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 PKN1 protein Q16512 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser339 PRGQRDSsYYWEIEA 9606 15849194 t llicata "P21-activated kinase 1 (pak1)-dependent phosphorylation of raf-1 regulates its mitochondrial localization, phosphorylation of bad, and bcl-2 association. moreover, the mitochondrial translocation of raf-1 and the interaction between raf-1 and bcl-2 are regulated by raf-1 phosphorylation at ser-338/ser-339." SIGNOR-135679 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 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1626 SPSYSPTsPSYSPTS 9606 BTO:0000567 22137580 t "In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator" SIGNOR-248736 ATR protein Q13535 UNIPROT RAD17 protein O75943 UNIPROT "up-regulates activity" phosphorylation Ser646 ETWSLPLsQNSASEL 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-111248 FZD7 protein O75084 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" 23290138 f "Simone Vumbaca" "We observed that overexpression of Fzd7 or stimulation with FN resulted in increased levels of active Rac1 in primary myoblasts" SIGNOR-255647 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 MAP2K5 protein Q13163 UNIPROT MAPK7 protein Q13164 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-255453 PRKCD protein Q05655 UNIPROT RPS3 protein P23396 UNIPROT up-regulates phosphorylation Ser6 sKKRKFVA 9606 15950189 t lperfetto "It has been shown previously that ribosomal protein s3 (rps3)" SIGNOR-137967 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 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1616 TPQSPSYsPTSPSYS 9606 BTO:0000567 22137580 t "In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator" SIGNOR-248734 SSH2 protein Q76I76 UNIPROT CFL1 protein P23528 UNIPROT "up-regulates activity" dephosphorylation Ser3 sGVAVSDG 9606 14531860 t "Differential activities, subcellular distribution and tissue expression patterns of three members of Slingshot family phosphatases that dephosphorylate cofilin.|Cofilin, a key regulator of actin filament dynamics, is inactivated by phosphorylation at Ser-3 by LIM-kinases and is reactivated by dephosphorylation by a family of protein phosphatases, termed Slingshot (SSH)." SIGNOR-248733 WNT3A protein P56704 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-255650 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 AMER1 protein Q5JTC6 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates activity" binding 9606 BTO:0000007;BTO:0000038 21498506 t lperfetto "We show that Amer1 binds directly to beta-catenin via a novel interaction motif, the REA repeats. This amino acid motif, including the core sequence arginine, glutamic acid and alanine, and this REA repeats mediate binding of Amer1 to the armadillo repeats of beta-catenin. The data suggest that Amer1 exerts its negative regulatory role in Wnt signaling by acting as a scaffold protein for the beta-catenin destruction complex and promoting stabilization of Axin at the plasma membrane." SIGNOR-217950 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 MAP3K14 protein Q99558 UNIPROT CHUK protein O15111 UNIPROT "up-regulates activity" phosphorylation Ser176 AKDVDQGsLCTSFVG 9606 BTO:0000007;BTO:0000567 SIGNOR-C14 9520446 t lperfetto "Nf-kappab-inducing kinase activates ikk-alpha by phosphorylation of ser-176. Nik preferentially phosphorylates ikk-alpha over ikk-beta, leading to the activation of ikk-alpha kinase activity; the accumulated nik phosphorylates ikkalfa." SIGNOR-55942 ROCK1 protein Q13464 UNIPROT ADD1 protein P35611 UNIPROT up-regulates phosphorylation Thr480 TKEDGHRtSTSAVPN 9606 BTO:0000671 10209029 t lperfetto "Rho-associated kinase (rho- kinase), which is activated by the small guanosine triphosphatase rho, phosphorylates alpha-adducin and thereby enhances the f-actin-binding activity of alpha-adducin in vitro. Here we identified the sites of phosphorylation of alpha-adducin by rho-kinase as thr445 and thr480" SIGNOR-66996 AURKB protein Q96GD4 UNIPROT TP53 protein P04637 UNIPROT down-regulates phosphorylation Ser215 DRNTFRHsVVVPYEP 9606 22611192 t gcesareni "We show that aurora b phosphorylates p53 at s183, t211, and s215 to accelerate the degradation of p53 through the polyubiquitination-proteasome pathway, thus functionally suppressing the expression of p53 target genes involved in cell cycle inhibition and apoptosis (e.g., p21 and puma)." SIGNOR-197602 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1647 SPSYSPTsPSYSPTS 9606 BTO:0000567 22137580 t "In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator" SIGNOR-248737 CDC42 protein P60953 UNIPROT PAK2 protein Q13177 UNIPROT "up-regulates activity" binding 10090 BTO:0000142 8107774 t gcesareni "A new brain serine/threonine protein kinase may be a target for the p21ras-related proteins Cdc42 and Rac1. The kinase sequence is related to that of the yeast protein STE20, implicated in pheromone-response pathways." SIGNOR-248253 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 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 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1654 SPSYSPTsPSYSPTS 9606 BTO:0000567 22137580 t "In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator" SIGNOR-248738 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 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 CDK1 protein P06493 UNIPROT KAT5 protein Q92993 UNIPROT up-regulates phosphorylation Ser86 TKNGLPGsRPGSPER 9606 BTO:0000671 16103124 t gcesareni "Moreover, app stabilized tip60 through cdk-dependent phosphorylation" SIGNOR-139649 CDK1 protein P06493 UNIPROT KAT5 protein Q92993 UNIPROT up-regulates phosphorylation Ser90 LPGSRPGsPEREVPA 9606 BTO:0000671 16103124 t lperfetto "Moreover, app stabilized tip60 through cdk-dependent phosphorylation" SIGNOR-139653 CDON protein Q4KMG0 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-150279 DLK1 protein P80370 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 9606 22640926 f fspada "We conclude that DLK1(PREF1) is well expressed in human ASC and acts as a negative regulator of adipogenesis." SIGNOR-197634 FBXW11 protein Q9UKB1 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates ubiquitination Lys21 EGPRDGLkKERLLDD 9606 9990853 t gcesareni "We report here the identification of an ikappab-ubiquitin (ub) ligase complex containing the f-box/wd40-repeat protein, beta-trcp, a vertebrate homolog of drosophila slimb. beta-trcp binds to ikappabalpha only when the latter is specifically phosphorylated by an ikappab kinase complex. here we provide evidence that lysine residues 21 and 22 serve as the primary sites for signal-induced ubiquitination of i kappa b alpha." SIGNOR-64317 FRZB protein Q92765 UNIPROT WNT8A protein Q9H1J5 UNIPROT down-regulates binding 9606 BTO:0000671 9326585 t gcesareni "We and others demonstrated that fzb-1 blocks wnt-1 and xwnt-8 signaling in xenopus embryos," SIGNOR-51798 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 PTK2 protein Q05397 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr577 YMEDSTYyKASKGKL 9606 BTO:0000671 15694384 t llicata "Once stimulated, fak undergoes autophosphorylation at tyrosine (y) 397, followed by phosphorylation of several sites including y576/y577 which increases fak's kinase activity, as well as at y407, y861, and y925." SIGNOR-133845 PRKACA protein P17612 UNIPROT KCNN2 protein Q9H2S1 UNIPROT down-regulates phosphorylation Ser464 QAIHQLRsVKMEQRK 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-145028 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1675 SPSYSPTsPSYSPTS 9606 BTO:0000567 22137580 t "In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator" SIGNOR-248740 SET protein Q01105 UNIPROT PPP2CA protein P67775 UNIPROT down-regulates binding 9606 BTO:0000142 21806989 t miannu "Here we report that both the amino terminal fragment (i(2ntf);aa 1-175) and the carboxy terminal fragment (i(2ctf);aa 176-277) of i(2)(pp2a) inhibit pp2a by binding to its catalytic subunit pp2ac" SIGNOR-175719 SKIL protein P12757 UNIPROT SMAD2 protein Q15796 UNIPROT "down-regulates activity" binding 9606 10531062 t lperfetto "Thus, SnoN can interact with Smad4 and Smad2 and inhibit their abilities to activate transcription." SIGNOR-227479 NFKB1 protein P19838 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "form complex" binding 9606 9450761 t gcesareni "Here we report the crystal structure at 2.9 a resolution of the p50/p65 heterodimer bound to the kappab dna" SIGNOR-55375 PDP1 protein Q9P0J1 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates dephosphorylation 9606 16510868 t lpetrilli "We show that the mammalian pdps are important in dephosphorylation of bmp-activated smad1 but not tgf-beta-activated smad2 or smad3. Thus, pdps specifically inactivate smads in the bmp/dpp pathway. [...] These observations suggest that pdp1 and pdp2 are important for dephosphorylation of smad1." SIGNOR-144876 PPP2CB protein P62714 UNIPROT AKT3 protein Q9Y243 UNIPROT "down-regulates activity" dephosphorylation Thr305 TDAATMKtFCGTPEY 9606 18160256 t llicata "Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A." SIGNOR-248611 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 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 PTPN11 protein Q06124 UNIPROT GAB1 protein Q13480 UNIPROT down-regulates dephosphorylation Tyr627 KGDKQVEyLDLDLDS 9606 BTO:0000782;BTO:0000776 10068651 t lperfetto "Tyrosine phosphorylation of gab2 was induced by stimulation through gp130, il-2r, il-3r, tpor, scfr, and tcr. Gab1 and gab2 were shown to be substrates for shp-2 in vitro." SIGNOR-236262 RELA protein Q04206 UNIPROT HDAC4 protein P56524 UNIPROT up-regulates binding 9606 15988006 t gcesareni "P65 and histone deacetylases 4 cooperate to inhibit the ability of mef2 factors to induce the klf2 promoter" SIGNOR-138368 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 RPS6KA1 protein Q15418 UNIPROT TSC1/TSC2 complex SIGNOR-C101 SIGNOR "down-regulates activity" phosphorylation 9606 BTO:0000007 15342917 t lperfetto "The mitogen-activated protein kinase (mapk)-activated kinase, p90 ribosomal s6 kinase (rsk) 1, was found to interact with and phosphorylate tuberin at a regulatory site, ser-1798, located at the evolutionarily conserved c terminus of tuberin. Rsk1 phosphorylation of ser-1798 inhibits the tumor suppressor function of the tuberin/hamartin complex, resulting in increased mtor signaling to s6k1" SIGNOR-217900 TCL1A protein P56279 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-81434 TP53 protein P04637 UNIPROT BIRC5 protein O15392 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 11965534 f acerquone "Further analyses suggested that the modification of chromatin within the survivin promoter could be a molecular explanation for silencing of survivin gene transcription by p53." SIGNOR-117328 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1787 SPNYSPTsPSYSPTS 9606 BTO:0000567 22137580 t "In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator" SIGNOR-248746 RPS6KA1 protein Q15418 UNIPROT H3F3A 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-138467 SPTAN1 protein Q13813 UNIPROT Membrane_blebbing phenotype SIGNOR-PH24 SIGNOR up-regulates 9606 BTO:0000150;BTO:0000567 9624143 f "Cleaved by CASP3" amattioni "A-fodrin cleavage contributes to blebbing" SIGNOR-57897 TSC1 protein Q92574 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-217910 ATM protein Q13315 UNIPROT CDC25C protein P30307 UNIPROT down-regulates 9606 10097108 f gcesareni "Atm also contributes to the cdc25c activity, particularly in ir-damaged cells, by activating chk2." SIGNOR-65966 TSC1/TSC2 complex SIGNOR-C101 SIGNOR 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-217907 BTRC protein Q9Y297 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates ubiquitination 9606 10228155 t gcesareni "Here we show that fwd1 (the mouse homologue of slimb/betatrcp), an f-box/wd40-repeat protein, specifically formed a multi-molecular complex with beta-catenin, axin, gsk-3beta and apc. Mutations at the signal-induced phosphorylation site of beta-catenin inhibited its association with fwd1. Fwd1 facilitated ubiquitination and promoted degradation of beta-catenin, resulting in reduced cytoplasmic beta-catenin levels." SIGNOR-67374 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 DUSP5 protein Q16690 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates dephosphorylation 9606 10224087 t gcesareni "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" SIGNOR-67358 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR FOS protein P01100 UNIPROT up-regulates 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-251524 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1763 TPTSPSYsPTSPSYS 9606 BTO:0000567 22137580 t "In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator" SIGNOR-248756 MAP3K10 protein Q02779 UNIPROT TCF3 protein P15923 UNIPROT down-regulates phosphorylation Ser341 KALASIYsPDHSSNN 9606 BTO:0000938 19801649 t llicata "Mlk2 inhibits e47 transactivation activity on the trkb promote" SIGNOR-161523 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 PDXP protein Q96GD0 UNIPROT CFL1 protein P23528 UNIPROT "down-regulates activity" dephosphorylation Ser3 sGVAVSDG -1 15580268 t "Chronophin, a novel HAD-type serine protein phosphatase, regulates cofilin-dependent actin dynamics|Cofilin is a key regulator of actin cytoskeletal dynamics whose activity is controlled by phosphorylation of a single serine residue. We report the biochemical isolation of chronophin (CIN), a unique cofilin-activating phosphatase of the haloacid dehalogenase (HAD) superfamily." SIGNOR-248764 CDC42 protein P60953 UNIPROT PAK proteinfamily SIGNOR-PF13 SIGNOR "up-regulates activity" binding 10090 BTO:0000142 8107774 t gcesareni "A new brain serine/threonine protein kinase may be a target for the p21ras-related proteins Cdc42 and Rac1. The kinase sequence is related to that of the yeast protein STE20, implicated in pheromone-response pathways." SIGNOR-248259 CDK1 protein P06493 UNIPROT PTHLH protein P12272 UNIPROT down-regulates phosphorylation Thr121 YKEQPLKtPGKKKKG 9606 10373465 t lperfetto "Phosphorylation at the cyclin-dependent kinases site (thr85) of parathyroid hormone-related protein negatively regulates its nuclear localization" SIGNOR-68544 GNAI3 protein P08754 UNIPROT ADCY1 protein Q08828 UNIPROT down-regulates binding 9606 17419683 t gcesareni "Members of the gi family are linked with reductions in camp through adenylyl cyclase, but have many other actions as well." SIGNOR-154246 LCK protein P06239 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-48850 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 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 PPM1K protein Q8N3J5 UNIPROT BCKDHA protein P12694 UNIPROT "up-regulates activity" dephosphorylation Ser337 TYRIGHHsTSDDSSA 10090 19411760 t "BCKD is inhibited by phosphorylation of its E1alpha subunit at Ser293, which is catalyzed by BCKD kinase. During BCAA excess, phosphorylated Ser293 (pSer293) becomes dephosphorylated through the concerted inhibition of BCKD kinase and the activity of an unknown intramitochondrial phosphatase. Using unbiased, proteomic approaches, we have found that a mitochondrial-targeted phosphatase, PP2Cm, specifically binds the BCKD complex and induces dephosphorylation of Ser293 in the presence of BCKD substrates" SIGNOR-248758 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 RAC1 protein P63000 UNIPROT PAK proteinfamily SIGNOR-PF13 SIGNOR "up-regulates activity" binding 10090 BTO:0000142 8107774 t gcesareni "A new brain serine/threonine protein kinase may be a target for the p21ras-related proteins Cdc42 and Rac1. The kinase sequence is related to that of the yeast protein STE20, implicated in pheromone-response pathways." SIGNOR-248256 TNIK protein Q9UKE5 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT up-regulates phosphorylation Ser177 QALKDARsPSPAHIV 9606 BTO:0000586 20530691 t llicata "Here, we report that tnik is an activating kinase for tcf4 and essential for colorectal cancer growth. Tnik, but not its catalytically inactive mutant, phosphorylated the conserved serine 154 residue of tcf4." SIGNOR-165946 TSSK4 protein Q6SA08 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser133 EILSRRPsYRKILND 9606 BTO:0000007 15964553 t gcesareni "Tssk5, a novel member of the testis-specific serine/threonine kinase family, phosphorylates creb at ser-133, and stimulates the cre/creb responsive pathway." SIGNOR-138289 UCHL5 protein Q9Y5K5 UNIPROT SMAD7 protein O15105 UNIPROT up-regulates binding 9606 16027725 t gcesareni "Here, we report a novel interaction between smads and ubiquitin c-terminal hydrolase uch37, a deubiquitinating enzyme that could potentially reverse smurf-mediated ubiquitination. In gst pull down experiments, uch37 bound weakly to smad2 and smad3, and bound very strongly to smad7 in a region that is distinct from the -py- motif in smad7 that interacts with smurf ubiquitin ligases." SIGNOR-138879 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 CTCFL protein Q8NI51 UNIPROT BAG1 protein Q99933 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0003293 18413740 t lperfetto "DNA methyltransferase 1 and 3B activate BAG-1 expression via recruitment of CTCFL/BORIS and modulation of promoter histone methylation" SIGNOR-254107 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 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 PPARGC1A protein Q9UBK2 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0001103 20404331 f lperfetto "capacity of PGC-1alpha and PGC-1beta to inhibit FoxO3 and NFkappaB actions and proteolysis helps explain how exercise prevents muscle atrophy.overexpression of PGC-1_ inhibits muscle wasting induced by denervation, starvation, and even caFoxO3 expression" SIGNOR-217966 SIRT1 protein Q96EB6 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT "up-regulates activity" deacetylation 10090 BTO:0001103 24003218 t lperfetto "SIRT1 overexpression reduces muscle wasting by blocking the activation of FoxO1 and 3 SIRT1 activation has been reported to increase dramatically endurance exercise through the activation of PGC-1_ in muscle, which stimulates fatty acid oxidation" SIGNOR-217963 TTL protein Q8NG68 UNIPROT TUBA4A protein P68366 UNIPROT down-regulates tyrosination 9606 22020298 t miannu "Tubulin tyrosine ligase (ttl) adds a c-terminal tyr to __tubulin as part of a tyrosination/detyrosination cycle present in most eukaryotic cells. / ttl inhibits spontaneous tubulin polymerization" SIGNOR-176927 TTL protein Q8NG68 UNIPROT TUBA8 protein Q9NY65 UNIPROT down-regulates tyrosination 9606 22020298 t miannu "Tubulin tyrosine ligase (ttl) adds a c-terminal tyr to __tubulin as part of a tyrosination/detyrosination cycle present in most eukaryotic cells. / ttl inhibits spontaneous tubulin polymerization" SIGNOR-176930 XIAP protein P98170 UNIPROT CASP9 protein P55211 UNIPROT "down-regulates quantity by destabilization" binding -1 12620238 t lperfetto "This paper reports the crystal structure of caspase-9 in an inhibitory complex with the third baculoviral iap repeat (bir3) of xiap at 2.4 a resolution. X-linked inhibitor-of-apoptosis protein (xiap) interacts with caspase-9 and inhibits its activity." SIGNOR-98988 MLST8 protein Q9BVC4 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-205609 MMP1 protein P03956 UNIPROT COL2A1 protein P02458 UNIPROT "down-regulates quantity by destabilization" cleavage Gly906 EGPPGPQGLAGQRGI 9606 8609233 t miannu "MMP-1 cleaves type II collagen at the peptide bond Gly906-Leu907 Proteolysis of triple-helical collagen is an important step in the progression toward irreversible tissue damage in osteoarthritis. Earlier work on the expression of enzymes in cartilage suggested that collagenase-1 (MMP-1) contributes to the process." SIGNOR-256341 PRKCH protein P24723 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-188585 TCF12 protein Q99081 UNIPROT NOTCH3 protein Q9UM47 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 22577461 f miannu "Hebalt positively regulates t-cell genes, such as pt_ and notch3" SIGNOR-197517 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 CTDSP1 protein Q9GZU7 UNIPROT NLI/Lmx1.1/Isl1 complex SIGNOR-C103 SIGNOR "form complex" binding 9606 BTO:0000007 9452425 t lperfetto "Interactions between LIM transcription factors were also evaluated in vivo. Cotransfected FLAG-Lmx1.1 and HA-Isl1 were capable of interacting. the NLI-dependent interaction observed between Isl1 and Lmx1.1 is likely to represent a physiologically significant complex found in the endocrine cells of the pancreas." SIGNOR-236839 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1654 SPSYSPTsPSYSPTS -1 22137580 t "Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat." SIGNOR-248771 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 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 SSH1 protein Q8WYL5 UNIPROT CFL1 protein P23528 UNIPROT "up-regulates activity" dephosphorylation Ser3 sGVAVSDG 9606 14531860 t "Differential activities, subcellular distribution and tissue expression patterns of three members of Slingshot family phosphatases that dephosphorylate cofilin.|Cofilin, a key regulator of actin filament dynamics, is inactivated by phosphorylation at Ser-3 by LIM-kinases and is reactivated by dephosphorylation by a family of protein phosphatases, termed Slingshot (SSH)." SIGNOR-248762 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 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 DLK2 protein Q6UY11 UNIPROT NOTCH1 protein P46531 UNIPROT "down-regulates activity" binding 10090 BTO:0002572 21419176 t lperfetto "Moreover, the interaction of DLK1 with NOTCH1 caused an inhibition of basal NOTCH signaling in preadipocytes and mesenchymal multipotent cells. In this work, we demonstrate, for the first time, that DLK2 interacts with itself, with DLK1, and with the same NOTCH1 receptor region as DLK1 does. We demonstrate also that the interaction of DLK2 with NOTCH1 similarly results in an inhibition of NOTCH signaling in preadipocytes and Mouse Embryo fibloblasts." SIGNOR-219377 MAP3K10 protein Q02779 UNIPROT TCF3 protein P15923 UNIPROT down-regulates phosphorylation Thr355 NFSSSPStPVGSPQG 9606 BTO:0000938 19801649 t llicata "Mlk2 inhibits e47 transactivation activity on the trkb promote" SIGNOR-161544 MAP3K14 protein Q99558 UNIPROT CHUK protein O15111 UNIPROT "up-regulates activity" phosphorylation Ser180 DQGSLCTsFVGTLQY 9606 BTO:0000007;BTO:0000567 SIGNOR-C14 9520446 t lperfetto "NIK preferentially phosphorylates ikk-alpha over ikk-beta, leading to the activation of ikk-alpha kinase activity; the accumulated nik phosphorylates ikkalfa." SIGNOR-55946 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 MAP3K10 protein Q02779 UNIPROT TCF3 protein P15923 UNIPROT down-regulates phosphorylation Ser352 SSNNFSSsPSTPVGS 9606 BTO:0000938 19801649 t llicata "Mlk2 inhibits e47 transactivation activity on the trkb promote" SIGNOR-161527 MAP3K10 protein Q02779 UNIPROT TCF3 protein P15923 UNIPROT down-regulates phosphorylation Ser359 SPSTPVGsPQGLAGT 9606 BTO:0000938 19801649 t llicata "Mlk2 inhibits e47 transactivation activity on the trkb promote" SIGNOR-161531 MAP3K10 protein Q02779 UNIPROT TCF3 protein P15923 UNIPROT down-regulates phosphorylation Ser379 AGAPGALsPSYDGGL 9606 BTO:0000938 19801649 t llicata "Mlk2 inhibits e47 transactivation activity on the trkb promote" SIGNOR-161540 MAP3K14 protein Q99558 UNIPROT IKBKB protein O14920 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C14 9520446 t gcesareni "Activation of the transcription factor nf-kappab by inflammatory cytokines involves the successive action of nf-kappab-inducing kinase (nik) and two ikappab kinases, ikk-alpha and ikk-beta. Here we show that nik preferentially phosphorylates ikk-alpha over ikk-beta" SIGNOR-55949 MAP3K14 protein Q99558 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 9520446 t lperfetto "Nf-kappab-inducing kinase activates ikk-alpha by phosphorylation of ser-176.Nik preferentially phosphorylates ikk-alpha over ikk-beta, leading to the activation of ikk-alpha kinase activity; the accumulated nik phosphorylates ikkalfa." SIGNOR-217433 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 PRDM16 protein Q9HAZ2 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR down-regulates 9606 BTO:0000222 BTO:0000887;BTO:0001103 18719582 f fspada "Loss of prdm16 from brown fat precursors causes a loss of brown fat characteristics and promotes muscle differentiation. Conversely, ectopic expression of prdm16 in myoblasts induces their differentiation into brown fat cells." SIGNOR-180301 PRKCA protein P17252 UNIPROT PLD1 protein Q13393 UNIPROT up-regulates phosphorylation Ser561 PRKFSKFsLYKQLHR 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-69934 PRKCZ protein Q05513 UNIPROT MYH10 protein P35580 UNIPROT down-regulates phosphorylation Ser1937 RGGPISFsSSRSGRR 9606 16611744 t lperfetto "After egf stimulation, apkc_ translocates from the nucleus to the cytoplasm (figure 3) and is therefore able to interact with myosin ii-b. apkc_ phosphorylates nmhc ii-b on ser1937, which is located on the nonhelical tailpiece, leading to filament disassembly at certain sites of the cell" SIGNOR-146100 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 sirolimus chemical CHEBI:9168 ChEBI mTORC1 complex SIGNOR-C3 SIGNOR down-regulates "chemical inhibition" -1 17350953 t lperfetto "Rapamycin is an immunosuppressive drug that binds simultaneously to the 12-kDa FK506- and rapamycin-binding protein (FKBP12, or FKBP) and the FKBP-rapamycin binding (FRB) domain of the mammalian target of rapamycin (mTOR) kinase. The resulting ternary complex has been used to conditionally perturb protein function, and one such method involves perturbation of a protein of interest through its mislocalization." SIGNOR-219385 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 PRKCA protein P17252 UNIPROT PLD1 protein Q13393 UNIPROT up-regulates phosphorylation Ser2 sLKNEPRV 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-69930 PRKCD protein Q05655 UNIPROT LIMK2 protein P53671 UNIPROT down-regulates phosphorylation Ser283 EGTLRRRsLRRSNSI 9606 16820362 t "Translocation from Cytosol to Nucleus" gcesareni "Recently we have shown that limk2 shuttles between cytoplasm and nucleus in endothelial cells and that nuclear import is inhibited by protein kinase c-mediated phosphorylation of ser-283." SIGNOR-147716 PRKD1 protein Q15139 UNIPROT PIP4K2A protein P48426 UNIPROT down-regulates phosphorylation Thr376 KAAHAAKtVKHGAGA 9606 16563698 t lperfetto "We conclude that the type ii pip kinases are physiological targets for pkd phosphorylation, and that this modification is likely to regulate inositol lipid turnover by inhibition of these lipid kinases." SIGNOR-145370 RET protein P07949 UNIPROT GRB10 protein Q13322 UNIPROT up-regulates binding 9606 8631863 t gcesareni "Grb7 and grb10, likely relay signals emanating from ret to other, as yet, unidentified targets within the cell" SIGNOR-41699 STK3 protein Q13188 UNIPROT MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation Thr74 QINMLYGtITEFCTE 9606 BTO:0000007 18362890 t gcesareni "These findings indicate that the phosphorylation of mob1 at thr74 by mst2 is essential to make a complex of mob1, mst2 and ndr1, and to fully activate ndr1" SIGNOR-177977 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 AURKB protein Q96GD4 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-176363 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 EPHA3 protein P29320 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. 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-52312 IKBKE protein Q14164 UNIPROT IRF3 protein Q14653 UNIPROT "up-regulates activity" phosphorylation Ser385 MARVGGAsSLENTVD -1 18440553 t lperfetto "Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikkepsilon And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404." SIGNOR-178363 MAP3K20 protein Q9NYL2 UNIPROT MAP3K20 protein Q9NYL2 UNIPROT up-regulates phosphorylation Thr162 SRFHNHTtHMSLVGT 9606 15342622 t gcesareni "Ionizing radiation induces mrk autophosphorylation and activation. Within the mrk kinase loop between the dfg (subdomain vii) and ape (subdomain viii) residues, there are three conserved threonine/serine residues (thr161, thr162, and ser165) that are important for activation." SIGNOR-128581 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 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 ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR AMBRA1 protein Q9C0C7 UNIPROT "up-regulates activity" phosphorylation 10090 20921139 t lperfetto "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-219388 MAPK14 protein Q16539 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" phosphorylation Ser208 DAGSPNLsPNPMSPA 9606 BTO:0001939 15520018 t miannu "Smad3 was phosphorylated at both Ser203 and Ser207 in untreated MCF10CA1h cells and the p38 and ROCK inhibitors each down-regulated phosphorylation at these sites. we demonstrate that phosphorylation at Ser203 and Ser207 residues is required for the full transactivation potential of Smad3, and that these residues are targets of the p38 and Rho/ROCK pathways." SIGNOR-250112 PTPRH protein Q9HD43 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-248802 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 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1619 SPSYSPTsPSYSPTS -1 15125841 t "Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro" SIGNOR-248804 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1626 SPSYSPTsPSYSPTS -1 15125841 t "Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro" SIGNOR-248805 ACD protein Q96AP0 UNIPROT TERT protein O14746 UNIPROT up-regulates binding 9606 17237768 t miannu "We find that tpp1 and pot1 form a complex with telomeric dna that increases the activity and processivity of the human telomerase core enzyme." SIGNOR-152321 BBC3 protein Q9BXH1 UNIPROT BCL2 protein P10415 UNIPROT "down-regulates activity" binding 9606 BTO:0001938 11463392 t lperfetto "Puma localizes to the mitochondria, interacts with bcl-2, and function to induce cytochrome c release" SIGNOR-109506 BIRC6 protein Q9NR09 UNIPROT CASP3 protein P42574 UNIPROT down-regulates binding 9606 15200957 t gcesareni "Bruce binds and thereby inhibits caspases, in particular effector caspase-3." SIGNOR-125956 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 DLL4 protein Q9NR61 UNIPROT NOTCH1 protein P46531 UNIPROT "up-regulates activity" binding 9606 BTO:0000574 11739188 t lperfetto "Expression analysis of known notch ligands suggests that dll4 is the only ligand that exhibits spatial and temporal expression consistent with the activation of notch1 and notch4 during vascular development. The identification of dll4 reveals a candidate ligand for notch receptors involved in blood vessel biology" SIGNOR-112649 DYRK1A protein Q13627 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-183670 MAPK14 protein Q16539 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" phosphorylation Ser204 NHSMDAGsPNLSPNP 9606 BTO:0001939 15520018 t miannu "Smad3 was phosphorylated at both Ser203 and Ser207 in untreated MCF10CA1h cells and the p38 and ROCK inhibitors each down-regulated phosphorylation at these sites. we demonstrate that phosphorylation at Ser203 and Ser207 residues is required for the full transactivation potential of Smad3, and that these residues are targets of the p38 and Rho/ROCK pathways." SIGNOR-250113 AKT1 protein P31749 UNIPROT MTOR protein P42345 UNIPROT "down-regulates activity" phosphorylation Thr2446 NKRSRTRtDSYSAGQ 9606 BTO:0000007 10910062 t "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. These results demonstrate that mTOR is a direct target of the PI3K-AKT signaling pathway in mitogen-stimulated cells, and that the identified AKT phosphorylation sites are nested within a repressor domain that negatively regulates the catalytic activity of mTOR. " SIGNOR-251482 SCF-betaTRCP complex SIGNOR-C5 SIGNOR NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "up-regulates activity" ubiquitination 9534 BTO:0004055 11295495 t lperfetto "The scf-betatrcp complex is responsible for the ubiquitination of p100 and p105 following their phosphorylation by ikk." SIGNOR-235305 SFN protein P31947 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates relocalization 9606 BTO:0000150;BTO:0001130 20940406 t lperfetto "Pkd1 phosphorylates ser(11) (s11) on transcription factor snail, a master emt regulator and repressor of e-cadherin expression, triggering nuclear export of snail via 14-3-3_ binding" SIGNOR-168540 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1647 SPSYSPTsPSYSPTS -1 15125841 t "Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro" SIGNOR-248806 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1654 SPSYSPTsPSYSPTS -1 15125841 t "Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro" SIGNOR-248807 TNFRSF17 protein Q02223 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates 9606 10903733 f miannu "Overexpression of bcma activates jnk" SIGNOR-79489 DYRK1A protein Q13627 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-183677 LPAR2 protein Q9HBW0 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates binding 9606 11093753 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. lpa2 also can couple to the gi/o, g12/13, and gqfamilies." SIGNOR-84559 MAP3K2 protein Q9Y2U5 UNIPROT MAP2K4 protein P45985 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007 11343802 t lperfetto "Both mekk2 and mekk3 are able to activate the jun kinase pathway in vivo. However, following routine immunoprecipitation in triton x-100, mekk2 but not mekk3 is able to effectively phosphorylate both sek-1 and mek-1 and to undergo autophosphorylation" SIGNOR-107695 NRARP protein Q7Z6K4 UNIPROT RBPJ/NOTCH complex SIGNOR-C97 SIGNOR down-regulates binding 8355 11485984 t lperfetto "Overexpression of nrarp in embryos blocks notch signaling and inhibits the activation of notch target genes by icd. We show that nrarp forms a ternary complex with the icd of xnotch1 and the csl protein xsu(h) and that in embryos nrarp promotes the loss of icd." SIGNOR-219228 PRKCA protein P17252 UNIPROT PLA2G4A protein P47712 UNIPROT up-regulates phosphorylation 9606 BTO:0000876 16963226 t gcesareni "Pkcalfa, but not pkcbeta, is the predominant cpkc isoenzyme required for cpla2 protein phosphorylation and maximal induction of cpla2 enzymatic activity." SIGNOR-149406 SB-202190 chemical CHEBI:79090 ChEBI PCSK7 protein Q16549 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000876 9738669 t gcesareni "Sb202190, a selective inhibitor of p38 mitogen activated protein kinase, is a powerful regulator of lps-induced mrnas in monocytes." SIGNOR-60130 EPGN protein Q6UW88 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 16829981 t gcesareni "Areg (amphiregulin), btc (beta-cellulin), egf, epgn (epigen), ereg (epiregulin), hbegf, nrg1, nrg2, nrg3, nrg4 and tgfa (tgfalpha) constitute egf family ligands for erbb family receptors." SIGNOR-147835 TP53 protein P04637 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates binding 9606 15073170 t gcesareni "Rather, p53 expression stimulates the serine/threonine kinase ribosomal s6 kinase 1 (rsk1), which in turn phosphorylates the p65 subunit of nf-kb." SIGNOR-124038 ATG14 protein Q6ZNE5 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT "up-regulates activity" binding 10090 BTO:0000944 19270693 t lperfetto "Characterization of the new proteins revealed that atg14l enhances vps34 lipid kinase activity and upregulates autophagy," SIGNOR-235448 DUSP22 protein Q9NRW4 UNIPROT ESR1 protein P03372 UNIPROT "down-regulates activity" dephosphorylation Ser118 LHPPPQLsPFLQPHG 9606 17384676 t "These results strongly suggest that DUSP22 acts as a negative regulator of the ERalpha-mediated signaling pathway|whereas E2-induced phosphorylation and activation of ERalpha was suppressed by overexpression of DUSP22 but not catalytically inactive mutants." SIGNOR-248827 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 MAP3K3 protein Q99759 UNIPROT MAP2K4 protein P45985 UNIPROT "up-regulates activity" binding 9606 BTO:0000298 9162092 t lperfetto "These data indicate that mkk3 is preferentially activated by mekk3, whereas mkk4 is activated both by mekk2 and mekk3." SIGNOR-48628 MAP3K3 protein Q99759 UNIPROT RCAN1 protein P53805 UNIPROT up-regulates phosphorylation Ser167 FLISPPAsPPVGWKQ 9606 BTO:0000782 12809556 t gcesareni "Essential role of mekk3 signaling in angiotensin ii-induced calcineurin/nuclear factor of activated t-cells activation" SIGNOR-102294 MAP3K4 protein Q9Y6R4 UNIPROT MAP2K3 protein P46734 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000298 9305639 t lperfetto "These results, therefore, suggest that mtk1 directly phosphorylates and activates mkk3, mkk6 and sek1." SIGNOR-50891 MAPK14 protein Q16539 UNIPROT BCL2 protein P10415 UNIPROT down-regulates phosphorylation Thr56 FSSQPGHtPHPAASR 9606 16714293 t gcesareni "Bcl-2 phosphorylation by p38 mapkin this study, we identify, by using mass spectrometry techniques and specific anti-phosphopeptide antibodies, ser(87) and thr(56) as the bcl-2 residues phosphorylated by p38 mapk and show that phosphorylation of these residues is always associated with a decrease in the antiapoptotic potential of bcl-2 protein." SIGNOR-146786 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 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 PPM1D protein O15297 UNIPROT CHEK2 protein O96017 UNIPROT "up-regulates activity" dephosphorylation Thr68 SSLETVStQELYSIP -1 16311512 t "an in vitro phosphatase assay revealed that Wip1 (WT), but not Wip1 (D314A), dephosphorylates Thr68 on phosphorylated Chk2 in vitro, resulting in the inhibition of Chk2 kinase activity toward glutathione S-transferase-Cdc25C." SIGNOR-248318 PRKCA protein P17252 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Ser24 GYLRKPKsMHKRFFV 9606 16574739 t flangone "We show that pkcalpha is likely to be directly involved in ser24 phosphorylation...Using Ser24asp irs-1 mutants to mimic the phosphorylated residue, we demonstrate that the phosphorylation status of ser24 does play an important role in regulating phosphoinositide binding to, and the intracellular localization of, the irs1-ph domain, which can ultimately impinge on insulin-stimulated glucose uptake" SIGNOR-145398 PTPN11 protein Q06124 UNIPROT CTNNA1 protein P35221 UNIPROT down-regulates dephosphorylation Tyr148 LADMADVyKLLVQLK 9606 16767162 t gcesareni "Tyr148 of beta-catenin is an shp2 target dephosphorylation site. Together, these results suggest that beta-catenin plays a suppressor role in cell transformation and that shp2, by dephosphorylating beta-catenin, promotes mitogenic, cell survival and transformation signals." SIGNOR-147075 SMO protein Q99835 UNIPROT GNG12 protein Q9UBI6 UNIPROT up-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-152817 SOS1 protein Q07889 UNIPROT NRAS protein P01111 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000938 11560935 t lperfetto "Sos and Ras-GRF are two families of guanine nucleotide exchange factors that activate Ras proteins in cells. Sos proteins are ubiquitously expressed and are activated in response to cell-surface tyrosine kinase stimulation Sos1 and Ras-GRF1 activate the Ras proteins Ha-Ras, N-Ras, and Ki-Ras" SIGNOR-110566 PAK2 protein Q13177 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Thr286 RLEEKVKtLKAQNSE 9606 BTO:0000848 21177766 t lperfetto "P21-activated protein kinase (pak2)-mediated c-jun phosphorylation at 5 threonine sites promotes cell transformationour data showed that pak2 binds and phosphorylates c-jun at five threonine sites (thr2, thr8, thr89, thr93 and thr286)" SIGNOR-170764 PBRM1 protein Q86U86 UNIPROT RARB protein P10826 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000562 15601824 f miannu "We found that baf180 deficiency leads to a decreased expression of select target genes, such as s100a13 and ra targets rar_2 and crabpii in heart tissues." SIGNOR-132378 CTDSP1 protein Q9GZU7 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-148396 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1675 SPSYSPTsPSYSPTS -1 15125841 t "Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro" SIGNOR-248809 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1714 SPTSPSYsPTSPSYS -1 15125841 t "Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro" SIGNOR-248822 TIRAP protein P58753 UNIPROT MYD88 protein Q99836 UNIPROT "up-regulates activity" binding 9606 25948473 t lperfetto "Stimulation of Toll-like receptor (TLR) 4 leads to the activation of both MyD88-dependent and MyD88-independent pathways through the recruitment of adaptors TIRAP/MyD88 and TRIF/TRAM, respectively." SIGNOR-110215 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 LPAR2 protein Q9HBW0 UNIPROT GNAI1 protein P63096 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. Lpa2also can couple to the gi/o, g12/13, and gqfamilies." SIGNOR-135840 MAP3K4 protein Q9Y6R4 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" 9606 21152872 f lperfetto "We found that mekk1/mekk4 as opposed to ask1, are responsible for trail-induced c-jun nh2-terminal kinase (jnk) or p38 activation," SIGNOR-170534 MAPK14 protein Q16539 UNIPROT RBSN protein Q9H1K0 UNIPROT up-regulates phosphorylation Ser215 ESLSTHTsPSQSPNS 9606 16138080 t lperfetto "We found that p38alpha can phosphorylate the rab5 effectors eea1 and rabenosyn-5 on thr-1392 and ser-215, respectively, and these phosphorylation events regulate the recruitment of eea1 and rabenosyn-5 to membranes" SIGNOR-140143 SOCS3 protein O14543 UNIPROT IL6ST protein P40189 UNIPROT "down-regulates activity" binding 9606 BTO:0000887;BTO:0001103 19620279 t miannu "We now show that SOCS1, SOCS3, and PIAS1 promote myogenic differentiation by specifically inhibiting the LIF-induced JAK1/STAT1/STAT3 pathway via distinct targets; whereas SOCS1 and SOCS3 selectively bind and inhibit JAK1 and gp130, respectively, PIAS1 targets mainly the activated STAT1 and prevents its binding to DNA." SIGNOR-202045 SOCS3 protein O14543 UNIPROT IRS1 protein P35568 UNIPROT down-regulates binding 9606 BTO:0000887;BTO:0001103 23115649 t gcesareni "Irs-1 is the major signaling protein that socs3 targets to inhibit insulin signaling" SIGNOR-199361 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1623 SPTSPSYsPTSPSYS -1 15125841 t "Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro" SIGNOR-248816 PRKDC protein P78527 UNIPROT WRN protein Q14191 UNIPROT up-regulates phosphorylation Ser440 DTSYVIEsDEDLEME 9606 BTO:0000007 24429382 t llicata "Here, we identify ser-440 and -467 in wrn as major phosphorylation sites mediated by dna-pk our findings indicate that phosphorylation of ser-440 and -467 in wrn are important for relocalization of wrn to nucleoli, and that it is required for efficient dsb repair." SIGNOR-203737 PTPN22 protein Q9Y2R2 UNIPROT LCK protein P06239 UNIPROT "down-regulates activity" dephosphorylation Tyr394 RLIEDNEyTAREGAK 9606 16461343 t "In vitro experiments with purified recombinant proteins demonstrated that PTPN22-D195A/C227S interacted directly with activated Lck, Zap70, and TCRzeta, confirming the initial substrate trap results. Native PTPN22 dephosphorylated Lck and Zap70 at their activating tyrosine residues Tyr-394 and Tyr-493, respectively, but not at the regulatory tyrosines Tyr-505 (Lck) or Tyr-319 (Zap70). Native PTPN22 also dephosphorylated TCRzeta in vitro and in cells, and its substrate trap variant co-immunoprecipitated with TCRzeta when both were coexpressed in 293T cells, establishing TCRzeta as a direct substrate of PTPN22." SIGNOR-248836 PTPN22 protein Q9Y2R2 UNIPROT ZAP70 protein P43403 UNIPROT "down-regulates activity" dephosphorylation Tyr493 LGADDSYyTARSAGK 9606 16461343 t "In vitro experiments with purified recombinant proteins demonstrated that PTPN22-D195A/C227S interacted directly with activated Lck, Zap70, and TCRzeta, confirming the initial substrate trap results. Native PTPN22 dephosphorylated Lck and Zap70 at their activating tyrosine residues Tyr-394 and Tyr-493, respectively, but not at the regulatory tyrosines Tyr-505 (Lck) or Tyr-319 (Zap70). Native PTPN22 also dephosphorylated TCRzeta in vitro and in cells, and its substrate trap variant co-immunoprecipitated with TCRzeta when both were coexpressed in 293T cells, establishing TCRzeta as a direct substrate of PTPN22." SIGNOR-248838 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 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 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 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 MAPK3 protein P27361 UNIPROT up-regulates phosphorylation Tyr204 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-140298 SRC protein P12931 UNIPROT DDR2 protein Q16832 UNIPROT up-regulates phosphorylation Tyr740 RNLYSGDyYRIQGRA 9606 16186108 t gcesareni "Here, using baculoviral co-expression of the ddr2 cytosolic domain and src, we show that src targets three tyrosine residues (tyr-736, tyr-740, and tyr-741) in the activation loop of ddr2 for phosphorylation. This phosphorylation by src stimulates ddr2 cis-autophosphorylation of additional tyrosine residues." SIGNOR-140763 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1721 SPTSPSYsPTSPSYS -1 15125841 t "Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro" SIGNOR-248823 TAX1BP1 protein Q86VP1 UNIPROT TNFAIP3 protein P21580 UNIPROT "up-regulates activity" binding 9606 BTO:0000782;BTO:0001271 10435631 t lperfetto "Tx1bp1 appears to be a novel a20-binding protein which mediate the anti-apoptotic activity of a20; tax1bp1 phosphorylation was pivotal for cytokine-dependent interactions among tax1bp1, a20, itch and rnf11 and downregulation of signaling by the transcription factor nf-Kb." SIGNOR-69921 TEAD1 protein P28347 UNIPROT BMP4 protein P12644 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150;BTO:0000551 23673366 f gcesareni "Taz induces bmp4 transcription through the tead family of transcription factors, which mediate bmp4 promoter activation through binding to tead response element 1 (tre1)." SIGNOR-202049 MAP3K5 protein Q99683 UNIPROT MAP3K5 protein Q99683 UNIPROT "up-regulates activity" phosphorylation Thr842 CTETFTGtLQYMAPE 9606 17937911 t lperfetto "Reporter gene assays showed that all three identified in vitro autophosphorylation sites (thr813, thr838, thr842) regulate ask1 signalingmutation of thr838 drastically reduced reporter gene activity when compared to unstimulated control levels. Interestingly, mutation of the other two sites also provided a significant reduction in ask1 function (figure 6a), suggesting that autophosphorylation at the residues thr842 and thr813 regulates ask1 signaling." SIGNOR-158431 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 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 ATR protein Q13535 UNIPROT KMT2A protein Q03164 UNIPROT up-regulates phosphorylation Ser516 VHPPLPIsQSPENES 9606 4709074 t lperfetto "Mll is phosphorylated at serine 516 by atr in response to genotoxic stress in the s phase, which disrupts its interaction with, and hence its degradation by, the scf(skp2) e3 ligase, leading to its accumulation." SIGNOR-25151 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 MAP3K5 protein Q99683 UNIPROT DAXX protein Q9UER7 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser184 QSPRTRGsRRQIQRL 9606 BTO:0000567 19789335 t lperfetto "we show that TNFalpha treatment induces the accumulation of Daxx protein through ASK1 activation by preventing its proteasome-dependent degradation. ASK1 directly phosphorylates Daxx at Ser(176) and Ser(184) and Daxx is required for the sustained activation of JNK. Our results indicate that Daxx not only activates ASK1 but also is a downstream target of ASK1 and that accumulated Daxx further activates ASK1." SIGNOR-109684 MAP3K5 protein Q99683 UNIPROT MAP3K5 protein Q99683 UNIPROT "up-regulates activity" phosphorylation Thr838 GINPCTEtFTGTLQY 9606 17937911 t lperfetto "Reporter gene assays showed that all three identified in vitro autophosphorylation sites (thr813, thr838, thr842) regulate ask1 signalingmutation of thr838 drastically reduced reporter gene activity when compared to unstimulated control levels. Interestingly, mutation of the other two sites also provided a significant reduction in ask1 function (figure 6a), suggesting that autophosphorylation at the residues thr842 and thr813 regulates ask1 signaling." SIGNOR-158427 MAPK1 protein P28482 UNIPROT PDE4D protein Q08499 UNIPROT down-regulates phosphorylation Ser715 YQSTIPQsPSPAPDD 9606 10828059 t "The effect has been demonstrated using Q08499-5" 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-77571 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 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 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 PRKCH protein P24723 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-66730 PRKDC protein P78527 UNIPROT WRN protein Q14191 UNIPROT up-regulates phosphorylation Ser467 DTSYVIEsDEDLEME 9606 BTO:0000007 24429382 t llicata "Here, we identify ser-440 and -467 in wrn as major phosphorylation sites mediated by dna-pk our findings indicate that phosphorylation of ser-440 and -467 in wrn are important for relocalization of wrn to nucleoli, and that it is required for efficient dsb repair." SIGNOR-203741 PTPN11 protein Q06124 UNIPROT EGFR protein P00533 UNIPROT "down-regulates activity" dephosphorylation Tyr1016 DVVDADEyLIPQQGF 9534 BTO:0004055 12582165 t lperfetto "Given that substrate trapping occurred in intact cells and that the interaction was very specific, it is highly likely that egfr and gab1 represent physiological shp2 substrates.To further confirm that phosphotyrosyl proteins trapped by SHP2 are target substrates, we carried out an immunocomplex in vitrophosphatase assay.The WT protein partially dephosphorylated both the EGFR and Gab1, whereas the DM protein did not" SIGNOR-236424 ROCK1 protein Q13464 UNIPROT LPP protein Q93052 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887;BTO:0001260 22886954 f miannu "Inactivation of rho kinase (rok) with rok inhibitors significantly inhibited lpp mrna expression" SIGNOR-198118 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 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 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 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 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 PRKCA protein P17252 UNIPROT CD5 protein P06127 UNIPROT unknown phosphorylation Thr434 MSFHRNHtATVRSHA 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-249070 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 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 SOCS1 protein O15524 UNIPROT JAK1 protein P23458 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-202042 EP300 protein Q09472 UNIPROT PLAG1 protein Q6DJT9 UNIPROT up-regulates acetylation 9606 16207715 t miannu "Plag1 and plagl2 are also regulated by acetylation. They are acetylated and activated by p300 and deacetylated and repressed by hdac7." SIGNOR-140915 EP300 protein Q09472 UNIPROT PLAGL2 protein Q9UPG8 UNIPROT up-regulates acetylation 9606 16207715 t miannu "Plag1 and plagl2 are also regulated by acetylation. They are acetylated and activated by p300 and deacetylated and repressed by hdac7." SIGNOR-140947 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 CHGA protein P10645 UNIPROT Peptide_hormone_processing phenotype SIGNOR-PH88 SIGNOR up-regulates 10090 BTO:0002691 12456801 f "CgA was initially identified as the major soluble matrix protein of secretory vesicles formed in neuroendocrine cells. Its functions include modulation of secretory granule stability, prohormone processing, and regulation of peptide sorting into secretory pathways" SIGNOR-254275 CTDSPL protein O15194 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-248313 FGF12 protein P61328 UNIPROT SCN11A protein Q9UI33 UNIPROT "down-regulates activity" binding 9606 BTO:0000938 20679355 t miannu "Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels." SIGNOR-253436 MAP3K7 protein O43318 UNIPROT MAP2K6 protein P52564 UNIPROT "up-regulates activity" phosphorylation 9606 11460167 t lperfetto "The activity of tak1 to phosphorylate mkk6, which activates the jnk-p38 kinase pathway, is directly regulated by k63-linked polyubiquitination" SIGNOR-109497 MAP3K7 protein O43318 UNIPROT MAP3K4 protein Q9Y6R4 UNIPROT "up-regulates activity" 9606 BTO:0000007 9890973 f lperfetto "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-63979 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 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 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Ser171 HLQTCCGsLAYAAPE 9606 16216881 t gcesareni "We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk." SIGNOR-140958 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 PPARGC1A protein Q9UBK2 UNIPROT SLC2A4 protein P14672 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887;BTO:0001103 17609368 f gcesareni "Pgc-1alpha protein is required for ampk action on glut4 gene expression and mitochondrial function." SIGNOR-156769 SRC protein P12931 UNIPROT DDR2 protein Q16832 UNIPROT up-regulates phosphorylation Tyr741 NLYSGDYyRIQGRAV 9606 16186108 t gcesareni "Here, using baculoviral co-expression of the ddr2 cytosolic domain and src, we show that src targets three tyrosine residues (tyr-736, tyr-740, and tyr-741) in the activation loop of ddr2 for phosphorylation. This phosphorylation by src stimulates ddr2 cis-autophosphorylation of additional tyrosine residues." SIGNOR-140767 RIPK1 protein Q13546 UNIPROT TAB3 protein Q8N5C8 UNIPROT "up-regulates activity" binding 9606 19927120 t lperfetto "Tab2 and tab3 activate the jun n-terminal kinase and nuclear factor-kappab pathways through the specific recognition of lys 63-linked polyubiquitin chains by its npl4 zinc-finger (nzf) domain." SIGNOR-161787 SGK1 protein O00141 UNIPROT NDRG2 protein Q9UN36 UNIPROT up-regulates phosphorylation Ser332 LSRSRTAsLTSAASV 9606 BTO:0000567 BTO:0000887;BTO:0001103;BTO:0000763 15461589 t llicata "Sgk1 phosphorylated ndrg2 at thr330, ser332 and thr348 in vitro. for example, the phosphorylation of thr330 or ser332 by sgk1 may prime ndrg2 for phosphorylation by gsk3 at ser326 and ser328 respectively, for example, the phosphorylation of thr330 or ser332 by sgk1 may prime ndrg2 for phosphorylation by gsk3 at ser326 and ser328 respectively, the phosphorylation of thr348 by sgk1 may prime for phosphorylation at ser344" SIGNOR-129672 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 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 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Thr398 SQFTKYWtESNGVES 9606 16216881 t lperfetto "We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase." SIGNOR-141026 PRKAA1 protein Q13131 UNIPROT SLC2A4 protein P14672 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887;BTO:0001103 17609368 f gcesareni "Several in vivo studies using aicar to activate ampk chronically determined that mitochondrial enzymes [e.g., cytochrome c, uncoupling protein 3 (ucp-3)] and proteins involved in glucose uptake (glut4)are increased at the transcriptional level in skeletal muscle." SIGNOR-156786 PRKAA1 protein Q13131 UNIPROT UCP3 protein P55916 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887;BTO:0001103 17609368 f gcesareni "Severalin vivostudies using aicar to activate ampk chronically determined that mitochondrial enzymes [e.g., cytochromec, uncoupling protein 3 (ucp-3)] (1518) and proteins involved in glucose uptake (glut4) (1820) are increased at the transcriptional level in skeletal muscle." SIGNOR-156831 PTCH1 protein Q13635 UNIPROT SMO protein Q99835 UNIPROT "down-regulates activity" binding 9606 14556242 t lperfetto "In the responding cell, active Hedgehog binds to its receptor Patched, a 12-pass transmembrane protein, which frees Smoothened, an adjacent 7-pass transmembrane protein, for downstream signaling.Thus, a balance is created by the antagonism of Hedgehog and Patched, whose relative concentrations alternate with respect to each other." SIGNOR-118609 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 TICAM1 protein Q8IUC6 UNIPROT TBK1 protein Q9UHD2 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 14530355 t lperfetto "Toll/il-1 receptor domain-containing adaptor inducing ifn-beta (trif) associates with tnf receptor-associated factor 6 and tank-binding kinase 1, and activates two distinct transcription factors, nf-kappa b and ifn-regulatory factor-3, in the toll-like receptor signaling" SIGNOR-118458 HES6 protein Q96HZ4 UNIPROT E2F1 protein Q01094 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150;BTO:0000938 19891787 f gcesareni "Expression of hes-6 resulted in induction of e2f-1, a crucial target gene for the transcriptional repressor hes-1" SIGNOR-189101 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 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 MAP4K1 protein Q92918 UNIPROT MAP3K11 protein Q16584 UNIPROT up-regulates phosphorylation Ser281 WHKTTQMsAAGTYAW 9606 11053428 t gcesareni "Hpk1 also phosphorylated mlk-3 activation loop in vitro, and ser281 was found to be the major phosphorylation site, indicating that hpk1 also activates mlk-3 via phosphorylation of the kinase activation loop." SIGNOR-83415 "PAX7/MLL2 complex" complex SIGNOR-C91 SIGNOR MYF5 protein P13349 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002314 BTO:0000887;BTO:0001103 22863532 f 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-198641 CYLD protein Q9NQC7 UNIPROT TRAF2 protein Q12933 UNIPROT "down-regulates activity" deubiquitination 9606 12917691 t lperfetto "Cyld also interacts directly with tumour-necrosis factor receptor (tnfr)-associated factor 2 (traf2), an adaptor molecule involved in by members of the family of tnf/nerve growth factor receptors. (articolo-abstract)" SIGNOR-117860 CYLD protein Q9NQC7 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT down-regulates deubiquitination 9606 BTO:0001253 12917689 t lperfetto "The nf-kappab activation by cyld is mediated, at least in part, by the deubiquitination and inactivation of tnfr-associated factor 2 (traf2) and, to a lesser extent, traf6." SIGNOR-117856 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 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 FGF12 protein P61328 UNIPROT SCN2A protein Q99250 UNIPROT "down-regulates activity" binding 9606 BTO:0000938 20679355 t miannu "Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels." SIGNOR-253428 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 MAP3K9 protein P80192 UNIPROT MAP3K9 protein P80192 UNIPROT "up-regulates activity" phosphorylation Thr312 TKMSAAGtYAWMAPE 10029 BTO:0000246 15610029 t lperfetto "We present here biochemical and biophysical evidence that MLK1 is activated by autophosphorylation in (or near) the activation loop. The activation loops of the MLK family are highly homologous, and so one might predict that the same residues would be key to their activation. Functional data presented here, however, demonstrate that the key residue for activation of MLK1, Thr312, differs from the key residue for activation of MLK3." SIGNOR-249388 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 3-(1-methyl-3-indolyl)-4-[1-[1-(2-pyridinylmethyl)-4-piperidinyl]-3-indolyl]pyrrole-2,5-dione chemical CHEBI:91368 ChEBI PRKCE protein Q02156 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191496 RARA protein P10276 UNIPROT NR4A1 protein P22736 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000782;BTO:0001271;BTO:0000661 10772826 f lperfetto "Retinoic acid and its receptors repress the expression and transactivation functions of nur77" SIGNOR-76980 SRC protein P12931 UNIPROT WASF1 protein Q92558 UNIPROT up-regulates phosphorylation Tyr125 PIPLQETyDVCEQPP 9606 16317717 t lperfetto "The wave/scar proteins regulate actin polymerisation at the leading edge of motile cells via activation of the arp2/3 complex in response to extracellular cues.Src-dependent phosphorylation of scar1 promotes its association with the arp2/3 complex" SIGNOR-142724 TAF3 protein Q5VWG9 UNIPROT TAF3/TRF3 complex SIGNOR-C23 SIGNOR "form complex" binding 9606 BTO:0000887;BTO:0001103;BTO:0001760 18851836 t lperfetto "We recently identified taf3 as a subunit specifically associated with trf3 to form a complex that is required for myogenic differentiation" SIGNOR-181611 TBPL2 protein Q6SJ96 UNIPROT TAF3/TRF3 complex SIGNOR-C23 SIGNOR "form complex" binding 9606 BTO:0000887;BTO:0001103;BTO:0001760 18851836 t lperfetto "We recently identified taf3 as a subunit specifically associated with trf3 to form a complex that is required for myogenic differentiation" SIGNOR-181614 AMPK complex SIGNOR-C15 SIGNOR TBC1D1 protein Q86TI0 UNIPROT down-regulates phosphorylation Ser237 RPMRKSFsQPGLRSL 9606 BTO:0001760 17995453 t lperfetto "In rat l6 myotubes, endogenous tbc1d1 is strongly phosphorylated on ser237 and binds to 14-3-3s in response to the ampk activators aicar" SIGNOR-216631 MMP2 protein P08253 UNIPROT Laminin-5 complex SIGNOR-C184 SIGNOR "up-regulates activity" cleavage 9211848 t lperfetto "Induction of Cell Migration by Matrix Metalloprotease-2 Cleavage of Laminin-5|MMP2 cleaved the Ln-5 gamma2 subunit at residue 587, exposing a putative cryptic promigratory site on Ln-5 that triggers cell motility. This altered form of Ln-5 is found in tumors and in tissues undergoing remodeling, but not in quiescent tissues. Cleavage of Ln-5 by MMP2 and the resulting activation of the Ln-5 cryptic site may provide new targets for modulation of tumor cell invasion and tissue remodeling." SIGNOR-253239 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 PPM1D protein O15297 UNIPROT ATM protein Q13315 UNIPROT "down-regulates activity" dephosphorylation Ser1981 SLAFEEGsQSTTISS 9606 16949371 t "Here, we report that deficiency of Wip1 resulted in activation of the ataxia-telangiectasia mutated (ATM) kinase. In turn, overexpression of Wip1 was sufficient to reduce activation of the ATM-dependent signaling cascade after DNA damage. Wip1 dephosphorylated ATM Ser1981, a site critical for ATM monomerization and activation" SIGNOR-248325 PPM1D protein O15297 UNIPROT MDM2 protein Q00987 UNIPROT "down-regulates quantity by destabilization" dephosphorylation Ser395 SQESEDYsQPSTSSS 9606 17936559 t "Here we show that the wild-type p53-induced phosphatase 1 (Wip1), or PPM1D, downregulates p53 protein levels by stabilizing Mdm2 and facilitating its access to p53. Wip1 interacts with and dephosphorylates Mdm2 at serine 395, a site phosphorylated by the ATM kinase." SIGNOR-248324 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 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 TNK2 protein Q07912 UNIPROT SNX9 protein Q9Y5X1 UNIPROT up-regulates phosphorylation 9606 16316319 t gcesareni "We have previously shown that sh3px1, phosphorylated by ack2 (activated cdc42-associated tyrosine kinase 2), regulates the degradation of egf (epidermal growth factor) receptor." SIGNOR-142569 DFFB protein O76075 UNIPROT DNA_fragmentation phenotype SIGNOR-PH22 SIGNOR up-regulates 9606 BTO:0000661 9422513 f "Cleavage of ICAD/DFF-45" amattioni "The specific cleavage of icad/dff-45 by caspase-3 relieves the inhibition and promotes the endonuclease activity of cad, resulting in apoptotic dna fragmentation" SIGNOR-54358 TGFB2 protein P61812 UNIPROT TGFB2 protein P61812 UNIPROT up-regulates binding 9606 16885528 t gcesareni "The active form of tgf-b is a dimer stabilized by hydrophobic interactions and usually further strengthened by an intersubunit disulfide bridge" SIGNOR-148608 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 AMBRA1 protein Q9C0C7 UNIPROT BECN1 protein Q14457 UNIPROT "up-regulates activity" binding 9606 17589504 t lperfetto "Here we show that Ambra1 (activating molecule in Beclin1-regulated autophagy), a large, previously unknown protein bearing a WD40 domain at its amino terminus, regulates autophagy and has a crucial role in embryogenesis. We found that Ambra1 is a positive regulator of the Becn1-dependent programme of autophagy" SIGNOR-156409 CSNK2A1 protein P68400 UNIPROT ANP32B protein Q92688 UNIPROT up-regulates phosphorylation Thr244 GEKRKREtDDEGEDD 9606 BTO:0000661 17178712 t gcesareni "Here, we are able to report that casein kinase 2 (ck2) phosphorylates april on residue threonine244 (thr(244)) and demonstrate that the ck2-specific inhibitor 4,5,6,7-tetrabromo-2-azabenzimidazole abolishes cd83 expression in activated jurkat t cells by interfering with the nucleocytoplasmic translocation of cd83 mrna" SIGNOR-151261 CSNK2A1 protein P68400 UNIPROT CD5 protein P06127 UNIPROT up-regulates phosphorylation Ser482 SSMQPDNsSDSDYDL 9606 BTO:0000661 9834084 t lperfetto "In this study, we use jurkat t cell transfectants of cd5 cytoplasmic tail mutants to reveal phosphorylation sites relevant to signal transduction. Our results show that casein kinase ii (ckii) is responsible for the constitutive phosphorylation of cd5 molecules at a cluster of three serine residues located at the extreme c terminus (s458, s459, and s461)" SIGNOR-62303 HCK protein P08631 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-112919 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 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 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 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 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 UHMK1 protein Q8TAS1 UNIPROT SF1 protein Q15637 UNIPROT up-regulates phosphorylation Ser82 NPEDRSPsPEPIYNS 9606 16420481 t "The effect has been demonstrated using Q15637-2" gcesareni "Sf1 is phosphorylated on serines 80 and 82 in vitro and in vivo. Kis can phosphorylate sf1f on serine 80 and 82 with a high efficiency that particularly relies on the anchoring of its uhm domain to sf1. Serine phosphorylation of a conserved ser80-pro81-ser82-pro83 motif rigidifies a long unstructured linker in the sf1 helix hairpin and slightly enhances rna binding." SIGNOR-143841 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 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 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 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 AKT3 protein Q9Y243 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-81118 AMBRA1 protein Q9C0C7 UNIPROT BECN1 protein Q14457 UNIPROT "up-regulates activity" binding 9606 BTO:0000459 20921139 t lperfetto "we show that the BECLIN 1-VPS34 complex is tethered to the cytoskeleton through an interaction between the BECLIN 1-interacting protein AMBRA1 and dynein light chains 1/2." SIGNOR-168252 CREBBP protein Q92793 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates acetylation 9606 BTO:0000887 SIGNOR-C6 10944526 t gcesareni "Our results provide direct evidence that myod acetylation functionally activates the protein and show that both pcaf and cbp/p300 are candidate enzymes for myod acetylation in vivo." SIGNOR-81050 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR MYOD1 protein P15172 UNIPROT down-regulates phosphorylation Ser200 YSGDSDAsSPRSNCS 9606 21902831 t lperfetto "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-216706 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 mTORC2 complex SIGNOR-C2 SIGNOR mTORC2 complex SIGNOR-C2 SIGNOR "up-regulates activity" phosphorylation 10090 BTO:0000944 20022946 t lperfetto "These data suggest that mTORC1- and likely mTORC2-associated mTOR Ser-2481 autophosphorylation directly monitors intrinsic mTORC-specific catalytic activity" SIGNOR-235484 PAX7 protein P23759 UNIPROT "PAX7/MLL1 complex" complex SIGNOR-C90 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-198632 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 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 TAB3 protein Q8N5C8 UNIPROT MAP3K7 protein O43318 UNIPROT "up-regulates activity" binding 9606 BTO:0000801 14670075 t lperfetto "We have identified a new binding partner of the tgfbeta (transforming growth factor-beta)-activated protein kinase (tak1), termed tab.two distinct tak1 complexes are present in cells. One comprises tak1 complexed with tab1 and tab2, and the other tak1 complexed with tab1 and tab3 (tak1-binding protein-3). Both complexes are activated in response to tumour necrosis factor-alpha or interleukin-1." SIGNOR-120325 CDK5 protein Q00535 UNIPROT PPP1CA protein P62136 UNIPROT down-regulates phosphorylation Thr320 NPGGRPItPPRNSAK 9606 BTO:0000661 12202491 t gcesareni "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. Increasing doses of cdk2 resulted in increased phosphorylation of the thr-320 site. Phosphorylation of this site in pp1 corresponded to decreased pp1 activity." SIGNOR-92269 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 MAPK14 protein Q16539 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser389 ARIQAAAsTPTNATA 9606 BTO:0000142 17726008 t gcesareni "However p38alfa also inactivates gsk3b by direct phosphorilation of the c-terminal residue ser389. this non-canonicl p38 mapk-dependent phosphorilation of gsk3b seems to occur primarily in the brain and thymocytes." SIGNOR-157548 MAPK1 protein P28482 UNIPROT BCL2L11 protein O43521 UNIPROT "down-regulates quantity by destabilization" phosphorylation 9606 BTO:0000776 16282323 t lperfetto "Erk phosphorylation serves as a signal for bim ubiquitination and proteasomal degradation" SIGNOR-141584 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 NFYA protein P23511 UNIPROT NFY complex SIGNOR-C1 SIGNOR "form complex" binding 9606 BTO:0000801;BTO:0000876 9885213 t lperfetto "Nf-y is one of the best characterized ccaat binding proteins, and its unique structure and evolutionary conservation suggest that it plays a crucial role in transcription of eukaryotic genes.It Is a ubiquitous heteromeric transcription factor, composed of three subunits, nf-ya, nf-yb, and nf-yc, all necessary for dna binding." SIGNOR-63013 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 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 SCHEMBL14517914 chemical CID:10016910 PUBCHEM CHEK1 protein O14757 UNIPROT down-regulates "chemical inhibition" 9606 20068082 t gcesareni "Xl844 (exelixis) a potent atp-competitive inhibitor of chk1 (ki, 2.2nm) and chk2 (ki, 0.07nm)." SIGNOR-163231 SCHEMBL14517914 chemical CID:10016910 PUBCHEM CHEK2 protein O96017 UNIPROT down-regulates "chemical inhibition" 9606 20068082 t gcesareni "Xl844 (exelixis) a potent atp-competitive inhibitor of chk1 (ki, 2.2nm) and chk2 (ki, 0.07nm)." SIGNOR-163234 SLC16A3 protein O15427 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 26384349 f lperfetto "Treatment with _-cyano-4-hydroxy cinnamate (CHC), a known inhibitor of MCT1, MCT2 and MCT4, dose-dependently induced cell death in MM cell lines and primary MM cells (Figure 1C). Thus, monocarboxylate transportation across membranes appears crucial for MM cell survival." SIGNOR-242468 SMURF2 protein Q9HAU4 UNIPROT SMAD1 protein Q15797 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0001593 BTO:0000140 22298955 t lperfetto "Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps" SIGNOR-120647 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 EPN1 protein Q9Y6I3 UNIPROT EGFR protein P00533 UNIPROT down-regulates relocalization 9606 19054389 t gcesareni "Epsin 1 is involved in recruitment of ubiquitinated egf receptors into clathrin-coated pits this supports the contention that epsin 1 promotes endocytosis of the ubiquitinated egfr." SIGNOR-182562 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 MN1 protein Q10571 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 10090 BTO:0004850 17494859 f irozzo "MN1 is a unique oncogene in hematopoiesis that both promotes proliferation/self-renewal and blocks differentiation, and may become useful as a predictive marker in AML treatment." SIGNOR-256016 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 ZSTK-474 chemical CHEBI:90545 ChEBI PIK3CB protein P42338 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207938 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 ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT "up-regulates activity" phosphorylation Tyr1139 TCSPQPEyVNQPDVR -1 1706616 t " Y1023 and Y1248, Y1139 and Y1222 also serve as autophosphorylation sites of HER2." SIGNOR-251127 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 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 OLIG1 protein Q8TAK6 UNIPROT OLIG2 protein Q13516 UNIPROT up-regulates 9606 BTO:0000938 25206819 f miannu "During central nervous system development, olig1 assists olig2 in formation of the motor neuron progenitor domain (pmn), the area responsible for generation of motor neurons and oligodendrocytes" SIGNOR-205304 PLK2 protein Q9NYY3 UNIPROT SNCA protein P37840 UNIPROT up-regulates phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 BTO:0000142 21849493 t lperfetto "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. Pathological serine 129 phosphorylation regulates membrane accumulation of mutant alpha-synuclein." SIGNOR-176067 PLK2 protein Q9NYY3 UNIPROT SNCB protein Q16143 UNIPROT up-regulates phosphorylation Ser118 LMEPEGEsYEDPPQE 9606 BTO:0000142 21849493 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-176071 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 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 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 SFRP1 protein Q8N474 UNIPROT WNT4 protein P56705 UNIPROT down-regulates binding 9606 BTO:0000671 11287180 t gcesareni "Sfrp-1 binds wnt-4 with considerable avidity and inhibits the dna-binding activity of tcf, an effector of wnt signaling," SIGNOR-106556 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 PAX7-FOXO1 "fusion protein" SIGNOR-FP11 SIGNOR FGFR4 protein P22455 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25211658 f miannu "Several deregulated signalling pathways enhance cell growth by modulating cell-cycle regulatory factors in RMS. The most frequently affected signalling pathways include the insulin-like growth factor (IGF), fibroblast growth factor (FGF), hepatocyte growth factor, and platelet-derived growth factor. In ARMS, PAX-FOXO1 activates these pathways by transcriptional activation of receptor genes including IGFR1, FGFR4, MET (c-Met), and PDGFRA." SIGNOR-251565 NMS protein Q5H8A3 UNIPROT NMUR1 protein Q9HB89 UNIPROT up-regulates binding 9606 BTO:0000142 15635449 t gcesareni "Here we identify a novel neuropeptide of 36 amino-acid residues in rat brain as an endogenous ligand for the orphan g protein-coupled receptor fm-4/tgr-1, which was identified to date as the neuromedin u (nmu) receptor, and designate this peptide 'neuromedin s (nms)' because it is specifically expressed in the suprachiasmatic nuclei (scn) of the hypothalamus." SIGNOR-133074 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 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 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 RHOA protein P61586 UNIPROT "down-regulates activity" phosphorylation Ser188 ARRGKKKsGCLVL 10090 BTO:0000944 12654918 t miannu "PKA phosphorylates RhoA on Ser188. the addition of a negative charge to Ser188 is sufficient to diminish both RhoA activation and activity within the context of a cell." SIGNOR-250047 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 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 SCF-betaTRCP complex SIGNOR-C5 SIGNOR WEE1 protein P30291 UNIPROT down-regulates binding 9606 15340381 t lperfetto "Scfb-trcp continues to have a role in this phase, however, through its induced degradation of the cdk1 inhibitor, wee1." SIGNOR-217184 UCHL5 protein Q9Y5K5 UNIPROT SMAD2 protein Q15796 UNIPROT "up-regulates activity" deubiquitination 9606 16027725 t lperfetto "Here, we report a novel interaction between smads and ubiquitin c-terminal hydrolase uch37, a deubiquitinating enzyme that could potentially reverse smurf-mediated ubiquitination. In gst pull down experiments, uch37 bound weakly to smad2 and smad3, and bound very strongly to smad7 in a region that is distinct from the -py- motif in smad7 that interacts with smurf ubiquitin ligases" SIGNOR-217610 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 UVRAG protein Q9P2Y5 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 18843052 t lperfetto "Although both human atg14 and uvrag interact with beclin 1 and vps34." SIGNOR-181554 YWHAQ protein P27348 UNIPROT MEF2D protein Q14814 UNIPROT up-regulates binding 9606 BTO:0000887 11433030 t gcesareni "14-3-3tau associates with and activates the mef2d transcription factor during muscle cell differentiation." SIGNOR-109139 ATM protein Q13315 UNIPROT WRN protein Q14191 UNIPROT unknown phosphorylation Ser1141 PEKAYSSsQPVISAQ -1 10608806 t llicata "We determined a general phosphorylation consensus sequence for ATM and identified putative in vitro targets by using glutathione S-transferase peptides as substrates. Putative ATM in vitro targets include p95/nibrin, Mre11, Brca1, Rad17, PTS, WRN, and ATM (S440) itself." SIGNOR-250577 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 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 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 TRAF2 protein Q12933 UNIPROT MAP3K14 protein Q99558 UNIPROT "down-regulates quantity by destabilization" binding 10090 BTO:0000785 15084608 t lperfetto "We report here that one important mechanism of nik regulation is through its dynamic interaction with the tumor necrosis factor receptor-associated factor 3 (traf3). Traf3 physically associates 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-124233 "3',5'-cyclic AMP" smallmolecule CHEBI:17489 ChEBI PRKACA protein P17612 UNIPROT up-regulates "chemical activation" 9606 BTO:0000007 22863277 t milica "The cAMP signaling cascade can activate protein kinase a (PKA)" SIGNOR-198492 PHB2 protein Q99623 UNIPROT MEF2A protein Q02078 UNIPROT down-regulates binding 10090 BTO:0000165 BTO:0000887 15173318 t lperfetto "Phb2 interacts with both myod and mef2, and represses both myod- and mef2-dependent gene transcription. Furthermore, binding of phb2 to both myod and mef2 significantly decreases upon myogenic differentiation." SIGNOR-235840 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 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 SRC protein P12931 UNIPROT CDH2 protein P19022 UNIPROT down-regulates phosphorylation Tyr852 NDPTAPPyDSLLVFD 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-143234 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 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 DYRK1B protein Q9Y463 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103 15546868 f lperfetto "Mirk activated mef2 not through direct phosphorylation of mef2 but by phosphorylation of its inhibitors, the class ii histone deacetylases (hdacs). Mef2 is sequestered by class ii hdacs such as hdac5 and mef2-interacting transcriptional repressor (mitr). Mirk antagonized the inhibition of mef2c by mitr, whereas kinase-inactive mirk was ineffective. Mirk phosphorylates class ii hdacs at a conserved site within the nuclear localization region, reducing their nuclear accumulation in a dose-dependent and kinase-dependent manner" SIGNOR-235816 IGF1 protein P05019 UNIPROT PPP3CC protein P48454 UNIPROT up-regulates 10090 BTO:0000165;BTO:0002314 BTO:0000887;BTO:0001103;BTO:0001760 10448861 f 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-235828 IRF3 protein Q14653 UNIPROT Interferon_Production phenotype SIGNOR-PH16 SIGNOR up-regulates 10090 BTO:0002572 20610653 f lperfetto "Type 1 IFNs are induced in a cell type-specific manner through Toll-like receptor and RIG-I-like receptor pathways, both of which activate interferon regulatory factors (IRFs) and nuclear factor _B (NF-_B) transcription factors." SIGNOR-126962 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 SHH protein Q15465 UNIPROT PTCH1 protein Q13635 UNIPROT "down-regulates activity" binding 9606 15618519 t lperfetto "Binding of sonic hedgehog (shh) to patched (ptc) relieves the latter's tonic smoothened (smo), a receptor that spans the cell membrane seven times. .Ptch Exists in vertebrates as two isoforms, ptch1 and ptch2, which seem to be equivalent in terms of binding the three hh isoforms." SIGNOR-132675 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 SUFU protein Q9UMX1 UNIPROT GLI3 protein P10071 UNIPROT "down-regulates activity" relocalization 10090 10433919 t lperfetto "Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: implication of Gli2 and Gli3 as primary mediators of Shh signaling" SIGNOR-129068 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 MAPK14 protein Q16539 UNIPROT TAB1 protein Q15750 UNIPROT "down-regulates activity" phosphorylation Ser423 QMVNGAHsASTLDEA 9606 19393267 t lperfetto "Egfr-mediated phosphorylation of tab1 was completely inhibited by a chemical inhibitor and sirna of p38alpha. The phosphorylation of tab1 was occurred at ser-423 and thr-431, the residues underlying the p38-mediated feedback inhibition of tak1." SIGNOR-185580 MAPK14 protein Q16539 UNIPROT TAB1 protein Q15750 UNIPROT "down-regulates activity" phosphorylation Thr431 ASTLDEAtPTLTNQS 9606 19393267 t lperfetto "Egfr-mediated phosphorylation of tab1 was completely inhibited by a chemical inhibitor and sirna of p38alpha. The phosphorylation of tab1 was occurred at ser-423 and thr-431, the residues underlying the p38-mediated feedback inhibition of tak1." SIGNOR-185584 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 RANBP3 protein Q9H6Z4 UNIPROT SMAD2 protein Q15796 UNIPROT "down-regulates activity" relocalization 9606 20704570 t lperfetto "Importantly, PPM1A facilitates the interaction of dephosphorylated Smad2/3 with RanBP3, a nuclear export factor [75]. As a result, PPM1A-mediated dephosphorylation of Smad2/3 promotes nuclear export of Smad2/3 and shuts off TGF-_-induced anti-proliferative and transcriptional responses" SIGNOR-217625 RIPK1 protein Q13546 UNIPROT IKBKG protein Q9Y6K9 UNIPROT "up-regulates activity" binding 9606 BTO:0000661 16603398 t lperfetto "Interestingly, polyubiquitinated rip1 recruits ikk through the binding between the polyubiquitin chains and nemo, a regulatory subunit of the ikk complex. Mutations of nemo that disrupt its polyubiquitin binding also abolish ikk activation." SIGNOR-145858 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 TNFSF13B protein Q9Y275 UNIPROT TNFRSF13C protein Q96RJ3 UNIPROT "up-regulates activity" binding 9606 BTO:0000776 15644327 t lperfetto "Baff interacts with baff receptor (baffr)." SIGNOR-133210 TNFSF13B protein Q9Y275 UNIPROT TNFRSF13C protein Q96RJ3 UNIPROT "up-regulates activity" binding 9606 BTO:0000782 15851487 t lperfetto "Baff specifically binds baff receptor" SIGNOR-135713 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 MAPK14 protein Q16539 UNIPROT USF1 protein P22415 UNIPROT "up-regulates activity" phosphorylation Thr153 EALLGQAtPPGTGQF 9606 19389701 t lperfetto "Following uv irradiation, usf-1 is phosphorylated by the p38 stress-activated kinase on threonine 153 and directly up-regulates expression of the pomc, mc1r, tyr, tyrp-1 and dct genes" SIGNOR-185572 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 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 PLK1 protein P53350 UNIPROT SNCA protein P37840 UNIPROT up-regulates phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 BTO:0000142 21849493 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-176063 TNFRSF1B protein P20333 UNIPROT TRAF1 protein Q13077 UNIPROT up-regulates binding 9606 8069916 t gcesareni "Traf1 interacts with tnf-r2 indirectly through heterodimer formation with traf2." SIGNOR-33133 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 KNL1 protein Q8NG31 UNIPROT BUB1 protein O43683 UNIPROT up-regulates binding 9606 17981135 t gcesareni "Association of the amino and middle domain of blinkin with the tpr domains in the amino termini of bubr1 and bub1 is essential for bubr1 and bub1 to execute their distinct mitotic functions" SIGNOR-158378 MAPK14 protein Q16539 UNIPROT MYOD1 protein P15172 UNIPROT "up-regulates activity" 9606 BTO:0000887;BTO:0001103 15466486 f lperfetto "Here, we show that p38 activity facilitates myod and mef2 binding at a subset of late-activated promoters, and the binding of mef2d recruits pol ii." SIGNOR-129702 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0003316 10781582 t lperfetto "Serine 15 phosphorylation of p53 leads to a stabilization of p53 by reducing its interaction with murine double minute 2, a negative regulatory partner[...]These results strongly suggest that both ERKs and p38 kinase have a direct role in UVB-induced phosphorylation of p53 at serine 15 in vivo." SIGNOR-226614 PRKACA protein P17612 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser16 KELEKRAsGQAFELI 9606 BTO:0000142 8376365 t gcesareni "Phosphorylation at either ser(16) or ser(63) strongly reduced or abolished the ability of stathmin to bind to and sequester soluble tubulin and its ability to act as a catastrophe factor by directly binding to the microtubules. The known in vivo phosphorylation sites of stathmin are ser-16 and ser-63 for cyclic amp-dependent protein kinase (pka)." SIGNOR-38318 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 EPHA3 protein P29320 UNIPROT "down-regulates activity" dephosphorylation Tyr779 EDDPEAAyTTRGGKI 9606 21135139 t "Nevertheless, the finding that phosphorylation of the activation loop tyrosine (EphA3-Y779), a recently identified PTP1B substrate (Mertins et al., 2008), is essential for ligand-induced endocytosis (Janes et al., 2009)" SIGNOR-248426 PTPN1 protein P18031 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-248419 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 PTPRF protein P10586 UNIPROT FYN protein P06241 UNIPROT down-regulates dephosphorylation Tyr420 RLIEDNEyTARQGAK 9606 BTO:0000661 BTO:0000142;BTO:0000671 12496362 t lperfetto "Regulation of lck and fyn tyrosine kinase activities by transmembrane protein tyrosine phosphatase leukocyte common antigen-related molecule." SIGNOR-96768 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 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 RSPO3 protein Q9BXY4 UNIPROT SDC4 protein P31431 UNIPROT up-regulates binding 9606 21397842 t gcesareni "Here, we show that rspo3 binds syndecan 4 (sdc4) and that together they activate wnt/pcp signaling." SIGNOR-172756 RUNX2 protein Q13950 UNIPROT COL1A1 protein P02452 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11331591 f "Osteoblast-like cell lines" lpetrilli "In addition to osteocalcin, cbfa1 regulates expression of several other genes that are activated during osteoblast differentiation, including alkaline phosphatase, a1 and a2 collagen, osteopontin and osteoprotegerin ligand." SIGNOR-107163 "1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate" smallmolecule CHEBI:16618 ChEBI WIPI2 protein Q9Y4P8 UNIPROT up-regulates binding 9606 22082875 t gcesareni "We identified the human wipi protein family and found that wipi-1 specifically binds ptdins(3)p, accumulates at the phagophore and becomes a membrane protein of generated autophagosomes." SIGNOR-177226 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT "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-249682 DYRK1A protein Q13627 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Ser272 EEPSPLPsPTASPNH 9606 BTO:0000142 15262992 t lperfetto "Recent studies show that phosphorylation of amphiphysin1 prd by cdk5 inhibited the association of amphiphysin1 with ap-2 in synaptic vesicle endocytosis (7, 8) similar to that by mapk (present report). Cdk5 appears to phosphorylate amphiphysin1 at serines 261, 272, 276, and 285 and threonine 310, located in the prd" SIGNOR-126843 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 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 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 PTCRA protein Q6ISU1 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" binding 9606 BTO:0000782 1717999 t lperfetto "Stimulation of the T-cell antigen receptor (TCR) leads to tyrosine phosphorylation of a number of cellular proteins, including phospholipase C (PLC) gamma 1 and the TCR zeta chain. We describe here a 70-kDa tyrosine phosphoprotein (ZAP-70) that associates with zeta within 15 sec following TCR stimulation. The phosphorylation of ZAP-70 and its association with zeta is independent of the other TCR chains" SIGNOR-134325 SIK2 protein Q9H0K1 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates phosphorylation Ser171 SALNRTSsDSALHTS 9606 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-142218 PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT "up-regulates activity" phosphorylation Ser241 SKQARANsFVGTAQY 9606 BTO:0000007 11481331 t miannu "In terms of the modulation of PDK1 activity by reversible phosphorylation, five pS sites have been identified on PDK1 in vivo, but only one of these sites, Ser-241 in the activation loop of PDK1, is essential for activity. It seems likely that PDK1 autophosphorylates itself on this residue." SIGNOR-250268 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 PRKACA protein P17612 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser63 AAEERRKsHEAEVLK 9606 BTO:0000142 8376365 t gcesareni "Phosphorylation at either ser(16) or ser(63) strongly reduced or abolished the ability of stathmin to bind to and sequester soluble tubulin and its ability to act as a catastrophe factor by directly binding to the microtubules. The known in vivo phosphorylation sites of stathmin are ser-16 and ser-63 for cyclic amp-dependent protein kinase (pka)." SIGNOR-38322 PRKDC protein P78527 UNIPROT DCLRE1C protein Q96SD1 UNIPROT up-regulates phosphorylation Ser516 SSTVAGGsQSPKLFS 9606 16600297 t lperfetto "Artemis is a nuclear phosphoprotein required for genomic integrity whose phosphorylation is increased subsequent to dna damage. Artemis phosphorylation by the dna-dependent protein kinase (dna-pk). However, regardless of its association with dna-pkcs, phosphorylation of artemis at both s516 and s645 was stimulated in response to the double-stranded dna-damaging agent bleomycin" SIGNOR-145837 CDK2 protein P24941 UNIPROT FOXO1 protein Q12778 UNIPROT 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-150028 MAP3K1 protein Q13233 UNIPROT MAP2K1 protein Q02750 UNIPROT "up-regulates activity" phosphorylation Ser218 VSGQLIDsMANSFVG 10090 BTO:0000944 8131746 t lperfetto "Phosphorylation at ser-218 and ser-222 by map kinase kinase kinases (raf or mekk1) positively regulates mek1 kinase activity." SIGNOR-235587 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 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 PTPN6 protein P29350 UNIPROT NTRK1 protein P04629 UNIPROT "down-regulates activity" dephosphorylation Tyr681 DIYSTDYyRVGGRTM 10116 BTO:0001009 "phosphorylation: tyr496" HIIENPQyFSDACVH 14662744 t "Here, we identify SHP-1 as a phosphotyrosine phosphatase that negatively regulates TrkA. SHP-1 formed complexes with TrkA at Y490, and dephosphorylated it at Y674/675." SIGNOR-248469 PTPRF protein P10586 UNIPROT RET protein P07949 UNIPROT down-regulates dephosphorylation Tyr1062 TWIENKLyGMSDPNW 9606 11121408 t gcesareni "Lar expression significantly reduced tyrosine-1062 phosphorylation in ret-men2a but not in ret-men2b" SIGNOR-85170 SFRP1 protein Q8N474 UNIPROT WNT1 protein P04628 UNIPROT down-regulates binding 9606 BTO:0000782 10347172 t gcesareni "Frp inhibits wnt signaling through interactions with wnt and/or formation of nonfunctional complexes with the frizzled receptor. here we demonstrate that frza, a sfrp that is highly expressed in vascular endothelium and a variety of epithelium, specifically binds to wnt-1 protein, but not wnt-5a protein, and modulates wnt-1 signaling." SIGNOR-67806 SIRT7 protein Q9NRC8 UNIPROT TP53 protein P04637 UNIPROT down-regulates deacetylation 9606 18239138 t gcesareni "We found that sirt7 interacts with p53 and efficiently deacetylates p53 in vitro, which corresponds to hyperacetylation of p53 in vivo." SIGNOR-160539 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 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 ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT "up-regulates activity" phosphorylation Ser1387 EDCSGLSsQSDILTT 9606 BTO:0000773 11278964 t lperfetto "Brca1 is phosphorylated at ser-1423 and ser-1524 after ir and uv;however, ser-1387 is specifically phosphorylated after ir, and ser-1457 is predominantly phosphorylated after uv.atr controls brca1 phosphorylation in vivo. Taken together, our results support a model in which atm and atr act in parallel but somewhat overlapping pathways of dna damage signaling but respond primarily to different types of dna lesion." SIGNOR-106432 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 BMPR2 protein Q13873 UNIPROT BMPR1B protein O00238 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C29 SIGNOR-C29 18756288 t gcesareni "Bmp ligands bind to the bmp receptors bmpr1 and bmpr2, and bmpr2 then phosphorylates and activates bmpr1." SIGNOR-180548 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 ILK protein Q13418 UNIPROT MYL12B protein O14950 UNIPROT "up-regulates activity" phosphorylation Ser20 KRPQRATsNVFAMFD 9606 BTO:0000887;BTO:0001260 11278951 t lperfetto "Integrin-linked kinase cdna was cloned, sequenced, expressed in e. coli, and shown to phosphorylate myosin light chain in the absence of ca(2+) at ser(19) and thr(18). Smooth muscle contraction follows an increase in cytosolic Ca(2+) concentration, activation of myosin light chain kinase, and phosphorylation of the 20-kDa light chain of myosin at Ser(19)." SIGNOR-106423 KMT2D protein O14686 UNIPROT ESR1 protein P03372 UNIPROT up-regulates binding 9606 16603732 t miannu "A novel estrogen receptor (er)alpha coactivator complex, the mll2 complex, which consists of mll2, ash2, rbq3, and wdr5, was identified / disrupting the interaction between eralpha and the mll2 complex with small interfering rnas specific against mll2 or an mll2 fragment representing the interacting region with eralpha significantly inhibited the eralpha transcription activity." SIGNOR-145865 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 PELI1 protein Q96FA3 UNIPROT IRAK1 protein P51617 UNIPROT "up-regulates quantity by expression" ubiquitination 9606 17997719 t lperfetto "These results were consistent with the observations made in vitro, namely that pellino isoforms are activated by irak1-catalysed phosphorylation and that, once activated, can ubiquitinate irak1 in cells." SIGNOR-159055 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 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 SRC protein P12931 UNIPROT KIT protein P10721 UNIPROT "up-regulates activity" phosphorylation Tyr900 EHAPAEMyDIMKTCW 9606 12878163 t lperfetto "C-src phosphorylates tyr900 in the second part of the kinase domain of c-kit." SIGNOR-103999 STK24 protein Q9Y6E0 UNIPROT STK24 protein Q9Y6E0 UNIPROT up-regulates phosphorylation Thr190 DTQIKRNtFVGTPFW 9606 BTO:0000671 17046825 t gcesareni "Inhibition of cell migration by autophosphorylated mammalian sterile 20-like kinase 3 (mst3) involves paxillin and protein-tyrosine phosphatase-pest." SIGNOR-150131 STUB1 protein Q9UNE7 UNIPROT SMAD5 protein Q99717 UNIPROT down-regulates ubiquitination 9606 21454478 t gcesareni "In addition, some proteins (e.g. Chip, carboxyl terminus of hsc70-interacting protein) inhibit the signaling activities of smad1/5 by recruiting smad1/5 from the functional r/co-smad complex and further promoting the ubiquitination and degradation of smad1/5 in a chaperone-independent manner" SIGNOR-172996 TP53 protein P04637 UNIPROT MDM2 protein Q00987 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 7958853 f gcesareni "The p53 tumor suppressor protein trans-activates mdm2 itself, which is therefore considered a component of a p53 negative feedback loop." SIGNOR-34962 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 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 DYRK1A protein Q13627 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Thr310 VPPLPKVtPTKELQQ 9606 BTO:0000142 15262992 t lperfetto "Recent studies show that phosphorylation of amphiphysin1 prd by cdk5 inhibited the association of amphiphysin1 with ap-2 in synaptic vesicle endocytosis (7, 8) similar to that by mapk (present report). Cdk5 appears to phosphorylate amphiphysin1 at serines 261, 272, 276, and 285 and threonine 310, located in the prd" SIGNOR-126855 EXTL1 protein Q92935 UNIPROT SHH protein Q15465 UNIPROT down-regulates binding 9606 BTO:0000142 15614771 t gcesareni "A study in mice suggests that ext1 proteins might negatively regulate shh signaling by synthesizing hspgs, which sequester the ligand" SIGNOR-132606 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 CALM1 protein P62158 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 CDON protein Q4KMG0 UNIPROT SPAG9 protein O60271 UNIPROT "up-regulates activity" binding 9606 BTO:0000222 17074887 t lperfetto "In this study, we report that the cdo intracellular region interacts with jlp, a scaffold protein for the p38alpha/beta mapk pathway." SIGNOR-150282 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 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 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 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 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 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 PRKDC protein P78527 UNIPROT DCLRE1C protein Q96SD1 UNIPROT up-regulates phosphorylation Ser645 NLSTNADsQSSSDFE 9606 16600297 t lperfetto "Artemis is a nuclear phosphoprotein required for genomic integrity whose phosphorylation is increased subsequent to dna damage. Artemis phosphorylation by the dna-dependent protein kinase (dna-pk). However, regardless of its association with dna-pkcs, phosphorylation of artemis at both s516 and s645 was stimulated in response to the double-stranded dna-damaging agent bleomycin" SIGNOR-145841 RUNX2 protein Q13950 UNIPROT BGLAP protein P02818 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11331591 f gcesareni "Tgf-beta inhibited the expression of the cbfa1 and osteocalcin genes, whose expression is controlled by cbfa1 in osteoblast-like cell lines. This inhibition was mediated by smad3, which interacts physically with cbfa1 and represses its transcriptional activity at the cbfa1-binding ose2 promoter sequence" SIGNOR-107160 TAOK2 protein Q9UL54 UNIPROT MAP2K3 protein P46734 UNIPROT "up-regulates activity" phosphorylation Ser218 ISGYLVDsVAKTMDA 9606 BTO:0000007 11279118 t lperfetto "Suggesting that tao2 selectively activates mek3 and mek6 of the p38 pathway in intact cells" SIGNOR-106462 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 PLK1 protein P53350 UNIPROT CENPU protein Q71F23 UNIPROT down-regulates phosphorylation Ser77 TFDPPLHsTAIYADE 9606 17081991 t lperfetto "S77 and t78 of pbip1 are important for plk1-dependent pbip1 phosphorylation and degradation. Here, we demonstrate that a pbd-binding protein, pbip1, is crucial for recruiting plk1 to the interphase and mitotic kinetochores. Unprecedentedly, plk1 phosphorylated pbip1 at t78. Later in mitosis, plk1 also induced pbip1 degradation in a t78-dependent manner, thereby enabling itself to interact with other components critical for proper kinetochore functions" SIGNOR-150453 PLK1 protein P53350 UNIPROT CENPU protein Q71F23 UNIPROT down-regulates phosphorylation Thr78 FDPPLHStAIYADEE 9606 17081991 t lperfetto "S77 and t78 of pbip1 are important for plk1-dependent pbip1 phosphorylation and degradation. Here, we demonstrate that a pbd-binding protein, pbip1, is crucial for recruiting plk1 to the interphase and mitotic kinetochores. Unprecedentedly, plk1 phosphorylated pbip1 at t78. Later in mitosis, plk1 also induced pbip1 degradation in a t78-dependent manner, thereby enabling itself to interact with other components critical for proper kinetochore functions" SIGNOR-150457 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 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 GUCY1A3 protein Q02108 UNIPROT GUCY1A3-B2 complex SIGNOR-C139 SIGNOR "form complex" binding 9606 10977868 t gcesareni "This enzyme is a heterodimeric protein consisting of - and ²-subunits, and expression of both subunits is required for catalytic activity" SIGNOR-244116 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 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 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 MAPK1 protein P28482 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Ser293 PAPARPRsPSQTRKG 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-126859 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 THEM4 protein Q5T1C6 UNIPROT AKT1 protein P31749 UNIPROT down-regulates binding 9606 11598301 t gcesareni "Here, we describe a protein partner for pkbalpha termed ctmp, or carboxyl-terminal modulator protein, that binds specifically to the carboxyl-terminal regulatory domain of pkbalpha at the plasma membrane. Binding of ctmp reduces the activity of pkbalpha by inhibiting phosphorylation on serine 473 and threonine 308." SIGNOR-111003 CLK4 protein Q9HAZ1 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-181052 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 LCK protein P06239 UNIPROT LCP2 protein Q13094 UNIPROT unknown phosphorylation Tyr423 NSLNEEWyVSYITRP -1 8702662 t "Ability of p56lck to phosphorylate Tyr-423/426 within SLP-76 in vitro" SIGNOR-251381 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 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 PASK protein Q96RG2 UNIPROT PASK protein Q96RG2 UNIPROT "up-regulates activity" phosphorylation Thr1165 LFYTFCGtIEYCAPE -1 11459942 t lperfetto "We present evidence that the activity of pask is regulated by two mechanisms. Autophosphorylation at two threonine residues located within the activation loop significantly increases catalytic activity." SIGNOR-109485 PTPN6 protein P29350 UNIPROT NTRK1 protein P04629 UNIPROT "down-regulates activity" dephosphorylation Tyr680 RDIYSTDyYRVGGRT 10116 BTO:0001009 "phosphorylation: tyr496" HIIENPQyFSDACVH 14662744 t "Here, we identify SHP-1 as a phosphotyrosine phosphatase that negatively regulates TrkA. SHP-1 formed complexes with TrkA at Y490, and dephosphorylated it at Y674/675." SIGNOR-248468 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 "RNA helicases p68/p72" complex SIGNOR-C34 SIGNOR MYOD1 protein P15172 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103 17011493 t miannu "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-149967 SKP2 protein Q13309 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates ubiquitination 9606 17409098 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-154194 SET protein Q01105 UNIPROT PPP2CB protein P62714 UNIPROT down-regulates binding 9606 BTO:0000142 21806989 t miannu "Here we report that both the amino terminal fragment (i(2ntf);aa 1-175) and the carboxy terminal fragment (i(2ctf);aa 176-277) of i(2)(pp2a) inhibit pp2a by binding to its catalytic subunit pp2ac" SIGNOR-175722 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 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 MAPK3 protein P27361 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Thr581 PDNQPLKtPCFTLHY 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-131383 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 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 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 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 SHH protein Q15465 UNIPROT CP protein P00450 UNIPROT down-regulates binding 9606 17419683 t gcesareni "Binding of sonic hedgehog (shh) to patched (ptc) relieves the latter's tonic smoothened (smo), a receptor that spans the cell membrane seven times. Ptch exists in vertebrates as two isoforms, ptch1 and ptch2, which seem to be equivalent in terms of binding the three hh isoforms." SIGNOR-154285 SMAD2 protein Q15796 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates binding 10090 BTO:0000165 BTO:0001760 SIGNOR-C8 11160896 t lperfetto "Our studies indicate that smad2 and 4 (smad2/4) complexes cooperate with mef2 regulatory proteins in a gal4-based one-hybrid reporter gene assay." SIGNOR-235846 SMARCD3 protein Q6STE5 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 indire" SIGNOR-136945 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 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 CDK5 protein Q00535 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-198111 CDO1 protein Q16878 UNIPROT SHH protein Q15465 UNIPROT up-regulates binding 9606 BTO:0000887 16647304 t gcesareni "Cdo and boc bind shh through a high-affinity interaction with a specific fibronectin repeat that is essential for activity. We propose a model where cdo and boc enhance shh signaling within its target field." SIGNOR-146461 CTNNBIP1 protein Q9NSA3 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates activity" binding -1 12408824 t llicata "The crystal structure of the beta-catenin/ICAT complex reveals the inhibitory mechanism of ICAT." SIGNOR-238012 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 CDON protein Q4KMG0 UNIPROT BNIP2 protein Q12982 UNIPROT "up-regulates activity" binding 9606 BTO:0000222 18678706 t lperfetto "Bnip-2 and jlp are brought together through mutual interaction with cdo. the cdo-bnip-2 interaction stimulates cdc42 activity, which in turn promotes p38alpha/beta activity and cell differentiation." SIGNOR-179864 PAX7 protein P23759 UNIPROT Quiescence phenotype SIGNOR-PH25 SIGNOR up-regulates 9606 BTO:0000887 15843801 f gcesareni "We have identified a new cell population that expresses the transcription factors pax3 and pax7 (paired box proteins 3 and 7) but no skeletal-muscle-specific markers." SIGNOR-135626 PCM1 protein Q15154 UNIPROT PCNT protein O95613 UNIPROT up-regulates relocalization 9606 12403812 t miannu "Rna silencing of pcm-1 leads to reduced assembly of centrin, pericentrin, and ninein at the centrosome" SIGNOR-95117 CSNK2A1 protein P68400 UNIPROT FHOD3 protein Q2V2M9 UNIPROT down-regulates phosphorylation 9606 BTO:0000887 21149568 t tpavlidou "We have identified a novel striated muscle-specific splice variant of the formin fhod3 that introduces a casein kinase 2 (ck2) phosphorylation site. The specific targeting of muscle fhod3 to the myofibrils in cardiomyocytes is abolished in phosphomutants or by the inhibition of ck2. Phosphorylation of muscle fhod3 also prevents its interaction with p62/sequestosome 1 and its recruitment to autophagosomes." SIGNOR-170525 DAPK1 protein P53355 UNIPROT RPL5 protein P46777 UNIPROT unknown phosphorylation 9606 BTO:0000007;BTO:0000567 18283219 t lperfetto "Here we adapted this strategy to successfully screen for dapk substrates. We report the identification of two substrates, ribosomal protein l5 and mcm3." SIGNOR-160954 N-(5-{[(5-tert-butyl-1,3-oxazol-2-yl)methyl]sulfanyl}-1,3-thiazol-2-yl)piperidine-4-carboxamide chemical CHEBI:91399 ChEBI CDK9 protein P50750 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207090 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 NRG3 protein P56975 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 BTO:0000887 9275162 t gcesareni "The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4." SIGNOR-50614 "2-[[(1R)-1-[7-methyl-2-(4-morpholinyl)-4-oxo-9-pyrido[1,2-a]pyrimidinyl]ethyl]amino]benzoic acid" chemical CHEBI:91359 ChEBI PIK3CB protein P42338 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190200 HNF4A protein P41235 UNIPROT G6PC 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 PBRM1 protein Q86U86 UNIPROT S100A13 protein Q99584 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000562 15601824 f miannu "We found that baf180 deficiency leads to a decreased expression of select target genes, such as s100a13 and ra targets rar_2 and crabpii in heart tissues." SIGNOR-132431 RPA2 protein P15927 UNIPROT MRE11 protein P49959 UNIPROT up-regulates binding 9606 19586055 t fstefani "The response to replication stress requires the recruitment of rpa and the mre11-rad50-nbs1 (mrn) complex." SIGNOR-186648 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 LCK protein P06239 UNIPROT LCP2 protein Q13094 UNIPROT unknown phosphorylation Tyr426 NEEWYVSyITRPEAE -1 8702662 t "Ability of p56lck to phosphorylate Tyr-423/426 within SLP-76 in vitro" SIGNOR-251382 MAP3K20 protein Q9NYL2 UNIPROT MAP2K4 protein P45985 UNIPROT "up-regulates activity" phosphorylation 9606 11416147 t gcesareni "We show here that members of the mixed-lineage kinase (MLK) family (including MLK1, MLK2, MLK3, and dual leucine zipper kinase [DLK]) are expressed in neuronal cells and are likely to act between Rac1/Cdc42 and MKK4 and -7 in death signaling." SIGNOR-243348 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 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 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 PRKACA protein P17612 UNIPROT GLI2 protein P10070 UNIPROT down-regulates phosphorylation 9606 16885213 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-148478 resveratrol smallmolecule CHEBI:27881 ChEBI SIRT1 protein Q96EB6 UNIPROT "up-regulates activity" binding -1 12939617 t gcesareni "We show that the potent activator resveratrol, a polyphenol found in red wine, lowers the Michaelis constant of SIRT1 for both the acetylated substrate and NAD(+), and increases cell survival by stimulating SIRT1-dependent deacetylation of p53" SIGNOR-238786 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 AMPK complex SIGNOR-C15 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR "down-regulates activity" phosphorylation 9606 23863160 t lperfetto "AMPK inhibits mTORC1 through two means: first, through phosphorylation of TSC2 to activate its GAP (GTPase-activating protein) activity that converts Rheb into an inactive GDP-bound state, thus switching off mitogenic stimulation of mTORC1 [31], and, secondly, through phosphorylation of raptor at Ser722 and Ser792, which leads to 14-3-3 protein binding and mTORC1 inhibition" SIGNOR-209862 ACVR1 protein Q04771 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation 9606 9748228 t fspada "Bmp7 stimulated phosphorylation of endogenous smad1 and 5, formation of complexes with smad4 and induced the promoter for the homeobox gene, tlx2" SIGNOR-60174 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 DDB1 protein Q16531 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-54093 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 1038915-60-4 chemical CID:24958200 PUBCHEM PARP2 protein Q9UGN5 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194402 CAY10505 chemical CID:1204893 PUBCHEM PIK3CG protein P48736 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190859 CDK3 protein Q00526 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 19118012 t gcesareni "Egf-induced cdk3 activation caused c-jun phosphorylation at ser63 and ser73, resulting in increased ap-1 transactivation." SIGNOR-183009 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR SF3B1 protein O75533 UNIPROT up-regulates phosphorylation Thr244 GRAKGSEtPGATPGS 9606 12105215 t lperfetto "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 phosphopeptide). Three phosphorylation sites were identified as thr244, thr248, and thr313" SIGNOR-216686 DNMT3A protein Q9Y6K1 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-90842 5,15-Diphenyl-21H,23H-porphine chemical CID:10895852 PUBCHEM STAT3 protein P40763 UNIPROT "down-regulates activity" "chemical inhibition" 9606 26260587 t gcesareni "15-DPP is an effective STAT3 inhibitor and blocks IL10-mediated signalling in macrophages leading to altered regulation of CNV" SIGNOR-238549 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 IC-87114 chemical CHEBI:90686 ChEBI PIK3CG