNF treatment, suggesting that the mode of action for that up-regulation is not directly connected to the regulation of GTPCH I transcription" SIGNOR-252221 GDNF protein P39905 UNIPROT ID1 protein P41134 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0002881 15212950 f miannu "We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression." SIGNOR-252179 GDNF protein P39905 UNIPROT PAFAH1B1 protein P43034 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10116 BTO:0002881 15212950 f miannu "We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells. GDNF down-regulates doublecortin, Paf-ah1b (Lis1), dynamin, and a-tubulin, which are involved in neocortical lamination and cytoskeletal reorganization." SIGNOR-252171 GDNF protein P39905 UNIPROT DNM2 protein P50570 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10116 BTO:0002881 15212950 f miannu "We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells. GDNF down-regulates doublecortin, Paf-ah1b (Lis1), dynamin, and a-tubulin, which are involved in neocortical lamination and cytoskeletal reorganization." SIGNOR-252173 GDNF protein P39905 UNIPROT GFRA1 protein P56159 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 9182803 t gcesareni "A receptor complex comprised of trnr1 (gdnfr alpha) and ret was recently identified and found to be capable of mediating both gdnf and ntn signaling" SIGNOR-49091 GDNF protein P39905 UNIPROT NRG1 protein Q02297 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0002881 15212950 f miannu "We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression." SIGNOR-252182 GDNF protein P39905 UNIPROT ID2 protein Q02363 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0002881 15212950 f miannu "We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression." SIGNOR-252180 GDNF protein P39905 UNIPROT ID3 protein Q02535 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0002881 15212950 f miannu "We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression." SIGNOR-252181 GDNF protein P39905 UNIPROT PTK2 protein Q05397 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0002881 15212950 f miannu "We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression." SIGNOR-252184 GDNF protein P39905 UNIPROT ALCAM protein Q13740 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0002881 15212950 f miannu "We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression." SIGNOR-252177 GDNF protein P39905 UNIPROT LAMA3 protein Q16787 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0002881 15212950 f miannu "We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression." SIGNOR-252175 GDNF protein P39905 UNIPROT TUBA1A protein Q71U36 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10116 BTO:0002881 15212950 f miannu "We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells. GDNF down-regulates doublecortin, Paf-ah1b (Lis1), dynamin, and a-tubulin, which are involved in neocortical lamination and cytoskeletal reorganization." SIGNOR-252174 GDNF protein P39905 UNIPROT MAP1LC3B protein Q9GZQ8 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0002881 15212950 f miannu "We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression." SIGNOR-252176 GDNF protein P39905 UNIPROT NRN1 protein Q9NPD7 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0002881 15212950 f miannu "We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression." SIGNOR-252183 ADCY8 protein P40145 UNIPROT "3',5'-cyclic AMP" smallmolecule CHEBI:17489 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 15385642 t miannu "Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions." SIGNOR-265002 IL6ST protein P40189 UNIPROT JAK2 protein O60674 UNIPROT "up-regulates activity" phosphorylation Tyr1007 VLPQDKEyYKVKEPG 9606 9716487 t 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 IL6ST protein P40189 UNIPROT JAK2 protein O60674 UNIPROT "up-regulates activity" phosphorylation Tyr1008 LPQDKEYyKVKEPGE 9606 9716487 t 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 IL6ST protein P40189 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 24710148 t 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 IL6ST protein P40189 UNIPROT JAK1 protein P23458 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 23663276 t 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 IL6ST protein P40189 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 9606 9126968 t milica "Shc mediates IL-6 signaling by interacting with gp130 and Jak2 kinase." SIGNOR-250574 IL6ST protein P40189 UNIPROT IL6ST protein P40189 UNIPROT "up-regulates activity" phosphorylation Ser659 WPNVPDPsKSHIAQW -1 8511589 t 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 IL6ST protein P40189 UNIPROT IL6ST protein P40189 UNIPROT "up-regulates activity" phosphorylation Ser661 NVPDPSKsHIAQWSP -1 8511589 t 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 IL6ST protein P40189 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 16306329 f 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 GP5 protein P40197 UNIPROT "GPIb-IX-V complex" complex SIGNOR-C270 SIGNOR "form complex" binding 9606 BTO:0000132 16293600 t lperfetto "The GPIb-V-IX receptor consists of 4 transmembrane subunits: GPIbα, disulfide-linked to GPIbβ, and the noncovalently associated GPIX and GPV components, in ratios of 2:2:2:1." SIGNOR-261849 THPO protein P40225 UNIPROT MPL protein P40238 UNIPROT up-regulates binding 9606 11784712 t miannu "Thrombopoietin(tpo) controls the formation of megakaryocytes and platelets from hematopoietic stem cells via activation of the c-mplreceptorand multiple downstream signal transduction pathways." SIGNOR-113955 CD79B protein P40259 UNIPROT TP53 protein P04637 UNIPROT up-regulates 9606 BTO:0000776 12324477 f gcesareni "Bcr ligation resulted in p53 activation including its phosphorylation at ser15" SIGNOR-93526 VHL protein P40337 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000007 16678111 t "Here we found that pVHL directly associates with and stabilizes p53 by suppressing Mdm2-mediated ubiquitination and nuclear export of p53." SIGNOR-256594 VHL protein P40337 UNIPROT SPARC protein P09486 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000037 15824735 f miannu "three of the nine targets had been identified previously as candidate TSGs (DOC-2/DAB2, CDKN1C and SPARC) and all were upregulated by wild-type pVHL." SIGNOR-255603 VHL protein P40337 UNIPROT CDKN1C protein P49918 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000037 15824735 f miannu "three of the nine targets had been identified previously as candidate TSGs (DOC-2/DAB2, CDKN1C and SPARC) and all were upregulated by wild-type pVHL." SIGNOR-255601 VHL protein P40337 UNIPROT DAB2 protein P98082 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000037 15824735 f miannu "three of the nine targets had been identified previously as candidate TSGs (DOC-2/DAB2, CDKN1C and SPARC) and all were upregulated by wild-type pVHL." SIGNOR-255602 VHL protein P40337 UNIPROT CARD9 protein Q9H257 UNIPROT "down-regulates activity" binding 9606 BTO:0000567 17936701 t "We found that pVHL associates with the NF-kappaB agonist Card9 but does not target Card9 for destruction. Instead, pVHL serves as an adaptor that promotes the phosphorylation of the Card9 C terminus by CK2." SIGNOR-266899 VHL protein P40337 UNIPROT CARD9 protein Q9H257 UNIPROT "down-regulates activity" binding 9606 BTO:0000567 17936701 t "We found that pVHL associates with the NF-kappaB agonist Card9 but does not target Card9 for destruction. Instead, pVHL serves as an adaptor that promotes the phosphorylation of the Card9 C terminus by CK2." SIGNOR-257603 PBX1 protein P40424 UNIPROT HOXB1 protein P14653 UNIPROT "up-regulates activity" binding -1 10052460 t 2 miannu "Pbx1 and exd act as cofactors that enhance the DNA binding specificity of Hox proteins. The structure of the HoxB1–Pbx1–DNA ternary complex shows that HoxB1 and Pbx1 bind to overlapping binding sites located on opposite faces of the DNA." SIGNOR-241219 PBX1 protein P40424 UNIPROT MYOD1 protein P15172 UNIPROT "up-regulates activity" binding 9606 BTO:0000887;BTO:0001103 15149596 t "Pbx is constitutively bound close to the Myogenin promoter and can recruit MyoD" lperfetto "These domains are necessary for the stable binding of myod to the myogenin promoter through an interaction with an adjacent protein complex containing the homeodomain protein pbx, which appears to be constitutively bound at this site" SIGNOR-124834 PBX1 protein P40424 UNIPROT FGF8 protein P55075 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0003560 10026229 t miannu "Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription" SIGNOR-265777 PBX1 protein P40424 UNIPROT FGF8 protein P55075 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0003560 10026229 t miannu "Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription" SIGNOR-265803 PBX1 protein P40424 UNIPROT "MYOD1/SWI/SNF complex" complex SIGNOR-C93 SIGNOR "form complex" binding 9606 BTO:0001103 17194702 t miannu "Myod targets brg1 to the myogenin promoter during the initiation of myogenesis in tissue culture models for skeletal muscle differentiation /initiation of myogenin transcription is dependent upon myod, the pbx homeodomain factor, and swi/snf chromatin-remodeling enzymes" SIGNOR-151700 PBX2 protein P40425 UNIPROT FGF8 protein P55075 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0003560 10026229 t miannu "Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription" SIGNOR-265778 PBX2 protein P40425 UNIPROT FGF8 protein P55075 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0003560 10026229 t miannu "Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription" SIGNOR-265804 PBX3 protein P40426 UNIPROT FGF8 protein P55075 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0003560 10026229 t miannu "Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription" SIGNOR-265779 PBX3 protein P40426 UNIPROT FGF8 protein P55075 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0003560 10026229 t miannu "Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription" SIGNOR-265805 RPL13A protein P40429 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262485 MLH1 protein P40692 UNIPROT MLH1/PMS2 complex SIGNOR-C59 SIGNOR "form complex" binding 9606 10542278 t miannu "Hmlh1 and hpms2 function in postreplicative mismatch repair in the form of a heterodimer referred to as hmutl_" SIGNOR-71771 STAT3 protein P40763 UNIPROT SOCS3 protein O14543 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002553 12565872 t "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 STAT3 protein P40763 UNIPROT BIRC5 protein O15392 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 26512963 f miannu "DAB2IP could interact with the signal transducer and activator of transcription 3 (STAT3) via its unique PR domain and suppress STAT3 phosphorylation and transactivation, leading to the inhibition of survivin expression in PCa cells." SIGNOR-254762 IL15 protein P40933 UNIPROT IL2RG protein P31785 UNIPROT up-regulates binding 9606 11418623 t gcesareni "The common gamma-chain (gamma(c)) is an indispensable subunit of the functional receptor complexes for il-4, il-7, il-9, and il-15 as well as il-2. Here we show that the gamma(c) is also shared with the il-21r complex." SIGNOR-108815 STAT3 protein P40763 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity by expression" 9606 BTO:0001103 21408055 f "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 STAT3 protein P40763 UNIPROT POMC protein P01189 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007 19049975 t miannu "We show that phospho-STAT3 activates POMC promoter in response to leptin signaling through a mechanism that requires an SP1-binding site in the POMC promoter." SIGNOR-263497 STAT3 protein P40763 UNIPROT S100A9 protein P06702 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 18809714 f miannu "Accumulation of myeloid-derived suppressor cells (MDSCs) associated with inhibition of dendritic cell (DC) differentiation is one of the major immunological abnormalities in cancer and leads to suppression of antitumor immune responses. The molecular mechanism of this phenomenon remains unclear. We report here that STAT3-inducible up-regulation of the myeloid-related protein S100A9 enhances MDSC production in cancer." SIGNOR-261931 STAT3 protein P40763 UNIPROT HSPA1A protein P0DMV8 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19754877 f miannu "Hsp105beta upregulates hsp70 gene expression through signal transducer and activator of transcription-3. Hsp105beta induces Hsp70 expression markedly through the STAT3 pathway in heat-shocked cells. This may represent the mechanism that connects the heat shock protein and STAT families for cell defense against deleterious stress." SIGNOR-255240 STAT3 protein P40763 UNIPROT HSPA1B protein P0DMV9 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19754877 f miannu "Hsp105beta upregulates hsp70 gene expression through signal transducer and activator of transcription-3. Hsp105beta induces Hsp70 expression markedly through the STAT3 pathway in heat-shocked cells. This may represent the mechanism that connects the heat shock protein and STAT families for cell defense against deleterious stress." SIGNOR-255241 STAT3 protein P40763 UNIPROT MYOD1 protein P15172 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 25194572 f 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 STAT3 protein P40763 UNIPROT CD46 protein P15529 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17699108 f miannu "The CD46 promoter contains two binding sites for activated STAT3 and mutations introduced into the major site abolished STAT3 binding. Chromatin immunoprecipitation confirms binding of STAT3 to the CD46 promoter. CD46 promoter activity is induced by activation of STAT3 and blocked by a dominant-negative form of STAT3 in luciferase reporter assays." SIGNOR-255238 STAT3 protein P40763 UNIPROT VEGFA protein P15692 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12545153 t luana "Stat3 directly regulated the promoter of the VEGF gene. Blockade of activated Stat3 by ectopic expression of dominant-negative Stat3 significantly inhibited VEGF expression, and the growth and metastasis of human pancreatic cancer cells. " SIGNOR-259456 STAT3 protein P40763 UNIPROT GAP43 protein P17677 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0000099 26865625 t miannu " In this study, we demonstrated for the first time that growth-associated protein 43 (GAP43), a well known growth cone protein that promotes axonal regeneration, can be induced in rat brain astrocytes by the proinflammatory endotoxin lipopolysaccharide via both nuclear factor-κB and signal transducer and activator of transcription 3-mediated transcriptional activation." SIGNOR-266772 STAT3 protein P40763 UNIPROT IL1RN protein P18510 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000130;BTO:0000876 20032313 f miannu "The interleukin 1 receptor antagonist (IL-1ra) is an important negative regulator of the inflammatory response, whose genetic deficiency has been recently shown to cause a severe autoinflammatory syndrome in humans. In this study we characterized the molecular mechanisms whereby interleukin 10 (IL-10) potentiates IL-1ra transcription in LPS-stimulated monocytes and neutrophils. our findings uncover a novel mechanism whereby IL-10-activated STAT3 modulates IL-1ra transcription in LPS-treated phagocytes by making IL-1ra promoter accessible to readily available nuclear NF-kappaB." SIGNOR-254795 STAT3 protein P40763 UNIPROT IL10 protein P22301 UNIPROT up-regulates "transcriptional regulation" 9606 28713870 f 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 STAT3 protein P40763 UNIPROT CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16510571 f 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 STAT3 protein P40763 UNIPROT CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001103 18177723 f "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 STAT3 protein P40763 UNIPROT STAT1 protein P42224 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000356 22693070 t miannu "In summary, we report in this study that STAT1 expression is upregulated by nuclear EGFR, EGFRvIII and HER2, and that STAT3 synergizes with the three receptors to further enhance STAT1 expression. These novel findings establish a novel link between the mitogenic ErbB signaling pathway and the inflammatory pathway mediated by STAT1. The oncogenic transcription factor STAT3 binds to the STAT1 promoter and synergizes with nuclear EGFR to significantly enhance STAT1 gene expression." SIGNOR-263650 STAT3 protein P40763 UNIPROT CASP3 protein P42574 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 25787076 f miannu "We determined that Stat3 activation increases caspase-3 expression in C2C12 cells." SIGNOR-255335 STAT3 protein P40763 UNIPROT CEBPD protein P49716 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 24011072 f 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 STAT3 protein P40763 UNIPROT CEBPD protein P49716 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 25787076 f 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 STAT3 protein P40763 UNIPROT RORC protein P51449 UNIPROT up-regulates 9606 18454151 f "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 STAT3 protein P40763 UNIPROT HAMP protein P81172 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001950 18671304 f miannu "HCV-induced ROS stabilized the expression of two negative hepcidin regulators, HIF1alpha and HIF2alpha, and its expression was decreased by a HDAC inhibitor or an anti-oxidant. HCV-induced ROS also caused hypoacetylation of histones and inhibited binding of two positive regulators, C/EBPalpha and STAT3, to the hepcidin promoter, whereas anti-oxidant treatment of cells recovered C/EBPalpha and STAT3 binding to the hepcidin promoter." SIGNOR-255239 STAT3 protein P40763 UNIPROT KRT17 protein Q04695 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000667 21796151 f miannu "IL-17A upregulates keratin 17 expression in keratinocytes through STAT1- and STAT3-dependent mechanisms." SIGNOR-255234 STAT3 protein P40763 UNIPROT FBXO32 protein Q969P5 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 22669242 f 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 STAT3 protein P40763 UNIPROT FOXP3 protein Q9BZS1 UNIPROT down-regulates 9606 18156621 f "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 STAT3 protein P40763 UNIPROT CD274 protein Q9NZQ7 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 27141364 t irozzo "STAT3 and HIF-1α cooperatively enhance PD-L1 expression in EML4-ALK-translocated pADC cells under hypoxia.The protein-DNA binding assay revealed that pSTAT3 was bound to the PD-L1 promoter region in H23 cells transfected with EML4-ALK." SIGNOR-259188 STAT3 protein P40763 UNIPROT SALL4 protein Q9UJQ4 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000815 19151334 f miannu "We further tested the functional relationship between STAT3 and SALL4 using MDA-MB-231, a breast cell line carrying constitutive SALL4 expression and STAT3 activity. Down-regulation of the STAT3 activity using a dominant-negative construct resulted in a significant decrease in the expression of SALL4." SIGNOR-255244 STAT3 protein P40763 UNIPROT STAT1/STAT3 complex SIGNOR-C118 SIGNOR "form complex" binding 10090 BTO:0000667 15284024 t lperfetto "Stimulation of EGFR induces Tyr701 phosphorylation of STAT1 and initiates complex formation of STAT1 and STAT3 with JAK1 and JAK2. Thereafter, the STATs translocate to the nucleus within 15 min." SIGNOR-235664 STAT3 protein P40763 UNIPROT JAK1/STAT1/STAT3 complex SIGNOR-C120 SIGNOR "form complex" binding 10090 BTO:0000667 15284024 t lperfetto "Stimulation of EGFR induces Tyr701 phosphorylation of STAT1 and initiates complex formation of STAT1 and STAT3 with JAK1 and JAK2. Thereafter, the STATs translocate to the nucleus within 15 min." SIGNOR-235658 USP8 protein P40818 UNIPROT EGFR protein P00533 UNIPROT "down-regulates quantity" destabilization 9606 BTO:0000567 16520378 t "Degradation of acutely stimulated receptor tyrosine kinases, epidermal growth factor receptor and Met, is strongly inhibited in UBPY knockdown cells suggesting that UBPY function is essential for growth factor receptor down-regulation." SIGNOR-266902 USP8 protein P40818 UNIPROT EGFR protein P00533 UNIPROT "up-regulates quantity by stabilization" deubiquitination 9606 BTO:0000567 16120644 t irozzo "Here, we describe the role of a deubiquitinating enzyme UBPY/USP8 in the down-regulation of epidermal growth factor (EGF) receptor (EGFR). Overexpression of UBPY reduced the ubiquitination level of EGFR and delayed its degradation in EGF-stimulated cells." SIGNOR-259103 USP8 protein P40818 UNIPROT EGFR protein P00533 UNIPROT "up-regulates quantity by stabilization" deubiquitination 9606 BTO:0000567 20736164 t irozzo "USP8 is known to deubiquitinate EGFR in response to ligand stimulation. USP8 depletion accelerates receptor turnover, whereas loss of hepatocyte growth factor-regulated substrate (Hrs) rescues this phenotype, indicating that USP8 protects EGFR from degradation via an Hrs-dependent pathway. [..]As EGFR stabilization against lysosomal turnover requires deubiquitination by USP8." SIGNOR-259102 USP8 protein P40818 UNIPROT MET protein P08581 UNIPROT "down-regulates quantity" destabilization 9606 BTO:0000567 16520378 t "Degradation of acutely stimulated receptor tyrosine kinases, epidermal growth factor receptor and Met, is strongly inhibited in UBPY knockdown cells suggesting that UBPY function is essential for growth factor receptor down-regulation." SIGNOR-266903 USP8 protein P40818 UNIPROT BACE1 protein P56817 UNIPROT "up-regulates quantity" deubiquitination 9606 BTO:0003704 27302062 t "Here, we report that RNAi-mediated depletion of USP8 reduced levels of both ectopically expressed and endogenous BACE1 in H4 human neuroglioma cells. Moreover, USP8 depletion increased BACE1 ubiquitination, promoted BACE1 accumulation in the early endosomes and late endosomes/lysosomes, and decreased levels of BACE1 in the recycling endosomes." SIGNOR-266905 USP8 protein P40818 UNIPROT BACE1 protein P56817 UNIPROT "up-regulates quantity by stabilization" deubiquitination Lys501 ADDISLLk 9606 BTO:0003704 27302062 t irozzo "Accordingly, we reported that BACE1 is ubiquitinated at lysine 501 and that lack of ubiquitination at lysine 501 produces BACE1 stabilization.Our findings demonstrate that USP8 plays a key role in the trafficking and degradation of BACE1 by deubiquitinating lysine 501." SIGNOR-259101 USP8 protein P40818 UNIPROT STAM protein Q92783 UNIPROT "up-regulates quantity" binding 9606 BTO:0000567 16520378 t "Stability of the UBPY binding partner STAM is dramatically compromised in UBPY knockdown cells." SIGNOR-266904 USP8 protein P40818 UNIPROT RNF41 protein Q9H4P4 UNIPROT "up-regulates quantity by stabilization" deubiquitination 9606 BTO:0002181 23750007 t irozzo "Ubiquitin-specific protease 8 (USP8), an RNF41-interacting deubiquitylating enzyme (DUB) stabilizes RNF41 and is involved in trafficking of various transmembrane proteins." SIGNOR-259105 MDH1 protein P40925 UNIPROT "oxaloacetic acid" smallmolecule CHEBI:30744 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 24068518 t miannu "Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle" SIGNOR-266550 MDH2 protein P40926 UNIPROT "oxaloacetic acid" smallmolecule CHEBI:30744 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 24068518 t miannu "Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle" SIGNOR-266551 IL15 protein P40933 UNIPROT IL15RA protein Q13261 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103 17709786 t "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 RFC5 protein P40937 UNIPROT "RF-C complex" complex SIGNOR-C375 SIGNOR "form complex" binding 12930972 t lperfetto "RF‐C, a complex of five subunits, is conserved in all eukaryotes (reviewed in 5). In yeast, all subunits of RF‐C are essential for viability. The genes encoding all five subunits of mammalian RF‐C (145, 40, 38, 37 and 36 kDa) have been cloned" SIGNOR-265509 RFC3 protein P40938 UNIPROT "RF-C complex" complex SIGNOR-C375 SIGNOR "form complex" binding 12930972 t lperfetto "RF‐C, a complex of five subunits, is conserved in all eukaryotes (reviewed in 5). In yeast, all subunits of RF‐C are essential for viability. The genes encoding all five subunits of mammalian RF‐C (145, 40, 38, 37 and 36 kDa) have been cloned" SIGNOR-265507 ID1 protein P41134 UNIPROT MYOD1 protein P15172 UNIPROT "down-regulates activity" binding 10090 BTO:0000222 8380166 t 2 miannu "Id1 and Id2 interacted strongly with MyoD and Myf-5.Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo." SIGNOR-240265 ID1 protein P41134 UNIPROT TCF4 protein P15884 UNIPROT "down-regulates activity" binding 10090 BTO:0004058 SIGNOR-C129 9242638 t 2 miannu "All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo." SIGNOR-241385 ID1 protein P41134 UNIPROT TCF3 protein P15923 UNIPROT "down-regulates activity" binding 10090 BTO:0004058 SIGNOR-C127 9242638 t 2 miannu "All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo." SIGNOR-241107 ID1 protein P41134 UNIPROT AKT1 protein P31749 UNIPROT up-regulates binding 9606 BTO:0004136 26084673 t apalma "We have determined that Id1 physically interacts with AKT1, through its C-terminal region, and promotes AKT1 phosphorylation;" SIGNOR-255658 ID1 protein P41134 UNIPROT TCF12 protein Q99081 UNIPROT "down-regulates activity" binding 10090 BTO:0004058 SIGNOR-C128 9242638 t 2 miannu "All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo." SIGNOR-241104 ID1 protein P41134 UNIPROT MYOD/E12E47 complex SIGNOR-C127 SIGNOR "down-regulates activity" binding 10090 BTO:0004058 9242638 t 2 miannu "All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo." SIGNOR-241128 ID1 protein P41134 UNIPROT MYOD/HEB complex SIGNOR-C128 SIGNOR "down-regulates activity" binding 10090 BTO:0004058 9242638 t 2 miannu "All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo." SIGNOR-241110 ID1 protein P41134 UNIPROT MYOD/E2-2 complex SIGNOR-C129 SIGNOR "down-regulates activity" binding 10090 BTO:0004058 9242638 t 2 miannu "All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo." SIGNOR-241125 ID1 protein P41134 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates binding 9606 BTO:0004136 26084673 t apalma "We have determined that Id1 physically interacts with AKT1, through its C-terminal region, and promotes AKT1 phosphorylation;" SIGNOR-255942 OPRD1 protein P41143 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256962 OPRD1 protein P41143 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256826 OPRD1 protein P41143 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256683 OPRK1 protein P41145 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256853 CASP3 protein P42574 UNIPROT IKBKB protein O14920 UNIPROT down-regulates cleavage Asp373 PATQCISdGKLNEGH 9606 11741536 t gcesareni "Ikappab kinase (ikk) beta was specifically proteolyzed by caspase-3-related caspases at aspartic acid residues 78, 242, 373, and 546 during tumor necrosis factor (tnf)-alpha-induced apoptosis." SIGNOR-112792 OPRK1 protein P41145 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256989 OPRK1 protein P41145 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257105 OPRK1 protein P41145 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256710 OPRL1 protein P41146 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257209 OPRL1 protein P41146 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256865 OPRL1 protein P41146 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257001 OPRL1 protein P41146 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257117 OPRL1 protein P41146 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256722 LEP protein P41159 UNIPROT LEPR protein P48357 UNIPROT up-regulates binding 9606 9463481 t gcesareni "Both ob-ra and ob-rb bind leptin with the same affinity, whereas only ob-rb can elicit intracellular response" SIGNOR-55656 ETV3 protein P41162 UNIPROT ETV3 protein P41162 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000944 22028471 t miannu "ETV3 target genes including etv3, ddx20, and dusp6 provide negative feedback regulation of ETV3 production and activity. Negative feedback along with constitutive instability may serve to tightly regulate ETV3 abundance. Our date suggest that phosphorylation by ERK2 relieves repression by ETV3, allowing activation of cell cycle control genes including myc, components of the NF-κB pathway, and genes required form RNA processing and translation." SIGNOR-262778 ETV3 protein P41162 UNIPROT DUSP6 protein Q16828 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000944 22028473 t miannu "ETV3 target genes including etv3, ddx20, and dusp6 provide negative feedback regulation of ETV3 production and activity. Negative feedback along with constitutive instability may serve to tightly regulate ETV3 abundance. Our date suggest that phosphorylation by ERK2 relieves repression by ETV3, allowing activation of cell cycle control genes including myc, components of the NF-κB pathway, and genes required form RNA processing and translation." SIGNOR-262780 ETV3 protein P41162 UNIPROT DDX20 protein Q9UHI6 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000944 22028472 t miannu "ETV3 target genes including etv3, ddx20, and dusp6 provide negative feedback regulation of ETV3 production and activity. Negative feedback along with constitutive instability may serve to tightly regulate ETV3 abundance. Our date suggest that phosphorylation by ERK2 relieves repression by ETV3, allowing activation of cell cycle control genes including myc, components of the NF-κB pathway, and genes required form RNA processing and translation." SIGNOR-262779 BCL6 protein P41182 UNIPROT FCER2 protein P06734 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000776 11342629 f "In this study, we report that PRDI-BF1/Blimp1 can bind to the same functional element in the human CD23b promoter to which BCL-6 and IRF-4 had previously been shown to bind, and that, like BCL-6, Blimp1 can repress IRF-4-transactivating ability" SIGNOR-253928 BCL6 protein P41182 UNIPROT CD80 protein P33681 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000776 12860928 f "Upon CD40 signaling, transcription of the CD80 gene is induced by the nuclear factor (NF)-kappaB transcription factor. Our results show that BCL6 prevents CD40-induced expression of CD80 by binding its promoter region in vivo and suppressing its transcriptional activation by NF-kappaB. Consistent with a physiologic role for BCL6 in suppressing CD80, the expression of these two genes is mutually exclusive in B cells, and BCL6-defective mice show increased expression of CD80 in B cells." SIGNOR-253931 BCL6 protein P41182 UNIPROT SUMO1 protein P63165 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000182 22723377 f "QPCR analysis of the resulting gene expression levels identified three genes that were affected in opposite sense by the downregulation of either BCL-6 or STAT5, namely cyclin D2 (CCND2), cyclin-dependent kinase inhibitor p15INK4B (CDKN2B), and SUMO1" SIGNOR-253929 BCL6 protein P41182 UNIPROT LITAF protein Q99732 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001518 23795761 f miannu "BCL6 silencing increased LITAF expression, and chromatin immunoprecipitation and luciferase reporter assays demonstrated a direct transcriptional repression of LITAF by BCL6." SIGNOR-253758 ETV6 protein P41212 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0002883 16828711 f miannu "Forced expression of TEL stimulated transcription via the p53-responsive element and increased the expression of cellular target genes for p53 such as cell cycle regulator p21 and apoptosis inducer Puma." SIGNOR-254138 ETV6 protein P41212 UNIPROT HBB protein P68871 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15958056 f "Regulation of expression" miannu "Upon erythropoietin exposure, overexpressed TEL stimulated hemoglobin synthesis" SIGNOR-251793 ETV6 protein P41212 UNIPROT HBA1 protein P69905 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15958056 f "Regulation of expression" miannu "Upon erythropoietin exposure, overexpressed TEL stimulated hemoglobin synthesis" SIGNOR-251794 ETV6 protein P41212 UNIPROT BBC3 protein Q96PG8 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0002883 16828711 f miannu "Forced expression of TEL stimulated transcription via the p53-responsive element and increased the expression of cellular target genes for p53 such as cell cycle regulator p21 and apoptosis inducer Puma." SIGNOR-254137 WNT5A protein P41221 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates 9606 SIGNOR-C110 21078818 f gcesareni "We demonstrate here that prototype canonical wnt3a and noncanonical wnt5a ligands specifically trigger completely unrelated endogenous coreceptors-lrp5/6 and ror1/2, respectively-through a common mechanism that involves their wnt-dependent coupling to the frizzled (fzd) coreceptor and recruitment of shared components, including dishevelled (dvl), axin, and glycogen synthase kinase 3 (gsk3)." SIGNOR-169663 WNT5A protein P41221 UNIPROT FZD6 protein O60353 UNIPROT "up-regulates activity" binding 9606 BTO:0000551;BTO:0000848 16273260 t gcesareni "Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors." SIGNOR-141437 WNT5A protein P41221 UNIPROT LRP6 protein O75581 UNIPROT "up-regulates activity" binding 9606 15578921 t 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-131841 WNT5A protein P41221 UNIPROT MYF5 protein P13349 UNIPROT "up-regulates activity" 10090 BTO:0000887;BTO:0001103 9753670 f gcesareni "Wnt4, wnt5a and wnt6 exert an intermediate effect activating both myf5 and myod equivalently in paraxial mesoderm." SIGNOR-60376 WNT5A protein P41221 UNIPROT RYK protein P34925 UNIPROT up-regulates binding 9606 22773843 t areggio "Purified human RYK binds to mouse Wnt1, 3a and 5a expressed in HEK293 cells. Separate experiments show that human RYK also immunopreciptitates human VANGL2 when the proteins are co-expressed in HEK293 cells." SIGNOR-258970 WNT5A protein P41221 UNIPROT GSK3B protein P49841 UNIPROT up-regulates 9606 21078818 f gcesareni "We demonstrate here that prototype canonical wnt3a and noncanonical wnt5a ligands specifically trigger completely unrelated endogenous coreceptors-lrp5/6 and ror1/2, respectively-through a common mechanism that involves their wnt-dependent coupling to the frizzled (fzd) coreceptor and recruitment of shared components, including dishevelled (dvl), axin, and glycogen synthase kinase 3 (gsk3)" SIGNOR-169669 WNT5A protein P41221 UNIPROT ROR1 protein Q01973 UNIPROT up-regulates binding 9606 BTO:0001546 26690702 t gcesareni "Wnt5a induces ROR1/ROR2 heterooligomerization to enhance leukemia chemotaxis and proliferation|Evolutionarily conserved receptor tyrosine kinase–like orphan receptor-1 and -2 (ROR1/2) are considered distinct receptors for Wnt5a and are implicated in noncanonical Wnt signaling in organogenesis and cancer metastasis." SIGNOR-173331 WNT5A protein P41221 UNIPROT ROR2 protein Q01974 UNIPROT up-regulates binding 9606 BTO:0001546 26690702 t gcesareni "Wnt5a induces ROR1/ROR2 heterooligomerization to enhance leukemia chemotaxis and proliferation|Evolutionarily conserved receptor tyrosine kinase–like orphan receptor-1 and -2 (ROR1/2) are considered distinct receptors for Wnt5a and are implicated in noncanonical Wnt signaling in organogenesis and cancer metastasis." SIGNOR-199647 WNT5A protein P41221 UNIPROT FZD5 protein Q13467 UNIPROT up-regulates binding 9606 9054360 t gcesareni "These results identify hfz5 as a receptor for wnt-5a." SIGNOR-46897 WNT5A protein P41221 UNIPROT FZD2 protein Q14332 UNIPROT down-regulates binding 9606 19910923 t gcesareni "Fz2 was also required for the wnt3a-dependent accumulation of beta-catenin, and wnt5a competed with wnt3a for binding to fz2 in vitro and in intact cells, thereby inhibiting the beta-catenin pathway.Wnt5a Internalized fz2 probably with ror1 or ror2 through the clathrin-mediated route, whereas wnt5a competed with wnt3a for binding to fz2 to inhibit the beta-catenin pathway." SIGNOR-189120 WNT5A protein P41221 UNIPROT FZD2 protein Q14332 UNIPROT down-regulates binding 9606 2808370 t gcesareni "Fz2 was also required for the wnt3a-dependent accumulation of beta-catenin, and wnt5a competed with wnt3a for binding to fz2 in vitro and in intact cells, thereby inhibiting the beta-catenin pathway." SIGNOR-23441 WNT5A protein P41221 UNIPROT FZD2 protein Q14332 UNIPROT "up-regulates activity" binding 9606 19008118 t FFerrentino "Perhaps through Wnt5a acting via FZD2, might also inhibit adipocyte differentiation." SIGNOR-253520 WNT5A protein P41221 UNIPROT FZD3 protein Q9NPG1 UNIPROT "up-regulates activity" binding 9606 15578921 t 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-131838 WNT5A protein P41221 UNIPROT FZD3 protein Q9NPG1 UNIPROT "up-regulates activity" binding 9606 BTO:0000551;BTO:0000848 16273260 t gcesareni "Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors." SIGNOR-141434 WNT5A protein P41221 UNIPROT FZD3 protein Q9NPG1 UNIPROT "up-regulates activity" binding 9606 BTO:0000393 21903638 t gcesareni "It has been shown that wnt5a activates the calcium signaling pathway in the presence of receptor fz2, 3, 4, 6 and receptor fz 5." SIGNOR-176579 WNT5A protein P41221 UNIPROT Frizzled proteinfamily SIGNOR-PF11 SIGNOR "up-regulates activity" binding 18697834 t "Simone Vumbaca" "Wnt1, Wnt3a and Wnt5a all induced a statistically greater degree of proliferation than control cells" SIGNOR-255651 SOX3 protein P41225 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 10549281 t gcesareni "Two additional sox proteins, xsox17alfa and xsox3, likewise bind to beta-catenin and inhibit its tcf-mediated signaling activity." SIGNOR-72039 KDM5C protein P41229 UNIPROT SYN1 protein P17600 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 31691806 f miannu "The KDM5C decrease was associated with a lack of repression of downstream target genes Scn2a, Syn1 and Bdnf in the embryonic brain of Arx-null mice." SIGNOR-264314 KDM5C protein P41229 UNIPROT BDNF protein P23560 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 31691806 f miannu "The KDM5C decrease was associated with a lack of repression of downstream target genes Scn2a, Syn1 and Bdnf in the embryonic brain of Arx-null mice." SIGNOR-264315 KDM5C protein P41229 UNIPROT PTEN protein P60484 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 30921702 f miannu "KDM5C performs its oncogenic function by suppressing PTEN epigenetically." SIGNOR-264312 KDM5C protein P41229 UNIPROT H3C1 protein P68431 UNIPROT "up-regulates activity" demethylation Lys5 kQTARKST 9606 30246379 t miannu "KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing." SIGNOR-264305 KDM5C protein P41229 UNIPROT H3-4 protein Q16695 UNIPROT "up-regulates activity" demethylation Lys5 kQTARKST 9606 30246379 t miannu "KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing." SIGNOR-264306 KDM5C protein P41229 UNIPROT SCN2A protein Q99250 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 31691806 f miannu "The KDM5C decrease was associated with a lack of repression of downstream target genes Scn2a, Syn1 and Bdnf in the embryonic brain of Arx-null mice." SIGNOR-264313 P2RY2 protein P41231 UNIPROT GNA15 protein P30679 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257031 P2RY2 protein P41231 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256902 P2RY2 protein P41231 UNIPROT H3-3A protein P84243 UNIPROT "up-regulates activity" demethylation Lys5 kQTARKST 9606 30246379 t miannu "KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing." SIGNOR-264307 P2RY2 protein P41231 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257145 MAP3K8 protein P41279 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates phosphorylation Ser222 LIDSMANsFVGTRSY 9606 8131746 t gcesareni "Activation of mek family kinases requires phosphorylation of two conserved ser/thr residues.Phosphopeptide analysis demonstrated that serine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf" SIGNOR-36449 P2RY2 protein P41231 UNIPROT GNA13 protein Q14344 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257233 P2RY2 protein P41231 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256759 HNF4A protein P41235 UNIPROT F12 protein P00748 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000599 9794469 f miannu "Orphan receptor hepatocyte nuclear factor-4 antagonizes estrogen receptor alpha-mediated induction of human coagulation factor XII gene. In conclusion, our findings address a direct role for HNF-4 in modulating estrogen-dependent transcription of the FXII gene promoter." SIGNOR-254073 HNF4A protein P41235 UNIPROT LDLR protein P01130 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000398 21123766 f miannu "Recent studies have demonstrated that PCSK9 mRNA expression was upregulated to a greater extent than that of the LDL receptor in human hepatocytes in primary culture. Our findings also support the role of SREBP-2 as a transcriptional regulator of both the LDL receptor and PCSK9 in human enterocytes." SIGNOR-254454 HNF4A protein P41235 UNIPROT AFP protein P02771 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000972 9792724 f miannu "AFP promoter-chloramphenicol acetyltransferase transient transfection assays demonstrated that the level of HNF1 had a direct impact on basal transcription as well as RA-mediated down-regulation of the AFP gene, and that co-transfection of HNF1 and HNF4, but not transfection of either factor alone, reversed the RA-mediated inhibition. Taken together these data point to an interaction among the RA, HNF1, and HNF4 signals, which is reflected in decreased expression of AFP." SIGNOR-254446 HNF4A protein P41235 UNIPROT AKR1C4 protein P17516 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003846 2044952 f 2 miannu "Hepatocyte nuclear factor (HNF)-4_/_, HNF-1_, and vHNF-1 regulate the cell-specific expression of the human dihydrodiol dehydrogenase (DD)4/AKR1C4 gene. HNF-4_ is a necessary factor for the activation of the human DD4 gene. is much higher than that of vHNF-1-C." SIGNOR-240016 HNF4A protein P41235 UNIPROT GK protein P32189 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18805788 f gcesareni "In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription" SIGNOR-181274 HNF4A protein P41235 UNIPROT PCK1 protein P35558 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16308421 f gcesareni "Pgc1alfa is thought to mediate transcription downstream of the nuclear receptor hepatocyte nuclear factor 4alfa (hnf4alfa) and the transcription factor foxo1 in the promoters of key gluconeogenic enzymes, including glucose-6-phosphatase (g6pase) and phosphoenolpyruvate carboxylase (pepck)" SIGNOR-142204 HNF4A protein P41235 UNIPROT PCK1 protein P35558 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20577053 f gcesareni "Pgc1alfa is thought to mediate transcription downstream of the nuclear receptor hepatocyte nuclear factor 4alfa (hnf4alfa) and the transcription factor foxo1 in the promoters of key gluconeogenic enzymes, including glucose-6-phosphatase (g6pase) and phosphoenolpyruvate carboxylase (pepck)" SIGNOR-166358 HNF4A protein P41235 UNIPROT G6PC1 protein P35575 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16308421 f gcesareni "In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription." SIGNOR-142153 HNF4A protein P41235 UNIPROT G6PC1 protein P35575 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18805788 f gcesareni "In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription." SIGNOR-181271 HNF4A protein P41235 UNIPROT G6PC1 protein P35575 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20577053 f gcesareni "In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription." SIGNOR-166355 HNF4A protein P41235 UNIPROT GFER protein P55789 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000599 18513187 f miannu "We also confirmed that activation and repression of hHSS transcription induced by Sp1 and HNF4alpha resulted from binding of these factors to these two cis-elements respectively. Overexpression of HNF4alpha led to a dramatic repression of the promoter activity and, in contrast, the activity was markedly elevated by overexpression of Sp1." SIGNOR-254449 HNF4A protein P41235 UNIPROT CYP27A1 protein Q02318 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 11867220 f miannu "Therefore, Sp1, Sp3 and HNF4 co-operate in the expression of the human CYP27 gene in HepG2 cells." SIGNOR-255198 HNF4A protein P41235 UNIPROT PCSK9 protein Q8NBP7 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000398 21123766 f miannu "Recent studies have demonstrated that PCSK9 mRNA expression was upregulated to a greater extent than that of the LDL receptor in human hepatocytes in primary culture. Our findings also support the role of SREBP-2 as a transcriptional regulator of both the LDL receptor and PCSK9 in human enterocytes." SIGNOR-254451 HNF4A protein P41235 UNIPROT C1QTNF5 protein Q9BXJ0 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000224 20621834 f miannu "Here we demonstrate the mechanism by which the CTRP5 gene is transcriptionally activated in the liver. CTRP5 is activated by HNF4alpha via the region -206/-167 of the human CTRP5 promoter." SIGNOR-254448 HNF4A protein P41235 UNIPROT ABCG8 protein Q9H221 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000398 21123766 f miannu "these results indicate that HMG-CoAR inhibition with atorvastatin stimulates intestinal expression of NPC1L1 and PCSK9, increases cholesterol absorption, and reduces ABCG5/8 expression; these effects are mediated most likely by stimulation of the transcription factors SREBP-2 and HNF-4α." SIGNOR-254458 HNF4A protein P41235 UNIPROT ABCG5 protein Q9H222 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000398 21123766 f miannu "these results indicate that HMG-CoAR inhibition with atorvastatin stimulates intestinal expression of NPC1L1 and PCSK9, increases cholesterol absorption, and reduces ABCG5/8 expression; these effects are mediated most likely by stimulation of the transcription factors SREBP-2 and HNF-4α." SIGNOR-254457 HNF4A protein P41235 UNIPROT NPC1L1 protein Q9UHC9 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000398 21123766 f miannu "Our results showed a positive correlation between changes in NPC1L1 and changes in both SREBP-2 and HNF-4α mRNA expression, a finding that supports the notion that these transcription factors stimulate intestinal NPC1L1 expression." SIGNOR-254460 PPP1R2 protein P41236 UNIPROT PPP1CA protein P62136 UNIPROT down-regulates binding 9606 18250156 t gcesareni "Atm phosphorylates i-2 on serine 43, leading to the dissociation of the pp1-i-2 complex and the activation of pp1." SIGNOR-160651 CSK protein P41240 UNIPROT LCK protein P06239 UNIPROT down-regulates phosphorylation Tyr505 FTATEGQyQPQP 9606 BTO:0000782 1639064 t gcesareni "P50csk tyrosine kinase phosphorylates p56lck at tyr-505 and down regulates its catalytic activity." SIGNOR-20371 CSK protein P41240 UNIPROT LYN protein P07948 UNIPROT down-regulates phosphorylation Tyr508 YTATEGQyQQQP 9606 BTO:0000776 15626731 t gcesareni "Lyn tyr507 kinase, csk, is recruited by pag, which targets lipid rafts by palmitoylation.Thus, our data suggest that il-6 treatment induces the translocation of cd45 to lipid rafts sequentially, followed by the association of cd45 with lyn and pag;dephosphorylation of lyn tyr507 and pag tyr314;lyn activation;and csk release from lipid rafts" SIGNOR-132912 CSK protein P41240 UNIPROT PTPRC protein P08575 UNIPROT up-regulates phosphorylation Tyr1218 MVSTFEQyQFLYDVI 9606 BTO:0000782 7507203 t llicata "Tyrosine phosphorylation of cd45 phosphotyrosine phosphatase by p50csk kinase creates a binding site for p56lck tyrosine kinase and activates the phosphatase." SIGNOR-26785 CSK protein P41240 UNIPROT FGR protein P09769 UNIPROT "down-regulates activity" phosphorylation Tyr523 FTSAEPQyQPGDQT -1 7515063 t llicata "CSK catalyzed phosphorylation affects Tyr-511 of c-Fgr, homologous to Tyr-527 of c-Src and it prevents the autophosphorylation normally occurring at c-Fgr Tyr-400, homologous to c-Src Tyr-416. | Once phosphorylated at Tyr-511 and down-regulated by CSK, c-Fgr is no more susceptible to polylysine stimulation." SIGNOR-250779 CSK protein P41240 UNIPROT SRC protein P12931 UNIPROT down-regulates phosphorylation Tyr530 FTSTEPQyQPGENL 9606 18614016 t gcesareni "The catalytic activity of the src family of tyrosine kinases is suppressed by phosphorylation on a tyrosine residue located near the c terminus (tyr 527 in c-src), which is catalyzed by c-terminal src kinase (csk)." SIGNOR-179417 CSK protein P41240 UNIPROT PECAM1 protein P16284 UNIPROT "up-regulates activity" phosphorylation Tyr713 KKDTETVySEVRKAV 9534 BTO:0001538 9624175 t miannu "We demonstrated that phosphorylation of PECAM-1 by Src or Csk family kinases was sufficient to trigger its association with SHP-2. Moreover, it was able to promote binding of PECAM-1 to SHP-1, a SHP-2-related protein-tyrosine phosphatase expressed in hemopoietic cells. Taken together, these findings indicated that the Src and Csk families of kinases are strong candidates for mediating tyrosine phosphorylation of PECAM-1 and triggering its association with SH2 domain-containing phosphatases under physiological circumstances." SIGNOR-262741 CSK protein P41240 UNIPROT CSK protein P41240 UNIPROT "up-regulates activity" phosphorylation Tyr304 DVCEAMEyLEGNNFV -1 9148770 t llicata "Taken together these results indicate that Csk can be phosphorylated in vivo at Tyr-184 by an as yet unknown tyrosine kinase, and that autophosphorylation of Tyr-304 occurs only at abnormally high Csk concentrations in vitro. Furthermore, Tyr-304 is required for the maintenance of the structure of the Csk kinase domain." SIGNOR-250778 CSK protein P41240 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 22479394 t "Leads to Furin-cleavage activity" gcesareni "We found that the notch-1-furin interaction is regulated by the non-receptor tyrosine kinase, c-src. c-src and notch-1 are physically associated, and this association is responsible for notch-1 processing and activation" SIGNOR-196824 CSK protein P41240 UNIPROT ITCH protein Q96J02 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000007 16888620 t gcesareni "CISK strongly interacts and colocalizes with the E3 ubiquitin ligase AIP4, which is important for the ubiquitin-dependent lysosomal degradation of CXCR4. Moreover, the observed inhibition is both dependent on the interaction between CISK and AIP4 and on the activation status of CISK. Consistent with this, an activated form of CISK but not of the related kinase SGK1 phosphorylates specific sites of AIP4 in vitro." SIGNOR-245327 MAP3K8 protein P41279 UNIPROT MAP2K2 protein P36507 UNIPROT up-regulates phosphorylation Ser222 VSGQLIDsMANSFVG 9606 BTO:0000007 15466476 t lperfetto "Cot proteins were used in an in vitro kinase assay using mek as a substrate. Samples were analyzed by western blotting. As seen in the cascade activity assay only wild-type cot was active against mekregulation of cot is of great interest to the signaling field since the cot/mek/erk pathway potentially plays a role in the etiology of inflammatory autoimmune diseases." SIGNOR-129694 MAP3K8 protein P41279 UNIPROT MAP2K2 protein P36507 UNIPROT up-regulates phosphorylation Ser226 LIDSMANsFVGTRSY 9606 BTO:0000007 15466476 t lperfetto "Cot proteins were used in an in vitro kinase assay using mek as a substrate. Samples were analyzed by western blotting. As seen in the cascade activity assay only wild-type cot was active against mekregulation of cot is of great interest to the signaling field since the cot/mek/erk pathway potentially plays a role in the etiology of inflammatory autoimmune diseases." SIGNOR-129698 MAP3K8 protein P41279 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates phosphorylation 9606 22435554 t gcesareni "Furthermore, we found that immunoprecipitated tpl-2 could directly phosphorylate and activate both mek-1 and mkk4 (also known as sek-1)" SIGNOR-196744 MAP3K8 protein P41279 UNIPROT PLK1 protein P53350 UNIPROT up-regulates phosphorylation Thr210 YDGERKKtLCGTPNY 9606 BTO:0000567 12207013 t miannu "Xplkk1 phosphorylates and activates mammalian plk / xplkk1 phosphorylates thr-210" SIGNOR-92274 MAP3K8 protein P41279 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates phosphorylation Ser218 VSGQLIDsMANSFVG 9606 BTO:0000007 15466476 t lperfetto "Cot proteins were used in an in vitro kinase assay using mek as a substrate. Samples were analyzed by western blotting. As seen in the cascade activity assay only wild-type cot was active against mekregulation of cot is of great interest to the signaling field since the cot/mek/erk pathway potentially plays a role in the etiology of inflammatory autoimmune diseases." SIGNOR-129690 MAP3K8 protein P41279 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates phosphorylation Ser244 GTHYSVQsDIWSMGL 9606 8131746 t gcesareni "Activation of mek family kinases requires phosphorylation of two conserved ser/thr residues.Phosphopeptide analysis demonstrated that serine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf" SIGNOR-36453 MAP3K8 protein P41279 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates phosphorylation Ser248 SVQSDIWsMGLSLVE 9606 8131746 t gcesareni "Activation of mek family kinases requires phosphorylation of two conserved ser/thr residues.Phosphopeptide analysis demonstrated that serine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf" SIGNOR-36457 MAP3K8 protein P41279 UNIPROT MAP3K14 protein Q99558 UNIPROT "up-regulates activity" phosphorylation Thr559 TGDYIPGtETHMAPE 9606 9742107 t lperfetto "In studies of NIK, we found that Thr-559 located within the activation loop of its kinase domain regulates NIK action. Alanine substitution of Thr-559 but not other serine or threonine residues within the activation loop abolishes its activity and its ability to phosphorylate and activate IKKalpha" SIGNOR-249387 MAP3K8 protein P41279 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "up-regulates activity" 10090 "BTO:0000776; BTO:0000801" 16484370 f "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 MAP3K8 protein P41279 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 BTO:0000007 15466476 t lperfetto "Cot proteins were used in an in vitro kinase assay using mek as a substrate. Samples were analyzed by western blotting. As seen in the cascade activity assay only wild-type cot was active against mekregulation of cot is of great interest to the signaling field since the cot/mek/erk pathway potentially plays a role in the etiology of inflammatory autoimmune diseases." SIGNOR-244904 MAP3K8 protein P41279 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 8131746 t lperfetto "Activation of mek family kinases requires phosphorylation of two conserved ser/thr residues.Phosphopeptide analysis demonstrated that serine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf" SIGNOR-244892 GRM5 protein P41594 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000938 29953871 t miannu "Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening." SIGNOR-264936 HTR2B protein P41595 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257228 HTR2B protein P41595 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256886 HTR2B protein P41595 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257022 HTR2B protein P41595 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257138 HTR2B protein P41595 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256743 CCR2 protein P41597 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "up-regulates activity" phosphorylation 10090 20219869 t 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 TSPAN7 protein P41732 UNIPROT DRD2 protein P14416 UNIPROT "down-regulates quantity" binding 9606 BTO:0000007 28223337 t miannu "Tetraspanin-7 (TSPAN7) is expressed to variable degrees in different tissues, with the highest level in the brain, and multiple mutations in TSPAN7 have been implicated in intellectual disability. Our results showed that TSPAN7 was associated with DRD2 and reduced its surface expression by enhancing DRD2 internalization.Finally, TSPAN7 negatively affects DRD2-mediated signaling." SIGNOR-265557 PRKCI protein P41743 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Thr567 QGRDKYKtLRQIRQG 9606 BTO:0000195 18270268 t llicata "Pkciota phosphorylated ezrin on t567 in vitro, and in sf9 cells that do not activate human ezrin. we conclude that, although other molecular mechanisms contribute to ezrin activation, apically localized phosphorylation by pkciota is essential for the activation and normal distribution of ezrin at the early stages of intestinal epithelial cell differentiation." SIGNOR-160855 PRKCI protein P41743 UNIPROT LLGL1 protein Q15334 UNIPROT "up-regulates activity" phosphorylation Ser659 RVKSLKKsLRQSFRR 9615 BTO:0000837 12725730 t miannu "This finding indicates that both mLgl-2 and mLgl-1 are phosphorylated in vivo in an aPKC lambda activity-dependent manner." SIGNOR-263179 PRKCI protein P41743 UNIPROT LLGL2 protein Q6P1M3 UNIPROT "up-regulates activity" phosphorylation Ser653 LKKSLRQsFRRMRRS 9615 BTO:0000837 12725730 t miannu "This finding indicates that both mLgl-2 and mLgl-1 are phosphorylated in vivo in an aPKC lambda activity-dependent manner." SIGNOR-263180 PRKCI protein P41743 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 BTO:0000527 21419810 t lperfetto "In-vitro kinase activity assay showed that pkc-_ directly phosphorylated bad at phospho specific residues, ser-112, ser-136 and ser-155 which in turn induced inactivation of bad and disruption of bad/bcl-xl dimer" SIGNOR-172886 PRKCI protein P41743 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000527 21419810 t lperfetto "In-vitro kinase activity assay showed that pkc-_ directly phosphorylated bad at phospho specific residues, ser-112, ser-136 and ser-155 which in turn induced inactivation of bad and disruption of bad/bcl-xl dimer" SIGNOR-172890 PRKCI protein P41743 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000527 21419810 t lperfetto "In-vitro kinase activity assay showed that pkc-_ directly phosphorylated bad at phospho specific residues, ser-112, ser-136 and ser-155 which in turn induced inactivation of bad and disruption of bad/bcl-xl dimer" SIGNOR-172894 PRKCI protein P41743 UNIPROT ECT2 protein Q9H8V3 UNIPROT up-regulates phosphorylation Thr359 YLYEKANtPELKKSV 9606 BTO:0000551 21189248 t gcesareni "Our data support a model in which pkc?-Mediated phosphorylation regulates ect2 binding to the oncogenic pkc?-Par6 complex thereby activating rac1 activity and driving transformed growth and invasion." SIGNOR-170790 MC3R protein P41968 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257298 MC3R protein P41968 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256891 MC3R protein P41968 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257026 MC3R protein P41968 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257142 MC3R protein P41968 UNIPROT GNA15 protein P30679 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257358 STAT5A protein P42229 UNIPROT PIM2 protein Q9P1W9 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 15769897 t "The serine-threonine kinase Pim-2 is a functionally relevant downstream target of STAT5. Here, we observed only a weak induction of Pim-2 by Flt3-D835Y compared to the effects of Flt3-ITD." SIGNOR-261543 MC3R protein P41968 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256748 MC3R protein P41968 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257230 MC3R protein P41968 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257407 ELK3 protein P41970 UNIPROT MYH6 protein P13533 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000567 12933792 f miannu "From HeLa cells an Ets family of protein, Ets-related protein (ERP), binds to double-stranded PNR element. The ERP.PNR complex inhibited the activity of the basal transcription complex from homologous as well as heterologous promoters in a PNR position-independent manner, suggesting that ERP acts as a silencer of alpha-MHC gene expression in non-muscle cells." SIGNOR-253900 ASIP protein P42127 UNIPROT ATRN protein O75882 UNIPROT up-regulates binding 9606 BTO:0001253 11137996 t gcesareni "Attractin is a low-affinity receptor for agouti protein, but not agrp, in vitro and in vivo." SIGNOR-85496 ASIP protein P42127 UNIPROT MC1R protein Q01726 UNIPROT "down-regulates activity" binding 9606 BTO:0000847 14500544 t miannu "The antagonist agouti signal protein (ASP) interacts with the Mc1r and blocks its stimulation by MSH." SIGNOR-252378 STAT1 protein P42224 UNIPROT TLR3 protein O15455 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000667 16628196 f miannu "The activation of STAT1 by IFNs not only induces chemokine production, but also results in the expression of IRF-7 and TLR3, thus amplifying the dsRNA-provoked reaction in a positive-feedback manner during viral infection." SIGNOR-255230 STAT1 protein P42224 UNIPROT IRF2 protein P14316 UNIPROT "up-regulates activity" binding 9606 15778351 t miannu "We show that IRF-2 forms a complex with STAT1 and the cytokine-responsive region of the TAP1 promoter in any TPO or IFN-gamma target cells tested. Interaction of IRF-2 and STAT1 on the promoter depends on the DNA-binding domain of IRF-2." SIGNOR-254532 STAT1 protein P42224 UNIPROT IL12A protein P29459 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000801 19029990 f 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-249499 STAT1 protein P42224 UNIPROT IL12B protein P29460 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000801 19029990 f 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-249500 STAT1 protein P42224 UNIPROT CIITA protein P33076 UNIPROT up-regulates "transcriptional regulation" 9606 BTO:0001103 21576360 t "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 STAT1 protein P42224 UNIPROT CIITA protein P33076 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 BTO:0001103 9551976 f "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 STAT1 protein P42224 UNIPROT CIITA protein P33076 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000801 19029990 f 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 STAT1 protein P42224 UNIPROT MMP13 protein P45452 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000249 17179173 f 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 STAT1 protein P42224 UNIPROT S100A10 protein P60903 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567;BTO:0002923 12645529 f miannu "IFN-gamma induced a rapid tyrosine phosphorylation and nuclear translocation of STAT1 protein, which is involved in the binding to the GAS-2 site in the p11 promoter by EMSA analysis. These data suggest that IFN-gamma-induced p11 expression is mediated through the binding of STAT1 to GAS sites in the p11 promoter." SIGNOR-255237 CASP3 protein P42574 UNIPROT IKBKB protein O14920 UNIPROT down-regulates cleavage Asp546 ALQTDIVdLQRSPMG 9606 11741536 t gcesareni "Ikappab kinase (ikk) beta was specifically proteolyzed by caspase-3-related caspases at aspartic acid residues 78, 242, 373, and 546 during tumor necrosis factor (tnf)-alpha-induced apoptosis." SIGNOR-112796 STAT1 protein P42224 UNIPROT TAP1 protein Q03518 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15778351 f miannu "We also show that this cytokine-dependent expression of TAP1 transcripts depends on STAT1 and IFN regulatory factor-2 (IRF-2), but not on IRF-1, and provide evidence that IRF-2 constitutively binds to the TAP1 gene promoter and enhances TAP1 promoter activity. We show that IRF-2 forms a complex with STAT1 and the cytokine-responsive region of the TAP1 promoter in any TPO or IFN-gamma target cells tested." SIGNOR-254531 STAT1 protein P42224 UNIPROT KRT17 protein Q04695 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000667 21796151 f miannu "IL-17A upregulates keratin 17 expression in keratinocytes through STAT1- and STAT3-dependent mechanisms." SIGNOR-255233 STAT1 protein P42224 UNIPROT IRF7 protein Q92985 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000667 16628196 f miannu "The activation of STAT1 by IFNs not only induces chemokine production, but also results in the expression of IRF-7 and TLR3, thus amplifying the dsRNA-provoked reaction in a positive-feedback manner during viral infection." SIGNOR-255231 STAT1 protein P42224 UNIPROT MUC4 protein Q99102 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001861 19757157 t lperfetto "Through promoter screening, overexpressing methods and luciferase reporter studies, we found that transcription factors CREB, Ets-1, Elk-1 and STAT1 can positively regulate MUC4 expression at the promoter and mRNA level." SIGNOR-254099 STAT1 protein P42224 UNIPROT TBX21 protein Q9UL17 UNIPROT up-regulates 9606 16386358 f "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 STAT1 protein P42224 UNIPROT STAT1/STAT3 complex SIGNOR-C118 SIGNOR "form complex" binding 10090 BTO:0000667 15284024 t lperfetto "Stimulation of EGFR induces Tyr701 phosphorylation of STAT1 and initiates complex formation of STAT1 and STAT3 with JAK1 and JAK2. Thereafter, the STATs translocate to the nucleus within 15 min." SIGNOR-235661 STAT1 protein P42224 UNIPROT JAK1/STAT1/STAT3 complex SIGNOR-C120 SIGNOR "form complex" binding 10090 BTO:0000667 15284024 t lperfetto "Stimulation of EGFR induces Tyr701 phosphorylation of STAT1 and initiates complex formation of STAT1 and STAT3 with JAK1 and JAK2. Thereafter, the STATs translocate to the nucleus within 15 min." SIGNOR-235612 STAT1 protein P42224 UNIPROT "ISGF3 complex" complex SIGNOR-C124 SIGNOR "form complex" binding -1 8943351 t 2 miannu "The first STAT-containing transcription factor to be studied, the alpha-interferon-induced ISGF3, is composed of a Stat1:2 heterodimer and a weak DNA-binding protein, p48. The p48 and Stat1:2 heterodimer do not associate stably in the absence of DNA, but we show that amino acids approximately 150 to 250 of Stat1 and a COOH-terminal portion of p48 exhibit physical interaction, implying contact that stabilizes ISGF3" SIGNOR-240606 STAT1 protein P42224 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates binding 9606 16481475 t lperfetto "Acetylated stat1 is able to interact with nf-kappab p65. As a consequence, p65 dna binding, nuclear localization, and expression of anti-apoptotic nf-kappab target genes decrease." SIGNOR-217418 STAT6 protein P42226 UNIPROT KDM6B protein O15054 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000801 19567879 f 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 STAT6 protein P42226 UNIPROT SOCS1 protein O15524 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000801 17093501 t 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 STAT6 protein P42226 UNIPROT KLF4 protein O43474 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000801 22378047 t lperfetto "STAT6 coordinates and synergizes with both PPAR? and KrŸppel-like factor 4 (KLF4), a member of a family of proteins that contribute to macrophage function." SIGNOR-249568 STAT6 protein P42226 UNIPROT KLF4 protein O43474 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25934862 f miannu "IL-4-induced macrophage polarization involves induction of STAT6 and KLF4 that induce each other and promote M2 polarization." SIGNOR-254519 STAT6 protein P42226 UNIPROT SLC26A4 protein O43511 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24429829 f miannu "We then examined the ability of STAT6 to bind each of the N4 GAS motifs in vivo with a site-specific ChIP assay, the results of which showed that STAT6 interacted with only the N4 GAS motif that was functionally implicated in increasing the activity of the pendrin promoter following IL-4 treatment." SIGNOR-255250 STAT6 protein P42226 UNIPROT ARG1 protein P05089 UNIPROT up-regulates BTO:0000801 BTO:0001103 25386178 f 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 STAT6 protein P42226 UNIPROT ALOX15 protein P16050 UNIPROT up-regulates 9606 BTO:0000018 12517954 f lperfetto "IL-4 has been shown to up-regulate 15-lipoxygenase and produce 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) in A549 cells via the Janus kinase/STAT6 pathway under coactivation of CREB binding protein/p300." SIGNOR-254101 STAT6 protein P42226 UNIPROT GATA3 protein P23771 UNIPROT up-regulates 9606 12947222 t "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 STAT6 protein P42226 UNIPROT HSD3B2 protein P26439 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15632317 f miannu "IL-4 induces HSD3B1 gene expression, along with IL-13, through STAT 6 activation." SIGNOR-255249 STAT6 protein P42226 UNIPROT CHI3L1 protein P36222 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000801 20508200 f 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-249537 STAT6 protein P42226 UNIPROT PPARG protein P37231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000801 20508200 f 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 PIK3CA protein P42336 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" 9606 BTO:0000150 19573809 f 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-252634 STAT6 protein P42226 UNIPROT STAT1 protein P42224 UNIPROT "down-regulates activity" binding 9606 BTO:0000801 10982806 t 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 STAT6 protein P42226 UNIPROT PPARA protein Q07869 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000801 20508200 f 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-249534 STAT6 protein P42226 UNIPROT RETN protein Q9HD89 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000801 20508200 f 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-249536 STAT6 protein P42226 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000801 20508200 f 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-249538 STAT6 protein P42226 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "down-regulates activity" binding 9606 BTO:0000801 10982806 t 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 STAT5A protein P42229 UNIPROT SOCS2 protein O14508 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 12468433 t "We have also found SOCS2 and SOCS3 specifically induced in 32D/Flt3-ITD, both of which are STAT3/5 target genes and known negative regulators of receptor signaling" SIGNOR-261547 STAT5A protein P42229 UNIPROT SOCS3 protein O14543 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 12468433 t "We have also found SOCS2 and SOCS3 specifically induced in 32D/Flt3-ITD, both of which are STAT3/5 target genes and known negative regulators of receptor signaling" SIGNOR-261548 STAT5A protein P42229 UNIPROT IGF1 protein P05019 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000972 10050749 t lperfetto "Growth hormone induces insulin-like growth factor-I gene transcription by a synergistic action of STAT5 and HNF-1α" SIGNOR-251743 STAT5A protein P42229 UNIPROT PIM1 protein P11309 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 15498859 t "Pim-1 is a proto-oncogene and is known to be up-regulated by signal transducer and activator of transcription 5 (STAT5), which itself is a downstream target of FLT3 signaling. constitutively activated FLT3 signaling up-regulates Pim-1 expression in leukemia cells." SIGNOR-261517 STAT5A protein P42229 UNIPROT PIM1 protein P11309 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 16146838 t lperfetto "The results of 2 microarray experiments demonstrated that the aberrant activation of STAT proteins by Flt3-ITDs resulted in the up-regulation of several STAT5-responsive genes, such as Pim-1, Pim-2, and members of the SOCS (suppressor of cytokine signaling) protein family. These results are particularly interesting because recent data point to an important role of Pim kinases in the antiapoptosis of hematopoietic cells." SIGNOR-249621 STAT5A protein P42229 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 15003515 f "Flt3 Mutation Activates p21WAF1/CIP1 Gene Expression Through the Action of STAT5. Co-transfection of p21 promoter-luciferase constructs with Flt3-ITD plasmid into K562 and BaF3 cells results in the induction of p21 promoter activity and a -692/-684 STAT site is important for the induction. STAT5a binds specifically to this element and Flt3-ITD enhances the protein binding to this site." SIGNOR-261518 STAT5A protein P42229 UNIPROT HBB protein P68871 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000574 9168989 f Regulation miannu "We describe the roles of Stat5 and of these tyrosine residues in the EPOR in the erythroid differentiation of murine hematopoietic cell line SKT6 which produces hemoglobin in response to EPO. Chimeric receptors carrying the extracellular domain of the EGF receptor and the intracellular domain of the EPOR were introduced into SKT6 cells. Like EPO, EGF equally activated Stat5 and induced hemoglobin." SIGNOR-251784 STAT5A protein P42229 UNIPROT HBA1 protein P69905 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000574 9168989 f Regulation miannu "We describe the roles of Stat5 and of these tyrosine residues in the EPOR in the erythroid differentiation of murine hematopoietic cell line SKT6 which produces hemoglobin in response to EPO. Chimeric receptors carrying the extracellular domain of the EGF receptor and the intracellular domain of the EPOR were introduced into SKT6 cells. Like EPO, EGF equally activated Stat5 and induced hemoglobin." SIGNOR-251787 STAT5A protein P42229 UNIPROT RAD51 protein Q06609 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 15626738 t "FLT3-ITD-TKD dual mutants induce hyperactivation of STAT5 and up-regulation of its downstream targets Bcl-x(L) and RAD51 in Ba/F3 cells" SIGNOR-261552 STAT5A protein P42229 UNIPROT BCL2L1 protein Q07817 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 15626738 t "FLT3-ITD-TKD dual mutants induce hyperactivation of STAT5 and up-regulation of its downstream targets Bcl-x(L) and RAD51 in Ba/F3 cells" SIGNOR-261551 STAT5A protein P42229 UNIPROT IRF5 protein Q13568 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000801 25506346 t lperfetto "The GM-CSF receptor forms a dodecamer structure and recruits JAK2, leading to the activation of STAT5, extracellular signal-regulated kinase (ERK), V-Akt murine thymoma viral oncogene homolog 1 (AKT), and the nuclear translocation of NF-kappaB and IRF5" SIGNOR-249508 STAT5A protein P42229 UNIPROT FOXP3 protein Q9BZS1 UNIPROT up-regulates 9606 18270368 t "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 STAT5A protein P42229 UNIPROT FOXP3 protein Q9BZS1 UNIPROT up-regulates 9606 18270368 t "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 STAT5A protein P42229 UNIPROT PIM2 protein Q9P1W9 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 16146838 t lperfetto "The results of 2 microarray experiments demonstrated that the aberrant activation of STAT proteins by Flt3-ITDs resulted in the up-regulation of several STAT5-responsive genes, such as Pim-1, Pim-2, and members of the SOCS (suppressor of cytokine signaling) protein family. These results are particularly interesting because recent data point to an important role of Pim kinases in the antiapoptosis of hematopoietic cells." SIGNOR-249622 STAT5A protein P42229 UNIPROT DNMT3A protein Q9Y6K1 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 26059451 t "… these data suggest that STAT5A positively regulates levels of DNMT3A, resulting in inactivation of tumor suppressor genes by epigenetic mechanisms in AML cells" SIGNOR-255631 STAT5A protein P42229 UNIPROT NR3C1/STAT5A complex SIGNOR-C84 SIGNOR "form complex" binding 9606 8878484 t fspada "We show here that the glucocorticoid receptor can act as a transcriptional co-activator for stat5 and enhance stat5-dependent transcription. Stat5 forms a complex with the gluco-corticoid receptor which binds to dna independently of the gre. This complex formation between stat5 and the glucocorticoid receptor diminishes the glucocorticoid response of a gre-con-taining promoter." SIGNOR-44379 STAT5A protein P42229 UNIPROT PIM proteinfamily SIGNOR-PF34 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 15498859 t lperfetto "Pim-1 is know to be up regulated by signal transducer and activator of transcription 5 (stat5)" SIGNOR-259436 STAT5A protein P42229 UNIPROT PIM proteinfamily SIGNOR-PF34 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004479 29507660 f irozzo "FLT3-ITD is the most frequent tyrosine kinase mutation in acute myeloid leukemia (AML) associated with poor prognosis. We previously reported that activation of STAT5 confers resistance to PI3K/Akt inhibitors on the FLT3-ITD-positive AML cell line MV4-11 and 32D cells driven by FLT3-ITD (32D/ITD) but not by FLT3 mutated in the tyrosine kinase domain (32D/TKD). Here, we report the involvement of Pim kinases expressed through STAT5 activation in acquisition of this resistance." SIGNOR-255733 GRIA1 protein P42261 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000938 29953871 t miannu "Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial." SIGNOR-264947 GRIA2 protein P42262 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000938 29953871 t miannu "Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial." SIGNOR-264948 GRIA3 protein P42263 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000938 29953871 t miannu "Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial." SIGNOR-264949 PIK3CA protein P42336 UNIPROT "1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate" smallmolecule CHEBI:16618 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 24367090 t "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 PIK3CA protein P42336 UNIPROT "1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate" smallmolecule CHEBI:16618 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 24647478 t "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 PIK3CA protein P42336 UNIPROT TPM1 protein P09493 UNIPROT "up-regulates activity" phosphorylation Ser61 EDELDKYsEALKDAQ -1 16094730 t miannu "Here, we demonstrate a requirement for the protein kinase activity of PI(3)K in agonist-dependent beta-adrenergic receptor (betaAR) internalization. Using PI(3)K mutants with either protein or lipid phosphorylation activity, we identify the cytoskeletal protein non-muscle tropomyosin as a substrate of PI(3)K, which is phosphorylated in a wortmannin-sensitive manner on residue Ser 61. A constitutively dephosphorylated (S61A) tropomyosin mutant blocks agonist-dependent betaAR internalization, whereas a tropomyosin mutant that mimics constitutive phosphorylation (S61D) complements the PI(3)K mutant, with only lipid phosphorylation activity reversing the defective betaAR internalization." SIGNOR-263027 PIK3CA protein P42336 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" 9606 BTO:0000150 12167717 f 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-236353 PIK3CA protein P42336 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" 9606 BTO:0000586 16293724 f lperfetto "We show that PGE2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein;G protein)-coupled receptor, EP2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase Akt" SIGNOR-235914 PIK3CA protein P42336 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" 9606 BTO:0000938 9346240 f lperfetto "Growth factors can promote cell survival by activating the phosphatidylinositide-3'-OH kinase and its downstream target, the serine-threonine kinase Akt" SIGNOR-236428 PIK3CA protein P42336 UNIPROT AKT2 protein P31751 UNIPROT up-regulates 9606 BTO:0000586 16293724 f gcesareni "We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein)coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin." SIGNOR-141814 PIK3CA protein P42336 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" 9606 11160134 f lperfetto "Ly294002 or wortmannin were used to determine whether pi 3-kinasedependent pathways mediate ser307 phosphorylation during insulin/igf-1 or TNF-alpha Stimulation. As expected, the pi-3 kinase inhibitors ly294002 or wortmannin inhibited activation of pkb/akt in insulin or igf-1 stimulated 3t3-l1 preadipocytes, but were without effect on erk1/2. these results suggest that elements of the pi 3-kinase cascade mediate insulin/igf-1stimulated phosphorylation of ser307" SIGNOR-104911 PIK3CA protein P42336 UNIPROT MTOR protein P42345 UNIPROT up-regulates 9606 18721898 f lperfetto "Phosphoinositide 3-kinase (pi3k)-dependent activation of the rheb-mtor pathway triggers the simultaneous local synthesis of tc10 and par3." SIGNOR-180453 PIK3CA protein P42336 UNIPROT BTK protein Q06187 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0000899 10201980 t lperfetto "Activation of Btk occurs by transphosphorylation of tyrosine 551 in the catalytic domain, resulting in a dramatic increase in the catalytic activity of the kinase (11, 12, 13). This allows for autophosphorylation at tyrosine 223 in the SH3 domain (14). Both Lyn and Syk have been demonstrated to be involved in BCR-mediated Btk activation (11), but processes that drive colocalization of these kinases are ill-defined. Recently, it was suggested that phosphatidylinositol 3-kinase (PI3-K) is also involved in Btk activation" SIGNOR-249610 PIK3CA protein P42336 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "form complex" binding 9606 19805105 t miannu "Phosphoinositol 3- kinase alpha (PI3Kα) is a heterodimeric enzyme formed by a catalytic subunit (p110α, encoded by PIK3CA) and one of several regulatory subunits (a major one being p85α, encoded by PI3KR1)." SIGNOR-255299 PIK3CA protein P42336 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation 9606 12167717 t 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 PIK3CA protein P42336 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" 9606 BTO:0000150 19573809 f 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-236436 PIK3CB protein P42338 UNIPROT "1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate" smallmolecule CHEBI:16618 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 21779497 t lperfetto "The activation of pi3k results in the generation of the second messenger, phosphatidylinositol 3,4,5-triphosphate (pip3) from phosphatidylinositol 4,5-bisphosphate (pip2). In vivo, class i pi3ks primarily generate phosphatidylinositol-3,4,5-trisphosphate (pip3) from phosphatidylinositol- 4,5-bisphosphate (pi-4,5-p2)" SIGNOR-175241 PIK3CB protein P42338 UNIPROT PIK3CB protein P42338 UNIPROT "down-regulates activity" phosphorylation Ser1070 TVRKDYRs -1 12502714 t lperfetto "Autophosphorylation sites of both pi3k isoforms were mapped to c-terminal serine residues of the catalytic p110 subunit (i.e. serine 1070 of p110 beta and serine 1101 of p110 gamma). autophosphorylation of p110 beta On serine 1070 results in down-regulation of the lipid kinase activity of pi3k beta" SIGNOR-96776 MTOR protein P42345 UNIPROT SGK1 protein O00141 UNIPROT up-regulates phosphorylation Ser422 AEAFLGFsYAPPTDS 9606 SIGNOR-C3 18570873 t llicata "Mtor phosphorylated sgk1, but not sgk1-s422a, in vitro. Sgk1 phosphorylated p27 in vitro. These data implicate sgk1 as an mtorc1 (mtor-raptor) substrate. mtor may promote g1 progression in part through sgk1 activation" SIGNOR-179113 MTOR protein P42345 UNIPROT SGK1 protein O00141 UNIPROT up-regulates phosphorylation Ser422 AEAFLGFsYAPPTDS 9606 BTO:0000567 BTO:0000671 SIGNOR-C2 18925875 t gcesareni "Mtorc2 immunoprecipitated from wild-type, but not from mlst8- or rictor-knockout cells, phosphorylated sgk1 at ser(422)" SIGNOR-181531 MTOR protein P42345 UNIPROT EIF4EBP3 protein O60516 UNIPROT up-regulates phosphorylation 9606 14967450 t gcesareni "While promoting initiation of protein translation through mtor, eukaryoticinitiation factor 4e, and the ribosomal p70-s6 kinase." SIGNOR-122035 MTOR protein P42345 UNIPROT ATG13 protein O75143 UNIPROT down-regulates phosphorylation 9606 19211837 t gcesareni "Mtor phosphorylates a mammalian homologue of atg13 and the mammalian atg1 homologues ulk1 and ulk2." SIGNOR-183965 MTOR protein P42345 UNIPROT ULK1 protein O75385 UNIPROT "down-regulates activity" phosphorylation 9606 SIGNOR-C3 19690328 t lperfetto "The complementary inhibitory mechanism in which mtorc1 phosphorylates the autophagy regulatory complex containing unc-51-like kinase 1 (ulk1), the mammalian atg13 protein, and focal adhesion kinase interacting protein of 200 kd (fip200) has also been elucidated." SIGNOR-187611 MTOR protein P42345 UNIPROT ULK1 protein O75385 UNIPROT "down-regulates activity" phosphorylation Ser758 PVVFTVGsPPSGSTP 9606 BTO:0001938 21383122 t lperfetto "When cells are replenished with rich medium, mtor is activated;it phosphorylates serine 638 and serine 758. The phosphorylation of ulk1 at serine 758 then leads to reassociation between ulk1 and ampk." SIGNOR-172541 MTOR protein P42345 UNIPROT ULK1 protein O75385 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000007 21460634 t lperfetto "mTORC1, which is often referred to as the gatekeeper to autophagy, is a key regulator of the Ulk1-Atg13-FIP200 kinase complex.11,14,25 Under nutrient-rich conditions, active mTORC1 associates with and inactivates the Ulk1-Atg13-FIP200 complex by phosphorylating Ulk1 and Atg13." SIGNOR-183903 MTOR protein P42345 UNIPROT TFEB protein P19484 UNIPROT "down-regulates activity" phosphorylation Ser142 AGNSAPNsPMAMLHI 9606 BTO:0000007 22343943 t "Here, we have used an mTORC1 in-vitro kinase assay and a phosphoantibody to demonstrate that serine S142, which we previously found to be phosphorylated by ERK2, is also phosphorylated by mTOR and that this phosphorylation has a crucial role in controlling TFEB subcellular localization and activity." SIGNOR-255310 MTOR protein P42345 UNIPROT TFEB protein P19484 UNIPROT "down-regulates activity" phosphorylation Ser211 LVGVTSSsCPADLTQ 9606 BTO:0000567 SIGNOR-C3 22692423 t gcesareni "Our data points to the lysosome as the site where mTORC1-dependent phosphorylation of TFEB occurs. [...]Our study has revealed a specific role for phosphorylation of TFEB S211 in the negative regulation of the nuclear abundance of TFEB. This occurs through the promotion of 14-3-3 binding and the masking of the nearby NLS on TFEB." SIGNOR-248270 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT "up-regulates activity" phosphorylation Thr412 NQVFLGFtYVAPSVL -1 SIGNOR-C3 10567431 t lperfetto "We report here that a mammalian recombinant p70alpha polypeptide, extracted in an inactive form from rapamycin-treated cells, can be directly phosphorylated by the mTOR kinase in vitro predominantly at the rapamycin-sensitive site Thr-412. mTOR-catalyzed p70alpha phosphorylation in vitro is accompanied by a substantial restoration in p70alpha kinase activity toward its physiologic substrate" SIGNOR-72357 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT "up-regulates activity" phosphorylation Thr412 NQVFLGFtYVAPSVL 9606 BTO:0000007 SIGNOR-C3 10579915 t lperfetto "S6 kinases are under the control of the PI3K relative, mammalian Target Of Rapamycin (mTOR), which may serve an additional function as a checkpoint for amino acid availability." SIGNOR-72682 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT "up-regulates activity" phosphorylation Thr390 DSKFTRQtPVDSPDD 9600 BTO:0000007 11914378 t "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-255839 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT "up-regulates activity" phosphorylation Ser394 TRQTPVDsPDDSTLS 10090 BTO:0002572 12782654 t lperfetto "S6K1 is a positive regulator of protein synthesis, and its activity is induced by mTOR-mediated phosphorylation." SIGNOR-101328 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT "up-regulates activity" phosphorylation Ser434 SFEPKIRsPRRFIGS 10090 BTO:0002572 12782654 t lperfetto "S6K1 is a positive regulator of protein synthesis, and its activity is induced by mTOR-mediated phosphorylation." SIGNOR-101332 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT "up-regulates activity" phosphorylation Thr412 NQVFLGFtYVAPSVL 10090 BTO:0002572 12782654 t lperfetto "S6K1 is a positive regulator of protein synthesis, and its activity is induced by mTOR-mediated phosphorylation." SIGNOR-101336 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT "up-regulates activity" phosphorylation Thr412 NQVFLGFtYVAPSVL 10090 BTO:0000944 SIGNOR-C3 17510057 t lperfetto "mTORC1 catalyzes the phosphorylation of eIF4E binding protein-1 (4EBP1, also known as PHAS-I) and p70 S6 kinase 1 (S6K1)Phosphorylation of S6K1 at Thr-389" SIGNOR-235507 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT "up-regulates activity" phosphorylation Ser394 TRQTPVDsPDDSTLS 9823 BTO:0004712 23486913 t lperfetto "Collectively, these results indicate that Arg, Leu, and Gln act coordinately to stimulate proliferation of pTr cells through activation of the MTOR-RPS6K-RPS6-EIF4EBP1 signal transduction pathway" SIGNOR-201530 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT "up-regulates activity" phosphorylation Ser434 SFEPKIRsPRRFIGS 9823 BTO:0004712 23486913 t lperfetto "Collectively, these results indicate that Arg, Leu, and Gln act coordinately to stimulate proliferation of pTr cells through activation of the MTOR-RPS6K-RPS6-EIF4EBP1 signal transduction pathway" SIGNOR-201534 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT "up-regulates activity" phosphorylation Thr412 NQVFLGFtYVAPSVL 9823 BTO:0004712 23486913 t lperfetto "Collectively, these results indicate that Arg, Leu, and Gln act coordinately to stimulate proliferation of pTr cells through activation of the MTOR-RPS6K-RPS6-EIF4EBP1 signal transduction pathway" SIGNOR-201538 MTOR protein P42345 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000182;BTO:0000018 SIGNOR-C2 15718470 t lperfetto "The rictor-mtor complex directly phosphorylated akt/pkb on ser473 in vitro and facilitated thr308 phosphorylation by pdk1" SIGNOR-252599 MTOR protein P42345 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation Ser473 RPHFPQFsYSASGTA 9606 SIGNOR-C2 21157483 t lperfetto "Mammalian TOR complex 1 (mTORC1) and mTORC2 exert their actions by regulating other important kinases, such as S6 kinase (S6K) and Akt.Recent findings have revealed novel important roles for mTORC2 in the phosphorylation of AGC kinase family members. mTORC2 phosphorylates and activates Akt, SGK, and PKC, which regulate cell survival, cell cycle progression and anabolism" SIGNOR-170604 MTOR protein P42345 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000132 SIGNOR-C2 21592956 t 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-217869 MTOR protein P42345 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser307 TRRSRTEsITATSPA 10116 BTO:0000452 11287630 t lperfetto "Mtor induced the serine phosphorylation of irs-1 (ser-636/639), and such phosphorylation was inhibited by rapamycin. These results suggest that tnf impairs insulin signaling through irs-1 by activation of a pi 3-kinase/akt/mtor pathway, which is antagonized by pten" SIGNOR-106570 MTOR protein P42345 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser312 TESITATsPASMVGG 10116 BTO:0000452 11287630 t lperfetto "Mtor induced the serine phosphorylation of irs-1 (ser-636/639), and such phosphorylation was inhibited by rapamycin. These results suggest that tnf impairs insulin signaling through irs-1 by activation of a pi 3-kinase/akt/mtor pathway, which is antagonized by pten" SIGNOR-106574 MTOR protein P42345 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser315 ITATSPAsMVGGKPG 10116 BTO:0000452 11287630 t lperfetto "Mtor induced the serine phosphorylation of irs-1 (ser-636/639), and such phosphorylation was inhibited by rapamycin. These results suggest that tnf impairs insulin signaling through irs-1 by activation of a pi 3-kinase/akt/mtor pathway, which is antagonized by pten" SIGNOR-106578 MTOR protein P42345 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser616 DDGYMPMsPGVAPVP 10116 11287630 t lperfetto "Mtor induced the serine phosphorylation of irs-1 (ser-636/639), and such phosphorylation was inhibited by rapamycin. These results suggest that tnf impairs insulin signaling through irs-1 by activation of a pi 3-kinase/akt/mtor pathway, which is antagonized by pten" SIGNOR-106582 MTOR protein P42345 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser636 SGDYMPMsPKSVSAP 10116 11287630 t lperfetto "Mtor induced the serine phosphorylation of irs-1 (ser-636/639), and such phosphorylation was inhibited by rapamycin. These results suggest that tnf impairs insulin signaling through irs-1 by activation of a pi 3-kinase/akt/mtor pathway, which is antagonized by pten" SIGNOR-106586 MTOR protein P42345 UNIPROT MAF1 protein Q9H063 UNIPROT down-regulates phosphorylation Ser68 PPQTSGLsPSRLSKS 9606 20233713 t gcesareni "The identification of maf1 as an mtor-regulated phosphoprotein implicates mtor in the broader regulatory mechanisms governing pol iii activity in cancer cells." SIGNOR-164348 MTOR protein P42345 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser639 YMPMSPKsVSAPQQI 10116 BTO:0000452 11287630 t lperfetto "Mtor induced the serine phosphorylation of irs-1 (ser-636/639), and such phosphorylation was inhibited by rapamycin. These results suggest that tnf impairs insulin signaling through irs-1 by activation of a pi 3-kinase/akt/mtor pathway, which is antagonized by pten" SIGNOR-106590 MTOR protein P42345 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser307 TRRSRTEsITATSPA 9606 BTO:0000671 9335553 t lperfetto "These results indicate that activation of protein kinase c stimulates a kinase which can phosphorylate insulin receptor substrate-1 at serine 612, resulting in an inhibition of insulin signaling in the cell these data suggest that: 1) activation of pkctheta contributes to ikk and jnk activation by ffas;2) ikk and jnk mediate pkctheta signals for irs-1 serine phosphorylation and degradation; ser-302 phosphorylation is dependent on pi 3-kinase/mtor, whereas ser-307 depends on c-jun nh2-terminal kinase to inhibit irs1 tyrosine phosphorylation. Ser-636 is located around the pi 3-kinase binding site and, therefore, thought to inhibit pi 3-kinase signaling." SIGNOR-52700 MTOR protein P42345 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 BTO:0000527 16740698 t miannu "Serine phosphorylation and maximal activation of stat3 during cntf signaling is mediated by the rapamycin target mtor. / a stat3 peptide was efficiently phosphorylated on ser727 in a cntf-dependent manner by mtor" SIGNOR-146915 MTOR protein P42345 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 18691976 t gcesareni "Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle." SIGNOR-161439 MTOR protein P42345 UNIPROT MTOR protein P42345 UNIPROT "up-regulates activity" phosphorylation Ser2481 TVPESIHsFIGDGLV 9606 BTO:0000782 SIGNOR-C2 SIGNOR-C2 10702316 t lperfetto "We report here the identification of a FRAP autophosphorylation site. This site, Ser-2481, is located in a hydrophobic region near the conserved carboxyl-terminal FRAP tail. We demonstrate that the COOH-terminal tail is required for FRAP kinase activity and for signaling to the translational regulator p70(s6k) (ribosomal subunit S6 kinase)." SIGNOR-75394 MTOR protein P42345 UNIPROT MTOR protein P42345 UNIPROT "up-regulates activity" phosphorylation Ser2481 TVPESIHsFIGDGLV 10090 BTO:0000944 SIGNOR-C2 SIGNOR-C2 20022946 t lperfetto "We have found that in HEK293 cells and 3T3-L1 adipocytes, insulin promotes both raptor- and rictor-associated mTOR Ser(P)-2481 in a wortmannin-sensitive manner. Thus, insulin signals via PI3K to promote both mTORC1- and mTORC2-associated mTOR Ser-2481 autophosphorylation." SIGNOR-235427 MTOR protein P42345 UNIPROT DAP protein P51397 UNIPROT "down-regulates activity" phosphorylation Ser3 DQEWESPsPPKPTVF 9606 20537536 t miannu "A critical step in autophagy induction comprises the inactivation of a key negative regulator of the process, the Ser/Thr kinase mammalian target of rapamycin (mTOR). Here we identify death-associated protein 1 (DAP1) as a novel substrate of mTOR that negatively regulates autophagy. Mapping of the phosphorylation sites and analysis of phosphorylation mutants indicated that DAP1 is functionally silenced in growing cells through mTOR-dependent phosphorylations on Ser3 and Ser51." SIGNOR-259813 MTOR protein P42345 UNIPROT DAP protein P51397 UNIPROT "down-regulates activity" phosphorylation Ser51 DQEWESPsPPKPTVF 9606 20537536 t miannu "A critical step in autophagy induction comprises the inactivation of a key negative regulator of the process, the Ser/Thr kinase mammalian target of rapamycin (mTOR). Here we identify death-associated protein 1 (DAP1) as a novel substrate of mTOR that negatively regulates autophagy. Mapping of the phosphorylation sites and analysis of phosphorylation mutants indicated that DAP1 is functionally silenced in growing cells through mTOR-dependent phosphorylations on Ser3 and Ser51." SIGNOR-259812 MTOR protein P42345 UNIPROT GRB10 protein Q13322 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C3 21659604 t gcesareni "The adaptor protein grb10 was identified as an mtorc1 substrate that mediates the phosphoinositide 3-kinase." SIGNOR-174071 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Ser65 FLMECRNsPVTKTPP 9606 BTO:0002181 SIGNOR-C3 10942774 t lperfetto "PHAS-I in adipocytes and HEK293 cells is phosphorylated in the following five sites, all of which conform to a (S/T)P motif (9, 