protein P48736 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206193 3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-3-piperidinyl]-2-thiophenecarboxamide chemical CHEBI:131156 ChEBI CHEK1 protein O14757 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190203 ARRY-520 chemical CID:44224257 PUBCHEM KIF11 protein P52732 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189891 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 ENOBOSARM chemical CID:11326715 PUBCHEM AR protein P10275 UNIPROT up-regulates "chemical activation" 9606 Other t Selleck gcesareni SIGNOR-195892 "ER stress" stimulus SIGNOR-ST9 SIGNOR BCL2L11 protein O43521 UNIPROT up-regulates 9606 22492984 f gcesareni "Exposure to stress results in the induction of bh3-only proteins, which neutralise the pro-survival proteins" SIGNOR-196941 "ER stress" stimulus SIGNOR-ST9 SIGNOR BID protein P55957 UNIPROT up-regulates 9606 22492984 f gcesareni "Exposure to stress results in the induction of bh3-only proteins, which neutralise the pro-survival proteins" SIGNOR-196944 AT9283 chemical CID:11696609 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190014 AT9283 chemical CID:11696609 PUBCHEM JAK2 protein O60674 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190017 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 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 AV412 chemical CID:11700696 PUBCHEM EGFR protein P00533 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190050 AV412 chemical CID:11700696 PUBCHEM ERBB2 protein P04626 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190053 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 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 MEF2D protein Q14814 UNIPROT MYF6 protein P23409 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165;BTO:0000222 7739551 t lperfetto "Myogenin and MEF2 function synergistically to activate the MRF4 promoter during myogenesis." SIGNOR-238715 RPS6KA1 protein Q15418 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000007 10558990 t lperfetto "The rsks catalyze the phosphorylation of the pro-apoptotic protein bad at serine 112 to promote cell survival." SIGNOR-180910 sapitinib chemical CHEBI:132986 ChEBI EGFR protein P00533 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190149 SMURF1 protein Q9HCE7 UNIPROT SMAD4 protein Q13485 UNIPROT "down-regulates activity" ubiquitination 9606 BTO:0002181 15817471 t "In the presence of smad6 or smad7 acting as adaptors" lperfetto "Smurfs, which otherwise cannot directly bind to smad4, mediated poly-ubiquitination of smad4 in the presence of smad6 or smad7. Smad signaling is negatively regulated by inhibitory (i) smads and ubiquitin-mediated processes." SIGNOR-236096 SP1 protein P08047 UNIPROT SP1/STAT3 complex SIGNOR-C74 SIGNOR "form complex" binding 9606 19723038 t miannu "Sp1 and stat3 seem to synergistically augment renalase transcription." SIGNOR-187790 TWIST1 protein Q15672 UNIPROT CSNK2A1 protein P68400 UNIPROT down-regulates 9606 22975381 f amattioni "Ck2-mediated phosphorylation at ser392 of p53 was attenuated in the presence of recombinant twist1" SIGNOR-192064 ZNRF3 protein Q9ULT6 UNIPROT LRP6 protein O75581 UNIPROT down-regulates ubiquitination 9606 22575959 t gcesareni "Znrf3 is associated with the wnt receptor complex, and inhibits wnt by promoting the turnover of frizzled and lrp6. Frizzled receptors are regu__lated by cycles of ubiquitylation and deubiquitylation, and znrf3 and rnf43 act as frizzled ubiquitin ligases, removing frizzled and possibly lrp6 from the plasma membrane." SIGNOR-197420 Avasimibe chemical CID:166558 PUBCHEM SOAT1 protein P35610 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190119 "AZ 960" chemical CID:25099184 PUBCHEM JAK2 protein O60674 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190128 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR ID2 protein Q02363 UNIPROT down-regulates phosphorylation Ser5 sPVRSVRK 9606 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-216698 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR MCM3 protein P25205 UNIPROT up-regulates phosphorylation Thr722 EEMPQVHtPKTADSQ 9606 21965652 t lperfetto "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-216694 luminespib chemical CHEBI:83656 ChEBI HSP90AB1 protein P08238 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190041 LFNG protein Q8NES3 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 BTO:0000975 12486116 t gcesareni "We demonstrate that egf 12, a portion of the ligand-binding site, is modified with o-fucose and that this site is evolutionarily conserved. We also show that endogenous fringe proteins in chinese hamster ovary cells (lunatic fringe and radical fringe) as well as exogenous manic fringe modify o-fucose on many but not all egf repeats of mouse notch1." SIGNOR-96537 "MYOD1/SWI/SNF complex" complex SIGNOR-C93 SIGNOR ATP2A1 protein O14983 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887 15870273 f miannu "Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material)" SIGNOR-136300 "MYOD1/SWI/SNF complex" complex SIGNOR-C93 SIGNOR BIN1 protein O00499 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887 15870273 f miannu "Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material)" SIGNOR-136399 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 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 "MYOD1/SWI/SNF complex" complex SIGNOR-C93 SIGNOR MYL4 protein P12829 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887 15870273 f miannu "Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material)" SIGNOR-136697 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 CREB1 protein P16220 UNIPROT G6PC 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 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-256108 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 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR SF3B1 protein O75533 UNIPROT unknown phosphorylation Thr313 HGSGWAEtPRTDRGG 9606 12105215 t lperfetto "We indeed found that sap155-(223_322) and sap155-(1_491) are excellent substrates for in vitrophosphorylation by cyclin e-cdk2 as well as cyclin b-cdk1" SIGNOR-216717 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 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 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 "bisindolylmaleimide i" chemical CID:2396 PUBCHEM PRKCA protein P17252 UNIPROT down-regulates "chemical inhibition" 9606 Other t CellSignaling gcesareni SIGNOR-190344 "bisindolylmaleimide i" chemical CID:2396 PUBCHEM PRKCB protein P05771 UNIPROT down-regulates "chemical inhibition" 9606 Other t CellSignaling gcesareni SIGNOR-190347 (E)-3-tosylacrylonitrile chemical CHEBI:85928 ChEBI PTPN1 protein P18031 UNIPROT down-regulates "chemical inhibition" 9606 Other t "The anti-inflammatory compound BAY 11-7082 is a potent inhibitor of Protein Tyrosine Phosphatases." gcesareni SIGNOR-190254 N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(4-fluorophenyl)sulfonyl-2-hydroxy-2-methylpropanamide chemical CHEBI:91617 ChEBI AR protein P10275 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190323 A-966492 chemical CID:16666333 PUBCHEM PARP2 protein Q9UGN5 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-203622 abiraterone chemical CHEBI:68642 ChEBI CYP17A1 protein P05093 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-204810 ARHGEF7 protein Q14155 UNIPROT LRRK2 protein Q5S007 UNIPROT up-regulates binding 9606 21048939 t gcesareni "Arhgef7 is interacting with lrrk2 in vitro and in vivo. Gtpase activity of full-length lrrk2 increases in the presence of recombinant arhgef7. Arhgef7 might act as a guanine nucleotide exchange factor for lrrk2" SIGNOR-169217 BCL2L1 protein Q07817 UNIPROT CASP9 protein P55211 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 9539746 t lperfetto "Bcl2l1 associates with casp9 and apaf-1 in mammalian cells.Bcl-XL interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation" SIGNOR-56402 CREB5 protein Q02930 UNIPROT DGKG protein P49619 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002811 21132541 f miannu "Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition)," SIGNOR-253804 BTRC protein Q9Y297 UNIPROT GLI3 protein P10071 UNIPROT "down-regulates quantity by destabilization" ubiquitination Lys800 LNPILPPkAPAVSPL 9606 BTO:0000938 17283082 t lperfetto "Third, we and others have recently shown that only phosphorylated Ci/Gli3 are able to directly bind Slimb/BetaTrCP, that Gli3 is polyubiquitinated in the cell, and that mutations of 4 lysine residues, the putative ubiquitination sites in the Gli3 C-terminal region, inhibit Gli3 processing These observations further support the notion that Ci/Gli3 processing is carried out by the proteasome because the deletion of the cleavage site is expected to often disrupt the protease-mediated site-specific cleavage." SIGNOR-249578 CHIR-124 chemical CID:11502647 PUBCHEM CHEK1 protein O14757 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190973 dacomitinib chemical CHEBI:132268 ChEBI ERBB4 protein Q15303 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205942 3-methyladenine chemical CHEBI:38635 ChEBI PIK3C3 protein Q8NEB9 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205636 3-methyladenine chemical CHEBI:38635 ChEBI PIK3CG protein P48736 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205639 "abiraterone acetate" chemical CHEBI:68639 ChEBI CYP17A1 protein P05093 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205573 N-(5-{[(5-tert-butyl-1,3-oxazol-2-yl)methyl]sulfanyl}-1,3-thiazol-2-yl)piperidine-4-carboxamide chemical CHEBI:91399 ChEBI CDK2 protein P24941 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207084 N-(5-{[(5-tert-butyl-1,3-oxazol-2-yl)methyl]sulfanyl}-1,3-thiazol-2-yl)piperidine-4-carboxamide chemical CHEBI:91399 ChEBI CDK7 protein P50613 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207087 NFKBIA protein P25963 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "down-regulates activity" binding 9606 BTO:0000567 9914500 t lperfetto "In nonstimulated cells, nf-kappab is present in the cytosol where it is complexed to its inhibitor ikappab however, we found that only one of the activities, namely the ikk1/2 complex, exists as a pre-assembled kinase-substrate complex in which the ikks are directly or indirectly associated with several nf-kappab-related and ikappab-related proteins: rela, relb, crel, p100, p105, ikappa balpha, ikappa bbeta and ikappa bepsilon." SIGNOR-64092 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 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 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 2-(2-amino-3-methoxyphenyl)chromen-4-one chemical CHEBI:77954 ChEBI MAP2K2 protein P36507 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205746 dacomitinib chemical CHEBI:132268 ChEBI EGFR protein P00533 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205936 dacomitinib chemical CHEBI:132268 ChEBI ERBB2 protein P04626 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205939 EAF1 protein Q96JC9 UNIPROT ELL protein P55199 UNIPROT up-regulates binding 9606 16006523 t miannu "Positive regulation of ell elongation activity depends on stable binding of eaf1 to the ell n terminus" SIGNOR-138516 FGA protein P02671 UNIPROT ITGAX protein P20702 UNIPROT up-regulates binding 9606 BTO:0000130 7679388 t gcesareni "To map the binding sites for four distinct ligands for mac-l: ic3b, fibrinogen, icam-1. __the i domain on the ot chain of mac-1 is an important recognition site for all four ligands." SIGNOR-31320 N-(3-methoxy-5-methyl-2-pyrazinyl)-2-[4-(1,3,4-oxadiazol-2-yl)phenyl]-3-pyridinesulfonamide chemical CHEBI:94573 ChEBI EDNRA protein P25101 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207902 PAFAH1B2 protein P68402 UNIPROT APP protein P05067 UNIPROT up-regulates 9606 23238734 f miannu "We provide evidence that the loss of pafah1b2 potently reduces a_ by promoting the degradation of its immediate precursor, the _ctf." SIGNOR-200188 PAK1 protein Q13153 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser339 PRGQRDSsYYWEIEA 9606 18775988 t gcesareni "P21-activated protein kinases (paks) are serine/threonine protein kinases that phosphorylate raf-1 at ser-338 and ser-339." SIGNOR-180812 "Sitagliptin phosphate monohydrate" chemical CID:11591741 PUBCHEM DPP4 protein P27487 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206923 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 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 AKT3 protein Q9Y243 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-164306 cabozantinib chemical CHEBI:72317 ChEBI MET protein P08581 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207845 pemetrexed chemical CHEBI:63616 ChEBI DHFR protein P00374 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205819 SIRT1 protein Q96EB6 UNIPROT EP300 protein Q09472 UNIPROT down-regulates deacetylation Lys1024 TELKTEIkEEEDQPS 9606 BTO:0000150 19047049 t gcesareni "Sirt1 induces deacetylation and repression of p300 itself (81). Mutational analysis demonstrated that sirt1 repression of p300 involves both lysine 1020 and lysine 1024" SIGNOR-182511 1-[4-[1-(1,4-dioxaspiro[4.5]decan-8-yl)-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-pyrazolo[3,4-d]pyrimidinyl]phenyl]-3-methylurea chemical CHEBI:91364 ChEBI MTOR protein P42345 UNIPROT down-regulates "chemical inhibition" 9606 Other t "Selleck;ATP-competitive inhibitor mTOR" gcesareni SIGNOR-207800 2-[(3-bromo-5-tert-butyl-4-hydroxyphenyl)methylidene]propanedinitrile chemical CHEBI:93757 ChEBI IGF1R protein P08069 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189368 CAMK2A protein Q9UQM7 UNIPROT GFAP protein P14136 UNIPROT "down-regulates activity" phosphorylation Ser17 ARRSYVSsGEMMVGG -1 7822264 t llicata "On the other hand, GFAP was phosphorylated to approximately 1.9 mol of phosphate/mol of GFAP by Ca(2+)-CaM-dependent protein kinase II, and this phosphorylation did induce disassembly of the filament. Sequential analysis of the purified phosphopeptides revealed that only Ser8 on GFAP was phosphorylated by cdc2 kinase, whereas Ser13, Ser17, Ser34, and Ser389 on GFAP were phosphorylated by Ca(2+)-CaM-dependent protein kinase II." SIGNOR-250627 CUDC-907 chemical CID:54575456 PUBCHEM PIK3CA protein P42336 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191212 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 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 PEX6 protein Q13608 UNIPROT PEX1 protein O43933 UNIPROT "up-regulates activity" binding 10029 12717447 t "Pex26 recruits Pex6–Pex1 complexes to peroxisomes. Pex26 anchors Pex6 and Pex1 through Pex26–Pex6 and Pex6–Pex1 interactions." SIGNOR-253615 "tyrphostin AG 1478" chemical CHEBI:75404 ChEBI EGFR protein P00533 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189377 Bafetinib chemical CID:24853523 PUBCHEM LYN protein P07948 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190227 CAMK2A protein Q9UQM7 UNIPROT GFAP protein P14136 UNIPROT "down-regulates activity" phosphorylation Ser38 LGPGTRLsLARMPPP -1 7822264 t llicata "On the other hand, GFAP was phosphorylated to approximately 1.9 mol of phosphate/mol of GFAP by Ca(2+)-CaM-dependent protein kinase II, and this phosphorylation did induce disassembly of the filament. Sequential analysis of the purified phosphopeptides revealed that only Ser8 on GFAP was phosphorylated by cdc2 kinase, whereas Ser13, Ser17, Ser34, and Ser389 on GFAP were phosphorylated by Ca(2+)-CaM-dependent protein kinase II." SIGNOR-250628 DNMT3B protein Q9UBC3 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-90845 GSK3B protein P49841 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "down-regulates activity" phosphorylation 9606 BTO:0000007 17360711 t lperfetto "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-227982 ibrutinib chemical CHEBI:76612 ChEBI BTK protein Q06187 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189641 LSM-1131 chemical CHEBI:91398 ChEBI MET protein P08581 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189873 85375-15-1 chemical CID:6917797 PUBCHEM SLC6A11 protein P48066 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206990 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 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 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 CDH11 protein P55287 UNIPROT CTNNA1 protein P35221 UNIPROT unknown binding 9606 BTO:0000150 10029089 t miannu "Cadherin-11 is localized to a detergent-soluble pool and is associated with both alpha- and beta-catenin" SIGNOR-64859 CDH11 protein P55287 UNIPROT CTNNB1 protein P35222 UNIPROT unknown binding 9606 BTO:0000150 10029089 t miannu "Cadherin-11 is localized to a detergent-soluble pool and is associated with both alpha- and beta-catenin" SIGNOR-64862 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 AXIN2 protein Q9Y2T1 UNIPROT GSK3B protein P49841 UNIPROT "up-regulates activity" binding 9606 BTO:0000142;BTO:0000671;BTO:0000763 SIGNOR-C110 10911903 t gcesareni "It has been found that a multiprotein complex assembled by the cytoplasmic component conductin induces degradation of cytoplasmic beta-catenin. The complex includes apc, the serine/threonine kinase gsk3 beta, and beta-catenin, which bind to conductin at distinct domains." SIGNOR-79950 CCL25 protein O15444 UNIPROT CCR9 protein P51686 UNIPROT up-regulates binding 9606 BTO:0000782 11159507 t gcesareni "Ccr9 is a specific receptor for the beta-chemokine teck/ccl25." SIGNOR-104902 CCT129202 chemical CID:16202152 PUBCHEM AURKA protein O14965 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190877 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 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 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 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 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 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 E2F1 protein Q01094 UNIPROT PPARG protein P37231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12110166 f fspada "We show here that e2f1 induces ppar gamma transcription during clonal expansion, whereas e2f4 represses pparg amma expression during terminal adipocyte differentiation" SIGNOR-90459 GSK3B protein P49841 UNIPROT DPYSL3 protein Q14195 UNIPROT "down-regulates activity" phosphorylation Thr509 PVFDLTTtPKGGTPA 10116 BTO:0000938 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 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 E2F2 protein Q14209 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-240550 FBXO32 protein Q969P5 UNIPROT MYOD1 protein P15172 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0001103 19319192 t gcesareni "Here we present evidence that mafbx targets myod for degradation in several models of skeletal muscle atrophy." SIGNOR-184861 ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1466 KSSEYPIsQNPEGLS 9606 BTO:0000150 10550055 t lperfetto "The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. phosphorylation of brca1 by the checkpoint kinase atm may be critical for proper responses to dna double-strand breaks" SIGNOR-72060 CDK1 protein P06493 UNIPROT ECT2 protein Q9H8V3 UNIPROT up-regulates phosphorylation Thr444 TKSSKSStPVPSKQS 9606 BTO:0001938 16247472 t lperfetto "Here we show that two mitotic kinases, cdk1 and polo-like kinase 1 (plk1), phosphorylate ect2 in vitro.Moreover, ect2 t412a, but not phosphomimic t412d, displayed a diminished accumulation of gtp-bound rhoa compared with wt ect2, suggesting that phosphorylation of thr-412 is critical for the catalytic activity of ect2." SIGNOR-141175 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 CDK5 protein Q00535 UNIPROT HTT protein P42858 UNIPROT up-regulates phosphorylation Ser1199 EQASVPLsPKKGSEA 9606 BTO:0000938 17611284 t lperfetto "Huntingtin is an antiapoptotic proteinwe show here that huntingtin is phosphorylated by the cyclin-dependent kinase 5 (cdk5) at serines 1181 and 1201. Phosphorylation can be induced by dna damage in vitro and in vivo. The state of huntingtin phosphorylation is a crucial regulator of neuronal cell death. Absence of phosphorylation of huntingtin at serines 1181 and 1201 confers toxic properties to wild-type huntingtin in a p53-dependent manner in striatal neurons and accelerates neuronal death induced by dna damage." SIGNOR-156840 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 BOC protein Q9BWV1 UNIPROT CDON/BOC/PTCH1 complex SIGNOR-C95 SIGNOR "form complex" binding 10090 21664576 t lperfetto "Secreted Hedgehog (HH) ligands signal through the canonical receptor Patched (PTCH1). However, recent studies implicate three additional HH-binding, cell-surface proteins, GAS1, CDO, and BOC, as putative coreceptors for HH ligands." SIGNOR-209599 CDON protein Q4KMG0 UNIPROT CDON/BOC/PTCH1 complex SIGNOR-C95 SIGNOR "form complex" binding 10090 21664576 t lperfetto "Secreted Hedgehog (HH) ligands signal through the canonical receptor Patched (PTCH1). However, recent studies implicate three additional HH-binding, cell-surface proteins, GAS1, CDO, and BOC, as putative coreceptors for HH ligands." SIGNOR-209596 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 IL20 protein Q9NYY1 UNIPROT IL20RB protein Q6UXL0 UNIPROT up-regulates binding 9606 11163236 t gcesareni "An IL-20 receptor was identified as a heterodimer of two orphan class II cytokine receptor subunits. Both receptor subunits are expressed in skin and are dramatically upregulated in psoriatic skin. Taken together, these results demonstrate a role in epidermal function and psoriasis for IL-20, a novel cytokine identified solely by bioinformatics analysis." SIGNOR-151874 SMAD1 protein Q15797 UNIPROT PPARG protein P37231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0004058 12589053 f lperfetto "Overexpression of smad6, a natural antagonist for smad1, blocked ppargamma expression and adipocytic differentiation induced by bmp2" SIGNOR-236227 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 DOT1L protein Q8TEK3 UNIPROT MYC protein P01106 UNIPROT "up-regulates activity" binding 9606 BTO:0001939 26199140 t 1 miannu "Our data suggest that the c-Myc-dependent transcriptional switch is modulated by DOT1L, as in the presence of DOT1L c-Myc preferentially forms an active complex with p300 rather than a repressive complex containing HDAC1 and DNMT1" SIGNOR-239362 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 JAK1 protein P23458 UNIPROT JAK3 protein P52333 UNIPROT up-regulates 9606 10825200 f gcesareni "Syk activation required jak3, probably indirectly via activation of jak1." SIGNOR-77551 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 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT "down-regulates activity" phosphorylation Thr826 LPTPTKMtPRSRILV 9606 9139732 t lperfetto "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-216957 DAAM1 protein Q9Y4D1 UNIPROT RHOA protein P61586 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-185268 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 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 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 FZD3 protein Q9NPG1 UNIPROT RHOA protein P61586 UNIPROT "up-regulates activity" binding 9606 20828404 t gcesareni "Upon ligand binding, non-canonical wnt signaling controls tissue polarity and cell movement through the activation of rhoa, c-jun n-terminal kinase (jnk), and nemo-like kinase (nlk) signaling cascades." SIGNOR-167865 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 WNT3A protein P56704 UNIPROT FZD3 protein Q9NPG1 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 21078818 t 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-169654 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 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 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 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 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 CREBBP protein Q92793 UNIPROT MYB protein P10242 UNIPROT "up-regulates activity" binding 9534 BTO:0004055 8654374 t 2 miannu "the nuclear co-activator CREB binding protein (CBP). This protein interacts directly with both c-Myb and v-Myb and potentiates Myb-specific transcription" SIGNOR-240994 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 MAPK14 protein Q16539 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-173409 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 DDX17 protein Q92841 UNIPROT DDX5/DDX17 complex SIGNOR-C40 SIGNOR "form complex" binding 9606 12595555 t miannu "The highly related dead box rna helicases p68 and p72 exist as heterodimers in cells" SIGNOR-98403 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 PRDM2 protein Q13029 UNIPROT HMOX1 protein P09601 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 8654390 f 2 miannu "We show that a portion of MTB-Zf, including an N-terminal zinc-finger domain, binds in vitro to MTE and that the transient coexpression of MTB-Zf cDNA leads to transativation of the heme-oxygenase-1 gene promoter." SIGNOR-241047 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 PRKCB protein P05771 UNIPROT TYR protein P14679 UNIPROT up-regulates phosphorylation Ser523 MEKEDYHsLYQSHL 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-67866 PRKDC protein P78527 UNIPROT HSP90AA1 protein P07900 UNIPROT unknown phosphorylation Thr7 tQDQPMEE 9606 BTO:0000567 2507541 t lperfetto "Here we show that the dsDNA-activated protein kinase from human HeLa cells phosphorylates 2 threonine residues in the sequence PEETQTQDQPME at the amino terminus of human hsp90 alpha." SIGNOR-248888 PRKDC protein P78527 UNIPROT RPA2 protein P15927 UNIPROT "down-regulates activity" phosphorylation Ser12 GFESYGSsSYGGAGG -1 9295339 t lperfetto "We showed previously that UV irradiation increases phosphorylation of the p34 subunit of human replication protein A (RPA) and that this hyperphosphorylation correlated with loss of activity of the DNA replication complex. | we detected phosphorylation of the RPA complex by DNA-PK on RPA-p34 sites Ser-23, Ser-29, and Ser-11, -12, or -13" SIGNOR-248981 PRKDC protein P78527 UNIPROT RPA2 protein P15927 UNIPROT "down-regulates activity" phosphorylation Ser23 GAGGYTQsPGGFGSP -1 9295339 t lperfetto "We showed previously that UV irradiation increases phosphorylation of the p34 subunit of human replication protein A (RPA) and that this hyperphosphorylation correlated with loss of activity of the DNA replication complex. | we detected phosphorylation of the RPA complex by DNA-PK on RPA-p34 sites Ser-23, Ser-29, and Ser-11, -12, or -13" SIGNOR-248983 PRKDC protein P78527 UNIPROT RPA2 protein P15927 UNIPROT "down-regulates activity" phosphorylation Ser29 QSPGGFGsPAPSQAE -1 9295339 t lperfetto "We showed previously that UV irradiation increases phosphorylation of the p34 subunit of human replication protein A (RPA) and that this hyperphosphorylation correlated with loss of activity of the DNA replication complex. | we detected phosphorylation of the RPA complex by DNA-PK on RPA-p34 sites Ser-23, Ser-29, and Ser-11, -12, or -13" SIGNOR-248984 CREB5 protein Q02930 UNIPROT MAPKAPK3 protein Q16644 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002814 21132541 f miannu "Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition)," SIGNOR-253807 "1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate" smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT "up-regulates activity" relocalization 9606 21798082 t lperfetto "Pip3 acts in turn as a docking site for two kinases, phosphoinositide-dependent kinase 1 (PDK1) and AKT, and the subsequent phosphorylation of AKT at serine 308 by PDK1, leading to AKT activation." SIGNOR-175253 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 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 BAP1 protein Q92560 UNIPROT CDKN2B protein P42772 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 26470845 t lperfetto "Since we found that ASXL1 and BAP1 both are enriched at the INK4B locus, our results suggest that activation of the INK4B locus requires ASXL1/BAP1-mediated deubiquitinylation of H2AK119ub1." SIGNOR-241656 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 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 GPER1 protein Q99527 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 BTO:0000130 22203955 t gcesareni "However, grpr preferentially couples to galfaq proteins." SIGNOR-195320 RIPK1 protein Q13546 UNIPROT Necrosis phenotype SIGNOR-PH3 SIGNOR up-regulates 9606 14965271 f amattioni "Fas-induced necrosis requires rip" SIGNOR-121901 CASP8 protein Q14790 UNIPROT CASP3 protein P42574 UNIPROT "up-regulates activity" cleavage 9606 BTO:0000007 16964285 t amattioni "Casp8 induces apoptosis by directly activating casp3." SIGNOR-149420 CCND3 protein P30281 UNIPROT Cell_cycle_exit phenotype SIGNOR-PH41 SIGNOR up-regulates 10090 BTO:0000165 21898542 f gcesareni "Our findings suggest that cyclin D3 primes myoblasts for differentiation by enhancing muscle specific gene expression and cell cycle exit" SIGNOR-241960 DLX5 protein P56178 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 19497851 t gcesareni "DLX5 (Distal-less Homeobox 5) Promotes Tumor Cell Proliferation by Transcriptionally Regulating MYC" SIGNOR-241914 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 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 CTNNB1 protein P35222 UNIPROT SOX2 protein P48431 UNIPROT "down-regulates activity" binding 9606 BTO:0000093 24291232 t flangone "The interaction between Sox2 and _-catenin provides a novel mechanism underlying the functional dichotomy of BC cells, which carries potential therapeutic implications." SIGNOR-241994 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 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 EP300 protein Q09472 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates binding 9606 SIGNOR-C6 22298955 t gcesareni "Ski and snon also prevent smads from binding to the transcriptional coactivator p300/cbp" SIGNOR-195582 PIN1 protein Q13526 UNIPROT MYC protein P01106 UNIPROT up-regulates binding 9606 BTO:0000150 23716601 t esanto "Pin1 prolyl isomerase enhances recruitment of serine 62-phosphorylated myc and its coactivators to select promoters during gene activation." SIGNOR-202134 CDK1 protein P06493 UNIPROT TSC1 protein Q92574 UNIPROT unknown phosphorylation Thr417 SLPQATVtPPRKEER 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-86696 CDK2 protein P24941 UNIPROT ARID4A protein P29374 UNIPROT down-regulates phosphorylation Ser864 RKILGQSsPEKKIRI 9606 BTO:0000150 21148318 t gcesareni "In the present study we identified rbp1 as a novel cdk substrate. Rbp1 is phosphorylated by cdk2 on serines 864 and 1007, which are n- and c-terminal to the lxcxe motif, respectively. Cdk2-mediated phosphorylation of rbp1 or prb destabilizes their interaction in vitro, with concurrent phosphorylation of both proteins leading to their dissociation" SIGNOR-170455 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 FOXA1 protein P55317 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 19127412 f miannu "Overexpression of foxa1 promoted apoptosis" SIGNOR-183153 KAT2B protein Q92831 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates acetylation 9606 BTO:0000887 10944526 t gcesareni "Our results provide direct evidence that myod acetylation functionally activates the protein and show that both pcaf and cbp/p300 are candidate enzymes for myod acetylation in vivo" SIGNOR-81056 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 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 ATG5 protein Q9H1Y0 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-226693 BID protein P55957 UNIPROT BAK/BAX complex SIGNOR-C96 SIGNOR "up-regulates activity" binding 9606 16243507 t lperfetto "Letai et al. [ 16] proposed that BH3-only proteins comprised both sensitisers, which only inactivate the pro-survival proteins, and activators, which directly engage Bax and Bak. In this model ( Figure 4a), the activators, proposed to include tBid and Bim, may normally be sequestered by the pro-survival proteins." SIGNOR-209669 Cell_cycle_exit phenotype SIGNOR-PH41 SIGNOR Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 10090 9388774 f gcesareni "Myogenic precursor cells withdraw irreversibly from the cell cycle as they differentiate into mature myotubes. Cell cycle exit occurs early during the differentiation program and is required for normal expression of the contractile phenotype." SIGNOR-243206 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 CSNK2A1 protein P68400 UNIPROT SEPT2 protein Q15019 UNIPROT down-regulates phosphorylation Ser218 YHLPDAEsDEDEDFK 9606 BTO:0000567 16857012 t lperfetto "Here we show that human septin 2 is phosphorylated in vivo at ser218 by casein kinase ii. Septin 2 binds and hydrolyses gtp. The purified protein has the capacity to polymerize into long filaments when loaded with gtp or gdp. Moreover, we show that the endogenous protein in hela cells, like that produced in insect cells, is phosphorylated by casein kinase ii and that this phosphorylation alters nucleotide binding." SIGNOR-148010 IKBKG protein Q9Y6K9 UNIPROT IKBKB protein O14920 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 SIGNOR-C14 12192055 t lperfetto "The n-terminal domain of ikkgamma is required both for the binding of ikkalfa and ikkbeta and their assembly into a high-molecular-weight complex essential for activation" SIGNOR-91705 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 BCL2 protein P10415 UNIPROT BAK/BAX complex SIGNOR-C96 SIGNOR "down-regulates activity" binding 9606 16243507 t lperfetto "Displacement model. BH3-only proteins are proposed to activate Bax and Bak by displacing them from the Bcl-2 pro-survival proteins that sequester their active forms" SIGNOR-209681 SEPT12 protein Q8IYM1 UNIPROT SEPT6 protein Q14141 UNIPROT down-regulates binding 9606 BTO:0000567 18047794 t miannu "Sept12 interacts with sept6 and this interaction alters the filament structure of sept6 in hela cells." SIGNOR-159537 BAK/BAX complex SIGNOR-C96 SIGNOR CYCS protein P99999 UNIPROT "up-regulates activity" relocalization 9606 21195116 t lperfetto "Once activated, Bax and Bak oligomerize to form pores in the mitochondrial outer membrane that release cytochrome c. Cytosolic cytochrome c leads to caspase activation and subsequent cell death" SIGNOR-209678 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 BIRC2 protein Q13490 UNIPROT TRAF2 protein Q12933 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 18997794 t lperfetto "Traf3-binding receptors stabilize nik by activating ciap-dependent degradation of traf2 and traf3." SIGNOR-182128 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 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 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 CHN1 protein P15882 UNIPROT CDK5R1 protein Q15078 UNIPROT up-regulates binding 9606 BTO:0000567;BTO:0000938 BTO:0000142 15013773 t miannu "_-chimaerin was identified to interact with the p35 activator of cdk5. The complex of _-chimaerin, cdk5 and p35 is enzymatically functional" SIGNOR-123439 BCL2L11 protein O43521 UNIPROT BCL2L1 protein Q07817 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 15694340 t lperfetto "Bim binds bcl-2, bcl2l1, bcl2l2, mcl1 and a1 tightly" SIGNOR-133826 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR AMPH protein P49418 UNIPROT unknown phosphorylation Ser272 EEPSPLPsPTASPNH -1 11113134 t llicata "Amphiphysin is phosphorylated by cdk5 in a region including serines 272, 276, and 285. Amphiphysin 1 is also phosphorylated by the cdc2/cyclin B kinase complex in the same region and undergoes mitotic phosphorylation in dividing cells. " SIGNOR-250644 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR1B protein P28222 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-257517 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR1D protein P28221 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-257518 IKBKG protein Q9Y6K9 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates binding 9606 12192055 t lperfetto "The n-terminal domain of ikkgamma is required both for the binding of ikkalfa and ikkbeta and their assembly into a high-molecular-weight complex essential for activation" SIGNOR-217436 AMPK complex SIGNOR-C15 SIGNOR 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-249655 CDK5 protein Q00535 UNIPROT AMPH protein P49418 UNIPROT unknown phosphorylation Ser272 EEPSPLPsPTASPNH -1 11113134 t llicata "Amphiphysin is phosphorylated by cdk5 in a region including serines 272, 276, and 285. Amphiphysin 1 is also phosphorylated by the cdc2/cyclin B kinase complex in the same region and undergoes mitotic phosphorylation in dividing cells. " SIGNOR-250648 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 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 MUTYH protein Q9UIF7 UNIPROT TOPBP1 protein Q92547 UNIPROT up-regulates binding 9606 BTO:0000007 21615992 t miannu "Binding of myh directly participates in atr and topbp1 activation in dna damage signaling, leading to apoptosis." SIGNOR-173972 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 SMAD3 protein P84022 UNIPROT CDKN2B protein P42772 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 23032366 f lperfetto "PD-1 inhibits T cell proliferation by upregulating p27 and p15 and suppressing Cdc25A." SIGNOR-245441 SMARCC2 protein Q8TAQ2 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-132936 SMARCD1 protein Q96GM5 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-132939 SMG1 protein Q96Q15 UNIPROT UPF1 protein Q92900 UNIPROT up-regulates phosphorylation Thr28 AELLGADtQGSEFEF 9606 23356578 t lperfetto "Smg-1 directly phosphorylates upf1 helicase, another key component of nmd, upon recognition of ptc on postspliced mrna during the initial round of translation. Phosphorylated-upf1 recruits the smg-5/smg-7 complex to induce ribosome dissociation and decapping-mediated decay. T28 and s1096 are responsible for phospho-specific recruitment of smg-6 to the n-terminal conserved region, and the smg-5/smg-7 heterodimer complex to the c-terminal sq-rich region of upf1, respectively" SIGNOR-200793 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR AMPH protein P49418 UNIPROT unknown phosphorylation Ser285 NHTLAPAsPAPARPR -1 11113134 t llicata "Amphiphysin is phosphorylated by cdk5 in a region including serines 272, 276, and 285. Amphiphysin 1 is also phosphorylated by the cdc2/cyclin B kinase complex in the same region and undergoes mitotic phosphorylation in dividing cells. " SIGNOR-250646 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 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 HSPA1B protein P0DMV9 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-252417 SGK1 protein O00141 UNIPROT NDRG2 protein Q9UN36 UNIPROT up-regulates phosphorylation Thr348 GNRSRSRtLSQSSES 9606 BTO:0000567 BTO:0000887;BTO:0001103;BTO:0000763 15461589 t llicata "Sgk1 phosphorylated ndrg2 at thr330, ser332 and thr348 in vitro. for example, the phosphorylation of thr330 or ser332 by sgk1 may prime ndrg2 for phosphorylation by gsk3 at ser326 and ser328 respectively, for example, the phosphorylation of thr330 or ser332 by sgk1 may prime ndrg2 for phosphorylation by gsk3 at ser326 and ser328 respectively, the phosphorylation of thr348 by sgk1 may prime for phosphorylation at ser344" SIGNOR-129680 PPP1CA protein P62136 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-174859 PTPN6 protein P29350 UNIPROT KDR protein P35968 UNIPROT "down-regulates activity" dephosphorylation Tyr1059 DIYKDPDyVRKGDAR 9606 18377662 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-248474 HIPK2 protein Q9H2X6 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser46 AMDDLMLsPDDIEQW 9606 BTO:0001271 17210684 t llicata "Based on all these observations, it is legitimate to suggest that axin and daxx seem to adopt both parallel routes and a convergent means to activate p53. In either case, hipk2 seems to be the protein kinase that catalyzes the ser46 phosphorylation." SIGNOR-151930 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 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 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 Ser863 LTQSAPAsPTNKGVH 10090 BTO:0002572 SIGNOR-C3 21757713 t lperfetto "Arsenite treatment of cells activates p38_ and induces interaction between p38_ and Raptor, a regulatory component of mTORC1, resulting in phosphorylation of Raptor on Ser(863) and Ser(771). The phosphorylation of Raptor on these sites enhances mTORC1 activity, and contributes largely to arsenite-induced mTORC1 activation" SIGNOR-174878 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 "phosphatidic acid" smallmolecule CHEBI:16337 ChEBI PRKCZ protein Q05513 UNIPROT up-regulates binding 9606 12401205 t gcesareni "The pkc isoform pkc-zeta appear to be activated by direct interactions with pa" SIGNOR-94867 PPP2CA protein P67775 UNIPROT PP2Ca_R1A_Ba 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-243424 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 RAB23 protein Q9ULC3 UNIPROT GLI3 protein P10071 UNIPROT down-regulates 9606 16364285 f gcesareni "Based on su(fu) function, we predict that rab23 can interact with all gli1 molecules including gli1, gli2 and gli3, and inhibit their transcriptional activities and nuclear localization." SIGNOR-143160 RANBP17 protein Q9H2T7 UNIPROT TCF3 protein P15923 UNIPROT up-regulates binding 9606 20503194 t miannu "Yeast two-hybrid, mammalian two-hybrid, and co-immunoprecipitation analyses demonstrate specific interaction of e12 with ranbp17, a novel member of the importin-beta superfamily;this interaction maps to the crm1 homology region of ranbp17. Ectopic expression of ranbp17 leads to a approximately 3-fold increase in e2a/myod mediated transactivation of an e-box regulated luciferase reporter gene." SIGNOR-165655 SBDS protein Q9Y3A5 UNIPROT EIF6 protein P56537 UNIPROT up-regulates 9606 BTO:0001271 21536732 f miannu "Human sbds is an essential cofactor for the efl1 gtpase, and together they cooperate to directly catalyze the release of eif6 from mammalian pre-60s ribosomal subunits" SIGNOR-173536 SMAD7 protein O15105 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates 9606 17438144 f gcesareni "Smad7 repressed smad3/4-, smad2/4-, and smad1/4-enhanced reporter gene expression." SIGNOR-154390 SRC protein P12931 UNIPROT ANXA2 protein P07355 UNIPROT up-regulates phosphorylation Tyr24 HSTPPSAyGSVKAYT 9606 BTO:0001271 15302870 t lperfetto "Translocation requires the presence of the annexin 2 binding partner p11 (s100a10) and the phosphorylation of annexin 2 at tyr23 through a src-like tyrosine kinase-dependent mechanism both in vitro and in vivo." SIGNOR-127872 TLR4 protein O00206 UNIPROT TLR4 protein O00206 UNIPROT up-regulates binding 9606 BTO:0000782 24352680 t fstefani "Upon activation, tlrs hetero- or homodimerize inducing the recruitment of adaptor proteins via the cytoplasmic tir domain" SIGNOR-203484 CSNK2B protein P67870 UNIPROT IKZF1 protein Q13422 UNIPROT down-regulates phosphorylation Ser101 GSHRDQGsSALSGVG 9606 BTO:0001271 21750978 t miannu "We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway" SIGNOR-174840 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-244281 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 LIF protein P15018 UNIPROT LIFR protein P42702 UNIPROT up-regulates binding 9606 BTO:0001271 16051226 t gcesareni "Lif binds at low-affinity to lifr, the structure of which is closely related to that of gp130 (42). Lifr then becomes heterodimerized with gp130 to form the high-affinity and signaling-competent complex (43). Osm utilizes this type of heterodimer, i.e. the lifr/gp130 complex (43, 44)." SIGNOR-139102 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 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 PRKACA protein P17612 UNIPROT TAL1 protein P17542 UNIPROT up-regulates phosphorylation Ser172 NRVKRRPsPYEMEIT 9606 BTO:0001271 22310283 t llicata "The phosphorylation of serine 172 of tal1 specifically destabilizes tal1 interaction with histone demethylase lsd1 and, therefore, leads to the activation of the certain tal1 target genes in differentiated erythroid cells or t-cell leukemia." SIGNOR-195983 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 PTPN11 protein Q06124 UNIPROT HOXA10 protein P31260 UNIPROT up-regulates dephosphorylation 9606 BTO:0001271 19022774 t fspada "We also identified hoxa10 as a substrate for shp2 in undifferentiated myeloid cells, an effect that diminished during myelopoiesis. However, a constitutively active form of shp2 dephosphorylated hoxa10 throughout ex vivo myelopoiesis and sustained repression of hoxa10 target genes involved in phagocyte effector functions." SIGNOR-182475 SGK1 protein O00141 UNIPROT FBXW7 protein Q969H0 UNIPROT up-regulates phosphorylation Ser227 QQRRRITsVQPPTGL 9606 BTO:0001271 21147854 t lperfetto "Here, we report that the serum- and glucocorticoid-inducible protein kinase sgk1 remarkably reduced the protein stability of the active form of notch1 through fbw7activated sgk1 phosphorylated fbw7 at serine 227" SIGNOR-170404 SRC protein P12931 UNIPROT CHN2 protein P52757 UNIPROT down-regulates phosphorylation Tyr21 VSSDAEEyQPPIWKS 9606 17560670 t llicata "Here we report that beta2-chimaerin is tyrosine-phosphorylated by src-family kinases (sfks) upon cell stimulation with epidermal growth factor (egf). Mutational analysis identified tyr-21 in the n-terminal regulatory region as a major phosphorylation site. these results suggest tyr-21 phosphorylation as a novel, sfk-dependent mechanism that negatively regulates beta2-chimaerin rac-gap activity." SIGNOR-155713 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 SRPK2 protein P78362 UNIPROT ACIN1 protein Q9UKV3 UNIPROT up-regulates phosphorylation Ser1180 GPRSRSRsRDRRRKE 9606 BTO:0001271 18559500 t lperfetto "Here, we show that srpk2 binds and phosphorylates acinus, an sr protein essential for rna splicing, and redistributes it from the nuclear speckles to the nucleoplasm, resulting in cyclin a1 but not a2 up-regulation. Acinus s422d, an srpk2 phosphorylation mimetic, enhances cyclin a1 transcription, whereas acinus s422a, an unphosphorylatable mutant, blocks the stimulatory effect of srpk2" SIGNOR-179006 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 TNF protein P01375 UNIPROT PIK3CA protein P42336 UNIPROT "up-regulates activity" 10090 10485710 f lperfetto "Tnf activates phosphatidylinositol-3-oh kinase (pi(3)k)." SIGNOR-70616 "3-[({4-[4-({[1-(2-chlorophenyl)ethoxy]carbonyl}amino)-3-methyl-1,2-oxazol-5-yl]phenyl}methyl)sulfanyl]propanoic acid" chemical CHEBI:91194 ChEBI LPAR3 protein Q9UBY5 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193564 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 MAPK14 protein Q16539 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" 9606 20626350 f lperfetto "On the other hand, p38 alfa may negatively modulate akt activity, indipendently of pi3k by regulating the interaction between caveolin 1 and pp2a through a mechanism dependent on cell attachment." SIGNOR-244461 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR MDM2 protein Q00987 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 20921405 f gcesareni "Nf-kb activation following t-cell receptor engagement induces the expression of mdm2 through interaction with nf-kb sites in its p1 promoter" SIGNOR-168296 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 PRKCE protein Q02156 UNIPROT OCLN protein Q16625 UNIPROT up-regulates phosphorylation Thr424 IREYPPItSDQQRQL 9606 BTO:0000195 BTO:0000671 21545357 t lperfetto "Thr403, thr404, thr424 and thr438 in the occludin c-terminal domain are the predominant sites of pkc_-dependent phosphorylation . The present study demonstrates that pkc_ phosphorylates occludin on specific threonine residues and promotes assembly of epithelial tight junctions." SIGNOR-173639 PRKCE protein Q02156 UNIPROT OCLN protein Q16625 UNIPROT up-regulates phosphorylation Thr438 LYKRNFDtGLQEYKS 9606 BTO:0000195 BTO:0000671 21545357 t lperfetto "Thr403, thr404, thr424 and thr438 in the occludin c-terminal domain are the predominant sites of pkc_-dependent phosphorylation . The present study demonstrates that pkc_ phosphorylates occludin on specific threonine residues and promotes assembly of epithelial tight junctions." SIGNOR-173643 RELA protein Q04206 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "form complex" binding 9606 9450761 t gcesareni "Here we report the crystal structure at 2.9 a resolution of the p50/p65 heterodimer bound to the kappab dna" SIGNOR-55381 TCL1A protein P56279 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates binding 9606 BTO:0000782;BTO:0001271 10983986 t lperfetto "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-244449 WNT5B protein Q9H1J7 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates 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-141440 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 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 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 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 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 CSNK2B protein P67870 UNIPROT IKZF1 protein Q13422 UNIPROT down-regulates phosphorylation Ser13 GQDMSQVsGKESPPV 9606 BTO:0001271 21750978 t miannu "We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway" SIGNOR-174844 HMGB1 protein P09429 UNIPROT HOXC6 protein P09630 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-219937 KAT6A protein Q92794 UNIPROT TP53 protein P04637 UNIPROT up-regulates acetylation Lys382 QSTSRHKkLMFKTEG 9606 BTO:0001271 SIGNOR-C54 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-201486 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 NFKBIE protein O00221 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates binding 9606 BTO:0001271 SIGNOR-C13 12835716 t gcesareni "Nf-kb is normally sequestered in the cell cytoplasm by binding to ikbx, ikbb, ikbe" SIGNOR-102774 PDK4 protein Q16654 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates phosphorylation Ser300 SMSDPGVsYRTREEI 9606 17474719 t gcesareni "In mammals, pdhc is tightly regulated by phosphorylation-dephosphorylation of three serine residues in the thiamin-dependent pyruvate dehydrogenase (e1) component. In vivo, inactivation of human pdhc correlates mostly with phosphorylation of serine 264, which is located at the entrance of the substrate channel leading to the active site of e1." SIGNOR-154656 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 PIK3AP1 protein Q6ZUJ8 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 BTO:0000801 22187458 t gcesareni "This accumulation of tyrosine-phosphorylated bcap at the membrane with its associated pi3k would then allow for the catalysis of ptd ins p2 to ptd ins p3 and downstream pi3k-dependent signals. Therefore, bcap is an essential activator of the pi3k pathway downstream of tlr signaling, providing a brake to limit potentially pathogenic excessive tlr responses." SIGNOR-191670 CSNK2A1 protein P68400 UNIPROT MAZ protein P56270 UNIPROT up-regulates phosphorylation Ser460 PTAVGSLsGAEGVPV 9606 BTO:0000567 10448092 t lperfetto "Site-specific mutagenesis of maz revealed that the serine residue at position 480 was the major site of phosphorylation by ckii both in vitro and in vivo. Phosphorylation of maz by ckii at this serine residue was required for maximum binding of maz to the pyrimidine-rich dna of the nuclease-hypersensitive element (nhe) in the 5'-end promoter region of the c-myc gene. Mutation of serine at position 480 to alanine eliminated the dna-binding activity of maz to this element." SIGNOR-70082 GAB1 protein Q13480 UNIPROT ARHGAP32 protein A7KAX9 UNIPROT up-regulates relocalization 9606 BTO:0000007 12819203 t gcesareni "Gc-gap, a rho family gtpase-activating protein that interacts with signaling adapters gab1 and gab2." SIGNOR-102586 PTPN1 protein P18031 UNIPROT PTK2 protein Q05397 UNIPROT down-regulates dephosphorylation 9606 16291744 t gcesareni "We show that coexpression of wild-type alpha-actinin and ptp 1b causes dephosphorylation at tyr-397 in fak." SIGNOR-141637 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 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 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 CCK protein P06307 UNIPROT CCKBR protein P32239 UNIPROT up-regulates binding 9606 BTO:0000142 10368033 t gcesareni "Cck8 interacts with nanomolar affinities with two different receptors designated cck-a and cck-b" SIGNOR-66339 CD274 protein Q9NZQ7 UNIPROT PDCD1 protein Q15116 UNIPROT up-regulates binding 9606 BTO:0000782 11015443 t miannu "Pd-l1, was found to bind pd-1 specifically. The functional significance of this interaction has been demonstrated in t cell assays, in which engagement of pd-1 by pd-l1 leads to the inhibition of tcr-mediated lymphocyte proliferation and cytokine secretion." SIGNOR-82604 DDX20 protein Q9UHI6 UNIPROT FOXL2 protein P58012 UNIPROT up-regulates binding 9606 BTO:0000975 16153597 t miannu "Dp103 further increased the cell killing effect induced by foxl2 probably due to the direct association of dp103 with foxl2 protein." SIGNOR-140388 PAX3 protein P23760 UNIPROT PITX2 protein Q99697 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887;BTO:0001103 21143873 f gcesareni "Pitx genes, such as pitx2, which is positively regulated by pax3, have been implicated in myogenesis." SIGNOR-170343 CSNK2A1 protein P68400 UNIPROT PIP4K2A protein P48426 UNIPROT up-regulates phosphorylation Ser304 DGEEEGEsDGTHPVG 9606 BTO:0000567 10508590 t lperfetto "Here, we demonstrate the partial purification of a protein kinase that phosphorylates the type iialpha pip kinase at a single site unique to that isoform - ser304. This kinase was identified as protein kinase ck2 (formerly casein kinase 2). Mutation of ser304 to aspartate to mimic its phosphorylation had no effect on pip kinase activity, but promoted both redistribution of the green fluorescent protein (gfp)-tagged enzyme in hela cells from the cytosol to the plasma membrane, and membrane ruffling." SIGNOR-71014 MAPK14 protein Q16539 UNIPROT RBSN protein Q9H1K0 UNIPROT up-regulates phosphorylation 9606 16138080 t gcesareni "We found that p38alpha can phosphorylate the rab5 effectors eea1 and rabenosyn-5 on thr-1392 and ser-215, respectively, and these phosphorylation events regulate the recruitment of eea1 and rabenosyn-5 to membranes." SIGNOR-140146 MTMR3 protein Q13615 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR "down-regulates activity" 9606 BTO:0000007 26787466 t lperfetto "The PtdIns3-phosphatase MTMR3 interacts with mTORC1 and suppresses its activity." SIGNOR-245108 NCSTN protein Q92542 UNIPROT APH1A protein Q96BI3 UNIPROT up-regulates binding 9606 BTO:0000142 12297508 t gcesareni "We show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain. Similar to the loss of presenilin or nicastrin, the inactivation of endogenous maph-1 using small interfering rnas results in the decrease of presenilin levels, accumulation of gamma-secretase substrates (app carboxyl-terminal fragments), and reduction of gamma-secretase products (amyloid-beta peptides and the intracellular domains of app and notch)." SIGNOR-93313 PBK protein Q96KB5 UNIPROT PRDX1 protein Q06830 UNIPROT up-regulates phosphorylation Ser32 QFKDISLsDYKGKYV 9606 BTO:0000782;BTO:0000848;BTO:0001286 20647304 t lperfetto "We report that prx1 is newly discovered direct target of topk. Our results demonstrate that topk phosphorylation of prx1 at ser-32 inhibits uvb-induced apoptosis in rpmi7951 melanoma cells by increasing prx1 peroxidase activity and decreasing the intracellular accumulation of h2o2." SIGNOR-166901 PRDM16 protein Q9HAZ2 UNIPROT Brown_adipogenesis phenotype SIGNOR-PH27 SIGNOR up-regulates 9606 BTO:0000222 BTO:0000887;BTO:0001103 18719582 f fspada "Loss of prdm16 from brown fat precursors causes a loss of brown fat characteristics and promotes muscle differentiation. Conversely, ectopic expression of prdm16 in myoblasts induces their differentiation into brown fat cells." SIGNOR-180295 TAOK2 protein Q9UL54 UNIPROT MAP2K6 protein P52564 UNIPROT "up-regulates activity" binding 9606 10497253 t lperfetto "Cotransfection experiments suggested that tao2 selectively activates mek3 and mek6 but not meks 1, 4, or 7." SIGNOR-70950 USP28 protein Q96RU2 UNIPROT MYC protein P01106 UNIPROT up-regulates deubiquitination 9606 BTO:0000150 17558397 t esanto "Usp28, an ubiquitin-specific protease, binds to myc through an interaction with fbw7alpha, an f-box protein that is part of an scf-type ubiquitin ligase. Therefore, it stabilizes myc." SIGNOR-155590 VRK1 protein Q99986 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 BTO:0000567 10951572 t gcesareni "Vrk1 phosphorylates murine p53 in threonine 18. This threonine is within the p53 hydrophobic loop (residues 13-23) required for the interaction of p53 with the cleft of its inhibitor mdm-2." SIGNOR-81222 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 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 GUCY1A2-B3 complex SIGNOR-C138 SIGNOR "3',5'-cyclic GMP" smallmolecule CHEBI:16356 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 10977868 t gcesareni "Guanylyl cyclases are a family of enzymes that catalyze the conversion of GTP to cGMP. The family comprises both membrane-bound and soluble isoforms that are expressed in nearly all cell types" SIGNOR-244093 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 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 profenamine chemical CHEBI:313639 ChEBI MAPK10 protein P53779 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000142 19261605 t "Inhibitor of p38;ATP binding pocket" gcesareni "Indazole-based inhibitors exemplified by sr-3737 were potent inhibitors of both jnk3 (ic50 12 nm)." SIGNOR-184443 SETBP1 protein Q9Y6X0 UNIPROT SET protein Q01105 UNIPROT up-regulates binding 9606 BTO:0001271 22566606 t miannu "Setbp1 was shown to form a complex with set and pp2a, enhancing the stability of set and its inhibition of pp2a." SIGNOR-197324 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 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 PRKACA protein P17612 UNIPROT VIM protein P08670 UNIPROT "down-regulates activity" phosphorylation Ser51 LRPSTSRsLYASSPG -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-250069 PRKACA protein P17612 UNIPROT VIM protein P08670 UNIPROT "down-regulates activity" phosphorylation Ser66 GVYATRSsAVRLRSS -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-250068 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 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 UBA3 protein Q8TBC4 UNIPROT NAE complex SIGNOR-C131 SIGNOR "form complex" binding 9606 25504797 t lperfetto "the NEDD8 E1-activating enzyme (NAE) is a heterodimer of APPBP1 and UBA3 corresponding to the N-terminal and C-terminal of the single polypeptide of the ubiquitin E1 respectively" SIGNOR-242904 CSNK2A1 protein P68400 UNIPROT CDK1 protein P06493 UNIPROT up-regulates phosphorylation Ser39 MKKIRLEsEEEGVPS 9606 BTO:0000567;BTO:0001271 15788687 t lperfetto "Additionally, transfection of cdc2 with a mutation at ser(39) to ala, which is the ck2 phosphorylation site, partially inhibits cell cycle progression in g(1) to g(2) phase following 6-tg treatment." SIGNOR-134846 CTBP1 protein Q13363 UNIPROT BHLHE41 protein Q9C0J9 UNIPROT up-regulates binding 9606 16287852 t gcesareni "We identify the ctip and ctbp corepressors as novel components of the human rbp-jkappa/sharp-corepressor complex and show that ctip binds directly to the sharp repression domain. Functionally, ctip and ctbp augment sharp-mediated repression." SIGNOR-141613 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 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 PTGER3 protein P43115 UNIPROT GNG12 protein Q9UBI6 UNIPROT up-regulates binding 9606 BTO:0000938 12038972 t gcesareni "Ep3 receptor signals are primarily involved in adenylyl cyclase via g(i) activation, and in ca(2+)-mobilization through g(beta)(gamma) from g(i)" SIGNOR-88195 ROBO proteinfamily SIGNOR-PF14 SIGNOR CCND2 protein P30279 UNIPROT down-regulates phosphorylation Thr280 DELDQAStPTDVRDI 9606 17486076 t lperfetto "These results indicate that cyclin d2 expression in normal and malignant hematopoietic cells is regulated by ubiquitin/proteasome-dependent degradation that is triggered by thr280 phosphorylation by gsk3beta or p38" SIGNOR-154672 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 HTR1D protein P28221 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-257208 CDKN2AIP protein Q9NXV6 UNIPROT TP53 protein P04637 UNIPROT up-regulates binding 9606 16803988 t miannu "In the nucleoplasm, carf interacts with p53 and enhances its function." SIGNOR-147360 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 "lysophosphatidic acids" smallmolecule CHEBI:32957 ChEBI LPAR1 protein Q92633 UNIPROT up-regulates binding 9606 BTO:0000150;BTO:0001130 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 pictrelisib chemical CHEBI:65326 ChEBI PIK3CG protein P48736 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000149 21876152 t gcesareni "Currently, several pi3k inhibitors, including gdc0941 (genentech) and bez235 (novartis pharmaceuticals), have entered phase i clinical trials, and in addition, isoform-specific compounds are being developed" SIGNOR-176301 PLA2G16 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 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 CSNK2A1 protein P68400 UNIPROT DEK protein P35659 UNIPROT up-regulates phosphorylation Ser32 MPGPREEsEEEEDED 9606 16809543 t amattioni "Dek phosphorylated at serines 19 and 32. Dek and its phosphorylation are required for intron removal" SIGNOR-147365 CSNK2B protein P67870 UNIPROT IKZF1 protein Q13422 UNIPROT down-regulates phosphorylation Thr23 ESPPVSDtPDEGDEP 9606 BTO:0001271 21750978 t miannu "We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway" SIGNOR-174856 FKBP8 protein Q14318 UNIPROT MTOR protein P42345 UNIPROT down-regulates binding 9606 17991864 t gcesareni "Fkbp38 binds to mtor and inhibits its activity in a manner similar to that of the fkbp12-rapamycin complex." SIGNOR-159013 MAPK1 protein P28482 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser294 QLSKWPGsPTSRSSD 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-160407 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 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 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 PAK2 protein Q13177 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Thr93 GHITTTPtPTQFLCP 9606 BTO:0000848 21177766 t lperfetto "P21-activated protein kinase (pak2)-mediated c-jun phosphorylation at 5 threonine sites promotes cell transformationour data showed that pak2 binds and phosphorylates c-jun at five threonine sites (thr2, thr8, thr89, thr93 and thr286)" SIGNOR-170776 PHF6 protein Q8IWS0 UNIPROT UBTF protein P17480 UNIPROT down-regulates binding 9606 BTO:0001271 23229552 t miannu "We demonstrate that phf6 is a nucleolus, ribosomal rna promoter-associated protein. Phf6 directly interacts with upstream binding factor (ubf) through its phd1 domain and suppresses ribosomal rna (rrna) transcription by affecting the protein level of ubf" SIGNOR-200133 PPP2CB protein P62714 UNIPROT RALA protein P11233 UNIPROT down-regulates dephosphorylation Ser194 NGKKKRKsLAKRIRE 9606 17540176 t miannu "Pp2a abeta-containing complexes dephosphorylate rala at ser183 and ser194, inactivating rala and abolishing its transforming function" SIGNOR-155353 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 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 PTK2B protein Q14289 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr407 IIDEEDTyTMPSTRD 9606 16760434 t gcesareni "Activated rock phosphorylates fak on ser732, which is essential for phosphorylation of tyr407 and for cell migration. We further show that pyk2 is activated by vegf-induced clustering of integrin v 3 and is responsible for the phosphorylation of tyr407." SIGNOR-147070 RAF1 protein P04049 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 17535812 t lperfetto "The activation of several major anti-apoptotic signaling pathways correlates with an increase in the phosphorylation of bad on ser-112, ser-136, and ser-155. These phosphorylation events result in bad inactivation through sequestration by 14-3-3 proteins" SIGNOR-155293 "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 ADIPOQ protein Q15848 UNIPROT ADIPOR1 protein Q96A54 UNIPROT up-regulates binding 9606 BTO:0000142 16622416 t milica "Two adiponectin receptors, adipor1 and adipor2, have recently been identified." SIGNOR-146170 IL11 protein P20809 UNIPROT IL6ST protein P40189 UNIPROT up-regulates binding 9606 BTO:0001271 9143707 t gcesareni "Some of these biological activities of il-6 are also often exerted by other cytokines, i.e. Il-11, lif, osm, cntf, and ct-4" SIGNOR-48033 GSK3A protein P49840 UNIPROT MAFA protein Q8NHW3 UNIPROT down-regulates 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 KAT6B protein Q8WYB5 UNIPROT KAT6A/KAT6B complex SIGNOR-C54 SIGNOR "form complex" binding 9606 BTO:0001271 17694082 t miannu "Like gcn5/pcaf and p300/cbp, moz and morf are transcriptional co-activators with intrinsic hat activity." SIGNOR-157307 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 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 H3F3A 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 IRS1 protein P35568 UNIPROT "up-regulates activity" phosphorylation Ser616 DDGYMPMsPGVAPVP 10090 BTO:0002662 14579029 t lperfetto "MAP kinases and mTOR mediate insulin-induced phosphorylation of insulin receptor substrate-1 on serine residues 307, 612 and 632.|The phosphorylation of Serine(612/632) required the activation of the MAP kinase pathway following short-term insulin stimulation and activation of the PI 3-kinase/mTOR pathway following prolonged insulin stimulation" SIGNOR-249408 MECOM protein Q03112 UNIPROT PBX1 protein P40424 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001271 19767769 f miannu "In this study, we identified pbx1, a proto-oncogene in hematopoietic malignancy, as a target gene of evi-1. Overexpression of evi-1 increased pbx1 expression in hematopoietic stem/progenitor cells" SIGNOR-188155 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 PPP2CA protein P67775 UNIPROT RELA protein Q04206 UNIPROT down-regulates dephosphorylation 9606 BTO:0000848 SIGNOR-C13 11591705 t gcesareni "Rela was dephosphorylated by a purified pp2a core enzyme, a heterodimer formed by the catalytic subunit of pp2a (pp2ac) and pr65, in a concentration-dependent manner.These data suggest that the constitutive activation of rela in melanoma cells could be due, at least in part, to the deficiency of pp2a, which exhibits decreased dephosphorylation of nf-kappa b/rela." SIGNOR-110959 PRKAA1 protein Q13131 UNIPROT GBF1 protein Q92538 UNIPROT down-regulates phosphorylation Thr1337 GKIHRSAtDADVVNS 9606 SIGNOR-C15 18063581 t lperfetto "These results indicate that gbf1 is a novel ampk substrate and that the ampk-mediated phosphorylation of gbf1 at thr(1337) has a critical role, presumably by attenuating the function of gbf1, in the disassembly of the golgi apparatus induced under stress conditions that lower the intracellular atp concentration." SIGNOR-159639 RUNX1 protein Q01196 UNIPROT ELF4/RUNX1 complex SIGNOR-C47 SIGNOR "form complex" binding 9606 BTO:0001271 10207087 t miannu "We readily detected an in vivo physical interaction between mef and aml1 proteins in kasumi-1 cells/ coexpression of mef and aml1b synergistically activates promoter function" SIGNOR-66963 SMO protein Q99835 UNIPROT GNG3 protein P63215 UNIPROT up-regulates binding 9606 16885213 t gcesareni "Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling." SIGNOR-148598 acetylcholine smallmolecule CHEBI:15355 ChEBI CHRM4 protein P08173 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-257471 CDK1 protein P06493 UNIPROT ERCC6L protein Q2NKX8 UNIPROT up-regulates phosphorylation Thr1063 VKQFDAStPKNDISP 9606 17218258 t lperfetto "Following phosphorylation of pich on the cdk1 site t1063, plk1 is recruited to pich and controls its localization. Starting in prometaphase, pich accumulates at kinetochores and inner centromeres." SIGNOR-152133 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 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 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 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 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-249412 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 NCOA1 protein Q15788 UNIPROT STAT5A protein P42229 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-100258 PAK1 protein Q13153 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser305 IKRSKKNsLALSLTA 9606 BTO:0000149 12374744 t lperfetto "Pak1 directly phosphorylated the activation function-2 domain of the er at the n-terminal residue ser305, and its mutation to ala (s305a) abolished the pak1-mediated phosphorylation and transactivation functions of the er" SIGNOR-94206 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 RPS6KA1 protein Q15418 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. erk_rsk phosphorylation of kibra is required for proper cell proliferation and rsk-mediated phosphorylation also positively modulates kibra's migratory activity." SIGNOR-203294 RPS6KA1 protein Q15418 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-203298 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 SS18 protein Q15532 UNIPROT SS18/MLLT10 complex SIGNOR-C75 SIGNOR "form complex" binding 9606 BTO:0001271 11423977 t miannu "Based on these results, a model is proposed in which the syt and af10 proteins act in concert as bipartite transcription factors" SIGNOR-108927 TNFSF15 protein O95150 UNIPROT TNFRSF25 protein Q93038 UNIPROT up-regulates binding 9606 14585074 t amattioni "The ligand of dr3 is tl1a" SIGNOR-103078 CSNK2A1 protein P68400 UNIPROT PPP1R2 protein P41236 UNIPROT up-regulates phosphorylation Ser122 RIQEQESsGEEDSDL 9606 9405437 t gcesareni "Recombinant inh2 was phosphorylated by kinases in cytosols prepared from g1 and s phase cells. The amount of inh2 kinase attributed to casein kinase 2, based on inhibition by heparin, increased 2.6-fold from g1 to s phase" SIGNOR-53861 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 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 FOXO1 protein Q12778 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 18423396 f fspada "Akt1/Pkb-alpha was found to be the major regulator of phosphorylation and nuclear export of Foxo1, whose presence in the nucleus strongly attenuates adipocyte differentiation." SIGNOR-178281 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 MAP2K1 protein Q02750 UNIPROT "down-regulates activity" phosphorylation Thr386 IGLNQPStPTHAAGV 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-236498 PAK1 protein Q13153 UNIPROT DYNLL1 protein P63167 UNIPROT down-regulates phosphorylation Ser88 VAILLFKsG 9606 BTO:0000149 18084006 t lperfetto "Dlc1 phosphorylation on ser(88) by p21-activated kinase 1 (pak1), a signaling nodule, promotes mammalian cell survival by regulating its interaction with bim and the stability of bim. Here we discovered that phosphorylation of ser(88), which juxtapose each other at the interface of the dlc dimer, disrupts dlc1 dimer formation and consequently impairs its interaction with bim" SIGNOR-159995 PAK1 protein Q13153 UNIPROT NF2 protein P35240 UNIPROT down-regulates phosphorylation Ser518 DTDMKRLsMEIEKEK 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-159764 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 PLK3 protein Q9H4B4 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Thr80 RMGSSEStDSGFCLD 9606 18167338 t lperfetto "Here, we demonstrate that glycogen synthase kinase-3beta (gsk-3beta) phosphorylates cdc25a to promote its proteolysis in early cell-cycle phases. Phosphorylation by gsk-3beta requires priming of cdc25a, and this can be catalyzed by polo-like kinase 3 (plk-3)" SIGNOR-160228 POT1 protein Q9NUX5 UNIPROT TERT protein O14746 UNIPROT up-regulates binding 9606 17237768 t miannu "We find that tpp1 and pot1 form a complex with telomeric dna that increases the activity and processivity of the human telomerase core enzyme." SIGNOR-152327 PRKCD protein Q05655 UNIPROT G6PD protein P11413 UNIPROT up-regulates phosphorylation Ser180 FGRDLQSsDRLSNHI 9606 BTO:0001260 20649491 t lperfetto "A pkc activator, significantly increased g6pd phosphorylation and activity, whereas single (s210a, t266a) and double (s210a/t266a) mutations at sites flanking the g6pd active site significantly inhibited phosphorylation, shifted the isoelectric point, and reduced enzyme activity." SIGNOR-167049 PRKCD protein Q05655 UNIPROT G6PD protein P11413 UNIPROT up-regulates phosphorylation Thr236 NIACVILtFKEPFGT 9606 BTO:0001260 20649491 t lperfetto "A pkc activator, significantly increased g6pd phosphorylation and activity, whereas single (s210a, t266a) and double (s210a/t266a) mutations at sites flanking the g6pd active site significantly inhibited phosphorylation, shifted the isoelectric point, and reduced enzyme activity." SIGNOR-167053 RPS6KA1 protein Q15418 UNIPROT MXD1 protein Q05195 UNIPROT down-regulates phosphorylation Ser145 IERIRMDsIGSTVSS 9606 18451027 t lperfetto "In this study, we showed that mad1 is a substrate of p90 ribosomal kinase (rsk) and p70 s6 kinase (s6k). 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" SIGNOR-178586 SMO protein Q99835 UNIPROT GNG2 protein P59768 UNIPROT up-regulates binding 9606 16885213 t gcesareni "Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling." SIGNOR-148595 ADORA3 protein P0DMS8 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-256814 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 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 PLK3 protein Q9H4B4 UNIPROT PTEN protein P60484 UNIPROT "down-regulates activity" phosphorylation Ser370 TSVTPDVsDNEPDHY 9606 20940307 t gcesareni "Plk3 phosphorylates pten on thr-366 and ser-370. Plk3-mediated phosphorylation facilitates pten stabilization, thereby negatively regulating the pi3k/pdk1/akt1 signaling axis" SIGNOR-168469 PRKACA protein P17612 UNIPROT VIM protein P08670 UNIPROT "down-regulates activity" phosphorylation Ser7 sSSSYRRM -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-250071 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 DLX3 protein O60479 UNIPROT "up-regulates activity" phosphorylation Thr134 KKVRKPRtIYSSYQL -1 11343707 t lperfetto "Dlx3 is primarily phosphorylated by PKC alpha. By deletion and mutational analysis, we show that the serine residue S(138), located in the homeodomain of Dlx3 protein, was specifically phosphorylated by PKC. The phosphorylation of purified Dlx3 proteins by PKC partially inhibited formation of complexes between Dlx3 protein and DNA. These results suggest that Dlx3 protein can be directly phosphorylated by PKC and this affects the DNA binding activity of Dlx3." SIGNOR-249097 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 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 PRKDC protein P78527 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 9363941 t gcesareni "We demonstrate that phosphorylation of p53 at serines 15 and 37 impairs the ability of mdm2 to inhibit p53-dependent transactivation. We present evidence that these effects are most likely due to a conformational change induced upon phosphorylation of p53. Our studies provide a plausible mechanism by which the induction of p53 can be modulated by dna-pk (or other protein kinases with similar specificity) in response to dna damage." SIGNOR-53030 RND1 protein Q92730 UNIPROT MAPK8 protein P45983 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-152811 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 RPS6KB2 protein Q9UBS0 UNIPROT MXD1 protein Q05195 UNIPROT down-regulates phosphorylation Ser145 IERIRMDsIGSTVSS 9606 18451027 t lperfetto "In this study, we showed that mad1 is a substrate of p90 ribosomal kinase (rsk) and p70 s6 kinase (s6k). 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" SIGNOR-178594 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 CSNK2A1 protein P68400 UNIPROT SIRT1 protein Q96EB6 UNIPROT unknown phosphorylation Ser661 GAEVYSDsEDDVLSS 9606 19236849 t llicata "We demonstrate that sirt1 is a substrate for protein kinase ck2 both in vitro and in vivo. Both, deletion construct analyses and serine-to-alanine mutations identified sirt1 ser-659 and ser-661 as major ck2 phosphorylation sites that are phosphorylated in vivo as well." SIGNOR-184155 ADRB2 protein P07550 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-257192 HLA-G protein P17693 UNIPROT KLRC1 protein P26715 UNIPROT up-regulates binding 9606 9560253 t gcesareni "Current models of nk cell function have supposed that the cd94/nkg2a heterodimer is interacting with an epitope common to classical hla class i" SIGNOR-56714 JAK2 protein O60674 UNIPROT STAT5A protein P42229 UNIPROT up-regulates phosphorylation 9606 9575217 t lperfetto "Jak2 kinase induces tyrosine phosphorylation, dimerization, nuclear translocation, and dna binding of a concomitantly expressed stat5 protein" SIGNOR-56830 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 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 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 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 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 PRKCZ protein Q05513 UNIPROT PRKCZ protein Q05513 UNIPROT up-regulates phosphorylation Thr560 TSEPVQLtPDDEDAI 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 autophosphorylation" SIGNOR-85505 RELA protein Q04206 UNIPROT EGR1 protein P18146 UNIPROT up-regulates binding 9606 SIGNOR-C13 10671503 t gcesareni "The early growth response transcription factor egr-1 can also interact with rela in vitro and regulate nf-kappab transcriptional activity in vivo" SIGNOR-75001 SMO protein Q99835 UNIPROT GNAT2 protein P19087 UNIPROT up-regulates binding 9606 16885213 t gcesareni "Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling." SIGNOR-148534 SMO protein Q99835 UNIPROT GNB3 protein P16520 UNIPROT up-regulates binding 9606 17251915 t gcesareni "Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling 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-152814 STK3 protein Q13188 UNIPROT NEK2 protein P51955 UNIPROT up-regulates phosphorylation Ser438 EKNYQLKsRQILGMR 9606 21076410 t lperfetto "Our data suggest that mst2 phosphorylates nek2a thereby recruiting nek2a to centrosomes and promoting phosphorylation and displacement of centrosomal linker proteins" SIGNOR-169539 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 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 AKT proteinfamily SIGNOR-PF24 SIGNOR CDKN1B protein P46527 UNIPROT "down-regulates activity" phosphorylation Thr157 GIRKRPAtDDSSTQN 9606 18570873 t lperfetto "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-244202 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-245304 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 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 MAP3K1 protein Q13233 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates phosphorylation Thr211 LVDSVAKtIDAGCKP 9606 9712898 t gcesareni "Both wild type and kinase-inactive mutant rip immunoprecipitates can active mkk6 in vitrohe sapks are activated by at least two meks, sapk/erk kinase-1 (sek1, also called mapk-kinase (mkk)) and mkk7" SIGNOR-59679 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 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 PPP2R5B protein Q15173 UNIPROT BCL2 protein P10415 UNIPROT down-regulates dephosphorylation Ser70 RDPVARTsPLQTPAA 9606 18845789 t gcesareni "Pp2a directly interacts with the bh4 domain of bcl2 as a docking site to potentially bridge pp2a to bcl2's flexible loop domain containing the target serine 70 phosphorylation site." SIGNOR-181559 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 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT unknown phosphorylation Ser503 KENIFGEsRASTFCG 9606 19366211 t llicata "This study identifies novel in vitro pkcdelta autophosphorylation sites at thr(141) adjacent to the pseudosubstrate domain, thr(218) in the c1a-c1b interdomain, ser(295), ser(302), and ser(304) in the hinge region, and ser(503) adjacent to thr(505) in the activation loop." SIGNOR-185299 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT unknown phosphorylation Thr218 TAANSRDtIFQKERF 9606 19366211 t llicata "This study identifies novel in vitro pkcdelta autophosphorylation sites at thr(141) adjacent to the pseudosubstrate domain, thr(218) in the c1a-c1b interdomain, ser(295), ser(302), and ser(304) in the hinge region, and ser(503) adjacent to thr(505) in the activation loop." SIGNOR-185303 RAC2 protein P15153 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates binding 9606 9705280 t gcesareni "This report shows that rac1 binds to and stimulates the kinase activity of pak1 approximately 2- and 4-5-fold, respectively, better than rac2." SIGNOR-59546 SMO protein Q99835 UNIPROT GNB1 protein P62873 UNIPROT up-regulates binding 9606 16885213 t gcesareni "Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling." SIGNOR-148537 SMO protein Q99835 UNIPROT GNB2 protein P62879 UNIPROT up-regulates binding 9606 16885213 t gcesareni "Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling." SIGNOR-148589 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 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-248008 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-95247 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 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-89696 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 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 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 EIF3I protein Q13347 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates binding 9606 9774674 t gcesareni "Another receptor-associated protein is trip-1, which interacts with and is phosphorylated by tbrii and contains five wd-40 repeats. The association of wd-40 repeat proteins may then allow them to play a role in signaling by the serine/threonine kinase receptors." SIGNOR-60700 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 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 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 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 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT unknown phosphorylation Ser302 TQRASRRsDSASSEP 9606 19366211 t llicata "This study identifies novel in vitro pkcdelta autophosphorylation sites at thr(141) adjacent to the pseudosubstrate domain, thr(218) in the c1a-c1b interdomain, ser(295), ser(302), and ser(304) in the hinge region, and ser(503) adjacent to thr(505) in the activation loop." SIGNOR-185291 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT unknown phosphorylation Ser304 RASRRSDsASSEPVG 9606 19366211 t llicata "This study identifies novel in vitro pkcdelta autophosphorylation sites at thr(141) adjacent to the pseudosubstrate domain, thr(218) in the c1a-c1b interdomain, ser(295), ser(302), and ser(304) in the hinge region, and ser(503) adjacent to thr(505) in the activation loop." SIGNOR-185295 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 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 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 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 CSNK1A1 protein P48729 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser114 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 FBXW11 protein Q9UKB1 UNIPROT SKP1 protein P63208 UNIPROT up-regulates binding 9606 10023660 t gcesareni "The scf is composed of skp1, cdc53/cul1, and a specificity-conferring f-box protein. F-box proteins contain two domains, an f-box motif that binds skp1 and allows assembly into skp1/cdc53 complexes, and a second proteinprotein interaction domain that interacts specifically with one or more target proteins. Cdc53/cul1, in turn, interacts with both the e2 and the skp1/f-box protein complex." SIGNOR-64505 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 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 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 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 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 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 Ser907 TDASRRSsEASQSDG 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-75355 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 TFAP2A protein P05549 UNIPROT up-regulates phosphorylation Ser239 AEVQRRLsPPECLNA 9606 10037142 t llicata "Recombinant ap-2 was phosphorylated in vitro by protein kinase a (pka) at ser239. Mutation of ser239 to ala abolished in vitro phosphorylation of ap-2 by pka, but not the dna binding activity of ap-2. Cotransfection studies showed that pka stimulated the effect of ap-2 on the apoe promoter, but not that of the s239a mutant." SIGNOR-64955 PRKG1 protein Q13976 UNIPROT TRPC3 protein Q13507 UNIPROT down-regulates phosphorylation 9606 BTO:0000007 16331690 t "The effect has been demonstrated using Q13507-3" llicata "The present study demonstrates that human trpc3 expressed in hek293 cells forms store-operated ca2+ influx channels, the activity of which is inhibited by pkg. The inhibition is due to a direct phosphorylation of pkg on trpc3 channels at position t11 and s263." SIGNOR-142964 RBPJ protein Q06330 UNIPROT CIR1 protein Q86X95 UNIPROT up-regulates binding 9606 9874765 t amattioni "In the mechanism of cbf1-mediated repression, cbf1 binds to a unique corepressor cir. Targeting of cir to cbf1 is an important component of repression. Cir binds to histone deacetylase and to sap30 and serves as a linker between cbf1 and the histone deacetylase complex." SIGNOR-62932 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 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 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 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 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 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 CHUK protein O15111 UNIPROT H3F3A protein P84243 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 12588998 t gcesareni "Cascade of distinct histone modifications during collagenase gene activation." SIGNOR-98365 EGFR protein P00533 UNIPROT HGS protein O14964 UNIPROT up-regulates phosphorylation Tyr329 IDPELARyLNRNYWE 9606 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-86689 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 FGF14 protein Q92915 UNIPROT SCN2A protein Q99250 UNIPROT "down-regulates activity" binding 9606 BTO:0000938 20679355 t miannu "Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels." SIGNOR-253429 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 MAPK1 protein P28482 UNIPROT NUP50 protein Q9UKX7 UNIPROT up-regulates 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 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 MAPK8 protein P45983 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates phosphorylation Ser130 SGEQAEGsPGGPGDS 9606 12058028 t gcesareni "The stress-activated protein kinases p38 alpha and jnk1 stabilize p21(cip1) by phosphorylation." SIGNOR-89440 PLK1 protein P53350 UNIPROT SRI protein P30626 UNIPROT unknown phosphorylation Thr155 YSTNGKItFDDYIAC 9606 24427308 t lperfetto "Sorcin interacts physically with plk1, is phosphorylated by plk1 and induces plk1 autophosphorylation, thereby regulating kinase activity." SIGNOR-203732 PRKCE protein Q02156 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates phosphorylation Ser706 ARIIGEKsFRRSVVG 9606 12058027 t gcesareni "Furthermore, we show that pkd2 can be activated by classical and novel members of the protein kinase c (pkc) family such as pkc alpha, pkc epsilon, and pkc eta. These pkcs are activated by gastrin in ags-b cells. Thus, pkd2 is likely to be a novel downstream target of specific pkcs upon the stimulation of ags-b cells with gastrin." SIGNOR-89411 RPS6KA3 protein P51812 UNIPROT TINF2 protein Q9BSI4 UNIPROT unknown phosphorylation Ser295 FPFRNLGsPTQVISK 9606 23977114 t lperfetto "Phosphorylation of serines 295 and 330 appeared to be mediated, at least in part, by the mitotic kinase rsk2. The consequence of tin2 phosphorylation during mitosis remains to be determined" SIGNOR-202532 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 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ADAM17 protein P78536 UNIPROT up-regulates phosphorylation Thr735 KPFPAPQtPGRLQPA 9606 12058067 t lperfetto "We report that the cytosolic tail of the tumor necrosis factor alpha-converting enzyme (tace) is phosphorylated by erk at threonine 735.These results demonstrate that secretases are able to discriminate between the different stimuli that trigger membrane protein ectodomain cleavage and indicate that phosphorylation by mapks may regulate the proteolytic function of membrane secretases." SIGNOR-89614 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 MAPK7 protein Q13164 UNIPROT ETS1 protein P14921 UNIPROT up-regulates phosphorylation Thr38 CADVPLLtPSSKEMM 9606 12048211 t gcesareni "9-cis retinoid x receptor alpha (rxr alpha) interacted with erk2 but not erk5 in intact cells, whereas ets-1 interacted preferentially with erk5. Increased phosphorylation of rxr alpha and ets-1 was detected in response to 1,25d. Activated erk2 and erk5 specifically phosphorylated rxr alpha and ets-1, respectively.Mutagenesis of ets-1 (t38a) reduced cyp24 promoter activity to levels observed with the dominant-negative mek5(a) and inhibited erk5-directed phosphorylation. Mutated rxr alpha (s260a) inhibited 1,25d-induced cyp24 promoter activity and abolished phosphorylation by activated erk2." SIGNOR-88666 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 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 PCSK7 protein Q16549 UNIPROT ATF6 protein P18850 UNIPROT up-regulates phosphorylation 9606 12076252 t gcesareni "We discovered that azc, an agent that causes the formation of abnormal proteins, stimulates the stress-activated kinase p38 mapk, which phosphorylates atf6" SIGNOR-89813 PLK1 protein P53350 UNIPROT RAN protein P62826 UNIPROT up-regulates phosphorylation Ser135 DRKVKAKsIVFHRKK 9606 16930555 t lperfetto "Plk1 is capable of phosphorylating co-immunoprecipitated ran in vitro on serine-135 and ran is phosphorylated in vivo at the same site during mitosis when plk1 is normally activated. Deregulation of ran phosphorylation disrupts normal spindle structure and segregation of chromosomes." SIGNOR-149073 PRKCD protein Q05655 UNIPROT TP73 protein O15350 UNIPROT up-regulates phosphorylation Ser289 GQVLGRRsFEGRICA 9606 12097319 t llicata "The results show that pkcdeltacf phosphorylates the p73beta transactivation and dna-binding domains. pkcdeltacf-mediated phosphorylation of p73beta is associated with accumulation of p73beta and induction of p73beta-mediated transactivation." SIGNOR-90279 PRKCH protein P24723 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates phosphorylation Ser710 GEKSFRRsVVGTPAY 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-89427 PRKG1 protein Q13976 UNIPROT PRKG1 protein Q13976 UNIPROT up-regulates phosphorylation Ser65 TTRAQGIsAEPQTYR 9606 12080049 t miannu "Serines 64 and 79 are homologous residues that are juxtaposed to the autoinhibitory pseudosubstrate site in cgmp-dependent protein kinase type ialpha and type ibeta (pkg-ialpha and pkg-ibeta), respectively. Autophosphorylation of this residue is associated with activation of type i pkgs." SIGNOR-89839 PRKG1 protein Q13976 UNIPROT SLC6A4 protein P31645 UNIPROT up-regulates phosphorylation Thr276 SIWKGVKtSGKVVWV 9606 BTO:0000567 17913921 t gcesareni "These results are consistent with the hypothesis that pkg phosphorylates hsert at thr-276 and increases its activity by modifying the substrate permeation pathway formed, in part, by tm5." SIGNOR-158186 IL2 protein P60568 UNIPROT IL2RA protein P01589 UNIPROT up-regulates binding 9606 16477002 t miannu "Il-2 is a cytokine that functions as a growth factor and central regulator in the immune system and mediates its effects through ligand-induced hetero-trimerization of the receptor subunits il-2r alpha, il-2r beta, and gamma(c)." SIGNOR-144537 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 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 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 PRKACA protein P17612 UNIPROT ETV1 protein P50549 UNIPROT up-regulates phosphorylation Ser191 HRFRRQLsEPCNSFP 9606 12213813 t lperfetto "The camp-dependent protein kinase a (pka) phosphorylates er81 on ser(191)/ser(216)ser(191) and ser(216), were identified, whose mutation to alanine reduces er81 activity upon erk-mapk stimulation." SIGNOR-92447 PRKACA protein P17612 UNIPROT ETV1 protein P50549 UNIPROT up-regulates phosphorylation Ser334 PTYQRRGsLQLWQFL 9606 12213813 t lperfetto "Pka targets er81 on ser(334) in vivo. Surprisingly, phosphorylation of ser(334) severely reduces the dna-binding ability of er81 but also enhances the transactivation potential of er81. These counteractive effects of pka phosphorylation on er81-dependent transcription may cause the selective up-regulation of promoters with high but not low affinity for er81." SIGNOR-92455 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 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 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 PTPRR protein Q15256 UNIPROT MAPK1 protein P28482 UNIPROT "down-regulates activity" dephosphorylation Tyr187 HTGFLTEyVATRWYR 9534 BTO:0004055 11493009 t "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.|PTP-SL dephosphorylates the regulatory phosphotyrosine on the active loop of ERK1/2. Tyrosine dephosphorylation of ERK1/2 causes the inactivation of ERK1/2 and its retention in the cytoplasm" SIGNOR-248840 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 ROCK1 protein Q13464 UNIPROT MYL12B protein O14950 UNIPROT up-regulates phosphorylation Ser20 KRPQRATsNVFAMFD 9606 12185584 t lperfetto "Here we found that rho-kinase has an activity for mrlc diphosphorylation at both threonine 18 and serine 19 in nonmuscle cells using sequential column chromatographies." SIGNOR-91542 ROCK1 protein Q13464 UNIPROT MYL12B protein O14950 UNIPROT up-regulates phosphorylation Thr19 KKRPQRAtSNVFAMF 9606 12185584 t gcesareni "Here we found that rho-kinase has an activity for mrlc diphosphorylation at both threonine 18 and serine 19 in nonmuscle cells using sequential column chromatographies." SIGNOR-91546 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 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 SEMA4D protein Q92854 UNIPROT PLXNB1 protein O43157 UNIPROT up-regulates binding 9606 12198496 t gcesareni "Binding of sema 4d to plexin b1 stimulates the tyrosine kinase activity of met, resulting in tyrosine phosphorylation of both receptors." SIGNOR-92201 UHMK1 protein Q8TAS1 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates phosphorylation Ser10 NVRVSNGsPSLERMD 9606 12093740 t lperfetto "Hkis is a nuclear protein that binds the c-terminal domain of p27(kip1) and phosphorylates it on s10 in vitro and in vivo, promoting its nuclear export to the cytoplasm.Phosphorylation at serine 10, a major phosphorylation site of p27(kip1), increases its protein stability" SIGNOR-90274 AKT1 protein P31749 UNIPROT VIM protein P08670 UNIPROT up-regulates 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 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 CHEK1 protein O14757 UNIPROT FANCE protein Q9HB96 UNIPROT up-regulates phosphorylation Ser374 LFLGRILsLTSSASR 9606 17296736 t llicata "Chk1 directly phosphorylates the fance subunit of the fa core complex on two conserved sites (threonine 346 and serine 374). chk1-mediated phosphorylation of fance is required for the fanconi anemia/brca pathway." SIGNOR-153023 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 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 FGR protein P09769 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr925 DRSNDKVyENVTGLV 9606 12387730 t gcesareni "Phosphorylated on tyrosine residues upon activation. Phosphorylation at tyr-925 is important for interaction with grb2 and depends on the complex formation between fak and the src-kinase fgr." SIGNOR-94405 GRK2 protein P25098 UNIPROT RPLP2 protein P05387 UNIPROT up-regulates phosphorylation Ser102 KDEKKEEsEESDDDM 9606 12379128 t gcesareni "The phosphorylation sites in grk2-phosphorylated p2 are identified (s102 and s105) and are identical to the sites known to regulate p2 activity." SIGNOR-94254 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 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 PML protein P29590 UNIPROT up-regulates phosphorylation Thr28 PTMPPPEtPSEGRQP 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-124313 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 MAPK3 protein P27361 UNIPROT MED1 protein Q15648 UNIPROT up-regulates phosphorylation Thr1032 SSSNRPFtPPTSTGG 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-93989 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 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 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 DYRK2 protein Q92630 UNIPROT CARHSP1 protein Q9Y2V2 UNIPROT unknown phosphorylation Ser30 TPRSRERsPSPLRGN 9606 BTO:0000671 15910284 t lperfetto "Dyrk2 (dual-specificity tyrosine-phosphorylated and -regulated protein kinase 2) phosphorylated crhsp24 at ser30, ser32 and ser41 in vitro, and ser41 was identified as a site phosphorylated in cells." SIGNOR-137474 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 CHEK1 protein O14757 UNIPROT FANCE protein Q9HB96 UNIPROT up-regulates phosphorylation Thr346 LGLLRLCtWLLALSP 9606 17296736 t llicata "Chk1 directly phosphorylates the fance subunit of the fa core complex on two conserved sites (threonine 346 and serine 374). chk1-mediated phosphorylation of fance is required for the fanconi anemia/brca pathway." SIGNOR-153027 DYRK1A protein Q13627 UNIPROT GLI1 protein P08151 UNIPROT up-regulates phosphorylation 9606 12138125 t "Dyrk1 acts synergistically with Shh to induce transcription of a Gli-promoter-driven luciferase reporter gene and of endogenous alkaline phosphatase." gcesareni "Dyrk1 phosphorylates gli1 on more than one domain." SIGNOR-90809 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 EP300 protein Q09472 UNIPROT MAML1 protein Q92585 UNIPROT up-regulates acetylation 9606 17300219 t gcesareni "The n-terminal domain of maml1 directly interacts with both p300 and histones, and the p300-maml1 complex specifically acetylates histone h3 and h4 tails in chromatin. Furthermore, p300 acetylates maml1 and evolutionarily conserved lysine residues in the maml1 n-terminus are direct substrates for p300-mediated acetylation." SIGNOR-153035 EP300 protein Q09472 UNIPROT SMAD7 protein O15105 UNIPROT up-regulates acetylation Lys70 GKAVRGAkGHHHPHP 9606 12408818 t gcesareni "Here we present evidence that smad7 interacts with the transcriptional coactivator p300, resulting in acetylation of smad7 on two lysine residues in its n terminus. Acetylation or mutation of these lysine residues stabilizes smad7 and protects it from tgfbeta-induced degradation. we have recently shown that smad7 is acetylated on lysine residues 64 and 70 by p300" SIGNOR-95169 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 IFNL1 protein Q8IU54 UNIPROT IL10RB protein Q08334 UNIPROT up-regulates binding 9606 12469119 t gcesareni "Il-28 and il-29 interacted with a heterodimeric class ii cytokine receptor that consisted of il-10 receptor beta (il-10rbeta) and an orphan class ii receptor chain, designated il-28ralpha." SIGNOR-96177 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 PRKCZ protein Q05513 UNIPROT PARD3 protein Q8TEW0 UNIPROT up-regulates phosphorylation Ser827 REGFGRQsMSEKRTK 9606 12390250 t gcesareni "These results imply that serine 827 in the apkc binding site of par-3 is a target of apkc and that the regulated interaction between a protein kinase, apkc, and its substrate, par-3, plays an essential role in the establishment of cell polarity" SIGNOR-94523 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 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 SRC protein P12931 UNIPROT MYLK protein Q15746 UNIPROT up-regulates phosphorylation Tyr471 YEDAGSHyLCLLKAR 9606 12408982 t gcesareni "Ec mlck-1 is phosphorylated by p60(src) on tyr(464) and tyr(471), resulting in a 2- to 3-fold increase in ec mlck-1 enzymatic activity." SIGNOR-95242 STK4 protein Q13043 UNIPROT TNNI3 protein P19429 UNIPROT unknown phosphorylation Thr51 SRKLQLKtLLLQIAK 9606 BTO:0000671 18986304 t llicata "Ms analysis indicated that mst1 phosphorylates ctni at thr(31), thr(51), thr(129) and thr(143)." SIGNOR-182061 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 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation Ser227 DHEKKAYsFCGTVEY 9606 10980595 t lperfetto "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-244692 AMPK complex SIGNOR-C15 SIGNOR BAIAP2 protein Q9UQB8 UNIPROT down-regulates phosphorylation Ser366 KTLPRSSsMAAGLER 9606 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-216608 FGF14 protein Q92915 UNIPROT SCN4A protein P35499 UNIPROT "down-regulates activity" binding 9606 BTO:0001103 20679355 t miannu "Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels." SIGNOR-253433 FGF14 protein Q92915 UNIPROT SCN5A protein Q14524 UNIPROT "down-regulates activity" binding 9606 BTO:0000199 20679355 t miannu "Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels." SIGNOR-253417 ITK protein Q08881 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-98090 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 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 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 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 NR0B2 protein Q15466 UNIPROT ESRRG protein P62508 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000671 11705994 f gcesareni "The current study also demonstrates that shp inhibits err_ transactivation." SIGNOR-111620 NTN4 protein Q9HB63 UNIPROT UNC5A protein Q6ZN44 UNIPROT up-regulates binding 9606 12598531 t gcesareni "The unc5hs are axon guidance receptors that mediate netrin-1-dependent chemorepulsion, and dependence receptors that mediate netrin-1-independent apoptosis." SIGNOR-98483 PAK1 protein Q13153 UNIPROT ILK protein Q13418 UNIPROT up-regulates phosphorylation Thr173 DTFWKGTtRTRPRNG 9606 17420447 t lperfetto "We found that pak1 phosphorylates ilk at threonine-173 and serine-246 in vitro and in vivo. together, these results suggest that ilk is a pak1 substrate, undergoes phosphorylation-dependent shuttling between the cell nucleus and cytoplasm, and interacts with gene-regulatory chromatin." SIGNOR-154307 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 RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser619 SLPKINRsASEPSLH 9606 12551925 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-97648 PRKCD protein Q05655 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Ser139 EEWTRHGsFVNKPTR 9606 16963224 t "The effect has been demonstrated using P29353-2" gcesareni "Pkc delta phosphorylates p52shca at ser29 to regulate erk activation in response to h2o2." SIGNOR-149398 PRKCG protein P05129 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-97558 REL protein Q04864 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-46945 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 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 APOA1 protein P02647 UNIPROT HDL_assembly phenotype SIGNOR-PH61 SIGNOR up-regulates 9606 23077142 f miannu "Cholesterol efflux is the first step in the formation of HDL, which is initiated through the action of ATP binding cassette transporter (ABC) A1 on apolipoprotein (apo) A-I that produces nascent HDL (nHDL)." SIGNOR-252110 JNK proteinfamily SIGNOR-PF15 SIGNOR BCL2L11 protein O43521 UNIPROT up-regulates phosphorylation Ser118 DKSTQTPsPPCQAFN 9606 12591950 t lperfetto "Biml (bim long) was induced and phosphorylated parallel to jnk activitythese data demonstrate that biml is phosphorylated in vivo on thr-56 and that jnk also phosphorylates biml on at least one serine residue (ser-44 and/or ser-58)" SIGNOR-98388 APH1A protein Q96BI3 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates binding 9606 BTO:0000142 12297508 t "Gamma secretase subunit that leads to PS1/PS2 eterodimer complex stabilisation." gcesareni "By using co-immunoprecipitation and nickel affinity pull-down approaches, we now show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain." SIGNOR-93262 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 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1878 SPKYSPTsPTYSPTT 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 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 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 PLCG1 protein P19174 UNIPROT PRKCA protein P17252 UNIPROT up-regulates phosphorylation 9606 12645577 t gcesareni "Tnf-alfa binds to tnfr1 and activates pc-plc to induce pkcalfa and c-src activation, leading to tyrosine phosphorylation of ikkbeta at tyr188 and tyr199." SIGNOR-99310 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 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 PRKCG protein P05129 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT up-regulates 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-97295 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 SRC protein P12931 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Tyr341 GQRDSSYyWEIEASE 9606 12551923 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-97639 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 AR protein P10275 UNIPROT BTG1 protein P62324 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-253673 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 THRB protein P10828 UNIPROT up-regulates phosphorylation Ser142 IQKNLHPsYSCKYEG 9606 12809513 t gcesareni "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-102212 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 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 RAC1 protein P63000 UNIPROT USP6 protein P35125 UNIPROT up-regulates relocalization 9606 12612085 t miannu "In quiescent cells, tre17 is localized to intracellular filamentous and punctate structures in the cytoplasm, folded in an inactive conformation. Upon growth factor addition, cdc42 and rac1 become activated and recruit tre17 to the plasma membrane. Stable membrane localization of tre17 also requires polymerized actin. This recruitment process leads to a conformational change in tre17, such that the n-terminal portion of the molecule further stimulates the accumulation of cortical actin." SIGNOR-98938 SIK2 protein Q9H0K1 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Ser794 QHLRLSTsSGRLLYA 9606 12624099 t gcesareni "These results suggest that highly expressed sik2 in insulin-stimulated adipocytes phosphorylates ser794_ of irs-1 and, as a result, might modulate the efficiency ofinsulinsignal transduction" SIGNOR-99055 SRC protein P12931 UNIPROT IKBKB protein O14920 UNIPROT up-regulates phosphorylation Tyr199 ELLEQQKyTVTVDYW 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-99318 SSH1 protein Q8WYL5 UNIPROT CORO1B protein Q9BR76 UNIPROT up-regulates dephosphorylation Ser2 sFRKVVRQ 9606 17350576 t gcesareni "Coronin 1b inhibits filament nucleation by arp2/3 complex and this inhibition is attenuated by phosphorylation of coronin 1b at serine 2, a site targeted by ssh1l." SIGNOR-153604 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 CSNK2A1 protein P68400 UNIPROT RRN3 protein Q9NYV6 UNIPROT down-regulates phosphorylation Ser170 KEGDVDVsDSDDEDD 9606 18559419 t llicata "Here we show that ck2 phosphorylates the transcription initiation factor tif-ia at serines 170 and 172 (ser170/172), and this phosphorylation triggers the release of tif-ia from pol i after transcription initiation." SIGNOR-178939 CSNK2A1 protein P68400 UNIPROT RRN3 protein Q9NYV6 UNIPROT down-regulates phosphorylation Ser172 GDVDVSDsDDEDDNL 9606 18559419 t llicata "Here we show that ck2 phosphorylates the transcription initiation factor tif-ia at serines 170 and 172 (ser170/172), and this phosphorylation triggers the release of tif-ia from pol i after transcription initiation." SIGNOR-178943 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 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 ARNTL2 protein Q8WYA1 UNIPROT CLOCK/ARNTL2 complex SIGNOR-C196 SIGNOR "form complex" binding 19605937 t lperfetto "Like BMAL1, its paralog BMAL2 dimerizes with CLOCK to activate the E-box-dependent transcription" SIGNOR-253710 ARNT protein P27540 UNIPROT CYP1A1 protein P04798 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-253705 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 FOS protein P01100 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-253696 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 MAPK14 protein Q16539 UNIPROT CCND1 protein P24385 UNIPROT up-regulates phosphorylation 9606 20626350 t gcesareni "A large number of cytosolic proteins can be phosphorylated by p38 mapks, including phospholipase a2, the microtubule-associated protein tau, nhe-1, cyclin d1, cdk inhibitors, bcl2 family proteins, growth factor receptors or keratins" SIGNOR-166594 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 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 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 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser737 EPLERRLsLVPDSEQ 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-21316 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates dephosphorylation Tyr1009 LDTSSVLyTAVQPNE 9606 18567737 t gcesareni "Ptp1b blocked pdgf-induced tyr716 and tyr751 phosphorylation of the pdgfr." SIGNOR-179064 MAPK1 protein P28482 UNIPROT RAF1 protein P04049 UNIPROT "down-regulates activity" phosphorylation Ser296 SPSALSSsPNNLSPT 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-249442 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 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 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 MAPK7 protein Q13164 UNIPROT MAP2K5 protein Q13163 UNIPROT up-regulates phosphorylation Ser137 QHSSPAVsDSLPSNS 9606 BTO:0000671 12628002 t lperfetto "Phosphorylation and activation of extracellular-signal-regulated protein kinase 5 (erk5) by mitogen-activated protein kinase kinase 5 (mkk5)activated erk5 also phosphorylated mitogen-activated protein kinase kinase 5 (mkk5) extensively at ser(129), ser(137), ser(142) and ser(149)" SIGNOR-99131 PPM1B protein O75688 UNIPROT CDK9 protein P50750 UNIPROT unknown dephosphorylation Thr186 NSQPNRYtNRVVTLW 9606 18829461 t gcesareni "Phosphatase ppm1a regulates phosphorylation of thr-186 in the cdk9 t-loop" SIGNOR-181396 PRKCA protein P17252 UNIPROT EGFR protein P00533 UNIPROT up-regulates 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 PRKG1 protein Q13976 UNIPROT GTF2I protein P78347 UNIPROT up-regulates phosphorylation Ser784 GVPFRRPsTFGIPRL 9606 BTO:0000671 12082086 t lperfetto "G-kinase phosphorylated tfii-i in vitro and in vivo on ser(371) and ser(743) outside of the interaction domain. G-kinase strongly enhanced tfii-i transactivation of a serum-response element-containing promoter in cos7 cells" SIGNOR-89853 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates dephosphorylation Tyr1021 PNEGDNDyIIPLPDP 9606 18567737 t gcesareni "Interestingly, resveratrol increased the activity of protein tyrosine phosphatase ptp1b, which