10): Thr-36, Thr-45, Ser-64, Thr-69, and Ser-82. Thr-45 and Ser-64 flank the eIF4E-binding motif (7, 8), and phosphorylation of either site blocks eIF4E binding in vitro (10, 11). Insulin stimulates the phosphorylation of Thr-36, Thr-45, Ser-64, and Thr-69 in both fat cells and HEK293 cells, and incubating cells with rapamycin decreases the phosphorylation of these sites.Immunoprecipitated epitope-tagged mammalian target of rapamycin (mTOR) phosphorylated Thr-36/45. mTOR also phosphorylated Thr-69 and Ser-64 but only when purified immune complexes were incubated with the activating antibody, mTAb1." SIGNOR-226714 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr70 RNSPVTKtPPRDLPT 9606 BTO:0002181 SIGNOR-C3 10942774 t lperfetto "PHAS-I in adipocytes and HEK293 cells is phosphorylated in the following five sites, all of which conform to a (S/T)P motif (9, 10): Thr-36, Thr-45, Ser-64, Thr-69, and Ser-82. Thr-45 and Ser-64 flank the eIF4E-binding motif (7, 8), and phosphorylation of either site blocks eIF4E binding in vitro (10, 11). Insulin stimulates the phosphorylation of Thr-36, Thr-45, Ser-64, and Thr-69 in both fat cells and HEK293 cells, and incubating cells with rapamycin decreases the phosphorylation of these sites.Immunoprecipitated epitope-tagged mammalian target of rapamycin (mTOR) phosphorylated Thr-36/45. mTOR also phosphorylated Thr-69 and Ser-64 but only when purified immune complexes were incubated with the activating antibody, mTAb1." SIGNOR-226710 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr70 RNSPVTKtPPRDLPT 9606 BTO:0000007 SIGNOR-C3 10942774 t lperfetto "Mammalian target of rapamycin-dependent phosphorylation of phas-i in four (s/t)p sites detected by phospho-specific antibodies." SIGNOR-80797 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Ser65 FLMECRNsPVTKTPP 9606 BTO:0000007 SIGNOR-C3 12747827 t lperfetto "Here, we show that a functional TOS motif is required for 4E-BP1 to bind to raptor (a recently identified mTOR-interacting protein), for 4E-BP1 to be efficiently phosphorylated in vitro by themTOR/raptor complex, and for 4E-BP1 to be phosphorylated in vivo at all identified mTOR-regulated sites. mTOR/raptor regulated phosphorylation is necessary for 4E-BP’s efficient release from the translational initiation factor eIF4E. We find that the TOS motif is absolutely required for efficient phosphorylation of 4E-BP1 at all the identified mTOR-regulated sites, namely, Thr37/46, Ser65, and Thr70 in vivo." SIGNOR-101115 CASP3 protein P42574 UNIPROT IKBKB protein O14920 UNIPROT down-regulates cleavage Asp242 VRQKSEVdIVVSEDL 9606 11741536 t gcesareni "Ikappab kinase (ikk) beta was specifically proteolyzed by caspase-3-related caspases at aspartic acid residues 78, 242, 373, and 546 during tumor necrosis factor (tnf)-alpha-induced apoptosis." SIGNOR-112788 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr37 PPGDYSTtPGGTLFS 9606 BTO:0000007 SIGNOR-C3 12747827 t lperfetto "Here, we show that a functional TOS motif is required for 4E-BP1 to bind to raptor (a recently identified mTOR-interacting protein), for 4E-BP1 to be efficiently phosphorylated in vitro by themTOR/raptor complex, and for 4E-BP1 to be phosphorylated in vivo at all identified mTOR-regulated sites. mTOR/raptor regulated phosphorylation is necessary for 4E-BP’s efficient release from the translational initiation factor eIF4E. We find that the TOS motif is absolutely required for efficient phosphorylation of 4E-BP1 at all the identified mTOR-regulated sites, namely, Thr37/46, Ser65, and Thr70 in vivo." SIGNOR-101119 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr46 GGTLFSTtPGGTRII 9606 BTO:0000007 SIGNOR-C3 12747827 t lperfetto "Here, we show that a functional TOS motif is required for 4E-BP1 to bind to raptor (a recently identified mTOR-interacting protein), for 4E-BP1 to be efficiently phosphorylated in vitro by themTOR/raptor complex, and for 4E-BP1 to be phosphorylated in vivo at all identified mTOR-regulated sites. mTOR/raptor regulated phosphorylation is necessary for 4E-BP’s efficient release from the translational initiation factor eIF4E. We find that the TOS motif is absolutely required for efficient phosphorylation of 4E-BP1 at all the identified mTOR-regulated sites, namely, Thr37/46, Ser65, and Thr70 in vivo." SIGNOR-101123 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr70 RNSPVTKtPPRDLPT 9606 BTO:0000007 SIGNOR-C3 12747827 t lperfetto "Here, we show that a functional TOS motif is required for 4E-BP1 to bind to raptor (a recently identified mTOR-interacting protein), for 4E-BP1 to be efficiently phosphorylated in vitro by themTOR/raptor complex, and for 4E-BP1 to be phosphorylated in vivo at all identified mTOR-regulated sites. mTOR/raptor regulated phosphorylation is necessary for 4E-BP’s efficient release from the translational initiation factor eIF4E. We find that the TOS motif is absolutely required for efficient phosphorylation of 4E-BP1 at all the identified mTOR-regulated sites, namely, Thr37/46, Ser65, and Thr70 in vivo." SIGNOR-101127 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr36 LPPGDYStTPGGTLF 9606 BTO:0000007;BTO:0000443 SIGNOR-C3 17510057 t lperfetto "In response to insulin and nutrients, mTORC1, consisting of mTOR, raptor (regulatory-associated protein of mTOR), and mLST8, is activated and phosphorylates eukaryotic initiation factor 4E-binding protein (4EBP) and p70 S6 kinase to promote protein synthesis and cell size." SIGNOR-154810 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr45 PGGTLFStTPGGTRI 9606 BTO:0000007;BTO:0000443 SIGNOR-C3 17510057 t lperfetto "In response to insulin and nutrients, mTORC1, consisting of mTOR, raptor (regulatory-associated protein of mTOR), and mLST8, is activated and phosphorylates eukaryotic initiation factor 4E-binding protein (4EBP) and p70 S6 kinase to promote protein synthesis and cell size." SIGNOR-154814 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr36 LPPGDYStTPGGTLF 10090 BTO:0002572 SIGNOR-C3 20670887 t lperfetto "Specifically as part of mTORC1, mTOR directly phosphorylates the ribo- somal protein S6 kinases (S6K1 and S6K2) and the eukaryotic initiation factor 4E (eIF4E)-binding proteins (4E-BP1 and 4E-BP2), both of which control specific steps in the initiation of cap-dependent translation" SIGNOR-167180 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr45 PGGTLFStTPGGTRI 10090 BTO:0002572 SIGNOR-C3 20670887 t lperfetto "Specifically as part of mTORC1, mTOR directly phosphorylates the ribo- somal protein S6 kinases (S6K1 and S6K2) and the eukaryotic initiation factor 4E (eIF4E)-binding proteins (4E-BP1 and 4E-BP2), both of which control specific steps in the initiation of cap-dependent translation" SIGNOR-167184 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Ser65 FLMECRNsPVTKTPP 9823 BTO:0001840 SIGNOR-C3 23486913 t lperfetto "These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. Specifically as part of mtorc1, mtor directly phosphorylates the ribosomal protein s6 kinases (s6k1 and s6k2) and the eukaryotic initiation factor 4e (eif4e)-binding proteins (4e-bp1 and 4e-bp2), both of which control specific steps in the initiation of cap-dependent translation" SIGNOR-219257 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr37 PPGDYSTtPGGTLFS 9823 BTO:0001840 SIGNOR-C3 23486913 t lperfetto "These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. Specifically as part of mtorc1, mtor directly phosphorylates the ribosomal protein s6 kinases (s6k1 and s6k2) and the eukaryotic initiation factor 4e (eif4e)-binding proteins (4e-bp1 and 4e-bp2), both of which control specific steps in the initiation of cap-dependent translation" SIGNOR-219262 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr46 GGTLFSTtPGGTRII 9823 BTO:0001840 SIGNOR-C3 23486913 t lperfetto "These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. Specifically as part of mtorc1, mtor directly phosphorylates the ribosomal protein s6 kinases (s6k1 and s6k2) and the eukaryotic initiation factor 4e (eif4e)-binding proteins (4e-bp1 and 4e-bp2), both of which control specific steps in the initiation of cap-dependent translation" SIGNOR-219266 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr70 RNSPVTKtPPRDLPT 9823 BTO:0001840 SIGNOR-C3 23486913 t lperfetto "These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. Specifically as part of mtorc1, mtor directly phosphorylates the ribosomal protein s6 kinases (s6k1 and s6k2) and the eukaryotic initiation factor 4e (eif4e)-binding proteins (4e-bp1 and 4e-bp2), both of which control specific steps in the initiation of cap-dependent translation" SIGNOR-219273 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Ser83 PTIPGVTsPSSDEPP 9606 BTO:0000007 9204908 t miannu "MTOR phosphorylated PHAS-I on serine and threonine residues in vitro, and these modifications inhibited the binding of PHAS-I to eIF-4E." SIGNOR-250292 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr36 LPPGDYStTPGGTLF 9606 BTO:0000007 SIGNOR-C3 9465032 t lperfetto "Mtorc1 promotes protein synthesis by phosphorylating the eukaryotic initiation factor 4e (eif4e)- binding protein 1 (4e-bp1) and the p70 ribosomal s6 kinase 1 (s6k1). Raft1 phosphorylation of 4e-bp1 on thr-36 and thr-45 blocks its association with the cap-binding protein, eif-4e,in vitro. in response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size." SIGNOR-55697 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr45 PGGTLFStTPGGTRI 9606 BTO:0000007 SIGNOR-C3 9465032 t lperfetto "Mtorc1 promotes protein synthesis by phosphorylating the eukaryotic initiation factor 4e (eif4e)- binding protein 1 (4e-bp1) and the p70 ribosomal s6 kinase 1 (s6k1). Raft1 phosphorylation of 4e-bp1 on thr-36 and thr-45 blocks its association with the cap-binding protein, eif-4e,in vitro. in response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size." SIGNOR-55701 MTOR protein P42345 UNIPROT EIF4EBP2 protein Q13542 UNIPROT down-regulates phosphorylation 9606 14967450 t gcesareni "Here, we show that cancer cells acquire resistance to astori by downregulating eukaryotic translation initiation factor (eif4e)-binding proteins (4e-bps-eif4ebp1, eif4ebp2)." SIGNOR-122014 MTOR protein P42345 UNIPROT EIF4EBP2 protein Q13542 UNIPROT down-regulates phosphorylation 9606 23100465 t gcesareni "Here, we show that cancer cells acquire resistance to astori by downregulating eukaryotic translation initiation factor (eif4e)-binding proteins (4e-bps-eif4ebp1, eif4ebp2)." SIGNOR-199258 MTOR protein P42345 UNIPROT ULK2 protein Q8IYT8 UNIPROT down-regulates phosphorylation 9606 19211836 t gcesareni "Mtor phosphorylates a mammalian homologue of atg13 and the mammalian atg1 homologues ulk1 and ulk2" SIGNOR-183961 MTOR protein P42345 UNIPROT RPTOR protein Q8N122 UNIPROT "up-regulates activity" phosphorylation Ser859 DTSSLTQsAPASPTN 9606 BTO:0000007 19346248 t lperfetto "The phosphorylation of raptor is stimulated by insulin and inhibited by rapamycin. Importantly, the site-directed mutation of raptor at one phosphorylation site, Ser(863), reduced mTORC1 activity both in vitro and in vivo." SIGNOR-184959 MTOR protein P42345 UNIPROT RPTOR protein Q8N122 UNIPROT "up-regulates activity" phosphorylation Ser855 QRVLDTSsLTQSAPA 9606 BTO:0000007 19864431 t lperfetto "Strikingly, raptor Ser(863) phosphorylation is absolutely required for raptor Ser(859) and Ser(855) phosphorylation. These data suggest that mTORC1 activation leads to raptor multisite phosphorylation and that raptor Ser(863) phosphorylation functions as a master biochemical switch that modulates hierarchical raptor phosphorylation (e.g. on Ser(859) and Ser(855))" SIGNOR-174882 MTOR protein P42345 UNIPROT RPTOR protein Q8N122 UNIPROT "up-regulates activity" phosphorylation Ser859 DTSSLTQsAPASPTN 9606 BTO:0000007 19864431 t lperfetto "Strikingly, raptor Ser(863) phosphorylation is absolutely required for raptor Ser(859) and Ser(855) phosphorylation. These data suggest that mTORC1 activation leads to raptor multisite phosphorylation and that raptor Ser(863) phosphorylation functions as a master biochemical switch that modulates hierarchical raptor phosphorylation (e.g. on Ser(859) and Ser(855))" SIGNOR-188920 MTOR protein P42345 UNIPROT RPTOR protein Q8N122 UNIPROT "up-regulates activity" phosphorylation Ser863 LTQSAPAsPTNKGVH 9606 BTO:0000007 SIGNOR-C3 SIGNOR-C3 19864431 t lperfetto "Our data that insulin-stimulated raptor ser863 phosphorylation requires kinase-active mtorc1 and displays rapamycin sensitivity in intact cells, together with the data of wang et al. (67) that mtor phosphorylates raptor ser863 in vitro, strongly suggest that mtor itself mediates raptor ser863 phosphorylation. / strikingly, raptor ser863 phosphorylation is absolutely required for raptor ser859 and ser855 phosphorylation. These data suggest that mtorc1 activation leads to raptor multisite phosphorylation and that raptor ser863 phosphorylation functions as a master biochemical switch that modulates hierarchical raptor phosphorylation" SIGNOR-188924 MTOR protein P42345 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser293 SSGYFSSsPTLSSSP 9606 22017875 t llicata "Our data reveal critical roles for mtor itself as well as cki in generating a degron in deptor that is recognized by _-trcp, and promotes deptor turnover by the proteasome." SIGNOR-176849 MTOR protein P42345 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser299 SSPTLSSsPPVLCNP 9606 22017875 t llicata "Our data reveal critical roles for mtor itself as well as cki in generating a degron in deptor that is recognized by _-trcp, and promotes deptor turnover by the proteasome." SIGNOR-176853 MTOR protein P42345 UNIPROT AKT1S1 protein Q96B36 UNIPROT "down-regulates activity" phosphorylation Ser183 PTQQYAKsLPVSVPV 9606 BTO:0000007 SIGNOR-C3 SIGNOR-C3 17517883 t lperfetto "The proline-rich Akt substrate of 40 kilodaltons (PRAS40) was identified as a raptor-binding protein that is phosphorylated directly by mammalian target of rapamycin (mTOR) complex 1 (mTORC1) but not mTORC2 in vitro, predominantly at PRAS40 (Ser(183)).PRAS40 binding to raptor was also abolished by mutation of the major mTORC1 phosphorylation site, Ser(183), to Asp." SIGNOR-154956 MTOR protein P42345 UNIPROT AKT1S1 protein Q96B36 UNIPROT "down-regulates activity" phosphorylation Ser183 PTQQYAKsLPVSVPV -1 SIGNOR-C3 SIGNOR-C3 18372248 t lperfetto "Pras40 functions as a negative regulator when bound to mtorc1, and it dissociates from mtorc1 in response to insulin. Pras40 has been demonstrated to be a substrate of mtorc1, and one phosphorylation site, ser-183, has been identified." SIGNOR-178120 MTOR protein P42345 UNIPROT AKT1S1 protein Q96B36 UNIPROT "down-regulates activity" phosphorylation Ser212 EENGPPSsPDLDRIA -1 SIGNOR-C3 SIGNOR-C3 18372248 t lperfetto "In this study, we used two-dimensional phosphopeptide mapping in conjunction with mutational analysis to show that in addition to ser-183, mtorc1 also phosphorylates ser-212 and ser-221 in pras40 when assayed in vitro." SIGNOR-178124 MTOR protein P42345 UNIPROT AKT1S1 protein Q96B36 UNIPROT "down-regulates activity" phosphorylation Ser221 DLDRIAAsMRALVLR -1 SIGNOR-C3 SIGNOR-C3 18372248 t lperfetto "We propose that after mtorc1 kinase activation by upstream regulators, pras40 is phosphorylated directly by mtor, thus contributing to the relief of pras40-mediated substrate competitionwe also find that mutation of ser-221 to ala increases the inhibitory activity of pras40 toward mtorc1." SIGNOR-178128 MTOR protein P42345 UNIPROT NRBF2 protein Q96F24 UNIPROT "up-regulates activity" phosphorylation Ser113 AEDAEGQsPLSQKYS 9606 BTO:0001938 28059666 t miannu "Human NRBF2 is phosphorylated by MTORC1 at S113 and S120. Upon nutrient starvation or MTORC1 inhibition, NRBF2 phosphorylation is diminished. Phosphorylated NRBF2 preferentially interacts with PIK3C3/PIK3R4. Suppression of NRBF2 phosphorylation by MTORC1 inhibition alters its binding preference from PIK3C3/PIK3R4 to ATG14/BECN1, leading to increased autophagic PtdIns3K complex assembly, as well as enhancement of ULK1 protein complex association." SIGNOR-265874 MTOR protein P42345 UNIPROT NRBF2 protein Q96F24 UNIPROT "up-regulates activity" phosphorylation Ser120 SPLSQKYsPSTEKCL 9606 BTO:0001938 28059666 t miannu "Human NRBF2 is phosphorylated by MTORC1 at S113 and S120. Upon nutrient starvation or MTORC1 inhibition, NRBF2 phosphorylation is diminished. Phosphorylated NRBF2 preferentially interacts with PIK3C3/PIK3R4. Suppression of NRBF2 phosphorylation by MTORC1 inhibition alters its binding preference from PIK3C3/PIK3R4 to ATG14/BECN1, leading to increased autophagic PtdIns3K complex assembly, as well as enhancement of ULK1 protein complex association." SIGNOR-265875 MTOR protein P42345 UNIPROT MAF1 protein Q9H063 UNIPROT down-regulates phosphorylation Ser75 SPSRLSKsQGGEEEG 9606 20233713 t flangone "Employing an mtor active-site inhibitor wye-125132 (wye-132), we have performed quantitative phospho-proteomics and identified a ser-75-containing phosphopeptide from maf1, a known repressor of rna polymerase iii (pol iii) transcriptionmaf1 mutant proteins carrying s75a alone or with s60a, t64a, and s68a (maf1-s75a, maf1-4a) progressively enhanced basal repression of trna in actively proliferating cells and attenuated amino acid-induced trna transcription" SIGNOR-164352 MTOR protein P42345 UNIPROT MAF1 protein Q9H063 UNIPROT down-regulates phosphorylation Ser60 PHVLEALsPPQTSGL 9606 SIGNOR-C3 20516213 t fstefani "The protein is phosphorylated mainly on residues s60, s68, and s75, and this inhibits its pol iii repression function. The responsible kinase is mtorc1, which phosphorylates maf1 directly." SIGNOR-165791 MTOR protein P42345 UNIPROT MAF1 protein Q9H063 UNIPROT down-regulates phosphorylation Ser68 PPQTSGLsPSRLSKS 9606 SIGNOR-C3 20516213 t fstefani "The protein is phosphorylated mainly on residues s60, s68, and s75, and this inhibits its pol iii repression function. The responsible kinase is mtorc1, which phosphorylates maf1 directly." SIGNOR-165795 MTOR protein P42345 UNIPROT MAF1 protein Q9H063 UNIPROT down-regulates phosphorylation Ser75 SPSRLSKsQGGEEEG 9606 SIGNOR-C3 20516213 t fstefani "The protein is phosphorylated mainly on residues s60, s68, and s75, and this inhibits its pol iii repression function. The responsible kinase is mtorc1, which phosphorylates maf1 directly." SIGNOR-165799 MTOR protein P42345 UNIPROT MAF1 protein Q9H063 UNIPROT down-regulates phosphorylation Ser75 SPSRLSKsQGGEEEG 9606 BTO:0000567 20543138 t fstefani "Maf1, a repressor that binds and inhibits pol iii, is phosphorylated in a mtor-dependent manner both in vitro and in vivo at serine 75" SIGNOR-166054 MTOR protein P42345 UNIPROT ISCU protein Q9H1K1 UNIPROT up-regulates phosphorylation Ser14 FRLRRAAsALLLRSP 9606 SIGNOR-C3 23508953 t llicata "Here, we demonstrate that mtorc1 associates with iscu and phosphorylates iscu at serine 14. This phosphorylation stabilized iscu protein." SIGNOR-201595 MTOR protein P42345 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C3 17510057 t gcesareni "In response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size." SIGNOR-154821 MTOR protein P42345 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT up-regulates phosphorylation 9606 23486913 t "mTORC1 phosphorylation of EIF4EBP1 causes dissociation of the complex allowing EIF4G1/EIF4G3 to bind and consequent initiation of translation." gcesareni "These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway." SIGNOR-201541 MTOR protein P42345 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT "up-regulates activity" phosphorylation Ser370 TRQTPVDsPDDTALS -1 11733037 t miannu "In vitro phosphorylation and activation of p70β by mTOR and PDK1. replacement of Ser383 to Gly (S383G) reduced but still retained nearly half of the kinase activity of the wild-type." SIGNOR-250293 MTOR protein P42345 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT "up-regulates activity" phosphorylation Thr228 HEGAVTHtFCGTIEY -1 11733037 t miannu "In vitro phosphorylation and activation of p70β by mTOR and PDK1. We observed that the replacement of either Thr241 or Thr401 to Ala in p70β1(T241A, T401A) severely decreased the kinase activity." SIGNOR-250294 MTOR protein P42345 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT "up-regulates activity" phosphorylation Thr388 NQAFLGFtYVAPSVL -1 11733037 t miannu "In vitro phosphorylation and activation of p70β by mTOR and PDK1. We observed that the replacement of either Thr241 or Thr401 to Ala in p70β1(T241A, T401A) severely decreased the kinase activity." SIGNOR-250295 MTOR protein P42345 UNIPROT mTORC2 complex SIGNOR-C2 SIGNOR "form complex" binding 9606 25628925 t lperfetto "Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8)" SIGNOR-262534 MTOR protein P42345 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR "form complex" binding 9606 25628925 t lperfetto "Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8)" SIGNOR-205615 MTOR protein P42345 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000182;BTO:0000018 SIGNOR-C2 15718470 t lperfetto "The rictor-mtor complex directly phosphorylated akt/pkb on ser473 in vitro and facilitated thr308 phosphorylation by pdk1" SIGNOR-134185 MTOR protein P42345 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000132 SIGNOR-C2 21592956 t 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-244417 MTOR protein P42345 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR "up-regulates activity" phosphorylation Thr390 DSKFTRQtPVDSPDD 9600 BTO:0000007 11914378 t "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-255841 EPS15 protein P42566 UNIPROT EGFR protein P00533 UNIPROT "down-regulates activity" binding 10029 BTO:0002988 15383614 t gcesareni "We suggest that the ubiquitinated EGFR or another c-Cbl substrate that is ubiquitinated upon EGFR activation recruits Eps15 to the plasma membrane via its UIM. This event would facilitate EGFR internalization via a clathrin-dependent route in which Eps15 plays a role" SIGNOR-243278 EPS15 protein P42566 UNIPROT "AP-2/clathrin vescicle" complex SIGNOR-C249 SIGNOR "up-regulates quantity by stabilization" binding 24789820 t lperfetto "Early recruitment of FCHo1/2, Eps15, epsin, and intersectin to the rims of assembling coated pits is essential for their stability and further growth" SIGNOR-260713 MLLT3 protein P42568 UNIPROT SCNN1A protein P37088 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0005545 20159978 f Regulation miannu "AF9/MLLT3 contributes to the regulation of the gene encoding the epithelial sodium channel alpha, ENaCalpha, in renal tubular cells. Specifically, increases in AF9 protein lead to a reduction in ENaCalpha expression and changes in AF9 activity appear to be an important component of aldosterone signaling in the kidney." SIGNOR-251944 CASP3 protein P42574 UNIPROT IKBKB protein O14920 UNIPROT down-regulates cleavage Asp78 PNVVAARdVPEGMQN 9606 11741536 t gcesareni "Ikappab kinase (ikk) beta was specifically proteolyzed by caspase-3-related caspases at aspartic acid residues 78, 242, 373, and 546 during tumor necrosis factor (tnf)-alpha-induced apoptosis." SIGNOR-112800 CASP3 protein P42574 UNIPROT GAS2 protein O43903 UNIPROT up-regulates cleavage Asp278 MLQISRVdGKTSPIQ 9606 10564664 t gcesareni "We now demonstrate that gas2 is a substrate of caspase-3 but not of caspase-6. Proteolytic processing both in vitro and in vivo is dependent on aspartic residue 279." SIGNOR-72347 CASP3 protein P42574 UNIPROT PSIP1 protein O75475 UNIPROT down-regulates cleavage 9606 BTO:0001130 18708362 t miannu "Ledgf/ p75 has a cooh-terminally truncated splice variant, p52 / during apoptosis, caspase-3 cleaved p52 to generate a p38 fragment that lacked the nh2-terminal pwwp domain and failed to transactivate the hsp27 promoter in reporter assays. However, p38 retained chromatin association properties and repressed the transactivation potential of ledgf/p75" SIGNOR-180144 CASP3 protein P42574 UNIPROT DFFB protein O76075 UNIPROT up-regulates cleavage 9606 BTO:0000567 9108473 t gcesareni "Casp3_ cleaves the 45 kda subunit at two sites to generate an active factor that produces_ dna_ fragmentation" SIGNOR-47419 CASP3 protein P42574 UNIPROT GSN protein P06396 UNIPROT down-regulates cleavage 9606 BTO:0000130 9323209 t amattioni "Caspase-3 mediates cleavage of gelsolin, generating a fragment that severs actin filaments in an unregulated fashion. The cleavage of gelsolin causes cells to round up, detach and undergo nuclear fragmentation." SIGNOR-51652 CASP3 protein P42574 UNIPROT GSN protein P06396 UNIPROT "down-regulates activity" cleavage Asp403 WRDPDQTdGLGLSYL 9606 9671712 t miannu "We showed that human gelsolin was cleaved during Fas-mediated apoptosis in vivo and that the caspase-3 cleavage site of human gelsolin was at D352 of DQTD352G. gelsolin seems to have dual functions, i.e., it both prevents and, once cleaved, induces cell death." SIGNOR-256357 CASP3 protein P42574 UNIPROT PARP1 protein P09874 UNIPROT "down-regulates activity" cleavage 10090 BTO:0000331 11907276 t amattioni "Caspase-3 cleaves parp-1. During cd95-mediated apoptosis proteolytic inactivation of parp-1 by caspases prevents atp depletion and thereby ensures the execution of the apoptotic process" SIGNOR-116178 CASP3 protein P42574 UNIPROT NFKBIA protein P25963 UNIPROT "up-regulates quantity by stabilization" cleavage -1 9367996 t lperfetto "The cell-death protease cpp32 (caspase-3) in vitro specifically cleaved chicken and human ikappab-alpha at a conserved asp-ser sequence.Therefore, cleavage of I_B-_ by a CPP32-like protease could create what is sometimes called a super-repressor form of I_B-_ (20). That is, cleavage by CPP32 would block the ability of I_B-_ to undergo signal-induced degradation by removing the sites of signal-induced ubiquitination and by likely disrupting the ability of I_B-_ to become phosphorylated at critical Ser residues." SIGNOR-51936 CASP3 protein P42574 UNIPROT AKT1 protein P31749 UNIPROT "down-regulates activity" cleavage -1 10579725 t 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-252624 CASP3 protein P42574 UNIPROT BRCA1 protein P38398 UNIPROT "down-regulates quantity by destabilization" cleavage Asp1155 ETPDDLLdDGEIKED 9606 12149654 t miannu "We demonstrate the cleavage and the consequential downregulation of full-length BRCA1 by caspase-3 during UV-induced apoptosis. Finally, mutation of a caspase-3 specific cleavage site (D/A1154) rendered BRCA1 non-cleavable." SIGNOR-256326 CASP3 protein P42574 UNIPROT PSEN1 protein P49768 UNIPROT "up-regulates activity" cleavage Asp345 EEWEAQRdSHLGPHR -1 10069390 t lperfetto "Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis." SIGNOR-261756 CASP3 protein P42574 UNIPROT PSEN2 protein P49810 UNIPROT "up-regulates activity" cleavage Asp326 YDPEMEEdSYDSFGE -1 10069390 t lperfetto "In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329." SIGNOR-261743 CASP3 protein P42574 UNIPROT PSEN2 protein P49810 UNIPROT "up-regulates activity" cleavage Asp329 EMEEDSYdSFGEPSY -1 10069390 t lperfetto "In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329." SIGNOR-261749 CASP3 protein P42574 UNIPROT CASP9 protein P55211 UNIPROT "up-regulates activity" cleavage 9606 14585074 t lperfetto "Active caspase-3 itself is able to process its upstream , caspase-8 and caspase-9, establishing a self-amplifying loop of caspase activation" SIGNOR-90397 CASP3 protein P42574 UNIPROT CASP9 protein P55211 UNIPROT "up-regulates activity" cleavage Asp330 LRTFDQLdAISSLPT 9606 BTO:0001412 15657060 t lperfetto "In turn, casp3 directs feedback cleavage of casp9 at asp-330 to generate p37 and p10 subunits." SIGNOR-133264 CASP3 protein P42574 UNIPROT STK4 protein Q13043 UNIPROT "up-regulates activity" cleavage Asp326 NSEEDEMdSGTMVRA 9534 BTO:0004055 11517310 t lperfetto "In response to apoptotic stimuli, caspase cleavage of mst1 occurs at asp-326 and asp-349, resulting in the separation of its n-terminal kinase domain from the nes-containing c-terminal domain. Thus, caspase cleavage of mst1 serves two purposes: one is activation of mst1 kinase activity and the other is translocation of mst1 into the nucleus." SIGNOR-109874 CASP3 protein P42574 UNIPROT STK4 protein Q13043 UNIPROT "up-regulates activity" cleavage Asp349 RVASTMTdGANTMIE 9534 BTO:0004055 11517310 t lperfetto "In response to apoptotic stimuli, caspase cleavage of mst1 occurs at asp-326 and asp-349, resulting in the separation of its n-terminal kinase domain from the nes-containing c-terminal domain. Thus, caspase cleavage of mst1 serves two purposes: one is activation of mst1 kinase activity and the other is translocation of mst1 into the nucleus." SIGNOR-109878 CASP3 protein P42574 UNIPROT ROCK1 protein Q13464 UNIPROT up-regulates cleavage 9606 11283607 t gcesareni "Rock i is cleaved by casp3 at a conserved detd1113/g sequence and its carboxy-terminal inhibitory domain is removed, resulting in deregulated and constitutive kinase activity." SIGNOR-106546 CASP3 protein P42574 UNIPROT PTCH1 protein Q13635 UNIPROT down-regulates cleavage Asp1405 CPGYPETdHGLFEDP 9606 23074268 t gcesareni "Like other dependence receptors, ptc1 contains a dependence-as-associated receptor c-terminal motif that is cleaved by caspases at a conserved aspartic acid (asp 1392) in the absence of shh, to expose a proapoptotic domain." SIGNOR-199111 CASP3 protein P42574 UNIPROT PTCH1 protein Q13635 UNIPROT "down-regulates activity" cleavage Asp1405 CPGYPETdHGLFEDP 9606 12907805 t lperfetto "Like other dependence receptors, ptc1 contains a dependence-as-associated receptor c-terminal motif that is cleaved by caspases at a conserved aspartic acid (asp 1392) in the absence of shh, to expose a proapoptotic domain." SIGNOR-104585 CASP3 protein P42574 UNIPROT SPTAN1 protein Q13813 UNIPROT down-regulates cleavage 9606 BTO:0000150;BTO:0000567 9624143 t amattioni "Caspase-3 is required for alpha-fodrin cleavage but dispensable for cleavage of other death substrates in apoptosis." SIGNOR-57891 CASP3 protein P42574 UNIPROT GRIPAP1 protein Q4V328 UNIPROT "up-regulates activity" cleavage 9606 17761173 t Giorgia "These results suggest that the region of GRASP‐1 downstream of the Caspase‐3‐cleavage site is capable of activating the JNK signaling pathway by enhancing the phosphorylation of JNK. these results suggest that full length GRASP‐1 does not enhance JNK pathway activity, possibly due to the inhibitory effect of the N‐terminal fragment on the C‐terminal fragment. In contrast, Caspase‐3 cleavage of GRASP‐1 releases the C‐terminal fragment, which in turn activates JNK signaling by serving as a scaffold protein." SIGNOR-260641 CASP3 protein P42574 UNIPROT BAD protein Q92934 UNIPROT "up-regulates activity" cleavage 9606 BTO:0000938 15231831 t lperfetto "Casp3 cleaves bad at asp-61. In addition, caspases convert bad(l) into a pro-death fragment that resembles the short splice variant." SIGNOR-126727 CASP3 protein P42574 UNIPROT GORASP1 protein Q9BQQ3 UNIPROT "down-regulates quantity by destabilization" cleavage Asp317 VSGISLLdNSNASVW 9606 BTO:0000567 11815631 t Giulio "Together, our results strongly suggest GRASP65 is a specific substrate for caspase-3.|This suggests that GRASP65 cleavage is required for fragmentation of the Golgi ribbon during apoptosis.| we analyzed the sequence in this region and identified three potential cleavage sites as SLLD320S, SFPD375S, and TLPD393G|mutation of all three aspartic acid residues completely blocked cleavage" SIGNOR-260602 CASP3 protein P42574 UNIPROT GORASP1 protein Q9BQQ3 UNIPROT "down-regulates quantity by destabilization" cleavage Asp372 EFEVSFLdSPGAQAQ 9606 BTO:0000567 11815631 t Giulio "Together, our results strongly suggest GRASP65 is a specific substrate for caspase-3.|This suggests that GRASP65 cleavage is required for fragmentation of the Golgi ribbon during apoptosis.| we analyzed the sequence in this region and identified three potential cleavage sites as SLLD320S, SFPD375S, and TLPD393G|mutation of all three aspartic acid residues completely blocked cleavage" SIGNOR-260603 CASP3 protein P42574 UNIPROT GORASP1 protein Q9BQQ3 UNIPROT "down-regulates quantity by destabilization" cleavage Asp390 LPQLTLPdSLTSAAS 9606 11815631 t Giulio "Together, our results strongly suggest GRASP65 is a specific substrate for caspase-3.|This suggests that GRASP65 cleavage is required for fragmentation of the Golgi ribbon during apoptosis.| we analyzed the sequence in this region and identified three potential cleavage sites as SLLD320S, SFPD375S, and TLPD393G|mutation of all three aspartic acid residues completely blocked cleavage" SIGNOR-260604 CASP3 protein P42574 UNIPROT GORASP1 protein Q9BQQ3 UNIPROT "up-regulates activity" cleavage Asp390 LPQLTLPdSLTSAAS 17761173 t lperfetto "In contrast, Caspase‐3 cleavage of GRASP‐1 releases the C‐terminal fragment, which in turn activates JNK signaling by serving as a scaffold protein" SIGNOR-260613 CASP3 protein P42574 UNIPROT KDM4C protein Q9H3R0 UNIPROT "down-regulates activity" cleavage 9606 29207681 t miannu "JMJD2C as a novel substrate for caspase-3 (cysteine-aspartic acid protease-3), and cleavage of JMJD2C by caspase-3 led to inactivation of JMJD2C demethylase activity and elevation of H3K9 methylation levels." SIGNOR-263870 CASP3 protein P42574 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" cleavage -1 10579725 t 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 RPS27 protein P42677 UNIPROT "40S cytosolic small ribosomal subunit" complex SIGNOR-C286 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262444 MATK protein P42679 UNIPROT LYN protein P07948 UNIPROT "down-regulates activity" phosphorylation Tyr508 YTATEGQyQQQP -1 9171348 t miannu "In vitro phosphorylation assays showed that Chk suppressed Lyn activity by phosphorylating its C-terminal negative regulatory tyrosine." SIGNOR-250177 TEC protein P42680 UNIPROT TEC protein P42680 UNIPROT up-regulates phosphorylation Tyr206 RLERGQEyLILEKND 9606 12573241 t lperfetto "Tec family protein tyrosine kinases (tfks) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the sh3 domain via a transphosphorylation mechanism. Here, we could confirm that y223 is the only site in the btk-sh3 domain being detectably phosphorylated" SIGNOR-98098 TEC protein P42680 UNIPROT BMX protein P51813 UNIPROT up-regulates phosphorylation Tyr224 DSNSKKIyGSQPNFN 9606 12573241 t lperfetto "Tec family protein tyrosine kinases (tfks) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the sh3 domain via a transphosphorylation mechanism. For bmx, we obtained two phosphorylated sites, y215 and y223 (fig. 6c). The bmx-y215 is a conserved tyrosine, which is homologous to btk-y223 and itk-y180" SIGNOR-98094 TEC protein P42680 UNIPROT BMX protein P51813 UNIPROT "up-regulates activity" phosphorylation Tyr216 SSTSLAQyDSNSKKI 9606 BTO:0000873 12573241 t lperfetto "Tec family protein tyrosine kinases (TFKs) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop.The major phosphorylation sites were identified as conserved tyrosines, for Itk Y180 and for Bmx Y215, both sites being homologous to the Y223 site in Btk" SIGNOR-246647 TEC protein P42680 UNIPROT BTK protein Q06187 UNIPROT "down-regulates activity" phosphorylation Tyr223 LKKVVALyDYMPMNA 9606 12573241 t lperfetto "Tec family protein tyrosine kinases (TFKs) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the SH3 domain via a transphosphorylation mechanism, which for Bruton's tyrosine kinase (Btk) affects tyrosine 223.|In Btk, the SH3 domain mutation Y223F results in enhanced fibroblast transformation, implying that the SH3 domain may play a negative regulatory role" SIGNOR-246652 TEC protein P42680 UNIPROT STAP1 protein Q9ULZ2 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007 10518561 t miannu "In 293 cells expressing recombinant BRDG1 and various PTKs, Tec and Pyk2, but not Btk, Bmx, Lyn, Syk, or c-Abl, induced marked phosphorylation of BRDG1 on tyrosine residues. BRDG1 was also phosphorylated by Tec directly in vitro. Efficient phosphorylation of BRDG1 by Tec required the PH and SH2 domains as well as the kinase domain of the latter. Furthermore, BRDG1 was shown to participate in a positive feedback loop by increasing the activity of Tec. BRDG1 transcripts are abundant in the human B cell line Ramos, and the endogenous protein underwent tyrosine phosphorylation in response to BCR stimulation. BRDG1 thus appears to function as a docking protein acting downstream of Tec in BCR signaling." SIGNOR-261817 TXK protein P42681 UNIPROT CTLA4 protein P16410 UNIPROT "up-regulates quantity by stabilization" phosphorylation Tyr201 SPLTTGVyVKMPPTE 9606 9813138 t lperfetto "We demonstrate that rlk (resting lymphocyte kinase) is capable of phosphorylating ctla-4 at the yvkm motif. Consistent with this finding, rlk is capable of providing conditions for the binding of the sh2 domains of pi 3-kinase to the receptor. Ctla-4 is therefore the first known substrate for rlk suggesting the possibility that this kinase may participate in ctla-4 function" SIGNOR-61624 TXK protein P42681 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr145 PVEDDADyEPPPSND 9606 BTO:0000782 10660534 t lperfetto "Resting lymphocyte kinase (rlk/txk) targets lymphoid adaptor slp-76 in the cooperative activation of interleukin-2 transcription in t-cells. In this study, we report that rlk phosphorylates slp-76 at its n-terminal yesp/yepp sites. A third tyrosine within the amino-terminal region (y145) appears to be the most important for optimal slp-76 function" SIGNOR-74848 TXK protein P42681 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr113 SSFEEDDyESPNDDQ 9606 BTO:0000782 8892604 t lperfetto "Resting lymphocyte kinase (rlk/txk) targets lymphoid adaptor slp-76 in the cooperative activation of interleukin-2 transcription in t-cells. In this study, we report that rlk phosphorylates slp-76 at its n-terminal yesp/yepp sites. A third tyrosine within the amino-terminal region (y145) appears to be the most important for optimal slp-76 function" SIGNOR-44665 TXK protein P42681 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr145 PVEDDADyEPPPSND 9606 BTO:0000782 8892604 t lperfetto "Resting lymphocyte kinase (rlk/txk) targets lymphoid adaptor slp-76 in the cooperative activation of interleukin-2 transcription in t-cells. In this study, we report that rlk phosphorylates slp-76 at its n-terminal yesp/yepp sites. A third tyrosine within the amino-terminal region (y145) appears to be the most important for optimal slp-76 function" SIGNOR-44669 ABL2 protein P42684 UNIPROT PSMA7 protein O14818 UNIPROT down-regulates phosphorylation Tyr153 QTDPSGTyHAWKANA 9606 16678104 t lperfetto "Proteasome-mediated proteolysis is a primary protein degradation pathway in cells. The present study demonstrates that c-abl and arg (abl-related gene) tyrosine kinases associate with and phosphorylate the proteasome psma7 (alpha4) subunit at tyr-153. Consequently, proteasome-dependent proteolysis is compromised" SIGNOR-146589 ABL2 protein P42684 UNIPROT SIVA1 protein O15304 UNIPROT up-regulates phosphorylation Tyr34 RGVCAERySQEVFEK 9606 11278261 t llicata "Our results also demonstrate that mutation of the siva-1 tyr48 site abrogates the apoptotic function of siva-1 and that apoptosis induced by siva-1 is dependent on expression of kinase-active arg." SIGNOR-104992 ABL2 protein P42684 UNIPROT CAT protein P04040 UNIPROT up-regulates phosphorylation Tyr231 NANGEAVyCKFHYKT 9606 12950161 t lperfetto "C-abl and arg phosphorylated catalase at tyr231 and tyr386 in vitrocatalase is a major effector in the defense of aerobic cells against oxidative stress. Recent studies have shown that catalase activity is stimulated by the c-abl and arg tyrosine kinases" SIGNOR-86680 ABL2 protein P42684 UNIPROT CAT protein P04040 UNIPROT up-regulates phosphorylation Tyr386 YRARVANyQRDGPMC 9606 12950161 t lperfetto "C-abl and arg phosphorylated catalase at tyr231 and tyr386 in vitrocatalase is a major effector in the defense of aerobic cells against oxidative stress. Recent studies have shown that catalase activity is stimulated by the c-abl and arg tyrosine kinases" SIGNOR-86684 ABL2 protein P42684 UNIPROT CAT protein P04040 UNIPROT "up-regulates activity" phosphorylation Tyr231 NANGEAVyCKFHYKT 9606 BTO:0000093 12777400 t lperfetto "C-abl and arg phosphorylated catalase at tyr231 and tyr386 in vitrocatalase is a major effector in the defense of aerobic cells against oxidative stress. Recent studies have shown that catalase activity is stimulated by the c-abl and arg tyrosine kinases" SIGNOR-101306 ABL2 protein P42684 UNIPROT CAT protein P04040 UNIPROT "up-regulates activity" phosphorylation Tyr231 NANGEAVyCKFHYKT 9606 12777400 t Manara "These findings indicate that (i) ABL1 and Arg activate catalase by phosphorylation at both Tyr231 and Tyr386" SIGNOR-260771 ABL2 protein P42684 UNIPROT CAT protein P04040 UNIPROT "up-regulates activity" phosphorylation Tyr386 YRARVANyQRDGPMC 9606 12777400 t Manara "These findings indicate that (i) ABL1 and Arg activate catalase by phosphorylation at both Tyr231 and Tyr386" SIGNOR-260772 ABL2 protein P42684 UNIPROT CAT protein P04040 UNIPROT "up-regulates activity" phosphorylation Tyr386 YRARVANyQRDGPMC 9606 BTO:0000093 12777400 t lperfetto "C-abl and arg phosphorylated catalase at tyr231 and tyr386 in vitrocatalase is a major effector in the defense of aerobic cells against oxidative stress. Recent studies have shown that catalase activity is stimulated by the c-abl and arg tyrosine kinases" SIGNOR-101310 ABL2 protein P42684 UNIPROT GPX1 protein P07203 UNIPROT "up-regulates activity" phosphorylation Tyr98 EILNSLKyVRPGGGF 9606 12893824 t lperfetto "GPx1 also functions as a substrate for c-Abl- and Arg-mediated phosphorylation on Tyr-96. The results further show that c-Abl and Arg stimulate GPx activity and that these kinases contribute to GPx-mediated protection of cells against oxidative stress." SIGNOR-104328 ABL2 protein P42684 UNIPROT CEBPB protein P17676 UNIPROT up-regulates phosphorylation Tyr78 RAIDFSPyLEPLGAP 9606 BTO:0000007 19563810 t gcesareni "The y79 amino acid residue of c/ebpbeta was phosphorylated by c-abl or arg. The phosphorylation of c/ebpbeta resulted in an increased c/ebpbeta stability and a potentiation of c/ebpbeta transcription activation activity in cells" SIGNOR-186427 ABL2 protein P42684 UNIPROT LGALS3 protein P17931 UNIPROT up-regulates phosphorylation Tyr118 AGPLIVPyNLPLPGG 9606 20150913 t llicata "The sh (src homology)3 domains of c-abl/arg bind to a p(80)gppsgp motif of gal3, and tyr79 and tyr118 are the major tyrosine phosphorylation sites. A consequence of this interaction and phosphorylation is the significant impairment of chaperone-mediated autophagy of gal3." SIGNOR-163743 ABL2 protein P42684 UNIPROT LGALS3 protein P17931 UNIPROT up-regulates phosphorylation Tyr79 GAPAPGVyPGPPSGP 9606 20150913 t llicata "The sh (src homology)3 domains of c-abl/arg bind to a p(80)gppsgp motif of gal3, and tyr79 and tyr118 are the major tyrosine phosphorylation sites. A consequence of this interaction and phosphorylation is the significant impairment of chaperone-mediated autophagy of gal3." SIGNOR-163747 ABL2 protein P42684 UNIPROT ABL2 protein P42684 UNIPROT up-regulates phosphorylation Tyr261 GLVTTLHyPAPKCNK 9606 15735735 t lperfetto "The results show that arg is stabilized in response to 0.1 mm h2o2 by autophosphorylation of y-261, consistent with involvement of the arg kinase function in regulating arg levels. The results further demonstrate that c-abl-mediated phosphorylation of arg on y-261 similarly confers arg stabilization" SIGNOR-134400 ABL2 protein P42684 UNIPROT CRK protein P46108 UNIPROT down-regulates phosphorylation Tyr221 GGPEPGPyAQPSVNT 10090 15886098 t gcesareni "Rin1 binds to the abl sh3 and sh2 domains, and these interactions stimulate abl2 catalytic activity. This leads to increased phosphorylation of crk and crkl, inhibiting these cytoskeletal regulators by promoting intramolecular over intermolecular associations. the ability of crk to function as an adaptor protein is negatively regulated and terminated by phosphorylation on y221, which results in an intramolecular sh2-ptyr clamp, thereby resulting in the disassembly of crk-mediated signaling complexes" SIGNOR-136955 ABL2 protein P42684 UNIPROT CRK protein P46108 UNIPROT down-regulates phosphorylation 9606 BTO:0000149 15886098 t amattioni "Abl2 kinase activity toward crk leads to increased phosphorylation of crk, inhibiting this cytoskeletal regulator by promoting intramolecular over intermolecular associations." SIGNOR-136958 NCAPD3 protein P42695 UNIPROT "Condensin II" complex SIGNOR-C342 SIGNOR "form complex" binding 9606 32445620 t miannu "The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction." SIGNOR-263912 LIFR protein P42702 UNIPROT IL6ST protein P40189 UNIPROT up-regulates binding 9606 24710148 t 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-204850 RPL35 protein P42766 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262466 WAS protein P42768 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR "up-regulates activity" binding 9606 BTO:0000567 20498093 t lperfetto "Members of the Wiskott-Aldrich syndrome protein (WASP) family, which includes WASP, N-WASP, WAVE (1–3), WHAMM, JMY, and WASH, control actin cytoskeletal dynamics throughout biology. They act in large part by regulating the actin nucleating activity of the ubiquitous Arp2/3 complex. WASP proteins stimulate Arp2/3 complex using a conserved C-terminal VCA (Verprolin homologous, central hydrophobic, and acidic) region. They contain distinct N-terminal elements, which facilitate integration into unique macromolecular complexes." SIGNOR-261001 CDKN2B protein P42772 UNIPROT CDK4 protein P11802 UNIPROT down-regulates binding 9606 BTO:0000763 9042862 t gcesareni "We present evidence that the different subcellular location of p15 and p27 ensures the prior access of p15 to cdk4. In the cell, p15 is localized mostly in the cytoplasm, whereas p27 is nuclear. p15 prevails over p27 or a p27 construct consisting of the cdk inhibitory domain tagged with a nuclear localization signal. However, when p15 and p27 are forced to reside in the same subcellular location, either the cytoplasm or the nucleus, p15 no longer prevents p27 from binding to cdk4. These properties allow p15 and p27 to coordinately inhibit cdk4 and cdk2." SIGNOR-46758 CDKN2C protein P42773 UNIPROT CDK6 protein Q00534 UNIPROT down-regulates binding 9606 8891723 t miannu "The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks,cdk4and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb." SIGNOR-44601 PRCP protein P42785 UNIPROT POMC protein P01189 UNIPROT "down-regulates activity" 10090 20694162 f miannu "Prolylcarboxypeptidase (PRCP) was found to be responsible for the control of food intake and energy expenditure at a central level. The molecular mechanisms underlying the suppression of food intake in PRCP-deficient mice or by the inhibitor of PRCP clearly provide physiological evidence that PRCP is an inactivator of α-MSH" SIGNOR-252372 MTHFR protein P42898 UNIPROT "(6R)-5,10-methylenetetrahydrofolic acid" smallmolecule CHEBI:1989 ChEBI "down-regulates quantity" 10720211 t lperfetto "Methylenetetrahydrofolate reductase (MTHFR) plays a central role in the folate cycle and contributes to the metabolism of the amino acid homocysteine. It catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, thus generating the active form of folate required for remethylation of homocysteine to methionine." SIGNOR-253140 MTHFR protein P42898 UNIPROT 5-methyltetrahydrofolate smallmolecule CHEBI:20612 ChEBI "up-regulates quantity" "small molecule catalysis" 10720211 t lperfetto "Methylenetetrahydrofolate reductase (MTHFR) plays a central role in the folate cycle and contributes to the metabolism of the amino acid homocysteine. It catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, thus generating the active form of folate required for remethylation of homocysteine to methionine." SIGNOR-253139 SLC1A3 protein P43003 UNIPROT "glutamic acid" smallmolecule CHEBI:18237 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000524 26687113 t miannu "After release from presynaptic nerve terminals, glutamate is quickly removed from the synaptic cleft by a family of five glutamate transporters, the so-called excitatory amino acid transporters (EAAT1-5). In glia or in neurons, EAATs mediate the re-uptake of synaptically released glutamate via the coupled co-transport of three Na+, one H+, and one glutamate, in counter-transport to one K+." SIGNOR-264802 SLC1A2 protein P43004 UNIPROT "glutamic acid" smallmolecule CHEBI:18237 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000524 26687113 t miannu "After release from presynaptic nerve terminals, glutamate is quickly removed from the synaptic cleft by a family of five glutamate transporters, the so-called excitatory amino acid transporters (EAAT1-5)." SIGNOR-264803 SLC1A1 protein P43005 UNIPROT "glutamic acid" smallmolecule CHEBI:18237 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000524 26687113 t miannu "After release from presynaptic nerve terminals, glutamate is quickly removed from the synaptic cleft by a family of five glutamate transporters, the so-called excitatory amino acid transporters (EAAT1-5)." SIGNOR-264804 MAPK9 protein P45984 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser154 SSVSSSPsPPFGHSA 9606 12050114 t gcesareni "Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro." SIGNOR-88744 GDF5 protein P43026 UNIPROT BMPR1B protein O00238 UNIPROT "up-regulates activity" binding 10090 15890363 t "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 GDF5 protein P43026 UNIPROT ID1 protein P41134 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004291 16716349 f Regulation miannu "GDF5 induces ID1 and ID3 in HUVSMC by a smad-dependent, MAPK-independent pathway. GDF5 binds to specific receptors, thereby inducing phosphorylation and translocation of smad1 to the nucleus where it is involved in the regulation of transcription." SIGNOR-251871 GDF5 protein P43026 UNIPROT ID3 protein Q02535 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004291 16716349 f Regulation miannu "GDF5 induces ID1 and ID3 in HUVSMC by a smad-dependent, MAPK-independent pathway. GDF5 binds to specific receptors, thereby inducing phosphorylation and translocation of smad1 to the nucleus where it is involved in the regulation of transcription." SIGNOR-251872 GDF5 protein P43026 UNIPROT TRPS1 protein Q9UHF7 UNIPROT "up-regulates activity" relocalization 10090 BTO:0005092 18363966 t "Regulation of localization" miannu "Treatment of cells with Gdf5 enhanced Trps1 protein levels and phosphorylation of p38 mitogen-activated protein kinase (MAPK) in a dose-dependent manner. Nuclear translocation of Trps1 was also induced by Gdf5. These effects were blocked by a dominant negative form of activin-linked kinase 6 (dn-Alk6) and by SB203580, an inhibitor of the p38 MAPK pathway. Conversely, Gdf5 expression was suppressed by the over-expression of Trps1." SIGNOR-251867 PAFAH1B1 protein P43034 UNIPROT CLIP1 protein P30622 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 11940666 t miannu "Here we demonstrate colocalization and direct interaction between CLIP-170 and LIS1. In mammalian cells, LIS1 recruitment to kinetochores is dynein/dynactin dependent, and recruitment there of CLIP-170 is dependent on its site of binding to LIS1, located in the distal zinc finger motif." SIGNOR-252166 PAFAH1B1 protein P43034 UNIPROT DYNC1H1 protein Q14204 UNIPROT "up-regulates activity" binding 10090 BTO:0000938 11163259 t miannu "We demonstrate that LIS1 directly interacts with the cytoplasmic dynein heavy chain (CDHC) and NUDEL. LIS1 specifically binds the P1 loop domain of CDHC, while NUDEL binds the C-terminal region as well as a distinct binding site in the P1 loop domain. LIS1 and NUDEL regulate CDHC localization and motor function. Reduction of LIS1 leads to mislocalization of NUDEL, CDHC, β-tubulin, and the Golgi complex" SIGNOR-252158 PAFAH1B1 protein P43034 UNIPROT NDEL1 protein Q9GZM8 UNIPROT "up-regulates activity" binding 10090 BTO:0000938 11163259 t miannu "We demonstrate that LIS1 directly interacts with the cytoplasmic dynein heavy chain (CDHC) and NUDEL. LIS1 is required for the proper distribution of NUDEL and cellular components regulated by CDHC function. Reduction of LIS1 leads to mislocalization of NUDEL, CDHC, β-tubulin, and the Golgi complex" SIGNOR-252157 PTGFR protein P43088 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257193 PTGFR protein P43088 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257082 PTGFR protein P43088 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256810 PTGER3 protein P43115 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256859 PTGER3 protein P43115 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256995 PTGER3 protein P43115 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257111 PTGER3 protein P43115 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256716 PTGER3 protein P43115 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257203 PTGER2 protein P43116 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256899 PTGER2 protein P43116 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256756 PTGIR protein P43119 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256949 PTGIR protein P43119 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257078 PTGIR protein P43119 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256806 MSH2 protein P43246 UNIPROT BLM protein P54132 UNIPROT up-regulates binding 9606 SIGNOR-C60 15064730 t miannu "We show that the recombinant hmsh2/6 protein complex stimulated the ability of the bloom's syndrome gene product, blm, to process holliday junctions in vitro" SIGNOR-123699 MSH2 protein P43246 UNIPROT MSH2/MSH6 complex SIGNOR-C60 SIGNOR "form complex" binding 9606 15064730 t miannu "The human msh2/6 complex is essential for mismatch recognition during the repair of replication errors." SIGNOR-123702 MAPK8 protein P45983 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr739 SEGSGTAtPSALITT 9606 19245816 t gcesareni "In addition, for mutation of the jnk-1 phosphorylated residues of sp1, namely, sp1(t278/739a) and sp1(t278/739d), the effect of ga on sp1 stability was reversed." SIGNOR-184194 GRK6 protein P43250 UNIPROT SLC9A3R1 protein O14745 UNIPROT "down-regulates activity" phosphorylation Ser290 PALVRSAsSDTSEEL 9606 BTO:0000007 10446210 t "GRK6A phosphorylates NHERF on Ser289, the primary site of constitutive phosphorylation of NHERF in HEK-293 cells. The interaction of NHERF and NHE3 is mediated by the region of NHERF encompassing the second PDZ domain and the tail (25), and it is therefore reasonable that phosphorylation of the serine-rich stretch in the center of this region (including Ser289) might affect the physical interaction of NHERF with NHE3." SIGNOR-251214 GRK6 protein P43250 UNIPROT BDKRB2 protein P30411 UNIPROT "down-regulates activity" phosphorylation Ser366 EPIQMENsMGTLRTS 9606 BTO:0000007 11517230 t "Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration." SIGNOR-251207 GRK6 protein P43250 UNIPROT BDKRB2 protein P30411 UNIPROT "down-regulates activity" phosphorylation Ser373 SMGTLRTsISVERQI 9606 BTO:0000007 11517230 t "Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration." SIGNOR-251205 GRK6 protein P43250 UNIPROT BDKRB2 protein P30411 UNIPROT "down-regulates activity" phosphorylation Ser375 GTLRTSIsVERQIHK 9606 BTO:0000007 11517230 t "Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration." SIGNOR-251206 GRK6 protein P43250 UNIPROT GRK6 protein P43250 UNIPROT unknown phosphorylation Ser484 VLDIEQFsTVKGVEL 9534 BTO:0000298 10334944 t "GRK6 Is Autophosphorylated in COS-7 Cells. GRK6, like GRK5, is autophosphorylated on Ser484 and Thr485. Whether the autophosphorylation of GRK6 modulates its activity remains however to be established." SIGNOR-251211 GRK6 protein P43250 UNIPROT GRK6 protein P43250 UNIPROT unknown phosphorylation Thr485 LDIEQFStVKGVELE 9534 BTO:0000298 10334944 t "GRK6 Is Autophosphorylated in COS-7 Cells. GRK6, like GRK5, is autophosphorylated on Ser484 and Thr485. Whether the autophosphorylation of GRK6 modulates its activity remains however to be established." SIGNOR-251212 GRK6 protein P43250 UNIPROT LTB4R protein Q15722 UNIPROT "down-regulates activity" phosphorylation Thr308 VAKLLEGtGSEASST 9534 BTO:0000298 12077128 t "Thr(308) is a major residue involved in GRK6-mediated desensitization of BLT1 signaling." SIGNOR-251213 ETV4 protein P43268 UNIPROT VIM protein P08670 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000093;BTO:0000815 8895512 f miannu "Our results suggest that PEA3 specifically transactivates vimentin promoter through PEA3 site. Among members of the ETS transcription factor family only Erg showed ability to transactivate vimentin promoter besides PEA3." SIGNOR-254070 ETV4 protein P43268 UNIPROT POU5F1 protein Q01860 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24983502 f miannu "Transcriptional activation of oct4 by the ets transcription factor pea3 in nccit human embryonic carcinoma cells" SIGNOR-205173 CRYBB2 protein P43320 UNIPROT CRYBB3 protein P26998 UNIPROT "up-regulates activity" binding 9606 16319073 t miannu "At high concentrations or in the lens, βB2-crystallin forms hetero-oligomers with other β-crystallins. These oligomeric β-crystallins further participate in the formation of a supramolecular assembly that is important in lens function-lens transparency." SIGNOR-252152 CRYBB2 protein P43320 UNIPROT CRYBB2 protein P43320 UNIPROT "up-regulates activity" binding 9606 16319073 t miannu "βB2-crystallin is the major component of β-crystallin and is a dimer at low concentrations. At high concentrations or in the lens, βB2-crystallin forms hetero-oligomers with other β-crystallins. These oligomeric β-crystallins further participate in the formation of a supramolecular assembly that is important in lens function-lens transparency." SIGNOR-252154 CRYBB2 protein P43320 UNIPROT CRYBB1 protein P53674 UNIPROT "up-regulates activity" binding 9606 16319073 t miannu "At high concentrations or in the lens, βB2-crystallin forms hetero-oligomers with other β-crystallins. These oligomeric β-crystallins further participate in the formation of a supramolecular assembly that is important in lens function-lens transparency." SIGNOR-252153 PTPN9 protein P43378 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 16679294 t gcesareni "Ectopic expression of ptp-meg2 in cells inhibited insulin-induced phosphorylation of the insulin receptor, while rnai-mediated reduction of ptp-meg2 transcript levels enhanced insulin action" SIGNOR-146668 PTPN9 protein P43378 UNIPROT GHR protein P10912 UNIPROT down-regulates dephosphorylation 9606 12907755 t fspada "Using ghr hyper-phosphorylated by elk kinase, we have identified tc-ptp, ptp- , pyst-2, sap1, meg-2, ptp1b, and ptph1 as having substrate specificity for this receptor. In addition, we have shown that these same ptps (or rather their nonmutated counterparts) can dephosphorylate the ghr." SIGNOR-104577 PTPN9 protein P43378 UNIPROT GHR protein P10912 UNIPROT "down-regulates activity" dephosphorylation 10029 BTO:0000246 12907755 t "Protein tyrosine phosphatases (PTPs) play key roles in switching off tyrosine phosphorylation cascades, such as initiated by cytokine receptors. We have used substrate-trapping mutants of a large set of PTPs to identify members of the PTP family that have substrate specificity for the phosphorylated human GH receptor (GHR) intracellular domain. Among 31 PTPs tested, T cell (TC)-PTP, PTP-beta, PTP1B, stomach cancer-associated PTP 1 (SAP-1), Pyst-2, Meg-2, and PTP-H1 showed specificity for phosphorylated GHR" SIGNOR-248505 PTPN9 protein P43378 UNIPROT NSF protein P46459 UNIPROT down-regulates dephosphorylation Tyr83 QEIEVSLyTFDKAKQ 9606 15322554 t gcesareni "Our results suggest that the molecular mechanism by which ptp-meg2 promotes secretory vesicle fusion involves the local release of nsf from a tyrosine-phosphorylated, inactive state." SIGNOR-128348 MAPK9 protein P45984 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser164 FGHSAAVsPTFMPRS 9606 12050114 t gcesareni "Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro." SIGNOR-88748 ZAP70 protein P43403 UNIPROT LAT protein O43561 UNIPROT "up-regulates activity" phosphorylation Tyr156 ADEDEDDyHNPGYLV 9606 BTO:0000782 11368773 t lperfetto "In the present study we reconstituted the LAT signalling pathway by demonstrating that a direct tyrosine phosphorylation of LAT with activated protein-tyrosine kinase Zap70 is necessary and sufficient for the association and activation of signalling proteins. Zap-70 efficiently phosphorylates LAT on tyrosine residues at positions 226, 191, 171, 132 and 127." SIGNOR-247018 ZAP70 protein P43403 UNIPROT LAT protein O43561 UNIPROT "up-regulates activity" phosphorylation Tyr161 DDYHNPGyLVVLPDS 9606 BTO:0000782 11368773 t lperfetto "In the present study we reconstituted the LAT signalling pathway by demonstrating that a direct tyrosine phosphorylation of LAT with activated protein-tyrosine kinase Zap70 is necessary and sufficient for the association and activation of signalling proteins. Zap-70 efficiently phosphorylates LAT on tyrosine residues at positions 226, 191, 171, 132 and 127." SIGNOR-247022 ZAP70 protein P43403 UNIPROT LAT protein O43561 UNIPROT "up-regulates activity" phosphorylation Tyr200 SMESIDDyVNVPESG 9606 BTO:0000782 11368773 t lperfetto "In the present study we reconstituted the LAT signalling pathway by demonstrating that a direct tyrosine phosphorylation of LAT with activated protein-tyrosine kinase Zap70 is necessary and sufficient for the association and activation of signalling proteins. Zap-70 efficiently phosphorylates LAT on tyrosine residues at positions 226, 191, 171, 132 and 127." SIGNOR-247026 ZAP70 protein P43403 UNIPROT LAT protein O43561 UNIPROT "up-regulates activity" phosphorylation Tyr220 SLDGSREyVNVSQEL 9606 BTO:0000782 11368773 t lperfetto "In the present study we reconstituted the LAT signalling pathway by demonstrating that a direct tyrosine phosphorylation of LAT with activated protein-tyrosine kinase Zap70 is necessary and sufficient for the association and activation of signalling proteins. Zap-70 efficiently phosphorylates LAT on tyrosine residues at positions 226, 191, 171, 132 and 127." SIGNOR-247030 ZAP70 protein P43403 UNIPROT LAT protein O43561 UNIPROT "up-regulates activity" phosphorylation Tyr255 EEEGAPDyENLQELN 9606 BTO:0000782 11368773 t lperfetto "In the present study we reconstituted the LAT signalling pathway by demonstrating that a direct tyrosine phosphorylation of LAT with activated protein-tyrosine kinase Zap70 is necessary and sufficient for the association and activation of signalling proteins. Zap-70 efficiently phosphorylates LAT on tyrosine residues at positions 226, 191, 171, 132 and 127." SIGNOR-247034 ZAP70 protein P43403 UNIPROT MUC1 protein P15941 UNIPROT "up-regulates activity" phosphorylation Tyr1203 IFPARDTyHPMSEYP 9606 BTO:0000661 14766232 t lperfetto "Indeed, the present results demonstrate that ZAP-70 phosphorylates MUC1-CD and that the MUC1-CD Y-20 site functions, at least in part, as a ZAP-70 substrate (Fig. 4C). In this regard, the in vivo phosphorylation data indicate that ZAP-70 may also contribute to phosphorylation of MUC1-CD Y-46.The results further show that ZAP-70 phosphorylation of MUC1-CD stimulates the interaction of MUC1 andBeta-catenin." SIGNOR-247039 ZAP70 protein P43403 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr349 EEPPDHQyYNDFPGK 9606 BTO:0000782 9710204 t gcesareni "The syk-family kinases (syk and zap-70) were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site on shc1 (iso2)." SIGNOR-59647 ZAP70 protein P43403 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr350 EPPDHQYyNDFPGKE 9606 BTO:0000782 9710204 t gcesareni "The syk-family kinases (syk and zap-70) were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site on shc1 (iso2)." SIGNOR-59651 ZAP70 protein P43403 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr427 ELFDDPSyVNVQNLD 9606 BTO:0000782 9710204 t gcesareni "The syk-family kinases (syk and zap-70) were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site on shc1 (iso2)." SIGNOR-59659 ZAP70 protein P43403 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" phosphorylation Tyr319 TSVYESPySDPEELK 9606 BTO:0000661 10037717 t lperfetto "We show here that Tyr315 and Tyr319 in the interdomain B of ZAP-70 are autophosphorylated in vitro and become phosphorylated in vivo upon TCR triggering. Moreover, by mutational analysis, we demonstrate that phosphorylation of Tyr319 is required for the positive regulation of ZAP-70 function." SIGNOR-247053 ZAP70 protein P43403 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" phosphorylation Tyr315 MPMDTSVyESPYSDP 9606 BTO:0000661 11828374 t lperfetto "We show here that Tyr315 and Tyr319 in the interdomain B of ZAP-70 are autophosphorylated in vitro and become phosphorylated in vivo upon TCR triggering. Moreover, by mutational analysis, we demonstrate that phosphorylation of Tyr319 is required for the positive regulation of ZAP-70 function." SIGNOR-247048 ZAP70 protein P43403 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" phosphorylation Tyr126 RDAMVRDyVRQTWKL 9606 BTO:0000661 7961936 t lperfetto "We show that ZAP-70 has a primary autophosphorylation site at Tyr-292, with a secondary site at Tyr-126. We also show additional phosphorylation at Tyr-69, Tyr-178, Tyr-492, and Tyr-493 upon the addition of the protein tyrosine kinase, p56lck. By comparative two-dimensional phosphopeptide mapping, we show that ZAP-70 isolated from Jurkat T cells also autophosphorylates at Tyr-292 and Tyr-126" SIGNOR-247044 ZAP70 protein P43403 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" phosphorylation Tyr292 DTLNSDGyTPEPARI 9606 BTO:0000782;BTO:0000776 8756661 t lperfetto "The data further support a model in which ZAP-70 is first phosphorylated by Lck at Tyr-493 to upregulate the catalytic activity of ZAP-70. This in turn per- mits additional phosphorylation of ZAP-70 mediated, in part, by autophosphorylation at sites including Tyr-292 and -492" SIGNOR-43324 ZAP70 protein P43403 UNIPROT DUSP3 protein P51452 UNIPROT up-regulates phosphorylation Tyr138 SPTLVIAyLMMRQKM 9606 12447358 t gcesareni "We report here that vhr, a vaccinia virus vh1-related dual-specific protein phosphatase that inactivates the mitogen-activated kinases erk2 and jnk, is phosphorylated at y138 by zap-70. Tyr138 phosphorylation was required for vhr to inhibit the erk2-elk-1 pathway" SIGNOR-95877 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr128 DGEDDGDyESPNEEE 9606 BTO:0000782 8702662 t lperfetto "A fourth peptide derived from slp-76 encompassing tyr residues 423 and 426 was also phosphorylated by zap-70 but with a 10-15-fold lesser efficiency compared to tyr-113, _128, and _145. Phosphorylation of slp-76 by the zap-70 protein-tyrosine kinase is required for t-cell receptor function" SIGNOR-42960 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr145 PVEDDADyEPPPSND 9606 BTO:0000782 8702662 t lperfetto "A fourth peptide derived from slp-76 encompassing tyr residues 423 and 426 was also phosphorylated by zap-70 but with a 10-15-fold lesser efficiency compared to tyr-113, _128, and _145. Phosphorylation of slp-76 by the zap-70 protein-tyrosine kinase is required for t-cell receptor function" SIGNOR-42968 MAPK8 protein P45983 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser130 SGEQAEGsPGGPGDS 9606 12058028 t gcesareni "The stress-activated protein kinases p38 alpha and jnk1 stabilize p21(cip1) by phosphorylation.|p38 alpha and JNK1 phosphorylated p21 in vivo, and both p38 alpha and JNK1 phosphorylated p21 at Ser(130) in vitro." SIGNOR-89440 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr423 NSLNEEWyVSYITRP 9606 BTO:0000782 8702662 t lperfetto "A fourth peptide derived from slp-76 encompassing tyr residues 423 and 426 was also phosphorylated by zap-70 but with a 10-15-fold lesser efficiency compared to tyr-113, _128, and _145. Phosphorylation of slp-76 by the zap-70 protein-tyrosine kinase is required for t-cell receptor function" SIGNOR-42972 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr426 NEEWYVSyITRPEAE 9606 BTO:0000782 8702662 t lperfetto "A fourth peptide derived from slp-76 encompassing tyr residues 423 and 426 was also phosphorylated by zap-70 but with a 10-15-fold lesser efficiency compared to tyr-113, _128, and _145. Phosphorylation of slp-76 by the zap-70 protein-tyrosine kinase is required for t-cell receptor function" SIGNOR-42976 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr128 DGEDDGDyESPNEEE 9606 BTO:0000782 9047237 t lperfetto "Zap-70 phosphorylates slp-76 at specific sites that allow vav sh2 domain bindingwe also show by in vitro and in vivo analysis that two slp-76 pyesp motifs (y113 and y128) mediate binding, the first being more efficient." SIGNOR-46859 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT "up-regulates activity" phosphorylation Tyr113 SSFEEDDyESPNDDQ 9606 BTO:0000782 12817019 t lperfetto "Phosphorylation of slp-76 is required for prolonged erk activation in response to sdf-1_ cr signal transduction results in slp-76 tyrosine phosphorylation at the amino-terminal tyrosines 113, 128, and 145 via a mechanism requiring the zap-70 tyrosine kinase." SIGNOR-102507 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT "up-regulates activity" phosphorylation Tyr128 DGEDDGDyESPNEEE 9606 BTO:0000782 12817019 t lperfetto "Phosphorylation of slp-76 is required for prolonged erk activation in response to sdf-1_ cr signal transduction results in slp-76 tyrosine phosphorylation at the amino-terminal tyrosines 113, 128, and 145 via a mechanism requiring the zap-70 tyrosine kinase." SIGNOR-102511 ZAP70 protein P43403 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" phosphorylation Tyr323 DEPVADPyDQSFESR 9606 BTO:0000782 15735648 t lperfetto "Thus, phosphorylation of tyr323 dependent on the tyrosine kinase lck and mediated by zap70 serves as an important mechanism for tcr activation of p38 in t cells." SIGNOR-134329 ZAP70 protein P43403 UNIPROT DBNL protein Q9UJU6 UNIPROT up-regulates phosphorylation Tyr334 QAEEEAVyEEPPEQE 9606 BTO:0000782 14557276 t lperfetto "We found an interaction between the tyrosine kinase zap-70 and hip-55, which was induced by tcr stimulation. Zap-70 phosphorylated hip-55 at tyr-334 and tyr-344, which were shown to be the tyrosine phosphorylation sites of hip-55 in stimulated t cells.Our results demonstrate for the first time that hip-55 is an important adaptor protein for the jnk kinase cascade in tcr signaling." SIGNOR-118691 ZAP70 protein P43403 UNIPROT DBNL protein Q9UJU6 UNIPROT up-regulates phosphorylation Tyr344 PPEQETFyEQPPLVQ 9606 BTO:0000782 14557276 t lperfetto "We found an interaction between the tyrosine kinase zap-70 and hip-55, which was induced by tcr stimulation. Zap-70 phosphorylated hip-55 at tyr-334 and tyr-344, which were shown to be the tyrosine phosphorylation sites of hip-55 in stimulated t cells.Our results demonstrate for the first time that hip-55 is an important adaptor protein for the jnk kinase cascade in tcr signaling." SIGNOR-118695 ZAP70 protein P43403 UNIPROT GAB2 protein Q9UQC2 UNIPROT "up-regulates activity" phosphorylation Tyr614 KSTGSVDyLALDFQP 9606 BTO:0000782 11572860 t lperfetto "In the present study, we found that gab2 is phosphorylated by zap-70, associates with the tcr signaling complex, and acts as an inhibitory adaptor molecule via recruitment of shp-2 following tcr ligation." SIGNOR-110731 ZAP70 protein P43403 UNIPROT SH2B3 protein Q9UQQ2 UNIPROT up-regulates phosphorylation Tyr273 LEMPDNLyTFVLKVK 9606 BTO:0000782 9169414 t lperfetto "In vitro tyrosine phosphorylation of lnk by lck and zap-70. Tyrosine 297 would appear to be an attractive target for phosphorylation within the c-terminal domain. Our studies suggest that although lnk may participate in tcr signaling, its functions are in no way limiting during t cell development or activation." SIGNOR-48854 SYK protein P43405 UNIPROT SLC4A1 protein P02730 UNIPROT unknown phosphorylation Tyr21 ENLEQEEyEDPDIPE -1 10942405 t "The primary phosphorylation of band 3 catalyzed by p72syk generates the SH2 binding motifs that are a prerequisite for the following recruitment of Lyn. p72syk as the most likely candidate to perform this task and indicates Y8 and Y21. Syk and Lyn phosphorylate band 3 at both cytosolic and membrane domains, Y-phosphorylation/dephosphorylation is likely involved in the regulation of several erythrocyte functions (ie, glycolysis, cell shape, cytoskeleton" SIGNOR-251411 SYK protein P43405 UNIPROT SLC4A1 protein P02730 UNIPROT unknown phosphorylation Tyr8 MEELQDDyEDMMEEN -1 10942405 t "The primary phosphorylation of band 3 catalyzed by p72syk generates the SH2 binding motifs that are a prerequisite for the following recruitment of Lyn. p72syk as the most likely candidate to perform this task and indicates Y8 and Y21. Syk and Lyn phosphorylate band 3 at both cytosolic and membrane domains, Y-phosphorylation/dephosphorylation is likely involved in the regulation of several erythrocyte functions (ie, glycolysis, cell shape, cytoskeleton" SIGNOR-251413 SYK protein P43405 UNIPROT SLC4A1 protein P02730 UNIPROT up-regulates phosphorylation Tyr21 ENLEQEEyEDPDIPE 9606 10942405 t llicata "Our findings suggest that, upon phosphorylation by p72syk, y8 and y21 act as docking sites for the sh2 domain of lyn, which subsequently phosphorylates band 3 at additional secondary sites." SIGNOR-80788 SYK protein P43405 UNIPROT SLC4A1 protein P02730 UNIPROT up-regulates phosphorylation Tyr8 MEELQDDyEDMMEEN 9606 10942405 t llicata "Our findings suggest that, upon phosphorylation by p72syk, y8 and y21 act as docking sites for the sh2 domain of lyn, which subsequently phosphorylates band 3 at additional secondary sites." SIGNOR-80792 SYK protein P43405 UNIPROT LCK protein P06239 UNIPROT "down-regulates activity" phosphorylation Tyr192 NLDNGGFyISPRITF 9606 BTO:0000782 8798764 t lperfetto "Our experiments indicate that the TCR-induced activation of Erk2 depends on the function of SH2 domain of Lck and is reduced by phosphorylation of wild type Lck at Tyr192 or by mutation of this site to a negatively charged amino acid. Such dependence on the SH2 domain has also been reported for the bulk of TCR-induced tyrosine phosphorylation and activation of the interleukin 2 gene (26). Thus, phosphorylation of Lck at Tyr192 may represent a negative feedback mechanism in the interplay between Src and Syk family PTKs in TCR signaling" SIGNOR-246562 SYK protein P43405 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Tyr18 MEDHAGTyGLGDRKD 9606 BTO:0000938 18070606 t lperfetto "We established that tyrosine 18 was the primary residue in tau phosphorylated by sykphosphorylation of tau by syk could be involved in neurite outgrowth." SIGNOR-159648 MAPK8 protein P45983 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr57 NFDFVTEtPLEGDFA -1 12058028 t miannu "P38Œ± and JNK1 Phosphorylate p21 in Vitro at Thr57 and Ser130. These data suggest that phosphorylation at Thr57 is necessary for stabilization of p21." SIGNOR-250118 SYK protein P43405 UNIPROT FCGR2A protein P12318 UNIPROT "up-regulates activity" phosphorylation Tyr281 LEETNNDyETADGGY -1 8756631 t lperfetto "To identify the FcgammaRII-phosphorylating protein tyrosine kinase (PTK), we used the combination of an in vitro and an in vivo approach. In an in vitro assay using recombinant cytoplasmic tails of the different FcgammaRII isoforms as well as tyrosine exchange mutants, we show that each of the BCR-associated PTKs (Lyn, Blk, Fyn, and Syk) shows different phosphorylation patterns with regard to the different FcgammaR isoforms and pointFyn and Blk definitely phosphorylate Y-282 in the ITAM of Fc_RIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addi-tion to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation." SIGNOR-247590 SYK protein P43405 UNIPROT FCGR2A protein P12318 UNIPROT "up-regulates activity" phosphorylation Tyr304 TDDDKNIyLTLPPND -1 8756631 t lperfetto "To identify the FcgammaRII-phosphorylating protein tyrosine kinase (PTK), we used the combination of an in vitro and an in vivo approach. In an in vitro assay using recombinant cytoplasmic tails of the different FcgammaRII isoforms as well as tyrosine exchange mutants, we show that each of the BCR-associated PTKs (Lyn, Blk, Fyn, and Syk) shows different phosphorylation patterns with regard to the different FcgammaR isoforms and pointFyn and Blk definitely phosphorylate Y-282 in the ITAM of Fc_RIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addi-tion to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation." SIGNOR-246551 SYK protein P43405 UNIPROT HCLS1 protein P14317 UNIPROT up-regulates phosphorylation Tyr397 EDEPEGDyEEVLEPE 9606 BTO:0000776 9104825 t llicata "Here, we show that bcr-associated tyrosine kinases lyn and syk synergistically phosphorylate hs1, and that tyr-378 and tyr-397 of hs1 are the critical residues for its bcr-induced phosphorylation. once the two tyrosine residues are both phosphorylated, processive phosphorylation of hs1 by lyn and the other src family kinases would take place, producing hyperphosphorylated form of hs1. Finally, it is this hyperphosphorylated form of hs1 that translocates to the nucleus and activates b cell apoptosis." SIGNOR-47342 SYK protein P43405 UNIPROT VAV1 protein P15498 UNIPROT up-regulates phosphorylation 9606 11331248 t gcesareni "Vav interacts with the tyrosine kinase syk. inhibition of syk kinase activity prevents tyrosine phosphorylation of vav and its interaction with pi 3-k." SIGNOR-107046 SYK protein P43405 UNIPROT PRKCA protein P17252 UNIPROT "up-regulates activity" phosphorylation Tyr658 SDFEGFSyVNPQFVH 9606 BTO:0000830 12881490 t lperfetto "We present evidence that Tyr-662 and Tyr-658 of PKCbetaI and PKCalpha, respectively, are phosphorylated by Syk in the membrane compartment of FcepsilonRI-stimulated mast cells. These phosphorylations require prior PKC autophosphorylation of the adjacent serine residues (Ser-661 and Ser-657, respectively) and generate a binding site for the SH2 domain of the adaptor protein Grb-2." SIGNOR-246581 SYK protein P43405 UNIPROT PLCG1 protein P19174 UNIPROT "up-regulates activity" phosphorylation Tyr771 IGTAEPDyGALYEGR 9606 BTO:0000776 8657103 t lperfetto "Syk isolated from antigen receptor-activated B cells phosphorylated PLC-gamma1 on Tyr-771 and the key regulatory residue Tyr-783 in vitro, whereas Lyn from the same B cells phosphorylated PLC-gamma1 only on Tyr-771." SIGNOR-246572 SYK protein P43405 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr349 EEPPDHQyYNDFPGK 9606 BTO:0000782 9710204 t gcesareni "The syk-family kinases (syk and zap-70) were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site on sch1 (iso2)." SIGNOR-59635 SYK protein P43405 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr350 EPPDHQYyNDFPGKE 9606 BTO:0000782 9710204 t gcesareni "The syk-family kinases (syk and zap-70) were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site on sch1 (iso2)." SIGNOR-59639 SYK protein P43405 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr427 ELFDDPSyVNVQNLD 9606 BTO:0000782 9710204 t gcesareni "The syk-family kinases (syk and zap-70) were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site on sch1 (iso2)." SIGNOR-59643 SYK protein P43405 UNIPROT FCGR2C protein P31995 UNIPROT "up-regulates activity" phosphorylation Tyr287 PEETNNDyETADGGY -1 8756631 t miannu "Fyn and Blk definitely phosphorylate Y-282 in the ITAM of FcgRIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addition to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation" SIGNOR-262674 SYK protein P43405 UNIPROT FCGR2C protein P31995 UNIPROT "up-regulates activity" phosphorylation Tyr310 TDDDKNIyLTLPPND -1 8756631 t miannu "Fyn and Blk definitely phosphorylate Y-282 in the ITAM of FcgRIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addition to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation" SIGNOR-262675 SYK protein P43405 UNIPROT SNCA protein P37840 UNIPROT down-regulates phosphorylation Tyr125 VDPDNEAyEMPSEEG 9606 BTO:0000975;BTO:0000142 11744621 t llicata "Here, we show that alpha-synuclein (alpha-syn) is an outstanding substrate for the protein tyrosine kinase p72syk (syk), which phosphorylates three tyrosyl residues in its c-terminal domain (y-125, y-133, and y-136), here, we show that _-syn is an outstanding substrate for syk and that once it is tyrosine phosphorylated, it loses the ability to form oligomers." SIGNOR-113061 SYK protein P43405 UNIPROT SNCA protein P37840 UNIPROT down-regulates phosphorylation Tyr133 EMPSEEGyQDYEPEA 9606 BTO:0000975;BTO:0000142 11744621 t llicata "Here, we show that alpha-synuclein (alpha-syn) is an outstanding substrate for the protein tyrosine kinase p72syk (syk), which phosphorylates three tyrosyl residues in its c-terminal domain (y-125, y-133, and y-136), here, we show that _-syn is an outstanding substrate for syk and that once it is tyrosine phosphorylated, it loses the ability to form oligomers." SIGNOR-113065 GATA4 protein P43694 UNIPROT α-Catenin proteinfamily SIGNOR-PF72 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002320 21598020 t miannu "GATA-4 and MEF2C are known to bind to the GATA box 2 in the major promoter of CTNNA3 and this element is essential in directly regulating expression of CTNNA3 in cardiac muscle cells. The co-transfection of GATA-4 with MEF2C leads to a synergistic activation of the CTNNA3 promoter" SIGNOR-265815 SYK protein P43405 UNIPROT SNCA protein P37840 UNIPROT down-regulates phosphorylation Tyr136 SEEGYQDyEPEA 9606 BTO:0000975;BTO:0000142 11744621 t llicata "Here, we show that alpha-synuclein (alpha-syn) is an outstanding substrate for the protein tyrosine kinase p72syk (syk), which phosphorylates three tyrosyl residues in its c-terminal domain (y-125, y-133, and y-136), here, we show that _-syn is an outstanding substrate for syk and that once it is tyrosine phosphorylated, it loses the ability to form oligomers." SIGNOR-113069 SYK protein P43405 UNIPROT SYK protein P43405 UNIPROT "up-regulates activity" phosphorylation Tyr131 KENLIREyVKQTWNL 9606 BTO:0000776 9820500 t lperfetto "These represented sites of tyrosine phosphorylation previously identified from the study of in vitro autophosphorylated Syk. Phosphorylation was observed on peptides corresponding to Tyr130, Tyr317, Tyr342, Tyr346, Tyr519, and Tyr520" SIGNOR-246601 SYK protein P43405 UNIPROT SYK protein P43405 UNIPROT "up-regulates activity" phosphorylation Tyr323 STVSFNPyEPELAPW 9606 BTO:0000776 9820500 t lperfetto "These represented sites of tyrosine phosphorylation previously identified from the study of in vitro autophosphorylated Syk. Phosphorylation was observed on peptides corresponding to Tyr130, Tyr317, Tyr342, Tyr346, Tyr519, and Tyr520" SIGNOR-246605 SYK protein P43405 UNIPROT SYK protein P43405 UNIPROT "up-regulates activity" phosphorylation Tyr348 LPMDTEVyESPYADP 9606 BTO:0000776 9820500 t lperfetto "These represented sites of tyrosine phosphorylation previously identified from the study of in vitro autophosphorylated Syk. Phosphorylation was observed on peptides corresponding to Tyr130, Tyr317, Tyr342, Tyr346, Tyr519, and Tyr520" SIGNOR-246609 SYK protein P43405 UNIPROT SYK protein P43405 UNIPROT "up-regulates activity" phosphorylation Tyr526 LRADENYyKAQTHGK 9606 BTO:0000776 9820500 t lperfetto "These represented sites of tyrosine phosphorylation previously identified from the study of in vitro autophosphorylated Syk. Phosphorylation was observed on peptides corresponding to Tyr130, Tyr317, Tyr342, Tyr346, Tyr519, and Tyr520" SIGNOR-246621 SYK protein P43405 UNIPROT TUBA4A protein P68366 UNIPROT "up-regulates activity" phosphorylation Tyr432 MAALEKDyEEVGIDS 9606 BTO:0000776 9490415 t lperfetto "Syk, Activated by Cross-linking the B-cell Antigen Receptor, Localizes to the Cytosol Where It Interacts with and Phosphorylates alpha-Tubulin on Tyrosine" SIGNOR-246626 SYK protein P43405 UNIPROT SH3BP2 protein P78314 UNIPROT "up-regulates activity" phosphorylation Tyr183 HDDEDDSyLEPDSPE 9534 BTO:0004055 12709437 t lperfetto "By using the transient expression system in COS-7 cells, we have demonstrated that 3BP2 was predominantly phosphorylated on Tyr174, Tyr183, and Tyr446 when it was coexpressed with Syk" SIGNOR-246592 SYK protein P43405 UNIPROT SH3BP2 protein P78314 UNIPROT "up-regulates activity" phosphorylation Tyr448 GDDSDEDyEKVPLPN 9534 BTO:0004055 12709437 t lperfetto "By using the transient expression system in COS-7 cells, we have demonstrated that 3BP2 was predominantly phosphorylated on Tyr174, Tyr183, and Tyr446 when it was coexpressed with Syk." SIGNOR-246596 SYK protein P43405 UNIPROT IL15RA protein Q13261 UNIPROT "up-regulates activity" phosphorylation Tyr227 AVSLLACyLKSRQTP 9606 BTO:0001154 11714793 t lperfetto "Mutation of a defined region of the intracellular signaling portion of IL-15Ralpha (Tyr227) abrogates both the IL-15Ralpha/Syk association and IL-15Ralpha phosphorylation. Taken together, this suggests that Syk kinase physically and functionally associates with the IL-15Ralpha chain in B cells and that Syk plays a key role in mediating IL-15-induced signal transduction, thus accounting for the distinct functional consequences of IL-15 vs IL-2 binding to B cells" SIGNOR-246556 SYK protein P43405 UNIPROT IKZF1 protein Q13422 UNIPROT up-regulates phosphorylation Ser361 LAEGTPRsNHSAQDS 9606 BTO:0001271 23071339 t miannu "Syk phoshorylatesikarosat unique c-terminal serine phosphorylation sites s358 and s361, thereby augmenting its nuclear localization and sequence-specific dna binding activity. Mechanistically, we establish that syk-inducedikarosactivation is essential for its nuclear localization and optimal transcription factor function." SIGNOR-199096 SYK protein P43405 UNIPROT IKZF1 protein Q13422 UNIPROT up-regulates phosphorylation Ser364 GTPRSNHsAQDSAVE 9606 BTO:0001271 23071339 t miannu "Syk phoshorylatesikarosat unique c-terminal serine phosphorylation sites s358 and s361, thereby augmenting its nuclear localization and sequence-specific dna binding activity. Mechanistically, we establish that syk-inducedikarosactivation is essential for its nuclear localization and optimal transcription factor function." SIGNOR-199100 SYK protein P43405 UNIPROT BLNK protein Q8WV28 UNIPROT up-regulates phosphorylation Tyr72 SDDFDSDyENPDEHS 9606 BTO:0000776 12456653 t llicata "The phosphorylation of multiple tyrosine residues not only amplifies plcgamma-mediated signaling but also supports 'cis'-mediated interaction between distinct signaling effectors within a large molecular complex." SIGNOR-96044 SYK protein P43405 UNIPROT BLNK protein Q8WV28 UNIPROT up-regulates phosphorylation Tyr84 EHSDSEMyVMPAEEN 9606 BTO:0000776 12456653 t llicata "The phosphorylation of multiple tyrosine residues not only amplifies plcgamma-mediated signaling but also supports 'cis'-mediated interaction between distinct signaling effectors within a large molecular complex." SIGNOR-96048 SYK protein P43405 UNIPROT MAP4K1 protein Q92918 UNIPROT "up-regulates activity" phosphorylation Tyr381 SESSDDDyDDVDIPT 9606 11514608 t lperfetto "BCR ligation induced rapid tyrosine-phosphorylation of HPK1 mainly by Syk and Lyn, resulting in its association with BASH and catalytic activation. BCR-mediated activation of HPK1 was impaired in Syk- or BASH-deficient B cells. The functional SH2 domain of BASH and Tyr-379 within HPK1 which we identified as a Syk-phosphorylation site were both necessary for interaction of both proteins and efficient HPK1 activation after BCR stimulation." SIGNOR-246567 NAMPT protein P43490 UNIPROT NAD(1-) smallmolecule CHEBI:57540 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 12555668 t gcesareni "Pre-B-cell colony-enhancing factor, whose expression is up-regulated in activated lymphocytes, is a nicotinamide phosphoribosyltransferase, a cytosolic enzyme involved in NAD biosynthesi" SIGNOR-238602 NAMPT protein P43490 UNIPROT CLOCK/ARNTL complex SIGNOR-C195 SIGNOR down-regulates 19299583 f lperfetto "Using Per2:luciferase transcriptional reporter assays in HEK293 cells (Fig. 2C-E; S2), we show that inhibition of NAMPT by FK866 led to a significant increase in the CLOCK:BMAL1-driven transcription of the Per2:luciferase reporter (Fig. 2C), indicating that reduced NAMPT-mediated NAD+ biosynthesis released CLOCK:BMAL1 from the SIRT1-dependent suppression." SIGNOR-253721 NKX2-1 protein P43699 UNIPROT SFTPB protein P07988 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004299 18003659 f miannu "TGF-beta represses transcription of pulmonary surfactant protein-B gene in lung epithelial cells. Repression is mediated by SMAD3 through interactions with NKX2.1 and FOXA1, two key transcription factors that are positive regulators of SpB transcription." SIGNOR-254172 MAPK8 protein P45983 UNIPROT ELK3 protein P41970 UNIPROT "down-regulates activity" phosphorylation 11042694 t miannu "JNK binds to the J box in the middle of the protein, and binding is required for phosphorylation of the adjacent EXport motif. Both the binding and phosphorylation sites (the JEX element) are important for Net export." SIGNOR-250139 LPAR6 protein P43657 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257212 LPAR6 protein P43657 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256868 LPAR6 protein P43657 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257004 LPAR6 protein P43657 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257120 LPAR6 protein P43657 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 15856019 t gcesareni "Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13." SIGNOR-135822 LPAR6 protein P43657 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256725 LPAR6 protein P43657 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257286 LPAR6 protein P43657 UNIPROT GNA13 protein Q14344 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257347 PSMC4 protein P43686 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "form complex" binding 9606 BTO:0000007 29636472 t lperfetto "Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line" SIGNOR-263371 GATA4 protein P43694 UNIPROT HAMP protein P81172 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 21609320 f miannu "Co-transfection of a GATA-4 expression vector with a hepcidin promoter reporter construct enhanced hepcidin promoter transcriptional activity." SIGNOR-254196 GATA4 protein P43694 UNIPROT CTNNA3 protein Q9UI47 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002320 21598020 t miannu "GATA-4 and MEF2C are known to bind to the GATA box 2 in the major promoter of CTNNA3 and this element is essential in directly regulating expression of CTNNA3 in cardiac muscle cells. The co-transfection of GATA-4 with MEF2C leads to a synergistic activation of the CTNNA3 promoter" SIGNOR-265490 MMP13 protein P45452 UNIPROT F12 protein P00748 UNIPROT "down-regulates quantity by destabilization" cleavage Gly376 SMTRVVGgLVALRGA -1 10930399 t lperfetto "The data presented in this study show for the first time the degradation of Factor XII of the blood clotting system by matrix metalloproteinases. MMP-12, MMP-13, and MMP-14 cleave at Gly376Leu377|However, no activity of Factor XII can be observed after MMPinduced cleavage." SIGNOR-263609 MMP13 protein P45452 UNIPROT COL2A1 protein P02458 UNIPROT "down-regulates quantity by destabilization" cleavage Gly906 EGPPGPQgLAGQRGI 9606 8609233 t miannu "Although it appears that MMP-1 and MMP-13 both cleave type II collagen initially at the same site, MMP-13 affects a secondary cleavage to produce a 1/4-size collagen fragment with an NH2 terminus three amino acids removed from the primary cleavage site.The present work has demonstrated expression of MMP-13 in human osteoarthritic cartilage and shown that MMP-13 has significant type II collagen degrading activity." SIGNOR-256340 MMP13 protein P45452 UNIPROT FGA protein P02671 UNIPROT "down-regulates quantity by destabilization" cleavage Ala20 VVGTAWTaDSGEGDF -1 10930399 t lperfetto "Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-13 27YVATRDN g-chain| 20ADSGEGD a-chain| 124RNSVDXLNXN b-chain| 442LRTGKEKV a-chain" SIGNOR-263612 MMP13 protein P45452 UNIPROT FGA protein P02671 UNIPROT "down-regulates quantity by destabilization" cleavage Leu442 TSKGDKElRTGKEKV -1 10930399 t lperfetto "Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-13 27YVATRDN g-chain| 20ADSGEGD a-chain| 124RNSVDXLNXN b-chain| 442LRTGKEKV a-chain" SIGNOR-263613 MMP13 protein P45452 UNIPROT FGB protein P02675 UNIPROT "down-regulates quantity by destabilization" cleavage Arg124 LQQERPIrNSVDELN -1 10930399 t lperfetto "Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-13 27YVATRDN g-chain| 20ADSGEGD a-chain| 124RNSVDXLNXN b-chain| 442LRTGKEKV a-chain" SIGNOR-263615 MMP13 protein P45452 UNIPROT FGG protein P02679 UNIPROT "down-regulates quantity by destabilization" cleavage Tyr27 LSSTCVAyVATRDNC -1 10930399 t lperfetto "Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-13 27YVATRDN g-chain| 20ADSGEGD a-chain| 124RNSVDXLNXN b-chain| 442LRTGKEKV a-chain" SIGNOR-263614 CBX5 protein P45973 UNIPROT H3C1 protein P68431 UNIPROT "up-regulates activity" binding 9606 methylation:Lys10 RTKQTARkSTGGKAP 19111658 t miannu "A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing." SIGNOR-264490 CBX5 protein P45973 UNIPROT H3-3A protein P84243 UNIPROT "up-regulates activity" binding 9606 methylation:Lys10 RTKQTARkSTGGKAP 19111658 t miannu "A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing." SIGNOR-264488 CBX5 protein P45973 UNIPROT H3-4 protein Q16695 UNIPROT "up-regulates activity" binding 9606 methylation:Lys10 RTKQTARkSTGGKAP 19111658 t miannu "A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing." SIGNOR-264489 MAPK8 protein P45983 UNIPROT BCL2L11 protein O43521 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser69 GPLAPPAsPGPFATR 10090 15486195 t miannu "Ser69 can also be phosphorylated by JNK and p38MAPK at least in vitro. Phosphorylation of BimEL on Ser69 promotes its ubiquitination." SIGNOR-250132 MAPK8 protein P45983 UNIPROT BCL2L11 protein O43521 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser69 GPLAPPAsPGPFATR 9606 18174237 t gcesareni "Constitutive activation of the c-jun n-terminal kinase (jnk) pathway in sup-t1 cells promoted phosphorylation and degradation of bimel via the proteosome." SIGNOR-160323 MAPK8 protein P45983 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates phosphorylation Thr116 SCDKSTQtPSPPCQA 9606 12591950 t "The effect has been demonstrated using O43521-2" gcesareni "Here, we demonstrate that jnk phosphorylates two members of the bh3-only subgroup of bcl2-related proteins (bim and bmf) that are normally sequestered by binding to dynein and myosin v motor complexes. Phosphorylation by jnk causes release from the motor complexes" SIGNOR-98396 MAPK8 protein P45983 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates phosphorylation 9606 12591950 t gcesareni "Jnk phosphorylates two members of the bh3-only sub of bcl2-related proteins (bim and bmf)." SIGNOR-98399 MAPK8 protein P45983 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates phosphorylation 9606 18498746 t gcesareni "Jnk phosphorylates two members of the bh3-only sub of bcl2-related proteins (bim and bmf)." SIGNOR-178686 MAPK8 protein P45983 UNIPROT BCL2L11 protein O43521 UNIPROT "up-regulates activity" phosphorylation Ser77 PGPFATRsPLFIFMR 10090 BTO:0000938 12818176 t miannu "Mitochondrially localized JNKs but not their upstream activators MLKs or MKKs phosphorylated BIMEL at Ser65, potentiating its cytotoxicity without altering its subcellular distribution or integration into mitochondrial membranes. JNKs specifically phosphorylate BIMEL at Ser55, 65, and/or 73" SIGNOR-250133 MAPK8 protein P45983 UNIPROT LAT protein O43561 UNIPROT down-regulates phosphorylation Thr184 PSAPALStPGIRDSA 9606 BTO:0000782 15192708 t "The effect has been demonstrated using Q43561-2" gcesareni "Lat, an adapter protein essential for t-cell signaling, is phosphorylated at its thr 155 by erk in response to t-cell receptor stimulation. Thr 155 phosphorylation reduces the ability of lat to recruit plcgamma1 and slp76, leading to attenuation of subsequent downstream events such as [ca2+]i mobilization and activation of the erk pathway.Mutational analysis revealed that t155 but not t94 or t140 is the site of jnk-mediated phosphorylation (figure 2b). Erk also phosphorylated lat at t155 (figure 2c), whereas p38, which was able to phosphorylate atf2, failed to induce threonine phosphorylation of lat (figure 2d). These results indicate that lat is directly phosphorylated by erk and jnk at the same site, t155." SIGNOR-125774 MAPK8 protein P45983 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation 9606 BTO:0000007 20974802 t gcesareni "We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. External stimuli, which control the activity of mapks, such as phorbol esters and fibroblast growth factor 2 (fgf2) control the choice of the lrp6-ppps/tp kinase and regulate the amplitude of lrp6 phosphorylation and wnt/beta-catenin-dependent transcription." SIGNOR-169007 MAPK8 protein P45983 UNIPROT MYC protein P01106 UNIPROT "up-regulates activity" phosphorylation Ser62 LLPTPPLsPSRRSGL 9606 BTO:0000007;BTO:0000567 10551811 t lperfetto "The jnk pathway is selectively involved in the c-myc-mediated apoptosis and that the apoptotic function of c-myc is directly regulated by jnk pathway through