dephosphorylates pdgf-stimulated phosphorylation at tyrosine-751 and tyrosine-716 on pdgfr with concomitant reduction in akt and erk1/2 kinase activity. these results for the first time provide evidence that the stilbene resveratrol targets ptp1b to inhibit pdgfr mitogenic signaling." SIGNOR-179068 RPS6KA1 protein Q15418 UNIPROT RPS6 protein P62753 UNIPROT up-regulates phosphorylation Ser235 IAKRRRLsSLRASTS 9606 17360704 t gcesareni "We demonstrate that while ribosomal s6 kinase 1 (s6k1) phosphorylates rps6 at all sites, rsk exclusively phosphorylates rps6 at ser(235/236) in vitro and in vivo using an mtor-independent mechanism." SIGNOR-153618 Serdemetan chemical CID:11609586 PUBCHEM MDM2 protein Q00987 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193504 SRC protein P12931 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates phosphorylation Tyr242 FFQQQMIyDSPPSRA 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-236314 STK4 protein Q13043 UNIPROT TNNI3 protein P19429 UNIPROT unknown phosphorylation Thr31 SNYRAYAtEPHAKKK 9606 BTO:0000671 18986304 t llicata "Ms analysis indicated that mst1 phosphorylates ctni at thr(31), thr(51), thr(129) and thr(143)." SIGNOR-182057 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 ATF4 protein P18848 UNIPROT FGF21 protein Q9NSA1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 22233381 f miannu "These results add FGF21 gene induction to the transcriptional programme initiated by increased levels of ATF4 and offer a new mechanism for the induction of the FGF21 gene expression under nutrient deprivation." SIGNOR-253748 KIT protein P10721 UNIPROT KIT protein P10721 UNIPROT up-regulates phosphorylation Tyr703 DHAEAALyKNLLHSK 9606 10377264 t miannu "Identification of tyr-703 and tyr-936 as autophosphorylation sites in c-kit/scfr" SIGNOR-68643 MAPK14 protein Q16539 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 10085140 t gcesareni "On the other hand, sapks such as jnks and p38 phosphorylate atf-2 at thr-69, thr-71, and ser-90 which lie close to the n-terminal transcriptional activation domain and stimulate itstrans-activating capacity our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf- signaling via tak1 and p38." SIGNOR-65601 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 DDIT4 protein Q9NX09 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19439225 f lperfetto "We additionally identified Redd1 as a downstream effector of C/EBP-beta stimulated by ATF4 activated under the stress conditions examined. RNA interference studies provided further evidence of the requirement of C/EBP-beta for Redd1 expression. We conclude that the Redd1 gene is transactivated by the ATF4 and C/EBP family of transcription factors, leading to mTOR inhibition in response to oxidative and ER stress." SIGNOR-253726 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 MAPK14 protein Q16539 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 10085140 t gcesareni "On the other hand, sapks such as jnks and p38 phosphorylate atf-2 at thr-69, thr-71, and ser-90 which lie close to the n-terminal transcriptional activation domain and stimulate itstrans-activating capacity our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf- signaling via tak1 and p38." SIGNOR-65597 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 MAPK7 protein Q13164 UNIPROT MAP2K5 protein Q13163 UNIPROT up-regulates phosphorylation Ser149 SNSLKKSsAELKKIL 9606 BTO:0000671 12628002 t lperfetto "Phosphorylation and activation of extracellular-signal-regulated protein kinase 5 (erk5) by mitogen-activated protein kinase kinase 5 (mkk5)activated erk5 also phosphorylated mitogen-activated protein kinase kinase 5 (mkk5) extensively at ser(129), ser(137), ser(142) and ser(149)" SIGNOR-99139 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates dephosphorylation Tyr716 RPPSAELySNALPVG 9606 18567737 t gcesareni "Ptp1b blocked pdgf-induced tyr716 and tyr751 phosphorylation of the pdgfr." SIGNOR-179072 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 RASGEF1A protein Q8N9B8 UNIPROT HRAS protein P01112 UNIPROT up-regulates binding 9606 19201597 t gcesareni "Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras." SIGNOR-183823 RPS6KA3 protein P51812 UNIPROT TH protein P07101 UNIPROT up-regulates phosphorylation Ser40 GQGAPGPsLTGSPWP 9606 7901013 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-34682 STK4 protein Q13043 UNIPROT TNNI3 protein P19429 UNIPROT unknown phosphorylation Thr143 RGKFKRPtLRRVRIS 9606 BTO:0000671 18986304 t llicata "Ms analysis indicated that mst1 phosphorylates ctni at thr(31), thr(51), thr(129) and thr(143)." SIGNOR-182053 MAPK14 protein Q16539 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser389 ARIQAAAsTPTNATA 9606 BTO:0000142 18451303 t gcesareni "Here, we show that p38 mitogen-activated protein kinase (mapk) also inactivates gsk3beta by direct phosphorylation at its c terminus, and this inactivation can lead to an accumulation of beta-catenin." SIGNOR-178603 ATR protein Q13535 UNIPROT ATRIP protein Q8WXE1 UNIPROT up-regulates phosphorylation Ser72 TLASQALsQCPAAAR 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-129473 SMARCB1 protein Q12824 UNIPROT SMARCA4 protein P51532 UNIPROT "up-regulates activity" 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-65438 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 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 NCOA1 protein Q15788 UNIPROT PGR protein P06401 UNIPROT up-regulates 9606 10449719 f miannu "Progesterone receptor (pr) functions as a transcription factor that modulates the transcription of target genes in response to progesterone and other signals. The transcriptional activity of pr requires the involvement of coactivators such as steroid receptor coactivator-1 (src-1)." SIGNOR-70149 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 PDPK2P protein Q6A1A2 UNIPROT SGK1 protein O00141 UNIPROT up-regulates phosphorylation Thr256 EHNSTTStFCGTPEY 9606 10191262 t gcesareni "Our results are consistent with a model in which activation of sgk by igf-1 or hydrogen peroxide is initiated by a ptdins(3,4, 5)p3-dependent activation of pdk2, which phosphorylates ser422." SIGNOR-66234 PRKACA protein P17612 UNIPROT H3F3A 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 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 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 PRKD1 protein Q15139 UNIPROT HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser486 RPLSRAQsSPAAPAS 9606 18617643 t gcesareni "We show for the first time that vegf stimulated phosphorylation of hdac7 at the sites of ser178, ser344, and ser479we found that phospholipase cgamma/protein kinase c/protein kinase d1 (pkd1)-dependent signal pathway mediated hdac7 phosphorylation and cytoplasmic accumulation by vegf." SIGNOR-179430 RPS6KA1 protein Q15418 UNIPROT H3F3A 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-70428 SMARCA4 protein P51532 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-65441 SMARCA4 protein P51532 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-65444 SRC protein P12931 UNIPROT CLTC protein Q00610 UNIPROT up-regulates phosphorylation Tyr1477 LFITEEDyQALRTSI 9606 10089883 t gcesareni "Egf-mediated clathrin phosphorylation is followed by clathrin redistribution to the cell periphery and is the product of downstream activation of src kinase by egf receptor (egfr) signaling" SIGNOR-65714 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 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 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 RPS6KA1 protein Q15418 UNIPROT "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-219320 AURKB protein Q96GD4 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT "up-regulates activity" phosphorylation Ser185 KKREKRRsTSRQFVD 9606 BTO:0000567 14744859 t llicata "It was found that the 5A fragment in which five Ser/Thr residues were substituted with Ala (S144A/T145A/S185A/T186A/S187A) fully prevented phosphorylation (Fig. 5B), confirming that Aurora B primarily phosphorylates five Ser/Thr residues in the basic region of MgcRacGAP. | the strong phosphorylation of the basic region of MgcRacGAP by Aurora B kinase was demonstrated, and this phosphorylation prevents the inhibition of MgcRacGAP GAP activity by PRC1" SIGNOR-250587 AVP protein P01185 UNIPROT BAD protein Q92934 UNIPROT down-regulates 9606 BTO:0000938 BTO:0000142 18402937 f gcesareni "Vp induces phosphorylation of the pro-apoptotic protein bad and prevents cytochrome c release." SIGNOR-178197 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 PDE4D protein Q08499 UNIPROT up-regulates phosphorylation 9606 10828059 t "The effect has been demonstrated using Q08499-4" llicata "The short pde4d1 isoenzyme is activated by erk2 phosphorylation this signifies that erk2 phosphorylated pde4d1 at a single site, ser491, that is cognate to the single erk2 phosphorylation site (ser579) found in pde4d3." SIGNOR-77559 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 RPS6KA3 protein P51812 UNIPROT H3F3A 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-70432 RPS6KA5 protein O75582 UNIPROT H3F3A 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 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 BAG1 protein Q99933 UNIPROT HSPA8 protein P11142 UNIPROT "up-regulates activity" binding -1 27474739 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-254115 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 BAG1 protein Q99933 UNIPROT BCL2 protein P10415 UNIPROT "up-regulates activity" binding 9606 BTO:0000661 7834747 t lperfetto "Cloning and functional analysis of BAG-1: A novel Bcl-2-binding protein with anti-cell death activity|" SIGNOR-254118 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 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 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 KPNB1 protein Q14974 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates relocalization 9606 10846168 t gcesareni "Here we show that the isolated smad 3 mh1 domain displays significant specific binding to importin beta. we propose that activation of all of the pathway-specific smad proteins (smads 1, 2, 3, 5, 8, and 9) exposes the conserved nls motif, which then binds directly to importin beta and triggers nuclear translocation." SIGNOR-78191 LRRK2 protein Q5S007 UNIPROT LRRK2 protein Q5S007 UNIPROT up-regulates phosphorylation Thr2035 GIKTSEGtPGFRAPE 9606 BTO:0000938 20595391 t lperfetto "Three putative autophosphorylation sites (thr-2031, ser-2032, and thr-2035) have been identified within the activation segment of the lrrk2 kinase domain based on sequence homology to mixed-lineage kinases. Phosphorylation at one or more of these sites is critical for the kinase activity of lrrk2." SIGNOR-166474 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 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-161518 MAPK1 protein P28482 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Ser360 TEMDPTYsPAALPQS 9606 15568999 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-131311 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 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 PRKG1 protein Q13976 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser660 FSAERRNsILTETLH 9606 10581361 t lperfetto "Direct amino acid sequencing and peptide mapping of cf-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by pka and pkgcftr possesses a large cluster of strict dibasic consensus sites for phosphorylation by protein kinase a (pka) in the r-domain and an obligatory dependence on phosphorylation is a hallmark of cftr cl(-) channel function" SIGNOR-72712 PRKG1 protein Q13976 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser737 EPLERRLsLVPDSEQ 9606 10581361 t lperfetto "Direct amino acid sequencing and peptide mapping of cf-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by pka and pkgcftr possesses a large cluster of strict dibasic consensus sites for phosphorylation by protein kinase a (pka) in the r-domain and an obligatory dependence on phosphorylation is a hallmark of cftr cl(-) channel function" SIGNOR-72716 PTK2 protein Q05397 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr397 SVSETDDyAEIIDEE 9606 10816598 t miannu "Fak autophosphorylation site, tyr397. / extracellular matrix (ecm)-induced autophosphorylation of fak on tyr397 creates a high affinity binding site for the sh2 domain of c-src, and mutation (tyr to phe) of this residue inhibits association" SIGNOR-77434 SMAD7 protein O15105 UNIPROT STRAP protein Q9Y3F4 UNIPROT up-regulates binding 9606 10757800 t gcesareni "Strap recruits smad7 to the activated type i receptor and forms a complex" SIGNOR-76771 UHMK1 protein Q8TAS1 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates phosphorylation Ser10 NVRVSNGsPSLERMD 9606 10831586 t lperfetto "Hkis is a nuclear protein that binds the c-terminal domain of p27(kip1) and phosphorylates it on s10 in vitro and in vivo, promoting its nuclear export to the cytoplasm.Phosphorylation at serine 10, a major phosphorylation site of p27(kip1), increases its protein stability" SIGNOR-77705 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 PTPN1 protein P18031 UNIPROT ROS1 protein P08922 UNIPROT down-regulates dephosphorylation Tyr2114 RDIYKNDyYRKRGEG 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-154203 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 ICK protein Q9UPZ9 UNIPROT ICK protein Q9UPZ9 UNIPROT up-regulates phosphorylation Tyr159 SKPPYTDyVSTRWYR 9606 15988018 t lperfetto "Ick is activated by dual phosphorylation of the tdy motif. Phosphorylation of tyr-159 in the tdy motif requires ick autokinase activity" SIGNOR-138424 IL11 protein P20809 UNIPROT IL11RA protein Q14626 UNIPROT up-regulates binding 9606 10948192 t gcesareni "Il-11 has been shown to induce gp130-dependent signaling through the formation of a high affinity complex with the il-11 receptor (il-11r) and gp130" SIGNOR-81102 MAPK1 protein P28482 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Ser360 TEMDPTYsPAALPQS 9606 BTO:0000567 9687510 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-59435 MAPK1 protein P28482 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Thr581 PDNQPLKtPCFTLHY 9606 18267068 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-160787 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 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 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 PLCG1 protein P19174 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates binding 9606 10913276 t gcesareni "We provide evidence that sos1, a p21ras-specific guanine nucleotide exchange factor, directly binds to the sh3 domain of plc-gamma1, and that the sh3 domain of plc-gamma1 is involved in sos1-mediated p21ras activation." SIGNOR-80024 PPP2CA protein P67775 UNIPROT KRT8 protein P05787 UNIPROT unknown dephosphorylation Ser432 SAYGGLTsPGLSYSL 9606 BTO:0000182 16554440 t "K8 Ser431-P is a physiologic substrate to PP2A during hyposmotic conditions and possibly other biologic contexts." SIGNOR-248623 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 PTPN1 protein P18031 UNIPROT ROS1 protein P08922 UNIPROT down-regulates dephosphorylation Tyr2110 FGLARDIyKNDYYRK 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-154199 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 WNT6 protein Q9Y6F9 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates 9606 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. Wnt4, wnt5a and wnt6 exert an intermediate effect activating both myf5 and myod equivalently in paraxial mesoderm." SIGNOR-198916 CALM1 protein P62158 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 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 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 CREBBP protein Q92793 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates binding 9606 SIGNOR-C6 11062529 t gcesareni "The cofactors grip-1, cbp/p300 and pcaf have hat activity and function as co-activators for mef-2c during myogenesis." SIGNOR-83843 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 GRIP1 protein Q9Y3R0 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates binding 9606 11062529 t gcesareni "The cofactors grip-1, cbp/p300 and pcaf have hat activity and function as co-activators for mef-2c during myogenesis." SIGNOR-83883 KSR1 protein Q8IVT5 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Thr269 NVHMVSTtLPVDSRM 9606 11134016 t lperfetto "Here we show that phosphorylation of c-raf-1 on thr(269) by ksr is necessary for optimal activation in response to egf stimulation." SIGNOR-85386 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 MAPK1 protein P28482 UNIPROT MKL1 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 NUMA1 protein Q14980 UNIPROT TUBA1B protein P68363 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-116472 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 PRKACA protein P17612 UNIPROT TAL1 protein P17542 UNIPROT down-regulates phosphorylation Ser122 DGRMVQLsPPALAAP 9606 BTO:0001271 22310283 t gcesareni "Thus, our data revealed a novel interplay between pka phosphorylation and tal1-mediated epigenetic regulation that regulates hematopoietic transcription and differentiation programs during hematopoiesis and leukemogenesis." SIGNOR-195987 PRKD1 protein Q15139 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Ser205 GVRRRRLsNVSLTGV 9606 10867018 t llicata "Activation of the serine/threonine kinase, protein kinase d (pkd/pkc mu) via a phorbol ester/pkc-dependent pathway involves phosphorylation events. the second autophosphorylation site (ser(203)) lies in that region of the regulatory domain" SIGNOR-78676 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 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 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 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 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 IFNW1 protein P05000 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-105979 JNK proteinfamily SIGNOR-PF15 SIGNOR HNRNPK protein P61978 UNIPROT up-regulates phosphorylation Ser353 DSAIDTWsPSEWQMA 9606 11259409 t lperfetto "Using modified jnk and its atp analogue enables the detection of novel jnk substrates. Among substrates identified using this approach is heterogeneous nuclear ribonucleoprotein k, which is involved in transcription and post-transcriptional mrna metabolism. The newly identified substrate can be phosphorylated by jnk on amino acids 216 and 353, which contribute to heterogeneous nuclear ribonucleoprotein k mediated transcriptional activities." SIGNOR-105762 BMPR1A protein P36894 UNIPROT SMAD5/SMAD4 complex SIGNOR-C205 SIGNOR "up-regulates activity" phosphorylation 9606 "BTO:0000165;BTO:0002974; BTO:0002809" 9442019 f 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 BTO:0004058 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-255786 IFNW1 protein P05000 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-105982 JNK proteinfamily SIGNOR-PF15 SIGNOR HNRNPK protein P61978 UNIPROT up-regulates phosphorylation Ser216 ILDLISEsPIKGRAQ 9606 11259409 t lperfetto "Using modified jnk and its atp analogue enables the detection of novel jnk substrates. Among substrates identified using this approach is heterogeneous nuclear ribonucleoprotein k, which is involved in transcription and post-transcriptional mrna metabolism. The newly identified substrate can be phosphorylated by jnk on amino acids 216 and 353, which contribute to heterogeneous nuclear ribonucleoprotein k mediated transcriptional activities." SIGNOR-105758 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 PRKACA protein P17612 UNIPROT AANAT protein Q16613 UNIPROT "up-regulates activity" phosphorylation Ser205 HPFLRRNsGC -1 11336675 t miannu "AANAT1–207 was phosphorylated in vitro at both PKA sites, Thr-31 and Ser-205. regulation is achieved by binding to 14-3-3, which structurally modulates the substrate binding sites, leading to measurable effects on the affinity of AANAT for its substrates with an accompanying increase in activity at low substrate concentrations. " SIGNOR-250324 PRKCG protein P05129 UNIPROT CD5 protein P06127 UNIPROT up-regulates phosphorylation Thr436 FHRNHTAtVRSHAEN 9606 11123317 t amattioni "Cd5 is a good pkc substrate. Phosphorylation of cd5 is necessary for cd5-mediated lipid second messenger generation." SIGNOR-85183 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 SRC protein P12931 UNIPROT MYLK protein Q15746 UNIPROT up-regulates phosphorylation Tyr464 QEGSIEVyEDAGSHY 9606 11113114 t gcesareni "Ec mlck-1 is phosphorylated by p60(src) on tyr(464) and tyr(471), resulting in a 2- to 3-fold increase in ec mlck-1 enzymatic activity." SIGNOR-85005 TAF1 protein P21675 UNIPROT GTF2A1 protein P52655 UNIPROT up-regulates phosphorylation Ser321 LNSEDDVsDEEGQEL 9606 11278496 t llicata "Taf(ii) 250 phosphorylates human transcription factor iia on serine residues important for tbp binding and transcription activity." SIGNOR-105745 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 CDK2 protein P24941 UNIPROT RUNX1 protein Q01196 UNIPROT down-regulates phosphorylation Ser276 VHPATPIsPGRASGM 9606 SIGNOR-C83 16046550 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-138949 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 Calcineurin complex SIGNOR-C155 SIGNOR 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-252316 Calcineurin complex SIGNOR-C155 SIGNOR 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-252326 CSNK2A1 protein P68400 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates phosphorylation Ser423 CEEEFSDsEEEGEGG 9606 11602581 t gcesareni "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-111015 FLT1 protein P17948 UNIPROT FLT1 protein P17948 UNIPROT up-regulates phosphorylation Tyr1213 GSSDDVRyVNAFKFM 9606 11583921 t tpavlidou "Vegfr-1 mutated at y1213, y1242, and y1333 were constructed and expressed in pae cells, to the same level as that of pae/vegfr-1 cells. The mutated vegfr-1 y1213f expressed in pae cells was kinase inactive." SIGNOR-110850 GRP protein P07492 UNIPROT GRPR protein P30550 UNIPROT up-regulates binding 9606 17251915 t gcesareni "Indeed, many potent mitogens such as thrombin, lysophosphatidic acid (lpa), gastrin-releasing peptide (grp), endothelin and prostaglandins stimulate cell proliferation by acting on their cognate gpcrs in various cell types." SIGNOR-152676 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 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 NR0B2 protein Q15466 UNIPROT PPARA protein Q07869 UNIPROT up-regulates binding 9606 11369442 t gcesareni "Surprisingly, shp potentiated transcription by pparalpha/rxralpha heterodimers from the hd-ppre. This is the first demonstration of positive transcriptional activity attributable to shp. Together, these results suggest that shp can modulate pparalpha/rxralpha-mediated transcription in a response element-specific manner." SIGNOR-108252 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 PRKCD protein Q05655 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation Ser727 TDNLLPMsPEEFDEV 9606 17502367 t gcesareni "All stats are phosphorylated on at least one serine residue in their tad specifically, ser727 in stats 1 and 3 and ser721 in stat4. Stat serine kinases have been identified through the use of inhibitors, dominant-negative alleles, and in vitro kinase assays. They include mapk (p38mapk: stats 1, 3, 4;erk: stat3, 5;jnk: stat3), pkc_ (stat1, stat3), mtor (stat3), nlk (stat3 (42)), and camkii and ikk_ (stat1 (39, 40, 43)).STAT Serine phosphorylation regulates transcriptional activity (see below)." SIGNOR-154791 RPS6KB1 protein P23443 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-180771 TGFB1 protein P01137 UNIPROT TGFBR1 protein P36897 UNIPROT "up-regulates activity" binding 9606 BTO:0000801 22703233 t lperfetto "TGFbeta signals are transmitted via a cell surface receptor complex consisting of the TGFbeta type I receptor (TbetaRI) and TGFbeta type II receptor (TbetaRII). To initiate signal transduction, TGFbeta binds to TbetaRII, which in turn recruits TbetaRI, leading to the formation of a tetrameric receptor complex." SIGNOR-249548 WAY-600 chemical CID:25229526 PUBCHEM MTOR protein P42345 UNIPROT down-regulates "chemical inhibition" 9606 Other t "Selleck;ATP-competitive inhibitor mTOR" gcesareni SIGNOR-207788 XL-647 chemical CID:10458325 PUBCHEM EGFR protein P00533 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207857 "1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate" smallmolecule CHEBI:16618 ChEBI WIPI1 protein Q5MNZ9 UNIPROT up-regulates binding 9606 22082875 t gcesareni "We identified the human wipi protein family and found that wipi-1 specifically binds ptdins(3)p, accumulates at the phagophore and becomes a membrane protein of generated autophagosomes." SIGNOR-177169 IL18 protein Q14116 UNIPROT IL18R1 protein Q13478 UNIPROT up-regulates binding 9606 9792649 t gcesareni "Acpl was required for il-18 responsiveness in terms of nf?B Induction and jnk activation" SIGNOR-60991 ITK protein Q08881 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-112471 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 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 PYY protein P10082 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-29767 "Rigosertib sodium" chemical CID:23696523 PUBCHEM PLK1 protein P53350 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-195028 RUNX2 protein Q13950 UNIPROT COL1A2 protein P08123 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11331591 f gcesareni "In addition to osteocalcin, cbfa1 regulates expression of several other genes that are activated during osteoblast" SIGNOR-107166 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 STAT3 protein P40763 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 BTO:0000801 10347215 f lperfetto "The data presented this far show that the JAK-STAT signaling pathway and specifically Stat3 and Jak1 are required for induction of IL-10-dependent anti-inflammatory and developmental responses in macrophages." SIGNOR-249547 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 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 STK11 protein Q15831 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser392 FKTEGPDsD 9606 17108107 t gcesareni "We show that lkb1 physically associates with p53 in the nucleus and directly or indirectly phosphorylates p53 ser15 (previously shown to be phosphorylated by amp-dependent kinase) and p53 ser392" SIGNOR-150834 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 BAIAP2 protein Q9UQB8 UNIPROT WASF1 protein Q92558 UNIPROT up-regulates binding 9606 11130076 t gcesareni "Here we demonstrate that irsp53, a substrate forinsulinreceptor with unknown function, is the 'missing link' between rac and wave. Activated rac binds to the amino terminus of irsp53, and carboxy-terminal src-homology-3 domain of irsp53 binds to wave to form a trimolecular complex." SIGNOR-85299 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 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 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 JAK3 protein P52333 UNIPROT SIGLEC10 protein Q96LC7 UNIPROT up-regulates phosphorylation Tyr667 ESQEELHyATLNFPG 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. Phosphorylation of the tyrosine located at position 667 in an itim motif appears to be necessary for the recruitment of shp-1 and partial recruitment of shp-2" SIGNOR-112483 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 SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Thr179 PQSNIPEtPPPGYLS 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-66746 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 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 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 "phosphatidic acid" smallmolecule CHEBI:16337 ChEBI MTOR protein P42345 UNIPROT up-regulates binding 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 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 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 WNT10A protein Q9GZT5 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-131619 C5 protein P01031 UNIPROT C5AR2 protein Q9P296 UNIPROT up-regulates binding 9606 11773063 t 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 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SPHK1 protein Q9NYA1 UNIPROT up-regulates phosphorylation Ser225 VGSKTPAsPVVVQQG 9606 14532121 t gcesareni "Activation of sphingosine kinase 1 by erk1/2-mediated phosphorylation." SIGNOR-118542 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 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 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 NUMA1 protein Q14980 UNIPROT TUBB2A protein Q13885 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-116936 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 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates phosphorylation Ser299 NQVTQRAsRRSDSAS 9606 17603046 t gcesareni "Here, we demonstrate that pkcdelta undergoes in vitro autophosphorylation at three sites within its v3 region (s299, s302, s304), each of which is unique to this pkc isoform and evolutionarily conserved" SIGNOR-156523 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 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 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 WNT10A protein Q9GZT5 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-131616 CSNK2A1 protein P68400 UNIPROT WASF2 protein Q9Y6W5 UNIPROT down-regulates phosphorylation Ser488 YSDSEDDsSEFDEDD 9606 19012317 t gcesareni "Here we identify five casein kinase 2 (ck2) phosphorylation sites within the vca domain of wave2, serines 482, 484, 488, 489, and 497. Phosphorylation of these sites is required for a high affinity interaction with the arp2/3 complex;we and show that their mutation to non-phosphorylatable alanine residues inhibits wave2 function in vivo." SIGNOR-182358 CAMKK1 protein Q8N5S9 UNIPROT CAMK1D protein Q8IU85 UNIPROT "up-regulates activity" phosphorylation Thr180 GKGDVMStACGTPGY BTO:0000567 12935886 t llicata "CaM-KIdelta exhibits Ca(2+)/CaM-dependent activity that is enhanced (approximately 30-fold) in vitro by phosphorylation of its Thr180 by CaM-K kinase (CaM-KK)alpha, consistent with detection of CaM-KIdelta-activating activity in HeLa cells. | This sustained activation of CaM-KIdelta was completely abolished by Thr180Ala mutation and inhibited by CaM-KK inhibitor, STO-609, indicating a functional CaM-KK/CaM-KIdelta cascade in HeLa cells." SIGNOR-250715 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 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 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 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 NUMA1 protein Q14980 UNIPROT TUBG1 protein P23258 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-117203 PKN1 protein Q16512 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation 9606 17251915 t gcesareni "At the same time, rho signals to c-jun n-terminal kinase (jnk) and p38 through rock and protein kinase n (pkn), leading to the transcriptional regulation of jun" SIGNOR-152765 PRKCD protein Q05655 UNIPROT IRS1 protein P35568 UNIPROT down-regulates 9606 BTO:0000671 9335553 f 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-52707 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 SRC protein P12931 UNIPROT DGKA protein P23743 UNIPROT up-regulates phosphorylation Tyr335 ILPPSSIyPSVLASG 9606 17700527 t llicata "Diacylglycerol kinase-alpha phosphorylation by src on y335 is required for activation, membrane recruitment and hgf-induced cell motility." SIGNOR-157365 STK38 protein Q15208 UNIPROT STK38 protein Q15208 UNIPROT up-regulates phosphorylation Ser281 NRRQLAFsTVGTPDY 9606 12493777 t lperfetto "We found that ndr1 autophosphorylates in vitro predominantly on ser-281 and to a lesser extent on thr-74 and thr-444. All of these residues proved to be crucial also for ndr1 activity in vivo" SIGNOR-96679 SUFU protein Q9UMX1 UNIPROT SAP18 protein O00422 UNIPROT up-regulates binding 9606 11960000 t gcesareni "Here we report that the mouse homolog of su(fu) [msu(fu)] specifically interacts with sap18, a component of the msin3 and histone deacetylase complex. In addition, we demonstrate that msu(fu) functionally cooperates with sap18 to repress transcription by recruiting the sap18-msin3 complex to promoters containing the gli-binding element." SIGNOR-117311 WNT10B protein O00744 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 9606 12055200 f fspada "We have identified wnt10b as a potent inhibitor of adipogenesis that must be suppressed for preadipocytes to differentiate in vitro" SIGNOR-89131 ID2 protein Q02363 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-241146 KAT5 protein Q92993 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates acetylation Lys2049 DAAVVLLkNGANKDM 9606 17636029 t gcesareni "This result implies that the residues k2019, k2039, k2044, and k2068 of notch1-ic are the major targets of the acetyltransferase activity of tip60." SIGNOR-156915 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 AURKB protein Q96GD4 UNIPROT HIST1H3A 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-118894 CSNK2A1 protein P68400 UNIPROT PTEN protein P60484 UNIPROT "down-regulates activity" phosphorylation Ser385 RYSDTTDsDPENEPF 9606 21779440 t gcesareni "The C-terminal tail of PTEN is also the target of mutations in tumors. As mentioned, this region contains the main phosphorylation sites mapped to residues Ser362, Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385, and the kinases involved are casein kinase 2 (CK2), GSK3_, LKB1, and MAST.84,97-101 The phosphorylation of the tail has been shown to enhance PTEN stability but at the same time decrease its phosphatase activity" SIGNOR-89822 F2RL3 protein Q96RI0 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates binding 9606 17158345 t gcesareni "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-151162 FOXO proteinfamily SIGNOR-PF27 SIGNOR FBXO32 protein Q969P5 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165 15109499 t "The activity of the PI3K/AKT pathway decreases, leading to activation of Foxo transcription factors and atrogin-1 induction. IGF-1 treatment or AKT overexpression inhibits Foxo and atrogin-1 expression." SIGNOR-252926 FOXO proteinfamily SIGNOR-PF27 SIGNOR G6PC 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-252921 HMGA2 protein P52926 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 25300915 f miannu "This study unraveled a novel function ofhmga2in induction of apoptosis in human primary cell lines" SIGNOR-205465 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 MAPK3 protein P27361 UNIPROT FOS protein P01100 UNIPROT up-regulates phosphorylation Thr331 CTPVVTCtPSCTAYT 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-118031 MKNK1 protein Q9BUB5 UNIPROT EIF4E protein P06730 UNIPROT up-regulates phosphorylation Ser209 DTATKSGsTTKNRFV 9606 17724079 t lperfetto "Inhibition of mammalian target of rapamycin induces phosphatidylinositol 3-kinase-dependent and mnk-mediated eukaryotic translation initiation factor 4e phosphorylation.Therefore, eif4e is considered a survival protein involved in cell cycle progression, cell transformation, and apoptotic resistance. Phosphorylation of eif4e (usually at ser209) increases its binding affinity for the cap of mrna and may also favor its entry into initiation complexes." SIGNOR-157533 NRTN protein Q99748 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-49119 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 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 PTPRJ protein Q12913 UNIPROT KDR protein P35968 UNIPROT down-regulates dephosphorylation Tyr1054 FGLARDIyKDPDYVR 9606 18936167 t gcesareni "The autoactivation residues y1054 and y1059 are targeted by dep-1 and this results in the inhibition of kinase activity and the consequent general dephosphorylation of vegfr2." SIGNOR-181672 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR LEF1 protein Q9UJU2 UNIPROT up-regulates "transcriptional regulation" 9606 10890911 f lperfetto "Coexpression of smad2 and smad4, smad3 alone, or smad3 and smad4 resulted in strong enhancement of lef1-dependent transcriptional activity" SIGNOR-217169 XAF1 protein Q6GPH4 UNIPROT XIAP protein P98170 UNIPROT down-regulates binding 9606 17613533 t gcesareni "Immunoprecipitation studies indicate that xaf1 binds to xiap,birc2,birc3." SIGNOR-155637 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR 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-256447 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR 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-256432 MAPK14 protein Q16539 UNIPROT HBP1 protein O60381 UNIPROT up-regulates phosphorylation Ser402 GFSKNCGsPGSSQLS 9606 14612426 t lperfetto "A mutation of the p38 map kinase phosphorylation site at aa 401 [(s-a)401hbp1] also triggered hbp1 protein instability. While protein stability was compromised by mutation, the specific activities of (s-a)401hbp1 and of wild-type hbp1 appeared comparable for transcriptional repression." SIGNOR-119138 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 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 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 UBTF protein P17480 UNIPROT down-regulates phosphorylation Thr117 DFPKKPLtPYFRFFM 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-112805 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 NEK9 protein Q8TD19 UNIPROT NEK9 protein Q8TD19 UNIPROT up-regulates phosphorylation Thr210 SEYSMAEtLVGTPYY 9606 14660563 t lperfetto "A previous study (19) using the peptide substrate demonstrated that nek9 was able to phosphorylate in vitro the thr210 residue within the activation loop, thus indicating the potential ability of nek9 to autophosphorylate.Nek9 forms a stable, approximately 600-kda complex with fact in the interphase nuclei. Its active form is characterized by phosphorylation-dependent electrophoretic mobility shift and phosphorylation at a conserved residue within the activation loop (thr(210))" SIGNOR-119897 NRG2 protein O14511 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 14967450 t gcesareni "The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4." SIGNOR-122056 PLK3 protein Q9H4B4 UNIPROT PTEN protein P60484 UNIPROT "down-regulates activity" phosphorylation Thr366 ASSSTSVtPDVSDNE 9606 20940307 t gcesareni "Plk3 phosphorylates pten on thr-366 and ser-370. Plk3-mediated phosphorylation facilitates pten stabilization, thereby negatively regulating the pi3k/pdk1/akt1 signaling axis" SIGNOR-168473 PRKAA1 protein Q13131 UNIPROT PRKAB1 protein Q9Y478 UNIPROT up-regulates phosphorylation Ser108 SKLPLTRsHNNFVAI 9606 SIGNOR-C15 SIGNOR-C15 17728241 t gcesareni "Mutation of serine 108 to alanine, an autophosphorylation site within the glycogen binding domain of the beta1 subunit, almost completely abolishes activation of ampk by a-769662 in cells and in vitro, while only partially reducing activation by amp" SIGNOR-157553 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 PRKCD protein Q05655 UNIPROT PEBP1 protein P30086 UNIPROT up-regulates phosphorylation Ser153 RGKFKVAsFRKKYEL 9606 14654844 t miannu "Here we show that the raf kinase inhibitor protein (rkip) is a physiological inhibitor of grk-2. After stimulation of gpcr, rkip dissociates from its known target, raf-1 (refs 6-8), to associate with grk-2 and block its activity. This switch is triggered by protein kinase c (pkc)-dependent phosphorylation of the rkip on serine 153." SIGNOR-119551 Telatinib chemical CID:9808844 PUBCHEM PDGFRB protein P09619 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207230 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 VRK1 protein Q99986 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr73 ADQTPTPtRFLKNCE 9606 15105425 t gcesareni "Vrk1 phosphorylates atf2 mainly on thr-73, stabilizing the atf2 protein and increasing its intracellular level." SIGNOR-124334 "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 "Caspase 8 complex" complex SIGNOR-C231 SIGNOR 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-256466 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 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 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 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR 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-256445 "Caspase 6 complex" complex SIGNOR-C228 SIGNOR 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-256468 "Caspase 6 complex" complex SIGNOR-C228 SIGNOR LMNA protein P02545 UNIPROT down-regulates cleavage 9606 11058599 t amattioni "Lamin a breakdown is largely mediated by caspase-6 during the execution phase of apoptosis." SIGNOR-256457 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CDK2 protein P24941 UNIPROT up-regulates phosphorylation Thr160 GVPVRTYtHEVVTLW 9606 SIGNOR-C16 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-244614 PRKCZ protein Q05513 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser311 RTYETFKsIMKKSPF 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-151432 PTPRJ protein Q12913 UNIPROT LAT protein O43561 UNIPROT "down-regulates activity" 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-248696 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr1096 RYPNDSVyANWMLSP 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." SIGNOR-121149 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr806 PLLLIVEyAKYGSLR 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-121153 SIRT1 protein Q96EB6 UNIPROT SMAD7 protein O15105 UNIPROT down-regulates deacetylation Lys64 RAGCCLGkAVRGAKG 9606 BTO:0000671 17098745 t gcesareni "Sirt1 reversed acetyl-transferase (p300)-mediated acetylation of two lysine residues (lys-64 and -70) on smad7. sirt1-mediated deacetylation of smad7 enhanced smad ubiquitination regulatory factor 1 (smurf1)-mediated ubiquitin proteasome degradation, which contributed to the low expression of smad7 in sirt1-overexpressing mesangial cells." SIGNOR-150595 SIRT1 protein Q96EB6 UNIPROT SMAD7 protein O15105 UNIPROT down-regulates deacetylation Lys70 GKAVRGAkGHHHPHP 9606 BTO:0000671 17098745 t gcesareni "Sirt1 reversed acetyl-transferase (p300)-mediated acetylation of two lysine residues (lys-64 and -70) on smad7. sirt1-mediated deacetylation of smad7 enhanced smad ubiquitination regulatory factor 1 (smurf1)-mediated ubiquitin proteasome degradation, which contributed to the low expression of smad7 in sirt1-overexpressing mesangial cells." SIGNOR-150599 STAG2 protein Q8N3U4 UNIPROT CD69 protein Q07108 UNIPROT up-regulates 9606 14660624 f miannu "Stag2 is able to enhance the activity of the tumor necrosis factor alpha, the cd69, and the human immunodeficiency virus long terminal repeat promoters in a nf-kappab-dependent manner." SIGNOR-119985 TLK1 protein Q9UKI8 UNIPROT RAD9A protein Q99638 UNIPROT unknown phosphorylation Ser328 VLPSISLsPGPQPPK 9606 24376897 t "The effect has been demonstrated using Q9UKI8-2" llicata "Here we show that rad9 is phosphorylated in a tlk-dependent manner in vitro and in vivo, and that t355 within the c-terminal tail is the primary targeted residue." SIGNOR-203499 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 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR EP300 protein Q09472 UNIPROT up-regulates phosphorylation Ser2315 RSPQPVPsPRPQSQP 9606 17623675 t lperfetto "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-244634 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 FZD3 protein Q9NPG1 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 9606 14977528 t gcesareni "Gpcrs signal through four relatively small families of galfa proteins (galfas, galfai/o, galfaq, and galfa12/13), and if fzd receptors are classic gpcrs, they should signal through one of these four galfa families." SIGNOR-122889 MAPK10 protein P53779 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-178926 MAPK10 protein P53779 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation 9606 14699954 t amattioni "The targets of jnk include the transcription factors p53. P75ntr-mediated apoptosis was shown to be dependent of p53" SIGNOR-120552 MAPK11 protein Q15759 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-114063 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 NRG4 protein Q8WWG1 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 14967450 t "Does not bind to the ERBB1, ERBB2 and ERBB3 receptors" gcesareni "The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4." SIGNOR-122062 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 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT up-regulates phosphorylation Ser2056 VQSYSYSsQDPRPAT 9606 17189255 t llicata "Ir-induced dna-pkcs phosphorylation at thr-2609 and ser-2056, however, exhibits distinct kinetics indicating that they are differentially regulated. Although dna-pkcs autophosphorylates itself at ser-2056 after ir, in addition, our data suggest that dna-pkcs- and atm-mediated dna-pkcs phosphorylations are cooperative and required for the full activation of dna-pkcs and the subsequent dsb repair." SIGNOR-151445 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT up-regulates phosphorylation Thr2609 LTPMFVEtQASQGTL 9606 17189255 t gcesareni "Ir-induced dna-pkcs phosphorylation at thr-2609 and ser-2056, however, exhibits distinct kinetics indicating that they are differentially regulated. Although dna-pkcs autophosphorylates itself at ser-2056 after ir, we have reported here that atm mediates dna-pkcs phosphorylation at thr-2609 as well as at the adjacent (s/t)q motifs within the thr-2609 cluster." SIGNOR-151449 RPS6KA4 protein O75676 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser276 SMQLRRPsDRELSEP 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) 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-151436 STK11 protein Q15831 UNIPROT PTEN protein P60484 UNIPROT "down-regulates activity" phosphorylation Thr382 DHYRYSDtTDSDPEN 9606 21779440 t gcesareni "The C-terminal tail of PTEN is also the target of mutations in tumors. As mentioned, this region contains the main phosphorylation sites mapped to residues Ser362, Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385, and the kinases involved are casein kinase 2 (CK2), GSK3_, LKB1, and MAST.84,97-101 The phosphorylation of the tail has been shown to enhance PTEN stability but at the same time decrease its phosphatase activity" SIGNOR-161122 VAV1 protein P15498 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 9013873 f lperfetto "Vav may link gp130 activation to downstream mapk activation in hematopoietic cells." SIGNOR-244640 MAPK11 protein Q15759 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Ser360 TEMDPTYsPAALPQS 9606 BTO:0000567 9687510 t gcesareni "Mitogen- and stress-activated protein kinase-1 (msk1) is directly activated by mapk and sapk2/p38, and may mediate activation of crebactivated by phosphorylation at ser-360, thr-581 and thr-700 by mapk1/erk2, mapk3/erk1 and mapk14/p38-alpha" SIGNOR-59443 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 WDR83 protein Q9BRX9 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates binding 9606 15118098 t gcesareni "Morg1 specifically associates with several components of the erk pathway, including mp1, raf-1, mek, and erk, and stabilizes their assembly into an oligomeric complex." SIGNOR-124470 CCT137690 chemical CID:25154041 PUBCHEM AURKA protein O14965 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190892 MAPK11 protein Q15759 UNIPROT HBA1 protein P69905 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20162623 f Indirect:regulation miannu "Our results demonstrate that activin A induced Hb synthesis and promoter activation of the specific erythroid gene, ζ-globin, through p38α and p38β isoforms and their activator, MKK6 (mitogen-activated protein kinase kinase 6)." SIGNOR-251834 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 PPM1A protein P35813 UNIPROT CDK9 protein P50750 UNIPROT "down-regulates activity" dephosphorylation Thr186 NSQPNRYtNRVVTLW 9606 18829461 t "Phosphatase PPM1A regulates phosphorylation of Thr-186 in the Cdk9 T-loop|Cdk9 is the catalytic subunit of a general RNA polymerase II elongation factor known as positive transcription elongation factor b (P-TEFb). The kinase function of P-TEFb requires phosphorylation of Thr-186 in the T-loop of Cdk9 to allow substrates to access the catalytic core of the enzyme." SIGNOR-248490 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 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 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 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 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 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 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 rivaroxaban chemical CHEBI:68579 ChEBI F10 protein P00742 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206550 RPL11 protein P62913 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-205514 TAB2 protein Q9NYJ8 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates binding 9606 25290089 t lperfetto "The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex." SIGNOR-205443 CDK1 protein P06493 UNIPROT PITPNM1 protein O00562 UNIPROT up-regulates phosphorylation Ser382 DFIDAFAsPVEAEGT 9606 15125835 t lperfetto "Here we show that, at the onset of mitosis, cdk1 phosphorylates the peripheral golgi protein nir2 at multiple sites;of these, s382 is the most prominent. Phosphorylation of nir2 by cdk1 facilitates its dissociation from the golgi apparatus, and phospho-nir2(ps382) is localized in the cleavage furrow and midbody during cytokinesis." SIGNOR-124638 CDC14A protein Q9UNH5 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-248833 CSNK2A1 protein P68400 UNIPROT PTGES3 protein Q15185 UNIPROT up-regulates phosphorylation Ser113 WKDWEDDsDEDMSNF 9606 15040786 t gcesareni "Several lines of evidence suggest that a cpges-activating protein kinase is ck-ii (casein kinase ii). Recombinant cpges was phosphorylated directly by and associated with ck-ii in vitro, resulting in marked reduction of the k m for the substrate pgh2." SIGNOR-123594 GHRL protein Q9UBU3 UNIPROT GHSR protein Q92847 UNIPROT up-regulates binding 9606 15070777 t fspada "In contrast to wild-type mice, acute treatment of ghsr- mice with ghrelin stimulated neither gh release nor food intake, showing that the ghsr is a biologically relevant ghrelin receptor." SIGNOR-123948 IFNLR1 protein Q8IU57 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 15120645 t gcesareni "Each r1-type chain (il-10r1, il-20r1, il-22r1, ifn-_r1 and ifn-_r1) is associated with jak1 tyrosine kinase and mediates recruitment of a variety of signaling molecules after being phosphorylated on its intracellular domain." SIGNOR-124480 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 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 PRKCD protein Q05655 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Ser738 ARIIGEKsFRRSVVG 9606 15024053 t llicata "Here we show that activation of pkd in response to oxidative stress requires two sequential signaling events, i.e., phosphorylation of tyr463 by abl, which in turn promotes a second step, phosphorylation of the pkd activation loop (ser738/ser742). We show that this is mediated by pkcdelta (protein kinase cdelta)" SIGNOR-123449 PRKCD protein Q05655 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Ser742 GEKSFRRsVVGTPAY 9606 15024053 t llicata "Here we show that activation of pkd in response to oxidative stress requires two sequential signaling events, i.e., phosphorylation of tyr463 by abl, which in turn promotes a second step, phosphorylation of the pkd activation loop (ser738/ser742). We show that this is mediated by pkcdelta (protein kinase cdelta)" SIGNOR-123453 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr1015 MMVKRRDyLDLAAST 9606 14981541 t llicata "Opn upregulation depended on the integrity of the ret/ptc kinase and tyrosines y1015 and y1062, two major ret/ptc autophosphorylation sites. ret signalling mainly depends on three key tyrosine residues: tyrosine 905, in the activation loop, whose phosphorylation stabilizes the active conformation of the catalytic domain , tyrosine 1015, a docking site for phospholipase citalic gamma and tyrosine 1062." SIGNOR-122915 RXRA protein P19793 UNIPROT NR1H2 protein P55055 UNIPROT up-regulates binding 9606 14993927 t lperfetto "We provide genetic and molecular evidence that cholesterol homeostasis in scs does not require pparalpha and beta, but depends upon the tif2 coactivator and rxrbeta/lxrbeta heterodimers, in which rxrbeta af-2 is transcriptionally active." SIGNOR-123091 RXRB protein P28702 UNIPROT NR1H2 protein P55055 UNIPROT up-regulates binding 9606 14993927 t gcesareni "We provide genetic and molecular evidence that cholesterol homeostasis in scs does not require pparalpha and beta, but depends upon the tif2 coactivator and rxrbeta/lxrbeta heterodimers, in which rxrbeta af-2 is transcriptionally active." SIGNOR-123094 SRC protein P12931 UNIPROT WWOX protein Q9NZC7 UNIPROT up-regulates phosphorylation Tyr33 TTKDGWVyYANHTEE 9606 15070730 t llicata "The tyrosine kinase, src, phosphorylates wwox at tyrosine 33 in the first ww domain and enhances its binding to p73." SIGNOR-123819 TESK1 protein Q15569 UNIPROT TESK1 protein Q15569 UNIPROT "up-regulates activity" phosphorylation Ser220 EPLAVVGsPYWMAPE 9606 BTO:0000567 10207045 t lperfetto "Site-directed mutagenesis analyses revealed that Ser-215 within the activation loop of the kinase domain is the site of serine autophosphorylation of TESK1. Replacement of Ser-215 by alanine almost completely abolished serine autophosphorylation and histone H3 kinase activities." SIGNOR-246667 WNK1 protein Q9H4A3 UNIPROT STK39 protein Q9UEW8 UNIPROT up-regulates phosphorylation Thr231 TRNKVRKtFVGTPCW 9606 17190791 t gcesareni "Activation of wnk1 coincides with the phosphorylation and activation of two wnk1 substrates, namely, the protein kinases ste20/sps1-related proline alanine-rich kinase (spak) and oxidative stress response kinase-1 (osr1)." SIGNOR-151671 CDK1 protein P06493 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-140882 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 KREMEN1 protein Q96MU8 UNIPROT LRP6 protein O75581 UNIPROT up-regulates 9606 12050670 f gcesareni "Dkk1 has been shown to inhibit wnt signalling 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 block wnt/beta-catenin signalling." SIGNOR-88891 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 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 MAPK10 protein P53779 UNIPROT BAX protein Q07812 UNIPROT up-regulates 9606 15071501 f gcesareni "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; these results strongly indicate that jnk regulates the activity of bax by phosphorylating 14-3-3 proteins." SIGNOR-124001 MAPK11 protein Q15759 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Thr581 PDNQPLKtPCFTLHY 9606 BTO:0000567 9687510 t gcesareni "Mitogen- and stress-activated protein kinase-1 (msk1) is directly activated by mapk and sapk2/p38, and may mediate activation of crebactivated by phosphorylation at ser-360, thr-581 and thr-700 by mapk1/erk2, mapk3/erk1 and mapk14/p38-alpha" SIGNOR-59447 MSH6 protein P52701 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-123705 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 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 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 PTK2B protein Q14289 UNIPROT PTK2B protein Q14289 UNIPROT up-regulates phosphorylation Tyr402 CSIESDIyAEIPDET 9606 15105428 t llicata "Overexpression of pyk2 alone led to its spontaneous activation and tyrosine phosphorylation, resulting in activation of stat5b, indicated by the reporter gfp-stat5b. These effects were completely dependent upon tyr(402), the autophosphorylation site of pyk2, which allows recruitment of src family members for further activating phosphorylations at other sites on pyk2." SIGNOR-124339 PTPN21 protein Q16825 UNIPROT SRC protein P12931 UNIPROT up-regulates dephosphorylation Tyr530 FTSTEPQyQPGENL 9606 15143158 t gcesareni "Ptpd1 activates src tyrosine kinase and increases the magnitude and duration of epidermal growth factor (egf) signaling." SIGNOR-124774 RPS6KA3 protein P51812 UNIPROT ATF4 protein P18848 UNIPROT up-regulates phosphorylation Ser245 TRGSPNRsLPSPGVL 9606 15109498 t lperfetto "Here, we show that rsk2 is required for osteoblast differentiation and function. We identify the transcription factor atf4 as a critical substrate of rsk2 that is required for the timely onset of osteoblast differentiation, for terminal differentiation of osteoblasts, and for osteoblast-specific gene expression" SIGNOR-124436 SMG1 protein Q96Q15 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 15175154 t gcesareni "Hsmg-1 is a stress-activated kinase that phosphorylates p53 and hupf1 in vitrothe observation that hsmg-1 exhibits p53 (ser-15) kinase activity in vitro suggested that this pikk might be involved in genotoxic stress-induced p53 phosphorylation and stabilization in intact cells." SIGNOR-125135 WDR83 protein Q9BRX9 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 15118098 t gcesareni "Morg1 specifically associates with several components of the erk pathway, including mp1, raf-1, mek, and erk, and stabilizes their assembly into an oligomeric complex." SIGNOR-124476 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 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 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 MAPK11 protein Q15759 UNIPROT RPTOR protein Q8N122 UNIPROT unknown phosphorylation Ser771 SASSTLGsPENEEHI 9606 SIGNOR-C3 21757713 t llicata "Arsenite treatment of cells activates p38_ and induces interaction between p38_ and raptor, a regulatory component of mtorc1, resulting in phosphorylation of raptor on ser(863) and ser(771). The phosphorylation of raptor on these sites enhances mtorc1 activity, and contributes largely to arsenite-induced mtorc1 activation." SIGNOR-174870 MAPK11 protein Q15759 UNIPROT RPTOR protein Q8N122 UNIPROT unknown phosphorylation Ser863 LTQSAPAsPTNKGVH 9606 SIGNOR-C3 21757713 t llicata "Arsenite treatment of cells activates p38_ and induces interaction between p38_ and raptor, a regulatory component of mtorc1, resulting in phosphorylation of raptor on ser(863) and ser(771). The phosphorylation of raptor on these sites enhances mtorc1 activity, and contributes largely to arsenite-induced mtorc1 activation." SIGNOR-174874 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 PLK1 protein P53350 UNIPROT BUB1B protein O60566 UNIPROT up-regulates phosphorylation Ser676 LSPIIEDsREATHSS 9606 17785528 t lperfetto "We identify s676 as a plk1-specific phosphorylation site on bubr1. These findings describe the first in vivo verified phosphorylation site for human bubr1, identify plk1 as the kinase responsible for causing the characteristic mitotic bubr1 upshift, and attribute a kt-specific function to the hyperphosphorylated form of bubr1 in the stabilization of kt-mt interactions." SIGNOR-157646 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 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 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 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 PTPN1 protein P18031 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-248418 WWP1 protein Q9H0M0 UNIPROT SMAD7 protein O15105 UNIPROT up-regulates binding 9606 15221015 t gcesareni "Wwp1 associated with smad7 and induced its nuclear export, and enhanced binding of smad7 to tgf-beta type i receptor to cause ubiquitination and degradation of the receptor." SIGNOR-126128 NKD1 protein Q969G9 UNIPROT DVL3 protein Q92997 UNIPROT down-regulates binding 9606 BTO:0000671 15064403 t gcesareni "Naked (nkd)1 and nkd2 are mammalian homologs of drosophila naked cuticle, which negatively regulates canonical wnt signaling by binding dishevelled. various reports using cell culture assays indicate that nkd-mediated wnt antagonism involves dvl degradation" SIGNOR-123695 NUMA1 protein Q14980 UNIPROT TUBA1C protein Q9BQE3 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-116677 CDK2 protein P24941 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-187457 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 PLK1 protein P53350 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates phosphorylation Ser260 SLDSEDYsLSEEGQE 9606 12383858 t gcesareni "Here we show that the oncogenic and cell cycle-regulatory protein kinase, polo-like kinase-1 (plk1), phosphorylates mdm2 at one of these residues, ser260, and stimulates mdm2-mediated turnover of p53. These data are consistent with the idea that deregulation of plk1 during tumourigenesis may help suppress p53 function." SIGNOR-94272 POFUT1 protein Q9H488 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 12909620 t Fucosylation gcesareni "Notch_ is modified in its epidermal growth factor-like domains by the addition of_ fucose_ to serine or threonine residues. O-fucosylation is mediated by protein o-fucosyltransferase 1 and down-regulation of this enzyme by rna interference or mutation of the ofut1 gene in drosophila or by mutation of the pofut1 gene in mouse prevents notch signaling." SIGNOR-104627 PP2B proteinfamily SIGNOR-PF18 SIGNOR MAPT protein P10636 UNIPROT up-regulates dephosphorylation Thr529 TPGSRSRtPSLPTPP 9606 BTO:0000142 20308788 t "The effect has been demonstrated using P10636-8" lperfetto "Among the sites studied, thr205, thr212, ser214, and ser262 were the most favorable sites, and ser199 and ser404 were the least favorable sites for pp2a in vitro." SIGNOR-164675 PRKCE protein Q02156 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates phosphorylation Ser876 QGLAERIsVL 9606 12058027 t gcesareni "Furthermore, we show that pkd2 can be activated by classical and novel members of the protein kinase c (pkc) family such as pkc alpha, pkc epsilon, and pkc eta. These pkcs are activated by gastrin in ags-b cells. Thus, pkd2 is likely to be a novel downstream target of specific pkcs upon the stimulation of ags-b cells with gastrin." SIGNOR-89419 PTPN1 protein P18031 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-248420 PTPN1 protein P18031 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-248421 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 JAK2 protein O60674 UNIPROT "down-regulates activity" dephosphorylation Tyr1008 LPQDKEYyKVKEPGE 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-248405 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 PTPRF protein P10586 UNIPROT DAPK1 protein P53355 UNIPROT up-regulates dephosphorylation Tyr490 HCAAWHGyYSVAKAL 9606 17803936 t gcesareni "Here, we show that the leukocyte common antigen-related (lar) tyrosine phosphatase dephosphorylates dapk at py491/492 to stimulate the catalytic, proapoptotic, and antiadhesion/antimigration activities of dapk." SIGNOR-157702 SIAH2 protein O43255 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates 9606 17003045 f gcesareni "The ring finger ubiquitin ligase siah2 controls the stability of various substrates involved in stress and hypoxia responses, including the phd3, which controls the stability of hif-1alpha" SIGNOR-149893 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 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 CDK2 protein P24941 UNIPROT NFYA protein P23511 UNIPROT "up-regulates activity" phosphorylation Ser326 FSPKEKDsPHMQDPN BTO:0000007 12857729 t llicata "Cdk2 phosphorylates two serine residues near the DNA-binding domain of the YA subunit of NF-Y. Cyclin A-cdk2 appears to associate with NF-Y both in vitro and in vivo. Furthermore, YA protein is phosphorylated in parallel with a cell cycle-dependent activation of cdk2 kinase and cyclin A expression. YA phosphorylation is unnecessary for heterotrimer formation with the YB-YC dimer. However, NF-Y containing a phosphorylation-deficient mutant form of YA, YA-aa, has its DNA binding activity impaired. \ To examine whether cdk2 phosphorylates the two serine residues at positions 320 and 326 in YA, we replaced either or both with alanine by site-directed mutagenesis. In a kinase assay using purified GST fusion proteins in vitro, cdk2 phosphorylated the wild type and both of the single-mutant proteins (YA-as and -sa), but not the double-mutant protein (YA-aa)" SIGNOR-250743 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 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 PPP4C protein P60510 UNIPROT HDAC3 protein O15379 UNIPROT "down-regulates activity" dephosphorylation Ser424 DHDNDKEsDVEI 9606 15805470 t "Here we demonstrate that, in addition to protein-protein interactions with NCoR/SMRT, the activity of HDAC3 is regulated by both phosphorylation and dephosphorylation. A protein kinase CK2 phosphoacceptor site in the HDAC3 protein was identified at position Ser424, which is a nonconserved residue among the class I HDACs. Mutation of this residue was found to reduce deacetylase activity.|Significantly, both overexpression and siRNA knock-down approaches, and analysis of cells devoid of PP4c, unequivocally show that HDAC3 activity is inversely proportional to the cellular abundance of PP4(c)." SIGNOR-248548 PPP4C protein P60510 UNIPROT NDEL1 protein Q9GZM8 UNIPROT "down-regulates activity" dephosphorylation Thr219 ASLSLPAtPVGKGTE 9606 18347064 t "Protein phosphatase 4 catalytic subunit regulates Cdk1 activity and microtubule organization via NDEL1 dephosphorylation|PP4c selectively dephosphorylates NDEL1 at Cdk1 sites. We also demonstrate that PP4c negatively regulates Cdk1 activity at the centrosome.|We next examined the ability of PP4c to dephosphorylate a Cdk1 phosphorylation site, phospho-T219" SIGNOR-248550 PPP4C protein P60510 UNIPROT RELA protein Q04206 UNIPROT "up-regulates activity" dephosphorylation Thr435 PTQAGEGtLSEALLQ 9606 BTO:0002210 15073167 t "Suppression of MEK/ERK signaling pathway enhances cisplatin-induced NF-kappaB activation by protein phosphatase 4-mediated NF-kappaB p65 Thr dephosphorylation" SIGNOR-248549 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 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 PRKCD protein Q05655 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser323 MVGGKPGsFRVRASS 9606 BTO:0000671 15069075 t gcesareni "Here we show in various cell models that the adipose hormone leptin, a putative mediator in obesity-related insulin resistance, promotes phosphorylation of ser-318 in irs1 by a janus kinase 2, irs2, and pkc-dependent pathway. we observed that insulin stimulates phosphorylation of ser(318) in irs-1, which is mediated, at least partially, by pkc-zeta." SIGNOR-123734 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 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 CDK5 protein Q00535 UNIPROT LMTK2 protein Q8IWU2 UNIPROT up-regulates phosphorylation Ser1450 LQTSKYFsPPPPARS 9606 BTO:0000938 BTO:0000142 22220831 t gcesareni "Here, we demonstrate that lmtk2 is phosphorylated on serine-1418 (lmtk2ser ) by cdk5/p35 and present evidence that this regulates its ability to phosphorylate pp1cthr __" SIGNOR-195329 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 CDK5 protein Q00535 UNIPROT HTT protein P42858 UNIPROT up-regulates phosphorylation Ser1179 LTNPPSLsPIRRKGK 9606 BTO:0000938 17611284 t lperfetto "Huntingtin is an antiapoptotic proteinwe show here that huntingtin is phosphorylated by the cyclin-dependent kinase 5 (cdk5) at serines 1181 and 1201. Phosphorylation can be induced by dna damage in vitro and in vivo. The state of huntingtin phosphorylation is a crucial regulator of neuronal cell death. Absence of phosphorylation of huntingtin at serines 1181 and 1201 confers toxic properties to wild-type huntingtin in a p53-dependent manner in striatal neurons and accelerates neuronal death induced by dna damage." SIGNOR-156836 KTN1 protein Q86UP2 UNIPROT KIF5B protein P33176 UNIPROT up-regulates binding 9606 15316074 t miannu "This study demonstrated the effect of kinectin-kinesin interaction on lysosome dynamics and observed that the kinesin-binding domain of kinectin can significantly enhance the mt-stimulated atpase activity of kinesin." SIGNOR-128092 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 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 MAPK1 protein P28482 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Ser59 GGQESQPsPLALLAA 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-116158 PPP1CA protein P62136 UNIPROT CASP9 protein P55211 UNIPROT "up-regulates activity" dephosphorylation Thr125 PEVLRPEtPRPVDIG 9606 16888006 t "ERK/MAPK phosphorylates caspase-9 at Thr(125), and this phosphorylation is crucial for caspase-9 inhibition. Until now, the phosphatase responsible for Thr(125) dephosphorylation has not been described. Here, we demonstrate that in IL-2-proliferating cells, phosphorylated serine/threonine phosphatase type 1alpha (PP1alpha) associates with phosphorylated caspase-9." SIGNOR-248565 PPP1CA protein P62136 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-248566 PPP1CB protein P62140 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-248572 PRKAA2 protein P54646 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR up-regulates phosphorylation 9606 SIGNOR-C15 20647423 t gcesareni "Ampk recruitment and h2b ser36 phosphorylation colocalized within genes activated by ampk-dependent pathways, both in promoters and in transcribed regions." SIGNOR-166905 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 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 PRSS21 protein Q9Y6M0 UNIPROT RAD21 protein O60216 UNIPROT up-regulates cleavage 9606 11875078 t miannu "Rad21 is a component of the cohesin complex that holds sister chromatids together during mitosis and repairs double-strand dna breaks. Interestingly, rad21 is cleaved by a caspase-like esp1/separase at the onset of anaphase to trigger sister chromatid separation." SIGNOR-115426 EP300 protein Q09472 UNIPROT KPNA2 protein P52292 UNIPROT up-regulates acetylation Lys22 HRFKNKGkDSTEMRR 9606 15342649 t lperfetto "Ampk triggered the acetylation of importin alpha1 on lys(22), a process dependent on the acetylase activity of p300" SIGNOR-128625 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR DCX protein O43602 UNIPROT unknown phosphorylation Thr326 TSSSQLStPKSKQSP 9606 BTO:0000007 14741103 t llicata "In order to determine the sites of phosphorylation by Cdk5, serine or threonine in the nine potential sites were substituted with alanine by site-directed mutagenesis to create mutant Dcx proteins. hese were analyzed by co-transfection of 293T cells with cdk5/p35. All-sites-A mutant Dcx showed no slower migrating species on Western analysis, indicating that removal of all nine possible sites is sufficient to block the phosphorylation by Cdk5/p35. However, each single mutant Dcx retains the slower migrating species similar to the wild-type Dcx, suggesting that any single mutation is not sufficient to block phosphorylation by Cdk5/p35." SIGNOR-250659 ITCH protein Q96J02 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates ubiquitination 9606 15350225 t gcesareni "Itch promotes ubiquitination of smad2 and augments smad2 phosphorylation that requires an intact ligase activity of itch. Moreover, itch facilitates complex formation between tgf-beta receptor and smad2 and enhances tgf-beta-induced transcription." SIGNOR-128647 MAP3K11 protein Q16584 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates phosphorylation Ser257 ISGQLVDsIAKTRDA 9606 15328343 t gcesareni "These data suggest that mlk-3 phosphorylates sek1 directly and that it does so specifically on those residues known to activate sek1 in vivo." SIGNOR-128420 MAPK12 protein P53778 UNIPROT Satellite_cells_self-renewal phenotype SIGNOR-PH100 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0002314 BTO:0001103 29681515 f apalma "[...] we observed a significant diminution in the number of symmetric satellite stem cell (YFP–) divisions in p38 gamma siRNA-treated fibers, suggesting that p38 gamma is required for symmetric stem cell maintenance. Thus, loss of p38gamma greatly skewed the ratio of asymmetric to symmetric satellite stem cell divisions to favor asymmetric divisions and myogenic commitment at the expense of self-renewal" SIGNOR-255902 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 PAK1 protein Q13153 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 19162178 t gcesareni "The hgf-induced wave2 transport, lamellipodia formation, stathmin/op18 phosphorylation at ser38 and binding to kinesin-wave2 complex, but not stathmin/op18 phosphorylation at ser25 and microtubule growth, were abrogated by pak1 inhibitor ipa-3" SIGNOR-183503 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 PPP1CB protein P62140 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-248577 PPP1CB protein P62140 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-248573 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 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 RB1 protein P06400 UNIPROT HDAC3 protein O15379 UNIPROT up-regulates 9606 14560017 f gcesareni "We find that active rb mediates histone deacetylation on cyclin a, cdc2, topoisomerase iialfa, and thymidylate synthase promoters. We also demonstrate that this deacetylation is hdac dependent, since the hdac inhibitor trichostatin a (tsa) prevented histone deacetylation at each promoter." SIGNOR-118839 STK11 protein Q15831 UNIPROT PRKAA2 protein P54646 UNIPROT up-regulates phosphorylation Thr172 SDGEFLRtSCGSPNY 9606 SIGNOR-C15 14614828 t gcesareni "We demonstrated that lkb1 phosphorylates ampk on the activation loop threonine (thr172) within the catalytic subunit and activates ampk in vitro. Here, we have investigated whether lkb1 corresponds to the major ampkk activity present in cell extracts. Ampkk purified from rat liver corresponds to lkb1, and blocking lkb1 activity in cells abolishes ampk activation in response to different stimuli" SIGNOR-119179 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 MAPK12 protein P53778 UNIPROT SNTA1 protein Q13424 UNIPROT up-regulates phosphorylation Ser193 GWDSPPAsPLQRQPS 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-67061 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 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 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 PPP1CB protein P62140 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-248574 PPP2CB protein P62714 UNIPROT BCL2 protein P10415 UNIPROT "up-regulates activity" dephosphorylation Ser87 AAAGPALsPVPPVVH 9606 15225643 t "The phosphorylation of Bcl-2 resulted in a reduction in anti-apoptotic function, implying that dephosphorylation promoted the anti-apoptotic activity of Bcl-2 protein in human tumor cell lines. Thus, the present findings suggest that ERK and PP2A are physiological regulators of Bcl-2 phosphorylation, and these enzymes exert an influence on the anti-apoptotic function of Bcl-2.phosphorylation of Bcl2 at Ser70 is proposed to be a dynamic process regulated by the sequential action of an agonist-activated Bcl2 kinase and PP2A." SIGNOR-248589 PPP2CB protein P62714 UNIPROT CHEK1 protein O14757 UNIPROT "down-regulates activity" dephosphorylation Ser317 ENVKYSSsQPEPRTG 9606 17015476 t "Phosphorylation of Chk1 by ATR is antagonized by a Chk1-regulated protein phosphatase 2A circuit|In response to genotoxic stress, Chk1 is phosphorylated on serines 317 (S317) and 345 (S345) by the ataxia-telangiectasia-related (ATR) protein kinase. Phosphorylation of Chk1 on these C-terminal serine residues is used as an indicator of Chk1 activation in vivo." SIGNOR-248579 PPP2CB protein P62714 UNIPROT CHEK1 protein O14757 UNIPROT "down-regulates activity" dephosphorylation Ser345 LVQGISFsQPTCPDH 9606 17015476 t "Phosphorylation of Chk1 by ATR is antagonized by a Chk1-regulated protein phosphatase 2A circuit|In response to genotoxic stress, Chk1 is phosphorylated on serines 317 (S317) and 345 (S345) by the ataxia-telangiectasia-related (ATR) protein kinase. Phosphorylation of Chk1 on these C-terminal serine residues is used as an indicator of Chk1 activation in vivo." SIGNOR-248578 PPP2CB protein P62714 UNIPROT CHEK2 protein O96017 UNIPROT "up-regulates activity" dephosphorylation Thr68 SSLETVStQELYSIP 9606 BTO:0001023 16596250 t "Protein phosphatase 2A interacts with Chk2 and regulates phosphorylation at Thr-68 after cisplatin treatment of human ovarian cancer cells|In response to DNA damage, Chk2 is initially phosphorylated at Thr-68, which leads to its full activation." SIGNOR-248582 PPP2CB protein P62714 UNIPROT KRT8 protein P05787 UNIPROT unknown dephosphorylation Ser432 SAYGGLTsPGLSYSL 9606 BTO:0000182 16554440 t "K8 Ser431-P is a physiologic substrate to PP2A during hyposmotic conditions and possibly other biologic contexts." SIGNOR-248588 ROS stimulus SIGNOR-ST2 SIGNOR SNCA protein P37840 UNIPROT "up-regulates quantity" 9606 BTO:0000938 16000336 f lperfetto "The increased concentration of neuronal alpha-synuclein and pigment in normal A9 neurons may already predispose these neurons to precipitate alpha-synuclein around pigment-associated lipid under oxidative conditions." SIGNOR-249699 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 STK11 protein Q15831 UNIPROT PRKAA2 protein P54646 UNIPROT up-regulates phosphorylation Thr172 SDGEFLRtSCGSPNY 9606 SIGNOR-C15 14976552 t gcesareni "We demonstrated that lkb1 phosphorylates ampk on the activation loop threonine (thr172) within the catalytic subunit and activates ampk in vitro. Here, we have investigated whether lkb1 corresponds to the major ampkk activity present in cell extracts. Ampkk purified from rat liver corresponds to lkb1, and blocking lkb1 activity in cells abolishes ampk activation in response to different stimuli" SIGNOR-122725 TOP2B protein Q02880 UNIPROT EPHA7 protein Q15375 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24463367 f lperfetto "While Top2a is essential in proliferating cells and has been linked to DNA replication and chromosome condensation/segregation, Top2b has been clearly indicated in regulating gene expression (e.g. Reln, Dab1, Catna2, Cdh13, Sst, Pbx3, and Epha7) during brain development" SIGNOR-242311 MAPK13 protein O15264 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-114075 CDK9 protein P50750 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser206 SSSTYPHsPTSSDPG 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-161662 MAPK14 protein Q16539 UNIPROT ADAM17 protein P78536 UNIPROT "up-regulates activity" phosphorylation Thr735 KPFPAPQtPGRLQPA 10029 BTO:0000246 20188673 t gcesareni "We show that p38 MAP kinase, which is activated in response to inflammatory or stress signals, directly activates TACE, a membrane-associated metalloprotease that is also known as ADAM17 and effects shedding in response to growth factors and Erk MAP kinase activation. p38alpha MAP kinase interacts with the cytoplasmic domain of TACE and phosphorylates it on Thr(735), which is required for TACE-mediated ectodomain shedding" SIGNOR-163970 PPP2CA protein P67775 UNIPROT CHEK1 protein O14757 UNIPROT "down-regulates activity" dephosphorylation Ser317 ENVKYSSsQPEPRTG 9606 17015476 t "Phosphorylation of Chk1 by ATR is antagonized by a Chk1-regulated protein phosphatase 2A circuit|In response to genotoxic stress, Chk1 is phosphorylated on serines 317 (S317) and 345 (S345) by the ataxia-telangiectasia-related (ATR) protein kinase. Phosphorylation of Chk1 on these C-terminal serine residues is used as an indicator of Chk1 activation in vivo." SIGNOR-248616 PPP2CA protein P67775 UNIPROT CHEK2 protein O96017 UNIPROT "up-regulates activity" dephosphorylation Thr68 SSLETVStQELYSIP 9606 BTO:0001023 16596250 t "Protein phosphatase 2A interacts with Chk2 and regulates phosphorylation at Thr-68 after cisplatin treatment of human ovarian cancer cells|In response to DNA damage, Chk2 is initially phosphorylated at Thr-68, which leads to its full activation." SIGNOR-248617 PPP2CB protein P62714 UNIPROT AKT3 protein Q9Y243 UNIPROT "down-regulates activity" dephosphorylation Ser474 HFPQFSYsASGRE 9606 18160256 t "Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A." SIGNOR-248609 PPP2CB protein P62714 UNIPROT MAPK1 protein P28482 UNIPROT "down-regulates activity" dephosphorylation Thr185 HDHTGFLtEYVATRW 10116 7780739 t "Inactivation of p42 MAP kinase by protein phosphatase 2A and a protein tyrosine phosphatase, but not CL100, in various cell lines|Protein phosphatase-2A was the only vanadate-insensitive phosphatase acting on Thr 183 of p42mapk or on MAPKK to be detected in PC12 cell extracts." SIGNOR-248590 PPP2CB protein P62714 UNIPROT MDM2 protein Q00987 UNIPROT "up-regulates activity" dephosphorylation Thr216 RSSSSEStGTPSNPD 10090 11983168 t "cyclin G also binds in vivo and in vitro to Mdm2 and markedly stimulates the ability of PP2A to dephosphorylate Mdm2 at T216. Consistent with these data, cyclin G null cells have both Mdm2 that is hyperphosphorylated at T216 and markedly higher levels of p53 protein when compared to wild-type cells" SIGNOR-248593 PRKAA1 protein Q13131 UNIPROT KPNA2 protein P52292 UNIPROT up-regulates phosphorylation Ser105 QAARKLLsREKQPPI 9606 SIGNOR-C15 15342649 t lperfetto "Ampk phosphorylated importin alpha1 on ser(105). Accordingly, expression of importin alpha1 proteins bearing k22r or s105a mutations failed to mediate the nuclear import of hur in intact cells. Our results point to importin alpha1 as a critical downstream target of ampk and key mediator of ampk-triggered hur nuclear import." SIGNOR-128629 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 PRKCA protein P17252 UNIPROT IQGAP1 protein P46940 UNIPROT up-regulates phosphorylation Ser1443 DKMKKSKsVKEDSNL 9606 15355962 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-128714 PRKCE protein Q02156 UNIPROT IQGAP1 protein P46940 UNIPROT up-regulates phosphorylation Ser1443 DKMKKSKsVKEDSNL 9606 15355962 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-128718 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 SNCA protein P37840 UNIPROT Lewy_body_formation phenotype SIGNOR-PH56 SIGNOR up-regulates 9606 BTO:0000938 12666095 f lperfetto "A key observation linking alpha-synuclein to PD was the demonstration that it is one of the principal components of Lewy bodies. Furthermore, mutant isoforms of alpha-synuclein more readily oligomerize, and it has been suggested that its tendency to aggregate into misfolded structures may confer toxic properties to the protein." SIGNOR-249700 WNT3A protein P56704 UNIPROT RYK protein P34925 UNIPROT up-regulates binding 9606 15454084 t gcesareni "Here, we report that ryk directly binds wnt-1 and wnt-3a via its wif domain and is required for the tcf." SIGNOR-129580 CDX2 protein Q99626 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-253969 MAPK14 protein Q16539 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" 9606 12181443 f lperfetto "We show [] that the kinase activity and s473 phosphorylation of akt induced by lpa and s1p requires both mitogen-activated protein (map) kinase kinase (mek) and p38 map kinase. [] among different stimuli tested, platelet-derived growth factor stimulates s473 phosphorylation of akt in a mek- and p38-dependent manner. However, epidermal growth factor, thrombin, and endothelin-1?stimulated Akt s473 phosphorylation require p38 but not mek." SIGNOR-244465 CDX2 protein Q99626 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-253968 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 PPP2CA protein P67775 UNIPROT AKT1 protein P31749 UNIPROT "down-regulates activity" dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 18160256 t "Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A." SIGNOR-248628 PPP2CA protein P67775 UNIPROT AKT1 protein P31749 UNIPROT "down-regulates activity" dephosphorylation Thr308 KDGATMKtFCGTPEY 9606 18160256 t "Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A." SIGNOR-248626 PPP2CA protein P67775 UNIPROT AKT2 protein P31751 UNIPROT "down-regulates activity" dephosphorylation Ser474 RTHFPQFsYSASIRE 9606 18160256 t "Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A." SIGNOR-248632 PPP2CA protein P67775 UNIPROT AKT2 protein P31751 UNIPROT "down-regulates activity" dephosphorylation Thr309 SDGATMKtFCGTPEY 9606 18160256 t "Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A." SIGNOR-248630 PPP2CA protein P67775 UNIPROT AKT3 protein Q9Y243 UNIPROT "down-regulates activity" dephosphorylation Ser472 RPHFPQFsYSASGRE 9606 18160256 t "Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A." SIGNOR-248653 PPP2CA protein P67775 UNIPROT ATM protein Q13315 UNIPROT "down-regulates activity" dephosphorylation Ser1981 SLAFEEGsQSTTISS 9606 15510216 t "Ionizing radiation induces autophosphorylation of the ataxia-telangiectasia mutated (ATM) protein kinase on serine 1981; however, the precise mechanisms that regulate ATM activation are not fully understood. Here, we show that the protein phosphatase inhibitor okadaic acid (OA) induces autophosphorylation of ATM on serine 1981 in unirradiated cells at concentrations that inhibit protein phosphatase 2A-like activity in vitro." SIGNOR-248644 PPP2CB protein P62714 UNIPROT PRKCD protein Q05655 UNIPROT "down-regulates activity" dephosphorylation Ser645 LNEKARLsYSDKNLI 10090 BTO:0000944 11959144 t "PP2A(c) displayed the highest specific activity towards PKCdelta. The role of PP2A(c) in the dephosphorylation of PKCdelta in cells was supported by the demonstration that these proteins could be co-immunoprecipitated from NIH3T3 cells.|In conclusion, the evidence here indicates that PKCdelta de-phosphorylation and hence inactivation is effected by PP2A with which it forms a complex" SIGNOR-248595 PPP2CB protein P62714 UNIPROT PRKCD protein Q05655 UNIPROT "down-regulates activity" dephosphorylation Ser664 QSAFAGFsFVNPKFE 10090 BTO:0000944 11959144 t "PP2A(c) displayed the highest specific activity towards PKCdelta. The role of PP2A(c) in the dephosphorylation of PKCdelta in cells was supported by the demonstration that these proteins could be co-immunoprecipitated from NIH3T3 cells.|In conclusion, the evidence here indicates that PKCdelta de-phosphorylation and hence inactivation is effected by PP2A with which it forms a complex" SIGNOR-248596 PRKCD protein Q05655 UNIPROT EIF2S1 protein P05198 UNIPROT unknown phosphorylation Ser52 MILLSELsRRRIRSI -1 1677563 t lperfetto "Of four other protein kinases tested only protein kinase C (PKC) phosphorylated P(45-56), with complete dependence on phosphatidylserine. Only the residue corresponding to serine-51 in eIF-2 alpha was phosphorylated by HCR, dsI or PKC." SIGNOR-248853 RXRB protein P28702 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-79449 SRC protein P12931 UNIPROT SPRY2 protein O43597 UNIPROT up-regulates phosphorylation Tyr55 AIRNTNEyTEGPTVV 9606 15564375 t lperfetto "Activation of signalling by fibroblast growth factor receptor leads to phosphorylation of the signalling attenuator human sprouty 2 (hspry2) on residue y55. we show that hspry2 is a direct substrate for src family kinases, including src itself.Phosphorylation of hspry2 is required for hspry2 to inhibit activation of the extracellular signal-regulated kinase pathway." SIGNOR-131189 MAP1LC3B protein Q9GZQ8 UNIPROT ATG3 protein Q9NT62 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-191549 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 CHEK1 protein O14757 UNIPROT CDC25C protein P30307 UNIPROT down-regulates phosphorylation Ser216 SGLYRSPsMPENLNR 9606 20068082 t gcesareni "The signal for ubiquitination after uv and ir exposure is created by phosphorylation of cdc25a mediated by chk1 and chk2, respectively. Chk1 is a major kinase phosphorylating cdc25a (ser76/124) and cdc25c (ser216). regulation;btrc(induces);14-3-3 beta(induces);apoptosis, altered;14-3-3 beta(induces);ccna1(disrupts);cdk2(disrupts);cdk1(disrupts);ccnb1(disrupts);" SIGNOR-163158 MAPK14 protein Q16539 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-90521 MAPK14 protein Q16539 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-90525 MAPK14 protein Q16539 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-163250 PPP2CA protein P67775 UNIPROT AKT3 protein Q9Y243 UNIPROT "down-regulates activity" dephosphorylation Thr305 TDAATMKtFCGTPEY 9606 18160256 t "Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A." SIGNOR-248651 PPP2CA protein P67775 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" dephosphorylation 9606 18160256 t "Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A." SIGNOR-248655 PPP2CA protein P67775 UNIPROT CARD11 protein Q9BXL7 UNIPROT "down-regulates activity" dephosphorylation Ser644 NLMFRKFsLERPFRP 9606 21157432 t "NF-kappaB activation is triggered by PKCtheta-dependent phosphorylation of Carma1 after TCR/CD28 co-stimulation. PKCtheta-phosphorylated Carma1 was suggested to function as a molecular scaffold that recruits preassembled Bcl10-Malt1 complexes to the membrane|we demonstrate that PP2A removes PKCtheta-dependent phosphorylation of Ser645 in Carma1, and show that maintenance of this phosphorylation is correlated with increased T-cell activation." SIGNOR-248650 PPP2CA protein P67775 UNIPROT HDAC7 protein Q8WUI4 UNIPROT "up-regulates activity" dephosphorylation Ser181 NPLLRKEsAPPSLRR 9606 18339811 t "Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. |Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs.|we demonstrate that PP2A constitutively dephosphorylates the class IIa member HDAC7 to control its biological functions as a regulator of T cell apoptosis and endothelial cell functions." SIGNOR-248647 PPP2CA protein P67775 UNIPROT MAPK1 protein P28482 UNIPROT "down-regulates activity" dephosphorylation Thr185 HDHTGFLtEYVATRW 10116 7780739 t "Inactivation of p42 MAP kinase by protein phosphatase 2A and a protein tyrosine phosphatase, but not CL100, in various cell lines|Protein phosphatase-2A was the only vanadate-insensitive phosphatase acting on Thr 183 of p42mapk or on MAPKK to be detected in PC12 cell extracts." SIGNOR-248625 PTPN12 protein Q05209 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates activity" dephosphorylation Tyr1007 VLPQDKEyYKVKEPG 9606 BTO:0003892 11731619 t "PTP-PEST-Containing Lysates from EGF-Treated HC11 Cells Dephosphorylate JAK2 More Efficiently than Lysates from Control Cells|phospho-JAK2-specific rabbit polyclonal antiserum (44-426, BioSource Technologies, Inc., Camarillo, CA) which recognizes Tyr1007/1008 in the activation site" SIGNOR-248657 PTPN12 protein Q05209 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates activity" dephosphorylation Tyr1008 LPQDKEYyKVKEPGE 9606 BTO:0003892 11731619 t "PTP-PEST-Containing Lysates from EGF-Treated HC11 Cells Dephosphorylate JAK2 More Efficiently than Lysates from Control Cells|phospho-JAK2-specific rabbit polyclonal antiserum (44-426, BioSource Technologies, Inc., Camarillo, CA) which recognizes Tyr1007/1008 in the activation site" SIGNOR-248658 PTPN12 protein Q05209 UNIPROT PTK2 protein Q05397 UNIPROT "down-regulates activity" dephosphorylation Tyr397 SVSETDDyAEIIDEE 10090 BTO:0000944 19595712 t "We demonstrate here that activated Ras induces tyrosine dephosphorylation and inhibition of FAK mediated by the Ras downstream Fgd1-Cdc42-PAK1-MEK-ERK signaling cascade.| PIN1 binding and prolyl isomerization of FAK cause PTP-PEST to interact with and dephosphorylate FAK Y397. Inhibition of FAK mediated by this signal relay promotes Ras-induced cell migration, invasion, and metastasis." SIGNOR-248661 LRRK2 protein Q5S007 UNIPROT ARHGEF7 protein Q14155 UNIPROT up-regulates phosphorylation Thr164 LGSQSLHtRTSKLFQ 9606 21048939 t gcesareni "Arhgef7 is interacting with lrrk2 in vitro and in vivo. Lrrk2 phosphorylates arhgef7 in vitro.Two Threonine residues, t107 and t143, within the arhgef7 n-terminus were identified with high confidence" SIGNOR-169225 MAPK14 protein Q16539 UNIPROT ATF2 protein P15336 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007 10085140 t lperfetto "On the other hand, sapks such as jnks and p38 phosphorylate atf-2 at thr-69, thr-71, and ser-90 which lie close to the n-terminal transcriptional activation domain and stimulate itstrans-activating capacity our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf- signaling via tak1 and p38." SIGNOR-65593 MAPK14 protein Q16539 UNIPROT ATF2 protein P15336 UNIPROT "up-regulates activity" phosphorylation Ser90 GLFNELAsPFENEFK 9606 BTO:0000599 10085140 t miannu "P38 directly phosphorylates ATF-2 at Thr-69, Thr-71, and Ser-90, resulting in stimulation of its trans-activating capacity." SIGNOR-250090 MAPK14 protein Q16539 UNIPROT BCL2 protein P10415 UNIPROT down-regulates phosphorylation Ser87 AAAGPALsPVPPVVH 9606 19336399 t gcesareni "The protein's reduced antiapoptotic capacity was related to phosphorylation of its threonine 56 and serine 87 residues by virally activated p38mapk" SIGNOR-184936 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 PAK1 protein Q13153 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser405 KTQTPPVsPAPQPTE 9606 21079800 t gcesareni "Strikingly, we find that pak1 phosphorylation of cortactin on serine residues 405 and 418 increases its association with n-wasp. Thus, pak1, by controlling the interaction between cortactin and n-wasp, could regulate the polymerization of actin during clathrin-independent endocytosis." SIGNOR-169690 PAK1 protein Q13153 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser418 TEERLPSsPVYEDAA 9606 21079800 t gcesareni "Strikingly, we find that pak1 phosphorylation of cortactin on serine residues 405 and 418 increases its association with n-wasp. Thus, pak1, by controlling the interaction between cortactin and n-wasp, could regulate the polymerization of actin during clathrin-independent endocytosis." SIGNOR-169694 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 PRKCA protein P17252 UNIPROT DGKZ protein Q13574 UNIPROT unknown phosphorylation Ser454 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 PTPN12 protein Q05209 UNIPROT ABL1 protein P00519 UNIPROT "down-regulates activity" dephosphorylation 10090 BTO:0004055 11163214 t gcesareni "Several experiments suggest that the PEST-type PTPs negatively regulate c-Abl activity: c-Abl was hyperphosphorylated in PTP-PEST-deficient cells; disruption of the c-Abl-PSTPIP1-PEST-type PTP ternary complex by overexpression of PSTPIP1 mutants increased c-Abl phosphotyrosine content" SIGNOR-246222 PTPN12 protein Q05209 UNIPROT SRC protein P12931 UNIPROT "down-regulates activity" dephosphorylation Tyr419 RLIEDNEyTARQGAK 10090 18482983 t "we identify SHP-2 and PTP-PEST as negative regulators of c-Src kinase | Inactivation of catalytically active c-Src kinase by the phosphatases SHP-2 or PTP-PEST by dephosphorylation of the tyrosine residue Tyr-416 within the c-Src kinase domain prevents the phosphorylation of villin" SIGNOR-248659 PTPN12 protein Q05209 UNIPROT WAS protein P42768 UNIPROT "down-regulates activity" dephosphorylation Tyr291 AETSKLIyDFIEDQG 10090 14707117 t "mutation of tyrosine residue Y291, identified here as the major site of TCR-induced WASp tyrosine phosphorylation, abrogated induction of WASp tyrosine phosphorylation and its effector activities|WASp was tyrosine dephosphorylated by protein tyrosine phosphatase (PTP)-PEST" SIGNOR-248660 RPS6KA2 protein Q15349 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 19282669 t gcesareni "The rsks catalyze the phosphorylation of the pro-apoptotic protein bad at serine 112 to promote cell survival." SIGNOR-184591 STK4 protein Q13043 UNIPROT FOXO1 protein Q12778 UNIPROT up-regulates phosphorylation Ser212 SSAGWKNsIRHNLSL 9606 18394876 t gcesareni "Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity. The other major signaling modules that directly regulate the activity of the foxo factors include the stress-activated jun-n-terminal kinase (jnk), the mammalian ortholog of the ste20-like protein kinase (mst1), and the deacetylase sirt1." SIGNOR-178186 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 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 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 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 MAPK14 protein Q16539 UNIPROT CDKN1C protein P49918 UNIPROT up-regulates phosphorylation 9606 22820251 t gcesareni "G1-s control by p38/hog1 sapks upon osmostress. Upon osmostress, activated p38 and hog1 sapks phosphorylate the s/cdk inhibitor p57 or sic1 respectively at one single residue. In mammalian cells (left panel), p57 phosphorylation on thr143 leads to an increase of the affinity of p57 towards the cyclin a/cdk2 complex leading to a g1 arrest." SIGNOR-198390 MAPK14 protein Q16539 UNIPROT CDX2 protein Q99626 UNIPROT "up-regulates activity" phosphorylation Ser295 LQASVPGsVPGVLGP 9606 BTO:0001112 16027724 t miannu "ERK2, p38alpha and GSK-3beta can phosphorylate Cdx2 in vitro and that the 4S motif is required for phosphorylation by GSK-3beta and p38alpha but dispensable for phosphorylation by ERK2. phosphorylation of Cdx2 by the kinase p38 accompanies cell differentiation and enhances its transcriptional activity" SIGNOR-250095 PLK3 protein Q9H4B4 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 21098032 t gcesareni "Kinase activity of plk3 was significantly activated by hyperosmotic stimulation. Further downstream, active plk3 phosphorylated atf-2 at the thr-71 site in vivo and in vitro." SIGNOR-170008 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 PRKCA protein P17252 UNIPROT MYOD1 protein P15172 UNIPROT "down-regulates activity" phosphorylation Thr115 ADRRKAAtMRERRRL 9534 BTO:0001538 1335366 t lperfetto "FGF inactivates myogenic helix-loop-helix proteins through phosphorylation of a conserved protein kinase C site in their DNA-binding domains." SIGNOR-248845 PRKCZ protein Q05513 UNIPROT AKT3 protein Q9Y243 UNIPROT "up-regulates activity" phosphorylation Ser472 RPHFPQFsYSASGRE 9534 BTO:0001538 12162751 t lperfetto "Full activation of the PKB enzyme requires phosphorylation of a threonine in the activation" SIGNOR-249153 PRKD1 protein Q15139 UNIPROT PLCG1 protein P19174 UNIPROT "down-regulates activity" phosphorylation Ser1248 HGRAREGsFESRYQQ 9606 BTO:0000661 1370476 t lperfetto "Thus, phosphorylation of PLC-gamma 1 by PKC or PKA at serine 1248 may modulate the interaction of PLC-gamma 1 with the protein tyrosine kinase or the protein tyrosine phosphatase; this altered interaction may, at least in part, be responsible for the decreased tyrosine phosphorylation of PLC-gamma 1 seen in PMA- and forskolin-treated Jurkat cells." SIGNOR-248846 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 RHOA protein P61586 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 9606 23450633 f gcesareni "Ga12/13 recruitment of rho-gefs causes rhoa activation and f-actin assembly, which promotes lats1/lat2 inactivation by an unknown, but myosin-independent mechanism." SIGNOR-192114 RUBCN protein Q92622 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT down-regulates binding 9606 19270693 t gcesareni "The run or cysteine-rich domain of rubicon appears to be inhibitory to the binding of rubicon to beclin 1 and vps34" SIGNOR-184547 SGK3 protein Q96BR1 UNIPROT GSK3B protein P49841 UNIPROT "down-regulates activity" phosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000007 16543730 t lperfetto "Phosphorylation of GSK3 by PKB or SGK1 inhibits GSK3 activity|estern blotting using an antibody specific for the PKB/SGK1 consensus phosphorylation site in GSK3a/beta (serine 21 and 9 respectively) revealed an increase in GSK3a/beta phosphorylation in human embryonic kidney 293 (HEK293) cells overexpressing wild type SGK1, constitutively active SGK1, but not catalytically inactive SGK1.|The effect of SGK1 was mimicked by PKB and SGK3." SIGNOR-249167 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 CHRM5 protein P08912 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-256873 CSNK2A1 protein P68400 UNIPROT CBX5 protein P45973 UNIPROT up-regulates phosphorylation Ser11 KTKRTADsSSSEDEE 9606 21245376 t gcesareni "Hp1_ was multiply phosphorylated at n-terminal serine residues (s11-14) in human and mouse cells and that this phosphorylation enhanced hp1_'s affinity for h3k9me. Unphosphorylatable mutant hp1_ exhibited severe heterochromatin localization defects in vivo, and its prolonged expression led to increased chromosomal instability." SIGNOR-171695 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 CLOCK protein O15516 UNIPROT PER1 protein O15534 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-253633 CLOCK protein O15516 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-253635 MAPK14 protein Q16539 UNIPROT EEA1 protein Q15075 UNIPROT "up-regulates activity" phosphorylation Thr1392 CSAKNALtPSSKKPV 10090 BTO:0002572 16138080 t lperfetto "We found that p38alpha can phosphorylate the rab5 effectors eea1 and rabenosyn-5 on thr-1392 and ser-215, respectively, and these phosphorylation events regulate the recruitment of eea1 and rabenosyn-5 to membranes" SIGNOR-140082 MAPK14 protein Q16539 UNIPROT EGFR protein P00533 UNIPROT down-regulates phosphorylation 9606 16932740 t "In this case, the phosphorylation of EGFR by p38 or a downstream kinase like MAPKAP-2, triggers receptor internalization." gcesareni "In conclusion, the use of pharmacological agents suggests that p38 mapk is the enzyme involved in egfr phosphorylation, as well as internalization, following exposure of cells to various stress-inducing conditions." SIGNOR-149089 MAPK14 protein Q16539 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates 9606 11777913 f gcesareni "Phosphorylation of 4e-bp1 is mediated by the p38/msk1 pathway in response to uvb irradiation. In the present study we demonstrated that uvb induced 4e-bp1 phosphorylation at multiple sites, thr-36, thr-45, ser-64, and thr-69, leading to dissociation of 4e-bp1 from eif-4e. Uvb-induced phosphorylation of 4e-bp1 was blocked by p38 kinase inhibitors, pd169316 and sb202190, and msk1 inhibitor, h89, but not by mitogen-activated protein kinase kinase inhibitors, pd98059 or u0126." SIGNOR-113566 MAPK14 protein Q16539 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Ser65 FLMECRNsPVTKTPP 9606 BTO:0003316 11777913 t miannu "4E-BP1 Is Phosphorylated in Vitro by Active p38 Kinase. In the present study we demonstrated that UVB induced 4E-BP1 phosphorylation at multiple sites, Thr-36, Thr-45, Ser-64, and Thr-69, leading to dissociation of 4E-BP1 from eIF-4E." SIGNOR-250097 MAPK1 protein P28482 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates phosphorylation Ser130 SGEQAEGsPGGPGDS 9606 19364816 t gcesareni "Extracellular signal-regulated kinase 2-dependent phosphorylation induces cytoplasmic localization and degradation of p21cip1." SIGNOR-185215 PPM1D protein O15297 UNIPROT ATM protein Q13315 UNIPROT down-regulates dephosphorylation 9606 19360021 t gcesareni "The negative regulator wip1 plays an important role in inhibiting atm, resulting in a pulse of atm activity." SIGNOR-185135 PRKCA protein P17252 UNIPROT CFTR protein P13569 UNIPROT "up-regulates activity" phosphorylation Ser790 IHRKTTAsTRKVSLA -1 1377674 t lperfetto "Direct amino acid sequencing and peptide mapping of CF-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by PKA and PKG, and serines 686 and 790 were phosphorylated by PKC." SIGNOR-248851 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 TCEA1 protein P23193 UNIPROT UBR5 protein O95071 UNIPROT up-regulates binding 9606 21127351 t miannu "We show that the e3 ubiquitin ligase ubr5 associates with the cdk9 subunit of positive transcription elongation factor b to mediate its polyubiquitination in human cells. Tfiis also binds ubr5 to stimulate cdk9 polyubiquitination." SIGNOR-170258 TRPM7 protein Q96QT4 UNIPROT EEF2K protein O00418 UNIPROT up-regulates phosphorylation Ser78 SSGSPANsFHFKEAW 9606 21112387 t gcesareni "Here, we show that under conditions where cell growth is limited by mg(2+) availability, trpm7 via its kinase mediates enhanced thr56 phosphorylation of eef2." SIGNOR-170134 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 COL18A1 protein P39060 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 BTO:0001103;BTO:0002319 21949456 t "Muscle basement membrane consists primarily of a type IV collagen network, however types VI, XV, and XVIII are also present. Types XV and XVIII collagen are classified as multiplexins, which are heparan sulfate proteoglycans (HSPGs). The multiplexins can bind growth factors and also aid in linking the basement membrane to other basement membrane glycoproteins and endomysium" SIGNOR-254679 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 CDK7 protein P50613 UNIPROT NR5A1 protein Q13285 UNIPROT up-regulates phosphorylation Ser203 EYPEPYAsPPQPGLP 9606 17901130 t llicata "In conclusion, our results indicate that cdk7, as part of the cak complex and tfiih, phosphorylates sf1 at s203 followed by increased transcriptional activity of sf1" SIGNOR-157952 COL15A1 protein P39059 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 BTO:0001103;BTO:0002319 21949456 t "Muscle basement membrane consists primarily of a type IV collagen network, however types VI, XV, and XVIII are also present. Types XV and XVIII collagen are classified as multiplexins, which are heparan sulfate proteoglycans (HSPGs). The multiplexins can bind growth factors and also aid in linking the basement membrane to other basement membrane glycoproteins and endomysium" SIGNOR-254678 CSNK2A1 protein P68400 UNIPROT CBX5 protein P45973 UNIPROT up-regulates phosphorylation Ser14 RTADSSSsEDEEEYV 9606 21245376 t gcesareni "Hp1_ was multiply phosphorylated at n-terminal serine residues (s11-14) in human and mouse cells and that this phosphorylation enhanced hp1_'s affinity for h3k9me. Unphosphorylatable mutant hp1_ exhibited severe heterochromatin localization defects in vivo, and its prolonged expression led to increased chromosomal instability." SIGNOR-171707 GABARAP protein O95166 UNIPROT TBC1D25 protein Q3MII6 UNIPROT up-regulates binding 9606 21383079 t gcesareni "In this study, we report evidence demonstrating that oatl1, a putative rab guanosine triphosphatase-activating protein (gap), is a novel binding partner of atg8 homologues in mammalian cells. Oatl1 is recruited to isolation membranes and autophagosomes through direct interaction with atg8 homologues and is involved in the fusion between autophagosomes and lysosomes through its gap activity." SIGNOR-172536 MAPK14 protein Q16539 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr37 PPGDYSTtPGGTLFS 9606 BTO:0003316 11777913 t miannu "4E-BP1 Is Phosphorylated in Vitro by Active p38 Kinase. In the present study we demonstrated that UVB induced 4E-BP1 phosphorylation at multiple sites, Thr-36, Thr-45, Ser-64, and Thr-69, leading to dissociation of 4E-BP1 from eIF-4E." SIGNOR-250098 MAPK14 protein Q16539 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser383 IHFWSTLsPIAPRSP 9606 9130707 t gcesareni "We demonstrate here that elk-1 is barely activated by a third subclass of map kinases (p38), most likely because the critical residues ser383 and ser389 are poorly phosphorylated by p38 map kinase." SIGNOR-47630 MAPK14 protein Q16539 UNIPROT ELK3 protein P41970 UNIPROT up-regulates phosphorylation Ser357 IHFWSSLsPVAPLSP 9606 9130707 t gcesareni "Tcf sap-1a is efficiently phosphorylated by p38 map kinase in vitro and in vivo on the homologous residues ser381 and ser387. Mutation of these sites to alanine severely reduces c-fos sre-dependent transcription mediated by sap-1a and p38 map kinase." SIGNOR-47681 PRKAA1 protein Q13131 UNIPROT FOXO4 protein P98177 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 phosphorylation sites, resulting in foxo activation" SIGNOR-157947 PRKCD protein Q05655 UNIPROT DAP3 protein P51398 UNIPROT up-regulates phosphorylation Thr237 ITRVRNAtDAVGIVL 9606 18227431 t amattioni "Dap3 is phosphorylated by protein kinase cdelta on thr237. Dap3 was originally identified as a pro-apoptotic protein. The mutation of the phosphorylation site thr237 to alanine reversed the cell death caused by the wild-type dap3" SIGNOR-160488 PRKG1 protein Q13976 UNIPROT CFTR protein P13569 UNIPROT "up-regulates activity" phosphorylation Ser700 FGEKRKNsILNPINS -1 1377674 t lperfetto "Direct amino acid sequencing and peptide mapping of CF-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by PKA and PKG, and serines 686 and 790 were phosphorylated by PKC." SIGNOR-248850 PYY protein P10082 UNIPROT NPY5R protein Q15761 UNIPROT up-regulates binding 9606 11825645 t esanto "Maml3 forms complexes in vivo with icn and csl and functiosn as transcriptional coactivators for notch signaling." SIGNOR-114749 RAP1GDS1 protein P52306 UNIPROT RHOC protein P08134 UNIPROT up-regulates binding 9606 21242305 t miannu "Smggds is a guanine nucleotide exchange factor that specifically activates rhoa and rhoc" SIGNOR-171399 RPS6KA1 protein Q15418 UNIPROT RPS6 protein P62753 UNIPROT up-regulates phosphorylation Ser244 LRASTSKsESSQK 9606 21233202 t lperfetto "In response to mitogenic stimuli, rps6 undergoes ordered c-terminal phosphorylation by p70 s6 kinases and p90 ribosomal s6 kinases on four conserved ser residues (ser-235, ser-236, ser-240, and ser-244) whose modification potentiates rps6 cap binding activity" SIGNOR-171247 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 CRTC2 protein Q53ET0 UNIPROT G6PC 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-256103 CSNK2A1 protein P68400 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation Ser20 ADDSLSNsEEEPDRQ 9606 21559372 t llicata "Further investigation revealed that il-6 stabilizes twist in scchn cell lines through casein kinase 2 (ck2) phosphorylation of twist residues s18 and s20, and that this phosphorylation inhibits degradation of twist." SIGNOR-173672 CRTC2 protein Q53ET0 UNIPROT CREB1 protein P16220 UNIPROT "up-regulates activity" binding 9600 BTO:0000567 26652733 t "The cAMP-response element-binding protein (CREB)-regulated transcription coactivator 2 (CRTC2) is a coactivator known to be specific to CREB and plays a central role in the glucagon-mediated activation of gluconeogenesis in the early phase of fasting" SIGNOR-256102 MAPK14 protein Q16539 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr46 GGTLFSTtPGGTRII 9606 BTO:0003316 11777913 t miannu "4E-BP1 Is Phosphorylated in Vitro by Active p38 Kinase. In the present study we demonstrated that UVB induced 4E-BP1 phosphorylation at multiple sites, Thr-36, Thr-45, Ser-64, and Thr-69, leading to dissociation of 4E-BP1 from eIF-4E." SIGNOR-250099 MAPK14 protein Q16539 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser383 IHFWSTLsPIAPRSP 9606 BTO:0000150 20727996 t gcesareni "Elk-1 is a member of the e-twenty-six (ets) domain superfamily of transcription factors and has been traditionally associated with mitogen-induced immediate early gene transcription upon phosphorylation by mitogen activated protein kinases (erk/mapk)." SIGNOR-167539 MAPK14 protein Q16539 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser389 LSPIAPRsPAKLSFQ 9606 9130707 t gcesareni "We demonstrate here that elk-1 is barely activated by a third subclass of map kinases (p38), most likely because the critical residues ser383 and ser389 are poorly phosphorylated by p38 map kinase." SIGNOR-47634 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 NFX1 protein Q12986 UNIPROT TERT protein O14746 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004117 17267499 f miannu "NFX1-123 augments the activation of hTERT expression through interactions with PABPCs" SIGNOR-226015 PRKAB1 protein Q9Y478 UNIPROT ULK1 protein O75385 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C15 21460634 t gcesareni "Ampk and ulk1 interact and that the latter is phosphorylated by ampk. This phosphorylation leads to the direct activation of ulk1 by ampk bypassing mtor-inhibition" SIGNOR-173044 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 PRKCE protein Q02156 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-172239 PTK2 protein Q05397 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr905 DVYEEDSyVKRSQGR 9606 21454698 t llicata "Focal adhesion kinase (fak) binds ret kinase via its ferm domain, priming a direct and reciprocal ret-fak transactivation mechanism. following gdnf stimulation, increased phosphorylation of fak at tyr-576/577 as well as phosphorylation of ret at tyr-905 was observed." SIGNOR-173009 RACK1 protein P63244 UNIPROT PTK7 protein Q13308 UNIPROT up-regulates binding 9606 21350015 t gcesareni "Here, we identify rack1 as a novel interaction partner of ptk7. Mechanistically, rack1 is necessary for the ptk7-mediated membrane localization of dishevelled (dsh). Rack1 facilitates the ptk7-dsh interaction by recruiting pkcdelta1, a known effector of dsh membrane translocation." SIGNOR-172322 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 PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr925 DRSNDKVyENVTGLV 9606 21454698 t gcesareni "Strikingly, when fak and ret kinases were co-incubated in the presence of atp, a marked increased in fak tyr-576/577 and tyr-925 phosphorylation was observed together with a shift in mobility of fak, indicating conversion to an activated state" SIGNOR-173021 RPS6KA1 protein Q15418 UNIPROT RPS6 protein P62753 UNIPROT up-regulates phosphorylation Ser240 RLSSLRAsTSKSESS 9606 21233202 t lperfetto "In response to mitogenic stimuli, rps6 undergoes ordered c-terminal phosphorylation by p70 s6 kinases and p90 ribosomal s6 kinases on four conserved ser residues (ser-235, ser-236, ser-240, and ser-244) whose modification potentiates rps6 cap binding activity" SIGNOR-171243 SH3GLB1 protein Q9Y371 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates binding 9606 21311563 t gcesareni "Bif-1 forms a complex with beclin1 through uvrag and promotes the activation of the class iii pi3 kinase, vps34, in mammalian cells." SIGNOR-171899 CSNK1A1L protein Q8N752 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation 9606 21606194 t gcesareni "Ck1 also phosphorylates lrp6 at the second ser residue in the pppspxs motif ck1_ in the lrp5/e-cadherin/p120-catenin complex temporally coincides with p120-catenin phosphorylation in ser268. moreover, and considering the close similarity between the catalytic domains of ck1_ and ck1_, it is possible that ck1_ is indeed responsible for the phosphorylation at ser1420 and ser1430 in lrp5/6 that negatively affects wnt signaling by still not defined mechanisms" SIGNOR-173853 CDK20 protein Q8IZL9 UNIPROT CDK2 protein P24941 UNIPROT up-regulates phosphorylation Thr160 GVPVRTYtHEVVTLW 9606 14597612 t gcesareni "P42 is essential for the phosphorylation of thr-160 and activation of cdk2." SIGNOR-118986 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 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR FGFR1 protein P11362 UNIPROT down-regulates phosphorylation Ser777 SMPLDQYsPSFPDTR 9606 23405013 t lperfetto "Erk-mediated phosphorylation of fibroblast growth factor receptor 1 on ser777 inhibits signaling" SIGNOR-244541 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 HRAS protein P01112 UNIPROT PIK3CD protein O00329 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-175192 KRAS protein P01116 UNIPROT PIK3CD protein O00329 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-175210 MAP3K5 protein Q99683 UNIPROT ZNF622 protein Q969S3 UNIPROT up-regulates phosphorylation Ser314 WCNEKGKsFYSTEAV 9606 21771788 t gcesareni "Ask1 directly phosphorylated zpr9 at ser(314) and thr(318), suggesting that zpr9 can act as an ask1 substrate. Ask1-mediated phosphorylation of zpr9 at ser(314) and thr(318) was also responsible for zpr9-induced apoptosis." SIGNOR-175113 MAP3K5 protein Q99683 UNIPROT ZNF622 protein Q969S3 UNIPROT up-regulates phosphorylation Thr318 KGKSFYStEAVQAHM 9606 21771788 t gcesareni "Ask1 directly phosphorylated zpr9 at ser(314) and thr(318), suggesting that zpr9 can act as an ask1 substrate. Ask1-mediated phosphorylation of zpr9 at ser(314) and thr(318) was also responsible for zpr9-induced apoptosis." SIGNOR-175117 MAPK14 protein Q16539 UNIPROT ELK3 protein P41970 UNIPROT up-regulates phosphorylation Ser363 LSPVAPLsPARLQGP 9606 9130707 t gcesareni "Tcf sap-1a is efficiently phosphorylated by p38 map kinase in vitro and in vivo on the homologous residues ser381 and ser387. Mutation of these sites to alanine severely reduces c-fos sre-dependent transcription mediated by sap-1a and p38 map kinase." SIGNOR-47685 MAPK14 protein Q16539 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 15879307 t gcesareni "Conversely, constitutively active mkk6 induced p38 mapk activation that recapitulated the effects of polyphenols by inducing eralpha phosphorylation and downstream activation of akt, and enos. The key role of eralpha ser-118 phosphorylation was confirmed in enos-transfected cos-7 cells" SIGNOR-136950 MAPK14 protein Q16539 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 . but the p38_/p38_ mapks were the major kinases phosphorylating ews-fli1. It will be important to investigate how the p38_/p38_-stimulated phosphorylation of ews-fusion proteins affects their ability to transactivate and their oncogenic potential." SIGNOR-182778 MAPK14 protein Q16539 UNIPROT EZH2 protein Q15910 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr367 NNSSRPStPTINVLE 10090 BTO:0000165 28067271 t "Here, we show that p38α kinase promotes EZH2 degradation in differentiating muscle cells through phosphorylation of threonine 372" SIGNOR-255663 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 PDE4DIP protein Q5VU43 UNIPROT PRKAR2A protein P13861 UNIPROT up-regulates binding 9606 21569246 t miannu "Mmgl acts as a dual-specific akap by anchoring pka regulatory isoforms r1a and r2a." SIGNOR-173831 TFG protein Q92734 UNIPROT SEC16A protein O15027 UNIPROT up-regulates binding 9606 21478858 t miannu "We identify tfg-1, a new conserved regulator of protein secretion that interacts directly with sec-16 and controls the export of cargoes from the endoplasmic reticulum in caenorhabditis elegans. Hydrodynamic studies indicate that tfg-1 forms hexamers that facilitate the co-assembly of sec-16 with copii subunits." SIGNOR-173242 UHMK1 protein Q8TAS1 UNIPROT PIMREG protein Q9BSJ6 UNIPROT up-regulates phosphorylation Ser131 GAQKGSGsPTHSLSQ 9606 23419774 t lperfetto "Cats is a substrate of kis and mapped the phosphorylation site to cats serine 131 (s131). Kis enhances the transcriptional repressor activity of cats" SIGNOR-192702 MAPK14 protein Q16539 UNIPROT HBB protein P68871 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20162623 f Indirect:regulation miannu "Our results demonstrate that activin A induced Hb synthesis and promoter activation of the specific erythroid gene, ζ-globin, through p38α and p38β isoforms and their activator, MKK6 (mitogen-activated protein kinase kinase 6)." SIGNOR-251837 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 MAPK14 protein Q16539 UNIPROT MAPKAPK2 protein P49137 UNIPROT "up-regulates activity" phosphorylation Thr317 PTQRMTItEFMNHPW -1 7592979 t miannu "In Vitro Activation of MAPKAP Kinase 2 by p38/40. the constitutively active mutant T205E,T317E shows no changes in activity after treatment with the p38/40 fraction" SIGNOR-250102 PIK3CA protein P42336 UNIPROT RAC1 protein P63000 UNIPROT up-regulates 9606 21779497 f gcesareni "Pi3k can also activate rac, and this activation is involved in cytoskeleton reorganization." SIGNOR-175238 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 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 PRKCD protein Q05655 UNIPROT ADRB2 protein P07550 UNIPROT "down-regulates activity" phosphorylation Ser262 GHGLRRSsKFCLKEH -1 1848190 t lperfetto "We investigate the role of the beta 2-adrenergic receptor phosphorylation by protein kinase C in this regulatory process. Mutation of the serine-261, -262, -344 and -345 of the beta 2-adrenergic receptor prevented the phorbol-ester-induced phosphorylation of the receptor. This mutation also abolished the phorbol-ester-induced decrease in high-affinity agonist binding and potency of the beta 2-adrenergic receptor. We suggest that protein kinase C mediated phosphorylation of the receptor promotes its functional uncoupling." SIGNOR-248855 PRKCD protein Q05655 UNIPROT ADRB2 protein P07550 UNIPROT "down-regulates activity" phosphorylation Ser345 ELLCLRRsSLKAYGN -1 1848190 t lperfetto "We investigate the role of the beta 2-adrenergic receptor phosphorylation by protein kinase C in this regulatory process. Mutation of the serine-261, -262, -344 and -345 of the beta 2-adrenergic receptor prevented the phorbol-ester-induced phosphorylation of the receptor. This mutation also abolished the phorbol-ester-induced decrease in high-affinity agonist binding and potency of the beta 2-adrenergic receptor. We suggest that protein kinase C mediated phosphorylation of the receptor promotes its functional uncoupling." SIGNOR-248857 PRKCD protein Q05655 UNIPROT EGFR protein P00533 UNIPROT "down-regulates activity" phosphorylation Thr678 RHIVRKRtLRRLLQE 10090 BTO:0001867 1860884 t lperfetto "These data indicate that activation of protein kinase C and subsequent phosphorylation of the EGF receptor at T654 lead to rapid physiological attenuation of EGF receptor signaling." SIGNOR-248858 PTPRC protein P08575 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates activity" dephosphorylation 10090 BTO:0003620 11201744 t "CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling" SIGNOR-248347 RAD50 protein Q92878 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-175053 ROCK1 protein Q13464 UNIPROT PPP1R12A protein O14974 UNIPROT "down-regulates activity" phosphorylation Thr853 PREKRRStGVSFWTQ 10090 BTO:0005065 10601309 t lperfetto "Phosphorylation by Rho-kinase inhibited MP activity and this reflected a decrease in V(max). Activity of MP with different substrates also was inhibited by phosphorylation. Two major sites of phosphorylation on MYPT1 were Thr(695) and Thr(850)." SIGNOR-249034 SOS2 protein Q07890 UNIPROT KRAS protein P01116 UNIPROT up-regulates "guanine nucleotide exchange factor" 9606 21779497 t gcesareni "Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85." SIGNOR-175265 MAPK12 protein P53778 UNIPROT SH3BP5 protein O60239 UNIPROT unknown phosphorylation Ser351 PGSLDLPsPVSLSEF -1 15158451 t miannu "Activated SAPK3 phosphorylates the mitochondrial protein Sab. 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-250140 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 MAPK12 protein P53778 UNIPROT SH3BP5 protein O60239 UNIPROT unknown phosphorylation Ser421 SKSQSSTsPEGQALE -1 15158451 t miannu "Activated SAPK3 phosphorylates the mitochondrial protein Sab. 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-250141 MAPK14 protein Q16539 UNIPROT JUNB protein P17275 UNIPROT up-regulates phosphorylation Ser79 QGSDTGAsLKLASSE 9606 15308641 t lperfetto "These results clearly demonstrate that phosphorylation by p38 kinase is essential for the regulation of dmp1 transcription by junb and p300. phosphorylation of junb at ser-79 was found to be essential for its interaction with p300." SIGNOR-127545 MAPK14 protein Q16539 UNIPROT KHSRP protein Q92945 UNIPROT "down-regulates activity" phosphorylation Thr692 QAAYYGQtPGPGGPQ 10090 BTO:0000165 16364914 t lperfetto "KSRP, an important factor for AU-rich element (ARE)-directed mRNA decay, undergoes p38-dependent phosphorylation during muscle differentiation. KSRP phosphorylated by p38 displays compromised binding to ARE-containing transcripts and fails to promote their rapid decay, although it retains the ability to interact with the mRNA degradation machinery" SIGNOR-235856 MAPK14 protein Q16539 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates BTO:0000801 22933625 f apalma "The IL-10-mediated shift in macrophage phenotype in injured muscle may be amplified by activation of mitogen-activated protein kinase (MAPK), especially p38 MAPK, through signaling that is antagonized by MAPK phosphatase-1 (MKP-1)." SIGNOR-255447 PPM1D protein O15297 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates dephosphorylation Ser395 SQESEDYsQPSTSSS 9606 17936559 t gcesareni "Wip1 interacts with and dephosphorylates mdm2 at serine 395, a site phosphorylated by the atm kinase. Dephosphorylated mdm2 has increased stability and affinity for p53, facilitating p53 ubiquitination and degradation." SIGNOR-158328 PPP2CA protein P67775 UNIPROT MAP3K3 protein Q99759 UNIPROT down-regulates dephosphorylation Ser526 MSGTGMRsVTGTPYW 9606 20448038 t lperfetto "Pp2ac binds to the phosphorylated mekk3 and subsequently dephosphorylate mekk3 at thr-516, ser-520, and ser-526 residues to terminate mekk3-mediated ikkbeta/Nf-kappaB Activation" SIGNOR-165233 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 KIT protein P10721 UNIPROT "down-regulates activity" phosphorylation Ser746 RRSVRIGsYIERDVT 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-248899 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 PRKDC protein P78527 UNIPROT HSP90AA1 protein P07900 UNIPROT unknown phosphorylation Thr5 tQTQDQPM 9606 BTO:0000567 2507541 t lperfetto "Here we show that the dsDNA-activated protein kinase from human HeLa cells phosphorylates 2 threonine residues in the sequence PEETQTQDQPME at the amino terminus of human hsp90 alpha." SIGNOR-248887 ROCK1 protein Q13464 UNIPROT ADD1 protein P35611 UNIPROT up-regulates phosphorylation Thr445 QKQQREKtRWLNSGR 9606 BTO:0000671 10209029 t lperfetto "Rho-associated kinase (rho- kinase), which is activated by the small guanosine triphosphatase rho, phosphorylates alpha-adducin and thereby enhances the f-actin-binding activity of alpha-adducin in vitro. Here we identified the sites of phosphorylation of alpha-adducin by rho-kinase as thr445 and thr480" SIGNOR-66992 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 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 CSNK2A1 protein P68400 UNIPROT EIF5 protein P55010 UNIPROT up-regulates phosphorylation Ser389 LKEAEEEsSGGEEED 9606 18649047 t gcesareni "We find that eif5 is associated with ck2 when the kinase activity is at the highest level in vivo, and is phosphorylated at ser389 and ser390 by ck2." SIGNOR-179542 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 CSNK2A1 protein P68400 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" phosphorylation Thr112 EGMQIPStQFDAAHP 9606 BTO:0000007 12432063 t llicata "We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin" SIGNOR-250848 PRKCB protein P05771 UNIPROT ANXA2 protein P07355 UNIPROT unknown phosphorylation Ser2 sTVHEILC -1 8898866 t lperfetto "A comparison of the phosphorylation patterns obtained identified Ser-II as the protein kinase C site responsible for regulating the annexin II-p11 interaction. Ser-II lies within the sequence mediating p11 binding, i.e. amino-acid residues 1 to 14 of annexin II, and phosphorylation at this site most likely leads to a direct spatial interference with p11 binding." SIGNOR-248956 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 MARCKS protein P29966 UNIPROT unknown phosphorylation Ser159 KKKKKRFsFKKSFKL -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-248923 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 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-248963 PRKCD protein Q05655 UNIPROT ADD2 protein P35612 UNIPROT unknown phosphorylation Ser713 KKKFRTPsFLKKSKK -1 8810272 t lperfetto "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 for PKC." SIGNOR-248952 PRKCD protein Q05655 UNIPROT FSCN1 protein Q16658 UNIPROT "down-regulates activity" phosphorylation Ser39 KVNASASsLKKKQIW 9606 BTO:0000931 8647875 t lperfetto "Phosphorylation of human fascin inhibits its actin binding and bundling activities." SIGNOR-248944 PRKCD protein Q05655 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-248927 PRKCD protein Q05655 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-248930 PRKCG protein P05129 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-248947 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 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 SGK1 protein O00141 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser214 GGKERPGsKEEVDED 9606 BTO:0000007;BTO:0000567 16982696 t lperfetto "Second, sgk1 indirectly depolymerized mts through the phosphorylation of tau at ser214" SIGNOR-161288 SRC protein P12931 UNIPROT CFL1 protein P23528 UNIPROT down-regulates phosphorylation Tyr68 GQTVDDPyATFVKML 9606 19802004 t lperfetto "Tyrosine phosphorylation of cofilin at y68 by v-src leads to its degradation through ubiquitin-proteasome pathway" SIGNOR-188352 TESK2 protein Q96S53 UNIPROT DSTN protein P60981 UNIPROT "down-regulates activity" phosphorylation Ser3 sGVQVADE 9606 BTO:0001363 11418599 t lperfetto "The present study provides evidence that TESK2 can phosphorylate cofilin and ADF specifically at Ser-3. Since actin-depolymerizing and -severing activities of cofilin/ADF are abrogated by phosphorylation at Ser-3, TESK2 seems to play an important role in actin filament dynamics by inhibiting cofilin/ADF activity." SIGNOR-246707 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 CSNK2A1 protein P68400 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-250871 PRKCA protein P17252 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-248976 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 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 PRKDC protein P78527 UNIPROT JUN protein P05412 UNIPROT unknown phosphorylation Ser249 LSPIDMEsQERIKAE -1 8464713 t lperfetto "Here, we show that the DNA-PK modifies c-Jun in vitro and that serine residue 249 (Ser-249) is required for phosphorylation to occur. This residue corresponds to one of three sites of c-Jun that are phosphorylated in vivo and which negatively regulate c-Jun DNA binding in vitro. However, we find that phosphorylation of c-Jun by the DNA-PK does not interfere with DNA binding, indicating that phosphorylation at other sites is required for this effect." SIGNOR-248934 PRKDC protein P78527 UNIPROT NR3C1 protein P04150 UNIPROT unknown phosphorylation Ser508 QQATTGVsQETSENP -1 9038175 t lperfetto "Phosphorylation of the GR fusion protein by DNA-PK mapped to a single site, Ser-527. This site occurs adjacent the GR nuclear localization sequence between the DNA and ligand binding domains of GR, and thus its phosphorylation, if confirmed, has the potential to affect receptor function in vivo." SIGNOR-248965 PRKDC protein P78527 UNIPROT RPA2 protein P15927 UNIPROT "down-regulates activity" phosphorylation Ser11 SGFESYGsSSYGGAG -1 9295339 t lperfetto "We showed previously that UV irradiation increases phosphorylation of the p34 subunit of human replication protein A (RPA) and that this hyperphosphorylation correlated with loss of activity of the DNA replication complex. | we detected phosphorylation of the RPA complex by DNA-PK on RPA-p34 sites Ser-23, Ser-29, and Ser-11, -12, or -13" SIGNOR-248980 PRKDC protein P78527 UNIPROT RPA2 protein P15927 UNIPROT unknown phosphorylation Ser33 GFGSPAPsQAEKKSR -1 9139719 t lperfetto "In this study, we show that efficient phosphorylation of HSSB-p34 by DNA-PK requires Ku as well as DNA. The DNA-PK phosphorylation sites in HSSB-p34 have been mapped at Thr-21 and Ser-33. Kinetic studies demonstrated that a phosphate residue is first incorporated at Thr-21 followed by the incorporation of a second phosphate residue at Ser-33." SIGNOR-248971 RAF1 protein P04049 UNIPROT RAF1 protein P04049 UNIPROT unknown phosphorylation Thr268 PNVHMVStTLPVDSR -1 8349614 t lperfetto "Furthermore, we find that Thr268 is the predominant Raf-1 residue phosphorylated in in vitro autokinase assays." SIGNOR-248917 RHOA protein P61586 UNIPROT FHL2 protein Q14192 UNIPROT up-regulates relocalization 9606 BTO:0001130 11847121 t gcesareni "Here, we show that stimulation of the rho pathway induces translocation of the transcriptional lim-only coactivator fhl2 to the nucleus and subsequent activation of fhl2- and androgen receptor-dependent genes." SIGNOR-114071 RPS6KA1 protein Q15418 UNIPROT L1CAM protein P32004 UNIPROT "up-regulates activity" phosphorylation Ser1152 RSKGGKYsVKDKEDT 10116 BTO:0001009 8663493 t lperfetto "Western blot analysis demonstrated that the L1 kinase activity from PC12 cells that phosphorylated this site was co-eluted with the S6 kinase, p90(rsk). Moreover, S6 kinase activity and p90(rsk) immunoreactivity co-immunoprecipitate with L1 from brain, and metabolic labeling studies have demonstrated that Ser1152 is phosphorylated in vivo in the developing rat brain. | These data demonstrate that the membrane-proximal 15 amino acids of the cytoplasmic domain of L1 are important for neurite outgrowth on L1, and the interactions it mediates may be regulated by phosphorylation of Ser1152." SIGNOR-248948 RPS6KA3 protein P51812 UNIPROT CREB1 protein P16220 UNIPROT "up-regulates activity" phosphorylation Ser133 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 PKN1 protein Q16512 UNIPROT PKN1 protein Q16512 UNIPROT "up-regulates activity" phosphorylation Thr531 PNATGTGtFSPGASP -1 10467162 t lperfetto "Autophosphorylation of wild-type PKN increased the protein kinase activity, however, substitution of Thr64, Ser374, or Thr531 in the regulatory region of PKN with alanine, abolished this effect." SIGNOR-249020 PPARGC1A protein Q9UBK2 UNIPROT Mitochondrial_biogenesis phenotype SIGNOR-PH32 SIGNOR up-regulates 9606 23277535 f gcesareni "PGC1a is a positive regulator of mitochondrial biogenesis and respiration, adaptive thermogenesis, gluconeogenesis as well as many other metabolic proc" SIGNOR-228618 CSNK2A1 protein P68400 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-133540 CSNK2A1 protein P68400 UNIPROT IKZF1 protein Q13422 UNIPROT down-regulates phosphorylation Thr23 ESPPVSDtPDEGDEP 9606 BTO:0001271 21750978 t miannu "We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway / these results suggest that ck2 kinase directly phosphorylates amino acids 13, 23, 63, 101 and 294 in vivo" SIGNOR-174836 PPP2R5C protein Q13362 UNIPROT ATF1 protein P18846 UNIPROT up-regulates dephosphorylation Ser38 QVSSLSEsEESQDSS 9606 20730097 t lperfetto "We propose that constitutive hyperphosphorylation by ck1/ck2 maintains atf1 in an inactive state that promotes transcriptional repression. Pp2a/b56c antagonizes phosphorylation of atm sites in both creb and atf5" SIGNOR-167564 PRKCA protein P17252 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-249023 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 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 PRKCD protein Q05655 UNIPROT NCF4 protein Q15080 UNIPROT "up-regulates activity" phosphorylation Thr154 LRRLRPRtRKVKSVS 9606 BTO:0000738 9804763 t lperfetto "P40(phox) is phosphorylated on threonine 154 and serine 315 during activation of the phagocyte NADPH oxidase. Implication of a protein kinase c-type kinase in the phosphorylation process." SIGNOR-249012 PRKCZ protein Q05513 UNIPROT IKBKB protein O14920 UNIPROT "up-regulates activity" phosphorylation Ser181 DQGSLCTsFVGTLQY 9606 BTO:0000007 10022904 t lperfetto "Activation of IkappaB kinase beta by protein kinase C isoforms. | Interestingly, recombinant active zetaPKC and alphaPKC are able to stimulate in vitro the activity of IKKbeta but not that of IKKalpha. In addition, evidence is presented here that recombinant zetaPKC directly phosphorylates IKKbeta in vitro, involving Ser177 and Ser181. Collectively, these results demonstrate a critical role for the PKC isoforms in the NF-kappaB pathway at the level of IKKbeta activation and IkappaB degradation." SIGNOR-249016 ROCK1 protein Q13464 UNIPROT DES protein P17661 UNIPROT unknown phosphorylation Thr77 RASRLGTtRTPSSYG 9606 BTO:0000971 10574968 t lperfetto "We developed antibodies specifically recognizing the kinase-dependent phosphorylation of desmin at Thr-16, Thr-75, and Thr-76. With these antibodies, phosphorylation of desmin was observed specifically at the cleavage furrow in late mitotic Saos-2 cells. We then found that treatment of the interphase cells with calyculin A revealed phosphorylation at all the three sites of desmin" SIGNOR-249033 ROCK1 protein Q13464 UNIPROT MSN protein P26038 UNIPROT "up-regulates activity" phosphorylation Thr558 LGRDKYKtLRQIRQG 9534 BTO:0000298 9856983 t lperfetto "Rho-associated kinase (Rho-kinase), which is activated by the small GTPase Rho, phosphorylates moesin at Thr558 in vitro. Here, using a site- and phosphorylation state-specific antibody, we found that the expression of dominant active RhoA in COS7 cells induced moesin phosphorylation and the formation of microvilli-like structures at apical membranes where the Thr558-phosphorylated moesin accumulated, whereas the expression of dominant negative Rho-kinase inhibited both of these processes." SIGNOR-249014 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT up-regulates phosphorylation Tyr1165 RDIYETDyYRKGGKG -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-246264 MAP3K2 protein Q9Y2U5 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates phosphorylation 9606 11343802 t gcesareni "Both mekk2 and mekk3 are able to activate the jun kinase pathway in vivo. However, following routine immunoprecipitation in triton x-100, mekk2 but not mekk3 is able to effectively phosphorylate both sek-1 and mek-1 and to undergo autophosphorylation" SIGNOR-107692 MAPK14 protein Q16539 UNIPROT MEF2D protein Q14814 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000887 18026121 t lperfetto "Targeting of ash2l to specific genes is mediated by the transcriptional regulator mef2d. Furthermore, this interaction is modulated during differentiation through activation of the p38 mapk signaling pathway via phosphorylation of mef2d." SIGNOR-159331 BAK1 protein Q16611 UNIPROT CYCS protein P99999 UNIPROT up-regulates relocalization 9606 11175253 t "Translocation from Mitochondria to Cytosol" amattioni "Allosteric activation of bak induces its intramembranous oligomerization into a proposed pore for cytochrome c efflux" SIGNOR-105206 LFNG protein Q8NES3 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 11346656 t Fucosylation 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. 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-107702 MAPK14 protein Q16539 UNIPROT MEF2D protein Q14814 UNIPROT "up-regulates activity" phosphorylation 9606 21902831 t lperfetto "Through phosphorylation of mef2d, p38 recruits an ash2l-containing complex to myogenic loci during differentiation, which results in the marking of these genes for expression." SIGNOR-176554 MAPK14 protein Q16539 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-253011 MAPK14 protein Q16539 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT "up-regulates activity" phosphorylation Ser505 SPVAGVHsPMASSGN 9606 BTO:0000093 15383283 t miannu "P38 MAPK and JNK can phosphorylate multiple sites on SRC-3, including S505, S543, S860, and S867. Our results suggest that several kinases are important for phosphorylating SRC-3 and enhancing its interaction with DNA-dependent transcription factors and other coactivators." SIGNOR-250103 PPP1CA protein P62136 UNIPROT STAT3 protein P40763 UNIPROT "down-regulates activity" dephosphorylation Ser727 NTIDLPMsPRTLDSL 9606 BTO:0000599;BTO:0001594 19440292 t "Avicins dephosphorylate Stat3 in a variety of human tumor cell lines, leading to a decrease in the transcriptional activity of Stat3.| However, PD98059, an inhibitor of MEK1/2, had no significant effects on avicin-induced dephosphorylation of Stat3 (Ser 727)" SIGNOR-248563 PRKAB1 protein Q9Y478 UNIPROT NOS3 protein P29474 UNIPROT up-regulates phosphorylation Ser1177 TSRIRTQsFSLQERQ 9606 SIGNOR-C15 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-112367 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 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 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 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 TOPORS protein Q9NS56 UNIPROT TP53 protein P04637 UNIPROT down-regulates ubiquitination 9606 phosphorylation:Ser718 KDRDGYEsSYRRRTL 19473992 t lperfetto "Plk1-mediated phosphorylation of topors regulates p53 stabilityherein, 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-185848 ZIC1 protein Q15915 UNIPROT GLI3 protein P10071 UNIPROT up-regulates relocalization 9606 11238441 t lperfetto "Co-expression of zic1 resulted in gli1 and gli3 proteins being translocated to the nucleus in varying levels" SIGNOR-105497 orantinib chemical CHEBI:91088 ChEBI FGFR1 protein P11362 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207435 CSNK2A1 protein P68400 UNIPROT SNCA protein P37840 UNIPROT up-regulates phosphorylation Ser129 NEAYEMPsEEGYQDY 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-73803 orantinib chemical CHEBI:91088 ChEBI PDGFRB protein P09619 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207441 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 PRKCB protein P05771 UNIPROT GJA1 protein P17302 UNIPROT "down-regulates activity" phosphorylation Ser368 QRPSSRAsSRASSRP 10116 BTO:0002931 10871288 t lperfetto "Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication." SIGNOR-249049 PRKCD protein Q05655 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-249059 PRKCD protein Q05655 UNIPROT TAGLN protein Q01995 UNIPROT "down-regulates activity" phosphorylation Ser181 VIGLQMGsNRGASQA -1 11053353 t lperfetto "Of the three consensus protein kinase C or casein kinase II phosphorylation sites in SM22, only Ser-181 was readily phosphorylated by protein kinase C in vitro, and such phosphorylation greatly decreased actin binding." SIGNOR-249061 PRKCE protein Q02156 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-249064 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 GJA1 protein P17302 UNIPROT "down-regulates activity" phosphorylation Ser368 QRPSSRAsSRASSRP 10116 BTO:0002931 10871288 t lperfetto "Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication." SIGNOR-249050 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 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-249091 ROCK1 protein Q13464 UNIPROT DES protein P17661 UNIPROT unknown phosphorylation Thr17 RVSSYRRtFGGAPGF 9606 BTO:0000971 10574968 t lperfetto "We developed antibodies specifically recognizing the kinase-dependent phosphorylation of desmin at Thr-16, Thr-75, and Thr-76. With these antibodies, phosphorylation of desmin was observed specifically at the cleavage furrow in late mitotic Saos-2 cells. We then found that treatment of the interphase cells with calyculin A revealed phosphorylation at all the three sites of desmin" SIGNOR-249032 ROCK1 protein Q13464 UNIPROT DES protein P17661 UNIPROT unknown phosphorylation Thr76 LRASRLGtTRTPSSY 9606 BTO:0000971 10574968 t lperfetto "We developed antibodies specifically recognizing the kinase-dependent phosphorylation of desmin at Thr-16, Thr-75, and Thr-76. With these antibodies, phosphorylation of desmin was observed specifically at the cleavage furrow in late mitotic Saos-2 cells. We then found that treatment of the interphase cells with calyculin A revealed phosphorylation at all the three sites of desmin" SIGNOR-249031 PAK2 protein Q13177 UNIPROT RPS6 protein P62753 UNIPROT unknown phosphorylation Ser235 IAKRRRLsSLRASTS -1 1985906 t miannu "The synthetic peptide AKRRRLSSLRASTSKSESSQK (S6-21) which corresponds to the carboxyl-terminal 21 amino acids of human ribosomal protein S6 was synthesized and tested as a substrate for S6/H4 kinase purified from human placenta. The principal phosphorylation sites were serines in the acidic carboxyl-terminal domain of the peptide." SIGNOR-250231 CSNK2A1 protein P68400 UNIPROT WAS protein P42768 UNIPROT up-regulates phosphorylation Ser484 RSRAIHSsDEGEDQA 9606 12769847 t gcesareni "Here 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-101268 PRKCG protein P05129 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-249085 PRKCG protein P05129 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-249088 PRKCG protein P05129 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-249107 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 PRKG1 protein Q13976 UNIPROT GKAP1 protein Q5VSY0 UNIPROT unknown phosphorylation Ser106 SNPVQKDsREENWQE 9534 BTO:0000298 10671526 t lperfetto "Although both cGK-Ialpha and -Ibeta, but not cAMP-dependent protein kinase, phosphorylated GKAP42 in vitro, GKAP42 was a good substrate only for cGK-Ialpha in intact cells, suggesting that the association with kinase protein is required for the phosphorylation in vivo." SIGNOR-249037 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 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 R547 chemical CID:6918852 PUBCHEM CCNB1 protein P14635 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206349 R547 chemical CID:6918852 PUBCHEM CDK1 protein P06493 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206358 R547 chemical CID:6918852 PUBCHEM CDK2 protein P24941 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206361 RPS6KA2 protein Q15349 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser118 GRELRRMsDEFVDSF 9606 BTO:0000007 10837486 t lperfetto "We report here that the phosphorylation of BAD at Ser-155 within the BH3 domain is a second phosphorylation-dependent mechanism that inhibits the death-promoting activity of BAD. Protein kinase A, RSK1, and survival factor signaling stimulate phosphorylation of BAD at Ser-155, blocking the binding of BAD to Bcl-XL. RSK1 phosphorylates BAD at both Ser-112 and Ser-155 and rescues BAD-mediated cell death in a manner dependent upon phosphorylation at both sites." SIGNOR-249044 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 TAOK3 protein Q9H2K8 UNIPROT TAOK3 protein Q9H2K8 UNIPROT "up-regulates activity" phosphorylation Tyr183 NSFVGTPyWMAPEVI 9534 BTO:0004055 10559204 t lperfetto "These data indicate that JIK is indeed the protein kinase present in the immune complex responsible for autophosphorylation and for the phosphorylation of the exogenous substrate. Moreover, our observations suggest that JIK (A181F183) acts as the catalytically inactive mutant of JIK, which is no longer able to potently undergo autophosphorylation and dramatically phosphorylate MBP, as compared with the wild type JIK." SIGNOR-246302 MAPK14 protein Q16539 UNIPROT PRC2 complex SIGNOR-C130 SIGNOR "up-regulates activity" phosphorylation 10029 BTO:0005787 20887952 t "The chromatin redistribution of PRC2 in differentiating SCs is regulated by the p38a kinase, which promotes the formation of a complex containing p38a, EZH2, and YY1, via direct phosphorylation of EZH2." SIGNOR-253599 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 MAPK14 protein Q16539 UNIPROT PTPN7 protein P35236 UNIPROT "down-regulates activity" phosphorylation Ser93 ALQRQPPsPKQLEEE -1 10206983 t miannu "The noncatalytic N terminus of HePTP binds Erk and p38 and is phosphorylated at Ser-72 and Thr-45 by these kinases. the N terminus of HePTP binds Erk and p38 but may release them upon phosphorylation.it is clear that phosphorylation of HePTP at Thr-45 and/or Ser-72 is not required for inhibition of MAP kinase. Rather, it seems that phosphorylation has the opposite effect, namely to lessen the inhibitory effect of HePTP." SIGNOR-250109 MAPK14 protein Q16539 UNIPROT RPS6KA4 protein O75676 UNIPROT up-regulates phosphorylation 9606 9792677 t gcesareni "Rsk-b is a p38alphamapk substrate, and activated by p38alphamapk and, more weakly, by erk1" SIGNOR-60995 MAPK3 protein P27361 UNIPROT TCF3 protein P15923 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr355 NFSSSPStPVGSPQG 10090 BTO:0000944 14592976 t lperfetto "Notch-induced degradation requires phosphorylation of E47 by p42/p44 MAP kinases. |Wild_type E47 but not the Mm mutant reacted to the antibodies, suggesting that E47 is at least phosphorylated at the M2 site (Figure 3A)|anti_phospho_M2 peptide (SSPSpTPVGSPQG)" SIGNOR-249117 PPP2R5C protein Q13362 UNIPROT ATF1 protein P18846 UNIPROT up-regulates dephosphorylation Ser44 ESEESQDsSDSIGSS 9606 20730097 t lperfetto "We propose that constitutive hyperphosphorylation by ck1/ck2 maintains atf1 in an inactive state that promotes transcriptional repression. Pp2a/b56c antagonizes phosphorylation of atm sites in both creb and atf4" SIGNOR-167572 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 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 PRKCD protein Q05655 UNIPROT BDKRB2 protein P30411 UNIPROT "down-regulates activity" phosphorylation Ser373 SMGTLRTsISVERQI 9606 BTO:0000007 11517230 t lperfetto "In addition, we found a protein kinase C-dependent phosphorylation of Ser(346) that was mutually exclusive with the basal phosphorylation at Ser(348) and therefore may be implicated in differential regulation of B2 receptor activation. Functional analysis of receptor mutants revealed that a low phosphorylation stoichiometry is sufficient to initiate receptor sequestration while a clustered phosphorylation around Ser(346) is necessary for desensitization of the B2 receptor-induced phospholipase C activation." SIGNOR-249108 PRKCD protein Q05655 UNIPROT PTPRA protein P18433 UNIPROT "up-regulates activity" phosphorylation Ser213 PLLARSPsTNRKYPP 9606 BTO:0000017 11676480 t lperfetto "In this process, PTPalpha Ser-180 and Ser-204 phosphorylation is critical for the induction of phosphatase activity, which is required for dephosphorylation of pp60(c-src). Taken together, we demonstrate the physical and functional association between PI 3-kinase, PKCdelta and PTPalpha in a signaling complex that mediates the antitumor activity of the somatostatin analogue TT-232." SIGNOR-249114 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 PTPN22 protein Q9Y2R2 UNIPROT CD247 protein P20963 UNIPROT down-regulates dephosphorylation 9606 BTO:0000007 16461343 t amattioni "T cell signaling is negatively regulated by the activity of protein-tyrosine phosphatases. Native ptpn22 dephosphorylated tcrzeta in vitro and in cells." SIGNOR-144337 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 ZIC1 protein Q15915 UNIPROT GLI1 protein P08151 UNIPROT up-regulates relocalization 9606 11238441 t lperfetto "Co-expression of zic1 resulted in gli1 and gli3 proteins being translocated to the nucleus in varying levels" SIGNOR-105491 MAPK14 protein Q16539 UNIPROT PTPN7 protein P35236 UNIPROT "down-regulates activity" phosphorylation Thr66 EPICSVNtPREVTLH -1 10206983 t miannu "The noncatalytic N terminus of HePTP binds Erk and p38 and is phosphorylated at Ser-72 and Thr-45 by these kinases. the N terminus of HePTP binds Erk and p38 but may release them upon phosphorylation.it is clear that phosphorylation of HePTP at Thr-45 and/or Ser-72 is not required for inhibition of MAP kinase. Rather, it seems that phosphorylation has the opposite effect, namely to lessen the inhibitory effect of HePTP." SIGNOR-250110 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 MAPK14 protein Q16539 UNIPROT RPS6KA4 protein O75676 UNIPROT up-regulates phosphorylation Ser343 TRLEPVYsPPGSPPP 9606 BTO:0000567 10806207 t llicata "Rskb, a 90-kda ribosomal s6 protein kinase family (rsk) member with two complete catalytic domains connected by a linker, is activated through p38- and erk-mitogen-activated protein kinases. unlike other rsks, the activation loop phosphorylation sites of both catalytic domains of rskb, ser(196) and thr(568), were required for activity. Rskb activation depended on phosphorylation of linker ser(343) and ser(360) and associated with phosphorylation of nonconserved ser(347), but ser(347)-deficient rskb retained partial activity." SIGNOR-77208 MAPK3 protein P27361 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates phosphorylation Ser294 DPRQAQSsPPWSYDQ 9606 19801668 t llicata "In this study, we identified two phosphorylation sites in runx2 at ser301 and ser319 that are required for mapk-dependent activation of runx2 transcriptional activity and osteoblast differentiation." SIGNOR-188343 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 PRKCB protein P05771 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-249122 PRKCD protein Q05655 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-249120 PRKCD protein Q05655 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-249124 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 PTK2B protein Q14289 UNIPROT NOS3 protein P29474 UNIPROT down-regulates phosphorylation Tyr657 FGLGSRAyPHFCAFA 9606 BTO:0000007 18483407 t gcesareni "We found that fluid shear stress induces the association of enos with the proline-rich tyrosine kinase 2 (pyk2) in endothelial cells and that the enos immunoprecipitated from enos- and pyk2-overexpressing hek293 cells was tyrosine-phosphorylated on tyr657." SIGNOR-178648 PTPN12 protein Q05209 UNIPROT GIT2 protein Q14161 UNIPROT down-regulates dephosphorylation Tyr592 NSTPESDyDNTPNDM 9606 16317044 t fspada "Conversely, a gfp-pkl phosphorylation mutant, y286/392/592f (gfp-pkl triple yf) (brown et al., 2005), was not phosphorylated during adhesion and the addition of ptp-pest had no effect, suggesting one or more of these tyrosine residues are dephosphorylated by ptppest. Taken together, these data strongly suggest pkl as a direct substrate for ptp-pest." SIGNOR-142719 PTPN22 protein Q9Y2R2 UNIPROT ZAP70 protein P43403 UNIPROT down-regulates dephosphorylation Tyr493 LGADDSYyTARSAGK 9606 BTO:0000007 16461343 t miannu "Native ptpn22 dephosphorylated lck and zap70 at their activating tyrosine residues tyr-394 and tyr-493, respectively, but not at the regulatory tyrosines tyr-505 (lck) or tyr-319 (zap70)." SIGNOR-144345 IL4R protein P24394 UNIPROT JAK1 protein P23458 UNIPROT up-regulates 9606 7538655 f lperfetto "We demonstrate that il4r triggering induced the tyrosine phosphorylation of jak3" SIGNOR-34756 CSNK2A2 protein P19784 UNIPROT UBE2R2 protein Q712K3 UNIPROT "up-regulates activity" phosphorylation Ser233 DCYDDDDsGNEES 9606 BTO:0000567 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 KNL1 protein Q8NG31 UNIPROT BUB1B protein O60566 UNIPROT up-regulates binding 9606 17981135 t gcesareni "Association of the amino and middle domain of blinkin with the tpr domains in the amino termini of bubr1 and bub1 is essential for bubr1 and bub1 to execute their distinct mitotic functions" SIGNOR-158894 MAPK14 protein Q16539 UNIPROT RPS6KA4 protein O75676 UNIPROT up-regulates phosphorylation Ser360 PRIFQGYsFVAPSIL 9606 BTO:0000567 10806207 t llicata "Rskb, a 90-kda ribosomal s6 protein kinase family (rsk) member with two complete catalytic domains connected by a linker, is activated through p38- and erk-mitogen-activated protein kinases. unlike other rsks, the activation loop phosphorylation sites of both catalytic domains of rskb, ser(196) and thr(568), were required for activity. Rskb activation depended on phosphorylation of linker ser(343) and ser(360) and associated with phosphorylation of nonconserved ser(347), but ser(347)-deficient rskb retained partial activity." SIGNOR-77216 PPP2CA protein P67775 UNIPROT MDM2 protein Q00987 UNIPROT "up-regulates activity" dephosphorylation Thr216 RSSSSEStGTPSNPD 10090 11983168 t "cyclin G also binds in vivo and in vitro to Mdm2 and markedly stimulates the ability of PP2A to dephosphorylate Mdm2 at T216. Consistent with these data, cyclin G null cells have both Mdm2 that is hyperphosphorylated at T216 and markedly higher levels of p53 protein when compared to wild-type cells" SIGNOR-248636 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 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 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 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 PRKCD protein Q05655 UNIPROT ADRA2A protein P08913 UNIPROT "up-regulates activity" phosphorylation Ser232 RRTRVPPsRRGPDAV 10029 BTO:0000246 11732925 t lperfetto "Taken together, these results indicate that S232 acts as a selective, PKC-sensitive, modulator of effector coupling of the alpha(2A)AR to inositol phosphate stimulation. This represents one mechanism by which cells route stimuli directed to multifunctional receptors to selected effectors so as to attain finely targeted signaling." SIGNOR-249126 PRKCD protein Q05655 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser1101 GCRRRHSsETFSSTP 10029 BTO:0000246 15364919 t lperfetto "Protein kinase C Theta inhibits insulin signaling by phosphorylating IRS1 at Ser(1101)." SIGNOR-249267 PRKCE protein Q02156 UNIPROT SLC4A3 protein P48751 UNIPROT "up-regulates activity" phosphorylation Ser67 EKPSRSYsERDFEFH 9606 BTO:0000007 11739292 t lperfetto "We conclude that following Ang II stimulation of cells, PKCepsilon phosphorylates serine 67 of the AE3 cytoplasmic domain, inducing the Ang II-induced increase in anion transport observed in the hypertrophic myocardium." SIGNOR-249127 PRKCE protein Q02156 UNIPROT TRPV1 protein Q8NER1 UNIPROT "up-regulates activity" phosphorylation Ser502 YFLQRRPsMKTLFVD 9606 BTO:0000007 11884385 t lperfetto "Direct phosphorylation of capsaicin receptor VR1 by protein kinase Cepsilon and identification of two target serine residues. | Patch clamp analysis of the point mutants where Ser or Thr residues were replaced with Ala in the total 16 putative phosphorylation sites showed that two Ser residues, Ser(502) and Ser(800) were involved in the potentiation of the capsaicin-evoked currents by either PMA or ATP." SIGNOR-249141 PRKCE protein Q02156 UNIPROT TRPV1 protein Q8NER1 UNIPROT "up-regulates activity" phosphorylation Ser801 VPLLREAsARDRQSA 9606 BTO:0000007 11884385 t lperfetto "Direct phosphorylation of capsaicin receptor VR1 by protein kinase Cepsilon and identification of two target serine residues. | Patch clamp analysis of the point mutants where Ser or Thr residues were replaced with Ala in the total 16 putative phosphorylation sites showed that two Ser residues, Ser(502) and Ser(800) were involved in the potentiation of the capsaicin-evoked currents by either PMA or ATP." SIGNOR-249142 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 SIRT1 protein Q96EB6 UNIPROT FOXL2 protein P58012 UNIPROT down-regulates deacetylation 9606 19010791 t miannu "We find that foxl2 activity is repressed by the sirt1 deacetylase." SIGNOR-182306 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR JUN protein P05412 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000762 12509763 t lperfetto "Substrates for ERK1/2 include nuclear proteins such as C-JUN, this leads to activation of the AP-1 transcription factor, which is made up of FOS-JUN heterodimers." SIGNOR-253214 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 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1693 SPTSPSYsPTSPSYS -1 22137580 t "Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat." SIGNOR-248785 PTK6 protein Q13882 UNIPROT PTK6 protein Q13882 UNIPROT "up-regulates activity" phosphorylation Tyr447 RLSSFTSyENPT 9606 BTO:0000007 12121988 t lperfetto "Mutation of a C-terminal tyrosine (Tyr-447) increases enzyme activity and SH2 domain accessibility, consistent with a role for this residue in autoinhibition. | These results suggest that the Y447F and W44A mutations disrupt the normal intramolecular regulation of Brk and increase the catalytic activity of Brk." SIGNOR-249152 RPS6KA1 protein Q15418 UNIPROT ETV1 protein P50549 UNIPROT "up-regulates activity" phosphorylation Ser191 HRFRRQLsEPCNSFP 9606 BTO:0002181 12213813 t lperfetto "Here we describe that the 90-kDa ribosomal S6 kinase 1 (RSK1), a protein kinase downstream of the extracellular signal-regulated kinase (ERK) subclass of MAPKs, binds to ER81, phosphorylates it, and enhances ER81-dependent transcription. Two in vivo RSK1 phosphorylation sites within ER81, Ser(191) and Ser(216), were identified, whose mutation to alanine reduces ER81 activity upon ERK-MAPK stimulation." SIGNOR-249162 RPS6KA1 protein Q15418 UNIPROT ETV1 protein P50549 UNIPROT "up-regulates activity" phosphorylation Ser216 PMYQRQMsEPNIPFP 9606 BTO:0002181 12213813 t lperfetto "Here we describe that the 90-kDa ribosomal S6 kinase 1 (RSK1), a protein kinase downstream of the extracellular signal-regulated kinase (ERK) subclass of MAPKs, binds to ER81, phosphorylates it, and enhances ER81-dependent transcription. Two in vivo RSK1 phosphorylation sites within ER81, Ser(191) and Ser(216), were identified, whose mutation to alanine reduces ER81 activity upon ERK-MAPK stimulation." SIGNOR-249163 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 SGK3 protein Q96BR1 UNIPROT GSK3B protein P49841 UNIPROT "down-regulates activity" phosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000007 12054501 t lperfetto "Human serum and glucocorticoid-inducible kinase-like kinase (SGKL) phosphorylates glycogen syntheses kinase 3 beta (GSK-3beta) at serine-9 through direct interaction" SIGNOR-249166 SH3KBP1 protein Q96B97 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 9606 24167568 t gcesareni "The cin85 sh3 domains interact with c-cbl, an e3 ubiquitin ligase, via an unconventional pxxxpr ligand sequence, with the highest affinity displayed by the sh3-b domain. Interaction with cin85 recruits c-cbl to the amap1 complex where its ubiquitination activity is necessary for cancer cells to develop an invasive phenotype and to degrade the matrix." SIGNOR-203139 SIK1 protein P57059 UNIPROT CRTC2 protein Q53ET0 UNIPROT "down-regulates activity" phosphorylation Ser348 PSLQSSLsNPNLQAS 9606 BTO:0000567 16306228 t lperfetto "We found that QSK and SIK phosphorylated TORC2 at Ser171 as well as at least two additional residues, namely Ser70 and Ser348|QIK also phosphorylates the CREB co-activator TORC2, in unstimulated cells, to sequester it in the cell cytoplasm, thereby inhibiting CREB-dependent gene-expression" SIGNOR-249168 SIK1 protein P57059 UNIPROT CRTC2 protein Q53ET0 UNIPROT "down-regulates activity" phosphorylation Ser70 RSSHYGGsLPNVNQI 9606 BTO:0000567 16306228 t lperfetto "We found that QSK and SIK phosphorylated TORC2 at Ser171 as well as at least two additional residues, namely Ser70 and Ser348|QIK also phosphorylates the CREB co-activator TORC2, in unstimulated cells, to sequester it in the cell cytoplasm, thereby inhibiting CREB-dependent gene-expression" SIGNOR-249169 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 MAPK14 protein Q16539 UNIPROT RPS6KA5 protein O75582 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000567 9687510 t lperfetto "Mitogen- and stress-activated protein kinase-1 (msk1) is directly activated by mapk and sapk2/p38,." SIGNOR-59454 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 PDPK1 protein O15530 UNIPROT AHCYL1 protein O43865 UNIPROT "down-regulates activity" phosphorylation Ser68 RSLSRSIsQSSTDSY 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| We found that phosphorylation of Ser71 and Ser74 were sufficient to enable inhibition of IP3 binding to the IP3R" SIGNOR-249174 PLK1 protein P53350 UNIPROT CHEK2 protein O96017 UNIPROT unknown phosphorylation Thr26 SQPHGSVtQSQGSSS -1 12493754 t lperfetto "Plk1 overexpression enhances phosphorylation of Chk2 at Thr-68. Plk1 phosphorylates recombinant Chk2 in vitro." SIGNOR-249180 PRKCA protein P17252 UNIPROT NFATC1 protein O95644 UNIPROT "down-regulates activity" phosphorylation Ser294 PHGSPRVsVTDDSWL 9606 BTO:0000007 12351631 t lperfetto "Protein kinase A negatively modulates the nuclear accumulation of NF-ATc1. | 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 domain, and that mutation of these serines blocks the effect of PKA. Activation of endogenous PKA is similarly able to promote phosphorylation of these sites on NF-ATc1 in two lymphoid cell lines." SIGNOR-249175 PRKCA protein P17252 UNIPROT SNAP25 protein P60880 UNIPROT unknown phosphorylation Ser187 RIMEKADsNKTRIDE 9606 BTO:0000567 12459461 t lperfetto "This study establishes that SNAP-25 is differentially phosphorylated by protein kinase C and protein kinase A in neuroendocrine PC12 cells. Using phosphopeptide mapping and site-directed mutagenesis we identified both Thr138 and Ser187 as the targets of SNAP-25 phosphorylation by protein kinase C" SIGNOR-249178 PRKCA protein P17252 UNIPROT SNAP25 protein P60880 UNIPROT unknown phosphorylation Thr138 GGFIRRVtNDARENE 9606 BTO:0000567 12459461 t lperfetto "This study establishes that SNAP-25 is differentially phosphorylated by protein kinase C and protein kinase A in neuroendocrine PC12 cells. Using phosphopeptide mapping and site-directed mutagenesis we identified both Thr138 and Ser187 as the targets of SNAP-25 phosphorylation by protein kinase C" SIGNOR-249179 PRKCD protein Q05655 UNIPROT IL6ST protein P40189 UNIPROT "up-regulates activity" phosphorylation Thr909 PKSYLPQtVRQGGYM -1 12361954 t lperfetto "Finally, we identified Thr-890, a putative PKC phosphorylation site on gp130, to be critical for the effect of PKCdelta. Our data indicate that PKCdelta plays important regulatory roles in IL-6 signaling." SIGNOR-249177 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 PRKCQ protein Q04759 UNIPROT WIPF1 protein O43516 UNIPROT "up-regulates activity" phosphorylation Ser488 RNESRSGsNRRERGA -1 12504004 t lperfetto "TCR engagement also causes PKCtheta-dependent phosphorylation of WIP, causing the disengagement of WASP from the WIP-WASP complex, thereby releasing it from WIP inhibition. These results suggest that the ZAP-70-CrkL-WIP pathway and PKCtheta link TCR to WASP activation. | These results suggest that phosphorylation at S488 disrupts WIP binding to WASP." SIGNOR-249181 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 SIK3 protein Q9Y2K2 UNIPROT CRTC2 protein Q53ET0 UNIPROT "down-regulates activity" phosphorylation Ser171 SALNRTSsDSALHTS 9606 BTO:0000567 16306228 t lperfetto "We found that QSK and SIK phosphorylated TORC2 at Ser171 as well as at least two additional residues, namely Ser70 and Ser348|QIK also phosphorylates the CREB co-activator TORC2, in unstimulated cells, to sequester it in the cell cytoplasm, thereby inhibiting CREB-dependent gene-expression" SIGNOR-249172 SIK3 protein Q9Y2K2 UNIPROT CRTC2 protein Q53ET0 UNIPROT "down-regulates activity" phosphorylation Ser70 RSSHYGGsLPNVNQI 9606 BTO:0000567 16306228 t lperfetto "We found that QSK and SIK phosphorylated TORC2 at Ser171 as well as at least two additional residues, namely Ser70 and Ser348|QIK also phosphorylates the CREB co-activator TORC2, in unstimulated cells, to sequester it in the cell cytoplasm, thereby inhibiting CREB-dependent gene-expression" SIGNOR-249171 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 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 NME1 protein P15531 UNIPROT NME1 protein P15531 UNIPROT unknown phosphorylation Ser120 GRNIIHGsDSVESAE -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-250300 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 CTDSPL2 protein Q05D32 UNIPROT HBG2 protein P69892 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000664 20932329 f "Indirect:regulation of transcription" miannu "CTD small phosphatase like 2 (CTDSPL2) can increase ε- and γ-globin gene expression in K562 cells and CD34+ cells derived from umbilical cord blood." SIGNOR-251777 CTDSPL protein O15194 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-248312 NME1 protein P15531 UNIPROT NME1 protein P15531 UNIPROT unknown phosphorylation Ser122 NIIHGSDsVESAEKE -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-250301 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 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 PRKCB protein P05771 UNIPROT PTPN11 protein Q06124 UNIPROT unknown phosphorylation Ser580 CAEMREDsARVYENV 9606 BTO:0000007 11781100 t lperfetto " In summary, SHP2 is phosphorylated on serine residues 576 and 591 by PKC isoforms alpha, beta 1, beta 2, and eta." SIGNOR-249136 PRKCB protein P05771 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-249195 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 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 PRKCQ protein Q04759 UNIPROT CARD11 protein Q9BXL7 UNIPROT "up-regulates activity" phosphorylation Ser644 NLMFRKFsLERPFRP 9606 BTO:0000782 21157432 t lperfetto "NF-kappaB activation is triggered by PKCteta-dependent phosphorylation of Carma1 after TCR/CD28 co-stimulation. PKCteta-phosphorylated Carma1 was suggested to function as a molecular scaffold that recruits preassembled Bcl10-Malt1 complexes to the membrane|we demonstrate that PP2A removes PKCteta-dependent phosphorylation of Ser645 in Carma1, and show that maintenance of this phosphorylation is correlated with increased T-cell activation." SIGNOR-249193 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 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 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 VAV2 protein P52735 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-198941 CTNND2 protein Q9UQB3 UNIPROT CDH1 protein P12830 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-252134 RPS6KA3 protein P51812 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-249215 MAPK14 protein Q16539 UNIPROT SMARCD3 protein Q6STE5 UNIPROT "up-regulates activity" phosphorylation 9606 21902831 t lperfetto "p38 phosphorylates the baf60 subunit of the swi-snf chromatin remodelling complex, and p38 recruits this complex to differentiation-specific loci." SIGNOR-176557 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 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 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 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 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 PRKCD protein Q05655 UNIPROT CHAT protein P28329 UNIPROT "up-regulates quantity" phosphorylation Ser594 HKAAVPAsEKLLLLK 9606 BTO:0000930 15381704 t lperfetto "Finally, basal ChAT phosphorylation in neurons is mediated predominantly by PKC at Ser-476, with PKC activation increasing phosphorylation at Ser-440 and enhancing ChAT activity." SIGNOR-249272 PRKCD protein Q05655 UNIPROT YWHAZ protein P63104 UNIPROT "down-regulates activity" phosphorylation Ser58 VVGARRSsWRVVSSI 9606 BTO:0000007 12861023 t lperfetto "We confirmed that MAPKAPK2 interacted with and phosphorylated 14-3-3zeta in vitro and in HEK293 cells. | Experimentally, S58D mutation significantly impaired both 14-3-3zeta dimerization and binding to Raf-1." SIGNOR-249222 PRKCE protein Q02156 UNIPROT GAD1 protein Q99259 UNIPROT "down-regulates activity" phosphorylation Thr91 RDARFRRtETDFSNL -1 15147202 t lperfetto "We have identified one specific phosphorylation site, threonine 91 (T91), in hGAD67 that can be phosphorylated by PKA using MALDI-TOF. Site-directed mutation of T91 to alanine abolished PKA-mediated phosphorylation and inhibition of GAD activity." SIGNOR-249264 PRKCQ protein Q04759 UNIPROT PRKCQ protein Q04759 UNIPROT "up-regulates activity" phosphorylation Thr219 SAINSREtMFHKERF 9606 BTO:0000661 16252004 t lperfetto "Critical role of novel Thr-219 autophosphorylation for the cellular function of PKCtheta in T lymphocytes." SIGNOR-249298 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 RPS6KA5 protein O75582 UNIPROT HIST3H3 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 HIST3H3 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 SEMA3F protein Q13275 UNIPROT NRP2 protein O60462 UNIPROT up-regulates binding 9606 BTO:0000938 16816121 t esanto "In the nervous system, neuropilins mediate axon retraction and guidance by binding class iii semaphorins. We found that sema3f could compete with metabolically labeled vegf-c for the binding to np1-ig and np2-ig fusion proteins." SIGNOR-147608 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 DCC-2036 chemical CHEBI:62166 ChEBI ABL1 protein P00519 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191313 MAPK14 protein Q16539 UNIPROT SP7 protein Q8TDD2 UNIPROT "up-regulates activity" phosphorylation 10090 20682789 t ggiuliani "We therefore propose that Osterix binds to Sp1 sequences on target gene promoters and that its phosphorylation by p38 enhances recruitment of coactivators to form transcriptionally active complexes" SIGNOR-255791 MAPK14 protein Q16539 UNIPROT STAT1 protein P42224 UNIPROT "up-regulates activity" phosphorylation Ser727 TDNLLPMsPEEFDEV 9606 17502367 t lperfetto "All stats are phosphorylated on at least one serine residue in their tad specifically, ser727 in stats 1 and 3 and ser721 in stat4. Stat serine kinases have been identified through the use of inhibitors, dominant-negative alleles, and in vitro kinase assays. They include mapk (p38mapk: stats 1, 3, 4;erk: stat3, 5;jnk: stat3), pkc_ (stat1, stat3), mtor (stat3), nlk (stat3 (42)), and camkii and ikk_ (stat1 (39, 40, 43)).STAT Serine phosphorylation regulates transcriptional activity (see below)." SIGNOR-154779 MAPK14 protein Q16539 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 17502367 t gcesareni "All stats are phosphorylated on at least one serine residue in their tad specifically, ser727 in stats 1 and 3 and ser721 in stat4. Stat serine kinases have been identified through the use of inhibitors, dominant-negative alleles, and in vitro kinase assays. They include mapk (p38mapk: stats 1, 3, 4;erk: stat3, 5;jnk: stat3), pkc_ (stat1, stat3), mtor (stat3), nlk (stat3 (42)), and camkii and ikk_ (stat1 (39, 40, 43)).STAT Serine phosphorylation regulates transcriptional activity (see below)." SIGNOR-154783 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 MAPKAPK3 protein Q16644 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-249709 PIK3R3 protein Q92569 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 9415396 t gcesareni "The region between the src homology 2 (sh2) domains of p55pik bound to the nh2 terminus region of p110alpha" SIGNOR-53597 PKN1 protein Q16512 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser170 SFKLSGFsFKKNKKE 9534 BTO:0000298 8557118 t lperfetto "PRK1 phosphorylates MARCKS at the PKC sites: serine 152, serine 156 and serine 163." SIGNOR-248939 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 PRKCE protein Q02156 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-249281 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 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 PRKCZ protein Q05513 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-249291 PRKCZ protein Q05513 UNIPROT PPP1R14A protein Q96A00 UNIPROT unknown phosphorylation Thr38 QKRHARVtVKYDRRE -1 15003508 t lperfetto "For that purpose, PKCa, e, l, and f were incubated with CPI-17 in the presence of 50 lM [c- 32P]ATP and kinase buffer. The results indicated that all PKC isoforms were able to phosphorylate CPI-17 in vitro (Table 1). PKCa phosphorylated CPI-17 to a similar extent to PKCe and to a much greater extent than f and l." SIGNOR-249261 SOSTDC1 protein Q6X4U4 UNIPROT WNT7B protein P56706 UNIPROT "down-regulates activity" 10090 22829579 f lperfetto "Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells." SIGNOR-242733 SOSTDC1 protein Q6X4U4 UNIPROT WNT9B protein O14905 UNIPROT "down-regulates activity" 10090 22829579 f lperfetto "Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells." SIGNOR-242739 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 FOXO1 protein Q12778 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 12530968 f "�The present data provide a direct link between insulin signaling through Irs _ PI 3-kinase _ Akt and adipogenesis through Foxo1 phosphorylation. Inhibition of Foxo1 via phosphorylation appears to be required during the clonal expansion phase, and our data show that unrestrained Foxo1 activity prevents terminal differentiation." SIGNOR-254981 FYN protein P06241 UNIPROT PLCG2 protein P16885 UNIPROT "up-regulates activity" phosphorylation Tyr753 ERDINSLyDVSRMYV -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-249339 FYN protein P06241 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-249340 FYN protein P06241 UNIPROT TXK protein P42681 UNIPROT "up-regulates activity" phosphorylation Tyr420 RYVLDDEyVSSFGAK BTO:0000782 11353545 t lperfetto "We further demonstrate that Rlk can be phosphorylated and activated by Src kinases, leading to a decrease in its half-life. A specific tyrosine in the activation loop of Rlk, Y420, is required for phosphorylation and activation, as well as for decreased stability, but is not required for lipid RAFT association." SIGNOR-249341 MAPK14 protein Q16539 UNIPROT TCF3 protein P15923 UNIPROT "up-regulates activity" phosphorylation Ser139 LNSPGPLsPSGMKGT 9606 BTO:0000887 15719023 t lperfetto "Here we show that p38 mapk, whose activity is essential for myogenesis, regulates myod/e47 heterodimerization. Phosphorylation of e47 at ser140 by p38 induces myod/e47 association and activation of muscle-specific transcription" SIGNOR-134194 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0000093 11258706 t lperfetto "P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site." SIGNOR-105737 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser33 LPENNVLsPLPSQAM 9606 BTO:0000093 11258706 t lperfetto "P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site." SIGNOR-105741 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 PKN1 protein Q16512 UNIPROT MAP3K20 protein Q9NYL2 UNIPROT up-regulates phosphorylation 9606 17251915 t gcesareni "Phosphorylation of mltkalpha by pknalpha enhances its kinase activity" SIGNOR-152768 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 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 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 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 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 TDRD3 protein Q9H7E2 UNIPROT SNRPN protein P63162 UNIPROT unknown binding -1 15955813 t miannu "the TDRD3 GST-Tudor protein interacted strongly with methylated SmB/B′ and SmD but not with SmE. These results suggest that the Tudor domains of SMN and SPF30 likely interact with assembled snRNPs, whereas the Tudor domain of TDRD3 might bind unassembled methylated Sm proteins." SIGNOR-253518 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser33 LPENNVLsPLPSQAM 9606 BTO:0000093 17535811 t lperfetto "P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site." SIGNOR-155242 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser33 LPENNVLsPLPSQAM 9606 BTO:0000093 22975381 t lperfetto "P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site." SIGNOR-192057 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 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 ELK1 protein P19419 UNIPROT up-regulates phosphorylation 9606 7618106 t lperfetto "The tcf protein elk-1 is phosphorylated by the jnk and erk groups of mitogen-activated protein (map) kinases causing increased dna binding, ternary complex formation, and transcriptional activation" SIGNOR-29923 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 PLK1 protein P53350 UNIPROT TOP2A protein P11388 UNIPROT up-regulates phosphorylation Ser1525 PIKYLEEsDEDDLF 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-160237 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 CFTR protein P13569 UNIPROT "up-regulates activity" phosphorylation Ser737 EPLERRLsLVPDSEQ -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-250350 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 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 PRKCA protein P17252 UNIPROT GJA1 protein P17302 UNIPROT "down-regulates activity" phosphorylation Ser368 QRPSSRAsSRASSRP 10116 BTO:0002931 10871288 t lperfetto "Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication." SIGNOR-249048 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 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-248894 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 PRKCD protein Q05655 UNIPROT EEF1A1 protein P68104 UNIPROT unknown phosphorylation Thr432 AVRDMRQtVAVGVIK 7890750 t lperfetto "PKC delta phosphorylates eEF-1 alpha at Thr-431" SIGNOR-248902 RAC1 protein P63000 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates binding 9606 18423204 t gcesareni "We show that rac1 activates jnk2 that in turn phosphorylates beta-catenin on critical residues and controls its nuclear translocation." SIGNOR-178265 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 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 TEAD1 protein P28347 UNIPROT MSLN protein Q13421 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17909009 f miannu "The presence of TEF-1 was required for MSLN protein overexpression as determined by TEF-1 knockdown experiments." SIGNOR-255395 MAPK3 protein P27361 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-178141 MAPK3 protein P27361 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-178145 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 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 JUN protein P05412 UNIPROT up-regulates phosphorylation Ser73 VGLLKLAsPELERLI 9606 12169099 t gcesareni "Up-regulation of c-jun mrna in cardiac myocytes requires the extracellular signal-regulated kinase cascade, but c-jun n-terminal kinases are required for efficient up-regulation of c-jun protein." SIGNOR-91383 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 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 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 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 NTRK1 protein P04629 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 9606 BTO:0000938 10708759 t esanto "Autophosphorylated trka binds directly to plc?, Abl, and shc." SIGNOR-75408 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 PTK2B protein Q14289 UNIPROT SNCA protein P37840 UNIPROT unknown phosphorylation Tyr125 VDPDNEAyEMPSEEG 9534 BTO:0000298 12096713 t lperfetto "The present report demonstrates that the protein tyrosine kinase Pyk2/RAFTK is involved in cell stress-induced tyrosine phosphorylation of alpha S. Hyperosmotic stress induced tyrosine phosphorylation of alpha S via Pyk2/RAFTK at tyrosine residue 125." SIGNOR-249151 RAGAC complex SIGNOR-C113 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR "up-regulates activity" relocalization 9606 20381137 t gcesareni "The Rag GTPases interact with mTORC1 and are proposed to activate it in response to amino acids by promoting mTORC1 translocation to a membrane-bound compartment that contains the mTORC1 activator, Rheb" SIGNOR-228158 RPS6KA3 protein P51812 UNIPROT HMGN1 protein P05114 UNIPROT "down-regulates activity" phosphorylation Ser25 KRRSARLsAKPPAKV 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-249101 TBK1 protein Q9UHD2 UNIPROT IRF3 protein Q14653 UNIPROT "up-regulates activity" phosphorylation Thr404 NSHPLSLtSDQYKAY -1 18440553 t lperfetto "Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404." SIGNOR-178420 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 CUL1 protein Q13616 UNIPROT SCF-FBW7 complex SIGNOR-C135 SIGNOR "form complex" binding 9606 15340381 t gcesareni "The F-box family of proteins €” which are the substrate-recognition components of the Skp1€“Cul1€“F-box-protein (SCF) ubiquitin ligase €” are important players in many mammalian functions." SIGNOR-243763 FYN protein P06241 UNIPROT GRIN2B protein Q13224 UNIPROT unknown phosphorylation Tyr1474 GSSNGHVyEKLSSIE 11483655 t lperfetto "We have investigated the tyrosine phosphorylation of NMDA receptor subunits NR2A and NR2B by exogenous Src and Fyn and compared this to phosphorylation by tyrosine kinases associated with the postsynaptic density (PSD)|Phosphorylation-site specific antibodies identified NR2B Tyr1472 as a phosphorylation site for intrinsic PSD tyrosine kinases" SIGNOR-249338 MAPK3 protein P27361 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-249466 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 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 NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser345 QARPGPQsPGSPLEE 9606 8626435 t esanto "Upon activation, several serine residues on the cytosolic oxidase subunit p47phox become phosphorylated. Mitogen-activated protein kinase phophorylated only the peptide containing ser345/348." SIGNOR-40821 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 PAX8 protein Q06710 UNIPROT SLC3A1 protein Q07837 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000671 15673291 f miannu "Expression of SLC3A1 mRNA was found to be tenfold higher in postnatal vs. fetal kidney; SLC3A1 expression is doubled by the proximal tubule transcription factor, PAX8. rBAT is expressed in the proximal convoluted and straight tubules in both fetal and adult kidney." SIGNOR-254907 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 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 SKP1 protein P63208 UNIPROT SCF-FBW7 complex SIGNOR-C135 SIGNOR "form complex" binding 9606 15340381 t gcesareni "The F-box family of proteins €” which are the substrate-recognition components of the Skp1€“Cul1€“F-box-protein (SCF) ubiquitin ligase €” are important players in many mammalian functions." SIGNOR-243760 SKP1 protein P63208 UNIPROT SCF-SKP2 complex SIGNOR-C136 SIGNOR "form complex" binding 9606 15340381 t gcesareni "The F-box family of proteins €” which are the substrate-recognition components of the Skp1€“Cul1€“F-box-protein (SCF) ubiquitin ligase €” are important players in many mammalian functions." SIGNOR-243554 SKP2 protein Q13309 UNIPROT SCF-SKP2 complex SIGNOR-C136 SIGNOR "form complex" binding 9606 15340381 t gcesareni "The F-box family of proteins €” which are the substrate-recognition components of the Skp1€“Cul1€“F-box-protein (SCF) ubiquitin ligase €” are important players in many mammalian functions." SIGNOR-243560 STK3 protein Q13188 UNIPROT MOB1B protein Q7L9L4 UNIPROT up-regulates phosphorylation Thr12 FGSRSSKtFKPKKNI 9606 21808241 t "The regulation of MOB1 and LATS1/2 by MST1/2 may be organ and disease-specific." gcesareni "Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2 mob1 interaction." SIGNOR-175813 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 WNT1 protein P04628 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-131577 WNT3A protein P56704 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-131826 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 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 NFE2L2 protein Q16236 UNIPROT GCLC protein P48506 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 24024136 f irozzo "In both models, the inducer-modified and Nrf2-bound Keap1 is inactivated and, consequently, newly synthesized Nrf2 proteins bypass Keap1 and translocate into the nucleus, bind to the ARE and drive the expression of Nrf2 target genes such as NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), glutamate-cysteine ligase (GCL) and glutathione S transferases (GSTs)." SIGNOR-256277 NFYC protein Q13952 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-255211 MAPK1 protein P28482 UNIPROT DUSP16 protein Q9BY84 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser446 TNKLCQFsPVQELSE 9534 BTO:0004055 15689616 t lperfetto "Phosphorylation of Ser-446 determines stability of MKP-7.|We also determined that MKP-7 phosphorylated at Ser-446 has a longer half-life than unphosphorylated form of the wild type protein, as does a phospho-mimic mutant of MKP-7. These results indicate that activation of the ERK pathway strongly blocks JNK activation through stabilization of MKP-7 mediated by phosphorylation." SIGNOR-249389 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 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 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 SCNN1G protein P51170 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr622 LGTQVPGtPPPKYNT -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-249449 MAPK3 protein P27361 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation 9606 BTO:0000763;BTO:0000149 10197981 t gcesareni "Ras signaling was shown previously to induce the phosphorylation of the bmp mediator smad1 at four erk consensus sites in the linker domain (kretzschmar et al. 1997a). Phosphorylation of these four sites inhibits smad1 accumulation in the nucleus" SIGNOR-66755 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 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-66778 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 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 NVP-ADW742 chemical CID:9825149 PUBCHEM IGF1R protein P08069 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194883 NVP-BEP800 chemical CID:25210273 PUBCHEM HSP90AB1 protein P08238 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194904 "NVP-BSK805 dihydrochloride" chemical CID:57339395 PUBCHEM JAK2 protein O60674 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194934 PRKAA1 protein Q13131 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser259 FPLRKTAsEPNLKVR 9606 SIGNOR-C15 21892142 t gcesareni "Another recently described set of transcriptional regulators targeted by ampk and its related family members across a range of eukaryotes are the class iia family of histone deacetylases (hdacs)" SIGNOR-176479 PRKCD protein Q05655 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates phosphorylation Thr143 RGKFKRPtLRRVRIS 9606 18550549 t gcesareni "Src phosphorylates pkcdelta at tyr311 and tyr332 leading to enhanced pkcdelta autophosphorylation at thr505 (its activation loop) and pkcdelta-dependent ctni phosphorylation at both ser23/ser24 and thr144." SIGNOR-178888 SMURF1 protein Q9HCE7 UNIPROT BMPR2 protein Q13873 UNIPROT down-regulates ubiquitination 9606 22298955 t gcesareni "Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps." SIGNOR-195654 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT "down-regulates activity" phosphorylation Tyr179 GGPAQDIyQVPPSAG 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" SIGNOR-246389 TRAF6 protein Q9Y4K3 UNIPROT MALT1 protein Q9UDY8 UNIPROT up-regulates ubiquitination 9606 BTO:0000782 17948050 t gcesareni "Traf6 associates with malt1 in response to t-cell activation and can function as an e3 ligase for malt1 in vitro and in vivo, mediating lysine 63-linked ubiquitination of malt1. Multiple lysine residues in the c-terminus of malt1 serve as acceptor sites for the assembly of polyubiquitin chains. (articolo-abstract)" SIGNOR-158554 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 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 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 PHKG1 protein Q16816 UNIPROT PHKG1 protein Q16816 UNIPROT unknown phosphorylation Ser82 VDILRKVsGHPNIIQ -1 7935360 t miannu "Phosphopeptides correspond to sequences occurring in the gamma-subunit of phosphorylase kinase […] undergoes autophosphorylation. phosphorylation occurs primarily at Ser30 while in the latter an additional reaction takes place at Ser81." SIGNOR-250389 PLK1 protein P53350 UNIPROT CLIP1 protein P30622 UNIPROT up-regulates phosphorylation Ser195 LTKTASEsISNLSEA 9606 20664522 t gcesareni "Furthermore, we provide evidence that plk1 phosphorylation of clip-170 at s195 enhances its association with ck2" SIGNOR-167172 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 PRKCA protein P17252 UNIPROT DGKD protein Q16760 UNIPROT "down-regulates activity" phosphorylation Ser70 QNNSFQRsKRRYFKL 9534 BTO:0000298 15228384 t lperfetto "The plasma membrane translocation of diacylglycerol kinase delta1 is negatively regulated by conventional protein kinase C-dependent phosphorylation at Ser-22 and Ser-26 within the pleckstrin homology domain." SIGNOR-249266 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 PRKCH protein P24723 UNIPROT PTPN11 protein Q06124 UNIPROT unknown phosphorylation Ser580 CAEMREDsARVYENV 9606 BTO:0000007 11781100 t lperfetto " In summary, SHP2 is phosphorylated on serine residues 576 and 591 by PKC isoforms alpha, beta 1, beta 2, and eta" SIGNOR-249137 PRKCQ protein Q04759 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-249250 PRKCQ protein Q04759 UNIPROT ICAM3 protein P32942 UNIPROT "up-regulates activity" phosphorylation Ser518 REHQRSGsYHVREES 9606 BTO:0000661 9268366 t lperfetto "Ser489 was a phosphorylation site in vitro for recombinant protein kinase Ctheta. Finally, treatment of Jurkat cells with chelerythrine chloride, a protein kinase C inhibitor, prevented ICAM-3-triggered spreading. " SIGNOR-248979 PTEN protein P60484 UNIPROT STAT5A protein P42229 UNIPROT down-regulates dephosphorylation 9606 BTO:0001271 20596030 t miannu "The forced expression of pten in the eol-1r cells dephosphorylated akt, erk and stat5 /eol-1r cells showed epigenetic silencing of the phosphatase and tensin homolog deleted on chromosome ten (pten) gene. Exposure of eol-1r cells to imatinib failed to dephosphorylate akt, erk and stat5, although pdgfr? Was effectively inactivated. The forced expression of pten negatively regulated these signal pathways and sensitized eol-1r cells to imatinib." SIGNOR-166481 PTK6 protein Q13882 UNIPROT KHDRBS1 protein Q07666 UNIPROT unknown phosphorylation Tyr435 ARPVKGAyREHPYGR 9606 BTO:0000567 16179349 t lperfetto "We show that BRK phosphorylates Sam68 on all three tyrosines in the nuclear localization signal." SIGNOR-249293 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 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 ODC1 protein P11926 UNIPROT spermine smallmolecule CHEBI:15746 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-256036 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 "Orexin A" smallmolecule CHEBI:80319 ChEBI HCRTR1 protein O43613 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-257510 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 IRF4 protein Q15306 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 BTO:0000801 20729857 f lperfetto "We found Irf4 to be one of the direct targets of Jmjd3-mediated demethylation. Finally, we found that Irf4 is a transcription factor crucial for the induction of M2 macrophage responses." SIGNOR-249543 MAPK3 protein P27361 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-249468 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 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 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 Thr220 QSNYIPEtPPPGYIS 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-91742 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 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 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 RPS6KA2 protein Q15349 UNIPROT NR4A1 protein P22736 UNIPROT "up-regulates activity" phosphorylation Ser351 GRRGRLPsKPKQPPD 10116 BTO:0001009 11883936 t lperfetto "Phosphorylation of a residue in the DNA-binding region (Ser-350 of NGFI-B and 354 of Nur77) has been described in detail to have effect on the transcriptional function of the protein [11, 24]. Growth-related kinase pp90rsk, but not ERK1 (pp44mapk), was shown to phosphorylate recombinant Nur77 in vitro in the DNA binding domain, but not the amino-terminus, using an immune complex kinase as- say [11]." SIGNOR-249429 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT "down-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" SIGNOR-246397 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT "down-regulates activity" phosphorylation Tyr267 SQYGQEVyDTPPMAV 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" SIGNOR-246401 SRC protein P12931 UNIPROT DLG4 protein P78352 UNIPROT up-regulates phosphorylation Tyr523 REDSVLSyETVTQME 9606 BTO:0000938 24981431 t llicata "These results indicate that psd-95 phosphorylation by src facilitates the integration of pyk2 to psd-95 signal complex, the activation of pyk2/src, as well as the subsequent tyrosine phosphorylation of nr2a, which ultimately results in the upregulation of nmda receptor function and synaptic transmission." SIGNOR-205120 "SWI/SNF complex" complex SIGNOR-C92 SIGNOR "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-151703 Calcineurin complex SIGNOR-C155 SIGNOR NFATC3 protein Q12968 UNIPROT up-regulates dephosphorylation 9606 21880741 t gcesareni "Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat." SIGNOR-252312 Calcineurin complex SIGNOR-C155 SIGNOR NFATC4 protein Q14934 UNIPROT up-regulates dephosphorylation 9606 21880741 t gcesareni "Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat." SIGNOR-252322 EGR1 protein P18146 UNIPROT SF1 protein Q15637 UNIPROT "up-regulates activity" binding 10090 BTO:0004467 19106114 t miannu "GNRH1 induces expression of early growth response 1 (EGR1), which interacts with steroidogenic factor 1 (SF1) and paired-like homeodomain transcription factor 1 (PITX1) to regulate Lhb promoter activity." SIGNOR-254914 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR 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-244549 FBXO11 protein Q86XK2 UNIPROT BCL6 protein P41182 UNIPROT down-regulates binding 9606 BTO:0000785 22113614 t miannu "Fbxo11 targets bcl6 for degradation" SIGNOR-177652 FOXO3 protein O43524 UNIPROT MIR1-1 mirna MI0000651 miRBase "up-regulates quantity" "transcriptional regulation" 10090 BTO:0000165 19933931 t "The activation state of the IGF-1 signal transduction cascade reciprocally regulates miR-1 expression through the Foxo3a transcription factor;" SIGNOR-255720 MIR1-1 mirna MI0000651 miRBase IGF1 protein P05019 UNIPROT "down-regulates quantity" "post transcriptional regulation" 10090 BTO:0000165 19933931 t "On the basis of bioinformatics tools, biochemical assays, and in vivo models, we demonstrate that (1) insulin-like growth factor-1 (IGF-1) and IGF-1 receptor are targets of miR-1" SIGNOR-255721 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 MAPK3 protein P27361 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-248079 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 PRKCA protein P17252 UNIPROT GRIA1 protein P42261 UNIPROT unknown phosphorylation Ser832 LIEFCYKsRSESKRM 9606 BTO:0000007 8663994 t lperfetto "In addition, protein kinase C specifically phosphorylates Ser-831 of GluR1 in HEK-293 cells and in cultured neurons." SIGNOR-248950 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 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 PRKCQ protein Q04759 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-249256 PRKCZ protein Q05513 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-249257 PTK6 protein Q13882 UNIPROT KHDRBS1 protein Q07666 UNIPROT unknown phosphorylation Tyr440 GAYREHPyGRY 9606 BTO:0000567 16179349 t lperfetto "We show that BRK phosphorylates Sam68 on all three tyrosines in the nuclear localization signal. |Tyrosine 440 was identified as a principal modulator of Sam68 localization and this site was phosphorylated in response to EGF treatment in human breast tumor cell lines." SIGNOR-249294 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 TGFB3 protein P10600 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates binding 9606 11157754 t miannu "T?RII Is known to bind the isoforms tgf??1 And tgf??3. Binding of these ligands causes recruitment of the type i receptor (t?RI) into a signalling receptor complex followed by activation of t?RI Through transphosphorylation" SIGNOR-104798 WNT3 protein P56703 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-131823 "Av/b5 integrin" complex SIGNOR-C178 SIGNOR 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-257723 PER2 protein O15055 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 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-256370 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 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 MAPK9 protein P45984 UNIPROT H2AFX 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 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 MYOD1 protein P15172 UNIPROT SMARCA4 protein P51532 UNIPROT up-regulates binding 9606 BTO:0001103 SIGNOR-C92 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-151685 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 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 PLK3 protein Q9H4B4 UNIPROT TOP2A protein P11388 UNIPROT up-regulates phosphorylation Thr1343 FSDFDEKtDDEDFVP 9606 18062778 t llicata "The direct phosphorylation of thr(1342) of topoisomerase iialpha by plk3 was demonstrated with an in vitro kinase assay, and overexpression of plk3 induced the phosphorylation of thr(1342) in cellular topoisomerase iialpha. it is possible that plk3 regulates the activity of topoisomerase iia by phosphorylation in a cell-cycle dependent manner. Another possibility is that plk3 regulates the activity of topoisomerase iia when the checkpoint is activated." SIGNOR-159596 PPP3CA protein Q08209 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-84041 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 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 PRKCA protein P17252 UNIPROT HLA-A protein P01892 UNIPROT unknown phosphorylation Ser359 SAQGSDVsLTACKV 2941417 t lperfetto "As shown in Fig. 6A, the HLA heavy chain was phosphorylated by kinase C. | The major site of in vivo phosphorylation of the HLA-B7 heavy chain was localized to Ser-335 which is conserved in all specificitie" SIGNOR-248891 PRKCD protein Q05655 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser159 KKKKKRFsFKKSFKL -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-248924 PTPRE protein P23469 UNIPROT INSR protein P06213 UNIPROT "down-regulates activity" dephosphorylation Tyr999 YASSNPEyLSASDVF 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-248443 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 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 PTPN11 protein Q06124 UNIPROT "up-regulates activity" phosphorylation Tyr546 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 PKN1 protein Q16512 UNIPROT ARHGEF2 protein Q92974 UNIPROT down-regulates phosphorylation Ser886 PVDPRRRsLPAGDAL 9606 14970201 t lperfetto "Here we identify a region in the carboxyl terminus of gef-h1 that is important for suppression of its guanine nucleotide exchange activity by microtubules. This portion of the protein includes a coiled-coil motif, a proline-rich motif that may interact with src homology 3 domain-containing proteins, and a potential binding site for 14-3-3 proteins. 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-122191 PRKACA protein P17612 UNIPROT GRIA1 protein P42261 UNIPROT "up-regulates activity" phosphorylation Ser863 TSTLPRNsGAGASSG 9606 BTO:0000007 8663994 t miannu "Phosphorylation of Ser-845 on GluR1 by PKA potentiates its response to glutamate." SIGNOR-249987 PRKACA protein P17612 UNIPROT HMGCR protein P04035 UNIPROT "down-regulates activity" phosphorylation Ser872 SHMIHNRsKINLQDL 10116 BTO:0000759 2369897 t miannu "The intact, 100 kd microsomal enzyme and the 53 kd catalytic fragment of rat HMG-CoA reductase are both phosphorylated and inactivated by the AMP-activated protein kinase. this site is highly phosphorylated in intact liver under these conditions (Ser872 in the human enzyme)." SIGNOR-249992 PRKACA protein P17612 UNIPROT HMGN1 protein P05114 UNIPROT "down-regulates activity" phosphorylation Ser7 sSAEGAAK 9606 BTO:0000567 11438671 t miannu "PKA preferentially phosphorylates serine 6 in human HMGN1. specific phosphorylation of the NBD of HMGN proteins serves to prevent the interaction of these proteins with their chromatin targets during mitosis." SIGNOR-249993 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 RAF1 protein P04049 UNIPROT "down-regulates activity" phosphorylation Ser233 VSSQHRYsTPHAFTF 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-250040 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 RNF111 protein Q6ZNA4 UNIPROT AP2M1 protein Q96CW1 UNIPROT up-regulates ubiquitination 9606 20965945 t gcesareni "Arkadia ubiquitylated the _?2 Subunit at lys130. In addition, arkadia interacted with the ap2 complex, and modified endocytosis of epidermal growth factor receptor (egfr) induced by egf. Arkadia thus appears to regulate egf signalling by modulating endocytosis of egfr through interaction with ap2 complex." SIGNOR-168931 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 ROCK1 protein Q13464 UNIPROT FHOD1 protein Q9Y613 UNIPROT up-regulates phosphorylation Ser1137 RSRGNRKsLRRTLKS 9606 18239683 t lperfetto "Rock phosphorylates the c-terminal residues ser1131, ser1137, and thr1141 of formin homology domain protein 1 (fhod1). Phosphorylation of fhod1 at the three residues fully disrupts the autoinhibitory interaction, which culminates in formation of stress fibres." SIGNOR-160548 SRC protein P12931 UNIPROT CDCP1 protein Q9H5V8 UNIPROT unknown phosphorylation Tyr734 KDNDSHVyAVIEDTM 9606 BTO:0000667 14739293 t lperfetto "Phosphorylation of gp140 and p80 are mediated by Src family kinases at multiple Tyr residues including Tyr(734)." SIGNOR-246457 WNT4 protein P56705 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-131832 WNT4 protein P56705 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-131835 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 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 VASP protein P50552 UNIPROT "up-regulates activity" phosphorylation Ser239 GAKLRKVsKQEEASG 9606 BTO:0000132 12576312 t miannu "PKA activation is indeed sufficient to induce phosphorylation of VASP Ser239 in platelets PKA plays a predominant role in the cGMP-induced phosphorylation of VASP and platelet inhibition in human platelets." SIGNOR-250063 PRKCE protein Q02156 UNIPROT KRT18 protein P05783 UNIPROT unknown phosphorylation Ser53 ISVSRSTsFRGGMGS -1 1374067 t lperfetto "In conclusion, we have shown that the PKCe catalytic fragment physically associates with and phosphorylates CK8/18 HT29 cells. The nature of this association and its physiological significance remain to be determined." SIGNOR-248847 PRKCZ protein Q05513 UNIPROT YWHAB protein P31946 UNIPROT "down-regulates activity" phosphorylation Thr143 SGDNKQTtVSNSQQA 9534 BTO:0004055 10620507 t lperfetto "Our results with the 14-3-3 mutants indirectly imply a new phosphorylation site, 130Ser (and to a lesser extent 141Thr), in 14-3-3b that regulates the association}dissociation of 14-3-3b and PKC-f." SIGNOR-249035 PRKG1 protein Q13976 UNIPROT RYR1 protein P21817 UNIPROT unknown phosphorylation Ser2843 KKKTRKIsQSAQTYD -1 8380342 t lperfetto "Automated Edman sequence analysis of the major phosphopeptide obtained from PK-A and PK-G phosphorylation and one phosphopeptide obtained from PK-CaM phosphorylation yielded the sequence KISQTAQTYDPR (residues 2841€“2852) with serine 2843 as phosphorylation site" SIGNOR-248918 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 ROCK1 protein Q13464 UNIPROT FHOD1 protein Q9Y613 UNIPROT up-regulates phosphorylation Thr1141 NRKSLRRtLKSGLGD 9606 18239683 t lperfetto "Rock phosphorylates the c-terminal residues ser1131, ser1137, and thr1141 of formin homology domain protein 1 (fhod1). Phosphorylation of fhod1 at the three residues fully disrupts the autoinhibitory interaction, which culminates in formation of stress fibres." SIGNOR-160552 RPS6KA1 protein Q15418 UNIPROT NR4A3 protein Q92570 UNIPROT unknown phosphorylation Ser376 GRRGRLPsKPKSPLQ 9606 BTO:0000007 16223362 t lperfetto "We have established that two related proteins, Nurr1 and Nor1, are also phosphorylated on the equivalent site by RSK in cells in response to mitogenic stimulation. | Similar to Nur77, when FLAG€“Nor1 was expressed in HEK-293 cells, its phosphorylation on Ser377 was stimulated by both PMA and EGF" SIGNOR-249297 RPS6KB1 protein P23443 UNIPROT RICTOR protein Q6R327 UNIPROT down-regulates phosphorylation Thr1135 NRRIRTLtEPSVDFN 9606 19995915 t gcesareni "Phosphorylation of rictor on thr1135 did not affect mtorc2 assembly, kinase activity, or cellular localization. However, cells expressing a rictor t1135a mutant were found to have increased mtorc2-dependent phosphorylation of akt" SIGNOR-161995 RUNX3 protein Q13761 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates binding 9606 19800882 t gcesareni "To investigate the possible mechanism of the down-regulation of hes-1 by runx3, we performed western blot and reporter assay and found that runx3 suppressed intracellular domain of notch1 (icn1)-mediated transactivation of notch signaling while it did not alter the expression of icn1 and recombination signal binding protein-j kappa (rbp-j) in smmc7721 cells." SIGNOR-188338 SBDS protein Q9Y3A5 UNIPROT EFL1 protein Q7Z2Z2 UNIPROT up-regulates binding 9606 BTO:0001271 21536732 t miannu "Sbds stimulates 60s-dependent gtp hydrolysis by efl1" SIGNOR-173533 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR CEBPA protein P49715 UNIPROT "down-regulates activity" binding 9606 12524424 t lperfetto "C/EBPbeta and C/EBPdelta were found to physically interact with Smad3 and Smad4, and Smad3 cooperated with Smad4 and TGF-beta signaling to repress the transcriptional activity of C/EBPs." SIGNOR-250571 SUFU protein Q9UMX1 UNIPROT GLIS2 protein Q9BZE0 UNIPROT down-regulates relocalization 9606 BTO:0001130 16316410 t gcesareni "Negative regulation of gli1 and gli2 activator function by suppressor of fused through multiple mechanisms.Together, these observations reveal that su(fu) regulates the activity of gli1 and gli2 through distinct cytoplasmic and nuclear mechanisms." SIGNOR-142608 TESK2 protein Q96S53 UNIPROT CFL2 protein Q9Y281 UNIPROT "down-regulates activity" phosphorylation Ser3 sGVTVNDE 9606 BTO:0001363 11418599 t lperfetto "Like TESK1, TESK2 phosphorylated cofilin specifically at Ser-3 and induced formation of actin stress fibers and focal adhesionsExpression of cofilin or S3A-cofilin into HeLa cells induced marked decreases in rhodamine-phalloidin staining due to the actin binding and -depolymerizing activity of cofilin" SIGNOR-246711 CEBPA protein P49715 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0000011 25451943 f gcesareni "Adipogenesis is controlled by a transcriptional cascade composed of a large number of transcriptional factors, among which CCAAT/enhancer-binding protein (C/EBP) ² plays an essential role." SIGNOR-250562 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 DTX4 protein Q9Y2E6 UNIPROT TBK1 protein Q9UHD2 UNIPROT down-regulates ubiquitination 9606 BTO:0000938 10531053 t gcesareni "Nlrp4 negatively regulates type i interferon signaling by targeting the kinase tbk1 for degradation via the ubiquitin ligase dtx4" SIGNOR-71565 FLT3 protein P36888 UNIPROT CEBPB protein P17676 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 16146838 t lperfetto "Oncogenic mutations of Flt3 also result in the activation of aberrant signaling pathways, including strong activation of STAT5, induction of STAT target genes, and repression of myeloid transcription factors c/EBP-3 and Pu.1." SIGNOR-250563 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 KLF5 protein Q13887 UNIPROT PPARG protein P37231 UNIPROT up-regulates "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-210010 MAP3K1 protein Q13233 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "up-regulates activity" phosphorylation 10090 BTO:0000944 8131746 t lperfetto "Phosphorylation at ser-218 and ser-222 by map kinase kinase kinases (raf or mekk1) positively regulates mek1 kinase activity." SIGNOR-244881 MAPK3 protein P27361 UNIPROT THRB protein P10828 UNIPROT up-regulates phosphorylation Ser142 IQKNLHPsYSCKYEG 9606 12809513 t lperfetto "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-102220 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 TSC2 protein P49815 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto "Phosphorylation 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-183695 MDK protein P21741 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 18469519 t gcesareni "We showed that mk binds to the notch2 receptor in hacat keratinocytes. We further found that mk activates notch2" SIGNOR-161427 NFE2L1 protein Q14494 UNIPROT NQO1 protein P15559 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000599 8962164 f irozzo "These results indicated that hARE-mediated expression of the NQO1 gene and its induction by xenobiotics and antioxidants are mediated by Nrf1 and Nrf2." SIGNOR-256280 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 PLK3 protein Q9H4B4 UNIPROT CDC25C protein P30307 UNIPROT unknown phosphorylation Ser216 SGLYRSPsMPENLNR -1 10557092 t lperfetto "The physical association and phosphorylation of Cdc25C protein phosphatase by Prk. | Further studies reveal that His6-Prk phosphorylates Cdc25C on serine216, a residue also phosphorylated by Chk1 and Chk2. Together, these observations strongly suggest that Prk's role in mitosis is at least partly mediated through direct regulation of Cdc25C." SIGNOR-249030 PRKAA1 protein Q13131 UNIPROT RRN3 protein Q9NYV6 UNIPROT down-regulates phosphorylation Ser635 DTHFRSPsSSVGSPP 9606 SIGNOR-C15 19815529 t llicata "We show that ampk down-regulates rrna synthesis under glucose restriction by phosphorylating the rna polymerase i (pol i)-associated transcription factor tif-ia at a single serine residue (ser-635)." SIGNOR-188403 PTPN12 protein Q05209 UNIPROT PTK2 protein Q05397 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 11432829 t gcesareni "This function correlated with the ability of ptp-pest to induce dephosphorylation of shc, pyk2, fak and cas, and inactivate the ras pathway." SIGNOR-109035 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 STK11 protein Q15831 UNIPROT STK11 protein Q15831 UNIPROT "down-regulates activity" phosphorylation Thr189 LLLTTGGtLKISDLG 9606 BTO:0000781 11430832 t lperfetto "These data suggest that the phosphorylation of thr-189 negatively regulates lkb1 activity." SIGNOR-109028 WDR83 protein Q9BRX9 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates binding 9606 15118098 t gcesareni "Morg1 specifically associates with several components of the erk pathway, including mp1, raf-1, mek, and erk, and stabilizes their assembly into an oligomeric complex." SIGNOR-124473 CDK5 protein Q00535 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0000938 17591690 t gcesareni "Here, we demonstrate for the first time that cdk5 interacts with p53 and increases its stability through posttranslational regulation, leading to accumulation of p53, particularly in the nucleus. We show that cdk5 phosphorylates p53 on ser15, ser33 and ser46 in vitro," SIGNOR-156414 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT "down-regulates activity" phosphorylation Ser795 SPYKFPSsPLRIPGG 9606 BTO:0000150 23336272 t lperfetto "Cyclin d1 is known to activate cdk4, which then phosphorylates the rb protein, leading to cell cycle progression." SIGNOR-216992 EPHA2 protein P29317 UNIPROT EPHA2 protein P29317 UNIPROT up-regulates phosphorylation Tyr772 EDDPEATyTTSGGKI 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-178181 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 MAPK14 protein Q16539 UNIPROT CDC25C protein P30307 UNIPROT "down-regulates activity" phosphorylation Ser216 SGLYRSPsMPENLNR -1 9543386 t miannu "P38 binds and phosphorylates Cdc25B at serines 309 and 361, and Cdc25C at serine 216; phosphorylation of these residues is required for binding to 14-3-3 proteins." SIGNOR-250091 MAPK3 protein P27361 UNIPROT UBTF protein P17480 UNIPROT down-regulates phosphorylation Thr117 DFPKKPLtPYFRFFM 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-112813 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 PRKCA protein P17252 UNIPROT RHO protein P08100 UNIPROT unknown phosphorylation Ser334 PLGDDEAsATVSKTE -1 9099669 t lperfetto "Thus, the primary protein kinase C sites are Ser334 and Ser338, with minor phosphorylation of Thr335/336 and Ser343." SIGNOR-248966 PRKCA protein P17252 UNIPROT RHO protein P08100 UNIPROT unknown phosphorylation Ser338 DEASATVsKTETSQV -1 11910029 t lperfetto "Thus, the primary protein kinase C sites are Ser334 and Ser338, with minor phosphorylation of Thr335/336 and Ser343." SIGNOR-249147 PRKCA protein P17252 UNIPROT RHO protein P08100 UNIPROT unknown phosphorylation Ser338 DEASATVsKTETSQV -1 9099669 t lperfetto "Thus, the primary protein kinase C sites are Ser334 and Ser338, with minor phosphorylation of Thr335/336 and Ser343." SIGNOR-248967 PRKCD protein Q05655 UNIPROT GNAZ protein P19086 UNIPROT unknown phosphorylation Ser27 DRHLRSEsQRQRREI 9606 BTO:0000007 8429024 t lperfetto "Gz alpha variants containing selected substitutions of alanine for serine residues were expressed in human kidney 293 cells, and the ability of each to be phosphorylated in response to phorbol 12-myristate 13-acetate was examined. A focus was placed on Ser25 and Ser27, the 2 serine residues within a sequence of Gz alpha used to obtain a phosphorylation-sensitive antibody. The results demonstrate that Ser27 is the primary site of phosphorylation. Conversion of Ser27 to an alanine resulted in a 65% decrease in incorporation of [32P] phosphate; conversion of Ser25 had no effect." SIGNOR-248932 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 PTPN12 protein Q05209 UNIPROT PTK2B protein Q14289 UNIPROT "down-regulates activity" dephosphorylation Tyr579 RYIEDEDyYKASVTR 9606 BTO:0000887;BTO:0001260 11337490 t lperfetto "Inhibition of the catalytic activity of cell adhesion kinase beta by protein-tyrosine phosphatase-pest-mediated dephosphorylation. / dephosphorylation of tyr402 and tyr579/580 by ptp-pest" SIGNOR-107502 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 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 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-16247 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 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 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 BCL2L11 protein O43521 UNIPROT down-regulates phosphorylation 9606 BTO:0000782;BTO:0001271 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-160326 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 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 MKNK1 protein Q9BUB5 UNIPROT SPRY2 protein O43597 UNIPROT down-regulates phosphorylation Ser121 VSSGSRSsTRTSTSS 9606 19864419 t llicata "The spry2/nedd4 association involves the ww domains of nedd4 and requires phosphorylation of the mnk2 kinase sites, ser(112) and ser(121), on spry2. mnk2 silencing decreased spry2-nedd4 interactions and also augmented the ability of spry2 to inhibit fibroblast growth factor signaling. endogenous and overexpressed nedd4 polyubiquitinate spry2 via lys(48) on ubiquitin and decrease its stability." SIGNOR-188893 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 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 PRKAA1 protein Q13131 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-250402 PRKCA protein P17252 UNIPROT RHO protein P08100 UNIPROT unknown phosphorylation Thr336 GDDEASAtVSKTETS -1 9099669 t lperfetto "Thus, the primary protein kinase C sites are Ser334 and Ser338, with minor phosphorylation of Thr335/336 and Ser343." SIGNOR-248969 PRKCA protein P17252 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" phosphorylation Ser371 AHSSHLKsKKGQSTS -1 9571186 t lperfetto "Here, we demonstrate that cotransfection of p53 with either PKC alpha or PKC zeta increases p53's transcriptional activity. Mutagenesis of p53 indicates that serine 371 is the major site for phosphorylation by PKC alpha in vitro." SIGNOR-248999 PRKG1 protein Q13976 UNIPROT CRIP2 protein P52943 UNIPROT unknown phosphorylation Ser104 RAEERKAsGPPKGPS 9534 BTO:0000298 10681529 t lperfetto " Cyclic GMP kinase I phosphorylated CRP2 at Ser-104, because the mutation to Ala completely prevented the in vivo phosphorylation." SIGNOR-249038 RASGEF1B protein Q0VAM2 UNIPROT NRAS protein P01111 UNIPROT up-regulates binding 9606 19201597 t gcesareni "Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras." SIGNOR-161481 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT "up-regulates activity" phosphorylation Thr576 NSCRSSTtTCPEQDF 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-249300 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 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 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 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 CDKN1A protein P38936 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr57 NFDFVTEtPLEGDFA -1 12058028 t miannu "P38α 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 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 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 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 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 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 PRKCE protein Q02156 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).‚ | The phosphorylation site analysis was carried out twice after phosphorylation of centaurin-alpha1‚ with PKCalpha and once with PKC_. A similar pattern of phosphopeptides was obtained each time." SIGNOR-249226 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 PTPRJ protein Q12913 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 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-21307 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 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 WNT2B protein Q93097 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-131777 WNT7B protein P56706 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-131978 KLF6 protein Q99612 UNIPROT DLK1 protein P80370 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15917248 f "Repression of Dlk1 requires HDAC3 deacetylase activity" fspada "We have identified kr?ppel-like factor-6 (klf6), a recently described tumor suppressor gene, as a repressor of the proto-oncogene delta-like 1 (dlk1), a gene encoding a transmembrane protein that inhibits adipocyte differentiation." SIGNOR-137836 CDK5 protein Q00535 UNIPROT CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR "form complex" binding 9606 11331872 t lperfetto "Induced p35 forms a complex with Cdk5 and activates its kinase activity" SIGNOR-250683 CDK8 protein P49336 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation Ser206 SSSTYPHsPTSSDPG 9606 19914168 t llicata "As receptor-activated smads form transcriptional complexes, they are phosphorylated at an interdomain linker region by cdk8 and cdk9, which are components of transcriptional mediator and elongation complexes. These phosphorylations promote smad transcriptional action" SIGNOR-161622 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 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 FANCM protein Q8IYD8 UNIPROT TOPBP1 protein Q92547 UNIPROT up-regulates relocalization 9606 20372056 t gcesareni "The enzymatic activity of fan cm is then required to remodel and stabilize the fork to allow topbp1 access to activate atr , in a 9-1-1-independent manner." SIGNOR-164765 FCGR1A protein P12314 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 BTO:0000801 24445665 f lperfetto "Although crosslinking of activating FcgammaRs on monocytes and macrophages induces the production of several pro-inflammatory cytokines and chemokines, immune complex-mediated signalling via activating FcgammaRs together with Toll-like receptor (TLR) triggering induces a specific M2 activation state in macrophages macrophages in this state were termed M2b or regulatory macrophages." SIGNOR-249524 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 GRB10 protein Q13322 UNIPROT PIK3R1 protein P27986 UNIPROT "up-regulates activity" binding 10090 BTO:0001516 23246379 t "Grb10 transduces signal from FLT3 by direct interaction with p85 and Ba/F3-FLT3-ITD cells expressing Grb10 exhibits higher STAT5 activation" SIGNOR-255945 MAP1LC3A protein Q9H492 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates binding 9606 19250911 t gcesareni "Sqstm1/p62 (named a170 in the mouse;hereafter p62) is the first proposed example of such proteins (bj_?_?Rk_?