phosphorylation at ser-62 and ser-71." SIGNOR-236018 MAPK8 protein P45983 UNIPROT MYC protein P01106 UNIPROT "up-regulates activity" phosphorylation Ser71 SRRSGLCsPSYVAVT 9606 BTO:0000007;BTO:0000567 10551811 t lperfetto "The jnk pathway is selectively involved in the c-myc-mediated apoptosis and that the apoptotic function of c-myc is directly regulated by jnk pathway through phosphorylation at ser-62 and ser-71." SIGNOR-236384 MAPK8 protein P45983 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates phosphorylation Ser226 IDENCLLsPLAGEDD 9606 12351702 t gcesareni "Taken together, these findings suggest that jnk-mediated phosphorylation of the gr-ser226 enhances gr nuclear export and may contribute to termination of gr-mediated transcription." SIGNOR-93558 MAPK8 protein P45983 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser20 PLSQETFsDLWKLLP 9606 11896587 t llicata "These findings strongly suggest that jnks are the major direct signaling mediators of uvb-induced p53 phosphorylation at serine 20. furthermore, phosphorylation of p53 at serine 20 by uvb-activated jnks and uvb-induced p53-dependent transcriptional activity were suppressed in jnk1 or jnk2 knockout (jnk1(-/-) or jnk2(-/-)) cells." SIGNOR-115831 MAPK8 protein P45983 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Thr81 APAPAAPtPAAPAPA 9606 12531896 t gcesareni "Wr1065 activates the jnk (c-jun n-terminal kinase), decreases complex formation between p53 and inactive jnk, and phosphorylates p53 at thr-81, a known site of phosphorylation by jnk." SIGNOR-97405 MAPK8 protein P45983 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation 9606 BTO:0000150;BTO:0000093 9724739 t amattioni "Activated jnk phosphorylates p53" SIGNOR-59812 MAPK8 protein P45983 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" phosphorylation Ser20 PLSQETFsDLWKLLP 10090 BTO:0004831 11896587 t lperfetto "Serine 20 phosphorylation of p53 has been shown to be required for the activation of p53 following UV radiation. we determined the role of map kinases in uvb-induced phosphorylation and found that jnks are directly involved in the phosphorylation of p53 at serine 20" SIGNOR-106538 MAPK8 protein P45983 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr81 APAPAAPtPAAPAPA 9606 BTO:0000007 11283254 t lperfetto "Jnk phosphorylated p53 at t81 in response to dna damage and stress-inducing agents, as determined by phospho-specific antibodies to t81 . Jun NH2-terminal kinase phosphorylation of p53 on Thr-81 is important for p53 stabilization and transcriptional activities in response to stress." SIGNOR-106542 MAPK8 protein P45983 UNIPROT APP protein P05067 UNIPROT up-regulates phosphorylation Thr743 VEVDAAVtPEERHLS 9606 BTO:0000793 12917434 t lperfetto "Phosphorylation of amyloid precursor protein at threonine 668 is essential for its copper-responsive trafficking in sh-sy5y neuroblastoma cells. We found that the threonine 668 within the abetapp intracellular domain (aid or elsewhere aicd) is indeed phosphorylated by jnk1" SIGNOR-117852 MAPK8 protein P45983 UNIPROT APP protein P05067 UNIPROT up-regulates phosphorylation Thr743 VEVDAAVtPEERHLS 9606 BTO:0000793 24610780 t lperfetto "Phosphorylation of amyloid precursor protein at threonine 668 is essential for its copper-responsive trafficking in sh-sy5y neuroblastoma cells. We found that the threonine 668 within the abetapp intracellular domain (aid or elsewhere aicd) is indeed phosphorylated by jnk1" SIGNOR-204679 MAPK8 protein P45983 UNIPROT JUN protein P05412 UNIPROT "up-regulates activity" phosphorylation Ser63 KNSDLLTsPDVGLLK 9534 BTO:0004055 8137421 t lperfetto "The jnk-mediated phosphorylation of both ser63 and ser73 within the transactivation domain of c-jun potentiates its transcriptional activity." SIGNOR-235766 MAPK8 protein P45983 UNIPROT JUN protein P05412 UNIPROT "up-regulates activity" phosphorylation Ser73 VGLLKLAsPELERLI 9534 BTO:0000298 8137421 t miannu "JNK1 binds to the c-Jun transactivation domain and phosphorylates it on Ser-63 and Ser-73. The effect on AP-1 transcriptional activity results, in part, from enhanced phosphorylation of the c-Jun NH2-terminal activation domain." SIGNOR-250122 MAPK8 protein P45983 UNIPROT KRT8 protein P05787 UNIPROT up-regulates phosphorylation Ser74 TVNQSLLsPLVLEVD 9606 11781324 t lperfetto "Kinase assays showed that c-jun n-terminal kinase (jnk) was also activated with activation kinetics corresponding to that of k8 phosphorylation. Furthermore, k8 was also phosphorylated on ser-73 by jnk in vitro. The ser-73 --> ala-associated filament reorganization defect is rescued by a ser-73 --> asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis." SIGNOR-113645 MAPK8 protein P45983 UNIPROT KRT8 protein P05787 UNIPROT up-regulates phosphorylation Ser74 TVNQSLLsPLVLEVD 9606 11788583 t lperfetto "Kinase assays showed that c-jun n-terminal kinase (jnk) was also activated with activation kinetics corresponding to that of k8 phosphorylation. Furthermore, k8 was also phosphorylated on ser-73 by jnk in vitro. The ser-73 --> ala-associated filament reorganization defect is rescued by a ser-73 --> asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis." SIGNOR-114083 MAPK8 protein P45983 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr278 SVSAATLtPSSQAVT 9606 19245816 t gcesareni "In addition, for mutation of the jnk-1 phosphorylated residues of sp1, namely, sp1(t278/739a) and sp1(t278/739d), the effect of ga on sp1 stability was reversed." SIGNOR-184190 MAPK8 protein P45983 UNIPROT BCL2 protein P10415 UNIPROT down-regulates phosphorylation Thr69 SRDPVARtSPLQTPA 9606 10567572 t gcesareni "G(2)/m-phase cells proved more susceptible to death signals, and phosphorylation of bcl-2 appeared to be responsible, as a ser70ala substitution restored resistance to apoptosis. We noted that ask1 and jnk1 were normally activated at g(2)/m phase, and jnk was capable of phosphorylating bcl-2.." SIGNOR-72361 MAPK8 protein P45983 UNIPROT BCL2 protein P10415 UNIPROT down-regulates phosphorylation Thr69 SRDPVARtSPLQTPA 9606 18570871 t gcesareni "Together, our findings demonstrate that jnk1-mediated multisite phosphorylation of bcl-2 stimulates starvation-induced autophagy by disrupting the bcl-2/beclin 1 complex." SIGNOR-179096 MAPK8 protein P45983 UNIPROT BCL2 protein P10415 UNIPROT "down-regulates activity" phosphorylation Ser87 AAAGPALsPVPPVVH 9606 10567572 t gcesareni "Jnk1-mediated phosphorylation of bcl-2 regulates starvation-induced autophagy." SIGNOR-48038 MAPK8 protein P45983 UNIPROT BCL2 protein P10415 UNIPROT "down-regulates activity" phosphorylation Ser87 AAAGPALsPVPPVVH 9606 18570871 t gcesareni "Jnk1-mediated phosphorylation of bcl-2 regulates starvation-induced autophagy." SIGNOR-179092 MAPK8 protein P45983 UNIPROT BCL2 protein P10415 UNIPROT up-regulates phosphorylation Ser70 RDPVARTsPLQTPAA 9606 10567572 t gcesareni "G(2)/m-phase cells proved more susceptible to death signals, and phosphorylation of bcl-2 appeared to be responsible, as a ser70ala substitution restored resistance to apoptosis. We noted that ask1 and jnk1 were normally activated at g(2)/m phase, and jnk was capable of phosphorylating bcl-2.." SIGNOR-72125 MAPK8 protein P45983 UNIPROT BCL2 protein P10415 UNIPROT up-regulates phosphorylation Ser70 RDPVARTsPLQTPAA 9606 18570871 t gcesareni "Together, our findings demonstrate that jnk1-mediated multisite phosphorylation of bcl-2 stimulates starvation-induced autophagy by disrupting the bcl-2/beclin 1 complex." SIGNOR-179088 MAPK8 protein P45983 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 7737130 t gcesareni "Stimulation of atf-2-dependent transactivation by genotoxic agents requires the presence of threonines 69 and 71 located in the n-terminal transactivation domain. These sites are the target of p54 and p46 stress-activated protein kinases (sapks) which bind to, and phosphorylate atf-2 in vitro." SIGNOR-32421 MAPK8 protein P45983 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 7737130 t gcesareni "Stimulation of atf-2-dependent transactivation by genotoxic agents requires the presence of threonines 69 and 71 located in the n-terminal transactivation domain. These sites are the target of p54 and p46 stress-activated protein kinases (sapks) which bind to, and phosphorylate atf-2 in vitro." SIGNOR-32425 MAPK8 protein P45983 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 7824938 t gcesareni "Activating transcription factor-2 (atf2) was found to be a target of the jnk signal transduction pathway. Atf2 was phosphorylated by jnk on two closely spaced threonine residues within the nh2-terminal activation domain." SIGNOR-33914 MAPK8 protein P45983 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 7824938 t gcesareni "Activating transcription factor-2 (atf2) was found to be a target of the jnk signal transduction pathway. Atf2 was phosphorylated by jnk on two closely spaced threonine residues within the nh2-terminal activation domain." SIGNOR-33918 MAPK8 protein P45983 UNIPROT H2AX protein P16104 UNIPROT up-regulates phosphorylation Ser140 GKKATQAsQEY 9606 BTO:0000671 19234442 t gcesareni "The stress-response kinase jnk1, activated by dna damage and initiating a pro-apoptotic program, has been recently shown to translocate into the nucleus upon activation where it phosphorylates substrates including h2ax s139, an event critical for dna degradation mediated by caspase-activated dnase (cad) in apoptotic cells" SIGNOR-184146 MAPK8 protein P45983 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 20630875 t gcesareni "Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. Here we show that in response to hyperosmotic stress, jnk phosphorylates a key cytoplasmic microtubule regulatory protein, stathmin (stmn), on conserved ser-25 and ser-38 residues. In in vitro biochemical studies, we identified stmn ser-38 as the critical residue required for efficient phosphorylation by jnk and identified a novel kinase interaction domain in stmn required for recognition by jnk. We revealed that jnk was required for microtubule stabilization in response to hyperosmotic stress." SIGNOR-166694 MAPK8 protein P45983 UNIPROT JUNB protein P17275 UNIPROT "up-regulates activity" phosphorylation Thr104 GVITTTPtPPGQYFY 10090 9889198 t miannu "JunB-control of IL-4 expression is mediated by the phosphorylation of JunB at Thr102 and -104 by JNK MAP kinase. The synergy between c-Maf and JunB can be attributed to cooperative DNA binding, which is facilitated by JunB phosphorylation." SIGNOR-250121 MAPK8 protein P45983 UNIPROT JUND protein P17535 UNIPROT up-regulates phosphorylation Ser100 LGLLKLAsPELERLI 9606 22327296 t gcesareni "Menin binds the jun family transcription factor jund and inhibits its transcriptional activity. The menin-jund interaction blocks jun n-terminal kinase (jnk)-mediated jund phosphorylation and suppresses jund-induced transcription. We found a role for phosphorylation of the ser100 residue of jund;jund phosphorylation were prevented by inhibitors of calcium, calmodulin, or erk1/2 kinase." SIGNOR-196038 MAPK8 protein P45983 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser383 IHFWSTLsPIAPRSP 9606 8846788 t gcesareni "However, both of these stimuli strongly activate two other mapks, jnk1 and jnk2, and stimulate elk-1 transcriptional activity and phosphorylation jnk phosphorylation sites include ser383 and ser389, the major residues whose phosphorylation is responsible for enhancement of elk-1 trascriptional activity." SIGNOR-44356 MAPK8 protein P45983 UNIPROT ELK1 protein P19419 UNIPROT "up-regulates activity" phosphorylation Ser389 LSPIAPRsPAKLSFQ 9606 BTO:0000567 7651411 t lperfetto "However, both of these stimuli strongly activate two other mapks, jnk1 and jnk2, and stimulate elk-1 transcriptional activity and phosphorylation jnk phosphorylation sites include ser383 and ser389, the major residues whose phosphorylation is responsible for enhancement of elk-1 trascriptional activity." SIGNOR-236432 MAPK8 protein P45983 UNIPROT ELK1 protein P19419 UNIPROT "up-regulates activity" phosphorylation Ser389 LSPIAPRsPAKLSFQ 9606 BTO:0000567 8846788 t lperfetto "We find that the JNKs are the predominant Elk-1 activation domain kinases in extracts of UV-irradiated cells and that immunopurified JNK1/2 phosphorylate Elk-1 on the same major sites recognized by ERK1/2, that potentiate its transcriptional activity." SIGNOR-236455 MAPK8 protein P45983 UNIPROT STAT1 protein P42224 UNIPROT "up-regulates activity" phosphorylation Tyr701 DGPKGTGyIKTELIS 10090 BTO:0001086 24913968 t "SP600125 prevented phosphorylation of STAT1 at Tyr701 site [..] Western blot analysis confirmed that blocking p-JNK using SP600125 markedly reduced STAT3 localization in the nucleus and STAT1 phosphorylation" SIGNOR-251101 MAPK8 protein P45983 UNIPROT RXRA protein P19793 UNIPROT "down-regulates activity" phosphorylation Ser260 NMGLNPSsPNDPVTN 9606 16551633 t gcesareni "Under stress conditions, hyperphosphorylated by activated jnk on ser-56, ser-70, thr-82 and ser-260. These findings indicate that inflammation-mediated cell signaling leads to rapid and profound reductions in nuclear rxralpha levels, via a multistep, jnk-dependent mechanism involving ser260, nuclear export, and proteasomal degradation." SIGNOR-145297 MAPK8 protein P45983 UNIPROT NR4A1 protein P22736 UNIPROT down-regulates phosphorylation Ser95 TSSSSATsPASASFK 9606 17023523 t llicata "We also identified the exact phosphorylation site of jnk to be serine 95 at the n terminus of tr3, around which a classical jnk phosphorylation motif exists. Furthermore, we demonstrated that tr3 phosphorylation by jnk coincided with its ubiquitination and degradation, resulting in the loss of its mitogenic activity." SIGNOR-149998 MAPK8 protein P45983 UNIPROT CDC25C protein P30307 UNIPROT down-regulates phosphorylation Ser168 SEMKYLGsPITTVPK 9606 20220133 t gcesareni "Here we show that jnk directly phosphorylates cdc25c at serine 168 during g(2) phase of the cell cycle. Cdc25c phosphorylation by jnk negatively regulates its phosphatase activity and thereby cdk1 activation, enabling a timely control of mitosis onset." SIGNOR-164089 MAPK8 protein P45983 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation Thr450 TAQMITItPPDQDDS 10116 BTO:0003324 16306447 t gcesareni "We report that JNKs are necessary for the reactivation of Akt after ischemic injury. We identified Thr450 of Akt as a residue that is phosphorylated by JNKs, and the phosphorylation status of Thr450 regulates reactivation of Akt after hypoxia, apparently by priming Akt for subsequent phosphorylation by 3-phosphoinositide-dependent protein kinase." SIGNOR-252426 MAPK8 protein P45983 UNIPROT YWHAB protein P31946 UNIPROT down-regulates phosphorylation Ser186 FYYEILNsPEKACSL 9606 15696159 t llicata "The c-jun n-terminal kinase (jnk) protein is activated in the cellular response to dna damage and phosphorylates 14-3-3 on ser 184 these results support a role for 14-3-3 proteins in inhibiting c-abl-mediated apoptosis by sequestering c-abl into the cytoplasm. these findings support a model in which jnk phosphorylation of 14-3-3 proteins induces dissociation of the c-abl_14-3-3 complex and thereby targeting of c-abl to the nucleus." SIGNOR-133875 MAPK8 protein P45983 UNIPROT SFN protein P31947 UNIPROT down-regulates phosphorylation Ser186 FHYEIANsPEEAISL 9606 15071501 t "JNK1 and JNK2 are required for apoptosis of thymocites,Ser residues in the reagion between alpha-helices 7 and 8" gcesareni "Jnk phosphorylates 14-3-3zeta_ at ser-184 and 14-3-3sigma_ at ser-187." SIGNOR-124016 MAPK8 protein P45983 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser307 TRRSRTEsITATSPA 9606 12510059 t gcesareni "Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1." SIGNOR-96936 MAPK8 protein P45983 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser315 ITATSPAsMVGGKPG 9606 12510059 t gcesareni "Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1." SIGNOR-96940 MAPK8 protein P45983 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser307 TRRSRTEsITATSPA 9606 BTO:0000887;BTO:0001103 14579029 t gcesareni "Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1." SIGNOR-118857 MAPK8 protein P45983 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser315 ITATSPAsMVGGKPG 9606 BTO:0000887;BTO:0001103 14579029 t gcesareni "Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1." SIGNOR-118861 MAPK8 protein P45983 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser312 TESITATsPASMVGG 9606 18728222 t gcesareni "Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1." SIGNOR-180532 MAPK8 protein P45983 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser616 DDGYMPMsPGVAPVP 9606 12510059 t gcesareni "Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1." SIGNOR-96944 MAPK8 protein P45983 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser636 SGDYMPMsPKSVSAP 9606 12510059 t gcesareni "Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1." SIGNOR-96948 MAPK8 protein P45983 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser312 TESITATsPASMVGG 10116 BTO:0004428 12510059 t lperfetto "Modulation of insulin-stimulated degradation of human insulin receptor substrate-1 by Serine 312 phosphorylationOne of the specific Ser phosphorylation sites in IRS-1 that has been proposed to negatively modulate the insulin signal is Ser312 (numbered according to the human sequence). Prior studies have demonstrated that IRS-1 associates with and is phosphorylated by JNK in vitro on Ser312" SIGNOR-236591 MAPK8 protein P45983 UNIPROT PPARG protein P37231 UNIPROT "down-regulates activity" phosphorylation Ser112 AIKVEPAsPPYYSEK 9606 9030579 t llicata "The a/b domain of human ppargamma1 was phosphorylated in vivo, and this was abolished either by mutation of serine 84 to alanine (s84a) or coexpression of a phosphoprotein phosphatase. In vitro, this domain was phosphorylated by erk2 and jnk, and this was markedly reduced in the s84a mutant. Thus, phosphorylation of a mitogen-activated protein kinase site in the a/b region of ppargamma inhibits both ligand-independent and ligand-dependent transactivation functions." SIGNOR-46518 NCOA4 protein Q13772 UNIPROT AR protein P10275 UNIPROT up-regulates binding 9606 10347167 t miannu "We demonstrated that ara70 and ar physically interact and that ara70 can function as an androgen-dependent coactivator for ar." SIGNOR-67684 MAPK8 protein P45983 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates phosphorylation 9606 17525747 t gcesareni "Our studies revealed a novel mechanism in which phosphorylation of jnk2 is mediated by jnk1 before phosphorylation of p53, and then p53 is directly phosphorylated by jnk2 at ser6." SIGNOR-155205 MAPK8 protein P45983 UNIPROT PXN protein P49023 UNIPROT "up-regulates activity" phosphorylation Ser178 PPLPGALsPLYGVPE 10116 BTO:0004316 12853963 t miannu "JNK1 phosphorylates serine 178 on paxillin, a focal adhesion adaptor, both in vitro and in intact cells. NBT-II cells expressing the Ser 178 --> Ala mutant of paxillin (Pax(S178A)) formed focal adhesions and exhibited the limited movement associated with such contacts in both single-cell-migration and wound-healing assays. In contrast, cells expressing wild-type paxillin moved rapidly and retained close contacts as the predominant adhesion." SIGNOR-250129 MAPK8 protein P45983 UNIPROT ATN1 protein P54259 UNIPROT "down-regulates activity" phosphorylation Ser739 EEYETPEsPVPPARS 9606 BTO:0000142 12812981 t lperfetto "Dentatorubral-pallidoluysian atrophy protein is phosphorylated by c-jun nh2-terminal kinase. serine 734 of the drpla protein is a phospho-acceptor site by jnk. The phosphorylation may be coupled to the activation of a protease. The molecular size of drpla protein detected in the rat brain with the specific phosphopeptide antibody was 150_kda, which was slightly smaller than that expected from the sequence and the results with the human protein. The phosphorylated forms of ha-tagged human drpla gradually disappeared after osmotic treatment," SIGNOR-102398 MAPK8 protein P45983 UNIPROT HNRNPK protein P61978 UNIPROT up-regulates phosphorylation Ser216 ILDLISEsPIKGRAQ 9606 11259409 t gcesareni "The current studies demonstrate the identification of hnrnp-k as a jnk and erk substrate. The phosphoacceptor sites for jnk and erk on the k protein are different, and indeed, erk phosphorylation results in biological consequences different from those of phosphorylation by jnk (49). Whereas erk phosphorylation on aa 284 and 353 contributes to k protein nuclear export and concomitant inhibition of rna translation (49), phosphorylation by k protein on aa 216 and 353 increases the transcriptional effects of the k protein." SIGNOR-105766 MAPK8 protein P45983 UNIPROT HNRNPK protein P61978 UNIPROT up-regulates phosphorylation Ser353 DSAIDTWsPSEWQMA 9606 11259409 t gcesareni "The current studies demonstrate the identification of hnrnp-k as a jnk and erk substrate. The phosphoacceptor sites for jnk and erk on the k protein are different, and indeed, erk phosphorylation results in biological consequences different from those of phosphorylation by jnk (49). Whereas erk phosphorylation on aa 284 and 353 contributes to k protein nuclear export and concomitant inhibition of rna translation (49), phosphorylation by k protein on aa 216 and 353 increases the transcriptional effects of the k protein." SIGNOR-105770 MAPK8 protein P45983 UNIPROT HNRNPK protein P61978 UNIPROT "up-regulates activity" phosphorylation Ser216 ILDLISEsPIKGRAQ 9606 11259409 t lperfetto "The current studies demonstrate the identification of hnrnp-k as a jnk and erk substrate. The phosphoacceptor sites for jnk and erk on the k protein are different, and indeed, erk phosphorylation results in biological consequences different from those of phosphorylation by jnk (49). Whereas erk phosphorylation on aa 284 and 353 contributes to k protein nuclear export and concomitant inhibition of rna translation (49), phosphorylation by k protein on aa 216 and 353 increases the transcriptional effects of the k protein." SIGNOR-105247 MAPK8 protein P45983 UNIPROT HNRNPK protein P61978 UNIPROT "up-regulates activity" phosphorylation Ser353 DSAIDTWsPSEWQMA 9606 11259409 t lperfetto "The current studies demonstrate the identification of hnrnp-k as a jnk and erk substrate. The phosphoacceptor sites for jnk and erk on the k protein are different, and indeed, erk phosphorylation results in biological consequences different from those of phosphorylation by jnk (49). Whereas erk phosphorylation on aa 284 and 353 contributes to k protein nuclear export and concomitant inhibition of rna translation (49), phosphorylation by k protein on aa 216 and 353 increases the transcriptional effects of the k protein." SIGNOR-105251 MAPK8 protein P45983 UNIPROT YWHAZ protein P63104 UNIPROT down-regulates phosphorylation Ser184 FYYEILNsPEKACSL 9606 15071501 t "JNK1 and JNK2 are required for apoptosis of thymocites,Ser residues in the reagion between alpha-helices 7 and 8." gcesareni "Jnk phosphorylated 14-3-3 at ser-184 and 14-3-3 at ser-186 both in vitro and in vivo, and such phosphorylation reduced the affinity of 14-3-3 proteins for bax" SIGNOR-124020 MAPK8 protein P45983 UNIPROT H3-3A protein P84243 UNIPROT up-regulates phosphorylation Ser29 ATKAARKsAPSTGGV 9606 15994958 t gcesareni "Phosphorylation of histone h3 at serine 10 is indispensable for neoplastic cell transformation. When h3 wt was overexpressed, egf induction of c-fos and c-jun promoter activity was significantly increased compared with control cells but not in the h3 mutant s10a or s28a cells." SIGNOR-138459 MAPK8 protein P45983 UNIPROT FOXO4 protein P98177 UNIPROT up-regulates phosphorylation Thr451 PIPKALGtPVLTPPT 9606 15538382 t lperfetto "Upon treatment of cells with h2o2, the small gtpase ral is activated and this results in a jnk-dependent phosphorylation of foxo4 on threonine 447 and threonine 451. This ral-mediated, jnk-dependent phosphorylation is involved in the nuclear translocation and transcriptional activation of foxo4 after h2o2 treatment." SIGNOR-130381 MAPK8 protein P45983 UNIPROT FOXO4 protein P98177 UNIPROT up-regulates phosphorylation Thr455 ALGTPVLtPPTEAAS 9606 15538382 t lperfetto "Upon treatment of cells with h2o2, the small gtpase ral is activated and this results in a jnk-dependent phosphorylation of foxo4 on threonine 447 and threonine 451. This ral-mediated, jnk-dependent phosphorylation is involved in the nuclear translocation and transcriptional activation of foxo4 after h2o2 treatment." SIGNOR-130385 MAPK8 protein P45983 UNIPROT HSF1 protein Q00613 UNIPROT "down-regulates activity" phosphorylation Ser363 DTEGRPPsPPPTSTP 9606 BTO:0000567 10747973 t miannu "JNK is activated by heat shock and phosphorylates HSF-1 on serine 363. JNK Phosphorylation of HSF-1 Leads to Reduction in Its Transcriptional Activity" SIGNOR-250119 MAPK8 protein P45983 UNIPROT APLP2 protein Q06481 UNIPROT up-regulates phosphorylation Thr736 VEVDPMLtPEERHLN 9606 14970211 t lperfetto "Phosphorylation at the thr(668) residue of app (with respect to the numbering conversion for the app 695 isoform) and the thr(736) residue of aplp2 (with respect to the numbering conversion for the aplp2 763 isoform) in their cytoplasmic domains acts as a molecular switch for their protein-protein interaction and is implicated in neural function(s) and/or alzheimer's disease pathogenesis. Here we demonstrate that both app and aplp2 can be phosphorylated by jnk at the thr(668) and thr(736) residues, respectively, in response to cellular stress." SIGNOR-122196 MAPK8 protein P45983 UNIPROT BAX protein Q07812 UNIPROT up-regulates 9606 15071501 f "JNK-mediated phosphorylation of 14-3-3 at Ser184 reduces its affinity for Bax." gcesareni "We demonstrate that jnk-mediated phosphorylation of 14-3-3 induces the release of bax from 14-3-3 and triggers its translocation to the mitochondria here we demonstrate that activated jnk promotes bax translocation to mitochondria through phosphorylation of 14-3-3, a cytoplasmic anchor of bax. Phosphorylation of 14-3-3 led to dissociation of bax from this protein." SIGNOR-124012 MAPK8 protein P45983 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates phosphorylation Ser62 PSWHLADsPAVNGAT 9606 BTO:0001130 12633850 t gcesareni "By site-directed mutagenesis studies, we have identified that serine 62 is the necessary site for taxol- or 2-me-induced bcl-xl phosphorylation in prostate cancer cells. Further studies with the inhibitor of jun kinase (jnk) and phosphorylation mutant of bcl-xl reveal the augmentative role of jnk-mediated bcl-xl phosphorylation in apoptosis of prostate cancer cells. In summary, our studies suggest that the phosphorylation of bcl-xl by stress response kinase signaling might oppose the anti-apoptotic function of bcl-xl to permit prostate cancer cells to die by apoptosis" SIGNOR-99219 MAPK8 protein P45983 UNIPROT MCL1 protein Q07820 UNIPROT up-regulates phosphorylation Thr163 TDGSLPStPPPAEEE 9606 12223490 t gcesareni "We found that jnk phosphorylated ser-121 and thr-163 of mcl-1 in response to stimulation with h(2)o(2) and that transfection of unphosphorylatable mcl-1 resulted in an enhanced anti-apoptotic activity in response to stimulation with h(2)o(2). Jnk-dependent phosphorylation and thus inactivation of mcl-1 may be one of the mechanisms through which oxidative stress induces cellular damage." SIGNOR-92597 MAPK8 protein P45983 UNIPROT MCL1 protein Q07820 UNIPROT up-regulates phosphorylation Thr163 TDGSLPStPPPAEEE 9606 BTO:0000150 18676833 t gcesareni "Mcl-1 can be rapidly degraded by certain death-inducing signals, but it is able to be readily induced by diverse survival cytokines such as epidermal growth factor, vascular endothelial growth factor, granulocyt-macrophage colony-stimulating factor, and interleukin 3 through phosphatidy-linositol-3-oh kinase/akt, mek/mapk, or janus-activated kinase/stat signaling cascades" SIGNOR-179816 MAPK8 protein P45983 UNIPROT AIMP1 protein Q12904 UNIPROT down-regulates phosphorylation Ser140 KKEKKQQsIAGSADS 9606 20510162 t llicata "We further demonstrated that serine-140 residue of aimp1 was phosphorylated by jnk and alanine mutation of serine-140 suppressed lps-induced cell surface altogether, these results suggest that aimp1 is phosphorylated by jnk through tlr-myd88 pathway and lose the regulatory activity for er retention of gp96expression of gp96." SIGNOR-165763 MAPK8 protein P45983 UNIPROT NFATC3 protein Q12968 UNIPROT down-regulates phosphorylation 9606 BTO:0000782 14517246 t gcesareni "Jnks directly phosphorylate nuclear factor of activated t-cell (nfat) transcription factors, thus antagonizing the effects of calcium-regulated signaling through the protein phosphatase calcineurin" SIGNOR-118220 MAPK8 protein P45983 UNIPROT STK4 protein Q13043 UNIPROT up-regulates phosphorylation Ser82 SIMQQCDsPHVVKYY 9606 20028971 t llicata "C-jun n-terminal kinase enhances mst1-mediated pro-apoptotic signaling through phosphorylation at serine 82." SIGNOR-162327 MAPK8 protein P45983 UNIPROT CTBP1 protein Q13363 UNIPROT down-regulates phosphorylation Ser422 AHPPHAPsPGQTVKP 9606 BTO:0000551 16984892 t lperfetto "In this study, we found that c-jun nh2-terminal kinase 1 activation triggered ctbp phosphorylation on ser-422 and subsequent degradation," SIGNOR-149721 MAPK8 protein P45983 UNIPROT NFATC2 protein Q13469 UNIPROT down-regulates phosphorylation 9606 BTO:0000782 14517246 t gcesareni "Jnks directly phosphorylate nuclear factor of activated t-cell (nfat) transcription factors, thus antagonizing the effects of calcium-regulated signaling through the protein phosphatase calcineurin jnk directly regulated nuclear factor of activated t-cell (nfat) activation in culture and in transgenic mice containing an nfat-dependent luciferase reporter." SIGNOR-118217 MAPK8 protein P45983 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates phosphorylation Ser173 PCPQPLRsPSLDNPT 9606 19153595 t lperfetto "In this study, we show that another kinase, c-jun-nh(2)-terminal kinase (jnk), phosphorylates irf3 on its n-terminal serine 173 residuejnk1 can synergize the action of irf3(5d), but not the s173a-irf3(5d) mutant" SIGNOR-183489 MAPK8 protein P45983 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation Ser68 GGGDEPGsPAQGKRG 9606 BTO:0000150 21502402 t gcesareni "Phosphorylation of serine 68 of twist1 by mapks stabilizes twist1 protein and promotes breast cancer cell invasiveness." SIGNOR-173417 MAPK8 protein P45983 UNIPROT PPM1J protein Q5JR12 UNIPROT down-regulates phosphorylation Ser93 HAGRAVQsPPDTGRR 9606 18553930 t gcesareni "Specific phosphorylation of pp2czeta at ser (92) by stress-activated jnk attenuates its phosphatase activity in cells." SIGNOR-178930 MAPK8 protein P45983 UNIPROT RCSD1 protein Q6JBY9 UNIPROT "down-regulates activity" phosphorylation Ser216 SKSKAPGsPLSSEGA -1 15850461 t miannu "CapZIP was also phosphorylated rapidly by SAPK3/p38γ and SAPK4/p38δ, and even faster and more extensively by JNK1α1, these protein kinases phosphorylating CapZIP in vitro to >3, approx. 2 and >5 mol of phosphate/mol of protein respectively within a few minutes. Following tryptic digestion and C18 chromatography, further sites phosphorylated by JNK1α1 were identified as Ser-68, Ser-83 and Ser-216 (results not shown), and are highlighted in Figure 3.Using this antibody, we showed by immunoblotting that bacterially expressed CapZIP was phosphorylated at Ser-108 by SAPK4/p38δ, JNK1α1 and ERK2 in vitro, as well as by SAPK3/p38γ (results not shown).An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ." SIGNOR-263087 MAPK8 protein P45983 UNIPROT RCSD1 protein Q6JBY9 UNIPROT "down-regulates activity" phosphorylation Ser68 GQNGEEKsPPNASHP -1 15850461 t miannu "CapZIP was also phosphorylated rapidly by SAPK3/p38γ and SAPK4/p38δ, and even faster and more extensively by JNK1α1, these protein kinases phosphorylating CapZIP in vitro to >3, approx. 2 and >5 mol of phosphate/mol of protein respectively within a few minutes. Following tryptic digestion and C18 chromatography, further sites phosphorylated by JNK1α1 were identified as Ser-68, Ser-83 and Ser-216 (results not shown), and are highlighted in Figure 3.Using this antibody, we showed by immunoblotting that bacterially expressed CapZIP was phosphorylated at Ser-108 by SAPK4/p38δ, JNK1α1 and ERK2 in vitro, as well as by SAPK3/p38γ (results not shown).An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ." SIGNOR-263085 MAPK8 protein P45983 UNIPROT EIF4ENIF1 protein Q9NRA8 UNIPROT up-regulates phosphorylation Ser374 GLEQAILsPGQNSGN 9606 22966201 t llicata "Identification of 4e-t phosphorylation sites regulated by jnk. identification of these residues as phosphorylation sites (ser301, ser374, ser513, ser587, ser693, and ser752) was obtained by ms/ms sequencing, these results demonstrate that jnk activity is required to stimulate the assembly of pbs in response to oxidative stress." SIGNOR-198988 MAPK9 protein P45984 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates phosphorylation Thr320 SKYNAEStERESQDT 9606 18667537 t llicata "This jnk phosphorylation of ps1 at ser(319)thr(320) enhances the stability of the ps1 c-terminal fragment that is necessary for gamma-secretase activity." SIGNOR-179680 MAPK8 protein P45983 UNIPROT RCSD1 protein Q6JBY9 UNIPROT "down-regulates activity" phosphorylation Ser83 PKFKVKSsPLIEKLQ -1 15850461 t miannu "CapZIP was also phosphorylated rapidly by SAPK3/p38γ and SAPK4/p38δ, and even faster and more extensively by JNK1α1, these protein kinases phosphorylating CapZIP in vitro to >3, approx. 2 and >5 mol of phosphate/mol of protein respectively within a few minutes. Following tryptic digestion and C18 chromatography, further sites phosphorylated by JNK1α1 were identified as Ser-68, Ser-83 and Ser-216 (results not shown), and are highlighted in Figure 3.Using this antibody, we showed by immunoblotting that bacterially expressed CapZIP was phosphorylated at Ser-108 by SAPK4/p38δ, JNK1α1 and ERK2 in vitro, as well as by SAPK3/p38γ (results not shown).An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ." SIGNOR-263086 MAPK8 protein P45983 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation 9606 14967141 t gcesareni "Jnk phosphorylates bad at threonine 201, thereby inhibiting bad association with the antiapoptotic molecule bcl-x(l)" SIGNOR-121940 MAPK8 protein P45983 UNIPROT OSBP2 protein Q969R2 UNIPROT "up-regulates activity" phosphorylation 30925160 t lperfetto "CK1a1, JNK1 and CDK1 had the highest site-specific activity for ORP4L, while CDK1, GSK3a, CK1a1 and GSK3b showed the highest specificity for the site when corrected for background activity with ORP4L-S4A. Because of the complexity of the serine/proline-rich site, we did not determine which serine(s) in ORP4L were phosphorylated by candidate kinases.|We conclude that phosphorylation of a unique serine/proline motif in the ORD induces a conformation change in ORP4L that enhances interaction with vimentin and cholesterol extraction from membranes." SIGNOR-264876 MAPK8 protein P45983 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates phosphorylation Ser27 ADREAASsPAGEPLR 9606 20027304 t "This phosphorylation increased sirt1 nuclear localization" gcesareni "Human sirt1 was phosphorylated by jnk1 on three sites: ser27, ser47, and thr530 and this phosphorylation of sirt1 increased its nuclear localization and enzymatic activity. Surprisingly, jnk1 phosphorylation of sirt1 showed substrate specificity resulting in deacetylation of histone h3, but not p53." SIGNOR-162314 MAPK8 protein P45983 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates phosphorylation Ser47 DGPGLERsPGEPGGA 9606 20027304 t "This phosphorylation increased sirt1 nuclear localization" gcesareni "Human sirt1 was phosphorylated by jnk1 on three sites: ser27, ser47, and thr530 and this phosphorylation of sirt1 increased its nuclear localization and enzymatic activity. Surprisingly, jnk1 phosphorylation of sirt1 showed substrate specificity resulting in deacetylation of histone h3, but not p53." SIGNOR-162318 MAPK8 protein P45983 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates phosphorylation Thr530 YLSELPPtPLHVSED 9606 20027304 t "This phosphorylation increased sirt1 nuclear localization" gcesareni "Human sirt1 was phosphorylated by jnk1 on three sites: ser27, ser47, and thr530 and this phosphorylation of sirt1 increased its nuclear localization and enzymatic activity. Surprisingly, jnk1 phosphorylation of sirt1 showed substrate specificity resulting in deacetylation of histone h3, but not p53." SIGNOR-162322 MAPK8 protein P45983 UNIPROT ITCH protein Q96J02 UNIPROT up-regulates phosphorylation 9606 16469705 t gcesareni "Here we show that tnfalpha-mediated jnk activation accelerates turnover of the nf-kappab-induced antiapoptotic protein c-flip, an inhibitor of caspase-8. This is not due to direct c-flip phosphorylation but depends on jnk-mediated phosphorylation and activation of the e3 ubiquitin ligase itch, which specifically ubiquitinates c-flip and induces its proteasomal degradation." SIGNOR-144456 MAPK8 protein P45983 UNIPROT ITCH protein Q96J02 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0002417 15358865 t gcesareni "Activation of the Jun amino-terminal kinase (JNK) mitogen-activated protein kinase cascade after T cell stimulation accelerated degradation of c-Jun and JunB through phosphorylation-dependent activation of the E3 ligase Itch." SIGNOR-245315 MAPK8 protein P45983 UNIPROT ITCH protein Q96J02 UNIPROT "up-regulates activity" phosphorylation Ser240 RRVSGNNsPSLSNGG 9606 BTO:0000007 16446428 t gcesareni "Itch undergoes JNK1-mediated phosphorylation that greatly enhances its enzymatic activity. To investigate how phosphorylation activates an E3 Ub ligase we have identified the JNK1 phosphorylation sites within Itch as S199, S232, and T222" SIGNOR-245323 MAPK8 protein P45983 UNIPROT ITCH protein Q96J02 UNIPROT "up-regulates activity" phosphorylation Ser273 RPASVNGsPSATSES 9606 BTO:0000007 16446428 t gcesareni "Itch undergoes JNK1-mediated phosphorylation that greatly enhances its enzymatic activity. To investigate how phosphorylation activates an E3 Ub ligase we have identified the JNK1 phosphorylation sites within Itch as S199, S232, and T222" SIGNOR-249580 MAPK8 protein P45983 UNIPROT ITCH protein Q96J02 UNIPROT "up-regulates activity" phosphorylation Thr263 PSRPPPPtPRRPASV 9606 BTO:0000007 16446428 t gcesareni "Itch undergoes JNK1-mediated phosphorylation that greatly enhances its enzymatic activity. To investigate how phosphorylation activates an E3 Ub ligase we have identified the JNK1 phosphorylation sites within Itch as S199, S232, and T222" SIGNOR-249579 MAPK8 protein P45983 UNIPROT ITCH protein Q96J02 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0000575 16469705 t gcesareni "This is not due to direct c-FLIP phosphorylation but depends on JNK-mediated phosphorylation and activation of the E3 ubiquitin ligase Itch," SIGNOR-245310 MAPK8 protein P45983 UNIPROT BMF protein Q96LC9 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007 12591950 t miannu "Activated JNK causes BimL and Bmf phosphorylation in vivo. It is known that UV radiation causes the release of Bim and Bmf from dynein and myosin V motor complexes and that these proteins cause Bax/Bak-dependent apoptosis . The results of this study demonstrate that JNK can engage this apoptotic pathway by phosphorylation of BH3-only proteins, including Bim and Bmf." SIGNOR-250116 MAPK8 protein P45983 UNIPROT PKMYT1 protein Q99640 UNIPROT up-regulates phosphorylation 9606 BTO:0001286 19204086 t "The results showed that residues 140 to 205 of JNK1 have the ability to interact with Myt1." gcesareni "A kinase assay using gst-myt1 revealed that active jnk1 or jnk3, but not jnk2, phosphorylated myt1 in vitro." SIGNOR-183899 MAPK8 protein P45983 UNIPROT EIF4ENIF1 protein Q9NRA8 UNIPROT up-regulates phosphorylation Ser301 DAVLPEQsPGDFDFN 9606 22966201 t llicata "Identification of 4e-t phosphorylation sites regulated by jnk. identification of these residues as phosphorylation sites (ser301, ser374, ser513, ser587, ser693, and ser752) was obtained by ms/ms sequencing, these results demonstrate that jnk activity is required to stimulate the assembly of pbs in response to oxidative stress." SIGNOR-198984 MAPK9 protein P45984 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 20068231 t gcesareni "Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity." SIGNOR-163262 MAPK8 protein P45983 UNIPROT EIF4ENIF1 protein Q9NRA8 UNIPROT up-regulates phosphorylation Ser513 NLESHLMsPAEIPGQ 9606 22966201 t llicata "Identification of 4e-t phosphorylation sites regulated by jnk. identification of these residues as phosphorylation sites (ser301, ser374, ser513, ser587, ser693, and ser752) was obtained by ms/ms sequencing, these results demonstrate that jnk activity is required to stimulate the assembly of pbs in response to oxidative stress." SIGNOR-198992 MAPK8 protein P45983 UNIPROT EIF4ENIF1 protein Q9NRA8 UNIPROT up-regulates phosphorylation Ser587 YLRPRIPsPIGFTPG 9606 22966201 t llicata "Identification of 4e-t phosphorylation sites regulated by jnk. identification of these residues as phosphorylation sites (ser301, ser374, ser513, ser587, ser693, and ser752) was obtained by ms/ms sequencing, these results demonstrate that jnk activity is required to stimulate the assembly of pbs in response to oxidative stress." SIGNOR-198996 MAPK8 protein P45983 UNIPROT EIF4ENIF1 protein Q9NRA8 UNIPROT up-regulates phosphorylation Ser693 ASITSMLsPSFTPTS 9606 22966201 t llicata "Identification of 4e-t phosphorylation sites regulated by jnk. identification of these residues as phosphorylation sites (ser301, ser374, ser513, ser587, ser693, and ser752) was obtained by ms/ms sequencing, these results demonstrate that jnk activity is required to stimulate the assembly of pbs in response to oxidative stress." SIGNOR-199000 MAPK8 protein P45983 UNIPROT EIF4ENIF1 protein Q9NRA8 UNIPROT up-regulates phosphorylation Ser752 PSADRDSsPTTNSKL 9606 22966201 t llicata "Identification of 4e-t phosphorylation sites regulated by jnk. identification of these residues as phosphorylation sites (ser301, ser374, ser513, ser587, ser693, and ser752) was obtained by ms/ms sequencing, these results demonstrate that jnk activity is required to stimulate the assembly of pbs in response to oxidative stress." SIGNOR-199004 MAPK8 protein P45983 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Thr265 GQSSAAAtPSTTGTK 9606 15767678 t gcesareni "Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro." SIGNOR-134541 MAPK8 protein P45983 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Thr275 TTGTKSNtPTSSVPS 9606 15767678 t gcesareni "Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro." SIGNOR-134545 MAPK8 protein P45983 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Thr286 SVPSAAVtPLNESLQ 9606 15767678 t gcesareni "Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro." SIGNOR-134549 MAPK8 protein P45983 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT unknown phosphorylation Ser15 GLGGGAAsPPAASPF 9534 BTO:0000298 12756254 t miannu "After mapping JNK-dependent JIP1 phosphorylation sites and testing their functional significance, it was observed that phosphorylation by JNK of JIP1 on Thr-103 and not other phosphorylated JIP1 residues is necessary for the regulation of DLK association with JIP1, DLK activation, and subsequent module activation. The data presented corroborates our previous observations using endogenous proteins, demonstrates that JNK binding to JIP1 is necessary for module activation, and shows that activation of JIP1-JNK module dynamics requires phosphorylation of JIP1 on Thr-103 by JNK. and Thr-205 are phosphorylated directly by JNK after JNK binds to JIP1." SIGNOR-250123 MAPK8 protein P45983 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT unknown phosphorylation Ser197 DRVSRSSsPLKTGEQ 9534 BTO:0000298 12756254 t miannu "After mapping JNK-dependent JIP1 phosphorylation sites and testing their functional significance, it was observed that phosphorylation by JNK of JIP1 on Thr-103 and not other phosphorylated JIP1 residues is necessary for the regulation of DLK association with JIP1, DLK activation, and subsequent module activation. The data presented corroborates our previous observations using endogenous proteins, demonstrates that JNK binding to JIP1 is necessary for module activation, and shows that activation of JIP1-JNK module dynamics requires phosphorylation of JIP1 on Thr-103 by JNK. and Thr-205 are phosphorylated directly by JNK after JNK binds to JIP1." SIGNOR-250124 MAPK8 protein P45983 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT unknown phosphorylation Ser29 FLGLHIAsPPNFRLT 9534 BTO:0000298 12756254 t miannu "After mapping JNK-dependent JIP1 phosphorylation sites and testing their functional significance, it was observed that phosphorylation by JNK of JIP1 on Thr-103 and not other phosphorylated JIP1 residues is necessary for the regulation of DLK association with JIP1, DLK activation, and subsequent module activation. The data presented corroborates our previous observations using endogenous proteins, demonstrates that JNK binding to JIP1 is necessary for module activation, and shows that activation of JIP1-JNK module dynamics requires phosphorylation of JIP1 on Thr-103 by JNK. and Thr-205 are phosphorylated directly by JNK after JNK binds to JIP1." SIGNOR-250125 MAPK8 protein P45983 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT unknown phosphorylation Ser421 DNCASVSsPYESAIG 9534 BTO:0000298 12756254 t miannu "After mapping JNK-dependent JIP1 phosphorylation sites and testing their functional significance, it was observed that phosphorylation by JNK of JIP1 on Thr-103 and not other phosphorylated JIP1 residues is necessary for the regulation of DLK association with JIP1, DLK activation, and subsequent module activation. The data presented corroborates our previous observations using endogenous proteins, demonstrates that JNK binding to JIP1 is necessary for module activation, and shows that activation of JIP1-JNK module dynamics requires phosphorylation of JIP1 on Thr-103 by JNK. and Thr-205 are phosphorylated directly by JNK after JNK binds to JIP1." SIGNOR-250126 MAPK8 protein P45983 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT unknown phosphorylation Thr205 PLKTGEQtPPHEHIC 9534 BTO:0000298 12756254 t miannu "After mapping JNK-dependent JIP1 phosphorylation sites and testing their functional significance, it was observed that phosphorylation by JNK of JIP1 on Thr-103 and not other phosphorylated JIP1 residues is necessary for the regulation of DLK association with JIP1, DLK activation, and subsequent module activation. The data presented corroborates our previous observations using endogenous proteins, demonstrates that JNK binding to JIP1 is necessary for module activation, and shows that activation of JIP1-JNK module dynamics requires phosphorylation of JIP1 on Thr-103 by JNK. and Thr-205 are phosphorylated directly by JNK after JNK binds to JIP1." SIGNOR-250127 MAPK9 protein P45984 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 20068231 t gcesareni "Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity." SIGNOR-163266 MAPK8 protein P45983 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT "up-regulates activity" phosphorylation Thr103 LIDATGDtPGAEDDE 9534 BTO:0000298 12756254 t miannu "After mapping JNK-dependent JIP1 phosphorylation sites and testing their functional significance, it was observed that phosphorylation by JNK of JIP1 on Thr-103 and not other phosphorylated JIP1 residues is necessary for the regulation of DLK association with JIP1, DLK activation, and subsequent module activation. The data presented corroborates our previous observations using endogenous proteins, demonstrates that JNK binding to JIP1 is necessary for module activation, and shows that activation of JIP1-JNK module dynamics requires phosphorylation of JIP1 on Thr-103 by JNK. and Thr-205 are phosphorylated directly by JNK after JNK binds to JIP1." SIGNOR-250128 MAPK8 protein P45983 UNIPROT AP1 complex SIGNOR-C154 SIGNOR "up-regulates activity" phosphorylation Ser63 KNSDLLTsPDVGLLK 9534 BTO:0004055 8137421 t lperfetto "The jnk-mediated phosphorylation of both ser63 and ser73 within the transactivation domain of c-jun potentiates its transcriptional activity." SIGNOR-252354 MAPK8 protein P45983 UNIPROT AP1 complex SIGNOR-C154 SIGNOR "up-regulates activity" phosphorylation Ser73 VGLLKLAsPELERLI 9534 BTO:0000298 8137421 t miannu "JNK1 binds to the c-Jun transactivation domain and phosphorylates it on Ser-63 and Ser-73. The effect on AP-1 transcriptional activity results, in part, from enhanced phosphorylation of the c-Jun NH2-terminal activation domain." SIGNOR-252355 MAPK8 protein P45983 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Thr451 PIPKALGtPVLTPPT 9606 15538382 t lperfetto "Upon treatment of cells with h2o2, the small gtpase ral is activated and this results in a jnk-dependent phosphorylation of foxo4 on threonine 447 and threonine 451. This ral-mediated, jnk-dependent phosphorylation is involved in the nuclear translocation and transcriptional activation of foxo4 after h2o2 treatment." SIGNOR-252964 MAPK8 protein P45983 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Thr455 ALGTPVLtPPTEAAS 9606 15538382 t lperfetto "Upon treatment of cells with h2o2, the small gtpase ral is activated and this results in a jnk-dependent phosphorylation of foxo4 on threonine 447 and threonine 451. This ral-mediated, jnk-dependent phosphorylation is involved in the nuclear translocation and transcriptional activation of foxo4 after h2o2 treatment." SIGNOR-252965 MAPK9 protein P45984 UNIPROT BCL2L11 protein O43521 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser69 GPLAPPAsPGPFATR 18174237 t gcesareni "Constitutive activation of the c-jun n-terminal kinase (jnk) pathway in sup-t1 cells promoted phosphorylation and degradation of bimel via the proteosome." SIGNOR-250136 MAPK9 protein P45984 UNIPROT BCL2L11 protein O43521 UNIPROT "up-regulates activity" phosphorylation Ser77 PGPFATRsPLFIFMR 12818176 t miannu "JNKs specifically phosphorylate BIMEL at Ser55, 65, and/or 73. several observations demonstrate that the phosphorylation of BIMEL is a physiologically important mechanism for enhancing its proapoptotic activity." SIGNOR-250135 MAPK9 protein P45984 UNIPROT SH3BP5 protein O60239 UNIPROT unknown phosphorylation Ser351 PGSLDLPsPVSLSEF -1 15158451 t miannu "we have identified serine 321 as the major site of phosphorylation by both SAPK3 and JNK2. SAPK3 but not JNK2 also phosphorylates serine 391" SIGNOR-250142 MAPK9 protein P45984 UNIPROT MFN2 protein O95140 UNIPROT down-regulates phosphorylation Ser27 HMAEVNAsPLKHFVT 9606 22748923 t lperfetto "Jnk phosphorylation of mitofusin 2 in response to cellular stress leads to recruitment of the ubiquitin ligase (e3) huwe1/mule/arf-bp1/hecth9/e3histone/lasu1 to mitofusin 2, with the bh3 domain of huwe1 implicated in this interaction. This results in ubiquitin-mediated proteasomal degradation of mitofusin 2these data establish that mfn2 is phosphorylated on ser27 in response to a variety of cellular stresses and implicate jnk in this process" SIGNOR-198054 MAPK9 protein P45984 UNIPROT MYC protein P01106 UNIPROT up-regulates phosphorylation Ser62 LLPTPPLsPSRRSGL 9606 10551811 t gcesareni "The jnk pathway is selectively involved in the c-myc-mediated apoptosis and that the apoptotic function of c-myc is directly regulated by jnk pathway through phosphorylation at ser-62 and ser-71." SIGNOR-72104 MAPK9 protein P45984 UNIPROT MYC protein P01106 UNIPROT up-regulates phosphorylation Ser71 SRRSGLCsPSYVAVT 9606 10551811 t gcesareni "The jnk pathway is selectively involved in the c-myc-mediated apoptosis and that the apoptotic function of c-myc is directly regulated by jnk pathway through phosphorylation at ser-62 and ser-71." SIGNOR-72108 MAPK9 protein P45984 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser20 PLSQETFsDLWKLLP 9606 11896587 t llicata "These findings strongly suggest that jnks are the major direct signaling mediators of uvb-induced p53 phosphorylation at serine 20. furthermore, phosphorylation of p53 at serine 20 by uvb-activated jnks and uvb-induced p53-dependent transcriptional activity were suppressed in jnk1 or jnk2 knockout (jnk1(-/-) or jnk2(-/-)) cells." SIGNOR-115835 MAPK9 protein P45984 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser6 sDPSVEPP 9606 17525747 t gcesareni "Our studies revealed a novel mechanism in which phosphorylation of jnk2 is mediated by jnk1 before phosphorylation of p53, and then p53 is directly phosphorylated by jnk2 at ser6. |Role of map kinases in uvb-induced phosphorylation of p53 at serine 20." SIGNOR-155209 MAPK9 protein P45984 UNIPROT JUN protein P05412 UNIPROT down-regulates binding 9606 9405416 t "Inactive c-Jun NH2-terminal kinase (JNK)." gcesareni "C-jun is targeted for ubiquitination by its association with inactive c-jun nh2-terminal kinase (jnk).Phosphorylation By activated jnk protects c-jun from ubiquitination." SIGNOR-53791 MAPK9 protein P45984 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 BTO:0000938 12040039 t gcesareni "Stress in primary cultured cns neurons induces phosphorylation of c-jun serines 63 and 73 and increased c-jun protein. Jnk2/3 activity selectively targets c-jun." SIGNOR-88208 MAPK9 protein P45984 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser73 VGLLKLAsPELERLI 9606 BTO:0000938 12040039 t gcesareni "Stress in primary cultured cns neurons induces phosphorylation of c-jun serines 63 and 73 and increased c-jun protein. Jnk2/3 activity selectively targets c-jun." SIGNOR-88212 MAPK9 protein P45984 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 19118012 t gcesareni "Phosphorylation by activated jnk protects c-jun from ubiquitination;phosphorylation of c-jun on ser73 by jnk is sufficient to protect c-jun from ubiquitination c-jun is targeted for ubiquitination by its association with inactive c-jun nh2-terminal kinase (jnk). Phosphorylation by activated jnk protects c-jun from ubiquitination, thus by prolonging its half-life targets of the jnk signal transduction pathway include the transcription factors atf2 and c-jun apoptosis, altered;apoptosis, induced;transcription, altered;cell growth, altered;jnk1(disrupts);pin1(induces);dna(disrupts) transcription, altered;cell growth, altered;jnk1(disrupts);pin1(induces);dna(disrupts)" SIGNOR-183017 NCOA1 protein Q15788 UNIPROT STAT5B protein P51692 UNIPROT up-regulates binding 9606 BTO:0000149 12954634 t miannu "Ncoa-1/src-1 is an essential coactivator of stat5 that binds to the fdl motif in the alpha-helical region of the stat5 transactivation domain." SIGNOR-100261 MAPK9 protein P45984 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 7737130 t gcesareni "Stimulation of atf-2-dependent transactivation by genotoxic agents requires the presence of threonines 69 and 71 located in the n-terminal transactivation domain. These sites are the target of p54 and p46 stress-activated protein kinases (sapks) which bind to, and phosphorylate atf-2 in vitro." SIGNOR-32429 MAPK9 protein P45984 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 7737130 t gcesareni "Stimulation of atf-2-dependent transactivation by genotoxic agents requires the presence of threonines 69 and 71 located in the n-terminal transactivation domain. These sites are the target of p54 and p46 stress-activated protein kinases (sapks) which bind to, and phosphorylate atf-2 in vitro." SIGNOR-32433 MAPK9 protein P45984 UNIPROT H2AX protein P16104 UNIPROT up-regulates phosphorylation Ser140 GKKATQAsQEY 9606 18158901 t gcesareni "H2ax interacts with numerous proteins required for dna damage signaling and repair when phosphorylated on ser-140. Phosphorylation of ser-140 (h2ax139ph) in response to ionizing radiation is mediated by both atm and prkdc. Our data showed that h2ax is phosphorylated by uva-activated jnk." SIGNOR-160210 MAPK9 protein P45984 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 20630875 t gcesareni "Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. Here we show that in response to hyperosmotic stress, jnk phosphorylates a key cytoplasmic microtubule regulatory protein, stathmin (stmn), on conserved ser-25 and ser-38 residues. In in vitro biochemical studies, we identified stmn ser-38 as the critical residue required for efficient phosphorylation by jnk and identified a novel kinase interaction domain in stmn required for recognition by jnk. We revealed that jnk was required for microtubule stabilization in response to hyperosmotic stress." SIGNOR-166698 MAPK9 protein P45984 UNIPROT JUNB protein P17275 UNIPROT down-regulates binding 9606 9405416 t gcesareni "Jnk targets junb ubiquitination" SIGNOR-53827 MAPK9 protein P45984 UNIPROT ELK1 protein P19419 UNIPROT "up-regulates activity" phosphorylation Ser389 LSPIAPRsPAKLSFQ 9606 BTO:0000567 8846788 t lperfetto "However, both of these stimuli strongly activate two other mapks, jnk1 and jnk2, and stimulate elk-1 transcriptional activity and phosphorylation jnk phosphorylation sites include ser383 and ser389, the major residues whose phosphorylation is responsible for enhancement of elk-1 trascriptional activity." SIGNOR-247062 MAPK9 protein P45984 UNIPROT RXRA protein P19793 UNIPROT "down-regulates activity" phosphorylation Ser260 NMGLNPSsPNDPVTN 9606 16551633 t gcesareni "Under stress conditions, hyperphosphorylated by activated jnk on ser-56, ser-70, thr-82 and ser-260. These findings indicate that inflammation-mediated cell signaling leads to rapid and profound reductions in nuclear rxralpha levels, via a multistep, jnk-dependent mechanism involving ser260, nuclear export, and proteasomal degradation." SIGNOR-145301 MAPK9 protein P45984 UNIPROT CDC25C protein P30307 UNIPROT down-regulates phosphorylation Ser168 SEMKYLGsPITTVPK 9606 20220133 t gcesareni "Here we show that jnk directly phosphorylates cdc25c at serine 168 during g(2) phase of the cell cycle. Cdc25c phosphorylation by jnk negatively regulates its phosphatase activity and thereby cdk1 activation, enabling a timely control of mitosis onset." SIGNOR-164093 MAPK9 protein P45984 UNIPROT SFN protein P31947 UNIPROT down-regulates phosphorylation Ser186 FHYEIANsPEEAISL 9606 15071501 t "JNK1 and JNK2 are required for apoptosis of thymocites,Ser residues in the reagion between alpha-helices 7 and 8" gcesareni "Jnk phosphorylates 14-3-3zeta_ at ser-184 and 14-3-3sigma_ at ser-189" SIGNOR-124027 MAPK9 protein P45984 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Ser191 SRHAIMRsPQMVSAI 9606 18423204 t amattioni "Beta-catenin, upon entering the nucleus, in turn activates transcription of downstream target genes. Jnk2 phosphorylates Beta-catenin on critical residues (ser191 and ser605). Jnk activity is required for Beta-catenin nuclear localization in response to wnt." SIGNOR-178258 MAPK9 protein P45984 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Ser605 LFVQLLYsPIENIQR 9606 18423204 t amattioni "Beta-catenin, upon entering the nucleus, in turn activates transcription of downstream target genes. Jnk2 phosphorylates Beta-catenin on critical residues (ser191 and ser605). Jnk activity is required for Beta-catenin nuclear localization in response to wnt." SIGNOR-178262 MAPK9 protein P45984 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser307 TRRSRTEsITATSPA 9606 BTO:0000887;BTO:0001103 14579029 t gcesareni "Map kinases and mtor mediate insulin-induced phosphorylation ofinsulinreceptor substrate-1 on serine residues 307, 612 and 632" SIGNOR-118881 MAPK9 protein P45984 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser315 ITATSPAsMVGGKPG 9606 BTO:0000671 9335553 t gcesareni "These results indicate that activation of protein kinase c stimulates a kinase which can phosphorylate insulin receptor substrate-1 at serine 612, resulting in an inhibition of insulin signaling in the cell these data suggest that: 1) activation of pkctheta contributes to ikk and jnk activation by ffas;2) ikk and jnk mediate pkctheta signals for irs-1 serine phosphorylation and degradation; ser-302 phosphorylation is dependent on pi 3-kinase/mtor, whereas ser-307 depends on c-jun nh2-terminal kinase to inhibit irs1 tyrosine phosphorylation. Ser-636 is located around the pi 3-kinase binding site and, therefore, thought to inhibit pi 3-kinase signaling." SIGNOR-52696 MAPK9 protein P45984 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr612 TLHTDDGyMPMSPGV 9606 BTO:0000887;BTO:0001103 14579029 t gcesareni "Map kinases and mtor mediate insulin-induced phosphorylation of insulin receptor substrate-1 on serine residues 307, 612 and 632" SIGNOR-118873 MAPK9 protein P45984 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr632 GRKGSGDyMPMSPKS 9606 BTO:0000887;BTO:0001103 14579029 t gcesareni "Map kinases and mtor mediate insulin-induced phosphorylation ofinsulinreceptor substrate-1 on serine residues 307, 612 and 632" SIGNOR-118877 MAPK9 protein P45984 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 18691976 t "The effect has been demonstrated using P45984-2" gcesareni "Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle." SIGNOR-179275 MAPK9 protein P45984 UNIPROT ELK3 protein P41970 UNIPROT "down-regulates activity" phosphorylation 11042694 t miannu "JNK binds to the J box in the middle of the protein, and binding is required for phosphorylation of the adjacent EXport motif. Both the binding and phosphorylation sites (the JEX element) are important for Net export." SIGNOR-250138 MAPK9 protein P45984 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates phosphorylation Ser319 NSKYNAEsTERESQD 9606 18667537 t llicata "This jnk phosphorylation of ps1 at ser(319)thr(320) enhances the stability of the ps1 c-terminal fragment that is necessary for gamma-secretase activity." SIGNOR-179676 MAPK9 protein P45984 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Thr286 SVPSAAVtPLNESLQ 9606 15767678 t gcesareni "Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro." SIGNOR-134576 MAPK9 protein P45984 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT "up-regulates activity" phosphorylation Thr103 LIDATGDtPGAEDDE 9606 BTO:0000298 12756254 t lperfetto "Recruitment of jnk to jip1 and jnk-dependent jip1 phosphorylation regulates jnk module dynamics and activation it was observed that phosphorylation by jnk of jip1 on thr-103 and not other phosphorylated jip1 residues is necessary for the regulation of dlk association with jip1, dlk activation, and subsequent module activation." SIGNOR-101201 MAP2K4 protein P45985 UNIPROT RXRA protein P19793 UNIPROT down-regulates phosphorylation Tyr249 VEPKTETyVEANMGL 9606 10938283 t miannu "Phosphorylation by mkk4/sek1 had profound effects on the biochemical properties of rxr, inhibiting the expression of genes activated by rxr-retinoic acid receptor complexes. Tyr-249 in the rxr de region was required for the inhibitory effect of mkk4/sek1." SIGNOR-80619 MAP2K4 protein P45985 UNIPROT MAPK8 protein P45983 UNIPROT "up-regulates activity" phosphorylation Tyr185 TSFMMTPyVVTRYYR -1 11062067 t "Stress-activated protein kinase 1 (SAPK1), also called c-Jun N-terminal kinase (JNK), becomes activated in vivo in response to pro-inflammatory cytokines or cellular stresses. Its full activation requires the phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif, which can be catalysed by the protein kinases mitogen-activated protein kinase kinase (MKK)4 and MKK7. Here we report that MKK4 shows a striking preference for the tyrosine residue (Tyr-185), and MKK7 a striking preference for the threonine residue (Thr-183) in three SAPK1/JNK1 isoforms tested (JNK1 alpha 1, JNK2 alpha 2 and JNK3 alpha 1)." SIGNOR-251419 MAP2K4 protein P45985 UNIPROT MAPK8 protein P45983 UNIPROT "up-regulates activity" phosphorylation Thr183 AGTSFMMtPYVVTRY 9606 BTO:0000007 9724739 t gcesareni "MKK4/7, in turn, phosphorylates JNK on residues 183 and 185 (17ƒ‚€“20). Activated JNK phosphorylates its substrates, c-Jun, ATF2, ELK1, and p53" SIGNOR-244982 MAP2K4 protein P45985 UNIPROT MAPK8 protein P45983 UNIPROT "up-regulates activity" phosphorylation Tyr185 TSFMMTPyVVTRYYR 9606 BTO:0000007 9724739 t gcesareni "MKK4/7, in turn, phosphorylates JNK on residues 183 and 185 (17ƒ‚€“20). Activated JNK phosphorylates its substrates, c-Jun, ATF2, ELK1, and p53" SIGNOR-249654 MAP2K4 protein P45985 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates phosphorylation Thr183 ACTNFMMtPYVVTRY 9606 BTO:0000007 17761173 t lperfetto "We next examined whether the phosphorylation of JNK at threonine 183 (Thr183) and tyrosine 185 (Tyr185) was enhanced by GRASP‐1 expression. Phosphorylation of Thr183 and Tyr185 by SEK1/MKK4, which is in turn phosphorylated and activated by several kinases including MEKK1, is known to activate JNK1/2/3" SIGNOR-260615 MAP2K4 protein P45985 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates phosphorylation Tyr185 TNFMMTPyVVTRYYR 9606 BTO:0000149;BTO:0001129 22730327 t gcesareni "Mkk4, which activates p38gamma, p38delta, and jnk2 to phosphorylate p53 on ser-33 and cause a transient g(1) arrest. A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subs 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) here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1)" SIGNOR-197998 MAP2K4 protein P45985 UNIPROT MAP2K4 protein P45985 UNIPROT "up-regulates activity" phosphorylation Ser257 ISGQLVDsIAKTRDA -1 9162092 t "Ser221 and, to a lesser extent, Thr225 in MKK4 as necessary sites for basal and MEKK-induced autophosphorylation and activation of MKK4." SIGNOR-251420 MAP2K4 protein P45985 UNIPROT MAP2K4 protein P45985 UNIPROT "up-regulates activity" phosphorylation Thr261 LVDSIAKtRDAGCRP -1 9162092 t "Ser221 and, to a lesser extent, Thr225 in MKK4 as necessary sites for basal and MEKK-induced autophosphorylation and activation of MKK4." SIGNOR-251421 MAP2K4 protein P45985 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates phosphorylation 9606 10715136 t "Phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif." gcesareni "A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subs 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 subs of map kinases, respectively. Here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1)." SIGNOR-75792 MAP2K4 protein P45985 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates phosphorylation 9606 11062067 t "Phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif." gcesareni "A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subs 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 subs of map kinases, respectively. Here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1)." SIGNOR-83721 MAP2K4 protein P45985 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates phosphorylation 9606 11242034 t "Phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif." gcesareni "A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subs 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 subs of map kinases, respectively. Here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1)." SIGNOR-105692 MAP2K4 protein P45985 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates phosphorylation Tyr223 TSFMMTPyVVTRYYR 9606 15911620 t lperfetto "Two mapkks, sek1 and mkk7, synergistically activate jnk. Sek1 prefers the tyr-185 residue, and mkk7 prefers the thr-183 residue (17, 19)." SIGNOR-137605 MAP2K4 protein P45985 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates phosphorylation Thr221 AGTSFMMtPYVVTRY 9606 BTO:0000007 17761173 t lperfetto "We next examined whether the phosphorylation of JNK at threonine 183 (Thr183) and tyrosine 185 (Tyr185) was enhanced by GRASP‐1 expression. Phosphorylation of Thr183 and Tyr185 by SEK1/MKK4, which is in turn phosphorylated and activated by several kinases including MEKK1, is known to activate JNK1/2/3" SIGNOR-260614 MAP2K4 protein P45985 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates phosphorylation 9606 8974401 t "Phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif." gcesareni "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. here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1)." SIGNOR-45360 MAP2K4 protein P45985 UNIPROT MAPK10 protein P53779 UNIPROT "up-regulates activity" phosphorylation Tyr223 TSFMMTPyVVTRYYR -1 10715136 t "Activation of JNK3 alpha 1 requires both MKK4 and MKK7. both MKK4 and MKK7 were required for bisphosphorylation and maximal enzyme activity. a processive mechanism for JNK3R1 activation that requires phosphorylation of Thr 221 by MKK7 prior to phosphorylation of Tyr 223 by MKK4" SIGNOR-251423 MAP2K4 protein P45985 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" phosphorylation Thr180 RHTDDEMtGYVATRW 9606 7535770 t 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-27973 MAP2K4 protein P45985 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" phosphorylation 9606 7839144 t lperfetto "Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase." SIGNOR-34121 MAP2K4 protein P45985 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR "up-regulates activity" phosphorylation 9606 11062067 t lperfetto "Here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1)." SIGNOR-83729 MAP2K4 protein P45985 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0001950 21561061 t Luana "Activation of JNK pathway components in 3b-expressing cells was assessed by analyzing levels of active phosphorylated formsof JNK and its upstream kinase MEK4. An enhanced phosphor-ylation of JNK and MEK4 was observed in cells expressing 3b ascompared to control cells expressing GFP" SIGNOR-260759 MAP2K4 protein P45985 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000298 8974401 t 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-236110 MAP2K4 protein P45985 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR "up-regulates activity" phosphorylation 9534 BTO:0000298 7839144 t Luana "Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase." SIGNOR-260722 PHKA1 protein P46020 UNIPROT PHKA1 protein P46020 UNIPROT "up-regulates activity" phosphorylation Ser1007 TGIMQLKsEIKQVEF -1 10487978 t miannu "Phk is activated in vitro by autophosphorylation. Ser1018 and at least three of the other six serine residues (Ser972, -985, and -1007) can be phosphorylated in vitro by Phk itself (autophosphorylation)" SIGNOR-250280 PHKA1 protein P46020 UNIPROT PHKA1 protein P46020 UNIPROT "up-regulates activity" phosphorylation Ser972 KEFGVERsVRPTDSN -1 10487978 t miannu "Phk is activated in vitro by autophosphorylation. Ser1018 and at least three of the other six serine residues (Ser972, -985, and -1007) can be phosphorylated in vitro by Phk itself (autophosphorylation)" SIGNOR-250281 PHKA1 protein P46020 UNIPROT PHKA1 protein P46020 UNIPROT "up-regulates activity" phosphorylation Ser985 SNVSPAIsIHEIGAV -1 10487978 t miannu "Phk is activated in vitro by autophosphorylation. Ser1018 and at least three of the other six serine residues (Ser972, -985, and -1007) can be phosphorylated in vitro by Phk itself (autophosphorylation)" SIGNOR-250282 RANGAP1 protein P46060 UNIPROT MYCBP2 protein O75592 UNIPROT "down-regulates quantity by destabilization" relocalization 10090 26304119 t Monia "SUMOylated RanGAP1 Inhibits MYCBP2 Activity and Mediates Its Transport to the Nucleus. Surprisingly, we did not find MYCBP2-dependent ubiquitylation of SUMOylated RanGAP1 but instead a strong inhibition of the ubiquitin ligase activity of MYCBP2 in the presence of SUMOylated RanGAP1, as determined by the presence of ubiquitylated proteins. this effect was specific for SUMOylated RanGAP1, because the unmodified form of RanGAP1 did not affect MYCBP2-dependent protein ubiquitylation. , SUMOylated RanGAP1 inhibited the ubiquitin ligase activity of MYCBP2, and it is tempting to speculate that SUMOylated RanGAP1 inhibits the ubiquitin ligase activity of MYCBP2 to ensure MYCBP2 silencing during its transport to the nucleus" SIGNOR-261203 ATRX protein P46100 UNIPROT ZBED1 protein O96006 UNIPROT "up-regulates activity" binding 7227 BTO:0001138 22021382 t 1 miannu "XNP/dATRX physically interacts with DREF. our results show that DREF is required for the proper expression of pnr and that XNP/dATRX binds to DREF at the DRE sites, resulting in the repression of pnr gene expression." SIGNOR-239729 ATRX protein P46100 UNIPROT GATA4 protein P43694 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 7227 BTO:0001138 22021382 f 1 miannu "XNP/dATRX physically interacts with DREF. our results show that DREF is required for the proper expression of pnr and that XNP/dATRX binds to DREF at the DRE sites, resulting in the repression of pnr gene expression." SIGNOR-239733 CRK protein P46108 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271 8524328 t gcesareni "These results indicate that crk binds to c-cbl in a tyrosine phosphorylation-dependent manner." SIGNOR-39241 CRK protein P46108 UNIPROT PTK2 protein Q05397 UNIPROT "up-regulates activity" phosphorylation Tyr397 SVSETDDyAEIIDEE 9606 BTO:0000007 11314030 t llicata "Tyrosine phosphorylation FAK was strictly dependent upon c-Crk II expression | Crk-inducible FAK tyrosine phosphorylation was completely abrogated by co-expression with R38K Crk (lane 2), and decreased by co-expression with W170K Crk (lane 3), indicating that the SH2 domain of c-Crk is absolutely essential for this effect. In contrast, mutants in the C-terminus of Crk that include Y222F c-Crk, which abrogates the c-Abl phosphorylation site, and W276K Crk, which mutates the C-terminal SH3 domain, modestly increased FAK activation compared to wild-type c-Crk II." SIGNOR-250777 CRK protein P46108 UNIPROT RAPGEF1 protein Q13905 UNIPROT up-regulates binding 9606 7806500 t gcesareni "The endogenous c3g could be coprecipitated with crk from cell lysates of cells expressing high levels of c-crk or v-crk, suggesting high binding affinity and a possible interaction in vivo." SIGNOR-33732 MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000130;BTO:0000801;BTO:0000876 7535770 t 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 CRK protein P46108 UNIPROT MAP4K1 protein Q92918 UNIPROT up-regulates binding 9606 BTO:0000782 9891069 t "HPK1 phosphorylated Crk mainly on threonine and weakly on serine" gcesareni "We found that hpk1 interacted with crk and crkl adaptor proteins in vitro and in vivo and that the proline-rich motifs within hpk1 were involved in the differential interaction of hpk1 with the crk proteins and grb2. Crk and crkl not only activated hpk1 but also synergized with hpk1 in the activation of jnk." SIGNOR-63988 CRK protein P46108 UNIPROT MAP4K5 protein Q9Y4K4 UNIPROT "up-regulates activity" binding -1 9788432 t lperfetto "Two novel candidates for signalling partners of Crk family adapter proteins, the hematopoietic progenitor kinase 1 (HPK1) and the kinase homologous to SPS1/STE20 (KHS), were found to bind with great selectivity to the first SH3 domains of c-Crk and CRKL.|These results make it likely that HPK1 and KHS participate in the signal transduction of Crk family adapter proteins in certain cell types." SIGNOR-262830 CRKL protein P46109 UNIPROT PIK3CB protein P42338 UNIPROT "up-regulates activity" binding 9606 BTO:0005029 28723560 t irozzo "Here, we identify CRKL as a member of the class of PI3Kβ-interacting proteins. Silencing CRKL expression in PTEN-null human cancer cells leads to a decrease in p110β-dependent PI3K signaling and cell proliferation.In conclusion, our study identified CRKL as an important regulator of PI3K activity in PTEN-deficient tumor cells through its association with p110β/p85." SIGNOR-255821 CRKL protein P46109 UNIPROT MAP4K1 protein Q92918 UNIPROT up-regulates binding 9606 BTO:0000782 9891069 t "HPK1 phosphorylated CrkL mainly on serine and weakly on threonine" gcesareni "We found that hpk1 interacted with crk and crkl adaptor proteins in vitro and in vivo and that the proline-rich motifs within hpk1 were involved in the differential interaction of hpk1 with the crk proteins and grb2. Crk and crkl not only activated hpk1 but also synergized with hpk1 in the activation of jnk." SIGNOR-63991 NSF protein P46459 UNIPROT SNAP25 protein P60880 UNIPROT "down-regulates activity" binding 9606 BTO:0000938 SIGNOR-C346 16679567 t miannu "NSF is an important regulator of SNARE assembly/disassembly. NSF binds to SNAP-25, while in complex with other SNAREs, and hydrolyzes adenosine triphosphate to disassemble the SNARE complex down to monomers" SIGNOR-263974 CDKN1B protein P46527 UNIPROT CDK1 protein P06493 UNIPROT down-regulates binding 9606 15340381 t gcesareni "P21 and p27 are key inhibitors of both cdk1 and cdk2." SIGNOR-128445 CDKN1B protein P46527 UNIPROT CDK2 protein P24941 UNIPROT down-regulates binding 9606 SIGNOR-C16 17409098 t gcesareni "P27, an important cell cycle regulator, blocks the g(1)/s transition in cells by binding and inhibiting cdk2/cyclin a and cdk2/cyclin e complexes (cdk2/e)." SIGNOR-154191 CDKN1B protein P46527 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR "down-regulates activity" binding 9606 17409098 t lperfetto "P27, an important cell cycle regulator, blocks the g(1)/s transition in cells by binding and inhibiting cdk2/cyclin a and cdk2/cyclin e complexes (cdk2/e)." SIGNOR-217505 NOTCH1 protein P46531 UNIPROT FABP7 protein O15540 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000938 16554461 f gcesareni "Here we demonstrate that neuronal induction of radial glia formation is the result of sequential signaling through notch1 and erbb receptors. First, notch1 activation by neuronal contact induces the glial expression of the brain lipid binding protein (blbp) and erbb2 genes." SIGNOR-145365 NOTCH1 protein P46531 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782;BTO:0001271;BTO:0000785 16847353 f gcesareni "We identified c-myc as a direct target of notch1" SIGNOR-147944 NOTCH1 protein P46531 UNIPROT IL2RA protein P01589 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001454 10933396 f gcesareni "Activation of notch1 signaling in dp thymocytes and thymoma cell lines results in the upregulation of cd25 and cd44 expression." SIGNOR-80336 NOTCH1 protein P46531 UNIPROT ERBB2 protein P04626 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000938 16554461 f gcesareni "Notch1 activation by neuronal contact induces the glial expression of the brain lipid binding protein (blbp) and erbb2 genes." SIGNOR-145322 NOTCH1 protein P46531 UNIPROT BCL2 protein P10415 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 16990763 f gcesareni "Other notch target genes identi__ed in the thymoma cell line were dtx1 (gene for deltex1), i__-202, i__-204, i__-d3, adam19 (meltrinb).24 a number of other genes have been reported as being notch targets, including notch1 itself,28 nrarp in xenopus embryos,29 bcl2 in thymoma cells,30 ccnd1 (gene for cyclin d1) in a kidney cell line,31 dkn1a (gene for cyclindependent kinase inhibitor 1a (p21, cip1)) in keratinocytes32 and tcf3 (gene for e2a)." SIGNOR-149730 NOTCH1 protein P46531 UNIPROT TCF3 protein P15923 UNIPROT down-regulates binding 9606 BTO:0000776 9528794 t gcesareni "We provide evidence that notch and deltex may act on e47 by inhibiting signaling through ras because (i) full e47 activity was found to be dependent on ras and (ii) both notch and deltex inhibited gal4-jun, a hybrid transcription factor whose activity is dependent on signaling from ras to sapk/jnk." SIGNOR-56150 NOTCH1 protein P46531 UNIPROT CD44 protein P16070 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001454 10933396 f gcesareni "Activation of notch1 signaling in dp thymocytes and thymoma cell lines results in the upregulation of cd25 and cd44 expression" SIGNOR-80333 NOTCH1 protein P46531 UNIPROT IL7R protein P16871 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 22577461 f miannu "E2a positively regulates notch1 expression, which induces the expression of hebalt, bcl11b, and il7r." SIGNOR-197452 NOTCH1 protein P46531 UNIPROT NFKB1 protein P19838 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000776 11591772 f lperfetto "Nf-kappab activity is regulated by notch-1 via transcriptional control of nf-kappab." SIGNOR-110963 NOTCH1 protein P46531 UNIPROT HOXA5 protein P20719 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 16990763 f gcesareni "Other than a role in t-cell development, the hox genes may be involved in alternative notchregulated processes in hematopoietic stem cells. Notch signaling is clearly important for self-renewal of hematopoietic progenitors (reviewed by radkte et al. 57). Interestingly, hoxa5, a9 and a10 were found to be part of the stem cell profile'" SIGNOR-149770 NOTCH1 protein P46531 UNIPROT PAX7 protein P23759 UNIPROT "up-regulates quantity by expression" 9606 BTO:0001103;BTO:0002314 22493066 f lperfetto "Constitutive Notch Activation Upregulates Pax7 and Promotes the Self-Renewal of Skeletal Muscle Satellite Cells" SIGNOR-219374 NOTCH1 protein P46531 UNIPROT PPARG protein P37231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001253 12107827 f gcesareni "Addition of jag-1 peptide induced ikkalpha mediated nf-kappab activation, as well as increased ppargamma expression." SIGNOR-90455 MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" phosphorylation 9534 7839144 t lperfetto "Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase." SIGNOR-232156 NOTCH1 protein P46531 UNIPROT NOTCH1 protein P46531 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 16990763 f lperfetto "Other notch target genes identi?ed In the thymoma cell line were dtx1 (gene for deltex1), i?-202, i?-204, i?-D3, adam19 (meltrinb).24 a number of other genes have been reported as being notch targets, including notch1 itself,28 nrarp in xenopus embryos,29 bcl2 in thymoma cells,30 ccnd1 (gene for cyclin d1) in a kidney cell line,31 dkn1a (gene for cyclindependent kinase inhibitor 1a (p21, cip1)) in keratinocytes32 and tcf3 (gene for e2a)." SIGNOR-149777 NOTCH1 protein P46531 UNIPROT NFKB2 protein Q00653 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9528780 f gcesareni "In transient-transfection assays we show that truncated notch-1 strongly induces nf-kappab2 promoter activity." SIGNOR-56097 NOTCH1 protein P46531 UNIPROT RBPJ protein Q06330 UNIPROT up-regulates binding 9606 19165418 t gcesareni "The intracellular part of the notch receptor is cleaved off and translocates to the nucleus, where it binds to the transcription factor rbp-j." SIGNOR-183510 NOTCH1 protein P46531 UNIPROT SNW1 protein Q13573 UNIPROT up-regulates binding 9606 10713164 t gcesareni "SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function." SIGNOR-75782 NOTCH1 protein P46531 UNIPROT SNW1 protein Q13573 UNIPROT up-regulates binding 9606 11404076 t gcesareni "Contact with skip is required for biological activity of notchic. A mutation in the fourth ankyrin repeat that abolished notch signal transduction did not affect interaction with cbf1 but abolished interaction with skip." SIGNOR-86125 NOTCH1 protein P46531 UNIPROT HES1 protein Q14469 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19165418 f lperfetto "Several lines of evidence have suggested that these genes are indeed direct notch target genes: a) the promoters of hes1, hes5 and hes7 as well as hey1, hey2 and heyl subfamily of hes, related with yrpw motif) can be activated by a constitutive active form of notch1." SIGNOR-183507 NOTCH1 protein P46531 UNIPROT HIF1A protein Q16665 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000938 16256737 t lperfetto "The notch intracellular domain interacts with hif-1alpha and hif-1alpha is recruited to notch-responsive promoters upon notch activation under hypoxic conditions." SIGNOR-141315 NOTCH1 protein P46531 UNIPROT LFNG protein Q8NES3 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165 15207708 f gcesareni "Notch signal transduction pathway genes, lfng, hey1, and hes1, are differen-tially regulated by bmp-2 and tgf-beta." SIGNOR-236845 NOTCH1 protein P46531 UNIPROT LFNG protein Q8NES3 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22298955 f gcesareni "Notch signal transduction pathway genes, lfng, hey1, and hes1, are differen-tially regulated by bmp-2 and tgf-beta." SIGNOR-195621 NOTCH1 protein P46531 UNIPROT TCF12 protein Q99081 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 22577461 f miannu "E2a positively regulates notch1 expression, which induces the expression of hebalt, bcl11b, and il7r." SIGNOR-197514 NOTCH1 protein P46531 UNIPROT BCL11B protein Q9C0K0 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 22577461 f miannu "E2a positively regulates notch1 expression, which induces the expression of hebalt, bcl11b, and il7r." SIGNOR-197449 NOTCH1 protein P46531 UNIPROT ADAM19 protein Q9H013 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782;BTO:0001454 10933396 f gcesareni "Deltex, meltrin beta, ifi-202, and ifi-204 were also upregulated by notchic in the 2b4.11 t cell hybridoma, whereas ifi-d3 was expressed constitutively at relatively high levels and slightly upregulated by notchic, and pre-talfa was not expressed. Deltex, meltrin beta, pre-talfa, ifi-202, and ifi-204 were upregulated by notchic expression in the akr1 dp thymoma cell line, whereas ifi-d3 was not expressed" SIGNOR-80330 NOTCH1 protein P46531 UNIPROT HEYL protein Q9NQ87 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887;BTO:0001260 11044625 f gcesareni "These data confirm heyl as a notch1 target gene that is likely involved in somite formation and patterning." SIGNOR-83399 NOTCH1 protein P46531 UNIPROT TCFL5 protein Q9UL49 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 16990763 f gcesareni "Interestingly, in absence of delta signal, both hes-1 and tcfl5 decreased, and further decreased by incubation with dapt. (figure 4). This pharmacological approach therefore provides additional evidence that tcfl5, similar to hes1, is a true notch target gene." SIGNOR-149807 NOTCH1 protein P46531 UNIPROT ZMIZ1 protein Q9ULJ6 UNIPROT "up-regulates activity" binding 10090 BTO:0001825 26522984 t miannu "The N-terminal domain (NTD) is critical for Zmiz1 to function as a Notch collaborator. Zmiz1 and Notch1 cooperatively recruit each other to chromatin through the TPR domain. The N-terminal domain (NTD) of Zmiz1 is important for enhancing Notch reporter activity and contains tetratricopeptide repeats (TPR) that mediate protein-protein interactions" SIGNOR-263937 NOTCH1 protein P46531 UNIPROT HEY1 protein Q9Y5J3 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 11486044 t lperfetto "These data establish that HERP2 is a novel primary target gene of Notch that, together with HES, may effect diverse biological activities of Notch" SIGNOR-235397 NOTCH1 protein P46531 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates 9606 22298955 f gcesareni "Similar synergy is found in notch and bmp crosstalk: activating notch signaling enhanced bmp-induced alp activity and formation of calcified nodules in vitro." SIGNOR-114592 NOTCH1 protein P46531 UNIPROT RBPJ/NOTCH complex SIGNOR-C97 SIGNOR "form complex" binding 9606 7566092 t "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 ASMT protein P46597 UNIPROT melatonin smallmolecule CHEBI:16796 ChEBI "up-regulates quantity" "small molecule catalysis" -1 22775292 t miannu "Here, we present the X-ray crystal structure of human N-acetyl serotonin methyltransferase (ASMT), the last enzyme of the melatonin biosynthesis pathway. Melatonin synthesis requires serotonin, which is first acetylated by the arylalkylamine N-acetyltransferase (AA-NAT) to produce N-acetyl serotonin (NAS) (Fig. 1A). Then, acetyl serotonin methyltransferase (ASMT, also known as hydroxyindole O-methyltransferase or HIOMT) produces melatonin by transferring a methyl group from the cofactor S-adenosyl-L-methionine (SAM) to NAS" SIGNOR-265475 MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" phosphorylation Thr180 RHTDDEMtGYVATRW 9606 8622669 t 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 MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" phosphorylation Tyr182 TDDEMTGyVATRWYR 9606 8622669 t 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 BDKRB1 protein P46663 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257362 BDKRB1 protein P46663 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257149 BDKRB1 protein P46663 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257237 BDKRB1 protein P46663 UNIPROT GNA15 protein P30679 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257411 BDKRB1 protein P46663 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256907 BDKRB1 protein P46663 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257304 BDKRB1 protein P46663 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257036 BDKRB1 protein P46663 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256764 IER3 protein P46695 UNIPROT PPP2R5C protein Q13362 UNIPROT down-regulates binding 9606 16456541 t gcesareni "Iex-1 binds to b56 subunits and perk independently, enhances b56 phosphorylation by erk at a conserved ser/pro site in this complex and triggers dissociation from the catalytic subunit." SIGNOR-144309 MAP2K3 protein P46734 UNIPROT MAPK12 protein P53778 UNIPROT up-regulates phosphorylation 9606 11062067 t fstefani "Mkk3, mkk4 and mkk6 all show a strong preference for phosphorylation of the tyrosine residue of the thr-gly-tyr motifs in their known substrates sapk2a/p38, sapk3/p38 gamma and sapk4/p38 delta. we therefore examined the phosphorylation of sapk2a/p38, sapk3/p38? And sapk4/p38? By mkk3, mkk4 and mkk6, which are all known to be capable of activating these enzymes in vitro." SIGNOR-83718 MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" phosphorylation 9606 8622669 t 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 MAP2K3 protein P46734 UNIPROT DYRK1B protein Q9Y463 UNIPROT up-regulates phosphorylation 9606 BTO:0000887;BTO:0001103 11980910 t amattioni "Mkk3 enhanced mirk kinase activity. Mkk3 possibly activates mirk by phosphorylating it." SIGNOR-86731 MAP2K3 protein P46734 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR "up-regulates activity" phosphorylation 9534 BTO:0000298 7839144 t Luana "Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase." SIGNOR-260723 BRCC3 protein P46736 UNIPROT H2AC11 protein P0C0S8 UNIPROT down-regulates deubiquitination 9606 20656690 t gcesareni "Brcc36 regulates the abundance of lys(63)-linked ubiquitin chains at chromatin and that one of its substrates is diubiquitinated histone h2a" SIGNOR-167142 BRCC3 protein P46736 UNIPROT "BRCC ubiquitin ligase complex" complex SIGNOR-C295 SIGNOR "form complex" binding 9606 BTO:0000007 14636569 t lperfetto "These findings identify BRCC as a ubiquitin E3 ligase complex that enhances cellular survival following DNA damage.|Reconstitution of a recombinant four-subunit complex containing BRCA1/BARD1/BRCC45/BRCC36 revealed an enhanced E3 ligase activity compared to that of BRCA1/BARD1 heterodimer" SIGNOR-263205 BRCC3 protein P46736 UNIPROT "BRCA1-A complex" complex SIGNOR-C296 SIGNOR "form complex" binding 9606 BTO:0000007 20656690 t lperfetto "We and others showed previously that BRCC36 is a component of the BRCA1-A complex, which consists of RAP80, CCDC98/ABRAXAS, BRCC45/BRE, MERIT40/NBA1, BRCC36, and BRCA1. " SIGNOR-263213 RPL27A protein P46776 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262473 RPL5 protein P46777 UNIPROT TP73 protein O15350 UNIPROT up-regulates binding 9606 25301064 t miannu "We report that rpl5 and rpl11 can also enhance the transcriptional activity of a p53 homolog tap73" SIGNOR-205517 RPL5 protein P46777 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262457 RPL21 protein P46778 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262478 RPL28 protein P46779 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262472 RPS9 protein P46781 UNIPROT "40S cytosolic small ribosomal subunit" complex SIGNOR-C286 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262415 RPS5 protein P46782 UNIPROT "40S cytosolic small ribosomal subunit" complex SIGNOR-C286 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262419 RPS10 protein P46783 UNIPROT "40S cytosolic small ribosomal subunit" complex SIGNOR-C286 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262442 NEDD4 protein P46934 UNIPROT KCNH2 protein Q12809 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0002181 26363003 t SARA "We have previously shown that the E3 ubiquitin (Ub) ligase Nedd4-2 (neural precursor cell expressed developmentally down-regulated protein 4-2) targets the PY motif of hERG channels to initiate channel degradation. Although both immature and mature hERG channels contain the PY motif, Nedd4-2 selectively mediates the degradation of mature hERG channels." SIGNOR-260998 YAP1 protein P46937 UNIPROT DVL1 protein O14640 UNIPROT down-regulates binding 9606 23178811 t gcesareni "Yap restricts elevated wnt independently of the axinapcgsk-3beta complex partly by limiting the activity of dishevelled (dvl)." SIGNOR-199806 YAP1 protein P46937 UNIPROT TP73 protein O15350 UNIPROT up-regulates binding 9606 21808241 t "The WW domain of YAP binds to PPXY-containing p73 family members." gcesareni "Yap also interacts with p73, a p53 family pro-apoptotic transcription factor, to induce expression of genes such as bax, puma and pml." SIGNOR-175934 PRKAA2 protein P54646 UNIPROT PFKFB2 protein O60825 UNIPROT "up-regulates activity" phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000007 11069105 t miannu "AMPK phosphorylates and activates heart PFK-2 in vitro and in intact cells.  activation of PFK-2 was due to the phosphorylation of Ser466" SIGNOR-250323 YAP1 protein P46937 UNIPROT FSTL3 protein O95633 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000222;BTO:0002314 BTO:0000887;BTO:0001103 23038772 f gcesareni "In our analysis bmp4 (bone morphogenetic protein 4) and fstl3 (follistatin-related protein 3) increased their expression in response to hyap1 s127a overexpression." SIGNOR-199072 YAP1 protein P46937 UNIPROT BMP4 protein P12644 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000222;BTO:0002314 BTO:0000887;BTO:0001103 23038772 f gcesareni "In our analysis bmp4 (bone morphogenetic protein 4) and fstl3 (follistatin-related protein 3) increased their expression in response to hyap1 s127a overexpression." SIGNOR-199066 YAP1 protein P46937 UNIPROT MYF6 protein P23409 UNIPROT down-regulates 9606 BTO:0000222;BTO:0002314 BTO:0000887;BTO:0001103 23038772 f gcesareni "Myf6 (mrf4) is repressed by hyap1 s127a overexpression." SIGNOR-199075 YAP1 protein P46937 UNIPROT TEAD1 protein P28347 UNIPROT up-regulates binding 9606 23431053 t "Crystallographic data revealed that the N-terminal TEAD-binding domain of YAP wraps around a globular structure formed by the C-terminal domains of TEAD1, 2 and 4" gcesareni "When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14." SIGNOR-201465 YAP1 protein P46937 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates binding 9606 BTO:0000562 23607968 t gcesareni "Additionally, the hippo and wnts also cooperate in the nucleus, where yap interacts with beta-catenin and induces the expression of canonical wnt target genes, such as sox2 and snai2 in mouse heart tissue." SIGNOR-201939 YAP1 protein P46937 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates binding 9606 14765127 t "Regulation of Runx activity by TAZ or YAP affects mesenchymal stem cell differentiation." gcesareni "Here we show that the endogenous yes-associated protein (yap), a mediator of src/yes signaling, interacts with the native runx2 protein, an osteoblast-related transcription factor, and suppresses runx2 transcriptional activity in a dose-dependent manner." SIGNOR-121803 YAP1 protein P46937 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates binding 9606 22153608 t "Regulation of Runx activity by TAZ or YAP affects mesenchymal stem cell differentiation." gcesareni "Here we show that the endogenous yes-associated protein (yap), a mediator of src/yes signaling, interacts with the native runx2 protein, an osteoblast-related transcription factor, and suppresses runx2 transcriptional activity in a dose-dependent manner." SIGNOR-195221 YAP1 protein P46937 UNIPROT TEAD4 protein Q15561 UNIPROT up-regulates binding 9606 23431053 t "Crystallographic data revealed that the N-terminal TEAD-binding domain of YAP wraps around a globular structure formed by the C-terminal domains of TEAD1, 2 and 4" gcesareni "When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14." SIGNOR-201474 YAP1 protein P46937 UNIPROT TEAD2 protein Q15562 UNIPROT up-regulates binding 9606 23431053 t "Crystallographic data revealed that the N-terminal TEAD-binding domain of YAP wraps around a globular structure formed by the C-terminal domains of TEAD1, 2 and 4." gcesareni "When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14." SIGNOR-201468 YAP1 protein P46937 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates binding 9606 23431053 t "YAP can specifically recognize the phosphorylated SMAD linker sequence containing the PY motif, and its presence is required for efficient transcription of BMP target genes." gcesareni "Yap binds to the phosphorylated smad1 to activate gene transcription." SIGNOR-201462 YAP1 protein P46937 UNIPROT WWC1 protein Q8IX03 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007 21233212 f miannu "We also found that KIBRA mRNA is induced by YAP overexpression in both murine and human cells, suggesting the evolutionary conservation of KIBRA as a transcriptional target of the Hippo signaling pathway. Thus, our study revealed a new connection between KIBRA and mammalian Hippo signaling." SIGNOR-263660 YAP1 protein P46937 UNIPROT FBXO32 protein Q969P5 UNIPROT down-regulates 9606 BTO:0000222;BTO:0002314 BTO:0000887;BTO:0001103 23038772 f gcesareni "The downregulation of fbox32 expression by high yap activity in activated satellite cells may contribute to sustaining high levels of myod in activated satellite cells." SIGNOR-199069 YAP1 protein P46937 UNIPROT TEAD3 protein Q99594 UNIPROT up-regulates binding 9606 23431053 t "Crystallographic data revealed that the N-terminal TEAD-binding domain of YAP wraps around a globular structure formed by the C-terminal domains of TEAD1, 2 and 4" gcesareni "When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14." SIGNOR-201471 IQGAP1 protein P46940 UNIPROT CDC42 protein P60953 UNIPROT "down-regulates activity" binding 15695813 t lperfetto "Although the name implies that it functions as a GTPase-activating protein, IQGAP1 actually stabilizes Cdc42 and Rac1 in the active, GTP-bound form (5, 8, 17). Thus, IQGAP1 acts as an “anti-GTPase-activating protein” for Cdc42 and Rac1, with marked effects on the cytoskeleton. " SIGNOR-261888 IQGAP1 protein P46940 UNIPROT RAC1 protein P63000 UNIPROT "down-regulates activity" binding 15695813 t lperfetto "Although the name implies that it functions as a GTPase-activating protein, IQGAP1 actually stabilizes Cdc42 and Rac1 in the active, GTP-bound form (5, 8, 17). Thus, IQGAP1 acts as an “anti-GTPase-activating protein” for Cdc42 and Rac1, with marked effects on the cytoskeleton. " SIGNOR-261889 GALR1 protein P47211 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256830 GALR1 protein P47211 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256966 HDAC4 protein P56524 UNIPROT MEF2C protein Q06413 UNIPROT down-regulates binding 9606 BTO:0000887 10737771 t gcesareni "We discovered that mef2 interacts with histone deacetylases (hdacs) 4 and 5, resulting in repression of the transcriptional activity of mef2." SIGNOR-76234 GALR1 protein P47211 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256687 CSN1S1 protein P47710 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser529 GLPNGLLsGDEDFSS 9606 21232017 t gcesareni "Phosphorylation of serine 529 of p65 is mediated by casein kinase ii, but is prevented in nonstimulated cells by the interaction with ikba" SIGNOR-171222 PLA2G4A protein P47712 UNIPROT "arachidonic acid" smallmolecule CHEBI:15843 ChEBI up-regulates "small molecule catalysis" 9606 6810878 t acerquone "Alternatively, a phospholipase a2 may indeed deacylate the phosphatidylinositol, but the point of debate here is whether deacylation constitutes a significant component of the arachidonate liberation." SIGNOR-25633 GABRA2 protein P47869 UNIPROT "GABA-A (a2-b1-g2) receptor" complex SIGNOR-C331 SIGNOR "form complex" binding 9606 BTO:0000227 18790874 t "brain, See table 3 for identified complexes" lperfetto "The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon." SIGNOR-263753 GABRB2 protein P47870 UNIPROT "GABA-A (a4-b2-d) receptor" complex SIGNOR-C326 SIGNOR "form complex" binding 9606 BTO:0000227 18790874 t "brain, See table 3 for identified complexes" lperfetto "The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon." SIGNOR-263744 GABRB2 protein P47870 UNIPROT "GABA-A (a6-b2-d) receptor" complex SIGNOR-C328 SIGNOR "form complex" binding 9606 BTO:0000227 18790874 t "brain, See table 3 for identified complexes" lperfetto "The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon." SIGNOR-263769 ALDH1A3 protein P47895 UNIPROT retinal smallmolecule CHEBI:15035 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 21621639 t lperfetto "All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step." SIGNOR-265128 ALDH1A3 protein P47895 UNIPROT "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 21621639 t lperfetto "All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step." SIGNOR-265129 P2RY1 protein P47900 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257185 P2RY1 protein P47900 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257273 P2RY1 protein P47900 UNIPROT GNA15 protein P30679 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257339 P2RY1 protein P47900 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256943 P2RY1 protein P47900 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257072 P2RY1 protein P47900 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257394 P2RY1 protein P47900 UNIPROT GNA13 protein Q14344 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257442 P2RY1 protein P47900 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256800 AVPR1B protein P47901 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257176 AVPR1B protein P47901 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256934 AVPR1B protein P47901 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257264 AVPR1B protein P47901 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257063 AVPR1B protein P47901 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256791 RPL29 protein P47914 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262471 ID4 protein P47928 UNIPROT SOX2 protein P48431 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21531766 f miannu "We found that ID4 enhanced SOX2 protein expression by suppressing microRNA-9* (miR-9*), which can repress SOX2 by targeting its 3'-untranslated region. " SIGNOR-255180 UQCRFS1 protein P47985 UNIPROT "Mitochondrial respiratory chain complex III" complex SIGNOR-C279 SIGNOR "form complex" binding 30030361 t lperfetto "Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits" SIGNOR-262190 XCL1 protein P47992 UNIPROT XCR1 protein P46094 UNIPROT up-regulates binding 9606 BTO:0000763 10518929 t gcesareni "Scm-1 showed a high-affinity binding to xcr1 with a kd of 10 nm and induced vigorous chemotaxis and calcium mobilization in xcr1-transfected murine l1.2 cells." SIGNOR-71164 FASLG protein P48023 UNIPROT FAS protein P25445 UNIPROT "up-regulates activity" binding 9606 14965271 t lperfetto "Fas (CD95) is activated by its natural ligand FasL" SIGNOR-216292 FASLG protein P48023 UNIPROT FAS protein P25445 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 BTO:0000671 9228058 t lperfetto "The death-inducing receptor fas is activated when cross-linked by the type ii membrane protein faslg (fasl)" SIGNOR-49688 SLC6A8 protein P48029 UNIPROT creatine smallmolecule CHEBI:16919 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000142 18652074 t miannu "CRT is essential for normal brain function as mutations in the CRT gene (SLC6A8) result in X-linked mental retardation, associated with the almost complete lack of creatine in the brain, severe speech and language delay, epilepsy, and autistic behaviour." SIGNOR-265782 SLC6A8 protein P48029 UNIPROT creatine smallmolecule CHEBI:16919 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000142 18652074 t miannu "CRT is essential for normal brain function as mutations in the CRT gene (SLC6A8) result in X-linked mental retardation, associated with the almost complete lack of creatine in the brain, severe speech and language delay, epilepsy, and autistic behaviour." SIGNOR-265808 MTNR1A protein P48039 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256849 MTNR1A protein P48039 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256985 MTNR1A protein P48039 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257101 MTNR1A protein P48039 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256706 GRIA4 protein P48058 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000938 29953871 t miannu "Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial." SIGNOR-264950 LIMS1 protein P48059 UNIPROT "IPP complex" complex SIGNOR-C380 SIGNOR "up-regulates activity" binding 16493410 t lperfetto "Integrin-linked kinase (ILK), PINCH and parvin form a ternary complex (the IPP complex) that binds to ECM-ligated integrins. This complex regulates signalling pathways and connects the ECM with the actin cytoskeleton." SIGNOR-265763 CXCL12 protein P48061 UNIPROT ACKR3 protein P25106 UNIPROT up-regulates binding 9606 BTO:0000782 16107333 t gcesareni "Here we show that cxcl12, the only known natural ligand for cxcr4, binds to and signals through rdc1." SIGNOR-139709 CXCL12 protein P48061 UNIPROT CXCR4 protein P61073 UNIPROT up-regulates binding 9606 11859124 t gcesareni "To study the role of the sdf-1/cxcr4-chemokine/receptor system as a regulator of vertebrate development, we isolated and characterized a cdna encoding sdf-1 of the lower vertebrate xenopus laevis (xsdf-1). Recombinant xsdf-1 was produced in insect cells, purified, and functionally characterized. Although xsdf-1 is only 64-66% identical with its mammalian counterparts, it is indistinguishable from human (h)sdf-1alpha in terms of activating both x. laevis cxcr4 and hcxcr4. Thus, both xsdf-1 and hsdf-1alpha promoted cxcr4-mediated activation of heterotrimeric g(i2) in a cell-free system and induced release of intracellular calcium ions in and chemotaxis of intact lymphoblastic cells." SIGNOR-115029 NPBWR1 protein P48145 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256818 NPBWR1 protein P48145 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256675 ME1 protein P48163 UNIPROT NADPH(4-) smallmolecule CHEBI:57783 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 24769394 t miannu "The major NADPH-producing enzymes in the cell are glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) in the pentose phosphate pathway (PPP), malic enzyme (ME) in the pyruvate cycling pathway, and isocitrate dehydrogenase (IDH) in the tricarboxylic acid (TCA) cycle" SIGNOR-267055 GABRA4 protein P48169 UNIPROT "GABA-A (a4-b2-d) receptor" complex SIGNOR-C326 SIGNOR "form complex" binding 9606 BTO:0000227 18790874 t "brain, See table 3 for identified complexes" lperfetto "The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon." SIGNOR-263745 GABRA4 protein P48169 UNIPROT "GABA-A (a4-b3-d) receptor" complex SIGNOR-C327 SIGNOR "form complex" binding 9606 BTO:0000227 18790874 t "brain, See table 3 for identified complexes" lperfetto "The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon." SIGNOR-263748 GABRA4 protein P48169 UNIPROT "GABA-A (a4-b1-g2) receptor" complex SIGNOR-C333 SIGNOR "form complex" binding 9606 BTO:0000227 18790874 t "brain, See table 3 for identified complexes" lperfetto "The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon." SIGNOR-263759 LEPR protein P48357 UNIPROT AGRP protein O00253 UNIPROT "down-regulates quantity" 27154742 f lperfetto "Leptin binding inhibits the neuropeptide Y/agouti-related protein (NPY/AgRP) production and stimulates pro-opiomelanocortin (POMC) production" SIGNOR-253076 LEPR protein P48357 UNIPROT POMC protein P01189 UNIPROT "up-regulates quantity" 27154742 f lperfetto "Leptin binding inhibits the neuropeptide Y/agouti-related protein (NPY/AgRP) production and stimulates pro-opiomelanocortin (POMC) production" SIGNOR-253074 LEPR protein P48357 UNIPROT NPY protein P01303 UNIPROT "down-regulates quantity" 27154742 f lperfetto "Leptin binding inhibits the neuropeptide Y/agouti-related protein (NPY/AgRP) production and stimulates pro-opiomelanocortin (POMC) production" SIGNOR-253075 LEPR protein P48357 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 11018044 t miannu "LRb signaling is initiated by leptin binding to the extracellular domain of the LRb dimer, leading to Jak2 transphosphorylation and activation. Activated Jak2 mediates the tyrosine phosphorylation of Tyr985 and Tyr1138of LRb. These phosphotyrosine residues immediately function as binding sites (double-ended lines) for SHP-2 and STAT3, both of which quickly become tyrosine-phosphorylated by Jak2." SIGNOR-263495 LEPR protein P48357 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0001282 18718905 t miannu "These observations indicate that leptin stimulates tyrosine phosphorylation of STAT3 via LEPRb but independent of JAK2." SIGNOR-263492 LEPR protein P48357 UNIPROT PTPN11 protein Q06124 UNIPROT "up-regulates activity" binding 9606 11085989 t miannu "Because the long leptin receptor lacking tyrosine 985 exhibits a significantly reduced ability to activate ERK phosphorylation, this residue is at least in part mediating stimulation of the ERK pathway by ObRb. This residue binds SHP-2 and is required for tyrosine phosphorylation of SHP-2" SIGNOR-263506 LEPR protein P48357 UNIPROT SH2B1 protein Q9NRF2 UNIPROT "up-regulates activity" binding 27154742 t lperfetto "The SH2B adaptor protein 1 (SH2B1) is a key regulator of leptin, as it enhances leptin signalling by both stimulating Janus kinase 2 (JAK2) activity and assembling a JAK2/IRS1/2 signalling complex" SIGNOR-253077 LEPR protein P48357 UNIPROT AMPK complex SIGNOR-C15 SIGNOR "down-regulates activity" 9606 BTO:0003336 25343030 f miannu "Leptin exerts an inhibitory effect on AMPK in the hypothalamus, thereby stimulating ACC and subsequently suppressing food intake." SIGNOR-263510 RFX3 protein P48380 UNIPROT FOXJ1 protein Q92949 UNIPROT "up-regulates activity" binding 9606 BTO:0000939 23822649 t miannu "RFX3 acts as a transcriptional co-activator to FOXJ1 that enhances the expression of cilia-associated genes. FOXJ1 is an important regulator of cilia gene expression during ciliated cell differentiation, with RFX3 as a transcriptional co-activator to FOXJ1, helping to induce the expression of cilia genes in the process of ciliated cell differentiation of basal/progenitor cells." SIGNOR-266929 RFX5 protein P48382 UNIPROT HLA-DRA protein P01903 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000460 10586057 t Luana "In this report, we correlate the loss of IFN-γ induction of MHC class II genes with the identification of a molecular defect in an essential regulator, namely RFX5. | We have further confirmed this finding by showing that new RFX5 leucine mutants created in vitro are incapable of transactivating a class II promoter, suggesting the identification of residues essential for RFX activity." SIGNOR-266228 RFX5 protein P48382 UNIPROT "RFX complex" complex SIGNOR-C104 SIGNOR "form complex" binding -1 10825209 t miannu "RFXANK and RFXAP bind to each other and form a heterodimer (step 1) that subsequently interacts with RFX5 Upon binding, the conformation of RFX5 changes (step 2) in a way that enables the RFX complex to bind to DNA (step 3) and to recruit other proteins that are required for the transcription of MHC II genes" SIGNOR-221565 SOX2 protein P48431 UNIPROT ABCC3 protein O15438 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21531766 f miannu "ID4-mediated SOX2 induction enhanced ABCC3 and ABCC6 expression through direct transcriptional regulation, indicating that ID4 regulates the chemoresistance of iGSCs by promoting SOX2-mediated induction of ABC transporters." SIGNOR-255181 SOX2 protein P48431 UNIPROT NR2E1 protein Q9Y466 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22194602 f miannu "Sox2 positively regulates tlx expression" SIGNOR-191714 SOX2 protein P48431 UNIPROT SOX2/POU5F1 complex SIGNOR-C73 SIGNOR "form complex" binding 9606 7590241 t miannu "Sox2 can form a ternary complex with either the ubiquitous oct-1 or the embryonic-specific oct-3 protein on fgf-4 enhancer dna sequences. However, only the sox2/oct-3 complex is able to promote transcriptional activation." SIGNOR-29512 SOX9 protein P48436 UNIPROT MITF protein O75030 UNIPROT "up-regulates activity" binding 10090 20530484 t miannu "BEST1 promoter activity was increased by SOX9 overexpression and decreased by siRNA-mediated SOX9 knockdown. SOX9 physically interacted with MITF and OTX2 and orchestrated synergistic activation of the BEST1 promoter with the paired SOX site playing essential roles." SIGNOR-255183 SOX9 protein P48436 UNIPROT BEST1 protein O76090 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 20530484 f miannu "BEST1 promoter activity was increased by SOX9 overexpression and decreased by siRNA-mediated SOX9 knockdown." SIGNOR-255187 SOX9 protein P48436 UNIPROT COL2A1 protein P02458 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10980415 f miannu "Since Sox9 also contains a potent transcription activation domain, it is a typical transcription factor. Sox9 which binds and activates this enhancer element, is required for chondrocyte differentiation and for expression of a series of chondrocyte-specific marker genes including Col2a1, Col9a2, Col11a2 and Aggrecan." SIGNOR-251756 SOX9 protein P48436 UNIPROT COL11A2 protein P13942 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10980415 f miannu "Since Sox9 also contains a potent transcription activation domain, it is a typical transcription factor. Sox9 which binds and activates this enhancer element, is required for chondrocyte differentiation and for expression of a series of chondrocyte-specific marker genes including Col2a1, Col9a2, Col11a2 and Aggrecan." SIGNOR-251758 SOX9 protein P48436 UNIPROT CEBPB protein P17676 UNIPROT down-regulates "transcriptional regulation" 9606 19254573 f fspada "Sox9 directly binds to the promoter regions of c/ebpbeta and c/ebpdelta to suppress their promoter activity, preventing adipocyte differentiation" SIGNOR-210037 SOX9 protein P48436 UNIPROT OTX2 protein P32243 UNIPROT "up-regulates activity" binding 10090 20530484 t miannu "BEST1 promoter activity was increased by SOX9 overexpression and decreased by siRNA-mediated SOX9 knockdown. SOX9 physically interacted with MITF and OTX2 and orchestrated synergistic activation of the BEST1 promoter with the paired SOX site playing essential roles." SIGNOR-255184 SOX9 protein P48436 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000849 19273910 f miannu "Overexpression of SOX9 in both human and mouse melanoma cell lines induced cell cycle arrest by increasing p21 transcription and restored sensitivity to RA by downregulating expression of PRAME, a melanoma antigen." SIGNOR-255190 SOX9 protein P48436 UNIPROT DCC protein P43146 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003858 19745029 f miannu "Promoter analysis and transfection studies showed that the up-regulation of DCC in OA chondrocytes may be mediated by the transcription factors Sox9 and AP-2." SIGNOR-255188 SOX9 protein P48436 UNIPROT CEBPD protein P49716 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 19254573 t fspada "Sox9 directly binds to the promoter regions of c/ebpbeta and c/ebpdelta to suppress their promoter activity, preventing adipocyte differentiation" SIGNOR-184283 SOX9 protein P48436 UNIPROT PRAME protein P78395 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000849 19273910 f miannu "Overexpression of SOX9 in both human and mouse melanoma cell lines induced cell cycle arrest by increasing p21 transcription and restored sensitivity to RA by downregulating expression of PRAME, a melanoma antigen." SIGNOR-255191 SOX9 protein P48436 UNIPROT COL9A2 protein Q14055 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10980415 f miannu "Since Sox9 also contains a potent transcription activation domain, it is a typical transcription factor. Sox9 which binds and activates this enhancer element, is required for chondrocyte differentiation and for expression of a series of chondrocyte-specific marker genes including Col2a1, Col9a2, Col11a2 and Aggrecan." SIGNOR-251757 PPP3CC protein P48454 UNIPROT DNM1L protein O00429 UNIPROT "up-regulates activity" dephosphorylation Ser637 VPVARKLsAREQRDC 9606 18838687 t "When mitochondrial depolarization is associated with sustained cytosolic Ca(2+) rise, it activates the cytosolic phosphatase calcineurin that normally interacts with Drp1. Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria as substantiated by site directed mutagenesis." SIGNOR-248506 PPP3CC protein P48454 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates relocalization 9606 BTO:0001103 11062529 t 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-84053 PPP3CC protein P48454 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates relocalization 9606 BTO:0000222 BTO:0000887;BTO:0001103 18676376 t 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-179796 CSNK1D protein P48730 UNIPROT PRH1 protein P02810 UNIPROT up-regulates phosphorylation Ser24 QDLDEDVsQEDVPLV 9606 BTO:0000007 BTO:0000671 10684652 t lperfetto "Ser22 may be phosphorylated by a g-ck that recognizes an atypical substrate sequence or by a novel kinase. While prp1 secreted from salivary glands is fully phosphorylated at ser8 and 22" SIGNOR-75272 PPP3CC protein P48454 UNIPROT IL6 protein P05231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 18177723 f lperfetto "Interestingly, since IL-6 production by nerve-mediated skeletal muscle contraction has recently been shown to be partly dependent on the activation of the calcineurin pathway |The fact that IL-6 is produced not only by proliferating satellite cells but also by growing myofibers during hypertrophy" SIGNOR-251735 PPP3CC protein P48454 UNIPROT FLNA protein P21333 UNIPROT "down-regulates quantity by destabilization" dephosphorylation Ser2152 TRRRRAPsVANVGSH 9606 16442073 t "Filamin is a phosphoprotein that organizes actin filaments into networks. We report that a purified C-terminal recombinant region of filamin is a suitable substrate for calcineurin |Mutagenesis analysis showed that a dephosphorylation step occurred in Ser 2152, which was previously shown to provide resistance to calpain cleavage when endogenous PKA is activated. In contrast, phosphorylation of Ser 2152 was recently reported to be necessary for membrane dynamic changes. In this regard, we found that CsA protects filamin in platelets from calpain degradation." SIGNOR-248507 PPP3CC protein P48454 UNIPROT DNM2 protein P50570 UNIPROT unknown dephosphorylation Ser764 LQSASSHsPTPQRRP 10116 20496096 t "CaN is activated, targeting a set of proteins for dephosphorylation, including dynamin II |We have recently discovered that the ubiquitously expressed dynamin isoform, dynII, is phosphorylated at S764 specifically during mitosis (unpublished data). We now show that S764 is phosphorylated throughout mitosis and is dephosphorylated at the time of cytokinesis(dynII)." SIGNOR-248508 PPP3CC protein P48454 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates 9606 BTO:0001103 11062529 f 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-83740 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates dephosphorylation 9606 18676376 t lperfetto "Calcineurin dephosphorylates members of the nuclear factor of activated T cells (NFAT)2 transcription factor family, allowing NFAT to translocate to the nucleus where it cooperates with other transcription factors to induce transcription of target genes." SIGNOR-233441 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates relocalization 9606 BTO:0001103 11062529 t 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-84056 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser168 YREPLCLsPASSGSS 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248509 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser171 PLCLSPAsSGSSASF 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248510 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser172 LCLSPASsGSSASFI 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248511 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser174 LSPASSGsSASFISD 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248512 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser175 SPASSGSsASFISDT 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248513 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser177 ASSGSSAsFISDTFS 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248514 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser180 GSSASFIsDTFSPYT 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248515 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser217 AHYSPRTsPIMSPRT 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248517 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser221 PRTSPIMsPRTSLAE 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248518 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser268 VALPPGAsPQRSRSP 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248519 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser274 ASPQRSRsPSPQPSS 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248520 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser276 PQRSRSPsPQPSSHV 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248521 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser280 RSPSPQPsSHVAPQD 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248522 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser326 PPKMWKTsPDPSPVS 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248523 PPP3CC protein P48454 UNIPROT PPP1R1A protein Q13522 UNIPROT unknown dephosphorylation Ser67 LKSTLAMsPRQRKKM 10116 11278334 t "In vitro and in vivo studies indicated that phospho-Ser-67 inhibitor-1 was dephosphorylated by protein phosphatases-2A and -2B. | However, inhibitor-1 phosphorylated at Ser-67 was a less efficient substrate for cAMP-dependent protein kinase. These results demonstrate regulation of a Cdk5-dependent phosphorylation site in inhibitor-1 and suggest a role for this site in modulating the amplitude of signal transduction events that involve cAMP-dependent protein kinase activation." SIGNOR-248524 PPP3CC protein P48454 UNIPROT KSR2 protein Q6VAB6 UNIPROT "up-regulates activity" dephosphorylation Ser198 IRTHLSQsPRVPSKC 10090 19560418 t "These findings indicate that calcineurin modulates the phosphorylation state of KSR2, but not KSR1, and identifies S198, T287, and the S310 14-3-3 binding site as the KSR2 residues targeted by calcineurin.|the negative regulators 14-3-3" SIGNOR-248525 PPP3CC protein P48454 UNIPROT KSR2 protein Q6VAB6 UNIPROT "up-regulates activity" dephosphorylation Ser313 TALHRSKsHEFQLGH 10090 19560418 t "These findings indicate that calcineurin modulates the phosphorylation state of KSR2, but not KSR1, and identifies S198, T287, and the S310 14-3-3 binding site as the KSR2 residues targeted by calcineurin.|the negative regulators 14-3-3" SIGNOR-248527 PPP3CC protein P48454 UNIPROT KSR2 protein Q6VAB6 UNIPROT "up-regulates activity" dephosphorylation Thr290 NKLKPPGtPPPSSRK 10090 19560418 t "These findings indicate that calcineurin modulates the phosphorylation state of KSR2, but not KSR1, and identifies S198, T287, and the S310 14-3-3 binding site as the KSR2 residues targeted by calcineurin.|the negative regulators 14-3-3" SIGNOR-248526 PPP3CC protein P48454 UNIPROT BAD protein Q92934 UNIPROT "up-regulates activity" dephosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000007 10195903 t "Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis." SIGNOR-248528 PPP3CC protein P48454 UNIPROT BAD protein Q92934 UNIPROT "up-regulates activity" dephosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000007 10195903 t "Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis." SIGNOR-248529 KCNJ5 protein P48544 UNIPROT KCNJ5/KCNJ3 complex SIGNOR-C56 SIGNOR "form complex" binding 9606 BTO:0000562 22362083 t miannu "The muscarinic k(+) channel (i (k,ach)) is a heterotetramer composed of girk1 (kir3.1) andgirk4(kir3.4) subunits of a g protein-coupled inwardly rectifying channel, and plays an important role in mediating electrical responses to the vagal stimulation in the heart." SIGNOR-196205 KCNC1 protein P48547 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI "down-regulates quantity" relocalization 9606 BTO:0000938 11506885 t miannu "Kv3 currents are activated specifically during action potential repolarization. Analysis of the Kv3 subfamily of K+ channel subunits has lead to the discovery of a new class of neuronal voltage-gated K+ channels characterized by positively shifted voltage dependencies and very fast deactivation rates. These properties are adaptations that allow these channels to produce currents that can specifically enable fast repolarization of action potentials without compromising spike initiation or height" SIGNOR-265586 KCNJ3 protein P48549 UNIPROT KCNJ5/KCNJ3 complex SIGNOR-C56 SIGNOR "form complex" binding 9606 BTO:0000562 22362083 t miannu "The muscarinic k(+) channel (i (k,ach)) is a heterotetramer composed of girk1 (kir3.1) andgirk4(kir3.4) subunits of a g protein-coupled inwardly rectifying channel, and plays an important role in mediating electrical responses to the vagal stimulation in the heart." SIGNOR-196202 IFNAR2 protein P48551 UNIPROT IFNAR complex SIGNOR-C243 SIGNOR "form complex" binding 9606 11278538 t miannu "The human type I interferons, IFN-alpha, IFN-beta, and IFN-omega, induce somewhat different cellular effects but act through a common receptor complex, IFNAR, composed of subunits IFNAR-1 and IFNAR-2. Human IFNAR-2 binds all type I IFNs but with lower affinity and different specificity than the IFNAR complex. Human IFNAR-1 has low intrinsic binding of human IFNs but strongly affects the affinity and differential ligand specificity of the IFNAR complex." SIGNOR-260333 PSMD8 protein P48556 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "form complex" binding 9606 BTO:0000007 29636472 t lperfetto "Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line" SIGNOR-263345 SLC1A6 protein P48664 UNIPROT "glutamic acid" smallmolecule CHEBI:18237 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000524 26687113 t miannu "After release from presynaptic nerve terminals, glutamate is quickly removed from the synaptic cleft by a family of five glutamate transporters, the so-called excitatory amino acid transporters (EAAT1-5)." SIGNOR-264805 CSNK1D protein P48730 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser20 PLSQETFsDLWKLLP 9606 10606744 t gcesareni "Protein kinase ck1 is a p53-threonine 18 kinase which requires prior phosphorylation of serine 15." SIGNOR-73266 CSNK1A1 protein P48729 UNIPROT MDM4 protein O15151 UNIPROT up-regulates phosphorylation Ser289 DDLEDSKsLSDDTDV 9606 23028042 t lperfetto "Previous studies showed that casein kinase 1? (ck1?) Stably associates with mdmx, stimulates mdmx-p53 binding, and cooperates with mdmx to inactivate p53ck1? Binding to the mdmx central domain and phosphorylation of s289 disrupts the intramolecular interaction, allowing the n terminus to bind p53 with increased affinity. After dna damage, the mdmx-ck1? Complex is disrupted by chk2-mediated phosphorylation of mdmx at s367, leading to reduced mdmx-p53 binding." SIGNOR-199015 CSNK1A1 protein P48729 UNIPROT AXIN1 protein O15169 UNIPROT "up-regulates activity" phosphorylation Ser469 AHEENPEsILDEHVQ -1 17318175 t lperfetto "Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated (Supplementary Figure 3). Three of them (S80, S82, and S473) were also phosphorylated in vitro by CKI and are conserved between axin1 and axin2/conductin.|This suggests that cumulative phosphorylation of axin is required for it to fully downregulate Wnt/beta_catenin signaling." SIGNOR-249192 CSNK1A1 protein P48729 UNIPROT AXIN1 protein O15169 UNIPROT "up-regulates activity" phosphorylation Ser75 LGYEPEGsASPTPPY -1 17318175 t lperfetto "Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated (Supplementary Figure 3). Three of them (S80, S82, and S473) were also phosphorylated in vitro by CKI and are conserved between axin1 and axin2/conductin.|This suggests that cumulative phosphorylation of axin is required for it to fully downregulate Wnt/beta_catenin signaling." SIGNOR-249189 CSNK1A1 protein P48729 UNIPROT AXIN1 protein O15169 UNIPROT "up-regulates activity" phosphorylation Ser77 YEPEGSAsPTPPYLK -1 17318175 t lperfetto "Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated (Supplementary Figure 3). Three of them (S80, S82, and S473) were also phosphorylated in vitro by CKI and are conserved between axin1 and axin2/conductin.|This suggests that cumulative phosphorylation of axin is required for it to fully downregulate Wnt/beta_catenin signaling." SIGNOR-249191 CSNK1A1 protein P48729 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni "Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity." SIGNOR-183661 CSNK1A1 protein P48729 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser318 SRTNSNAsTVSGRLS 9606 20110348 t lperfetto "Casein kinase (ck) 1 mediates the hierarchical phosphorylation of foxo3a at s318 and s321, which like foxo1 (rena et al., 2002 blue right-pointing triangle, 2004 blue right-pointing triangle), is probably to enhance its rate of nuclear export" SIGNOR-163672 CSNK1A1 protein P48729 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser321 NSNASTVsGRLSPIM 9606 20110348 t lperfetto "Casein kinase (ck) 1 mediates the hierarchical phosphorylation of foxo3a at s318 and s321, which like foxo1 (rena et al., 2002 blue right-pointing triangle, 2004 blue right-pointing triangle), is probably to enhance its rate of nuclear export" SIGNOR-163676 CSNK1A1 protein P48729 UNIPROT AHCYL1 protein O43865 UNIPROT unknown phosphorylation Ser77 SSTDSYSsAASYTDS 9534 BTO:0004055 17635105 t lperfetto "Residue 68 resides in a consensus phosphorylation site for PKD (Figure 1A) [22,23]. Interestingly, phosphorylation of Ser68 could allow for subsequent phosphorylation of Ser71, Ser74, Ser77 and Ser80 by CK1, for which the consensus phosphorylation site is pS/T-X-X-S/T" SIGNOR-249185 CSNK1A1 protein P48729 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation Thr1493 NPPPSPAtERSHYTM 9606 16341017 t lperfetto "We show that wnt induces sequential phosphorylation of lrp6 by gsk3 and casein kinase 1, and this dual phosphorylation promotes the engagement of lrp6 with the scaffolding protein axin.Site ii, like site i, was phosphorylated, as detected by means of a phospho-specific antibody (ab1493, for phosphorylated t1493 in lrp6)" SIGNOR-143034 CSNK1A1 protein P48729 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation 9606 16341017 t gcesareni "We show that wnt induces sequential phosphorylation of lrp6 by gsk3 and casein kinase 1, and this dual phosphorylation promotes the engagement of lrp6 with the scaffolding protein axin." SIGNOR-143037 CSNK1A1 protein P48729 UNIPROT HNRNPC protein P07910 UNIPROT down-regulates phosphorylation Ser253 ETNVKMEsEGGADDS 9606 15687492 t gcesareni "A kinase activity was identified in mouse liver that phosphorylates the acd of hnrnp-c at ser(240) and at two sites at ser(225)-ser(228). The kinase was purified and identified by tandem mass spectrometry as protein kinase ck1alpha (formerly casein kinase 1alpha).hnrnp-c1 that was also modified at the ck1alpha phosphorylation sites exhibited a 14-500-fold decrease in binding affinity, demonstrating that ck1alpha-mediated phosphorylation modulates the mrna binding ability of hnrnp-c." SIGNOR-133528 CSNK1A1 protein P48729 UNIPROT HNRNPC protein P07910 UNIPROT "down-regulates activity" phosphorylation Ser260 SEGGADDsAEEGDLL 9606 15687492 t gcesareni "In contrast, hnRNP-C1 that was also modified at the CK1alpha phosphorylation sites exhibited a 14-500-fold decrease in binding affinity, demonstrating that CK1alpha-mediated phosphorylation modulates the mRNA binding ability of hnRNP-C." SIGNOR-133532 CSNK1A1 protein P48729 UNIPROT HNRNPC protein P07910 UNIPROT "down-regulates activity" phosphorylation Ser299 EGEDDRDsANGEDDS 9606 15687492 t gcesareni "In contrast, hnRNP-C1 that was also modified at the CK1alpha phosphorylation sites exhibited a 14-500-fold decrease in binding affinity, demonstrating that CK1alpha-mediated phosphorylation modulates the mRNA binding ability of hnRNP-C." SIGNOR-133536 CSNK1A1 protein P48729 UNIPROT GLI2 protein P10070 UNIPROT down-regulates phosphorylation 9606 16611981 t gcesareni "Gli2 can also be phosphorylated directly by ck-1 at the non-optimal sites" SIGNOR-146112 CSNK1A1 protein P48729 UNIPROT GLI2 protein P10070 UNIPROT down-regulates phosphorylation 9606 17419683 t gcesareni "In the absence of hedgehog signaling, gli1 is transcriptionally repressed, gli2 is phosphorylated by gsk3 and ck1 for the fbxw11 (betatrcp2)-mediated degradation, and gli3 is processed to a cleaved repressor." SIGNOR-154222 CSNK1A1 protein P48729 UNIPROT GLI3 protein P10071 UNIPROT down-regulates phosphorylation 9606 11955435 t gcesareni "In principle, pka, ck-1 and gsk3 can phosphorylate as many as 19 serine residues in gli3: fourpkasites, three primarygsk3sites, four primary ck-1 sites and eight secondary gsk3 and ck-1 sites" SIGNOR-116512 CSNK1A1 protein P48729 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser100 ESEDSQEsVDSVTDS 9606 9931297 t lperfetto "Ser108, ser111 and ser114, located in a region matching the consensus sequence for the casein kinase ii target, were required.These results strongly suggest that the casein kinase ii target region is involved in cell cycle-regulated phosphorylation of the creb protein and also in transcriptional enhancement." SIGNOR-64258 CSNK1D protein P48730 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 10606744 t gcesareni "Protein kinase ck1 is a p53-threonine 18 kinase which requires prior phosphorylation of serine 15." SIGNOR-73270 CSNK1A1 protein P48729 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser94 QISTIAEsEDSQESV 9606 9931297 t lperfetto "Ser108, ser111 and ser114, located in a region matching the consensus sequence for the casein kinase ii target, were required.These results strongly suggest that the casein kinase ii target region is involved in cell cycle-regulated phosphorylation of the creb protein and also in transcriptional enhancement." SIGNOR-64250 CSNK1A1 protein P48729 UNIPROT CREB1 protein P16220 UNIPROT "up-regulates activity" phosphorylation Ser97 TIAESEDsQESVDSV 9606 9931297 t lperfetto "Ser108, ser111 and ser114, located in a region matching the consensus sequence for the casein kinase ii target, were required.These results strongly suggest that the casein kinase ii target region is involved in cell cycle-regulated phosphorylation of the creb protein and also in transcriptional enhancement." SIGNOR-64254 CSNK1A1 protein P48729 UNIPROT LGALS3 protein P17931 UNIPROT unknown phosphorylation Ser12 FSLHDALsGSGNPNP -1 8253806 t llicata "L-29, a soluble lactose-binding lectin, is phosphorylated on serine 6 and serine 12 in vivo and by casein kinase I." SIGNOR-250789 CSNK1A1 protein P48729 UNIPROT LGALS3 protein P17931 UNIPROT up-regulates phosphorylation Ser6 sLHDALSG 9606 BTO:0000150 15121858 t llicata "These results indicate that phosphorylation of gal-3 promotes its nuclear export after apoptotic stimuli through enhanced nuclear export." SIGNOR-124583 CSNK1A1 protein P48729 UNIPROT YWHAQ protein P27348 UNIPROT "down-regulates activity" phosphorylation Ser232 LTLWTSDsAGEECDA -1 9360956 t llicata "This protein kinase has been identified as casein kinase Ialpha (CKIalpha) by peptide mapping analysis and sequencing. Among mammalian 14-3-3, only 14-3-3 tau possesses a phosphorylatable residue at the same position (Ser-233), and we show that this residue is also phosphorylated by CKI. In addition, we show that 14-3-3 zeta is exclusively phosphorylated on Thr-233 in human embryonic kidney 293 cells. The residue 233 is located within a region shown to be important for the association of 14-3-3 to target proteins. " SIGNOR-250795 CSNK1A1 protein P48729 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser79 QRMGSSEsTDSGFCL 9606 20348946 t lperfetto "Here, we report that casein kinase 1 alpha (ck1alpha) phosphorylates cdc25a on both s79 and s82 in a hierarchical manner requiring prior phosphorylation of s76 by chk1 or gsk-3beta. This facilitates beta-trcp binding and ubiquitin-mediated proteolysis of cdc25a" SIGNOR-164734 CSNK1A1 protein P48729 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser82 GSSESTDsGFCLDSP 9606 20348946 t lperfetto "Here, we report that casein kinase 1 alpha (ck1alpha) phosphorylates cdc25a on both s79 and s82 in a hierarchical manner requiring prior phosphorylation of s76 by chk1 or gsk-3beta. This facilitates beta-trcp binding and ubiquitin-mediated proteolysis of cdc25a" SIGNOR-164738 CSNK1A1 protein P48729 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Ser45 GATTTAPsLSGKGNP 9606 20419129 t lperfetto "Specifically, ck1_ phosphorylates _-catenin at s45, which primes this n-terminal region for subsequent phosphorylations by gsk3 at t41, s37 and s33 [7]. These latter two phosphorylations are recognized by the e3-ligase component, _-trcp, for ultimate ubiquitylation and destruction by the proteosome" SIGNOR-165022 CSNK1A1 protein P48729 UNIPROT SNCA protein P37840 UNIPROT "down-regulates activity" phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 10617630 t lperfetto "In vitro experiments and two-dimensional phosphopeptide mapping provided further evidence that serine 129 was phosphorylated by ck-1 and ck-2. Moreover, phosphorylation of serine 129 was reduced in vivo upon inhibition of ck-1 or ck-2.| together, these data may indicate that ck-1 and ck-2 are involved in the regulation of neuronal function and one may speculate that phosphorylation of alpha-synuclein could affect its binding to membranes." SIGNOR-73795 CSNK1A1 protein P48729 UNIPROT SNCA protein P37840 UNIPROT up-regulates phosphorylation Ser87 KTVEGAGsIAAATGF 9606 BTO:0000938 10617630 t lperfetto "In vitro experiments and two-dimensional phosphopeptide mapping provided further evidence that serine 129 was phosphorylated by ck-1 and ck-2. Moreover, phosphorylation of serine 129 was reduced in vivo upon inhibition of ck-1 or ck-2. These data demonstrate that alpha-synuclein is constitutively phosphorylated within its c terminus and may indicate that the function of alpha-synuclein is regulated by phosphorylation/dephosphorylation.From these data we conclude that _-synuclein is predominantly phosphorylated at serine residue 129. However, a second serine at position 87 is also used for phosphorylation to some extent. together, these data may indicate that ck-1 and ck-2 are involved in the regulation of neuronal function and one may speculate that phosphorylation of _-synuclein could affect its binding to membranes." SIGNOR-73799 CSNK1A1 protein P48729 UNIPROT PSEN2 protein P49810 UNIPROT unknown phosphorylation Ser19 EVCDERTsLMSAESP -1 8972483 t llicata "In vivo phosphorylation of PS-2 was mapped to serine residues 7, 9, and 19 within an acidic stretch at the N terminus, which is absent in PS-1. casein kinase (CK)-1 and CK-2 were shown to phosphorylate the N terminus of PS-2 in vitro. " SIGNOR-250790 CSNK1A1 protein P48729 UNIPROT PSEN2 protein P49810 UNIPROT unknown phosphorylation Ser7 sDSEEEVC -1 8972483 t llicata "In vivo phosphorylation of PS-2 was mapped to serine residues 7, 9, and 19 within an acidic stretch at the N terminus, which is absent in PS-1. casein kinase (CK)-1 and CK-2 were shown to phosphorylate the N terminus of PS-2 in vitro. " SIGNOR-250791 CSNK1A1 protein P48729 UNIPROT PSEN2 protein P49810 UNIPROT unknown phosphorylation Ser9 LTFMASDsEEEVCDE -1 8972483 t llicata "In vivo phosphorylation of PS-2 was mapped to serine residues 7, 9, and 19 within an acidic stretch at the N terminus, which is absent in PS-1. casein kinase (CK)-1 and CK-2 were shown to phosphorylate the N terminus of PS-2 in vitro. " SIGNOR-250792 CSNK1A1 protein P48729 UNIPROT GSK3B protein P49841 UNIPROT "up-regulates activity" binding 9606 SIGNOR-C110 19293931 t gcesareni "In the absence of secreted wnt ligands, cytosolic beta-catenin is phosphorylated at ser45 by the priming kinase casein kinase 1 (ck1). Consequently, glycogen synthase kinase 3 (gsk3), in complex with axin and adenomatous polyposis coli (apc), phosphorylates beta-catenin at thr41, ser37, and ser33 apc cooperates with axin to promote the phosphorylation of b-catenin by gsk3 [which requires priming phosphorylation by casein kinase 1, alpha-isoform (ck1alpha)]" SIGNOR-184696 CSNK1A1 protein P48729 UNIPROT GSK3B protein P49841 UNIPROT "up-regulates activity" binding 9606 SIGNOR-C110 22083140 t gcesareni "In the absence of secreted wnt ligands, cytosolic beta-catenin is phosphorylated at ser45 by the priming kinase casein kinase 1 (ck1). Consequently, glycogen synthase kinase 3 (gsk3), in complex with axin and adenomatous polyposis coli (apc), phosphorylates beta-catenin at thr41, ser37, and ser33 apc cooperates with axin to promote the phosphorylation of b-catenin by gsk3 [which requires priming phosphorylation by casein kinase 1, alpha-isoform (ck1alpha)]" SIGNOR-177233 CSNK1A1 protein P48729 UNIPROT FOXG1 protein P55316 UNIPROT up-regulates phosphorylation Ser19 MIPKSSFsINSLVPE 9606 BTO:0000938 BTO:0000142 17435750 t llicata "Cki phosphorylation of ser 19 of foxg1 promotes nuclear import" SIGNOR-154386 CSNK1A1 protein P48729 UNIPROT BID protein P55957 UNIPROT "up-regulates activity" phosphorylation Ser64 LQTDGNRsSHSRLGR 9606 BTO:0000567 11583622 t llicata "Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid." SIGNOR-250785 CSNK1A1 protein P48729 UNIPROT BID protein P55957 UNIPROT "up-regulates activity" phosphorylation Thr59 EGYDELQtDGNRSSH 9606 BTO:0000567 11583622 t llicata "Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid." SIGNOR-250786 CSNK1A1 protein P48729 UNIPROT RHOB protein P62745 UNIPROT down-regulates phosphorylation Ser185 ALQKRYGsQNGCINC 9606 BTO:0000567 18590726 t llicata "Mass spectrometry analysis demonstrates that rhob is monophosphorylated by ck1, in its c-terminal end, on serine 185. lastly we show that the inhibition of ck1 activates rhob and promotes rhob dependent actin fiber formation and egf-r level." SIGNOR-179255 CSNK1A1 protein P48729 UNIPROT YWHAZ protein P63104 UNIPROT "down-regulates activity" phosphorylation Thr232 LTLWTSDtQGDEAEA 9606 BTO:0000007 9360956 t llicata "This protein kinase has been identified as casein kinase Ialpha (CKIalpha) by peptide mapping analysis and sequencing. Among mammalian 14-3-3, only 14-3-3 tau possesses a phosphorylatable residue at the same position (Ser-233), and we show that this residue is also phosphorylated by CKI. In addition, we show that 14-3-3 zeta is exclusively phosphorylated on Thr-233 in human embryonic kidney 293 cells. The residue 233 is located within a region shown to be important for the association of 14-3-3 to target proteins. | We have now shown that in vivo phosphorylation of 14-3-3 zeta at the CKIalpha site (Thr-233) negatively regulates its binding to c-Raf, and may be important in Raf-mediated signal transduction." SIGNOR-250796 CSNK1A1 protein P48729 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates phosphorylation 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni "Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity." SIGNOR-183664 CSNK1A1 protein P48729 UNIPROT SLC18A2 protein Q05940 UNIPROT unknown phosphorylation Ser511 PIGEDEEsESD -1 9045708 t llicata "Purified CKI and CKII phosphorylate the wild-type carboxyl terminus of VMAT2, but not a double mutant with both serines 512 and 514 replaced by alanine. The protein kinase inhibitor CKI-7 and unlabeled GTP both block in vitro phosphorylation by cell homogenates, indicating a role for CKII and possibly CKI in vivo. Both kinases phosphorylate the VMAT2 fusion protein to a much greater extent than a similar fusion protein containing the carboxyl terminus of VMAT1, consistent with differential phosphorylation of the two transporters observed in intact cells. " SIGNOR-250794 CSNK1A1 protein P48729 UNIPROT SLC18A2 protein Q05940 UNIPROT unknown phosphorylation Ser513 GEDEESEsD -1 9045708 t llicata "Purified CKI and CKII phosphorylate the wild-type carboxyl terminus of VMAT2, but not a double mutant with both serines 512 and 514 replaced by alanine. The protein kinase inhibitor CKI-7 and unlabeled GTP both block in vitro phosphorylation by cell homogenates, indicating a role for CKII and possibly CKI in vivo. Both kinases phosphorylate the VMAT2 fusion protein to a much greater extent than a similar fusion protein containing the carboxyl terminus of VMAT1, consistent with differential phosphorylation of the two transporters observed in intact cells. " SIGNOR-250793 CSNK1A1 protein P48729 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates phosphorylation 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni "Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity" SIGNOR-183658 CSNK1A1 protein P48729 UNIPROT NFATC3 protein Q12968 UNIPROT "down-regulates activity" phosphorylation Ser207 AARFTLGsPLTSPGG 9606 BTO:0001131 9630228 t lperfetto "Dominant-negative cki? Induces nuclear import of nf-at4these results demonstrated that the cki? Phosphorylation sites identified in vitro were also specifically phosphorylated by cki? In vivo, and that these residues were crucial for the masking of the nls of nf-at4." SIGNOR-109800 CSNK1A1 protein P48729 UNIPROT NFATC3 protein Q12968 UNIPROT "down-regulates activity" phosphorylation Ser211 TLGSPLTsPGGSPGG 9606 BTO:0001131 9630228 t lperfetto "Dominant-negative cki alpha Induces nuclear import of nf-at4 these results demonstrated that the cki alpha Phosphorylation sites identified in vitro were also specifically phosphorylated by cki alpha In vivo, and that these residues were crucial for the masking of the nls of nf-at4." SIGNOR-109763 CSNK1A1 protein P48729 UNIPROT NFATC3 protein Q12968 UNIPROT "down-regulates activity" phosphorylation Ser215 PLTSPGGsPGGCPGE 9606 BTO:0001131 9630228 t lperfetto "Dominant-negative cki alpha Induces nuclear import of nf-at4 these results demonstrated that the cki alpha Phosphorylation sites identified in vitro were also specifically phosphorylated by cki alpha In vivo, and that these residues were crucial for the masking of the nls of nf-at4." SIGNOR-109781 CSNK1A1 protein P48729 UNIPROT NFATC3 protein Q12968 UNIPROT "down-regulates activity" phosphorylation Thr210 FTLGSPLtSPGGSPG 9606 BTO:0001131 9630228 t lperfetto "Dominant-negative cki alpha Induces nuclear import of nf-at4 these results demonstrated that the cki alpha Phosphorylation sites identified in vitro were also specifically phosphorylated by cki alpha In vivo, and that these residues were crucial for the masking of the nls of nf-at4." SIGNOR-109776 CSNK1A1 protein P48729 UNIPROT EIF2B5 protein Q13144 UNIPROT unknown phosphorylation Ser466 DEDDGEFsDDSGADQ 9606 BTO:0000007 11500362 t llicata "The fifth site, which lies outside the catalytic domain of eIF2Bepsilon, can be phosphorylated by casein kinase 1. All five sites are phosphorylated in the eIF2B complex in vivo. | A phosphopeptide corresponding to this region was identified in Asp‐N digests of eIF2Bϵ phosphorylated in vitro by CK1, suggesting that Ser461 or Ser464 may be phosphorylated by this kinase in vivo." SIGNOR-250787 CSNK1A1 protein P48729 UNIPROT EIF2B5 protein Q13144 UNIPROT unknown phosphorylation Ser469 DGEFSDDsGADQEKD 9606 BTO:0000007 11500362 t llicata "The fifth site, which lies outside the catalytic domain of eIF2Bepsilon, can be phosphorylated by casein kinase 1. All five sites are phosphorylated in the eIF2B complex in vivo. | A phosphopeptide corresponding to this region was identified in Asp‐N digests of eIF2Bϵ phosphorylated in vitro by CK1, suggesting that Ser461 or Ser464 may be phosphorylated by this kinase in vivo." SIGNOR-250788 CSNK1A1 protein P48729 UNIPROT FADD protein Q13158 UNIPROT "down-regulates activity" phosphorylation Ser194 QNRSGAMsPMSWNSD 9606 16061179 t gcesareni "FADD is essential for death receptor (DR)-induced apoptosis.|Phosphorylation of FADD at serine 194 by CKIalpha regulates its nonapoptotic activities" SIGNOR-139307 CSNK1D protein P48730 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation 9606 20708156 t gcesareni "Phosphorylation by casein kinase i promotes the turnover of the mdm2 oncoprotein via the scf(beta-trcp) ubiquitin ligase." SIGNOR-167520 CSNK1A1 protein P48729 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser286 SSMSSCGsSGYFSSS 9606 22017877 t llicata "Phosphorylation of all three serine residues in the deptor degron (ser286, ser287, and ser291) is necessary for - and directly mediates - the interaction with _trcp. ck1 phosphorylated the degron of deptor, as shown by western blotting with the phospho-specific antibody (fig. S3e-f). In contrast, mtor alone was unable to induce phosphorylation of deptor on ser286, ser287, and ser291." SIGNOR-176871 CSNK1A1 protein P48729 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser287 SMSSCGSsGYFSSSP 9606 22017877 t llicata "Phosphorylation of all three serine residues in the deptor degron (ser286, ser287, and ser291) is necessary for - and directly mediates - the interaction with _trcp. ck1 phosphorylated the degron of deptor, as shown by western blotting with the phospho-specific antibody (fig. S3e-f). In contrast, mtor alone was unable to induce phosphorylation of deptor on ser286, ser287, and ser291." SIGNOR-176875 CSNK1A1 protein P48729 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser291 CGSSGYFsSSPTLSS 9606 22017877 t llicata "Phosphorylation of all three serine residues in the deptor degron (ser286, ser287, and ser291) is necessary for - and directly mediates - the interaction with _trcp. ck1 phosphorylated the degron of deptor, as shown by western blotting with the phospho-specific antibody (fig. S3e-f). In contrast, mtor alone was unable to induce phosphorylation of deptor on ser286, ser287, and ser291." SIGNOR-176879 CSNK1A1 protein P48729 UNIPROT OSBP2 protein Q969R2 UNIPROT "up-regulates activity" phosphorylation 30925160 t lperfetto "CK1a1, JNK1 and CDK1 had the highest site-specific activity for ORP4L, while CDK1, GSK3a, CK1a1 and GSK3b showed the highest specificity for the site when corrected for background activity with ORP4L-S4A. Because of the complexity of the serine/proline-rich site, we did not determine which serine(s) in ORP4L were phosphorylated by candidate kinases.|We conclude that phosphorylation of a unique serine/proline motif in the ORD induces a conformation change in ORP4L that enhances interaction with vimentin and cholesterol extraction from membranes." SIGNOR-264877 CSNK1A1 protein P48729 UNIPROT SMO protein Q99835 UNIPROT up-regulates phosphorylation 9606 21695114 t gcesareni "We demonstrate that mammalian Smo (mSmo) is activated through multi-site phosphorylation of its carboxyl-terminal tail by CK1α and GRK2. Phosphorylation of mSmo induces its active conformation and simultaneously promotes its ciliary accumulation." SIGNOR-174542 CSNK1A1 protein P48729 UNIPROT CTPS2 protein Q9NRF8 UNIPROT down-regulates phosphorylation Ser568 LSSSDRYsDASDDSF 9606 20739275 t gcesareni "Hctps2 ser(568) was phosphorylated by casein kinase 1 both in vitro and in vivo. Mutation of ser(568) (s568a) significantly increased hctps2 activity, demonstrating that ser(568) is a major inhibitory phosphorylation site." SIGNOR-167623 CSNK1A1 protein P48729 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "up-regulates activity" binding 9606 19293931 t lperfetto "In the absence of secreted wnt ligands, cytosolic beta-catenin is phosphorylated at ser45 by the priming kinase casein kinase 1 (ck1). Consequently, glycogen synthase kinase 3 (gsk3), in complex with axin and adenomatous polyposis coli (apc), phosphorylates beta-catenin at thr41, ser37, and ser33 apc cooperates with axin to promote the phosphorylation of b-catenin by gsk3 [which requires priming phosphorylation by casein kinase 1, alpha-isoform (ck1alpha)]" SIGNOR-227964 CSNK1A1 protein P48729 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "up-regulates activity" binding 9606 22083140 t lperfetto "In the absence of secreted wnt ligands, cytosolic beta-catenin is phosphorylated at ser45 by the priming kinase casein kinase 1 (ck1). Consequently, glycogen synthase kinase 3 (gsk3), in complex with axin and adenomatous polyposis coli (apc), phosphorylates beta-catenin at thr41, ser37, and ser33 apc cooperates with axin to promote the phosphorylation of b-catenin by gsk3 [which requires priming phosphorylation by casein kinase 1, alpha-isoform (ck1alpha)]" SIGNOR-227967 CSNK1A1 protein P48729 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni "Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity." SIGNOR-252898 CSNK1A1 protein P48729 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser318 SRTNSNAsTVSGRLS 9606 20110348 t lperfetto "Casein kinase (ck) 1 mediates the hierarchical phosphorylation of foxo3a at s318 and s321, which like foxo1 (rena et al., 2002 blue right-pointing triangle, 2004 blue right-pointing triangle), is probably to enhance its rate of nuclear export" SIGNOR-252899 CSNK1A1 protein P48729 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser321 NSNASTVsGRLSPIM 9606 20110348 t lperfetto "Casein kinase (ck) 1 mediates the hierarchical phosphorylation of foxo3a at s318 and s321, which like foxo1 (rena et al., 2002 blue right-pointing triangle, 2004 blue right-pointing triangle), is probably to enhance its rate of nuclear export" SIGNOR-252900 CSNK1D protein P48730 UNIPROT DVL2 protein O14641 UNIPROT up-regulates phosphorylation Thr224 MSRFSSStEQSSASR 9606 22609948 t lperfetto "Ck1_/__dependent phosphorylation of dvl2 at s143 and t224and that this event is critical to interact with plk1 in early stages of the cell cycle" SIGNOR-197551 CSNK1D protein P48730 UNIPROT PER2 protein O15055 UNIPROT up-regulates phosphorylation Ser662 ALPGKAEsVASLTSQ 9606 17218255 t gcesareni "Phosphorylation of s662 promotes casein kinase i to phosphorylate nearby residues. Cki does not appear to phosphorlyate this residue (requires priming kinase). Phosphorylation increased period length (tau). Nonphosphorylated protein is mainly nuclear (as opposed to nuclear and cytoplasmic). Phosphorylated per2 promotes its own transcription.;Phosphorylation occurs during the circadium cycle." SIGNOR-152090 CSNK1D protein P48730 UNIPROT PER2 protein O15055 UNIPROT up-regulates phosphorylation Ser662 ALPGKAEsVASLTSQ 9606 21324900 t gcesareni "Phosphorylation of s662 promotes casein kinase i to phosphorylate nearby residues. Cki does not appear to phosphorlyate this residue (requires priming kinase). Phosphorylation increased period length (tau). Nonphosphorylated protein is mainly nuclear (as opposed to nuclear and cytoplasmic). Phosphorylated per2 promotes its own transcription.;Phosphorylation occurs during the circadium cycle." SIGNOR-172118 CSNK1D protein P48730 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates binding 9606 SIGNOR-C110 12000790 t gcesareni "We conclude that a major role of axin in the wnt is to provide the kinase activity that initiates the beta-catenin phosphorylation cascade at s45. This process is mediated by cki, the alfa, delta, or epsilon isoform, all detected in association with axin by lc/ms." SIGNOR-87433 CSNK1D protein P48730 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates phosphorylation Ser46 PASYSFCsGKGVGIK 9606 SIGNOR-C110 12000790 t gcesareni "We conclude that a major role of axin in the wnt is to provide the kinase activity that initiates the betBeta-catenin phosphorylation cascade at s45 . This process is mediated by cki, the alfa, delta, or ? Isoform, all detected in association with axin by lc/mscomplex of axin and casein kinase i (cki) induces betBeta-catenin phosphorylation at a single site: serine 45 (s45)" SIGNOR-87437 CSNK1D protein P48730 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser20 PLSQETFsDLWKLLP 9606 10734067 t gcesareni "Here we show that the direct association between a p53 n-terminal peptide and mdm2 is disrupted by phosphorylation of the peptide on thr(18) but not by phosphorylation at other n-terminal sites, including ser(15) and ser(37). Thr(18) was phosphorylated in vitro by casein kinase (ck1)." SIGNOR-75889 CSNK1D protein P48730 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser396 DDKKAKTsTRSSAKT 9606 BTO:0000007 14761950 t lperfetto "Casein kinase 1 delta phosphorylates tau and disrupts its binding to microtubules.Here we characterized the contribution of one ck1 isoform, ckidelta, to the phosphorylation of tau at residues ser202/thr205 and ser396/ser404 in human embryonic kidney 293 cells." SIGNOR-121709 CSNK1D protein P48730 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser519 SGYSSPGsPGTPGSR 9606 BTO:0000007 14761950 t "The effect has been demonstrated using P10636-8" lperfetto "Casein kinase 1 delta phosphorylates tau and disrupts its binding to microtubules.Here we characterized the contribution of one ck1 isoform, ckidelta, to the phosphorylation of tau at residues ser202/thr205 and ser396/ser404 in human embryonic kidney 293 cells." SIGNOR-121705 CSNK1D protein P48730 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser721 PVVSGDTsPRHLSNV 9606 BTO:0000007 14761950 t "The effect has been demonstrated using P10636-8" lperfetto "Casein kinase 1 delta phosphorylates tau and disrupts its binding to microtubules.Here we characterized the contribution of one ck1 isoform, ckidelta, to the phosphorylation of tau at residues ser202/thr205 and ser396/ser404 in human embryonic kidney 293 cells." SIGNOR-121713 CSNK1D protein P48730 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr522 SSPGSPGtPGSRSRT 9606 BTO:0000007 14761950 t "The effect has been demonstrated using P10636-8" lperfetto "Casein kinase 1 delta phosphorylates tau and disrupts its binding to microtubules.Here we characterized the contribution of one ck1 isoform, ckidelta, to the phosphorylation of tau at residues ser202/thr205 and ser396/ser404 in human embryonic kidney 293 cells." SIGNOR-121717 CSNK1D protein P48730 UNIPROT GJA1 protein P17302 UNIPROT "up-regulates activity" phosphorylation Ser325 NRMGQAGsTISNSHA 10116 BTO:0000067 12270943 t lperfetto "We have examined the role of casein kinase 1 (CK1) in connexin-43 (Cx43) gap junction assembly. Cellular co-immunoprecipitation experiments and in vitro CK1 phosphorylation reactions indicate that CK1 interacted with and phosphorylated Cx43, initially on serine(s) 325, 328, or 330.| To examine CK1 function, normal rat kidney cells were treated with CKI-7, and Cx43 content was analyzed by Triton X-100 extraction, cell-surface biotinylation, and immunofluorescence. Western blot analysis indicated a slight increase in total Cx43, whereas gap junctional (Triton-insoluble) Cx43 decreased, and non-junctional plasma membrane Cx43 increased (as detected by cell surface biotinylation)." SIGNOR-249329 CSNK1D protein P48730 UNIPROT GJA1 protein P17302 UNIPROT "up-regulates activity" phosphorylation Ser328 GQAGSTIsNSHAQPF 10116 BTO:0000067 12270943 t lperfetto "We have examined the role of casein kinase 1 (CK1) in connexin-43 (Cx43) gap junction assembly. Cellular co-immunoprecipitation experiments and in vitro CK1 phosphorylation reactions indicate that CK1 interacted with and phosphorylated Cx43, initially on serine(s) 325, 328, or 330.| To examine CK1 function, normal rat kidney cells were treated with CKI-7, and Cx43 content was analyzed by Triton X-100 extraction, cell-surface biotinylation, and immunofluorescence. Western blot analysis indicated a slight increase in total Cx43, whereas gap junctional (Triton-insoluble) Cx43 decreased, and non-junctional plasma membrane Cx43 increased (as detected by cell surface biotinylation)." SIGNOR-249330 CSNK1D protein P48730 UNIPROT GJA1 protein P17302 UNIPROT "up-regulates activity" phosphorylation Ser330 AGSTISNsHAQPFDF 10116 BTO:0000067 12270943 t lperfetto "We have examined the role of casein kinase 1 (CK1) in connexin-43 (Cx43) gap junction assembly. Cellular co-immunoprecipitation experiments and in vitro CK1 phosphorylation reactions indicate that CK1 interacted with and phosphorylated Cx43, initially on serine(s) 325, 328, or 330.| To examine CK1 function, normal rat kidney cells were treated with CKI-7, and Cx43 content was analyzed by Triton X-100 extraction, cell-surface biotinylation, and immunofluorescence. Western blot analysis indicated a slight increase in total Cx43, whereas gap junctional (Triton-insoluble) Cx43 decreased, and non-junctional plasma membrane Cx43 increased (as detected by cell surface biotinylation)." SIGNOR-249331 CSNK1D protein P48730 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Ser45 GATTTAPsLSGKGNP 9606 12000790 t gcesareni "However, ckiepsilon has been recently shown to interact with axin (sakanaka et al. 1999;rubinfeld et al. 2001), and it was proposed that this kinase mediates axin-induced apc phosphorylation, thereby stabilizing the -catenin degradation complex (rubinfeld et al. 2001). We have, therefore, evaluated cki as a candidate s45-kinase in several assays, both in vitro and in vivo." SIGNOR-87441 CSNK1D protein P48730 UNIPROT KIR3DL1 protein P43629 UNIPROT up-regulates phosphorylation Ser385 AGNRTANsEDSDEQD 9606 17911614 t gcesareni "In this study, we have mapped constitutive phosphorylation sites for casein kinases, protein kinase c, and an unidentified kinase on the kir cytoplasmic domain. Three of these phosphorylation sites are highly conserved in human inhibitory kir. Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of ser(394) by protein kinase c slightly suppresses kir3dl1 inhibitory function, and reduces receptor internalization and turnover." SIGNOR-158121 CSNK1D protein P48730 UNIPROT KIR3DL1 protein P43629 UNIPROT up-regulates phosphorylation Ser388 RTANSEDsDEQDPEE 9606 17911614 t gcesareni "In this study, we have mapped constitutive phosphorylation sites for casein kinases, protein kinase c, and an unidentified kinase on the kir cytoplasmic domain. Three of these phosphorylation sites are highly conserved in human inhibitory kir. Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of ser(394) by protein kinase c slightly suppresses kir3dl1 inhibitory function, and reduces receptor internalization and turnover." SIGNOR-158125 CSNK1D protein P48730 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser400 SRDESTDsGLSMSSY 9606 phosphorylation:Ser127 PQHVRAHsSPASLQL 23431053 t milica "Phosphorylation of YAP (S381) and TAZ (S311) by Lats1/2 primes subsequent phosphorylation events by casein kinase 1 (CK1d/e); this sequential phosphorylation results in recruitment of b-transducin repeat-containing proteins (b-TRCP; a subunit of the SCF ubiquitin E3 ligase) and consequently leads to degradation of YAP/TAZ" SIGNOR-201143 CSNK1D protein P48730 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser403 ESTDSGLsMSSYSVP 9606 phosphorylation:Ser127 PQHVRAHsSPASLQL 23431053 t milica "Phosphorylation of YAP (S381) and TAZ (S311) by Lats1/2 primes subsequent phosphorylation events by casein kinase 1 (CK1d/e); this sequential phosphorylation results in recruitment of b-transducin repeat-containing proteins (b-TRCP; a subunit of the SCF ubiquitin E3 ligase) and consequently leads to degradation of YAP/TAZ" SIGNOR-201154 CSNK1D protein P48730 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser400 SRDESTDsGLSMSSY 9606 phosphorylation:Ser127 PQHVRAHsSPASLQL 24715453 t milica "LATS1/2-mediated phosphorylation of a conserved serine in this region (Ser311 in human TAZ; Ser397 in human YAP) primes for further phosphorylation by CK1_/_ kinases (Ser314 on human TAZ; Ser400/403 in human YAP)" SIGNOR-230738 CSNK1D protein P48730 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser403 ESTDSGLsMSSYSVP 9606 phosphorylation:Ser127 PQHVRAHsSPASLQL 24715453 t milica "LATS1/2-mediated phosphorylation of a conserved serine in this region (Ser311 in human TAZ; Ser397 in human YAP) primes for further phosphorylation by CK1_/_ kinases (Ser314 on human TAZ; Ser400/403 in human YAP)" SIGNOR-230743 CSNK1D protein P48730 UNIPROT PSEN2 protein P49810 UNIPROT unknown phosphorylation Ser19 EVCDERTsLMSAESP -1 8972483 t llicata "In vivo phosphorylation of PS-2 was mapped to serine residues 7, 9, and 19 within an acidic stretch at the N terminus, which is absent in PS-1. casein kinase (CK)-1 and CK-2 were shown to phosphorylate the N terminus of PS-2 in vitro. " SIGNOR-250799 CSNK1D protein P48730 UNIPROT PSEN2 protein P49810 UNIPROT unknown phosphorylation Ser7 sDSEEEVC -1 8972483 t llicata "In vivo phosphorylation of PS-2 was mapped to serine residues 7, 9, and 19 within an acidic stretch at the N terminus, which is absent in PS-1. casein kinase (CK)-1 and CK-2 were shown to phosphorylate the N terminus of PS-2 in vitro. " SIGNOR-250803 CSNK1D protein P48730 UNIPROT PSEN2 protein P49810 UNIPROT unknown phosphorylation Ser9 LTFMASDsEEEVCDE -1 8972483 t llicata "In vivo phosphorylation of PS-2 was mapped to serine residues 7, 9, and 19 within an acidic stretch at the N terminus, which is absent in PS-1. casein kinase (CK)-1 and CK-2 were shown to phosphorylate the N terminus of PS-2 in vitro. " SIGNOR-250804 CSNK1D protein P48730 UNIPROT PSEN2 protein P49810 UNIPROT "up-regulates activity" phosphorylation Ser327 DPEMEEDsYDSFGEP -1 9558331 t llicata "In vitro the large hydrophilic loop of PS-2 between transmembrane domains 6 and 7 can be phosphorylated by casein kinase-1 (CK-1) and CK-2, but not by PKA or PKC. Quantitative analysis of in vitro phosphorylation demonstrates the presence of two phosphorylation sites for CK-1 and a single site for CK-2. A deletion analysis revealed that the CTF of PS-2 is phosphorylated in vivo within an acidic sequence containing three potential phosphorylation sites for CKs (serines 327, 330, and 335). These data suggest that CK type protein kinases phosphorylate the CTF of PS-2 within its hydrophilic loop domain in vivo. Interestingly, the potential phosphorylation sites are located directly adjacent to the recently identified caspase cleavage sites." SIGNOR-250800 CSNK1D protein P48730 UNIPROT PSEN2 protein P49810 UNIPROT "up-regulates activity" phosphorylation Ser330 MEEDSYDsFGEPSYP -1 9558331 t llicata "In vitro the large hydrophilic loop of PS-2 between transmembrane domains 6 and 7 can be phosphorylated by casein kinase-1 (CK-1) and CK-2, but not by PKA or PKC. Quantitative analysis of in vitro phosphorylation demonstrates the presence of two phosphorylation sites for CK-1 and a single site for CK-2. A deletion analysis revealed that the CTF of PS-2 is phosphorylated in vivo within an acidic sequence containing three potential phosphorylation sites for CKs (serines 327, 330, and 335). These data suggest that CK type protein kinases phosphorylate the CTF of PS-2 within its hydrophilic loop domain in vivo. Interestingly, the potential phosphorylation sites are located directly adjacent to the recently identified caspase cleavage sites." SIGNOR-250801 CSNK1D protein P48730 UNIPROT PSEN2 protein P49810 UNIPROT "up-regulates activity" phosphorylation Ser335 YDSFGEPsYPEVFEP -1 9558331 t llicata "In vitro the large hydrophilic loop of PS-2 between transmembrane domains 6 and 7 can be phosphorylated by casein kinase-1 (CK-1) and CK-2, but not by PKA or PKC. Quantitative analysis of in vitro phosphorylation demonstrates the presence of two phosphorylation sites for CK-1 and a single site for CK-2. A deletion analysis revealed that the CTF of PS-2 is phosphorylated in vivo within an acidic sequence containing three potential phosphorylation sites for CKs (serines 327, 330, and 335). These data suggest that CK type protein kinases phosphorylate the CTF of PS-2 within its hydrophilic loop domain in vivo. Interestingly, the potential phosphorylation sites are located directly adjacent to the recently identified caspase cleavage sites." SIGNOR-250802 CSNK1D protein P48730 UNIPROT BACE1 protein P56817 UNIPROT unknown phosphorylation Ser498 DDFADDIsLLK 9606 BTO:0000007 11278841 t llicata "Here, we report that BACE can be phosphorylated within its cytoplasmic domain at serine residue 498 by casein kinase 1. Phosphorylation exclusively occurs after full maturation of BACE by propeptide cleavage and complex N-glycosylation. | After reinternalization, BACE wild type as well as BACE S498D are efficiently retrieved from early endosomal compartments and further targeted to later endosomal compartments and/or the trans-Golgi network. In contrast, nonphosphorylatable BACE S498A is retained within early endosomes." SIGNOR-250797 CSNK1D protein P48730 UNIPROT CDK5 protein Q00535 UNIPROT "up-regulates activity" phosphorylation Ser159 GIPVRCYsAEVVTLW -1 10500146 t llicata "We also show that casein kinase I, but not casein kinase II, can phosphorylate and activate cdk5 in vitro." SIGNOR-250798 CSNK1D protein P48730 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation Ser253 SVEFEVEsLDSEDYS 9606 12167711 t gcesareni "Hypophosphorylation of mdm2 augments p53 stability." SIGNOR-91195 CSNK1D protein P48730 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation Ser262 DSEDYSLsEEGQELS 9606 12167711 t gcesareni "Hypophosphorylation of mdm2 augments p53 stability." SIGNOR-91199 CSNK1D protein P48730 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation Ser118 NQQESSDsGTSVSEN 9606 20708156 t gcesareni "Phosphorylation by casein kinase i promotes the turnover of the mdm2 oncoprotein via the scf(beta-trcp) ubiquitin ligase." SIGNOR-167497 CSNK1D protein P48730 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation Ser121 ESSDSGTsVSENRCH 9606 20708156 t gcesareni "Phosphorylation by casein kinase i promotes the turnover of the mdm2 oncoprotein via the scf(beta-trcp) ubiquitin ligase." SIGNOR-167501 CSNK1D protein P48730 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation Ser246 DSVSDQFsVEFEVES 9606 20708156 t gcesareni "Cki phosphorylates mdm2 at multiple sites to trigger mdm2/beta-trcp1 interactionbeta-trcp promotes mdm2 turnover and ubiquitination" SIGNOR-167509 CSNK1D protein P48730 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation Ser253 SVEFEVEsLDSEDYS 9606 20708156 t gcesareni "Cki phosphorylates mdm2 at multiple sites to trigger mdm2/beta-trcp1 interactionbeta-trcp promotes mdm2 turnover and ubiquitination" SIGNOR-167513 CSNK1D protein P48730 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation Ser262 DSEDYSLsEEGQELS 9606 20708156 t gcesareni "Cki phosphorylates mdm2 at multiple sites to trigger mdm2/beta-trcp1 interactionbeta-trcp promotes mdm2 turnover and ubiquitination" SIGNOR-167517 HDAC4 protein P56524 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates deacetylation 9606 16613856 t gcesareni "Hdac4 and hdac5 deacetylate runx2 and lead to a smurf-mediated degradation." SIGNOR-146122 CSNK1D protein P48730 UNIPROT HIF1A protein Q16665 UNIPROT down-regulates phosphorylation Ser247 KTFLSRHsLDMKFSY 9606 20699359 t lperfetto "In this work, we investigate the phosphorylation of the n-terminal heterodimerization (pas) domain of hif-1alpha and identify ser247 as a major site of in vitro modification by casein kinase 1delta (ck1delta). Mutation of this site to alanine, surprisingly, enhanced the transcriptional activity of hif-1alpha" SIGNOR-167476 CSNK1D protein P48730 UNIPROT ZNF322 protein Q6U7Q0 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser396 ELSPPHAsEASQMS 9606 BTO:0002552 28581525 t lperfetto "CK1delta and GSK3beta kinases sequentially phosphorylate ZNF322A at serine-396 and then serine-391. Moreover, the doubly phosphorylated ZNF322A protein creates a destruction motif for the ubiquitin ligase FBXW7alpha leading to ZNF322A protein destruction." SIGNOR-264892 CSNK1D protein P48730 UNIPROT UHRF1 protein Q96T88 UNIPROT up-regulates phosphorylation Ser95 SELSDTDsGCCLGQS 9606 23297342 t llicata "We further show that uhrf1 physically interacts with _-trcp1 in a manner dependent on phosphorylation of serine 108 (s108(uhrf1)) within the dsg degron. Furthermore, we demonstrate that s108(uhrf1) phosphorylation is catalyzed by casein kinase 1 delta (ck1_) and is important for the recognition of uhrf1 by scf(_-trcp)." SIGNOR-200349 CSNK1D protein P48730 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates phosphorylation Ser314 SREQSTDsGLGLGCY 9606 24715453 t lperfetto "LATS1/2-mediated phosphorylation of a conserved serine in this region (Ser311 in human TAZ; Ser397 in human YAP) primes for further phosphorylation by CK1_/_ kinases (Ser314 on human TAZ; Ser400/403 in human YAP)" SIGNOR-234438 CSNK1D protein P48730 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates phosphorylation Ser601 SDKESKEsSVEGAEN 9606 BTO:0000150 19339517 t lperfetto "In this study, we show that both eralpha and aib1 are substrates for ck1delta in vitro, and identify a novel aib1 phosphorylation site (s601) targeted by ck1delta, significant for the co-activator function of aib1." SIGNOR-184946 CSNK1D protein P48730 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates binding 9606 12000790 t lperfetto "We conclude that a major role of axin in the wnt is to provide the kinase activity that initiates the beta-catenin phosphorylation cascade at s45. This process is mediated by cki, the alfa, delta, or epsilon isoform, all detected in association with axin by lc/ms." SIGNOR-227973 CSNK1D protein P48730 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates phosphorylation 9606 12000790 t lperfetto "We conclude that a major role of axin in the wnt is to provide the kinase activity that initiates the betBeta-catenin phosphorylation cascade at s45 . This process is mediated by cki, the alfa, delta, or ? Isoform, all detected in association with axin by lc/mscomplex of axin and casein kinase i (cki) induces betBeta-catenin phosphorylation at a single site: serine 45 (s45)" SIGNOR-227970 IDH2 protein P48735 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 BTO:0001690 26178471 t lperfetto "Isocitrate dehydrogenases (IDH) convert isocitrate to alpha-ketoglutarate (α-KG)" SIGNOR-261827 IDH2 protein P48735 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 29090344 t miannu "Two of the most commonly mutated genes in AML encode for two isoforms of isocitrate dehydrogenase (IDH), IDH1 and IDH2. IDH1 and IDH2 are two isoforms of isocitrate dehydrogenase that perform crucial roles in cellular metabolism. Somatic mutations in either of these two genes impart a neomorphic enzymatic activity upon the encoded enzymes resulting in the ability to convert α-ketoglutarate (αKG) into the oncometabolite R2-hydroxyglutarate (R2-HG), which can competitively inhibit multiple αKG-dependent dioxygenases." SIGNOR-253134 PIK3CG protein P48736 UNIPROT "1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate" smallmolecule CHEBI:16618 ChEBI up-regulates "small molecule catalysis" 9606 16847462 t gcesareni "The activation of pi3k results in the generation of the second messenger, phosphatidylinositol 3,4,5-triphosphate (pip3) from phosphatidylinositol 4,5-bisphosphate (pip2). In vivo, class i pi3ks primarily generate phosphatidylinositol-3,4,5-trisphosphate (pip3) from phosphatidylinositol- 4,5-bisphosphate (pi-4,5-p2)" SIGNOR-147954 PIK3CG protein P48736 UNIPROT "1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate" smallmolecule CHEBI:16618 ChEBI up-regulates "small molecule catalysis" 9606 21779497 t gcesareni "The activation of pi3k results in the generation of the second messenger, phosphatidylinositol 3,4,5-triphosphate (pip3) from phosphatidylinositol 4,5-bisphosphate (pip2). In vivo, class i pi3ks primarily generate phosphatidylinositol-3,4,5-trisphosphate (pip3) from phosphatidylinositol- 4,5-bisphosphate (pi-4,5-p2)" SIGNOR-175244 PIK3CG protein P48736 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates binding 9606 9768361 t gcesareni "Recent reports have also shown that the phosphoinositide-dependent protein kinase-1 (pdk-1), which binds with high affinity to the pi 3-kinase lipid product phosphatidylinositol-3,4,5-trisphosphate (ptdins-3,4,5-p), phosphorylates and potently activates two other pi 3-kinase targets, the protein kinases akt/pkb and p70s6k." SIGNOR-60567 PIK3CG protein P48736 UNIPROT TPM2 protein P07951 UNIPROT "up-regulates activity" phosphorylation Ser61 EDEVEKYsESVKEAQ -1 16094730 t miannu "Here, we demonstrate a requirement for the protein kinase activity of PI(3)K in agonist-dependent beta-adrenergic receptor (betaAR) internalization. Using PI(3)K mutants with either protein or lipid phosphorylation activity, we identify the cytoskeletal protein non-muscle tropomyosin as a substrate of PI(3)K, which is phosphorylated in a wortmannin-sensitive manner on residue Ser 61. A constitutively dephosphorylated (S61A) tropomyosin mutant blocks agonist-dependent betaAR internalization, whereas a tropomyosin mutant that mimics constitutive phosphorylation (S61D) complements the PI(3)K mutant, with only lipid phosphorylation activity reversing the defective betaAR internalization." SIGNOR-263028 MASP1 protein P48740 UNIPROT C2 protein P06681 UNIPROT "up-regulates activity" cleavage Arg243 KTKESLGrKIQIQRS 9606 BTO:0000392 11907111 t lperfetto "The MASPs in the preparations had proteolytic activities against C4, C2, and C3 in the fluid phase" SIGNOR-263417 MASP1 protein P48740 UNIPROT C2 protein P06681 UNIPROT "up-regulates activity" cleavage Ser20 LYPGLADsAPSCPQN 9606 BTO:0000392 11907111 t lperfetto "The MASPs in the preparations had proteolytic activities against C4, C2, and C3 in the fluid phase" SIGNOR-263420 MAPKAPK2 protein P49137 UNIPROT BAG2 protein O95816 UNIPROT up-regulates phosphorylation Ser20 GRFCRSSsMADRSSR 9606 BTO:0000567 15271996 t lperfetto "We provided definite evidence that mapkapk2 phosphorylates bag2 at ser 20 in vitro and in vivo. These results demonstrate that bag2 is a novel component of the p38 mapk signaling pathways." SIGNOR-126953 MASP1 protein P48740 UNIPROT C4A protein P0C0L4 UNIPROT "up-regulates activity" cleavage Arg679 EKTTRKKrNVNFQKA -1 9087411 t lperfetto "The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots." SIGNOR-263432 MASP1 protein P48740 UNIPROT C4A protein P0C0L4 UNIPROT "up-regulates activity" cleavage Arg756 KGQAGLQrALEILQE -1 9087411 t lperfetto "The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots." SIGNOR-263435 MASP1 protein P48740 UNIPROT C4A protein P0C0L4 UNIPROT "up-regulates activity" cleavage Gly1446 TPLQLFEgRRNRRRR -1 9087411 t lperfetto "The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots." SIGNOR-263438 MASP1 protein P48740 UNIPROT C4B protein P0C0L5 UNIPROT "up-regulates activity" cleavage Arg679 EKTTRKKrNVNFQKA -1 9087411 t lperfetto "The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots." SIGNOR-263423 MASP1 protein P48740 UNIPROT C4B protein P0C0L5 UNIPROT "up-regulates activity" cleavage Arg756 KGQAGLQrALEILQE -1 9087411 t lperfetto "The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots." SIGNOR-263426 MASP1 protein P48740 UNIPROT C4B protein P0C0L5 UNIPROT "up-regulates activity" cleavage Gly1446 TPLQLFEgRRNRRRR -1 9087411 t lperfetto "The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots." SIGNOR-263429 LHX1 protein P48742 UNIPROT OTX2 protein P32243 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 10623575 t miannu "Here we show that OTX2 directly associates with LIM1 and HNF-3beta. The luciferase assay with the P3C sequence, a specific DNA binding sequence for paired-class homeobox genes, has demonstrated that LIM1 enhances, but HNF-3beta represses, OTX2-directed gene expression." SIGNOR-221161 POLD2 protein P49005 UNIPROT "DNA polymerase delta" complex SIGNOR-C376 SIGNOR "form complex" binding -1 12403614 t lperfetto "Reconstitution and characterization of the human DNA polymerase delta four-subunit holoenzyme." SIGNOR-265516 PXN protein P49023 UNIPROT BCAR1 protein P56945 UNIPROT "up-regulates activity" 9606 BTO:0000182 phosphorylation:Tyr88 PQSSSPVyGSSAKTS 27447856 f lperfetto "Together, our data suggest that phosphorylation of paxillin Y88 activates AKT through the paxillin-p130Cas-p85/PI3K-AKT signaling axis and promotes colorectal tumorigenesis" SIGNOR-263979 PXN protein P49023 UNIPROT ILK protein Q13418 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001260 11304546 t gcesareni "Co-immunoprecipitation from fibroblasts confirmed that the association between paxillin and ilk occurs in vivo in both adherent cells and cells in suspension. [__] thus, paxillin binding is necessary for efficient focal adhesion targeting of ilk and may therefore impact the role of ilk in integrin-mediated signal transduction events." SIGNOR-106824 PXN protein P49023 UNIPROT "IPP complex" complex SIGNOR-C380 SIGNOR "up-regulates activity" relocalization 16493410 t lperfetto "Integrin-linked kinase (ILK), and isoforms of particularly interesting Cys-His-rich protein (PINCH) and parvin form the IPP complex (Fig. 2) in the cytoplasm, and this complex is recruited to focal adhesions through interactions with other factors, such as paxillin." SIGNOR-265767 MAPKAPK2 protein P49137 UNIPROT EEF2K protein O00418 UNIPROT unknown phosphorylation Ser377 PPLLRPLsENSGDEN -1 12171600 t miannu "Identification of Ser-377 as the site on eEF2 kinase phosphorylated in vitro by MAPKAP-K2, MAPKAP-K3 and MAPKAP-K5. Maximal phosphorylation of eEF2 kinase by MAPKAP-K2 (Figure 5) or MAPKAP-K5 (results not shown) had no effect on its activity." SIGNOR-249710 MAPKAPK2 protein P49137 UNIPROT ARPC5 protein O15511 UNIPROT unknown phosphorylation Ser77 AVKDRAGsIVLKVLI -1 12829704 t miannu "MAPKAPK2 also phosphorylated p16-Arc in intact Arp2/3 complexes precipitated from neutrophil lysates. Mutation of serine-77 to alanine on the A isoform prevented phosphorylation by MAPKAPK2." SIGNOR-250144 MAPKAPK2 protein P49137 UNIPROT PIAS1 protein O75925 UNIPROT up-regulates phosphorylation Ser522 DTSYINTsLIQDYRH 9606 BTO:0001253 23202365 t llicata "T he mitogen-activated protein kinase (mapk)-activated protein kinase-2 is a proinflammatory kinase and phosphorylates pias1 at the ser522 residue. Activation of mapk-activated protein kinase-2 enhances p53-sumoylation, but a pias1 phosphorylation mutant, pias1-s522a, abolished this p53-sumoylation, suggesting a critical role for pias1-s522 phosphorylation in its sumo ligase activity." SIGNOR-199944 MAPKAPK2 protein P49137 UNIPROT PARN protein O95453 UNIPROT down-regulates phosphorylation Ser557 NHYYRNNsFTAPSTV 9606 20932473 t lperfetto "Mk2 phosphorylates parn, blocking gadd45_ mrna degradation. Parn can serve as a direct substrate for mk2, and demonstrating that ser-557 is the dominant mk2 phosphorylation site." SIGNOR-168377 CEBPA protein P49715 UNIPROT GFI1 protein Q99684 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20924107 f irozzo "We show here that C/EBPα interacts with a functional C/EBP binding site in the Gfi-1 5'-flanking region and enhances the promoter activity of Gfi-1." SIGNOR-256068 MAPKAPK2 protein P49137 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser78 PAYSRALsRQLSSGV 9606 BTO:0000938 12367505 t "10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro." gcesareni "Notably mk2 is well known to play an important role in actin filament remodellng by phosphorylating hsp27." SIGNOR-94021 MAPKAPK2 protein P49137 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser82 RALSRQLsSGVSEIR 9606 BTO:0000938 12367505 t "10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro." gcesareni "Notably mk2 is well known to play an important role in actin filament remodellng by phosphorylating hsp27." SIGNOR-94025 MAPKAPK2 protein P49137 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser15 FSLLRGPsWDPFRDW 9606 20626350 t "10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro." gcesareni "Notably mk2 is well known to play an important role in actin filament remodellng by phosphorylating hsp27." SIGNOR-166629 MAPKAPK2 protein P49137 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser78 PAYSRALsRQLSSGV 9606 20626350 t "10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro." gcesareni "Notably mk2 is well known to play an important role in actin filament remodellng by phosphorylating hsp27." SIGNOR-166633 MAPKAPK2 protein P49137 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser82 RALSRQLsSGVSEIR 9606 20626350 t "10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro." gcesareni "Notably mk2 is well known to play an important role in actin filament remodellng by phosphorylating hsp27." SIGNOR-166637 MAPKAPK2 protein P49137 UNIPROT TH protein P07101 UNIPROT "up-regulates activity" phosphorylation Ser19 KGFRRAVsELDAKQA -1 11359875 t miannu "MAPKAP-K2 phosphorylates both Ser19 and Ser40 of TH. Tyrosine hydroxylase (TH) has been reported to require binding of 14-3-3 proteins for optimal activation by phosphorylation." SIGNOR-250149 MAPKAPK2 protein P49137 UNIPROT TH protein P07101 UNIPROT "up-regulates activity" phosphorylation Ser40 GQGAPGPsLTGSPWP -1 11359875 t miannu "MAPKAP-K2 phosphorylates both Ser19 and Ser40 of TH. Tyrosine hydroxylase (TH) has been reported to require binding of 14-3-3 proteins for optimal activation by phosphorylation." SIGNOR-250150 MAPKAPK2 protein P49137 UNIPROT ALOX5 protein P09917 UNIPROT "up-regulates activity" phosphorylation Ser272 CSLERQLsLEQEVQQ -1 11844797 t miannu "Arachidonic acid promotes phosphorylation of 5-lipoxygenase at Ser-271 by MAPK-activated protein kinase 2 (MK2). when stimulated with only exogenous arachidonic acid, activity for the S271A mutant was significantly lower as compared with wild type 5-LO." SIGNOR-250143 MAPKAPK2 protein P49137 UNIPROT SRF protein P11831 UNIPROT unknown phosphorylation Ser103 RGLKRSLsEMEIGMV 9606 BTO:0000567 10318869 t llicata "Mk2 phosphorylates srf in vitro at ser-103" SIGNOR-67448 MAPKAPK2 protein P49137 UNIPROT SRF protein P11831 UNIPROT up-regulates phosphorylation 9606 20626350 t gcesareni "Neverthless, some transcription factors, such as e47, er81, srf and creb are also phosphorylated by mk2" SIGNOR-166640 MAPKAPK2 protein P49137 UNIPROT TCF3 protein P15923 UNIPROT up-regulates phosphorylation 9606 20626350 t gcesareni "Neverthless, some transcription factors, such as e47, er81, srf and creb are also phosphorylated by mk2" SIGNOR-166643 MAPKAPK2 protein P49137 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser119 EILSRRPsYRKILND 9606 17389598 t lperfetto "Neverthless, some transcription factors, such as e47, er81, srf and creb are also phosphorylated by mk2." SIGNOR-153944 MAPKAPK2 protein P49137 UNIPROT CREB1 protein P16220 UNIPROT "up-regulates activity" phosphorylation Ser119 EILSRRPsYRKILND 9606 20626350 t lperfetto "Neverthless, some transcription factors, such as e47, er81, srf and creb are also phosphorylated by mk2." SIGNOR-166619 MAPKAPK2 protein P49137 UNIPROT CREB1 protein P16220 UNIPROT "up-regulates activity" phosphorylation Ser119 EILSRRPsYRKILND 9606 8887554 t lperfetto "We show that mapkap kinase-2 phosphorylates creb at ser133 in vitro." SIGNOR-44384 MAPKAPK2 protein P49137 UNIPROT ZFP36 protein P26651 UNIPROT "down-regulates activity" phosphorylation Ser113 TELCRTFsESGRCRY -1 14688255 t miannu "We confirm phosphorylation of TTP by MK2 and identify specific phosphorylation sites at Ser52, Ser105, Ser58, Ser176, Ser178, and Ser316. If MK2 regulates translation in part by TTP phosphorylation, TTP should be a repressor of translation when dephosphorylated and an activator of (or neutral to) translation when phosphorylated." SIGNOR-250156 MAPKAPK2 protein P49137 UNIPROT ZFP36 protein P26651 UNIPROT "down-regulates activity" phosphorylation Ser184 HPPVLRQsISFSGLP -1 14688255 t miannu "We confirm phosphorylation of TTP by MK2 and identify specific phosphorylation sites at Ser52, Ser105, Ser58, Ser176, Ser178, and Ser316. If MK2 regulates translation in part by TTP phosphorylation, TTP should be a repressor of translation when dephosphorylated and an activator of (or neutral to) translation when phosphorylated." SIGNOR-250153 MAPKAPK2 protein P49137 UNIPROT ZFP36 protein P26651 UNIPROT "down-regulates activity" phosphorylation Ser186 PVLRQSIsFSGLPSG -1 14688255 t miannu "We confirm phosphorylation of TTP by MK2 and identify specific phosphorylation sites at Ser52, Ser105, Ser58, Ser176, Ser178, and Ser316. If MK2 regulates translation in part by TTP phosphorylation, TTP should be a repressor of translation when dephosphorylated and an activator of (or neutral to) translation when phosphorylated." SIGNOR-250152 MAPKAPK2 protein P49137 UNIPROT ZFP36 protein P26651 UNIPROT "down-regulates activity" phosphorylation Ser60 RLPGRSTsLVEGRSC -1 14688255 t miannu "We confirm phosphorylation of TTP by MK2 and identify specific phosphorylation sites at Ser52, Ser105, Ser58, Ser176, Ser178, and Ser316. If MK2 regulates translation in part by TTP phosphorylation, TTP should be a repressor of translation when dephosphorylated and an activator of (or neutral to) translation when phosphorylated." SIGNOR-250155 MAPKAPK2 protein P49137 UNIPROT ZFP36 protein P26651 UNIPROT "down-regulates activity" phosphorylation Ser66 TSLVEGRsCGWVPPP -1 14688255 t miannu "We confirm phosphorylation of TTP by MK2 and identify specific phosphorylation sites at Ser52, Ser105, Ser58, Ser176, Ser178, and Ser316. If MK2 regulates translation in part by TTP phosphorylation, TTP should be a repressor of translation when dephosphorylated and an activator of (or neutral to) translation when phosphorylated." SIGNOR-250154 MAPKAPK2 protein P49137 UNIPROT PDE4A protein P27815 UNIPROT "down-regulates activity" phosphorylation Ser152 SFLYRSDsDYDMSPK 9606 BTO:0000801 21323643 t miannu "Phosphorylation of cAMP-specific PDE4A5 (phosphodiesterase-4A5) by MK2 (MAPKAPK2) attenuates its activation through protein kinase A phosphorylation. In the present study, we show that PDE4A5 is phosphorylated at Ser147, within the regulatory UCR1 (ultraconserved region 1) domain conserved among PDE4 long isoforms, by MK2 (MAPK-activated protein kinase 2, also called MAPKAPK2). Phosphorylation by MK2, although not altering PDE4A5 activity, markedly attenuates PDE4A5 activation through phosphorylation by protein kinase A. This modification confers the amplification of intracellular cAMP accumulation in response to adenylate cyclase activation by attenuating a major desensitization system to cAMP." SIGNOR-263078 MAPKAPK2 protein P49137 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation 9606 17292828 t amattioni "Mk2 was required for the degradation of cdc25a. Mk2 phosphorylates cdc25a in vitro. Phosphorylation of cdc25a in vivo has been shown to facilitate its ubiquitin-mediated proteolysis" SIGNOR-152996 MAPKAPK2 protein P49137 UNIPROT LSP1 protein P33241 UNIPROT unknown phosphorylation Ser204 KLIDRTEsLNRSIEK -1 8995217 t miannu "LSP1 is the major substrate for mitogen-activated protein kinase-activated protein kinase 2 in human neutrophils" SIGNOR-250147 MAPKAPK2 protein P49137 UNIPROT LSP1 protein P33241 UNIPROT unknown phosphorylation Ser252 PKLARQAsIELPSMA -1 8995217 t miannu "LSP1 is the major substrate for mitogen-activated protein kinase-activated protein kinase 2 in human neutrophils. . Inspection of the human LSP1 protein sequence (22) identifies two serine residues at positions 204 and 252 as potential phosphorylation sites. The results show that LSP1 is a substrate for MAPKAP kinase 2 in vitro and that the phosphorylation site(s) are located in the C-terminal 152 amino acid residues, as predicted from the sequence." SIGNOR-250148 MAPKAPK2 protein P49137 UNIPROT KRT20 protein P35900 UNIPROT "up-regulates activity" phosphorylation Ser13 RSFHRSLsSSLQAPV -1 20724476 t miannu "P38 phosphorylates the type II keratin, K8 at Ser73, whereas MK2 phosphorylates the binding partners K18 at Ser52 and K20 at Ser13." SIGNOR-263071 MAPKAPK2 protein P49137 UNIPROT KRT20 protein P35900 UNIPROT "up-regulates activity" phosphorylation Ser13 RSFHRSLsSSLQAPV -1 20724476 t miannu "P38 phosphorylates the type II keratin, K8 at Ser73, whereas MK2 phosphorylates the binding partners K18 at Ser52 and K20 at Ser13." SIGNOR-263072 MAPKAPK2 protein P49137 UNIPROT ETV1 protein P50549 UNIPROT "down-regulates activity" phosphorylation Ser191 HRFRRQLsEPCNSFP 452646 11551945 t miannu "MK2 phosphorylates ER81 in vitro within its central inhibitory domain, and overexpression of MK2 leads to increased in vivo phosphorylation of ER81. Two serine residues, ER81 amino acids 191 and 216, were identified as MK2 phosphorylation sites. MK2 suppresses basal ER81-dependent transcription" SIGNOR-250145 MAPKAPK2 protein P49137 UNIPROT ETV1 protein P50549 UNIPROT "down-regulates activity" phosphorylation Ser216 PMYQRQMsEPNIPFP 452646 11551945 t miannu "MK2 phosphorylates ER81 in vitro within its central inhibitory domain, and overexpression of MK2 leads to increased in vivo phosphorylation of ER81. Two serine residues, ER81 amino acids 191 and 216, were identified as MK2 phosphorylation sites. MK2 suppresses basal ER81-dependent transcription" SIGNOR-250146 MAPKAPK2 protein P49137 UNIPROT ETV1 protein P50549 UNIPROT up-regulates phosphorylation 9606 20626350 t gcesareni "Neverthless, some transcription factors, such as e47, er81, srf and creb are also phosphorylated by mk2" SIGNOR-166625 MAPKAPK2 protein P49137 UNIPROT PLK1 protein P53350 UNIPROT up-regulates phosphorylation Ser326 LTIPPRFsIAPSSLD 9606 18695677 t llicata "Here, we have identified mk2 as a major plk1 kinase toward ser326, whose phosphorylation is critical to recruit ?