_?Y et al.,2005). It binds polyubiquitinated protein aggregates via its uba domain and interacts with lc3 on the autophagosome/ this interaction is necessary for autophagic degradation of p62-positive cytoplasmic inclusion bodies containing ubiquitinated proteins. We also demonstrate that alis are indistinguishable from p62 inclusion bodies and that p62 is required for their formation." SIGNOR-184198 MAPK3 protein P27361 UNIPROT NCOA1 protein Q15788 UNIPROT up-regulates phosphorylation Thr1179 NYGTNPGtPPASTSP 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-91143 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 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 PAMPs stimulus SIGNOR-ST11 SIGNOR TLR4 protein O00206 UNIPROT "up-regulates activity" 9606 BTO:0000801 19946286 f lperfetto "The lipopolysaccharide (LPS) of Gram negative bacteria is a wellknown inducer of the innate immune response1. Toll-like receptor (TLR) 4 and myeloid differentiation factor 2 (MD-2) form a heterodimer that recognizes a common pattern in structurally diverse LPS molecules." SIGNOR-249516 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 PRKCZ protein Q05513 UNIPROT TRAF2 protein Q12933 UNIPROT unknown phosphorylation Ser55 QCGHRYCsFCLASIL 9606 BTO:0000785 19336568 t llicata "Here, we report that protein kinase czeta phosphorylates traf2 at ser(55), within the ring domain of the protein, after tnfalpha stimulation" SIGNOR-184941 PTEN protein P60484 UNIPROT PPM1A protein P35813 UNIPROT up-regulates binding 9606 18482992 t lpetrilli "Upon complex formation with pten, ppm1a is protected from degradation induced by the tgf-? Signaling. this study establishes a novel role for nuclear pten in the stabilization of ppm1a." SIGNOR-178643 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 CDK5R1 protein Q15078 UNIPROT CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR "form complex" binding 9606 11331872 t lperfetto "Induced p35 forms a complex with Cdk5 and activates its kinase activity" SIGNOR-250682 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 EPHA2 protein P29317 UNIPROT EPHA2 protein P29317 UNIPROT up-regulates phosphorylation Tyr594 TYVDPHTyEDPNQAV 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-178173 MAPK14 protein Q16539 UNIPROT SLC9A1 protein P19634 UNIPROT up-regulates phosphorylation Ser729 ASPQSPEsVDLVNEE 9606 18701649 t gcesareni "Such results suggest that during apoptosis, oxidative stress could activate p38 mapk, phosphorylating nhe1 at s726 and s729." SIGNOR-180048 MAPK3 protein P27361 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-184180 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 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 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 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-178934 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 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 PAK1 protein Q13153 UNIPROT GNAZ protein P19086 UNIPROT up-regulates phosphorylation Ser16 EKEAARRsRRIDRHL 9606 BTO:0000671 9166747 t gcesareni "Phosphorylation of either ser(16) by pak1 or ser(27) by pkc decreased the affinity of galpha(z) for gbetagamma;phosphorylation of both residues by pkc caused no further effect. Pak1 thus regulates galpha(z) function by attenuating the inhibitory effects of both gaps and gbetagamma." SIGNOR-48673 PHKG1 protein Q16816 UNIPROT PHKG1 protein Q16816 UNIPROT unknown phosphorylation Ser31 EILGRGVsSVVRRCI -1 7935360 t miannu "Phosphopeptides correspond to sequences occurring in the gamma-subunit of phosphorylase kinase […] undergoes autophosphorylation. phosphorylation occurs primarily at Ser30 while in the latter an additional reaction takes place at Ser81." SIGNOR-250388 PLK1 protein P53350 UNIPROT HSF1 protein Q00613 UNIPROT down-regulates phosphorylation Ser216 IPLMLNDsGSAHSMP 9606 18794143 t lperfetto "Hsf1 was phosphorylated by plk1 at ser(216) of the dsgxxs motif during the timing of mitosis and a phospho-defective mutant form of hsf1 inhibited mitotic progression. Phosphorylated hsf1 during spindle pole localization underwent ubiquitin degradation through the scf(beta-trcp) pathway." SIGNOR-180915 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 PRKCQ protein Q04759 UNIPROT HSF1 protein Q00613 UNIPROT up-regulates phosphorylation 9606 23352416 t gcesareni "At the same time, ea causes pkc?-Mediated phosphorylation and activation of the transcription factor heat shock factor 1, an inducer of glucose dependence." SIGNOR-200576 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 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 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT unknown phosphorylation Thr440 LDSCNSLtPKSTPVK BTO:0000007 10095772 t llicata "In summary, our work has identified several phosphorylation sites for cyclin A/Cdk2 in B-Myb and shown that mutation of at least one of these sites has a strong effect on the inducibility of the B-Myb transactivation potential by cyclin A/Cdk2." SIGNOR-250738 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 g-secretase complex SIGNOR-C98 SIGNOR NOTCH2 protein Q04721 UNIPROT "up-regulates activity" cleavage 9606 25610395 t lperfetto "The membrane-bound Notch segment that results from this cleavage, known as Notch Intracellular Truncation domain (NEXT), is a -secretase substrate (Kopan and Ilagan, 2009). -Secretase performs the subsequent cleavage at S3 (De Strooper et al., 1999), releasing Notch intracellular domain (NICD) from the membrane and allowing for signal transduction through binding with the CBL-1, Su(H), Lag-1 (CSL; Schroeter et al., 1998; Struhl and Adachi, 1998) family of DNA binding proteins." SIGNOR-209723 ITCH protein Q96J02 UNIPROT TNFAIP3 protein P21580 UNIPROT "up-regulates activity" binding 9606 BTO:0000782;BTO:0001271 18246070 t lperfetto "Here we demonstrate that the regulatory molecule tax1bp1 recruited the e3 ligase itch to a20 via two 'ppxy' motifs. Itch was essential for the termination of tumor necrosis factor receptor signaling by controlling a20-mediated recruitment and inactivation of rip1. (abstract)" SIGNOR-160621 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 H3F3A 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 NCSTN protein Q92542 UNIPROT g-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-209711 PRKACA protein P17612 UNIPROT POLD3 protein Q15054 UNIPROT down-regulates phosphorylation Ser458 GKANRQVsITGFFQR 9606 22148433 t llicata "In this study, we identified s458, located in the pcna-interacting protein (pip-box) motif of p68, as a phosphorylation site for pka. Phosphomimetic mutation of s458 resulted in a decrease in p68 affinity for pcna as well as the processivity of pol _." SIGNOR-195203 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 PTK6 protein Q13882 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates phosphorylation Tyr664 EGGWMEDyDYVHLQG 9606 BTO:0001130 22084245 t lperfetto "Protein-tyrosine kinase 6 promotes peripheral adhesion complex formation and cell migration by phosphorylating p130 crk-associated substrate. Tyrosine residues 165 and 664 of p130cas were both phosphorylated by ptk6 in vitro" SIGNOR-177242 PTN protein P21246 UNIPROT ALK protein Q9UM73 UNIPROT up-regulates binding 9606 BTO:0000785 11278720 t gcesareni "We conclude from this series of experiments that ptn specifically binds to the alk orphan receptor as a high affinity ligand at least in part via the putative ligand binding domain described above." SIGNOR-106411 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 SOCS6 protein O14544 UNIPROT KIT protein P10721 UNIPROT down-regulates ubiquitination 9606 21030588 t miannu "Suppressor of cytokine signaling 6 (socs6) is a member of the socs family of e3 ubiquitin ligases that can interact with c-kit and suppress c-kit-dependent pathways. / we demonstrate that socs6 has ubiquitin ligase activity toward c-kit and regulates c-kit protein turnover in cells" SIGNOR-169145 CDK4 protein P11802 UNIPROT RBL1 protein P28749 UNIPROT "up-regulates activity" phosphorylation Ser964 MMDAPPLsPFPHIKQ 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-250764 CREB5 protein Q02930 UNIPROT CREB5 protein Q02930 UNIPROT "up-regulates activity" binding 9534 BTO:0000318 8378084 t miannu "CRE-BPa specifically binds to CRE as a homodimer or heterodimer with c-Jun or CRE-BP1. In CAT cotransfection experiments using CV-1 cells, transient expression of each of four CRE-BPa proteins caused a 1.6- to 3.4-fold increase of CRE-dependent transcription" SIGNOR-219602 CSNK2A1 protein P68400 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-250860 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CDC7 protein O00311 UNIPROT "up-regulates activity" phosphorylation Thr376 QVAPRAGtPGFRAPE 10846177 t llicata "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. In vitro, Cdk2-Cyclin E, Cdk2-Cyclin A, and Cdc2-Cyclin B, but not Cdk4-Cyclin D1, phosphorylates the Thr-376 residue of huCdc7, suggesting possible regulation of huCdc7 by Cdks." SIGNOR-250725 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR PRC1 protein O43663 UNIPROT unknown phosphorylation Thr470 LYGSAPRtPSKRRGL BTO:0000567 9885575 t llicata "We have shown that PRC1 is a good in vitro substrate for several CDKs, and that it is also phosphorylated in a cell cycle–dependent manner in vivo at Thr-481 (major mitosis. and Thr-470 (minor site), which are the in vitro phosphorylation sites." SIGNOR-250745 DDB1 protein Q16531 UNIPROT CRL4(CRBN) complex SIGNOR-C119 SIGNOR "form complex" binding 9606 22649780 t gcesareni "The CUL4 family employs the structurally distinct triple WD40 ²-propeller domain-containing DDB1 adaptor to recruit members of the DDB1€“CUL4 associated factors (DCAF) family of substrate receptors" SIGNOR-234802 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 FOXA1 protein P55317 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 19127412 f miannu "Overexpression of foxa1 promoted apoptosis" SIGNOR-256642 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 LRRK2 protein Q5S007 UNIPROT Autophagy phenotype SIGNOR-PH31 SIGNOR up-regulates 9606 BTO:0000007 22012985 f gcesareni "We report that LRRK2 activates a calcium-dependent protein kinase kinase-² (CaMKK-²)/adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway which is followed by a persistent increase in autophagosome formation." SIGNOR-237005 MAPK8 protein P45983 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser636 SGDYMPMsPKSVSAP 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-118869 MAPK8 protein P45983 UNIPROT JUNB protein P17275 UNIPROT "up-regulates activity" phosphorylation Thr102 SNGVITTtPTPPGQY 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-250120 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 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 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 NFE2L2 protein Q16236 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0000599 26194347 f irozzo "Nrf2 was up-regulated in HCC, and expression of Nrf2 was correlated with tumor differentiation, metastasis, and tumor size. Further studies demonstrated that inhibition of Nrf2 expression inhibited proliferation by inducing apoptosis and repressed invasion, and up-regulation of Nrf2 expression resulted in opposite phenotypes." SIGNOR-256263 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 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 CSNK2A1 protein P68400 UNIPROT EGR1 protein P18146 UNIPROT "down-regulates activity" phosphorylation Ser378 RICMRNFsRSDHLTT 10090 BTO:0000944 8662759 t llicata "Casein kinase II associates with Egr-1 and acts as a negative modulator of its DNA binding and transcription activities in NIH 3T3 cells. | There are three CKII recognition sites (S376XXD, T389XE, and T516XXXD) in fragment 10." SIGNOR-250856 CSNK2A1 protein P68400 UNIPROT GPI protein P06744 UNIPROT "down-regulates activity" phosphorylation Ser185 GPRVWYVsNIDGTHI 9606 BTO:0000459 15637053 t llicata "It is known that human PGI/AMF is phosphorylated at Ser(185) by protein kinase CK2 (CK2) | These results demonstrate that phosphorylation affects the allosteric kinetic properties of the enzyme, resulting in a less active form of PGI, whereas non-phosphorylated protein species retain cytokine activity. " SIGNOR-250869 CUL4A protein Q13619 UNIPROT CRL4(CRBN) complex SIGNOR-C119 SIGNOR "form complex" binding 9606 22649780 t gcesareni "The CUL4 family employs the structurally distinct triple WD40 ²-propeller domain-containing DDB1 adaptor to recruit members of the DDB1€“CUL4 associated factors (DCAF) family of substrate receptors" SIGNOR-234793 IL5RA protein Q01344 UNIPROT SOX4 protein Q06945 UNIPROT "up-regulates activity" binding 10090 BTO:0003104 11498591 t miannu "Sox4 activation by IL-5R_ appears to be direct, with syntenin functioning as an adaptor molecule. Syntenin mediates IL-5–induced Sox4 activation." SIGNOR-223010 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 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 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 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 NFE2L2 protein Q16236 UNIPROT CAT protein P04040 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000093 22493435 f miannu "BTG2 was found to up-regulate expression of antioxidant enzymes known to be regulated by NFE2L2, including catalase, SOD1, and SOD2" SIGNOR-254651 NMBR protein P28336 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 8026589 t fspada "G-proteins of the q family have been implicated as mediators of bombesin receptors action. This suggests that nmb-r couples to g?q, and that grp-r and nmb-r show distinct g-protein coupling preferences in the xenopus oocyte." SIGNOR-35864 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 PRKCA protein P17252 UNIPROT ARHGDIB protein P52566 UNIPROT down-regulates phosphorylation Ser31 YKPPPQKsLKELQEM 9606 22469974 t llicata "These results reveal a mechanism of downregulation of rhogdi2 activity through pkc-mediated phosphorylation of ser31." SIGNOR-196765 RBX1 protein P62877 UNIPROT CRL4(CRBN) complex SIGNOR-C119 SIGNOR "form complex" binding 9606 22649780 t gcesareni "The CUL4 family employs the structurally distinct triple WD40 ²-propeller domain-containing DDB1 adaptor to recruit members of the DDB1€“CUL4 associated factors (DCAF) family of substrate receptors" SIGNOR-234799 RLF protein Q13129 UNIPROT RIT1 protein Q92963 UNIPROT "up-regulates activity" binding 9606 10545207 t miannu "Rit and Rin were found to interact with the known Ras binding proteins RalGDS, Rlf, and AF-6/Canoe. These interactions were GTP and effector domain dependent and suggest that RalGDS, Rlf, and AF-6 are Rit and Rin effectors." SIGNOR-220799 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 GNA13 protein Q14344 UNIPROT ARHGEF11 protein O15085 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 11799111 t "This RGS-like (RGL) domain provides a structural motif by which heterotrimeric G protein alpha subunits of the Galpha(12) family can bind and regulate the activity of RhoGEFs. Hence, these newly discovered RGL domain-containing RhoGEFs provide a direct link from Galpha(12) and Galpha(13) to Rho" SIGNOR-256517 GNA13 protein Q14344 UNIPROT ARHGEF12 protein Q9NZN5 UNIPROT "up-regulates activity" binding 10090 BTO:0000944 12024019 t "P115 RhoGEF stimulates the intrinsic GTP hydrolysis activity of G alpha 12/13 subunits and acts as an effector for G13-coupled receptors by linking receptor activation to RhoA activation." SIGNOR-256519 JAG1 protein P78504 UNIPROT NOTCH3 protein Q9UM47 UNIPROT up-regulates binding 9606 18660822 t "Binding Calcium-dependent" gcesareni "Here we report the first x-ray structure of a functional fragment of a notch ligand, the dsl-egf3 domains of human jagged-1 (j-1dsl-egf3). The structure identifies a highly conserved face of the dsl domain and we show, by functional analysis of drosophila ligand mutants, that this surface is required for both cis- and trans-regulatory interactions with notch." SIGNOR-179625 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 "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 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 PIM1 protein P11309 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates phosphorylation Ser166 SSRRRAIsETEENSD 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-178615 PLK3 protein Q9H4B4 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 18650425 t gcesareni "Stress-induced c-jun activation mediated by polo-like kinase 3 in corneal epithelial cells. Hypoxia/reoxygenation activated plk3 in hce cells to directly phosphorylate c-jun proteins at phosphorylation sites ser-63 and ser-73, and to increase dna binding activity of c-jun." SIGNOR-179551 PLK3 protein Q9H4B4 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser73 VGLLKLAsPELERLI 9606 18650425 t gcesareni "Stress-induced c-jun activation mediated by polo-like kinase 3 in corneal epithelial cells. Hypoxia/reoxygenation activated plk3 in hce cells to directly phosphorylate c-jun proteins at phosphorylation sites ser-63 and ser-73, and to increase dna binding activity of c-jun." SIGNOR-179555 PRKAA1 protein Q13131 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser259 SQRQRSTsTPNVHMV 9606 SIGNOR-C15 11971957 t gcesareni "Mutation of serine 259 increased the basal raf-1 activity and rendered it largely resistant to inhibition by pka." SIGNOR-86133 SDCBP protein O00560 UNIPROT SOX4 protein Q06945 UNIPROT "up-regulates activity" binding 10090 BTO:0003104 11498591 t miannu "Sox4 activation by IL-5R_ appears to be direct, with syntenin functioning as an adaptor molecule. Syntenin mediates IL-5–induced Sox4 activation." SIGNOR-223089 SMARCB1 protein Q12824 UNIPROT CCNA1 protein P78396 UNIPROT down-regulates 9606 12226744 f miannu "We show that the ectopic expression of wild-type hsnf5/ini1, but not that of truncated versions, leads to a cell cycle arrest by inhibiting the entry into s phase of mrt cells. This g1 arrest is associated with down-regulation of a subset of e2f targets including cyclin a, e2f1 and cdc6." SIGNOR-92779 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 CSNK2A1 protein P68400 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-250921 CSNK2A1 protein P68400 UNIPROT PGR protein P06401 UNIPROT unknown phosphorylation Ser81 TQDQQSLsDVEGAYS -1 7983041 t llicata "Although human PR contains 11 potential CKII consensus sequences, CKII in vitro phosphorylated purified PR-B only at Ser81 suggesting that this may be an authentic site for CKII in vivo." SIGNOR-250926 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Ser251 MIQFAINsTERKRMT 9606 19737929 t lperfetto "A conserved phosphorylation site within the forkhead domain of foxm1b is required for its activation by cyclin-cdk1the phosphorylation at ser-251 is critical for the activation of foxm1." SIGNOR-216833 FKBP1A protein P62942 UNIPROT TGFBR1 protein P36897 UNIPROT "down-regulates activity" binding 9606 BTO:0005493 8756725 t lperfetto "Blocking fkbp12/type i receptor interaction with fk506 nonfunctional derivatives enhances the ligand activity, indicating that fkbp12 binding is inhibitory to the signaling pathways of the tgf beta family ligands" SIGNOR-236142 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 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 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 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 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 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 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 PRKACA protein P17612 UNIPROT LRP1 protein Q07954 UNIPROT "up-regulates activity" phosphorylation Ser4520 GGHGSRHsLASTDEK 10029 BTO:0000246 11158305 t miannu "LRP phosphorylation is mediated by PKA at residue serine 76 of its cytoplasmic tail and that this phosphorylation contributes to receptor-mediated endocytosis." SIGNOR-250000 PRKACA protein P17612 UNIPROT LRRK2 protein Q5S007 UNIPROT "down-regulates activity" phosphorylation Ser1444 NIKARASsSPVILVG -1 24351927 t gcesareni "Furthermore, our work establishes S1444 as a PKA-regulated 14-3-3 docking site€.Strikingly, 14-3-3 binding to phospho-S1444 decreased LRRK2 kinase activity in vitro." SIGNOR-237444 STK3 protein Q13188 UNIPROT MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation Thr35 LLKHAEAtLGSGNLR 9606 21808241 t "The regulation of MOB1 and LATS1/2 by MST1/2 may be organ and disease-specific." gcesareni "Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2 mob1 interaction." SIGNOR-175809 TBK1 protein Q9UHD2 UNIPROT IRF3 protein Q14653 UNIPROT "up-regulates activity" phosphorylation Ser398 VDLHISNsHPLSLTS -1 18440553 t lperfetto "Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404." SIGNOR-178403 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 TNFRSF10A protein O00220 UNIPROT FADD protein Q13158 UNIPROT up-regulates binding 9606 14585074 t amattioni "Fadd binds to ligated trailr1 or trail-r2" SIGNOR-97869 CSNK2A1 protein P68400 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-250937 CSNK2A1 protein P68400 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser299 KMAFRAKsKSCHDLS -1 9677319 t llicata "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." SIGNOR-250946 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 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 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 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 PPARG protein P37231 UNIPROT down-regulates 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 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 NFE2L2 protein Q16236 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 BTO:0000599 26194347 f irozzo "Nrf2 was up-regulated in HCC, and expression of Nrf2 was correlated with tumor differentiation, metastasis, and tumor size. Further studies demonstrated that inhibition of Nrf2 expression inhibited proliferation by inducing apoptosis and repressed invasion, and up-regulation of Nrf2 expression resulted in opposite phenotypes." SIGNOR-256652 PRKD1 protein Q15139 UNIPROT CDH1 protein P12830 UNIPROT up-regulates phosphorylation 9606 BTO:0001130 15695390 t gcesareni "Our study has identified e-cadherin as a novel substrate of pkd1, and phosphorylation of e-cadherin by pkd1 is associated with increased cellular aggregation and decreased cellular motility in prostate cancer." SIGNOR-133856 PRKD1 protein Q15139 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Thr120 QFDAAHPtNVQRLAE 9606 BTO:0001130 19141652 t lperfetto "This study provides evidence that pkd1 interacts with and phosphorylates beta-catenin at thr(112) and thr(120) we postulate that pkd1 phosphorylation is required to maintain _-catenin transcription activity." SIGNOR-183388 PRKD1 protein Q15139 UNIPROT PI4KB protein Q9UBF8 UNIPROT up-regulates phosphorylation Ser294 SNLKRTAsNPKVENE 9606 16912074 t "The effect has been demonstrated using Q9UBF8-2" gcesareni "Binding of 14-3-3 proteins to pi4kiiibeta involved the pkd phosphorylation site ser294, evident from reduced 14-3-3 binding to a s294a pi4kiiibeta mutant. Phospho-specific binding of 14-3-3 proteins to phosphatidylinositol 4-kinase iii beta protects from dephosphorylation and stabilizes lipid kinase activity." SIGNOR-148876 PRKD1 protein Q15139 UNIPROT SSH1 protein Q8WYL5 UNIPROT down-regulates phosphorylation Ser978 SPLKRSHsLAKLGSL 9606 BTO:0000150 19567672 t llicata "Pkd-mediated phosphorylation of serines 937 and 978 regulates ssh1l subcellular localization by binding of 14-3-3 proteins 14-3-3 proteins associate with ssh1l when phosphorylated at serines 937 and 978, thereby sequestering ssh1l in the cytoplasm and preventing translocation of the phosphatase to f-actin_rich membrane protrusions" SIGNOR-186471 RCOR1 protein Q9UKL0 UNIPROT REST-CoREST complex SIGNOR-C111 SIGNOR "form complex" binding 9606 20080105 t 1 miannu "Transcriptional repression of neural-specific genes in nonneuronal cells is dependent on the REST (RE1-silencing transcription factor)–CoREST complex." SIGNOR-239220 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 TAB1 protein Q15750 UNIPROT ROR2 protein Q01974 UNIPROT down-regulates phosphorylation 9606 18762249 t gcesareni "Tak1 (tgf-beta activated kinase 1), a map3k, interacts with ror2 and phosphorylates its intracellular carboxyterminal serine/thronine/proline-rich (stp) domain" SIGNOR-180566 CSNK2A1 protein P68400 UNIPROT HSP90AA1 protein P07900 UNIPROT unknown phosphorylation Ser231 KERDKEVsDDEAEEK 9606 BTO:0000567 2492519 t llicata "Both hsp 90 proteins are phosphorylated at two homologous sites. For the alpha protein, these sites correspond to serine 231 and serine 263. | Dephosphorylated hsp 90 is phosphorylated at both sites by casein kinase II from HeLa cells, calf thymus, or rabbit reticulocytes; no other hsp 90 residues were phosphorylated by casein kinase II in vitro." SIGNOR-250899 CSNK2A1 protein P68400 UNIPROT SP1 protein P08047 UNIPROT "down-regulates activity" phosphorylation Thr579 GDGIHDDtAGGEEGE 9606 BTO:0000664 9153193 t llicata "Casein kinase II-mediated phosphorylation of the C terminus of Sp1 decreases its DNA binding activity. | Mutation of a consensus CKII site at amino acid 579, within the second zinc finger, eliminates phosphorylation of this site and the CKII-mediated inhibition of Sp1 binding." SIGNOR-250954 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 EPHB2 protein P29323 UNIPROT SYNJ1 protein O43426 UNIPROT down-regulates phosphorylation 9606 BTO:0000938 15821731 t lperfetto "Ephb2 causes tyrosine phosphorylation in the proline-rich domain of synaptojanin 1, and inhibits both the interaction with endophilin and the 5'-phosphatase activity of synaptojanin 1" SIGNOR-135274 FOXL2 protein P58012 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 BTO:0000975 16153597 f miannu "We observed that foxl2 induces apoptosis in the ovarian cells unveiling a novel function of foxl2" SIGNOR-256643 g-secretase complex SIGNOR-C98 SIGNOR NOTCH1 protein P46531 UNIPROT "up-regulates activity" cleavage 9606 25610395 t lperfetto "The membrane-bound Notch segment that results from this cleavage, known as Notch Intracellular Truncation domain (NEXT), is a γ-secretase substrate. γ-Secretase performs the subsequent cleavage at S3, releasing Notch intracellular domain (NICD) from the membrane and allowing for signal transduction through binding with the CBL-1, Su(H), Lag-1 family of DNA binding proteins." SIGNOR-209717 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 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 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 RXRA protein P19793 UNIPROT down-regulates phosphorylation Ser260 NMGLNPSsPNDPVTN 9606 16551633 t gcesareni "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 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 RPS6KA1 protein Q15418 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates phosphorylation Ser719 PCTPRLRsVSSYGNI 9606 SIGNOR-C3 18722121 t llicata "Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity" SIGNOR-180458 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 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 STK38 protein Q15208 UNIPROT STK38 protein Q15208 UNIPROT up-regulates phosphorylation Thr444 DWVFINYtYKRFEGL 9606 12493777 t lperfetto "We found that ndr1 autophosphorylates in vitro predominantly on ser-281 and to a lesser extent on thr-74 and thr-444. All of these residues proved to be crucial also for ndr1 activity in vivo" SIGNOR-96683 WNK1 protein Q9H4A3 UNIPROT WNK1 protein Q9H4A3 UNIPROT up-regulates phosphorylation Ser382 KRASFAKsVIGTPEF 9606 17190791 t gcesareni "We finally establish that full-length wnk1, wnk2 and wnk3, but not wnk4, are capable of directly phosphorylating ser382 of wnk1 in vitro. This supports the notion that t-loop phosphorylation of wnk isoforms is controlled by trans-autophosphorylation." SIGNOR-151675 DLX5 protein P56178 UNIPROT MSX2 protein P35548 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-240925 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 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 MAPK8IP1 protein Q9UQF2 UNIPROT RBPJ protein Q06330 UNIPROT down-regulates binding 9606 20508646 t "Interferes with binding to Noth1-ICD." gcesareni "Here, we show that jip1 suppresses notch1 activity. Jip1 was found to physically associate with either intracellular domain of notch1 or rbp-jk and interfere with the interaction between them." SIGNOR-165713 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 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 PDPK1 protein O15530 UNIPROT ITGB3 protein P05106 UNIPROT "down-regulates activity" phosphorylation Thr779 LYKEATStFTNITYR -1 10896934 t miannu "PDK1 specifically phosphorylates Thr-753 in 3. Our data argue that phosphorylation of Thr-753, which is conserved in many subunits, reduces the ability of PTB-containing proteins to bind the NXX(pY) motif in 3." SIGNOR-250266 PDPK1 protein O15530 UNIPROT SGK1 protein O00141 UNIPROT "up-regulates activity" phosphorylation Ser422 AEAFLGFsYAPPTDS -1 10191262 t miannu "The activation of SGK by PDK1 in vitro is unaffected by PtdIns(3,4,5)P3, abolished by the mutation of Ser422 to Ala, and greatly potentiated by mutation of Ser422 to Asp" SIGNOR-250274 PDPK1 protein O15530 UNIPROT SGK2 protein Q9HBY8 UNIPROT "up-regulates activity" phosphorylation Thr253 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 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 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 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 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 RPS6KA1 protein Q15418 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates phosphorylation Ser722 PRLRSVSsYGNIRAV 9606 SIGNOR-C3 18722121 t llicata "Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity" SIGNOR-180466 WNT3A protein P56704 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.All the frizzled genes studied have" SIGNOR-169660 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT "up-regulates activity" phosphorylation Tyr763 DMKGDVKyADIESSN 9823 BTO:0004007 10391677 t miannu "Activation of the beta-receptor for platelet-derived growth factor (PDGF) by its ligand leads to autophosphorylation on a number of tyrosine residues. Here we show that Tyr763 in the kinase insert region is a novel autophosphorylation site, which after phosphorylation binds the protein tyrosine phosphatase SHP-2." SIGNOR-250258 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 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 PIM1 protein P11309 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000007 16403219 t lperfetto "All three Pim kinase family members predominantly phosphorylate Bad on Ser112 and in addition are capable of phosphorylating Bad on multiple sites associated with the inhibition of the pro-apoptotic function of Bad in HEK-293 cells. This would be consistent with the proposed function of Pim kinases in promoting cell proliferation and preventing cell death." SIGNOR-249607 PIP5K1A protein Q99755 UNIPROT 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-180800 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 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 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 PLN protein P26678 UNIPROT "up-regulates activity" phosphorylation Ser16 RSAIRRAsTIEMPQQ 10090 10988285 t miannu "Phospholamban (PLB) can be phosphorylated at Ser(16) by cyclic AMP-dependent protein kinase. phosphorylation of Ser(16) is sufficient for mediating the maximal cardiac responses to beta-adrenergic stimulation." SIGNOR-250030 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 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 SMC3 protein Q9UQE7 UNIPROT MXI1 protein P50539 UNIPROT "down-regulates activity" binding 9534 BTO:0000318 9528857 t 2 miannu "We identified a novel ZIP-containing protein, Mmip1 (Mad member interacting protein 1) that strongly dimerizes with all four Mad members, but not with c-myc. Mmip1 can inhibit DNA binding by Max-Mad heterodimers and, in vivo, can reverse the suppressive e€ects of Mad proteins on c-myc functions." SIGNOR-241223 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 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 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 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 "lysophosphatidic acids" smallmolecule CHEBI:32957 ChEBI GNB3 protein P16520 UNIPROT up-regulates binding 9606 17251915 t gcesareni "Lpa through galfai and gbetagamma subunits also activates phosphatidylinositol 3-kinase (pi3k), which results in the stimulation of the akt survival pathway and increased protein translation by the activation of the mammalian target of rapamycin (mtor) pathway." SIGNOR-152759 CTF1 protein Q16619 UNIPROT LIFR protein P42702 UNIPROT up-regulates binding 9606 11834704 t gcesareni "We conclude that gp130/lif receptor and et(a) receptor activation are essential for cardiac fibroblast growth by ct-1" SIGNOR-114758 FOXA1 protein P55317 UNIPROT SFTPB protein P07988 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12161428 f miannu "A homeodomain and a forkhead transcription factor, NKX2.1 and HNF-3, respectively, are known activators of Sp-B transcription" SIGNOR-254181 N-[(2S)-2,3-dihydroxypropyl]-3-(2-fluoro-4-iodoanilino)-4-pyridinecarboxamide chemical CHEBI:94793 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck lperfetto SIGNOR-244820 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 ITCH protein Q96J02 UNIPROT GLI1 protein P08151 UNIPROT down-regulates ubiquitination 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. we demonstrate that the hedgehog transcription factor gli1 is targeted by numb for itch-dependent ubiquitination, which suppresses hedgehog signals, thus arresting growth and promoting cell differentiation" SIGNOR-167838 MAP3K1 protein Q13233 UNIPROT FADD protein Q13158 UNIPROT down-regulates phosphorylation Ser194 QNRSGAMsPMSWNSD 9606 BTO:0001130 15001534 t gcesareni "The results clearly show that fadd phosphorylation at ser194 affects functions both upstream and downstream of the mekk1/mkk7/jnk1 pathway and is closely associated with chemosensitivity in prostate cancer cells" SIGNOR-123168 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 MAPK8IP3 protein Q9UPT6 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates binding 9606 15767678 t gcesareni "The c-jun nh2-terminal kinase (jnk)-interacting protein (jip) group of scaffold proteins (jip1, jip2, and jip3) can interact with components of the jnk signaling pathway and potently activate jnk." SIGNOR-134555 MAPK8IP3 protein Q9UPT6 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates binding 9606 15767678 t gcesareni "The c-jun nh2-terminal kinase (jnk)-interacting protein (jip) group of scaffold proteins (jip1, jip2, and jip3) can interact with components of the jnk signaling pathway and potently activate jnk." SIGNOR-134558 MAPK8IP3 protein Q9UPT6 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates binding 9606 15767678 t gcesareni "The c-jun nh2-terminal kinase (jnk)-interacting protein (jip) group of scaffold proteins (jip1, jip2, and jip3) can interact with components of the jnk signaling pathway and potently activate jnk." SIGNOR-134561 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 CACNG2 protein Q9Y698 UNIPROT "down-regulates activity" phosphorylation Thr321 NTANRRTtPV 9534 BTO:0000298 11805122 t miannu "phosphorylation of stargazin at T321 by PKA inhibits its interaction with PSD-95." SIGNOR-250342 PRKACA protein P17612 UNIPROT PPP1R8 protein Q12972 UNIPROT "down-regulates activity" phosphorylation Ser199 PKRKRKNsRVTFSED -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-250033 PRKACA protein P17612 UNIPROT RAP1A protein P62834 UNIPROT "down-regulates activity" phosphorylation Ser180 KKKPKKKsCLLL 9534 BTO:0000298 9867809 t miannu "Phosphorylation of Rap1A by PKA abolished its binding activity to CRR. a mutant Rap1A(S180E), whose sole PKA phosphorylation residue, Ser-180, was substituted by an acidic residue, Glu, to mimic its phosphorylated form, failed to suppress Ras-dependent Raf-1 activation in COS-7 cells." SIGNOR-250042 PRKACA protein P17612 UNIPROT RYR2 protein Q92736 UNIPROT "up-regulates activity" phosphorylation Ser2808 YNRTRRIsQTSQVSV -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-250079 PRKACA protein P17612 UNIPROT SPTBN1 protein Q01082 UNIPROT "down-regulates activity" phosphorylation Thr2159 NGATEQRtSSKESSP -1 17088250 t miannu "Short C-terminal splice variant of betaII-spectrin (betaIISigma2) is a substrate for phosphorylation. protein kinase A phosphorylates Thr-2159. Mammalian alphaII- and betaII-spectrin subunits form dimers that associate head to head with high affinity to form tetramers In vitro, protein kinase A phosphorylation of an active fragment of betaIISigma2 greatly reduced its interaction with alphaII-spectrin at the tetramerization site." SIGNOR-250054 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 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 TBL1XR1 protein Q9BZK7 UNIPROT AR protein P10275 UNIPROT up-regulates binding 9606 BTO:0001130 24243687 t miannu "We showed that tblr1 physically interacts with ar and directly occupies the androgen-response elements of the affected ar target genes in an androgen-dependent manner. / we characterized tblr1 as a coactivator of ar" SIGNOR-203235 GNAI1 protein P63096 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR "down-regulates activity" binding -1 10224115 f "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-256523 GNAI1 protein P63096 UNIPROT PLD2 protein O14939 UNIPROT down-regulates binding 9606 BTO:0000938 9148895 t gcesareni "The results of this study suggest that membrane phospholipase d activity can be negatively regulated via gi" SIGNOR-48256 GNAI1 protein P63096 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" binding 10090 BTO:0000944 11099498 t "These findings indicate that both G alpha(i) and G beta gamma stimulate Rac and Cdc42 pathways with lysophosphatidic acid-induced cell spreading on fibronectin" SIGNOR-256530 GNAI1 protein P63096 UNIPROT SRC protein P12931 UNIPROT "up-regulates activity" binding -1 11007482 t "Here we demonstrate that Galphas and Galphai, but neither Galphaq, Galpha12 nor Gbetay, directly stimulate the kinase activity of downregulated c-Src" SIGNOR-256526 GNAI2 protein P04899 UNIPROT ADCY1 protein Q08828 UNIPROT down-regulates binding 9606 8327893 t gcesareni "Evidence suggests that both alpha and beta gamma subunits of heterotrimeric guanine nucleotide-binding regulatory proteins (g proteins) inhibit adenylyl cyclase." SIGNOR-37973 GNAI3 protein P08754 UNIPROT ADCY1 protein Q08828 UNIPROT down-regulates binding 9606 8327893 t gcesareni "Members of the gi family are linked with reductions in camp through adenylyl cyclase, but have many other actions as well." SIGNOR-38029 GNAO1 protein P09471 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR "down-regulates activity" binding -1 10224115 f "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-256525 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 GNAS protein P63092 UNIPROT HCK protein P08631 UNIPROT "up-regulates activity" binding -1 11007482 t "Galphas and Galphai similarly modulate Hck, another member of Src-family tyrosine kinases." SIGNOR-256529 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 MAPK11 protein Q15759 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates phosphorylation 9606 20820849 t gcesareni "Smads can also be phosphorylated in the linker region most prominently by the action of mitogen-activated protein (map) kinaseslinker region phosphorylation can prevent nuclear translocation of smads and inhibit tgf-_ signalling, potentially leading to oncogenesis." SIGNOR-167848 MAPK14 protein Q16539 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates phosphorylation Ser7 sPAPLSPL 9606 BTO:0000150 22128155 t gcesareni "Ogether, our results suggest that p38 phosphorylation of foxo3a on ser-7 is essential for its nuclear relocalization in response to doxorubicin" SIGNOR-177927 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 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 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 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 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 NSD1 protein Q96L73 UNIPROT RELA protein Q04206 UNIPROT up-regulates methylation Lys221 LLCDKVQkEDIEVYF 9606 SIGNOR-C13 20080798 t miannu "Fbxl11 and nsd1 have opposite effects on nf-kb; both bind to p65 subunit after activation of nf-kb. / nsd1 activates nf-kb and reverses the inhibitory effect of fbxl11 / these data confirm that fbxl11 and nsd1 constitute an enzyme pair that methylates and demethylates p65 on k218 and 221 in response to cytokine stimulation." SIGNOR-163458 PRKAA2 protein P54646 UNIPROT RPTOR protein Q8N122 UNIPROT down-regulates phosphorylation Ser863 LTQSAPAsPTNKGVH 9606 SIGNOR-C15 SIGNOR-C3 20083114 t lperfetto "A recent study revealed that ampk can inhibit mtorc1 independently of tsc2 by phosphorylating raptor at ser863." SIGNOR-163463 MAPK9 protein P45984 UNIPROT BCL2L11 protein O43521 UNIPROT "up-regulates activity" phosphorylation Ser59 GDSCPHGsPQGPLAP 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-250134 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 NTRK2 protein Q16620 UNIPROT FRS3 protein O43559 UNIPROT "up-regulates activity" phosphorylation Tyr455 PARSSDSyAVIDLKK 9606 BTO:0000007 11432792 t miannu "The tyrosine phosphoryla tion of FRS2/SNT2 was stimulated dependently on the TrkB activation. to explore the possibility that tyrosine residues 417 and 455 on FRS2/SNT2 function as the binding sites for Shp2, we coexpressed Y417F or Y455F phenylalanine mutants and the Y417/455F double phenylalanine mutant of Myc/Histagged FRS2/SNT2 with TrkB. The active TrkB induced somewhat reduced tyrosine phosphorylation of all of the phenylalanine mutants of FRS2/SNT2 in comparison with tyrosine phosphorylation of the wild type" SIGNOR-250203 NTRK2 protein Q16620 UNIPROT NTRK2 protein Q16620 UNIPROT "up-regulates activity" phosphorylation Tyr516 PVIENPQyFGITNSQ 10090 BTO:0000944 10533983 t miannu "TrkB autophosphorylation occurs on five cytoplasmic tyrosines: Y484, Y670, Y674, Y675, and Y785. Mutagenesis of Y484 inhibits the interaction between Shc and TrkB, and also block the E3DNF-inducible tyrosine phoslphorylation of Shc" SIGNOR-250204 PDK1 protein Q15118 UNIPROT ITGB3 protein P05106 UNIPROT "down-regulates activity" phosphorylation Thr779 LYKEATStFTNITYR -1 10896934 t miannu "PDK1 specifically phosphorylates Thr-753 in 3. Our data argue that phosphorylation of Thr-753, which is conserved in many subunits, reduces the ability of PTB-containing proteins to bind the NXX(pY) motif in 3." SIGNOR-250264 PRKAA1 protein Q13131 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-250157 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 PRKCB protein P05771 UNIPROT CD5 protein P06127 UNIPROT unknown phosphorylation Thr434 MSFHRNHtATVRSHA 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-249073 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 PTPN11 protein Q06124 UNIPROT unknown phosphorylation Ser595 GLMQQQKsFR 9606 BTO:0000007 11781100 t lperfetto " In summary, SHP2 is phosphorylated on serine residues 576 and 591 by PKC isoforms alpha, beta 1, beta 2, and eta." SIGNOR-249139 PRKCG protein P05129 UNIPROT CD5 protein P06127 UNIPROT unknown phosphorylation Thr434 MSFHRNHtATVRSHA 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-249072 PRKCG protein P05129 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-249074 ROCK1 protein Q13464 UNIPROT PPP1R12B protein O60237 UNIPROT down-regulates phosphorylation Thr646 ARQTRRStQGVTLTD 9606 22937917 t lperfetto "Phosphorylation of ppp1r12b on threonine 646 by rho kinase inhibits the activity of the pp1c-ppp1r12b complex." SIGNOR-198812 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 WNT16 protein Q9UBV4 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-131677 WNT2B protein Q93097 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15578921 t gcesareni "Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors andinitiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation." SIGNOR-131780 WNT2 protein P09544 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-131727 MAPK9 protein P45984 UNIPROT H3F3A 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-138463 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 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 PHKG1 protein Q16816 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser554 RTPPKSPsSAKSRLQ -1 8999860 t miannu "Muscle phosphorylase kinase phosphorylates Ser237, Ser262, Ser285, Ser305, and Ser352 of human tau. in vitro phosphorylation of tau on Ser262 alone strongly reduced the ability of tau to bind microtubules whereas the phosphorylation of many Ser/Thr-Pro motif sites of tau showed moderate effects on the binding of tau to microtubules" SIGNOR-250283 PHKG1 protein Q16816 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser622 KHVPGGGsVQIVYKP -1 8999860 t miannu "Muscle phosphorylase kinase phosphorylates Ser237, Ser262, Ser285, Ser305, and Ser352 of human tau. in vitro phosphorylation of tau on Ser262 alone strongly reduced the ability of tau to bind microtubules whereas the phosphorylation of many Ser/Thr-Pro motif sites of tau showed moderate effects on the binding of tau to microtubules" SIGNOR-250286 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 TOP2A protein P11388 UNIPROT up-regulates phosphorylation Ser1525 PIKYLEEsDEDDLF 9606 19098900 t gcesareni "Here we report that when phosphorylated, ser 1524 of topo iialpha acts as a binding site for the brct domain of mdc1 (mediator of dna damage checkpoint protein-1), thereby recruiting mdc1 to chromatin" SIGNOR-182844 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 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 HAND1 protein O96004 UNIPROT unknown phosphorylation Ser109 KERRRTEsINSAFAE 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-249242 PRKCH protein P24723 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation Ser21 SGRARTSsFAEPGGG 9606 BTO:0000007 11884598 t gcesareni "Furthermore, several pkc isotypes phosphorylate gsk-3 in vitro and in vivo. in the presence of atp, several isoforms (?, ___, _, ?, And of pkc phosphorylated both gsk-3? At ser 21 and gsk-3_ at ser 9" SIGNOR-115730 RPS6KA1 protein Q15418 UNIPROT EEF2K protein O00418 UNIPROT "down-regulates activity" phosphorylation Ser366 SPQVRTLsGSRPPLL 9606 BTO:0000669 11500364 t lperfetto "We show that two such kinases, p70 s6 kinase (regulated via mtor) and p90(rsk1) (activated by erk), phosphorylate eef2k at a conserved serine and inhibit its activity" SIGNOR-109708 RSPO2 protein Q6UXX9 UNIPROT LGR4 protein Q9BXB1 UNIPROT up-regulates binding 9606 21693646 t gcesareni "Here we demonstrate that lgr4 and lgr5 bind the r-spondins with high affinity and mediate the potentiation of wnt/betBeta-catenin signaling by enhancing wnt-induced lrp6 phosphorylation." SIGNOR-174486 WNT3 protein P56703 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-131820 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 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 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 MAPK14 protein Q16539 UNIPROT F3 protein P13726 UNIPROT down-regulates phosphorylation Ser290 GQSWKENsPLNVS 9606 23195225 t lperfetto "We previously showed that the phosphorylation of ser253 within the cytoplasmic domain of human tissue factor (tf) initiates the incorporation and release of this protein into cell-derived microparticles. Furthermore, subsequent phosphorylation of ser258 terminates this process. Our current study has identified p38_ as a major kinase, responsible for the phosphorylation of ser258 within the cytoplasmic domain of tf" SIGNOR-199868 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 JUNB protein P17275 UNIPROT down-regulates binding 9606 9405416 t gcesareni "Jnk targets junb ubiquitination" SIGNOR-53827 MAPK9 protein P45984 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-134568 MAPK9 protein P45984 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-134572 MIF protein P14174 UNIPROT CD74 protein P04233 UNIPROT up-regulates binding 9606 BTO:0000801;BTO:0000876 12782713 t miannu "Mif binds to the extracellular domain of cd74, and cd74 is required for mif-induced activation of the extracellular signal-regulated kinase-1/2 map kinase cascade, cell proliferation, and pge2 production." SIGNOR-101526 PLK3 protein Q9H4B4 UNIPROT VRK1 protein Q99986 UNIPROT up-regulates phosphorylation Ser342 DDGKLDLsVVENGGL 9606 19103756 t llicata "Vrk1 does not phosphorylate plk3, but plk3 phosphorylates the c-terminal region of vrk1 in ser342. Vrk1 with substitutions in s342 is catalytically active but blocks golgi fragmentation, indicating that its specific phosphorylation is necessary for this process." SIGNOR-182858 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 RPL10 protein P27635 UNIPROT unknown phosphorylation Ser168 GRQKIHIsKKWGFTK -1 9016777 t lperfetto "Moreover, 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-248958 PRKCD protein Q05655 UNIPROT CREBBP protein Q92793 UNIPROT unknown phosphorylation Ser437 CLPLKNAsDKRNQQT 11463380 t lperfetto "This study demonstrates that transcriptional control of mitogen-responsive genes by AP-1 and Pit-1 response elements involves direct phosphorylation of CBP and that growth factor€“dependent phosphorylation of CBP within the GF box is indispensable for signaling via these sites. " SIGNOR-249104 PRKCD protein Q05655 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-249205 PRKD1 protein Q15139 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Ser910 KALGERVsIL 9606 19029298 t llicata "We show that pkd1-ser916 autophosphorylation does not necessarily correlate with pkd1 activity. Rather, autophosphorylation at ser916 is required for subsequent autophosphorylation at ser748." SIGNOR-182480 PRKDC protein P78527 UNIPROT SRF protein P11831 UNIPROT "up-regulates activity" phosphorylation Ser435 LTVLNAFsQAPSTMQ -1 8407951 t lperfetto " The carboxyl-terminal transcription activation domain was mapped within a 71-amino acid region that contains both DNA-PK phosphorylation sites. Amino acid substitutions that interfered with phosphorylation by DNA-PK at Ser-435/446 in GAL4-SRF fusion proteins were reduced in transactivation potency. From these data we suggest that DNA-PK phosphorylation may modulate SRF activity in vivo." SIGNOR-248921 PTK6 protein Q13882 UNIPROT KHDRBS1 protein Q07666 UNIPROT unknown phosphorylation Tyr443 REHPYGRy 9606 BTO:0000567 16179349 t lperfetto "We show that BRK phosphorylates Sam68 on all three tyrosines in the nuclear localization signal." SIGNOR-249292 ROBO proteinfamily SIGNOR-PF14 SIGNOR 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-150285 RSPO1 protein Q2MKA7 UNIPROT ZNRF3 protein Q9ULT6 UNIPROT down-regulates relocalization 9606 23151663 t gcesareni "This is counteracted by respondin 1, which induces znrf3 internalization" SIGNOR-199629 RSPO3 protein Q9BXY4 UNIPROT LGR5 protein O75473 UNIPROT up-regulates binding 9606 21693646 t gcesareni "Here we demonstrate that lgr4 and lgr5 bind the r-spondins with high affinity and mediate the potentiation of wnt/betBeta-catenin signaling by enhancing wnt-induced lrp6 phosphorylation" SIGNOR-174535 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 WWTR1 protein Q9GZV5 UNIPROT Apoptosis phenotype SIGNOR-PH2 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-199208 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 CDK1 protein P06493 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser315 LPNNTSSsPQPKKKP 9606 BTO:0000093 11078726 t gcesareni "Stoichiometric phosphorylation of human p53 at ser315 stimulates p53-dependent transcription." SIGNOR-84256 CDK3 protein Q00526 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser73 VGLLKLAsPELERLI 9606 19118012 t gcesareni "Egf-induced cdk3 activation caused c-jun phosphorylation at ser63 and ser73, resulting in increased ap-1 transactivation." SIGNOR-183013 CHUK protein O15111 UNIPROT TSC2 protein P49815 UNIPROT down-regulates phosphorylation 9606 BTO:0000093 18490760 t gcesareni "Insulin activation of mtor requires akt in a manner that involves ikkalpha, preferentially to ikkbeta, and tsc2 phosphorylation" SIGNOR-178664 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 LCK protein P06239 UNIPROT FOXP3 protein Q9BZS1 UNIPROT down-regulates phosphorylation Tyr342 NMRPPFTyATLIRWA 9606 24155921 t llicata "Lck phosphorylated tyr-342 of foxp3 by immunoprecipitation and in vitro kinase assay, and the replacement of tyr-342 with phenylalanine (y342f) abolished the ability to suppress mmp9 expression." SIGNOR-203089 MAPK13 protein O15264 UNIPROT EEF2K protein O00418 UNIPROT "down-regulates activity" phosphorylation Ser396 TFDSLPSsPSSATPH -1 11500363 t miannu "eEF2 kinase is phosphorylated and inhibited by SAPK4/p38delta. eEF2K[S359A] was phosphorylated (presumably at Ser396) by the high concentrations of SAPK4/p38 used in this experiment. However, the inhibition of eEF2K under these conditions was reduced from 82% in the wild-type enzyme to 19% in eEF2K[S359A]" SIGNOR-250089 MAPK13 protein O15264 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser33 LPENNVLsPLPSQAM 9606 BTO:0000093 10581258 t gcesareni "In mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site." SIGNOR-72687 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 NFATC3 protein Q12968 UNIPROT down-regulates phosphorylation Ser163 SYRESSLsPSPASSI 9606 BTO:0000782 9374467 t lperfetto "Ser163 and ser165 represent the major sites of in vitro phosphorylation of nfat4 by jnk. / the negative regulation of nfat4 nuclear accumulation caused by jnk provides a mechanism for cell type?specific Responses to extracellular stimulation" SIGNOR-53364 MAPK9 protein P45984 UNIPROT NFATC3 protein Q12968 UNIPROT down-regulates phosphorylation Ser165 RESSLSPsPASSISS 9606 BTO:0000782 9374467 t lperfetto "Ser163 and ser165 represent the major sites of in vitro phosphorylation of nfat4 by jnk. / the negative regulation of nfat4 nuclear accumulation caused by jnk provides a mechanism for cell type?specific Responses to extracellular stimulation" SIGNOR-53368 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 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 NODAL protein Q96S42 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 BTO:0004094 15531507 f Regulation miannu "Nodal induces apoptosis and inhibits proliferation in human epithelial ovarian cancer cells via activin receptor-like kinase 7." SIGNOR-256656 Obatoclax chemical CID:16681698 PUBCHEM BCL2 protein P10415 UNIPROT down-regulates "chemical inhibition" 9606 23336025 t gcesareni "Bcl-2 inhibitors physically antagonize their anti-apoptotic actions to create a synergistic effect. Numerous compounds have been specifically developed or identified as bcl-2 inhibitors. These compounds include abt-737 and abt-263, obatoclax, gossypol." SIGNOR-200478 PAK1 protein Q13153 UNIPROT KIF2C protein Q99661 UNIPROT down-regulates phosphorylation Ser111 KESLRSRsTRMSTVS 9606 23055517 t lperfetto "Here we found that mcak is a cognate substrate of pak1 wherein pak1 phosphorylates mcak on serines 192 and 111 both in vivo and in vitro. Furthermore, we found that pak1 phosphorylation of mcak on serines 192 and 111 preferentially regulates its microtubule depolymerization activity and localization to centrosomes" SIGNOR-199080 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 SRC protein P12931 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates phosphorylation Tyr284 KIFPYEEyASWKTEK 9606 19114990 t gcesareni "Tbetarii can also be phosphorylated by src, a non-rtk, on y284, which can serve as a docking site for the recruitment of grb2 and shc, thereby bridging tbetarii to mapk activation." SIGNOR-182963 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 KEAP1 protein Q14145 UNIPROT NFE2L2 protein Q16236 UNIPROT down-regulates binding 9606 24997453 t miannu "Keap1 is an oxidative stress-sensing protein and is a negative regulator of nuclear factor-erythroid-2-related factor 2 (nrf2)." SIGNOR-205229 CSNK2A1 protein P68400 UNIPROT PIAS1 protein O75925 UNIPROT up-regulates phosphorylation Ser467 IDLTIDSsSDEEEEE 9606 19217413 t llicata "Ck2 phosphorylates serine residues adjacent to the sim of pias1 these findings show that the phosphosim module mediates binding to free sumo and sumo conjugates in a phosphorylation-dependent mode, with ck2 being the critical kinase involvedin this process." SIGNOR-184043 DUSP26 protein Q9BV47 UNIPROT FADD protein Q13158 UNIPROT down-regulates phosphorylation Ser194 QNRSGAMsPMSWNSD 9606 24548998 t lperfetto "This multi-functionality of fadd may depend primarily on its subcellular location. Fadd shuttles between the cytosol and the nucleus and this signal is unclear;however, fadd trafficking requires phosphorylation of the protein on ser194dusp26 suppresses cell proliferation by fadd dephosphorylation" SIGNOR-204559 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 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 IRAK3 protein Q9Y616 UNIPROT IRAK4 protein Q9NWZ3 UNIPROT down-regulates binding 9606 25290089 t flangone "Irak3 exerts negative regulatory effects through preventing (i) the dissociation of irak1 and irak4 from myd88 irak3 negatively regulates irak signalling through suppression of irak4 and irak1 activation" SIGNOR-205434 IRF5 protein Q13568 UNIPROT IL1B protein P01584 UNIPROT up-regulates "transcriptional regulation" 10090 26315890 f svumbaca "IL-1b was present in the sera of wild-type mice but was not detected in the sera of IRF5-/- mice" SIGNOR-255340 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 PIM3 protein Q86V86 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000007 16403219 t lperfetto "All three Pim kinase family members predominantly phosphorylate Bad on Ser112 and in addition are capable of phosphorylating Bad on multiple sites associated with the inhibition of the pro-apoptotic function of Bad in HEK-293 cells. This would be consistent with the proposed function of Pim kinases in promoting cell proliferation and preventing cell death." SIGNOR-249605 PPP2CA protein P67775 UNIPROT STK3 protein Q13188 UNIPROT down-regulates dephosphorylation Thr180 DTMAKRNtVIGTPFW 9606 23431053 t gcesareni "Rassf1a apparently protects mst1/2 against inactivation by pp2a, the phosphatases that dephosphorylate the stimulatory thr-183 and thr-180 of mst1 andmst2, respectively." SIGNOR-201266 PPP2CA protein P67775 UNIPROT STK4 protein Q13043 UNIPROT down-regulates dephosphorylation Thr183 DTMAKRNtVIGTPFW 9606 23431053 t gcesareni "Rassf1a apparently protects mst1/2 against inactivation by pp2a , the phosphatases that dephosphorylate the stimulatory thr-183 and thr-180 of mst1 andmst2, respectively." SIGNOR-201270 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 PRKCD protein Q05655 UNIPROT FLI1 protein Q01543 UNIPROT down-regulates phosphorylation Thr312 TNGEFKMtDPDEVAR 9606 24058639 t miannu "After tgf-_ stimulation, fli1 phosphorylation by protein kinase c-_ induces disassembly of this transcription repressor complex and the acetylation of fli1 by pcaf, leading to the loss of fli1 dna binding. / phosphorylation of fli1 at threonine 312 decreases its interactions with p300 and hdac1" SIGNOR-202693 PRKDC protein P78527 UNIPROT CASP2 protein P42575 UNIPROT up-regulates phosphorylation Ser139 LSCDYDLsLPFPVCE 9606 19203584 t lperfetto "Here we show that dna damage induced by gamma-radiation triggers the phosphorylation of nuclear caspase-2 at the s122 site within its prodomain, leading to its cleavage and activation. This phosphorylation is carried out by the nuclear serine/threonine protein kinase dna-pkcs" SIGNOR-183895 RAPGEF5 protein Q92565 UNIPROT HRAS protein P01112 UNIPROT up-regulates "guanine nucleotide exchange factor" 9606 19201597 t gcesareni "Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras." SIGNOR-183732 RPS6KA1 protein Q15418 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser295 TKRRKSMsGASPKES 9606 23708659 t lperfetto "Rsk promotes g2/m transition through activating phosphorylation of cdc25a and cdc25b rsk is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of t359/s363 in rsk. Together, these findings indicate that rsk promotes g2/m transition in mammalian cells through activating phosphorylation of cdc25a and cdc25b." SIGNOR-202117 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 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 VRK2 protein Q86Y07 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates phosphorylation Ser31 PQDELDFsILFDYEY 9606 23105117 t gcesareni "We demonstrate that vrk2 directly interacts and phosphorylates nfat1 in ser-32 within its n-terminal transactivation domain." SIGNOR-199263 MAML1 protein Q92585 UNIPROT EP300 protein Q09472 UNIPROT up-regulates relocalization 9606 19304754 t gcesareni "We show that maml1 potentiates p300 autoacetylation and p300 transcriptional activation. Maml1 directly enhances p300 hat activity, and this coincides with the translocation of maml1, p300 and acetylated histones to nuclear bodies." SIGNOR-184853 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 MAPK9 protein P45984 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." SIGNOR-91071 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 MAPK9 protein P45984 UNIPROT YWHAZ protein P63104 UNIPROT down-regulates phosphorylation Ser184 FYYEILNsPEKACSL 9606 15071501 t gcesareni "Jnk phosphorylates 14-3-3zetaat ser-184 and 14-3-3sigmaat ser-188" SIGNOR-124031 NIN protein Q8N4C6 UNIPROT JAK2 protein O60674 UNIPROT down-regulates binding 9606 25332239 t miannu "We showed that jak2 directly phosphorylates the n-terminus ofnineinwhile the c-terminus ofnineininhibits jak2 kinase activity in vitro." SIGNOR-205581 PALB2 protein Q86YC2 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates binding 9606 19423707 t miannu "We propose that both palb2 chromatin association and its oligomerization serve to secure the brca2 x rad51 repair machinery at the sites of dna damage." SIGNOR-185656 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 PIM2 protein Q9P1W9 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000007 16403219 t lperfetto "All three Pim kinase family members predominantly phosphorylate Bad on Ser112 and in addition are capable of phosphorylating Bad on multiple sites associated with the inhibition of the pro-apoptotic function of Bad in HEK-293 cells. This would be consistent with the proposed function of Pim kinases in promoting cell proliferation and preventing cell death." SIGNOR-249604 PRKACA protein P17612 UNIPROT PPP1R1B protein Q9UD71 UNIPROT "up-regulates activity" phosphorylation Thr34 MIRRRRPtPAMLFRL 10604473 t miannu "DARPP-32 (dopamine and cyclic AMP-regulated phospho-protein, relative molecular mass 32,000) is converted into an inhibitor of protein phosphatase 1 when it is phosphorylated by protein kinase A (PKA) at threonine 34.‚ " SIGNOR-250031 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 MYL9 protein P24844 UNIPROT down-regulates phosphorylation Thr10 SKRAKAKtTKKRPQR 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-191536 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 PRKCD protein Q05655 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates phosphorylation Thr143 RGKFKRPtLRRVRIS 9606 24585778 t miannu "Length-dependent activation is modulated by cardiac troponin i bisphosphorylation at ser23 and ser24 but not by thr143 phosphorylation. Thr143 is a known target of protein kinase c (pkc) whose activity is increased in cardiac disease" SIGNOR-204666 PRKDC protein P78527 UNIPROT USF1 protein P22415 UNIPROT up-regulates phosphorylation 9606 19303849 t miannu "Feeding induces the recruitment of dna-pk to usf-1 and its phosphorylation, which then allows recruitment of p/caf, resulting in usf-1 acetylation and fas promoter activation." SIGNOR-184849 PRMT1 protein Q99873 UNIPROT CNBP protein P62633 UNIPROT down-regulates methylation Arg25 ECPTGGGrGRGMRSR 9606 24726729 t miannu "Cnbp interacts with protein arginine methyltransferase prmt1 / r25 or r27 appear to be the major methylation sites in cnbp /arginine methylation of cnbp impedes rna binding" SIGNOR-204958 PTPN11 protein Q06124 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates dephosphorylation 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-184604 RAPGEF5 protein Q92565 UNIPROT KRAS protein P01116 UNIPROT up-regulates "guanine nucleotide exchange factor" 9606 19201597 t gcesareni "Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras." SIGNOR-183735 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 CSNK2A1 protein P68400 UNIPROT NR1H3 protein Q13133 UNIPROT down-regulates phosphorylation Ser198 SLPPRASsPPQILPQ 9606 BTO:0000801 18250151 t llicata "Ck2? Also phosphorylated lxr? At s198 in vitro, suggesting that ck2 may be a bona fide s198 kinase. our results show that macrophage lxr? Phosphorylation at s198 affects the transcriptional activity of the receptor in a gene-specific manner (fig. ?(Fig.3a)3a) and restricts the repertoire of genes regulated by lxr?" SIGNOR-160640 CSNK2A1 protein P68400 UNIPROT SPTBN1 protein Q01082 UNIPROT down-regulates phosphorylation Ser2110 PEPSTKVsEEAESQQ 9606 BTO:0000938 17088250 t miannu "We show here that the short c-terminal splice variant of betaii-spectrin (betaiisigma2) is a substrate for phosphorylation. In vitro, protein kinase ck2 phosphorylates ser-2110 and thr-2159 / phosphorylation of ?II?2 C-terminal fragment inhibits its interaction with ?II N-terminal fragment." SIGNOR-150467 CSNK2A1 protein P68400 UNIPROT SPTBN1 protein Q01082 UNIPROT down-regulates phosphorylation Thr2159 NGATEQRtSSKESSP 9606 BTO:0000938 17088250 t miannu "We show here that the short c-terminal splice variant of betaii-spectrin (betaiisigma2) is a substrate for phosphorylation. In vitro, protein kinase ck2 phosphorylates ser-2110 and thr-2159 / phosphorylation of ?II?2 C-terminal fragment inhibits its interaction with ?II N-terminal fragment." SIGNOR-150471 DYRK1A protein Q13627 UNIPROT SF3B1 protein O75533 UNIPROT unknown phosphorylation Thr434 PARKLTAtPTPLGGM 9606 BTO:0000007 16512921 t llicata "The present data show that the splicing factor sf3b1 is a substrate of the protein kinase dyrk1a and suggest that dyrk1a may be involved in the regulation of pre mrna-splicing. by mass spectrometry and mutational analysis of sf3b1, thr434 was identified as the major phosphorylation site for dyrk1a." SIGNOR-144975 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 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 MAGED1 protein Q9Y5V3 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates 9606 BTO:0001760 20646279 f gcesareni "By comparing in vitro differentiation of myoblasts derived from wild-type or maged1 knockout mice, we observed that maged1 deficiency results in reduced levels of p21cip1/waf1, defective cell cycle exit and impaired myotube maturation." SIGNOR-166893 PPP2CA protein P67775 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates dephosphorylation Thr32 QSRPRSCtWPLQRPE 9606 20110348 t gcesareni "Protein phosphatase 2a reactivates foxo3a through a dynamic interplay with 14-3-3 and aktpp2a-mediated dephosphorylation of t32/s253 is required for dissociation of 14-3-3, nuclear translocation, and transcriptional activation of foxo3a." SIGNOR-163684 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 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 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 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 NFKBIA protein P25963 UNIPROT up-regulates phosphorylation Tyr42 DSMKDEEyEQMVKEL 9606 BTO:0000801 9792645 t llicata "C-src phosphorylates i?B? On tyrosine 42 the prolonged expression and activation of c-src in response to tnf (19) and, its extended connection with i?B?, Suggest this association prompts prolonged tyrosine phosphorylation and perhaps tof i?B? Compared with the short survival of the serine-phosphorylated inhibitory protein." SIGNOR-60879 TESK2 protein Q96S53 UNIPROT CFL1 protein P23528 UNIPROT "down-regulates activity" phosphorylation Ser3 sGVAVSDG 9606 BTO:0000567 11418599 t lperfetto "Like tesk1, tesk2 phosphorylated cofilin specifically at ser-3 and induced formation of actin stress fibers and focal adhesions." SIGNOR-108753 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 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 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 GNAS protein P63092 UNIPROT SRC protein P12931 UNIPROT "up-regulates activity" binding -1 11007482 t "Here we demonstrate that Galphas and Galphai, but neither Galphaq, Galpha12 nor Gbetay, directly stimulate the kinase activity of downregulated c-Src" SIGNOR-256527 GNB/GNG complex SIGNOR-C202 SIGNOR PI3K complex SIGNOR-C156 SIGNOR up-regulates 23994464 t apalma "Similar to PLCβ activation, PI3K-activation by neutrophil GPCRs also occurs primarily through Gβγ subunits, through the unique PI3Kγ isoform which is directly activated by Gβγ dimers" SIGNOR-255010 GNB/GNG complex SIGNOR-C202 SIGNOR PLCB3 protein Q01970 UNIPROT up-regulates 23994464 t apalma "However, it was later shown that other PLCβ isoforms (particularly PLCβ2 and PLCβ3) can also be directly activated by Gβγ subunits" SIGNOR-255016 MAPK14 protein Q16539 UNIPROT ELAVL1 protein Q15717 UNIPROT up-regulates phosphorylation Thr118 SGLPRTMtQKDVEDM 9606 19528229 t lperfetto "P38 mapk phosphorylates the mrna binding protein hur on thr118, which results in cytoplasmic accumulation of hur and its enhanced binding to the p21cip1 mrna." SIGNOR-186135 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 KARS 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 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 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 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 MAPKAPK2 protein P49137 UNIPROT CREB1 protein P16220 UNIPROT "up-regulates activity" phosphorylation Ser133 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 phosphorylation Ser133 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 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 MAPKAPK2 protein P49137 UNIPROT ETV1 protein P50549 UNIPROT "down-regulates activity" phosphorylation Ser191 HRFRRQLsEPCNSFP 452646 BTO:0005493 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 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 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 PAK2 protein Q13177 UNIPROT VIM protein P08670 UNIPROT "down-regulates activity" phosphorylation Ser39 TTSTRTYsLGSALRP -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-250239 PLK1 protein P53350 UNIPROT DVL2 protein O14641 UNIPROT up-regulates phosphorylation Thr206 MTSELEStSLGDSDE 9606 20823832 t lperfetto "Dvl2 bound to and was phosphorylated at thr206 by a mitotic kinase, polo-like kinase 1 (plk1), and this phosphorylation was required for spindle orientation and stable microtubule (mt)-kt attachment" SIGNOR-167858 PPP1CA protein P62136 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates dephosphorylation 9606 12840032 t fstefani "P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3). the dual specificity phosphatases that specifically dephosphorylate and inactivate the p-erk1/2 are called mapk phosphatases" SIGNOR-103155 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 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 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 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 MAPK14 protein Q16539 UNIPROT ELAVL1 protein Q15717 UNIPROT up-regulates phosphorylation 9606 19528229 t gcesareni "P38 mapk phosphorylates the mrna binding protein hur on thr118, which results in cytoplasmic accumulation of hur and its enhanced binding to the p21cip1 mrna." SIGNOR-186138 MAPKAPK2 protein P49137 UNIPROT ETV1 protein P50549 UNIPROT "down-regulates activity" phosphorylation Ser216 PMYQRQMsEPNIPFP 452646 BTO:0005493 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 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 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 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 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 PTPN13 protein Q12923 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 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-132555 RPA2 protein P15927 UNIPROT NBN protein O60934 UNIPROT up-regulates binding 9606 19586055 t esanto "The response to replication stress requires the recruitment of rpa and the mre11-rad50-nbs1 (mrn) complex. We observe a direct interaction between rpa with both nbs1 and mre11. By utilizing rpa bound to ssdna, we demonstrate that substituting rpa with phosphorylated rpa or a phosphomimetic weakens the interaction with the mrn complex." SIGNOR-186651 RUNX2 protein Q13950 UNIPROT ALPL protein P05186 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11331591 f gcesareni "In addition to osteocalcin, cbfa1 regulates expression of several other genes that are activated during osteoblast" SIGNOR-107123 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 WNT5B protein Q9H1J7 UNIPROT PPARG protein P37231 UNIPROT up-regulates 9606 19577541 f fspada "Wnt5b additionally appears to be a potent enhancer of adipogenic capacity by stimulation of ppargamma" SIGNOR-186625 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 CSNK2A1 protein P68400 UNIPROT CTNNA1 protein P35221 UNIPROT down-regulates phosphorylation Ser641 TPEELDDsDFETEDF 9606 BTO:0000527 19941816 t gcesareni "We demonstrate here that egfr activation results in disruption of the complex of beta-catenin and alpha-catenin, thereby abrogating the inhibitory effect of alpha-catenin on beta-catenin transactivation via ck2alpha-dependent phosphorylation of alpha-catenin at s641." SIGNOR-161847 CSNK2A1 protein P68400 UNIPROT LEF1 protein Q9UJU2 UNIPROT up-regulates phosphorylation 9606 19623618 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-187209 CSNK2A1 protein P68400 UNIPROT PDCD5 protein O14737 UNIPROT up-regulates phosphorylation Ser119 NRRKVMDsDEDDDY 9606 BTO:0001938 19616514 t lperfetto "Programmed cell death 5 (pdcd5), a protein involved in cell death and down-regulated in different forms of human tumors. Pdcd5 is phosphorylated in vitro by both ck2alpha subunit and by the ck2 holoenzyme at a residue, s118, which is found phosphorylated in vivo. Transfection of the non-phosphorylatable mutant (s118a) impairs the pdcd5 acceleration of either doxorubimicin- or uv-induced apoptosis in u2os cells" SIGNOR-187106 CYLD protein Q9NQC7 UNIPROT BCL3 protein P20749 UNIPROT down-regulates deubiquitination 9606 BTO:0001286 16713561 t gcesareni "Cyld binds and deubiquitinates bcl-3in cyld+/+ keratinocytes, tpa or uv light triggers the translocation of cyld from the cytoplasm to the perinuclear region, where cyld binds and deubiquitinates bcl-3, thereby preventing nuclear accumulation of bcl-3 and p50/bcl-3- or p52/bcl-3-dependent proliferation." SIGNOR-146774 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 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 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 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 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 NCOR2 protein Q9Y618 UNIPROT SPEN protein Q96T58 UNIPROT up-regulates binding 9606 11331609 t gcesareni "Sharp is a potent transcriptional repressor whose repression domain (rd) interacts directly with smrt" SIGNOR-107260 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 PRKACA protein P17612 UNIPROT MC4R protein P32245 UNIPROT "up-regulates activity" phosphorylation Ser329 LGGLCDLsSRY 9606 BTO:0000007 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-250016 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 TNFRSF17 protein Q02223 UNIPROT MAPK12 protein P53778 UNIPROT up-regulates 9606 10903733 f miannu "Overexpression of bcma activates the p38 mapk" SIGNOR-79498 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 GAS7 protein O60861 UNIPROT RUNX2 protein Q13950 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 23840221 f miannu "Downregulation of gas7 using short-hairpin rna decreased the expression of runx2, a master regulator of osteogenesis, and its target genes (alkaline phosphatase, type i collagen, osteocalcin, and osteopontin)." SIGNOR-202242 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 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 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 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 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 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 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 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 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 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 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 PCM1 protein Q15154 UNIPROT NEK2 protein P51955 UNIPROT up-regulates relocalization 9606 15659651 t miannu "Recruitment of nek2 and c-nap1 to the centrosome is dependent on pcm-1" SIGNOR-133337 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 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 SRC protein P12931 UNIPROT KCNA3 protein P22001 UNIPROT up-regulates phosphorylation Tyr499 EGEEQSQyMHVGSCQ 9606 BTO:0000142 11812778 t gcesareni "The shaker family k+ channel protein, kv1.3, is tyrosine phosphorylated by v-src kinase at tyr137 and tyr449 to modulate current magnitude and kinetic properties." SIGNOR-114645 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1766 SPSYSPTsPSYSPTS -1 15125841 t "Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro" SIGNOR-248814 CDK9 protein P50750 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates phosphorylation Thr179 PQSNIPEtPPPGYLS 9606 19914168 t llicata "As receptor-activated smads form transcriptional complexes, they are phosphorylated at an interdomain linker region by cdk8 and cdk9, which are components of transcriptional mediator and elongation complexes. These phosphorylations promote smad transcriptional action" SIGNOR-161670 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 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 MAPK14 protein Q16539 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-67535 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 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 NFY complex SIGNOR-C1 SIGNOR CCNB2 protein O95067 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10086339 f gcesareni "In this study, we analysed the mechanisms leading to activation of the cyclin b2 ccaat boxes: a combination of (i) genomic footprinting, (ii) transfections with single, double and triple mutants, (iii) emsas with nuclear extracts, antibodies and nf-y recombinant proteins and (iv) transfections with an nf-ya dominant negative mutant established the positive role of the three ccaat sequences and proved that nf-y plays a crucial role in their activation." SIGNOR-65638 PLK1 protein P53350 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Ser730 VLDTMNDsLSKILLD 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-187888 PLK1 protein P53350 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates phosphorylation Ser260 SLDSEDYsLSEEGQE 9606 19833129 t gcesareni "Polo-like kinase-1 phosphorylates mdm2 at ser260 and stimulates mdm2-mediated p53 turnover." SIGNOR-188471 RARG protein P13631 UNIPROT THRA protein P10827 UNIPROT up-regulates binding 9606 15650024 t lperfetto "We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs" SIGNOR-133237 RELA protein Q04206 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." SIGNOR-59542 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 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates phosphorylation Tyr128 SKAQQGLyQVPGPSP 9606 22710723 t lperfetto "Furthermore, we demonstrate that src phosphorylates p130cas y128. We engineered crc cells homozygous for a p130cas y128f knock-in mutant and found that these cells exhibit significantly reduced migration and colony formation" SIGNOR-197927 SRC protein P12931 UNIPROT CTNND1 protein O60716 UNIPROT "up-regulates activity" phosphorylation Tyr112 PGQIVETyTEEDPEG -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-246480 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 YAP1 protein P46937 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-256669 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 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 MAPKAPK5 protein Q8IW41 UNIPROT DNAJB1 protein P25685 UNIPROT up-regulates phosphorylation Ser149 TNVNFGRsRSAQEPA 9606 24309468 t lperfetto "Phosphorylation of heat shock protein 40 (hsp40/dnajb1) by mitogen-activated protein kinase-activated protein kinase 5 (mk5/prak). Mk5 phosphorylates hsp40/dnajb1 in vivo at ser-149 or/and ser-151 and ser-171 in the c-terminal domain of hsp40/dnajb1. Mk5 modestly stimulates the atp hydrolyse activity of hsp40/hsp70 complex and enhances the repression of heat shock factor 1 driven transcription by hsp40/dnajb1." SIGNOR-203456 MAPKAPK5 protein Q8IW41 UNIPROT DNAJB1 protein P25685 UNIPROT up-regulates phosphorylation Ser151 VNFGRSRsAQEPARK 9606 24309468 t lperfetto "Phosphorylation of heat shock protein 40 (hsp40/dnajb1) by mitogen-activated protein kinase-activated protein kinase 5 (mk5/prak). Mk5 phosphorylates hsp40/dnajb1 in vivo at ser-149 or/and ser-151 and ser-171 in the c-terminal domain of hsp40/dnajb1. Mk5 modestly stimulates the atp hydrolyse activity of hsp40/hsp70 complex and enhances the repression of heat shock factor 1 driven transcription by hsp40/dnajb1." SIGNOR-203460 MARK1 protein Q9P0L2 UNIPROT MAP4 protein P27816 UNIPROT "down-regulates activity" phosphorylation Ser1073 KAQAKVGsLDNVGHL -1 8631898 t miannu "Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability." SIGNOR-250169 MARK1 protein Q9P0L2 UNIPROT MAP4 protein P27816 UNIPROT "down-regulates activity" phosphorylation Ser928 SRLATNTsAPDLKNV -1 8631898 t miannu "Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability." SIGNOR-250170 NR0B2 protein Q15466 UNIPROT NR5A2 protein O00482 UNIPROT down-regulates binding 9606 BTO:0000195 12198243 t gcesareni "Here we show that shp can interact with the liver x receptors lxralpha (nr1h3) and lxrbeta (nr1h2), as demonstrated by glutathione-s-transferase pull-down assays, mammalian two-hybrid, and coimmunoprecipitation experiments. In transfection assays, shp inhibits the expression of an artificial reporter driven by an lxr-response element and represses the transcriptional activation by lxr of the human atp-binding cassette transporter 1 (abca1) promoter" SIGNOR-92060 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 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 RUNX2 protein Q13950 UNIPROT SPP1 protein P10451 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11331591 f gcesareni "In addition to osteocalcin, cbfa1 regulates expression of several other genes that are activated during osteoblast" SIGNOR-107175 RUNX2 protein Q13950 UNIPROT TNFSF11 protein O14788 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11331591 f gcesareni "In addition to osteocalcin, cbfa1 regulates expression of several other genes that are activated during osteoblast" SIGNOR-107242 SIAH1 protein Q8IUQ4 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates relocalization 9606 20940030 t gcesareni "The overexpression of siah1 causes the re-localization of notch from the cell surface to the cytoplasm and to the nucleus, which is indicative of notch activation" SIGNOR-168460 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 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 WNT3A protein P56704 UNIPROT FZD2 protein Q14332 UNIPROT up-regulates binding 9606 19910923 t gcesareni "It was also shown that wnt5a inhibits the beta-catenin pathway by competing with wnt3a for binding to fz2, and that the impairment of clathrin-mediated internalization does not affect this wnt5a inhibitory action." SIGNOR-189117 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 JUN protein P05412 UNIPROT AP1 complex SIGNOR-C154 SIGNOR "form complex" binding 9606 25875593 t irozzo "C-Fos dimerizes with c-Jun to form the transcription activator protein-1 (AP-1) which binds to the specific recognition site." SIGNOR-256367 PLK3 protein Q9H4B4 UNIPROT BCL2L1 protein Q07817 UNIPROT up-regulates phosphorylation Ser49 ESEMETPsAINGNPS 9606 21336504 t lperfetto "Polo kinase 3 (plk3) was implicated in bcl-xl(ser49) phosphorylation. These data indicate that, during g2 checkpoint, phospho-bcl-xl(ser49) is another downstream target of plk3, acting to stabilize g2 arrest." SIGNOR-172230 PPP2CA protein P67775 UNIPROT RPS3 protein P23396 UNIPROT down-regulates dephosphorylation Ser6 sKKRKFVA 9606 15950189 t lperfetto "We identified that pp2a interacts with wild-type rps3, but not with mutants (s6a/t221a) (fig. 8), and that it associates with the n-terminal region of rps3 (fig. 2). From our results presented here, we conclude that pp2a is involved in the dephosphorylation of phosphorylated rps3 by pkc, and that serine 6 on the n-terminal region of rps3 appears to mediate the pp2a recruitment." SIGNOR-137963 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 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR PBK protein Q96KB5 UNIPROT "up-regulates activity" phosphorylation Thr9 EGISNFKtPSKLSEK 15541388 t llicata "During mitosis, TOPK-Thr-9 was phosphorylated by cdk1/cyclin B and TOPK significantly associates with mitotic spindles. When TOPK expression was suppressed, formation of spindle midzone was thinned and dimmed and cytokinesis was disturbed." SIGNOR-250720 EDA protein Q92838 UNIPROT EDA2R protein Q9HAV5 UNIPROT up-regulates binding 9606 BTO:0001253 12084975 t gcesareni "Identification of the major product of the eda gene (ectodysplasin a), a protein belonging to a group of tnf ligands, and molecular cloning of the cdna, encoding its receptor (edar), a member of the tnf receptor family, are presented. The role of an alternative eda receptor, localised on the x chromosome (xedar) in the developmental control of the differentiation of skin appendages, is discussed." SIGNOR-90040 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 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 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 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 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 PTPRF protein P10586 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 15896785 t "10226025:Protein kinase B (PKB) is activated by phosphorylation of Thr308 and of Ser473." acerquone "Knock-down of lar by the l3 sirna probe markedly inhibited the insulin-stimulated increase in the phosphorylation of protein kinase b (pkb, also called akt) on serine 473 by >90%" SIGNOR-137246 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 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 LAMTOR3 protein Q9UHA4 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates binding 9606 15547943 t lperfetto "We analyzed the ability of mp1 to bind to mek1, erk1, and to itself, and the regulation of these interactions. Gel filtration of cell lysates revealed two major mp1 peaks: a broad high molecular weight peak and a 28 kda complex. An mp1 mutant that lost mek1 binding no longer enhanced rasv12-stimulated erk1 activity, and functioned as a dominant negative, consistent with the concept that mp1 function depends on facilitating these oligomerizations." SIGNOR-244874 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 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR PRC1 protein O43663 UNIPROT unknown phosphorylation Thr481 RRGLAPNtPGKARKL BTO:0000567 9885575 t llicata "We have shown that PRC1 is a good in vitro substrate for several CDKs, and that it is also phosphorylated in a cell cycle–dependent manner in vivo at Thr-481 (major mitosis. and Thr-470 (minor site), which are the in vitro phosphorylation sites." SIGNOR-250746 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 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 MAP2K7 protein O14733 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates phosphorylation Thr183 ACTNFMMtPYVVTRY 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-63976 MARK1 protein Q9P0L2 UNIPROT MAP4 protein P27816 UNIPROT "down-regulates activity" phosphorylation Ser941 NVRSKVGsTENIKHQ -1 8631898 t miannu "Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability." SIGNOR-250171 MARK1 protein Q9P0L2 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser579 NVKSKIGsTENLKHQ -1 10090741 t miannu "We have studied the relationship between the phosphorylation of tau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. MARK and PKA phosphorylate several sites within the repeats (notably the KXGS motifs including Ser262, Ser324, and Ser356, plus Ser320). This type of phosphorylation strongly reduces tau's affinity for microtubules, and at the same time inhibits tau's assembly into PHFs." SIGNOR-250172 MARK1 protein Q9P0L2 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser637 VDLSKVTsKCGSLGN -1 10090741 t miannu "We have studied the relationship between the phosphorylation of tau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. MARK and PKA phosphorylate several sites within the repeats (notably the KXGS motifs including Ser262, Ser324, and Ser356, plus Ser320). This type of phosphorylation strongly reduces tau's affinity for microtubules, and at the same time inhibits tau's assembly into PHFs." SIGNOR-250173 MARK1 protein Q9P0L2 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser641 KVTSKCGsLGNIHHK -1 10090741 t miannu "We have studied the relationship between the phosphorylation of tau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. MARK and PKA phosphorylate several sites within the repeats (notably the KXGS motifs including Ser262, Ser324, and Ser356, plus Ser320). This type of phosphorylation strongly reduces tau's affinity for microtubules, and at the same time inhibits tau's assembly into PHFs." SIGNOR-250174 PPP2CA protein P67775 UNIPROT MAPK15 protein Q8TD08 UNIPROT down-regulates dephosphorylation Thr175 GPEDQAVtEYVATRW 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-142977 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 KDM4C protein Q9H3R0 UNIPROT JAG1 protein P78504 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 23698634 f miannu "The expression of KDM4C gene was increased in spheres from colorectal cancer (CRC) cells and the knockdown (KD) of KDM4C eliminated colonosphere formation. KDM4C KD decreased the expression of JAG1 gene, and the downregulation of JAG1 gene recapitulated the impaired colonosphere formation." SIGNOR-254542 MARK1 protein Q9P0L2 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser673 RVQSKIGsLDNITHV -1 10090741 t miannu "We have studied the relationship between the phosphorylation of tau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. MARK and PKA phosphorylate several sites within the repeats (notably the KXGS motifs including Ser262, Ser324, and Ser356, plus Ser320). This type of phosphorylation strongly reduces tau's affinity for microtubules, and at the same time inhibits tau's assembly into PHFs." SIGNOR-250175 "DNA damage" stimulus SIGNOR-ST1 SIGNOR TP53 protein P04637 UNIPROT "up-regulates quantity" 9606 19879762 f lperfetto "In the case of DNA-damage, phosphorylation of both p53 and Mdm2 by the checkpoint kinases ATM, ATR, Chk1 and Chk2 contributes to the dissociation of the Mdm2-p53 complex, leading to enhanced cellular p53 levels that primarily accumulate in the nucleus." SIGNOR-209690 KDM2B protein Q8NHM5 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 BTO:0000011 25533466 f miannu "Here, we show that FBXL10/KDM2B is an anti-adipogenic factor that is up-regulated during the early phase of 3T3-L1 preadipocyte differentiation and in adipose tissue in a diet-induced model of obesity. These results suggest that FBXL10 represses adipogenesis by targeting a noncanonical PRC1 complex to repress key genes (e.g. Pparg) that control conversion of pluripotent cells into the adipogenic lineage." SIGNOR-252243 MAPKAPK3 protein Q16644 UNIPROT HSPB1 protein P04792 UNIPROT unknown phosphorylation Ser82 RALSRQLsSGVSEIR -1 8774846 t miannu "MAPKAP kinase-3 and MAPKAP kinase-2 phosphorylated peptide substrates with similar kinetic constants and phosphorylated the same serine residues in HSP27 at the same relative rates.The three serine residues in HSP27 phosphorylated by MAPKAPK2 were also phosphorylated at the same relative rates by MAPKAP-K3 (Ser-82>>Ser-78 >Ser-15)" SIGNOR-250161 MARK2 protein Q7KZI7 UNIPROT ARHGEF2 protein Q92974 UNIPROT down-regulates phosphorylation Ser886 PVDPRRRsLPAGDAL 9606 22072711 t "The effect has been demonstrated using Q92974-2" gcesareni "We also show that par1b-induced serine 885/serine 959 phosphorylation inhibits rhoa-specific gef activity of gef-h1. As a consequence, gef-h1 phosphorylated on both of the serine residues loses the ability to stimulate rhoa and thereby fails to induce rhoa-dependent stress fiber formation" SIGNOR-177096 MARK2 protein Q7KZI7 UNIPROT ARHGEF2 protein Q92974 UNIPROT down-regulates phosphorylation Ser960 SRLSPPHsPRDFTRM 9606 22072711 t "The effect has been demonstrated using Q92974-2" gcesareni "We also show that par1b-induced serine 885/serine 959 phosphorylation inhibits rhoa-specific gef activity of gef-h1. As a consequence, gef-h1 phosphorylated on both of the serine residues loses the ability to stimulate rhoa and thereby fails to induce rhoa-dependent stress fiber formation" SIGNOR-177100 MARK2 protein Q7KZI7 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-149583 MARK2 protein Q7KZI7 UNIPROT RAB11FIP2 protein Q7L804 UNIPROT up-regulates phosphorylation Ser227 QRLSSAHsMSDLSGS 9606 BTO:0000671 16775013 t lperfetto "We identified the kinase that phosphorylated rab11-fip2 as mark2/emk1/par-1balpha (mark2), and recombinant mark2 phosphorylated rab11-fip2 only on serine 227. In calcium switch assays, cells expressing rab11-fip2(s227a) showed a defect in the timely reestablishment of p120-containing junctional complexes." SIGNOR-147118 PLK3 protein Q9H4B4 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 21098032 t gcesareni "Kinase activity of plk3 was significantly activated by hyperosmotic stimulation. Further downstream, active plk3 phosphorylated atf-2 at the thr-71 site in vivo and in vitro." SIGNOR-170004 PRKCA protein P17252 UNIPROT PDE3A protein Q14432 UNIPROT up-regulates phosphorylation Ser428 IPKRLRRsLPPGLLR 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-184452 PTH protein P01270 UNIPROT PTH1R protein Q03431 UNIPROT up-regulates binding 9606 18981475 t gcesareni "Here we show that binding of pth to its receptor pth1r induced association of lrp6, a coreceptor of wnt, with pth1r. The formation of the ternary complex containing pth, pth1r, and lrp6 promoted rapid phosphorylation of lrp6, which resulted in the recruitment of axin to lrp6, and stabilization of beta-catenin." SIGNOR-182039 TLK1 protein Q9UKI8 UNIPROT RAD9A protein Q99638 UNIPROT up-regulates phosphorylation Ser328 VLPSISLsPGPQPPK 9606 18940270 t llicata "Tlk1b phosphorylates hrad9 at s328 after the induction of dsb, occupancy of rad9 adjacent to the break increased during repair while that of asf1 decreased, and the effect was more pronounced in tlk1b-overexpressing cells. We propose that following genotoxic stress, tlk1/1b is first recruited to the dsb in a complex with rad9. It then exchanges with asf1 to promote nucleosomes eviction at the dsb and access of the repair machinery to unencumbered dna." SIGNOR-181748 TP53 protein P04637 UNIPROT TNFRSF10B protein O14763 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15964798 f gcesareni "Reduction in p53 expression also blocks p65 binding to the intronic region of the dr5 gene, indicating cooperation between p53 and p65 in dr5 expression. (articolo-abstract)" SIGNOR-138293 LRIG1 protein Q96JA1 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 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-127298 KIT protein P10721 UNIPROT SRC proteinfamily SIGNOR-PF32 SIGNOR up-regulates phosphorylation 9606 BTO:0000830 15526160 t apalma "Binding of SCF to c-Kit leads to a rapid increase in SFK kinase activity" SIGNOR-254995 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 DTX1 protein Q86Y01 UNIPROT ERBB2 protein P04626 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16554461 f gcesareni "Notch1-induced erbb2 expression in cerebellar astroglia occurs via dtx1" SIGNOR-145319 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 JUN protein P05412 UNIPROT SMAD3/JUN complex SIGNOR-C86 SIGNOR "form complex" binding 9606 9732876 t gcesareni "These results show a ligand-dependent association of smad3 with c-jun" SIGNOR-59867 KITLG protein P21583 UNIPROT KIT protein P10721 UNIPROT "up-regulates activity" binding 9606 BTO:0000830 17259966 t mainnu "The most relevant and still unique mast-cell growth factor is SCF, which is the ligand of KIT, a receptor with tyrosine-kinase activity that is expressed on the surface of all human and murine mast cells" SIGNOR-254946 MAST2 protein Q6P0Q8 UNIPROT PTEN protein P60484 UNIPROT up-regulates phosphorylation 9606 15951562 t gcesareni "We further demonstrate that binding of pten to specific pdz domains diminishes its degradation rate and facilitates its phosphorylation by mast kinases. Our results suggest a regulatory role of pdz domain binding on pten function by controlling its stability and phosphorylation status." SIGNOR-138051 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 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 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates phosphorylation Ser645 LNEKARLsYSDKNLI 9606 15731106 t gcesareni "Taken together, our results demonstrate that serine 643 of pkc-delta is a major autophosphorylation site, and phosphorylation of this site plays an important role in controlling its enzymatic activity and biological function. The enzymatic activity of pkc-deltas643a mutant as measured by phosphorylating the pkc-delta pseudosubstrate region-derived substrate was also reduced more than 70% in comparison to that of pkc-deltawt." SIGNOR-134207 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates phosphorylation Thr295 AEALNQVtQRASRRS 9606 19366211 t gcesareni "These results implicate pkcdelta-thr(295) autophosphorylation as a lipid-dependent modification that links pkcdelta-thr(505) phosphorylation to src-dependent regulation of pkcdelta catalytic function." SIGNOR-185283 PRKDC protein P78527 UNIPROT HNRNPU protein Q00839 UNIPROT up-regulates phosphorylation Ser59 AMEPGNGsLDLGGDS 9606 19351595 t lperfetto "We identify heterogeneous nuclear ribonucleoprotein u (hnrnp-u), also termed scaffold attachment factor a (saf-a), as a specific substrate for dna-pk. We show that hnrnp-u is phosphorylated at ser59 by dna-pk in vitro and in cells in response to dna double-strand breaks" SIGNOR-185058 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 ROCK1 protein Q13464 UNIPROT FHOD1 protein Q9Y613 UNIPROT up-regulates phosphorylation Ser1131 AARERKRsRGNRKSL 9606 18239683 t lperfetto "Rock phosphorylates the c-terminal residues ser1131, ser1137, and thr1141 of formin homology domain protein 1 (fhod1). Phosphorylation of fhod1 at the three residues fully disrupts the autoinhibitory interaction, which culminates in formation of stress fibres." SIGNOR-160544 VRK1 protein Q99986 UNIPROT BANF1 protein O75531 UNIPROT down-regulates phosphorylation Thr2 tTSQKHRD 9606 16495336 t lperfetto "Herein, we demonstrate that b1, vrk1, and vrk2 efficiently phosphorylate the extreme n' terminus of the baf protein. We demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain" SIGNOR-144787 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 KMT2A protein Q03164 UNIPROT SPI1 protein P17947 UNIPROT "up-regulates quantity by expression" methylation 10090 BTO:0002884 22012064 t irozzo "Furthermore, we show that both MLL and AML1/CBFβ are required for maintaining the H3K4-me3 mark at the PU.1 upstream regulatory element (URE) and promoter region, and for full PU.1 gene expression." SIGNOR-255874 MASTL protein Q96GX5 UNIPROT ENSA protein O43768 UNIPROT "up-regulates activity" phosphorylation Ser67 KGQKYFDsGDYNMAK -1 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-243690 MAVS protein Q7Z434 UNIPROT CASP8 protein Q14790 UNIPROT up-regulates relocalization 9606 16406812 t gcesareni "Another protein suggested to play a role in caspase-8 translocation to mitochondria is the mitochondrial membrane protein cardif" SIGNOR-143572 CHUK protein O15111 UNIPROT IKBKB protein O14920 UNIPROT "up-regulates activity" phosphorylation Ser177 AKELDQGsLCTSFVG -1 10022904 t llicata "Our data indicate that IKKα stimulates IKKβ kinase activity for the IκBα substrate. Finally, we demonstrate that IKKα can phosphorylate IKKβ in in vitro kinase assays." SIGNOR-250771 CHUK protein O15111 UNIPROT IKBKB protein O14920 UNIPROT "up-regulates activity" phosphorylation Ser181 DQGSLCTsFVGTLQY -1 10022904 t llicata "Our data indicate that IKKα stimulates IKKβ kinase activity for the IκBα substrate. Finally, we demonstrate that IKKα can phosphorylate IKKβ in in vitro kinase assays." SIGNOR-250772 CSNK2A1 protein P68400 UNIPROT CORO1C protein Q9ULV4 UNIPROT up-regulates phosphorylation Ser463 CNQDERIsKLEQQMA 9606 22355754 t lperfetto "We demonstrate that crn2 is a binding partner and substrate of protein kinase ck2, which phosphorylates crn2 at s463 in its c-terminal coiled coil domain" SIGNOR-196193 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 F2R protein P25116 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates binding 9606 22318735 t gcesareni "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-196009 FOXO1 protein Q12778 UNIPROT CDKN2B protein P42772 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17873901 f gcesareni "Foxo1a strongly activated p15ink4b transcription and p19ink4d transcription, while foxo3a showed higher p19ink4d transcription activity than p15ink4b transcription activity" SIGNOR-157794 KMT2A protein Q03164 UNIPROT RUNX1 protein Q01196 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0002181 22012064 t irozzo "Similar to CBFβ, we show that MLL binds to AML1 abrogating its proteasome-dependent degradation.Furthermore, we demonstrate that MLL binds to a region of AML1 (that is conserved in AML2 and AML3) and increases AML1 (AML2 and AML3) protein levels" SIGNOR-255707 KMT2D protein O14686 UNIPROT HMT complex SIGNOR-C19 SIGNOR "form complex" binding 9606 17500065 t lperfetto "The evolutionarily conserved hdpy-30, ash2l, rbbp5, and wdr5 likely constitute a subcomplex that is shared by all human set1-like hmt complexes." SIGNOR-154763 MASTL protein Q96GX5 UNIPROT ARPP19 protein P56211 UNIPROT "up-regulates activity" phosphorylation Ser62 KGQKYFDsGDYNMAK -1 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-243611 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 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 RPS6KA1 protein Q15418 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-169883 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 VRK2 protein Q86Y07 UNIPROT BANF1 protein O75531 UNIPROT down-regulates phosphorylation Thr2 tTSQKHRD 9606 16495336 t lperfetto "Herein, we demonstrate that b1, vrk1, and vrk2 efficiently phosphorylate the extreme n' terminus of the baf protein. We demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain" SIGNOR-144799 MAP3K5 protein Q99683 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates phosphorylation Ser98 GGRRPGTsPALLQGT 9606 17325029 t lperfetto "P21cip1 is phosphorylated in vitro by both ask1 and jnk1 at s98. /phosphorylation of p21cip1 at s98, which in vivo appears to be regulated by ask1, may therefore mediate negative feedback in the ask1 signaling pathway." SIGNOR-153440 CHEK1 protein O14757 UNIPROT RB1 protein P06400 UNIPROT up-regulates phosphorylation Ser612 MYLSPVRsPKKKGST 9606 17380128 t llicata "These results suggest that ser612 is phosphorylated by chk1/2 after dna damage, leading to the formation of prb-e2f-1. phosphorylation of prb at ser612 enhanced the formation of a complex between prb and e2f-1" SIGNOR-153904 CDKN2A protein P42771 UNIPROT CDK6 protein Q00534 UNIPROT down-regulates binding 9606 16161044 t gcesareni "In addition, cytoplasmic p16 bound cyclin dependent kinase (cdk)4/6, potentially indicating that p16 could have a function in the cytoplasm." SIGNOR-140412 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 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 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AR protein P10275 UNIPROT down-regulates phosphorylation Ser516 VSRVPYPsPTCVKSE 9606 BTO:0001130 18511414 t lperfetto "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-244606 FOXO1 protein Q12778 UNIPROT CDKN2D protein P55273 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17873901 f gcesareni "Foxo1a strongly activated p15ink4b transcription and p19ink4d transcription, while foxo3a showed higher p19ink4d transcription activity than p15ink4b transcription activity" SIGNOR-157839 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 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 JAK1 protein P23458 UNIPROT STAT2 protein P52630 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-?, They become rapidly activated by tyrosine phosphorylation at a single site catalyzed by receptor associated jak (janus) kinases." SIGNOR-88285 LAMTOR3 protein Q9UHA4 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates binding 9606 15547943 t gcesareni "We analyzed the ability of mp1 to bind to mek1, erk1, and to itself, and the regulation of these interactions. Gel filtration of cell lysates revealed two major mp1 peaks: a broad high molecular weight peak and a 28 kda complex. An mp1 mutant that lost mek1 binding no longer enhanced rasv12-stimulated erk1 activity, and functioned as a dominant negative, consistent with the concept that mp1 function depends on facilitating these oligomerizations." SIGNOR-130924 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 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 PKM protein P14618 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 22306293 t llicata "Pkm2 activates transcription of mek5 by phosphorylating stat3 at y705. pkm2 regulates mek5 transcription via activation of stat3" SIGNOR-195766 PPP1CA protein P62136 UNIPROT CASP9 protein P55211 UNIPROT up-regulates dephosphorylation Thr125 PEVLRPEtPRPVDIG 9606 22311969 t gcesareni "Pp1 dephosphorylated thr125 site of caspase-9 and activated caspase-9 to mediate il-2 deprivation-induced apoptosis." SIGNOR-195992 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 USP9X protein Q93008 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates deubiquitination Lys519 DYPRQSIkETPCWIE 9606 22298955 t gcesareni "Smad4 is monoubiquitinated in lysine 519 in vivo, a modification that inhibits smad4 by impeding association with phospho-smad2. Fam reverts this negative modification, re-empowering smad4 function;control of smad4 is a good way to regulate bone formation. Fam and ectodermin/tif1gamma (ecto) were reported to respectively regulate the de-ubiquitination and ubiquitination of smad4." SIGNOR-195697 ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates phosphorylation Ser831 EPVEQDSsQPSLPLV 9606 22621922 t gcesareni "Here we report phosphorylation of 53bp1 at several novel residues, using mass spectrometry and phospho-specific antibodies, and show that ionising radiation-stimulated phosphorylation of these residues requires atm." SIGNOR-197615 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 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 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 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 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 CSNK2A1 protein P68400 UNIPROT MDC1 protein Q14676 UNIPROT up-regulates phosphorylation Ser299 SQPPGEDsDTDVDDD 9606 18678890 t gcesareni "The mdc1-nbs1 interaction occurs through a specific region (residues 200-420) of mdc1, which contains multiple consensus casein kinase 2 (ck2) phosphorylation sites." SIGNOR-179875 lapatinib chemical CHEBI:49603 ChEBI RET protein P07949 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001949 21443688 t Luana "YN968D1 potently suppressed the kinase activities of VEGFR-2, c-kit and c-src, and inhibited cellular phosphorylation of VEGFR-2, c-kit and PDGFRβ." SIGNOR-257899 LEF1 protein Q9UJU2 UNIPROT ELANE protein P08246 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004850 14594802 f miannu "We find that LEF-1 and CBFalpha co-activate ELA2 expression." SIGNOR-254550 LEF1 protein Q9UJU2 UNIPROT FST protein P19883 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165 24344199 t lperfetto "We further demonstrate that Fst is a direct target of the WNT/β-catenin pathway. Activation and inactivation of β-catenin induced and inhibited Fst expression, respectively, in both C2C12 cells and mouse embryos. Specific TCF/LEF1 binding sites within the promoter and intron 1 region of the Fst gene were required for RSPO2 and WNT/β-catenin-induced Fst expression." SIGNOR-251722 lenalidomide chemical CHEBI:63791 ChEBI CRBN protein Q96SW2 UNIPROT "up-regulates activity" binding 9606 BTO:0000670 26131937 t gcesareni "Lenalidomide, like thalidomide and pomalidomide, binds CRBN and induces degradation of specific substrates" SIGNOR-236891 LMO1 protein P25800 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-46114 PIAS1 protein O75925 UNIPROT PRDM1 protein O75626 UNIPROT up-regulates sumoylation Lys816 PLVPVKVkQETVEPM 9606 22555612 t miannu "Blimp_1 is subjected to pias1_mediated sumoylation at lysine 816 / it appears that sumo_modified blimp_1 is a more potent transcriptional repressor." SIGNOR-197265 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 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 SIRT1 protein Q96EB6 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0000007 14976264 f lperfetto "Sirt1 inhibited foxo3's ability to induce cell death." SIGNOR-217884 USF1 protein P22415 UNIPROT POMC protein P01189 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19389701 f gcesareni "Following uv irradiation, usf-1 is phosphorylated by the p38 stress-activated kinase on threonine 153 and directly up-regulates expression of the pomc, mc1r, tyr, tyrp-1 and dct genes" SIGNOR-185575 MAPK10 protein P53779 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 BTO:0001253 20395206 t gcesareni "With epidermal growth factor treatment, overexpression of erk8 in jb6 cl41 cells caused an increased phosphorylation of c-jun at ser(63) and ser(73), resulting in increased activator protein-1 transactivation." SIGNOR-164800 MAX protein P61244 UNIPROT MAD1L1 protein Q9Y6D9 UNIPROT "up-regulates activity" binding 9606 7954804 t 2 miannu "the role MAX plays in transcription is thought to be primarily as a cofactor for DNA binding. In this capacity, however, it appears to be essential for most, if not all, the known biological activities of MYC. MAX also functions as a cofactor for DNA binding for a group of bHLHZip proteins related to MYC, including MNT, MXD1-4 (formerly Mad1, Mxi1, Mad3 and Mad4), and MGA. Like MYC, these proteins do not homodimerize and appear to be incapable of binding DNA on their own, but when bound to MAX, they recognize E-box sequences." SIGNOR-240357 MAX protein P61244 UNIPROT MNT protein Q99583 UNIPROT "up-regulates activity" binding 9606 7954804 t 2 miannu "the role MAX plays in transcription is thought to be primarily as a cofactor for DNA binding. In this capacity, however, it appears to be essential for most, if not all, the known biological activities of MYC. MAX also functions as a cofactor for DNA binding for a group of bHLHZip proteins related to MYC, including MNT, MXD1-4 (formerly Mad1, Mxi1, Mad3 and Mad4), and MGA. Like MYC, these proteins do not homodimerize and appear to be incapable of binding DNA on their own, but when bound to MAX, they recognize E-box sequences." SIGNOR-240354 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Thr611 ETLPISStPSKSVLP 9606 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-216837 LPAR1 protein Q92633 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 20331961 t milica "The receptor, now called lpa1, is a gpcr that couples to heterotrimeric g proteins (gi, gq, g12/13alpha subunits)." SIGNOR-230761 LPAR1 protein Q92633 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 20331961 t gcesareni "The receptor, now called lpa1, is a gpcr that couples to heterotrimeric g proteins (gi, gq, g12/13alpha subunits)" SIGNOR-164682 LPAR2 protein Q9HBW0 UNIPROT GNA12 protein Q03113 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. lpa2 also can couple to the gi/o, g12/13, and gqfamilies." SIGNOR-135834 MBD1 protein Q9UIS9 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-254030 PIAS4 protein Q8N2W9 UNIPROT RPA2 protein P15927 UNIPROT up-regulates phosphorylation Ser4 sGFESYGS 9606 20016603 t gcesareni "Pias1 and pias4 promote brca1 accumulation and sumoylation, rpa phosphorylation, and dsb repair furthermore, phosphorylation of the 34 kda subunit of rpa on ser-4 and ser-8 (ps4/ps8) in response to ir or camptothecin treatment was diminished by pias4 depletion, while pias1 depletion impaired ir-induced but not camptothecin-induced rpa phosphorylation" SIGNOR-162160 PRKAA1 protein Q13131 UNIPROT SNAI1 protein O95863 UNIPROT up-regulates phosphorylation Ser11 SFLVRKPsDPNRKPN 9606 19923321 t lperfetto "Serines 11 and 92 participate in the control of snail1 stability and positively regulate snail1 repressive function and its interaction with msin3a corepressor. Furthermore, serines 11 and 92 are required for snail1-mediated emt and cell viability, respectively. Pka and ck2 have been characterized as the main kinases responsible for in vitro snail1 phosphorylation at serine 11 and 92, respectively." SIGNOR-161779 PRKAA1 protein Q13131 UNIPROT SNAI1 protein O95863 UNIPROT up-regulates phosphorylation Ser92 VAELTSLsDEDSGKG 9606 19923321 t lperfetto "Serines 11 and 92 participate in the control of snail1 stability and positively regulate snail1 repressive function and its interaction with msin3a corepressor. Furthermore, serines 11 and 92 are required for snail1-mediated emt and cell viability, respectively. Pka and ck2 have been characterized as the main kinases responsible for in vitro snail1 phosphorylation at serine 11 and 92, respectively." SIGNOR-161783 PRKCA protein P17252 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-197285 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 MBD1 protein Q9UIS9 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-254036 FEV protein Q99581 UNIPROT ICAM1 protein P05362 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 12761502 f miannu "Fev acts as a transcriptional repressor through its dna-binding ets domain and alanine-rich domain. / we show here that fev dramatically represses both basal and ectopically ets-activated transcription driven by the icam-1 promoter, and that the effect is dose dependent." SIGNOR-101246 GNB1 protein P62873 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates 9606 23074268 f gcesareni "Furthermore, this work suggested that the gbetagamma subunits released upon gi activation activated phospholipase c-gamma (plc-gamma) to produce inositol 3 phosphate (ip3) which would subsequently increase intracellular ca2+ abundance." SIGNOR-199129 GRK2 protein P25098 UNIPROT SMO protein Q99835 UNIPROT up-regulates phosphorylation 9606 23074268 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-199104 MBD2 protein Q9UBB5 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-254026 MYOG protein P15173 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 BTO:0000887 8288123 f lperfetto "The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop--helix (bhlh) motif that mediates dimerization and dna binding. / myogenic bhlh proteins form heterodimers with ubiquitous bhlh proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enancers." SIGNOR-37461 NFE2L2 protein Q16236 UNIPROT GCLC protein P48506 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 22459801 f miannu "Different expression pattern of Nrf2 regulated genes in end-stage liver disease samples were observed: glutamate-cysteine ligase (GCLC) and glutathione-S-transferase A1 (GSTA1) were significantly down-regulated in most liver disease groups, whereas heme oxidase 1 (HMOX1) and NAD(P)H dehydrogenase [quinone] 1 (NQO1) were not significantly suppressed." SIGNOR-254643 NR0B2 protein Q15466 UNIPROT HNF4A protein P41235 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 10594021 f gcesareni "Here we show that shp inhibits transactivation by the orphan receptor hepatocyte nuclear factor 4 (hnf-4) and the retinoid x receptor (rxr) by at least two mechanisms shp also competes with coactivators for binding to ligand-activated rxr, and based on the ligand-dependent interaction with other nuclear receptors, it is likely that coactivator competition is a general feature of shp-mediated repression." SIGNOR-73032 PIAS4 protein Q8N2W9 UNIPROT RPA2 protein P15927 UNIPROT up-regulates phosphorylation Ser8 MWNSGFEsYGSSSYG 9606 20016603 t gcesareni "Pias1 and pias4 promote brca1 accumulation and sumoylation, rpa phosphorylation, and dsb repair furthermore, phosphorylation of the 34 kda subunit of rpa on ser-4 and ser-8 (ps4/ps8) in response to ir or camptothecin treatment was diminished by pias4 depletion, while pias1 depletion impaired ir-induced but not camptothecin-induced rpa phosphorylation" SIGNOR-162164 PRKACA protein P17612 UNIPROT TH protein P07101 UNIPROT "up-regulates activity" phosphorylation Ser40 GQGAPGPsLTGSPWP -1 11359875 t miannu "HTH1 was phosphorylated at Ser40 by PKA. Tyrosine hydroxylase (TH) has been reported to require binding of 14-3-3 proteins for optimal activation by phosphorylation. phosphorylationof hTH1‚4 at Ser40, to a stoichiometry of up to 1.0 molphosphate per mol TH subunit, dramatically increases their binding to 14-3-3 proteins." SIGNOR-250061 RPS6KA3 protein P51812 UNIPROT HIST1H2BB 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 SOX9 protein P48436 UNIPROT CEBPB protein P17676 UNIPROT "down-regulates quantity by repression" "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-184280 LPAR5 protein Q9H1C0 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-256861 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 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 NFE2L2 protein Q16236 UNIPROT GSTA1 protein P08263 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 22459801 f miannu "Different expression pattern of Nrf2 regulated genes in end-stage liver disease samples were observed: glutamate-cysteine ligase (GCLC) and glutathione-S-transferase A1 (GSTA1) were significantly down-regulated in most liver disease groups, whereas heme oxidase 1 (HMOX1) and NAD(P)H dehydrogenase [quinone] 1 (NQO1) were not significantly suppressed." SIGNOR-254644 EP300 protein Q09472 UNIPROT FLI1 protein Q01543 UNIPROT up-regulates binding 9606 24058639 t miannu "P300 promotes the interaction of fli1 with hdac1 and increases the dna binding ability of fli1 through deacetylation of lysine 380" SIGNOR-202682 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 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 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 MBD2 protein Q9UBB5 UNIPROT CHD4 protein Q14839 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000776 23071088 f lperfetto "MBD2 and multiple domains of CHD4 are required for transcriptional repression by Mi-2/NuRD complexes" SIGNOR-254102 PRKCD protein Q05655 UNIPROT BAG3 protein O95817 UNIPROT up-regulates phosphorylation Ser187 SSSSSSAsLPSSGRS 9606 23108398 t lperfetto "Pkc_-mediated phosphorylation of bag3 at ser187 site induces epithelial-mesenchymal transition and enhances invasiveness in thyroid cancer fro cells. we showed that bag3 was implicated in epithelial-mesenchymal transition (emt) procedure, and phosphorylation state at ser187 site had a critical role in emt regulation by bag3." SIGNOR-199316 PTGER2 protein P43116 UNIPROT EGFR protein P00533 UNIPROT up-regulates 9606 BTO:0000586 17251915 f gcesareni "Ep2 can also promote the transactivation of epidermal growth factor receptor (egfr) expressed in colon cancer cells through src, which activates the proteolytic release of the egfr ligands amphiregulin (ar) and transforming growth factor-alfa (tgfalfa)." SIGNOR-152805 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT "down-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" SIGNOR-246417 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 LTB4R2 protein Q9NPC1 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-256817 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 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 lapatinib chemical CHEBI:49603 ChEBI CSK protein P41240 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001949 21443688 t Luana "YN968D1 potently suppressed the kinase activities of VEGFR-2, c-kit and c-src, and inhibited cellular phosphorylation of VEGFR-2, c-kit and PDGFRβ." SIGNOR-257900 MARK1 protein Q9P0L2 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser579 NVKSKIGsTENLKHQ 9606 21215781 t "The effect has been demonstrated using P10636-8" lperfetto "Mark and pka phosphorylate several sites within the repeats (notably the kxgs motifs including ser262, ser324, and ser356, plus ser320)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-171050 NFE2L2 protein Q16236 UNIPROT HMOX1 protein P09601 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 22459801 f miannu "Different expression pattern of Nrf2 regulated genes in end-stage liver disease samples were observed: glutamate-cysteine ligase (GCLC) and glutathione-S-transferase A1 (GSTA1) were significantly down-regulated in most liver disease groups, whereas heme oxidase 1 (HMOX1) and NAD(P)H dehydrogenase [quinone] 1 (NQO1) were not significantly suppressed." SIGNOR-254641 NFE2L2 protein Q16236 UNIPROT HMOX1 protein P09601 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 24024136 f irozzo "In both models, the inducer-modified and Nrf2-bound Keap1 is inactivated and, consequently, newly synthesized Nrf2 proteins bypass Keap1 and translocate into the nucleus, bind to the ARE and drive the expression of Nrf2 target genes such as NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), glutamate-cysteine ligase (GCL) and glutathione S transferases (GSTs)." SIGNOR-256276 PHKG1 protein Q16816 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser602 INKKLDLsNVQSKCG -1 8999860 t miannu "Muscle phosphorylase kinase phosphorylates Ser237, Ser262, Ser285, Ser305, and Ser352 of human tau. in vitro phosphorylation of tau on Ser262 alone strongly reduced the ability of tau to bind microtubules whereas the phosphorylation of many Ser/Thr-Pro motif sites of tau showed moderate effects on the binding of tau to microtubules" SIGNOR-250285 PLK3 protein Q9H4B4 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" phosphorylation Ser20 PLSQETFsDLWKLLP 9606 BTO:0000452 11447225 t lperfetto "Upon exposure of cells to hydrogen peroxide (h(2)o(2)) phosphorylation of p53 was rapidly induced in human fibroblast gm00637, and this phosphorylation occurred on serine 9, serine 15, serine 20, but not on serine 392. In addition, h(2)o(2)-induced phosphorylation of p53 was followed by induction of p21, suggesting functional activation of p53. Ectopic expression of a plk3 dominant negative mutant, plk3(k52r), in gm00637 cells suppressed h(2)o(2)-induced serine 20 phosphorylation. Taken together, our studies strongly suggest that the oxidative stress-induced activation of p53 is at least in part mediated by plk3." SIGNOR-109239 PPP2CA protein P67775 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates dephosphorylation 9606 20704570 t gcesareni "Accordingly, smad3-associated pp2a activity was found under hypoxic conditions. Hypoxia attenuated the nuclear accumulation of tgf-beta-induced smad3 but did not affect smad2. Moreover, the influence of tgf-beta on a set of smad3-activated genes was attenuated by hypoxia, and this was reversed by chemical pp2a inhibition. Our data demonstrate the existence of a smad3-specific phosphatase and identify a novel role for pp2a." SIGNOR-167480 SMAD7 protein O15105 UNIPROT TAB2 protein Q9NYJ8 UNIPROT up-regulates binding 9606 BTO:0001253 17384642 t lperfetto "The formation of smad7-tab2 and smad7-tab3 complexes resulted in the suppression of tnf signaling" SIGNOR-153917 TTBK1 protein Q5TCY1 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser519 SGYSSPGsPGTPGSR 9606 BTO:0000938 16923168 t "The effect has been demonstrated using P10636-8" lperfetto "Direct tau phosphorylation by ttbk1 at ser198, ser199, ser202 and ser422, which are also phosphorylated in phfs. Ttbk1 also induces tau aggregation in human neuronal cells in a dose-dependent manner. We conclude that ttbk1 is a neuron-specific dual kinase involved in tau phosphorylation at ad-related sites and is also associated with tau aggregation." SIGNOR-148974 "lysophosphatidic acid" smallmolecule CHEBI:132742 ChEBI LPAR6 protein P43657 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-257533 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 MARK1 protein Q9P0L2 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser673 RVQSKIGsLDNITHV 9606 21215781 t "The effect has been demonstrated using P10636-8" lperfetto "Mark and pka phosphorylate several sites within the repeats (notably the kxgs motifs including ser262, ser324, and ser356, plus ser320)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-171058 CSNK2A1 protein P68400 UNIPROT FAF1 protein Q9UNN5 UNIPROT "up-regulates activity" phosphorylation Ser291 DVHMVSDsDGDDFED 9534 BTO:0001538 12832043 t llicata "We previously identified the Fas-associated factor FAF1 as an in vitro substrate of protein kinase CK2 and determined Ser289 and Ser291 as phosphorylation sites. Here we demonstrate that these two serine residues are the only sites phosphorylated by CK2 in vitro, and that at least one site is phosphorylated in vivo. Furthermore, we analyzed putative physiological functions of FAF1 phosphorylation. The ability of FAF1 to potentiate Fas-induced apoptosis is not influenced by the FAF1 phosphorylation status; however, the nuclear import of a phosphorylation-deficient FAF1 mutant was delayed in comparison to wild-type FAF1." SIGNOR-250864 CSNK2A1 protein P68400 UNIPROT GMFB protein P60983 UNIPROT unknown phosphorylation Ser53 DEELEGIsPDELKDE -1 7598724 t llicata "We report that recombinant glia maturation factor (GMF), a 17-kD brain protein, can be phosphorylated in vitro at the serine residue by protein kinase C (PKC), protein kinase A (PKA), and casein kinase II (CKII), and at the threonine residue by p90 ribosomal S6 kinase (RSK). " SIGNOR-250868 EIF2AK3 protein Q9NZJ5 UNIPROT EIF2A protein Q9BY44 UNIPROT "down-regulates activity" phosphorylation Ser265 YIATNGEsAVVQLPK 9606 BTO:0000567 25329545 t gcesareni "One of the key cellular responses to stress is the attenuation of mRNA translation and protein synthesis via the phosphorylation of eIF2 (eukaryotic translation initiation factor 2). This is mediated by four eIF2 kinases" SIGNOR-246153 EIF2AK4 protein Q9P2K8 UNIPROT EIF2A protein Q9BY44 UNIPROT "down-regulates activity" phosphorylation Ser265 YIATNGEsAVVQLPK 9606 BTO:0000567 25329545 t gcesareni "One of the key cellular responses to stress is the attenuation of mRNA translation and protein synthesis via the phosphorylation of eIF2 (eukaryotic translation initiation factor 2). This is mediated by four eIF2 kinases" SIGNOR-246157 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 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 MAP2K6 protein P52564 UNIPROT MAPK13 protein O15264 UNIPROT "up-regulates activity" phosphorylation Thr180 RHADAEMtGYVVTRW -1 9218798 t "SKK3 mediates the activation of SAPK4. Phosphorylation and activation of SAPK4 and SAPK2a by purified SKK3." SIGNOR-251424 PASK protein Q96RG2 UNIPROT PASK protein Q96RG2 UNIPROT "up-regulates activity" phosphorylation Thr1161 ERGKLFYtFCGTIEY -1 11459942 t lperfetto "We present evidence that the activity of pask is regulated by two mechanisms. Autophosphorylation at two threonine residues located within the activation loop significantly increases catalytic activity." SIGNOR-109481 PP2B proteinfamily SIGNOR-PF18 SIGNOR MAPT protein P10636 UNIPROT up-regulates dephosphorylation Ser579 NVKSKIGsTENLKHQ 9606 BTO:0000142 20308788 t "The effect has been demonstrated using P10636-8" lperfetto "Among the sites studied, thr205, thr212, ser214, and ser262 were the most favorable sites, and ser199 and ser404 were the least favorable sites for pp2a in vitro." SIGNOR-164663 RRAGC protein Q9HB90 UNIPROT RAGAC complex SIGNOR-C113 SIGNOR "form complex" binding 9606 20381137 t gcesareni "Mammals express four Rag proteins€”RagA, RagB, RagC, and RagD€”that form heterodimers consisting of RagA or RagB with RagC or RagD. RagA and RagB, like RagC and RagD, are highly similar to each other and are functionally redundant" SIGNOR-228161 SIK2 protein Q9H0K1 UNIPROT CEP250 protein Q9BV73 UNIPROT down-regulates phosphorylation Ser2392 AGLHHSLsHSLLAVA 9606 20708153 t lperfetto "Here, we show that the salt inducible kinase 2 (sik2) localizes at the centrosome, plays a key role in the initiation of mitosis, and regulates the localization of the centrosome linker protein, c-nap1, through s2392 phosphorylation" SIGNOR-167488 SMG1 protein Q96Q15 UNIPROT UPF1 protein Q92900 UNIPROT up-regulates phosphorylation Ser1107 SQIDVALsQDSTYQG 9606 23356578 t lperfetto "Smg-1 directly phosphorylates upf1 helicase, another key component of nmd, upon recognition of ptc on postspliced mrna during the initial round of translation. Phosphorylated-upf1 recruits the smg-5/smg-7 complex to induce ribosome dissociation and decapping-mediated decay. T28 and s1096 are responsible for phospho-specific recruitment of smg-6 to the n-terminal conserved region, and the smg-5/smg-7 heterodimer complex to the c-terminal sq-rich region of upf1, respectively" SIGNOR-200789 TAOK1 protein Q7L7X3 UNIPROT STK3 protein Q13188 UNIPROT up-regulates phosphorylation 9606 23431053 t gcesareni "In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2." SIGNOR-201321 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 NFE2L2 protein Q16236 UNIPROT KRT16 protein P08779 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000552 18629308 f miannu "When overexpressed in HaCaT cells, NRF2 was also directly involved in not only the up-regulation of the detoxification gene thioredoxin but also K16 gene expression." SIGNOR-254645 NFE2L2 protein Q16236 UNIPROT NQO1 protein P15559 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 22459801 f miannu "Different expression pattern of Nrf2 regulated genes in end-stage liver disease samples were observed: glutamate-cysteine ligase (GCLC) and glutathione-S-transferase A1 (GSTA1) were significantly down-regulated in most liver disease groups, whereas heme oxidase 1 (HMOX1) and NAD(P)H dehydrogenase [quinone] 1 (NQO1) were not significantly suppressed." SIGNOR-254642 MAP3K7 protein O43318 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 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-217445 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 PAK1 protein Q13153 UNIPROT PAK1 protein Q13153 UNIPROT "up-regulates activity" phosphorylation Ser57 KKDRFYRsILPGDKT 9534 BTO:0000298 9032240 t miannu "Cdc42 and Rac1 cause alpha-PAK autophosphorylation and kinase activation." SIGNOR-250219 PPP1CB protein P62140 UNIPROT NF2 protein P35240 UNIPROT up-regulates dephosphorylation Ser518 DTDMKRLsMEIEKEK 9606 18071304 t lperfetto "When serine 518 is dephosphorylated by the myosin phosphatase mypt-1-pp1?, The tumor suppressor function of merlin is activated, inhibiting the ras signaling pathway and leading to growth arrest" SIGNOR-159836 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 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 PRKCD protein Q05655 UNIPROT RPS3 protein P23396 UNIPROT up-regulates phosphorylation Ser6 sKKRKFVA 9606 19059439 t llicata "Here we show that pkcdelta phosphorylates rps3 resulting in its mobilization in the nucleus to repair damaged dna. pkc? Kinase assay then indicated that at least two residues, serine 6 and threonine 221, are phosphorylated by pkc?" SIGNOR-182619 RPS6KA1 protein Q15418 UNIPROT CDC25B protein P30305 UNIPROT up-regulates phosphorylation Thr355 NKRRRSVtPPEEQQE 9606 23708659 t lperfetto "Rsk promotes g2/m transition through activating phosphorylation of cdc25a and cdc25b rsk is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of t359/s363 in rsk. Together, these findings indicate that rsk promotes g2/m transition in mammalian cells through activating phosphorylation of cdc25a and cdc25b." SIGNOR-202125 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 SHH protein Q15465 UNIPROT MYF5 protein P13349 UNIPROT up-regulates 9606 BTO:0002314 18662193 f gcesareni "Shh reactivation plays a regulatory role on myogenesis, as its inhibition impairs the activation of the myogenic regulatory factors myf-5 and myod, decreases the up-regulation of insulin-like growth factor (igf)-1 and reduces the number of myogenic satellite cells at injured site." SIGNOR-179629 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 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 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 MAPK1 protein P28482 UNIPROT JUN protein P05412 UNIPROT "up-regulates activity" phosphorylation 9606 23616010 t lperfetto "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-201943 MECP2 protein P51608 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-254579 CSNK2A1 protein P68400 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Thr811 ADDSSSStSSDSLGG -1 8349691 t llicata "These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1." SIGNOR-250910 CSNK2A1 protein P68400 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Thr88 KHLVALYtRDEHFAI -1 8349691 t llicata "These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1." SIGNOR-250911 CSNK2A1 protein P68400 UNIPROT KIF1C protein O43896 UNIPROT unknown phosphorylation Ser1092 PRMRRQRsAPDLKES -1 10559254 t llicata "Serine 1092 was a substrate for the protein kinase casein kinase II in vitro, and inhibition of casein kinase II in cells diminished the association of KIF1C with 14-3-3gamma. Our data thus suggest that KIF1C can form dimers and is associated with proteins of the 14-3-3 family." SIGNOR-250912 CSNK2A1 protein P68400 UNIPROT L1CAM protein P32004 UNIPROT unknown phosphorylation Ser1181 GEYRSLEsDNEEKAF 10116 BTO:0000142 8592152 t llicata "Serine to alanine substitutions in these peptides indicate that the CKII phosphorylation site is at Ser1,181. | Finally, in vivo radiolabeling indicates that Ser1,181 is phosphorylated in newborn rat brain. These data show that CKII is associated with and able to phosphorylate L1." SIGNOR-250913 CSNK2A1 protein P68400 UNIPROT MYB protein P10242 UNIPROT "down-regulates activity" phosphorylation Ser11 RPRHSIYsSDEDDED -1 7735324 t llicata "For c-Myb mutational analysis of the CKII phosphorylation sites showed altered steady state DNA binding. Replacing Ser-11/12 by alanine residues resulted in increased DNA binding compared to wt c-Myb or Myb Asp-11/12 as demonstrated by up to 10-fold differences in the dissociation constants. " SIGNOR-250918 HDAC3 protein O15379 UNIPROT SMAD7 protein O15105 UNIPROT up-regulates binding 9606 23213415 t gcesareni "We show here that smad7 can form a complex with endogenous histone deacetylase proteins hdac-1 and hdac-3 in nih 3t3 mouse fibroblast cells" SIGNOR-199967 MAPK1 protein P28482 UNIPROT GRB10 protein Q13322 UNIPROT up-regulates phosphorylation Ser476 MNILGSQsPLHPSTL 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-138167 PAK1 protein Q13153 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-250235 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 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 SHH protein Q15465 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates 9606 BTO:0002314 18662193 f gcesareni "In addition, shh reactivation plays a regulatory role on myogenesis, as its inhibition impairs the activation of the myogenic regulatory factors myf-5 and myod, decreases the up-regulation of insulin-like growth factor (igf)-1 and reduces the number of myogenic satellite cells at injured site." SIGNOR-179632 SRC protein P12931 UNIPROT IKBKB protein O14920 UNIPROT "up-regulates activity" phosphorylation Tyr188 SFVGTLQyLAPELLE 9606 BTO:0002418 SIGNOR-C14 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-100784 TNFSF13B protein Q9Y275 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-81360 UHMK1 protein Q8TAS1 UNIPROT SF1 protein Q15637 UNIPROT up-regulates phosphorylation Ser82 NPEDRSPsPEPIYNS 9606 23175611 t "The effect has been demonstrated using Q15637-2" gcesareni "Sf1 is phosphorylated on serines 80 and 82 in vitro and in vivo. Kis can phosphorylate sf1f on serine 80 and 82 with a high efficiency that particularly relies on the anchoring of its uhm domain to sf1. Serine phosphorylation of a conserved ser80-pro81-ser82-pro83 motif rigidifies a long unstructured linker in the sf1 helix hairpin and slightly enhances rna binding." SIGNOR-199797 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 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 CSNK2A1 protein P68400 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-250931 CSNK2A1 protein P68400 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-250934 EP300 protein Q09472 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-70960 MAPK14 protein Q16539 UNIPROT EPS15 protein P42566 UNIPROT up-regulates phosphorylation Ser796 RSINKLDsPDPFKLN 9606 24269888 t lperfetto "Tnf-_ induces phosphorylation of eps15 at ser-796eps15 is a substrate for p38_these results suggest an attractive model in which p38 phosphorylates both eps15 and egfr to trigger efficient endocytosis" SIGNOR-203315 MAPK1 protein P28482 UNIPROT MCL1 protein Q07820 UNIPROT up-regulates phosphorylation Thr163 TDGSLPStPPPAEEE 9606 BTO:0000150 18676833 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-179808 NFE2L2 protein Q16236 UNIPROT NQO1 protein P15559 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 24024136 f irozzo "In both models, the inducer-modified and Nrf2-bound Keap1 is inactivated and, consequently, newly synthesized Nrf2 proteins bypass Keap1 and translocate into the nucleus, bind to the ARE and drive the expression of Nrf2 target genes such as NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), glutamate-cysteine ligase (GCL) and glutathione S transferases (GSTs)." SIGNOR-256275 PCSK7 protein Q16549 UNIPROT ETV6 protein P41212 UNIPROT down-regulates phosphorylation 9606 12435397 t gcesareni "In vivo p38-dependent phosphorylation reduced trans-repressional abilities of tel through ets-binding consensus site" SIGNOR-95622 PPP4C protein P60510 UNIPROT BANF1 protein O75531 UNIPROT up-regulates dephosphorylation Ser4 sQKHRDFV 9606 24265311 t lperfetto "Herein, we demonstrate we demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain. We have identified the major phosphatase responsible for dephosphorylation of ser-4 to be protein phosphatase 4 catalytic subunit." SIGNOR-203281 TRPM7 protein Q96QT4 UNIPROT ANXA1 protein P04083 UNIPROT up-regulates phosphorylation Ser5 sEFLKQAW 9606 24103589 t lperfetto "Trpm7 was responsible for phosphorylation of the serine 5 (ser5) residue [29]. In 2009, the study focused on an association between anxa1 and trpm7 confirmed the presence of a trpm7/annexin a1/mg2_+ complex, suggesting a novel pathway in bradykinin signaling, dependent on pkc and c-src [30]. Even though that pathway is not fully characterized, the same team that discovered the ser5 phosphorylation of anxa1 also reported crucial relevance of this modification for anxa1 membrane binding and especially for the interaction between annexin a1 and its known partner, the calcium binding protein s100a11" SIGNOR-202804 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 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 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 CSNK2A1 protein P68400 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-250940 DYRK1A protein Q13627 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr529 TPGSRSRtPSLPTPP 9606 21215781 t "The effect has been demonstrated using P10636-8" lperfetto "Dyrk1a phosphorylates tau at least at s202, t212 and s404, but t212 phosphorylation is known to initiate tau hyperphosphorylation by gsk3b (ryoo et al., 2007;woods et al., 2001) and has been demonstrated to have a role in alternative splicing of taumrna" SIGNOR-171038 EXT2 protein Q93063 UNIPROT EXT1/EXT2 complex SIGNOR-C51 SIGNOR "form complex" binding 9606 11518722 t miannu "Biochemical analysis shows that ext1 and ext2 are type ii transmembrane glycoproteins and form a golgi-localized hetero-oligomeric complex that catalyzes the polymerization of hs" SIGNOR-109941 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 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 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 PP2B proteinfamily SIGNOR-PF18 SIGNOR MAPT protein P10636 UNIPROT up-regulates dephosphorylation Thr522 SSPGSPGtPGSRSRT 9606 BTO:0000142 20308788 t "The effect has been demonstrated using P10636-8" lperfetto "Among the sites studied, thr205, thr212, ser214, and ser262 were the most favorable sites, and ser199 and ser404 were the least favorable sites for pp2a in vitro." SIGNOR-164671 SDHA protein P31040 UNIPROT SDHA/SDHB complex SIGNOR-C69 SIGNOR "form complex" binding 9606 23000077 t miannu "Complex ii (also known as succinate dehydrogenase (sdh) or succinate coenzyme q reductase (sqr)) is made up of only four subunits (sdha, sdhb, sdhc and sdhd) / sdha and sdhb constitute the catalytic core of the complex that on its own can oxidize succinate (which directly binds to sdha) to fumarate in the tca cycle." SIGNOR-192079 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 MCHR1 protein Q99705 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-257034 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 CSNK2A1 protein P68400 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT "up-regulates activity" phosphorylation Ser60 ETNQNSSsDSEAERR -1 11711551 t llicata "We show here that Tcf-4 can be phosphorylated in vitro by protein kinase CK2 stoichiometrically in amino acids Ser-58-Ser-59-Ser-60. Phosphorylation of these residues does not modify the interaction of Tcf-4 with beta-catenin but reduces its association to plakoglobin. | Experiments performed using a Tcf-4 mutant with decreased interaction to plakoglobin demonstrated that binding to this protein negatively affected the transcriptional activity of Tcf-4." SIGNOR-250964 CSNK2A1 protein P68400 UNIPROT TOP2A protein P11388 UNIPROT unknown phosphorylation Ser1377 KPQKSVVsDLEADDV 9606 BTO:0000567 7961967 t llicata "Tryptic phosphopeptide mapping revealed that casein kinase II phosphorylated the C-terminal domain primarily on 2 serine residues in vitro, which were shown to be sites of modification in vivo. Site-directed mutagenesis studies identified these casein kinase II-specific phosphorylation sites as serine 1524 and serine 1376." SIGNOR-250965 ERCC4 protein Q92889 UNIPROT ERCC4/ERCC1 complex SIGNOR-C50 SIGNOR "form complex" binding 9606 16338413 t miannu "Human ercc1/xpf interaction domains reveals a complementary role for the two proteins in nucleotide excision repair." SIGNOR-142992 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 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 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 MAPK1 protein P28482 UNIPROT SCNN1G protein P51170 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr622 LGTQVPGtPPPKYNT -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-249448 RAD51B protein O15315 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-111383 TBK1 protein Q9UHD2 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates phosphorylation Ser403 ESLSQMLsMGFSDEG 9606 BTO:0000801 22921120 t llicata "Tbk-1 coordinated assembly and function of the autophagic machinery and phosphorylated the autophagic adaptor p62 (sequestosome 1) on ser-403, a residue essential for its role in autophagic clearance." SIGNOR-191944 MCHR1 protein Q99705 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-257147 MDC1 protein Q14676 UNIPROT NBN protein O60934 UNIPROT up-regulates binding 9606 19230643 t gcesareni "Mdc1 also undergoes phosphorylation by ck2 after dna damage to generate a phospho-motif on mdc1, which binds directly to nbs1." SIGNOR-184141 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 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 MDFI protein Q99750 UNIPROT MYOD1 protein P15172 UNIPROT "down-regulates activity" binding 10090 BTO:0000944 8797820 t 2 miannu "We demonstrate that I-mf inhibits the transactivation activity of the MyoD family and represses myogenesis. I-mf associates with MyoD family members and retains them in the cytoplasm by masking their nuclear localization signals." SIGNOR-240436 CSNK2A1 protein P68400 UNIPROT MDC1 protein Q14676 UNIPROT up-regulates phosphorylation 9606 19230643 t gcesareni "Mdc1 also undergoes phosphorylation by ck2 after dna damage to generate a phospho-motif on mdc1, which binds directly to nbs1." SIGNOR-184130 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 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 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 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 MCL1 protein Q07820 UNIPROT BAK/BAX complex SIGNOR-C96 SIGNOR down-regulates binding 9606 17289999 t irozzo "Bax is held in check by mcl1, bcl-2, and either bcl2l1 or bcl2l2, or by all four. They bind a primed conformer of bak or bax" SIGNOR-256000 MCM10 protein Q7L590 UNIPROT RECQL4 protein O94761 UNIPROT down-regulates binding 9606 19696745 t miannu "Mcm10 inhibits recq4 helicase activity." SIGNOR-187701 MDM2 protein Q00987 UNIPROT EP300 protein Q09472 UNIPROT down-regulates binding 9606 BTO:0000567 11070080 t gcesareni "Mdm2, a negative-feedback regulator of p53, inhibited p300-mediated p53 acetylation by complexing with these two proteins." SIGNOR-84077 PRKAG3 protein Q9UGI9 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-139179 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 RASGEF1C protein Q8N431 UNIPROT NRAS protein P01111 UNIPROT up-regulates binding 9606 19201597 t gcesareni "Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras." SIGNOR-161511 TARBP2 protein Q15633 UNIPROT RISC(DICER1/AGO2/TARBP2) complex SIGNOR-C32 SIGNOR "form complex" binding 9606 16142218 t lperfetto "Dicer and trbp interact in vivo and in vitro /our data indicate that trbp is primarily required for the assembly and/or functioning of si_ or mi_riscs in mammalian cells, but it may also facilitate the cleavage of pre_mirnas by dicer." SIGNOR-140229 MDM2 protein Q00987 UNIPROT MDM4 protein O15151 UNIPROT down-regulates ubiquitination 9606 16511560 t lperfetto "The mdm2 homolog mdmx is an important regulator of p53 during mouse embryonic development. Dna damage promotes mdmx phosphorylation, nuclear translocation, and degradation by mdm2." SIGNOR-144970 MDM2 protein Q00987 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates ubiquitination 9606 23252402 t gcesareni "Although the interaction between notch1 and mdm2 results in ubiquitination of notch1, this does not result in degradation of notch1, but instead leads to activation of the intracellular domain of notch1." SIGNOR-200197 MDM2 protein Q00987 UNIPROT NOTCH4 protein Q99466 UNIPROT down-regulates ubiquitination 9606 BTO:0000149 21402876 t gcesareni "We demonstrate that the intracellular domain of notch 4 is targeted for ubiquitylation and hence degradation by the ubiquitin ligase mdm2." SIGNOR-172826 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 CAMK2A protein Q9UQM7 UNIPROT GABBR1 protein Q9UBS5 UNIPROT down-regulates phosphorylation Ser868 ITRGEWQsEAQDTMK 9606 BTO:0000938 BTO:0000142 20643921 t gcesareni "Nmda-dependent internalization of gabab receptors requires activation of ca2+/calmodulin-dependent protein kinase ii (camkii), which associates with gabab receptors in vivo and phosphorylates serine 867 (s867) in the intracellular c terminus of the gabab1 subunit." SIGNOR-166846 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 MAPK15 protein Q8TD08 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 12169099 t gcesareni "Up-regulation of c-jun mrna in cardiac myocytes requires the extracellular signal-regulated kinase cascade, but c-jun n-terminal kinases are required for efficient up-regulation of c-jun protein. these data suggest that erks, rather than jnks, are required for c- jun up-regulation." SIGNOR-91371 MAPK15 protein Q8TD08 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser73 VGLLKLAsPELERLI 9606 12169099 t gcesareni "Up-regulation of c-jun mrna in cardiac myocytes requires the extracellular signal-regulated kinase cascade, but c-jun n-terminal kinases are required for efficient up-regulation of c-jun protein. these data suggest that erks, rather than jnks, are required for c- jun up-regulation." SIGNOR-91375 MAPK15 protein Q8TD08 UNIPROT MAPK15 protein Q8TD08 UNIPROT up-regulates phosphorylation Thr175 GPEDQAVtEYVATRW 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.Our results suggest that the activity of erk8 in transfected hek-293 cells depends on the relative rates of erk8 autophosphorylation" SIGNOR-142969 MDM2 protein Q00987 UNIPROT TP73 protein O15350 UNIPROT "down-regulates activity" binding 9606 17700533 t miannu "Since HDM2, a key negative regulator of p53, also binds to and inhibits p73, we asked whether p73 could mediate Nutlin-3-induced apoptosis." SIGNOR-255470 MECOM protein Q03112 UNIPROT RUNX1 protein Q01196 UNIPROT "down-regulates activity" binding 10090 BTO:0000944 17575132 t irozzo "The results that we present here support this model and show that EVI1 interacts with and inhibits RUNX1. As for GATA1, EVI1 seems to repress RUNX1 function by interacting specifically with its DNA-binding domain Runt, leading to destabilization and dissolution of the DNA-RUNX1 complex." SIGNOR-255716 MECOM protein Q03112 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates binding 9606 9665135 t miannu "Evi-1 interacts with smad3, an intracellular mediator of tgf-beta signalling, thereby suppressing the transcriptional activity of smad3." SIGNOR-59132 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 PPM1L protein Q5SGD2 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates dephosphorylation Thr838 GINPCTEtFTGTLQY 9606 BTO:0000142;BTO:0000671 17456047 t gcesareni "Exogenous pp2cepsilon associated with exogenous ask1 in hek-293 cells under non-stressed conditions, inactivating ask1 by decreasing thr845 phosphorylation" SIGNOR-154554 PPP2CA protein P67775 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation Thr185 HDHTGFLtEYVATRW 9606 phosphorylation:Thr185 HDHTGFLtEYVATRW 16456541 t gcesareni "B56-containing pp2a dephosphorylate erk and their activity is controlled by the early gene iex-1 and erk" SIGNOR-143052 PRKG1 protein Q13976 UNIPROT TRPC3 protein Q13507 UNIPROT down-regulates phosphorylation Ser251 KNDYRKLsMQCKDFV 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-142953 MAPK3 protein P27361 UNIPROT CEBPB protein P17676 UNIPROT up-regulates phosphorylation Thr235 SSSSPPGtPSPADAK 9606 BTO:0000801 19327116 t gcesareni "Thr235 phosphorylation occurs in nuclei of differentiated macrophages, but not in monocytes." SIGNOR-184917 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 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 MAPK14 protein Q16539 UNIPROT GATA2 protein P23769 UNIPROT up-regulates phosphorylation 9606 25056917 t miannu "P38_ increases gata_2 activity at endogenous target genes by inducing gata_2 multi_site phosphorylation." SIGNOR-205242 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 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 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 DLX5 protein P56178 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 19195802 f "Expression of DLX5 is controlled by MECP2, and defect in MECP2 induced an over-expression of DLX5 in lymphocytes as well as in the brain" SIGNOR-254034 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 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 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 MPP5 protein Q8N3R9 UNIPROT AMOT/MPP5/INADL/LIN7C complex SIGNOR-C27 SIGNOR "form complex" binding 9606 24366813 t lperfetto "To gain a more detailed view on the organization of this cell polarity network linked to yap1 we included several proteins of the cell junction complex (amot, mpp5, lin7a)," SIGNOR-203494 NFE2L2 protein Q16236 UNIPROT TBXAS1 protein P24557 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000018 14565864 f miannu "Ecotopic expression of NF-E2 related factors showed that Nrf2, but not Nrf1, Nrf3, or Bach1, activated TXAS promoter in a dose-dependent manner." SIGNOR-253907 NFE2L2 protein Q16236 UNIPROT TXN protein P10599 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000552 18629308 f miannu "When overexpressed in HaCaT cells, NRF2 was also directly involved in not only the up-regulation of the detoxification gene thioredoxin but also K16 gene expression." SIGNOR-254646 NFIB protein O00712 UNIPROT EZH2 protein Q15910 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 24553933 f miannu "Nfibbinds to the ezh2 promoter and overexpression ofnfibrepresses ezh2 transcription." SIGNOR-204643 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 SMAD7 protein O15105 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-199970 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 MECP2 protein P51608 UNIPROT RELN protein P78509 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-254578 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 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 GNA12 protein Q03113 UNIPROT RHOA protein P61586 UNIPROT up-regulates binding 9606 23450633 t gcesareni "Ga12/13 recruitment of rho-gefs causes rhoa activation and f-actin assembly, which promotes lats1/lat2 inactivation by an unknown, but myosin-independent mechanism." SIGNOR-192108 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 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 MLST8 protein Q9BVC4 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-205612 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 p38 proteinfamily SIGNOR-PF16 SIGNOR MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr548 KKVAVVRtPPKSPSS 9606 21215781 t "The effect has been demonstrated using P10636-8" lperfetto "However, other kinases, such as cdk5, p38 and pka, also phosphorylate tau at t231tau phosphorylation at t231, s235 and s262 also contributes to the dissociation of tau from microtubules" SIGNOR-171062 PAK1 protein Q13153 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-205110 PRKACA protein P17612 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr548 KKVAVVRtPPKSPSS 9606 21215781 t "The effect has been demonstrated using P10636-8" lperfetto "However, other kinases, such as cdk5, p38 and pka, also phosphorylate tau at t231tau phosphorylation at t231, s235 and s262 also contributes to the dissociation of tau from microtubules" SIGNOR-171066 PRKCG protein P05129 UNIPROT ARHGEF7 protein Q14155 UNIPROT up-regulates phosphorylation Ser761 DSLGRRSsLSRLEPS 9606 25009260 t lperfetto "Pkc_ directly phosphorylates _pix at ser583 and indirectly at ser340 in cells. herefore, we propose that pkc_ positively modulates dopamine release through _2pix phosphorylation. The pkc_-_pix-cdc42/rac1 phosphorylation axis may provide a new therapeutic target for the treatment of parkinsonian syndrome" SIGNOR-205238 PRR5 protein P85299 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-205621 PTK2 protein Q05397 UNIPROT PXN protein P49023 UNIPROT "up-regulates activity" phosphorylation Tyr31 FLSEETPySYPTGNH 9606 15688067 t miannu "Paxillin is phosphorylated by FAK–Src on Tyr31 and Tyr118, and this can also promote SH2-mediated binding of Crk to paxillin. Overexpressing paxillin that is mutated at these phosphorylation sites inhibits the turnover of focal contacts6 and cell motility, which therefore supports the presence of multiple routes for FAK–Src-mediated signalling in modulating the dynamics of cell adhesion sites." SIGNOR-28247 SLX4 protein Q8IY92 UNIPROT ERCC4 protein Q92889 UNIPROT up-regulates binding 9606 SIGNOR-C50 24726326 t miannu "Slx4 is a tumor suppressor that stimulates the activity of the nuclease xpf-ercc1 in dna crosslink repair." SIGNOR-204890 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 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 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 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 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 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 PPP1CA protein P62136 UNIPROT PFN1 protein P07737 UNIPROT up-regulates dephosphorylation Ser138 MASHLRRsQY 9606 22479341 t lperfetto "Knockdown of the catalytic subunit of pp1 (pp1c_), but not pp2a (pp2ac_), increased ps137-pfn1 levels. Pp1c_ binds pfn1 in cultured cells, and this interaction was increased by a phosphomimetic mutation of pfn1 at ser-137 (s137d). Together, these data define pp1 as the principal phosphatase for ser-137 of pfn1" SIGNOR-196816 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 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 PRKCA protein P17252 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-197289 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 PTK2 protein Q05397 UNIPROT PXN protein P49023 UNIPROT "up-regulates activity" phosphorylation Tyr118 VGEEEHVySFPNKQK 9606 15688067 t miannu "Paxillin is phosphorylated by FAK–Src on Tyr31 and Tyr118, and this can also promote SH2-mediated binding of Crk to paxillin. Overexpressing paxillin that is mutated at these phosphorylation sites inhibits the turnover of focal contacts6 and cell motility, which therefore supports the presence of multiple routes for FAK–Src-mediated signalling in modulating the dynamics of cell adhesion sites." SIGNOR-28243 TAOK3 protein Q9H2K8 UNIPROT STK4 protein Q13043 UNIPROT up-regulates phosphorylation 9606 23431053 t gcesareni "In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2" SIGNOR-192762 TBK1 protein Q9UHD2 UNIPROT IRF5 protein Q13568 UNIPROT up-regulates phosphorylation Ser158 QRMLPSLsLTEDVKW 9606 22412986 t lperfetto "Activation of interferon regulatory factor 5 by site specific phosphorylation. Although the gene induction by irf5 in the presence of tbk-1 was modest, phosphorylation by tbk-1 produced a significant shift in the mobility of irf5 in sds-page. For this reason we identified the residues that are phosphorylated on irf5 by tbk-1 with mass spectrometry. Ser-158 and ser-309 were found to be phosphorylated" SIGNOR-196528 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 MEF2A protein Q02078 UNIPROT MYF6 protein P23409 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165;BTO:0000222 7739551 t lperfetto "Myogenin and MEF2 function synergistically to activate the MRF4 promoter during myogenesis." SIGNOR-238709 EFNB3 protein Q15768 UNIPROT EPHB3 protein P54753 UNIPROT up-regulates binding 9606 9484836 t gcesareni "Ephrin-b3, a ligand for the receptor ephb3, expressed at the midline of the developing neural tube." SIGNOR-54711 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 IRF4 protein Q15306 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 BTO:0000801 22378047 f lperfetto "IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing JMJD3-IRF4 axis to inhibit IRF5-mediated M1 polarization." SIGNOR-249559 MAP2K1 protein Q02750 UNIPROT PPARG protein P37231 UNIPROT "down-regulates activity" phosphorylation Ser112 AIKVEPAsPPYYSEK 9606 18596912 t lperfetto "In conclusion, PPAR emerges as a tumor-type and tumor-stage-specific modulator that is regulated by at least three mechanisms through the ERK cascade. Downregulation is carried out through (1) MAPK-mediated Ser84/114 phosphorylation, (2) ERK cascade activation through PPAR ligands, and (3) cooperation of PPAR with tumor modulating proteins (such as MEK1)" SIGNOR-179390 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 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 MEF2A protein Q02078 UNIPROT Myoblast_fusion phenotype SIGNOR-PH98 SIGNOR up-regulates 9606 BTO:0001103 19725819 f areggio "In response to increases in intracellular Ca2+ levels, activated CaMKII translocates into the nucleus where it phosphorylates and deactivates HDAC4 which, as a result, dissociates from theDNA-binding domain of MEF2. This dissociation allows MEF2 to bind to its DNA-binding domain to activate transcription of the MEF2-dependent target gene products MyoD and myogenin" SIGNOR-255957 PLK1 protein P53350 UNIPROT BUB1B protein O60566 UNIPROT up-regulates phosphorylation Thr680 IEDSREAtHSSGFSG 9606 23079597 t lperfetto "Phosphorylation of kard by plk1 promotes direct interaction of bubr1 with the pp2a-b56_ phosphatase that counters excessive aurora b activity at kinetochores. We propose that plk1 and bubr1 cooperate to stabilize kinetochore-microtubule interactions. Phosphorylation of t680 by plk1 is essential for kard function" SIGNOR-199222 PRKACA protein P17612 UNIPROT DYNLRB1 protein Q9NP97 UNIPROT up-regulates phosphorylation Ser73 LTFLRIRsKKNEIMV 9606 23333499 t llicata "Our results show that km23-1 is required for camp-responsive element (cre) transcriptional activation by tgf_, with s73-km23-1 being required for the cre-dependent tgf_ stimulation of fibronectin (fn) transcription." SIGNOR-200456 PRKACA protein P17612 UNIPROT VASP protein P50552 UNIPROT "up-regulates activity" phosphorylation Ser157 EHIERRVsNAGGPPA 9606 BTO:0000132 12576312 t miannu "PKA but not PKG plays a predominant role in cGMP- or NO donorinduced VASP phosphorylation at Ser239‚ and Ser157‚ in human platelets. PKA plays a predominant role in the cGMP-induced phosphorylation of VASP and platelet inhibition in human platelets." SIGNOR-250064 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 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 UHMK1 protein Q8TAS1 UNIPROT SF1 protein Q15637 UNIPROT up-regulates phosphorylation Ser80 PPNPEDRsPSPEPIY 9606 23175611 t "The effect has been demonstrated using Q15637-2" gcesareni "Sf1 is phosphorylated on serines 80 and 82 in vitro and in vivo. Kis can phosphorylate sf1f on serine 80 and 82 with a high efficiency that particularly relies on the anchoring of its uhm domain to sf1. Serine phosphorylation of a conserved ser80-pro81-ser82-pro83 motif rigidifies a long unstructured linker in the sf1 helix hairpin and slightly enhances rna binding." SIGNOR-199793 WWTR1 protein Q9GZV5 UNIPROT BAX protein Q07812 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001615 22470139 f miannu "Efficient knockdown of WWTR1, demonstrated by quantitative real-time PCR, led to upregulation of ASNS and downregulation of SMAD3, LTBR, BAX and BAK1 in WWTR1 knockdown cells, suggesting that these genes may be involved in the repression of cell proliferation." SIGNOR-255606 MAPK3 protein P27361 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-120260 MEF2C protein Q06413 UNIPROT CDKL5 protein O76039 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20513142 f "Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression|In these patients we found diminished MECP2 and CDKL5 expression in vivo, and transcriptional reporter assays indicated that MEF2C mutations diminish synergistic transactivation of E-box promoters including that of MECP2 and CDKL5." SIGNOR-254031 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 CSNK2A1 protein P68400 UNIPROT JUN protein P05412 UNIPROT down-regulates phosphorylation Thr231 ALKEEPQtVPEMPGE 9606 1516134 t lperfetto "Casein kinase ii is a negative regulator of c-jun dna binding and ap-1 activitywe show that two of these sites, thr-231 and ser-249, are phosphorylated by casein kinase ii (ckii)." SIGNOR-19607 H2AFX 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 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 SORBS3 protein O60504 UNIPROT unknown phosphorylation Ser530 DGPQLPTsPRLTAAA 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-125221 MAPK3 protein P27361 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-120256 PPP2CB protein P62714 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates dephosphorylation Thr216 RSSSSEStGTPSNPD 9606 11983168 t fstefani "Cyclin g also binds in vivo and in vitro to mdm2 and markedly stimulates the ability of pp2a to dephosphorylate mdm2 at t216. Our data imply that the function of cyclin g is to serve as a negative regulator of p53 by activating mdm2 through dephosphorylation." SIGNOR-86736 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 PRKD1 protein Q15139 UNIPROT ARFIP1 protein P53367 UNIPROT up-regulates phosphorylation Ser132 LELVRKWsLNTYKCT 9606 23695357 t lperfetto "We report that arfaptins contain an amphipathic helix (ah) preceding the bar domain, which is essential for their binding to phosphatidylinositol 4-phosphate (pi(4)p)-containing liposomes and the tgn of mammalian cells. The binding of arfaptin1, but not arfaptin2, to pi(4)p is regulated by protein kinase d (pkd) mediated phosphorylation at ser100 within the ah. We also found that only arfaptin1 is required for the pkd-dependent trafficking of chromogranin a by the regulated secretory pathway." SIGNOR-202101 ROCK1 protein Q13464 UNIPROT PTEN protein P60484 UNIPROT up-regulates phosphorylation Ser229 VKIYSSNsGPTRRED 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-134851 SERPINE1 protein P05121 UNIPROT Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 10368279 f gcesareni "Pai-1 is now being identified as a key player in the link between coagulation and the cell adhesion pathways involved in tissue remodeling and metastasis. Active pai-1 (but not its latent or cleaved forms) binds tightly to the adhesive glycoprotein vitronectin in the extracellular matrix." SIGNOR-68478 TBK1 protein Q9UHD2 UNIPROT IKBKB protein O14920 UNIPROT up-regulates binding 9606 14743216 t fstefani "A physical and functional map of the human tnf-alpha/nf-kappa b signal transduction pathway." SIGNOR-121576 WWTR1 protein Q9GZV5 UNIPROT LTBR protein P36941 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001615 22470139 f miannu "Efficient knockdown of WWTR1, demonstrated by quantitative real-time PCR, led to upregulation of ASNS and downregulation of SMAD3, LTBR, BAX and BAK1 in WWTR1 knockdown cells, suggesting that these genes may be involved in the repression of cell proliferation." SIGNOR-255604 WWTR1 protein Q9GZV5 UNIPROT TEAD2 protein Q15562 UNIPROT up-regulates binding 9606 23431053 t "YAP/TAZ mainly bind to the transcription factors TEAD1??4 to regulate genes involved in cell proliferation and cell death." gcesareni "When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14." SIGNOR-201382 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 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 DYRK2 protein Q92630 UNIPROT SIAH2 protein O43255 UNIPROT up-regulates phosphorylation Ser16 PSANKPCsKQPPPQP 9606 22878263 t llicata "In the present study, we identify the serine/threonine kinase dyrk2 as siah2 interaction partner that phosphorylates siah2 at five residues (ser16, thr26, ser28, ser68, and thr119). accordingly, phosphorylated siah2 is more active than the wild-type e3 ligase and shows an increased ability to trigger the hif-1?-Mediated transcriptional response and angiogenesis." SIGNOR-198721 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 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 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 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 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 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 PRKCG protein P05129 UNIPROT ARHGEF7 protein Q14155 UNIPROT up-regulates phosphorylation Ser518 LSASPRMsGFIYQGK 9606 25009260 t lperfetto "Pkc_ directly phosphorylates _pix at ser583 and indirectly at ser340 in cells. herefore, we propose that pkc_ positively modulates dopamine release through _2pix phosphorylation. The pkc_-_pix-cdc42/rac1 phosphorylation axis may provide a new therapeutic target for the treatment of parkinsonian syndrome" SIGNOR-205234 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 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 RAD50 protein Q92878 UNIPROT MRE11 protein P49959 UNIPROT up-regulates binding 9606 17713585 t fstefani "To organize the mrn complex, the mre11 exonuclease directly binds nbs1, dna, and rad50." SIGNOR-157478 SRPK2 protein P78362 UNIPROT CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000938 BTO:0000142 19592491 f lperfetto "Compared with control, srpk2 wild type evidently elevated cyclin d1 transcription, and the catalytic activity was lost in srpk2 kd, suggesting that kinase activity of srpk2 is required for this effect." SIGNOR-186763 TLR4 protein O00206 UNIPROT Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 20596954 f fstefani "Regulation of toll-like receptor signaling in the innate immunity." SIGNOR-166485 TLR4 protein O00206 UNIPROT Interferon_Production phenotype SIGNOR-PH16 SIGNOR up-regulates 9606 20596954 f fstefani "Regulation of toll-like receptor signaling in the innate immunity." SIGNOR-166488 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 PINK1 protein Q9BXM7 UNIPROT PRKN protein O60260 UNIPROT up-regulates phosphorylation Ser65 NCDLDQQsIVHIVQR 9606 22724072 t llicata "We show that human pink1 is specifically activated by mitochondrial membrane potential (??m) depolarization, enabling it to phosphorylate parkin at ser(65). We further show that phosphorylation of parkin at ser(65) leads to marked activation of its e3 ligase activity that is prevented by mutation of ser(65) or inactivation of pink1." SIGNOR-197976 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 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 CHEK2 protein O96017 UNIPROT PML protein P29590 UNIPROT unknown phosphorylation Ser117 ESLQRRLsVYRQIVD 9606 12402044 t llicata "Hcds1/chk2 phosphorylates pml at ser 117 in vitro. hcds1/chk2 phosphorylates pml in vivo." SIGNOR-94872 DYRK2 protein Q92630 UNIPROT SIAH2 protein O43255 UNIPROT up-regulates phosphorylation Ser68 GGGAGPVsPQHHELT 9606 22878263 t llicata "In the present study, we identify the serine/threonine kinase dyrk2 as siah2 interaction partner that phosphorylates siah2 at five residues (ser16, thr26, ser28, ser68, and thr119). accordingly, phosphorylated siah2 is more active than the wild-type e3 ligase and shows an increased ability to trigger the hif-1?-Mediated transcriptional response and angiogenesis." SIGNOR-198729 DYRK2 protein Q92630 UNIPROT SIAH2 protein O43255 UNIPROT up-regulates phosphorylation Thr119 PTCRGALtPSIRNLA 9606 22878263 t llicata "In the present study, we identify the serine/threonine kinase dyrk2 as siah2 interaction partner that phosphorylates siah2 at five residues (ser16, thr26, ser28, ser68, and thr119). accordingly, phosphorylated siah2 is more active than the wild-type e3 ligase and shows an increased ability to trigger the hif-1?-Mediated transcriptional response and angiogenesis." SIGNOR-198733 GSK3A protein P49840 UNIPROT JUN protein P05412 UNIPROT down-regulates phosphorylation Ser243 PGETPPLsPIDMESQ 9606 1846781 t lperfetto "Phosphorylation of recombinant human c-jun proteins in vitro by gsk-3 decreases their dna-binding activity." SIGNOR-21776 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 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 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 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 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 RPS6KA1 protein Q15418 UNIPROT CCT2 protein P78371 UNIPROT up-regulates phosphorylation Ser260 GSRVRVDsTAKVAEI 9606 21440620 t lperfetto "Furthermore, both the s260a and s260d mutants showed a decreased folding capacity as compared to cells expressing the wild-type cct_ subunit ( fig.?_5e), suggesting that a cyclic phosphorylation of the s260 site by s6k1 is likely to be important for chaperonin function and that mutation of this site interferes with this process." SIGNOR-172986 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 SEMA3A protein Q14563 UNIPROT PLXNA2 protein O75051 UNIPROT up-regulates binding 9606 10679438 t gcesareni "Plexins form stable complexes with neuropilin-1 or -2." SIGNOR-75168 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 MEF2C protein Q06413 UNIPROT CPT1B protein Q92523 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000167 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-254583 MEF2C protein Q06413 UNIPROT MECP2 protein P51608 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20513142 f "Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression|In these patients we found diminished MECP2 and CDKL5 expression in vivo, and transcriptional reporter assays indicated that MEF2C mutations diminish synergistic transactivation of E-box promoters including that of MECP2 and CDKL5." SIGNOR-254025 IL22RA1 protein Q8N6P7 UNIPROT STAT3 protein P40763 UNIPROT up-regulates 9606 12087100 f gcesareni "Il-22 also induced serine phosphorylation of stat3 on ser(727)." SIGNOR-90162 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 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 MAPK7 protein Q13164 UNIPROT KLF2 protein Q9Y5W3 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-255454 MEF2C protein Q06413 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-238754 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 NTRK2 protein Q16620 UNIPROT NCK2 protein O43639 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 12074588 t gcesareni "We identified the nck2 adaptor protein as a novel interaction partner of the active form of trkb. Additionally, we identified three tyrosines in icd-trkb (y694, y695, and y771) that are crucial for this interaction." SIGNOR-89764 NTRK2 protein Q16620 UNIPROT SHC3 protein Q92529 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 9507002 t gcesareni "Our present study established that n-shc and sck are expressed in a region-specific manner in the brain and that n-shc is a higher affinity adapter molecule than sck for trka and trkb receptors" SIGNOR-55864 PAK1 protein Q13153 UNIPROT FLNA protein P21333 UNIPROT up-regulates phosphorylation Ser2152 TRRRRAPsVANVGSH 9606 12198493 t gcesareni "In flna, the pak1-binding site involves tandem repeat 23 in the carboxyl terminus and phosphorylation takes place on serine 2152." SIGNOR-92065 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT "up-regulates activity" phosphorylation Tyr716 RPPSAELySNALPVG -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-250256 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT "up-regulates activity" phosphorylation Tyr740 TGESDGGyMDMSKDE -1 8195171 t miannu "Synthetic peptide analysis revealed that certain autophosphorylation sites in the PDGF beta-receptor (Tyr-579, Tyr-740, Tyr-751, and Tyr-771) were able to mediate the specific binding of the Shc SH2 domain as well as intact Shc proteins." SIGNOR-250257 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 SUFU protein Q9UMX1 UNIPROT up-regulates phosphorylation Ser342 LAHDRAPsRKDSLES 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-200492 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 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 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 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 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 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 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 FBXW11 protein Q9UKB1 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates ubiquitination Lys21 EGPRDGLkKERLLDD 9606 7479976 t gcesareni "Here we provide evidence that lysine residues 21 and 22 serve as the primary sites for signal-induced ubiquitination of i kappa b alpha." SIGNOR-26573 JNK proteinfamily SIGNOR-PF15 SIGNOR BCL2L1 protein Q07817 UNIPROT down-regulates phosphorylation Thr115 LTSQLHItPGTAYQS 9606 10617621 t lperfetto "Sapk phosphorylates bcl-x(l) on threonine 47 (thr-47) and threonine 115 (thr-115) in vitro and in vivo. In contrast to wild-type bcl-x(l), a mutant bcl-x(l) with the two threonines substituted by alanines (ala-47, ala-115) is a more potent inhibitor of ionizing radiation-induced apoptosis" SIGNOR-73638 JNK proteinfamily SIGNOR-PF15 SIGNOR BCL2L1 protein Q07817 UNIPROT down-regulates phosphorylation Thr47 GTESEMEtPSAINGN 9606 10617621 t lperfetto "Sapk phosphorylates bcl-x(l) on threonine 47 (thr-47) and threonine 115 (thr-115) in vitro and in vivo. In contrast to wild-type bcl-x(l), a mutant bcl-x(l) with the two threonines substituted by alanines (ala-47, ala-115) is a more potent inhibitor of ionizing radiation-induced apoptosis" SIGNOR-73642 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 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 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 PRKCD protein Q05655 UNIPROT HMGA1 protein P17096 UNIPROT down-regulates phosphorylation Ser44 PGTALVGsQKEPSEV 9606 10617144 t fspada "In this study, we showed that the pkc-mediated phosphorylation of hmg-i exerted a very potent inhibition on the binding of this protein to the at-rich promoter regions of both pkc g and ng genes. The purified hmg-i can be phosphorylated by pkc a,b, g, and d but is poorly phosphorylated by pkc e and z. We have mapped two major sites of phosphorylation by pkc at ser44 and ser64" SIGNOR-73606 PRKCD protein Q05655 UNIPROT HMGA1 protein P17096 UNIPROT down-regulates phosphorylation Ser64 PRGRPKGsKNKGAAK 9606 10617144 t fspada "In this study, we showed that the pkc-mediated phosphorylation of hmg-i exerted a very potent inhibition on the binding of this protein to the at-rich promoter regions of both pkc g and ng genes. The purified hmg-i can be phosphorylated by pkc a,b, g, and d but is poorly phosphorylated by pkc e and z. We have mapped two major sites of phosphorylation by pkc at ser44 and ser64" SIGNOR-73610 SIK2 protein Q9H0K1 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Ser794 QHLRLSTsSGRLLYA 9606 12624099 t lperfetto "Sik2 could phosphorylate ser(794) of human irs-1" SIGNOR-99059 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 PATZ1 protein Q9HBE1 UNIPROT RNF4 protein P78317 UNIPROT down-regulates binding 9606 10713105 t miannu "In vitro and in vivo interaction between rnf4 and patz was demonstrated / patz acted as a transcriptional repressor, whereas its partner rnf4 behaved as a transcriptional activator./ the association of patz with rnf4 switches activation to repression" SIGNOR-75775 FYN protein P06241 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Tyr18 MEDHAGTyGLGDRKD 9606 BTO:0000938 BTO:0000142 14999081 t lperfetto "In this study we determined that human tau tyr18 was phosphorylated by the src family tyrosine kinase fyn." SIGNOR-123099 GRK5 protein P34947 UNIPROT SNCA protein P37840 UNIPROT down-regulates phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 BTO:0000938 BTO:0000142 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 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 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 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 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 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 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 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 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 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 PLK1 protein P53350 UNIPROT SNCA protein P37840 UNIPROT up-regulates phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 BTO:0000938 BTO:0000142 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 PLK3 protein Q9H4B4 UNIPROT SNCA protein P37840 UNIPROT up-regulates phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 BTO:0000938 BTO:0000142 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-189053 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 MEF2C protein Q06413 UNIPROT MYOD1 protein P15172 UNIPROT "up-regulates activity" binding 9606 BTO:0000887;BTO:0001103 9418854 t lperfetto "Myod-e protein heterodimers interact with mef2 proteins to synergistically activate myogenesis." SIGNOR-54089 CSNK2A1 protein P68400 UNIPROT SPIB protein Q01892 UNIPROT down-regulates phosphorylation Ser129 PYPSPVLsEEEDLPL 9606 10618498 t lperfetto "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. Mutations of the ckii phosphorylation sites increase the ability of spi-b to transactivate. Spi-b phosphorylation by ckii reduces its stability" SIGNOR-73879 CSNK2A1 protein P68400 UNIPROT SPIB protein Q01892 UNIPROT down-regulates phosphorylation Ser144 DSPALEVsDSESDEA 9606 10618498 t lperfetto "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. Mutations of the ckii phosphorylation sites increase the ability of spi-b to transactivate. Spi-b phosphorylation by ckii reduces its stability" SIGNOR-73883 CSNK2A1 protein P68400 UNIPROT SPIB protein Q01892 UNIPROT down-regulates phosphorylation Ser146 PALEVSDsESDEALV 9606 10618498 t lperfetto "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. Mutations of the ckii phosphorylation sites increase the ability of spi-b to transactivate. Spi-b phosphorylation by ckii reduces its stability" SIGNOR-73887 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 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 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 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 MAPT protein P10636 UNIPROT "Neurofibrillary tangle formation" phenotype SIGNOR-PH58 SIGNOR up-regulates 9606 BTO:0000590 11578751 f lperfetto "Tau is a multifunctional microtubule-associated protein that plays major roles in the assembly of microtubules, the stabilization of microtubules against dynamic instability, and in bridging these polymers with other cytoskeletal filaments 43, 44, 45, 46 and 47. In normal brain, the equilibrium between phosphorylations and dephosphorylations of tau modulates the stability of the cytoskeleton and consequently axonal morphology. The earliest modification found in Alzheimer brains consists of hyperphosphorylations on tau by the action of different protein kinase and phosphatase systems that appear to lead to structural and conformational changes in this protein, thus affecting its binding with tubulin and the capacity to promote microtubule assembly" SIGNOR-251642 PELI3 protein Q8N2H9 UNIPROT JUN protein P05412 UNIPROT up-regulates 9606 12874243 f gcesareni "Pellino3 leads to activation of c-jun and elk-1, but not nf-kappab" SIGNOR-103989 PLK3 protein Q9H4B4 UNIPROT SNCB protein Q16143 UNIPROT up-regulates phosphorylation Ser118 LMEPEGEsYEDPPQE 9606 BTO:0000938 BTO:0000142 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-189057 PRKACA protein P17612 UNIPROT KCNJ12 protein Q14500 UNIPROT "down-regulates activity" phosphorylation Ser431 QRPYRREsEI 9534 BTO:0001538 11181181 t miannu "Phosphorylation of the Kir2.2 C terminus by protein kinase A inhibited the association with SAP97.‚ " SIGNOR-249998 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 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 PRKDC protein P78527 UNIPROT RPA2 protein P15927 UNIPROT unknown phosphorylation Thr21 YGGAGGYtQSPGGFG 9606 14872059 t llicata "We show that both dna-pk and atm phosphorylate rpa32 on thr21 in vitro." SIGNOR-121873 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 MEF2D protein Q14814 UNIPROT MYH10 protein P35580 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-238766 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 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 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 FADD protein Q13158 UNIPROT RIPK1 protein Q13546 UNIPROT "up-regulates activity" binding 9606 BTO:0002025 21525013 t lperfetto "Rip1 is required for the formation of a rip1/fadd/caspase-8 complex that drives caspase-8 activation, cleavage of bid into tbid, mitochondrial outer membrane permeabilization, full activation of caspase-3 and caspase-dependent apoptosis. Tweak induces assembly of a death-signaling complex containing rip1, fadd, and caspase-8" SIGNOR-173429 GNAT1 protein P11488 UNIPROT ADCY1 protein Q08828 UNIPROT down-regulates binding 9606 8327893 t gcesareni "Members of the gi family are linked with reductions in camp through adenylyl cyclase, but have many other actions as well" SIGNOR-38137 IL1R1 protein P14778 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 21304099 f lperfetto "The Il-1 family of ligands and receptors is primarily associated with acute and chronic inflammation." SIGNOR-171876 KHSRP protein Q92945 UNIPROT CDKN1A protein P38936 UNIPROT "down-regulates quantity by destabilization" "post transcriptional regulation" 10090 BTO:0000165 16364914 t lperfetto "Importantly, KSRP knockdown in C2C12 GM cells (Figure 2D) stabilized endogenous my- ogenin and p21 transcripts (Figure 2E). Furthermore, stable knockdown of KSRP, using shRNA, induced the accumulation of p21 mRNA in C2C12 GM while it did not affect the expression of late myogenic markers (MHC and muscle-creatine kinase [MCK])" SIGNOR-235859 MEF2D protein Q14814 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-238751 PPP2CA protein P67775 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates dephosphorylation 9606 19061640 t gcesareni "In the absence of the wt apc protein, phosphorylated beta-catenin is rapidly dephosphorylated by serine/threonine protein phosphatase 2a (pp2a). phosphorylated beta-catenin associated with the wild-type apc protein is recruited to the scf(beta-trcp) complex, ubiquitin conjugated, and degraded." SIGNOR-182637 PRKCD protein Q05655 UNIPROT TNNI3 protein P19429 UNIPROT up-regulates phosphorylation Ser23 PAPIRRRsSNYRAYA 9606 18550549 t gcesareni "Src phosphorylates pkcdelta at tyr311 and tyr332 leading to enhanced pkcdelta autophosphorylation at thr505 (its activation loop) and pkcdelta-dependent ctni phosphorylation at both ser23/ser24 and thr144." SIGNOR-178880 RB1 protein P06400 UNIPROT ABL1 protein P00519 UNIPROT down-regulates binding 9606 8242749 t gcesareni "A domain in the c-terminus of rb, outside of the a/b pocket, binds to the atp-binding lobe of the c-abl tyrosine kinase, resulting in kinase inhibition." SIGNOR-37139 RPS6KB1 protein P23443 UNIPROT POLDIP3 protein Q9BY77 UNIPROT unknown phosphorylation Ser383 ELPRRVNsASSSNPP 9606 15341740 t llicata "Here we identify skar as a novel and specific binding partner and substrate of s6k1 but not s6k2. We find that serines 383 and 385 of human skar are insulin-stimulated and rapamycin-sensitive s6k1 phosphorylation sites." SIGNOR-128495 SGK1 protein O00141 UNIPROT HTT protein P42858 UNIPROT down-regulates phosphorylation Ser419 GGRSRSGsIVELIAG 9606 BTO:0000938 BTO:0000142 14725621 t llicata "The serum- and glucocorticoid-induced kinase sgk inhibits mutant huntingtin-induced toxicity by phosphorylating serine 421 of huntingtin." SIGNOR-121349 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 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 EIF2AK1 protein Q9BQI3 UNIPROT EIF2S1 protein P05198 UNIPROT up-regulates phosphorylation Ser49 IEGMILLsELSRRRI 9606 10563826 t lperfetto "The wild-type and ser-48 mutant proteins became extensively phosphorylated by eif-2 kinases present in the reticulocyte lysate. These findings support the hypothesis that the serine 48 residue is required for high-affinity interaction between eif2 alpha(p) and eif2b." SIGNOR-72152 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 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 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 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 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 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 MAPK14 protein Q16539 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-74560 PTK2 protein Q05397 UNIPROT SH3GL1 protein Q99961 UNIPROT unknown phosphorylation Tyr315 QPSCKALyDFEPEND 9606 16054026 t llicata "These results identified y315 of endophilin a2 as a major phosphorylation site by fak/src complex. tyr315 phosphorylation inhibited endophilin/dynamin interactions, and blockade of tyr315 phosphorylation promoted endocytosis of mt1-mmp." SIGNOR-139146 PTPN12 protein Q05209 UNIPROT SHC1 protein P29353 UNIPROT down-regulates dephosphorylation Tyr349 EEPPDHQyYNDFPGK 9606 8939605 t gcesareni "The shc adaptor protein is highly phosphorylated at conserved, twin tyrosine residues (y239/240) that mediate protein-protein interactions." SIGNOR-44361 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 RASSF5 protein Q8WWW0 UNIPROT RASSF1 protein Q9NS23 UNIPROT "up-regulates activity" binding 9606 22195963 t lperfetto "NORE1A can heterodimerize with RASSF1A and, thus, mediate K-Ras regulation of RASSF1A" SIGNOR-249587 RYBP protein Q8N488 UNIPROT ABL1 protein P00519 UNIPROT down-regulates binding 9606 8943360 t gcesareni "We identified a novel protein, aap1 (abl-associated protein 1), that associates with these c-abl domains and fails to bind to the sh3 domain in the activated oncoprotein bcrabl. we conclude that aap1 inhibits c-abl tyrosine kinase activity" SIGNOR-45325 STK11 protein Q15831 UNIPROT PRKAA1 protein Q13131 UNIPROT "up-regulates activity" phosphorylation Thr183 SDGEFLRtSCGSPNY -1 16054095 t lperfetto "The AMP-activated protein kinase (AMPK) is a critical regulator of energy balance at both the cellular and whole-body levels. Two upstream kinases have been reported to activate AMPK in cell-free assays, i.e., the tumor suppressor LKB1 and calmodulin-dependent protein kinase kinase." SIGNOR-139297 TP53BP2 protein Q13625 UNIPROT PPP1R14A protein Q96A00 UNIPROT down-regulates binding 9606 8549741 t gcesareni "The phosphorylase phosphatase activity of pp1 was inhibited by p53bp2 at nanomolar concentrations." SIGNOR-39666 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 MEF2D protein Q14814 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-238712 CSNK2A1 protein P68400 UNIPROT MAPK9 protein P45984 UNIPROT unknown phosphorylation Thr404 SSMSTEQtLASDTDS 9606 11062067 t lperfetto "The phosphorylation of thr-404 and ser-407 is not increased in response to other agonists that activate mkk7 and sapk1/jnk, suggesting that phosphorylation of these residues is catalysed by another protein kinase, such as ck2, which also phosphorylates thr-404 and ser-407 in vitro." SIGNOR-83715 DAXX protein Q9UER7 UNIPROT FAS protein P25445 UNIPROT down-regulates binding 9606 9215629 t gcesareni "A c-terminal portion of daxx interacts with the fas death domain. The fas-binding domain of daxx is a dominant-negative inhibitor of both fas-induced apoptosis and jnk activation." SIGNOR-49473 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 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 HRK protein O00198 UNIPROT BCL2 protein P10415 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-47794 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 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 MEF2D protein Q14814 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-151679 MEIS1 protein O00470 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0001271 19109563 f irozzo "To discern the mechanisms by which Meis1 inhibition leads to reduced cell growth, we performed cell-cycle and apoptosis analyses.Meis1 knockdown also resulted in increased apoptosis, as evidenced by increased uptake of PI and a stain for activated caspases (CaspaTag) by M26-transduced cells compared with control cells. These results indicate that Meis1 is required for proliferation and survival of 4166 leukemia cells." SIGNOR-255860 MEIS1 protein O00470 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001271 19109563 f irozzo "These results show that MEIS1 expression is important for MLL-rearranged leukemias and suggest that MEIS1 promotes cell-cycle entry.Flow cytometric analysis of PI-stained nuclei showed that Meis1 knockdown led to a cell-cycle arrest in the G0/G1 phase." SIGNOR-255859 TBX2 protein Q13207 UNIPROT CDKN1A protein P38936 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002267 25211658 t lperfetto "TBX2 and TBX3 function as transcriptional repressors and both have been shown to inhibit myogenesis (Carlson et al, 2002; Zhu et al, 2014). Abnormal expression of TBX2 has been reported in several cancers including breast, pancreas, and melanoma, where it has been shown to drive proliferation (reviewed in Abrahams et al (2010)). As has been previously shown in other cell types, TBX2 was found to induce a downregulation of p14/19ARF and function as a direct repressor of p21 in RMS" SIGNOR-249593 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 TRADD protein Q15628 UNIPROT FADD protein Q13158 UNIPROT "up-regulates activity" binding 9606 18545270 t lperfetto "Tradd recruits fadd" SIGNOR-177958 MCHR2 protein Q969V1 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-257268 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 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 FZD8 protein Q9H461 UNIPROT LRP6 protein O75581 UNIPROT "up-regulates activity" binding 9606 BTO:0000971 21078818 t amattioni "Ligands such as Wnt1, Wnt3a, and Wnt8 couple the seven-transmembrane 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-169638 IKBKE protein Q14164 UNIPROT IRF3 protein Q14653 UNIPROT "up-regulates activity" phosphorylation Ser396 NTVDLHIsNSHPLSL -1 18440553 t lperfetto "Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404." SIGNOR-178371 METTL21C protein Q5VZV1 UNIPROT VCP protein P55072 UNIPROT "up-regulates activity" methylation Lys315 AIAPKREkTHGEVER 10090 BTO:0002319 29719249 t "We reveal that METTL21C trimethylates p97 on the Lys315 residue and found that loss of this modification reduced p97 hexamer formation and ATPase activity in vivo." SIGNOR-255918 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 PRKCA protein P17252 UNIPROT EWSR1 protein Q01844 UNIPROT down-regulates 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 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 PRKCB protein P05771 UNIPROT EWSR1 protein Q01844 UNIPROT down-regulates 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 PTK2 protein Q05397 UNIPROT ACTN1 protein P12814 UNIPROT down-regulates phosphorylation Tyr12 DSQQTNDyMQPEEDW 9606 23454549 t lperfetto "Phosphorylation at y12 by fak reduces _-actinin1's affinity for actin ." SIGNOR-192126 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 PTPN6 protein P29350 UNIPROT PTK2B protein Q14289 UNIPROT down-regulates dephosphorylation Tyr402 CSIESDIyAEIPDET 9606 10521452 t gcesareni "Raftk binds constitutively to the protein tyrosine phosphatase shptp1.SHPTP1 Plays a negative role in pyk2/raftk signaling by dephosphorylating raftk on tyr-402, thereby inhibiting the interaction of the sh2 domain of c-src with raftk" SIGNOR-71414 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 SF1 protein Q15637 UNIPROT FUS protein P35637 UNIPROT down-regulates binding 9606 9660765 t miannu "We speculate that zfm1 may inhibit transcription driven by the ntds of tls" SIGNOR-58967 SIRT3 protein Q9NTG7 UNIPROT IDH2 protein P48735 UNIPROT up-regulates deacetylation Lys413 VESGAMTkDLAGCIH 9606 22416140 t miannu "Site-specific, genetic incorporation of n(_)-acetyllysine into position 413 of idh2 revealed that acetylated idh2 displays a dramatic 44-fold loss in activity. Deacetylation by sirt3 fully restored maximum idh2 activity." SIGNOR-196617 TBK1 protein Q9UHD2 UNIPROT IRF3 protein Q14653 UNIPROT "up-regulates activity" phosphorylation Ser402 ISNSHPLsLTSDQYK -1 18440553 t lperfetto "Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404." SIGNOR-178407 MLL-AF9 "fusion protein" SIGNOR-FP5 SIGNOR RUNX1 protein Q01196 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9606 BTO:0001412 24449215 f irozzo "However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. We found that MLL-BP and the 3 MLL fusion proteins all decreased RUNX1 levels, and MLL-eleven nineteen leukemia (ENL) caused a greater decrease in RUNX1 compared with MLL-AF9 and MLL-AF4 fusion proteins." SIGNOR-255851 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 IKBKE protein Q14164 UNIPROT IRF3 protein Q14653 UNIPROT "up-regulates activity" phosphorylation Ser398 VDLHISNsHPLSLTS -1 18440553 t lperfetto "Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404." SIGNOR-178375 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR GSK3B protein P49841 UNIPROT "up-regulates activity" phosphorylation Tyr216 RGEPNVSyICSRYYR 9606 BTO:0001253 15020233 t lperfetto "In vitro kinase assay was carried out using a recombinant human active mek1 and we found that gsk-3beta was phosphorylated on tyr(216) by this kinase in a dose- and time-dependent manner. Further, the pretreatment of fibroblasts with u0126 inhibited serum-induced nuclear translocation of gsk-3beta. These results suggested that mek1/2 induces tyrosine phosphorylation of gsk-3beta and this cellular event might induce nuclear translocation of gsk-3beta." SIGNOR-244780 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser307 TRRSRTEsITATSPA 9606 BTO:0000887 11160134 t lperfetto "Thus, at least three kinases mediate phosphorylation of ser307, including jnk, serine kinases in the pi 3-kinase cascade that are activated byinsulinor igf-1, and mek1-sensitive kinase cascades during tnf-alfa stimulation." SIGNOR-244784 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MAPK1 protein P28482 UNIPROT "up-regulates activity" phosphorylation Thr185 HDHTGFLtEYVATRW 9606 BTO:0003807 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-244792 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MAPK1 protein P28482 UNIPROT "up-regulates activity" phosphorylation Tyr187 HTGFLTEyVATRWYR 9606 BTO:0003807 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-244788 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MAPK3 protein P27361 UNIPROT up-regulates phosphorylation 9606 12270934 t lperfetto "Mek1 as indicated by extensive phosphorylation of erk1 and erk2 during the initial 2 h of adipogenesis." SIGNOR-244798 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR TAL1 protein P17542 UNIPROT down-regulates phosphorylation Ser122 DGRMVQLsPPALAAP 9606 BTO:0000782;BTO:0001271 11904294 t lperfetto "We found that hypoxia greatly accelerated tal1 turnover in these cells through mitogen-activated protein kinase (mapk)2-mediated phosphorylation, ubiquitination, and proteasomal degradation." SIGNOR-244975 "Melanotan II" chemical CID:92432 PUBCHEM 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-253065 MLL-AF9 "fusion protein" SIGNOR-FP5 SIGNOR miR-495 mirna MI0003135 miRBase "down-regulates quantity by repression" "transcriptional repression" 9606 BTO:0000725 23132946 f irozzo "We then showed that ectopic expression of MLL fusion genes in both human and mouse normal hematopoietic stem/progenitor cells could significantly down-regulate endogenous expression of miR-495 and that the depletion of MLL fusions resulted in the up-regulation of miR-495. Thus, our data suggest that there is an MLL-fusion–mediated negative regulation of the production of miR-495 in hematopoietic cells." SIGNOR-255885 PRKCD protein Q05655 UNIPROT SRC protein P12931 UNIPROT "up-regulates activity" phosphorylation Ser12 KSKPKDAsQRRRSLE 9606 BTO:0001938 18069897 t gcesareni "We conclude that treatment with either UV or PMA induces the phosphorylation of the PKC site Ser12 on c-SRC and that this specific phosphorylation event is significantly diminished in cells overexpressing PR55" SIGNOR-247974 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 MMP9 protein P14780 UNIPROT TGFB1 protein P01137 UNIPROT up-regulates cleavage 9606 10652271 t gcesareni "We also demonstrate that mmp-9, as well as its relative, mmp-2, cleave latent transforming growth factor-_ (tgf-_), which constitutes a novel mechanism of tgf-_ activation." SIGNOR-74461 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 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 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 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NPM1 protein P06748 UNIPROT "down-regulates activity" phosphorylation Thr234 SFKKQEKtPKTPKGP 9606 12058066 t lperfetto "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-216745 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR NPM1 protein P06748 UNIPROT "down-regulates activity" phosphorylation Thr234 SFKKQEKtPKTPKGP 9606 12058066 t lperfetto "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-216662 FBXO11 protein Q86XK2 UNIPROT TP53 protein P04637 UNIPROT down-regulates neddylation Lys320 SSSPQPKkKPLDGEY 9606 17098746 t miannu "Fbxo11 promotes the neddylation of p53 and inhibits its transcriptional activity / we found that fbxo11 also neddylates p53 on two lysines, lys-320 and lys-321" SIGNOR-150669 FBXO11 protein Q86XK2 UNIPROT TP53 protein P04637 UNIPROT down-regulates neddylation Lys321 SSPQPKKkPLDGEYF 9606 17098746 t miannu "Fbxo11 promotes the neddylation of p53 and inhibits its transcriptional activity / we found that fbxo11 also neddylates p53 on two lysines, lys-320 and lys-321" SIGNOR-150673 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 IKBKE protein Q14164 UNIPROT IRF3 protein Q14653 UNIPROT "up-regulates activity" phosphorylation Ser402 ISNSHPLsLTSDQYK -1 18440553 t lperfetto "Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404." SIGNOR-178379 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates 9606 18481201 f lperfetto "Pd98059, a specific inhibitor of mek 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-244877 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR PPARG protein P37231 UNIPROT up-regulates binding 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-244971 MELK protein Q14680 UNIPROT CDC25B protein P30305 UNIPROT "down-regulates activity" phosphorylation Ser219 HALAEWAsRREAFAQ 9606 BTO:0001938 12400006 t "In the present study we show that the human pEg3 kinase is able to specifically phosphorylate CDC25B in vitro. One phosphorylation site was identified and corresponded to serine 323[Ä] Taken together these results suggest that pEg3 is a potential regulator of the G2/M progression and may act antagonistically to the CDC25B phosphatase" SIGNOR-255655 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Ser356 DIKSNNWsLEDVTAS 9606 16216881 t lperfetto "We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase." SIGNOR-140998 MMP7 protein P09237 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-256351 MTCH2 protein Q9Y6C9 UNIPROT BID protein P55957 UNIPROT up-regulates binding 9606 21295084 t gcesareni "Mtch2/mimp and its role in bid recruitment may synergise with cl-induced mitosome formation to facilitate momp." SIGNOR-171773 PDK2 protein Q15119 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation Ser473 RPHFPQFsYSASGTA 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. The phosphorylation of AKT on Ser473 by PDK2 acts as a €œgain control€ for AKT and regulates its degree of activation. The sirolimus-insensitive mTORC2 complex exhibits PDK2 activity" SIGNOR-249630 NFIL3 protein Q16649 UNIPROT NFIL3 protein Q16649 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-224248 FGFR1 protein P11362 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates phosphorylation Tyr128 SKAQQGLyQVPGPSP 9606 11019781 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-82760 IKBKE protein Q14164 UNIPROT IRF3 protein Q14653 UNIPROT "up-regulates activity" phosphorylation Ser405 SHPLSLTsDQYKAYL -1 18440553 t lperfetto "Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404." SIGNOR-178383 IKBKE protein Q14164 UNIPROT IRF3 protein Q14653 UNIPROT "up-regulates activity" phosphorylation Thr404 NSHPLSLtSDQYKAY -1 18440553 t lperfetto "Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404." SIGNOR-178387 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser206 SSSTYPHsPTSSDPG 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-161601 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Ser431 ENVYTPKsAVKNEEY 9606 16216881 t lperfetto "We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase." SIGNOR-141010 Membrane_blebbing phenotype SIGNOR-PH24 SIGNOR 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-249584 MRAP2 protein Q96G30 UNIPROT MC2R protein Q01718 UNIPROT "up-regulates activity" binding 10029 BTO:0000246 19329486 t miannu "We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling.We have previously identified MRAP as an accessory protein for MC2R, required for receptor trafficking to the cell surface and the formation of a functional MC2R. Here we have identified MRAP2 as a homologue of MRAP. Like MRAP, MRAP2 is able to support MC2R cell-surface expression, producing a functional ACTH-responsive receptor." SIGNOR-252361 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 PTPN11 protein Q06124 UNIPROT GAB2 protein Q9UQC2 UNIPROT down-regulates dephosphorylation Tyr614 KSTGSVDyLALDFQP 9606 15170389 t gcesareni "Expression of the gab2 tyr-614-->phe (y614f) mutant, defective in shp-2 association, prevents erk (extracellular-signal-regulated kinase) activation and expression of a luciferase reporter plasmid driven by the c-fos sre (serum response element), indicating that interaction of shp-2 with gab2 is required for erk activation in response to il-2." SIGNOR-124958 NFIL3 protein Q16649 UNIPROT SOSTDC1 protein Q6X4U4 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000093 25338303 f lperfetto "E4BP4 is a repressor of epigenetically regulated SOSTDC1 expression in breast cancer cells." SIGNOR-242767 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 CSNK2A2 protein P19784 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT "up-regulates activity" phosphorylation Ser60 ETNQNSSsDSEAERR -1 11711551 t llicata "We show here that Tcf-4 can be phosphorylated in vitro by protein kinase CK2 stoichiometrically in amino acids Ser-58-Ser-59-Ser-60. Phosphorylation of these residues does not modify the interaction of Tcf-4 with beta-catenin but reduces its association to plakoglobin. | Experiments performed using a Tcf-4 mutant with decreased interaction to plakoglobin demonstrated that binding to this protein negatively affected the transcriptional activity of Tcf-4." SIGNOR-251046 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 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Ser505 SPERRCRsVELDLNQ 9606 16216881 t lperfetto "We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase." SIGNOR-141014 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Ser529 KGAKVFGsLERGLDK 9606 16216881 t lperfetto "We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase." SIGNOR-141018 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Thr167 NKDYHLQtCCGSLAY 9606 16216881 t gcesareni "We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk." SIGNOR-141022 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Thr494 TGTDKLMtGVISPER 9606 16216881 t lperfetto "We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase." SIGNOR-141030 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 PTK2 protein Q05397 UNIPROT ACTN4 protein O43707 UNIPROT down-regulates phosphorylation Tyr31 GGGSMGDyMAQEDDW 9606 23454549 t lperfetto "Phosphorylation at y12 by fak reduces _-actinin1's affinity for actin [25] and [27]. _-actinin4 is phosphorylated at y4, y31, and y265. Phosphorylation at y4 or y31 decreases its binding to actin [28] while phosphorylation of y265 increases its affinity for actin" SIGNOR-192195 PTK2 protein Q05397 UNIPROT ACTN4 protein O43707 UNIPROT down-regulates phosphorylation Tyr4 yHAANQSY 9606 23454549 t lperfetto "Phosphorylation at y12 by fak reduces _-actinin1's affinity for actin [25] and [27]. _-actinin4 is phosphorylated at y4, y31, and y265. Phosphorylation at y4 or y31 decreases its binding to actin [28] while phosphorylation of y265 increases its affinity for actin" SIGNOR-192199 TBK1 protein Q9UHD2 UNIPROT IRF3 protein Q14653 UNIPROT "up-regulates activity" phosphorylation Ser396 NTVDLHIsNSHPLSL -1 18440553 t lperfetto "Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404." SIGNOR-178399 "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 MTCP1 protein P56278 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-81674 PRKD1 protein Q15139 UNIPROT SSH1 protein Q8WYL5 UNIPROT down-regulates phosphorylation Ser937 SNLTRSSsSDSIHSV 9606 BTO:0000150 19567672 t llicata "Pkd-mediated phosphorylation of serines 937 and 978 regulates ssh1l subcellular localization by binding of 14-3-3 proteins 14-3-3 proteins associate with ssh1l when phosphorylated at serines 937 and 978, thereby sequestering ssh1l in the cytoplasm and preventing translocation of the phosphatase to f-actin_rich membrane protrusions" SIGNOR-186467 TBK1 protein Q9UHD2 UNIPROT IRF3 protein Q14653 UNIPROT "up-regulates activity" phosphorylation Ser385 MARVGGAsSLENTVD -1 18440553 t lperfetto "Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404." SIGNOR-178391 CSNK2B protein P67870 UNIPROT CDC34 protein P49427 UNIPROT unknown phosphorylation Ser222 EVEEEADsCFGDDED 9606 BTO:0000567 11546811 t llicata "CDC34 is specifically phosphorylated in vitro by recombinant CK2 and HeLa nuclear extract at five sites within the carboxyl-terminal 36 amino acids of CDC34. | Mutation of CDC34 at CK2-targeted residues, Ser-203, Ser-222, Ser-231, Thr-233, and Ser-236, abolishes the phosphorylation of CDC34 observed in vivo and markedly shifts nuclearly localized CDC34 to the cytoplasm. " SIGNOR-251058 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 LYN protein P07948 UNIPROT CD19 protein P15391 UNIPROT up-regulates phosphorylation Tyr500 TSLGSQSyEDMRGIL 9606 BTO:0000776 10933394 t llicata "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." SIGNOR-80290 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 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 SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser204 NHSMDAGsPNLSPNP 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-161609 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser204 NHSMDAGsPNLSPNP 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-161698 MTCP1 protein P56278 UNIPROT AKT1 protein P31749 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-81671 MTMR4 protein Q9NYA4 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates dephosphorylation 9606 20061380 t gcesareni "Here we demonstrate that myotubularin-related protein 4" SIGNOR-163034 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR ABCB1 protein P08183 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19763573 f miannu "PSC833, cyclosporine analogue, downregulates MDR1 expression by activating JNK/c-Jun/AP-1 and suppressing NF-kappaB." SIGNOR-254654 TBK1 protein Q9UHD2 UNIPROT IRF3 protein Q14653 UNIPROT "up-regulates activity" phosphorylation Ser386 ARVGGASsLENTVDL -1 18440553 t lperfetto "Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404." SIGNOR-178395 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 PRKCD protein Q05655 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser303 RGAPPRRsSIRNAHS 9606 BTO:0000130 12056906 t esanto "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. The use of p47phox mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc?, ???, And ?." SIGNOR-89217 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 CSNK2B protein P67870 UNIPROT CDC34 protein P49427 UNIPROT unknown phosphorylation Ser231 FGDDEDDsGTEES 9606 BTO:0000567 11546811 t llicata "CDC34 is specifically phosphorylated in vitro by recombinant CK2 and HeLa nuclear extract at five sites within the carboxyl-terminal 36 amino acids of CDC34. | Mutation of CDC34 at CK2-targeted residues, Ser-203, Ser-222, Ser-231, Thr-233, and Ser-236, abolishes the phosphorylation of CDC34 observed in vivo and markedly shifts nuclearly localized CDC34 to the cytoplasm. " SIGNOR-251059 CSNK2B protein P67870 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Thr502 TPGTGLGtSPALAGD -1 8349691 t llicata "These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1." SIGNOR-251077 DDR1 protein Q08345 UNIPROT DDR1 protein Q08345 UNIPROT "up-regulates activity" phosphorylation Tyr513 LLLSNPAyRLLLATY 9606 BTO:0000007;BTO:0000356 9659899 t llicata "The discoidin domain receptor tyrosine kinases are activated by collagen | Here, we present evidence that stimulating DDR1- and DDR2-expressing cells with various types of collagen induces receptor autophosphorylation." SIGNOR-251086 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 MAPK9 protein P45984 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." SIGNOR-91075 MEN1 protein O00255 UNIPROT CDKN1B protein P46527 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000567 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-255889 MEN1 protein O00255 UNIPROT CDKN2C protein P42773 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000567 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 HOXA9 protein P31269 UNIPROT "up-regulates quantity by expression" methylation 9606 BTO:0004730 16415155 t irozzo "Men1 excision causes reduction of Hoxa9 expression, colony formation by hematopoietic progenitors, and the peripheral white blood cell count. Menin directly activates Hoxa9 expression, at least in part, by binding to the Hoxa9 locus, facilitating methylation of H3K4, and recruiting the methylated H3K4 binding protein chd1 to the locus. " SIGNOR-255894 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 MLL-AF4 "fusion protein" SIGNOR-FP4 SIGNOR "up-regulates activity" binding 10090 BTO:0004730 16239140 t irozzo "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-255868 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 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 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 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 LRRK2 protein Q5S007 UNIPROT LRRK2 protein Q5S007 UNIPROT unknown phosphorylation Thr1404 GREEFYStHPHFMTQ 9606 BTO:0000938 19824698 t lperfetto "We identified ser1403, thr1404, thr1410, thr1491 located within the roc domain, as well as thr1967 and thr1969 in the kinase domain, as the autophosphorylation sites." SIGNOR-188433 LYN protein P07948 UNIPROT CD19 protein P15391 UNIPROT up-regulates phosphorylation Tyr531 HEEDADSyENMDNPD 9606 BTO:0000776 10933394 t llicata "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." SIGNOR-80294 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 MEN1 protein O00255 UNIPROT MLL-AF9 "fusion protein" SIGNOR-FP5 SIGNOR "up-regulates activity" binding 10090 BTO:0004730 16239140 t irozzo "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-255867 MEN1 protein O00255 UNIPROT MLL-ENL "fusion protein" SIGNOR-FP7 SIGNOR "up-regulates activity" binding 10090 BTO:0004730 16239140 t irozzo "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-255866 MEN1 protein O00255 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 BTO:0000583 16415155 f irozzo "We also found that menin is important for the proliferation of MLL oncoprotein-transformed myeloid cells, pointing to a paradoxically oncogenic role for the tumor suppressor menin in proliferation of transformed myeloid cells." SIGNOR-255895 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 TERT protein O14746 UNIPROT down-regulates 9606 12837246 f miannu "The tumor suppressor menin, is a direct repressor of htert" SIGNOR-102874 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 PRKACA protein P17612 UNIPROT SREBF1 protein P36956 UNIPROT down-regulates phosphorylation Ser338 IEKRYRSsINDKIIE 9606 16381800 t llicata "Sterol regulatory element-binding protein 1 is negatively modulated by pka phosphorylation. ser338 of srebp-1a and ser314 of srebp-1c are pka phosphorylation sites." SIGNOR-143392 PRKCD protein Q05655 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser304 GAPPRRSsIRNAHSI 9606 BTO:0000130 12056906 t esanto "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. The use of p47phox mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc?, ???, And ?." SIGNOR-89221 PRKCD protein Q05655 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser315 AHSIHQRsRKRLSQD 9606 BTO:0000130 12056906 t esanto "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. The use of p47phox mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc?, ???, And ?." SIGNOR-89225 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 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 PRKCZ protein Q05513 UNIPROT STK11 protein Q15831 UNIPROT up-regulates phosphorylation Ser307 IRQIRQHsWFRKKHP 9606 BTO:0000887;BTO:0001103;BTO:0001260 19414597 t llicata "Here, we have identified s307 as a novel phosphorylation site in lkb1 and provide evidence that, in multiple cell types, phosphorylation of this site by protein kinase c ? (pkc-?) Induces nucleocytoplasmic transport of lkb1." SIGNOR-185640 DAPK1 protein P53355 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates binding 9606 15616583 t gcesareni "Conversely, dapk promotes the cytoplasmic retention of erk, thereby inhibiting erk signaling in the nucleus." SIGNOR-132610 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 DAPK2 protein Q9UIK4 UNIPROT DAPK2 protein Q9UIK4 UNIPROT "down-regulates activity" phosphorylation Ser318 VRRRWKLsFSIVSLC 9606 BTO:0000007;BTO:0000356 11230133 t llicata "Autophosphorylation restrains the apoptotic activity of DRP-1 kinase by controlling dimerization and calmodulin binding. | It comprises a single autophosphorylation event mapped to Ser308 within the CaM regulatory domain." SIGNOR-251084 DAPK3 protein O43293 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates activity" 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 FZD1 protein Q9UP38 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-80595 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 MEST protein Q5EB52 UNIPROT LRP6 protein O75581 UNIPROT "down-regulates activity" glycosylation 9606 21375506 f "Mest/Peg1 inhibited maturation of LRP6 by controlling the glycosylation of LRP6. Knockdown of Mest/Peg1, which might enhance Wnt signalling, blocked adipogenic differentiation of 3T3-L1 cells" SIGNOR-255826 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 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 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 RAB23 protein Q9ULC3 UNIPROT GLIS2 protein Q9BZE0 UNIPROT down-regulates 9606 16364285 f gcesareni "Based on su(fu) function, we predict that rab23 can interact with all gli1 molecules including gli1, gli2 and gli3, and inhibit their transcriptional activities and nuclear localization." SIGNOR-143163 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 Tyr96 EENADDSyEPPPVEQ 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-96052 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 PRKCZ protein Q05513 UNIPROT BAX protein Q07812 UNIPROT down-regulates phosphorylation Ser184 VAGVLTAsLTIWKKM 9606 BTO:0000551 17525161 t lperfetto "Protein kinase czeta abrogates the proapoptotic function of bax through phosphorylation. Overexpression of wild type or the constitutively active a119d but not the dominant negative k281w pkczeta mutant results in bax phosphorylation at serine 184." SIGNOR-155111 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 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 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 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 ITK protein Q08881 UNIPROT CD28 protein P10747 UNIPROT up-regulates phosphorylation Tyr209 TRKHYQPyAPPRDFA 9606 BTO:0000782;BTO:0001271 8992971 t lperfetto "We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tailother studies demonstrated that tyr191 within the p190yap motif is one of two major phosphorylation sites in cd28-stimulated jurkat t cells, and the only tyrosine residue within the cd28 cytoplasmic tail that is essential for delivery of costimulatory signals" SIGNOR-45516 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 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 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 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 SHH protein Q15465 UNIPROT CP protein P00450 UNIPROT down-regulates binding 9606 15618519 t gcesareni "Binding of sonic hedgehog (shh) to patched (ptc) relieves the latter's tonic smoothened (smo), a receptor that spans the cell membrane seven times. Ptch exists in vertebrates as two isoforms, ptch1 and ptch2, which seem to be equivalent in terms of binding the three hh isoforms." SIGNOR-132672 SMURF2 protein Q9HAU4 UNIPROT BMPR1A protein P36894 UNIPROT down-regulates ubiquitination 9606 22298955 t gcesareni "Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps" SIGNOR-192898 SMURF2 protein Q9HAU4 UNIPROT BMPR2 protein Q13873 UNIPROT down-regulates ubiquitination 9606 22298955 t gcesareni "Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps." SIGNOR-193119 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 TP53INP2 protein Q8IXH6 UNIPROT MAP1LC3A protein Q9H492 UNIPROT up-regulates binding 9606 19056683 t gcesareni "Tp53inp2 is a scaffold protein that recruits lc3 and/or lc3-related proteins to the autophagosome membrane by interacting with the transmembrane protein vmp1" SIGNOR-182614 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr46 GGTLFSTtPGGTRII 9606 BTO:0000007 12747827 t lperfetto "Phosphorylated on serine and threonine residues in response to insulin, egf and pdgf. Phosphorylation at thr-37, thr-46, ser-65 and thr-70, corresponding to the hyperphosphorylated form, is regulated by mtorc1 and abolishes binding to eif4e." SIGNOR-236698 PRKAB1 protein Q9Y478 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-139164 DYRK1A protein Q13627 UNIPROT CCNL2 protein Q96S94 UNIPROT unknown phosphorylation Ser338 PAPKLVEsPKEGKGS 9534 BTO:0000298 14623875 t llicata "DYRK1A interacted with cyclin L2 in pull-down assays, and overexpression of DYRK1A stimulated phosphorylation of cyclin L2 in COS-7 cells. | Three phosphoserines were identified in the slower migrating bands (Fig. 9; Ser-330, Ser-338, and Ser-369). All of these serine residues are located N-terminal of proline residues, consistent with our previous classification of DYRK1A as a “proline-directed” kinase." SIGNOR-251088 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 ITK protein Q08881 UNIPROT CD28 protein P10747 UNIPROT up-regulates phosphorylation Tyr218 PPRDFAAyRS 9606 BTO:0000782;BTO:0001271 8992971 t lperfetto "We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tail" SIGNOR-45520 MAPKAPK5 protein Q8IW41 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 BTO:0001286 17254968 t llicata "Furthermore, we show that prak activates p53 by direct phosphorylation. prak phosphorylates p53 at ser37" SIGNOR-152847 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr37 PPGDYSTtPGGTLFS 9606 BTO:0000007 12747827 t lperfetto "Phosphorylated on serine and threonine residues in response to insulin, egf and pdgf. Phosphorylation at thr-37, thr-46, ser-65 and thr-70, corresponding to the hyperphosphorylated form, is regulated by mtorc1 and abolishes binding to eif4e." SIGNOR-236694 PTPN11 protein Q06124 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-248671 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 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 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 STK11 protein Q15831 UNIPROT NUAK2 protein Q9H093 UNIPROT up-regulates phosphorylation Thr208 HQGKFLQtFCGSPLY 9606 14976552 t llicata "A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold." SIGNOR-122717 STK11 protein Q15831 UNIPROT SIK2 protein Q9H0K1 UNIPROT up-regulates phosphorylation Thr175 KSGELLAtWCGSPPY 9606 14976552 t llicata "A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold." SIGNOR-122788 STK3 protein Q13188 UNIPROT LATS1 protein O95835 UNIPROT up-regulates phosphorylation Ser909 HQRCLAHsLVGTPNY 9606 BTO:0000007 15688006 t "Two of these, S909 and T1079, were required for Lats1 activation." milica "Since the N-terminal half of Lats1 (residues 1–588) was dispensable for the activation of Lats1 by Mst2, mass spectrometry was used to identify phosphorylation sites within the C-terminal domain of Lats1." SIGNOR-133544 STK3 protein Q13188 UNIPROT LATS1 protein O95835 UNIPROT up-regulates phosphorylation Thr1079 EHAFYEFtFRRFFDD 9606 BTO:0000007 15688006 t "Two of these, S909 and T1079, were required for Lats1 activation." milica "Since the N-terminal half of Lats1 (residues 1–588) was dispensable for the activation of Lats1 by Mst2, mass spectrometry was used to identify phosphorylation sites within the C-terminal domain of Lats1." SIGNOR-132927 TAOK2 protein Q9UL54 UNIPROT STK3 protein Q13188 UNIPROT up-regulates phosphorylation 9606 23431053 t gcesareni "In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2." SIGNOR-201327 YWHAQ protein P27348 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-88300 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 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 GPER1 protein Q99527 UNIPROT GNB1 protein P62873 UNIPROT "up-regulates activity" binding 10696571 t "GPCRs transduce their signal via G-protein heterotrimers (αβγ) that dissociate in free Gα-subunit protein and Gβγ-subunit protein complexes following ligand stimulation; GNB1 stands for the subunit β, which dissociates from the receptor after the binding of GTP on α-subunit." SIGNOR-251103 GPER1 protein Q99527 UNIPROT GNG2 protein P59768 UNIPROT "up-regulates activity" binding 10696571 t "GPCRs transduce their signal via G-protein heterotrimers (αβγ) that dissociate in free Gα-subunit protein and Gβγ-subunit protein complexes following ligand stimulation; GNG2 stands for the subunit γ, which dissociates from the receptor after the binding of GTP on α-subunit." SIGNOR-251104 MAPK13 protein O15264 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser25 QAFELILsPRSKESV 9606 BTO:0000782;BTO:0001271 8125092 t gcesareni "Serine 25 of oncoprotein 18 is a major cytosolic target for the mitogen-activated protein kinase." SIGNOR-36362 MAPK3 protein P27361 UNIPROT LAT protein O43561 UNIPROT down-regulates phosphorylation Thr184 PSAPALStPGIRDSA 9606 BTO:0000782 15192708 t "The effect has been demonstrated using O43561-2" 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." SIGNOR-125770 MET protein P08581 UNIPROT GRAP protein Q13588 UNIPROT up-regulates binding 9606 8662889 t gcesareni "To efficiently promote transformation met requires direct binding with grb2." SIGNOR-42358 MET protein P08581 UNIPROT GRB2 protein P62993 UNIPROT "up-regulates activity" binding 9606 22128289 t irozzo "For activation of the mitogen-activated protein kinase (MAPK) cascades, c-MET activation stimulates the activity of the rat sarcoma viral oncogene homolog (RAS) guanine nucleotide exchanger son of sevenless (SOS) via binding with SHC and GRB2 leading to the activation of RAS." SIGNOR-256261 mTORC1 complex SIGNOR-C3 SIGNOR RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr412 NQVFLGFtYVAPSVL 9606 10579915 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). In vitro activation of p70alfa by mtor-catalyzed phosphorylation involving p70alfa thr-412. Mtor-catalyzed p70alfa phosphorylation in vitro is accompanied by a substantial restoration in p70alfa kinase activity toward its physiologic substrate, the 40 s ribosomal protein s6. In response toinsulinand 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-217060 PP2B proteinfamily SIGNOR-PF18 SIGNOR MAPT protein P10636 UNIPROT up-regulates dephosphorylation Ser721 PVVSGDTsPRHLSNV 9606 BTO:0000142 20308788 t "The effect has been demonstrated using P10636-8" lperfetto "Among the sites studied, thr205, thr212, ser214, and ser262 were the most favorable sites, and ser199 and ser404 were the least favorable sites for pp2a in vitro." SIGNOR-164667 S1PR2 protein O95136 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 22863277 t gcesareni "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 co-activators, which are oncoproteins repressed by lats1/2." SIGNOR-198559 SIRT6 protein Q8N6T7 UNIPROT TNF protein P01375 UNIPROT up-regulates deacetylation Lys20 AEEALPKkTGGPQGS 9606 23552949 t gcesareni "Sirt6 regulates tnf-alfa secretion through hydrolysis of long-chain fatty acyl lysine" SIGNOR-201662 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT "down-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" SIGNOR-246385 TCL1B protein O95988 UNIPROT AKT1 protein P31749 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-81713 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 TNFRSF10D protein Q9UBN6 UNIPROT TNFSF10 protein P50591 UNIPROT down-regulates binding 9606 9382840 t amattioni "One function of trail-r4 may be inhibition of trail cytotoxicy. Dcr2 functions as an inhibitory apo2l receptor." SIGNOR-53447 TTBK1 protein Q5TCY1 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser739 GSIDMVDsPQLATLA 9606 BTO:0000938 16923168 t "The effect has been demonstrated using P10636-8" lperfetto "Direct tau phosphorylation by ttbk1 at ser198, ser199, ser202 and ser422, which are also phosphorylated in phfs. Ttbk1 also induces tau aggregation in human neuronal cells in a dose-dependent manner. We conclude that ttbk1 is a neuron-specific dual kinase involved in tau phosphorylation at ad-related sites and is also associated with tau aggregation." SIGNOR-148978 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 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 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 CSNK2A2 protein P19784 UNIPROT SMC3 protein Q9UQE7 UNIPROT unknown phosphorylation Ser1067 GDVEGSQsQDEGEGS 9606 18442975 t gcesareni "Our data provide evidence that phosphorylation of a core cohesin subunit smc3 by atm plays an important role in dna damage response and suggest that a constitutive phosphorylation by ck2 may affect intra-s phase checkpoint by modulating smc3 phosphorylation by atm." SIGNOR-178487 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 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 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 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 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 mTORC2 complex SIGNOR-C2 SIGNOR AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000182;BTO:0000018 15718470 t lperfetto "The rictor-mtor complex directly phosphorylated akt/pkb on ser473 in vitro and facilitated thr308 phosphorylation by pdk1" SIGNOR-252600 S1PR2 protein O95136 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 9606 22863277 t gcesareni "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 co-activators, which are oncoproteins repressed by lats1/2." SIGNOR-198556 SIK2 protein Q9H0K1 UNIPROT CEP250 protein Q9BV73 UNIPROT unknown phosphorylation Ser2394 LHHSLSHsLLAVAQA 9606 20708153 t lperfetto "Remarkably, lc-ms confirmed that the predominant serine phosphorylation site of the recombinant carboxy-terminal domain of c-nap1 is s2392 at the predicted consensus phosphorylation sequence and to a lesser extent s2394." SIGNOR-167492 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 STK11 protein Q15831 UNIPROT MARK1 protein Q9P0L2 UNIPROT up-regulates phosphorylation Thr215 TVGNKLDtFCGSPPY 9606 14976552 t lperfetto "Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold" SIGNOR-122545 WWTR1 protein Q9GZV5 UNIPROT TEAD3 protein Q99594 UNIPROT up-regulates binding 9606 23431053 t "YAP/TAZ mainly bind to the transcription factors TEAD1??4 to regulate genes involved in cell proliferation and cell death." gcesareni "When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14." SIGNOR-201415 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 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 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 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 EPHA3 protein P29320 UNIPROT EPHA3 protein P29320 UNIPROT "up-regulates activity" phosphorylation Tyr602 TYVDPHTyEDPTQAV 9606 BTO:0000007 11870224 t "Eph receptor activation leads to tyrosine phosphorylation of three major autophosphorylation sites. these residues function to regulate kinase activity, their phosphorylation being required for full intrinsic enzyme activity. these tyrosines (EphA3 Y596, Y602 and Y779) as the prominent autophosphorylation sites of EphA3" SIGNOR-251116 FOXO proteinfamily SIGNOR-PF27 SIGNOR FBXO32 protein Q969P5 UNIPROT "up-regulates activity" "transcriptional regulation" 10090 18612045 f areggio "These findings present new insights into the role of the GR and FOXO family of transcription factors in the transcriptional regulation of the MuRF1 gene, a direct target of the GR in skeletal muscle." SIGNOR-254991 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 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 PRKACA protein P17612 UNIPROT GRK2 protein P25098 UNIPROT "up-regulates activity" phosphorylation Ser685 VPLVQRGsANGL -1 11278469 t miannu "PKA directly phosphorylates GRK2 on serine 685. This modification increases G subunit binding to GRK2 and thus enhances the ability of the kinase to translocate to the membrane and phosphorylate the receptor." SIGNOR-250334 PRKCA protein P17252 UNIPROT EIF6 protein P56537 UNIPROT unknown phosphorylation Ser235 QPSTIATsMRDSLID 9606 14654845 t llicata "Pkc stimulation led to eif6 phosphorylation, and mutation of a serine residue in the carboxy terminus of eif6 impaired rack1/pkc-mediated translational rescue." SIGNOR-119600 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 PTK2 protein Q05397 UNIPROT BCAR1 protein P56945 UNIPROT unknown phosphorylation Tyr664 EGGWMEDyDYVHLQG 11604500 t lperfetto "FAK phosphorylates CAS-SBD tyrosines 668 and/or 670, driving an SH2-mediated recruitment of Src which then phosphorylates CAS-SD." SIGNOR-249111 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 SMAD2 protein Q15796 UNIPROT SMAD2/SMURF2 complex SIGNOR-C11 SIGNOR "form complex" binding 9606 11389444 t gcesareni "We show that in the presence of tgf-beta, smad2 interacts through its proline-rich ppxy motif with the tryptophan-rich ww domains of smurf2, a recently identified e3 ubiquitin ligases." SIGNOR-108487 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 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 MYF5 protein P13349 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR "up-regulates activity" BTO:0001103 17495111 f "Simone Vumbaca" "In summary, the absence of Myf5 clearly reduced the initial expansion of satellite cell-derived transient amplifying cells and resulted in a shift of the ratio of satellite cell subpopulations but did not affect the specification and generation of specific subpopulations of satellite cell-derived cells such as reserve cells, amplifying cells, and differentiating mature myogenic cells." SIGNOR-255643 PAK5 protein Q9P286 UNIPROT PAK5 protein Q9P286 UNIPROT "up-regulates activity" phosphorylation His22 SNFEHRVhTGFDPQE -1 12860998 t miannu "Active form of Cdc42, but not Rac1 and Rho, protein was able to activate the purified GST-Pak5 autophosphorylation and kinase activity. Mutations of Pak5, which disrupted the interaction of Cdc42 and Pak5, also abolished the induction of autophosphorylation.  