-Tubulin to centrosomes and subsequent establishment of functional bipolar spindles. To our knowledge, this is the first direct evidence to demonstrate that the essential function of plk1 in centrosome maturation and bipolar spindle formation is controlled by its upstream kinase." SIGNOR-179968 MAPKAPK2 protein P49137 UNIPROT LIMK1 protein P53667 UNIPROT up-regulates phosphorylation Ser323 KDLGRSEsLRVVCRP 9606 16456544 t lperfetto "Mk2 activated limk1 by phosphorylation at ser-323." SIGNOR-144333 MAPKAPK2 protein P49137 UNIPROT YWHAZ protein P63104 UNIPROT "down-regulates activity" phosphorylation Ser58 VVGARRSsWRVVSSI 9606 BTO:0000007 12861023 t miannu "We confirmed that MAPKAPK2 interacted with and phosphorylated 14-3-3zeta in vitro and in HEK293 cells. Mutation analysis showed that MAPKAPK2 phosphorylated 14-3-3zeta at Ser-58. S58D mutation significantly impaired both 14-3-3zeta dimerization and binding to Raf-1." SIGNOR-250151 MAPKAPK2 protein P49137 UNIPROT MDM2 protein Q00987 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser166 SSRRRAIsETEENSD 9606 15688025 t gcesareni "Hdm2 phosphorylation by mapkap kinase 2 enhances hdm2 activity and promote the degradation of p53." SIGNOR-133560 MAPKAPK2 protein P49137 UNIPROT ZFP36L1 protein Q07352 UNIPROT down-regulates phosphorylation Ser203 PRLQHSFsFAGFPSA 9606 18326031 t lperfetto "Mk2-mediated inhibition of brf1 requires phosphorylation at s54, s92, and s203. Phosphorylation of brf1 by mk2 does not appear to alter its ability to interact with ares or to associate with mrna decay enzymes. Thus, mk2 inhibits brf1-dependent amd through direct phosphorylation." SIGNOR-161270 MAPKAPK2 protein P49137 UNIPROT ZFP36L1 protein Q07352 UNIPROT down-regulates phosphorylation Ser54 GGFPRRHsVTLPSSK 9606 18326031 t lperfetto "Mk2-mediated inhibition of brf1 requires phosphorylation at s54, s92, and s203. Phosphorylation of brf1 by mk2 does not appear to alter its ability to interact with ares or to associate with mrna decay enzymes. Thus, mk2 inhibits brf1-dependent amd through direct phosphorylation." SIGNOR-161274 MAPKAPK2 protein P49137 UNIPROT ZFP36L1 protein Q07352 UNIPROT down-regulates phosphorylation Ser92 RFRDRSFsEGGERLL 9606 18326031 t lperfetto "Mk2-mediated inhibition of brf1 requires phosphorylation at s54, s92, and s203. Phosphorylation of brf1 by mk2 does not appear to alter its ability to interact with ares or to associate with mrna decay enzymes. Thus, mk2 inhibits brf1-dependent amd through direct phosphorylation." SIGNOR-161278 MAPKAPK2 protein P49137 UNIPROT HNRNPA0 protein Q13151 UNIPROT "up-regulates activity" phosphorylation Ser84 VELKRAVsREDSARP 10090 BTO:0000801 12456657 t miannu "MAPKAP-K2 phosphorylated hnRNP A0 at Ser84 in vitro and this residue became phosphorylated in LPS-stimulated cells. The simplest explanation for these findings is that the phosphorylation of hnRNP A0 at Ser84 by MAPKAP-K2 enhances binding to the AREs of these mRNAs or allows hnRNP A0 to displace another protein(s) from the AREs." SIGNOR-262951 MAPKAPK2 protein P49137 UNIPROT ELAVL1 protein Q15717 UNIPROT up-regulates phosphorylation 9606 20626350 t gcesareni "Mk2 and mk3 participate in the control of gene expression mostly at the post-transcriptional level, by phosphorylating the are-binding proteins ttp and hur, and by regulating eef2k" SIGNOR-166622 CEBPA protein P49715 UNIPROT FTO protein Q9C0B1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007 24877091 f lperfetto "CCAAT/Enhancer-Binding Protein 𝛼 Is a Crucial" SIGNOR-261805 MAPKAPK2 protein P49137 UNIPROT RCSD1 protein Q6JBY9 UNIPROT "down-regulates activity" phosphorylation Ser179 RRFRRSQsDCGELGD -1 15850461 t miannu "Human CapZIP was phosphorylated at Ser-179 and Ser-244 by MAPKAP-K2 (mitogen-activated protein kinase-activated protein kinase 2) or MAPKAP-K3 in vitro. In the present paper we have identified CapZIP as a protein that is phosphorylated exceptionally rapidly by several SAPKs in vitro (Figure 4), and which is expressed in muscles and immune cells. Both MAPKAP-K2 and MAPKAP-K3 phosphorylated CapZIP at Ser-179 in vitro. An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ." SIGNOR-263079 MAPKAPK2 protein P49137 UNIPROT RCSD1 protein Q6JBY9 UNIPROT "down-regulates activity" phosphorylation Ser244 PPLRRSPsRTEKQEE -1 15850461 t miannu "Human CapZIP was phosphorylated at Ser-179 and Ser-244 by MAPKAP-K2 (mitogen-activated protein kinase-activated protein kinase 2) or MAPKAP-K3 in vitro. In the present paper we have identified CapZIP as a protein that is phosphorylated exceptionally rapidly by several SAPKs in vitro (Figure 4), and which is expressed in muscles and immune cells. Both MAPKAP-K2 and MAPKAP-K3 phosphorylated CapZIP at Ser-179 in vitro. An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ." SIGNOR-263080 MAPKAPK2 protein P49137 UNIPROT LPCAT2 protein Q7L5N7 UNIPROT "up-regulates activity" phosphorylation Ser34 PMVPRQAsFFPPPVP 10090 BTO:0002601 20663880 t miannu "Mass spectrometry and mutagenesis analyses identified Ser34 of LPCAT2 as the phosphorylation site to enhance the catalytic activities. The experiments using inhibitors and siRNA against MAPK cascades demonstrated that LPCAT2 phosphorylation through LPS-TLR4 signaling may directly depend on MAPK-activated protein kinase 2 (MAPKAP kinase 2 or MK2)." SIGNOR-263077 MAPKAPK2 protein P49137 UNIPROT RTN4 protein Q9NQC3 UNIPROT unknown phosphorylation Ser107 VAPERQPsWDPSPVS 9606 BTO:0000567;BTO:0000801 16095439 t llicata "Nogo-b is phosphorylated at ser107 in vitro by mapkap-k2" SIGNOR-139486 MAPKAPK2 protein P49137 UNIPROT AATF protein Q9NY61 UNIPROT up-regulates phosphorylation Thr366 FTVYRNRtLQKWHDK 9606 22909821 t lperfetto "Upon genotoxic stress, aatf is phosphorylated by the checkpoint kinase mk2. Phosphorylation results in the release of aatf from cytoplasmic mrlc3 and subsequent nuclear translocation where aatf binds to the puma, bax and bak promoter regions to repress p53-driven expression of these pro-apoptotic genes." SIGNOR-191935 MAPKAPK2 protein P49137 UNIPROT AGO2 protein Q9UKV8 UNIPROT up-regulates phosphorylation Ser387 SKLMRSAsFNTDPYV 9606 20626350 t gcesareni "Mk2 was found to phopsphorylate in vitro the ago2 protein in ser387, which was identified as the major ago2 phosphorylation site in cells.and mutation of ser387 to alanineimpairsago2 localization to therna-containing granules termedprocessing bodies" SIGNOR-166615 MAPKAPK2 protein P49137 UNIPROT UBE2J1 protein Q9Y385 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser184 KELARQIsFKAEVNS 9606 BTO:0000567 24020373 t miannu "Endoplasmic reticulum-associated ubiquitin-conjugating enzyme Ube2j1 is a novel substrate of MK2 (MAPKAP kinase-2) involved in MK2-mediated TNFα production. These findings strongly suggest that MK2 directly phosphorylates Ube2j1 at Ser(184) upon p38-activating stress in vivo." SIGNOR-263091 RPL34 protein P49207 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262467 RPIA protein P49247 UNIPROT "D-ribulose 5-phosphate" smallmolecule CHEBI:17363 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 34775382 t miannu "The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux." SIGNOR-267067 RPIA protein P49247 UNIPROT "D-ribofuranose 5-phosphate(2-)" smallmolecule CHEBI:78346 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 34775382 t miannu "The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux." SIGNOR-267070 MTNR1B protein P49286 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256850 MTNR1B protein P49286 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256986 CDK8 protein P49336 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser187 NSHPFPHsPNSSYPN 9606 19914161 t lpetrilli "Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3." SIGNOR-189129 MTNR1B protein P49286 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257102 MTNR1B protein P49286 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256707 FASN protein P49327 UNIPROT WNT1 protein P04628 UNIPROT "up-regulates activity" 9606 BTO:0001130 18838960 f lperfetto "Overexpression of fatty acid synthase is associated with palmitoylation of Wnt1 and cytoplasmic stabilization of beta-catenin in prostate cancer" SIGNOR-242881 FASN protein P49327 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates quantity by stabilization" 9606 BTO:0001130 18838960 f lperfetto "Overexpression of fatty acid synthase is associated with palmitoylation of Wnt1 and cytoplasmic stabilization of beta-catenin in prostate cancer" SIGNOR-242878 POU3F4 protein P49335 UNIPROT POU3F3 protein P20264 UNIPROT "up-regulates activity" binding -1 9105675 t miannu "POU proteins (Brain-1, Brain-2, Brain-4 and SCIP) serve as transcriptional transactivators. if they were to form homomeric and heteromeric complexes with each other, depending on the particular combination, they might have different DNA-binding specificities and, thus, activate different genes." SIGNOR-220127 POU3F4 protein P49335 UNIPROT POU3F2 protein P20265 UNIPROT "up-regulates activity" binding -1 9105675 t miannu "POU proteins (Brain-1, Brain-2, Brain-4 and SCIP) serve as transcriptional transactivators. if they were to form homomeric and heteromeric complexes with each other, depending on the particular combination, they might have different DNA-binding specificities and, thus, activate different genes." SIGNOR-220080 CDK8 protein P49336 UNIPROT CCNH protein P51946 UNIPROT down-regulates phosphorylation Ser304 YEDDDYVsKKSKHEE 9606 10993082 t lperfetto "Cdk8 phosphorylates mammalian cyclin h in the vicinity of its functionally unique amino-terminal and carboxy-terminal alpha-helical domains. This phosphorylation represses both the ability of tfiih to activate transcription and its ctd kinase activity" SIGNOR-82033 CDK8 protein P49336 UNIPROT CCNH protein P51946 UNIPROT down-regulates phosphorylation Ser5 sSQKRHWT 9606 10993082 t gcesareni "Here we show that cdk8/cyclin c can regulate transcription by targeting the cdk7/cyclin h subunits of the general transcription initiation factor iih (tfiih). cdk8 phosphorylates mammalian cyclin h in the vicinity of its functionally unique amino-terminal and carboxy-terminal alpha-helical domains. This phosphorylation represses both the ability of tfiih to activate transcription and its ctd kinase activity. In addition, mimicking cdk8 phosphorylation of cyclin h in vivo has a dominant-negative effect on cell growth." SIGNOR-82037 CDK8 protein P49336 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 19914161 t lpetrilli "Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3." SIGNOR-161557 CDK8 protein P49336 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 19914168 t lpetrilli "Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3." SIGNOR-161646 CDK8 protein P49336 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" phosphorylation Ser208 DAGSPNLsPNPMSPA 9606 19914161 t lpetrilli "Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3." SIGNOR-161553 CDK8 protein P49336 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" phosphorylation Thr179 PQSNIPEtPPPGYLS 9606 19914161 t lpetrilli "Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3." SIGNOR-161561 CDK8 protein P49336 UNIPROT E2F1 protein Q01094 UNIPROT down-regulates phosphorylation Ser375 PVDEDRLsPLVAADS 9606 18794899 t lperfetto "E2F1 activity is also repressed by cyclin-dependent kinase-8 (CDK8), a colorectal oncoprotein. Elevated levels of CDK8 protect beta-catenin/TCF-dependent transcription from inhibition by E2F1." SIGNOR-181078 CDK8 protein P49336 UNIPROT HES1 protein Q14469 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15546612 f gcesareni "Cycc:cdk8 and cyct1:cdk9/p-tefb are recruited with notch and associated coactivators (mam, skip) to the hes1 promoter in signaling cells." SIGNOR-130637 CDK8 protein P49336 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser195 PNSSYPNsPGSSSST 9606 19914161 t lpetrilli "Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3." SIGNOR-189133 CDK8 protein P49336 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser214 PTSSDPGsPFQMPAD 9606 19914161 t lpetrilli "Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3." SIGNOR-189141 CDK8 protein P49336 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser195 PNSSYPNsPGSSSST 9606 19914168 t lpetrilli "Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3." SIGNOR-161626 CDK8 protein P49336 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser214 PTSSDPGsPFQMPAD 9606 19914168 t lpetrilli "Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3." SIGNOR-161634 CDK8 protein P49336 UNIPROT SMAD1 protein Q15797 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser206 SSSTYPHsPTSSDPG 9606 19914161 t lpetrilli "Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3." SIGNOR-189137 CDK8 protein P49336 UNIPROT "CKM complex" complex SIGNOR-C406 SIGNOR "form complex" binding 9606 23563140 t miannu "The CDK8 kinase module (CKM) is a conserved, dissociable Mediator subcomplex whose component subunits were genetically linked to the RNA polymerase II (RNAPII) C-terminal domain (CTD) and individually recognized as transcriptional repressors before Mediator was identified as a pre-eminent complex in eukaryotic transcription regulation." SIGNOR-266686 FNTA protein P49354 UNIPROT MRAS protein O14807 UNIPROT "up-regulates activity" 9606 24294527 t lperfetto "Major investments have been made to target Ras through indirect routes. Inhibition of farnesyl transferase to block Ras maturation has failed in large clinical trials." SIGNOR-242553 FNTA protein P49354 UNIPROT HRAS protein P01112 UNIPROT "up-regulates activity" 9606 24294527 t lperfetto "Major investments have been made to target Ras through indirect routes. Inhibition of farnesyl transferase to block Ras maturation has failed in large clinical trials." SIGNOR-242568 FNTA protein P49354 UNIPROT KRAS protein P01116 UNIPROT "up-regulates activity" 9606 24294527 t lperfetto "Major investments have been made to target Ras through indirect routes. Inhibition of farnesyl transferase to block Ras maturation has failed in large clinical trials." SIGNOR-242559 FNTB protein P49356 UNIPROT MRAS protein O14807 UNIPROT "up-regulates activity" 9606 24294527 t lperfetto "Major investments have been made to target Ras through indirect routes. Inhibition of farnesyl transferase to block Ras maturation has failed in large clinical trials." SIGNOR-242562 FNTB protein P49356 UNIPROT HRAS protein P01112 UNIPROT "up-regulates activity" 9606 24294527 t lperfetto "Major investments have been made to target Ras through indirect routes. Inhibition of farnesyl transferase to block Ras maturation has failed in large clinical trials." SIGNOR-242565 FNTB protein P49356 UNIPROT KRAS protein P01116 UNIPROT "up-regulates activity" 9606 24294527 t lperfetto "Major investments have been made to target Ras through indirect routes. Inhibition of farnesyl transferase to block Ras maturation has failed in large clinical trials." SIGNOR-242556 MRPL19 protein P49406 UNIPROT "39S mitochondrial large ribosomal subunit" complex SIGNOR-C285 SIGNOR "form complex" binding -1 25838379 t lperfetto "We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules" SIGNOR-262375 ARRB1 protein P49407 UNIPROT KIF3A protein Q9Y496 UNIPROT up-regulates binding 9606 18497258 t gcesareni "Kif3a is essential for shh-mediated signaling in mammalian systems (5), and we identified kif3a as a arr1 binding partner in a proteomics screen (18). To test whether arrs, smo, and kif3a might work in concert." SIGNOR-178672 UBE2A protein P49459 UNIPROT PCNA protein P12004 UNIPROT up-regulates ubiquitination Lys164 AVVISCAkDGVKFSA 9606 12226657 t gcesareni "Pcna is mono-ubiquitinated through rad6 and rad18, modified by lysine-63-linked multi-ubiquitination--which additionally requires mms2, ubc13 and rad5--and is conjugated to sumo by ubc9. The first of these is monoubiquitination of lysine 164 on one or more of the pcna subunits by the e2-e3 complex of rad6-rad18." SIGNOR-92737 UBE2A protein P49459 UNIPROT PCNA protein P12004 UNIPROT up-regulates ubiquitination Lys164 AVVISCAkDGVKFSA 9606 19706603 t gcesareni "Pcna is mono-ubiquitinated through rad6 and rad18, modified by lysine-63-linked multi-ubiquitination--which additionally requires mms2, ubc13 and rad5--and is conjugated to sumo by ubc9. The first of these is monoubiquitination of lysine 164 on one or more of the pcna subunits by the e2-e3 complex of rad6-rad18." SIGNOR-187761 SIK1 protein P57059 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates phosphorylation Ser171 SALNRTSsDSALHTS 9606 BTO:0000007;BTO:0000567 16817901 t miannu "These results suggested that sik1 could phosphorylate all torcs and thereby repress their transactivation activities." SIGNOR-147707 SARS1 protein P49591 UNIPROT MYC protein P01106 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 24940000 t "Using in vitro, cell and animal experiments, we show here that SerRS intervenes by antagonizing c-Myc, the major transcription factor promoting VEGFA expression, through a tandem mechanism. First, by direct head-to-head competition, nuclear-localized SerRS blocks c-Myc from binding to the VEGFA promoter. Second, DNA-bound SerRS recruits the SIRT2 histone deacetylase to erase prior c-Myc-promoted histone acetylation." SIGNOR-259368 PPM1F protein P49593 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates dephosphorylation 9606 BTO:0000150;BTO:0000093 20016286 t gcesareni "Pop x2, a pp 2c serine/threonine phosphatase, is known to dephosphorylate pak and downregulate its activity." SIGNOR-162146 PPM1F protein P49593 UNIPROT PAK1 protein Q13153 UNIPROT "down-regulates activity" dephosphorylation Ser57 KKDRFYRsILPGDKT 10116 11864573 t "The p21-activated kinase PAK is negatively regulated by POPX1 and POPX2, a pair of serine/threonine phosphatases of the PP2C family|POPX Can Dephosphorylate and Downregulate PAK| To confirm that POPX2 acts on αPAK phospho-Thr422, a key regulator of activity in the kinase activation loop [9], we used phospho-specific antibodies against αPAK P-Thr422 (Figure 3B, lower panel), which proved to be an excellent substrate for POPX2. Similarly, complete loss of αPAK P-Ser57 with 0.2 μg POPX2 contrasts with the slight loss observed with 1.5 μg PP1. On the basis of these results, we suggest PAK is a substrate of POPX." SIGNOR-248530 PPM1F protein P49593 UNIPROT PAK1 protein Q13153 UNIPROT "down-regulates activity" dephosphorylation Thr423 PEQSKRStMVGTPYW 10116 11864573 t "The p21-activated kinase PAK is negatively regulated by POPX1 and POPX2, a pair of serine/threonine phosphatases of the PP2C family|POPX Can Dephosphorylate and Downregulate PAK| To confirm that POPX2 acts on αPAK phospho-Thr422, a key regulator of activity in the kinase activation loop [9], we used phospho-specific antibodies against αPAK P-Thr422 (Figure 3B, lower panel), which proved to be an excellent substrate for POPX2. Similarly, complete loss of αPAK P-Ser57 with 0.2 μg POPX2 contrasts with the slight loss observed with 1.5 μg PP1. On the basis of these results, we suggest PAK is a substrate of POPX." SIGNOR-248531 PPM1F protein P49593 UNIPROT PAK2 protein Q13177 UNIPROT down-regulates dephosphorylation 9606 BTO:0000150;BTO:0000093 20016286 t gcesareni "Pop x2, a pp 2c serine/threonine phosphatase, is known to dephosphorylate pak and downregulate its activity." SIGNOR-162149 PPM1F protein P49593 UNIPROT CAMK2A protein Q9UQM7 UNIPROT down-regulates dephosphorylation Thr286 SCMHRQEtVDCLKKF 9606 BTO:0000938 15140879 t gcesareni "Ppm1f specifically dephosphorylates the phospho-thr-286 in autophosphorylated camkii substrate and thus deactivates the camkii in vitro." SIGNOR-124309 EVX1 protein P49640 UNIPROT GSC protein P56915 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001086 22178155 f miannu "We found that EVX1 repressed GSC expression and promoted formation of posterior streak-like progeny in response to BMP4, and conversely that GSC repressed EVX1 expression and was required for development of anterior streak-like progeny in response to activin." SIGNOR-254139 PRIM1 protein P49642 UNIPROT "DNA primase complex" complex SIGNOR-C261 SIGNOR "form complex" binding -1 24043831 t lperfetto "Here, we describe the crystal structure of human primase in heterodimeric form consisting of full-length catalytic subunit and a C-terminally truncated large subunit." SIGNOR-261339 PRIM2 protein P49643 UNIPROT "DNA primase complex" complex SIGNOR-C261 SIGNOR "form complex" binding -1 24043831 t lperfetto "Here, we describe the crystal structure of human primase in heterodimeric form consisting of full-length catalytic subunit and a C-terminally truncated large subunit." SIGNOR-261340 CASP4 protein P49662 UNIPROT GSDMD protein P57764 UNIPROT "up-regulates activity" cleavage Asp275 CLHNFLTdGVPAEGA 9606 BTO:0000007 26375003 t lperfetto "Co-expression of GSDMD with caspase-1, 4, 5 or 11 but not apoptotic caspases (caspase-2, 8 and 9) in 293T cells induced the same cleavage of GSDMD|inflammatory caspases specifically cleave GSDMD after the 272FLTD275 (or 273LLSD276) sequence |" SIGNOR-256417 CSNK1E protein P49674 UNIPROT DVL1 protein O14640 UNIPROT "up-regulates activity" phosphorylation Ser139 DNETGTEsMVSHRRE 9606 BTO:0000007 16965538 t lperfetto "Phenotypic analysis of mutant mDvl-1 indicates that phosphorylation of these sites stimulates the Dvl-activated beta-catenin-dependent Wnt signaling pathway in both cell culture and in Xenopus development." SIGNOR-217845 CSNK1E protein P49674 UNIPROT DVL1 protein O14640 UNIPROT "up-regulates activity" phosphorylation Ser142 TGTESMVsHRRERAR 9606 BTO:0000007 16965538 t lperfetto "Phenotypic analysis of mutant mDvl-1 indicates that phosphorylation of these sites stimulates the Dvl-activated beta-catenin-dependent Wnt signaling pathway in both cell culture and in Xenopus development." SIGNOR-217849 CSNK1E protein P49674 UNIPROT DVL2 protein O14641 UNIPROT up-regulates phosphorylation Ser143 FHPNVSSsHENLEPE 9606 22609948 t lperfetto "We demonstrated that dvl2 is phosphorylated at s143 and t224 in a manner that requires both non-canonical wnt5a ligand and casein kinase 1 epsilon (ck1_), and that this event is critical to interact with plk1 in early stages of the cell cycle" SIGNOR-197063 CSNK1E protein P49674 UNIPROT DVL2 protein O14641 UNIPROT up-regulates phosphorylation Thr224 MSRFSSStEQSSASR 9606 22609948 t lperfetto "We demonstrated that dvl2 is phosphorylated at s143 and t224 in a manner that requires both non-canonical wnt5a ligand and casein kinase 1 epsilon (ck1_), and that this event is critical to interact with plk1 in early stages of the cell cycle" SIGNOR-197555 CSNK1E protein P49674 UNIPROT DVL2 protein O14641 UNIPROT "up-regulates activity" phosphorylation 6239 10517632 t gcesareni "In addition, CKI bound to and increased the phosphorylation of dishevelled, a known component of the Wnt pathway" SIGNOR-244097 CSNK1E protein P49674 UNIPROT PER2 protein O15055 UNIPROT up-regulates phosphorylation Ser662 ALPGKAEsVASLTSQ 9606 17218255 t gcesareni "Altering ckidelta dosage modulates the s662 phenotype demonstrating that ckidelta can regulate period through per2 in vivo." SIGNOR-152094 CSNK1E protein P49674 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C110 12000790 t gcesareni "We conclude that a major role of axin in the wnt is to provide the kinase activity that initiates the betBeta-catenin phosphorylation cascade at s45. This process is mediated by cki, the alfa, delta, or ? Isoform, all detected in association with axin by lc/ms." SIGNOR-87444 CSNK1E protein P49674 UNIPROT PER1 protein O15534 UNIPROT down-regulates phosphorylation 9606 15917222 t miannu "Ck1_ and ck1_2 can promote proteasome-dependent per1 degradation in mammalian tissue culture cells, and their removal by rnai leads to an increased abundance of per1." SIGNOR-137706 CSNK1E protein P49674 UNIPROT CTNND1 protein O60716 UNIPROT down-regulates phosphorylation Ser268 PQVRVGGsSVDLHRF 9606 BTO:0000782 3133391 t gcesareni "Moreover, in response to wnt3a, p120-catenin is phosphorylated at ser268, a modification dependent on ck1epsilon activity, which disrupts its interaction with e-cadherin and, subsequently, with lrp5/6, promoting the release of ck1epsilon/p120-catenin from the wnt receptor complex." SIGNOR-24443 CSNK1E protein P49674 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation Ser1420 YVVHGPAsVPLGYVP 9606 16513652 t gcesareni "We find that ckiepsilon binds to lrp5 and lrp6 in vitro and in vivo and identify three ckiepsilon-specific phosphorylation sites in lrp6. Two of the identified phosphorylation sites, ser1420 and ser1430, influence wnt signaling in vivo," SIGNOR-145049 CSNK1E protein P49674 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation Ser1430 LGYVPHPsSLSGSLP 9606 16513652 t gcesareni "We find that ckiepsilon binds to lrp5 and lrp6 in vitro and in vivo and identify three ckiepsilon-specific phosphorylation sites in lrp6. Two of the identified phosphorylation sites, ser1420 and ser1430, influence wnt signaling in vivo," SIGNOR-145053 CSNK1E protein P49674 UNIPROT TCF3 protein P15923 UNIPROT up-regulates phosphorylation 9606 11524435 t gcesareni "Tcf3 is a substrate for both glycogen synthase kinase (gsk) 3 and casein kinase (ck) 1epsilon, and phosphorylation of tcf3 by ckiepsilon stimulates its binding to beta-catenin, an effect reversed by gsk3." SIGNOR-110056 CSNK1E protein P49674 UNIPROT APC protein P25054 UNIPROT "up-regulates activity" phosphorylation Ser1279 SRCSSLSsLSSAEDE 9606 BTO:0000038 11487578 t lperfetto "Apc can be phosphorylated by ck1epsilon at ser1279 and ser1392. Mutation of conserved serine residues in the beta-catenin regulatory motifs of APC interfered with both axin-dependent phosphorylation and phosphorylation by CKIepsilon and impaired the ability of APC to regulate beta-catenin." SIGNOR-109660 CSNK1E protein P49674 UNIPROT APC protein P25054 UNIPROT "up-regulates activity" phosphorylation Ser1392 SRCTSVSsLDSFESR 9606 BTO:0000038 11487578 t lperfetto "Apc can be phosphorylated by ck1epsilon at ser1279 and ser1392. Mutation of conserved serine residues in the beta-catenin regulatory motifs of APC interfered with both axin-dependent phosphorylation and phosphorylation by CKIepsilon and impaired the ability of APC to regulate beta-catenin." SIGNOR-109664 CSNK1E protein P49674 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Ser45 GATTTAPsLSGKGNP 9606 12000790 t gcesareni "However, ck1epsilon has been recently shown to interact with axin (sakanaka et al. 1999;rubinfeld et al. 2001), and it was proposed that this kinase mediates axin-induced apc phosphorylation, thereby stabilizing the beta-catenin degradation complex (rubinfeld et al. 2001). We have, therefore, evaluated ck1epsilon as a candidate s45-kinase in several assays, both in vitro and in vivo." SIGNOR-87448 CSNK1E protein P49674 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Ser45 GATTTAPsLSGKGNP 9606 BTO:0000007 12176352 t gcesareni "Using mass spectrometry and phosphopeptide-specific antibodies, we show that a complex of axin and casein kinase I (CKI) induces Beta-catenin phosphorylation at a single site: serine 45 (S45)." SIGNOR-244102 CSNK1E protein P49674 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser400 SRDESTDsGLSMSSY 9606 phosphorylation:Ser127 PQHVRAHsSPASLQL 23431053 t milica "Phosphorylation of YAP (S381) and TAZ (S311) by Lats1/2 primes subsequent phosphorylation events by casein kinase 1 (CK1d/e); this sequential phosphorylation results in recruitment of b-transducin repeat-containing proteins (b-TRCP; a subunit of the SCF ubiquitin E3 ligase) and consequently leads to degradation of YAP/TAZ" SIGNOR-201165 CSNK1E protein P49674 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser403 ESTDSGLsMSSYSVP 9606 phosphorylation:Ser127 PQHVRAHsSPASLQL 23431053 t milica "Phosphorylation of YAP (S381) and TAZ (S311) by Lats1/2 primes subsequent phosphorylation events by Casein Kinase 1 (CK1d/e); this sequential phosphorylation results in recruitment of b-transducin repeat-containing proteins (b-TRCP; a subunit of the SCF ubiquitin E3 ligase) and consequently leads to degradation of YAP/TAZ" SIGNOR-201170 CSNK1E protein P49674 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser400 SRDESTDsGLSMSSY 9606 phosphorylation:Ser127 PQHVRAHsSPASLQL 24715453 t milica "LATS1/2-mediated phosphorylation of a conserved serine in this region (Ser311 in human TAZ; Ser397 in human YAP) primes for further phosphorylation by CK1_/_ kinases (Ser314 on human TAZ; Ser400/403 in human YAP)" SIGNOR-230728 CSNK1E protein P49674 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser403 ESTDSGLsMSSYSVP 9606 phosphorylation:Ser127 PQHVRAHsSPASLQL 24715453 t milica "LATS1/2-mediated phosphorylation of a conserved serine in this region (Ser311 in human TAZ; Ser397 in human YAP) primes for further phosphorylation by CK1_/_ kinases (Ser314 on human TAZ; Ser400/403 in human YAP)" SIGNOR-230733 CSNK1E protein P49674 UNIPROT CSNK1E protein P49674 UNIPROT "down-regulates activity" phosphorylation Ser323 RMGQLRGsATRALPP 9606 BTO:0000007 10542239 t llicata "Amino acids Ser-323, Thr-325, Thr-334, Thr-337, Ser-368, Ser-405, Thr-407, and Ser-408 in the carboxyl-terminal tail of CKIepsilon were identified as probable in vivo autophosphorylation sites. A recombinant CKIepsilon protein with serine and threonine to alanine mutations eliminating these autophosphorylation sites was 8-fold more active than wild-type CKIepsilon using IkappaBalpha as a substrate. T" SIGNOR-250807 CSNK1E protein P49674 UNIPROT CSNK1E protein P49674 UNIPROT "down-regulates activity" phosphorylation Ser368 NTSPRAIsRVDRERK 9606 BTO:0000007 10542239 t llicata "Amino acids Ser-323, Thr-325, Thr-334, Thr-337, Ser-368, Ser-405, Thr-407, and Ser-408 in the carboxyl-terminal tail of CKIepsilon were identified as probable in vivo autophosphorylation sites. A recombinant CKIepsilon protein with serine and threonine to alanine mutations eliminating these autophosphorylation sites was 8-fold more active than wild-type CKIepsilon using IkappaBalpha as a substrate. T" SIGNOR-250808 CSNK1E protein P49674 UNIPROT CSNK1E protein P49674 UNIPROT "down-regulates activity" phosphorylation Ser405 EVSRIPAsQTSVPFD 9606 BTO:0000007 10542239 t llicata "Amino acids Ser-323, Thr-325, Thr-334, Thr-337, Ser-368, Ser-405, Thr-407, and Ser-408 in the carboxyl-terminal tail of CKIepsilon were identified as probable in vivo autophosphorylation sites. A recombinant CKIepsilon protein with serine and threonine to alanine mutations eliminating these autophosphorylation sites was 8-fold more active than wild-type CKIepsilon using IkappaBalpha as a substrate. T" SIGNOR-250809 CSNK1E protein P49674 UNIPROT CSNK1E protein P49674 UNIPROT "down-regulates activity" phosphorylation Ser408 RIPASQTsVPFDHLG 9606 BTO:0000007 10542239 t llicata "Amino acids Ser-323, Thr-325, Thr-334, Thr-337, Ser-368, Ser-405, Thr-407, and Ser-408 in the carboxyl-terminal tail of CKIepsilon were identified as probable in vivo autophosphorylation sites. A recombinant CKIepsilon protein with serine and threonine to alanine mutations eliminating these autophosphorylation sites was 8-fold more active than wild-type CKIepsilon using IkappaBalpha as a substrate. T" SIGNOR-250810 CSNK1E protein P49674 UNIPROT CSNK1E protein P49674 UNIPROT "down-regulates activity" phosphorylation Thr325 GQLRGSAtRALPPGP 9606 BTO:0000007 10542239 t llicata "Amino acids Ser-323, Thr-325, Thr-334, Thr-337, Ser-368, Ser-405, Thr-407, and Ser-408 in the carboxyl-terminal tail of CKIepsilon were identified as probable in vivo autophosphorylation sites. A recombinant CKIepsilon protein with serine and threonine to alanine mutations eliminating these autophosphorylation sites was 8-fold more active than wild-type CKIepsilon using IkappaBalpha as a substrate. T" SIGNOR-250811 CSNK1E protein P49674 UNIPROT CSNK1E protein P49674 UNIPROT "down-regulates activity" phosphorylation Thr334 ALPPGPPtGATANRL 9606 BTO:0000007 10542239 t llicata "Amino acids Ser-323, Thr-325, Thr-334, Thr-337, Ser-368, Ser-405, Thr-407, and Ser-408 in the carboxyl-terminal tail of CKIepsilon were identified as probable in vivo autophosphorylation sites. A recombinant CKIepsilon protein with serine and threonine to alanine mutations eliminating these autophosphorylation sites was 8-fold more active than wild-type CKIepsilon using IkappaBalpha as a substrate. T" SIGNOR-250812 CSNK1E protein P49674 UNIPROT CSNK1E protein P49674 UNIPROT "down-regulates activity" phosphorylation Thr337 PGPPTGAtANRLRSA 9606 BTO:0000007 10542239 t llicata "Amino acids Ser-323, Thr-325, Thr-334, Thr-337, Ser-368, Ser-405, Thr-407, and Ser-408 in the carboxyl-terminal tail of CKIepsilon were identified as probable in vivo autophosphorylation sites. A recombinant CKIepsilon protein with serine and threonine to alanine mutations eliminating these autophosphorylation sites was 8-fold more active than wild-type CKIepsilon using IkappaBalpha as a substrate. T" SIGNOR-250813 CSNK1E protein P49674 UNIPROT CSNK1E protein P49674 UNIPROT "down-regulates activity" phosphorylation Thr407 SRIPASQtSVPFDHL 9606 BTO:0000007 10542239 t llicata "Amino acids Ser-323, Thr-325, Thr-334, Thr-337, Ser-368, Ser-405, Thr-407, and Ser-408 in the carboxyl-terminal tail of CKIepsilon were identified as probable in vivo autophosphorylation sites. A recombinant CKIepsilon protein with serine and threonine to alanine mutations eliminating these autophosphorylation sites was 8-fold more active than wild-type CKIepsilon using IkappaBalpha as a substrate. T" SIGNOR-250814 CSNK1E protein P49674 UNIPROT BID protein P55957 UNIPROT "up-regulates activity" phosphorylation Ser64 LQTDGNRsSHSRLGR 9606 BTO:0000567 11583622 t llicata "Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid." SIGNOR-250805 CSNK1E protein P49674 UNIPROT BID protein P55957 UNIPROT "up-regulates activity" phosphorylation Thr59 EGYDELQtDGNRSSH 9606 BTO:0000567 11583622 t llicata "Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid." SIGNOR-250806 CSNK1E protein P49674 UNIPROT PER3 protein P56645 UNIPROT "down-regulates activity" phosphorylation Ser622 ILSTAMLsLGSGISQ 9534 BTO:0000298 11865049 t llicata "The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. Moreover, CKIepsilon and CKIdelta are able to induce nuclear translocation of mPer3, which requires its nuclear localization signal. The mutation in potential phosphorylation sites on mPer3 decreased the extent of both nuclear translocation and degradation of mPer3 that are stimulated by CKIepsilon. | In mut7 in which all of the conserved serine and threonine residues in this region were mutated, the ratio of the shifted band was greatly reduced reproducibly. " SIGNOR-250815 CSNK1E protein P49674 UNIPROT PER3 protein P56645 UNIPROT "down-regulates activity" phosphorylation Ser625 TAMLSLGsGISQCGY 9534 BTO:0000298 11865049 t llicata "The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. Moreover, CKIepsilon and CKIdelta are able to induce nuclear translocation of mPer3, which requires its nuclear localization signal. The mutation in potential phosphorylation sites on mPer3 decreased the extent of both nuclear translocation and degradation of mPer3 that are stimulated by CKIepsilon. | In mut7 in which all of the conserved serine and threonine residues in this region were mutated, the ratio of the shifted band was greatly reduced reproducibly. " SIGNOR-250816 CSNK1E protein P49674 UNIPROT PER3 protein P56645 UNIPROT "down-regulates activity" phosphorylation Ser628 LSLGSGIsQCGYSST 9534 BTO:0000298 11865049 t llicata "The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. Moreover, CKIepsilon and CKIdelta are able to induce nuclear translocation of mPer3, which requires its nuclear localization signal. The mutation in potential phosphorylation sites on mPer3 decreased the extent of both nuclear translocation and degradation of mPer3 that are stimulated by CKIepsilon. | In mut7 in which all of the conserved serine and threonine residues in this region were mutated, the ratio of the shifted band was greatly reduced reproducibly. " SIGNOR-250817 CSNK1E protein P49674 UNIPROT PER3 protein P56645 UNIPROT "down-regulates activity" phosphorylation Ser633 GISQCGYsSTIVHVP 9534 BTO:0000298 11865049 t llicata "The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. Moreover, CKIepsilon and CKIdelta are able to induce nuclear translocation of mPer3, which requires its nuclear localization signal. The mutation in potential phosphorylation sites on mPer3 decreased the extent of both nuclear translocation and degradation of mPer3 that are stimulated by CKIepsilon. | In mut7 in which all of the conserved serine and threonine residues in this region were mutated, the ratio of the shifted band was greatly reduced reproducibly. " SIGNOR-250818 CSNK1E protein P49674 UNIPROT PER3 protein P56645 UNIPROT "down-regulates activity" phosphorylation Ser634 ISQCGYSsTIVHVPP 9534 BTO:0000298 11865049 t llicata "The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. Moreover, CKIepsilon and CKIdelta are able to induce nuclear translocation of mPer3, which requires its nuclear localization signal. The mutation in potential phosphorylation sites on mPer3 decreased the extent of both nuclear translocation and degradation of mPer3 that are stimulated by CKIepsilon. | In mut7 in which all of the conserved serine and threonine residues in this region were mutated, the ratio of the shifted band was greatly reduced reproducibly. " SIGNOR-250819 CSNK1E protein P49674 UNIPROT PER3 protein P56645 UNIPROT "down-regulates activity" phosphorylation Thr635 SQCGYSStIVHVPPP 9534 BTO:0000298 11865049 t llicata "The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. Moreover, CKIepsilon and CKIdelta are able to induce nuclear translocation of mPer3, which requires its nuclear localization signal. The mutation in potential phosphorylation sites on mPer3 decreased the extent of both nuclear translocation and degradation of mPer3 that are stimulated by CKIepsilon. | In mut7 in which all of the conserved serine and threonine residues in this region were mutated, the ratio of the shifted band was greatly reduced reproducibly. " SIGNOR-250820 CSNK1E protein P49674 UNIPROT ROR2 protein Q01974 UNIPROT up-regulates phosphorylation 9606 15375164 t gcesareni "We also show that ror2 is phosphorylated by ckiepsilon on serine/threonine residues." SIGNOR-129117 CSNK1E protein P49674 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates phosphorylation Thr41 YSTTPGGtLFSTTPG 9606 BTO:0000150 24247720 t lperfetto "Mechanistic investigations showed that ck1_ interacted with and phosphorylated 4e-bp1 at two novel sites t41 and t50, which were essential for 4e-bp1 inactivation along with increased mrna translation and cell proliferation." SIGNOR-203240 CSNK1E protein P49674 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates phosphorylation Thr50 FSTTPGGtRIIYDRK 9606 BTO:0000150 24247720 t lperfetto "Mechanistic investigations showed that ck1_ interacted with and phosphorylated 4e-bp1 at two novel sites t41 and t50, which were essential for 4e-bp1 inactivation along with increased mrna translation and cell proliferation." SIGNOR-203276 CSNK1E protein P49674 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates phosphorylation Ser314 SREQSTDsGLGLGCY 9606 24715453 t milica "LATS1/2-mediated phosphorylation of a conserved serine in this region (Ser311 in human TAZ; Ser397 in human YAP) primes for further phosphorylation by CK1_/_ kinases (Ser314 on human TAZ; Ser400/403 in human YAP)" SIGNOR-230747 CSNK1E protein P49674 UNIPROT LEF1 protein Q9UJU2 UNIPROT down-regulates phosphorylation 9606 15747065 t gcesareni "Here, we identify ck1 and ck2 as major kinases that directly bind to and phosphorylate lef-1 inducing distinct, kinase-specific changes in the lef-1/dna complex.CK1-dependent phosphorylation inhibits, whereas ck2 activates lef-1/beta-catenin transcriptional activity in reporter gene assays." SIGNOR-134497 CSNK1E protein P49674 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates phosphorylation 9606 12000790 t lperfetto "We conclude that a major role of axin in the wnt is to provide the kinase activity that initiates the betBeta-catenin phosphorylation cascade at s45. This process is mediated by cki, the alfa, delta, or ? Isoform, all detected in association with axin by lc/ms." SIGNOR-227976 STAR protein P49675 UNIPROT cholesterol smallmolecule CHEBI:16113 ChEBI "down-regulates quantity" relocalization 17579211 t lperfetto "StAR transfers cholesterol from the outer to the inner mitochondrial membranes, where the enzyme complex of cholesterol side chain cleavage cytochrome P450 (P450scc) converts it to the first steroid, pregnenolone" SIGNOR-265727 PRLHR protein P49683 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257198 PRLHR protein P49683 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256837 PRLHR protein P49683 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256973 PRLHR protein P49683 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257089 PRLHR protein P49683 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256694 PRLHR protein P49683 UNIPROT GNA13 protein Q14344 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257280 CTCF protein P49711 UNIPROT TERT protein O14746 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 1632686 f miannu "CTCF binds the proximal exonic region of hTERT and inhibits its transcription" SIGNOR-253832 CTCF protein P49711 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 12032779 f miannu "Several different transcription factors have been implicated in the down-regulation of c-myc expression during differentiation, including C/EBPalpha, CTCF, BLIMP-1, and RFX1." SIGNOR-253827 CTCF protein P49711 UNIPROT APP protein P05067 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11706010 f miannu "Depleting HeLa cell nuclear extract of endogenous CTCF specifically reduced transcriptional activity from the APP promoter. CTCF activates transcription from the APP promoter and that the activation domain is located on the N-terminal side of the zinc finger domain." SIGNOR-253823 CTCF protein P49711 UNIPROT BCL6 protein P41182 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001690 20733034 f miannu "Inhibition of DNA methyltransferases decreased BCL6 mRNA abundance, suggesting a role for these methylated CpGs in positively regulating BCL6 transcription. The enhancer-blocking transcription factor CTCF bound to this intronic region in a methylation-sensitive manner. Depletion of CTCF by short hairpin RNA in neoplastic plasma cells that do not express BCL6 resulted in up-regulation of BCL6 transcription." SIGNOR-253824 CTCF protein P49711 UNIPROT RARRES1 protein P49788 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000356 22615834 f miannu "Epigenetic repression of RARRES1 is mediated by methylation of a proximal promoter and a loss of CTCF binding. knocking-down CTCF expression hampered RARRES1 expression, suggesting CTCF positively regulated RARRES1 transcription presumably by binding to unmethylated promoter poised at transcription-ready state." SIGNOR-253831 CTCF protein P49711 UNIPROT MGAT5B protein Q3V5L5 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001976 21771782 f miannu "By EMSA and ChIP analyses we identified two regulatory proteins, NeuroD1 and CTCF that bind to and activate the GnT-IX promoter. We also revealed that GnT-IX expression was suppressed in CTCF- and NeuroD1-depleted cells, indicating that a NeuroD1- and CTCF-dependent epigenetic mechanism governs brain-specific GnT-IX expression." SIGNOR-253826 CEBPA protein P49715 UNIPROT PER2 protein O15055 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22260161 f apalma "We have previously shown that PER2 is a downstream CCAAT-enhancer-binding protein (C/EBP)-target gene, and its disruption might be involved in the initiation and progression of acute myelogenous leukemia (AML)" SIGNOR-256369 CEBPA protein P49715 UNIPROT F9 protein P00740 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 8075306 f "Transactivation by the CCAAT/enhancer binding protein alpha of the wild-type and mutated factor IX promoter (-192 to +38) resulted in an approximately four-fold and approximately two-fold, respectively, increase of CAT activity" SIGNOR-254040 CEBPA protein P49715 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 12032779 f miannu "Several different transcription factors have been implicated in the down-regulation of c-myc expression during differentiation, including C/EBPalpha, CTCF, BLIMP-1, and RFX1." SIGNOR-253830 CEBPA protein P49715 UNIPROT S100A9 protein P06702 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001370 9706399 t "Among several known transcription factor binding motifs, nuclear protein(s) of VD3-treated HL-60 cells and THP-1 cells bound to the CCAAT/enhancer binding protein (C/EBP)-binding motif that was located in the upstream region of the MRP14 gene (-81), as evidenced by the competitive gel mobility-shift assay.|Thus, it was concluded that C/EBP alpha and -beta were able to bind to the C/EBP motif, and that C/EBP alpha bound to the motif in THP-1 cells and C/EBP beta bound to that in the VD3-treated HL-60 cells." SIGNOR-254041 CEBPA protein P49715 UNIPROT ELANE protein P08246 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004408 19620402 f miannu "The ELA2 gene promoter is positively regulated by the direct binding of LEF-1 or C/EBPalpha, documenting the role of LEF1 in the diminished ELA2 expression." SIGNOR-253769 CEBPA protein P49715 UNIPROT SPI1 protein P17947 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 14592841 t "Activation of C/EBPα induces PU.1 expression, cell cycle arrest, and differentiation in 32D cells expressing FLT3/ITD" SIGNOR-261531 CEBPA protein P49715 UNIPROT SPI1 protein P17947 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 17671233 f irozzo "C/EBPα binds and activates the PU.1 distal enhancer to induce monocyte lineage commitment.Transcriptional induction of PU.1 by C/EBPα may play a role in myeloid lineage specification." SIGNOR-256055 CEBPA protein P49715 UNIPROT USF1 protein P22415 UNIPROT "up-regulates activity" binding 9606 BTO:0004116 7862113 t irozzo "Our studies show that the human C/EBPa protein stimulates USF to bind to a USF consensus element within C/EBPa promoter and activates it by two- to threefold.The mechanism by which C/EBPa enhances USF binding and transactivation is currently under study." SIGNOR-255701 CEBPA protein P49715 UNIPROT SFTPD protein P35247 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001910 11912209 t "Cotransfection of C/EBPalpha, C/EBPbeta, or C/EBPdelta cDNA in H441 lung adenocarcinoma cells significantly increased the luciferase activity of a wild-type SP-D promoter construct containing 698 bp of upstream sequence (SS698). Transfection of C/EBP also increased the level of endogenous SP-D mRNA in H441 cells| Thus, interactions among C/EBP elements in the near-distal promoter can modulate the promoter activity of SP-D." SIGNOR-254042 CEBPA protein P49715 UNIPROT STAR protein P49675 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003697 18583320 t "Electrophoretic mobility shift assay demonstrated that this region of the StAR promoter was bound by C/EBPalpha, C/EBPbeta, and CREB. Forced expression of either C/EBPalpha or C/EBPbeta alone was sufficient to up-regulate StAR promoter activity whereas PGE(2) was needed to induce StAR promoter activity in CREB-overexpressed cells." SIGNOR-254043 CEBPA protein P49715 UNIPROT CEBPA protein P49715 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 BTO:0001056 11283671 t apalma "Here, we demonstrate that C/EBPα indeed activates its promoter in transient transfection assays in myeloid cells." SIGNOR-255673 CEBPA protein P49715 UNIPROT HAMP protein P81172 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001950 18671304 f miannu "HCV-induced ROS stabilized the expression of two negative hepcidin regulators, HIF1alpha and HIF2alpha, and its expression was decreased by a HDAC inhibitor or an anti-oxidant. HCV-induced ROS also caused hypoacetylation of histones and inhibited binding of two positive regulators, C/EBPalpha and STAT3, to the hepcidin promoter, whereas anti-oxidant treatment of cells recovered C/EBPalpha and STAT3 binding to the hepcidin promoter." SIGNOR-253770 CEBPA protein P49715 UNIPROT SOX4 protein Q06945 UNIPROT down-regulates "transcriptional regulation" 9606 BTO:0001271 24183681 t apalma "In summary, our data demonstrate that C/EBPα negatively regulates Sox4 transcription via direct DNA-binding." SIGNOR-255675 CEBPD protein P49716 UNIPROT MSTN protein O14793 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 24011072 f 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 CEBPD protein P49716 UNIPROT SOD1 protein P00441 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000792 20385105 f miannu "Expression of CEBPD reduced cisplatin-induced reactive oxygen species (ROS) and apoptosis in NTUB1 cells by inducing the expression of Cu/Zn-superoxide dismutase (SOD1) via direct promoter transactivation." SIGNOR-253774 CEBPD protein P49716 UNIPROT CXCL1 protein P09341 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000801 23028973 f "CEBPD activated in macrophages played a functional role in promoting the tube formation of endothelial cells and the migration and proliferation of synoviocytes. In vivo DNA binding assays and reporter assays showed that CEBPD up-regulated CCL20, CXCL1, IL23A and TNFAIP6 transcripts through direct binding to their promoter regions." SIGNOR-254060 CEBPD protein P49716 UNIPROT PPARG protein P37231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000011 10649448 f 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 CEBPD protein P49716 UNIPROT CCL20 protein P78556 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000801 23028973 f "CEBPD activated in macrophages played a functional role in promoting the tube formation of endothelial cells and the migration and proliferation of synoviocytes. In vivo DNA binding assays and reporter assays showed that CEBPD up-regulated CCL20, CXCL1, IL23A and TNFAIP6 transcripts through direct binding to their promoter regions." SIGNOR-254056 CEBPD protein P49716 UNIPROT TNFAIP6 protein P98066 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000801 23028973 f "CEBPD activated in macrophages played a functional role in promoting the tube formation of endothelial cells and the migration and proliferation of synoviocytes. In vivo DNA binding assays and reporter assays showed that CEBPD up-regulated CCL20, CXCL1, IL23A and TNFAIP6 transcripts through direct binding to their promoter regions." SIGNOR-254057 CEBPD protein P49716 UNIPROT KLF5 protein Q13887 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 16054042 f 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 CEBPD protein P49716 UNIPROT IL23A protein Q9NPF7 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000801 23028973 f "CEBPD activated in macrophages played a functional role in promoting the tube formation of endothelial cells and the migration and proliferation of synoviocytes. In vivo DNA binding assays and reporter assays showed that CEBPD up-regulated CCL20, CXCL1, IL23A and TNFAIP6 transcripts through direct binding to their promoter regions." SIGNOR-254061 PSMB3 protein P49720 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "form complex" binding 9606 BTO:0000007 29636472 t lperfetto "Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line" SIGNOR-263359 PSMB2 protein P49721 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "form complex" binding 9606 BTO:0000007 29636472 t lperfetto "Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line" SIGNOR-263358 TMED10 protein P49755 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates binding 9606 16641999 t gcesareni "Here we report that tmp21, a member of the p24 cargo protein family, is a component of presenilin complexes and differentially regulates gamma-secretase cleavage" SIGNOR-146364 NUMB protein P49757 UNIPROT TP53 protein P04637 UNIPROT up-regulates binding 9606 BTO:0000150 18492217 t gcesareni "Numb can actually interact in vivo with endogenous mdm2 and p53, resulting in a trimeric complex between the three proteins [10]. This interaction appears to regulate the stability of p53, as reduction of numb levels by rna interference (rnai) causes a decrease in the half-life of p53 and consequently a reduction in steady-state levels of the protein. Consistent with this observation, overexpression of numb increases the level of p53 in both unstressed and stressed cells." SIGNOR-178668 NUMB protein P49757 UNIPROT TP53 protein P04637 UNIPROT up-regulates 9606 20940030 f gcesareni "Numb interacts with mdm2, and inhibits its ubiquitin-ligase function on tp53 (which in itself is inhibitory for tp53), thus numb activates (b) tp53." SIGNOR-168457 NUMB protein P49757 UNIPROT GLI1 protein P08151 UNIPROT down-regulates binding 9606 20818436 t gcesareni "The consequent activation of_ itch, together with the recruitment of gli1 through direct binding with_ numb, allows gli1 to enter into the complex, resulting in gli1 ubiquitination and degradation." SIGNOR-167841 NUMB protein P49757 UNIPROT NOTCH1 protein P46531 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 12682059 t lperfetto "Mammalian numb proteins promote notch1 receptor ubiquitination and degradation of the notch1 intracellular domain" SIGNOR-99762 NUMB protein P49757 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates binding 9606 20940030 t gcesareni "Numb interacts with mdm2, and inhibits its ubiquitin-ligase function on tp53 (which in itself is inhibitory for tp53), thus numb activates (b) tp53" SIGNOR-168454 NUMB protein P49757 UNIPROT ITCH protein Q96J02 UNIPROT up-regulates binding 9606 20818436 t gcesareni "Numb activates the catalytic activity of itch, releasing it from an inhibitory intramolecular interaction between its homologous to e6-ap c-terminus and ww domains." SIGNOR-167844 NUMB protein P49757 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates BTO:0001103 12361602 t 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 NUMB protein P49757 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates BTO:0001103 12361602 t 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 CLK1 protein P49759 UNIPROT ABL1 protein P00519 UNIPROT down-regulates phosphorylation Thr735 DTEWRSVtLPRDLQS 9606 18794806 t lperfetto "Here, we identify clk1, clk4, mst1, mst2 and ttk (also known as mps1) as novel thr735 kinases in vitro / phosphorylation of thr735 in c-abl is critical for binding to 14-3-3" SIGNOR-181031 CLK1 protein P49759 UNIPROT PTPN1 protein P18031 UNIPROT "up-regulates activity" phosphorylation Ser242 MDKRKDPsSVDIKKV -1 10480872 t llicata "The CLK family kinases, CLK1 and CLK2, phosphorylate and activate the tyrosine phosphatase, PTP-1B. | although CLK1 and CLK2 directly phosphorylate PTP-1B on both Ser50 and Ser242/Ser243, the preferred CLK phosphorylation site is Ser50, as it is preferentially phosphorylated at an approximate ratio of 9:1 over the Ser242/Ser243 site." SIGNOR-250773 CLK1 protein P49759 UNIPROT PTPN1 protein P18031 UNIPROT "up-regulates activity" phosphorylation Ser243 DKRKDPSsVDIKKVL -1 10480872 t llicata "The CLK family kinases, CLK1 and CLK2, phosphorylate and activate the tyrosine phosphatase, PTP-1B. | although CLK1 and CLK2 directly phosphorylate PTP-1B on both Ser50 and Ser242/Ser243, the preferred CLK phosphorylation site is Ser50, as it is preferentially phosphorylated at an approximate ratio of 9:1 over the Ser242/Ser243 site." SIGNOR-250774 CLK1 protein P49759 UNIPROT PTPN1 protein P18031 UNIPROT "up-regulates activity" phosphorylation Ser50 RNRYRDVsPFDHSRI 9606 10480872 t gcesareni "The clk family kinases, clk1 and clk2, phosphorylate and activate the tyrosine phosphatase, ptp-1b.|Phosphorylation of PTP-1B at Ser(50) by CLK1 or CLK2 is responsible for its enzymatic activation." SIGNOR-70563 CLK1 protein P49759 UNIPROT RBM17 protein Q96I25 UNIPROT "up-regulates activity" phosphorylation Ser202 EEDSRPRsQSSKAAI 9534 BTO:0001538 23519612 t miannu "In this work, we show that Cdc2-like kinase 1 (Clk1) phosphorylates SPF45 on eight serine residues. Clk1 promotes SPF45-induced exon 6 exclusion" SIGNOR-262705 CLK1 protein P49759 UNIPROT RBM17 protein Q96I25 UNIPROT "up-regulates activity" phosphorylation Ser204 DSRPRSQsSKAAIPP 9534 BTO:0001538 23519612 t miannu "In this work, we show that Cdc2-like kinase 1 (Clk1) phosphorylates SPF45 on eight serine residues." SIGNOR-262706 CLK1 protein P49759 UNIPROT RBM17 protein Q96I25 UNIPROT "up-regulates activity" phosphorylation Ser222 EEQDRPRsPTGPSNS 9534 BTO:0001538 23519612 t miannu "In this work, we show that Cdc2-like kinase 1 (Clk1) phosphorylates SPF45 on eight serine residues." SIGNOR-262707 CLK1 protein P49759 UNIPROT RBM17 protein Q96I25 UNIPROT "up-regulates activity" phosphorylation Ser266 QGLSTALsVEKTSKR 9534 BTO:0001538 23519612 t miannu "In this work, we show that Cdc2-like kinase 1 (Clk1) phosphorylates SPF45 on eight serine residues." SIGNOR-262708 CLK1 protein P49759 UNIPROT RBM17 protein Q96I25 UNIPROT "up-regulates activity" phosphorylation Ser288 DATEKDAsKKSDSNP 9534 BTO:0001538 23519612 t miannu "In this work, we show that Cdc2-like kinase 1 (Clk1) phosphorylates SPF45 on eight serine residues." SIGNOR-262709 CLK1 protein P49759 UNIPROT RBM17 protein Q96I25 UNIPROT "up-regulates activity" phosphorylation Ser291 EKDASKKsDSNPLTE 9534 BTO:0001538 23519612 t miannu "In this work, we show that Cdc2-like kinase 1 (Clk1) phosphorylates SPF45 on eight serine residues." SIGNOR-262710 CLK1 protein P49759 UNIPROT RBM17 protein Q96I25 UNIPROT "up-regulates activity" phosphorylation Ser48 KSQRTKQsTVLAPVI 9534 BTO:0001538 23519612 t miannu "In this work, we show that Cdc2-like kinase 1 (Clk1) phosphorylates SPF45 on eight serine residues." SIGNOR-262711 CLK1 protein P49759 UNIPROT RBM17 protein Q96I25 UNIPROT "up-regulates activity" phosphorylation Ser62 IDLKRGGsSDDRQIV 9534 BTO:0001538 23519612 t miannu "In this work, we show that Cdc2-like kinase 1 (Clk1) phosphorylates SPF45 on eight serine residues." SIGNOR-262712 CLK2 protein P49760 UNIPROT PTPN1 protein P18031 UNIPROT "up-regulates activity" phosphorylation Ser242 MDKRKDPsSVDIKKV -1 10480872 t llicata "The CLK family kinases, CLK1 and CLK2, phosphorylate and activate the tyrosine phosphatase, PTP-1B. | although CLK1 and CLK2 directly phosphorylate PTP-1B on both Ser50 and Ser242/Ser243, the preferred CLK phosphorylation site is Ser50, as it is preferentially phosphorylated at an approximate ratio of 9:1 over the Ser242/Ser243 site." SIGNOR-250775 CLK2 protein P49760 UNIPROT PTPN1 protein P18031 UNIPROT "up-regulates activity" phosphorylation Ser243 DKRKDPSsVDIKKVL -1 10480872 t llicata "The CLK family kinases, CLK1 and CLK2, phosphorylate and activate the tyrosine phosphatase, PTP-1B. | although CLK1 and CLK2 directly phosphorylate PTP-1B on both Ser50 and Ser242/Ser243, the preferred CLK phosphorylation site is Ser50, as it is preferentially phosphorylated at an approximate ratio of 9:1 over the Ser242/Ser243 site." SIGNOR-250776 CLK2 protein P49760 UNIPROT PTPN1 protein P18031 UNIPROT "up-regulates activity" phosphorylation Ser50 RNRYRDVsPFDHSRI 9606 10480872 t gcesareni "The clk family kinases, clk1 and clk2, phosphorylate and activate the tyrosine phosphatase, ptp-1b.|Phosphorylation of PTP-1B at Ser(50) by CLK1 or CLK2 is responsible for its enzymatic activation." SIGNOR-70603 CLK2 protein P49760 UNIPROT CLK2 protein P49760 UNIPROT up-regulates phosphorylation Ser142 HSSRRAKsVEDDAEG 9606 BTO:0000567 20682768 t lperfetto "Clk2 was reported to regulate its nuclear localization by autophosphorylating serine 141" SIGNOR-167344 VEGFC protein P49767 UNIPROT NRP2 protein O60462 UNIPROT up-regulates binding 9606 BTO:0000938 16816121 t gcesareni "The functional importance of the interaction of np2 with the lymphangiogenic growth factors was demonstrated by cointernalization of np2 along with vegfr-3 in endocytic vesicles of lymphatic endothelial cells upon stimulation with vegf-c or vegf-d." SIGNOR-147611 VEGFC protein P49767 UNIPROT FLT4 protein P35916 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103;BTO:0000763 9435229 t gcesareni "Vegf-c, was isolated as a ligand for the tyrosine kinase vegfr-3 (flt4)" SIGNOR-55205 VEGFC protein P49767 UNIPROT KDR protein P35968 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103;BTO:0000763 9435229 t gcesareni "Vegf-c is also a ligand for vegfr-2 (12), but the functional significance of this potential interaction in vivo is unknown" SIGNOR-55208 PSEN1 protein P49768 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 2195779 t gcesareni "Importantly, our data show that binding of ps1 to cadherin mediates the effects of ps1 on the phosphorylation, ubiquitination, and destabilization of beta-catenin. Thus, cadherins mediate both the association of ps1 and beta-catenin and the effects of ps1 on the cellular levels of beta-catenin" SIGNOR-22837 PSEN1 protein P49768 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates cleavage 9606 SIGNOR-C98 10593990 t "Gamma secretase subunit that leads a proteolitic cleavage through Asp257 and Asp385 after transport to cell surface." gcesareni "Presenilin-1 (ps1), a polytopic membrane protein primarily localized to the endoplasmic reticulum, is required for efficient proteolysis of both notch and beta-amyloid precursor protein (app) within their trans- membrane domains." SIGNOR-72886 PSEN1 protein P49768 UNIPROT gamma-secretase complex SIGNOR-C98 SIGNOR "form complex" binding 9606 25610395 t lperfetto "-Secretase is a four subunit, 19-pass transmembrane enzymeBiochemical studies indicated that -secretase activity is catalyzed by the presenilin (PS)-containing macromolecular complex (Li et al., 2000a). The search for other components of the complex revealed three additional proteins: nicastrin (Nct), anterior pharynx-defective-1 (Aph-1), and presenilin enhancer-2 (Pen-2)" SIGNOR-209705 PSEN1 protein P49768 UNIPROT gamma-secretase complex SIGNOR-C98 SIGNOR up-regulates cleavage 9606 10497236 t "Gamma secretase subunit that leads a proteolitic cleavage through Asp257 and Asp385 after transport to cell surface." lperfetto "Presenilin-1 (ps1), a polytopic membrane protein primarily localized to the endoplasmic reticulum, is required for efficient proteolysis of both notch and beta-amyloid precursor protein (app) within their trans- membrane domains." SIGNOR-217746 PSEN1 protein P49768 UNIPROT gamma-secretase complex SIGNOR-C98 SIGNOR up-regulates cleavage 9606 10593990 t "Gamma secretase subunit that leads a proteolitic cleavage through Asp257 and Asp385 after transport to cell surface." lperfetto "Presenilin-1 (ps1), a polytopic membrane protein primarily localized to the endoplasmic reticulum, is required for efficient proteolysis of both notch and beta-amyloid precursor protein (app) within their trans- membrane domains." SIGNOR-217743 PSEN1 protein P49768 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates cleavage 9606 SIGNOR-C98 10593990 t "Gamma secretase subunit that leads a proteolitic cleavage through Asp257 and Asp385 after transport to cell surface." gcesareni "Presenilin-1 (ps1), a polytopic membrane protein primarily localized to the endoplasmic reticulum, is required for efficient proteolysis of both notch and beta-amyloid precursor protein (app) within their trans- membrane domains." SIGNOR-254308 FLT3LG protein P49771 UNIPROT FLT3 protein P36888 UNIPROT up-regulates binding 9606 BTO:0001271 12681969 t gcesareni "Flt3 is activated by binding of its natural flt3-ligand (flt3-l)," SIGNOR-99750 FHIT protein P49789 UNIPROT BIRC5 protein O15392 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 18077326 f miannu "In binding to the beta-catenin c-terminal domain, fhit represses transcription of target genes such as cyclin d1, axin2, mmp-14, and survivin." SIGNOR-159870 FHIT protein P49789 UNIPROT TP53 protein P04637 UNIPROT up-regulates 9606 BTO:0000551 15313915 f miannu "We found that this synergistic inhibition of tumor cell growth corresponded with the fhit-mediated inactivation of mdm2, which thereby blocked the association of mdm2 with p53, thus stabilizing the p53 protein." SIGNOR-127915 FHIT protein P49789 UNIPROT AKT1 protein P31749 UNIPROT down-regulates 9606 BTO:0000551 16407838 f miannu "Fhit inhibited activity of akt, a key effector in the phosphatidylinositol 3-oh kinase (pi3k) pathway;loss of endogenous fhit expression caused increased akt activity in vitro and in vivo, and overexpression of constitutively active akt inhibited fhit-induced apoptosis" SIGNOR-252625 FHIT protein P49789 UNIPROT AKT2 protein P31751 UNIPROT down-regulates 9606 BTO:0000551 16407838 f miannu "Fhit inhibited activity of akt, a key effector in the phosphatidylinositol 3-oh kinase (pi3k) pathway;loss of endogenous fhit expression caused increased akt activity in vitro and in vivo, and overexpression of constitutively active akt inhibited fhit-induced apoptosis" SIGNOR-143703 FHIT protein P49789 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 18077326 t miannu "Fhit interacts with _-catenin in vitro and in vivo / the tumor suppressor fhit acts as a repressor of _-catenin transcriptional activity" SIGNOR-159873 FHIT protein P49789 UNIPROT MMP14 protein P50281 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 18077326 f miannu "In binding to the beta-catenin c-terminal domain, fhit represses transcription of target genes such as cyclin d1, axin2, mmp-14, and survivin." SIGNOR-159876 FHIT protein P49789 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates 9606 BTO:0000551 15313915 f miannu "We found that this synergistic inhibition of tumor cell growth corresponded with the fhit-mediated inactivation of mdm2, which thereby blocked the association of mdm2 with p53, thus stabilizing the p53 protein." SIGNOR-127610 FHIT protein P49789 UNIPROT AKT3 protein Q9Y243 UNIPROT down-regulates 9606 BTO:0000551 16407838 f miannu "Fhit inhibited activity of akt, a key effector in the phosphatidylinositol 3-oh kinase (pi3k) pathway;loss of endogenous fhit expression caused increased akt activity in vitro and in vivo, and overexpression of constitutively active akt inhibited fhit-induced apoptosis" SIGNOR-143706 FHIT protein P49789 UNIPROT AXIN2 protein Q9Y2T1 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 18077326 f miannu "In binding to the beta-catenin c-terminal domain, fhit represses transcription of target genes such as cyclin d1, axin2, mmp-14, and survivin." SIGNOR-159867 FHIT protein P49789 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates 9606 BTO:0000551 16407838 f miannu "Fhit inhibited activity of akt, a key effector in the phosphatidylinositol 3-oh kinase (pi3k) pathway;loss of endogenous fhit expression caused increased akt activity in vitro and in vivo, and overexpression of constitutively active akt inhibited fhit-induced apoptosis" SIGNOR-143700 NUP153 protein P49790 UNIPROT NPC complex SIGNOR-C263 SIGNOR "form complex" binding 27016207 t lperfetto "The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2)." SIGNOR-262069 RANBP2 protein P49792 UNIPROT CDKN1B protein P46527 UNIPROT "down-regulates quantity" relocalization 9606 BTO:0002932 28882106 t irozzo "RanBP2 can increase the sumoylation of p27kip1. In our study, the target protein p27kip1 mainly acts as a tumor-suppressor gene in the nucleus, RanBP2 and SUMO1 act as oncogenes by promoting the nuclear-cytoplasmic translocation and debilitate the G1-arrest brought by p27kip1 accumulation in the nucleus." SIGNOR-259115 RANBP2 protein P49792 UNIPROT BICD2 protein Q8TD16 UNIPROT "up-regulates quantity" relocalization 9606 BTO:0000567 20386726 t irozzo "We show that the dynein/dynactin adaptor BICD2 is specifically recruited to the NPC in G2phase through a direct interaction with the NPC componentRanBP2." SIGNOR-259122 RANBP2 protein P49792 UNIPROT TNPO1 protein Q92973 UNIPROT "up-regulates activity" binding 9606 BTO:0001938 32161167 t lperfetto "Nup358(806–1306), but not other regions, efficiently recruits importin β and transportin 1" SIGNOR-262111 RANBP2 protein P49792 UNIPROT NPC complex SIGNOR-C263 SIGNOR "form complex" binding 27016207 t lperfetto "The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2)." SIGNOR-262088 TSC2 protein P49815 UNIPROT MTOR protein P42345 UNIPROT "down-regulates activity" 9606 BTO:0000007;BTO:0001938 12271141 f lperfetto "These findings strongly implicate the tuberin-hamartin tumor suppressor complex as an inhibitor of mtor" SIGNOR-93133 TSC2 protein P49815 UNIPROT RHEB protein Q15382 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000142 15340059 t lperfetto "Tsc2 functions as a gap to inhibit rheb activity. Tsc2 displays gap (gtpase-activating protein) activity specifically towards the small g protein rheb and inhibits its ability to stimulate the mtor signaling pathway. It has recently been shown that tsc2 has gtpase-activating protein (gap) activity towards the ras family small gtpase rheb (ras homolog enriched in brain), and tsc1/2 antagonizes the mtor signaling pathway via stimulation of gtp hydrolysis of rheb." SIGNOR-128432 TSC2 protein P49815 UNIPROT TSC1 protein Q92574 UNIPROT "up-regulates activity" binding 9606 BTO:0000142;BTO:0000671 10807585 t lperfetto "Furthermore, tsc2 is directly phosphorylated by akt, which is involved in stimulating cell growth and is activated by growth stimulating signals, such as insulin. Tsc2 is inactivated by akt-dependent phosphorylation, which destabilizes tsc2 and disrupts its interaction with tsc1." SIGNOR-77400 TSC2 protein P49815 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT down-regulates 9606 12172553 f gcesareni "Here, we show that tsc1-tsc2 inhibits the p70 ribosomal protein s6 kinase 1 (an activator of translation) and activates the eukaryotic initiation factor 4e binding protein 1 (4e-bp1, an inhibitor of translational initiation)." SIGNOR-91395 TSC2 protein P49815 UNIPROT TSC1/TSC2 complex SIGNOR-C101 SIGNOR "form complex" binding 9606 12172553 t lperfetto "TSC1 and TSC2 proteins form a physical and functional complex in vivo. Here, we show that TSC1-TSC2 inhibits the p70 ribosomal protein S6 kinase 1 (an activator of translation) and activates the eukaryotic initiation factor 4E binding protein 1 (4E-BP1, an inhibitor of translational initiation). These functions of TSC1-TSC2 are mediated by inhibition of the mammalian target of rapamycin (mTOR)." SIGNOR-217913 NDUFV1 protein P49821 UNIPROT "Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24]." SIGNOR-262183 GSK3A protein P49840 UNIPROT ANKRD28 protein O15084 UNIPROT "down-regulates activity" phosphorylation Ser1007 INRYTNTsKTVSFEA -1 phosphorylation:Ser1011 TNTSKTVsFEALPIM 17023142 t lperfetto "We provide evidence for a dual kinase-mediated regulation of the PITK holoenzyme whereby PITK phosphorylation at S1017 is catalyzed by calcium/calmodulin-dependent kinase II-delta (CaMKIIdelta), promoting the subsequent phosphorylation of S1013 by glycogen synthase kinase-3 (GSK3) in vitro.|the phosphorylation of PITK at these specific residues altered PP1 binding and subsequent PITK-directed dephosphorylation of hnRNP K" SIGNOR-264792 GSK3A protein P49840 UNIPROT MITF protein O75030 UNIPROT up-regulates phosphorylation Ser405 QARAHGLsLIPSTGL 9606 10587587 t "The effect has been demonstrated using O75030-9" gcesareni "Glycogen synthase kinase 3 (gsk3) was found to phosphorylate ser298 in vitro, thereby enhancing the binding of mitf to the tyrosinase promoter" SIGNOR-72878 GSK3A protein P49840 UNIPROT MAF protein O75444 UNIPROT down-regulates phosphorylation 9606 18042454 t miannu "We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity." SIGNOR-159361 GSK3A protein P49840 UNIPROT MAF protein O75444 UNIPROT up-regulates phosphorylation 9606 18042454 t miannu "We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity." SIGNOR-159358 GSK3A protein P49840 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr58 KKFELLPtPPLSPSR 9606 16023596 t gcesareni "Similar to c-myc, similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation." SIGNOR-138596 GSK3A protein P49840 UNIPROT JUN protein P05412 UNIPROT down-regulates phosphorylation 9606 16023596 t gcesareni "Similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation." SIGNOR-138592 GSK3A protein P49840 UNIPROT JUN protein P05412 UNIPROT down-regulates phosphorylation Ser249 LSPIDMEsQERIKAE 9606 1846781 t lperfetto "Phosphorylation of recombinant human c-jun proteins in vitro by gsk-3 decreases their dna-binding activity." SIGNOR-21780 GSK3A protein P49840 UNIPROT JUN protein P05412 UNIPROT down-regulates phosphorylation Thr239 VPEMPGEtPPLSPID 9606 1846781 t lperfetto "Phosphorylation of recombinant human c-jun proteins in vitro by gsk-3 decreases their dna-binding activity." SIGNOR-21784 GSK3A protein P49840 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation 9606 BTO:0000938 7566348 t fstefani "The ability of p42 map and p44 map kinases, glycogen synthase kinases 3 alpha and 3 beta (gsk-3 alpha and gsk-3 beta) to phosphorylate tau in transfected cos cells was investigated. Both gsk-3 alpha and gsk-3 beta phosphorylated tau to produce a phf-like state of phosphorylation but the map kinases failed to induce such a transformation in tau." SIGNOR-29364 GSK3A protein P49840 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser579 NVKSKIGsTENLKHQ 9606 BTO:0000938 9771888 t "The effect has been demonstrated using P10636-8" gcesareni "Tau is phosphorylated by gsk-3 at several sites found in alzheimer disease and its biological activity markedly inhibited only after it is prephosphorylated by a-kinase." SIGNOR-60651 GSK3A protein P49840 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser641 KVTSKCGsLGNIHHK 9606 BTO:0000590 7706316 t lperfetto "Microtubule-associated protein/microtubule affinity-regulating kinase (p110mark). A novel protein kinase that regulates tau-microtubule interactions and dynamic instability by phosphorylation at the Alzheimer-specific site serine 262." SIGNOR-249342 GSK3A protein P49840 UNIPROT UNG protein P13051 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser64 EPGTPPSsPLSAEQL 9606 BTO:0000812 27875297 t lperfetto "Here we show that glycogen synthase kinase 3 (GSK-3) interacts with and phosphorylates UNG2 at Thr60 and that Thr60 phosphorylation requires a Ser64 priming phosphorylation event.|phosphorylation of Thr60 and Ser64 creates a cyclin E/c-Myc-like phosphodegron that promotes polyubiquitylation and proteasome-mediated degradation" SIGNOR-264886 GSK3A protein P49840 UNIPROT UNG protein P13051 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr60 AGQEEPGtPPSSPLS 9606 BTO:0000812 phosphorylation:Ser64 EPGTPPSsPLSAEQL 27875297 t lperfetto "Here we show that glycogen synthase kinase 3 (GSK-3) interacts with and phosphorylates UNG2 at Thr60 and that Thr60 phosphorylation requires a Ser64 priming phosphorylation event.|phosphorylation of Thr60 and Ser64 creates a cyclin E/c-Myc-like phosphodegron that promotes polyubiquitylation and proteasome-mediated degradation" SIGNOR-264887 GSK3A protein P49840 UNIPROT GYS1 protein P13807 UNIPROT down-regulates phosphorylation Ser641 YRYPRPAsVPPSPSL 9606 BTO:0000887;BTO:0001103 14593110 t gcesareni "Glycogen synthase kinase-3 (gsk-3) phosphorylates four serine residues in the cooh terminus of glycogen synthase. Phosphorylation of one of these residues, ser640 (site 3a), causes strong inactivation of glycogen synthase" SIGNOR-118927 GSK3A protein P49840 UNIPROT SFPQ protein P23246 UNIPROT down-regulates phosphorylation Thr687 PRGMGPGtPAGYGRG 9606 20932480 t miannu "Here we demonstrate that in resting tcells psf is directly phosphorylated by gsk3, thus promoting interaction of psf with trap150, which prevents psf from binding cd45 pre-mrna. Upon tcell activation, reduced gsk3 activity leads to reduced psf phosphorylation, releasing psf from trap150 and allowing it to bind cd45 splicing regulatory elements and repress exon inclusion." SIGNOR-168382 GSK3A protein P49840 UNIPROT SFPQ protein P23246 UNIPROT down-regulates phosphorylation 9606 20932480 t miannu "Psf is directly phosphorylated by gsk3, thus promoting interaction of psf with trap150, which prevents psf from binding cd45 pre-mrna. / threonine phosphorylation of psf by gsk3 primarily occurs on residue t687" SIGNOR-168385 GSK3A protein P49840 UNIPROT FCAR protein P24071 UNIPROT "down-regulates activity" phosphorylation Ser284 LTFARTPsVCK 10090 BTO:0001516 30766540 t lperfetto "GSK-3 is constitutively active in the absence of cytokine stimulation and can phosphorylate S263, keeping FcalphaRI in the inactive state." SIGNOR-264856 GSK3A protein P49840 UNIPROT AKT1 protein P31749 UNIPROT "down-regulates activity" phosphorylation Thr312 TMKTFCGtPEYLAPE 10090 BTO:0005655 23142783 t gcesareni "GSK3_ negatively regulates AKT activation by phosphorylating AKT at T312 in the substrate binding site, which inhibited IL-1-induced AKT activation and function." SIGNOR-252434 GSK3A protein P49840 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates phosphorylation 9606 19214430 t gcesareni "Taken together, our results indicate that gsk-3alfa is a negative regulator of notch1/nicd." SIGNOR-183969 GSK3A protein P49840 UNIPROT TSC2 protein P49815 UNIPROT up-regulates phosphorylation 9606 phosphorylation:Ser1387 QPLSKSSsSPELQTL 16959574 t gcesareni "Gsk3 inhibits the mtor pathway by phosphorylating tsc2 in a manner dependent on ampk-priming phosphorylation." SIGNOR-149377 GSK3A protein P49840 UNIPROT TSC2 protein P49815 UNIPROT up-regulates phosphorylation 9606 phosphorylation:Ser1387 QPLSKSSsSPELQTL 20226003 t gcesareni "Gsk3 inhibits the mtor pathway by phosphorylating tsc2 in a manner dependent on ampk-priming phosphorylation." SIGNOR-164098 GSK3A protein P49840 UNIPROT GSK3A protein P49840 UNIPROT up-regulates phosphorylation Tyr279 RGEPNVSyICSRYYR 9606 BTO:0000527 18701488 t gcesareni "Gsk3a is activated by phosphorylation at tyr-279." SIGNOR-180035 GSK3A protein P49840 UNIPROT RELA protein Q04206 UNIPROT "up-regulates activity" phosphorylation Thr254 RQVAIVFRtPPYADPS 10090 BTO:0000249 22761446 t "Redundant functions of GSK-3_ and GSK-3_ through phosphorylation of RelA at Thr-254 play a crucial role in early stages of chondrocyte differentiation" SIGNOR-255827 GSK3A protein P49840 UNIPROT MCL1 protein Q07820 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser159 NNTSTDGsLPSTPPP 9606 BTO:0000567 16543145 t " MCL-1 was phosphorylated by GSK-3 at a conserved GSK-3 phosphorylation site (S159). Glycogen Synthase Kinase-3 Regulates Mitochondrial Outer Membrane Permeabilization and Apoptosis by Destabilization of MCL-1. threonine 163, which represents the GSK-3 priming phosphorylation in this protein" SIGNOR-251217 GSK3A protein P49840 UNIPROT EIF2B5 protein Q13144 UNIPROT "down-regulates activity" phosphorylation Ser540 MDSEEPDsRGGSPQM 9606 BTO:0000007 11500362 t "We identify multiple phosphorylation sites in the largest, catalytic, subunit (epsilon) of mammalian eIF2B. Glycogen synthase kinase 3 (GSK3) is responsible for phosphorylating Ser535. This regulatory phosphorylation event requires both the fourth site (Ser539) and a distal region, which acts to recruit GSK3 to eIF2Bepsilon in vivo. eIF2Bϵ from mammals or insects is a substrate for glycogen synthase kinase 3 (GSK3), and this inhibits the activity of eIF2B" SIGNOR-251215 GSK3A protein P49840 UNIPROT PKD2 protein Q13563 UNIPROT unknown phosphorylation Ser76 AGAAASPsPPLSSCS 9606 BTO:0000007 BTO:0000671 16551655 t llicata "We report the identification of a new phosphorylation site for pc2 within its n-terminal domain (ser(76)) and demonstrate that this residue is phosphorylated by glycogen synthase kinase 3 (gsk3)." SIGNOR-145306 GSK3A protein P49840 UNIPROT GRB14 protein Q14449 UNIPROT "down-regulates activity" phosphorylation Ser358 MHPYQGRsGCSSQSI -1 28130417 t lperfetto "Phosphorylation of clustered serine residues in the N-terminus of BPS domain negatively regulates formation of the complex between human Grb14 and insulin receptor| In vitro kinase assay using the motif-derived peptides showed that the serine residues located in N-terminal (Ser358, Ser362 and Ser366) and C-terminal (Ser419 and Ser423) regions of the BPS domain were phosphorylated by GSK-3." SIGNOR-264871 GSK3A protein P49840 UNIPROT GRB14 protein Q14449 UNIPROT "down-regulates activity" phosphorylation Ser362 QGRSGCSsQSISPMR -1 28130417 t lperfetto "Phosphorylation of clustered serine residues in the N-terminus of BPS domain negatively regulates formation of the complex between human Grb14 and insulin receptor| In vitro kinase assay using the motif-derived peptides showed that the serine residues located in N-terminal (Ser358, Ser362 and Ser366) and C-terminal (Ser419 and Ser423) regions of the BPS domain were phosphorylated by GSK-3." SIGNOR-264870 GSK3A protein P49840 UNIPROT GRB14 protein Q14449 UNIPROT "down-regulates activity" phosphorylation Ser366 GCSSQSIsPMRSISE -1 28130417 t lperfetto "Phosphorylation of clustered serine residues in the N-terminus of BPS domain negatively regulates formation of the complex between human Grb14 and insulin receptor| In vitro kinase assay using the motif-derived peptides showed that the serine residues located in N-terminal (Ser358, Ser362 and Ser366) and C-terminal (Ser419 and Ser423) regions of the BPS domain were phosphorylated by GSK-3." SIGNOR-264872 GSK3A protein P49840 UNIPROT NBR1 protein Q14596 UNIPROT "down-regulates activity" phosphorylation Thr586 HNTPVDVtPCMSPLP -1 24879152 t lperfetto "The autophagy receptor NBR1 (neighbor of BRCA1 gene 1) binds UB/ubiquitin and the autophagosome-conjugated MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3) proteins, thereby ensuring ubiquitinated protein degradation|Here we show that NBR1 is a substrate of GSK3. NBR1 phosphorylation by GSK3 at Thr586 prevents the aggregation of ubiquitinated proteins and their selective autophagic degradation." SIGNOR-261794 GSK3A protein P49840 UNIPROT MAFA protein Q8NHW3 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser49 CHRLPPGsLSSTPLS 9606 18042454 t miannu "We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity." SIGNOR-159381 GSK3A protein P49840 UNIPROT STMN3 protein Q9NZ72 UNIPROT "up-regulates activity" phosphorylation Ser60 SFEVILKsPSDLSPE -1 22577147 t lperfetto "Altogether, these results indicate that CDK5 phosphorylates similarly serines 68 and 73, whereas ERK2 targets mostly serine 68 and GSK-3beta mostly serine 60.|This observation may support the hypothesis of a specific localization of stathmin 3 depending on its phosphorylation by GSK-3beta" SIGNOR-264883 GSK3A protein P49840 UNIPROT MAFA protein Q8NHW3 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser61 PLSTPCSsVPSSPSF 9606 18042454 t miannu "We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity." SIGNOR-159390 GSK3A protein P49840 UNIPROT MAFA protein Q8NHW3 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr53 PPGSLSStPLSTPCS 9606 18042454 t miannu "We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity." SIGNOR-159394 GSK3A protein P49840 UNIPROT MAFA protein Q8NHW3 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr57 LSSTPLStPCSSVPS 9606 18042454 t miannu "We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity." SIGNOR-159398 GSK3A protein P49840 UNIPROT MAFA protein Q8NHW3 UNIPROT "up-regulates activity" phosphorylation Ser49 CHRLPPGsLSSTPLS 9606 18042454 t miannu "We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity." SIGNOR-159365 GSK3A protein P49840 UNIPROT MAFA protein Q8NHW3 UNIPROT "up-regulates activity" phosphorylation Ser61 PLSTPCSsVPSSPSF 9606 18042454 t miannu "We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity." SIGNOR-159369 GSK3A protein P49840 UNIPROT MAFA protein Q8NHW3 UNIPROT "up-regulates activity" phosphorylation Thr53 PPGSLSStPLSTPCS 9606 18042454 t miannu "We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity." SIGNOR-159373 GSK3A protein P49840 UNIPROT MAFA protein Q8NHW3 UNIPROT "up-regulates activity" phosphorylation Thr57 LSSTPLStPCSSVPS 9606 18042454 t miannu "We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity." SIGNOR-159377 GSK3A protein P49840 UNIPROT GATA6 protein Q92908 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser37 REPSTPPsPISSSSS 9606 BTO:0000182 27273097 t lperfetto "Through bioinformatics and cell-based experiments, we identified the AKT-repressed signal as glycogen synthase kinase 3 (GSK3)-catalyzed phosphorylation of Ser(37) on the long form of the transcription factor GATA6. Phosphorylation of GATA6 on Ser(37) promoted its degradation, thereby preventing GATA6 from repressing transcripts that are induced by TNF and attenuated by insulin" SIGNOR-253156 GSK3A protein P49840 UNIPROT OSBP2 protein Q969R2 UNIPROT "up-regulates activity" phosphorylation 30925160 t lperfetto "CK1a1, JNK1 and CDK1 had the highest site-specific activity for ORP4L, while CDK1, GSK3a, CK1a1 and GSK3b showed the highest specificity for the site when corrected for background activity with ORP4L-S4A. Because of the complexity of the serine/proline-rich site, we did not determine which serine(s) in ORP4L were phosphorylated by candidate kinases.|We conclude that phosphorylation of a unique serine/proline motif in the ORD induces a conformation change in ORP4L that enhances interaction with vimentin and cholesterol extraction from membranes." SIGNOR-264875 GSK3A protein P49840 UNIPROT CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser129 ICPSLPYsPVSSPQS 9606 22778263 t lperfetto "Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity." SIGNOR-198122 GSK3A protein P49840 UNIPROT CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser133 LPYSPVSsPQSSPRL 9606 22778263 t lperfetto "Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity." SIGNOR-198126 GSK3A protein P49840 UNIPROT CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser137 PVSSPQSsPRLPRRP 9606 22778263 t lperfetto "Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity." SIGNOR-198130 GSK3A protein P49840 UNIPROT NIFK protein Q9BYG3 UNIPROT "up-regulates activity" phosphorylation Thr234 TVDSQGPtPVCTPTF -1 16244663 t miannu "The forkhead-associated (FHA) domain of human Ki67 interacts with the human nucleolar protein hNIFK, recognizing a 44-residue fragment, hNIFK226-269, phosphorylated at Thr234. Here we show that high-affinity binding requires sequential phosphorylation by two kinases, CDK1 and GSK3, yielding pThr238, pThr234 and pSer230. phosphorylation of Thr234 by GSK3 proceeds only after Thr238 is already phosphorylated by CDK1." SIGNOR-262697 GSK3A protein P49840 UNIPROT GPSM3 protein Q9Y4H4 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser35 STTRPWRsAPPSPPP 9606 BTO:0000876 22843681 t lperfetto "Co-immunoprecipitation of endogenous GPSM3 and 14-3-3 proteins from the human monocytic cell line THP-1 suggests basal phosphorylation of GPSM3 at serine 35 as potentially mediated by GSK3alpha. The GPSM3/14-3-3 interaction is seen to stabilize GPSM3 from degradation and also support the nuclear exclusion of both proteins." SIGNOR-264863 GSK3A protein P49840 UNIPROT MAFB protein Q9Y5Q3 UNIPROT down-regulates phosphorylation 9606 18042454 t miannu "We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity." SIGNOR-159432 GSK3A protein P49840 UNIPROT MAFB protein Q9Y5Q3 UNIPROT up-regulates phosphorylation 9606 18042454 t miannu "We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity." SIGNOR-159429 GSK3A protein P49840 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" phosphorylation Thr312 TMKTFCGtPEYLAPE 10090 BTO:0005655 23142783 t gcesareni "GSK3_ negatively regulates AKT activation by phosphorylating AKT at T312 in the substrate binding site, which inhibited IL-1-induced AKT activation and function." SIGNOR-252455 GSK3B protein P49841 UNIPROT ARNTL protein O00327 UNIPROT down-regulates phosphorylation Ser17 STISDFMsPGPTDLL 9606 BTO:0000938 20049328 t lperfetto "Gsk3beta phosphorylates bmal1 specifically on ser 17 and thr 21 and primes it for ubiquitylation. In the absence of gsk3beta-mediated phosphorylation, bmal1 becomes stabilized and bmal1 dependent circadian gene expression is dampened." SIGNOR-162786 GSK3B protein P49841 UNIPROT ARNTL protein O00327 UNIPROT down-regulates phosphorylation Thr21 DFMSPGPtDLLSSSL 9606 BTO:0000938 20049328 t lperfetto "Gsk3beta phosphorylates bmal1 specifically on ser 17 and thr 21 and primes it for ubiquitylation. In the absence of gsk3beta-mediated phosphorylation, bmal1 becomes stabilized and bmal1 dependent circadian gene expression is dampened." SIGNOR-162790 GSK3B protein P49841 UNIPROT CHEK1 protein O14757 UNIPROT "down-regulates activity" 10090 24260231 f miannu "Involvement of GSK3 Inhibition by the PI3K/Akt Pathway in Regulation of Etoposide-induced Chk1 Activation. GSK3ß regulates etoposide-induced Chk1 activation. GSK3 inhibitors, including LiCl and SB216763, restored the sustained Chk1 activation and mitigated apoptosis in cells treated with etoposide and the inhibitors for aberrant kinases, PI3K, or Akt. Thus, proteasomal degradation of Chk1 as well as GSK3 activation may be involved in negative regulation of etoposide-induced Chk1 by imatinib in these cells." SIGNOR-263050 GSK3B protein P49841 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates binding 9606 SIGNOR-C110 SIGNOR-C110 10318824 t lperfetto "From the binding experiments, we defined the domains of Axin that bind glycogen synthase kinase-3beta (GSK-3beta) and beta-catenin. We also examined the ability of each Axin mutant to inhibit lymphoid enhancer factor-1 (Lef-1) reporter activity in a cell line expressing high levels of beta-catenin." SIGNOR-67438 GSK3B protein P49841 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates binding 9606 BTO:0000586 SIGNOR-C110 SIGNOR-C110 9734785 t lperfetto "Interaction with beta-catenin and GSK-3beta was required for the Axin-mediated beta-catenin reduction." SIGNOR-60046 GSK3B protein P49841 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates phosphorylation 9606 BTO:0000007 SIGNOR-C110 SIGNOR-C110 23579495 t lperfetto "Phosphorylation by GSK3 kept Axin activated (open) for _-catenin interaction and poised for engagement of LRP6." SIGNOR-201683 GSK3B protein P49841 UNIPROT AXIN1 protein O15169 UNIPROT "up-regulates activity" phosphorylation Ser486 LRTPGRQsPGPGHRS 9606 BTO:0000007 10581160 t "Axin residues T609 and S614 are physiological GSK3beta targets. Axin phosphorylation in the regulation of b-catenin stability. When active (left), GSK3b phosphorylates Axin as well as APC and b-catenin. The phosphorylated form of Axin binds strongly to b-catenin and promotes the phosphorylation of b-catenin by GSK3b, leading to strong interaction with b-TrCP" SIGNOR-251221 GSK3B protein P49841 UNIPROT AXIN1 protein O15169 UNIPROT "up-regulates activity" phosphorylation Thr481 HVQRVLRtPGRQSPG 9606 BTO:0000007 10581160 t "Axin residues T609 and S614 are physiological GSK3beta targets. Axin phosphorylation in the regulation of b-catenin stability. When active (left), GSK3b phosphorylates Axin as well as APC and b-catenin. The phosphorylated form of Axin binds strongly to b-catenin and promotes the phosphorylation of b-catenin by GSK3b, leading to strong interaction with b-TrCP" SIGNOR-251222 GSK3B protein P49841 UNIPROT TCAP protein O15273 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser157 GALRRSLsRSMSQEA 9606 BTO:0000007 32937135 t lperfetto "GSK-3beta phosphorylates FBXL21 and TCAP to activate FBXL21-mediated, phosphodegron-dependent TCAP degradation.|These results show direct GSK-3beta phosphorylation of TCAP S157 and FBXL21 T33 sites." SIGNOR-264852 GSK3B protein P49841 UNIPROT DCX protein O43602 UNIPROT "up-regulates activity" phosphorylation Ser332 STPKSKQsPISTPTS 9606 BTO:0000142 21159948 t lperfetto "Gsk3b phosphorylates dcx at the distinct site of ser327 and thereby contributes to dcx function in the restriction of axon branching. Together, our data define a jip3-regulated gsk3_/dcx signaling pathway that restricts axon branching in the mammalian brain.Gsk3_ induces the phosphorylation of dcx at ser327, which contributes to dcx function in the inhibition of axon branching and self-contact." SIGNOR-170755 GSK3B protein P49841 UNIPROT PHLPP1 protein O60346 UNIPROT down-regulates phosphorylation Ser1359 VPRPHVQsVLLTPQD 9606 19797085 t llicata "In addition, we show that the beta-trcp-mediated degradation requires phosphorylation of phlpp1 by casein kinase i and glycogen synthase kinase 3beta (gsk-3beta), and activation of the phosphatidylinositol 3-kinase/akt pathway suppresses the degradation of phlpp1 by inhibiting the gsk-3beta activity." SIGNOR-188330 GSK3B protein P49841 UNIPROT CTNND1 protein O60716 UNIPROT unknown phosphorylation Ser252 MEGYRAPsRQDVYGP -1 12885254 t "GSK3beta selectively phosphorylates p120 on S252 and T310 in Vitro" SIGNOR-251234 GSK3B protein P49841 UNIPROT CTNND1 protein O60716 UNIPROT unknown phosphorylation Thr310 GTARRTGtPSDPRRR -1 12885254 t "GSK3beta selectively phosphorylates p120 on S252 and T310 in Vitro" SIGNOR-251235 GSK3B protein P49841 UNIPROT CLASP2 protein O75122 UNIPROT "down-regulates activity" phosphorylation Ser533 QGCSREAsRESSRDT 9534 BTO:0004055 19638411 t lperfetto "GSK-3beta directly phosphorylates CLASP2 at Ser533 and Ser537 within the region responsible for the IQGAP1 binding. Phosphorylation of CLASP2 results in the dissociation of CLASP2 from IQGAP1, EB1 and microtubules.| CLASPs were originally identified as CLIP-170-interacting proteins and later found to be required for microtubule stabilisation at the cortical regions of epithelial cells" SIGNOR-264825 CAMK4 protein Q16566 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser119 EILSRRPsYRKILND 9606 17389598 t gcesareni "Pka, ca2+-calmodulin-dependent kinase iv (camkiv), msk, p70s6k and rsk phosphorylate creb." SIGNOR-153940 GSK3B protein P49841 UNIPROT CLASP2 protein O75122 UNIPROT "down-regulates activity" phosphorylation Ser537 REASRESsRDTSPVR 9534 BTO:0004055 19638411 t lperfetto "GSK-3beta directly phosphorylates CLASP2 at Ser533 and Ser537 within the region responsible for the IQGAP1 binding. Phosphorylation of CLASP2 results in the dissociation of CLASP2 from IQGAP1, EB1 and microtubules.