The H19L/H22L mutant of Pak5 was insensitive to the Cdc42-induced autophosphorylation." SIGNOR-250249 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 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 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 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 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 MYF5 protein P13349 UNIPROT MIR1-1 mirna MI0000651 miRBase "up-regulates quantity" "transcriptional regulation" 10090 BTO:0000887 18619954 f "We found that directed expression of MRFs in the neural tube of chicken embryos induced ectopic expression of miR-1 and miR-206. Conversely, the lack of Myf5 but not of MyoD resulted in a loss of miR-1 and miR-206 expression." SIGNOR-255920 MYF5 protein P13349 UNIPROT mir-206 mirna MI0000490 miRBase "up-regulates quantity" "transcriptional regulation" 10090 BTO:0000887 18619954 f "We found that directed expression of MRFs in the neural tube of chicken embryos induced ectopic expression of miR-1 and miR-206. Conversely, the lack of Myf5 but not of MyoD resulted in a loss of miR-1 and miR-206 expression." SIGNOR-255919 PRKACA protein P17612 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser63 AAEERRKsHEAEVLK 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-36374 SRC protein P12931 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates phosphorylation Tyr536 QKGQESEyGNITYPP 9606 BTO:0000007 14699166 t llicata "Recombinant shp-1 had elevated activity subsequent to phosphorylation by src in vitro, and shp-1 variants with mutated phosphorylation sites in the c terminus, shp-1 y538f, and shp-1 y538f,y566f were less active toward src-generated phosphoproteins in intact cells." SIGNOR-120488 SRC protein P12931 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates phosphorylation Tyr564 SKHKEDVyENLHTKN 9606 BTO:0000007 14699166 t llicata "Recombinant shp-1 had elevated activity subsequent to phosphorylation by src in vitro, and shp-1 variants with mutated phosphorylation sites in the c terminus, shp-1 y538f, and shp-1 y538f,y566f were less active toward src-generated phosphoproteins in intact cells." SIGNOR-120492 STK11 protein Q15831 UNIPROT MARK3 protein P27448 UNIPROT "up-regulates activity" phosphorylation Ser215 KLDTFCGsPPYAAPE 9606 BTO:0000568 12879020 t lperfetto "Regulation of the wnt signalling component par1a by the peutz-jeghers syndrome kinase lkb1. Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1. Mark3 is activated by phosphorylation on thr-211." SIGNOR-104059 STK11 protein Q15831 UNIPROT MARK3 protein P27448 UNIPROT "up-regulates activity" phosphorylation Thr211 TVGGKLDtFCGSPPY 9606 BTO:0000568 12879020 t lperfetto "Regulation of the wnt signalling component par1a by the peutz-jeghers syndrome kinase lkb1. Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1. Mark3 is activated by phosphorylation on thr-211." SIGNOR-104063 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 RPS6KA1 protein Q15418 UNIPROT CREB1 protein P16220 UNIPROT "up-regulates activity" phosphorylation Ser133 EILSRRPsYRKILND 9606 BTO:0000938 10558990 t lperfetto "The rsks phosphorylate the trascription factor creb at serine 133 to promote cell survival." SIGNOR-72117 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 HES1 protein Q14469 UNIPROT DTX1 protein Q86Y01 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000970 20208568 f gcesareni "The notch target gene hes1 causes transcriptional inhibition of deltex1 by directly binding to the promoter of deltex1." SIGNOR-164071 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 LPAR1 protein Q92633 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 10090 BTO:0000944 15856019 t milica "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-236985 L-phenylalanine smallmolecule CHEBI:17295 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 MAPK3 protein P27361 UNIPROT BCL2 protein P10415 UNIPROT down-regulates phosphorylation Thr74 ARTSPLQtPAAPGAA 9606 10669763 t gcesareni "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-74943 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 MET protein P08581 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr407 IIDEEDTyTMPSTRD 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-147187 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 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 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 PRKDC protein P78527 UNIPROT NHEJ1 protein Q9H9Q4 UNIPROT unknown phosphorylation Ser245 PHTSNSAsLQGIDSQ 9606 18644470 t lperfetto "Here, we have identified two major in vitro dna-pk phosphorylation sites in the c-terminal region of xlf, serines 245 and 251. We show that these represent the major phosphorylation sites in xlf in vivo and that serine 245 is phosphorylated in vivo by dna-pk, while serine 251 is phosphorylated by ataxia-telangiectasia mutated (atm)." SIGNOR-179532 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 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 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 FGR protein P09769 UNIPROT SRC protein P12931 UNIPROT unknown phosphorylation Tyr530 FTSTEPQyQPGENL -1 9208935 t "An eicosapeptide encompassing the C-terminal tail of c-Src (Tyr527) which is conserved in most Src-related protein kinases, is phosphorylated by C-terminal Src kinase (CSK) and by the two Src-related protein kinases c-Fgr and Lyn, with similar kinetic constants. " SIGNOR-251145 IRAK4 protein Q9NWZ3 UNIPROT IRAK4 protein Q9NWZ3 UNIPROT "up-regulates activity" phosphorylation Thr342 ASEKFAQtVMTSRIV 9606 BTO:0000876 24567333 t lperfetto "We show irak4 autophosphorylation occurs by an intermolecular reaction and that autophosphorylation is required for full catalytic activity of the kinase. Phosphorylation of any two of the residues thr-342, thr-345, and ser-346 is required for full activity" SIGNOR-204657 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 MAPK14 protein Q16539 UNIPROT TAB1 protein Q15750 UNIPROT "down-regulates activity" phosphorylation Ser438 TPTLTNQsPTLTLQS 9606 BTO:0000801 14592977 t lperfetto "Tab1, a subunit of the kinase tak1, was phosphorylated by sapk2a/p38alpha at ser423, thr431 and ser438 in vitro. the results presented here also show that sapk2a/p38? Suppresses the activity of tak1 in cells, because the activation of tak1 by proinflammatory cytokines and lps is enhanced if cells are first pre?incubated With sb 203580 or in cells that do not express sapk2a/p38?." SIGNOR-118922 MET protein P08581 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr576 RYMEDSTyYKASKGK 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-147191 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 "MYOD1/SWI/SNF complex" complex SIGNOR-C93 SIGNOR TNNI2 protein P48788 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887 15870273 f miannu "Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material)" SIGNOR-136786 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 PP2Ca_R1A_Bd complex SIGNOR-C134 SIGNOR RAF1 protein P04049 UNIPROT "up-regulates activity" dephosphorylation Ser259 SQRQRSTsTPNVHMV 9606 BTO:0000007 16239230 t gcesareni "... the PP2A holoenzymes ABC and ABC act downstream of Ras and upstream of MEK1 to promote activation of this MAPK signaling cascade. Furthermore both PP2A holoenzymes were found to associate with Raf1 and catalyze dephosphorylation of inhibitory phospho-Ser-259." SIGNOR-243538 PTPN12 protein Q05209 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 10734133 t gcesareni "Autophosphorylated on tyrosine residues in response to insulin. Dephosphorylated by ptpreand ptpn1 at tyr-999, tyr-1185, tyr-1189 and tyr-1190." SIGNOR-75906 PTPN13 protein Q12923 UNIPROT NFKBIA protein P25963 UNIPROT "up-regulates quantity by stabilization" dephosphorylation Tyr42 DSMKDEEyEQMVKEL 9606 BTO:0000007 11106428 t "Identification of IkappaBalpha as a substrate of Fas-associated phosphatase-1|A full-length FAP-1 protein preferentially dephosphorylates Tyr-42 of IkBa|Moreover, other studies have shown that tyrosine phosphorylation of IkBa on Tyr-42 (which occurs with Fas ligand binging) protected against inducible degradation both in vitro [30] and in vivo [38]" SIGNOR-248712 SMO protein Q99835 UNIPROT GNAI2 protein P04899 UNIPROT "up-regulates activity" binding 10090 BTO:0002572 16885213 t lperfetto "Using this assay we determined that mouse Smo couples to all members of the Gi family but does not couple to those of other G protein families." SIGNOR-148490 SRC protein P12931 UNIPROT TGFA protein P01135 UNIPROT up-regulates cleavage 9606 BTO:0000586 17251915 t lperfetto "Ep2 can also promote the transactivation of epidermal growth factor receptor (egfr) expressed in colon cancer cells through src, which activates the proteolytic release of the egfr ligands amphiregulin (ar) and transforming growth factor-alfa (tgfalfa)125, thereby stimulating the egfr- network." SIGNOR-235888 STAT1 protein P42224 UNIPROT RELA protein Q04206 UNIPROT down-regulates binding 9606 SIGNOR-C13 16481475 t gcesareni "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-144561 NAB2 protein Q15742 UNIPROT GFI1 protein Q99684 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 10090 BTO:0000804 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-256042 PP2Ca_R1A_Ba complex SIGNOR-C132 SIGNOR RAF1 protein P04049 UNIPROT "up-regulates activity" dephosphorylation Ser259 SQRQRSTsTPNVHMV 9606 BTO:0000007 16239230 t gcesareni "... the PP2A holoenzymes ABC and ABC act downstream of Ras and upstream of MEK1 to promote activation of this MAPK signaling cascade. Furthermore both PP2A holoenzymes were found to associate with Raf1 and catalyze dephosphorylation of inhibitory phospho-Ser-259." SIGNOR-243534 CSNK2A1 protein P68400 UNIPROT PTPRC protein P08575 UNIPROT up-regulates phosphorylation Ser999 SKESEHDsDESSDDD 9606 10066810 t gcesareni "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," SIGNOR-65281 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 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 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 NAB2 protein Q15742 UNIPROT EGR3 protein Q06889 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000414 20506119 f miannu "Our results suggest that in many cells of neuroectodermal and epithelial origin EGR1, EGR2, and EGR3 activate NAB2 transcription which is in turn repressed by NAB2, thus establishing a negative feedback loop." SIGNOR-253887 PPP3CA protein Q08209 UNIPROT FLNA protein P21333 UNIPROT down-regulates dephosphorylation Ser2152 TRRRRAPsVANVGSH 9606 16442073 t gcesareni "We report that a purified c-terminal recombinant region of filamin is a suitable substrate for calcineurin in vitro. Furthermore, 1 microm cyclosporin a (csa), a specific calcineurin inhibitor, reduced the dephosphorylation of the recombinant fragment in 293ft cells" SIGNOR-143979 PRKAA1 protein Q13131 UNIPROT LIPE protein Q05469 UNIPROT down-regulates phosphorylation Ser855 EPMRRSVsEAALAQP 9606 SIGNOR-C15 9636039 t gcesareni "Phosphorylation of bovine hormone-sensitive lipase by the amp-activated protein kinase." SIGNOR-58255 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 PTPN2 protein P17706 UNIPROT INSR protein P06213 UNIPROT "down-regulates activity" dephosphorylation Tyr1190 DIYETDYyRKGGKGL 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-248386 SF1 protein Q15637 UNIPROT EWSR1 protein Q01844 UNIPROT down-regulates binding 9606 9660765 t miannu "Here we report that zfm1 also interacts withews / overexpression of zfm1 in hepg2 cells represses the transactivation of reporter gene expression driven by gal4-ews-ntd fusion protein and this repression correlates with zfm1 binding to ews." SIGNOR-58928 TSC1/TSC2 complex SIGNOR-C101 SIGNOR RHEB protein Q15382 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 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-235895 UBE2I protein P63279 UNIPROT MITF protein O75030 UNIPROT down-regulates ubiquitination Lys308 SEARALAkERQKKDN 9606 10673502 t lperfetto "Furthermore, we identified lysine 201 as a potential ubiquitination site. A lysine to arginine mutation abolished mitf (k201r) degradation by hubc9 in vivo." SIGNOR-75117 NANOG protein Q9H9S0 UNIPROT CGA protein P01215 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001086;BTO:0005511 15983365 f miannu "Transfection of NANOG-specific small interfering RNAs reduced levels of NANOG transcript and protein and induced activation of the extraembryonic endoderm-associated genes GATA4, GATA6, LAMININ B1, and AFP as well as upregulation of trophectoderm-associated genes CDX2, GATA2, hCG-alpha, and hCG-beta." SIGNOR-254623 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 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 FYN protein P06241 UNIPROT CD5 protein P06127 UNIPROT unknown phosphorylation Tyr487 DNSSDSDyDLHGAQR -1 11298344 t "Tyrosine-mutated CD5 molecules have been used to show that residues Y429 and Y463 are targeted in vivo by protein tyrosine kinases following cell stimulation with anti-CD3 mAb or pervanadate. This is in agreement with data from direct in vitro kinase assays using purified recombinant Lck and Fyn protein tyrosine kinases." SIGNOR-251152 IFNGR1 protein P15260 UNIPROT JAK2 protein O60674 UNIPROT up-regulates binding 9606 15864272 t gcesareni "The only type ii ifn, ifn-, binds a distinct cell-surface receptor, which is known as the type ii ifn receptor. This receptor is also composed of two subunits, ifngr1 and ifngr2, which are associated with jak1 and jak2, respectively. Activation of the jaks that are associated with the type i ifn receptor results in tyrosine phosphorylation of stat2" SIGNOR-135955 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 LPAR3 protein Q9UBY5 UNIPROT GNA12 protein Q03113 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-135843 MFF protein Q9GZY8 UNIPROT DNM1L protein O00429 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000567 21149567 t gcesareni "Mff functions as an essential factor in mitochondrial recruitment of Drp1." SIGNOR-245957 NANOG protein Q9H9S0 UNIPROT CDX2 protein Q99626 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001086;BTO:0005511 15983365 f miannu "Transfection of NANOG-specific small interfering RNAs reduced levels of NANOG transcript and protein and induced activation of the extraembryonic endoderm-associated genes GATA4, GATA6, LAMININ B1, and AFP as well as upregulation of trophectoderm-associated genes CDX2, GATA2, hCG-alpha, and hCG-beta." SIGNOR-254622 PRKAA1 protein Q13131 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 SIGNOR-C15 15866171 t gcesareni "Ampk activation induces phosphorylation of p53 on serine 15, and this phosphorylation is required to initiate ampk-dependent cell-cycle arrest" SIGNOR-135960 PRKCZ protein Q05513 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr668 SYCGKRFtRSDELQR 9606 BTO:0000887;BTO:0001260 18258854 t llicata "Here we have used a variety of approaches to identify 3 amino acids (thr668, ser670, and thr681) in the zinc finger domain of sp1 that are modified by pkc-zeta angiotensin ii, which activates pkc-? Phosphorylation (at thr410) via the angiotensin ii type 1 receptor, stimulates sp1 phosphorylation and increases sp1 binding to the platelet-derived growth factor-d promoter." SIGNOR-160770 PTPN6 protein P29350 UNIPROT LYN protein P07948 UNIPROT "down-regulates activity" dephosphorylation Tyr397 RVIEDNEyTAREGAK 10116 15537644 t "SHP-1 efficiently inhibits Lyn autophosphorylation and suppresses FcϵRI stimulation|We found that PTPα and SHP-1 both dephosphorylate Lyn exclusively at Tyr-397" SIGNOR-248471 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 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 TEK protein Q02763 UNIPROT TEK protein Q02763 UNIPROT "up-regulates activity" phosphorylation Tyr992 LSRGQEVyVKKTMGR -1 11513602 t lperfetto "Isoelectric focusing electrophoresis and mass spectrometric analysis of a tie2 autophosphorylation time course showed that tyr992 on the putative activation loop was phosphorylated first followed by tyr1108 in the c-terminal tail autophosphorylation of tie2 to produce ptie2 resulted in a 100-fold increase in kcat and a 460-fold increase in kcat/km." SIGNOR-109790 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 LAMA3 protein Q16787 UNIPROT Laminin-5 complex SIGNOR-C184 SIGNOR "form complex" binding 9211848 t lperfetto "Like the other laminins (3), Ln-5 comprises three disul- fide-bonded subunits: a3, b3, and g2." SIGNOR-253235 SRC protein P12931 UNIPROT ANXA1 protein P04083 UNIPROT unknown phosphorylation Thr216 AGERRKGtDVNVFNT 9606 24103589 t lperfetto "Location of sites in human lipocortin i that are phosphorylated by protein tyrosine kinases and protein kinases a and cthe primary site of phosphorylation by protein kinase c was also near the amino terminus at ser-27. The major site of phosphorylation by adenosine cyclic 3',5'-phosphate dependent protein kinase was on the carboxy-terminal half of the molecule at thr-216" SIGNOR-202800 SSH1 protein Q8WYL5 UNIPROT CORO1B protein Q9BR76 UNIPROT "up-regulates activity" dephosphorylation Ser2 sFRKVVRQ 9606 17350576 t "Coronin 1B inhibits filament nucleation by Arp2/3 complex and this inhibition is attenuated by phosphorylation of Coronin 1B at Serine 2, a site targeted by SSH1L. Coronin 1B also directs SSH1L to lamellipodia where SSH1L likely regulates Cofilin activity via dephosphorylation" SIGNOR-248763 STK4 protein Q13043 UNIPROT MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation Thr35 LLKHAEAtLGSGNLR 9606 21808241 t "MOB1a and MOB1b are near identical to each other with protein sequence homology>90%, and more importantly, both of them are putative tumor suppressors." gcesareni "Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2mob1 interaction." SIGNOR-175833 WWTR1 protein Q9GZV5 UNIPROT PAX3 protein P23760 UNIPROT up-regulates binding 10090 BTO:0000165;BTO:0000222 16300735 t gcesareni "These results indicate that pax3 specifically interacts with taz both in vitro and in vivo." SIGNOR-236879 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR TSC2 protein P49815 UNIPROT down-regulates phosphorylation Ser664 KKTSGPLsPPTGPPG 9606 15851026 t lperfetto "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-244765 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 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 LAMB1 protein P07942 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-253233 L-serine chemical CHEBI:17115 ChEBI PKM protein P14618 UNIPROT "up-regulates activity" binding 9606 BTO:0001109 23064226 t "We show that serine can bind to and activate human PKM2, and that PKM2 activity in cells is reduced in response to serine deprivation." SIGNOR-251557 PRKCZ protein Q05513 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Ser670 CGKRFTRsDELQRHK 9606 BTO:0000887;BTO:0001260 18258854 t llicata "Here we have used a variety of approaches to identify 3 amino acids (thr668, ser670, and thr681) in the zinc finger domain of sp1 that are modified by pkc-zeta angiotensin ii, which activates pkc-? Phosphorylation (at thr410) via the angiotensin ii type 1 receptor, stimulates sp1 phosphorylation and increases sp1 binding to the platelet-derived growth factor-d promoter." SIGNOR-160766 USP9X protein Q93008 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates deubiquitination Lys519 DYPRQSIkETPCWIE 10090 BTO:0000165 20016939 t gcesareni "Smad4 is monoubiquitinated in lysine 519 in vivo, a modification that inhibits smad4 by impeding association with phospho-smad2. Fam reverts this negative modification, re-empowering smad4 function;control of smad4 is a good way to regulate bone formation. Fam and ectodermin/tif1gamma (ecto) were reported to respectively regulate the de-ubiquitination and ubiquitination of smad4." SIGNOR-236855 VRK1 protein Q99986 UNIPROT BANF1 protein O75531 UNIPROT down-regulates phosphorylation Thr3 tSQKHRDF 9606 16495336 t gcesareni "We demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain. Coexpression of vrk1 and gfp-baf greatly diminishes the association of baf with the nuclear chromatin/matrix and leads to its dispersal throughout the cell" SIGNOR-144791 VRK2 protein Q86Y07 UNIPROT BANF1 protein O75531 UNIPROT down-regulates phosphorylation Ser4 sQKHRDFV 9606 16495336 t gcesareni "We demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain. Coexpression of vrk1 and gfp-baf greatly diminishes the association of baf with the nuclear chromatin/matrix and leads to its dispersal throughout the cell" SIGNOR-144795 PRKD1 protein Q15139 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Thr112 EGMQIPStQFDAAHP 9606 BTO:0001130 19141652 t lperfetto "This study provides evidence that pkd1 interacts with and phosphorylates beta-catenin at thr(112) and thr(120) we postulate that pkd1 phosphorylation is required to maintain _-catenin transcription activity." SIGNOR-183384 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 CTLA4 protein P16410 UNIPROT "down-regulates activity" phosphorylation Tyr201 SPLTTGVyVKMPPTE 9606 BTO:0000661 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 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 FYB1 protein O15117 UNIPROT "up-regulates activity" phosphorylation Tyr595 IEDDQEVyDDVAEQD 9606 BTO:0000661 10570256 t " two tyrosines, Tyr595 and Tyr651, of FYB are major sites of phosphorylation by FYN-T and mediate binding to SLP-76 in Jurkat T cells. We further demonstrate that the loss of SLP-76 binding by mutation of these sites markedly reduced the ability of FYN-T-FYB-SLP-76 to up-regulate IL-2 transcription." SIGNOR-251163 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 FYN protein P06241 UNIPROT JUP protein P14923 UNIPROT "down-regulates activity" phosphorylation Tyr550 AAGTQQPyTDGVRME 10116 BTO:0004604 14517306 t "Phosphorylation of plakoglobin by Fer and Fyn kinases decreases plakoglobin-desmoplakin interaction and increases plakoglobin-α-catenin association. Fyn mainly phosphorylated Tyr549" SIGNOR-251177 FYN protein P06241 UNIPROT JUP protein P14923 UNIPROT "up-regulates activity" phosphorylation Tyr550 AAGTQQPyTDGVRME 10116 BTO:0004604 14517306 t "Phosphorylation of plakoglobin by Fer and Fyn kinases decreases plakoglobin-desmoplakin interaction and increases plakoglobin-α-catenin association. Fyn mainly phosphorylated Tyr549 and that it phosphorylated Tyr133 with a much lower activity" SIGNOR-251176 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 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 "neuropeptide FF receptor agonist" smallmolecule CHEBI:141000 ChEBI NPFFR2 protein Q9Y5X5 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-257550 PCSK7 protein Q16549 UNIPROT CEBPA protein P49715 UNIPROT down-regulates phosphorylation 9606 BTO:0000130 19544470 t gcesareni "Addition of active p38a induced phosphorylation of wild-type c/ebp_? (c/ebp_?WT) on serine 21" SIGNOR-186202 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 GRK1 protein Q15835 UNIPROT GRK1 protein Q15835 UNIPROT "down-regulates activity" phosphorylation Ser21 AFIAARGsFDGSSSQ -1 1527025 t "The major autophosphorylation site yielded the following sequence: DVGAFS488T489VKGVAFEK, where Ser488 and Thr489 are phosphorylated. Additionally, a minor autophosphorylation site was identified at Ser21. we speculate that autophosphorylation of RK may lower the affinity of the enzyme for Rho* via repulsion between phosphorylated sites on Rho* and the kinase." SIGNOR-251186 GRK1 protein Q15835 UNIPROT GRK1 protein Q15835 UNIPROT "down-regulates activity" phosphorylation Ser491 IQDVGAFsTVKGVAF -1 1527025 t "The major autophosphorylation site yielded the following sequence: DVGAFS488T489VKGVAFEK, where Ser488 and Thr489 are phosphorylated. Additionally, a minor autophosphorylation site was identified at Ser21. we speculate that autophosphorylation of RK may lower the affinity of the enzyme for Rho* via repulsion between phosphorylated sites on Rho* and the kinase." SIGNOR-251187 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 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 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 NKX2-5 protein P52952 UNIPROT LYL1 protein P12980 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9060 BTO:0001106 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 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 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 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 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 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 NME1 protein P15531 UNIPROT NETO2 protein Q8NC67 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-255166 PDPK1 protein O15530 UNIPROT PRKCB protein P05771 UNIPROT up-regulates phosphorylation Thr500 WDGVTTKtFCGTPDY 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-150857 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 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 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 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 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 PPP2CB protein P62714 UNIPROT PAK1 protein Q13153 UNIPROT "down-regulates activity" dephosphorylation Thr423 PEQSKRStMVGTPYW 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-248600 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 PTPN6 protein P29350 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-248472 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates phosphorylation Tyr664 EGGWMEDyDYVHLQG 9606 11604500 t lperfetto "The loss of activity in the cas-f668/f670 mutant is consistent with the notion that src, once initially bound by its sh3 domain, phosphorylates the tyr668/670 site to further stabilize its interaction by sh2 binding." SIGNOR-111056 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates phosphorylation Tyr666 GWMEDYDyVHLQGKE 9606 11604500 t lperfetto "The loss of activity in the cas-f668/f670 mutant is consistent with the notion that src, once initially bound by its sh3 domain, phosphorylates the tyr668/670 site to further stabilize its interaction by sh2 binding." SIGNOR-111060 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 gelsolinrecently chellaiah et al. 1998 Showed that osteopontin stimulates association between gelsolin and c-src, leading to increased gelsolin associated pi-3 kinase activity and pip3 levels in osteoclasts" SIGNOR-67014 SRC protein P12931 UNIPROT MUC1 protein P15941 UNIPROT up-regulates phosphorylation Tyr1229 SSTDRSPyEKVSAGN 9606 11152665 t lperfetto "The c-src tyrosine kinase regulates signaling of the human df3/muc1 carcinoma-associated antigen with gsk3 beta and betBeta-catenin c-src phosphorylates the muc1 cytoplasmic domain at a yekv motif c-src-mediated phosphorylation of muc1 increases binding of muc1 and betBeta-catenin" SIGNOR-85938 DYRK1A protein Q13627 UNIPROT DYRK1A protein Q13627 UNIPROT "up-regulates activity" phosphorylation Tyr321 LGQRIYQyIQSRFYR 9606 BTO:0000298 11672423 t lperfetto "Direct identification of phosphorylated residues by tandem ms confirmed that tyr-321, but not tyr-319, was phosphorylated. When expressed in cos-7 cells, dyrk1a was found to be fully phosphorylated on tyr-321. A catalytically inactive mutant of dyrk1a contained no detectable phosphotyrosine, indicating that tyr-321 is autophosphorylated by dyrk1a." SIGNOR-111145 PRKCZ protein Q05513 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser9 SGRPRTTsFAESCKP 9606 14657655 t gcesareni "Phospho-gsk3b-specific antibodies also revolved that lkb1 regulates gsk3b phosphorylation at a known inhibitory site, serine-9. This localized phosphorylation is cdc42 and pkc-zeta-dependent." SIGNOR-119889 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 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 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 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 MAPK3 protein P27361 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser383 IHFWSTLsPIAPRSP 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-34657 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 MIB1 protein Q86YT6 UNIPROT DLL1 protein O00548 UNIPROT "up-regulates activity" ubiquitination 9606 16140393 t lperfetto "Mib physically interacts with Delta and promotes its ubiquitination and internalization [66], which have been shown to up-regulate Notch activity." SIGNOR-209750 MIB1 protein Q86YT6 UNIPROT JAG1 protein P78504 UNIPROT "up-regulates activity" ubiquitination 9606 BTO:0000938 12530964 t lperfetto "Mib1 is essential for the generation of functional notch ligands and regulates the classical notch ligands dll1, dll4, jag1, and jag2 in vertebrates mib1 is an essential e3 ubiquitin ligase for jag1 in the developing cerebellum." SIGNOR-97388 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 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 PPP2CA protein P67775 UNIPROT AKT2 protein P31751 UNIPROT "down-regulates activity" dephosphorylation Thr309 SDGATMKtFCGTPEY 10090 BTO:0000944 15367694 t "Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes" SIGNOR-248633 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 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 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 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 PTPRJ protein Q12913 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 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-76088 DLK1 protein P80370 UNIPROT SOX9 protein P48436 UNIPROT up-regulates "transcriptional regulation" 9606 19254573 f fspada "Pref-1 inhibits adipocyte differentiation through upregulating sox9 expression." SIGNOR-209968 DUSP1 protein P28562 UNIPROT MAPK14 protein Q16539 UNIPROT "down-regulates activity" dephosphorylation 10090 BTO:0000165 17158101 t gcesareni "Mpk1 inhibits p38 activity." SIGNOR-236867 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 GATA3 protein P23771 UNIPROT PPARG protein P37231 UNIPROT down-regulates "transcriptional regulation" 9606 15632071 f fspada "Constitutive expression of both gata-2 and gata-3 suppressed adipocyte differentiation, partially through direct binding to the peroxisome proliferator-activated receptor gamma (ppargamma) promoter and suppression of its basal activity" SIGNOR-210025 IL4 protein P05112 UNIPROT IL4R protein P24394 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000801;BTO:0000876 BTO:0000887;BTO:0000763;BTO:0001260 12704343 t milica "IL-4R Is a 140-kd protein that binds il-4 with high affinity" SIGNOR-100762 MAP2K1 protein Q02750 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "up-regulates activity" phosphorylation 10090 BTO:0000011 12270934 t lperfetto "MEK1 as indicated by extensive phosphorylation of ERK1 and ERK2 during the initial 2 h of adipogenesis." SIGNOR-235352 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 MAPK14 protein Q16539 UNIPROT MKNK1 protein Q9BUB5 UNIPROT up-regulates phosphorylation Thr255 ITTPELTtPCGSAEY 9606 9155017 t gcesareni "Mnk1, but not mnk2, also binds strongly to the stress-activated kinase, p38." SIGNOR-48346 MAPKAPK2 protein P49137 UNIPROT CREB1 protein P16220 UNIPROT "up-regulates activity" phosphorylation Ser133 EILSRRPsYRKILND 9606 8887554 t lperfetto "We show that mapkap kinase-2 phosphorylates creb at ser133 in vitro." SIGNOR-44384 MIB2 protein Q96AX9 UNIPROT JAG2 protein Q9Y219 UNIPROT up-regulates ubiquitination 9606 15920166 t gcesareni "Skeletrophin bound the intracellular regions of the notch ligand jagged-2, but not to those of delta-1, -3, -4, or jagged-1. Skeletrophin, but not its ring-mutated form, ubiquitinized the intracellular region of jagged-2." SIGNOR-137922 MIF protein P14174 UNIPROT CD74 protein P04233 UNIPROT "up-regulates activity" binding 9606 BTO:0000452 12782713 t gcesareni "MIF binds to the extracellular domain of CD74, and CD74 is required for MIF-induced activation of the extracellular signal-regulated kinase-1/2 MAP kinase cascade, cell proliferation, and PGE2 production" SIGNOR-252060 miR-142-3p mirna MI0000458 miRBase MLL-AF4 "fusion protein" SIGNOR-FP4 SIGNOR "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0000737 24057258 t miannu "MiR-142-3p downregulated MLL-AF4 expression in the RS4;11 leukemic cell line. the downregulation of MLL-AF4 by ectopically expressed miR-142-3p reduced the expression of MLL-AF4 downstream target genes, including HOXA7, HOXA9, and HOXA10, which may contribute to miR-142-3p-induced apoptosis and growth inhibition." SIGNOR-255760 mir-143 mirna MI0000459 miRBase IGFBP5 protein P24593 UNIPROT "down-regulates quantity" "post transcriptional regulation" 10090 BTO:0005787 26762731 t "We identified miR-143 as a regulator of the insulin growth factor-binding protein 5 (Igfbp5) in primary myoblasts and show that the expression of miR-143 and its target gene is disrupted in satellite cells from old mice." SIGNOR-255939 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT "up-regulates activity" phosphorylation Ser192 PRPDHTKsIYTRSVI -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-250225 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 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 PDK3 protein Q15120 UNIPROT PDHA1 protein P08559 UNIPROT "down-regulates activity" phosphorylation Ser293 TYRYHGHsMSDPGVS -1 11485553 t lperfetto "Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293." SIGNOR-109609 PKI-402 chemical CID:44187953 PUBCHEM PIK3CG protein P48736 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206259 CX3CL1 protein P78423 UNIPROT CX3CR1 protein P49238 UNIPROT up-regulates binding 9606 11432858 t gcesareni "Fractalkine/cx3cl1 is a membrane-tethered chemokine that functions as a chemoattractant and adhesion protein by interacting with the receptor cx3cr1." SIGNOR-109135 EGFR protein P00533 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates binding 9606 11279155 t gcesareni "These results demonstrate that egfr-erbb2 oligomers are potent activators of mapk and akt, and this signaling does not require egfr kinase activity" SIGNOR-106500 FGF2 protein P09038 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 11781339 f gcesareni "In these collagen gel cultures, p38 activation was induced more potently by fgf-2 treatment compared with that in proliferating cultures" SIGNOR-113649 IFNL3 protein Q8IZI9 UNIPROT IFNLR1 protein Q8IU57 UNIPROT up-regulates binding 9606 12469119 t gcesareni "Il-28 and il-29 interacted with a heterodimeric class ii cytokine receptor that consisted of il-10 receptor beta (il-10rbeta) and an orphan class ii receptor chain, designated il-28ralpha." SIGNOR-96243 MAPK11 protein Q15759 UNIPROT HBP1 protein O60381 UNIPROT up-regulates phosphorylation Ser402 GFSKNCGsPGSSQLS 9606 14612426 t lperfetto "A mutation of the p38 map kinase phosphorylation site at aa 401 [(s-a)401hbp1] also triggered hbp1 protein instability. While protein stability was compromised by mutation, the specific activities of (s-a)401hbp1 and of wild-type hbp1 appeared comparable for transcriptional repression." SIGNOR-119134 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 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 MAPK8IP3 protein Q9UPT6 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates binding 9606 10523642 t gcesareni "Overexpression of full-length jsap1 in cos-7 cells led to a considerable enhancement of jnk3 activation, and modest enhancement of jnk1 and jnk2 activation, by the mekk1-sek1 pathwaythe regions of jsap1 that bound jnk, sek1, and mekk1 were distinct from one another. Jnk and mekk1 also bound jsap1 in vitro, suggesting that these interactions are direct." SIGNOR-71471 miR-155 mirna MI0000681 miRBase AP1 complex SIGNOR-C154 SIGNOR "up-regulates quantity by expression" "post transcriptional regulation" 9606 BTO:0004620 24708856 t irozzo "In this study, bioinformatic prediction combined with pathway analysis and validation by qRT-PCR revealed that miR-155 expression positively correlates with the expression of the AP-1 genes c-JUN and FOS, which are known to induce myeloid differentiation" SIGNOR-256124 miR-155 mirna MI0000681 miRBase CEBPB protein P17676 UNIPROT "down-regulates quantity" "post transcriptional regulation" 10090 BTO:0000011 21986534 t "This overexpression of miR-155 may suppress the expression of C/EBPβ and CREB by directly targeting their 3' untranslated regions (3' UTRs)" SIGNOR-255936 miR-155 mirna MI0000681 miRBase FOS protein P01100 UNIPROT "up-regulates quantity by expression" "post transcriptional regulation" 9606 BTO:0004620 24708856 t miannu "We found overexpression of miR-155 led to increase in cJUN, FOS and TRIB2, and decrease in MEIS1, GFI1, cMYC and JARID2." SIGNOR-255762 miR-155 mirna MI0000681 miRBase GFI1 protein Q99684 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0004620 24708856 t miannu "We found overexpression of miR-155 led to increase in cJUN, FOS and TRIB2, and decrease in MEIS1, GFI1, cMYC and JARID2." SIGNOR-255765 PDK3 protein Q15120 UNIPROT PDHA1 protein P08559 UNIPROT "down-regulates activity" phosphorylation Ser232 NRYGMGTsVERAAAS -1 11485553 t lperfetto "Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293." SIGNOR-109613 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 PRKCZ protein Q05513 UNIPROT MARK2 protein Q7KZI7 UNIPROT down-regulates phosphorylation Thr596 RGVSSRStFHAGQLR 9606 15084291 t lperfetto "Hpar-1b is phosphorylated by apkc on threonine 595 importantly, phosphorylation of hpar-1b on t595 negatively regulates the kinase activity and plasma membrane localization of hpar-1b in vivo." SIGNOR-124217 PTEN protein P60484 UNIPROT "1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate" smallmolecule CHEBI:16618 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 11875759 t lperfetto "PTEN dephosphorylates PI3P, lowering its cellular levels and resulting in the down-regulation of AKT." SIGNOR-228145 SUFU protein Q9UMX1 UNIPROT SUFU protein Q9UMX1 UNIPROT up-regulates binding 9606 BTO:0001130;BTO:0000848;BTO:0000527 10564661 t miannu "Hsu(fu) associated with itself / homo- or heterodimers of hsu(fu) might function to bring together other effector proteins" SIGNOR-72311 TAOK2 protein Q9UL54 UNIPROT MAP2K6 protein P52564 UNIPROT "up-regulates activity" phosphorylation Ser207 ISGYLVDsVAKTIDA 9606 BTO:0000007 11279118 t lperfetto "Suggesting that tao2 selectively activates mek3 and mek6 of the p38 pathway in intact cells" SIGNOR-106465 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 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 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 PPP2CA protein P67775 UNIPROT AKT3 protein Q9Y243 UNIPROT "down-regulates activity" dephosphorylation Ser472 RPHFPQFsYSASGRE 10090 BTO:0000944 15367694 t "Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes" SIGNOR-248652 PPP2CA protein P67775 UNIPROT PAK1 protein Q13153 UNIPROT "down-regulates activity" dephosphorylation Ser199 PRPEHTKsVYTRSVI 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-248642 perifosine chemical CHEBI:67272 ChEBI AKT1 protein P31749 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0001130 14617782 t "Perifosine causes decrease in Akt Ser473 and Thr308 phosphorylation" gcesareni "Perifosine is an alkylphospholipid that targets the pleckstrin homology domain of akt and blocks its membrane translocation, hence preventing akt phosphorylation and activation" SIGNOR-252629 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 PPP2CA protein P67775 UNIPROT AKT3 protein Q9Y243 UNIPROT "down-regulates activity" dephosphorylation Thr305 TDAATMKtFCGTPEY 10090 BTO:0000944 15367694 t "Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes" SIGNOR-248654 PRKCA protein P17252 UNIPROT CD5 protein P06127 UNIPROT up-regulates phosphorylation Thr434 MSFHRNHtATVRSHA 9606 11123317 t amattioni "Cd5 is a good pkc substrate. Phosphorylation of cd5 is necessary for cd5-mediated lipid second messenger generation." SIGNOR-85175 PRKG1 protein Q13976 UNIPROT SF1 protein Q15637 UNIPROT "down-regulates activity" phosphorylation Ser20 PSKKRKRsRWNQDTM 10116 BTO:0000947 10449420 t lperfetto "PKG phosphorylates SF1 at Ser20, which inhibits the SF1-U2AF65 interaction leading to a block of pre-spliceosome assembly. Mutation of Ser20 to Ala or Thr also inhibits the interaction with U2AF65, indicating that Ser20 is essential for binding." SIGNOR-249018 RET protein P07949 UNIPROT GFRA1 protein P56159 UNIPROT up-regulates binding 9606 10829012 t gcesareni "Gdnfr-alpha-ligand complex, together with the tyrosine kinase receptor (cret) forms a functional receptor that activates downstream signal transduction pathways" SIGNOR-77587 RPS6KA4 protein O75676 UNIPROT HIST3H3 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 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 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 PI3K complex SIGNOR-C156 SIGNOR 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-252719 PPP2CA protein P67775 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-248641 BIRC3 protein Q13489 UNIPROT MAP3K14 protein Q99558 UNIPROT down-regulates ubiquitination 9606 20682767 t gcesareni "Ciap1/2 (cellular inhibitor of apoptosis 1 and 2) ubiquitinate nik for degradation." SIGNOR-167298 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 CSNK2A1 protein P68400 UNIPROT TOP2A protein P11388 UNIPROT unknown phosphorylation Thr1343 FSDFDEKtDDEDFVP 9606 BTO:0000568 9804834 t llicata "Casein kinase II catalyzes a mitotic phosphorylation on threonine 1342 of human DNA topoisomerase IIalpha" SIGNOR-250966 FBXO5 protein Q9UKT4 UNIPROT ANAPC7 protein Q9UJX3 UNIPROT down-regulates binding 9606 11751633 t gcesareni "Emi1 can inhibit apc already activated by cdc20 or cdh1." SIGNOR-113382 GRK2 protein P25098 UNIPROT ADRA2A protein P08913 UNIPROT "down-regulates activity" phosphorylation Ser297 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 Ser298 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 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 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 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 DCT protein P40126 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-254592 PI3K complex SIGNOR-C156 SIGNOR 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-252705 PPP2CA protein P67775 UNIPROT PAK1 protein Q13153 UNIPROT "down-regulates activity" dephosphorylation Thr423 PEQSKRStMVGTPYW 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-248643 PTPN3 protein P26045 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-248459 SRC protein P12931 UNIPROT CBLC protein Q9ULV8 UNIPROT up-regulates phosphorylation Tyr341 SEEQLQLyWAMDSTF 9606 20525694 t gcesareni "Phosphorylation of a critical tyrosine (tyr-341) in the linker region of cbl-c by src or a phosphomimetic mutation of this tyrosine (y341e) is sufficient to increase the e3 activity of cbl-c." SIGNOR-165862 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 (-)-anisomycin chemical CHEBI:338412 ChEBI MAPK8 protein P45983 UNIPROT up-regulates "chemical activation" 9606 Other t CellSignaling gcesareni SIGNOR-189702 CDK6 protein Q00534 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-138965 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 MITF protein O75030 UNIPROT PMEL protein P40967 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-254589 CDK1 protein P06493 UNIPROT ORC1 protein Q13415 UNIPROT up-regulates phosphorylation Thr375 AQNEATStPHRIRRK 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-116329 FYN protein P06241 UNIPROT CDK5 protein Q00535 UNIPROT "up-regulates activity" phosphorylation Tyr15 EKIGEGTyGTVFKAK 9606 BTO:0000007 14757045 t "Constitutively active Fyn phosphorylated Tyr15 of Cdk5. Fyn Facilitates Kinase Activity of Cdk5 Via Tyr15 Phosphorylation" SIGNOR-251156 FYN protein P06241 UNIPROT GRIN2B protein Q13224 UNIPROT unknown phosphorylation Tyr1039 HSQLSDLyGKFSFKS -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-251169 GSK3B protein P49841 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" phosphorylation Ser33 LPENNVLsPLPSQAM 9606 BTO:0000971 11483158 t "Glycogen synthase kinase3 beta phosphorylates serine 33 of p53 and activates p53's transcriptional activity." SIGNOR-251258 IKK-complex complex SIGNOR-C14 SIGNOR BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser25 AERGLGPsPAGDGPS 10090 BTO:0002572 23332762 t lperfetto "Ikk phosphorylates bad at serine-26 (ser26) and primes it for inactivation." SIGNOR-209776 JNK proteinfamily SIGNOR-PF15 SIGNOR ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 15916964 t lperfetto "Phosphorylation of atf2 by jnk/p38 on thr69/71 is prerequisite to its transcriptional activities" SIGNOR-137631 KDM6B protein O15054 UNIPROT M1_polarization phenotype SIGNOR-PH54 SIGNOR down-regulates 9606 BTO:0000801 22378047 f lperfetto "IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing JMJD3-IRF4 axis to inhibit IRF5-mediated M1 polarization." SIGNOR-249563 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 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 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 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 SRC protein P12931 UNIPROT BTK protein Q06187 UNIPROT "up-regulates activity" phosphorylation Tyr551 RYVLDDEyTSSVGSK 9606 BTO:0001528 8629002 t "This interaction of BTK with SRC kinases transphosphorylated BTK on tyrosine at residue 551, which led to BTK activation." SIGNOR-251100 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 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 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 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 ULK1 protein O75385 UNIPROT ATG13 protein O75143 UNIPROT up-regulates phosphorylation 9606 19211835 t gcesareni "Ulks directly phosphorylate atg13" SIGNOR-183957 MAPK1 protein P28482 UNIPROT RPS3 protein P23396 UNIPROT up-regulates phosphorylation Thr42 SGVEVRVtPTRTEII 9606 15950189 t lperfetto "Erk phosphorylates threonine 42 residue of ribosomal protein s3." SIGNOR-137955 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 ROBO proteinfamily SIGNOR-PF14 SIGNOR ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 15916964 t lperfetto "Phosphorylation of atf2 by jnk/p38 on thr69/71 is prerequisite to its transcriptional activities" SIGNOR-137639 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 GSK3B protein P49841 UNIPROT NACA protein E9PAV3 UNIPROT down-regulates phosphorylation Thr2022 NIQENTQtPTVQEES 9606 BTO:0000007 15005626 t gcesareni "Gsk3 beta-dependent phosphorylation of the alpha nac coactivator regulates its nuclear translocation and proteasome-mediated degradation." SIGNOR-123262 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 HCK protein P08631 UNIPROT down-regulates phosphorylation Tyr522 YTATESQyQQQP 9606 BTO:0000007 10934191 t gcesareni "We demonstrate that autophosphorylation of the recombinant src family kinase hck leads to a 20-fold increase in its specific enzymatic activity." SIGNOR-76996 KAT5 protein Q92993 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates acetylation Lys2029 NAVDDLGkSALHWAA 9606 17636029 t gcesareni "This result implies that the residues k2019, k2039, k2044, and k2068 of notch1-ic are the major targets of the acetyltransferase activity of tip60." SIGNOR-156911 KAT5 protein Q92993 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates acetylation Lys2054 LLKNGANkDMQNNRE 9606 17636029 t gcesareni "This result implies that the residues k2019, k2039, k2044, and k2068 of notch1-ic are the major targets of the acetyltransferase activity of tip60." SIGNOR-156919 KAT5 protein Q92993 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates acetylation Lys2078 EGSYETAkVLLDHFA 9606 17636029 t gcesareni "This result implies that the residues k2019, k2039, k2044, and k2068 of notch1-ic are the major targets of the acetyltransferase activity of tip60." SIGNOR-156923 LCK protein P06239 UNIPROT PTEN protein P60484 UNIPROT up-regulates phosphorylation Tyr315 RADNDKEyLVLTLTK 9606 11948419 t gcesareni "Thus, y240a and y315a are involved in the ability of mmac/pten to dephosphorylate ptdins and regulate tumor cell growth in vitro and in vivo." SIGNOR-116499 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 MAPK1 protein P28482 UNIPROT TCF3 protein P15923 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr355 NFSSSPStPVGSPQG 10090 BTO:0000944 14592976 t lperfetto "Notch-induced degradation requires phosphorylation of E47 by p42/p44 MAP kinases. |Wild_type E47 but not the Mm mutant reacted to the antibodies, suggesting that E47 is at least phosphorylated at the M2 site (Figure 3A)|anti_phospho_M2 peptide (SSPSpTPVGSPQG)" SIGNOR-249451 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 NUMA1 protein Q14980 UNIPROT TUBA1A protein Q71U36 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-116640 ROBO proteinfamily SIGNOR-PF14 SIGNOR ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 15916964 t lperfetto "Phosphorylation of atf2 by jnk/p38 on thr69/71 is prerequisite to its transcriptional activities" SIGNOR-137635 SMARCAD1 protein Q9H4L7 UNIPROT TRIM28 protein Q13263 UNIPROT "up-regulates activity" binding 9606 21549307 t 1 miannu "SMARCAD1 interacts with HDAC1 and KAP1 and is required for their binding to heterochromatin" SIGNOR-239838 SRC protein P12931 UNIPROT CHRNA7 protein P36544 UNIPROT down-regulates phosphorylation Tyr386 ASNGNLLyIGFRGLD 9606 BTO:0000938 16251431 t gcesareni "?7 Neuronal nicotinic acetylcholine receptors are negatively regulated by tyrosine phosphorylation and src-family kinases" SIGNOR-141307 VRK2 protein Q86Y07 UNIPROT BANF1 protein O75531 UNIPROT down-regulates phosphorylation Thr3 tSQKHRDF 9606 16495336 t gcesareni "We demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain. Coexpression of vrk1 and gfp-baf greatly diminishes the association of baf with the nuclear chromatin/matrix and leads to its dispersal throughout the cell" SIGNOR-144803 PRKCA protein P17252 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation Ser21 SGRARTSsFAEPGGG 9606 BTO:0000007 11884598 t lperfetto "Convergence of multiple signaling cascades at glycogen synthase kinase 3: edg receptor-mediated phosphorylation and inactivation by lysophosphatidic acid through a protein kinase c-dependent intracellular pathway." SIGNOR-115714 CAMK2A protein Q9UQM7 UNIPROT RCHY1 protein Q96PM5 UNIPROT down-regulates phosphorylation Thr154 ICLEDIHtSRVVAHV 9606 17568776 t lperfetto "Phosphorylation of pirh2 by calmodulin-dependent kinase ii impairs its ability to ubiquitinate p53" SIGNOR-156068 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 FYN protein P06241 UNIPROT AGAP2 protein Q99490 UNIPROT up-regulates phosphorylation Tyr1130 QGRTALFyARQAGSQ 9606 16841086 t llicata "We demonstrate that fyn is essential for phosphorylating pike-a and protects it from apoptotic cleavage. Active but not kinase-dead fyn interacts with pike-a and phosphorylates it on both y682 and y774 residues. Tyrosine phosphorylation in pike-a is required for its association with active fyn but not for akt. Mutation of d into a in pike-a protects it from caspase cleavage and promotes cell survival." SIGNOR-147936 GSK3A protein P49840 UNIPROT MAFA protein Q8NHW3 UNIPROT down-regulates 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 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 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 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 PAK2 protein Q13177 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Thr89 QSSNGHItTTPTPTQ 9606 BTO:0000848 21177766 t lperfetto "P21-activated protein kinase (pak2)-mediated c-jun phosphorylation at 5 threonine sites promotes cell transformationour data showed that pak2 binds and phosphorylates c-jun at five threonine sites (thr2, thr8, thr89, thr93 and thr286)" SIGNOR-170772 PAK2 protein Q13177 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Thr8 MTAKMETtFYDDALN 9606 BTO:0000848 21177766 t lperfetto "P21-activated protein kinase (pak2)-mediated c-jun phosphorylation at 5 threonine sites promotes cell transformationour data showed that pak2 binds and phosphorylates c-jun at five threonine sites (thr2, thr8, thr89, thr93 and thr286)" SIGNOR-170768 POU5F1 protein Q01860 UNIPROT THY1 protein P04216 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001086 17068183 f miannu "To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG." SIGNOR-254931 PRKD1 protein Q15139 UNIPROT COL4A3BP protein Q9Y5P4 UNIPROT down-regulates phosphorylation Ser132 SSLRRHGsMVSLVSG 9606 17591919 t lperfetto "In this study, we identify cert as a novel in vivo pkd substrate. Phosphorylation on serine 132 by pkd decreases the affinity of cert toward its lipid target phosphatidylinositol 4-phosphate at golgi membranes and reduces ceramide transfer activity" SIGNOR-156500 PRKG1 protein Q13976 UNIPROT TRPC3 protein Q13507 UNIPROT down-regulates phosphorylation Ser251 KNDYRKLsMQCKDFV 9606 BTO:0000007 14983059 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-122978 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 XAF1 protein Q6GPH4 UNIPROT BIRC2 protein Q13490 UNIPROT down-regulates binding 9606 17613533 t gcesareni "Immunoprecipitation studies indicate that xaf1 binds to xiap,birc2,birc3." SIGNOR-156843 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 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 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 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 MK-2461 chemical CID:44137946 PUBCHEM MERTK protein Q12866 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194381 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 PCM1 protein Q15154 UNIPROT CETN3 protein O15182 UNIPROT up-regulates relocalization 9606 12403812 t miannu "Rna silencing of pcm-1 leads to reduced assembly of centrin, pericentrin, and ninein at the centrosome" SIGNOR-95016 PLK1 protein P53350 UNIPROT BORA protein Q6PGQ7 UNIPROT down-regulates phosphorylation Ser497 SSNIQMDsGYNTQNC 9606 18378770 t gcesareni "Following cdk1-dependent recruitment, plk1 triggers hbora destruction by phosphorylating a recognition site for scf(beta-trcp)." SIGNOR-178150 PPM1D protein O15297 UNIPROT RPS6KA3 protein P51812 UNIPROT "down-regulates activity" dephosphorylation Ser386 HQLFRGFsFVAITSD 10090 15206906 t "RSK2 (p90 ribosomal S6 kinase 2) is activated via the ERK (extracellular-signal-regulated kinase) pathway by phosphorylation on four sites: Ser227 in the activation loop of the N-terminal kinase domain, Ser369 in the linker, Ser386 in the hydrophobic motif and Thr577 in the C-terminal kinase domain of RSK2. In the present study, we demonstrate that RSK2 is associated in vivo with PP2Cdelta (protein phosphatase 2Cdelta). In epidermal growth factorstimulated cells, RSK2 is partially dephosphorylated on all four sites in an Mn2+-dependent manner, leading to reduced protein kinase activity" SIGNOR-248322 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 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 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 PRKCE protein Q02156 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-158129 PRKCE protein Q02156 UNIPROT TICAM2 protein Q86XR7 UNIPROT up-regulates phosphorylation Ser16 NSCPLSLsWGKRHSV 9606 16757566 t llicata "Here we show that tram is transiently phosphorylated by pkcepsilon on serine-16 our study provides a possible target for these molecules in lps signaling. Dag may activate pkc?, Leading to the phosphorylation and activation of tram." SIGNOR-146991 PRKD1 protein Q15139 UNIPROT HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser486 RPLSRAQsSPAAPAS 9606 18509061 t gcesareni "We show for the first time that vegf stimulated phosphorylation of hdac7 at the sites of ser178, ser344, and ser479we found that phospholipase cgamma/protein kinase c/protein kinase d1 (pkd1)-dependent signal pathway mediated hdac7 phosphorylation and cytoplasmic accumulation by vegf." SIGNOR-178713 PRKD1 protein Q15139 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser498 RPLSRTQsSPLPQSP 9606 22865920 t lperfetto "When phosphorylated by camk/pkd, class iia hdacs bind 14-3-3 chaperone proteins, which facilitates their nuclear export, thereby relieving hdac-mediated transcriptional repression." SIGNOR-198662 "DNA damage" stimulus SIGNOR-ST1 SIGNOR ATR protein Q13535 UNIPROT up-regulates 9606 21034966 f lperfetto "the ATM-Chk2 and ATR-Chk1 pathways, which are activated by DNA double-strand breaks (DSBs) and single-stranded DNA respectively." SIGNOR-242609 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 IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT "up-regulates activity" phosphorylation Tyr1346 SFDERQPyAHMNGGR -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-246260 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 MKL1 protein Q969V6 UNIPROT KLF4 protein O43474 UNIPROT down-regulates 9606 BTO:0000887;BTO:0001260 21673106 f "miR-143 and miR-145 target KLF4" gcesareni "This result suggests that mrtf-a, but not myocd, is essential for bmp4-dependent induction ofmir-143/145gene transcription. Of the mirnas identified to target klf4, only mir-143 and mir-145 were induced at least 1.5-fold by both bmp4 and tgf- , suggesting that they may be critical for bmp4- and tgf- -mediated reduction of klf4." SIGNOR-174261 PLK1 protein P53350 UNIPROT TOPORS protein Q9NS56 UNIPROT down-regulates phosphorylation Ser718 KDRDGYEsSYRRRTL 9606 19473992 t lperfetto "Plk1-mediated phosphorylation of topors regulates p53 stabilityherein, 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-185838 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 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 PRKDC protein P78527 UNIPROT DCLRE1C protein Q96SD1 UNIPROT up-regulates phosphorylation Ser503 NDEITDEsLENFPSS 9606 16874298 t lperfetto "Artemis is a nuclear phosphoprotein required for genomic integrity whose phosphorylation is increased subsequent to dna damage. Artemis phosphorylation by the dna-dependent protein kinase (dna-pk). However, regardless of its association with dna-pkcs, phosphorylation of artemis at both s516 and s645 was stimulated in response to the double-stranded dna-damaging agent bleomycin" SIGNOR-148327 TGFB3 protein P10600 UNIPROT TGFB3 protein P10600 UNIPROT up-regulates binding 9606 16885528 t gcesareni "The active form of tgf-b is a dimer stabilized by hydrophobic interactions and usually further strengthened by an intersubunit disulfide bridge" SIGNOR-148611 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 USP9X protein Q93008 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates deubiquitination Lys519 DYPRQSIkETPCWIE 9606 19135894 t gcesareni "Smad4 is monoubiquitinated in lysine 519 in vivo, a modification that inhibits smad4 by impeding association with phospho-smad2. Fam reverts this negative modification, re-empowering smad4 function;control of smad4 is a good way to regulate bone formation. Fam and ectodermin/tif1gamma (ecto) were reported to respectively regulate the de-ubiquitination and ubiquitination of smad4." SIGNOR-183285 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 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 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 DLK1 protein P80370 UNIPROT SOX9 protein P48436 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19254573 f fspada "Pref-1 inhibits adipocyte differentiation through upregulating sox9 expression." SIGNOR-184277 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 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 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 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 MKNK1 protein Q9BUB5 UNIPROT PLA2G4A protein P47712 UNIPROT "up-regulates activity" phosphorylation Ser727 RQNPSRCsVSLSNVE 9606 BTO:0000007 10978317 t lperfetto "The results suggest that MNK1 or a closely related kinase is responsible for in vivo phosphorylation of cPLA2 on Ser-727." SIGNOR-226633 MKNK2 protein Q9HBH9 UNIPROT EIF4E protein P06730 UNIPROT up-regulates phosphorylation Ser209 DTATKSGsTTKNRFV 9606 17724079 t lperfetto "Inhibition of mammalian target of rapamycin induces phosphatidylinositol 3-kinase-dependent and mnk-mediated eukaryotic translation initiation factor 4e phosphorylation.Therefore, eif4e is considered a survival protein involved in cell cycle progression, cell transformation, and apoptotic resistance. Phosphorylation of eif4e (usually at ser209) increases its binding affinity for the cap of mrna and may also favor its entry into initiation complexes." SIGNOR-157537 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 PPP2CB protein P62714 UNIPROT HDAC7 protein Q8WUI4 UNIPROT "up-regulates activity" dephosphorylation Ser486 RPLSRAQsSPAAPAS 9606 18339811 t "Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. |Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs." SIGNOR-248606 PRKACA protein P17612 UNIPROT PRKAR2B protein P31323 UNIPROT up-regulates phosphorylation Ser114 NRFTRRAsVCAEAYN 9606 BTO:0000782 15187164 t gcesareni "Serine 114 phosphorylation is required for both nuclear localization and down-regulation of il-2 production by riibeta." SIGNOR-125545 PRKCA protein P17252 UNIPROT MET protein P08581 UNIPROT down-regulates phosphorylation Ser985 PHLDRLVsARSVSPT 9606 8294430 t fstefani "These data show that phosphorylation of ser985 is a key mechanism for the negative regulation of hgf/sf receptor." SIGNOR-37718 PRKCD protein Q05655 UNIPROT PLSCR3 protein Q9NRY6 UNIPROT up-regulates phosphorylation Thr21 PPPPYPVtPGYPEPA 9606 16267027 t gcesareni "Ad198-activated pkc-delta induces phosphorylation of mitochondrial pls3 at thr21;pls3 is a critical downstream effector of pkc-delta in ad198-induced apoptosis." SIGNOR-140759 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 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 ZNRF3 protein Q9ULT6 UNIPROT FZD2 protein Q14332 UNIPROT down-regulates relocalization 9606 23151663 t gcesareni "Znrf3 is associated with the wnt receptor complex, and inhibits wntby promoting the turnover of frizzled and lrp6." SIGNOR-199650 PRKACA protein P17612 UNIPROT RAP1B protein P61224 UNIPROT up-regulates phosphorylation Ser179 PGKARKKsSCQLL 9606 19651783 t llicata "These results provide a mechanistic explanation for the differential effects of rap1 phosphorylation by pka on effector protein interaction. camp is one among several pathways leading to rap1 activation" SIGNOR-187410 CSNK2A1 protein P68400 UNIPROT DDIT3 protein P35638 UNIPROT "down-regulates activity" phosphorylation Ser30 EDLQEVLsSDENGGT 9606 BTO:0000567 12876286 t llicata "CHOP transcription factor phosphorylation by casein kinase 2 inhibits transcriptional activation. | The serine to alanine substituted site CHOP mutant was not phosphorylated by CK2, indicating that serines 14–15 and 30–31 of CHOP are the CK2 phosphoacceptor sites" SIGNOR-250852 CSNK2A1 protein P68400 UNIPROT GYS1 protein P13807 UNIPROT unknown phosphorylation Ser649 VPPSPSLsRHSSPHQ -1 2117608 t llicata "With all four peptides, prior phosphorylation significantly stimulated phosphorylation by casein kinase I. From these results, we propose that there are substrates for casein kinase I for which prior phosphorylation is a critical determinant of protein kinase action." SIGNOR-250880 CSNK2A1 protein P68400 UNIPROT PKD2 protein Q13563 UNIPROT up-regulates phosphorylation Ser812 FPRSLDDsEEDDDED 9606 BTO:0000671 14742446 t gcesareni "Ser(812) can be phosphorylated by ck2 in vitro and substitution s812a results in failure to incorporate phosphate in cultured epithelial cells." SIGNOR-121572 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 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 HNF4A protein P41235 UNIPROT G6PC 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 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 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 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 MKNK1 protein Q9BUB5 UNIPROT SPRY2 protein O43597 UNIPROT down-regulates phosphorylation Ser112 APLSRSIsTVSSGSR 9606 19864419 t llicata "The spry2/nedd4 association involves the ww domains of nedd4 and requires phosphorylation of the mnk2 kinase sites, ser(112) and ser(121), on spry2. mnk2 silencing decreased spry2-nedd4 interactions and also augmented the ability of spry2 to inhibit fibroblast growth factor signaling. endogenous and overexpressed nedd4 polyubiquitinate spry2 via lys(48) on ubiquitin and decrease its stability." SIGNOR-188889 MLF1 protein P58340 UNIPROT COPS3 protein Q9UNS2 UNIPROT up-regulates binding 9606 BTO:0001271 15861129 t miannu "As downstream elements of mlf1 leading to cell growth arrest due to p53 accumulation, we identified two factors, csn3, the third component of the cop9 signalosome (csn), and cop1, a recently characterized e3 ubiquitin ligase for p53" SIGNOR-135937 MLF1 protein P58340 UNIPROT RFWD2 protein Q8NHY2 UNIPROT up-regulates 9606 BTO:0001271 15861129 f miannu "As downstream elements of mlf1 leading to cell growth arrest due to p53 accumulation, we identified two factors, csn3, the third component of the cop9 signalosome (csn), and cop1, a recently characterized e3 ubiquitin ligase for p53" SIGNOR-135940 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 PRKCG protein P05129 UNIPROT APTX protein Q7Z2E3 UNIPROT up-regulates phosphorylation Thr125 AKNPGLEtHRKRKRS 9606 19561170 t llicata "We show the novel molecular consequences of increased kinase activities of mutants: aprataxin (aptx), a dna repair protein causative for autosomal recessive ataxia, was found to be a preferential substrate of mutant pkc gamma, and phosphorylation inhibited its nuclear entry. ollectively, phosphorylation occurred at thr111, reducing nuclear aptx." SIGNOR-186409 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 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 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 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 ATM protein Q13315 UNIPROT CCDC6 protein Q16204 UNIPROT up-regulates phosphorylation Thr434 TPPPSPNtQTPVQPP 9606 BTO:0000551 23108047 t miannu "Phosphorylation of ccdc6 at thr434 by atm during dna damage response prevents fbxw7-mediated ccdc6 degradation." SIGNOR-199276 CDK1 protein P06493 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates phosphorylation Ser272 RSRLTPVsPESSSTE 9606 BTO:0000551 SIGNOR-C17 20974803 t gcesareni "Here we show that cdk1 phosphorylates p62 in vitro and in vivo at t269 and s272, which is necessary for the maintenance of appropriate cyclin b1 levels and the levels of cdk1 activity necessary to allow cells to properly enter and exit mitosis." SIGNOR-169012 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 MAP3K5 protein Q99683 UNIPROT DAXX protein Q9UER7 UNIPROT up-regulates phosphorylation Ser184 QSPRTRGsRRQIQRL 9606 19789335 t gcesareni "Our data demonstrated that ask1 controls the cytoplasmic localization of daxx (fig.1). our results indicate that daxx not only activates ask1 but also is a downstream target of ask1 and that accumulated daxx further activates ask1. Thus, the daxx-ask1 positive feedback loop amplifying jnk/p38 signaling plays an important role in the cell-killing effects of stressors, such as tnfalpha." SIGNOR-188325 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 MLL-AF4 "fusion protein" SIGNOR-FP4 SIGNOR "AEP complex" complex SIGNOR-C117 SIGNOR "up-regulates activity" binding 9606 BTO:0005261 19956800 t irozzo "Although the complex was initially termed ENL associated proteins (EAP), we now propose to redefine EAP as ‘‘elongation assisting proteins’’ to better reflect the function of this protein complex. In this report, we present evidence that the most frequently occurring MLL fusion proteins exploit molecular control mechanisms of transcriptional elongation to transform hematopoietic cells. MLL fusions become incorporated into an ‘‘elongation assisting protein’’ complex, recruit it to their respective target genes, and enforce ectopic transcription." SIGNOR-255877 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR BHMT protein Q93088 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 16953798 f miannu "SAM and MTA down-regulate BHMT expression in HepG2 cells in part by inducing NF-kappaB, which acts as a repressor for the human BHMT gene. While SAM's mechanism is NF-kappaB-dependent, MTA has both NF-kappaB-dependent and -independent mechanisms." SIGNOR-254659 NUMA1 protein Q14980 UNIPROT TUBA3C protein Q13748 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-116717 PKN1 protein Q16512 UNIPROT AR protein P10275 UNIPROT up-regulates phosphorylation 9606 17251915 t gcesareni "Rho can sensitize the ar to low levels of circulating androgens by promoting the nuclear translocation of a transcriptional co-activator, fhl2 (four and a half lim domains 2), which binds ar, and by stimulating protein kinase n (pkn), which phosphorylates ar directly." SIGNOR-152762 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 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 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 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 UBE2I protein P63279 UNIPROT FOXL2 protein P58012 UNIPROT up-regulates sumoylation Lys25 PETGRTVkEPEGPPP 9606 19744555 t miannu "Foxl2 is sumoylated by ubc9, and this ubc9-mediated sumoylation is essential to the transcriptional activity of foxl2 on the star promoter. / the sumoylation site was identified at lysine 25 of foxl2" SIGNOR-187901 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 PRKCZ protein Q05513 UNIPROT NR1H4 protein Q96RI1 UNIPROT up-regulates phosphorylation Thr456 GRLTELRtFNHHHAE 9606 BTO:0000195 18668687 t "The effect has been demonstrated using Q96RI1-2" gcesareni "The effect of fic1 on fxr phosphorylation and nuclear localization and its effects on bsep promoter activity could be blocked with protein kinase c zeta (pkc zeta) inhibitors (pseudosubstrate or small interfering rna silencing). Recombinant pkc zeta directly phosphorylated immunoprecipitated fxr. The mutation of threonine 442 of fxr to alanine yielded a dominant negative protein," SIGNOR-179771 RIPK2 protein O43353 UNIPROT IRF5 protein Q13568 UNIPROT up-regulates phosphorylation Ser446 DSIRLQIsNPDLKDR 9606 22412986 t lperfetto "Activation of interferon regulatory factor 5 by site specific phosphorylation. Phosphorylation of carboxyl serines 451 and 462 appear the primary trigger of irf5 function in nuclear accumulation, transcription, and apoptosis. Rip2 activation of the irf5 aspartic acid substitutions showed a similar positive effect of s451d and s462d function in this assay" SIGNOR-196524 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 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 MAPK1 protein P28482 UNIPROT CEBPB protein P17676 UNIPROT up-regulates phosphorylation Thr235 SSSSPPGtPSPADAK 9606 BTO:0000551 19723873 t gcesareni "Phosphorylation of cebpb at thr(235) peaked at 16 hours in il-1beta-stimulated cells. The mek inhibitor u0126 inhibited this phosphorylation and reduced mmp-1 gene induction." SIGNOR-187798 MAPK3 protein P27361 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." SIGNOR-169004 MAPK6 protein Q16659 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates phosphorylation Ser857 PPYNRAVsLDSPVSV 9606 BTO:0000551 22505454 t gcesareni "Here, we report that erk3 interacted with and phosphorylated steroid receptor coactivator 3 (src-3), an oncogenic protein overexpressed in multiple human cancers at serine 857 (s857)" SIGNOR-196957 MLL-AF4 "fusion protein" SIGNOR-FP4 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0000725 21389315 f irozzo "Consequently, cell cycle and apoptosis analyses suggest that MLL-AF4 conveys a selective proliferation coupled to a survival advantage, which correlates with changes in the expression of genes involved in apoptosis, sensing DNA damage and DNA repair." SIGNOR-255873 MLL-AF4 "fusion protein" SIGNOR-FP4 SIGNOR CBFB protein Q13951 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9606 BTO:0001412 24449215 f irozzo "However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. We found that MLL-BP and the 3 MLL fusion proteins all decreased RUNX1 levels, and MLL-eleven nineteen leukemia (ENL) caused a greater decrease in RUNX1 compared with MLL-AF9 and MLL-AF4 fusion proteins." SIGNOR-255856 MLL-AF4 "fusion protein" SIGNOR-FP4 SIGNOR Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 BTO:0000725 21389315 f irozzo "Consequently, cell cycle and apoptosis analyses suggest that MLL-AF4 conveys a selective proliferation coupled to a survival advantage, which correlates with changes in the expression of genes involved in apoptosis, sensing DNA damage and DNA repair." SIGNOR-256650 PML-RARalpha "fusion protein" SIGNOR-FP2 SIGNOR CCNA1 protein P78396 UNIPROT "up-regulates activity" 9606 11090075 t apalma "We show that the ectopic expression of PML-RARα is sufficient to elevate levels of cyclin A1 in U937 myeloid leukemia cells and cyclin A1 is negatively regulated by the RARα pathway." SIGNOR-256373 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 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 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 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 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 DUSP6 protein Q16828 UNIPROT FOXO1 protein Q12778 UNIPROT up-regulates dephosphorylation 9606 22521266 t gcesareni "Phosphorylated foxo1 is inactive and retained in the cytosol. Mkp-3 mediated dephosphorylation activates foxo1 and subsequentially promotes its nuclear translocation and binding to the promoters of gluconeogenic genes, such as phosphoenolpyruvate carboxykinase (pepck) and glucose-6-phosphatase (g6pase)." SIGNOR-197194 ICK protein Q9UPZ9 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates phosphorylation Thr908 LPSGRPGtTGPAGAQ 9606 SIGNOR-C3 22356909 t gcesareni "Our findings demonstrate an important role for ick in modulating the activity of mtorc1 through phosphorylation of raptor thr-908 and thus implicate a potential signaling mechanism by which ick regulates cell proliferation and division." SIGNOR-196198 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 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 MLL-AF4 "fusion protein" SIGNOR-FP4 SIGNOR DOT1L protein Q8TEK3 UNIPROT "up-regulates activity" binding 9606 BTO:0001133 18977325 t irozzo "Recent studies have identified association of multiple MLL-fusion partners including AF4, AF9, and AF10 with DOT1L, a histone H3K79 methyltransferase.This leads to a model where MLL-AF4 recruits DOT1L to MLL target genes, and promotes methylation of H3K79 at loci with existing H3K4 methylation (i.e., by wildtype MLL or other H3K4 methyltransferases) thus stimulating transcriptional elongation of genes that are normally primed but not fully transcribed." SIGNOR-255871 MLL-AF4 "fusion protein" SIGNOR-FP4 SIGNOR DOT1L protein Q8TEK3 UNIPROT "up-regulates activity" binding 9606 BTO:0005014 27856324 t irozzo "Previously, we found that MLL-AF4 binds to the BCL-2 gene and directly activates it through DOT1L recruitment and increased H3K79me2/3 levels. MLL-AF4 directly controls the active transcription of both BCL-2 and MCL-1 […]. Of all the BCL-2 family members, only BCL-2 and MCL-1 are directly activated by MLL-AF4." SIGNOR-255882 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 SRSF1 protein Q07955 UNIPROT up-regulates phosphorylation Ser119 YGPPSRRsENRVVVS 9606 22393468 t llicata "Here, we show that pka phosphorylates srsf1 on serine 119 in vitro. Phosphorylation of srsf1 on this site enhanced the rna binding capacity of srsf1 in vivo" SIGNOR-196397 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 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 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 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 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 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 CSNK1A1 protein P48729 UNIPROT NFATC3 protein Q12968 UNIPROT "down-regulates activity" phosphorylation Thr204 NEAAARFtLGSPLTS 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-109768 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 CSNK2A1 protein P68400 UNIPROT EIF5 protein P55010 UNIPROT up-regulates phosphorylation Ser390 KEAEEESsGGEEEDE 9606 18649047 t gcesareni "We find that eif5 is associated with ck2 when the kinase activity is at the highest level in vivo, and is phosphorylated at ser389 and ser390 by ck2." SIGNOR-179546 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GAB1 protein Q13480 UNIPROT down-regulates phosphorylation Ser454 YVPMNPNsPPRQHSS 9606 15379552 t lperfetto "Erk phosphorylation enhances hgf-dependent gab1/pi3k but inhibits egf-dependent gab1/pi3k association and activation implicates that mapk activation provides another specific regulatory mechanism which can result in divergent effects for distinct rtks.we identified four serine and two threonine residues that are phosphorylated by erk in vitro. Five of these phosphorylation sites (t312, s454, t476, s581, s597)" SIGNOR-129188 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 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 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 MLL-AF4 "fusion protein" SIGNOR-FP4 SIGNOR miR-495 mirna MI0003135 miRBase "down-regulates quantity by repression" "transcriptional repression" 9606 BTO:0000725 23132946 f irozzo "We then showed that ectopic expression of MLL fusion genes in both human and mouse normal hematopoietic stem/progenitor cells could significantly down-regulate endogenous expression of miR-495 and that the depletion of MLL fusions resulted in the up-regulation of miR-495. Thus, our data suggest that there is an MLL-fusion–mediated negative regulation of the production of miR-495 in hematopoietic cells." SIGNOR-255886 PRKCA protein P17252 UNIPROT SHC1 protein P29353 UNIPROT "down-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. | Thus, we have identified a new mechanism whereby serine phosphorylation of ShcA controls the ability of its phosphotyrosine-binding domain to bind PTP-PEST, which is responsible for the dephosphorylation and down-regulation of ShcA after insulin stimulation." SIGNOR-249150 VRK1 protein Q99986 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates phosphorylation 9606 22621922 t miannu "The kinase vrk1 is activated by dna double strand breaks induced by ionizing radiation (ir) and specifically phosphorylates 53bp1 in serum-starved cells./ Vrk1 knockdown resulted in the defective formation of 53bp1 foci in response to ir both in number and size" SIGNOR-197625 WNT3A protein P56704 UNIPROT FZD8 protein Q9H461 UNIPROT up-regulates binding 9606 22653731 t gcesareni "Structural basis of wnt recognition by frizzled." SIGNOR-197638 PRKCD protein Q05655 UNIPROT ENOX2 protein Q16206 UNIPROT up-regulates phosphorylation Ser504 ENLKEKEsCASRLCA 9606 22659163 t lperfetto "Tnox is phosphorylated by protein kinase c_ (pkc_) both in vitro and in vivo. Replacement of serine-504 with alanine significantly reduces phosphorylation by pkc_. C. overexpression of the s504a tnox mutant leads to diminished cell proliferation and migration, reflecting reduced stability of the unphosphorylatable tnox mutant protein." SIGNOR-197706 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 LATS2 protein Q9NRM7 UNIPROT YWHAG protein P61981 UNIPROT up-regulates phosphorylation Ser59 VVGARRSsWRVISSI 9606 25086053 t lperfetto "Phosphorylation of 14-3-3_ on s59 by lats2. Ser(58) phosphorylation and lys(49) acetylation of 14-3-3_ occur in a coordinated time-dependent manner to regulate 14-3-3_ homodimerization. 14-3-3_ ser(58) phosphorylation is required for star interactions under control conditions," SIGNOR-205247 MAPKAPK2 protein P49137 UNIPROT TSC2 protein P49815 UNIPROT unknown phosphorylation Ser1254 TALYKSLsVPAASTA 9606 12582162 t llicata "Both in vitro and in vivo experiments demonstrate that the p38-activated kinase mk2 (also known as mapkapk2) is directly responsible for the phosphorylation of ser(1210)." SIGNOR-98201 MLL-AF4 "fusion protein" SIGNOR-FP4 SIGNOR MLLT3 protein P42568 UNIPROT "down-regulates quantity" relocalization 9606 BTO:0000567 14603337 t irozzo "The AF4–AF9 interaction is maintained by the MLL–AF4 fusion protein, and expression of the MLL–AF4 fusion can alter the subnuclear localization of AF9. This fusion does, however, contain the AF9 interaction domain we have identified. These findings imply that the interaction that we have characterized plays an important role in MLL leukemogenesis. Furthermore, we show that MLL–AF4 does interact with AF9 and has the ability to misdirect AF9 expression from the AF4 body to alternative foci within the nucleolus." SIGNOR-255857 MLL-AF4 "fusion protein" SIGNOR-FP4 SIGNOR RUNX1 protein Q01196 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9606 BTO:0001412 24449215 f irozzo "However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. We found that MLL-BP and the 3 MLL fusion proteins all decreased RUNX1 levels, and MLL-eleven nineteen leukemia (ENL) caused a greater decrease in RUNX1 compared with MLL-AF9 and MLL-AF4 fusion proteins." SIGNOR-255855 NR3C1 protein P04150 UNIPROT AR protein P10275 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 9162033 f gcesareni "Androgen and glucocorticoid receptor heterodimer formation. A possible mechanism for mutual inhibition of transcriptional activity." SIGNOR-48516 PICALM protein Q13492 UNIPROT CLTC protein Q00610 UNIPROT up-regulates binding 9606 BTO:0001271;BTO:0000785 16491119 t miannu "Calm interacts with the clathrin heavy chain through its c-terminal third and with phophoinositides through its ap180 n-terminal homology (anth) domain, promoting assembly of clathrin triskelia into clathrin cagesin vitro" SIGNOR-144683 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 POU2F1 protein P14859 UNIPROT HOXD10 protein P28358 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25301728 f miannu "Knockdown of pou2f1 significantly reduced expression of hoxd10 and d11" SIGNOR-205540 POU2F1 protein P14859 UNIPROT HOXD11 protein P31277 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25301728 f miannu "Knockdown of pou2f1 significantly reduced expression of hoxd10 and d11" SIGNOR-205564 PRKACA protein P17612 UNIPROT PTPRR protein Q15256 UNIPROT "down-regulates activity" phosphorylation Ser339 GLQERRGsNVSLTLD 9534 BTO:0000298 10601328 t miannu "The PKA phosphorylation site on PTP-SL was identified as the Ser(231) residue. treatment of COS-7 cells with PKA activators, or overexpression of the Calpha catalytic subunit of PKA, inhibited the cytoplasmic retention of ERK2 and p38alpha by wild-type PTP-SL, but not by a PTP-SL S231A mutant.‚ " SIGNOR-250038 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 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 RBPJ protein Q06330 UNIPROT NFKB2 protein Q00653 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 9528780 f gcesareni "Rbp-jkappa is a strong transcriptional repressor of nf-kappab2. Moreover, this repression can be overcome by activated notch-1." SIGNOR-56100 TEK protein Q02763 UNIPROT TEK protein Q02763 UNIPROT "up-regulates activity" phosphorylation Tyr1048 GMTCAELyEKLPQGY -1 11513602 t lperfetto "Isoelectric focusing electrophoresis and mass spectrometric analysis of a tie2 autophosphorylation time course showed that tyr992 on the putative activation loop was phosphorylated first followed by tyr1108 in the c-terminal tail autophosphorylation of tie2 to produce ptie2 resulted in a 100-fold increase in kcat and a 460-fold increase in kcat/km." SIGNOR-109786 PRKCD protein Q05655 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-249280 PRKCD protein Q05655 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 BTO:0001253 16418226 t gcesareni "Abrogation of pkcdelta activity inhibited insulin-induced stat3 phosphorylation, pkcdelta-stat3 association and nuclear translocation." SIGNOR-143828 TBL1XR1 protein Q9BZK7 UNIPROT BCL3 protein P20749 UNIPROT down-regulates ubiquitination 9606 20547759 t miannu "We also defined the e3 ligase tblr1 as a protein involved in bcl-3 degradation" SIGNOR-166111 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT "down-regulates activity" phosphorylation Ser780 STRPPTLsPIPHIPR 9606 BTO:0000150 23336272 t lperfetto "Cyclin d1 is known to activate cdk4, which then phosphorylates the rb protein, leading to cell cycle progression." SIGNOR-216988 FZD3 protein Q9NPG1 UNIPROT GNGT1 protein P63211 UNIPROT up-regulates binding 9606 17251915 t gcesareni "In the non-canonical wnt signalling pathway, frizzled uses galphaq or galphai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat." SIGNOR-152606 IRS2 protein Q9Y4H2 UNIPROT PIK3CA protein P42336 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-251492 MAPK1 protein P28482 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-182770 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 MAPK8 protein P45983 UNIPROT BCL2L11 protein O43521 UNIPROT down-regulates phosphorylation Ser69 GPLAPPAsPGPFATR 9606 BTO:0000782;BTO:0001271 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 MLL-AF9 "fusion protein" SIGNOR-FP5 SIGNOR BCOR protein Q6W2J9 UNIPROT "up-regulates activity" binding 10090 BTO:0000944 12776190 t irozzo "As BCoR binds the C-terminus of AF9, it seems likely that BCoR will also bind chimeric MLL–AF9 proteins. As transcriptional repressors, BCoR or Pc3 bound to MLL–AF9 might interfere with the expression of genes required for normal hematopoiesis." SIGNOR-256142 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 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-89209 RARB protein P10826 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-133234 SMO protein Q99835 UNIPROT TIAM1 protein Q13009 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 20654717 t gcesareni "This latter work suggested that inactive smo prevents rac1 activation by interacting with the rac guanine nucleotide exchange factor (gef) t-lymphoma invasion and metastasis 1 (tiam1). This smo-tiam1 complex dissociates upon shh-mediated activation of smo, thus allowing tiam1 to activate rac1" SIGNOR-167070 WNK1 protein Q9H4A3 UNIPROT SLC12A6 protein Q9UHW9 UNIPROT down-regulates phosphorylation Thr1048 YQEKVHMtWTKDKYM 9606 BTO:0000938 BTO:0000142 19665974 t gcesareni "We have attempted to identify kinases and phosphatases involved in the modulation of phosphorylation at kcc3 t991 and t1048. the wnk kinases and spak/osr1 are strong candidates for kcc3 regulatory kinases." SIGNOR-187560 PTK6 protein Q13882 UNIPROT KHDRBS1 protein Q07666 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 10913193 t gcesareni "Sik/brk is the first identified tyrosine kinase that can phosphorylate sam68 and regulate its activity within the nucleus, where it resides during most of the cell cycle" SIGNOR-80020 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 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 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 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 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 MLL-AF9 "fusion protein" SIGNOR-FP5 SIGNOR "Core Binding Factor complex" complex SIGNOR-C214 SIGNOR "down-regulates quantity by repression" "transcriptional repression" 9606 BTO:0001412 24449215 f miannu "However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions." SIGNOR-255970 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 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR BIRC2 protein Q13490 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9916987 f gcesareni "The iaps have been shown to be induced by nf-kappab or v-rel in multiple cell lines and conversely, hiap1 and hiap2 have been shown to activate nf-kappab possibly forming a positive feed-back loop." SIGNOR-64100 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR BIRC3 protein Q13489 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9916987 f gcesareni "The iaps have been shown to be induced by nf-kappab or v-rel in multiple cell lines and conversely, hiap1 and hiap2 have been shown to activate nf-kappab possibly forming a positive feed-back loop." SIGNOR-64103 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 PLK2 protein Q9NYY3 UNIPROT SNCA protein P37840 UNIPROT up-regulates phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 BTO:0000938 BTO:0000142 19004816 t lperfetto "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. Pathological serine 129 phosphorylation regulates membrane accumulation of mutant alpha-synuclein." SIGNOR-182155 PLK2 protein Q9NYY3 UNIPROT SNCB protein Q16143 UNIPROT up-regulates phosphorylation Ser118 LMEPEGEsYEDPPQE 9606 BTO:0000938 BTO:0000142 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-189049 PRKACA protein P17612 UNIPROT ESR1 protein P03372 UNIPROT down-regulates phosphorylation Ser236 IDKNRRKsCQACRLR 9606 9891036 t lperfetto "Phosphorylation of human estrogen receptor alpha by protein kinase a regulates dimerizationeralpha is phosphorylated by protein kinase a (pka) on serine-236 within the dna binding domain. Mutation of serine-236 to glutamic acid prevents dna binding by inhibiting dimerization by eralpha" SIGNOR-63984 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 PRKCD protein Q05655 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser320 QRSRKRLsQDAYRRN 9606 BTO:0000130 12056906 t esanto "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. The use of p47phox mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc?, ???, And ?." SIGNOR-89229 PRKCQ protein Q04759 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-249283 PTPN12 protein Q05209 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 10734133 t gcesareni "Autophosphorylated on tyrosine residues in response to insulin. Dephosphorylated by ptpreand ptpn1 at tyr-999, tyr-1185, tyr-1189 and tyr-1190." SIGNOR-75898 TBK1 protein Q9UHD2 UNIPROT STAT6 protein P42226 UNIPROT up-regulates phosphorylation Tyr641 MGKDGRGyVPATIKM 9606 22000020 t gcesareni "We now show that stat6 is required for innate immune signaling in response to virus infection. Viruses or cytoplasmic nucleic acids trigger sting (also named mita/eris) to recruit stat6 to the endoplasmic reticulum, leading to stat6 phosphorylation on ser(407) by tbk1 and tyr(641), independent of jaks. Phosphorylated stat6 then dimerizes and translocates to the nucleus to induce specific target genes responsible for immune cell homing." SIGNOR-176775 CSNK1A1L protein Q8N752 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Ser45 GATTTAPsLSGKGNP 9606 12000790 t gcesareni "We show that a complex of axin and casein kinase i (cki) induces beta-catenin phosphorylation at a single site: serine 45 (s45)." SIGNOR-87430 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 ILK protein Q13418 UNIPROT PPP1R12A protein O14974 UNIPROT down-regulates phosphorylation Thr696 ARQSRRStQGVTLTD 9606 12030846 t lperfetto "Mypt1 was phosphorylated by ilk and phosphorylation sites in the n- and c-terminal fragments of mypt1 were detected. From sequence analyses, three sites were identified: a primary site at thr(709), and two other sites at thr(695) and thr(495)" SIGNOR-87924 "Immune complexes" stimulus SIGNOR-ST15 SIGNOR FCGR2B protein P31994 UNIPROT "up-regulates activity" 9606 BTO:0000801 25475856 f lperfetto "Low affinity-activating Fcgamma receptors (FcgammaRs) that bind immune complexes are controlled by a single inhibitory receptor, FcgammaRIIb (CD32b)." SIGNOR-249522 INSR protein P06213 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr242 FFQQQMIyDSPPSRA 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-251310 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 RXRA protein P19793 UNIPROT down-regulates phosphorylation Ser260 NMGLNPSsPNDPVTN 9606 12048211 t gcesareni "Mutated rxr alpha (s260a) inhibited 1,25d-induced cyp24 promoter activity and abolished phosphorylation by activated erk2." SIGNOR-88658 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 p38 proteinfamily SIGNOR-PF16 SIGNOR NFATC4 protein Q14934 UNIPROT down-regulates phosphorylation Ser168 QGGGAFFsPSPGSSS 9606 11997522 t lperfetto "Phosphorylation of nfatc4 by p38 mitogen-activated protein kinasesthe p38 map kinase phosphorylates multiple residues, including ser(168) and ser(170), in the nfat homology domain of nfatc4. Replacement of ser(168,170) with ala promotes nuclear localization of nfatc4 and increases nfat-mediated transcription activity." SIGNOR-87393 PRKCI protein P41743 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-251635 PRKCQ protein Q04759 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-249290 TP53INP1 protein Q96A56 UNIPROT MAP1LC3A protein Q9H492 UNIPROT up-regulates binding 9606 22421968 t gcesareni "Tp53inp1-lc3 interaction occurs via a functional lc3-interacting region (lir)." SIGNOR-196670 TP53INP1 protein Q96A56 UNIPROT MAP1LC3B protein Q9GZQ8 UNIPROT up-regulates binding 9606 22421968 t gcesareni "Tp53inp1-lc3 interaction occurs via a functional lc3-interacting region (lir)" SIGNOR-196673 PRKD1 protein Q15139 UNIPROT HDAC7 protein Q8WUI4 UNIPROT unknown phosphorylation Ser358 WPLSRTRsEPLPPSA -1 15738054 t lperfetto "We demonstrate that protein kinase D (PKD; also known as PKCmi), which is activated upon engagement of the TCR, stimulates HDAC7 nuclear export by direct phosphorylation on four serine residues. Conversely, selective PKD inhibition blocks TCR-induced HDAC7 nuclear export and Nur77 expression. In addition, an HDAC7 mutant specifically deficient in phosphorylation by PKD blocks TCR-mediated apoptosis. | PKD1 phosphorylates S155, S181, S321, and S449 of HDAC7 in vitro." SIGNOR-249274 SMAD4 protein Q13485 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 11689553 t lperfetto "Down-regulation of c-Myc is a critical event for growth inhibition induced by transforming growth factor-β (TGF-β) and is frequently impaired in cancer cells. We determined a Smad-responsive element in the c-mycpromoter." SIGNOR-251493 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR Mitotic_checkpoint phenotype SIGNOR-PH28 SIGNOR down-regulates 15549093 f lperfetto "The critical target of the G2 checkpoint is the mitosis-promoting activity of the cyclin B/CDK1 kinase, whose activation after various stresses is inhibited by ATM/ATR, CHK1/CHK2 and/or p38-kinase-mediated subcellular sequestration, degradation and/or inhibition of the CDC25 family of phosphatases that normally activate CDK1 at the G2/M boundary" SIGNOR-251496 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 IKBKB protein O14920 UNIPROT CYLD protein Q9NQC7 UNIPROT "up-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-204728 IKBKB protein O14920 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-204736 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CCL11 protein P51671 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16604092 f miannu "Rosmarinic acid also inhibited TNF-alpha-induced phosphorylation and degradation of IkappaB-alpha, as well as nuclear translocation of NF-kappaB heterodimer induced by TNF-alpha. This suggests that rosmarinic acid downregulates the expression of CCL11 and CCR3 via the inhibition of NF-kappaB activation signaling." SIGNOR-254661 p38 proteinfamily SIGNOR-PF16 SIGNOR NFATC4 protein Q14934 UNIPROT down-regulates phosphorylation Ser170 GGAFFSPsPGSSSLS 9606 11997522 t lperfetto "Phosphorylation of nfatc4 by p38 mitogen-activated protein kinasesthe p38 map kinase phosphorylates multiple residues, including ser(168) and ser(170), in the nfat homology domain of nfatc4. Replacement of ser(168,170) with ala promotes nuclear localization of nfatc4 and increases nfat-mediated transcription activity." SIGNOR-87397 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 PRKACA protein P17612 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser259 SQRQRSTsTPNVHMV 9606 11971957 t gcesareni "serines 43, 259, and 621 are phosphorylated by PKA in vitro and induced by cAMP in vivo.cAMP increased Raf-1 serine 259 phosphorylation in a PKA-dependent manner with kinetics that correlated with ERK deactivation." SIGNOR-86141 PRKACA protein P17612 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser43 FGYQRRAsDDGKLTD 9606 11971957 t gcesareni "Serine 43 phosphorylation decreased the binding to ras in serum-starved but not in mitogen-stimulated cells. However, the kinase activity of a rafs43a mutant was fully inhibited by pka." SIGNOR-86145 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 PRKD1 protein Q15139 UNIPROT HDAC7 protein Q8WUI4 UNIPROT unknown phosphorylation Ser181 NPLLRKEsAPPSLRR -1 15738054 t lperfetto "We demonstrate that protein kinase D (PKD; also known as PKCmi), which is activated upon engagement of the TCR, stimulates HDAC7 nuclear export by direct phosphorylation on four serine residues. Conversely, selective PKD inhibition blocks TCR-induced HDAC7 nuclear export and Nur77 expression. In addition, an HDAC7 mutant specifically deficient in phosphorylation by PKD blocks TCR-mediated apoptosis. | PKD1 phosphorylates S155, S181, S321, and S449 of HDAC7 in vitro." SIGNOR-249273 SMAD3 protein P84022 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 11689553 t lperfetto "Down-regulation of c-Myc is a critical event for growth inhibition induced by transforming growth factor-β (TGF-β) and is frequently impaired in cancer cells. We determined a Smad-responsive element in the c-mycpromoter." SIGNOR-251494 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 "prostaglandin F2alpha(1-)" smallmolecule CHEBI:57404 ChEBI PTGFR protein P43088 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-257573 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 PRKAA1 protein Q13131 UNIPROT FOXO3 protein O43524 UNIPROT "up-regulates activity" phosphorylation 6239 SIGNOR-C15 17900900 t lperfetto "The energy sensor amp-activated protein kinase (ampk) has been shown to directly phosphorylate foxo factors at six regulatory sites that are distinct from the akt." SIGNOR-219247 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 PTEN protein P60484 UNIPROT PIK3CA protein P42336 UNIPROT "down-regulates activity" 9606 BTO:0000938 18794881 f lperfetto "The pten tumour suppressor is a lipid and protein phosphatase that inhibits phosphoinositide 3-kinase (pi3k)-dependent by dephosphorylating phosphatidylinositol 3,4,5-trisphosphate (ptdinsp(3))." SIGNOR-209856 RHEB protein Q15382 UNIPROT MTOR protein P42345 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 20006481 t lperfetto "Rheb stimulates the phosphorylation of mtor and plays an essential role in regulation of s6k and 4ebp1 in response to nutrients and cellular energy status." SIGNOR-162006 SRC protein P12931 UNIPROT CAV2 protein P51636 UNIPROT down-regulates phosphorylation Tyr19 LFMDDDSySHHSGLE 9606 12091389 t lperfetto "We show that caveolin-2 undergoes src-induced phosphorylation on tyrosine 19. we conclude that the tyrosine phosphorylation of caveolin-2 (tyr(p)(19)) may function as a signal that is recognized by the cellular machinery to induce the dissociation of caveolin-2 from caveolin-1 oligomers" SIGNOR-90225 SRC protein P12931 UNIPROT GJA1 protein P17302 UNIPROT down-regulates phosphorylation Tyr265 KDCGSQKyAYFNGCS 9606 16916748 t lperfetto "The oncogenic tyrosine kinase, v-src, phosphorylates connexin43 (cx43) on y247 and y265 and inhibits cx43 gap junctional communication (gjc), the process of intercellular exchange of ions and metabolites." SIGNOR-148917 "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 PTPN1 protein P18031 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-248411 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 PTPN2 protein P17706 UNIPROT JAK1 protein P23458 UNIPROT "down-regulates activity" dephosphorylation Tyr1035 IETDKEYyTVKDDRD 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-248396 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 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 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1787 SPNYSPTsPSYSPTS -1 15125841 t "Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro" SIGNOR-248815 PTPRG protein P23470 UNIPROT PDGFRB protein P09619 UNIPROT "down-regulates activity" dephosphorylation Tyr716 RPPSAELySNALPVG -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-254715 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 PTPRG protein P23470 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" dephosphorylation Tyr292 DTLNSDGyTPEPARI -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-254732 "RFX complex" complex SIGNOR-C104 SIGNOR 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-254016 RFXAP protein O00287 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-221568 "RFX complex" complex SIGNOR-C104 SIGNOR HLA-DRB5 protein Q30154 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" -1 11258423 f "The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex" SIGNOR-254003 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1668 SPSYSPTsPSYSPTS 9606 BTO:0000567 22137580 t "In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator" SIGNOR-248739 RPS6K proteinfamily SIGNOR-PF26 SIGNOR CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser293 GSTKRRKsMSGASPK 9606 23708659 t lperfetto "Rsk promotes g2/m transition through activating phosphorylation of cdc25a and cdc25b rsk is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of t359/s363 in rsk. Together, these findings indicate that rsk promotes g2/m transition in mammalian cells through activating phosphorylation of cdc25a and cdc25b." SIGNOR-252793 RPS6K proteinfamily SIGNOR-PF26 SIGNOR CDC25B protein P30305 UNIPROT up-regulates phosphorylation Ser353 VQNKRRRsVTPPEEQ 9606 23708659 t lperfetto "Rsk promotes g2/m transition through activating phosphorylation of cdc25a and cdc25b rsk is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of t359/s363 in rsk. Together, these findings indicate that rsk promotes g2/m transition in mammalian cells through activating phosphorylation of cdc25a and cdc25b." SIGNOR-252781 RPS6K proteinfamily SIGNOR-PF26 SIGNOR CDC25B protein P30305 UNIPROT up-regulates phosphorylation Thr355 NKRRRSVtPPEEQQE 9606 23708659 t lperfetto "Rsk promotes g2/m transition through activating phosphorylation of cdc25a and cdc25b rsk is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of t359/s363 in rsk. Together, these findings indicate that rsk promotes g2/m transition in mammalian cells through activating phosphorylation of cdc25a and cdc25b." SIGNOR-252779 RPS6K proteinfamily SIGNOR-PF26 SIGNOR METTL1 protein Q9UBP6 UNIPROT down-regulates phosphorylation Ser27 YYRQRAHsNPMADHT 9606 BTO:0000007;BTO:0000567 15861136 t gcesareni "Pkb and ribosomal s6 kinase (rsk) both phosphorylated mettl1 at ser27 in vitro." SIGNOR-252800 RPS6K proteinfamily SIGNOR-PF26 SIGNOR MXD1 protein Q05195 UNIPROT down-regulates phosphorylation Ser145 IERIRMDsIGSTVSS 9606 18451027 t lperfetto "In this study, we showed that mad1 is a substrate of p90 ribosomal kinase (rsk) and p70 s6 kinase (s6k). 