| CLASPs were originally identified as CLIP-170-interacting proteins and later found to be required for microtubule stabilisation at the cortical regions of epithelial cells" SIGNOR-264826 GSK3B protein P49841 UNIPROT MAF protein O75444 UNIPROT down-regulates phosphorylation 9606 18042454 t miannu "We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity." SIGNOR-159438 GSK3B protein P49841 UNIPROT MAF protein O75444 UNIPROT up-regulates phosphorylation 9606 18042454 t miannu "We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity." SIGNOR-159435 GSK3B protein P49841 UNIPROT LRP6 protein O75581 UNIPROT "up-regulates activity" phosphorylation Ser1490 AILNPPPsPATERSH 9606 SIGNOR-C110 16341017 t gcesareni "Glycogen synthase kinase 3 (gsk3), which is known for its inhibitory role in wnt through the promotion of beta-catenin phosphorylation and degradation, mediates the phosphorylation and activation of lrp6. We show that wnt induces sequential phosphorylation of lrp6 by gsk3 and casein kinase 1, and this dual phosphorylation promotes the engagement of lrp6 with the scaffolding protein axin." SIGNOR-143041 GSK3B protein P49841 UNIPROT CABYR protein O75952 UNIPROT unknown phosphorylation Ser155 KTTTPPSsPPPTAVS -1 15752768 t "GSK3β interacts with and phosphorylates CABYR in vitro. GSK3β interacts with and phosphorylates CABYR in vitro. the functional extent of the CABYR phosphorylation sites to participate in cellular processes through GSK3β remains to be investigated." SIGNOR-251223 GSK3B protein P49841 UNIPROT CABYR protein O75952 UNIPROT unknown phosphorylation Thr151 PATPKTTtPPSSPPP -1 15752768 t "GSK3β interacts with and phosphorylates CABYR in vitro. GSK3β interacts with and phosphorylates CABYR in vitro. the functional extent of the CABYR phosphorylation sites to participate in cellular processes through GSK3β remains to be investigated." SIGNOR-251224 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser100 DEDSGKGsQPPSPPS 9606 15448698 t lperfetto "Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt" SIGNOR-129398 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser104 GKGSQPPsPPSPAPS 9606 15448698 t lperfetto "Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt" SIGNOR-129402 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser107 SQPPSPPsPAPSSFS 9606 15448698 t lperfetto "Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt" SIGNOR-129406 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser111 SPPSPAPsSFSSTSV 9606 15448698 t lperfetto "Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt" SIGNOR-129410 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser115 PAPSSFSsTSVSSLE 9606 15448698 t lperfetto "Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt" SIGNOR-129414 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser119 SFSSTSVsSLEAEAY 9606 15448698 t lperfetto "Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt" SIGNOR-129418 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser96 TSLSDEDsGKGSQPP 9606 15448698 t lperfetto "Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt" SIGNOR-129422 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser100 DEDSGKGsQPPSPPS 9606 20305697 t lperfetto "Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt" SIGNOR-164613 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser104 GKGSQPPsPPSPAPS 9606 20305697 t lperfetto "Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt" SIGNOR-164617 GSK3B protein P49841 UNIPROT APP protein P05067 UNIPROT unknown phosphorylation Thr743 VEVDAAVtPEERHLS -1 8764598 t "The sole site of phosphorylation in APPcyt by GSK-3beta was determined by phosphoamino acid analysis and phosphorylation of APPcyt mutant peptides to be Thr743 (numbering as for APP770)." SIGNOR-251220 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser107 SQPPSPPsPAPSSFS 9606 20305697 t lperfetto "Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt" SIGNOR-164621 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser111 SPPSPAPsSFSSTSV 9606 20305697 t lperfetto "Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt" SIGNOR-164625 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser115 PAPSSFSsTSVSSLE 9606 20305697 t lperfetto "Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt" SIGNOR-164629 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser119 SFSSTSVsSLEAEAY 9606 20305697 t lperfetto "Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt" SIGNOR-164633 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser96 TSLSDEDsGKGSQPP 9606 20305697 t lperfetto "Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt" SIGNOR-164637 GSK3B protein P49841 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr58 KKFELLPtPPLSPSR 10116 11018017 t "Phosphorylation of Thr 58, likely mediated by GSK-3 but dependent on the prior phosphorylation of Ser 62, is associated with degradation of Myc." SIGNOR-252080 GSK3B protein P49841 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr58 KKFELLPtPPLSPSR 9606 16023596 t gcesareni "Similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation." SIGNOR-138603 GSK3B protein P49841 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser102 GGFPPLNsVSPSPLM 9606 16076840 t gcesareni "The gsk-3 inhibitor lithium chloride was used to determine the role of gsk-3 in phosphorylation of ser-102, -104, and -106 and ser-118 in vivo and to explore the role of these serines in the regulation of eralpha function. Treatment of cells with lithium chloride resulted in dephosphorylation of ser-104 and -106 and ser-118, which suggests these serine residues as targets for gsk-3 in vivo. Our results further suggest that eralpha phosphorylation by gsk-3 stabilizes eralpha under resting conditions and modulates eralpha transcriptional activity upon ligand binding. Estradiol and phorbol ester cause phosphorylation of serine 118 in the human estrogen receptor. Potentiation of human estrogen receptor alpha transcriptional activation through phosphorylation of serines 104 and 106 by the cyclin a-cdk2 complex." SIGNOR-139312 GSK3B protein P49841 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser104 FPPLNSVsPSPLMLL 9606 16076840 t gcesareni "The gsk-3 inhibitor lithium chloride was used to determine the role of gsk-3 in phosphorylation of ser-102, -104, and -106 and ser-118 in vivo and to explore the role of these serines in the regulation of eralpha function. Treatment of cells with lithium chloride resulted in dephosphorylation of ser-104 and -106 and ser-118, which suggests these serine residues as targets for gsk-3 in vivo. Our results further suggest that eralpha phosphorylation by gsk-3 stabilizes eralpha under resting conditions and modulates eralpha transcriptional activity upon ligand binding. Estradiol and phorbol ester cause phosphorylation of serine 118 in the human estrogen receptor. Potentiation of human estrogen receptor alpha transcriptional activation through phosphorylation of serines 104 and 106 by the cyclin a-cdk2 complex." SIGNOR-139316 GSK3B protein P49841 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser106 PLNSVSPsPLMLLHP 9606 16076840 t gcesareni "The gsk-3 inhibitor lithium chloride was used to determine the role of gsk-3 in phosphorylation of ser-102, -104, and -106 and ser-118 in vivo and to explore the role of these serines in the regulation of eralpha function. Treatment of cells with lithium chloride resulted in dephosphorylation of ser-104 and -106 and ser-118, which suggests these serine residues as targets for gsk-3 in vivo. Our results further suggest that eralpha phosphorylation by gsk-3 stabilizes eralpha under resting conditions and modulates eralpha transcriptional activity upon ligand binding. Estradiol and phorbol ester cause phosphorylation of serine 118 in the human estrogen receptor. Potentiation of human estrogen receptor alpha transcriptional activation through phosphorylation of serines 104 and 106 by the cyclin a-cdk2 complex." SIGNOR-139320 GSK3B protein P49841 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 16076840 t gcesareni "The gsk-3 inhibitor lithium chloride was used to determine the role of gsk-3 in phosphorylation of ser-102, -104, and -106 and ser-118 in vivo and to explore the role of these serines in the regulation of eralpha function. Treatment of cells with lithium chloride resulted in dephosphorylation of ser-104 and -106 and ser-118, which suggests these serine residues as targets for gsk-3 in vivo. Our results further suggest that eralpha phosphorylation by gsk-3 stabilizes eralpha under resting conditions and modulates eralpha transcriptional activity upon ligand binding. Estradiol and phorbol ester cause phosphorylation of serine 118 in the human estrogen receptor. Potentiation of human estrogen receptor alpha transcriptional activation through phosphorylation of serines 104 and 106 by the cyclin a-cdk2 complex." SIGNOR-139324 GSK3B protein P49841 UNIPROT NR3C1 protein P04150 UNIPROT "down-regulates activity" phosphorylation Ser404 SMRPDVSsPPSSSST 9606 18838540 t gcesareni "We found hormone-dependent GR phosphorylation on serine 404 by GSK-3beta [ ]Cells expressing a GR that is incapable of GSK-3beta phosphorylation had a redirection of the global transcriptional response to hormone, including the activation of additional signaling pathways, in part due to the altered ability of unphosphorylatable GR to recruit transcriptional cofactors CBP/p300 and the p65 (RelA) subunit of NF-kappaB" SIGNOR-181541 GSK3B protein P49841 UNIPROT JUN protein P05412 UNIPROT "down-regulates activity" phosphorylation Ser243 PGETPPLsPIDMESQ 9606 BTO:0000007 16023596 t lperfetto "The c-jun and c-myc oncogenic transcription factors are highly unstable proteins due to polyubiquitination. Similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation.Phosphorylation of Thr-239 and Ser-243 is required for Fbw7-mediated c-Jun disappearance" SIGNOR-235892 GSK3B protein P49841 UNIPROT JUN protein P05412 UNIPROT "down-regulates activity" phosphorylation Thr239 VPEMPGEtPPLSPID 9606 BTO:0000007 16023596 t lperfetto "The c-jun and c-myc oncogenic transcription factors are highly unstable proteins due to polyubiquitination. Similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation.Phosphorylation of Thr-239 and Ser-243 is required for Fbw7-mediated c-Jun disappearance" SIGNOR-236717 GSK3B protein P49841 UNIPROT JUN protein P05412 UNIPROT "down-regulates activity" phosphorylation Ser249 LSPIDMEsQERIKAE -1 1846781 t lperfetto "Phosphorylation of recombinant human c-jun proteins in vitro by gsk-3 decreases their dna-binding activity." SIGNOR-18684 GSK3B protein P49841 UNIPROT GLI2 protein P10070 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser820 VSSAYTVsRRSSGIS 9606 BTO:0000007 16611981 t lperfetto "The degradation of Gli2 requires the phosphorylation of a cluster of numerous serine residues in its carboxyl terminus by protein kinase A and subsequently by casein kinase 1 and glycogen synthase kinase 3." SIGNOR-148472 GSK3B protein P49841 UNIPROT GLI2 protein P10070 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser832 GISPYFSsRRSSEAS 9606 BTO:0000007 16611981 t lperfetto "The degradation of Gli2 requires the phosphorylation of a cluster of numerous serine residues in its carboxyl terminus by protein kinase A and subsequently by casein kinase 1 and glycogen synthase kinase 3." SIGNOR-249589 GSK3B protein P49841 UNIPROT GLI2 protein P10070 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser863 DPISTDAsRRSSEAS 9606 BTO:0000007 16611981 t lperfetto "The degradation of Gli2 requires the phosphorylation of a cluster of numerous serine residues in its carboxyl terminus by protein kinase A and subsequently by casein kinase 1 and glycogen synthase kinase 3." SIGNOR-249590 GSK3B protein P49841 UNIPROT GLI3 protein P10071 UNIPROT "down-regulates quantity by destabilization" phosphorylation 7227 11955435 t lperfetto "We show that these phosphoserines prime further phosphorylation at adjacent Glycogen Synthase Kinase 3 (GSK3) and Casein Kinase I (CK1) sites. Alteration of the GSK3 or CK1 sites prevents Ci-155 proteolysis and activates Ci in the absence of Hedgehog." SIGNOR-219231 GSK3B protein P49841 UNIPROT GLI3 protein P10071 UNIPROT "down-regulates quantity by destabilization" phosphorylation 10090 16885213 t lperfetto "Gli2 and Gli3 (in vertebrates) are phosphorylated by protein kinase A and glycogen synthase kinase-3_ and are proteolytically processed" SIGNOR-148475 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser519 SGYSSPGsPGTPGSR 9606 17078951 t "The effect has been demonstrated using P10636-8" lperfetto "Here, we found that prephosphorylation by pka promotes gsk-3beta-catalyzed tau phosphorylation at thr181, ser199, ser202, thr205, thr217, thr231, ser396 and ser422" SIGNOR-150360 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr534 SRTPSLPtPPTREPK 9606 17078951 t "The effect has been demonstrated using P10636-8" lperfetto "Here, we found that prephosphorylation by pka promotes gsk-3beta-catalyzed tau phosphorylation at thr181, ser199, ser202, thr205, thr217, thr231, ser396 and ser422" SIGNOR-150364 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser516 GDRSGYSsPGSPGTP 9606 BTO:0000142 20308788 t "The effect has been demonstrated using P10636-8" lperfetto "Abnormal hyperphosphorylation of tau appears to be crucial in neurofibrillary degeneration in alzheimer's disease (ad). Gsk-3beta phosphorylated tau at many sites, with ser199, thr205, and ser396 being the most favorable sites in cells." SIGNOR-164651 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr522 SSPGSPGtPGSRSRT 9606 BTO:0000142 20308788 t "The effect has been demonstrated using P10636-8" lperfetto "Abnormal hyperphosphorylation of tau appears to be crucial in neurofibrillary degeneration in alzheimer's disease (ad). Gsk-3beta phosphorylated tau at many sites, with ser199, thr205, and ser396 being the most favorable sites in cells." SIGNOR-164655 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser396 DDKKAKTsTRSSAKT 9606 BTO:0000590 20679343 t lperfetto "Alzheimer disease neurons are characterized by extraneuronal plaques formed by aggregated amyloid-? Peptide and by intraneuronal tangles composed of fibrillar aggregates of the microtubule-associated tau protein. Tau is mostly found in a hyperphosphorylated form in these tangleswe find that three residues can be phosphorylated (ser-396, ser-400, and ser-404) by gsk3?" SIGNOR-167286 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser400 AKTSTRSsAKTLKNR 9606 BTO:0000590 20679343 t lperfetto "Alzheimer disease neurons are characterized by extraneuronal plaques formed by aggregated amyloid-? Peptide and by intraneuronal tangles composed of fibrillar aggregates of the microtubule-associated tau protein. Tau is mostly found in a hyperphosphorylated form in these tangleswe find that three residues can be phosphorylated (ser-396, ser-400, and ser-404) by gsk3?" SIGNOR-167290 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser721 PVVSGDTsPRHLSNV 9606 BTO:0000590 20679343 t "The effect has been demonstrated using P10636-8" lperfetto "Alzheimer disease neurons are characterized by extraneuronal plaques formed by aggregated amyloid-? Peptide and by intraneuronal tangles composed of fibrillar aggregates of the microtubule-associated tau protein. Tau is mostly found in a hyperphosphorylated form in these tangleswe find that three residues can be phosphorylated (ser-396, ser-400, and ser-404) by gsk3?" SIGNOR-167294 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser579 NVKSKIGsTENLKHQ 9606 21215781 t "The effect has been demonstrated using P10636-8" lperfetto "Tau pseudophosphorylation at specific sites such as s262, s293, s324 and s356 was reported to induce tau conformational change and attenuate tau binding to microtubules (fischer et al., 2009). Then, newly soluble tau proteins are targeted by post-translational modifications that directly or indirectly alter tau conformation, promoting tau dimerization in an anti-parallel manner. Stable tau dimers form tau oligomers, which continue in the aggregation process" SIGNOR-171042 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr548 KKVAVVRtPPKSPSS 9606 21215781 t "The effect has been demonstrated using P10636-8" lperfetto "Gsk3b phosphorylates tau at t231tau phosphorylation at t231, s235 and s262 also contributes to the dissociation of tau from microtubules" SIGNOR-171046 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation 21443865 t "The MAPT H1 haplotype and subhaplotypes may be associated with sporadic tauopathies including AD. And that, tau's phosphorylation is regulated by many protein kinases, including glycogen synthase kinase 3beta (GSK3B)." SIGNOR-255486 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser579 NVKSKIGsTENLKHQ 9606 BTO:0000938 9771888 t "The effect has been demonstrated using P10636-8" gcesareni "Tau is phosphorylated by gsk-3 at several sites found in alzheimer disease and its biological activity markedly inhibited only after it is prephosphorylated by a-kinase." SIGNOR-60655 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser516 GDRSGYSsPGSPGTP 9606 BTO:0000590 12387894 t lperfetto "We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235." SIGNOR-249352 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser519 SGYSSPGsPGTPGSR 9606 BTO:0000590 12387894 t lperfetto "We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235." SIGNOR-249343 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser531 GSRSRTPsLPTPPTR 9606 BTO:0000590 12387894 t lperfetto "We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235." SIGNOR-249344 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser713 GAEIVYKsPVVSGDT 9606 BTO:0000590 12387894 t lperfetto "We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235." SIGNOR-249345 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser717 VYKSPVVsGDTSPRH 9606 BTO:0000590 12387894 t lperfetto "Sequencing of 32P-labeled trypsin phosphopeptides from tau prephosphorylated by A-kinase (using unlabeled ATP) and further phosphorylated by GSK-3 in the presence of [gamma-32P]ATP revealed that Ser-195, Ser-198, Ser-199, Ser-202, Thr-205, Thr-231, Ser-235, Ser-262, Ser-356 and Ser-404 are phosphorylated, whereas if tau is not prephosphorylated by A-kinase, GSK-3 phosphorylates it at Thr-181, Ser-184, Ser-262, Ser-356 and Ser-400. These data suggest that (i) prephosphorylation of tau by A-kinase makes additional and different sites accessible for phosphorylation by GSK-3; (ii) phosphorylation of tau at these additional sites further inhibits the biological activity of tau in its ability to bind to microtubules and promote microtubule assembly." SIGNOR-249355 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser721 PVVSGDTsPRHLSNV 9606 BTO:0000590 12387894 t lperfetto "We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235." SIGNOR-249346 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Thr498 KTPPAPKtPPSSGEP 9606 BTO:0000590 12387894 t lperfetto "We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235." SIGNOR-249351 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Thr522 SSPGSPGtPGSRSRT 9606 BTO:0000590 12387894 t lperfetto "We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235." SIGNOR-249347 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Thr529 TPGSRSRtPSLPTPP 9606 BTO:0000590 12387894 t lperfetto "We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235." SIGNOR-249348 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Thr534 SRTPSLPtPPTREPK 9606 BTO:0000590 12387894 t lperfetto "We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235." SIGNOR-249349 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Thr548 KKVAVVRtPPKSPSS 9606 BTO:0000590 12387894 t lperfetto "We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235." SIGNOR-249350 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser512 PPKSGDRsGYSSPGS 9606 BTO:0000590 9771888 t lperfetto "Sequencing of 32P-labeled trypsin phosphopeptides from tau prephosphorylated by A-kinase (using unlabeled ATP) and further phosphorylated by GSK-3 in the presence of [gamma-32P]ATP revealed that Ser-195, Ser-198, Ser-199, Ser-202, Thr-205, Thr-231, Ser-235, Ser-262, Ser-356 and Ser-404 are phosphorylated, whereas if tau is not prephosphorylated by A-kinase, GSK-3 phosphorylates it at Thr-181, Ser-184, Ser-262, Ser-356 and Ser-400. These data suggest that (i) prephosphorylation of tau by A-kinase makes additional and different sites accessible for phosphorylation by GSK-3; (ii) phosphorylation of tau at these additional sites further inhibits the biological activity of tau in its ability to bind to microtubules and promote microtubule assembly." SIGNOR-249353 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser515 SGDRSGYsSPGSPGT 9606 BTO:0000590 9832145 t lperfetto "Sequencing of 32P-labeled trypsin phosphopeptides from tau prephosphorylated by A-kinase (using unlabeled ATP) and further phosphorylated by GSK-3 in the presence of [gamma-32P]ATP revealed that Ser-195, Ser-198, Ser-199, Ser-202, Thr-205, Thr-231, Ser-235, Ser-262, Ser-356 and Ser-404 are phosphorylated, whereas if tau is not prephosphorylated by A-kinase, GSK-3 phosphorylates it at Thr-181, Ser-184, Ser-262, Ser-356 and Ser-400. These data suggest that (i) prephosphorylation of tau by A-kinase makes additional and different sites accessible for phosphorylation by GSK-3; (ii) phosphorylation of tau at these additional sites further inhibits the biological activity of tau in its ability to bind to microtubules and promote microtubule assembly." SIGNOR-249354 GSK3B protein P49841 UNIPROT NEFH protein P12036 UNIPROT down-regulates phosphorylation Ser503 GGEEETKsPPAEEAA 9606 12130654 t lperfetto "Gsk3beta was shown to phosphorylate at ser-493 in vitro by phosphopeptide mapping and site-directed mutagenesis, and in vivo in hek293 cells. The role of ser-493 phosphorylation is also a question to be addressed in the future. Because the e-segment appears to be involved in filament formation (27, 42), phosphorylation in that region may also play a regulatory role in filament formation. Secondary structure prediction suggests that phosphorylation of ser-493 in combination with following the pro residue interrupts _-helix of the e-segment" SIGNOR-90668 GSK3B protein P49841 UNIPROT CDH1 protein P12830 UNIPROT "up-regulates activity" phosphorylation Ser847 SEAASLSsLNSSESD -1 10671552 t "Phosphorylation of the E-cadherin Cytoplasmic Domain by CKII and GSK-3β Increases the Binding to β-catenin. pre-phosphorylation by CKII at Ser-855 and/or Ser-853 of E-cadherin is required before GSK-3β can phosphorylate at Ser-849." SIGNOR-251225 GSK3B protein P49841 UNIPROT UNG protein P13051 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser64 EPGTPPSsPLSAEQL 9606 BTO:0000812 27875297 t lperfetto "Here we show that glycogen synthase kinase 3 (GSK-3) interacts with and phosphorylates UNG2 at Thr60 and that Thr60 phosphorylation requires a Ser64 priming phosphorylation event.|phosphorylation of Thr60 and Ser64 creates a cyclin E/c-Myc-like phosphodegron that promotes polyubiquitylation and proteasome-mediated degradation" SIGNOR-264884 GSK3B protein P49841 UNIPROT UNG protein P13051 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr60 AGQEEPGtPPSSPLS 9606 BTO:0000812 phosphorylation:Ser64 EPGTPPSsPLSAEQL 27875297 t lperfetto "Here we show that glycogen synthase kinase 3 (GSK-3) interacts with and phosphorylates UNG2 at Thr60 and that Thr60 phosphorylation requires a Ser64 priming phosphorylation event.|phosphorylation of Thr60 and Ser64 creates a cyclin E/c-Myc-like phosphodegron that promotes polyubiquitylation and proteasome-mediated degradation" SIGNOR-264885 GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT "down-regulates activity" phosphorylation Ser641 YRYPRPAsVPPSPSL 11427888 t "Glycogen synthase has multiple serines (residues 640, 644, 648 and 652) separated by three residues, and those Ser residues are phosphorylated sequentially by GSK3 from the C-terminal end after Ser 656 has been phosphorylated by casein kinase II." SIGNOR-251239 GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT "down-regulates activity" phosphorylation Ser645 RPASVPPsPSLSRHS 11427888 t "Glycogen synthase has multiple serines (residues 640, 644, 648 and 652) separated by three residues, and those Ser residues are phosphorylated sequentially by GSK3 from the C-terminal end after Ser 656 has been phosphorylated by casein kinase II." SIGNOR-251238 GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT "down-regulates activity" phosphorylation Ser649 VPPSPSLsRHSSPHQ 11427888 t "Glycogen synthase has multiple serines (residues 640, 644, 648 and 652) separated by three residues, and those Ser residues are phosphorylated sequentially by GSK3 from the C-terminal end after Ser 656 has been phosphorylated by casein kinase II." SIGNOR-251240 GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT "down-regulates activity" phosphorylation Ser653 PSLSRHSsPHQSEDE 11427888 t "Glycogen synthase has multiple serines (residues 640, 644, 648 and 652) separated by three residues, and those Ser residues are phosphorylated sequentially by GSK3 from the C-terminal end after Ser 656 has been phosphorylated by casein kinase II." SIGNOR-251241 GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT "down-regulates activity" phosphorylation Ser641 YRYPRPAsVPPSPSL 9606 BTO:0000887;BTO:0001103 14593110 t lperfetto "Glycogen synthase kinase-3 (gsk-3) phosphorylates four serine residues in the cooh terminus of glycogen synthase. Phosphorylation of one of these residues, ser640 (site 3a), causes strong inactivation of glycogen synthase" SIGNOR-235793 GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT "down-regulates activity" phosphorylation Ser641 YRYPRPAsVPPSPSL -1 6772446 t "Glycogen synthase kinase-3 phosphorylates three serine residues on glycogen synthase (sites 3a, 3b and 3c) which are all located in the same nine-amino-acid segment of the polypeptide chain. The sequence in this region is: Arg-Tyr-Pro-Arg-Pro-Ala-Ser(P)-Val-Pro-Pro-Ser(P)-Pro-Ser-Leu-Ser(P)-Arg-." SIGNOR-253005 GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT "down-regulates activity" phosphorylation Ser645 RPASVPPsPSLSRHS -1 6772446 t "Glycogen synthase kinase-3 phosphorylates three serine residues on glycogen synthase (sites 3a, 3b and 3c) which are all located in the same nine-amino-acid segment of the polypeptide chain. The sequence in this region is: Arg-Tyr-Pro-Arg-Pro-Ala-Ser(P)-Val-Pro-Pro-Ser(P)-Pro-Ser-Leu-Ser(P)-Arg-." SIGNOR-253006 GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT "down-regulates activity" phosphorylation Ser649 VPPSPSLsRHSSPHQ -1 6772446 t "Glycogen synthase kinase-3 phosphorylates three serine residues on glycogen synthase (sites 3a, 3b and 3c) which are all located in the same nine-amino-acid segment of the polypeptide chain. The sequence in this region is: Arg-Tyr-Pro-Arg-Pro-Ala-Ser(P)-Val-Pro-Pro-Ser(P)-Pro-Ser-Leu-Ser(P)-Arg-." SIGNOR-253007 GSK3B protein P49841 UNIPROT MUC1 protein P15941 UNIPROT "down-regulates activity" phosphorylation Ser1227 PPSSTDRsPYEKVSA BTO:0000567 9819408 t lperfetto "GSK3beta binds directly to an STDRSPYE site in MUC1 and phosphorylates the serine adjacent to proline. Phosphorylation of MUC1 by GSK3beta decreases binding of MUC1 to beta-catenin in vitro and in vivo." SIGNOR-249356 GSK3B protein P49841 UNIPROT CREB1 protein P16220 UNIPROT "up-regulates activity" phosphorylation Ser129 QKRREILsRRPSYRK 10116 12162494 t "GSK-3 can phosphorylate CREB at S129 Transactivation of CREB is significantly reduced (p ≤ 0.05) by 86% for the S129A mutant" SIGNOR-251233 GSK3B protein P49841 UNIPROT H1-5 protein P16401 UNIPROT up-regulates phosphorylation Thr11 TAPAETAtPAPVEKS 9606 BTO:0000567 19136008 t lperfetto "We found that threonine 10 of h1.5 can be phosphorylated by glycogen synthase kinase-3 in vitro. We have generated an antiserum specific for human h1.5 phosphorylated at threonine 10. Immunofluorescence labeling of hela cells with this antiserum revealed that the phosphorylation at this site appears in prometaphase and disappears in telophase, and that this hyperphosphorylated form of h1.5 is mainly chromatin-bound in metaphase when chromatin condensation is maximal." SIGNOR-183325 GSK3B protein P49841 UNIPROT CEBPB protein P17676 UNIPROT up-regulates phosphorylation Ser231 LSTSSSSsPPGTPSP 9606 phosphorylation:Thr235 IFGATDYtSSIDVWS 17601773 t fspada "Mass spectrometric analysis revealed that cdk2/cyclinA phosphorylates C/EBPbeta on Thr(188) and is required for phosphorylation (on Ser(184) or Thr(179)) of C/EBPbeta by GSK3beta and maintenance of DNA binding activity. However, the acquisition of dna binding and transactivation capacity of c/ebpbeta is delayed until further phosphorylation (on ser(184) or thr(179)) by gsk3beta occurs." SIGNOR-156514 GSK3B protein P49841 UNIPROT CEBPB protein P17676 UNIPROT up-regulates phosphorylation Ser231 LSTSSSSsPPGTPSP 9606 phosphorylation:Ser237 SSPPGTPsPADAKAP 22369944 t fspada "However, the acquisition of dna binding and transactivation capacity of c/ebpbeta is delayed until further phosphorylation (on ser(184) or thr(179)) by gsk3beta occurs." SIGNOR-196377 GSK3B protein P49841 UNIPROT CEBPB protein P17676 UNIPROT up-regulates phosphorylation Thr226 GSSGSLStSSSSSPP 9606 phosphorylation:Ser237 SSPPGTPsPADAKAP 22369944 t fspada "However, the acquisition of dna binding and transactivation capacity of c/ebpbeta is delayed until further phosphorylation (on ser(184) or thr(179)) by gsk3beta occurs." SIGNOR-210129 GSK3B protein P49841 UNIPROT CEBPB protein P17676 UNIPROT "up-regulates activity" phosphorylation Thr235 SSSSPPGtPSPADAK 10090 BTO:0001169 22355693 t "We found that expression of srebf1a depended on GSK3β activity and that GSK3β activity was necessary for C/EBPβ phosphorylation at Thr188" SIGNOR-251644 GSK3B protein P49841 UNIPROT LGALS3 protein P17931 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21821001 f miannu "Our study also showed that a number of K562 cells survived despite the apoptotic stimuli. Within these surviving cells, galectin-3 was upregulated through newly synthesized protein. Notably, inducible galectin-3, which stabilized the pro-survival Bcl-2 family proteins Mcl-1, Bcl-xL, and Bcl-2, was essential for anti-apoptosis. Unpredictably, GSK-3β was critical for inducible galectin-3 expression as well as for cell survival. As summarized in Fig. 4C, we not only found inducible galectin-3 has an anti-apoptotic effect, but we also identified a GSK-3β-regulated mechanism for apoptotic resistance in K562 cells." SIGNOR-261903 GSK3B protein P49841 UNIPROT NFKB1 protein P19838 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser903 KTTSQAHsLPLSPAS 10090 BTO:0000452 12871932 t "GSK-3 beta forms an in vivo complex with and specifically phosphorylates NF-kappa B1/p105 at Ser-903 and Ser-907 in vitro. GSK-3 beta has a dual effect on p105: it stabilizes p105 under resting conditions and primes p105 for degradation upon tumor necrosis factor (TNF)-alpha treatment. Indeed, constitutive processing of p105 to p50 occurs at a higher rate in cells lacking GSK-3 beta with respect to wild-type cells and can be reduced upon reintroduction of GSK-3 beta by transfection. S903A and S907A point mutations impair p105 proteolysis in response to TNF-α." SIGNOR-251251 GSK3B protein P49841 UNIPROT NFKB1 protein P19838 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser907 QAHSLPLsPASTRQQ 10090 BTO:0000452 12871932 t "GSK-3 beta forms an in vivo complex with and specifically phosphorylates NF-kappa B1/p105 at Ser-903 and Ser-907 in vitro. GSK-3 beta has a dual effect on p105: it stabilizes p105 under resting conditions and primes p105 for degradation upon tumor necrosis factor (TNF)-alpha treatment. Indeed, constitutive processing of p105 to p50 occurs at a higher rate in cells lacking GSK-3 beta with respect to wild-type cells and can be reduced upon reintroduction of GSK-3 beta by transfection. S903A and S907A point mutations impair p105 proteolysis in response to TNF-α." SIGNOR-251252 GSK3B protein P49841 UNIPROT NR1D1 protein P20393 UNIPROT up-regulates phosphorylation Ser55 CPTYFPPsPTGSLTQ 9606 16484495 t llicata "We show here that gsk3beta phosphorylates and stabilizes the orphan nuclear receptor rev-erbalpha, a negative component of the circadian clock." SIGNOR-144566 GSK3B protein P49841 UNIPROT NR1D1 protein P20393 UNIPROT up-regulates phosphorylation Ser59 FPPSPTGsLTQDPAR 9606 16484495 t llicata "We show here that gsk3beta phosphorylates and stabilizes the orphan nuclear receptor rev-erbalpha, a negative component of the circadian clock." SIGNOR-144570 GSK3B protein P49841 UNIPROT NEB protein P20929 UNIPROT down-regulates phosphorylation 9606 21798082 t gcesareni "Gsk3b is able to phosphorylate nebulin at two ser sites in the c-terminal region of nebulin localized to the z-disk, thus preventing the interaction of nebulin with neuronal wiscott-aldrich syndrome protein (nwasp), a ubiquitously expressed member of the wasp family, which is involved in actin assembly." SIGNOR-175659 GSK3B protein P49841 UNIPROT SFPQ protein P23246 UNIPROT down-regulates phosphorylation Thr687 PRGMGPGtPAGYGRG 9606 20932480 t lperfetto "We conclude that t687 is the primary site of threonine phosphorylation in psf. Gsk3 directly phosphorylates the splicing regulatory protein psf. In this phosphorylated form, psf is sequestered in a complex with trap150, precluding it from binding the ess1 sequence in cd45 alternatively spliced exons. Upon t?_Cell stimulation, reduced gsk3 activity leads to reduced psf phosphorylation, thereby releasing psf from trap150 and allowing it to participate in activation-induced cd45 exon skipping" SIGNOR-168389 GSK3B protein P49841 UNIPROT SFPQ protein P23246 UNIPROT down-regulates phosphorylation 9606 20932480 t miannu "Psf is directly phosphorylated by gsk3, thus promoting interaction of psf with trap150, which prevents psf from binding cd45 pre-mrna. / threonine phosphorylation of psf by gsk3 primarily occurs on residue t687" SIGNOR-168392 GSK3B protein P49841 UNIPROT FCAR protein P24071 UNIPROT "down-regulates activity" phosphorylation Ser284 LTFARTPsVCK 10090 BTO:0001516 30766540 t lperfetto "GSK-3 is constitutively active in the absence of cytokine stimulation and can phosphorylate S263, keeping FcalphaRI in the inactive state." SIGNOR-264857 GSK3B protein P49841 UNIPROT CCND1 protein P24385 UNIPROT down-regulates phosphorylation Thr286 EEVDLACtPTDVRDV 9606 BTO:0000150 16504004 t gcesareni "Phosphorylation of cyclin d1 on a single threonine residue near the carboxyl terminus (thr-286) positively regulates proteasomal degradation of d1. Now, we demonstrate that glycogen synthase kinase-3beta (gsk-3beta) phosphorylates cyclin d1 specifically on thr-286, thereby triggering rapid cyclin d1 turnover now, we demonstrate that glycogen synthase kinase-3beta (gsk-3beta) phosphorylates cyclin d1 specifically on thr-286, thereby triggering rapid cyclin d1 turnover." SIGNOR-144818 GSK3B protein P49841 UNIPROT CCND1 protein P24385 UNIPROT down-regulates phosphorylation Thr286 EEVDLACtPTDVRDV 9606 9832503 t gcesareni "Phosphorylation of cyclin d1 on a single threonine residue near the carboxyl terminus (thr-286) positively regulates proteasomal degradation of d1. Now, we demonstrate that glycogen synthase kinase-3beta (gsk-3beta) phosphorylates cyclin d1 specifically on thr-286, thereby triggering rapid cyclin d1 turnover now, we demonstrate that glycogen synthase kinase-3beta (gsk-3beta) phosphorylates cyclin d1 specifically on thr-286, thereby triggering rapid cyclin d1 turnover." SIGNOR-62265 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Thr41 GIHSGATtTAPSLSG 9606 BTO:0000938 BTO:0000142 SIGNOR-C110 19303846 t gcesareni "DISC1 inhibits GSK3beta activity through direct physical interaction, which reduces beta-catenin phosphorylation and stabilizes beta-catenin." SIGNOR-184789 GSK3B protein P49841 UNIPROT CCND1 protein P24385 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr286 EEVDLACtPTDVRDV 9606 phosphorylation:Ser9 SGRPRTTsFAESCKP 23552696 t lperfetto "Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3_ (GSK3_). The AKT-mediated phosphorylation of glycogen synthase kinase 3_ on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1" SIGNOR-245437 GSK3B protein P49841 UNIPROT CCNE1 protein P24864 UNIPROT down-regulates phosphorylation Thr395 PLPSGLLtPPQSGKK 9606 14536078 t gcesareni "Our experiments suggest that gsk3 is the kinase primarily responsible for phosphorylation of cyclin e on t380" SIGNOR-118559 GSK3B protein P49841 UNIPROT CCNE1 protein P24864 UNIPROT down-regulates phosphorylation Thr77 DPCSLIPtPDKEDDD 9606 14536078 t gcesareni "Our experiments suggest that gsk3 is the kinase primarily responsible for phosphorylation of cyclin e on t380" SIGNOR-118563 GSK3B protein P49841 UNIPROT APC protein P25054 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C110 SIGNOR-C110 10698523 t lperfetto "Gsk-3beta-dependent phosphorylation of apc." SIGNOR-75366 GSK3B protein P49841 UNIPROT CCND2 protein P30279 UNIPROT down-regulates phosphorylation Thr280 DELDQAStPTDVRDI 9606 17486076 t lperfetto "Glycogen synthase kinase-3beta and p38 phosphorylate cyclin d2 on thr280 to trigger its ubiquitin/proteasome-dependent degradation in hematopoietic cells" SIGNOR-154668 GSK3B protein P49841 UNIPROT CCND3 protein P30281 UNIPROT down-regulates phosphorylation Thr283 QGPSQTStPTDVTAI 9606 16331257 t lperfetto "We have previously shown that both basal and camp-induced degradation of cyclin d3 in reh cells is dependent on thr-283 phosphorylation by glycogen synthase kinase-3beta (gsk-3beta)." SIGNOR-142880 GSK3B protein P49841 UNIPROT CDC25A protein P30304 UNIPROT "down-regulates quantity by repression" phosphorylation Ser76 SNLQRMGsSESTDSG 9606 BTO:0000567 20348946 t lperfetto "Here, we report that casein kinase 1 alpha (ck1alpha) phosphorylates cdc25a on both s79 and s82 in a hierarchical manner requiring prior phosphorylation of s76 by chk1 or gsk-3beta. This facilitates beta-trcp binding and ubiquitin-mediated proteolysis of cdc25a" SIGNOR-164742 GSK3B protein P49841 UNIPROT PPIF protein P30405 UNIPROT "up-regulates activity" phosphorylation Ser191 IESFGSKsGRTSKKI 9606 BTO:0000007 32814770 t lperfetto "Phosphorylation of cyclophilin D at serine 191 regulates mitochondrial permeability transition pore opening and cell death after ischemia-reperfusion|We conclude that CypD phosphorylation at S191 residue leads to its binding to OSCP and thus sensitizes mPTP opening for the subsequent cell death.|Under baseline condition (WT group), the phosphorylation of CypD by a kinase (e.g. GSK3beta) at S191 induces its translocation to the OSCP, to favor mPTP opening and subsequent cell death at reperfusion." SIGNOR-264880 GSK3B protein P49841 UNIPROT CIITA protein P33076 UNIPROT up-regulates phosphorylation Ser373 VQARLERsSSKSLER 9606 17991736 t gcesareni "Here we report that CIITA represses collagen transcription through a phosphorylation-dependent interaction between its proline/serine/threonine domain and co-repressor molecules such as histone deacetylase (HDAC2) and Sin3B. Mutation of a serine (S373A) in CIITA, within a glycogen synthase kinase 3 (GSK3) consensus site, decreases repression of collagen transcription by blocking interaction with Sin3B" SIGNOR-158959 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 SIGNOR-C110 11955436 t gcesareni "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-116520 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Ser37 YLDSGIHsGATTTAP 9606 SIGNOR-C110 11955436 t gcesareni "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-116524 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Thr41 GIHSGATtTAPSLSG -1 11955436 t "β-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-260016 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Thr41 GIHSGATtTAPSLSG 9606 SIGNOR-C110 11955436 t gcesareni "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-116528 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 BTO:0000586 SIGNOR-C110 16293724 t gcesareni "This leads to the inactivation and release of glycogen synthase kinase 3beta from its complex with axin, thereby relieving the inhibitory phosphorylation of beta-catenin and activating its signaling pathway." SIGNOR-141799 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Ser37 YLDSGIHsGATTTAP 9606 BTO:0000586 SIGNOR-C110 16293724 t gcesareni "This leads to the inactivation and release of glycogen synthase kinase 3beta from its complex with axin, thereby relieving the inhibitory phosphorylation of beta-catenin and activating its signaling pathway." SIGNOR-141803 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Thr41 GIHSGATtTAPSLSG 9606 BTO:0000586 SIGNOR-C110 16293724 t gcesareni "This leads to the inactivation and release of glycogen synthase kinase 3beta from its complex with axin, thereby relieving the inhibitory phosphorylation of beta-catenin and activating its signaling pathway." SIGNOR-141807 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 BTO:0000938 BTO:0000142 SIGNOR-C110 19303846 t gcesareni "DISC1 inhibits GSK3beta activity through direct physical interaction, which reduces beta-catenin phosphorylation and stabilizes beta-catenin." SIGNOR-184781 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Ser37 YLDSGIHsGATTTAP 9606 BTO:0000938 BTO:0000142 SIGNOR-C110 19303846 t gcesareni "DISC1 inhibits GSK3beta activity through direct physical interaction, which reduces beta-catenin phosphorylation and stabilizes beta-catenin." SIGNOR-184785 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 SIGNOR-C110 23151663 t gcesareni "Beta-catenin phosphorylation in vivo is sequentially carried out by two distinct kinases, ckialfa and gsk-3. Ckialfa phosphorylation of s45 proceeds and is required for subsequent gsk-3 phosphorylation of t41, s37, and s33 one key substrate of gsk3 is the transcriptional co-activator beta catenin, whichis inactivated by gsk3 mediated phosphorylation and targeted for proteasomal degradation in unstimulated cells." SIGNOR-199504 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Thr41 GIHSGATtTAPSLSG 9606 SIGNOR-C110 23151663 t gcesareni "Beta-catenin phosphorylation in vivo is sequentially carried out by two distinct kinases, ckialfa and gsk-3. Ckialfa phosphorylation of s45 proceeds and is required for subsequent gsk-3 phosphorylation of t41, s37, and s33 one key substrate of gsk3 is the transcriptional co-activator beta catenin, whichis inactivated by gsk3 mediated phosphorylation and targeted for proteasomal degradation in unstimulated cells." SIGNOR-199512 GSK3B protein P49841 UNIPROT SREBF1 protein P36956 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser430 DTLTPPPsDAGSPFQ 9606 BTO:0000567 16825193 t lperfetto "The transcription factor SREBP1 is degraded by the ubiquitin-proteasome system following phosphorylation of Thr426 and Ser430 in its phosphodegron. We now demonstrate that the glycogen synthase kinase (GSK)-3beta-dependent phosphorylation of these residues in SREBP1 is enhanced in response to specific DNA binding" SIGNOR-236645 GSK3B protein P49841 UNIPROT SREBF1 protein P36956 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr426 TEVEDTLtPPPSDAG 9606 BTO:0000567 16825193 t lperfetto "The transcription factor SREBP1 is degraded by the ubiquitin-proteasome system following phosphorylation of Thr426 and Ser430 in its phosphodegron. We now demonstrate that the glycogen synthase kinase (GSK)-3beta-dependent phosphorylation of these residues in SREBP1 is enhanced in response to specific DNA binding" SIGNOR-236649 GSK3B protein P49841 UNIPROT SREBF1 protein P36956 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser430 DTLTPPPsDAGSPFQ 9606 BTO:0000007 19126544 t lperfetto "Importantly, we demonstrate that the mature form of endogenous SREBP1 is phosphorylated on Ser-434. Glycogen synthase kinase-3 phosphorylates Ser-434, and the phosphorylation of this residue is attenuated in response to insulin signaling. Interestingly, phosphorylation of Ser-434 promotes the glycogen synthase kinase-3-dependent phosphorylation of Thr-426 and Ser-430 and destabilizes SREBP1." SIGNOR-236030 GSK3B protein P49841 UNIPROT SREBF1 protein P36956 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser434 PPPSDAGsPFQSSPL 9606 BTO:0000007 19126544 t lperfetto "Importantly, we demonstrate that the mature form of endogenous SREBP1 is phosphorylated on Ser-434. Glycogen synthase kinase-3 phosphorylates Ser-434, and the phosphorylation of this residue is attenuated in response to insulin signaling. Interestingly, phosphorylation of Ser-434 promotes the glycogen synthase kinase-3-dependent phosphorylation of Thr-426 and Ser-430 and destabilizes SREBP1." SIGNOR-235797 GSK3B protein P49841 UNIPROT SREBF1 protein P36956 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr426 TEVEDTLtPPPSDAG 9606 BTO:0000007 19126544 t lperfetto "Importantly, we demonstrate that the mature form of endogenous SREBP1 is phosphorylated on Ser-434. Glycogen synthase kinase-3 phosphorylates Ser-434, and the phosphorylation of this residue is attenuated in response to insulin signaling. Interestingly, phosphorylation of Ser-434 promotes the glycogen synthase kinase-3-dependent phosphorylation of Thr-426 and Ser-430 and destabilizes SREBP1." SIGNOR-236667 GSK3B protein P49841 UNIPROT CDKN1A protein P38936 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser114 EEDHVDLsLSCTLVP 9606 BTO:0000093 17283049 t lperfetto "Glycogen synthase kinase 3beta phosphorylates p21waf1/cip1 for proteasomal degradation after uv irradiationhere, we show that ser-114 phosphorylation of p21 protein by glycogen synthase kinase 3beta (gsk-3beta) is required for its degradation in response to uv irradiation" SIGNOR-152941 GSK3B protein P49841 UNIPROT PPP1R2 protein P41236 UNIPROT "up-regulates activity" phosphorylation Thr73 MKIDEPStPYHSMMG 9913 BTO:0000142 11320080 t "Protein phosphatase 1 (PP1) is complexed with inhibitor 2 (I-2) in the cytosol. In rabbit muscle extract PP1.I-2 is activated upon preincubation with ATP/Mg. This activation is caused by phosphorylation of I-2 on Thr(72) by glycogen synthase kinase 3 (GSK3)." SIGNOR-251257 GSK3B protein P49841 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates phosphorylation 9606 12123574 t gcesareni "Here, we observed that gsk3beta was able to bind and phosphorylate notch1ic in vitro, and attenuation of gsk3beta activity reduced phosphorylation of notchic in vivo.Functionally, ligand-activated signaling through the endogenous notch1 receptor was reduced in gsk3beta fibroblasts, implying a positive role for gsk3beta in mammalian notch signaling." SIGNOR-90608 GSK3B protein P49841 UNIPROT MAP1B protein P46821 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000938 25040932 t lperfetto "GSK-3beta phosphorylates MAP1B and the adenomatous polyposis coil gene product (APC; Grimes and Jope 2001; Frame and Cohen 2001). The phosphorylation of MAP1B by GSK-3beta suppresses detyrosination of microtubules and decreases the numbers of stable microtubules" SIGNOR-264843 GSK3B protein P49841 UNIPROT CEBPA protein P49715 UNIPROT "up-regulates activity" phosphorylation Thr226 HLQPGHPtPPPTPVP 10090 BTO:0000944 10567568 t "Glycogen synthase kinase 3 (GSK3) phosphorylates T222 and T226, causing a conformational change in C/EBPα. GSK3-mediated phosphorylation does not, in itself, dramatically alter the activity of C/EBPα in our assays. phosphorylation of C/EBPalpha and other substrates by GSK3 may be required for adipogenesis, since treatment of differentiating preadipocytes with lithium inhibits their conversion to adipocytes." SIGNOR-251231 GSK3B protein P49841 UNIPROT CEBPA protein P49715 UNIPROT "up-regulates activity" phosphorylation Thr230 GHPTPPPtPVPSPHP 10090 BTO:0000944 10567568 t "Glycogen synthase kinase 3 (GSK3) phosphorylates T222 and T226, causing a conformational change in C/EBPα. GSK3-mediated phosphorylation does not, in itself, dramatically alter the activity of C/EBPα in our assays. phosphorylation of C/EBPalpha and other substrates by GSK3 may be required for adipogenesis, since treatment of differentiating preadipocytes with lithium inhibits their conversion to adipocytes." SIGNOR-251232 GSK3B protein P49841 UNIPROT PSEN1 protein P49768 UNIPROT "down-regulates activity" phosphorylation Ser353 SHLGPHRsTPESRAA 9606 BTO:0000007 SIGNOR-C110 17360711 t gcesareni "We demonstrate that phosphorylation of serines 353 and 357 by glycogen synthase kinase-3beta (gsk3beta) induces a structural change of the hydrophilic loop of ps1the structural change of ps1 reduces the interaction with beta-catenin leading to decreased phosphorylation and ubiquitination of beta-catenin." SIGNOR-153627 GSK3B protein P49841 UNIPROT EIF2B5 protein Q13144 UNIPROT down-regulates phosphorylation Ser540 MDSEEPDsRGGSPQM 9606 BTO:0000671 18701453 t lperfetto "Gsk3_ phosphorylates eif2b_ at ser-539 (ser-535 in the rat sequence) and inactivates it" SIGNOR-180022 GSK3B protein P49841 UNIPROT PSEN1 protein P49768 UNIPROT "down-regulates activity" phosphorylation Ser357 PHRSTPEsRAAVQEL 9606 BTO:0000007 SIGNOR-C110 17360711 t gcesareni "We demonstrate that phosphorylation of serines 353 and 357 by glycogen synthase kinase-3beta (gsk3beta) induces a structural change of the hydrophilic loop of ps1the structural change of ps1 reduces the interaction with beta-catenin leading to decreased phosphorylation and ubiquitination of beta-catenin." SIGNOR-153631 GSK3B protein P49841 UNIPROT EIF2B2 protein P49770 UNIPROT down-regulates binding 9606 21798082 t gcesareni "Akt also promotes protein synthesis by phosphorylating and inactivating gsk3b, thus releasing the gsk3b-dependent inhibition of the eukariotic translation initiation factor 2b (eif2b)." SIGNOR-175475 GSK3B protein P49841 UNIPROT TSC2 protein P49815 UNIPROT "up-regulates activity" phosphorylation 10116 BTO:0003293 16959574 t lperfetto "Gsk3 inhibits the mtor pathway by phosphorylating tsc2 in a manner dependent on ampk-priming phosphorylation." SIGNOR-149380 GSK3B protein P49841 UNIPROT GSK3B protein P49841 UNIPROT "up-regulates activity" phosphorylation Tyr216 RGEPNVSyICSRYYR 9606 BTO:0000007 14570592 t lperfetto "However, in the present study, we clearly demonstrate that GSK3_ is capable of catalysing the autophosphorylation of Tyr216 in vitro." SIGNOR-236564 GSK3B protein P49841 UNIPROT GSK3B protein P49841 UNIPROT "up-regulates activity" phosphorylation Tyr216 RGEPNVSyICSRYYR 9606 20331603 t lperfetto "Phosphorylation of the residue Tyrosine in 216 position results in the constitutive activity of GSK-3beta and believed to be important target for signal transduction." SIGNOR-217865 GSK3B protein P49841 UNIPROT MNX1 protein P50219 UNIPROT down-regulates phosphorylation Ser77 ADRLRAEsPSPPRLL 9606 24425879 t miannu "Here we show that gsk-3_ inactivates the proapoptotic activity of hlxb9 by phosphorylating hlxb9 at ser-78/ser-80 (phlxb9)." SIGNOR-203657 GSK3B protein P49841 UNIPROT MNX1 protein P50219 UNIPROT down-regulates phosphorylation Ser79 RLRAESPsPPRLLAA 9606 24425879 t miannu "Here we show that gsk-3_ inactivates the proapoptotic activity of hlxb9 by phosphorylating hlxb9 at ser-78/ser-80 (phlxb9)." SIGNOR-203661 GSK3B protein P49841 UNIPROT PDX1 protein P52945 UNIPROT "down-regulates quantity" phosphorylation Ser61 LGALEQGsPPDISPY 10090 BTO:0000783;BTO:0002284 16407209 t "Here we show that a minor portion of IPF1/PDX1 is phosphorylated on serine 61 and/or serine 66 in pancreatic beta-cells. This phosphorylated form of IPF1/PDX1 preferentially accumulates following proteasome inhibition, an effect that is prevented by inhibition of glycogen synthase kinase 3 (GSK3) activity." SIGNOR-255543 GSK3B protein P49841 UNIPROT PDX1 protein P52945 UNIPROT "down-regulates quantity" phosphorylation Ser66 QGSPPDIsPYEVPPL 10090 BTO:0000783;BTO:0002284 16407209 t "Here we show that a minor portion of IPF1/PDX1 is phosphorylated on serine 61 and/or serine 66 in pancreatic beta-cells. This phosphorylated form of IPF1/PDX1 preferentially accumulates following proteasome inhibition, an effect that is prevented by inhibition of glycogen synthase kinase 3 (GSK3) activity." SIGNOR-255544 GSK3B protein P49841 UNIPROT PDX1 protein P52945 UNIPROT "down-regulates quantity" phosphorylation Ser268 LPPGLSAsPQPSSVA 10090 BTO:0002284 19833727 t "We show that glucose levels modulate PDX1 protein phosphorylation at a novel C-terminal GSK3 consensus that maps to serines 268 and 272. A decrease in glucose levels triggers increased turnover of the PDX1 protein in a GSK3-dependent manner, such that PDX1 phosphomutants are refractory to the destabilizing effect of low glucose" SIGNOR-255566 GSK3B protein P49841 UNIPROT PDX1 protein P52945 UNIPROT "down-regulates quantity" phosphorylation Ser272 LSASPQPsSVAPRRP 10090 BTO:0002284 19833727 t "We show that glucose levels modulate PDX1 protein phosphorylation at a novel C-terminal GSK3 consensus that maps to serines 268 and 272. A decrease in glucose levels triggers increased turnover of the PDX1 protein in a GSK3-dependent manner, such that PDX1 phosphomutants are refractory to the destabilizing effect of low glucose" SIGNOR-255567 GSK3B protein P49841 UNIPROT ACLY protein P53396 UNIPROT "up-regulates activity" phosphorylation Ser451 STSTPAPsRTASFSE 10653665 t "Thr 446 and Ser 450, which are phosphorylated by glycogen synthase kinase-3 (GSK-3)" SIGNOR-251218 GSK3B protein P49841 UNIPROT ACLY protein P53396 UNIPROT "up-regulates activity" phosphorylation Thr447 NASGSTStPAPSRTA 10653665 t "Thr 446 and Ser 450, which are phosphorylated by glycogen synthase kinase-3 (GSK-3). Phosphorylation resulted in a 6-fold increase in V(max) and the conversion of citrate dependence from sigmoidal, displaying negative cooperativity, to hyperbolic." SIGNOR-251219 GSK3B protein P49841 UNIPROT RCAN1 protein P53805 UNIPROT "up-regulates activity" phosphorylation Ser163 PDKQFLIsPPASPPV 10090 BTO:0000165 12063245 t lperfetto "Consensus phosphorylation sites for p42/44 MAPK and GSK-3 are present in the SP repeat of MCIP1 at serine 112 and serine 108, respectively |Several endogenous proteins are capable of inhibiting the catalytic activity of calcineurin. Modulatory calcineurin interacting protein 1 (MCIP1) is unique among these proteins on the basis of its pattern of expression and its function in a negative feedback loop to regulate calcineurin activity. Here we show that MCIP1 can be phosphorylated by MAPK and glycogen synthase kinase-3 and that phosphorylated MCIP1 is a substrate for calcineurin." SIGNOR-249359 GSK3B protein P49841 UNIPROT ATXN3 protein P54252 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser256 LRRAIQLsMQGSSRN 9606 BTO:0000007 17434145 t lperfetto "Phosphorylation of ataxin-3 by glycogen synthase kinase 3beta at serine 256 regulates the aggregation of ataxin-3|" SIGNOR-264821 GSK3B protein P49841 UNIPROT HDAC4 protein P56524 UNIPROT down-regulates phosphorylation Ser298 ACSSAPGsGPSSPNN 9606 21118993 t lperfetto "The double mutation of serines 298/302 into alanines, but also the sole mutation of serine 302, abolishes hdac4 phosphorylation by gsk3_we have shown that cells lacking gsk3_ are unable to degrade hdac4 after serum starvation" SIGNOR-170144 GSK3B protein P49841 UNIPROT HDAC4 protein P56524 UNIPROT down-regulates phosphorylation Ser302 APGSGPSsPNNSSGS 9606 21118993 t lperfetto "The double mutation of serines 298/302 into alanines, but also the sole mutation of serine 302, abolishes hdac4 phosphorylation by gsk3_we have shown that cells lacking gsk3_ are unable to degrade hdac4 after serum starvation" SIGNOR-170148 GSK3B protein P49841 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr66 NVNTKCItIPRSLDG 9606 18172167 t lpetrilli "Mechanistically, axin facilitates gsk3-beta-mediated phosphorylation of smad3 at thr66, which triggers smad3 ubiquitination and degradation." SIGNOR-160318 GSK3B protein P49841 UNIPROT HSF1 protein Q00613 UNIPROT down-regulates phosphorylation Ser303 RVKEEPPsPPQSPRV 9606 8940068 t gcesareni "Sequential phosphorylation by mitogen-activated protein kinase and glycogen synthase kinase 3 represses transcriptional activation by heat shock factor-1." SIGNOR-44995 GSK3B protein P49841 UNIPROT CDX2 protein Q99626 UNIPROT unknown phosphorylation Ser295 LQASVPGsVPGVLGP -1 16027724 t "GSK-3, p38 and CDK2 can phosphorylate Cdx2 through the 4S motif in vitro, but only CDK2 was shown to be active in vivo. the compound mutant 4S>A (serines 281, 285, 289 and 293 replaced by alanines)" SIGNOR-251230 GSK3B protein P49841 UNIPROT HSF1 protein Q00613 UNIPROT "down-regulates activity" phosphorylation Ser303 RVKEEPPsPPQSPRV -1 8940068 t "Ser-303 is phosphorylated by glycogen synthase kinase 3 (GSK3) through a mechanism dependent on primary phosphorylation of Ser-307 by MAPK. Secondary phosphorylation of Ser-303 by GSK3 may thus repress the activity of HSF-1, and its requirement for priming by MAPK phosphorylation of Ser-307 provides a potential link between the MAPK cascade and HSF-1." SIGNOR-251216 GSK3B protein P49841 UNIPROT CAP1 protein Q01518 UNIPROT "up-regulates activity" phosphorylation Ser308 SAPKPQTsPSPKRAT 9606 BTO:0000763 30123351 t lperfetto "We found that GSK3 phosphorylates S307 and S309 by using inhibitors LiCl. Inhibition of GSK3beta can cause loss of cell polarity as well as accumulation of stress fibers. We propose that GSK3 regulates CAP1 through at least two mechanisms. First, GSK3 (and potentially other kinases) phosphorylate CAP1 at S309 and promote CAP1 localization to the cytosol. Second, phosphorylation at S309 affects protein-protein interactions with actin and cofilin. The loss of this phospho-regulation by GSK3 inhibition is expected to disrupt CAP1 function and actin dynamics." SIGNOR-264822 GSK3B protein P49841 UNIPROT CAP1 protein Q01518 UNIPROT "up-regulates activity" phosphorylation Ser310 PKPQTSPsPKRATKK 9606 BTO:0000763 30123351 t lperfetto "We found that GSK3 phosphorylates S307 and S309 by using inhibitors LiCl. Inhibition of GSK3beta can cause loss of cell polarity as well as accumulation of stress fibers. We propose that GSK3 regulates CAP1 through at least two mechanisms. First, GSK3 (and potentially other kinases) phosphorylate CAP1 at S309 and promote CAP1 localization to the cytosol. Second, phosphorylation at S309 affects protein-protein interactions with actin and cofilin. The loss of this phospho-regulation by GSK3 inhibition is expected to disrupt CAP1 function and actin dynamics." SIGNOR-264823 GSK3B protein P49841 UNIPROT ROR2 protein Q01974 UNIPROT "down-regulates activity" phosphorylation Ser864 PKPSSHHsGSGSTST 9606 SIGNOR-C110 21078818 t gcesareni "We identify ror2 ser 864 as a critical residue phosphorylated by gsk3 and required for noncanonical receptor activation by wnt5a, analogous to the priming phosphorylation of low-density receptor-related protein 6 (lrp6) in response to wnt3a." SIGNOR-169642 GSK3B protein P49841 UNIPROT PRKCE protein Q02156 UNIPROT up-regulates phosphorylation Ser346 SEEDRSKsAPTSPCD 9606 18604201 t llicata "Specifically, we have identified three phosphorylation sites within pkcepsilon that control its association with 14-3-3.kinase (ser 350), gsk3 (ser 346) and pkc itself (ser 368)" SIGNOR-179412 GSK3B protein P49841 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser468 AVFTDLAsVDNSEFQ 9606 BTO:0000782 SIGNOR-C13 16407239 t gcesareni "Rela is phosphorylated at: ser276 by the catalytic subunit of protein kinase a (pkac), msk1 and msk2; at ser311 by the atypical pkczeta; at ser468 by ikkbeta, ikkepsilon and glycogen-synthase kinase-3beta (gsk3beta); at ser529 by ck2; and at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1)) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k) ." SIGNOR-143581 GSK3B protein P49841 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser468 AVFTDLAsVDNSEFQ 9606 SIGNOR-C13 17183360 t gcesareni "Rela is phosphorylated at: ser276 by the catalytic subunit of protein kinase a (pkac), msk1 and msk2; at ser311 by the atypical pkczeta; at ser468 by ikkbeta, ikkepsilon and glycogen-synthase kinase-3beta (gsk3beta); at ser529 by ck2; and at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1)) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k) ." SIGNOR-151422 GSK3B protein P49841 UNIPROT RELA protein Q04206 UNIPROT "up-regulates activity" phosphorylation Thr254 RQVAIVFRtPPYADPS 10090 BTO:0000249 22761446 t "Redundant functions of GSK-3_ and GSK-3_ through phosphorylation of RelA at Thr-254 play a crucial role in early stages of chondrocyte differentiation" SIGNOR-255828 GSK3B protein P49841 UNIPROT NOTCH2 protein Q04721 UNIPROT "down-regulates activity" phosphorylation Ser2070 DEYNVTPsPPGTVLT 9606 BTO:0000007 12794074 t "Ser-2093 is efficiently phosphorylated by GSK-3β and, to a minor extent, residues Thr-2068 and/or Ser-2070 and Thr-2074 of Notch2 are also targets for GSK-3β-dependent phosphorylation. We also find that GSK-3β-dependent phosphorylation of Notch2 is inhibiting transcriptional activation of different Notch target genes." SIGNOR-251254 GSK3B protein P49841 UNIPROT NOTCH2 protein Q04721 UNIPROT "down-regulates activity" phosphorylation Ser2093 GPNRSFLsLKHTPMG 9606 BTO:0000007 12794074 t "Ser-2093 is efficiently phosphorylated by GSK-3β and, to a minor extent, residues Thr-2068 and/or Ser-2070 and Thr-2074 of Notch2 are also targets for GSK-3β-dependent phosphorylation. We also find that GSK-3β-dependent phosphorylation of Notch2 is inhibiting transcriptional activation of different Notch target genes." SIGNOR-251253 GSK3B protein P49841 UNIPROT NOTCH2 protein Q04721 UNIPROT "down-regulates activity" phosphorylation Thr2068 LLDEYNVtPSPPGTV 9606 BTO:0000007 12794074 t lperfetto "We show that gsk-3beta directly binds at c-terminal of the notch2 ankyrin repeats and phosphorylates thr-2068 and/or ser-2070, thr-2074, and thr-2093." SIGNOR-101570 GSK3B protein P49841 UNIPROT NOTCH2 protein Q04721 UNIPROT "down-regulates activity" phosphorylation Thr2074 VTPSPPGtVLTSALS 9606 BTO:0000007 12794074 t lperfetto "We show that gsk-3beta directly binds at c-terminal of the notch2 ankyrin repeats and phosphorylates thr-2068 and/or ser-2070, thr-2074, and thr-2093." SIGNOR-101574 GSK3B protein P49841 UNIPROT BAX protein Q07812 UNIPROT up-regulates phosphorylation Ser163 GGWDGLLsYFGTPTW 9606 BTO:0000938 15525785 t lperfetto "Glycogen synthase kinase-3beta phosphorylates bax and promotes its mitochondrial localization during neuronal apoptosis. Gsk-3beta directly phosphorylated bax(alpha) on ser163" SIGNOR-130141 GSK3B protein P49841 UNIPROT MCL1 protein Q07820 UNIPROT down-regulates phosphorylation Ser159 NNTSTDGsLPSTPPP 9606 16543145 t gcesareni "We investigated the role of glycogen synthase kinase-3 (gsk-3), which is inactivated by akt, for its role in the regulation of apoptosis. Upon il-3 withdrawal, protein levels of mcl-1 decreased but were sustained by pharmacological gsk-3, which prevented cytochrome c release and apoptosis. Mcl-1 was phosphorylated by gsk-3 at a conserved gsk-3 phosphorylation site (s159). S159 phosphorylation of mcl-1 was induced by il-3 withdrawal or pi3k inhibition and prevented by akt or gsk-3, and it led to increased ubiquitinylation and degradation of mcl-1." SIGNOR-145200 GSK3B protein P49841 UNIPROT MCL1 protein Q07820 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser159 NNTSTDGsLPSTPPP 10090 BTO:0003328 16543145 t "MCL-1 was phosphorylated by GSK-3 at a conserved GSK-3 phosphorylation site (S159). S159 phosphorylation of MCL-1 was induced by IL-3 withdrawal or PI3K inhibition and prevented by AKT or inhibition of GSK-3, and it led to increased ubiquitinylation and degradation of MCL-1." SIGNOR-251242 GSK3B protein P49841 UNIPROT EIF2B5 protein Q13144 UNIPROT down-regulates binding 9606 21798082 t gcesareni "Akt also promotes protein synthesis by phosphorylating and inactivating gsk3b, thus releasing the gsk3b-dependent inhibition of the eukariotic translation initiation factor 2b (eif2b)." SIGNOR-175621 GSK3B protein P49841 UNIPROT EIF2B5 protein Q13144 UNIPROT "down-regulates activity" phosphorylation Ser540 MDSEEPDsRGGSPQM 9606 BTO:0000007 11500362 t "We identify multiple phosphorylation sites in the largest, catalytic, subunit (epsilon) of mammalian eIF2B. Glycogen synthase kinase 3 (GSK3) is responsible for phosphorylating Ser535. This regulatory phosphorylation event requires both the fourth site (Ser539) and a distal region, which acts to recruit GSK3 to eIF2Bepsilon in vivo. eIF2Bϵ from mammals or insects is a substrate for glycogen synthase kinase 3 (GSK3), and this inhibits the activity of eIF2B" SIGNOR-251237 GSK3B protein P49841 UNIPROT EIF2B5 protein Q13144 UNIPROT "down-regulates activity" phosphorylation Ser535 ESEQSMDsEEPDSRG -1 12133000 t "The largest (epsilon) subunit of eIF2B is a substrate for glycogen synthase kinase (GSK)-3 in vitro, and phosphorylation by GSK3 inhibits the activity of eIF2B. The site of phosphorylation has previously been identified as Ser(535)." SIGNOR-251236 GSK3B protein P49841 UNIPROT NFATC2 protein Q13469 UNIPROT down-regulates phosphorylation 9606 15276472 t lperfetto "Gsk3 was previously shown to directly phosphorylate the n-terminal regulatory domain of nfatc1, thus antagonizing the action of calcineurin and inhibiting nuclear shuttling of nfat." SIGNOR-179784 GSK3B protein P49841 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr37 PPGDYSTtPGGTLFS 9606 BTO:0000671 18701453 t lperfetto "We found that gsk-3Beta phosphorylates and inactivates 4e-bp1, thereby increasing eif4e-dependent protein synthesis. upon stimulation, 4e-bp1 is phosphorylated on several threonine and serine residues, including thr-37/46 (36). This results in dissolution of the complex, freeing eif4e to bind with mrna cap to promote translation initiation." SIGNOR-236026 GSK3B protein P49841 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr46 GGTLFSTtPGGTRII 9606 BTO:0000671 18701453 t lperfetto "We found that gsk-3Beta phosphorylates and inactivates 4e-bp1, thereby increasing eif4e-dependent protein synthesis. upon stimulation, 4e-bp1 is phosphorylated on several threonine and serine residues, including thr-37/46 (36). This results in dissolution of the complex, freeing eif4e to bind with mrna cap to promote translation initiation." SIGNOR-236660 GSK3B protein P49841 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr46 GGTLFSTtPGGTRII 9606 23584478 t lperfetto "Glycogen synthase kinase-3_ positively regulates protein synthesis and cell proliferation through the regulation of translation initiation factor 4E-binding protein 1We found that GSK-3_ phosphorylates and inactivates 4E-BP1, thereby increasing eIF4E-dependent protein synthesis." SIGNOR-201699 GSK3B protein P49841 UNIPROT KLF5 protein Q13887 UNIPROT down-regulates phosphorylation Ser303 QATYFPPsPPSSEPG 9606 24398687 t lperfetto "Stability of the klf5 is mediated by proteasomal degradation via phosphorylation by glycogen synthase kinase 3_ (gsk3_) and recognition by f-box and wd repeat domain-containing 7 (fbw7) of a phosphodegron sequence surrounding serine 303 in klf5" SIGNOR-203627 GSK3B protein P49841 UNIPROT HNRNPD protein Q14103 UNIPROT down-regulates phosphorylation Ser83 DEGHSNSsPRHSEAA 9606 11903055 t gcesareni "In kinase assays pka phosphorylated ser-87 of hnrnp d, whereas glycogen synthase kinase-3 beta (gsk-3 beta) phosphorylated ser-83, but only if ser-87 had been pre-phosphorylated by pka. Phosphorylation of ser-87 enhanced, whereas phosphorylation of ser-83 repressed, transactivation." SIGNOR-116140 GSK3B protein P49841 UNIPROT HNRNPD protein Q14103 UNIPROT "down-regulates activity" phosphorylation Ser83 DEGHSNSsPRHSEAA 9606 BTO:0001271 11903055 t lperfetto "In kinase assays pka phosphorylated ser-87 of hnrnp d, whereas glycogen synthase kinase-3 beta (gsk-3 beta) phosphorylated ser-83, but only if ser-87 had been pre-phosphorylated by pka. Phosphorylation of ser-87 enhanced, whereas phosphorylation of ser-83 repressed, transactivation." SIGNOR-102582 GSK3B protein P49841 UNIPROT CRMP1 protein Q14194 UNIPROT up-regulates phosphorylation Ser518 KYATPAPsAKSSPSK 9606 BTO:0000938 16611631 t lperfetto "Using in vitro kinase assays and pharmacological inhibition of gsk3 as described above for crmp2 and crmp4, it was found that thr509 (and presumably ser518 and thr514) of human crmp1 is phosphorylated by gsk3, following priming of ser522 by cdk5" SIGNOR-145991 GSK3B protein P49841 UNIPROT CRMP1 protein Q14194 UNIPROT up-regulates phosphorylation Thr509 PVYEVPAtPKYATPA 9606 BTO:0000938 16611631 t lperfetto "In summary, phosphorylation of thr509 of human crmp1 appears to be regulated by two mechanisms; direct phosphorylation by cdk5, or by priming of ser522 by cdk5 followed by sequential phosphorylation of ser518, thr514, and thr509 by gsk3." SIGNOR-145995 GSK3B protein P49841 UNIPROT CRMP1 protein Q14194 UNIPROT up-regulates phosphorylation Thr514 PATPKYAtPAPSAKS 9606 BTO:0000938 16611631 t lperfetto "Using in vitro kinase assays and pharmacological inhibition of gsk3 as described above for crmp2 and crmp4, it was found that thr509 (and presumably ser518 and thr514) of human crmp1 is phosphorylated by gsk3, following priming of ser522 by cdk5" SIGNOR-145999 GSK3B protein P49841 UNIPROT DPYSL3 protein Q14195 UNIPROT "down-regulates activity" phosphorylation Ser522 PAGSARGsPTRPNPP 10116 BTO:0000938 16611631 t lperfetto "Primary rat cortical neurons were treated with purvalanol, a more potent inhibitor of cdk5 and dyrk2 than roscovitine (25). Phosphorylation was monitored using antibodies that specifically recognize crmp2 when phosphorylated at thr514/thr509, or crmp4 when phosphorylated at thr509. Loss of phosphorylation of ser522 will prevent subsequent phosphorylation of ser518/thr514/thr509 by gsk3. Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro" SIGNOR-146007 GSK3B protein P49841 UNIPROT DPYSL3 protein Q14195 UNIPROT "up-regulates activity" phosphorylation Ser518 KGGTPAGsARGSPTR 10116 16611631 t lperfetto "Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro" SIGNOR-146003 GSK3B protein P49841 UNIPROT DPYSL3 protein Q14195 UNIPROT "up-regulates activity" phosphorylation Thr509 PVFDLTTtPKGGTPA 10116 16611631 t lperfetto "Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro" SIGNOR-146011 IDH3A protein P50213 UNIPROT "Isocitrate Dehydrogenase" complex SIGNOR-C396 SIGNOR "form complex" binding 9606 28139779 t miannu "Human NAD-dependent isocitrate dehydrogenase existing as the α2βγ heterotetramer, catalyzes the decarboxylation of isocitrate into α-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP." SIGNOR-266248 GSK3B protein P49841 UNIPROT DPYSL3 protein Q14195 UNIPROT "up-regulates activity" phosphorylation Thr514 TTTPKGGtPAGSARG 10116 16611631 t lperfetto "Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro" SIGNOR-146015 GSK3B protein P49841 UNIPROT EIF2B1 protein Q14232 UNIPROT down-regulates binding 9606 21798082 t gcesareni "Akt also promotes protein synthesis by phosphorylating and inactivating gsk3b, thus releasing the gsk3b-dependent inhibition of the eukariotic translation initiation factor 2b (eif2b)." SIGNOR-175436 GSK3B protein P49841 UNIPROT GRB14 protein Q14449 UNIPROT "down-regulates activity" phosphorylation Ser358 MHPYQGRsGCSSQSI -1 28130417 t lperfetto "Phosphorylation of clustered serine residues in the N-terminus of BPS domain negatively regulates formation of the complex between human Grb14 and insulin receptor| In vitro kinase assay using the motif-derived peptides showed that the serine residues located in N-terminal (Ser358, Ser362 and Ser366) and C-terminal (Ser419 and Ser423) regions of the BPS domain were phosphorylated by GSK-3." SIGNOR-264868 GSK3B protein P49841 UNIPROT GRB14 protein Q14449 UNIPROT "down-regulates activity" phosphorylation Ser362 QGRSGCSsQSISPMR -1 28130417 t lperfetto "Phosphorylation of clustered serine residues in the N-terminus of BPS domain negatively regulates formation of the complex between human Grb14 and insulin receptor| In vitro kinase assay using the motif-derived peptides showed that the serine residues located in N-terminal (Ser358, Ser362 and Ser366) and C-terminal (Ser419 and Ser423) regions of the BPS domain were phosphorylated by GSK-3." SIGNOR-264867 GSK3B protein P49841 UNIPROT GRB14 protein Q14449 UNIPROT "down-regulates activity" phosphorylation Ser366 GCSSQSIsPMRSISE -1 28130417 t lperfetto "Phosphorylation of clustered serine residues in the N-terminus of BPS domain negatively regulates formation of the complex between human Grb14 and insulin receptor| In vitro kinase assay using the motif-derived peptides showed that the serine residues located in N-terminal (Ser358, Ser362 and Ser366) and C-terminal (Ser419 and Ser423) regions of the BPS domain were phosphorylated by GSK-3." SIGNOR-264869 GSK3B protein P49841 UNIPROT NFE2L1 protein Q14494 UNIPROT down-regulates phosphorylation Ser379 SQDFLLFsPEVESLP 9606 BTO:0000938 23623971 t lperfetto "Glycogen synthase kinase 3 regulates expression of nuclear factor-erythroid-2 related transcription factor-1 (nrf1) and inhibits pro-survival function of nrf1" SIGNOR-193450 GSK3B protein P49841 UNIPROT NBR1 protein Q14596 UNIPROT "down-regulates activity" phosphorylation Thr586 HNTPVDVtPCMSPLP -1 24879152 t lperfetto "The autophagy receptor NBR1 (neighbor of BRCA1 gene 1) binds UB/ubiquitin and the autophagosome-conjugated MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3) proteins, thereby ensuring ubiquitinated protein degradation|Here we show that NBR1 is a substrate of GSK3. NBR1 phosphorylation by GSK3 at Thr586 prevents the aggregation of ubiquitinated proteins and their selective autophagic degradation." SIGNOR-261795 GSK3B protein P49841 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation 9606 18045539 t gcesareni "Phosphorylation at the gsk3 sites represses the transcriptional activity of smad1 by enhancing proteasomal degradation of psmad1cter" SIGNOR-159484 GSK3B protein P49841 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates binding 9606 17726008 t gcesareni "Here we show that similar to the interaction with traf4 and axin, the kinase domain of mekk4 interacts with the multifunctional serine/threonine kinase gsk3beta. Gsk3beta binding to mekk4 blocks mekk4 dimerization that is required for mekk4 activation, effectively inhibiting mekk4 stimulation of the jnk and p38 mapk pathways" SIGNOR-157544 GSK3B protein P49841 UNIPROT DPYSL2 protein Q16555 UNIPROT "down-regulates activity" phosphorylation Ser518 KTVTPASsAKTSPAK 10116 BTO:0000938 15652488 t lperfetto "Ser-518 is also a potential phosphorylation site of CRMP-2 by GSK-3_." SIGNOR-133251 GSK3B protein P49841 UNIPROT DPYSL2 protein Q16555 UNIPROT "down-regulates activity" phosphorylation Thr514 SVTPKTVtPASSAKT 10116 BTO:0000938 15652488 t lperfetto "Here, we showed that glycogen synthase kinase-3beta (gsk-3beta) phosphorylated crmp-2 at thr-514 and inactivated it" SIGNOR-133255 GSK3B protein P49841 UNIPROT ARHGAP31 protein Q2M1Z3 UNIPROT "up-regulates activity" phosphorylation Thr789 PPAPPPPtPLEESTP 10090 BTO:0000944 17158447 t miannu "We show that GSK-3alpha and -beta interact with CdGAP in mammalian cells. We also demonstrate that GSK-3 phosphorylates CdGAP both in vitro and in vivo on Thr-776, which we have previously shown to be an ERK 1/2 phosphorylation site involved in CdGAP regulation." SIGNOR-262879 GSK3B protein P49841 UNIPROT BORA protein Q6PGQ7 UNIPROT up-regulates phosphorylation Ser274 TSPSPISsPTFSPIE 9606 23442801 t lperfetto "It suggests that gsk3_ activity is required for hbora-mediated mitotic entry through ser274 and ser278 phosphorylation" SIGNOR-201515 GSK3B protein P49841 UNIPROT BORA protein Q6PGQ7 UNIPROT up-regulates phosphorylation Ser278 PISSPTFsPIEFQIG 9606 23442801 t lperfetto "It suggests that gsk3_ activity is required for hbora-mediated mitotic entry through ser274 and ser278 phosphorylation" SIGNOR-201519 GSK3B protein P49841 UNIPROT ZNF322 protein Q6U7Q0 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser391 SEKGLELsPPHASEA 9606 BTO:0002552 28581525 t lperfetto "CK1delta and GSK3beta kinases sequentially phosphorylate ZNF322A at serine-396 and then serine-391. Moreover, the doubly phosphorylated ZNF322A protein creates a destruction motif for the ubiquitin ligase FBXW7alpha leading to ZNF322A protein destruction." SIGNOR-264891 GSK3B protein P49841 UNIPROT MYOCD protein Q8IZQ8 UNIPROT "down-regulates activity" phosphorylation Ser451 NGFYHFGsTSSSPPI 9606 BTO:0000007 16141410 t "In vitro and in vivo (HEK 293 cells) kinase assays with synthetic peptides and full-length myocardin demonstrated that myocardin was a primed GSK3beta substrate, with serines 455 to 467 and 624 to 636 being the major GSK3beta phosphorylation sites.  GSK3β phosphorylation at the sites identified inhibits myocardin intrinsic transcriptional activity" SIGNOR-251245 GSK3B protein P49841 UNIPROT DPYSL2 protein Q16555 UNIPROT "down-regulates activity" phosphorylation Thr514 SVTPKTVtPASSAKT 9606 phosphorylation:Ser522 PASSAKTsPAKQQAP 25040932 t lperfetto "Cdk5 and DYRK2 phosphorylate CRMP2 and CRMP4, respectively, priming these proteins at S522 before their subsequent phosphorylation by GSK-3b at T509, T516 and S518|e CRMP2 phosphorylation by GSK-3b disrupts its interaction with tubulin (Yamashita & Goshima, 2012), leading to growth inhibition" SIGNOR-264840 GSK3B protein P49841 UNIPROT MYOCD protein Q8IZQ8 UNIPROT "down-regulates activity" phosphorylation Ser455 HFGSTSSsPPISPAS 9606 BTO:0000007 16141410 t "In vitro and in vivo (HEK 293 cells) kinase assays with synthetic peptides and full-length myocardin demonstrated that myocardin was a primed GSK3beta substrate, with serines 455 to 467 and 624 to 636 being the major GSK3beta phosphorylation sites.  GSK3β phosphorylation at the sites identified inhibits myocardin intrinsic transcriptional activity" SIGNOR-251244 GSK3B protein P49841 UNIPROT MYOCD protein Q8IZQ8 UNIPROT "down-regulates activity" phosphorylation Ser459 TSSSPPIsPASSDLS 9606 BTO:0000007 16141410 t "In vitro and in vivo (HEK 293 cells) kinase assays with synthetic peptides and full-length myocardin demonstrated that myocardin was a primed GSK3beta substrate, with serines 455 to 467 and 624 to 636 being the major GSK3beta phosphorylation sites.  GSK3β phosphorylation at the sites identified inhibits myocardin intrinsic transcriptional activity" SIGNOR-251243 GSK3B protein P49841 UNIPROT MYOCD protein Q8IZQ8 UNIPROT "down-regulates activity" phosphorylation Ser463 PPISPASsDLSVAGS 9606 BTO:0000007 16141410 t "In vitro and in vivo (HEK 293 cells) kinase assays with synthetic peptides and full-length myocardin demonstrated that myocardin was a primed GSK3beta substrate, with serines 455 to 467 and 624 to 636 being the major GSK3beta phosphorylation sites.  GSK3β phosphorylation at the sites identified inhibits myocardin intrinsic transcriptional activity" SIGNOR-251246 GSK3B protein P49841 UNIPROT MYOCD protein Q8IZQ8 UNIPROT "down-regulates activity" phosphorylation Ser626 DQTNVLSsTFLSPQC 9606 BTO:0000007 16141410 t "In vitro and in vivo (HEK 293 cells) kinase assays with synthetic peptides and full-length myocardin demonstrated that myocardin was a primed GSK3beta substrate, with serines 455 to 467 and 624 to 636 being the major GSK3beta phosphorylation sites.  GSK3β phosphorylation at the sites identified inhibits myocardin intrinsic transcriptional activity" SIGNOR-251247 GSK3B protein P49841 UNIPROT MYOCD protein Q8IZQ8 UNIPROT "down-regulates activity" phosphorylation Ser630 VLSSTFLsPQCSPQH 9606 BTO:0000007 16141410 t "In vitro and in vivo (HEK 293 cells) kinase assays with synthetic peptides and full-length myocardin demonstrated that myocardin was a primed GSK3beta substrate, with serines 455 to 467 and 624 to 636 being the major GSK3beta phosphorylation sites.  GSK3β phosphorylation at the sites identified inhibits myocardin intrinsic transcriptional activity" SIGNOR-251248 GSK3B protein P49841 UNIPROT MYOCD protein Q8IZQ8 UNIPROT "down-regulates activity" phosphorylation Ser634 TFLSPQCsPQHSPLG 9606 BTO:0000007 16141410 t "In vitro and in vivo (HEK 293 cells) kinase assays with synthetic peptides and full-length myocardin demonstrated that myocardin was a primed GSK3beta substrate, with serines 455 to 467 and 624 to 636 being the major GSK3beta phosphorylation sites.  GSK3β phosphorylation at the sites identified inhibits myocardin intrinsic transcriptional activity" SIGNOR-251249 GSK3B protein P49841 UNIPROT MYOCD protein Q8IZQ8 UNIPROT "down-regulates activity" phosphorylation Ser638 PQCSPQHsPLGAVKS 9606 BTO:0000007 16141410 t "In vitro and in vivo (HEK 293 cells) kinase assays with synthetic peptides and full-length myocardin demonstrated that myocardin was a primed GSK3beta substrate, with serines 455 to 467 and 624 to 636 being the major GSK3beta phosphorylation sites.  GSK3β phosphorylation at the sites identified inhibits myocardin intrinsic transcriptional activity" SIGNOR-251250 GSK3B protein P49841 UNIPROT MAFA protein Q8NHW3 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser49 CHRLPPGsLSSTPLS 9606 18042454 t miannu "We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity." SIGNOR-159458 GSK3B protein P49841 UNIPROT MAFA protein Q8NHW3 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser61 PLSTPCSsVPSSPSF 9606 18042454 t miannu "We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity." SIGNOR-159462 GSK3B protein P49841 UNIPROT MAFA protein Q8NHW3 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr53 PPGSLSStPLSTPCS 9606 18042454 t miannu "We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity." SIGNOR-159466 GSK3B protein P49841 UNIPROT MAFA protein Q8NHW3 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr57 LSSTPLStPCSSVPS 9606 18042454 t miannu "We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity." SIGNOR-159470 GSK3B protein P49841 UNIPROT MAFA protein Q8NHW3 UNIPROT "up-regulates activity" phosphorylation Ser49 CHRLPPGsLSSTPLS 9606 18042454 t miannu "We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity." SIGNOR-159442 GSK3B protein P49841 UNIPROT MAFA protein Q8NHW3 UNIPROT "up-regulates activity" phosphorylation Ser61 PLSTPCSsVPSSPSF 9606 18042454 t miannu "We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity." SIGNOR-159446 GSK3B protein P49841 UNIPROT MAFA protein Q8NHW3 UNIPROT "up-regulates activity" phosphorylation Thr53 PPGSLSStPLSTPCS 9606 18042454 t miannu "We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity." SIGNOR-159450 GSK3B protein P49841 UNIPROT MAFA protein Q8NHW3 UNIPROT "up-regulates activity" phosphorylation Thr57 LSSTPLStPCSSVPS 9606 18042454 t miannu "We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity." SIGNOR-159454 GSK3B protein P49841 UNIPROT MAML1 protein Q92585 UNIPROT down-regulates phosphorylation 9606 19740771 t gcesareni "We found that gsk3beta inhibits maml1 transcriptional activity by directly targeting the n-terminal domain of maml1" SIGNOR-187896 GSK3B protein P49841 UNIPROT KAT5 protein Q92993 UNIPROT up-regulates phosphorylation Ser86 TKNGLPGsRPGSPER 9606 21658600 t gcesareni "We demonstrate that gsk-3 phosphorylates serine 86 of the p53-acetyltransferase tip60. A tip60(s86a) mutant was less active to induce p53 k120 acetylation, histone 4 acetylation, and expression of puma" SIGNOR-174049 GSK3B protein P49841 UNIPROT OSBP2 protein Q969R2 UNIPROT "up-regulates activity" phosphorylation 30925160 t lperfetto "CK1a1, JNK1 and CDK1 had the highest site-specific activity for ORP4L, while CDK1, GSK3a, CK1a1 and GSK3b showed the highest specificity for the site when corrected for background activity with ORP4L-S4A. Because of the complexity of the serine/proline-rich site, we did not determine which serine(s) in ORP4L were phosphorylated by candidate kinases.|We conclude that phosphorylation of a unique serine/proline motif in the ORD induces a conformation change in ORP4L that enhances interaction with vimentin and cholesterol extraction from membranes." SIGNOR-264874 GSK3B protein P49841 UNIPROT BICD1 protein Q96G01 UNIPROT "up-regulates activity" phosphorylation Ser585 SEPVAKEsTEASKEP 9606 BTO:0000567 17139249 t miannu "Therefore, at least Ser585 and Thr597 in BICD1 are important phosphorylation sites for BICD1 to exert its functions, and GSK-3β-dependent phosphorylation is required for the interaction of BICD1 with dynein." SIGNOR-262743 GSK3B protein P49841 UNIPROT BICD1 protein Q96G01 UNIPROT "up-regulates activity" phosphorylation Thr597 KEPSPTKtPTISPVI 9606 BTO:0000567 17139249 t miannu "Therefore, at least Ser585 and Thr597 in BICD1 are important phosphorylation sites for BICD1 to exert its functions, and GSK-3β-dependent phosphorylation is required for the interaction of BICD1 with dynein." SIGNOR-262744 GSK3B protein P49841 UNIPROT SPAG5 protein Q96R06 UNIPROT up-regulates phosphorylation Ser974 EESLAEMsIMTTELQ 9606 18055457 t lperfetto "Astrin acts as a substrate for gsk3beta and is phosphorylated at thr-111, thr-937 ((s/t)p motif) and ser-974/thr-978 ((s/t)xxx(s/t)-p motif;p is a phosphorylatable residue). Inhibition of gsk3beta impairs spindle and kinetochore accumulation of astrin and spindle formation at mitosis, suggesting that astrin association with the spindle microtubule and kinetochore may be dependent on phosphorylation by gsk3beta" SIGNOR-159574 GSK3B protein P49841 UNIPROT SPAG5 protein Q96R06 UNIPROT up-regulates phosphorylation Thr111 PIPQISStPKTSEEA 9606 18055457 t lperfetto "Astrin acts as a substrate for gsk3beta and is phosphorylated at thr-111, thr-937 ((s/t)p motif) and ser-974/thr-978 ((s/t)xxx(s/t)-p motif;p is a phosphorylatable residue). Inhibition of gsk3beta impairs spindle and kinetochore accumulation of astrin and spindle formation at mitosis, suggesting that astrin association with the spindle microtubule and kinetochore may be dependent on phosphorylation by gsk3beta" SIGNOR-159578 GSK3B protein P49841 UNIPROT SPAG5 protein Q96R06 UNIPROT up-regulates phosphorylation Thr937 ADEEPEStPVPLLGS 9606 18055457 t lperfetto "Astrin acts as a substrate for gsk3beta and is phosphorylated at thr-111, thr-937 ((s/t)p motif) and ser-974/thr-978 ((s/t)xxx(s/t)-p motif;p is a phosphorylatable residue). Inhibition of gsk3beta impairs spindle and kinetochore accumulation of astrin and spindle formation at mitosis, suggesting that astrin association with the spindle microtubule and kinetochore may be dependent on phosphorylation by gsk3beta" SIGNOR-159582 GSK3B protein P49841 UNIPROT SPAG5 protein Q96R06 UNIPROT up-regulates phosphorylation Thr978 AEMSIMTtELQSLCS 9606 18055457 t lperfetto "Astrin acts as a substrate for gsk3beta and is phosphorylated at thr-111, thr-937 ((s/t)p motif) and ser-974/thr-978 ((s/t)xxx(s/t)-p motif;p is a phosphorylatable residue). Inhibition of gsk3beta impairs spindle and kinetochore accumulation of astrin and spindle formation at mitosis, suggesting that astrin association with the spindle microtubule and kinetochore may be dependent on phosphorylation by gsk3beta" SIGNOR-159586 GSK3B protein P49841 UNIPROT CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser129 ICPSLPYsPVSSPQS 9606 22778263 t lperfetto "Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity." SIGNOR-198134 GSK3B protein P49841 UNIPROT CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser133 LPYSPVSsPQSSPRL 9606 22778263 t lperfetto "Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity." SIGNOR-198138 GSK3B protein P49841 UNIPROT CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser137 PVSSPQSsPRLPRRP 9606 22778263 t lperfetto "Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity." SIGNOR-198142 GSK3B protein P49841 UNIPROT CDX2 protein Q99626 UNIPROT unknown phosphorylation Ser283 RSVPEPLsPVSSLQA -1 16027724 t "GSK-3, p38 and CDK2 can phosphorylate Cdx2 through the 4S motif in vitro, but only CDK2 was shown to be active in vivo. the compound mutant 4S>A (serines 281, 285, 289 and 293 replaced by alanines)" SIGNOR-251227 GSK3B protein P49841 UNIPROT CDX2 protein Q99626 UNIPROT unknown phosphorylation Ser287 EPLSPVSsLQASVPG -1 16027724 t "GSK-3, p38 and CDK2 can phosphorylate Cdx2 through the 4S motif in vitro, but only CDK2 was shown to be active in vivo. the compound mutant 4S>A (serines 281, 285, 289 and 293 replaced by alanines)" SIGNOR-251228 GSK3B protein P49841 UNIPROT CDX2 protein Q99626 UNIPROT unknown phosphorylation Ser291 PVSSLQAsVPGSVPG -1 16027724 t "GSK-3, p38 and CDK2 can phosphorylate Cdx2 through the 4S motif in vitro, but only CDK2 was shown to be active in vivo. the compound mutant 4S>A (serines 281, 285, 289 and 293 replaced by alanines)" SIGNOR-251229 GSK3B protein P49841 UNIPROT DPYSL5 protein Q9BPU6 UNIPROT "up-regulates activity" phosphorylation Thr516 TPLADTPtRPVTRHG 9606 BTO:0000938 25040932 t lperfetto "The T516 phosphorylation was achieved by the glycogen synthase kinase-3beta (GSK-3beta), which can phosphorylate the wildtype protein but not the non-phosphorylatable mutant. Furthermore, we have shown that T516 phosphorylation is essential for the tubulin-binding property of CRMP5. Therefore, CRMP5-induced growth inhibition is dependent on T516 phosphorylation through the GSK-3beta pathway." SIGNOR-264835 GSK3B protein P49841 UNIPROT NIFK protein Q9BYG3 UNIPROT "up-regulates activity" phosphorylation Thr234 TVDSQGPtPVCTPTF -1 16244663 t miannu "The forkhead-associated (FHA) domain of human Ki67 interacts with the human nucleolar protein hNIFK, recognizing a 44-residue fragment, hNIFK226-269, phosphorylated at Thr234. Here we show that high-affinity binding requires sequential phosphorylation by two kinases, CDK1 and GSK3, yielding pThr238, pThr234 and pSer230. phosphorylation of Thr234 by GSK3 proceeds only after Thr238 is already phosphorylated by CDK1." SIGNOR-262698 GSK3B protein P49841 UNIPROT RBM38 protein Q9H0Z9 UNIPROT down-regulates phosphorylation Ser195 DQYPYAAsPATAASF 9606 24142875 t lperfetto "Here, we showed that rnpc1 is phosphorylated at ser195 by glycogen synthase kinase 3 (gsk3). We also provided evidence that ser195 phosphorylation converts rnpc1 from a repressor to an activator of p53." SIGNOR-203011 GSK3B protein P49841 UNIPROT BCL2L12 protein Q9HB09 UNIPROT up-regulates phosphorylation Ser156 SESPRPCsLPIRPCY 9606 BTO:0000527 22262180 t lperfetto "Gsk3b phosphorylates bcl2l12 at s156. Ectopic expression of gfp-fused bcl2l12 or bcl2l12a in u87mg cells leads to repression of apoptotic markers and protects against staurosporine (sts) insults, indicating an antiapoptotic role for both bcl2l12 and bcl2l12a. In contrast, no anti-apoptotic ability was seen in bcl2l12(s156a)" SIGNOR-195512 GSK3B protein P49841 UNIPROT GPHN protein Q9NQX3 UNIPROT down-regulates phosphorylation Ser270 LSTTPSEsPRAQATS 9606 BTO:0000142 23408424 t miannu "Identification of gsk3_ as the kinase targeting ser-270 /phosphorylation at ser-270 promotes gephyrin processing by calpain" SIGNOR-200957 GSK3B protein P49841 UNIPROT EIF2B3 protein Q9NR50 UNIPROT down-regulates binding 9606 21798082 t gcesareni "Akt also promotes protein synthesis by phosphorylating and inactivating gsk3b, thus releasing the gsk3b-dependent inhibition of the eukariotic translation initiation factor 2b (eif2b)." SIGNOR-175520 GSK3B protein P49841 UNIPROT DROSHA protein Q9NRR4 UNIPROT "up-regulates activity" phosphorylation Ser300 RHRDNRRsPSLERSY -1 25699712 t lperfetto "Our findings suggest that phosphorylation of Drosha at multiple sites including S300 promotes its translocation to the cytoplasm. Interestingly, GSK3beta can phosphorylate Drosha at S300 and S302 in vitro. This has been reported to promote the nuclear localization of Drosha under basal condition (Tang et al., 2011). Thus, it appears that phosphorylation of S300 by GSK3beta and p38 MAPK is involved in opposing processes. " SIGNOR-264845 GSK3B protein P49841 UNIPROT DROSHA protein Q9NRR4 UNIPROT "up-regulates activity" phosphorylation Ser302 RDNRRSPsLERSYKK -1 25699712 t lperfetto "Our findings suggest that phosphorylation of Drosha at multiple sites including S300 promotes its translocation to the cytoplasm. Interestingly, GSK3beta can phosphorylate Drosha at S300 and S302 in vitro. This has been reported to promote the nuclear localization of Drosha under basal condition (Tang et al., 2011). Thus, it appears that phosphorylation of S300 by GSK3beta and p38 MAPK is involved in opposing processes. " SIGNOR-264846 GSK3B protein P49841 UNIPROT STMN3 protein Q9NZ72 UNIPROT "up-regulates activity" phosphorylation Ser60 SFEVILKsPSDLSPE -1 22577147 t lperfetto "Altogether, these results indicate that CDK5 phosphorylates similarly serines 68 and 73, whereas ERK2 targets mostly serine 68 and GSK-3beta mostly serine 60.|This observation may support the hypothesis of a specific localization of stathmin 3 depending on its phosphorylation by GSK-3beta" SIGNOR-264882 GSK3B protein P49841 UNIPROT EIF2B4 protein Q9UI10 UNIPROT down-regulates binding 9606 21798082 t gcesareni "Akt also promotes protein synthesis by phosphorylating and inactivating gsk3b, thus releasing the gsk3b-dependent inhibition of the eukariotic translation initiation factor 2b (eif2b)." SIGNOR-175572 GSK3B protein P49841 UNIPROT AKAP11 protein Q9UKA4 UNIPROT "down-regulates activity" phosphorylation Thr1136 AKEFAPAtPPSTPHN 9606 BTO:0000007 26088133 t lperfetto "A-kinase anchoring protein 220 (AKAP220) is a multivalent anchoring protein that can sequester a variety of signal transduction enzymes. These include protein kinase A (PKA) and glycogen synthase kinase 3beta (GSK3beta). Using a combination of molecular and cellular approaches we show that GSK3beta phosphorylation of Thr-1132 on AKAP220 initiates recruitment of this kinase into the enzyme scaffold. We also find that AKAP220 anchors GSK3beta and its substrate beta-catenin in membrane ruffles." SIGNOR-264816 GSK3B protein P49841 UNIPROT FBXO4 protein Q9UKT5 UNIPROT up-regulates phosphorylation Ser12 EPRSGTNsPPPPFSD 9606 21242966 t lperfetto "Gsk3beta-mediated phosphorylation of fbx4 ser12 during the g1/s transition regulates fbx4 dimerization, which in turn governs fbx4-driven e3 ligase activity." SIGNOR-171648 GSK3B protein P49841 UNIPROT FBXL21P protein Q9UKT6 UNIPROT "up-regulates activity" phosphorylation Thr33 FYSSLNQtHTHTVLL 9606 BTO:0000007 32937135 t lperfetto "GSK-3beta phosphorylates FBXL21 and TCAP to activate FBXL21-mediated, phosphodegron-dependent TCAP degradation.|These results show direct GSK-3beta phosphorylation of TCAP S157 and FBXL21 T33 sites." SIGNOR-264851 GSK3B protein P49841 UNIPROT MACF1 protein Q9UPN3 UNIPROT "down-regulates activity" phosphorylation Ser7222 FRSRGRRsKPSSRAA 9606 BTO:0004905 21295697 t lperfetto "We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules." SIGNOR-264426 GSK3B protein P49841 UNIPROT MACF1 protein Q9UPN3 UNIPROT "down-regulates activity" phosphorylation Ser7230 KPSSRAAsPTRSSSS 9606 BTO:0004905 21295697 t lperfetto "We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules." SIGNOR-264428 GSK3B protein P49841 UNIPROT MACF1 protein Q9UPN3 UNIPROT "down-regulates activity" phosphorylation Ser7234 RAASPTRsSSSASQS 9606 BTO:0004905 21295697 t lperfetto "We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules." SIGNOR-264429 GSK3B protein P49841 UNIPROT MACF1 protein Q9UPN3 UNIPROT "down-regulates activity" phosphorylation Ser7310 ADPKKSAsRPGSRAG 9606 BTO:0004905 21295697 t lperfetto "We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules." SIGNOR-264430 GSK3B protein P49841 UNIPROT MACF1 protein Q9UPN3 UNIPROT "down-regulates activity" phosphorylation Ser7314 KSASRPGsRAGSRAG 9606 BTO:0004905 21295697 t lperfetto "We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules." SIGNOR-264431 GSK3B protein P49841 UNIPROT MACF1 protein Q9UPN3 UNIPROT "down-regulates activity" phosphorylation Ser7318 RPGSRAGsRAGSRAS 9606 BTO:0004905 21295697 t lperfetto "We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules." SIGNOR-264432 GSK3B protein P49841 UNIPROT MACF1 protein Q9UPN3 UNIPROT "down-regulates activity" phosphorylation Ser7322 RAGSRAGsRASSRRG 9606 BTO:0004905 21295697 t lperfetto "We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules." SIGNOR-264433 GSK3B protein P49841 UNIPROT MACF1 protein Q9UPN3 UNIPROT "down-regulates activity" phosphorylation Ser7326 RAGSRASsRRGSDAS 9606 BTO:0004905 21295697 t lperfetto "We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules." SIGNOR-264434 GSK3B protein P49841 UNIPROT MACF1 protein Q9UPN3 UNIPROT "down-regulates activity" phosphorylation Ser7330 RASSRRGsDASDFDL 9606 BTO:0004905 21295697 t lperfetto "We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules." SIGNOR-264435 GSK3B protein P49841 UNIPROT ZNF281 protein Q9Y2X9 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser638 PRVDLHTsGEHSELV 9606 BTO:0001615 29179460 t lperfetto "GSK-3beta phosphorylation-dependent degradation of ZNF281 by beta-TrCP2 suppresses colorectal cancer progression|" SIGNOR-264890 GSK3B protein P49841 UNIPROT MAFB protein Q9Y5Q3 UNIPROT down-regulates phosphorylation 9606 18042454 t miannu "We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity." SIGNOR-159476 GSK3B protein P49841 UNIPROT MAFB protein Q9Y5Q3 UNIPROT up-regulates phosphorylation 9606 18042454 t miannu "We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity." SIGNOR-159473 GSK3B protein P49841 UNIPROT SNCAIP protein Q9Y6H5 UNIPROT down-regulates phosphorylation Ser556 AQKSEGKsLPSSPSS 9606 BTO:0000938 16174773 t lperfetto "Synphilin-1 s556a mutant, which is less phosphorylated by gsk3beta, formed more inclusion bodies than wild type synphilin-1. Mutation analysis showed that ser556 is a major gsk3beta phosphorylation site in synphilin-1" SIGNOR-140609 GSK3B protein P49841 UNIPROT MAP3K4 protein Q9Y6R4 UNIPROT down-regulates binding 9606 17726008 t gcesareni "Gsk3beta binding to mekk4 blocks mekk4 dimerization that is required for mekk4 activation, effectively inhibiting mekk4 stimulation of the jnk and p38 mapk pathways" SIGNOR-157541 GSK3B protein P49841 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "form complex" binding 9606 BTO:0000586 9734785 t lperfetto "Axin, an inhibitor of the wnt pathway, interacts with beta-catenin, gsk-3beta and apc and reduces the beta-catenin level." SIGNOR-227299 GSK3B protein P49841 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 BTO:0000782 16407239 t lperfetto "Rela is phosphorylated at: ser276 by the catalytic subunit of protein kinase a (pkac), msk1 and msk2; at ser311 by the atypical pkczeta; at ser468 by ikkbeta, ikkepsilon and glycogen-synthase kinase-3beta (gsk3beta); at ser529 by ck2; and at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1)) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k) ." SIGNOR-217430 GSK3B protein P49841 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 17183360 t lperfetto "Rela is phosphorylated at: ser276 by the catalytic subunit of protein kinase a (pkac), msk1 and msk2; at ser311 by the atypical pkczeta; at ser468 by ikkbeta, ikkepsilon and glycogen-synthase kinase-3beta (gsk3beta); at ser529 by ck2; and at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1)) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k) ." SIGNOR-217367 GSK3B protein P49841 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "up-regulates activity" 25309941 f "Following GSK3β activation, NF-κB is translocated from the cytoplasm to the nucleus and binds transcriptional sites with CBP leading to an increase in the transcription of pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6)." SIGNOR-255485 GSK3B protein P49841 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR "down-regulates quantity by destabilization" phosphorylation 9606 phosphorylation:Ser9 SGRPRTTsFAESCKP 23552696 t lperfetto "Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3_ (GSK3_). The AKT-mediated phosphorylation of glycogen synthase kinase 3_ on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1" SIGNOR-245432 GSK3B protein P49841 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR "up-regulates activity" phosphorylation 9606 33081032 t miannu "GSK3β regulates S6K1 activity positively through modulating phosphorylation of S6K1 at p.Ser371." SIGNOR-263513 STK19 protein P49842 UNIPROT NRAS protein P01111 UNIPROT "up-regulates activity" phosphorylation Ser89 FAINNSKsFADINLY 9606 BTO:0003476 30712867 t lperfetto "STK19 Phosphorylates NRAS Protein at Serine 89|STK19 phosphorylates NRAS to enhance its binding to its downstream effectors and promotes oncogenic NRAS-mediated melanocyte malignant transformation.|" SIGNOR-264566 TAF6 protein P49848 UNIPROT TFIID complex SIGNOR-C343 SIGNOR "form complex" binding 9606 27096372 t miannu "The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences." SIGNOR-263922 DIO1 protein P49895 UNIPROT iodide smallmolecule CHEBI:16382 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 34674502 t scontino "Three different deiodinases have been described: iodothyronine deiodinase 1 (DIO1), DIO2, and DIO3. Deiodination is the first step in the activation/inactivation process of THs and involves the removal of removes one iodine atom from the outer tyrosyl ring of T4 to produce T3." SIGNOR-266954 DIO1 protein P49895 UNIPROT L-thyroxine smallmolecule CHEBI:18332 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 BTO:0004055 1400883 t scontino "The type I 5' iodothyronine deiodinase (5' DI) catalyzes the deiodination of T4 to the biologically active hormone T3 and accounts for a significant fraction of its production." SIGNOR-266944 DIO1 protein P49895 UNIPROT 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 BTO:0004055 1400883 t scontino "The type I 5' iodothyronine deiodinase (5' DI) catalyzes the deiodination of T4 to the biologically active hormone T3 and accounts for a significant fraction of its production." SIGNOR-266945 ZNF165 protein P49910 UNIPROT SMAD7 protein O15105 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000356 26567849 t Luana "ZNF165 drives the unrestrained activation of transforming growth factor β (TGFβ) signalling by directly inactivating the expression of negative feedback pathway regulators, SMURF2, SMAD7 and PMEPA1." SIGNOR-266093 ZNF165 protein P49910 UNIPROT PMEPA1 protein Q969W9 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000356 26567849 t Luana "ZNF165 drives the unrestrained activation of transforming growth factor β (TGFβ) signalling by directly inactivating the expression of negative feedback pathway regulators, SMURF2, SMAD7 and PMEPA1." SIGNOR-266094 ZNF165 protein P49910 UNIPROT SMURF2 protein Q9HAU4 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000356 26567849 t Luana "ZNF165 drives the unrestrained activation of transforming growth factor β (TGFβ) signalling by directly inactivating the expression of negative feedback pathway regulators, SMURF2, SMAD7 and PMEPA1." SIGNOR-266095 CAMP protein P49913 UNIPROT FPR2 protein P25090 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000876 11015447 t gcesareni "Ll-37 may contribute to innate and adaptive immunity by recruiting neutrophils, monocytes, and t cells to sites of microbial invasion by interacting with fprl1." SIGNOR-82701 GMPS protein P49915 UNIPROT TP53 protein P04637 UNIPROT up-regulates binding 9606 24462112 t miannu "In response to genotoxic stress or nucleotide deprivation, gmps becomes nuclear and facilitates p53 stabilization by promoting its transfer from mdm2 to a gmps-usp7 deubiquitylation complex." SIGNOR-204409 LIG4 protein P49917 UNIPROT "Lig4-Xrcc4 complex" complex SIGNOR-C354 SIGNOR "form complex" binding -1 19837014 t miannu "The DNA ligase IV-Xrcc4 complex is responsible for the ligation of broken DNA ends in the non-homologous end-joining (NHEJ) pathway of DNA double strand break repair in mammals." SIGNOR-264533 MRE11 protein P49959 UNIPROT NBN protein O60934 UNIPROT up-regulates binding 9606 17713585 t esanto "The mre11_rad50_nbs1 (mrn) complex is among the earliest respondents to dna double-strand breaks (dsbs). To organize the mrn complex, the mre11 exonuclease directly binds nbs1, dna, and rad50." SIGNOR-157475 MRE11 protein P49959 UNIPROT ATM protein Q13315 UNIPROT up-regulates binding 9606 18854157 t gcesareni "One of the earliest events is recruitment and activation of the atm at the damaged dna sites through the mre11rad50nbs1 (mrn) sensor complex. the mre11/rad50/nbs1 (mrn) complex maintains genomic stability by bridging dna ends and initiating dna damage signaling through activation of the atm kinase." SIGNOR-181628 MRE11 protein P49959 UNIPROT ATM protein Q13315 UNIPROT up-regulates binding 9606 21763684 t gcesareni "One of the earliest events is recruitment and activation of the atm at the damaged dna sites through the mre11rad50nbs1 (mrn) sensor complex. the mre11/rad50/nbs1 (mrn) complex maintains genomic stability by bridging dna ends and initiating dna damage signaling through activation of the atm kinase." SIGNOR-175006 AGTR2 protein P50052 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 BTO:0001130;BTO:0000551 11313903 t gcesareni "These neuropeptide gpcrs are coupled to the activation of phospholipase c, and therefore to calcium ele- vation and protein kinase c (pkc) activation, through g proteins of the alfaq family" SIGNOR-106995 KHK protein P50053 UNIPROT PRPS1 protein P60891 UNIPROT "up-regulates activity" phosphorylation Thr225 LVDDMADtCGTICHA 29074724 t lperfetto "Ketohexokinase-A (KHK-A; also known as fructokinase-A) phosphorylates PRPS1 T225 and activates PRPS1 by blocking the binding of ADP, AMP, and GDP, which is required for hepatocellular carcinoma development" SIGNOR-265735 RBP2 protein P50120 UNIPROT "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI "up-regulates quantity" relocalization 9606 31963453 t lperfetto "Either acting on the producing cell (autocrine signaling) or the receiving cell (paracrine signaling), RA is transferred into the nucleus by Cellular retinoic acid-binding protein 2 (CRABP2) [18]. Once inside the nucleus, RA binds to specific nuclear transcription factors named Retinoic acid receptors (RARs)" SIGNOR-265130 GNAQ protein P50148 UNIPROT RHOA protein P61586 UNIPROT up-regulates binding 9606 17606614 t gcesareni "Recently, the dbl-family guanine nucleotide exchange factor (gef) p63rhogef/geft has been described as a novel mediator of galpha(q/11) signaling to rhoa based on its ability to synergize with galpha(q/11) resulting in enhanced rhoa signaling in cells." SIGNOR-156534 GNAQ protein P50148 UNIPROT ARHGEF25 protein Q86VW2 UNIPROT "up-regulates activity" binding -1 17606614 t "P63RhoGEF is autoinhibited by the Dbl homology (DH)-associated pleckstrin homology (PH) domain; activated Galpha(q) relieves this autoinhibition by interacting with a highly conserved C-terminal extension of the PH domain" SIGNOR-256493 GNAQ protein P50148 UNIPROT TRIOBP protein Q9H2D6 UNIPROT "up-regulates activity" binding -1 17606614 t "We show that the C-terminal Rho-specific DH-PH cassette of Trio is similarly activated by Galpha(q)" SIGNOR-256494 GNAQ protein P50148 UNIPROT PLCB1 protein Q9NQ66 UNIPROT up-regulates binding 9606 8245028 t gcesareni "The beta- but not the gamma- and delta-type isozymes of inositol phospholipid-specific phospholipase c (plc) are activated by g protein alpha q and beta gamma subunits." SIGNOR-37149 GNAQ protein P50148 UNIPROT ARHGEF12 protein Q9NZN5 UNIPROT "up-regulates activity" binding 10090 BTO:0000944 12024019 t "Leukemia-associated Rho guanine nucleotide exchange factor promotes G alpha q-coupled activation of RhoA." SIGNOR-256520 GNAQ protein P50148 UNIPROT PLCE1 protein Q9P212 UNIPROT up-regulates binding 9606 17251915 t gcesareni "Typically galfas 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 manymolecules, including phospholipases, ion channels and lipid kinases." SIGNOR-152609 MMP14 protein P50281 UNIPROT F12 protein P00748 UNIPROT "down-regulates quantity by destabilization" cleavage Gly376 SMTRVVGgLVALRGA -1 10930399 t lperfetto "The data presented in this study show for the first time the degradation of Factor XII of the blood clotting system by matrix metalloproteinases. MMP-12, MMP-13, and MMP-14 cleave at Gly376Leu377|However, no activity of Factor XII can be observed after MMPinduced cleavage." SIGNOR-263610 MMP14 protein P50281 UNIPROT FGA protein P02671 UNIPROT "down-regulates quantity by destabilization" cleavage Leu105 NNKDSHSlTTNIMEI -1 10930399 t lperfetto "Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-14 27YVATRDN g-chain| 105XDAATLKSR g-chain | 92LTYNPDES g-chain |105LTTNIXEXL a-chain|433LVTSKGDKE a-chain| 117FXSANNRD a-chain" SIGNOR-263619 MMP14 protein P50281 UNIPROT FGA protein P02671 UNIPROT "down-regulates quantity by destabilization" cleavage Leu433 REYHTEKlVTSKGDK -1 10930399 t lperfetto "Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-14 27YVATRDN g-chain| 105XDAATLKSR g-chain | 92LTYNPDES g-chain |105LTTNIXEXL a-chain|433LVTSKGDKE a-chain| 117FXSANNRD a-chain" SIGNOR-263620 MMP14 protein P50281 UNIPROT FGA protein P02671 UNIPROT "down-regulates quantity by destabilization" cleavage Phe117 MEILRGDfSSANNRD -1 10930399 t lperfetto "Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-14 27YVATRDN g-chain| 105XDAATLKSR g-chain | 92LTYNPDES g-chain |105LTTNIXEXL a-chain|433LVTSKGDKE a-chain| 117FXSANNRD a-chain" SIGNOR-263621 MMP14 protein P50281 UNIPROT FGG protein P02679 UNIPROT "down-regulates quantity by destabilization" cleavage Ile105 ESSKPNMiDAATLKS -1 10930399 t lperfetto "Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-14 27YVATRDN g-chain| 105XDAATLKSR g-chain | 92LTYNPDES g-chain |105LTTNIXEXL a-chain|433LVTSKGDKE a-chain| 117FXSANNRD a-chain" SIGNOR-263618 MMP14 protein P50281 UNIPROT FGG protein P02679 UNIPROT "down-regulates quantity by destabilization" cleavage Leu92 QLIKAIQlTYNPDES -1 10930399 t lperfetto "Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-14 27YVATRDN g-chain| 105XDAATLKSR g-chain | 92LTYNPDES g-chain |105LTTNIXEXL a-chain|433LVTSKGDKE a-chain| 117FXSANNRD a-chain" SIGNOR-263617 MMP14 protein P50281 UNIPROT FGG protein P02679 UNIPROT "down-regulates quantity by destabilization" cleavage Tyr27 LSSTCVAyVATRDNC -1 10930399 t lperfetto "Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-14 27YVATRDN g-chain| 105XDAATLKSR g-chain | 92LTYNPDES g-chain |105LTTNIXEXL a-chain|433LVTSKGDKE a-chain| 117FXSANNRD a-chain" SIGNOR-263616 MMP14 protein P50281 UNIPROT ADAM9 protein Q13443 UNIPROT "down-regulates quantity by destabilization" cleavage 9606 BTO:0000007 22632802 t Giulio "Here we show that MT1-MMP forms a complex with FGFR2 and ADAM9 in osteoblasts and proteolytically inactivates ADAM9|Western blotting using antibodies against ectodomain of ADAM9 detected a fragment (around 26 kDa) of ADAM9 in the conditioned culture medium from cells cotransfected with wild-type MT1-MMP, but not in that with catalytic activity-dead MT1-MMP (Figure 6A, top)." SIGNOR-260301 HTR6 protein P50406 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257395 HTR6 protein P50406 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257186 CPT1A protein P50416 UNIPROT palmitoyl-CoA(4-) smallmolecule CHEBI:57379 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 14517227 t miannu "Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C)." SIGNOR-267126 HTR6 protein P50406 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257274 HTR6 protein P50406 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256944 HTR6 protein P50406 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257340 HTR6 protein P50406 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257073 HTR6 protein P50406 UNIPROT GNA13 protein Q14344 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257443 HTR6 protein P50406 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256801 CPT1A protein P50416 UNIPROT (R)-carnitine smallmolecule CHEBI:16347 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 14517225 t miannu "Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C)." SIGNOR-267120 CPT1A protein P50416 UNIPROT O-palmitoyl-L-carnitine smallmolecule CHEBI:17490 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 14517227 t miannu "Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C)." SIGNOR-267129 CPT1A protein P50416 UNIPROT "coenzyme A(4-)" smallmolecule CHEBI:57287 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 14517227 t miannu "Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C)." SIGNOR-267132 LHX2 protein P50458 UNIPROT CGA protein P01215 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9534 BTO:0001538 7513049 t Luana "In Cos cells, LH-2 activated the a-subunit promoter approximately twofold" SIGNOR-266055 CSRP3 protein P50461 UNIPROT MYOD1 protein P15172 UNIPROT "up-regulates activity" binding 10090 BTO:0004058 9234731 t 2 miannu "we found that nuclear MLP functions through a physical interaction with the muscle basic helix-loop-helix (bHLH) transcription factors MyoD, MRF4, and myogenin. we propose that it serves as a cofactor for the myogenic bHLH proteins by increasing their interaction with specific DNA regulatory elements." SIGNOR-241116 CSRP3 protein P50461 UNIPROT MYOG protein P15173 UNIPROT "up-regulates activity" binding 10090 BTO:0004058 9234731 t 2 miannu "we found that nuclear MLP functions through a physical interaction with the muscle basic helix-loop-helix (bHLH) transcription factors MyoD, MRF4, and myogenin. we propose that it serves as a cofactor for the myogenic bHLH proteins by increasing their interaction with specific DNA regulatory elements." SIGNOR-241113 CSRP3 protein P50461 UNIPROT MYF6 protein P23409 UNIPROT "up-regulates activity" binding 10090 BTO:0004058 9234731 t 2 miannu "we found that nuclear MLP functions through a physical interaction with the muscle basic helix-loop-helix (bHLH) transcription factors MyoD, MRF4, and myogenin. we propose that it serves as a cofactor for the myogenic bHLH proteins by increasing their interaction with specific DNA regulatory elements." SIGNOR-241096 MXI1 protein P50539 UNIPROT CCNB1 protein P14635 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002036 11875718 t Luana "Mxi1 inhibits the proliferation of U87 glioma cells through down-regulation of cyclin B1 gene expression | Mxi1 inhibits the promoter activity of the cyclin B1 gene." SIGNOR-266064 PEX5 protein P50542 UNIPROT SQSTM1 protein Q13501 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 ubiquitination:Lys209 VAKVDDPkLANSEFL 26344566 t "Specificity for autophagy of peroxisomes (pexophagy) is provided by ATM phosphorylation of PEX5 at Ser 141, which promotes PEX5 monoubiquitylation at Lys 209, and recognition of ubiquitylated PEX5 by the autophagy adaptor protein p62, directing the autophagosome to peroxisomes to induce pexophagy. " SIGNOR-262793 ASCL1 protein P50553 UNIPROT DKK1 protein O94907 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000527 23707066 t gcesareni "We demonstrate that a critical factor in the set, ASCL1, activates Wnt signaling by repressing the negative regulator DKK1." SIGNOR-245885 DNM2 protein P50570 UNIPROT MYO1C protein O00159 UNIPROT up-regulates binding 9606 17257598 t miannu "Dynamin bind directly to the sh3 domain of myo1e / an intriguing possibility is that binding of dynamin and synaptojanin to myo1e tail may activate motor activity since it has been demonstrated that myo1e atpase activity is autoinhibited by its sh3 domain" SIGNOR-152910 DNM2 protein P50570 UNIPROT VAV1 protein P15498 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000584 23537630 t "Disruption of the Dyn2-Vav1 interaction targets Vav1 to the lysosome for degradation via an interaction with the cytoplasmic chaperone Hsc70, resulting in a dramatic reduction of Vav1 protein stability." SIGNOR-259080 DNM2 protein P50570 UNIPROT GJB2 protein P29033 UNIPROT down-regulates binding 9606 25263585 t miannu "This study identifies dynamin 2 (dyn2) as a cx26 interactor in yeast and mammalian cells / we demonstrate that dyn2 regulates cx26 endocytosis and ubiquitination" SIGNOR-205372 TNFSF10 protein P50591 UNIPROT TNFRSF10A protein O00220 UNIPROT up-regulates binding 9606 14585074 t amattioni "Trail interacts with tril-r1 and trail-r2 and activetes them" SIGNOR-101082 TNFSF10 protein P50591 UNIPROT TNFRSF10B protein O14763 UNIPROT up-regulates binding 9606 14585074 t amattioni "Trail interacts with tril-r1 and trail-r2 and activetes them" SIGNOR-101313 TNFSF10 protein P50591 UNIPROT TNFRSF10B protein O14763 UNIPROT up-regulates binding 9606 BTO:0000150;BTO:0000551;BTO:0000785 15766588 t gcesareni "Tumour necrosis factor-related apoptosis inducing ligand (trail) receptor 2 (trail-r2) also known as tnfrsf10b (tumour necrosis factor receptor (tnfr) super family 10b) or killer/dr5, a member of the tnfr family, is a promising candidate tumour suppressor gene at 8p21-22." SIGNOR-134524 CDK7 protein P50613 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 10949034 t lperfetto "Activation of estrogen receptor alpha by s118 phosphorylation involves a ligand-dependent interaction with tfiih and participation of cdk7." SIGNOR-81170 CDK7 protein P50613 UNIPROT TP53 protein P04637 UNIPROT unknown phosphorylation Ser33 LPENNVLsPLPSQAM 9606 9372954 t llicata "We have mapped a major site of phosphorylation by cak to ser-33 of p53 and have demonstrated as well that p53 is phosphorylated at this site in vivo." SIGNOR-53311 CDK7 protein P50613 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser371 AHSSHLKsKKGQSTS 9606 9315650 t llicata "The cdk7-cych-p36 complex of transcription factor iih phosphorylates p53, enhancing its sequence-specific dna binding activity in vitro. serines 371, 376, 378, and 392 may be the potential sites for this kinase." SIGNOR-51280 CDK7 protein P50613 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser376 LKSKKGQsTSRHKKL 9606 9315650 t llicata "The cdk7-cych-p36 complex of transcription factor iih phosphorylates p53, enhancing its sequence-specific dna binding activity in vitro. serines 371, 376, 378, and 392 may be the potential sites for this kinase." SIGNOR-51284 CDK7 protein P50613 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser378 SKKGQSTsRHKKLMF 9606 9315650 t llicata "The cdk7-cych-p36 complex of transcription factor iih phosphorylates p53, enhancing its sequence-specific dna binding activity in vitro. serines 371, 376, 378, and 392 may be the potential sites for this kinase." SIGNOR-51288 CDK7 protein P50613 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser392 FKTEGPDsD 9606 9315650 t llicata "The cdk7-cych-p36 complex of transcription factor iih phosphorylates p53, enhancing its sequence-specific dna binding activity in vitro. serines 371, 376, 378, and 392 may be the potential sites for this kinase." SIGNOR-51292 CDK7 protein P50613 UNIPROT AR protein P10275 UNIPROT down-regulates phosphorylation Ser516 VSRVPYPsPTCVKSE 9606 21157430 t acerquone "Here, we show that the transcription factor tfiih, via its cdk7 kinase, phosphorylates the androgen receptor (ar) at position ar/s515. Strikingly, this phosphorylation is a key step for an accurate transactivation that includes the cyclic recruitment of the transcription machinery, the mdm2 e3 ligase, the subsequent ubiquitination of ar at the promoter of target genes and its degradation by the proteasome machinery" SIGNOR-170599 CDK7 protein P50613 UNIPROT RARA protein P10276 UNIPROT unknown phosphorylation Ser77 EIVPSPPsPPPLPRI 9606 11955452 t llicata "Thus, we demonstrate that the cdk7 kinase of tfiih phosphorylates the nuclear receptor, then allowing ligand-dependent control of the activation of the hormone-responsive genes." SIGNOR-116582 CDK7 protein P50613 UNIPROT RARA protein P10276 UNIPROT up-regulates phosphorylation Ser77 EIVPSPPsPPPLPRI 9606 BTO:0000567 9230306 t llicata "However, only the coexpression of cdk7 stimulated ser-77 phosphorylation in vivo and enhanced transactivation by rar alpha, but not by a s77a rar mutant." SIGNOR-49693 CDK7 protein P50613 UNIPROT CDK4 protein P11802 UNIPROT up-regulates phosphorylation Thr172 YSYQMALtPVVVTLW 9606 8139570 t lperfetto "Phosphorylation of cdk4 on threonine 172 by a cdk-activating kinase (cak). therefore, formation of the cyclin d-cdk4 complex and phosphorylation of the bound catalytic subunit are independently regulated, and in addition to the requirement for cak activity, serum stimulation is required to promote assembly of the complexes in mammalian cells." SIGNOR-36549 CDK7 protein P50613 UNIPROT RARG protein P13631 UNIPROT "up-regulates activity" phosphorylation Ser77 SEEMVPSsPSPPPPP 9534 10748061 t Luana "RARg Is Phosphorylated by cdk7 in Its B and F Regions | Mutation into alanine of Ser-77 and Ser-79 located in the A/B region reduced the transcriptional activity of hRARg1 (Fig. 9A), confirming that these phosphorylation sites are required for optimal transcription." SIGNOR-259853 CDK7 protein P50613 UNIPROT RARG protein P13631 UNIPROT "up-regulates activity" phosphorylation Ser79 EMVPSSPsPPPPPRV 9534 10748061 t Luana "RARg Is Phosphorylated by cdk7 in Its B and F Regions | Mutation into alanine of Ser-77 and Ser-79 located in the A/B region reduced the transcriptional activity of hRARg1 (Fig. 9A), confirming that these phosphorylation sites are required for optimal transcription." SIGNOR-259852 CDK7 protein P50613 UNIPROT CDK11B protein P21127 UNIPROT "up-regulates activity" phosphorylation Thr595 GSPLKAYtPVVVTLW 9606 BTO:0000567 16327805 t gcesareni "We conclude that CDK7 phsphorylates Cdk11, dependent on the conserved Thr219 residue in the CDK11 T loop, and it is therefore likely to be a genuine Cdk11 activating kinase" SIGNOR-245871 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1619 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-119992 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1626 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-119996 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1647 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120000 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1654 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120004 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1668 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120008 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1675 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120012 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1696 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120016 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1717 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120020 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1724 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120024 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1738 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120028 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1766 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120032 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1787 SPNYSPTsPSYSPTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120036 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1864 SPKYSPTsPKYSPTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120040 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1871 SPKYSPTsPKYSPTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120044 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1882 SPTSPTYsPTTPKYS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120048 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1892 TPKYSPTsPTYSPTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120052 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1899 SPTYSPTsPVYTPTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120056 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1913 SPKYSPTsPTYSPTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120060 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1920 SPTYSPTsPKYSPTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120064 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1927 SPKYSPTsPTYSPTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120068 AFF2 protein P51816 UNIPROT P-TEFb complex SIGNOR-C238 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 17135274 t miannu "Af4 associates with P-TEFb and stimulates its kinase activity. P-TEFb also phosphorylates AF4 which down-regulates its transactivation activity, providing a negative feedback mechanism for the control of P-TEFb elongation activity" SIGNOR-266801 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1934 SPTYSPTsPKGSTYS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120072 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1944 GSTYSPTsPGYSPTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120076 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1951 SPGYSPTsPTYSLTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120080 CDK7 protein P50613 UNIPROT CDK2 protein P24941 UNIPROT "up-regulates activity" phosphorylation Thr160 GVPVRTYtHEVVTLW -1 10085115 t llicata "Phosphorylation of monomeric human CDK2 by CAK1 is more efficient than phosphorylation of the binary CDK2-cyclin A complex. Phosphorylated CDK2 exhibits histone H1 kinase activity corresponding to approximately 0.3% of that observed with the fully activated phosphorylated CDK2-cyclin A complex. Fluorescence measurements have shown that Thr160 phosphorylation increases the affinity of CDK2 for both histone substrate and ATP and decreases its affinity for ADP." SIGNOR-250768 CDK7 protein P50613 UNIPROT MCM2 protein P49736 UNIPROT "up-regulates activity" phosphorylation Ser139 RRGLLYDsDEEDEER 9606 16899510 t Luana "Taken together, these results indicate that Cdc7/Dbf4 phosphorylation of MCM2 is essential for the initiation of DNA replication in mammalian cells. | Because MCM2 was phosphorylated in vivo at Ser27, Ser41, and Ser139, which were phosphorylated by Cdc7/Dbf4 in vitro, the results suggested that Ser27, Ser41, and Ser139 are in vivo Cdc7/Dbf4 phosphorylation sites in MCM2." SIGNOR-259850 CDK7 protein P50613 UNIPROT MCM2 protein P49736 UNIPROT "up-regulates activity" phosphorylation Ser27 GNDPLTSsPGRSSRR 9606 16899510 t Luana "Taken together, these results indicate that Cdc7/Dbf4 phosphorylation of MCM2 is essential for the initiation of DNA replication in mammalian cells. | Because MCM2 was phosphorylated in vivo at Ser27, Ser41, and Ser139, which were phosphorylated by Cdc7/Dbf4 in vitro, the results suggested that Ser27, Ser41, and Ser139 are in vivo Cdc7/Dbf4 phosphorylation sites in MCM2." SIGNOR-259848 CDK7 protein P50613 UNIPROT MCM2 protein P49736 UNIPROT "up-regulates activity" phosphorylation Ser41 RTDALTSsPGRDLPP 9606 16899510 t Luana "Taken together, these results indicate that Cdc7/Dbf4 phosphorylation of MCM2 is essential for the initiation of DNA replication in mammalian cells. | Because MCM2 was phosphorylated in vivo at Ser27, Ser41, and Ser139, which were phosphorylated by Cdc7/Dbf4 in vitro, the results suggested that Ser27, Ser41, and Ser139 are in vivo Cdc7/Dbf4 phosphorylation sites in MCM2." SIGNOR-259849 CDK7 protein P50613 UNIPROT E2F1 protein Q01094 UNIPROT down-regulates phosphorylation Ser403 PEEFISLsPPHEALD 9606 10428966 t lperfetto "These results suggest that tfiih-mediated phosphorylation of e2f-1 plays a role in triggering e2f-1 degradation during s phase. here we show that the e2f-1 activation domain interacts with a kinase activity which phosphorylates two sites, ser403 and thr433, within the activation domain." SIGNOR-69776 CDK7 protein P50613 UNIPROT E2F1 protein Q01094 UNIPROT down-regulates phosphorylation Thr433 DCDFGDLtPLDF 9606 10428966 t lperfetto "These results suggest that tfiih-mediated phosphorylation of e2f-1 plays a role in triggering e2f-1 degradation during s phase. here we show that the e2f-1 activation domain interacts with a kinase activity which phosphorylates two sites, ser403 and thr433, within the activation domain." SIGNOR-69780 CDK7 protein P50613 UNIPROT POU5F1 protein Q01860 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser12 LASDFAFsPPPGGGG 9606 BTO:0001086 31306665 t lperfetto "Here, we combined molecular and cellular biology with CRISPR/Cas9-mediated genome engineering to pinpoint the function of serine 12 of OCT4 in ESCs. Using chemical inhibitors and an antibody specific to OCT4 phosphorylated on S12, we identified cyclin-dependent kinase (CDK) 7 as upstream kinase. |Phosphorylation of OCT4 on S12 has been previously implicated to stabilize OCT4 by binding to PIN1, thereby preventing ubiquitinylation by WWP2." SIGNOR-264404 CDK7 protein P50613 UNIPROT PCGF6 protein Q9BYE7 UNIPROT unknown phosphorylation Ser30 LPPPPPVsPPALTPA -1 12167161 t llicata "In addition, we find that serine 32 of MBLR is specifically phosphorylated during mitosis, most likely by CDK7, a component of the basal transcriptional machinery. | These results indicate that, at least in vitro, MBLR is a substrate for CDK7 phosphorylation." SIGNOR-250769 CDK7 protein P50613 UNIPROT XRN2 protein Q9H0D6 UNIPROT "up-regulates activity" phosphorylation Thr439 FTPSGILtPHALGSR 9606 26728557 t Luana "CDKs and Xrn2 phosphorylation promote transcription termination. | Cdk7 phosphorylated Xrn2-Thr439 but was less efficient than Cdk9. |" SIGNOR-259851 KNTC1 protein P50748 UNIPROT "RZZ complex" complex SIGNOR-C357 SIGNOR "form complex" binding 9606 BTO:0000567 20462495 t lperfetto "The RZZ complex recruits dynein to kinetochores. We investigated structure, topology, and interactions of the RZZ subunits (ROD, ZWILCH, and ZW10) in vitro, in vivo, and in silico." SIGNOR-265015 CDK9 protein P50750 UNIPROT SUPT5H protein O00267 UNIPROT up-regulates phosphorylation Thr768 MTSTYGRtPMYGSQT 9606 16427012 t lperfetto "We describe an evolutionarily conserved repetitive heptapeptide motif (consensus = g-s-r/q-t-p) in the c-terminal region (ctr) of hspt5, which, like the c-terminal domain (ctd) of rna pol ii, is highly phosphorylated by p-tefb. Thr-4 residues of the ctr repeats are functionally important phosphorylation sites. In vitro, thr-4 phosphorylation is critical for the elongation activation activity of dsif" SIGNOR-143919 AFF1 protein P51825 UNIPROT "AEP complex" complex SIGNOR-C117 SIGNOR "form complex" binding 9606 BTO:0000664 20153263 t 1 miannu "These data demonstrate that AF4, AF5q31 and ENL associate in an endogenous higher-order complex (hereafter referred to as AEP for the AF4 family/ENL family/P-TEFb complex) containing P-TEFb in hematopoietic lineage cells." SIGNOR-239231 CDK9 protein P50750 UNIPROT SUPT5H protein O00267 UNIPROT up-regulates phosphorylation Thr775 TPMYGSQtPMYGSGS 9606 16427012 t lperfetto "We describe an evolutionarily conserved repetitive heptapeptide motif (consensus = g-s-r/q-t-p) in the c-terminal region (ctr) of hspt5, which, like the c-terminal domain (ctd) of rna pol ii, is highly phosphorylated by p-tefb. Thr-4 residues of the ctr repeats are functionally important phosphorylation sites. In vitro, thr-4 phosphorylation is critical for the elongation activation activity of dsif" SIGNOR-143923 CDK9 protein P50750 UNIPROT SUPT5H protein O00267 UNIPROT up-regulates phosphorylation Thr784 MYGSGSRtPMYGSQT 9606 16427012 t lperfetto "We describe an evolutionarily conserved repetitive heptapeptide motif (consensus = g-s-r/q-t-p) in the c-terminal region (ctr) of hspt5, which, like the c-terminal domain (ctd) of rna pol ii, is highly phosphorylated by p-tefb. Thr-4 residues of the ctr repeats are functionally important phosphorylation sites. In vitro, thr-4 phosphorylation is critical for the elongation activation activity of dsif" SIGNOR-143927 CDK9 protein P50750 UNIPROT SUPT5H protein O00267 UNIPROT up-regulates phosphorylation Thr791 TPMYGSQtPLQDGSR 9606 16427012 t lperfetto "We describe an evolutionarily conserved repetitive heptapeptide motif (consensus = g-s-r/q-t-p) in the c-terminal region (ctr) of hspt5, which, like the c-terminal domain (ctd) of rna pol ii, is highly phosphorylated by p-tefb. Thr-4 residues of the ctr repeats are functionally important phosphorylation sites. In vitro, thr-4 phosphorylation is critical for the elongation activation activity of dsif" SIGNOR-143931 CDK9 protein P50750 UNIPROT SUPT5H protein O00267 UNIPROT up-regulates phosphorylation Thr799 PLQDGSRtPHYGSQT 9606 16427012 t lperfetto "We describe an evolutionarily conserved repetitive heptapeptide motif (consensus = g-s-r/q-t-p) in the c-terminal region (ctr) of hspt5, which, like the c-terminal domain (ctd) of rna pol ii, is highly phosphorylated by p-tefb. Thr-4 residues of the ctr repeats are functionally important phosphorylation sites. In vitro, thr-4 phosphorylation is critical for the elongation activation activity of dsif" SIGNOR-143935 CDK9 protein P50750 UNIPROT SUPT5H protein O00267 UNIPROT up-regulates phosphorylation Thr806 TPHYGSQtPLHDGSR 9606 16427012 t lperfetto "We describe an evolutionarily conserved repetitive heptapeptide motif (consensus = g-s-r/q-t-p) in the c-terminal region (ctr) of hspt5, which, like the c-terminal domain (ctd) of rna pol ii, is highly phosphorylated by p-tefb. Thr-4 residues of the ctr repeats are functionally important phosphorylation sites. In vitro, thr-4 phosphorylation is critical for the elongation activation activity of dsif" SIGNOR-143939 CDK9 protein P50750 UNIPROT SUPT5H protein O00267 UNIPROT up-regulates phosphorylation Thr814 PLHDGSRtPAQSGAW 9606 16427012 t lperfetto "We describe an evolutionarily conserved repetitive heptapeptide motif (consensus = g-s-r/q-t-p) in the c-terminal region (ctr) of hspt5, which, like the c-terminal domain (ctd) of rna pol ii, is highly phosphorylated by p-tefb. Thr-4 residues of the ctr repeats are functionally important phosphorylation sites. In vitro, thr-4 phosphorylation is critical for the elongation activation activity of dsif" SIGNOR-143943 CDK9 protein P50750 UNIPROT TP53 protein P04637 UNIPROT unknown phosphorylation Ser33 LPENNVLsPLPSQAM 9606 16552184 t llicata "Here, we report for the first time that cyclin dependent kinase 9, whose well-known substrate is rna polymerase ii, can also phosphorylate p53. Specifically, ser33 on the n-terminus and, ser315 and ser392 on the c-terminus of p53 were found to be phosphorylated. The precise biological role of this phosphorylation remains to be elucidated." SIGNOR-145315 CDK9 protein P50750 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser392 FKTEGPDsD 9606 23603988 t gcesareni "We recently demonstrated that through their physical interaction, cdk9 phosphorylates p53 on ser-392, leading to p53 stability and accumulation" SIGNOR-201935 CDK9 protein P50750 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" phosphorylation Ser315 LPNNTSSsPQPKKKP 9606 24173284 t lperfetto "The N-terminus of E2F1 can interact directly with a region towards the C-terminus of p53, resulting in increased nuclear retention of p53 and p53-mediated transcription and apoptosis. This is inhibited by competition between p53 and cyclin A at the binding site within E2F19,10. The interaction between p53 and E2F1 is enhanced by phosphorylation of p53 on Ser315, a residue within the E2F1 binding region that is phosphorylated by cell cycle kinases such as cdk1, cdk2, cdk9 and Aurora kinase A" SIGNOR-145311 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1616 TPQSPSYsPTSPSYS 9606 24385927 t lperfetto "Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself. Cellular kinase cdk9 phosphorylates serine-2 in the c-terminal domain (ctd) of rnap ii" SIGNOR-203508 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1623 SPTSPSYsPTSPSYS 9606 24385927 t lperfetto "Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself" SIGNOR-203512 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1644 SPTSPSYsPTSPSYS 9606 24385927 t lperfetto "Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself" SIGNOR-203516 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1651 SPTSPSYsPTSPSYS 9606 24385927 t lperfetto "Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself. Cellular kinase cdk9 phosphorylates serine-2 in the c-terminal domain (ctd) of rnap ii" SIGNOR-203520 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1665 SPTSPSYsPTSPSYS 9606 24385927 t lperfetto "Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself" SIGNOR-203524 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1672 SPTSPSYsPTSPSYS 9606 24385927 t lperfetto "Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself" SIGNOR-203528 ADCY7 protein P51828 UNIPROT "3',5'-cyclic AMP" smallmolecule CHEBI:17489 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 15385642 t miannu "Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions." SIGNOR-265007 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1693 SPTSPSYsPTSPSYS 9606 24385927 t lperfetto "Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself. Cellular kinase cdk9 phosphorylates serine-2 in the c-terminal domain (ctd) of rnap ii" SIGNOR-203532 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1721 SPTSPSYsPTSPSYS 9606 24385927 t lperfetto "Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself" SIGNOR-203540 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1735 SPTSPSYsPTSPSYS 9606 24385927 t lperfetto "Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself. Cellular kinase cdk9 phosphorylates serine-2 in the c-terminal domain (ctd) of rnap ii" SIGNOR-203544 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1763 TPTSPSYsPTSPSYS 9606 24385927 t lperfetto "Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself" SIGNOR-203552 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1784 TPTSPNYsPTSPSYS 9606 24385927 t lperfetto "Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself" SIGNOR-203556 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1861 TPTSPKYsPTSPKYS 9606 24385927 t lperfetto "Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself" SIGNOR-203560 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1868 SPTSPKYsPTSPKYS 9606 24385927 t lperfetto "Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself" SIGNOR-203564 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1875 SPTSPKYsPTSPTYS 9606 24385927 t lperfetto "Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself. Cellular kinase cdk9 phosphorylates serine-2 in the c-terminal domain (ctd) of rnap ii" SIGNOR-203568 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1882 SPTSPTYsPTTPKYS 9606 24385927 t lperfetto "Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself" SIGNOR-203576 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1889 SPTTPKYsPTSPTYS 9606 24385927 t lperfetto "Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself. Cellular kinase cdk9 phosphorylates serine-2 in the c-terminal domain (ctd) of rnap ii" SIGNOR-203580 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1896 SPTSPTYsPTSPVYT 9606 24385927 t lperfetto "Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself" SIGNOR-203584 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1910 TPTSPKYsPTSPTYS 9606 24385927 t lperfetto "Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself" SIGNOR-203588 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1917 SPTSPTYsPTSPKYS 9606 24385927 t lperfetto "Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself. Cellular kinase cdk9 phosphorylates serine-2 in the c-terminal domain (ctd) of rnap ii" SIGNOR-203592 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1924 SPTSPKYsPTSPTYS 9606 24385927 t lperfetto "Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself" SIGNOR-203596 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1941 SPKGSTYsPTSPGYS 9606 24385927 t lperfetto "Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself" SIGNOR-203604 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1948 SPTSPGYsPTSPTYS 9606 24385927 t lperfetto "Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself" SIGNOR-203608 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1878 SPKYSPTsPTYSPTT 9606 24385927 t lperfetto "Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself" SIGNOR-203572 DAB2IP protein Q5VWQ8 UNIPROT ZEB1 protein P37275 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 27858941 f miannu "Through inhibition of PI3K–AKT signaling, DAB2IP also represses ZEB1, another CSC determinant." SIGNOR-254772 CDK9 protein P50750 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 19914161 t lpetrilli "Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3." SIGNOR-161585 CDK9 protein P50750 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 19914168 t lpetrilli "Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3." SIGNOR-161678 CDK9 protein P50750 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" phosphorylation Ser208 DAGSPNLsPNPMSPA 9606 19914161 t lpetrilli "Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3." SIGNOR-161581 CDK9 protein P50750 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" phosphorylation Thr179 PQSNIPEtPPPGYLS 9606 19914161 t lpetrilli "Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3." SIGNOR-161589 CDK9 protein P50750 UNIPROT HES1 protein Q14469 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15546612 f gcesareni "Cycc:cdk8 and cyct1:cdk9/p-tefb are recruited with notch and associated coactivators (mam, skip) to the hes1 promoter in signaling cells." SIGNOR-130703 CDK9 protein P50750 UNIPROT NCOA2 protein Q15596 UNIPROT "up-regulates activity" phosphorylation Ser469 NYALKMNsPSQSSPG 9606 BTO:0000801 29170386 t "Interestingly, GRIP1 is phosphorylated at an N-terminal serine cluster by cyclin-dependent kinase-9 (CDK9), which is recruited into GC-induced GR:GRIP1:CDK9 hetero-complexes, producing distinct GRE-specific GRIP1 phospho-isoforms. Phosphorylation potentiates GRIP1 coactivator but, remarkably, not its corepressor properties." SIGNOR-256096 CDK9 protein P50750 UNIPROT NCOA2 protein Q15596 UNIPROT "up-regulates activity" phosphorylation Ser487 GQPTSMLsPRHRMSP 9606 BTO:0000801 29170386 t "Interestingly, GRIP1 is phosphorylated at an N-terminal serine cluster by cyclin-dependent kinase-9 (CDK9), which is recruited into GC-induced GR:GRIP1:CDK9 hetero-complexes, producing distinct GRE-specific GRIP1 phospho-isoforms. Phosphorylation potentiates GRIP1 coactivator but, remarkably, not its corepressor properties." SIGNOR-256097 CDK9 protein P50750 UNIPROT NCOA2 protein Q15596 UNIPROT "up-regulates activity" phosphorylation Ser493 LSPRHRMsSPGVAGS 9606 BTO:0000801 29170386 t "Interestingly, GRIP1 is phosphorylated at an N-terminal serine cluster by cyclin-dependent kinase-9 (CDK9), which is recruited into GC-induced GR:GRIP1:CDK9 hetero-complexes, producing distinct GRE-specific GRIP1 phospho-isoforms. Phosphorylation potentiates GRIP1 coactivator but, remarkably, not its corepressor properties." SIGNOR-256098 CDK9 protein P50750 UNIPROT NCOA2 protein Q15596 UNIPROT "up-regulates activity" phosphorylation Ser499 MSPGVAGsPRIPPSQ 9606 BTO:0000801 29170386 t "Interestingly, GRIP1 is phosphorylated at an N-terminal serine cluster by cyclin-dependent kinase-9 (CDK9), which is recruited into GC-induced GR:GRIP1:CDK9 hetero-complexes, producing distinct GRE-specific GRIP1 phospho-isoforms. Phosphorylation potentiates GRIP1 coactivator but, remarkably, not its corepressor properties." SIGNOR-256099 CDK9 protein P50750 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser187 NSHPFPHsPNSSYPN 9606 19914161 t lpetrilli "Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3." SIGNOR-161565 CDK9 protein P50750 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser214 PTSSDPGsPFQMPAD 9606 19914168 t lpetrilli "Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3." SIGNOR-161666 CDK9 protein P50750 UNIPROT SMAD1 protein Q15797 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser206 SSSTYPHsPTSSDPG 9606 19914161 t lpetrilli "Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3." SIGNOR-161573 CDK9 protein P50750 UNIPROT RCHY1 protein Q96PM5 UNIPROT down-regulates phosphorylation Ser211 VAQTPMPsEYQNMTV 9606 23603988 t lperfetto "We showed that cdk9 phosphorylates pirh2 on ser-211 and thr-217 residues through their physical interaction. Phosphorylation of pirh2 renders it inactive and may contribute to p53-inhibition of transcriptional elongation of the hiv-1 ltr." SIGNOR-201923 CDK9 protein P50750 UNIPROT RCHY1 protein Q96PM5 UNIPROT down-regulates phosphorylation Thr217 PSEYQNMtVDILCND 9606 23603988 t lperfetto "We showed that cdk9 phosphorylates pirh2 on ser-211 and thr-217 residues through their physical interaction. Phosphorylation of pirh2 renders it inactive and may contribute to p53-inhibition of transcriptional elongation of the hiv-1 ltr." SIGNOR-201927 CDK9 protein P50750 UNIPROT "AEP complex" complex SIGNOR-C117 SIGNOR "form complex" binding 9606 BTO:0000664 20153263 t 1 miannu "These data demonstrate that AF4, AF5q31 and ENL associate in an endogenous higher-order complex (hereafter referred to as AEP for the AF4 family/ENL family/P-TEFb complex) containing P-TEFb in hematopoietic lineage cells." SIGNOR-239234 CASP5 protein P51878 UNIPROT GSDMD protein P57764 UNIPROT "up-regulates activity" cleavage Asp275 CLHNFLTdGVPAEGA 9606 BTO:0000007 26375003 t lperfetto "Co-expression of GSDMD with caspase-1, 4, 5 or 11 but not apoptotic caspases (caspase-2, 8 and 9) in 293T cells induced the same cleavage of GSDMD|inflammatory caspases specifically cleave GSDMD after the 272FLTD275 (or 273LLSD276) sequence |" SIGNOR-256418 RPL14 protein P50914 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262484 RAB5C protein P51148 UNIPROT EEA1 protein Q15075 UNIPROT "up-regulates activity" binding -1 12493736 t Federica "The Rab5 effector early endosome antigen 1 (EEA1) is a parallel coiled coil homodimer with an N-terminal C(2)H(2) Zn(2+) finger and a C-terminal FYVE domain. Rab5 binds to independent sites at the N and C terminus of EEA1.|The results demonstrate that the C(2)H(2) Zn(2+) finger is both essential and sufficient for the N-terminal interaction with Rab5." SIGNOR-261266 RAB7A protein P51149 UNIPROT PSMA7 protein O14818 UNIPROT "up-regulates activity" binding 10036 BTO:0000120 14998988 t Sara "Rab7 Forms a Complex with the Proteasome -Subunit XAPC. In this study the proteasome alpha-subunit XAPC7 (also known as PSMA7, RC6-1, and HSPC in mammals) was identified to interact specifically with Rab7 and was recruited to multivesicular late endosomes through this interaction." SIGNOR-261303 RAB7A protein P51149 UNIPROT NTRK1 protein P04629 UNIPROT "down-regulates activity" binding 10116 16306406 t Sara "Endogenous TrkA and Rab7 form a complex. Inhibition of Rab7 potentiates the signaling of TrkA in response to brief stimulations with NGF" SIGNOR-261305 RAB7A protein P51149 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" binding 10116 BTO:0000968 16040606 t Sara "Rab7-Rac1 interaction may mediate late endosomal transport between microtubules and microfilaments" SIGNOR-261304 RAB7A protein P51149 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" BTO:0001131 14617358 t Sara "The p150 adapter protein is in a complex with rab7. The hVPS34/p150 complex colocalized with rab7 on late endosomes and hVPS34 activity was dependent on nucleotide cycling of rab7" SIGNOR-261302 RAB9A protein P51151 UNIPROT PLIN3 protein O60664 UNIPROT "up-regulates activity" 18195106 t lperfetto "Rab9-dependent transport from late endosomes to the Golgi requires the Rab9 effectors p40 (Diaz et al., 1997) and TIP47 (Diaz and Pfeffer, 1998), a protein that recognizes the cytoplasmic domains of the two types of MPRs and packages them into nascent transport vesicles (Carroll et al., 2001). MPR recycling also utilizes a TGN-localized coiled-coil protein named GCC185 that is also a Rab9 effector" SIGNOR-253089 RAB9A protein P51151 UNIPROT RABEPK protein Q7Z6M1 UNIPROT "up-regulates activity" 9230071 t lperfetto "P40 is a very potent transport factor in that the pure, recombinant protein can stimulate, significantly, an in vitro transport assay that measures transport of mannose 6-phosphate receptors from endosomes to the trans-Golgi network. The functional importance of p40 is confirmed by the finding that anti-p40 antibodies inhibit in vitro transport. Finally, p40 shows synergy with Rab9 in terms of its ability to stimulate mannose 6-phosphate receptor transport. These data are consistent with a model in which p40 and Rab9 act together to drive the process of transport vesicle docking." SIGNOR-253088 RAB9A protein P51151 UNIPROT GCC2 protein Q8IWJ2 UNIPROT "up-regulates activity" 18195106 t lperfetto "Rab9-dependent transport from late endosomes to the Golgi requires the Rab9 effectors p40 (Diaz et al., 1997) and TIP47 (Diaz and Pfeffer, 1998), a protein that recognizes the cytoplasmic domains of the two types of MPRs and packages them into nascent transport vesicles (Carroll et al., 2001). MPR recycling also utilizes a TGN-localized coiled-coil protein named GCC185 that is also a Rab9 effector" SIGNOR-253087 DAP3 protein P51398 UNIPROT "28S mitochondrial small ribosomal subunit" complex SIGNOR-C266 SIGNOR "form complex" binding 9606 25838379 t miannu "The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins." SIGNOR-261459 RORC protein P51449 UNIPROT IL17A protein Q16552 UNIPROT up-regulates "transcriptional regulation" 9606 16990136 t 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 BLK protein P51451 UNIPROT FCGR2A protein P12318 UNIPROT "up-regulates activity" phosphorylation Tyr288 YETADGGyMTLNPRA -1 8756631 t lperfetto "To identify the FcgammaRII-phosphorylating protein tyrosine kinase (PTK), we used the combination of an in vitro and an in vivo approach. In an in vitro assay using recombinant cytoplasmic tails of the different FcgammaRII isoforms as well as tyrosine exchange mutants, we show that each of the BCR-associated PTKs (Lyn, Blk, Fyn, and Syk) shows different phosphorylation patterns with regard to the different FcgammaR isoforms and point|Fyn and Blk definitely phosphorylate Y-282 in the ITAM of Fc_RIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addi-tion to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation." SIGNOR-249311 BLK protein P51451 UNIPROT FCGR2A protein P12318 UNIPROT "up-regulates activity" phosphorylation Tyr304 TDDDKNIyLTLPPND -1 8756631 t lperfetto "To identify the FcgammaRII-phosphorylating protein tyrosine kinase (PTK), we used the combination of an in vitro and an in vivo approach. In an in vitro assay using recombinant cytoplasmic tails of the different FcgammaRII isoforms as well as tyrosine exchange mutants, we show that each of the BCR-associated PTKs (Lyn, Blk, Fyn, and Syk) shows different phosphorylation patterns with regard to the different FcgammaR isoforms and point|Fyn and Blk definitely phosphorylate Y-282 in the ITAM of Fc_RIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addi-tion to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation." SIGNOR-249312 BLK protein P51451 UNIPROT FCGR2C protein P31995 UNIPROT "up-regulates activity" phosphorylation Tyr294 YETADGGyMTLNPRA -1 8756631 t miannu "Fyn and Blk definitely phosphorylate Y-282 in the ITAM of FcgRIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addition to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation" SIGNOR-262672 BLK protein P51451 UNIPROT FCGR2C protein P31995 UNIPROT "up-regulates activity" phosphorylation Tyr310 TDDDKNIyLTLPPND -1 8756631 t miannu "Fyn and Blk definitely phosphorylate Y-282 in the ITAM of FcgRIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addition to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation" SIGNOR-262673 DUSP3 protein P51452 UNIPROT ERBB2 protein P04626 UNIPROT "down-regulates activity" dephosphorylation Tyr1221 SPAFDNLyYWDQDPP 9606 BTO:0002552 21262974 t "Expression of VHR inhibited the activation of phospholipase Cγ and protein kinase C, both downstream effectors of Tyr-992 phosphorylation of EGFR. | We found that VHR decreased ErbB2 phosphorylation in vitro and in a cellular context, and the dephosphorylation of ErbB2 was more evident at Tyr-877 and Tyr-1221 than those at Tyr-1139 and Tyr-1248 (supplemental Fig. S1). Our data indicated that VHR was a cellular PTP against EGFR and ErbB2." SIGNOR-248534 DUSP3 protein P51452 UNIPROT ERBB2 protein P04626 UNIPROT "down-regulates activity" dephosphorylation Tyr877 LDIDETEyHADGGKV 9606 BTO:0002552 21262974 t "Expression of VHR inhibited the activation of phospholipase Cγ and protein kinase C, both downstream effectors of Tyr-992 phosphorylation of EGFR. | We found that VHR decreased ErbB2 phosphorylation in vitro and in a cellular context, and the dephosphorylation of ErbB2 was more evident at Tyr-877 and Tyr-1221 than those at Tyr-1139 and Tyr-1248 (supplemental Fig. S1). Our data indicated that VHR was a cellular PTP against EGFR and ErbB2." SIGNOR-248533 DUSP3 protein P51452 UNIPROT MAPK3 protein P27361 UNIPROT "down-regulates activity" dephosphorylation Tyr204 HTGFLTEyVATRWYR 9534 BTO:0004055 10224087 t "Extracellular regulated kinases (ERK) 1 and ERK2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase VHR. A novel role in down-regulating the ERK pathway.|Catalysis by VHR requires the native structure of ERK and is specific for tyrosine 185 of ERK2" SIGNOR-248535 DUSP3 protein P51452 UNIPROT MAPK3 protein P27361 UNIPROT "down-regulates activity" dephosphorylation Tyr204 HTGFLTEyVATRWYR 9606 BTO:0004419 12840032 t lperfetto "The activation of the mapk activity requires the dual phosphorylation of the ser/thr and tyr residues in the txy kinase activation motif (1113), and deactivation occurs through the action of either ser/thr protein phosphatase (14), protein-tyrosine phosphatase (ptp) (14, 15), or dual specificity phosphatases" SIGNOR-103035 DUSP3 protein P51452 UNIPROT MAPK1 protein P28482 UNIPROT "down-regulates activity" dephosphorylation Tyr187 HTGFLTEyVATRWYR 9534 BTO:0004055 10224087 t "Extracellular regulated kinases (ERK) 1 and ERK2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase VHR. A novel role in down-regulating the ERK pathway.|Catalysis by VHR requires the native structure of ERK and is specific for tyrosine 185 of ERK2" SIGNOR-248536 SMARCA2 protein P51531 UNIPROT SMARCC2 protein Q8TAQ2 UNIPROT up-regulates binding 9606 10078207 t miannu "The remodeling activity of brg1 and hbrm is stimulated by baf170/baf155 and is further stimulated when ini1 is added." SIGNOR-65435 SMARCA2 protein P51531 UNIPROT SMARCC1 protein Q92922 UNIPROT up-regulates binding 9606 10078207 t miannu "The remodeling activity of brg1 and hbrm is stimulated by baf170/baf155 and is further stimulated when ini1 is added." SIGNOR-65432 SMARCA2 protein P51531 UNIPROT CERF complex SIGNOR-C340 SIGNOR "form complex" binding 9606 BTO:0000227 15640247 t miannu "Biochemical isolation of CECR2 revealed the presence of this protein as a component of a novel heterodimeric complex termed CECR2-containing remodeling factor (CERF). CERF comprises CECR2 and the ATP-dependent chromatin remodeler SNF2L, a mammalian ISWI ortholog expressed predominantly in the central nervous system. CERF is capable of remodeling chromatin in vitro and displays an ATP hydrolyzing activity that is stimulated by nucleosomes. Together, these data identify a novel chromatin remodeling complex with a critical role in neurulation." SIGNOR-263890 SMARCA4 protein P51532 UNIPROT TERT protein O14746 UNIPROT up-regulates binding 9606 19571879 t miannu "Tert activates wnt reporter plasmids in a brg1-dependent manner." SIGNOR-186607 SMARCA4 protein P51532 UNIPROT ZEB1 protein P37275 UNIPROT up-regulates binding 9606 20418909 t miannu "Zeb1 represses e-cadherin transcription / we reported that brg1 binds to the ntr of zeb1 acting as its co-repressor in the regulation of the e-cadherin promoter." SIGNOR-165017 IDH3G protein P51553 UNIPROT "Isocitrate Dehydrogenase" complex SIGNOR-C396 SIGNOR "form complex" binding 9606 28139779 t miannu "Human NAD-dependent isocitrate dehydrogenase existing as the α2βγ heterotetramer, catalyzes the decarboxylation of isocitrate into α-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP." SIGNOR-266247 P2RY4 protein P51582 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256870 P2RY4 protein P51582 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257006 P2RY4 protein P51582 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257122 P2RY4 protein P51582 UNIPROT GNA15 protein P30679 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257214 P2RY4 protein P51582 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-256727 P2RY4 protein P51582 UNIPROT GNA13 protein Q14344 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "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-257288 BRCA2 protein P51587 UNIPROT RAD51 protein Q06609 UNIPROT "up-regulates activity" binding 9606 17515904 t "We suggest that interactions of the BRCA2 C-terminal region with RAD51 may facilitate efficient nucleation of RAD51 multimers on DNA and thereby stimulate recombination-mediated repair." SIGNOR-259905 BRCA2 protein P51587 UNIPROT POLH protein Q9Y253 UNIPROT up-regulates binding 9606 24485656 t miannu "Palb2 and brca2 interact with pol_ and are required to sustain the recruitment of pol_ at blocked replication forks. Palb2 and brca2 stimulate pol_-dependent dna synthesis on d loop substrates" SIGNOR-204538 BRCA2 protein P51587 UNIPROT "BRCC ubiquitin ligase complex" complex SIGNOR-C295 SIGNOR "form complex" binding 9606 BTO:0000007 14636569 t lperfetto "These findings identify BRCC as a ubiquitin E3 ligase complex that enhances cellular survival following DNA damage.|Reconstitution of a recombinant four-subunit complex containing BRCA1/BARD1/BRCC45/BRCC36 revealed an enhanced E3 ligase activity compared to that of BRCA1/BARD1 heterodimer" SIGNOR-263207 BRCA2 protein P51587 UNIPROT "D1-D2-G-X3 complex" complex SIGNOR-C301 SIGNOR "form complex" binding 9606 BTO:0000567 18212739 t lperfetto "These results argue that FANCG has a role independent of the FA core complex, and we propose that phosphorylation of serine 7 is the signalling event required for forming a discrete complex comprising FANCD1/BRCA2-FANCD2-FANCG-XRCC3 (D1-D2-G-X3). " SIGNOR-263256 MECP2 protein P51608 UNIPROT SGK1 protein O00141 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000142 16002417 t Luana "These results are compatible with the hypothesis that MeCP2 associates with the Sgk and Fkbp5 promoters and has a repressive effect that is over-ridden by elevated glucocorticoids in response to stress." SIGNOR-264543 MECP2 protein P51608 UNIPROT DLL1 protein O00548 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0004091 25420914 t Luana "As the first step to reveal how MeCP2 phosphorylation may regulate Notch signaling, we conducted chromatin immunoprecipitation (ChIP) experiment to determine whether the phosphor-mutant MeCP2 protein has altered promoter occupancy at the promoters of Dll1 and Notch1. We found increased binding of the phosphor-mutant protein at the promoters of both Dll1 and Notch1 " SIGNOR-264674 MECP2 protein P51608 UNIPROT ESR1 protein P03372 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000093 15870696 f miannu "Valproate (VPA) induces silencing of the ERalpha, cyclin D1 and pS2 promoters. Chromatin immunoprecipitation (ChIP) analysis demonstrates that VPA induces recruitment of the 5-MeCpG binding protein MeCP2 to the ERalpha A promoter and also to the pS2 and cyclin D1 promoters" SIGNOR-254573 MECP2 protein P51608 UNIPROT ESR1 protein P03372 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001570 23242655 f "Our previous studies demonstrated that mutant p53 along with repression complex proteins including DNMT1, HDAC1 and MeCP2 is associated with ER-negative promoter in MDA-MB-468 cells." SIGNOR-254024 MECP2 protein P51608 UNIPROT TFF1 protein P04155 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000093 15870696 f miannu "Valproate (VPA) induces silencing of the ERalpha, cyclin D1 and pS2 promoters. Chromatin immunoprecipitation (ChIP) analysis demonstrates that VPA induces recruitment of the 5-MeCpG binding protein MeCP2 to the ERalpha A promoter and also to the pS2 and cyclin D1 promoters" SIGNOR-254572 MECP2 protein P51608 UNIPROT CRH protein P06850 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000142 17108082 t Luana "Collectively, these results point to a specific association between WT MeCP2 and the methylated promoter region of Crh in vivo. In contrast, the MeCP2308 protein was not detected at the Crh promoter. | Thus, the results of seqChIP indicate that MeCP2 preferentially associates with a transcriptionally inactive, dimethyl-histone H3 Lys-9-rich form of the Crh promoter in mice." SIGNOR-264548 MECP2 protein P51608 UNIPROT ABCB1 protein P08183 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 11865062 f "We have established that methyl-CpG binding protein 2 (MeCP2) is involved in methylation-dependent silencing of human MDR1 in cells that lack the known transcriptional repressors MBD2 and MBD3. In the repressed state the MDR1 promoter is methylated and assembled into chromatin enriched with MeCP2 and deacetylated histone. TSA induced significant acetylation of histones H3 and H4 but did not activate transcription. 5aC induced DNA demethylation, leading to the release of MeCP2, promoter acetylation, and partial relief of repression" SIGNOR-254033 MECP2 protein P51608 UNIPROT MET protein P08581 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0000007 24150225 t Luana "MeCP2 binding enhances MET expression in the presence of the rs1858830 C allele, but MET transcription is attenuated by RTT-specific mutations in MeCP2" SIGNOR-264683 MECP2 protein P51608 UNIPROT ALOX5 protein P09917 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001412 19781662 f "Human 5-lipoxygenase (5-LO) is the key enzyme in the formation of inflammatory leukotrienes. 5-LO gene expression is mainly restricted to B cells and cells of myeloid origin. It is known that basal 5-lipoxygenase promoter activity is regulated by DNA methylation.|Using ChIP assays, we found that the methyl-DNA binding proteins MBD1, MBD2 and MeCP2 bind to the methylated 5-LO core promoter in U937 cells. Knock down of each of the MBDs upregulates 5-LO mRNA expression in U937 cells indicating that these proteins are involved in silencing of the 5-LO gene." SIGNOR-254062 MECP2 protein P51608 UNIPROT CREB1 protein P16220 UNIPROT "up-regulates quantity by expression" "post transcriptional regulation" 10090 BTO:0000614 18511691 t Luana "Interestingly, Creb1 was one of the activated MeCP2 targets that we validated by quantitative real-time RT-PCR (Fig. 1C), and using ChIP analysis we found that in vivo MeCP2 binds to the promoter region of Creb1, with significantly enhanced binding in MECP2-Tg samples compared to WT (p < 0.05) | In addition, Sst and CREB1 protein levels were increased in MECP2-Tg hypothalami compared to WT, indicating that MeCP2 indeed enhances expression of Sst and Creb1" SIGNOR-264682 MECP2 protein P51608 UNIPROT MGMT protein P16455 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000567 15657354 f "Chromatin immunoprecipitation analysis of methyl-CpG binding domain containing proteins detected a greater amount of MeCP2, MBD1, and CAF-1 bound to the MGMT promoter in MGMT-silenced cells. Our findings implicate specific MBD proteins in methylation-mediated transcriptional silencing of MGMT." SIGNOR-254035 MECP2 protein P51608 UNIPROT IGFBP3 protein P17936 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000142 17278996 f miannu "We found that MeCP2 directly regulates expression of insulin-like growth factor binding protein 3 (IGFBP3) gene in human and mouse brains. IGFBP3 overexpression was observed in the brains of mecp2-null mice and human RTT patients using real-time quantitative polymerase chain reaction and Western blot analyses." SIGNOR-254580 MECP2 protein P51608 UNIPROT PTPN1 protein P18031 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000452 26214522 t Luana "In this study, we have demonstrated that the PTPN1 gene, which encodes PTP1B, was a direct target of MECP2 and that PTP1B protein levels were dramatically increased in Mecp2-mutant mice and in fibroblasts derived from patients with RTT." SIGNOR-264546 MECP2 protein P51608 UNIPROT PTPN1 protein P18031 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000478 26214522 f Luana " We demonstrated that the PTPN1 gene, which encodes PTP1B, was a target of MECP2 and that disruption of MECP2 function was associated with increased levels of PTP1B in RTT models." SIGNOR-264552 MECP2 protein P51608 UNIPROT BDNF protein P23560 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 18599437 f "MeCP2 is involved in gene silencing and known to affect the activity of brain-derived neurotrophic factor (BDNF)" SIGNOR-254023 MECP2 protein P51608 UNIPROT CCND1 protein P24385 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000093 15870696 f miannu "Valproate (VPA) induces silencing of the ERalpha, cyclin D1 and pS2 promoters. Chromatin immunoprecipitation (ChIP) analysis demonstrates that VPA induces recruitment of the 5-MeCpG binding protein MeCP2 to the ERalpha A promoter and also to the pS2 and cyclin D1 promoters" SIGNOR-254571 MECP2 protein P51608 UNIPROT DNMT1 protein P26358 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 12473678 t Luana "Thus, these results indicate that MeCP2-interacting Dnmt1 has significant maintenance DNA methyltransferase activity and that MeCP2 does not vanish Dnmt1 enzymatic activity." SIGNOR-264541 MECP2 protein P51608 UNIPROT OPRK1 protein P41145 UNIPROT "up-regulates quantity by expression" "post transcriptional regulation" 10090 BTO:0000614 18511691 t Luana "MeCP2 binds to the promoter region of six target genes. ChIP with anti-MeCP2 antibody shows that MeCP2 binds to the promoter regions of activated targets Sst, Oprk1, Gamt, and Gprin1, and repressed targets Mef2c and A2bp1." SIGNOR-264677 MECP2 protein P51608 UNIPROT MEF2C protein Q06413 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000614 18511691 t Luana "MeCP2 binds to the promoter region of six target genes. ChIP with anti-MeCP2 antibody shows that MeCP2 binds to the promoter regions of activated targets Sst, Oprk1, Gamt, and Gprin1, and repressed targets Mef2c and A2bp1." SIGNOR-264680 MECP2 protein P51608 UNIPROT GRIN2B protein Q13224 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10116 BTO:0004102 18952054 t Luana "The interaction of MeCP2 with the 2BI3 and 2BI5 sites was strikingly reduced in neurons maintained in the presence of TTX (Fig. 2C). This result is consistent with the classical view of MeCP2 as a general transcriptional repressor, in that the reduced association leads to increased expression of NR2B." SIGNOR-264685 MECP2 protein P51608 UNIPROT FKBP5 protein Q13451 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000142 16002417 t Luana "These results are compatible with the hypothesis that MeCP2 associates with the Sgk and Fkbp5 promoters and has a repressive effect that is over-ridden by elevated glucocorticoids in response to stress." SIGNOR-264542 MECP2 protein P51608 UNIPROT GAMT protein Q14353 UNIPROT "up-regulates quantity by expression" "post transcriptional regulation" 10090 BTO:0000614 18511691 t Luana "MeCP2 binds to the promoter region of six target genes. ChIP with anti-MeCP2 antibody shows that MeCP2 binds to the promoter regions of activated targets Sst, Oprk1, Gamt, and Gprin1, and repressed targets Mef2c and A2bp1." SIGNOR-264678 MECP2 protein P51608 UNIPROT RBFOX1 protein Q9NWB1 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000614 18511691 t Luana "MeCP2 binds to the promoter region of six target genes. ChIP with anti-MeCP2 antibody shows that MeCP2 binds to the promoter regions of activated targets Sst, Oprk1, Gamt, and Gprin1, and repressed targets Mef2c and A2bp1." SIGNOR-264681 HCFC1 protein P51610 UNIPROT CREB3 protein O43889 UNIPROT "up-regulates activity" binding -1 BTO:0000120 9658067 t 2 miannu "We also show that while interaction with HCF is not required for the ability of Luman to activate transcription when tethered to the GAL4 promoter, it appears to be essential for Luman to activate transcription through CRE sites." SIGNOR-241372 HCFC1 protein P51610 UNIPROT ZBTB17 protein Q13105 UNIPROT "down-regulates activity" binding 9534 BTO:0001538 12244100 t miannu "We show here that HCF-1 directly binds to the Myc-interacting protein Miz-1. HCF-1 Represses Gal4-Miz-1-mediated Transcriptional Activation" SIGNOR-223590 HCFC1 protein P51610 UNIPROT "Set1-Ash2 HMT complex" complex SIGNOR-C352 SIGNOR "up-regulates activity" binding 9606 BTO:0000567 12670868 t miannu "Our analysis of HCF-1-associated proteins suggests that a K4 histone H3 HMT complex has been conserved from yeast to humans in both structure and activity: the Set1/Ash2 HMT. The results presented here show that this Set1/Ash2 HMT complex, in mutually exclusive interactions, can associate with HCF-1 bound to the repressive Sin3 HDAC or the transcriptional activator VP16, indicating a diversity of transcriptional regulatory roles." SIGNOR-264481 HCFC1 protein P51610 UNIPROT "NSL histone acetyltransferase" complex SIGNOR-C413 SIGNOR "form complex" binding 9606 BTO:0000007 20018852 t miannu "Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. Two of its subunits, WD repeat domain 5 (WDR5) and host cell factor 1 (HCF1), are shared with members of the MLL/SET family of histone H3 lysine 4 (H3K4) methyltransferase complexes, and a third subunit, MCRS1, is shared with the human INO80 chromatin-remodeling complex." SIGNOR-267165 IRAK1 protein P51617 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 15465816 t gcesareni "Irak1 can directly use stat3 as a substrate and cause stat3 serine 727 phosphorylation." SIGNOR-129685 IRAK1 protein P51617 UNIPROT IRAK1 protein P51617 UNIPROT "up-regulates activity" phosphorylation Ser376 GSSPSQSsMVARTQT -1 11960013 t "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 IRAK1 protein P51617 UNIPROT IRAK1 protein P51617 UNIPROT "up-regulates activity" phosphorylation Thr387 RTQTVRGtLAYLPEE -1 11960013 t "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 IRAK1 protein P51617 UNIPROT IRAK1 protein P51617 UNIPROT "up-regulates activity" phosphorylation Thr66 CERSGQRtASVLWPW 9534 BTO:0001538 12138165 t "T66E mutations interfered with the ability of IRAK to autophosphorylate. Thr-66 mutations abolished the capacity of IRAK to dimerize." SIGNOR-251327 IRAK1 protein P51617 UNIPROT IRAK1 protein P51617 UNIPROT "up-regulates activity" phosphorylation Thr209 LCEISRGtHNFSEEL 9606 BTO:0000007 14625308 t 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 IRAK1 protein P51617 UNIPROT PELI3 protein Q8N2H9 UNIPROT up-regulates phosphorylation 9606 12874243 t gcesareni "Pellino3 physically interacts with il-1r-associated kinase-1, tnf receptor-associated factor-6, tgf-beta-activated kinase-1, and nf-kappab-inducing kinase in an il-1-dependent manner in the present study, we demonstrate that irak1 and irak4 phosphorylate pellino isoforms in vitro and that phosphorylation greatly enhances pellino's e3 ubiquitin ligase activity." SIGNOR-103983 IRAK1 protein P51617 UNIPROT PELI3 protein Q8N2H9 UNIPROT up-regulates phosphorylation 9606 17997719 t gcesareni "Pellino3 physically interacts with il-1r-associated kinase-1, tnf receptor-associated factor-6, tgf-beta-activated kinase-1, and nf-kappab-inducing kinase in an il-1-dependent manner in the present study, we demonstrate that irak1 and irak4 phosphorylate pellino isoforms in vitro and that phosphorylation greatly enhances pellino's e3 ubiquitin ligase activity." SIGNOR-159052 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT "up-regulates activity" phosphorylation Ser293 FNTLAFPsMKRKDVV 9606 BTO:0000007 12496252 t lperfetto "In this article we demonstrate that pellino 1 is phosphorylated at multiple sites by irak1 or irak4 in vitro. The key residues involved in activation are located between residues 76 and 86 (ser-76, ser-78, thr-80, ser-82, and thr-86) and at thr-288 and ser-293, just n-terminal to the ring-like domain that carries the e3 ligase activity. Unusually, we found that the phosphorylation of ser-76 or thr-288 or ser-293 alone was sufficient for maximal activation" SIGNOR-96735 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT "up-regulates activity" phosphorylation Ser76 ISNKDQHsISYTLSR 9606 BTO:0000007 12496252 t lperfetto "In this article we demonstrate that pellino 1 is phosphorylated at multiple sites by irak1 or irak4 in vitro. The key residues involved in activation are located between residues 76 and 86 (ser-76, ser-78, thr-80, ser-82, and thr-86) and at thr-288 and ser-293, just n-terminal to the ring-like domain that carries the e3 ligase activity. Unusually, we found that the phosphorylation of ser-76 or thr-288 or ser-293 alone was sufficient for maximal activation" SIGNOR-96739 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT "up-regulates activity" phosphorylation Ser78 NKDQHSIsYTLSRAQ 9606 BTO:0000007 12496252 t lperfetto "In this article we demonstrate that pellino 1 is phosphorylated at multiple sites by irak1 or irak4 in vitro. The key residues involved in activation are located between residues 76 and 86 (ser-76, ser-78, thr-80, ser-82, and thr-86) and at thr-288 and ser-293, just n-terminal to the ring-like domain that carries the e3 ligase activity. Unusually, we found that the phosphorylation of ser-76 or thr-288 or ser-293 alone was sufficient for maximal activation" SIGNOR-96743 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT "up-regulates activity" phosphorylation Ser82 HSISYTLsRAQTVVV 9606 BTO:0000007 12496252 t lperfetto "In this article we demonstrate that pellino 1 is phosphorylated at multiple sites by irak1 or irak4 in vitro. The key residues involved in activation are located between residues 76 and 86 (ser-76, ser-78, thr-80, ser-82, and thr-86) and at thr-288 and ser-293, just n-terminal to the ring-like domain that carries the e3 ligase activity. Unusually, we found that the phosphorylation of ser-76 or thr-288 or ser-293 alone was sufficient for maximal activation" SIGNOR-96747 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT "up-regulates activity" phosphorylation Thr288 QCPVGFNtLAFPSMK 9606 BTO:0000007 12496252 t lperfetto "In this article we demonstrate that pellino 1 is phosphorylated at multiple sites by irak1 or irak4 in vitro. The key residues involved in activation are located between residues 76 and 86 (ser-76, ser-78, thr-80, ser-82, and thr-86) and at thr-288 and ser-293, just n-terminal to the ring-like domain that carries the e3 ligase activity. Unusually, we found that the phosphorylation of ser-76 or thr-288 or ser-293 alone was sufficient for maximal activation" SIGNOR-96751 IRAK1 protein P51617 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 8837778 t lperfetto "Il-1 treatment of 293 cells induces the association of traf6 with irak." SIGNOR-44234 ALDH5A1 protein P51649 UNIPROT succinate(2-) smallmolecule CHEBI:30031 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 19300440 t miannu "Succinic semialdehyde dehydrogenase (SSADH) is involved in the final degradation step of the inhibitory neurotransmitter gamma-aminobutyric acid by converting succinic semialdehyde to succinic acid in the mitochondrial matrix." SIGNOR-266617 ALDH5A1 protein P51649 UNIPROT 4-oxobutanoate smallmolecule CHEBI:57706 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 19300440 t miannu "Succinic semialdehyde dehydrogenase (SSADH) is involved in the final degradation step of the inhibitory neurotransmitter gamma-aminobutyric acid by converting succinic semialdehyde to succinic acid in the mitochondrial matrix." SIGNOR-266616 GPC3 protein P51654 UNIPROT DPP4 protein P27487 UNIPROT down-regulates binding 9606 17549790 t miannu "The interaction occurred with both the glycosylated and unglycosylated forms of gpc3 and led to the inhibition of cd26 peptidase activity." SIGNOR-155527 PSMD7 protein P51665 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "form complex" binding 9606 BTO:0000007 29636472 t lperfetto "Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line" SIGNOR-263349 UBE2D1 protein P51668 UNIPROT PEX5 protein P50542 UNIPROT "up-regulates activity" ubiquitination -1 19687296 t miannu "Here we report on the identification of the protein-ubiquitin ligases that are responsible for the ubiquitination of the peroxisomal protein import receptor Pex5. It is demonstrated that each of the three RING peroxins Pex2, Pex10, and Pex12 exhibits ubiquitin-protein isopeptide ligase activity. Our results show that Pex2 mediates the Ubc4-dependent polyubiquitination whereas Pex12 facilitates the Pex4-dependent monoubiquitination of Pex5.While polyubiquitinated Pex5 is degraded by the proteasome, monoubiquitinated Pex5 is destined for a new round of the receptor cycle." SIGNOR-253022 CCL11 protein P51671 UNIPROT CCR3 protein P51677 UNIPROT up-regulates binding 9606 24702154 t "Eotaxin (CCL11) is a specific ligand for CCR3 and serves as a potent chemoattractant for eosinophils" SIGNOR-254356 CCL11 protein P51671 UNIPROT CCR3 protein P51677 UNIPROT "up-regulates activity" binding 9606 BTO:0000399 10706854 t "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 CCR3 protein P51677 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 11591790 f "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 CCR3 protein P51677 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "up-regulates activity" 9606 BTO:0000399 10706854 t "Activation of ERK2 and p38 by eotaxin is mediated through CCR3." SIGNOR-256093 CCR3 protein P51677 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates 9606 11591790 f "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 CCR3 protein P51677 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR "up-regulates activity" 9606 BTO:0000399 10706854 t "Activation of ERK2 and p38 by eotaxin is mediated through CCR3." SIGNOR-256092 CCR5 protein P51681 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "up-regulates activity" phosphorylation 10090 20219869 t 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 KCNQ1 protein P51787 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000562;BTO:0000269;BTO:0001307 19298256 t miannu "KCNQ genes encode five Kv7 K+ channel subunits (Kv7.1–Kv7.5). Four of these (Kv7.2–Kv7.5) are expressed in the nervous system. Kv7.2 and Kv7.3 are the principal molecular components of the slow voltage-gated M-channel, which widely regulates neuronal excitability, although other subunits may contribute to M-like currents in some locations." SIGNOR-265981 RPS6KA3 protein P51812 UNIPROT PFKFB2 protein O60825 UNIPROT "up-regulates activity" phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000562 9211863 t gcesareni "Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b." SIGNOR-49367 RPS6KA3 protein P51812 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser167 GGRERLAsTNDKGSM 9606 BTO:0000150 19112174 t gcesareni "S6k1 regulates estrogen receptor alpha (eralpha) by phosphorylating it on serine 167, leading to transcriptional activation of eralpha." SIGNOR-182958 RPS6KA3 protein P51812 UNIPROT HMGN1 protein P05114 UNIPROT "down-regulates activity" phosphorylation Ser21 KEEPKRRsARLSAKP 9606 BTO:0000567 11438671 t lperfetto "We report here that the NBD of the HMGN1 and -N2 protein family is highly and specifically phosphorylated during mitosis and that this phosphorylation has a major functional consequence: it abolishes the interaction of the proteins with its chromatin targets." SIGNOR-249100 RPS6KA3 protein P51812 UNIPROT HMGN2 protein P05204 UNIPROT "down-regulates activity" phosphorylation Ser25 KDEPQRRsARLSAKP 9606 BTO:0000567 11438671 t lperfetto "We report here that the NBD of the HMGN1 and -N2 protein family is highly and specifically phosphorylated during mitosis and that this phosphorylation has a major functional consequence: it abolishes the interaction of the proteins with its chromatin targets." SIGNOR-249102 RPS6KA3 protein P51812 UNIPROT HMGN2 protein P05204 UNIPROT "down-regulates activity" phosphorylation Ser29 QRRSARLsAKPAPPK 9606 BTO:0000567 11438671 t lperfetto "We report here that the NBD of the HMGN1 and -N2 protein family is highly and specifically phosphorylated during mitosis and that this phosphorylation has a major functional consequence: it abolishes the interaction of the proteins with its chromatin targets." SIGNOR-249103 RPS6KA3 protein P51812 UNIPROT KRT18 protein P05783 UNIPROT unknown phosphorylation Ser53 ISVSRSTsFRGGMGS -1 7523419 t lperfetto "Ser-52 in K18 is not glycosylated and matches consensus sequences for phosphorylation by CAM kinase, S6 kinase and protein kinase C, and all these kinases can phosphorylate K18 in vitro predominantly at that site." SIGNOR-248895 RPS6KA3 protein P51812 UNIPROT TH protein P07101 UNIPROT up-regulates phosphorylation Ser40 GQGAPGPsLTGSPWP 9606 12421349 t "The effect has been demonstrated using P07101-3" gcesareni "Mitogen-activated protein-kinase (map) kinase-activated protein kinases 1 and 2 (mapkap kinase-1, mapkap kinase-2), were found to phosphorylate bacterially expressed human tyrosine hydroxylaserecombinant human tyrosine hydroxylase (hth1) was found to be phosphorylated by mitogen and stress-activated protein kinase 1 (msk1) at ser40 and by p38 regulated/activated kinase (prak) on ser19. Phosphorylation by msk1 induced an increase in vmax" SIGNOR-95483 RPS6KA3 protein P51812 UNIPROT CREB1 protein P16220 UNIPROT "up-regulates activity" phosphorylation Ser119 EILSRRPsYRKILND 9606 8688081 t lperfetto "MAPK activates CREB kinase, which in turn phosphorylates and activates CREB. Purification, sequencing, and biochemical characterization of CREB kinase revealed that it is identical to a member of the pp90(RSK) family, RSK2. RSK2 was shown to mediate growth factor induction of CREB serine-133 phosphorylation both in vitro and in vivo. These findings identify a cellular function for RSK2 and define a mechanism whereby growth factor signals mediated by RAS and MAPK are transmitted to the nucleus to activate gene expression" SIGNOR-248951 RPS6KA3 protein P51812 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Thr451 KRTRSKGtLRYMSPE 9606 BTO:0001286 17404396 t gcesareni "Our data indicated that phosphorylation of pkr at thr(451) is mediated through erk2 and rsk2, but not through p38 kinase." SIGNOR-154183 RPS6KA3 protein P51812 UNIPROT NR4A1 protein P22736 UNIPROT unknown phosphorylation Ser351 GRRGRLPsKPKQPPD 9606 BTO:0000007 16223362 t lperfetto "In the present paper, we have re-examined the phosphorylation of Nur77 on Ser354. Using a combination of cell-permeable kinase inhibitors and mouse knockin mutations, we show that Nur77 is phosphorylated by RSK in response to mitogenic stimulation of cells. Phosphorylation of Nur77 on Ser354 did not, however, appear to affect the transcriptional activity of Nur77, or its ability to bind 14-3-3 proteins in vivo." SIGNOR-249295 RPS6KA3 protein P51812 UNIPROT H2BC3 protein P33778 UNIPROT up-regulates phosphorylation Ser33 DGKKRKRsRKESYSI 9606 BTO:0001253 21646345 t lperfetto "Here, we studied the histone h2b core domain and found that phosphorylation of h2b serine 32 occurs in normal cycling and mitogen-stimulated cells. Notably, this phosphorylation is elevated in skin cancer cell lines and tissues compared with normal counterparts. We identified ribosomal s6 kinase 2 (rsk2) as the kinase responsible for h2bs32 phosphorylation." SIGNOR-174026 RPS6KA3 protein P51812 UNIPROT GSK3A protein P49840 UNIPROT "down-regulates activity" phosphorylation Ser21 SGRARTSsFAEPGGG 9606 BTO:0000130 11583116 t lperfetto "P90-rsk and akt may promote rapid phosphorylation/inactivation of glycogen synthase kinase 3 in chemoattractant-stimulated neutrophils. These reactions were monitored with a phosphospecific antibody that only recognized the alpha- or beta-isoforms of GSK-3 when these proteins were phosphorylated on serine residues 21 and 9, respectively." SIGNOR-110827 RPS6KA3 protein P51812 UNIPROT YBX1 protein P67809 UNIPROT up-regulates phosphorylation Ser102 NPRKYLRsVGDGETV 9606 BTO:0000150 19036157 t lperfetto "We therefore conclude that rsk1/rsk2 are novel activators of yb-1, able to phosphorylate the serine 102 residue." SIGNOR-182165 RPS6KA3 protein P51812 UNIPROT H3C1 protein P68431 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 10464286 t gcesareni "Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun." SIGNOR-70436 RPS6KA3 protein P51812 UNIPROT H3C1 protein P68431 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 BTO:0000938 14625384 t gcesareni "Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun." SIGNOR-119229 RPS6KA3 protein P51812 UNIPROT H3-3A protein P84243 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 15994958 t gcesareni "Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun." SIGNOR-138471 RPS6KA3 protein P51812 UNIPROT CENPE protein Q02224 UNIPROT "up-regulates activity" 9606 BTO:0000567 20383198 f lperfetto "We also show that this kinase might also participate in the maintenance of the SAC in mammalian cells as Rsk2 knockdown in these cells prevents the kinetochore localization of Mad1, Mad2 and CENP-E under checkpoint conditions." SIGNOR-252037 RPS6KA3 protein P51812 UNIPROT MAD2L1 protein Q13257 UNIPROT "up-regulates activity" 9606 BTO:0000567 20383198 f lperfetto "We also show that this kinase might also participate in the maintenance of the SAC in mammalian cells as Rsk2 knockdown in these cells prevents the kinetochore localization of Mad1, Mad2 and CENP-E under checkpoint conditions." SIGNOR-252039 RPS6KA3 protein P51812 UNIPROT NFATC4 protein Q14934 UNIPROT up-regulates phosphorylation Ser676 SNGRRKRsPTQSFRF 9606 15657420 t esanto "We demonstrate that p90 ribosomal s6 kinase (rsk) is recruited to the nfat-dna transcription complex upon activation.Bound Rsk phosphorylates ser(676) and potentiates nfatc4 dna binding. Ser(676) is also targeted by the erk map kinase." SIGNOR-133283 RPS6KA3 protein P51812 UNIPROT NFATC4 protein Q14934 UNIPROT up-regulates phosphorylation Ser281 SGTPSSAsPALSRRG 10090 17213202 t lperfetto "Serines 281 and 285 of the nfat3 protein might be target amino acids of rsk2 phosphorylationrsk2 induced nuclear localization of nfat3. Rsk2 phosphorylated nfat3 in vitro (km=3.559 microm), and activation of nfat3 by rsk2 enhanced the promoter activity of nfat3 downstream target genes in vivo." SIGNOR-234465 RPS6KA3 protein P51812 UNIPROT NFATC4 protein Q14934 UNIPROT up-regulates phosphorylation Ser285 SSASPALsRRGSLGE 10090 17213202 t lperfetto "Serines 281 and 285 of the nfat3 protein might be target amino acids of rsk2 phosphorylationrsk2 induced nuclear localization of nfat3. Rsk2 phosphorylated nfat3 in vitro (km=3.559 microm), and activation of nfat3 by rsk2 enhanced the promoter activity of nfat3 downstream target genes in vivo." SIGNOR-234469 RPS6KA3 protein P51812 UNIPROT NFATC4 protein Q14934 UNIPROT up-regulates phosphorylation Ser289 PALSRRGsLGEEGSE 10090 17213202 t lperfetto "The results indicated that rsk2 phosphorylated two additional sites at ser289 (peptide 2) and ser344 (peptide 3)rsk2 induced nuclear localization of nfat3. Rsk2 phosphorylated nfat3 in vitro (km=3.559 microm), and activation of nfat3 by rsk2 enhanced the promoter activity of nfat3 downstream target genes in vivo." SIGNOR-234473 RPS6KA3 protein P51812 UNIPROT NFATC4 protein Q14934 UNIPROT up-regulates phosphorylation Ser344 QAVALPRsEEPASCN 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103;BTO:0001760 17213202 t lperfetto "The results indicated that rsk2 phosphorylated two additional sites at ser289 (peptide 2) and ser344 (peptide 3)rsk2 induced nuclear localization of nfat3. Rsk2 phosphorylated nfat3 in vitro (km=3.559 microm), and activation of nfat3 by rsk2 enhanced the promoter activity of nfat3 downstream target genes in vivo." SIGNOR-235652 RPS6KA3 protein P51812 UNIPROT WWC1 protein Q8IX03 UNIPROT up-regulates phosphorylation Ser947 CRLNRSDsDSSTLSK 9606 BTO:0000149 24269383 t llicata "Moreover, we found that rsk1/2 specifically phosphorylates kibra at two highly conserved sites (thr(929) and ser(947)) in vitro and in cells. Rsk-mediated phosphorylation is required for kibra binding to rsk1, but not rsk2." SIGNOR-203302 RPS6KA3 protein P51812 UNIPROT WWC1 protein Q8IX03 UNIPROT up-regulates phosphorylation Thr929 STIIRSKtFSPGPQS 9606 BTO:0000149 24269383 t llicata "Moreover, we found that rsk1/2 specifically phosphorylates kibra at two highly conserved sites (thr(929) and ser(947)) in vitro and in cells. Rsk-mediated phosphorylation is required for kibra binding to rsk1, but not rsk2." SIGNOR-203306 RPS6KA3 protein P51812 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 19282669 t lperfetto "The rsks catalyze the phosphorylation of the pro-apoptotic protein bad at serine 112 to promote cell survival." SIGNOR-184595 RPS6KA3 protein P51812 UNIPROT CIC protein Q96RK0 UNIPROT down-regulates phosphorylation Ser173 PGKRRTQsLSALPKE 9606 BTO:0000848 21087211 t gcesareni "Specifically, 14-3-3 binds to p90(rsk)-phosphorylated ser?_??_ Of capic?_A thereby modulating dna binding to its hmg (high-mobility group) box, whereas erk phosphorylations prevent binding of a c-terminal nls (nuclear localization sequence) to importin ?4 (kpna3)" SIGNOR-169887 NEK2 protein P51955 UNIPROT NDC80 protein O14777 UNIPROT up-regulates phosphorylation Ser165 LGYPFALsKSSMYTV 9606 12386167 t lperfetto "Phosphorylation of the mitotic regulator protein hec1 by nek2 kinase is essential for faithful chromosome segregation.Hec1 (highly expressed in cancer) plays essential roles in chromosome segregation by interacting through its coiled-coil domains with several proteins that modulate the g(2)/m phase.Nek2 phosphorylates hec1 on serine residue 165, both in vitro and in vivo." SIGNOR-94322 NEK2 protein P51955 UNIPROT PPP1CC protein P36873 UNIPROT down-regulates phosphorylation Thr307 EKKKPNAtRPVTPPR 9606 10880350 t miannu "Pp1 is a substrate for nek2 and phosphorylation of pp1gamma(1) on two c-terminal sites reduces its phosphatase activity. / threonine-307 and -318 appear to be equally well phosphorylated by nek2" SIGNOR-78306 NEK2 protein P51955 UNIPROT PPP1CC protein P36873 UNIPROT down-regulates phosphorylation Thr318 TPPRGMItKQAKK 9606 10880350 t gcesareni "Pp1 is a substrate for nek2 and phosphorylation of pp1gamma(1) on two c-terminal sites reduces its phosphatase activity." SIGNOR-78603 NEK2 protein P51955 UNIPROT NEK2 protein P51955 UNIPROT down-regulates phosphorylation Ser241 RRIPYRYsDELNEII 9606 17197699 t gcesareni "Enzymatic activity, inhibited;" SIGNOR-151767 NEK2 protein P51955 UNIPROT NEK2 protein P51955 UNIPROT down-regulates phosphorylation Thr179 FAKTFVGtPYYMSPE 9606 17197699 t gcesareni "Enzymatic activity, inhibited;" SIGNOR-151771 NEK2 protein P51955 UNIPROT CEP250 protein Q9BV73 UNIPROT down-regulates phosphorylation Ser2394 LHHSLSHsLLAVAQA 9606 24695856 t lperfetto "C-nap1 hyperphosphorylation triggers the loss of both oligomerization and, crucially, interaction with the core centriole proximal-end protein, cep135. All three of these sites were identified in our in vivo analysis but only two (s2234 and s2394) were identified as nek2 phosphorylation sites in vitro." SIGNOR-204837 NEK2 protein P51955 UNIPROT PP1 proteinfamily SIGNOR-PF54 SIGNOR down-regulates phosphorylation 9606 10880350 t lperfetto "Pp1 is a substrate for nek2 and phosphorylation of pp1gamma(1) on two c-terminal sites reduces its phosphatase activity. / threonine-307 and -318 appear to be equally well phosphorylated by nek2" SIGNOR-264655 NEK3 protein P51956 UNIPROT NEK3 protein P51956 UNIPROT "down-regulates activity" phosphorylation Thr165 FACTYVGtPYYVPPE -1 27489110 t Manara "Autophosphorylation at Thr-165 is required for NEK3 kinase activity in vitro." SIGNOR-260919 NDUFA8 protein P51970 UNIPROT "Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND1-module builds around the Q-module with the help of TIMMDC1/C3ORF1 [47,48], which remains bound to the Q/ND1 subassembly until the last maturation steps. MT-ND1 joins first and then NDUFA3, NDUFA8 and NDUFA13 are added" SIGNOR-262159 HNRNPA3 protein P51991 UNIPROT C9orf72 protein Q96LT7 UNIPROT "down-regulates quantity" 9606 BTO:0000142 27461252 f lperfetto "Thus, reduced hnRNPA3 expression in C9orf72 cases leads to increased levels of the repeat RNA as well as enhanced production and deposition of DPR proteins and RNA foci." SIGNOR-262117 MYOM1 protein P52179 UNIPROT OBSCN protein Q5VST9 UNIPROT "up-regulates quantity" relocalization 9606 BTO:0003324 19840192 t miannu "Ankyrin-B is targeted to the M-line via its interaction with the C-terminal domain of the large sarcomeric protein obscurin. Obscurin is targeted to the M-line via its N-terminal interactions with myomesin and titin. This population of ankyrin-B recruits B56α, a regulatory subunit of protein phosphatase 2A, to the M-line where the phosphatase may regulate the phosphorylation status of contractile and signalling proteins." SIGNOR-266727 PGD protein P52209 UNIPROT 6-phospho-D-gluconate smallmolecule CHEBI:16863 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 34775382 t miannu "6 PG undergoes oxidative decarboxylation by 6-phosphogluconate dehydrogenase (6PGD) producing Ru5P and the second NADPH molecule." SIGNOR-267060 PGD protein P52209 UNIPROT "D-ribulose 5-phosphate" smallmolecule CHEBI:17363 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 34775382 t miannu "6 PG undergoes oxidative decarboxylation by 6-phosphogluconate dehydrogenase (6PGD) producing Ru5P and the second NADPH molecule." SIGNOR-267061 PGD protein P52209 UNIPROT NADPH(4-) smallmolecule CHEBI:57783 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 24769394 t miannu "The major NADPH-producing enzymes in the cell are glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) in the pentose phosphate pathway (PPP), malic enzyme (ME) in the pyruvate cycling pathway, and isocitrate dehydrogenase (IDH) in the tricarboxylic acid (TCA) cycle" SIGNOR-267053 KPNA2 protein P52292 UNIPROT RNMT protein O43148 UNIPROT "down-regulates activity" binding 9606 BTO:0000567 26942677 t lperfetto "KPNA2 Inhibits RNMT Activity|We report that CDK1-cyclin B1 phosphorylates the RNMT regulatory domain on T77 during G2/M phase of the cell cycle. RNMT T77 phosphorylation activates the enzyme both directly and indirectly by inhibiting interaction with KPNA2, an RNMT inhibitor." SIGNOR-265502 RAP1GDS1 protein P52306 UNIPROT RAC2 protein P15153 UNIPROT up-regulates binding 9606 21242305 t miannu "Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob" SIGNOR-171421 RAP1GDS1 protein P52306 UNIPROT CDC42 protein P60953 UNIPROT up-regulates binding 9606 21242305 t miannu "Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob" SIGNOR-171412 RAP1GDS1 protein P52306 UNIPROT RAP1B protein P61224 UNIPROT up-regulates binding 9606 21242305 t miannu "Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob" SIGNOR-171552 RAP1GDS1 protein P52306 UNIPROT RHOB protein P62745 UNIPROT up-regulates binding 9606 21242305 t miannu "Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob" SIGNOR-171615 RAP1GDS1 protein P52306 UNIPROT RAP1A protein P62834 UNIPROT up-regulates binding 9606 21242305 t miannu "Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob" SIGNOR-171482 RAP1GDS1 protein P52306 UNIPROT RAC1 protein P63000 UNIPROT up-regulates binding 9606 21242305 t miannu "Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob" SIGNOR-171418 EFNA5 protein P52803 UNIPROT EPHA2 protein P29317 UNIPROT up-regulates binding 9606 9330863 t gcesareni "Members of the epha subfamily of receptor tyrosine kinases and their ephrin-a ligands have been implicated in the guidance of retinal axons along the anterior-posterior axis of the chick optic tectum." SIGNOR-52467 JAK3 protein P52333 UNIPROT PLD2 protein O14939 UNIPROT up-regulates phosphorylation Tyr415 ALGINSGySKRALML 9606 BTO:0000149 20176813 t miannu "We identified three kinases capable of phosphorylating pld2 in vitro-epidermal growth factor receptor (egfr), jak3, and src (with jak3 reported for the first time in this study)-that phosphorylate an inhibitory, an activator, and an ambivalent (one that can yield either effect) site, respectively. Mass spectrometry analyses indicated the target of each of these kinases as y(296) for egfr, y(415) for jak3, and y(511) for src." SIGNOR-163858 JAK3 protein P52333 UNIPROT JAK1 protein P23458 UNIPROT up-regulates phosphorylation 9606 BTO:0000782 17259970 t milica "Il-7r signalling is initiated when il-7 crosslinks the extracellular domains of il-7ralpha and gammac, bringing together jak1 and jak3, which mutually phosphorylate each other, increasing their kinase activity." SIGNOR-152917 JAK3 protein P52333 UNIPROT JAK1 protein P23458 UNIPROT "up-regulates activity" phosphorylation Tyr1034 AIETDKEyYTVKDDR -1 12559972 t "Phosphorylation by recombinant JAK3 of a peptide substrate corresponding to the JAK1 activation loop (KAIETDKEYYTVKD)" SIGNOR-251363 JAK3 protein P52333 UNIPROT JAK1 protein P23458 UNIPROT "up-regulates activity" phosphorylation Tyr1035 IETDKEYyTVKDDRD -1 12559972 t "Phosphorylation by recombinant JAK3 of a peptide substrate corresponding to the JAK1 activation loop (KAIETDKEYYTVKD)" SIGNOR-251364 JAK3 protein P52333 UNIPROT JAK3 protein P52333 UNIPROT up-regulates phosphorylation Tyr980 LLPLDKDyYVVREPG 9606 9391116 t gcesareni "We found that jak3 is autophosphorylated on multiple sites including y980 and y981. Compared with the activity of wild-type (wt) jak3, mutant y980f demonstrated markedly decreased kinase activity, and optimal phosphorylation of jak3 on other sites was dependent on y980 phosphorylation. The mutant y980f also exhibited reduced phosphorylation of its substrates, gammac and stat5a. In contrast, mutant y981f had greatly increased kinase activity, whereas the double mutant, yy980/981ff, had intermediate activity." SIGNOR-53590 JAK3 protein P52333 UNIPROT SIGLEC10 protein Q96LC7 UNIPROT unknown phosphorylation Tyr691 PKGTQADyAEVKFQ 9606 11733002 t lperfetto "These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. however, it is not clear whether y691 is capable of binding sap or a similar protein. Future studies will attempt to elucidate the signaling activities associated with y691" SIGNOR-112487 POLR2H protein P52434 UNIPROT "RNA Polymerase III" complex SIGNOR-C389 SIGNOR "form complex" binding 9606 BTO:0000567 12391170 t lperfetto "In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights." SIGNOR-266140 POLR2H protein P52434 UNIPROT "RNA Polymerase I" complex SIGNOR-C390 SIGNOR "form complex" binding 22260999 t lperfetto "In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1). " SIGNOR-266149 POLR2H protein P52434 UNIPROT "RNA Polymerase II" complex SIGNOR-C391 SIGNOR "form complex" binding 9606 BTO:0000567 9852112 t lperfetto "Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II" SIGNOR-266172 POLR2J protein P52435 UNIPROT "RNA Polymerase II" complex SIGNOR-C391 SIGNOR "form complex" binding 9606 BTO:0000567 9852112 t lperfetto "Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II" SIGNOR-266161 MAP2K6 protein P52564 UNIPROT MAPK13 protein O15264 UNIPROT up-regulates phosphorylation 9606 11242034 t gcesareni "Mapkk6 was shown to phosphorylate and specifically activate the p38/mpk2 sub of the mitogen-activated protein kinase superfamily." SIGNOR-105698 MAP2K6 protein P52564 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates phosphorylation 9606 8974401 t gcesareni "A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subs 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)" SIGNOR-45369 MAP2K6 protein P52564 UNIPROT CRK protein P46108 UNIPROT up-regulates phosphorylation 9606 8663074 t gcesareni "Mapkk6 was shown to phosphorylate and specifically activate the p38/mpk2 sub-family of the mitogen-activated protein kinase superfamily." SIGNOR-42384 MAP2K6 protein P52564 UNIPROT MAP2K6 protein P52564 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007 10347227 t lperfetto "However, the autocatalytic activities of both mkk6 and mkk7 were enhanced by their coexpression with either mekk3 or mekk2." SIGNOR-236122 MAP2K6 protein P52564 UNIPROT MAPK12 protein P53778 UNIPROT up-regulates phosphorylation Thr183 RQADSEMtGYVVTRW 9606 19230643 t gcesareni "Mapkk6 was shown to phosphorylate and specifically activate the p38/mpk2 sub of the mitogen-activated protein kinase superfamily . the p38 mapkinasekinasemkk6 is identified as a common activator of p38 alpha, p38 beta 2, and p38 gamma mapkinaseisoforms . p38mapks are activated by dual phosphorylation on a t-x-y motif in the activation loop through the action of map kinase kinases" SIGNOR-184134 MAP2K6 protein P52564 UNIPROT MAPK12 protein P53778 UNIPROT up-regulates phosphorylation Tyr185 ADSEMTGyVVTRWYR 9606 19230643 t gcesareni "Mapkk6 was shown to phosphorylate and specifically activate the p38/mpk2 sub of the mitogen-activated protein kinase superfamily . the p38 mapkinasekinasemkk6 is identified as a common activator of p38 alpha, p38 beta 2, and p38 gamma mapkinaseisoforms . p38mapks are activated by dual phosphorylation on a t-x-y motif in the activation loop through the action of map kinase kinases" SIGNOR-184138 EFNA5 protein P52803 UNIPROT EPHA3 protein P29320 UNIPROT up-regulates binding 9606 9330863 t gcesareni "Highly promiscuous for ephrin-a ligands it binds preferentially efna5 and became active." SIGNOR-52470 MAP2K6 protein P52564 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates phosphorylation 9606 8974401 t gcesareni "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)" SIGNOR-45363 MAP2K6 protein P52564 UNIPROT STAT4 protein Q14765 UNIPROT "up-regulates activity" phosphorylation Ser721 PSDLLPMsPSVYAVL 10090 BTO:0000944 10961885 t "MKK6, phosphorylate STAT4 on serine 721. IL-12 induces STAT4 phosphorylation on serine 721 and that mutation of serine 721 interferes with STAT4 transcriptional activity." SIGNOR-251425 MAP2K6 protein P52564 UNIPROT MAPK11 protein Q15759 UNIPROT up-regulates phosphorylation 9606 9430721 t gcesareni "The p38 mapkinasekinasemkk6 is identified as a common activator of p38 alpha, p38 beta 2, and p38 gamma mapkinaseisoforms." SIGNOR-54947 MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" phosphorylation 9606 10480932 t 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 MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" phosphorylation 9606 20551513 t 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 MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" phosphorylation Thr180 RHTDDEMtGYVATRW 9534 8622669 t 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 MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" phosphorylation Tyr182 TDDEMTGyVATRWYR 9534 8622669 t 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 MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000298 8974401 t 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 GTF2A1 protein P52655 UNIPROT TFIIA complex SIGNOR-C395 SIGNOR "form complex" binding 9606 BTO:0000567 7724559 t lperfetto "TFIIA purified from HeLa extracts consists of 35-, 19-, and 12-kDa subunits. Here we describe the isolation of a cDNA clone (hTFIIA gamma) encoding the 12-kDa subunit." SIGNOR-266197 GTF2A2 protein P52657 UNIPROT TFIIA complex SIGNOR-C395 SIGNOR "form complex" binding 9606 BTO:0000567 7724559 t lperfetto "TFIIA purified from HeLa extracts consists of 35-, 19-, and 12-kDa subunits. Here we describe the isolation of a cDNA clone (hTFIIA gamma) encoding the 12-kDa subunit." SIGNOR-266196 MSH6 protein P52701 UNIPROT MSH2/MSH6 complex SIGNOR-C60 SIGNOR "form complex" binding 9606 15064730 t miannu "The human msh2/6 complex is essential for mismatch recognition during the repair of replication errors." SIGNOR-123708 VAV2 protein P52735 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 10618391 t tpavlidou "Oligomerization of receptor protein tyrosine kinases such as the epidermal growth factor receptor (egfr) by their cognate ligands leads to activation of the receptor.We Demonstrate that vav-2 is phosphorylated on tyrosine residues in response to egf and associates with the egfr in vivo." SIGNOR-73874 VAV2 protein P52735 UNIPROT RHOA protein P61586 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260582 VAV2 protein P52735 UNIPROT RAC1 protein P63000 UNIPROT up-regulates "guanine nucleotide exchange factor" 9606 10982832 t miannu "Vav2 activates rac1 / vav2 is an exchange factor for rho family gtpases." SIGNOR-81645 VAV2 protein P52735 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260583 ZNF140 protein P52738 UNIPROT FCGR3B protein O75015 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" BTO:0002269 11470777 t Luana "Thus, these results indicate that these cloned ZNF140 and ZNF91 proteins function as repressors for the human Fc gamma RIIB transcription." SIGNOR-266214 CHN2 protein P52757 UNIPROT RAC1 protein P63000 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260500 EFNA3 protein P52797 UNIPROT EPHA2 protein P29317 UNIPROT up-regulates binding 9606 9330863 t gcesareni "The eph family of receptors." SIGNOR-52309 EFNA3 protein P52797 UNIPROT EPHA7 protein Q15375 UNIPROT up-regulates binding 9606 9330863 t gcesareni "The activation of eph receptors by their ligands, which are membrane-anchored molecules, involves a cell-cell recognition event that often causes cell repulsion" SIGNOR-52384 EFNA4 protein P52798 UNIPROT EPHA5 protein P54756 UNIPROT up-regulates binding 9606 9330863 t tpavlidou "Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor" SIGNOR-52430 EFNA5 protein P52803 UNIPROT EPHA4 protein P54764 UNIPROT up-regulates binding 9606 9330863 t tpavlidou "Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor" SIGNOR-52473 MRPL12 protein P52815 UNIPROT "39S mitochondrial large ribosomal subunit" complex SIGNOR-C285 SIGNOR "form complex" binding -1 25838379 t lperfetto "We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules" SIGNOR-262381 HMGA2 protein P52926 UNIPROT CCNA2 protein P20248 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 14645522 f miannu "Transcriptional activation of the cyclin a gene by the architectural transcription factor hmga2" SIGNOR-119496 HMGA2 protein P52926 UNIPROT SCNN1A protein P37088 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10116 BTO:0001003 11390395 f "Regulation of expression" miannu "Expression of endogenous alpha-ENaC gene in salivary Pa-4 cells is suppressed by an ectopic HMGI-C overexpression." SIGNOR-251946 PDX1 protein P52945 UNIPROT NKX6-1 protein P78426 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 11309388 t "In conclusion, Pdx1 confers the expression of pancreatic β-cell-specific genes, such as genes encoding insulin, islet amyloid polypeptide, Glut2, and Nkx6.1." SIGNOR-255542 NUP98 protein P52948 UNIPROT NPC complex SIGNOR-C263 SIGNOR "form complex" binding 27016207 t lperfetto "The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2)." SIGNOR-262074 NUP98 protein P52948 UNIPROT NPC complex SIGNOR-C263 SIGNOR "form complex" binding 27016207 t lperfetto "The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2)." SIGNOR-262098 NKX2-5 protein P52952 UNIPROT MYL2 protein P10916 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0003265 9043061 f "The mammalian homolog of the Drosophila tinman homeobox gene, Nkx2-5, is specifi- cally required for ventricular chamber-specific myosin light chain-2 (MLC-2v) expression and looping morphogenesis during mammalian heart development." SIGNOR-253645 NKX2-5 protein P52952 UNIPROT LYL1 protein P12980 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19608273 f "Sequence analysis of the LYL1 promoter region revealed potential binding sites for transcription factors HOXA10, LMO2 and NKX2-5. Overexpression analysis, reporter gene assays and chromatin immuno-precipitation confirmed their activating impact on LYL1 expression. In conclusion, we identified multiple mechanisms which activate LYL1 in leukemic cells, including structural genomic alterations, namely microdeletion or amplification, together with the involvement of prominent oncogenic transcription factors." SIGNOR-253655 NKX2-5 protein P52952 UNIPROT NPPB protein P16860 UNIPROT unknown "transcriptional regulation" 15837525 f "In comparison to the ANF gene, less is known about BNP promoter consensus elements that regulate gene expression by mechanical or neurohumoral agonists. A number of cis-acting elements for GATA, Nkx2.5, NF-kappaB and TEF transcription factors have recently been identified within the BNP promoter that regulate BNP expression in response to specific agonists. This review focuses on the information available regarding cis-acting determinants responsible for inducible BNP transcription." SIGNOR-253649 NKX2-5 protein P52952 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0003265 19479054 f "Using antisense inhibition we disrupted the expression of NKX2-5 and studied changes in expression of cardiac-associated genes. Down-regulation of NKX2-5 resulted in increased beta-catenin while GATA4 was decreased. We demonstrated that this regulation was conferred by binding of NKX2-5 to specific elements (NKEs) in the promoter region of the beta-catenin and GATA4 genes. Using promoter-luciferase reporter assay combined with mutational analysis of the NKEs we demonstrated that the identified NKX2-5 binding sites were essential for the suppression of beta-catenin, and upregulation of GATA4 by NKX2-5." SIGNOR-253653 NKX2-5 protein P52952 UNIPROT MEF2C protein Q06413 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21261500 f "Taken together, our results indicate that the expression of MEF2C in T-ALL cells is principally deregulated via activating leukemic transcription factors GFI1B or NKX2-5 and by escaping inhibitory developmental STAT5 signaling." SIGNOR-253656 NKX2-5 protein P52952 UNIPROT ANKRD1 protein Q15327 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0003265 9043061 f "Finally, a carp promoter-lacZ transgene, which displays cardiac-specific expression in wild-type and Nkx2-5(+/-) background, was also significantly reduced in Nkx2-5(-/-) embryos, indicating that Nkx2-5 either directly or indirectly regulates carp promoter activity during in vivo cardiogenesis as well as in cultured cardiac myocytes" SIGNOR-253646 NKX2-5 protein P52952 UNIPROT TBX5 protein Q99593 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 15095414 f "Mutation at the potential TBE-B and -C sites, and at the GC box and NKX2.5 sites significantly decreased luciferase activity, suggesting that the GC box and the potential TBE-B, -C, and NKX2.5 sites are functionally important for the activation of the promoter function." SIGNOR-253650 LBX1 protein P52954 UNIPROT SNAI1 protein O95863 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002181 19651985 t Luana "Compared with the empty vector, LBX1 induced increased promoter activity of threefold to fourfold and fivefold to sixfold for ZEB1 and Snail1, respectively " SIGNOR-266053 LBX1 protein P52954 UNIPROT ZEB1 protein P37275 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002181 19651985 t Luana "Compared with the empty vector, LBX1 induced increased promoter activity of threefold to fourfold and fivefold to sixfold for ZEB1 and Snail1, respectively " SIGNOR-266054 BLVRA protein P53004 UNIPROT PRKCB protein P05771 UNIPROT up-regulates phosphorylation Thr500 WDGVTTKtFCGTPDY 9606 17227757 t llicata "Human biliverdin reductase, a previously unknown activator of protein kinase c ?II the phosphorylation of thr500 was confirmed by immunoblotting of hbvr.pkc betaii immunocomplex." SIGNOR-152181 PRKAA2 protein P54646 UNIPROT ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser317 SHLASPPsLGEMQQL 9606 SIGNOR-C15 19584320 t gcesareni "In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy." SIGNOR-186633 PPP5C protein P53041 UNIPROT RAF1 protein P04049 UNIPROT "down-regulates activity" dephosphorylation Ser338 RPRGQRDsSYYWEIE -1 16892053 t "Protein phosphatase 5 (PP5) was identified as an inactivator that associates with Raf-1 on growth factor stimulation and selectively dephosphorylates an essential activating site, Ser 338. The PP5-mediated dephosphorylation of Ser 338 inhibited Raf-1 activity and downstream signalling to MEK" SIGNOR-248537 PPP5C protein P53041 UNIPROT NR3C1 protein P04150 UNIPROT "down-regulates activity" dephosphorylation Ser211 PGKETNEsPWRSDLL 9606 BTO:0000093 19586900 t "Estrogen inhibits glucocorticoid action via protein phosphatase 5 (PP5)-mediated glucocorticoid receptor dephosphorylation.|Inhibition of GR phosphorylation at Ser-211 is associated with decreased nuclear retention of GR and decreased gene transcription." SIGNOR-248538 PPP5C protein P53041 UNIPROT CDC37 protein Q16543 UNIPROT "down-regulates activity" dephosphorylation Ser13 VWDHIEVsDDEDETH 9606 18922470 t "Activation of protein kinase clients by the Hsp90 system is mediated by the cochaperone protein Cdc37. Cdc37 requires phosphorylation at Ser13|PP5/Ppt1 regulates phosphorylation of Ser13-Cdc37 in vivo, directly affecting activation of protein kinase clients by Hsp90-Cdc37." SIGNOR-248539 PPP5C protein P53041 UNIPROT MAP3K5 protein Q99683 UNIPROT "down-regulates activity" dephosphorylation Thr838 GINPCTEtFTGTLQY 9606 BTO:0000567 11689443 t lperfetto "Pp5 directly dephosphorylated an essential phospho-threonine residue within the kinase domain of ask1 and thereby inactivated ask1 activity in vitro and in vivo." SIGNOR-111301 PPP5C protein P53041 UNIPROT MAP3K5 protein Q99683 UNIPROT "down-regulates activity" dephosphorylation Thr842 CTETFTGtLQYMAPE 10090 11689443 t llicata "After exposure of cells to H2O2, ASK1 is transiently activated by autophosphorylation at Thr845. The protein then associates with PP5 (protein serine/threonine phosphatase 5), which inactivates ASK1 by dephosphorylation of Thr845." SIGNOR-248540 PPP5C protein P53041 UNIPROT CILK1 protein Q9UPZ9 UNIPROT "down-regulates activity" dephosphorylation Thr157 IRSKPPYtDYVSTRW 9606 16954377 t llicata "MAK and MRK require dual phosphorylation in a TDY motif catalyzed by an unidentified human threonine kinase and tyrosine autophosphorylation.| Protein phosphatase 5 (PP5) interacts with MRK in a complex and dephosphorylates MRK at T157 in vitro and in situ." SIGNOR-248541 PLK1 protein P53350 UNIPROT IKBKB protein O14920 UNIPROT down-regulates phosphorylation Ser733 TVREQDQsFTALDWS 9606 BTO:0000567 18957422 t lperfetto "Plk1 phosphorylates serines 733, 740, and 750 in the gammabd of ikkbeta in vitro. Phosphorylating gammabd with plk1 decreased its affinity for ikkgamma" SIGNOR-181798 PLK1 protein P53350 UNIPROT IKBKB protein O14920 UNIPROT down-regulates phosphorylation Ser740 SFTALDWsWLQTEEE 9606 BTO:0000567 18957422 t lperfetto "Plk1 phosphorylates serines 733, 740, and 750 in the gammabd of ikkbeta in vitro. Phosphorylating gammabd with plk1 decreased its affinity for ikkgamma" SIGNOR-181802 PLK1 protein P53350 UNIPROT IKBKB protein O14920 UNIPROT down-regulates phosphorylation Ser750 QTEEEEHsCLEQAS 9606 BTO:0000567 18957422 t lperfetto "Plk1 phosphorylates serines 733, 740, and 750 in the gammabd of ikkbeta in vitro. Phosphorylating gammabd with plk1 decreased its affinity for ikkgamma" SIGNOR-181806 PLK1 protein P53350 UNIPROT TP73 protein O15350 UNIPROT down-regulates phosphorylation Thr27 SSLEPDStYFDLPQS 9606 BTO:0000093 18418051 t llicata "P73-mediated transcriptional activity is negatively regulated by polo-like kinase 1. tap73 is phosphorylated by this kinase on threonine-27 (thr-27) within the ta domain." SIGNOR-178253 PLK1 protein P53350 UNIPROT BIRC5 protein O15392 UNIPROT up-regulates phosphorylation Ser20 FLKDHRIsTFKNWPF 9606 21148584 t lperfetto "Thus, we conclude that plk1-mediated phosphorylation of sur at ser20 is critical for accurate chromosome segregation" SIGNOR-170460 PLK1 protein P53350 UNIPROT BUB1B protein O60566 UNIPROT up-regulates phosphorylation Thr1008 LNANDEAtVSVLGEL 9606 17376779 t gcesareni "Bubr1 was phosphorylated by plk1 in vitro at two plk1 consensus sites in the kinase domain of bubr1" SIGNOR-153863 PLK1 protein P53350 UNIPROT KAT7 protein O95251 UNIPROT up-regulates phosphorylation Ser57 SQSSQDSsPVRNLQS 9606 18250300 t lperfetto "Here, we show that the interaction between plk1 and hbo1 is mitosis-specific and that plk1 phosphorylates hbo1 on ser-57 in vitro and in vivo. During mitosis, cdk1 phosphorylates hbo1 on thr-85/88, creating a docking site for plk1 to be recruited. Significantly, the overexpression of hbo1 mutated at the plk1 phosphorylation site (s57a) leads to cell-cycle arrest in the g1/s phase, inhibition of chromatin loading of the minichromosome maintenance (mcm) complex, and a reduced dna replication rate." SIGNOR-160751 PLK1 protein P53350 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates phosphorylation Thr68 SSLETVStQELYSIP 9606 12493754 t gcesareni "Plk1 overexpression enhances phosphorylation of chk2 at thr-68." SIGNOR-96637 PLK1 protein P53350 UNIPROT MYC protein P01106 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007;BTO:0001914 23887393 t gcesareni "Here, we report that PDK1 directly induces phosphorylation of Polo-like kinase 1 (PLK1), which in turn induces MYC phosphorylation and protein accumulation. We show that PDK1-PLK1-MYC signaling is critical for cancer cell growth and survival, and small-molecule inhibition of PDK1/PLK1 provides an effective approach for therapeutic targeting of MYC dependency" SIGNOR-243522 PLK1 protein P53350 UNIPROT TP53 protein P04637 UNIPROT down-regulates 9606 19473992 f lperfetto "Plk1-mediated phosphorylation of topors regulates p53 stability. Herein, we have identified topoisomerase i-binding protein (topors), a p53-binding protein, as a plk1 target. We show that plk1 phosphorylates topors on ser(718) in vivo. Significantly, expression of a plk1-unphosphorylatable topors mutant (s718a) leads to a dramatic accumulation of p53 through inhibition of p53 degradation. Topors is an ubiquitin and small ubiquitin-like modifier ubiquitin-protein isopeptide ligase (sumo e3) ligase. Plk1-mediated phosphorylation of topors inhibits topors-mediated sumoylation of p53, whereas p53 ubiquitination is enhanced, leading to p53 degradation." SIGNOR-185841 PLK1 protein P53350 UNIPROT NPM1 protein P06748 UNIPROT up-regulates phosphorylation Ser4 sMDMDMSP 9606 BTO:0000567 15190079 t gcesareni "Phosphorylated at ser-4 by plk1 and plk2. Phosphorylation at ser-4 by plk2 in s phase is required for centriole duplication and is sufficient to trigger centriole replication. Phosphorylation at ser-4 by plk1 takes place during mitosis." SIGNOR-125666 PLK1 protein P53350 UNIPROT VIM protein P08670 UNIPROT up-regulates phosphorylation Ser83 GVRLLQDsVDFSLAD 9606 BTO:0000150 18056432 t gcesareni "We observed that plk1 phosphorylates vimentin on ser82, which in turn regulates cell surface levels of 1 integrin." SIGNOR-159386 PLK1 protein P53350 UNIPROT TOP2A protein P11388 UNIPROT up-regulates phosphorylation Ser1337 LDSDEDFsDFDEKTD 9606 18171681 t llicata "Plk1 phosphorylates ser(1337) and ser(1524) of topoiialpha plk1-associated phosphorylation is essential for the functions of topoiialpha in mitosis" SIGNOR-160233 FGF8 protein P55075 UNIPROT MYOD1 protein P15172 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002314 BTO:0000887;BTO:0001103 24209627 f gcesareni "Loss of fgf signaling in fgf24 and fgf8 double-deficient zebrafish" SIGNOR-203148 PLK1 protein P53350 UNIPROT CCNB1 protein P14635 UNIPROT "up-regulates activity" phosphorylation Ser126 PILVDTAsPSPMETS 9606 BTO:0000567 11242082 t lperfetto "Phosphorylation of cyclin b1 is central to its nuclear translocationduring cell-cycle progression in hela cells, a change in the kinase activity of endogenous plk1 toward s147 and/or s133 correlates with a kinase activity in the cell extractsa mutant cyclin b1 in which s133 and s147 are replaced by alanines remains in the cytoplasm, whereas wild-type cyclin b1 accumulates in the nucleus during prophase.Together, these results suggest that phosphorylation of s133 and s147 is necessary for the nuclear translocation of cyclin b1 during prophase, and that phosphorylation of s126 and s128 may stimulate the nuclear translocation." SIGNOR-105707 PLK1 protein P53350 UNIPROT CCNB1 protein P14635 UNIPROT "up-regulates activity" phosphorylation Ser128 LVDTASPsPMETSGC 9606 BTO:0000567 11242082 t lperfetto "Phosphorylation of cyclin b1 is central to its nuclear translocationduring cell-cycle progression in hela cells, a change in the kinase activity of endogenous plk1 toward s147 and/or s133 correlates with a kinase activity in the cell extractsa mutant cyclin b1 in which s133 and s147 are replaced by alanines remains in the cytoplasm, whereas wild-type cyclin b1 accumulates in the nucleus during prophase.Together, these results suggest that phosphorylation of s133 and s147 is necessary for the nuclear translocation of cyclin b1 during prophase, and that phosphorylation of s126 and s128 may stimulate the nuclear translocation." SIGNOR-105711 PLK1 protein P53350 UNIPROT CCNB1 protein P14635 UNIPROT "up-regulates activity" phosphorylation Ser133 SPSPMETsGCAPAEE 9606 BTO:0000567 11242082 t lperfetto "Phosphorylation of cyclin b1 is central to its nuclear translocationduring cell-cycle progression in hela cells, a change in the kinase activity of endogenous plk1 toward s147 and/or s133 correlates with a kinase activity in the cell extractsa mutant cyclin b1 in which s133 and s147 are replaced by alanines remains in the cytoplasm, whereas wild-type cyclin b1 accumulates in the nucleus during prophase.Together, these results suggest that phosphorylation of s133 and s147 is necessary for the nuclear translocation of cyclin b1 during prophase, and that phosphorylation of s126 and s128 may stimulate the nuclear translocation." SIGNOR-105715 PLK1 protein P53350 UNIPROT CCNB1 protein P14635 UNIPROT "up-regulates activity" phosphorylation Ser147 EDLCQAFsDVILAVN 9606 BTO:0000567 11242082 t lperfetto "Phosphorylation of cyclin b1 is central to its nuclear translocationduring cell-cycle progression in hela cells, a change in the kinase activity of endogenous plk1 toward s147 and/or s133 correlates with a kinase activity in the cell extractsa mutant cyclin b1 in which s133 and s147 are replaced by alanines remains in the cytoplasm, whereas wild-type cyclin b1 accumulates in the nucleus during prophase.Together, these results suggest that phosphorylation of s133 and s147 is necessary for the nuclear translocation of cyclin b1 during prophase, and that phosphorylation of s126 and s128 may stimulate the nuclear translocation." SIGNOR-105719 PLK1 protein P53350 UNIPROT YY1 protein P25490 UNIPROT up-regulates phosphorylation Thr39 PVETIETtVVGEEEE 9606 23226345 t lperfetto "More recently, we identified and mapped multiple phosphorylation sites in yy1, including, threonine 39, serine 118, serine 247, threonine 348 and threonine 378. The first kinase proven to phosphorylate yy1 in vivo was plk1, which phosphorylates threonine 39 during g2/m stage of the cell cycle [25]. Ck2_ is another kinase identified as constitutively phosphorylating yy1 at serine 118. This modification protects yy1 cleavage by caspase 7 during apoptosis" SIGNOR-200087 PLK1 protein P53350 UNIPROT WEE1 protein P30291 UNIPROT down-regulates phosphorylation Ser53 GHSTGEDsAFQEPDS 9606 BTO:0000567 15070733 t gcesareni "Phosphorylation of serines 53 and 123 (s53 and s123) of wee1a by polo-like kinase 1 (plk1) and cdk, respectively, are required for binding to beta-trcp." SIGNOR-123832 PLK1 protein P53350 UNIPROT WEE1 protein P30291 UNIPROT down-regulates phosphorylation Ser53 GHSTGEDsAFQEPDS 9606 15350223 t gcesareni "Phosphorylation of serines 53 and 123 (s53 and s123) of wee1a by polo-like kinase 1 (plk1) and cdk, respectively, are required for binding to beta-trcp." SIGNOR-128643 PLK1 protein P53350 UNIPROT WEE1 protein P30291 UNIPROT down-regulates phosphorylation Ser123 EEGFGSSsPVKSPAA 9606 16085715 t gcesareni "Phosphorylation of serines 53 and 123 (s53 and s123) of wee1a by polo-like kinase 1 (plk1) and cdk, respectively, are required for binding to beta-trcp." SIGNOR-139473 PLK1 protein P53350 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser24 GYLRKPKsMHKRFFV 9606 15849359 t lperfetto "Phosphorylation of ser24 in the pleckstrin homology domain of insulin receptor substrate-1 by mouse pelle-like kinase/interleukin-1 receptor-associated kinase| irs-1 mutants s24d or s24e (mimicking phosphorylation at ser(24)) had impaired ability to associate with insulin receptors resulting in diminished tyrosine phosphorylation of irs-1 and impaired ability of irs-1 to bind and activate pi-3 kinase in response to insulin." SIGNOR-135688 PLK1 protein P53350 UNIPROT SNCA protein P37840 UNIPROT "down-regulates activity" phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 19889641 t lperfetto "Polo-like kinase (plk) family (plk1, plk2, and plk3) phosphorylate alpha-syn and beta-syn specifically at ser-129 and ser-118, respectively. Polo-like kinase 2 (plk2) phosphorylates alpha-synuclein at serine 129 in central nervous system. The membrane association of pd-linked mutant alpha -synuclein, but not wild-type -synuclein, was increased by serine 129 phosphorylation." SIGNOR-189045 PLK1 protein P53350 UNIPROT RAP1GAP protein P47736 UNIPROT down-regulates phosphorylation Ser525 AGQKTPDsGHVSQEP 9606 25329897 t lperfetto "Plk1 phosphorylates ser525 in conserved 524dsghvs529 degron of rap1gap and promotes its interaction with _-trcp. Together, these results further support a model in which plk1, but not cdk1 or gsk-3_-mediated phosphorylation of rap1gap is a prerequisite for mitotic degradation." SIGNOR-205577 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT "down-regulates activity" phosphorylation Ser193 AEVDPDMsWSSSLAT 9606 BTO:0001938 12815053 t lperfetto "M phase-specific phosphorylation of brca2 by polo-like kinase 1 correlates with the dissociation of the brca2-p/caf complex.Plk1 interacts with brca2 in vivo, and mutation of ser193, ser205/206, and thr203/207 to ala in br-n1 abolished plk1 phosphorylation, suggesting that brca2 is the substrate of plk1" SIGNOR-102486 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT "down-regulates activity" phosphorylation Ser205 LATPPTLsSTVLIVR 9606 BTO:0001938 12815053 t lperfetto "M phase-specific phosphorylation of brca2 by polo-like kinase 1 correlates with the dissociation of the brca2-p/caf complex.Plk1 interacts with brca2 in vivo, and mutation of ser193, ser205/206, and thr203/207 to ala in br-n1 abolished plk1 phosphorylation, suggesting that brca2 is the substrate of plk1" SIGNOR-102490 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT "down-regulates activity" phosphorylation Thr207 TPPTLSStVLIVRNE 9606 BTO:0001938 12815053 t lperfetto "M phase-specific phosphorylation of brca2 by polo-like kinase 1 correlates with the dissociation of the brca2-p/caf complex.Plk1 interacts with brca2 in vivo, and mutation of ser193, ser205/206, and thr203/207 to ala in br-n1 abolished plk1 phosphorylation, suggesting that brca2 is the substrate of plk1" SIGNOR-102502 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT unknown phosphorylation Ser193 AEVDPDMsWSSSLAT 9606 BTO:0001938 12815053 t lperfetto "Plk1 interacts with BRCA2 in vivo, and mutation of Ser193, Ser205/206, and Thr203/207 to Ala in BR-N1 abolished Plk1 phosphorylation, suggesting that BRCA2 is the substrate of Plk1. Furthermore, both the hyperphosphorylated and hypophosphorylated forms of BRCA2 bind to RAD51, whereas the M phase hyperphosphorylated form of BRCA2 no longer associates with the P/CAF, suggesting that the dissociation of P/CAF-BRCA2 complex is regulated by phosphorylation." SIGNOR-249217 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT unknown phosphorylation Ser205 LATPPTLsSTVLIVR 9606 BTO:0001938 12815053 t lperfetto "Plk1 interacts with BRCA2 in vivo, and mutation of Ser193, Ser205/206, and Thr203/207 to Ala in BR-N1 abolished Plk1 phosphorylation, suggesting that BRCA2 is the substrate of Plk1. Furthermore, both the hyperphosphorylated and hypophosphorylated forms of BRCA2 bind to RAD51, whereas the M phase hyperphosphorylated form of BRCA2 no longer associates with the P/CAF, suggesting that the dissociation of P/CAF-BRCA2 complex is regulated by phosphorylation." SIGNOR-249218 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT unknown phosphorylation Ser206 ATPPTLSsTVLIVRN 9606 BTO:0001938 12815053 t lperfetto "Plk1 interacts with BRCA2 in vivo, and mutation of Ser193, Ser205/206, and Thr203/207 to Ala in BR-N1 abolished Plk1 phosphorylation, suggesting that BRCA2 is the substrate of Plk1. Furthermore, both the hyperphosphorylated and hypophosphorylated forms of BRCA2 bind to RAD51, whereas the M phase hyperphosphorylated form of BRCA2 no longer associates with the P/CAF, suggesting that the dissociation of P/CAF-BRCA2 complex is regulated by phosphorylation." SIGNOR-249219 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT unknown phosphorylation Thr203 SSLATPPtLSSTVLI 9606 BTO:0001938 12815053 t lperfetto "Plk1 interacts with BRCA2 in vivo, and mutation of Ser193, Ser205/206, and Thr203/207 to Ala in BR-N1 abolished Plk1 phosphorylation, suggesting that BRCA2 is the substrate of Plk1. Furthermore, both the hyperphosphorylated and hypophosphorylated forms of BRCA2 bind to RAD51, whereas the M phase hyperphosphorylated form of BRCA2 no longer associates with the P/CAF, suggesting that the dissociation of P/CAF-BRCA2 complex is regulated by phosphorylation." SIGNOR-249220 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT unknown phosphorylation Thr207 TPPTLSStVLIVRNE 9606 BTO:0001938 12815053 t lperfetto "Plk1 interacts with BRCA2 in vivo, and mutation of Ser193, Ser205/206, and Thr203/207 to Ala in BR-N1 abolished Plk1 phosphorylation, suggesting that BRCA2 is the substrate of Plk1. Furthermore, both the hyperphosphorylated and hypophosphorylated forms of BRCA2 bind to RAD51, whereas the M phase hyperphosphorylated form of BRCA2 no longer associates with the P/CAF, suggesting that the dissociation of P/CAF-BRCA2 complex is regulated by phosphorylation." SIGNOR-249221 PLK1 protein P53350 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Ser739 SKILLDIsFPGLDED 9606 19737929 t lperfetto "It has been reported that plk1 could directly phosphorylate foxm1 at ser-715 and ser-724 for full activation and proper mitotic progression" SIGNOR-187892 PLK1 protein P53350 UNIPROT TP53BP1 protein Q12888 UNIPROT "down-regulates activity" phosphorylation Ser1618 LTKAADIsLDNLVEG -1 24703952 t lperfetto "Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks |Addition of the inhibitors for PLK1 and the p38 MAPK leads to a complete loss of pT1609/pS1618 signal within 3 hr in mitotic cells" SIGNOR-264413 PLK1 protein P53350 UNIPROT FADD protein Q13158 UNIPROT "down-regulates activity" phosphorylation Ser194 QNRSGAMsPMSWNSD 9606 20890306 t gcesareni "Fas-associated death domain-containing protein (FADD) was first identified as an adapter molecule involved in formation of a death-inducing signaling complex upon Fas stimulation| Plk1 phosphorylates fadd at ser-194 in response to treatment with taxol Phosphorylation by polo-like kinase 1 induces the tumor-suppressing activity of FADD" SIGNOR-168204 PLK1 protein P53350 UNIPROT PIN1 protein Q13526 UNIPROT up-regulates phosphorylation Ser65 SHLLVKHsQSRRPSS 9606 BTO:0000567 16118204 t llicata "Here we demonstrate that ser-65 in pin1 is the major site for plk1-specific phosphorylation, and the polo-box domain of plk1 is required for this phosphorylation. Interestingly, the phosphorylation of pin1 by plk1 does not affect its isomerase activity but rather is linked to its protein stability. pin1 is ubiquitinated in hela s3 cells, and substitution of glu for ser-65 reduces the ubiquitination of pin1." SIGNOR-139919 PLK1 protein P53350 UNIPROT DCTN1 protein Q14203 UNIPROT up-regulates phosphorylation Ser179 SASAGELsSSEPSTP 9606 20679239 t lperfetto "Plk1-mediated phosphorylation of p150(glued) at ser-179 positively regulates its accumulation at the nuclear envelope during prophase." SIGNOR-167281 PLK1 protein P53350 UNIPROT MAD2L1BP protein Q15013 UNIPROT "down-regulates activity" phosphorylation Ser102 KHFYRKPsPQAEEML 9606 BTO:0000567 31118282 t miannu "Purified Plk1 bound to p31comet and phosphorylated it, resulting in the suppression of its activity (with TRIP13) to disassemble checkpoint complexes. We conclude that Plk1 phosphorylates p31 on S102 and on five additional sites. The phosphorylation of the additional sites was possibly not detectable in HeLa cell extracts due to the opposing action of protein phosphatases." SIGNOR-265970 PLK1 protein P53350 UNIPROT SNCB protein Q16143 UNIPROT "down-regulates activity" phosphorylation Ser118 LMEPEGEsYEDPPQE 9606 19889641 t lperfetto "Polo-like kinase (plk) family (plk1, plk2, and plk3) phosphorylate alpha-syn and beta-syn specifically at ser-129 and ser-118, respectively. Polo-like kinase 2 (plk2) phosphorylates alpha-synuclein at serine 129 in central nervous system. The membrane association of pd-linked mutant alpha -synuclein, but not wild-type -synuclein, was increased by serine 129 phosphorylation." SIGNOR-176079 PLK1 protein P53350 UNIPROT KIZ protein Q2M2Z5 UNIPROT up-regulates phosphorylation Thr379 WSTSSDLtISISEDD 9606 16980960 t lperfetto "Here, we identify a novel centrosomal substrate of plk1, kizuna (kiz), depletion of which causes fragmentation and dissociation of the pericentriolar material from centrioles at prometaphase, resulting in multipolar spindles. Plk1 maintains the integrity of the spindle poles by phosphorylating kiz." SIGNOR-149630 PLK1 protein P53350 UNIPROT ERCC6L protein Q2NKX8 UNIPROT up-regulates relocalization 9606 17218258 t lperfetto "Human pich was identified as an interaction partner and substrate of plk1. Our data indicate that plk1 prevents the association of pich with chromosome arms and restricts its localization to the kt/centromere region" SIGNOR-152136 PLK1 protein P53350 UNIPROT PLEKHG6 protein Q3KR16 UNIPROT up-regulates phosphorylation Thr574 HLVVTEDtDEDAPLV 9606 BTO:0000567 18694934 t lperfetto "We reported previously that a guanine nucleotide exchange factor, myogef, localizes to the central spindle, activates rhoa, and is required for cytokinesis. In this study, we have found that plk1 (polo-like kinase 1) can phosphorylate myogef, thereby recruiting myogef to the central spindle as well as enhancing myogef activity toward rhoa. The in vitro kinase assay shows that plk1 can phosphorylate myogef on threonine 574." SIGNOR-179954 PLK1 protein P53350 UNIPROT MAP9 protein Q49MG5 UNIPROT up-regulates phosphorylation Ser289 SDENKENsFSADHVT 9606 20615875 t lperfetto "We also demonstrate that asap is a novel substrate of plk1 phosphorylation and have identified serine 289 as the major phosphorylation site by plk1 in vivo. Asap phosphorylated on serine 289 is localized to centrosomes during mitosis, but this phosphorylation is not required for its plk1-dependent localization at the spindle poles. We show that phosphorylated asap on serine 289 contributes to spindle pole stability in a microtubule-dependent manner" SIGNOR-166564 PLK1 protein P53350 UNIPROT CEP55 protein Q53EZ4 UNIPROT up-regulates phosphorylation Ser436 PTAALNEsLVECPKC 9606 16198290 t lperfetto "Upon mitotic entry, centrosome dissociation of cep55 is triggered by erk2/cdk1-dependent phosphorylation at s425 and s428. s425/428 phosphorylation is required for interaction with plk1, enabling phosphorylation of cep55 at s436...enabling it to relocate to the midbody to function in mitotic exit and cytokinesis." SIGNOR-140898 PLK1 protein P53350 UNIPROT BORA protein Q6PGQ7 UNIPROT down-regulates phosphorylation Thr501 QMDSGYNtQNCGSNI 9606 18378770 t gcesareni "Following cdk1-dependent recruitment, plk1 triggers hbora destruction by phosphorylating a recognition site for scf(beta-trcp)." SIGNOR-178154 PLK1 protein P53350 UNIPROT BORA protein Q6PGQ7 UNIPROT down-regulates phosphorylation Ser497 SSNIQMDsGYNTQNC 9606 18521620 t gcesareni "Following cdk1-dependent recruitment, plk1 triggers hbora destruction by phosphorylating a recognition site for scf(beta-trcp)." SIGNOR-178803 PLK1 protein P53350 UNIPROT BORA protein Q6PGQ7 UNIPROT down-regulates phosphorylation Thr501 QMDSGYNtQNCGSNI 9606 18521620 t gcesareni "Following cdk1-dependent recruitment, plk1 triggers hbora destruction by phosphorylating a recognition site for scf(beta-trcp)." SIGNOR-178807 PLK1 protein P53350 UNIPROT CENPQ protein Q7L2Z9 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser248 DLDILHNsSQMKSMS 9606 BTO:0000567 25670858 t lperfetto "Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites." SIGNOR-265227 PLK1 protein P53350 UNIPROT CENPQ protein Q7L2Z9 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser249 LDILHNSsQMKSMST 9606 BTO:0000567 25670858 t lperfetto "Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites." SIGNOR-265230 PLK1 protein P53350 UNIPROT CENPQ protein Q7L2Z9 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser253 HNSSQMKsMSTFIEE 9606 BTO:0000567 25670858 t lperfetto "Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites." SIGNOR-265232 PLK1 protein P53350 UNIPROT CENPQ protein Q7L2Z9 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser255 SSQMKSMsTFIEEAY 9606 BTO:0000567 25670858 t lperfetto "Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites." SIGNOR-265226 PLK1 protein P53350 UNIPROT CENPQ protein Q7L2Z9 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr123 RLLQQCEtLKVPPKK 9606 BTO:0000567 25670858 t lperfetto "Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites." SIGNOR-265231 PLK1 protein P53350 UNIPROT CENPQ protein Q7L2Z9 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr135 PKKMEDLtNVSSLLN 9606 BTO:0000567 25670858 t lperfetto "Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites." SIGNOR-265234 PLK1 protein P53350 UNIPROT CENPQ protein Q7L2Z9 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr256 SQMKSMStFIEEAYK 9606 BTO:0000567 25670858 t lperfetto "Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites." SIGNOR-265229 PLK1 protein P53350 UNIPROT KIF2B protein Q8N4N8 UNIPROT "up-regulates activity" phosphorylation Thr125 MIPQKNQtASGDSLD 9606 BTO:0001938 22535524 t lperfetto "We show that Plk1 directly phosphorylates Kif2b at threonine 125 (T125) and serine 204 (S204), and that these two sites differentially regulate Kif2b function. Phosphorylation of S204 is required for the kinetochore localization and activity of Kif2b in prometaphase, and phosphorylation of T125 is required for Kif2b activity in the correction of k-MT attachment errors." SIGNOR-252049 PLK1 protein P53350 UNIPROT CEP192 protein Q8TEP8 UNIPROT "up-regulates activity" phosphorylation Thr44 GLPVAVStLARDRSS 9606 BTO:0000007 26012549 t miannu "In the presence of AurA binding, Plk1 preferentially phosphorylates and interacts with the T44 motif of Cep192 through the “self-priming and binding” mechanism" SIGNOR-266405 CASP6 protein P55212 UNIPROT CASP8 protein Q14790 UNIPROT up-regulates cleavage 9606 11455969 t gcesareni "This pathway can either be ampli?ed By caspase- 8-mediated cleavage of bid and by the downstream, caspase-6- mediated cleavage of caspase-8." SIGNOR-109411 PLK1 protein P53350 UNIPROT PINX1 protein Q96BK5 UNIPROT down-regulates phosphorylation Ser110 SDKKEKKsFSLEEKS 9606 20573420 t lperfetto "Here, we show that polo-like kinase 1 (plk1) is a novel interacting protein of pinx1. Plk1 interacts with and phosphorylates pinx1 in vivo and in vitro. Moreover, plk1-mediated phosphorylation of pinx1 at five phosphorylation sites is essential for its plk1-induced degradation." SIGNOR-166317 PLK1 protein P53350 UNIPROT PINX1 protein Q96BK5 UNIPROT down-regulates phosphorylation Ser117 SFSLEEKsKISKNRV 9606 20573420 t lperfetto "Here, we show that polo-like kinase 1 (plk1) is a novel interacting protein of pinx1. Plk1 interacts with and phosphorylates pinx1 in vivo and in vitro. Moreover, plk1-mediated phosphorylation of pinx1 at five phosphorylation sites is essential for its plk1-induced degradation." SIGNOR-166321 PLK1 protein P53350 UNIPROT PINX1 protein Q96BK5 UNIPROT down-regulates phosphorylation Ser226 ATGKDVEsYLQPKAK 9606 20573420 t lperfetto "Here, we show that polo-like kinase 1 (plk1) is a novel interacting protein of pinx1. Plk1 interacts with and phosphorylates pinx1 in vivo and in vitro. Moreover, plk1-mediated phosphorylation of pinx1 at five phosphorylation sites is essential for its plk1-induced degradation." SIGNOR-166325 PLK1 protein P53350 UNIPROT PINX1 protein Q96BK5 UNIPROT down-regulates phosphorylation Thr141 DLSSRSKtDLDCIFG 9606 20573420 t lperfetto "Here, we show that polo-like kinase 1 (plk1) is a novel interacting protein of pinx1. Plk1 interacts with and phosphorylates pinx1 in vivo and in vitro. Moreover, plk1-mediated phosphorylation of pinx1 at five phosphorylation sites is essential for its plk1-induced degradation." SIGNOR-166329 PLK1 protein P53350 UNIPROT PINX1 protein Q96BK5 UNIPROT down-regulates phosphorylation Thr317 EDATLEEtLVKKKKK 9606 20573420 t lperfetto "Here, we show that polo-like kinase 1 (plk1) is a novel interacting protein of pinx1. Plk1 interacts with and phosphorylates pinx1 in vivo and in vitro. Moreover, plk1-mediated phosphorylation of pinx1 at five phosphorylation sites is essential for its plk1-induced degradation." SIGNOR-166333 PLK1 protein P53350 UNIPROT OPTN protein Q96CV9 UNIPROT up-regulates phosphorylation Ser177 SSGSSEDsFVEIRMA 9606 22365832 t lperfetto "Here we show that at mitotic entry, plk1 phosphorylates optineurin (optn) at serine 177 and that this dissociates optn from the golgi-localized gtpase rab8, inducing its translocation into the nucleus." SIGNOR-196367 PLK1 protein P53350 UNIPROT PKMYT1 protein Q99640 UNIPROT "down-regulates activity" phosphorylation Ser426 CSLLLDSsLSSNWDD -1 12738781 t miannu "Here, we have shown that Plk1 is responsible for part of the phosphorylation of Myt1 during M phase. The kinase activity of human Myt1 is reported to be decreased during M phase, and the decreased activity correlates with hyperphosphorylated forms of Myt1 (35, 37). We then tested the ability of these mutant forms of Myt1 (GST fusion proteins), to serve as a substrate for Plk1 in vitro. Quantification of the result (Fig. 5C) showed that Ser-426 is the major phosphorylation site by Plk1 in vitro and Thr-495 the second major site." SIGNOR-263096 PLK1 protein P53350 UNIPROT PKMYT1 protein Q99640 UNIPROT "down-regulates activity" phosphorylation Thr495 LLSLFEDtLDPT -1 12738781 t miannu "Here, we have shown that Plk1 is responsible for part of the phosphorylation of Myt1 during M phase. The kinase activity of human Myt1 is reported to be decreased during M phase, and the decreased activity correlates with hyperphosphorylated forms of Myt1 (35, 37). We then tested the ability of these mutant forms of Myt1 (GST fusion proteins), to serve as a substrate for Plk1 in vitro. Quantification of the result (Fig. 5C) showed that Ser-426 is the major phosphorylation site by Plk1 in vitro and Thr-495 the second major site." SIGNOR-263097 PLK1 protein P53350 UNIPROT PKMYT1 protein Q99640 UNIPROT unknown phosphorylation Ser426 CSLLLDSsLSSNWDD 9606 BTO:0000567 12738781 t lperfetto "These results suggest that Ser-426 is a major phosphorylation site by Plk1, and Thr-495 is a second major site. " SIGNOR-249207 PLK1 protein P53350 UNIPROT PKMYT1 protein Q99640 UNIPROT unknown phosphorylation Thr495 LLSLFEDtLDPT 9606 BTO:0000567 12738781 t lperfetto "These results suggest that Ser-426 is a major phosphorylation site by Plk1, and Thr-495 is a second major site. " SIGNOR-249208 PLK1 protein P53350 UNIPROT RIOK2 protein Q9BVS4 UNIPROT "up-regulates activity" phosphorylation Ser548 KSSLEAAsFWGE -1 21880710 t miannu "Here, we report that the atypical protein kinase Rio2 is a novel substrate of Plk1 and can be phosphorylated by Plk1 at Ser-335, Ser-380, and Ser-548. Overexpression of Rio2 causes a prolonged mitotic exit whereas knockdown of Rio2 accelerates mitotic progression, suggesting that Rio2 is required for the proper mitotic progression." SIGNOR-262939 PLK1 protein P53350 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT up-regulates phosphorylation Ser170 ESLDWDSsLVKTFKL 9606 19468302 t llicata "Tandem mass spectrometry analysis of a purified hscyk-4 fragment (hscyk-4n) phosphorylated by plk1 in vitro identified four major sites (s157, s170, s214, and s260 plk1 phosphorylation of hscyk-4 localizes ect2 at the midzone and stimulates rhoa-dependent contractile ring assembly at the equatorial cortex." SIGNOR-185750 PLK1 protein P53350 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT up-regulates phosphorylation Ser214 AVDQGNEsIVAKTTV 9606 19468302 t llicata "Tandem mass spectrometry analysis of a purified hscyk-4 fragment (hscyk-4n) phosphorylated by plk1 in vitro identified four major sites (s157, s170, s214, and s260 plk1 phosphorylation of hscyk-4 localizes ect2 at the midzone and stimulates rhoa-dependent contractile ring assembly at the equatorial cortex." SIGNOR-185754 PLK1 protein P53350 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT up-regulates phosphorylation Thr260 QPWNSDStLNSRQLE 9606 19468302 t llicata "Tandem mass spectrometry analysis of a purified hscyk-4 fragment (hscyk-4n) phosphorylated by plk1 in vitro identified four major sites (s157, s170, s214, and s260 plk1 phosphorylation of hscyk-4 localizes ect2 at the midzone and stimulates rhoa-dependent contractile ring assembly at the equatorial cortex." SIGNOR-185758 PLK1 protein P53350 UNIPROT ANAPC1 protein Q9H1A4 UNIPROT up-regulates phosphorylation Ser355 AALSRAHsPALGVHS 9606 14657031 t gcesareni "Our analysis revealed an unexpected and unprecedented complexity of mitotic phosphorylation sites and suggests that other kinases than cdk1 and plk1 also contribute to apc phosphorylation." SIGNOR-119881 PLK1 protein P53350 UNIPROT TRIOBP protein Q9H2D6 UNIPROT up-regulates phosphorylation Thr2229 QAEEREHtLRRCQQE 9606 22820163 t lperfetto "Here we show that tara is a novel polo-like kinase 1 (plk1) target protein. Plk1 interacts with and phosphorylates tara in vivo and in vitro. Actually, the thr-457 in tara was a bona fide in vivo phosphorylation site for plk1. Interestingly, we found that the centrosomal localization of tara depended on the thr-457 phosphorylation and the kinase activity of plk1" SIGNOR-198353 PLK1 protein P53350 UNIPROT TRIOBP protein Q9H2D6 UNIPROT up-regulates phosphorylation Thr447 ASSPSRAtRDNPTTS 9606 22820163 t lperfetto "Here we show that tara is a novel polo-like kinase 1 (plk1) target protein. Plk1 interacts with and phosphorylates tara in vivo and in vitro. Actually, the thr-457 in tara was a bona fide in vivo phosphorylation site for plk1. Interestingly, we found that the centrosomal localization of tara depended on the thr-457 phosphorylation and the kinase activity of plk1" SIGNOR-198357 PLK1 protein P53350 UNIPROT GTSE1 protein Q9NYZ3 UNIPROT up-regulates phosphorylation Ser435 RSIRRRDsCLNSKTK 9606 20577264 t lperfetto "In this study, we show that g2 and s-phase-expressed 1 (gtse1) protein, a negative regulator of p53, is required for g2 checkpoint recovery and that plk1 phosphorylation of gtse1 at ser 435 promotes its nuclear localization, and thus shuttles p53 out of the nucleus to lead to its degradation during the recovery." SIGNOR-166417 PLK1 protein P53350 UNIPROT ATXN10 protein Q9UBB4 UNIPROT down-regulates phosphorylation Ser77 QVENLASsLQLITEC 9606 21857149 t lperfetto "Phosphorylation of ataxin-10 by polo-like kinase 1 is required for cytokinesis. Plk1 phosphorylates ataxin-10 at s77 and t82 in vitro. we found that ataxin-10 is ubiquitinated, and is subject to proteasome-dependent degradation, which is delayed in the 2a mutant. We propose a model in which plk1 phosphorylation of ataxin-10 influences its degradation and cytokinesis" SIGNOR-176122 PLK1 protein P53350 UNIPROT ATXN10 protein Q9UBB4 UNIPROT down-regulates phosphorylation Thr82 ASSLQLItECFRCLR 9606 21857149 t lperfetto "Phosphorylation of ataxin-10 by polo-like kinase 1 is required for cytokinesis. Plk1 phosphorylates ataxin-10 at s77 and t82 in vitro. we found that ataxin-10 is ubiquitinated, and is subject to proteasome-dependent degradation, which is delayed in the 2a mutant. We propose a model in which plk1 phosphorylation of ataxin-10 influences its degradation and cytokinesis" SIGNOR-176126 PLK1 protein P53350 UNIPROT FBXO5 protein Q9UKT4 UNIPROT down-regulates phosphorylation 9606 15469984 t gcesareni "Plk1 regulates activation of the anaphase promoting complex by phosphorylating and triggering scfbetatrcp-dependent destruction of the apc inhibitor emi1." SIGNOR-129813 PLK1 protein P53350 UNIPROT FBXO5 protein Q9UKT4 UNIPROT down-regulates phosphorylation 9606 16439210 t gcesareni "We propose that the balance of evi5 and polo-like kinase activities determines the timely accumulation of emi1 and cyclin, ensuring mitotic fidelity." SIGNOR-142949 PLK1 protein P53350 UNIPROT NUDC protein Q9Y266 UNIPROT "up-regulates activity" phosphorylation Ser274 KKINPENsKLSDLDS 9606 BTO:0000567 12852857 t lperfetto "Here, we characterize the interaction between plk1 and nudc, show that plk1 phosphorylates nudc at conserved s274 and s326 residues in vitro, and present evidence that nudc is also a substrate for plk1 in vivo. Downregulation of nudc by rna interference results in multiple mitotic defects, including multinucleation and cells arrested at the midbody stage, which are rescued by ectopic expression of wild-type nudc, but not by nudc with mutations in the plk1 phosphorylation sites." SIGNOR-103403 PLK1 protein P53350 UNIPROT NUDC protein Q9Y266 UNIPROT "up-regulates activity" phosphorylation Ser326 QHPEMDFsKAKFN 9606 BTO:0000567 12852857 t lperfetto "Here, we characterize the interaction between plk1 and nudc, show that plk1 phosphorylates nudc at conserved s274 and s326 residues in vitro, and present evidence that nudc is also a substrate for plk1 in vivo. Downregulation of nudc by rna interference results in multiple mitotic defects, including multinucleation and cells arrested at the midbody stage, which are rescued by ectopic expression of wild-type nudc, but not by nudc with mutations in the plk1 phosphorylation sites." SIGNOR-103407 PLK1 protein P53350 UNIPROT NINL protein Q9Y2I6 UNIPROT "down-regulates activity" phosphorylation Ser686 LEELHEKsQEVIWGL -1 12852856 t lperfetto "Here, we identify a centrosomal plk1 substrate, termed nlp (ninein-like protein), whose properties suggest an important role in microtubule organization. Nlp interacts with two components of the gamma-tubulin ring complex and stimulates microtubule nucleation. Plk1 phosphorylates nlp and disrupts both its centrosome association and its gamma-tubulin interaction" SIGNOR-103348 DAPK1 protein P53355 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 BTO:0000776 17339337 t gcesareni "Dna damage-activated protein kinases like chk1/2 modify the box-i domain of p53 at thr18 and ser20 (46) by an allosteric mechanism (10)." SIGNOR-153491 DAPK1 protein P53355 UNIPROT TPM1 protein P09493 UNIPROT "up-regulates activity" phosphorylation Ser283 HALNDMTsI 9606 BTO:0000007 17895359 t miannu "We identified, for the first time, death-associated protein kinase 1 (DAP kinase 1) as the kinase that phosphorylates tropomyosin-1 in response to ERK activation by hydrogen peroxide (H(2)O(2)). We also report that the phosphorylation of tropomyosin-1 mediated by DAP kinase occurs on Ser283. Our finding that tropomyosin-1 is phosphorylated downstream of ERK and DAP kinase and that it helps regulate the formation of stress fibers will aid understanding the role of this protein in regulating the endothelial functions associated with cytoskeletal remodeling." SIGNOR-262845 DAPK1 protein P53355 UNIPROT MYL12A protein P19105 UNIPROT "up-regulates activity" phosphorylation Ser19 KRPQRATsNVFAMFD 9606 BTO:0000567 11485996 t miannu "DAPK Phosphorylates Myosin II RLC in Vitro and in Vivo. Together these results show that similar to the conventional MLCKs, Ser-19 is the primary RLC residue phosphorylated by DAPK and that phosphorylation of Thr-18 is also possible." SIGNOR-262842 DAPK1 protein P53355 UNIPROT MYL12A protein P19105 UNIPROT "up-regulates activity" phosphorylation Thr18 KKRPQRAtSNVFAMF 9606 BTO:0000567 11485996 t miannu "DAPK Phosphorylates Myosin II RLC in Vitro and in Vivo. Together these results show that similar to the conventional MLCKs, Ser-19 is the primary RLC residue phosphorylated by DAPK and that phosphorylation of Thr-18 is also possible." SIGNOR-262843 DAPK1 protein P53355 UNIPROT MAP1B protein P46821 UNIPROT up-regulates binding 9606 18806760 t gcesareni "Dapk-1 interacts with the microtubule-associated protein map1b, in particular in conditions of amino-acid starvation." SIGNOR-181305 DAPK1 protein P53355 UNIPROT DAPK1 protein P53355 UNIPROT "down-regulates activity" phosphorylation Ser308 ARKKWKQsVRLISLC 9606 BTO:0000007 11579085 t lperfetto "The pro-apoptotic function of death-associated protein kinase is controlled by a unique inhibitory autophosphorylation-based mechanism.These results are consistent with a molecular model in which phosphorylation on ser(308) stabilizes a locked conformation of the cam-regulatory domain within the catalytic cleft and simultaneously also interferes with cam binding." SIGNOR-110807 DAPK1 protein P53355 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates phosphorylation Thr119 LSRRLKVtGDLFDIM 9606 BTO:0000007 19180116 t gcesareni "The activated form of DAPK triggers autophagy in a beclin-1-dependent manner. DAPK phosphorylates beclin 1 on Thr 119 located at a crucial position within its BH3 domain, and thus promotes the dissociation of beclin 1 from Bcl-XL and the induction of autophagy." SIGNOR-183548 DAPK1 protein P53355 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates phosphorylation Thr119 LSRRLKVtGDLFDIM 9606 19395874 t gcesareni "We found that DAPk phosphorylates Beclin 1 on T119, a critical residue within its BH3 domain, and thus promotes Beclin 1 dissociation from Bcl-X(L) and autophagy induction. Here we report that T119 phosphorylation also reduces the interaction between Beclin 1 and Bcl-2, in line with the high degree of structural homology between the BH3 binding pockets of Bcl-2 and Bcl-X(L) proteins." SIGNOR-185589 RSPO2 protein Q6UXX9 UNIPROT SDC4 protein P31431 UNIPROT up-regulates binding 9606 21397842 t "Thrombospondin domains" gcesareni "We show that rspo3 binds syndecan 4 (sdc4) and that together they activate wnt/pcp signaling." SIGNOR-172719 DAPK1 protein P53355 UNIPROT STX1A protein Q16623 UNIPROT "down-regulates activity" phosphorylation Ser188 IIMDSSIsKQALSEI 9606 BTO:0000007;BTO:0000356 12730201 t llicata "Syntaxin-1A phosphorylation by DAP kinase or its S188D mutant, which mimics a state of complete phosphorylation, significantly decreases syntaxin binding to Munc18-1, a syntaxin-binding protein that regulates SNARE complex formation and is required for synaptic vesicle docking." SIGNOR-251083 DAPK1 protein P53355 UNIPROT CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser511 RREERSLsAPGNLLT 9606 BTO:0000938 BTO:0000142 15209507 t lperfetto "Dapk phosphorylates camkk. S511 was identified as the phosphorylation site . a potential mechanism of action was identified on the basis of the location of s511 near the cam recognition domain of camkk and demonstrated by attenuation of cam-stimulated camkk autophosphorylation after dapk phosphorylation." SIGNOR-126241 DAPK1 protein P53355 UNIPROT CAMKK2 protein Q96RR4 UNIPROT unknown phosphorylation Ser511 RREERSLsAPGNLLT 9606 BTO:0000938 BTO:0000142 15209507 t lperfetto "Dapk phosphorylates camkks511 was identified as the phosphorylation site" SIGNOR-126245 ACLY protein P53396 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 19286649 t miannu "ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor." SIGNOR-267102 COL4A4 protein P53420 UNIPROT "A2/b1 integrin" complex SIGNOR-C160 SIGNOR "up-regulates activity" binding 9606 BTO:0000664 12123670 t lperfetto "We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1." SIGNOR-253245 CEBPG protein P53567 UNIPROT LTF protein P02788 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007 15588942 f miannu "C/EBP_ interacts with C/EBP_ through the leucine-zipper–containing domain. C/EBP_ and C/EBP_ synergistically activate transcription of lactoferrin promoter" SIGNOR-225015 SUCLG1 protein P53597 UNIPROT "Succinyl-CoA ATP variant" complex SIGNOR-C398 SIGNOR "form complex" binding 9606 32627745 t miannu "Succinyl-CoA synthetase (SCS) catalyzes the only substrate-level phosphorylation in the tricarboxylic acid cycle.  In mammals, SCS is a mitochondrial enzyme and is an α,β-heterodimer with different isoforms: ATP-specific SCS (ATPSCS) and GTP-specific SCS (GTPSCS)." SIGNOR-266261 SUCLG1 protein P53597 UNIPROT "Succinyl-CoA GTP variant" complex SIGNOR-C399 SIGNOR "form complex" binding 9606 32627745 t miannu "Succinyl-CoA synthetase (SCS) catalyzes the only substrate-level phosphorylation in the tricarboxylic acid cycle.  In mammals, SCS is a mitochondrial enzyme and is an α,β-heterodimer with different isoforms: ATP-specific SCS (ATPSCS) and GTP-specific SCS (GTPSCS)." SIGNOR-266263 MVD protein P53602 UNIPROT NRAS protein P01111 UNIPROT "up-regulates activity" lipidation 9534 BTO:0000298 12646231 f miannu "An overexpression of mot-2 resulted in reduced level of Ras and phosphorylated ERK2. These were rescued by co-expression of MPD from an exogenous promoter demonstrating a functional link between mot-2, MPD, and Ras. Ras and its oncogenic forms act as key players in controlling proliferation of normal and cancerous cells. Assigning mot-2 upstream of p21Ras offers an important mechanism for influence over cell proliferation. Therefore, we ra tionaled to investigate if overexpression of MPD could affect the steady state levels of Ras by affecting its prenylationTransient transfections of MPD-myc in COS 7 cells resulted in higher stable levels of Ras as compared to the untransfected cells (Fig. 3A, compare lanes 4 and 8 and Fig. 3B)" SIGNOR-265889 MVD protein P53602 UNIPROT HRAS protein P01112 UNIPROT "up-regulates activity" lipidation 9534 BTO:0000298 12646231 f miannu "An overexpression of mot-2 resulted in reduced level of Ras and phosphorylated ERK2. These were rescued by co-expression of MPD from an exogenous promoter demonstrating a functional link between mot-2, MPD, and Ras. Ras and its oncogenic forms act as key players in controlling proliferation of normal and cancerous cells. Assigning mot-2 upstream of p21Ras offers an important mechanism for influence over cell proliferation. Therefore, we ra tionaled to investigate if overexpression of MPD could affect the steady state levels of Ras by affecting its prenylationTransient transfections of MPD-myc in COS 7 cells resulted in higher stable levels of Ras as compared to the untransfected cells (Fig. 3A, compare lanes 4 and 8 and Fig. 3B)" SIGNOR-265888 MVD protein P53602 UNIPROT KRAS protein P01116 UNIPROT "up-regulates activity" lipidation 9534 BTO:0000298 12646231 f miannu "An overexpression of mot-2 resulted in reduced level of Ras and phosphorylated ERK2. These were rescued by co-expression of MPD from an exogenous promoter demonstrating a functional link between mot-2, MPD, and Ras. Ras and its oncogenic forms act as key players in controlling proliferation of normal and cancerous cells. Assigning mot-2 upstream of p21Ras offers an important mechanism for influence over cell proliferation. Therefore, we ra tionaled to investigate if overexpression of MPD could affect the steady state levels of Ras by affecting its prenylationTransient transfections of MPD-myc in COS 7 cells resulted in higher stable levels of Ras as compared to the untransfected cells (Fig. 3A, compare lanes 4 and 8 and Fig. 3B)" SIGNOR-265887 RABGGTB protein P53611 UNIPROT RAB3A protein P20336 UNIPROT "up-regulates activity" lipidation 9606 BTO:0000007 18532927 t miannu "Prenylation (or geranylgeranylation) of Rab GTPases is catalysed by RGGT (Rab geranylgeranyl transferase) and requires REP (Rab escort protein). In the classical pathway, REP associates first with unprenylated Rab, which is then prenylated by RGGT. In the alternative pathway, REP associates first with RGGT; this complex then binds and prenylates Rab proteins. Rab GTPases need to be geranylgeranylated on either one or two cysteine residues in their Ctermini in order to localize to the correct intracellular membrane and be functional" SIGNOR-265575 RABGGTB protein P53611 UNIPROT RAB5A protein P20339 UNIPROT "up-regulates activity" lipidation 9606 BTO:0000007 18532927 t miannu "Prenylation (or geranylgeranylation) of Rab GTPases is catalysed by RGGT (Rab geranylgeranyl transferase) and requires REP (Rab escort protein). In the classical pathway, REP associates first with unprenylated Rab, which is then prenylated by RGGT. In the alternative pathway, REP associates first with RGGT; this complex then binds and prenylates Rab proteins. Rab GTPases need to be geranylgeranylated on either one or two cysteine residues in their Ctermini in order to localize to the correct intracellular membrane and be functional" SIGNOR-265573 LIMK1 protein P53667 UNIPROT CFL1 protein P23528 UNIPROT down-regulates phosphorylation Ser3 sGVAVSDG 9606 18079118 t gcesareni "Our results suggest that limk1-mediated cofilin phosphorylation is required for accurate spindle orientation by stabilizing cortical actin networks during mitosis" SIGNOR-159885 LIMK1 protein P53667 UNIPROT CFL2 protein Q9Y281 UNIPROT "down-regulates activity" phosphorylation Ser3 sGVTVNDE 9606 9655398 t lperfetto "Cofilin is known to be a potent regulator of actin filament dynamics, and its ability to bind and depolymerize actin is abolished by phosphorylation of serine residue at 3;. Here we show that lim-kinase 1 (limk-1), a serine/threonine kinase containing lim and pdz domains, phosphorylates cofilin at ser 3, both in vitro and in vivo" SIGNOR-58596 LIMK2 protein P53671 UNIPROT CFL1 protein P23528 UNIPROT "down-regulates activity" phosphorylation Ser3 sGVAVSDG 9606 BTO:0000567 11171090 t lperfetto "We report here that limk1 and limk2 phosphorylate both cofilin and actin-depolymerizing factor (adf) specifically at ser-3 and exhibit partially distinct substrate specificity when tested using site-directed cofilin mutants as substrates" SIGNOR-105098 CLTCL1 protein P53675 UNIPROT "AP-2/clathrin vescicle" complex SIGNOR-C249 SIGNOR "form complex" binding 9606 24789820 t lperfetto "AP2 adaptor complexes, associated at the membrane with PtdIns(4,5)P2 (PIP2), recruit clathin triskelions to initiate lattice assembly. " SIGNOR-260662 CLTCL1 protein P53675 UNIPROT "AP-3/clathrin vescicle" complex SIGNOR-C250 SIGNOR "form complex" binding 9606 23103167 t lperfetto "Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors" SIGNOR-260673 CLTCL1 protein P53675 UNIPROT "AP-1/clathrin vescicle" complex SIGNOR-C251 SIGNOR "form complex" binding 9606 23103167 t lperfetto "Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors" SIGNOR-260679 AP2S1 protein P53680 UNIPROT "AP-2 complex" complex SIGNOR-C245 SIGNOR "form complex" binding 31671891 t lperfetto "The most important endocytic adaptor is the heterotetrameric AP-2 complex made up of the large alpha- and beta2-adaptin subunits, the medium-sized mu2-subunit and a small sigma2-subunit" SIGNOR-260421 ITGA8 protein P53708 UNIPROT "A8/b1 integrin" complex SIGNOR-C165 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253181 MAPK12 protein P53778 UNIPROT EEF2K protein O00418 UNIPROT unknown phosphorylation Ser396 TFDSLPSsPSSATPH -1 12171600 t miannu "We have also shown that JNK11, JNK22 and SAPK3 p38 phosphorylate eEF2 kinase very poorly at Ser-396" SIGNOR-250137 MAPK12 protein P53778 UNIPROT KRT8 protein P05787 UNIPROT up-regulates phosphorylation Ser74 TVNQSLLsPLVLEVD 9606 11788583 t lperfetto "Keratin 8 (k8) serine 73 occurs within a relatively conserved type ii keratin motif . Here we show that ser-73 is exclusively phosphorylated in vitro by p38 mitogen-activated protein kinase. The ser-73 --> ala-associated filament reorganization defect is rescued by a ser-73 --> asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis." SIGNOR-114067 MAPK12 protein P53778 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser519 SGYSSPGsPGTPGSR -1 9199504 t miannu "Phosphorylation of tau by SAPK3 and SAPK4 markedly reduced the ability of tau to promote microtubule assembly. SAPK3 (also called ERK6 and p38) and SAPK4 phosphorylate recombinant tau protein at multiple Ser/Thr-Pro sites that are hyperphosphorylated in PHF-tau, with SAPK4 and SAPK3 being the most effective." SIGNOR-250084 MAPK12 protein P53778 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser637 VDLSKVTsKCGSLGN -1 9199504 t miannu "Phosphorylation of tau by SAPK3 and SAPK4 markedly reduced the ability of tau to promote microtubule assembly. SAPK3 (also called ERK6 and p38) and SAPK4 phosphorylate recombinant tau protein at multiple Ser/Thr-Pro sites that are hyperphosphorylated in PHF-tau, with SAPK4 and SAPK3 being the most effective." SIGNOR-250085 MAPK12 protein P53778 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Thr498 KTPPAPKtPPSSGEP -1 9199504 t miannu "Phosphorylation of tau by SAPK3 and SAPK4 markedly reduced the ability of tau to promote microtubule assembly. SAPK3 (also called ERK6 and p38) and SAPK4 phosphorylate recombinant tau protein at multiple Ser/Thr-Pro sites that are hyperphosphorylated in PHF-tau, with SAPK4 and SAPK3 being the most effective." SIGNOR-250086 MAPK12 protein P53778 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Thr522 SSPGSPGtPGSRSRT -1 9199504 t miannu "Phosphorylation of tau by SAPK3 and SAPK4 markedly reduced the ability of tau to promote microtubule assembly. SAPK3 (also called ERK6 and p38) and SAPK4 phosphorylate recombinant tau protein at multiple Ser/Thr-Pro sites that are hyperphosphorylated in PHF-tau, with SAPK4 and SAPK3 being the most effective." SIGNOR-250087 MAPK12 protein P53778 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Thr548 KKVAVVRtPPKSPSS -1 9199504 t miannu "Phosphorylation of tau by SAPK3 and SAPK4 markedly reduced the ability of tau to promote microtubule assembly. SAPK3 (also called ERK6 and p38) and SAPK4 phosphorylate recombinant tau protein at multiple Ser/Thr-Pro sites that are hyperphosphorylated in PHF-tau, with SAPK4 and SAPK3 being the most effective." SIGNOR-250088 MAPK12 protein P53778 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation 9606 10085140 t gcesareni "Our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf-beta signaling via tak1 and p38. The two pathways, smad and tak1, synergistically enhance the activity of atf-2 which acts as their common nuclear target" SIGNOR-65589 MAPK12 protein P53778 UNIPROT JUNB protein P17275 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10330170 f gcesareni "Moreover, in addition to jnk, erk5, p38alpha, and p38gamma were found to stimulate the c-jun promoter by acting on distinct responsive elements." SIGNOR-67532 MAPK12 protein P53778 UNIPROT TP53BP1 protein Q12888 UNIPROT "down-regulates activity" phosphorylation Thr1609 LGPYEAVtPLTKAAD -1 24703952 t lperfetto "Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks |phosphorylation of T1609 is likely to be mediated by p38 MAPK" SIGNOR-264448 MAPK12 protein P53778 UNIPROT SNTA1 protein Q13424 UNIPROT up-regulates phosphorylation Ser201 PLQRQPSsPGPTPRN 9606 BTO:0001103 10212242 t lperfetto "Sapk3 phosphorylates alpha1-syntrophin at serine residues 193 and 201 in vitro and phosphorylation is dependent on binding to the pdz domain of alpha1-syntrophin. The finding that sapk3 co-localizes with _1-syntrophin in skeletal muscle, that it binds to the pdz domain of _1-syntrophin, and that phosphorylation of _1-syntrophin depends on this interaction identifies a novel mechanism for targeting a protein kinase to its substrates." SIGNOR-67065 MAPK12 protein P53778 UNIPROT RCSD1 protein Q6JBY9 UNIPROT "down-regulates activity" phosphorylation Ser108 LPGASPKsPGLKAMV -1 15850461 t miannu "Peptide T2 was sequenced and shown to comprise residues 79–112 of CapZIP, phosphorylated at Ser-108 (Figure 2B). The identity of peptide T1 is unknown. These experiments established that the SAPK3/p38γ substrate was CapZIP. Using this antibody, we showed by immunoblotting that bacterially expressed CapZIP was phosphorylated at Ser-108 by SAPK4/p38δ, JNK1α1 and ERK2 in vitro, as well as by SAPK3/p38γ (results not shown). An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ." SIGNOR-263083 MAPK12 protein P53778 UNIPROT MAPK12/CARM1 complex SIGNOR-C218 SIGNOR "form complex" binding BTO:0001103 29681515 t 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 MAPK10 protein P53779 UNIPROT BCL2L11 protein O43521 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser69 GPLAPPAsPGPFATR -1 15486195 t miannu "Ser69 can also be phosphorylated by JNK and p38MAPK at least in vitro. Phosphorylation of BimEL on Ser69 promotes its ubiquitination." SIGNOR-250080 MAPK10 protein P53779 UNIPROT BCL2L11 protein O43521 UNIPROT "up-regulates activity" phosphorylation Ser59 GDSCPHGsPQGPLAP 10090 BTO:0000938 12818176 t miannu "JNKs specifically phosphorylate BIMEL at Ser55, 65, and/or 73. several observations demonstrate that the phosphorylation of BIMEL is a physiologically important mechanism for enhancing its proapoptotic activity." SIGNOR-250130 MAPK10 protein P53779 UNIPROT BCL2L11 protein O43521 UNIPROT "up-regulates activity" phosphorylation Ser77 PGPFATRsPLFIFMR 10090 BTO:0000938 12818176 t miannu "JNKs specifically phosphorylate BIMEL at Ser55, 65, and/or 73. several observations demonstrate that the phosphorylation of BIMEL is a physiologically important mechanism for enhancing its proapoptotic activity." SIGNOR-250131 MAPK10 protein P53779 UNIPROT KIF5C protein O60282 UNIPROT "down-regulates activity" phosphorylation Ser176 CTERFVSsPEEVMDV -1 19525941 t miannu "Mass spectrometry identified a residue in the kinesin-1 motor domain that was phosphorylated by JNK3 and this modification reduced kinesin-1 binding to microtubules. JNK3 phosphorylates kinesin-1 at Ser176" SIGNOR-262950 MAPK10 protein P53779 UNIPROT NFATC1 protein O95644 UNIPROT down-regulates phosphorylation Ser172 YRDPSCLsPASSLSS 9606 10652349 t "Translocation from Nucleus to Cytoplasm" esanto "We show that jnk, erk, and p38 physically associate with the nfatc n-terminal regulatory domain and can directly phosphorylate functionally important residues involved in regulating nfatc subcellular localization, namely ser(172) and the conserved nfatc ser-pro repeats." SIGNOR-74556 MAPK10 protein P53779 UNIPROT CDC25C protein P30307 UNIPROT down-regulates phosphorylation Ser168 SEMKYLGsPITTVPK 9606 20220133 t gcesareni "Here we show that jnk directly phosphorylates cdc25c at serine 168 during g(2) phase of the cell cycle. Cdc25c phosphorylation by jnk negatively regulates its phosphatase activity and thereby cdk1 activation, enabling a timely control of mitosis onset." SIGNOR-164085 MAPK10 protein P53779 UNIPROT SFN protein P31947 UNIPROT down-regulates phosphorylation Ser186 FHYEIANsPEEAISL 9606 15071501 t "Ser residues in the reagion between alpha-helices 7 and 8, JNK3 is essential for apoptosis of hippocampal neurons" gcesareni "Here we demonstrate that activated jnk promotes bax translocation to mitochondria through phosphorylation of 14-3-3, a cytoplasmic anchor of bax. Phosphorylation of 14-3-3 led to dissociation of bax from this protein.Jnk phosphorylates 14-3-3zeta_ at ser-184 and 14-3-3sigma_ at ser-191" SIGNOR-124005 MAPK10 protein P53779 UNIPROT ATN1 protein P54259 UNIPROT "down-regulates activity" phosphorylation Ser739 EEYETPEsPVPPARS 9606 BTO:0000142 12812981 t lperfetto "Dentatorubral-pallidoluysian atrophy protein is phosphorylated by c-jun nh2-terminal kinase. serine 734 of the drpla protein is a phospho-acceptor site by jnk. The phosphorylation may be coupled to the activation of a protease. The molecular size of drpla protein detected in the rat brain with the specific phosphopeptide antibody was 150_kda, which was slightly smaller than that expected from the sequence and the results with the human protein. The phosphorylated forms of ha-tagged human drpla gradually disappeared after osmotic treatment," SIGNOR-102394 MAPK10 protein P53779 UNIPROT HNRNPK protein P61978 UNIPROT "down-regulates activity" phosphorylation Ser284 RRDYDDMsPRRGPPP 11231586 t miannu "Mitogen-activated protein kinase/extracellular-signal-regulated kinase (MAPK/ERK) efficiently phosphorylates hnRNP-K both in vitro and in vivo at serines 284 and 353. Our results establish the role of MAPK/ERK in phosphorylation-dependent cellular localization of hnRNP-K, which is required for its ability to silence mRNA translation." SIGNOR-250082 MAPK10 protein P53779 UNIPROT HNRNPK protein P61978 UNIPROT "up-regulates activity" phosphorylation Ser353 DSAIDTWsPSEWQMA 9606 BTO:0000007 11259409 t miannu "JNK Phosphorylation of HnRNP K Increases Its Transcriptional Activity. the primary site for JNK phosphorylation consists of serines 216 and 353 on the K protein." SIGNOR-250083 MAPK10 protein P53779 UNIPROT YWHAZ protein P63104 UNIPROT down-regulates phosphorylation Ser184 FYYEILNsPEKACSL 9606 15071501 t "Ser residues in the reagion between alpha-helices 7 and 8, JNK3 is essential for apoptosis of hippocampal neurons" gcesareni "Jnk phosphorylates 14-3-3zetaat ser-184 and 14-3-3sigmaat ser-190" SIGNOR-124009 MAPK10 protein P53779 UNIPROT DIABLO protein Q9NR28 UNIPROT down-regulates phosphorylation 9606 BTO:0000567 17686459 t gcesareni "Here we demonstrate that jnk3 can phosphorylate smac. Phosphorylation of smac by jnk3 attenuates its interaction with xiap. These results suggest that jnk3 activity can attenuate the progression of apoptosis through a novel mechanism of action, the down-regulation of interaction between smac and xiap." SIGNOR-157280 MAPK10 protein P53779 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Thr265 GQSSAAAtPSTTGTK 9606 15767678 t gcesareni "Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro." SIGNOR-134529 MAPK10 protein P53779 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Thr275 TTGTKSNtPTSSVPS 9606 15767678 t gcesareni "Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro." SIGNOR-134533 MAPK10 protein P53779 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Thr286 SVPSAAVtPLNESLQ 9606 15767678 t gcesareni "Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro." SIGNOR-134537 POLR2K protein P53803 UNIPROT "RNA Polymerase III" complex SIGNOR-C389 SIGNOR "form complex" binding 9606 BTO:0000567 12391170 t lperfetto "In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights." SIGNOR-266141 POLR2K protein P53803 UNIPROT "RNA Polymerase I" complex SIGNOR-C390 SIGNOR "form complex" binding 22260999 t lperfetto "In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1). " SIGNOR-266150 POLR2K protein P53803 UNIPROT "RNA Polymerase II" complex SIGNOR-C391 SIGNOR "form complex" binding 9606 BTO:0000567 9852112 t lperfetto "Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II" SIGNOR-266168 TTC3 protein P53804 UNIPROT AKT1 protein P31749 UNIPROT "down-regulates quantity by destabilization" ubiquitination 10090 BTO:0000944 20059950 t gcesareni "TTC3 is an Akt-specific E3 ligase that binds to phosphorylated Akt and facilitates its ubiquitination and degradation within the nucleus" SIGNOR-252436 TTC3 protein P53804 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates quantity by destabilization" ubiquitination 10090 BTO:0000944 20059950 t gcesareni "TTC3 is an Akt-specific E3 ligase that binds to phosphorylated Akt and facilitates its ubiquitination and degradation within the nucleus" SIGNOR-252459 PLAAT3 protein P53816 UNIPROT PPP2CB protein P62714 UNIPROT down-regulates 9606 17374643 f miannu "The alpha-isoform of the regulatory subunit a of protein phosphatase 2a (pr65alpha) as a new interaction partner of hrsl3 / we demonstrate that hrsl3 binds to the endogenous pr65alpha, thereby partially sequestering the catalytic subunit pr36 from the pr65 protein complex, and inhibiting pp2a catalytic activity." SIGNOR-153775 PLAAT3 protein P53816 UNIPROT PPP2CA protein P67775 UNIPROT down-regulates 9606 17374643 f miannu "The alpha-isoform of the regulatory subunit a of protein phosphatase 2a (pr65alpha) as a new interaction partner of hrsl3 / we demonstrate that hrsl3 binds to the endogenous pr65alpha, thereby partially sequestering the catalytic subunit pr36 from the pr65 protein complex, and inhibiting pp2a catalytic activity." SIGNOR-153772 SEC24C protein P53992 UNIPROT "COPII vesicle" complex SIGNOR-C370 SIGNOR "form complex" binding 9606 BTO:0000567 30605680 t lperfetto "The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat" SIGNOR-265294 PMS1 protein P54277 UNIPROT MLH1/PMS1 complex SIGNOR-C58 SIGNOR "form complex" binding 9606 10542278 t miannu "We now show that hpms1 is expressed in human cells and that it interacts with hmlh1 with high affinity to form the heterodimer hmutl_." SIGNOR-71774 PMS2 protein P54278 UNIPROT MLH1/PMS2 complex SIGNOR-C59 SIGNOR "form complex" binding 9606 10542278 t miannu "Hmlh1 and hpms2 function in postreplicative mismatch repair in the form of a heterodimer referred to as hmutl_" SIGNOR-71777 USP14 protein P54578 UNIPROT CXCR4 protein P61073 UNIPROT "up-regulates quantity by stabilization" deubiquitination 9606 BTO:0000007 26523394 t lperfetto "The physical interaction of CXCR4 and USP14 is paralleled by USP14-catalyzed deubiquitination of the receptor|We also observed that ubiquitination of CXCR4 facilitated receptor degradation, whereas overexpression of USP14 or RNAi-induced knockdown of USP14 blocked CXCL12-mediated CXCR4 degradation" SIGNOR-265057 PRKAG1 protein P54619 UNIPROT PRKAA2 protein P54646 UNIPROT up-regulates binding 9606 16054041 t gcesareni "Gamma non-catalytic subunit mediates binding to amp, adp and atp, leading to activate or inhibit ampk: amp-binding results in allosteric activation of alpha catalytic subunit (prkaa1 or prkaa2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits." SIGNOR-139173 PRKAG1 protein P54619 UNIPROT AMPK complex SIGNOR-C15 SIGNOR "form complex" binding 9606 BTO:0000443 BTO:0001103;BTO:0000142;BTO:0000562;BTO:0000759 16054041 t lperfetto "Gamma non-catalytic subunit mediates binding to amp, adp and atp, leading to activate or inhibit ampk: amp-binding results in allosteric activation of alpha catalytic subunit (prkaa1 or prkaa2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits." SIGNOR-139170 PRKAA2 protein P54646 UNIPROT EEF2K protein O00418 UNIPROT "down-regulates activity" phosphorylation Ser366 SPQVRTLsGSRPPLL -1 14709557 t miannu "AMPK can phosphorylate three sites in eEF2 kinase in vitro. Of these, Ser-398 appears to be more efficiently phosphorylated than either Ser-78 or Ser-366. Ser-78 and Ser-366 do not appear to be phosphorylated by AMPK within cells. Ser-366 serves to decrease the activity of eEF2 kinase" SIGNOR-250319 PRKAA2 protein P54646 UNIPROT EEF2K protein O00418 UNIPROT "down-regulates activity" phosphorylation Ser78 SSGSPANsFHFKEAW -1 14709557 t miannu "AMPK can phosphorylate three sites in eEF2 kinase in vitro. Of these, Ser-398 appears to be more efficiently phosphorylated than either Ser-78 or Ser-366. Ser-78 and Ser-366 do not appear to be phosphorylated by AMPK within cells. Ser-366 serves to decrease the activity of eEF2 kinase" SIGNOR-250321 PRKAA2 protein P54646 UNIPROT EEF2K protein O00418 UNIPROT "up-regulates activity" phosphorylation Ser398 DSLPSSPsSATPHSQ -1 14709557 t miannu "Stimulation of the AMP-activated Protein Kinase Leads to Activation of Eukaryotic Elongation Factor 2 Kinase and to Its Phosphorylation at a Novel Site, Serine 398. phosphorylation of eEF2 kinase at Ser-398 leads to an increase in its activity." SIGNOR-250158 PRKAA2 protein P54646 UNIPROT ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser556 GLGCRLHsAPNLSDL 9606 SIGNOR-C15 19584320 t gcesareni "In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy." SIGNOR-186637 PRKAA2 protein P54646 UNIPROT ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser638 FDFPKTPsSQNLLAL 9606 SIGNOR-C15 19584320 t gcesareni "In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy." SIGNOR-186641 PRKAA2 protein P54646 UNIPROT ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser317 SHLASPPsLGEMQQL 9606 SIGNOR-C15 21205641 t gcesareni "In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy." SIGNOR-170859 PRKAA2 protein P54646 UNIPROT ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser556 GLGCRLHsAPNLSDL 9606 SIGNOR-C15 21205641 t gcesareni "In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy." SIGNOR-170863 PRKAA2 protein P54646 UNIPROT ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser638 FDFPKTPsSQNLLAL 9606 SIGNOR-C15 21205641 t gcesareni "In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy." SIGNOR-170867 PRKAA2 protein P54646 UNIPROT INSR protein P06213 UNIPROT up-regulates phosphorylation 9606 BTO:0000887 SIGNOR-C15 22207502 t gcesareni "Ampk phosphorylates and activates theinsulinreceptor, providing a direct link between ampk and theinsulin pathway." SIGNOR-195324 PRKAA2 protein P54646 UNIPROT CDC27 protein P30260 UNIPROT unknown phosphorylation Ser379 NALPRRSsRLFTSDS 9606 SIGNOR-C15 22137581 t lperfetto "Using this approach for ppp1r12c, baiap2, and cdc27, we found that mutation of a single serine to alanine (s452, s366, and s379, respectively) resulted in an almost complete loss of ampk phosphorylation in these proteins" SIGNOR-195106 PRKAA2 protein P54646 UNIPROT SREBF1 protein P36956 UNIPROT down-regulates phosphorylation Ser396 TAVHKSKsLKDLVSA 9606 SIGNOR-C15 21459323 t gcesareni "Here we demonstrate that ampk interacts with and directly phosphorylates sterol regulatory element binding proteins (srebp-1c and -2). Ser372" SIGNOR-173031 PRKAA2 protein P54646 UNIPROT HNF4A protein P41235 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser313 GKIKRLRsQVQVSLE 10029 BTO:0000246 12740371 t miannu "AMPK directly phosphorylates HNF4alpha and represses its transcriptional activity. AMPK-mediated phosphorylation of HNF4alpha on serine 304 had a 2-fold effect, reducing the ability of the transcription factor to form homodimers and bind DNA and increasing its degradation rate in vivo. Phosphorylation of HNF4α on Ser-304 reduces protein stability." SIGNOR-250322 PRKAA2 protein P54646 UNIPROT TSC2 protein P49815 UNIPROT up-regulates phosphorylation Ser1387 QPLSKSSsSPELQTL 9606 SIGNOR-C15 16959574 t gcesareni "We have observed that ampk directly phosphorylates tsc2, and the ampk-dependent phosphorylation of tsc2 is critical for the coordination between cell growth and cellular energy levels." SIGNOR-149388 PRKAA2 protein P54646 UNIPROT VASP protein P50552 UNIPROT down-regulates phosphorylation Ser322 TTLPRMKsSSSVTTS 9606 SIGNOR-C15 21945940 t lperfetto "Here we show that phosphorylation of vasp by ampk occurs at a novel site, serine 322, and that phosphorylation at this site alters actin filament binding. We also show that inhibition of ampk activity results in the accumulation of vasp at cell-cell adhesions and a concomitant increase in cell-cell adhesion." SIGNOR-176642 PRKAA2 protein P54646 UNIPROT ACACA protein Q13085 UNIPROT down-regulates phosphorylation Ser80 LHIRSSMsGLHLVKQ 9606 BTO:0000887;BTO:0001103 SIGNOR-C15 12015362 t gcesareni "Significant negative linear correlations between phospho-acc and acc activity were observed in all models (p < 0.01). The decline in acc activity was related to the decrease in pcr and the rise in amp. A relationship between phospho-ampk (threonine 172) and activity of ampk immunoprecipitated with anti-alpha(2) subunit antibody preparation was also observed." SIGNOR-87583 PRKAA2 protein P54646 UNIPROT PLD1 protein Q13393 UNIPROT up-regulates phosphorylation Ser505 GSVKRVTsGPSLGSL 9606 BTO:0000887;BTO:0001103 SIGNOR-C15 20231899 t gcesareni "Ampk-wild type (wt) stimulates pld activity, while ampk-dominant negative (dn) inhibits it. Ampk regulates pld1 activity through phosphorylation of the ser-505 and this phosphorylation is increased by the presence of amp." SIGNOR-164293 PRKAA2 protein P54646 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates phosphorylation Ser171 SALNRTSsDSALHTS 9606 SIGNOR-C15 16148943 t gcesareni "Phosphorylation on the ser171 residue of crtc2 by ampk and ampk-related kinases, including the salt-inducible kinases (siks), is critical for determining the activity, cellular localization, and degradation of crtc2" SIGNOR-140238 PRKAA2 protein P54646 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates phosphorylation Ser171 SALNRTSsDSALHTS 9606 SIGNOR-C15 16308421 t gcesareni "Phosphorylation on the ser171 residue of crtc2 by ampk and ampk-related kinases, including the salt-inducible kinases (siks), is critical for determining the activity, cellular localization, and degradation of crtc2" SIGNOR-142211 PRKAA2 protein P54646 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates phosphorylation Ser171 SALNRTSsDSALHTS 9606 SIGNOR-C15 20577053 t gcesareni "Phosphorylation on the ser171 residue of crtc2 by ampk and ampk-related kinases, including the salt-inducible kinases (siks), is critical for determining the activity, cellular localization, and degradation of crtc2" SIGNOR-166365 PRKAA2 protein P54646 UNIPROT RPTOR protein Q8N122 UNIPROT down-regulates phosphorylation Ser722 PRLRSVSsYGNIRAV 10090 SIGNOR-C3 18439900 t lperfetto "These results suggest that AMPK activation can induce phosphorylation of both serine 722 and serine 792.|Raptor phosphorylation is required for inhibition of mTORC1 by AMPK" SIGNOR-263045 PRKAA2 protein P54646 UNIPROT RPTOR protein Q8N122 UNIPROT "down-regulates activity" phosphorylation Ser792 LTQSAPAsPTNKGVH 10090 SIGNOR-C15 SIGNOR-C3 18439900 t lperfetto "These results suggest that AMPK activation can induce phosphorylation of both serine 722 and serine 792.|Raptor phosphorylation is required for inhibition of mTORC1 by AMPK" SIGNOR-163463 PRKAA2 protein P54646 UNIPROT TSC1 protein Q92574 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C15 14651849 t gcesareni "Under energy starvation conditions, the amp-activated protein kinase (ampk) phosphorylates tsc2 and enhances its activity." SIGNOR-119541 PRKAA2 protein P54646 UNIPROT PPP1R12C protein Q9BZL4 UNIPROT down-regulates phosphorylation Ser452 AGLQRSAsSSWLEGT 9606 SIGNOR-C15 22137581 t lperfetto "Ampk-induced phosphorylation is necessary for ppp1r12c interaction with 14-3-3 and phosphorylation of myosin regulatory light chain. Both ampk activity and ppp1r12c phosphorylation are increased in mitotic cells and are important for mitosis completion. The interaction between ppp1r12c and 14-3-3_ may inactivate the ppp1r12c-containing phosphatase complex in vivo." SIGNOR-195148 PRKAA2 protein P54646 UNIPROT BAIAP2 protein Q9UQB8 UNIPROT down-regulates phosphorylation Ser366 KTLPRSSsMAAGLER 9606 SIGNOR-C15 19933840 t lperfetto "Using this approach for ppp1r12c, baiap2, and cdc27, we found that mutation of a single serine to alanine (s452, s366, and s379 respectively) resulted in almost a complete loss of ampk phosphorylation in these proteins. Termination of irsp53 function is suggested to occur following cdc42 dissociation, kinase phosphorylation of t340 and t360, and subsequent 14-3-3 binding, which competes for sh3 partners, thus allowing filopodial retraction" SIGNOR-161810 PRKAA2 protein P54646 UNIPROT BAIAP2 protein Q9UQB8 UNIPROT down-regulates phosphorylation Ser366 KTLPRSSsMAAGLER 9606 SIGNOR-C15 22137581 t lperfetto "Using this approach for ppp1r12c, baiap2, and cdc27, we found that mutation of a single serine to alanine (s452, s366, and s379 respectively) resulted in almost a complete loss of ampk phosphorylation in these proteins. Termination of irsp53 function is suggested to occur following cdc42 dissociation, kinase phosphorylation of t340 and t360, and subsequent 14-3-3 binding, which competes for sh3 partners, thus allowing filopodial retraction" SIGNOR-195102 PRKAA2 protein P54646 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 BTO:0000876 21673972 t lperfetto "These results demonstrate that the ikk is a direct substrate of ampk_2 and that its phosphorylation on ser177 and ser181no initiates the activation of the ampk_2 in endothelial cells which in turn phosphorylates and activates the _-subunit of the ikk. The latter also induces a higher rate of ikk auto-inactivation and thus attenuates the activation of nf_b and the expression of inflammatory genes" SIGNOR-217457 EPHB3 protein P54753 UNIPROT EPHB3 protein P54753 UNIPROT "up-regulates activity" phosphorylation Tyr614 VYIDPFTyEDPNEAV -1 9674711 t "Tyrosine-614, the major autophosphorylation site of the receptor tyrosine kinase HEK2, functions as multi-docking site for SH2-domain mediated interactions. a single amino acid substitution (Y614F) clearly reduces the phosphotyrosine content of HEK2 and abrogates its ability to bind rasGAP, Crk and Fyn indicating that this residue functions as major phosphorylation and multi-docking site." SIGNOR-251126 EPHB1 protein P54762 UNIPROT EPHB1 protein P54762 UNIPROT "up-regulates activity" phosphorylation Tyr594 GSPGMKIyIDPFTYE 10029 BTO:0000246 12223469 t " Co-immunoprecipitation was used to confirm the interaction of Grb7 with the cytoplasmic domain of EphB1 as well as the full-length receptor in intact cells. This interaction is mediated by the SH2 domain of Grb7 and requires tyrosine autophosphorylation of EphB1. We also found that EphB1 could phosphorylate Grb7 and mutation of either Tyr-928 or Tyr-594 to Phe decreased this activity." SIGNOR-251122 EPHB1 protein P54762 UNIPROT EPHB1 protein P54762 UNIPROT "up-regulates activity" phosphorylation Tyr928 SAIKMVQyRDSFLTA 10029 BTO:0000246 12223469 t " Co-immunoprecipitation was used to confirm the interaction of Grb7 with the cytoplasmic domain of EphB1 as well as the full-length receptor in intact cells. This interaction is mediated by the SH2 domain of Grb7 and requires tyrosine autophosphorylation of EphB1. We also found that EphB1 could phosphorylate Grb7 and mutation of either Tyr-928 or Tyr-594 to Phe decreased this activity." SIGNOR-251123 EPHB1 protein P54762 UNIPROT NRCAM protein Q92823 UNIPROT "up-regulates activity" phosphorylation Tyr1276 DGSFIGQySGKKEKE 9606 BTO:0000007 24023801 t miannu "EphB receptors were found to induce phosphorylation of NrCAM on the tyrosine residue within the FIGQY ankyrin binding motif, inhibiting ankyrin recruitment. Furthermore, NrCAM phospho-FIGQY levels in the SC were decreased in EphB1/3 and EphB1/2/3 null mice and increased in mutant mice overexpressing constitutively active EphB2 kinase." SIGNOR-262862 EPHA4 protein P54764 UNIPROT EPHA4 protein P54764 UNIPROT "up-regulates activity" phosphorylation Tyr596 LNQGVRTyVDPFTYE -1 8622893 t "Two dimensional phosphopeptide mapping and site-directed mutagenesis defined juxtamembrane residue Y602 as a major site of in vitro autophosphorylation in Sek, whilst Y596 was phosphorylated to a lower stoichiometry." SIGNOR-251118 EPHA4 protein P54764 UNIPROT EPHA4 protein P54764 UNIPROT "up-regulates activity" phosphorylation Tyr602 TYVDPFTyEDPNQAV -1 8622893 t "Two dimensional phosphopeptide mapping and site-directed mutagenesis defined juxtamembrane residue Y602 as a major site of in vitro autophosphorylation in Sek, whilst Y596 was phosphorylated to a lower stoichiometry. Complimentary approaches of in vitro binding assays and BIAcore analysis revealed a high affinity association between the Y602 Sek autophosphorylation site and the cytoplasmic tyrosine kinase p59fyn, an interaction mediated through the SH2 domain of this intracellular signalling molecule." SIGNOR-251119 DVL1P1 protein P54792 UNIPROT PRKCB protein P05771 UNIPROT up-regulates binding 9606 23151663 t gcesareni "Taken together, these results suggest that site-specific dvl2 phosphorylation is required for dvl2 association with pkc_. This interaction is likely to be one of the mechanisms essential for wnt3a-dependent neurite outgrowth." SIGNOR-199457 DVL1P1 protein P54792 UNIPROT PRKCA protein P17252 UNIPROT up-regulates binding 9606 23151663 t gcesareni "Our findings suggest a molecular interaction between pka, hdpr1, and dvl and a possible contribution of this interaction to tumorigenesis." SIGNOR-199454 PRRX1 protein P54821 UNIPROT SRF protein P11831 UNIPROT up-regulates binding 9606 BTO:0000567 9334314 t miannu "The human homeodomain proteinphox1interacts functionally with serum response factor (srf) to impart serum responsive transcriptional activity to srf-binding sites in a hela cell cotransfection assay." SIGNOR-52657 PRRX1 protein P54821 UNIPROT MAFF protein Q9ULX9 UNIPROT "down-regulates activity" binding -1 11036080 t miannu "Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf." SIGNOR-221890 PRRX1 protein P54821 UNIPROT MAFB protein Q9Y5Q3 UNIPROT "down-regulates activity" binding -1 11036080 t miannu "Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf." SIGNOR-221899 PTPN5 protein P54829 UNIPROT FYN protein P06241 UNIPROT down-regulates dephosphorylation Tyr420 RLIEDNEyTARQGAK 9606 BTO:0000938 BTO:0000671 11983687 t lperfetto "Wild-type step(61) dephosphorylates fyn at tyr(420) but not at tyr(531). These results suggest that step regulates the activity of fyn by specifically dephosphorylating the regulatory tyr(420) and may be one mechanism by which fyn activity is decreased within psds." SIGNOR-86791 PTPN5 protein P54829 UNIPROT GRIN2B protein Q13224 UNIPROT "down-regulates activity" dephosphorylation Tyr1474 GSSNGHVyEKLSSIE 10090 BTO:0004102 20427654 t lperfetto " These previous results, together with the present findings, indicate that STEP61 dephosphorylates the NR2B subunit at its regulatory tyr1472 site, and dephosphorylation of this site leads to internalization of the NMDAR complex from neuronal surface membranes." SIGNOR-265744 PTPN5 protein P54829 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates binding 9606 BTO:0000938 23932588 t "A study conducted by Zhang et al. showed that STEP is significantly less efficient than PTPSL and HePTP at dephosphorylating p38a." gcesareni "First [] step prevents upstream activating kinases from promiscuously binding and activating p38a. Second, by blocking access to the mapk insert pocket, through the stepcat interaction, step can prevent the binding of allosteric signaling molecules that induce autoactivation of p38a." SIGNOR-194829 PTPN5 protein P54829 UNIPROT BAK1 protein Q16611 UNIPROT "up-regulates activity" dephosphorylation Tyr108 QPTAENAyEYFTKIA 9606 20959805 t "In this study, we report that on apoptotic stimulation Bak undergoes dephosphorylation at tyrosine residue 108 (Y108), a critical event that is necessary but not sufficient for Bak activation, but is required both for early exposure of the occluded N-terminal domain and multimerisation." SIGNOR-248542 NRL protein P54845 UNIPROT RHO protein P08100 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000007 15277472 f miannu "KLF15 repressed transactivation of rhodopsin and IRBP promoters alone and in combination with the transcriptional activators Crx and/or Nrl." SIGNOR-253819 NRL protein P54845 UNIPROT RBP3 protein P10745 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000007 15277472 f miannu "KLF15 repressed transactivation of rhodopsin and IRBP promoters alone and in combination with the transcriptional activators Crx and/or Nrl." SIGNOR-253818 SLC12A3 protein P55017 UNIPROT chloride smallmolecule CHEBI:17996 ChEBI "up-regulates quantity" phosphorylation 21613606 t lperfetto "Eukaryotic cells regulate their volume in the long term through the coordinated function of the Na+-coupled chloride (NKCC1/2 and NCC) and K+-coupled chloride (KCC1–4) cotransporters, which encompass two branches of the SLC12|The K+-Cl− cotransporters move chloride outside the cell, are inhibited by phosphorylation, and are activated by dephosphorylation. In contrast, the Na+-K+-2Cl− cotransporters introduce chloride into the cell, are inhibited by dephosphorylation, and are activated by phosphorylation gene family of solute transporters (12). " SIGNOR-264633 GEM protein P55040 UNIPROT ROCK2 protein O75116 UNIPROT "down-regulates activity" binding 9606 14701738 t miannu "Two functions for Gem have been demonstrated, including inhibition of voltage-gated calcium channel activity and inhibition of Rho kinase-mediated cytoskeletal reorganization, such as stress fiber formation and neurite retraction. These functions for Gem have been ascribed to its interaction with the calcium channel Β subunit and Rho kinase Β, respectively." SIGNOR-261721 GEM protein P55040 UNIPROT ROCK2 protein O75116 UNIPROT "down-regulates activity" binding 9534 BTO:0000298 16757346 t miannu "We have found that Gem binds specifically to ROKβ in the coiled‐coil domain adjacent to the Rho binding site. The interaction between Gem and ROKβ leads to inhibition of MLC and MBS phosphorylation but not phosphorylation of LIMK, indicating that Gem exerts its effect by