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" SIGNOR-252811 RPS6KB1 protein P23443 UNIPROT MTOR protein P42345 UNIPROT "up-regulates activity" phosphorylation Thr2446 NKRSRTRtDSYSAGQ 9606 BTO:0000150;BTO:0000093 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-137255 SCN2A protein Q99250 UNIPROT "sodium ion" smallmolecule "CID: 923" PUBCHEM "up-regulates quantity" relocalization 9606 BTO:0000938 27262167 t miannu "Voltage-gated Na1 channels (NaV channels) drive the rapid upstroke of action potentials in cardiac and skeletal muscle and in most neurons, thereby serving as initiators of electrical activity in excitable tissue. Nine genes encode a family of homologous of NaV channel pore-forming a subunits. While channels are open, Na1 ions flux through the central pore down an electrochemical gradient, further depolarizing the membrane and triggering an action potential." SIGNOR-253404 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 SGK2 protein Q9HBY8 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-249132 SNTG1 protein Q9NSN8 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-255994 SNW1 protein Q13573 UNIPROT NOTCH1 protein P46531 UNIPROT "up-regulates activity" binding -1 10713164 t llicata "SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function." SIGNOR-237617 SPRY4 protein Q9C004 UNIPROT MMP9 protein P14780 UNIPROT "down-regulates activity" 9606 BTO:0002058 20501643 f miannu "When Spry4 was stably transfected into H157 and H2122 NSCLC cell lines, decreased migration and invasion were observed. Matrix metalloproteinase-9 activity was decreased, and the expression of matrix metalloproteinase inhibitors TIMP1 and CD82 were increased. Stable expression of Spry4 led to reduced cell growth and reduced anchorage-independent growth in NSCLC cell lines, along with upregulation of tumor suppressors p53 and p21." SIGNOR-253037 SRC protein P12931 UNIPROT PRKD1 protein Q15139 UNIPROT "up-regulates activity" phosphorylation Tyr502 TTANVVYyVGENVVN 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-247328 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 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 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 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 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 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 1-[2-chloro-4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-3-(5-methyl-3-isoxazolyl)urea chemical CHEBI:91327 ChEBI KDR protein P35968 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207302 TGFBI protein Q15582 UNIPROT "a7/b1 integrin" complex SIGNOR-C126 SIGNOR "up-regulates activity" binding 26387839 t lperfetto "BIGH3 binds molecules of the ECM, including fibronectin, laminin and different collagens ( Hashimoto et al., 1997 ; Hanssen et al., 2003) and serves as a ligand for several integrins|BIGH3 has been shown to interact with α3β1, αvβ3, αvβ5, α1β1, α6β4 and α7β1 integrin heterodimers" SIGNOR-253266 TGFBI protein Q15582 UNIPROT "Av/b3 integrin" complex SIGNOR-C177 SIGNOR "up-regulates activity" binding 26387839 t lperfetto "BIGH3 binds molecules of the ECM, including fibronectin, laminin and different collagens ( Hashimoto et al., 1997 ; Hanssen et al., 2003) and serves as a ligand for several integrins|BIGH3 has been shown to interact with α3β1, αvβ3, αvβ5, α1β1, α6β4 and α7β1 integrin heterodimers" SIGNOR-253270 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 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 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 TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT "up-regulates activity" ubiquitination Lys377 NEPSLQSkLQDEANY 9606 BTO:0000459 18621737 t lperfetto "Following binding to tradd, traf2 was thought to mediate non-degradative lys-63-linked polyubiquitination of rip1 via its ring e3 ligase domain. Rip1 is known to directly interact with traf2." SIGNOR-179456 TWIST1 protein Q15672 UNIPROT FAP protein Q12884 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003879 20646316 f miannu "Individual genes upregulated by TWIST1 known to promote EMT and/or GBM invasion included SNAI2, MMP2, HGF, FAP and FN1." SIGNOR-255523 TWIST1 protein Q15672 UNIPROT FN1 protein P02751 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003879 20646316 f miannu "Individual genes upregulated by TWIST1 known to promote EMT and/or GBM invasion included SNAI2, MMP2, HGF, FAP and FN1." SIGNOR-255521 TWIST1 protein Q15672 UNIPROT FOS protein P01100 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004828 19051271 f miannu "we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion" SIGNOR-255526 TWIST1 protein Q15672 UNIPROT HGF protein P14210 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003879 20646316 f miannu "Individual genes upregulated by TWIST1 known to promote EMT and/or GBM invasion included SNAI2, MMP2, HGF, FAP and FN1." SIGNOR-255522 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 PTPN12 protein Q05209 UNIPROT JAK2 protein O60674 UNIPROT down-regulates dephosphorylation 9606 BTO:0000149 11731619 t gcesareni "In intact hc11 cells, ptp-pest was constitutively associated with jak2, and in response to egf treatment there was an increased level of ptp-pest in jak2 complexes. An in vitro phosphatase assay, using prl-activated jak2 as the substrate and lysates from hc11 cells as the source of ptp-pest, revealed that jak2 could serve as a ptp-pest substrate." SIGNOR-112383 SMO protein Q99835 UNIPROT GNAT1 protein P11488 UNIPROT up-regulates binding 9606 16885213 t gcesareni "Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling." SIGNOR-148496 UBR1 protein Q8IWV7 UNIPROT RECQL4 protein O94761 UNIPROT up-regulates binding 9606 BTO:0000567 15317757 t miannu "The isolated recql4, assayed as a complex with ubr1 and ubr2, exhibited dna-stimulated atpase activity but was inactive as either dna helicase or dna translocase / the discovery, in the present work, that these ub ligases, ubr1 and ubr2, interact with the putative helicase recql4 (fig. 2), and that recql4 is a long-lived, non-ubiquitylated protein in hela cells" SIGNOR-128169 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 ZNF224 protein Q9NZL3 UNIPROT ALDOA protein P04075 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 17900823 f miannu "We previously reported that ZNF224, a novel Krüppel-associated box-containing zinc-finger protein, represses aldolase A gene transcription by interacting with the KAP-1 co-repressor." SIGNOR-255627 ZNF239 protein Q16600 UNIPROT RBP3 protein P10745 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 12409453 f miannu "We have demonstrated that MOK2 can bind to the 8 bp present in the IRBP promoter and repress transcription from this promoter by competing with the CRX activator for DNA binding." SIGNOR-255629 ZNRF3 protein Q9ULT6 UNIPROT LRP6 protein O75581 UNIPROT down-regulates ubiquitination 9606 23151663 t gcesareni "Znrf3 is associated with the wnt receptor complex, and inhibits wnt by promoting the turnover of frizzled and lrp6. Frizzled receptors are regu__lated by cycles of ubiquitylation and deubiquitylation, and znrf3 and rnf43 act as frizzled ubiquitin ligases, removing frizzled and possibly lrp6 from the plasma membrane." SIGNOR-199656 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 PFKFB2 protein O60825 UNIPROT Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates 9606 20640476 f lperfetto "The decreased glycogen synthesis rates upon acute AMPK activation are generally coupled to an increase in the glycolytic flux, thanks to the activation of 6-phosphofructo-2-kinase (PFK-2) through direct phosphorylation on Ser466 [35]. PFK-2 catalyzes the synthesis of fructose 2,6-bisphosphate, a potent stimulator of glycolysis. Therefore, activation of AMPK rapidly mobilizes glucose into ATP-generating processes." SIGNOR-209950 POU2AF1 protein Q16633 UNIPROT POU2F1 protein P14859 UNIPROT up-regulates binding 9606 BTO:0000776 12727885 t miannu "Obf1 enhances transcriptional potential of oct1." SIGNOR-100968 PRKACA protein P17612 UNIPROT AICDA protein Q9GZX7 UNIPROT unknown phosphorylation Thr27 WAKGRREtYLCYVVK 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-178248 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 CD40 protein P25942 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 BTO:0000782;BTO:0000776 19904719 f fstefani "Cd40 has been found to be essential in mediating a broad variety of immune and inflammatory responses including t cell-dependent immunoglobulin class switching, memory b cell development" SIGNOR-189109 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 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 GSK2126458 chemical CID:25167777 PUBCHEM PIK3CB protein P42338 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192895 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 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 NOTCH2 protein Q04721 UNIPROT TCF3 protein P15923 UNIPROT down-regulates binding 9606 BTO:0000776 9528794 t gcesareni "In an effort to identify processes that regulate e47, and potentially b-cell development, we found that activated notch1 and notch2 effectively inhibit e47 activity." SIGNOR-56222 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 KIF7 protein Q2M1P5 UNIPROT GLI1 protein P08151 UNIPROT "up-regulates quantity by stabilization" binding 10090 19549984 t lperfetto "Kif7 physically interacted with Gli transcription factors and controlled their proteolysis and stability, and acted both positively and negatively in Hh signaling." SIGNOR-209608 MEF2A protein Q02078 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-238703 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 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 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 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 HTR2C protein P28335 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-257221 CEBPE protein Q15744 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-225012 DR1 protein Q01658 UNIPROT "NC2 complex" complex SIGNOR-C108 SIGNOR "form complex" binding 9606 BTO:0000567 18838386 t miannu "NC2_ co-fractionated with NC2_ only in the low molecular weight complex (fractions 86–94) and an NC2_ antibody co-immunoprecipitated NC2_ (but not GCN5) in these fractions, which thus contain the classical NC2 complex" SIGNOR-226405 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 ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser15 PSVEPPLsQETFSDL 9606 17967874 t lperfetto "In this study, we show that the increased interaction between B56gamma and p53 after DNA damage requires ATM-dependent phosphorylation of p53 at Ser15." SIGNOR-158632 ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser15 PSVEPPLsQETFSDL 9606 20663147 t gcesareni "Deltanp63 transcriptionally regulates atm to control p53 serine-15 phosphorylation." SIGNOR-167152 AURKB protein Q96GD4 UNIPROT INCENP protein Q9NQS7 UNIPROT up-regulates phosphorylation Ser893 PRYHKRTsSAVWNSP 9606 12925766 t gcesareni "Human incenp was a substrate of aurora b and mass spectrometry identified three consecutive residues (threonine 893, serine 894, and serine 895) containing at least two phosphorylation sites." SIGNOR-118011 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 CSNK2A1 protein P68400 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-73807 DOK4 protein Q8TEW6 UNIPROT CRK protein P46108 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103;BTO:0000671 12730241 t gcesareni "Insulin receptor-phosphorylated irs5/dok4 associates with rasgap, crk, src, and fyn, but not phosphatidylinositol 3-kinase p85, grb2, shp-2, nck, or phospholipase cgamma src homology 2 domains, and activates mapk in cells." SIGNOR-100996 SH3RF1 protein Q7Z6J0 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates binding 9606 BTO:0000938 12514131 t gcesareni "We confirmed that posh binds activated rac1 and find that it also binds all mlk family members tested and interacts with mkk4/7 as well as jnk1 and jnk2." SIGNOR-96952 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 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 NTRK1 protein P04629 UNIPROT SH2B2 protein O14492 UNIPROT up-regulates phosphorylation 9606 BTO:0000938 9856458 t lperfetto "Two substrates of trk kinases, raps and sh2-b. raps and sh2-b mediate trk signaling in developing neurons" SIGNOR-62619 DYRK1A protein Q13627 UNIPROT SNCA protein P37840 UNIPROT up-regulates phosphorylation Ser87 KTVEGAGsIAAATGF 9606 BTO:0000938 16959772 t lperfetto "In vitro kinase assay of anti-dyrk1a immunocomplexes demonstrated that dyrk1a could phosphorylate alpha-synuclein at ser-87. Furthermore, aggregates formed by phosphorylated alpha-synuclein have a distinct morphology and are more neurotoxic compared with aggregates composed of unmodified wild type alpha-synuclein. These findings suggest alpha-synuclein inclusion formation regulated by dyrk1a, potentially affecting neuronal cell viability." SIGNOR-149393 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 MAPK14 protein Q16539 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" phosphorylation 10116 BTO:0001946 14512875 t lperfetto "P38 mapk mediates fibrogenic signal through smad3 phosphorylation in rat myofibroblasts. the phosphorylation promoted hetero-complex formation and nuclear translocation of smad3 and smad4." SIGNOR-236136 CAMK2A protein Q9UQM7 UNIPROT GRIN2B protein Q13224 UNIPROT "up-regulates activity" phosphorylation Ser1303 NKLRRQHsYDTFVDL BTO:0003036 8940188 t llicata "By peptide mapping, automated sequencing, and mass spectrometry, we identified the major site of phosphorylation on the fusion protein as Ser-383, corresponding to Ser-1303 of full-length NR2B. The Km for phosphorylation of this site in the fusion protein was approximately 50 nM, much lower than that of other known substrates for CaM kinase II, suggesting that the receptor is a high affinity substrate. We show that serine 1303 in the full-length NR2B and/or the cognate site in NR2A is a major site of phosphorylation of the receptor both in the postsynaptic density fraction and in living hippocampal neurons." SIGNOR-250630 CLCF1 protein Q9UBD9 UNIPROT CNTFR protein P26992 UNIPROT up-regulates binding 9606 BTO:0000938 10966616 t gcesareni "Striking phenotypic differences between cntf- and cntfr-deficient mice suggest that cntfr serves as a receptor for a second, developmentally important ligand. We have identified this factor as a stable secreted complex of cardiotrophin-like cytokine (clc) and the soluble receptor cytokine-like factor-1 (clf)." SIGNOR-81376 CNTF protein P26441 UNIPROT CNTFR protein P26992 UNIPROT up-regulates binding 9606 BTO:0000938 10966616 t gcesareni "Ciliary neurotrophic factor (cntf) is a cytokine supporting the differentiation and survival of various cell types in the peripheral and central nervous systems. Its receptor complex consists of a non-signaling alpha chain, cntfr, and two signaling beta chains, gp130 and the leukemia inhibitory factor receptor (lifr)" SIGNOR-81379 CNTF protein P26441 UNIPROT LIFR protein P42702 UNIPROT up-regulates binding 9606 BTO:0000938 10966616 t gcesareni "Ciliary neurotrophic factor (cntf) is a cytokine supporting the differentiation and survival of various cell types in the peripheral and central nervous systems. Its receptor complex consists of a non-signaling alpha chain, cntfr, and two signaling beta chains, gp130 and the leukemia inhibitory factor receptor (lifr)" SIGNOR-81382 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 NOG protein Q13253 UNIPROT BMPR1A protein P36894 UNIPROT "down-regulates activity" binding 9606 BTO:0001593 BTO:0000140 22298955 t lperfetto "Noggin binds the domain that is re-quired for bmp-7 to interact with bmp type i and type ii receptorsNoggin Inhibits bmp by blocking the molecular interfaces of the binding epitopes for both type i and type ii receptors (pmid 12478285)" SIGNOR-192799 MYF5 protein P13349 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 BTO:0000887 8288123 f miannu "The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop--helix (bhlh) motif that mediates dimerization and dna binding. / myogenic bhlh proteins form heterodimers with ubiquitous bhlh proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enhancers." SIGNOR-37409 palbociclib chemical CHEBI:85993 ChEBI CCND2 protein P30279 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205701 PRKD1 protein Q15139 UNIPROT CTTN protein Q14247 UNIPROT down-regulates phosphorylation Ser348 EAVTSKTsNIRANFE 9606 BTO:0000150 19038333 t lperfetto "Here we have investigated the possible role of pkd as a cortactin kinase. Using a mass spectrometric approach, we found that pkd phosphorylates cortactin on ser 298 examination of cortactin phosphorylation kinetics revealed that ser 298 serves as a priming site for subsequent phosphorylation of ser 348" SIGNOR-182502 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 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 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR JUN protein P05412 UNIPROT "up-regulates activity" binding 9606 9732876 t lperfetto "Smad3 and smad4 also act together with c-jun and c-fos to activate transcription in response to tgf-beta, through a tgf-beta-inducible association of c-jun with smad3 and an interaction of smad3 and c-fos" SIGNOR-229545 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 CBP/p300 complex SIGNOR-C6 SIGNOR SMAD3 protein P84022 UNIPROT "up-regulates activity" acetylation Lys19 VKRLLGWkKGEQNGQ 9606 BTO:0000567;BTO:0002181;BTO:0000552 17074756 t lperfetto "We demonstrate that both smad2 and smad3 are acetylated by the coactivators p300 and cbp in a tgfb-dependent manner. the p300-dependent acetylation of smad3 was attenuated when lys19 was mutated, whereas mutation of lys20 had no effect, suggesting that lys19 is acetylated also in smad3." SIGNOR-236126 CDK4 protein P11802 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser780 STRPPTLsPIPHIPR 9606 BTO:0000150 SIGNOR-C18 23336272 t gcesareni "Cyclin d1 is known to activate cdk4, which then phosphorylates the rb protein, leading to cell cycle progression." SIGNOR-200483 CDK4 protein P11802 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser795 SPYKFPSsPLRIPGG 9606 BTO:0000150 SIGNOR-C18 23336272 t gcesareni "Cyclin d1 is known to activate cdk4, which then phosphorylates the rb protein, leading to cell cycle progression." SIGNOR-200487 INPPL1 protein O15357 UNIPROT AKT1 protein P31749 UNIPROT down-regulates 9606 BTO:0000776 10942391 f gcesareni "Taken together, the data presented here demonstrate that ship inhibits akt primarily through regulation of akt membrane localization." SIGNOR-80706 CDK5 protein Q00535 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Ser732 SSEGFYPsPQHMVQT 9606 BTO:0000938 12941275 t gcesareni "Here, we show that fak phosphorylation by cdk5 at s732 is important for microtubule organization, nuclear movement, and neuronal migration. In cultured neurons, s732-phosphorylated fak is enriched along a centrosome-associated microtubule fork that abuts the nucleus. Overexpression of the nonphosphorylatable mutant fak s732a results in disorganization of the microtubule fork and impairment of nuclear movement in vitro, and neuronal positioning defects in vivo." SIGNOR-86223 CD19 protein P15391 UNIPROT PIK3R1 protein P27986 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-242900 U0126.EtOH chemical CHEBI:90692 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207603 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 BORA protein Q6PGQ7 UNIPROT PLK1 protein P53350 UNIPROT up-regulates phosphorylation 9606 18615013 t gcesareni "Bora/aurora-a-dependent phosphorylation is a prerequisite for plk1 to promote mitotic entry after a checkpoint-dependent arrest." SIGNOR-179425 CCK protein P06307 UNIPROT CCKAR protein P32238 UNIPROT up-regulates binding 9606 BTO:0000142 10368033 t gcesareni "Cck8 interacts with nanomolar affinities with two different receptors designated cck-a and cck-b" SIGNOR-68474 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 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 IL26 protein Q9NPH9 UNIPROT IL20RA protein Q9UHF4 UNIPROT up-regulates binding 9606 BTO:0001253 17208301 t gcesareni "The mrna expression level of il10, il19, il20, il22, il24, il26, il28b, il29 and their receptors il10ra, il10rb, il20ra, il20rb, il22ra1, il22ra2, il28ra was compared in skin biopsies of children and adults and in childrens' skin cells by quantitative real-time pcr (qrt-pcr)." SIGNOR-151920 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 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 CSNK2A1 protein P68400 UNIPROT ATF1 protein P18846 UNIPROT up-regulates phosphorylation Ser63 GILARRPsYRKILKD 9606 8663317 t lperfetto "Camk ii phosphorylates only ser63 (corresponding to ser133 of creb), which is essential for the activation, and not ser72 (corresponding to ser142 of creb), which is a negative regulation site" SIGNOR-42565 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 BTRC protein Q9Y297 UNIPROT YAP1 protein P46937 UNIPROT down-regulates ubiquitination 9606 SIGNOR-C5 23431053 t gcesareni "This cascade of phosphorylation allows the binding of scfbetatrcp that promotes the ubiquitination and degradation of yap." SIGNOR-201138 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 MAPK8IP1 protein Q9UQF2 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates binding 9606 20508646 t "Interferes with binding to RBP-J" gcesareni "Here, we show that jip1 suppresses notch1 activity. Jip1 was found to physically associate with either intracellular domain of notch1 or rbp-jk and interfere with the interaction between them." SIGNOR-165710 AMER1 protein Q5JTC6 UNIPROT CSNK1G1 protein Q9HCP0 UNIPROT up-regulates binding 9606 21304492 t gcesareni "Amer1 binds ck1gamma, recruits axin and gsk3beta to the plasma membrane and promotes complex formation between axin and lrp6." SIGNOR-171889 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 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 CYCS protein P99999 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-53585 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 maraviroc chemical CHEBI:63608 ChEBI CCR5 protein P51681 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194248 AURKB protein Q96GD4 UNIPROT INCENP protein Q9NQS7 UNIPROT up-regulates phosphorylation Ser894 RYHKRTSsAVWNSPP 9606 12925766 t gcesareni "Human incenp was a substrate of aurora b and mass spectrometry identified three consecutive residues (threonine 893, serine 894, and serine 895) containing at least two phosphorylation sites." SIGNOR-118015 BIRC5 protein O15392 UNIPROT CASP3 protein P42574 UNIPROT down-regulates binding 9606 BTO:0000150;BTO:0000551 9850056 t amattioni "Survivin binds specifically to caspase-3. Survivin protected from apoptosis induced by overexpression of procaspase-3 and inhibited the processing of these zymogens into active caspases. Survivin, which is commonly expressed in human tumor cell lines, can bind the effector cell death proteases caspase-3 in vitro and inhibits caspase activity" SIGNOR-62484 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 CREBBP protein Q92793 UNIPROT P300/PCAF complex SIGNOR-C7 SIGNOR "form complex" binding 9606 21131905 t lperfetto "Histone acetyltransferases (hats) gcn5 and pcaf (gcn5/pcaf) and cbp and p300 (cbp/p300) are transcription co-activators." SIGNOR-170262 DLL1 protein O00548 UNIPROT NOTCH3 protein Q9UM47 UNIPROT up-regulates binding 9606 11006133 t gcesareni "These results suggest that delta1, jagged1, and jagged2 are ligands for notch1 and notch3 receptors." SIGNOR-82398 GRK2 protein P25098 UNIPROT MC4R protein P32245 UNIPROT "down-regulates activity" phosphorylation Thr312 RSQELRKtFKEIICC 9606 BTO:0000007 12639913 t gcesareni "Mutagenesis studies revealed that Thr312 and Ser329/330 in the C-terminal tail are potential sites for PKA and GRK phosphorylation and may play an essential role in the recruitment of beta-arrestin to the activated receptor." SIGNOR-247770 JUN protein P05412 UNIPROT SMAD4/JUN complex SIGNOR-C10 SIGNOR "form complex" binding 9606 9312063 t gcesareni "Our analysis of the regulation of dpc4 transcriptional activity by c-jun was consistent with the possibility that c-jun and dpc4 could interact and produce trans-activation of the 3tp-lux reporter." SIGNOR-51110 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" phosphorylation Tyr493 LGADDSYyTARSAGK -1 8756661 t lperfetto "these data suggest that phosphorylation of ZAP-70 is initiated by a heterologous trans-phosphorylation of ZAP-70 by Lck on Tyr- 493." SIGNOR-226628 PRKCB protein P05771 UNIPROT ORAI1 protein Q96D31 UNIPROT down-regulates phosphorylation Ser27 GGSTTSGsRRSRRRS 9606 20534587 t llicata "We propose that pkc suppresses soce and crac channel function by phosphorylation of orai1 at n-terminal serine residues ser-27 and ser-30." SIGNOR-166040 PAX7-FOXO1 "fusion protein" SIGNOR-FP11 SIGNOR JARID2 protein Q92833 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 23435416 t lperfetto "JARID2 is a direct target of the PAX3-FOXO1 fusion protein and inhibits myogenic differentiation of rhabdomyosarcoma cells| we demonstrated that JARID2 is a direct transcriptional target of the PAX3-FOXO1 fusion protein.| Therefore, JARID2 is a downstream effector of PAX3-FOXO1 that maintains an undifferentiated myogenic phenotype that is characteristic of RMS" SIGNOR-249597 BAX protein Q07812 UNIPROT BCL2 protein P10415 UNIPROT "down-regulates activity" binding 8358790 t lperfetto "Bax shows extensive amino acid homology with Bcl-2 and forms homodimers and heterodimers with Bcl-2 in vivo. When Bax predominates, programed cell death is accelerated, and the death repressor activity of Bcl-2 is countered." SIGNOR-249612 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 3-[2,4-diamino-7-(3-hydroxyphenyl)-6-pteridinyl]phenol chemical CHEBI:94691 ChEBI PIK3CD protein O00329 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207248 CDK2 protein P24941 UNIPROT RUNX1 protein Q01196 UNIPROT "up-regulates activity" 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-138932 CH5132799 chemical CID:49784945 PUBCHEM PIK3C2B protein O00750 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190940 CH5132799 chemical CID:49784945 PUBCHEM PIK3CA protein P42336 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190943 CH5132799 chemical CID:49784945 PUBCHEM PIK3CB protein P42338 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190946 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 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 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CCND1 protein P24385 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189972 CTNNB1 protein P35222 UNIPROT WISP1 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 "Fostamatinib disodium" chemical CID:25008120 PUBCHEM SYK protein P43405 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206373 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 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 CP-91149 chemical CID:9843900 PUBCHEM PYGL protein P06737 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191112 Crenolanib chemical CID:10366136 PUBCHEM PDGFRA protein P16234 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191121 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 CYC-116 chemical CID:6420138 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191224 D-106669 chemical CID:16048654 PUBCHEM PIK3CA protein P42336 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191256 E2F1 protein Q01094 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 8649818 f lperfetto "We have found that cell cycle regulation of cyclin E transcription is mediated by E2F binding sites present in the promoter. The activity of this promoter can be regulated negatively by pRB." SIGNOR-245471 ABT-737 chemical CID:11228183 PUBCHEM BCL2L2 protein Q92843 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0001271;BTO:0000776;BTO:0000785 17200714 t gcesareni "A cell-permeant compound, abt-737, binds with high affinity to bcl2, bcl2l1, and bcl2l2, antagonizes their antiapoptotic function, and induces apoptosis in select human tumor cell lines, primary patient-derived cells." SIGNOR-151790 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 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 CSNK2A1 protein P68400 UNIPROT MDC1 protein Q14676 UNIPROT up-regulates phosphorylation Thr378 ESQAGSDtDVEEGKA 9606 18678890 t gcesareni "The mdc1-nbs1 interaction occurs through a specific region (residues 200-420) of mdc1, which contains multiple consensus casein kinase 2 (ck2) phosphorylation sites." SIGNOR-179887 CSNK2A1 protein P68400 UNIPROT MDC1 protein Q14676 UNIPROT up-regulates phosphorylation Thr455 TTERDSDtDVEEEEL 9606 18678890 t gcesareni "The mdc1-nbs1 interaction occurs through a specific region (residues 200-420) of mdc1, which contains multiple consensus casein kinase 2 (ck2) phosphorylation sites." SIGNOR-179891 GSK1292263 chemical CID:24996872 PUBCHEM GPR119 protein Q8TDV5 UNIPROT up-regulates "chemical activation" 9606 Other t Selleck gcesareni SIGNOR-192859 CDK5 protein Q00535 UNIPROT EZR protein P15311 UNIPROT "up-regulates activity" phosphorylation Thr235 YEKDDKLtPKIGFPW 9606 BTO:0000971 12769842 t llicata "Increased ezrin expression and activation by CDK5 coincident with acquisition of the senescent phenotype." SIGNOR-250665 IRF9 protein Q00978 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-240600 CDK1 protein P06493 UNIPROT NPM1 protein P06748 UNIPROT "down-regulates activity" phosphorylation Thr234 SFKKQEKtPKTPKGP 10090 BTO:0000944 SIGNOR-C17 11278991 t lperfetto "CDK1-cyclin B phosphorylates NPM/B23 on Thr234." SIGNOR-235530 CHEK1 protein O14757 UNIPROT SYK protein P43405 UNIPROT down-regulates phosphorylation Ser295 GIISRIKsYSFPKPG 9606 22585575 t llicata "We found that chk1 phosphorylated the tumor suppressor spleen tyrosine kinase (l) (syk[l]) and identified the phosphorylation site at ser295. Furthermore, chk1 phosphorylation of syk(l) promoted its subsequent proteasomal degradation." SIGNOR-197528 CNTF protein P26441 UNIPROT CNTFR protein P26992 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000887;BTO:0001103 10812968 t amattioni "Signal transduction by cntf requires that it bind first to cntfr alpha. Cntf activates downstream signaling molecules" SIGNOR-77408 baicalein chemical CHEBI:2979 ChEBI CYP2C9 protein P11712 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190236 CDK6/CCND1 complex SIGNOR-C143 SIGNOR CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Ser45 GATTTAPsLSGKGNP -1 17208333 t llicata "We showed that CCND1-CDK6 phosphorylates beta-catenin on serine 45 (S45). This phosphorylation creates a priming site for glycogen synthase kinase 3beta (GSK3beta) and is both necessary and sufficient to initiate the beta-catenin phosphorylation-degradation cascade." SIGNOR-250647 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR 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-249652 3-isobutyl-1-methyl-7H-xanthine smallmolecule CHEBI:34795 ChEBI CEBPB protein P17676 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-209986 6-(N-carbamoyl-2,6-difluoroanilino)-2-(2,4-difluorophenyl)-3-pyridinecarboxamide chemical CHEBI:94489 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207681 CAMKK2 protein Q96RR4 UNIPROT PRKAA2 protein P54646 UNIPROT up-regulates phosphorylation Thr172 SDGEFLRtSCGSPNY 9606 BTO:0000567 SIGNOR-C15 19958286 t gcesareni "These data indicate that the camkks function in intact cells as ampkks, predicting wider roles for these kinases in regulating ampk activity in vivo." SIGNOR-161929 ABT-737 chemical CID:11228183 PUBCHEM BCL2L1 protein Q07817 UNIPROT down-regulates "chemical inhibition" 9606 Other t "The effect has been demonstrated using Q07817-1" gcesareni SIGNOR-189171 CAMKK2 protein Q96RR4 UNIPROT CAMKK2 protein Q96RR4 UNIPROT up-regulates phosphorylation Thr483 KHIPSLAtVILVKTM 9606 22778263 t lperfetto "It has been proposed that a major consequence of relief from autoinhibition is autophosphorylation of thr-482, a post-translational change that likely contributes to the increased autonomous activity of camkk2" SIGNOR-198107 PD318088 chemical CID:10231331 PUBCHEM MAP2K1 protein Q02750 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205737 DVL1 protein O14640 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "down-regulates activity" binding 9534 BTO:0004055 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-227917 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates activity" phosphorylation Ser523 GVSDVPTsPTLQRPT 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-176054 KRAS protein P01116 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." SIGNOR-175213 AMER1 protein Q5JTC6 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "up-regulates activity" relocalization 9606 BTO:0000007 21304492 t lperfetto "Amer1 binds ck1gamma, recruits axin and gsk3beta to the plasma membrane and promotes complex formation between axin and lrp6." SIGNOR-227991 "AMG 458" chemical CID:24764449 PUBCHEM MET protein P08581 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189516 Anacetrapib chemical CID:11556427 PUBCHEM CETP protein P11597 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189605 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 CAMK2A protein Q9UQM7 UNIPROT CAMK2A protein Q9UQM7 UNIPROT up-regulates phosphorylation Thr286 SCMHRQEtVDCLKKF 9606 BTO:0000975 1849884 t lperfetto "Role of threonine-286 as autophosphorylation site for appearance of ca2(+)-independent activity of calmodulin-dependent protein kinase ii alpha subunit" SIGNOR-21797 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 N-(1,3-benzodioxol-5-ylmethyl)-4-(4-benzofuro[3,2-d]pyrimidinyl)-1-piperazinecarbothioamide chemical CHEBI:91389 ChEBI KIT protein P10721 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189525 CAMK2A protein Q9UQM7 UNIPROT HRH1 protein P35367 UNIPROT down-regulates phosphorylation Ser398 WKRLRSHsRQYVSGL 9606 BTO:0000975 15107581 t "Translocation from Endosome to Lysosome" gcesareni "As we have shown previously, human h1r can be phosphorylated in vitro by several kinases includingpka, pkc, pkg, and camk ii in summary, these data suggest that thr140, thr142, ser396, ser398, and thr478 can be phosphorylated by the kinases described above (table 2)." SIGNOR-124344 CBL protein P22681 UNIPROT INSR protein P06213 UNIPROT down-regulates ubiquitination 9606 BTO:0000975 11498022 t gcesareni "Aps couples c-cbl to theinsulinreceptor, resulting in ubiquitination of theinsulinreceptor" SIGNOR-109688 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT "up-regulates activity" phosphorylation Thr179 SSPDKRLtLSQIYEW 9606 BTO:0000007 17711846 t gcesareni "Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization." SIGNOR-238813 DUSP2 protein Q05923 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 8626452 t fstefani "Pac1 and mkp-1 previously have been implicated in the in vivo inactivation of erk or of erk and jnk, respectively." SIGNOR-40915 CDK5 protein Q00535 UNIPROT NES protein P48681 UNIPROT unknown phosphorylation Thr315 AENSRLQtPGGGSKT 10090 BTO:0000165 12832492 t llicata "We identify nestin as a novel in vivo target for cdk5 and p35 kinase, a critical signaling determinant in development. Two cdk5-specific phosphorylation sites on nestin, Thr-1495 and Thr-316, were established, the latter of which was used as a marker for cdk5-specific phosphorylation in vivo. | Cdk5 activity is necessary for differentiation and the concomitant nestin reorganization in C2C12 myoblasts." SIGNOR-250670 CDK5 protein Q00535 UNIPROT PPP1R1B protein Q9UD71 UNIPROT "up-regulates activity" phosphorylation Thr75 RPNPCAYtPPSLKAV 10116 BTO:0000142 10604473 t llicata "We find that DARPP-32 is converted into an inhibitor of PKA when phosphorylated at threonine 75 by cyclin-dependent kinase 5 (Cdk5). Cdk5 phosphorylates DARPP-32 in vitro and in intact brain cells. Phospho-Thr 75 DARPP-32 inhibits PKA in vitro by a competitive mechanism." SIGNOR-250671 CDK2 protein P24941 UNIPROT SIRT2 protein Q8IXJ6 UNIPROT down-regulates phosphorylation Ser368 PNPSTSAsPKKSPPP 9606 BTO:0000938 SIGNOR-C16 18332217 t llicata "We define ser-331 as the site phosphorylated by cyclin e-cdk2, cyclin a-cdk2, and p35-cdk5 both in vitro and in cells. Importantly, phosphorylation at ser-331 inhibits the catalytic activity of sirt2." SIGNOR-177972 CDK5 protein Q00535 UNIPROT CDK5R1 protein Q15078 UNIPROT down-regulates phosphorylation Thr138 PAVTSAGtPKRVIVQ 9606 BTO:0000938 18326489 t lperfetto "P35 phosphorylation by cdk5 interferes with the microtubule-binding and polymerizing activities of p35. Using a mutational approach, we found that only phosphorylation at thr-138, one of the two residues primarily phosphorylated in vivo, inhibits the polymerizing activity" SIGNOR-177967 CREB5 protein Q02930 UNIPROT JUN protein P05412 UNIPROT "up-regulates activity" binding -1 8440710 t 2 miannu "CRE-BPa binds to CRE with higher affinity than to the 12-O-tetradecanoylphorbol-13-acetate response element as a homodimer or a CRE-BPa/c-Jun or CRE-BPa/CRE-BP1 heterodimer." SIGNOR-240397 FYN protein P06241 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Tyr323 DEPVADPyDQSFESR 9606 BTO:0000782 15735648 t fstefani "T cell src family kinases and zap70 activate p38 by phosphorylating tyr323." SIGNOR-134293 GSK3B protein P49841 UNIPROT MAFA protein Q8NHW3 UNIPROT down-regulates 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 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 letrozole chemical CHEBI:6413 ChEBI CYP19A1 protein P11511 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193651 CDK1 protein P06493 UNIPROT NUMA1 protein Q14980 UNIPROT down-regulates phosphorylation Thr2055 MAFSILNtPKKLGNS 9606 23921553 t llicata "Cdk1-mediated phosphorylation at t2055 negatively regulates numa cortical localization and that this phosphorylation is counteracted by ppp2ca phosphatase activity." SIGNOR-194825 CDK5 protein Q00535 UNIPROT NDEL1 protein Q9GZM8 UNIPROT "up-regulates activity" phosphorylation Ser198 TRKSAPSsPTLDCEK 10090 BTO:0000142 12796778 t llicata "Three specific phosphorylation sites (Ser198, Thr219 and Ser231) and two weak phosphorylation sites (Ser242 and Thr245) for CDK5/p35 are located in this region of NUDEL | Each single or double mutant compromised,and the triple mutant completely eliminated, interaction with 14-3-3ε. | 14-3-3ε sustains NUDEL phosphorylation and protects it from phosphatase.e dynein motor function." SIGNOR-250675 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 LCK protein P06239 UNIPROT ACP1 protein P24666 UNIPROT "up-regulates activity" phosphorylation Tyr133 LIIEDPYyGNDSDFE 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-251367 CASP3 protein P42574 UNIPROT DFFA protein O00273 UNIPROT "up-regulates activity" cleavage 9606 BTO:0000567 9108473 t lperfetto "DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. We have identified and purified from HeLa cytosol a protein that induces DNA fragmentation in coincubated nuclei after it is activated by caspase-3." SIGNOR-47416 CDK20 protein Q8IZL9 UNIPROT ICK protein Q9UPZ9 UNIPROT up-regulates phosphorylation Thr157 IRSKPPYtDYVSTRW 9606 15988018 t lperfetto "Recombinant cak1p phosphorylates thr-157 in the tdy motif of recombinant ick and activates its activity in vitro." SIGNOR-138420 CSNK2A1 protein P68400 UNIPROT PTEN protein P60484 UNIPROT "down-regulates activity" phosphorylation Ser380 EPDHYRYsDTTDSDP 9606 21779440 t gcesareni "The C-terminal tail of PTEN is also the target of mutations in tumors. As mentioned, this region contains the main phosphorylation sites mapped to residues Ser362, Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385, and the kinases involved are casein kinase 2 (CK2), GSK3_, LKB1, and MAST.84,97-101 The phosphorylation of the tail has been shown to enhance PTEN stability but at the same time decrease its phosphatase activity" SIGNOR-152348 CHEK1 protein O14757 UNIPROT NEK11 protein Q8NG66 UNIPROT up-regulates phosphorylation Ser273 SMLNKNPsLRPSAIE 9606 19734889 t lperfetto "We demonstrate that chk1 (checkpoint kinase 1) directly activates nek11 by phosphorylating it on ser 273" SIGNOR-187863 CSNK2A1 protein P68400 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates phosphorylation Ser112 KRAGGEEsQFEMDI 9606 12588975 t gcesareni "Phosphorylation at s112 directly affects binding of 4e-bp1 to eif4e without influencing phosphorylation of other sites." SIGNOR-98280 SRPK1 protein Q96SB4 UNIPROT SRPK1 protein Q96SB4 UNIPROT up-regulates phosphorylation Ser309 RPNKQEEsESPVERP 9606 22727668 t llicata "We found that activated akt binds and induces srpk1 autophosphorylation because akt-mediated phosphorylation depends on the kinase activity of srpk1" SIGNOR-197985 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 LCK protein P06239 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates 9606 BTO:0000782 17998336 f gcesareni "The sh3 domain of lck modulates t-cell receptor-dependent activation of extracellular signal-regulated kinase through activation of raf-1." SIGNOR-159164 CSNK2A1 protein P68400 UNIPROT ATF1 protein P18846 UNIPROT down-regulates phosphorylation Ser36 AQQVSSLsESEESQD 9606 20730097 t lperfetto "Although the functional impact of ck-mediated atf1 phosphorylation is still unclear, we found that mutation of ser-36 and ser-41 increased cbp kix domain binding by up to four fold (fig. 2g). This result is consistent with the negative impact of ck-mediated phosphorylation on cbp binding affinity of creb that we previously reported" SIGNOR-167544 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 LCK protein P06239 UNIPROT PRKCQ protein Q04759 UNIPROT unknown phosphorylation Tyr90 SETTVELySLAERCR 9606 BTO:0000782 10652356 t llicata "Tyrosine 90 (tyr-90) in the regulatory domain of pkctheta was identified as the major phosphorylation site by lck." SIGNOR-74574 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-244292 ATM protein Q13315 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates phosphorylation Ser112 KRAGGEEsQFEMDI 9606 11146653 t lperfetto "Here we report that atm... phosphorylates 4e-bp1 at ser 111cells lacking atm kinase activity exhibit a significant decrease in the insulin-induced dissociation of 4e-bp1 from eif-4e." SIGNOR-85619 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 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 LIF protein P15018 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-48108 LIF protein P15018 UNIPROT MYH7 protein P12883 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0002320 10212267 f "Regulation of expression" miannu "Increase of protein synthesis rate and β-MHC gene expression in cardiac myocytes by ET-1 and LIF." SIGNOR-251959 ATM protein Q13315 UNIPROT PNKP protein Q96T60 UNIPROT up-regulates phosphorylation Ser114 EETRTPEsQPDTPPG 9606 21824916 t lperfetto "We demonstrate that pnkp is phosphorylated by the dna-dependent protein kinase (dna-pk) and ataxia-telangiectasia mutated (atm) in vitro. The major phosphorylation site for both kinases was serine 114, with serine 126 being a minor site. Purified pnkp protein with mutation of serines 114 and 126 had decreased dna kinase and dna phosphatase activities and reduced affinity for dna in vitro." SIGNOR-176008 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 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 Saracatinib chemical CID:10302451 PUBCHEM SRC protein P12931 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206691 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1868 SPTSPKYsPTSPKYS 9606 22012619 t miannu "Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna" SIGNOR-176797 FYN protein P06241 UNIPROT ITCH protein Q96J02 UNIPROT "down-regulates activity" phosphorylation Tyr420 QFNQRFIyGNQDLFA 10090 BTO:0002417 16387660 t gcesareni "Tyrosine phosphorylation of Itch appears to reduce its interaction with its substrate JunB. The turnover of JunB is accelerated in Fyn-deficient T cells, which is further reconstituted by Itch Tyr371 mutation" SIGNOR-245332 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 IKK-complex complex SIGNOR-C14 SIGNOR BAD protein Q92934 UNIPROT down-regulates phosphorylation 9606 23332762 t lperfetto "Ikk phosphorylates bad at serine-26 (ser26) and primes it for inactivation." SIGNOR-216399 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 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 PPP2CA protein P67775 UNIPROT FOXO3 protein O43524 UNIPROT "up-regulates activity" phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 20110348 t gcesareni "Pp2a-mediated dephosphorylation of t32/s253 is required for dissociation of 14-3-3, nuclear translocation, and transcriptional activation of foxo3a." SIGNOR-163688 WNT5A protein P41221 UNIPROT ROR1 protein Q01973 UNIPROT up-regulates binding 9606 BTO:0000938 22343533 t gcesareni "Ror1 and ror2 bind wnt5a." SIGNOR-196133 INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT "up-regulates activity" phosphorylation Tyr999 YASSNPEyLSASDVF -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-106526 PRKAA1 protein Q13131 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT "up-regulates activity" phosphorylation Thr178 NHNHRIRtNPAIVKT 9606 BTO:0000887;BTO:0001103 SIGNOR-C15 17609368 t lperfetto "Ampk phosphorylates pgc-1alpha directly both in vitro and in cells. These direct phosphorylations of the pgc-1alpha protein at threonine-177 and serine-538." SIGNOR-156780 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 CSNK2A1 protein P68400 UNIPROT CD5 protein P06127 UNIPROT up-regulates phosphorylation Ser483 SMQPDNSsDSDYDLH 9606 BTO:0000661 9834084 t lperfetto "In this study, we use jurkat t cell transfectants of cd5 cytoplasmic tail mutants to reveal phosphorylation sites relevant to signal transduction. Our results show that casein kinase ii (ckii) is responsible for the constitutive phosphorylation of cd5 molecules at a cluster of three serine residues located at the extreme c terminus (s458, s459, and s461)" SIGNOR-62307 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 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 LIPH protein Q8WWY8 UNIPROT LPAR2 protein Q9HBW0 UNIPROT up-regulates binding 9606 BTO:0000661 9525886 t gcesareni "When overexpressed in jurkat t cells, the edg4 protein mediated lpa-induced activation of a serum response element reporter gene with lpa concentration dependence (ec50 of 10 nm) and specificity." SIGNOR-56093 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 CDK1 protein P06493 UNIPROT KIF22 protein Q14807 UNIPROT "up-regulates activity" phosphorylation Thr463 QGAPLLStPKRERMV 9606 SIGNOR-C17 12727876 t lperfetto "Cdc2-mediated phosphorylation of kid controls its distribution to spindle and chromosomes. We identify ser427 and thr463 as m phase-specific phosphorylation sites and cdc2-cyclin b as a thr463 kinase. Kid with a thr463 to alanine mutation fails to be localized on chromosomes and is only detected along spindles, although it retains the ability to bind dna or chromosomes" SIGNOR-100964 PTK2 protein Q05397 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr397 SVSETDDyAEIIDEE 9606 17828307 t gcesareni "Fak y397 phosphorylation promotes src sh2 domain binding to fak, presumably leading to conformational src activation with a fak-src complex." SIGNOR-157763 LPAR3 protein Q9UBY5 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-257229 LPAR4 protein Q99677 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-257325 LPAR5 protein Q9H1C0 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-257284 LPAR5 protein Q9H1C0 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-256997 SRC protein P12931 UNIPROT CAV2 protein P51636 UNIPROT down-regulates phosphorylation Tyr27 SHHSGLEyADPEKFA 9606 BTO:0000017 15504032 t lperfetto "Here, we show that cav-2 is phosphorylated at both tyrosines 19 and 27. We reconstituted this phosphorylation event by recombinantly coexpressing c-src and cav-2.Further functional analysis revealed that tyrosine phosphorylation of cav-2 has no effect on its targeting to lipid rafts, but clearly disrupts the hetero-oligomerization of cav-2 with cav-1." SIGNOR-129961 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 ARID2 protein Q68CP9 UNIPROT "SWI/SNF complex" complex SIGNOR-C92 SIGNOR "form complex" binding 9606 15627498 t lperfetto "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-241756 ASXL1 protein Q8IXJ9 UNIPROT CDKN2B protein P42772 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 26470845 t lperfetto "Tumor suppressor ASXL1 is essential for the activation of INK4B expression in response to oncogene activity and anti-proliferative signals" SIGNOR-241759 ATRX protein P46100 UNIPROT PRC2 complex SIGNOR-C130 SIGNOR "up-regulates activity" binding 9606 25417162 t lperfetto "ATRX is a required specificity determinant for PRC2 targeting and function." SIGNOR-241890 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 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 RELA protein Q04206 UNIPROT MET protein P08581 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 BTO:0002895 19530226 t gcesareni "Together, these results indicate that the Met gene is a direct target of NFkappaB and that Met participates in NFkappaB-mediated cell survival." SIGNOR-241929 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 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 CDK1 protein P06493 UNIPROT RAD9A protein Q99638 UNIPROT "up-regulates activity" phosphorylation Thr355 EPSTVPGtPPPKKFR 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-101059 CSNK2A1 protein P68400 UNIPROT CAV2 protein P51636 UNIPROT "up-regulates activity" phosphorylation Ser36 DPEKFADsDQDRDPH 9606 BTO:0001130 12743374 t lperfetto "We show that caveolin-2 is phosphorylated in vivo at two serine residues and that the phosphorylation of caveolin-2 is necessary for its actions as a positive regulator of caveolin-1 during organelle biogenesis in prostate cancer cells. Mutation of the primary phosphorylation sites on caveolin-2, serine 23 and 36, reduces the number of plasmalemma-attached caveolae" SIGNOR-101110 DYNLL1 protein P63167 UNIPROT AMBRA1 protein Q9C0C7 UNIPROT down-regulates binding 9606 20921139 t gcesareni "The beclin 1vps34 complex is tethered to the cytoskeleton through an interaction between the beclin 1interacting protein ambra1 and dynein light chains 1/2." SIGNOR-168255 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 BBC3 protein Q9BXH1 UNIPROT BCL2L2 protein Q92843 UNIPROT down-regulates binding 9606 15694340 t gcesareni "Only bimbh3 and bbc3 had comparable strong affinitiesfor all the prosurvival proteins. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1." SIGNOR-133814 CHEK2 protein O96017 UNIPROT CDC25C protein P30307 UNIPROT "up-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" SIGNOR-102779 "DNA damage" stimulus SIGNOR-ST1 SIGNOR TTK protein P33981 UNIPROT up-regulates 9606 19151762 f lperfetto "Cell cycle progression is monitored constantly to ensure faithful passage of genetic codes and genome stability. We have demonstrated previously that, upon DNA damage, TTK/hMps1 activates the checkpoint kinase CHK2 by phosphorylating CHK2 at Thr68" SIGNOR-242619 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 NEK9 protein Q8TD19 UNIPROT NEK6 protein Q9HC98 UNIPROT "up-regulates activity" phosphorylation Ser206 SETTAAHsLVGTPYY 9606 BTO:0000007 12840024 t lperfetto "Nercc1/nek9 activates the nek6 and nek7 kinases. Nercc1 catalyzes the direct phosphorylation of prokaryotic recombinant nek6 at ser206 in vitro concomitant with 20-25-fold activation of nek6 activity." SIGNOR-102996 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 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 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 CBLB protein Q13191 UNIPROT EGFR protein P00533 UNIPROT "down-regulates activity" ubiquitination 9606 BTO:0000007 11375397 t lperfetto "Cbl proteins function as ubiquitin protein ligases for the activated epidermal growth factor receptor and, thus, negatively regulate its activity." SIGNOR-236519 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 CDK6 protein Q00534 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-135189 FOXO6 protein A8MYZ6 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-236560 ATM protein Q13315 UNIPROT ATM protein Q13315 UNIPROT "up-regulates activity" phosphorylation Ser1981 SLAFEEGsQSTTISS 9606 21149446 t gcesareni "In human cells, the activation process involves autophosphorylation on three sites (ser367, ser1893, and ser1981) and acetylation on lys3016. We now describe the identification of a new atm phosphorylation site, thr(p)1885 and an additional autophosphorylation site, ser(p)2996, that is highly dna damage-inducible." SIGNOR-170469 CAMK4 protein Q16566 UNIPROT PHB2 protein Q99623 UNIPROT down-regulates phosphorylation Ser91 RARPRKIsSPTGSKD 9606 BTO:0000887 21689744 t lperfetto "Here we show that calcium/calmodulin-dependent kinase iv (camk iv) specifically binds to the c terminus of phb2 and phosphorylates phb2 at serine 91. Camk iv effectively decreased phb2-mediated repression of mef2 activity through phosphorylation" SIGNOR-174437 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 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 CDK5 protein Q00535 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT down-regulates phosphorylation Thr159 DGSEPTKtPGRTSST 9606 BTO:0000938 20513426 t llicata "Thr159 phosphorylation negatively regulates the ptdins3 kinase activity of vps34 and autophagy cdk5/p25, a neuronal cdk shown to play a role in alzheimer's disease, can also phosphorylate thr159 of vps34." SIGNOR-165772 CDK6 protein Q00534 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-138957 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 AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser428 GPQRERKsSSSSEDR 9606 10869359 t lperfetto "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-244160 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-244341 AKT proteinfamily SIGNOR-PF24 SIGNOR ZYX protein Q15942 UNIPROT down-regulates phosphorylation Ser142 PQPREKVsSIDLEID 9606 17572661 t lperfetto "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-244389 (S)-selisistat chemical CHEBI:90371 ChEBI SIRT1 protein Q96EB6 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191511 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CDKN1A protein P38936 UNIPROT down-regulates phosphorylation Thr57 NFDFVTEtPLEGDFA 9606 19364816 t lperfetto "We have shown that erk2 interacts with and phosphorylates p21cip1, promoting p21cip1_ubiquitination. We identified two erk2 phosphorylation sites, thr57 and ser130, in p21cip1_and showed that phosphorylation of these residues increases p21cip1_cytoplasmic distribution and proteasome-dependent degradation." SIGNOR-244513 CDK1 protein P06493 UNIPROT DDX3X protein O00571 UNIPROT down-regulates phosphorylation Thr323 GCHLLVAtPGRLVDM 9606 SIGNOR-C17 16280325 t lperfetto "Thr204 to glu204 ddx3 mutant protein lost its function, suggesting that phosphorylation at thr204 affects ddx3 function. Thr204 was phosphorylated by cyclin b/cdc2. Thr323 in motif ib was also phosphorylated by cyclin b/cdc2 kinase. We propose a novel function of cyclin b/cdc2 kinase in mitosis, which is to cause a loss of ddx3 function to repress cyclin a expression and to decrease ribosome biogenesis and translation during mitosis." SIGNOR-141569 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 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 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-167826 BUB1 protein O43683 UNIPROT Mitotic_checkpoint phenotype SIGNOR-PH28 SIGNOR up-regulates 9606 20888775 f gcesareni "The multidomain protein kinases bub1 and bubr1 (mad3 in yeast, worms and plants) are central components of the mitotic checkpoint for spindle assembly (sac)" SIGNOR-168192 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR TSC2 protein P49815 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto "Phosphorylation 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-244602 MAP2K1 protein Q02750 UNIPROT MAPK1 protein P28482 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000443 12270934 t lperfetto "Mek1 as indicated by extensive phosphorylation of erk1 and erk2 during the initial 2 h of adipogenesis." SIGNOR-235940 CAMKK1 protein Q8N5S9 UNIPROT CAMK4 protein Q16566 UNIPROT up-regulates phosphorylation Thr200 EHQVLMKtVCGTPGY 9606 15769749 t gcesareni "Phosphorylation of ca(2+)/cam-bound camkiv on its activation loop threonine (residue thr(200) in human camkiv) by ca(2+)/calmodulin-dependent kinase kinase leads to increased camkiv kinase activity." SIGNOR-134649 CHEK1 protein O14757 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates phosphorylation Thr309 LRKGRGEtRICKIYD 9606 15665856 t gcesareni "We demonstrate that chk1 interacts with rad51, and that rad51 is phosphorylated on thr 309 in a chk1-dependent manner" SIGNOR-133375 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 EP300 protein Q09472 UNIPROT SMAD7 protein O15105 UNIPROT up-regulates acetylation Lys70 GKAVRGAkGHHHPHP 9606 15831498 t gcesareni "Here we present evidence that smad7 interacts with the transcriptional coactivator p300, resulting in acetylation of smad7 on two lysine residues in its n terminus. Acetylation or mutation of these lysine residues stabilizes smad7 and protects it from tgfbeta-induced degradation. we have recently shown that smad7 is acetylated on lysine residues 64 and 70 by p300" SIGNOR-135473 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 CNKSR1 protein Q969H4 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 15845549 t gcesareni "Here we demonstrate that the connector enhancer of ksr1, cnk1, mediates src-dependent tyrosine phosphorylation and activation of raf-1. Cnk1 binds preactivated raf-1 and activated src and forms a trimeric complex." SIGNOR-135674 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 HCK protein P08631 UNIPROT ELMO1 protein Q92556 UNIPROT up-regulates phosphorylation Tyr511 SKLQNLSyTEILKIR 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-138154 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 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1619 SPSYSPTsPSYSPTS -1 22137580 t "Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat." SIGNOR-248768 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 PCM1 protein Q15154 UNIPROT CETN1 protein Q12798 UNIPROT up-regulates relocalization 9606 12403812 t miannu "Rna silencing of pcm-1 leads to reduced assembly of centrin, pericentrin, and ninein at the centrosome" SIGNOR-94947 DUSP26 protein Q9BV47 UNIPROT TP53 protein P04637 UNIPROT "down-regulates activity" dephosphorylation Ser37 NVLSPLPsQAMDDLM 9606 20562916 t "Dual-specificity phosphatase 26 is a novel p53 phosphatase and inhibits p53 tumor suppressor functions in human neuroblastoma|Inhibiting DUSP26 expression in the IMR-32 neuroblastoma cell line enhanced doxorubicin-induced p53 phosphorylation at Ser20 and Ser37, p21, Puma, Bax expression as well as apoptosis" SIGNOR-248766 GDF6 protein Q6KF10 UNIPROT BMPR2 protein Q13873 UNIPROT up-regulates binding 9606 SIGNOR-C29 16049014 t gcesareni "We found that transfection of small hairpin rna for bmprii and actriia in mc3t3 cells suppressed the signaling of gdf6, gdf7, and bmp10. Thus, the present approach provides a genomic paradigm for matching paralogous polypeptide ligands with a limited number of evolutionarily related receptors capable of activating specific downstream smad proteins." SIGNOR-139093 CD55 protein P08174 UNIPROT CD97 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 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 FYN protein P06241 UNIPROT RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation Tyr529 TITKTVEyLHAQGVV 9606 BTO:0000007 18156174 t llicata "Epidermal growth factor stimulates rsk2 activation through activation of the mek/erk pathway and src-dependent tyrosine phosphorylation of rsk2 at tyr-529. By mass spectroscopy-based studies, we identified src tyrosine kinase family members src and fyn as upstream kinases of rsk2 tyr-529." SIGNOR-160048 DTX1 protein Q86Y01 UNIPROT TCF3 protein P15923 UNIPROT down-regulates 9606 BTO:0000776 9528794 f gcesareni "Our experiments indicate that deltex expression alone is suffcient to inhibit e47." SIGNOR-56141 MAP3K14 protein Q99558 UNIPROT MAP3K14 protein Q99558 UNIPROT "up-regulates activity" phosphorylation 9606 20651737 t lperfetto "As nik levels increase, nik presumably becomes activated by autophosphorylation (p)." SIGNOR-167063 MAP3K14 protein Q99558 UNIPROT NFKB2 protein Q00653 UNIPROT "up-regulates activity" phosphorylation Ser870 KEDSAYGsQSVEQEA 9606 BTO:0000007 11239468 t lperfetto "NIK-induced p100 processing requires phosphorylation of p100 at serines 866 and 870" SIGNOR-105557 MAP3K20 protein Q9NYL2 UNIPROT MAP3K20 protein Q9NYL2 UNIPROT up-regulates phosphorylation Thr161 ASRFHNHtTHMSLVG 9606 15342622 t gcesareni "Ionizing radiation induces mrk autophosphorylation and activation. Within the mrk kinase loop between the dfg (subdomain vii) and ape (subdomain viii) residues, there are three conserved threonine/serine residues (thr161, thr162, and ser165) that are important for activation." SIGNOR-128577 MAP3K2 protein Q9Y2U5 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 11343802 t lperfetto "Both mekk2 and mekk3 are able to activate the jun kinase pathway in vivo. However, following routine immunoprecipitation in triton x-100, mekk2 but not mekk3 is able to effectively phosphorylate both sek-1 and mek-1 and to undergo autophosphorylation" SIGNOR-244888 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 CDC14A protein Q9UNH5 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-248834 MAP3K4 protein Q9Y6R4 UNIPROT MAP2K4 protein P45985 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007 9841871 t lperfetto "When truncated mapkkk4 (deltamapkkk4) was overexpressed in hek293 cells, it was constitutively activeco-expressed map kinase kinase (mkk)-1, mkk-4, mkk-3 and mkk-6 were activated in vivo by deltamapkkk4. All of the above mkks purified from escherichia coli were phosphorylated and activated by deltamapkkk4 immunoprecipitates in vitro." SIGNOR-62369 4-[[5-amino-1-[(2,6-difluorophenyl)-oxomethyl]-1,2,4-triazol-3-yl]amino]benzenesulfonamide chemical CHEBI:94506 ChEBI AURKA protein O14965 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193531 6-[difluoro-[6-(1-methyl-4-pyrazolyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl]methyl]quinoline chemical CHEBI:91417 ChEBI MET protein P08581 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193522 FOXO3 protein O43524 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates 10090 BTO:0001103 15109499 f gcesareni "Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy." SIGNOR-241949 BCL2L2 protein Q92843 UNIPROT BAK1 protein Q16611 UNIPROT down-regulates binding 9606 17289999 t gcesareni "Bax is held in check by mcl1, bcl-2, and either bcl2l1 or bcl2l2, or by all four. They bind a primed conformer of bak or bax." SIGNOR-152989 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 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 CDK5 protein Q00535 UNIPROT MEF2A protein Q02078 UNIPROT "down-regulates activity" phosphorylation Ser408 SIKSEPIsPPRDRMT 9606 BTO:0004102 12691662 t lperfetto "Cdk5-mediated inhibition of the protective effects of transcription factor mef2 in neurotoxicity-induced apoptosis.We have identified the prosurvival transcription factor mef2 as a direct nuclear target of cdk5. Cdk5 phosphorylates mef2 at a distinct serine in its transactivation domain to inhibit mef2 activity." SIGNOR-100574 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 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 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 CSNK2A1 protein P68400 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Ser129 SGSPSDNsGAEEMEV 9606 BTO:0000661 15818404 t gcesareni "Akt/pkb ser129 is phosphorylated by ck2 in vitro and in vivo;(4) such a phosphorylation of activated akt/pkb correlates with a further increase in catalytic activity." SIGNOR-135203 ADIPOR2 protein Q86V24 UNIPROT APPL1 protein Q9UKG1 UNIPROT up-regulates binding 9606 BTO:0000142 16622416 t milica "Appl1 interacts with adiponectin receptors in mammalian cells and the interaction is stimulated by adiponectin." SIGNOR-146215 CDK2 protein P24941 UNIPROT PPP1CA protein P62136 UNIPROT down-regulates phosphorylation Thr320 NPGGRPItPPRNSAK 9606 BTO:0000661 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 LRRK2 protein Q5S007 UNIPROT MSN protein P26038 UNIPROT up-regulates phosphorylation Thr558 LGRDKYKtLRQIRQG 9606 BTO:0000142 17447891 t lperfetto "This led to the discovery that moesin, a protein which anchors the actin cytoskeleton to the plasma membrane, is efficiently phosphorylated by lrrk2, at thr558. Moesin phosphorylation could be essential to support the cytoskeletal changes accompanying this process." SIGNOR-154498 DYRK1A protein Q13627 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Ser262 LRIAKTPsPPEEPSP 9606 BTO:0000142 15262992 t lperfetto "Recent studies show that phosphorylation of amphiphysin1 prd by cdk5 inhibited the association of amphiphysin1 with ap-2 in synaptic vesicle endocytosis (7, 8) similar to that by mapk (present report). Cdk5 appears to phosphorylate amphiphysin1 at serines 261, 272, 276, and 285 and threonine 310, located in the prd" SIGNOR-126839 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 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 CSNK1A1L protein Q8N752 UNIPROT GLI3 protein P10071 UNIPROT up-regulates phosphorylation 9606 16481469 t gcesareni "Ci is phosphorylated by pka at multiple sites priming phosphorylation by both gsk3 and cki, leading to partial proteolysis. The pka, gsk3, and cki sites are conserved in gli2 and gli3, vertebrate homologs of ci that are similarly processed" SIGNOR-144554 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 ATM protein Q13315 UNIPROT RAD9A protein Q99638 UNIPROT "up-regulates activity" phosphorylation Ser272 LSDTDSHsQDLGSPE 9606 BTO:0000763 11278446 t lperfetto "Hyperphosphorylation of hrad9 induced by ir is dependent on atm. Ser(272) of hrad9 is phosphorylated directly by atm in vitro. / our results suggest that the atm-mediated phosphorylation of hrad9 is required for ir-induced checkpoint activation." SIGNOR-105243 ATM protein Q13315 UNIPROT STK11 protein Q15831 UNIPROT up-regulates phosphorylation Thr367 IIYTQDFtVPGQVPE 9606 BTO:0000848 12234250 t gcesareni "We demonstrate that both dna-pk and atm efficiently phosphorylate lkb1 at thr-366 in vitro and provide evidence that atm mediates this phosphorylation in vivo." SIGNOR-92873 DTX1 protein Q86Y01 UNIPROT NOTCH1 protein P46531 UNIPROT "up-regulates activity" ubiquitination 10090 BTO:0000165 11226752 t gcesareni "Murine homologs of deltex define a novel gene family involved in vertebrate Notch signaling and neurogenesis" SIGNOR-236870 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 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 DYRK1A protein Q13627 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Ser295 PARPRSPsQTRKGPP 9606 BTO:0000142 16733250 t lperfetto "Here we report that amphiphysin i (amph i) is also a mnb/dyrk1a substrate. This kinase phosphorylated native amph i in rodent brains and recombinant human amph i expressed in escherichia coli. Serine 293 (ser-293) was identified as the major site, whereas serine 295 and threonine 310 were found as minor kinase sitesamph i phosphorylated by mnb/dyrk1a decreased endophilin binding in vitro. From these results we conclude that amph i at ser-293 is phosphorylated by mnb/dyrk1a and that the phosphorylation has physiological significance in controlling the interaction of amphiphysin with endocytic accessory proteins." SIGNOR-146906 DYRK1A protein Q13627 UNIPROT SRSF1 protein Q07955 UNIPROT unknown phosphorylation Ser238 SRGSPRYsPRHSRSR 9606 BTO:0000142 18658135 t gcesareni "Here, we demonstrate that dyrk1a, a kinase encoded by a gene in the ds critical region, phosphorylates alternative splicing factor (asf) at ser-227, ser-234, and ser-238, driving it into nuclear speckles and preventing it from facilitating tau exon 10 inclusion." SIGNOR-179615 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 EP300 protein Q09472 UNIPROT MN1 protein Q10571 UNIPROT up-regulates binding 9606 BTO:0001271 12569362 t miannu "Our results indicate that mn1 is a transcription coactivator rather than a sequence-specific transcription factor, and that it may stimulate rar/rxr-mediated transcription through interaction with p160 and p300." SIGNOR-97899 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 AKT proteinfamily SIGNOR-PF24 SIGNOR NCOR1 protein O75376 UNIPROT down-regulates phosphorylation Ser1450 TVRSRHTsVVSSGPS 9606 BTO:0001271 23940660 t lperfetto "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-244318 KAT6A protein Q92794 UNIPROT TP53 protein P04637 UNIPROT up-regulates acetylation Lys120 FLHSGTAkSVTCTYS 9606 BTO:0001271 SIGNOR-C54 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-201482 PLK2 protein Q9NYY3 UNIPROT CENPJ protein Q9HC77 UNIPROT up-regulates phosphorylation Ser589 EQAADEIsFSSNSSF 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." SIGNOR-165999 AKT proteinfamily SIGNOR-PF24 SIGNOR DNMT1 protein P26358 UNIPROT up-regulates phosphorylation Ser143 RTPRRSKsDGEAKPE 9606 21151116 t lperfetto "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-244232 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 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 CDK5 protein Q00535 UNIPROT PMAIP1 protein Q13794 UNIPROT down-regulates phosphorylation Ser13 ARKNAQPsPARAPAE 9606 BTO:0001271 21145489 t llicata "We show that noxa is phosphorylated on a serine residue (s(13)) in the presence of glucose. Phosphorylation promotes its cytosolic sequestration and suppresses its apoptotic function. We identify cdk5 as the noxa kinase" SIGNOR-170357 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 CDK5 protein Q00535 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. n hek293 cells, mass spectrometry shows phosphorylation of tonebp/orebp-s120, -s134, -t135, and -s155." SIGNOR-170886 CYC-116 chemical CID:6420138 PUBCHEM AURKA protein O14965 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191221 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 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 CCL21 protein O00585 UNIPROT CCR7 protein P32248 UNIPROT up-regulates binding 9606 BTO:0000671 11970971 t gcesareni "The regulated expression of the chemokine secondary lymphoid tissue chemokine (slc/ccl21) and its corresponding receptor, ccr7." SIGNOR-117566 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 ATM protein Q13315 UNIPROT PPP1R2 protein P41236 UNIPROT down-regulates phosphorylation Ser44 DEELSKKsQKWDEMN 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-160648 CAMK2A protein Q9UQM7 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser643 CFTPKGSsLKIEERA 9606 BTO:0001260 2170388 t gcesareni "Smooth muscle caldesmon was phosphorylated by smooth muscle calmodulin-dependent protein kinase. Ii" SIGNOR-22631 CAMK2A protein Q9UQM7 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser656 RAEFLNKsVQKSSGV 9606 BTO:0001260 2170388 t gcesareni "Smooth muscle caldesmon was phosphorylated by smooth muscle calmodulin-dependent protein kinase. Ii" SIGNOR-22635 ITGB4 protein P16144 UNIPROT PIK3CG protein P48736 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-54703 MAML1 protein Q92585 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 11101851 t gcesareni "Maml1 binds to the ankyrin repeat domain of all four mammalian notch receptors, forms a dna-binding complex with icn and rbp-jkappa, and amplifies notch-induced transcription of hes1." SIGNOR-84827 ATM protein Q13315 UNIPROT SP1 protein P08047 UNIPROT unknown phosphorylation Ser101 DLTATQLsQGANGWQ 9606 18619531 t llicata "Thus, phosphorylation of ser-101 on sp1 is a general response to dna damage, dependent on both atm and atr." SIGNOR-179435 CDK11A protein Q9UQ88 UNIPROT CDK11B protein P21127 UNIPROT up-regulates phosphorylation Thr726 KHEYFREtPLPIDPS 9606 21078675 t lperfetto "Overall, our data indicated that thr-370 is responsible for the autophosphorylation, dimerization, and kinase activity of cdk11(p58)" SIGNOR-169628 FRS2 protein Q8WU20 UNIPROT PTPN11 protein Q06124 UNIPROT up-regulates phosphorylation 9606 9632781 t gcesareni "In addition to the direct interactions with grb2, tyrosine-phosphorylated frs2 forms a complex with the sh2 domain-containing protein tyrosine phosphatase shp2. This interaction results in tyrosine phosphorylation of shp2 and complex formation between shp2 and grb2. the catalytic activity of shp2 is essential for a sustained map kinase response and for potentiation of fgf-induced neurite outgrowth in pc12 cells" SIGNOR-58196 GNA13 protein Q14344 UNIPROT ARHGEF1 protein Q92888 UNIPROT up-regulates binding 9606 9641916 t gcesareni "Galpha13 bound tightly top115 rhogefand stimulated its capacity to catalyze nucleotide exchange onrho." SIGNOR-58417 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 CDK2 protein P24941 UNIPROT RPL12 protein P30050 UNIPROT unknown phosphorylation Ser38 KIGPLGLsPKKVGDD 9606 18847512 t llicata "Finally, we selected one novel substrate, the ribosomal protein rl12, for further study: site-directed mutagenesis and phosphopeptide mapping confirmed that cdk2 phosphorylates rl12 in vitro and in vivo on the same site determined by our methods." SIGNOR-181603 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 CSNK2A1 protein P68400 UNIPROT SIRT1 protein Q96EB6 UNIPROT unknown phosphorylation Ser659 FHGAEVYsDSEDDVL 9606 19236849 t llicata "We demonstrate that sirt1 is a substrate for protein kinase ck2 both in vitro and in vivo. Both, deletion construct analyses and serine-to-alanine mutations identified sirt1 ser-659 and ser-661 as major ck2 phosphorylation sites that are phosphorylated in vivo as well." SIGNOR-184151 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 CASP3 protein P42574 UNIPROT CASP6 protein P55212 UNIPROT up-regulates cleavage 9606 9922454 t amattioni "Caspase-3 is required for the activation of caspases 6" SIGNOR-64179 NBR1 protein Q14596 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates binding 9606 19250911 t gcesareni "Nbr1 and p62 interact and form oligomers." SIGNOR-184273 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 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 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 BAX protein Q07812 UNIPROT HTRA2 protein O43464 UNIPROT up-regulates relocalization 9606 14585074 t "Translocation from Mitochondria to Cytosol" amattioni "Bax and/or bak-mediated release of pro-apoptotic mediators including smac/diablo and omi" SIGNOR-88590 CDC14A protein Q9UNH5 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-248835 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 CSNK2A1 protein P68400 UNIPROT UBE2R2 protein Q712K3 UNIPROT up-regulates phosphorylation Ser233 DCYDDDDsGNEES 9606 12037680 t lperfetto "Ck2-dependent phosphorylation of the e2 ubiquitin conjugating enzyme ubc3b induces its interaction with beta-trcp and enhances beta-catenin degradation" SIGNOR-88050 ATR protein Q13535 UNIPROT FANCD2 protein Q9BXW9 UNIPROT up-regulates phosphorylation Thr691 YGLEEYDtQDGIAIN 9606 16943440 t lperfetto "In the present study, we identify two novel dna damage-inducible phosphorylation sites on fancd2, threonine 691 and serine 717. Atr phosphorylates fancd2 on these two sites, thereby promoting fancd2 monoubiquitination and enhancing cellular resistance to dna cross-linking agents" SIGNOR-149309 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 CARD11 protein Q9BXL7 UNIPROT BCL10 protein O95999 UNIPROT up-regulates binding 9606 12356734 t gcesareni "Card11 cooperates with bcl10 in a card domain-dependent manner.;These results implicate card11 in factor- specific activation of nf-kappab" SIGNOR-93869 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 APH1A protein Q96BI3 UNIPROT PSENEN protein Q9NZ42 UNIPROT up-regulates binding 9606 12522139 t gcesareni "Furthermore, overexpression of aph-1 facilitates pen-2-mediated ps1 proteolysis, resulting in a significant increase in ps1 fragments. Our data reveal a direct role of pen-2 in proteolytic cleavage of ps1 and a regulatory function of aph-1, in coordination with pen-2, in the biogenesis of the ps1 complex." SIGNOR-97104 IFNL1 protein Q8IU54 UNIPROT IFNLR1 protein Q8IU57 UNIPROT up-regulates binding 9606 12469119 t gcesareni "Il-28 and il-29 interacted with a heterodimeric class ii cytokine receptor that consisted of il-10 receptor beta (il-10rbeta) and an orphan class ii receptor chain, designated il-28ralpha." SIGNOR-96174 BTK protein Q06187 UNIPROT BMX protein P51813 UNIPROT up-regulates phosphorylation Tyr216 SSTSLAQyDSNSKKI 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." SIGNOR-98028 BTK protein Q06187 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-98032 HCK protein P08631 UNIPROT ADAM15 protein Q13444 UNIPROT unknown phosphorylation Tyr715 LVMLGASyWYRARLH 9606 BTO:0000661 11741929 t llicata "Hck, and to a lesser extent lck, phosphorylated the adam15 cytoplasmic domain in vitro in immune complex kinase assays." SIGNOR-112927 CDK1 protein P06493 UNIPROT TP73 protein O15350 UNIPROT up-regulates phosphorylation Thr86 AASASPYtPEHAASV 9606 12676926 t llicata "We identified thr86 as a phosphorylation site for cdk complexes and showed that thr86 is phosphorylated in a cell cycle-dependent manner in vivo. Finally, we found that mutation of thr86 significantly affects p73 transcriptional activity, suggesting a regulatory role for the cdk complexes through this site." SIGNOR-99738 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 CTNNB1 protein P35222 UNIPROT HIST1H3A protein P68431 UNIPROT up-regulates trimethylation Lys5 kQTARKST 9606 1410807 t 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-19046 DYRK1A protein Q13627 UNIPROT RCAN1 protein P53805 UNIPROT up-regulates phosphorylation Ser167 FLISPPAsPPVGWKQ 9606 12809556 t gcesareni "In the present study, dyrk1a is shown to directly interact with and phosphorylate rcan1 at ser112 and thr192 residues. Dyrk1a-mediated phosphorylation of rcan1 at ser112 primes the protein for the gsk3_-mediated phosphorylation of ser108." SIGNOR-102290 IRAK4 protein Q9NWZ3 UNIPROT PELI2 protein Q9HAT8 UNIPROT up-regulates phosphorylation 9606 12860405 t gcesareni "Pellino2 is one of the firstsubstrates identified for irak1 andirak4." SIGNOR-103717 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 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 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 BMP4 protein P12644 UNIPROT BMPR2 protein Q13873 UNIPROT up-regulates binding 9606 8006002 t fspada "Bmp-4 bound to alk-3 and alk-6 efficiently" SIGNOR-35763 FGF14 protein Q92915 UNIPROT SCN9A protein Q15858 UNIPROT "down-regulates activity" binding 9606 BTO:0000938 20679355 t miannu "Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels." SIGNOR-253425 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 AURKB protein Q96GD4 UNIPROT H3F3A protein P84243 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 10464286 t gcesareni "Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis." SIGNOR-70420 CLK2 protein P49760 UNIPROT PTPN1 protein P18031 UNIPROT up-regulates phosphorylation Ser50 RNRYRDVsPFDHSRI 9606 10480872 t gcesareni "The clk family kinases, clk1 and clk2, phosphorylate and activate the tyrosine phosphatase, ptp-1b." SIGNOR-70603 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 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 DVL3 protein Q92997 UNIPROT CSNK1E protein P49674 UNIPROT up-regulates binding 9606 10535959 t gcesareni "Ckiepsilon was in a complex with axin and other downstream components of the wnt pathway, including dishevelled." SIGNOR-71759 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 MAPK1 protein P28482 UNIPROT RPS6KA1 protein Q15418 UNIPROT "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-102645 MAPK1 protein P28482 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR "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-252753 BAZ1B protein Q9UIG0 UNIPROT H2AFX protein P16104 UNIPROT up-regulates phosphorylation Tyr143 ATQASQEy 9606 19092802 t gcesareni "We show that wstf phosphorylates tyr 142 of h2a.x, and that wstf activity has an important role in regulating several events that are critical for the dna damage response" SIGNOR-182831 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 IKBKE protein Q14164 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation Ser727 TDNLLPMsPEEFDEV 9606 17502367 t gcesareni "All stats are phosphorylated on at least one serine residue in their tad specifically, ser727 in stats 1 and 3 and ser721 in stat4. Stat serine kinases have been identified through the use of inhibitors, dominant-negative alleles, and in vitro kinase assays. They include mapk (p38mapk: stats 1, 3, 4;erk: stat3, 5;jnk: stat3), pkc_ (stat1, stat3), mtor (stat3), nlk (stat3 (42)), and camkii and ikk_ (stat1 (39, 40, 43)).STAT Serine phosphorylation regulates transcriptional activity (see below)." SIGNOR-154775 CALM1 protein P62158 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 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Thr130 PAQLLCStPNGLDRG 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-78424 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 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 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 IKBKE protein Q14164 UNIPROT IRF7 protein Q92985 UNIPROT up-regulates phosphorylation Ser471 GTQREGVsSLDSSSL 9606 10893229 t gcesareni "In response to a viral infection, phosphorylated on ser-477 and ser-479 by tbk1 and ikbke1. Phosphorylation, and subsequent activation is inhibited by vaccinia virus protein e3." SIGNOR-79139 RXRB protein P28702 UNIPROT NR2F2 protein P24468 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-79452 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 AURKA protein O14965 UNIPROT FAF1 protein Q9UNN5 UNIPROT down-regulates phosphorylation Ser289 ITDVHMVsDSDGDDF 9606 18790738 t llicata "This study reports that aurora-a (aur-a) phosphorylates fas-associated factor-1 (faf1) at ser-289 and ser-29 our findings support the negative feedback regulation of aur-a via phosphorylation of the death-promoting protein, faf1" SIGNOR-180887 AURKB protein Q96GD4 UNIPROT INCENP protein Q9NQS7 UNIPROT up-regulates phosphorylation Thr892 KPRYHKRtSSAVWNS 9606 12925766 t gcesareni "Human incenp was a substrate of aurora b and mass spectrometry identified three consecutive residues (threonine 893, serine 894, and serine 895) containing at least two phosphorylation sites." SIGNOR-118019 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 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 CALM1 protein P62158 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 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 FAS protein P25445 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates binding 9606 11495919 t amattioni "Ask1 binds fas" SIGNOR-109676 AKT2 protein P31751 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser133 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 AKT3 protein Q9Y243 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser133 EILSRRPsYRKILND 9606 9829964 t gcesareni "When overexpressed in serum-stimulated cells, akt/pkb potently induced ser-133 phosphorylation of creb and promoted recruitment of cbp." SIGNOR-62257 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 CHEK1 protein O14757 UNIPROT AURKB protein Q96GD4 UNIPROT up-regulates phosphorylation Ser331 HPWVRANsRRVLPPS 9606 17276342 t lperfetto "Chk1 phosphorylates aurora-b and enhances its catalytic activity in vitro." SIGNOR-152926 CSNK2A1 protein P68400 UNIPROT PTEN protein P60484 UNIPROT "down-regulates activity" phosphorylation Ser370 TSVTPDVsDNEPDHY 9606 21779440 t gcesareni "The C-terminal tail of PTEN is also the target of mutations in tumors. As mentioned, this region contains the main phosphorylation sites mapped to residues Ser362, Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385, and the kinases involved are casein kinase 2 (CK2), GSK3_, LKB1, and MAST.84,97-101 The phosphorylation of the tail has been shown to enhance PTEN stability but at the same time decrease its phosphatase activity" SIGNOR-89818 CSNK2A1 protein P68400 UNIPROT WASF2 protein Q9Y6W5 UNIPROT down-regulates phosphorylation Ser482 RRIAVEYsDSEDDSS 9606 19012317 t gcesareni "Here we identify five casein kinase 2 (ck2) phosphorylation sites within the vca domain of wave2, serines 482, 484, 488, 489, and 497. Phosphorylation of these sites is required for a high affinity interaction with the arp2/3 complex;we and show that their mutation to non-phosphorylatable alanine residues inhibits wave2 function in vivo." SIGNOR-182350 GRK2 protein P25098 UNIPROT OPRM1 protein P35372 UNIPROT "down-regulates activity" phosphorylation Ser357 REFCIPTsSNIEQQN 9606 BTO:0000007 12123746 t "GRK2-mediated phosphorylation is involved in the development of agonist-induced μ-opioid receptor desensitization. two C-terminal amino acids, Ser355 and Thr357, are required for short-term homologous desensitization of μ-opioid receptors expressed in HEK 293 cells." SIGNOR-251458 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 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 CDK1 protein P06493 UNIPROT CDC27 protein P30260 UNIPROT up-regulates phosphorylation Thr446 EGKISTItPQIQAFN 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-119877 RASGEF1B protein Q0VAM2 UNIPROT KRAS protein P01116 UNIPROT up-regulates binding 9606 19201597 t gcesareni "Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras." SIGNOR-183835 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 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 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 EP300 protein Q09472 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 20660310 f amattioni "Switch to beta-catenin/p300-mediated gene expression is an essential first step in initiating normal cellular differentiation" SIGNOR-229780 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 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CDKN1A protein P38936 UNIPROT down-regulates phosphorylation Ser130 SGEQAEGsPGGPGDS 9606 19364816 t lperfetto "Extracellular signal-regulated kinase 2-dependent phosphorylation induces cytoplasmic localization and degradation of p21cip1." SIGNOR-244618 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CDKN1B protein P46527 UNIPROT up-regulates phosphorylation Ser10 NVRVSNGsPSLERMD 9606 10831586 t lperfetto "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-244622 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 MAPK1 protein P28482 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-123045 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 ATM protein Q13315 UNIPROT NFAT5 protein O94916 UNIPROT up-regulates phosphorylation Ser1247 AMQSNSPsQEQQQQQ 9606 15173573 t lperfetto "Tonebp/orebp contains atm consensus phosphorylation sites at ser-1197, ser-1247, and ser-1367. In conclusion, signaling via atm is necessary for full activation of tonebp/orebp" SIGNOR-125077 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 CDK5 protein Q00535 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates phosphorylation Thr354 HLGPHRStPESRAAV 9606 12056836 t lperfetto "Cyclin-dependent kinase-5/p35 phosphorylates presenilin 1 to regulate carboxy-terminal fragment stabilityhere we demonstrate that cyclin dependent kinase-5/p35 (cdk5/p35) phosphorylates ps1 on threonine(354) within c-ps1 both in vitro and in vivo. Threonine(354) phosphorylation functions to selectively stabilize c-ps1." SIGNOR-89145 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 VRK1 protein Q99986 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser73 VGLLKLAsPELERLI 9606 15378002 t flangone "Vrk1 phosphorylates c-jun in ser63 and ser73 in vitro...VRK1 Activates c-jun dependent transcription" SIGNOR-127073 CSNK2A1 protein P68400 UNIPROT PTEN protein P60484 UNIPROT "down-regulates activity" phosphorylation Thr383 HYRYSDTtDSDPENE 9606 21779440 t gcesareni "The C-terminal tail of PTEN is also the target of mutations in tumors. As mentioned, this region contains the main phosphorylation sites mapped to residues Ser362, Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385, and the kinases involved are casein kinase 2 (CK2), GSK3_, LKB1, and MAST.84,97-101 The phosphorylation of the tail has been shown to enhance PTEN stability but at the same time decrease its phosphatase activity" SIGNOR-89830 EP300 protein Q09472 UNIPROT SMAD7 protein O15105 UNIPROT up-regulates acetylation Lys64 RAGCCLGkAVRGAKG 9606 12408818 t gcesareni "Here we present evidence that smad7 interacts with the transcriptional coactivator p300, resulting in acetylation of smad7 on two lysine residues in its n terminus. Acetylation or mutation of these lysine residues stabilizes smad7 and protects it from tgfbeta-induced degradation. we have recently shown that smad7 is acetylated on lysine residues 64 and 70 by p300" SIGNOR-95165 GRB2 protein P62993 UNIPROT SOS2 protein Q07890 UNIPROT up-regulates binding 9606 21779497 t gcesareni "Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85." SIGNOR-175180 MAP3K2 protein Q9Y2U5 UNIPROT MAP2K5 protein Q13163 UNIPROT up-regulates phosphorylation 9606 12912994 t gcesareni "Mekk2 and mekk3 are mapk kinase kinases that bind, phosphorylate and activate mek5." SIGNOR-104634 MAP3K3 protein Q99759 UNIPROT MAP2K5 protein Q13163 UNIPROT up-regulates phosphorylation 9606 12912994 t gcesareni "Mekk2 and mekk3 are mapk kinase kinases that bind, phosphorylate and activate mek5." SIGNOR-104637 MAPK11 protein Q15759 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation 9606 BTO:0001286 17254968 t gcesareni "We show that prak activates p53 by direct phosphorylation." SIGNOR-152843 CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 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-182967 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 JNK proteinfamily SIGNOR-PF15 SIGNOR BCL2L11 protein O43521 UNIPROT up-regulates phosphorylation Thr116 SCDKSTQtPSPPCQA 9606 12591950 t lperfetto "Biml (bim long) was induced and phosphorylated parallel to jnk activitythese data demonstrate that biml is phosphorylated in vivo on thr-56 and that jnk also phosphorylates biml on at least one serine residue (ser-44 and/or ser-58)" SIGNOR-98392 linifanib chemical CHEBI:91435 ChEBI PDGFRA protein P16234 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193663 TSPAN12 protein O95859 UNIPROT NDP protein Q00604 UNIPROT up-regulates 9606 19837033 f "Genetic Interaction" gcesareni "Tspan12 genetically interacts with norrin or lrp5" SIGNOR-188661 CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates 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 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-182975 CDK4 protein P11802 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 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-182979 CHEK1 protein O14757 UNIPROT TP73 protein O15350 UNIPROT up-regulates phosphorylation Ser47 EVVGGTDsSMDVFHL 9606 14585975 t llicata "We found that endogenous p73alpha is serine phosphorylated by endogenous chk1 upon dna damage, which is a mechanism required for the apoptotic-inducing function of p73alpha." SIGNOR-118913 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 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 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 IKBKE protein Q14164 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser468 AVFTDLAsVDNSEFQ 9606 SIGNOR-C13 15489227 t gcesareni "Overexpressed ikkepsilon and tbk1 phosphorylate ser-536 in vivo and in vitro." SIGNOR-129939 IKBKE protein Q14164 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser536 SGDEDFSsIADMDFS 9606 SIGNOR-C13 15489227 t gcesareni "Overexpressed ikkepsilon and tbk1 phosphorylate ser-536 in vivo and in vitro." SIGNOR-129943 MAML1 protein Q92585 UNIPROT CCNC protein P24863 UNIPROT up-regulates relocalization 9606 15546612 t 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-130709 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 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 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1941 SPKGSTYsPTSPGYS 9606 22012619 t miannu "Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna" SIGNOR-176837 MAPK14 protein Q16539 UNIPROT AKT2 protein P31751 UNIPROT "down-regulates activity" 9606 20626350 f lperfetto "On the other hand, p38 alfa may negatively modulate akt activity, indipendently of pi3k by regulating the interaction between caveolin 1 and pp2a through a mechanism dependent on cell attachment." SIGNOR-166591 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 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 CDC7 protein O00311 UNIPROT MCM7 protein P33993 UNIPROT up-regulates phosphorylation 9606 21070963 t gcesareni "We propose that phosphorylation of mcm4/6 s/tp sites, which are already phosphorylated in g1, allows initial mcm2-7 phosphorylation by ddk and initiation from the first origins of replication ( fig. 7ai )." SIGNOR-169506 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 GNA13 protein Q14344 UNIPROT RHOA protein P61586 UNIPROT up-regulates binding 9606 23450633 t gcesareni "Ga12/13 recruitment of rho-gefs causes rhoa activation and f-actin assembly, which promotes lats1/lat2 inactivation by an unknown, but myosin-independent mechanism." SIGNOR-192111 MAPK14 protein Q16539 UNIPROT CDT1 protein Q9H211 UNIPROT up-regulates phosphorylation 9606 22820251 t gcesareni "Phosphorylation of cdt-1 by p38 decreases loading of mcm, inhibits origini firing , as well as it results in an increased" SIGNOR-198428 CDC7 protein O00311 UNIPROT MCM4 protein P33991 UNIPROT up-regulates phosphorylation 9606 21070963 t gcesareni "Activation of the eukaryotic replicative dna helicase, the mcm2-7 complex, requires phosphorylation by cdc7/dbf4 (dbf4-dependent kinase or ddk), which, in turn, depends on prior phosphorylation of mcm2-7 by an unknown kinase (or kinases).we propose that the resulting mec1 modification of mcm4 and mcm6 further activates ddk phosphorylation of mcm2-7 ( fig. 7aii )." SIGNOR-169453 HDAC6 protein Q9UBN7 UNIPROT SRSF2 protein Q01130 UNIPROT up-regulates deacetylation Lys52 IPRDRYTkESRGFAF 9606 21157427 t miannu "Our data support a model in which hdac6 has a key role in the maintenance of srsf2 protein level by inhibiting tip60_mediated acetylation and proteasomal degradation." SIGNOR-170590 carfilzomib chemical CHEBI:65347 ChEBI PSMB8 protein P28062 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000873 19348473 t Luana "Carfilzomib selectively inhibits the CT-L activity of the 20S proteasome and displays equivalent potency against β5 and LMP7 with minimal cross reactivity to other protease classes." SIGNOR-257819 CDK4 protein P11802 UNIPROT RUNX3 protein Q13761 UNIPROT down-regulates phosphorylation Ser356 SSSGGDRsPTRMLAS 9606 SIGNOR-C18 19351720 t llicata "Our findings demonstrate that the cell cycle proteins cyclin d1 and cdk4 induce runx2 and runx3 phosphorylation, ubiquitylation and proteasomal degradation." SIGNOR-185120 PKN1 protein Q16512 UNIPROT PGM1 protein P36871 UNIPROT up-regulates phosphorylation Thr467 SANDKVYtVEKADNF 9606 BTO:0001271 15378030 t llicata "Pak1-mediated phosphorylation of pgm selectively on threonine 466 significantly increased pgm enzymatic activity" SIGNOR-128722 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 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-244236 CDK1 protein P06493 UNIPROT NUP98 protein P52948 UNIPROT up-regulates phosphorylation Ser623 RDSENLAsPSEYPEN 9606 21335236 t gcesareni "We show that npc disassembly is a phosphorylation-driven process, dependent on cdk1 activity and supported by members of the nima-related kinase (nek) family. mitotic hyperphosphorylation of nup98 is accomplished by multiple kinases, including cdk1 and neks." SIGNOR-172221 CDK1 protein P06493 UNIPROT NUP98 protein P52948 UNIPROT up-regulates phosphorylation Thr670 IAKPIPQtPESAGNK 9606 21335236 t gcesareni "We show that npc disassembly is a phosphorylation-driven process, dependent on cdk1 activity and supported by members of the nima-related kinase (nek) family. mitotic hyperphosphorylation of nup98 is accomplished by multiple kinases, including cdk1 and neks." SIGNOR-172225 CSNK2A1 protein P68400 UNIPROT DAXX protein Q9UER7 UNIPROT up-regulates phosphorylation Ser739 EIIVLSDsD 9606 21474068 t lperfetto "Daxx-sim is phosphorylated by ck2 kinase at residues s737 and s739. Phosphorylation promotes daxx-sim binding affinity toward sumo-1 over sumo-2/3, causing daxx preference for sumo-1 conjugation and interaction with sumo-1-modified factors." SIGNOR-173109 MAPK1 protein P28482 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-172877 CDK1 protein P06493 UNIPROT IREB2 protein P48200 UNIPROT down-regulates phosphorylation Ser157 LQKAGKLsPVKVQPK 9606 SIGNOR-C17 18574241 t lperfetto "Irp2 ser-157 is phosphorylated by cdk1/cyclin b1 during g(2)/m / ser-157 phosphorylation during g(2)/m reduces irp2 rna-binding activity" SIGNOR-179171 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 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-175083 KRAS protein P01116 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-175207 MAPK14 protein Q16539 UNIPROT MAPKAPK2 protein P49137 UNIPROT "up-regulates activity" phosphorylation Thr206 PNAILKLtDFGFAKE -1 7592979 t miannu "In Vitro Activation of MAPKAP Kinase 2 by p38/40. the constitutively active mutant T205E,T317E shows no changes in activity after treatment with the p38/40 fraction" SIGNOR-250101 CSNK2A1 protein P68400 UNIPROT PRPF3 protein O43395 UNIPROT up-regulates phosphorylation Thr494 TEAVQDPtKVEAHVR 9606 17932117 t lperfetto "Our findings provide new insights into the biology of hprp3p and suggest that the loss of hprp3p phosphorylation at thr494 is a key step for initiating thr494met aberrant interactions within u4/u6 snrnp complex and that these are likely linked to the rp18 phenotype." SIGNOR-158319 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 MAPK14 protein Q16539 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates 9606 17003045 f gcesareni "The ring finger ubiquitin ligase siah2 controls the stability of various substrates involved in stress and hypoxia responses, including the phd3, which controls the stability of hif-1alpha. In the present study we determined the role of siah2 phosphorylation in the regulation of its activity toward phd3. We show that siah2 is subject to phosphorylation by p38 mapk, which increases siah2-mediated degradation of phd3." SIGNOR-149887 MAPK14 protein Q16539 UNIPROT HIST1H3A protein P68431 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 20626350 t gcesareni "The p38 mapk pathway can positevely regulate nf-kb activity by different mechanisms, including chromatin remodelling through ser10 phosphorylation of histone h3 at nf-kb dependent promoters such as il-8 and mcp or by impinging on ikk or the p65 subunit in a direct or indirect manner." SIGNOR-166602 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 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 MAPK1 protein P28482 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-123079 MAPK1 protein P28482 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates phosphorylation Thr57 NFDFVTEtPLEGDFA 9606 19364816 t lperfetto "We have shown that erk2 interacts with and phosphorylates p21cip1, promoting p21cip1_ubiquitination. We identified two erk2 phosphorylation sites, thr57 and ser130, in p21cip1_and showed that phosphorylation of these residues increases p21cip1_cytoplasmic distribution and proteasome-dependent degradation." SIGNOR-185219 MAPK14 protein Q16539 UNIPROT MAPKAPK2 protein P49137 UNIPROT "up-regulates activity" phosphorylation Thr222 TSHNSLTtPCYTPYY 9606 BTO:0000130 14499342 t lperfetto "Mapk-activated protein kinase-2 (mk2) is activated by p38 mapk in human neutrophils." SIGNOR-118040 MAPK14 protein Q16539 UNIPROT MAPKAPK3 protein Q16644 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0000944 11157753 t lperfetto "These results, taken together, suggest the importance of the docking interaction in the efficient phosphorylation and activation of 3pk by p38." SIGNOR-235451 PRKCA protein P17252 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-248928 MAPK10 protein P53779 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates phosphorylation Thr116 SCDKSTQtPSPPCQA 9606 18498746 t gcesareni "Jnk is the physiogically relevant uv-stimulated kinase that phosphorylates bimel on thr-112/jnk-induced bim apoptotic activity" SIGNOR-178683 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 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 TLE2 protein Q04725 UNIPROT LEF1 protein Q9UJU2 UNIPROT down-regulates binding 9606 19460168 t gcesareni "Mapping studies reveal that groucho/tle binds two regions in lef-1." SIGNOR-185736 bortezomib chemical CHEBI:52717 ChEBI PSMB5 protein P28074 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000567 19428245 t Luana "MG-132, which was one of the first synthetic inhibitors, interacts reversibly with the N-terminal threonine residue of the β5 active site." SIGNOR-257820 MAPK14 protein Q16539 UNIPROT MEF2C protein Q06413 UNIPROT "up-regulates activity" phosphorylation Thr293 QSAQSLAtPVVSVAT 9606 9069290 t "The effect has been demonstrated using Q06413-3" lperfetto "We found that in monocytic cells, lps increases the transactivation activity of mef2c through p38-catalysed phosphorylation." SIGNOR-47136 MAPK14 protein Q16539 UNIPROT MEF2C protein Q06413 UNIPROT "up-regulates activity" phosphorylation Thr300 TPVVSVAtPTLPGQG 9606 9858528 t "The effect has been demonstrated using Q06413-3" lperfetto "Our studies showed that p38 specifically phosphorylates serine 387 and threonines 293 and 300 within the mef2c transactivation domain" SIGNOR-62796 CSNK2A1 protein P68400 UNIPROT CBX1 protein P83916 UNIPROT down-regulates phosphorylation Thr51 GFSDEDNtWEPEENL 9606 19657222 t lperfetto "Two recent papers suggest that hp1 recruitment to damage sites, rather than its rapid mobilization, is the predominant behaviour exhibited by this protein. Our findings reconcile recent findings in a new model, wherein rapid hp1beta mobilization from dsbs is mediated by its phosphorylation on thr51 by ck2" SIGNOR-187450 ERBB3 protein P21860 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 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. In this study, we identify grb2 as a specific binding partner to tyrosines y1199 and y1268 of erbb3." SIGNOR-121971 MAPK14 protein Q16539 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT "up-regulates activity" phosphorylation Ser543 SLLSTLSsPGPKLDN 9606 BTO:0000093 15383283 t miannu "P38 MAPK and JNK can phosphorylate multiple sites on SRC-3, including S505, S543, S860, and S867. Our results suggest that several kinases are important for phosphorylating SRC-3 and enhancing its interaction with DNA-dependent transcription factors and other coactivators." SIGNOR-250104 MAPK14 protein Q16539 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT "up-regulates activity" phosphorylation Ser860 NRAVSLDsPVSVGSS 9606 BTO:0000093 15383283 t miannu "P38 MAPK and JNK can phosphorylate multiple sites on SRC-3, including S505, S543, S860, and S867. Our results suggest that several kinases are important for phosphorylating SRC-3 and enhancing its interaction with DNA-dependent transcription factors and other coactivators." SIGNOR-250105 MAPK14 protein Q16539 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT "up-regulates activity" phosphorylation Ser867 SPVSVGSsPPVKNIS 9606 BTO:0000093 15383283 t miannu "P38 MAPK and JNK can phosphorylate multiple sites on SRC-3, including S505, S543, S860, and S867. Our results suggest that several kinases are important for phosphorylating SRC-3 and enhancing its interaction with DNA-dependent transcription factors and other coactivators." SIGNOR-250106 PRKCA protein P17252 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-249086 MAPK14 protein Q16539 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates phosphorylation Ser266 SLPLTPEsPNDPKGS 9606 BTO:0000887 11741533 t gcesareni "Cytokine stimulation of energy expenditure through p38 map kinase activation of ppargamma coactivator-1we show here that many cytokines activate the transcriptional ppar gamma coactivator-1 (pgc-1) through phosphorylation by p38 kinase, resulting in stabilization and activation of pgc-1 proteinp38 mapk directly phosphorylates pgc-1 on residues threonine 262, serine 265, and threonine 298" SIGNOR-112766 MAPK14 protein Q16539 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates phosphorylation Thr263 TTLSLPLtPESPNDP 9606 BTO:0000887 11741533 t gcesareni "Cytokine stimulation of energy expenditure through p38 map kinase activation of ppargamma coactivator-1we show here that many cytokines activate the transcriptional ppar gamma coactivator-1 (pgc-1) through phosphorylation by p38 kinase, resulting in stabilization and activation of pgc-1 proteinp38 mapk directly phosphorylates pgc-1 on residues threonine 262, serine 265, and threonine 298" SIGNOR-112770 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 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 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 OTUB1 protein Q96FW1 UNIPROT UBE2N protein P61088 UNIPROT down-regulates binding 9606 21763684 t gcesareni "The deubiquitinating enzyme otub1 suppresses rnf168 dependent ubiquitination by direct the e2 ligase ubc13" SIGNOR-175050 AKT3 protein Q9Y243 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-186780 AURKB protein Q96GD4 UNIPROT TP53 protein P04637 UNIPROT down-regulates phosphorylation Ser269 GNLLGRNsFEVRVCA 9606 20959462 t llicata "Importantly, the aurora b-mediated phosphorylation on ser(269) or thr(284) significantly compromises p53 transcriptional activity." SIGNOR-168745 FGFR1 protein P11362 UNIPROT PDK1 protein Q15118 UNIPROT up-regulates phosphorylation Tyr243 ARRLCDLyYINSPEL 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-191723 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Thr273 SPSVHPAtPISPGRA 9606 BTO:0002181 16046550 t "The effect has been demonstrated using Q01196-8" lperfetto "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-244715 FLT1 protein P17948 UNIPROT FLT1 protein P17948 UNIPROT up-regulates phosphorylation Tyr1169 VQQDGKDyIPINAIL 9606 BTO:0000801;BTO:0000876 9299537 t lperfetto "Tyr-1169 and tyr-1213 on flt-1 were found to be auto-phosphorylated these results strongly suggest that tyr-1169 on flt-1 is a major binding site for plcgamma and important for flt-1 signal transduction within the cell" SIGNOR-50834 GNG3 protein P63215 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 BTO:0000938 16537363 t gcesareni "Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt" SIGNOR-145125 seliciclib chemical CHEBI:45307 ChEBI CDK1 protein P06493 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206568 ANGPT1 protein Q15389 UNIPROT MYOG protein P15173 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000222 26042050 f lperfetto "Exogenous Ang-1 enhanced myogenic (MyoD and Myogenin) mRNA in differentiating myoblasts and increased myosin heavy chain protein." SIGNOR-241554 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 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 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 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 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 GOPC protein Q9HD26 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates binding 9606 21311563 t gcesareni "Npist binds beclin 1 by a ccd" SIGNOR-171896 MAPK14 protein Q16539 UNIPROT RPS6KA4 protein O75676 UNIPROT up-regulates phosphorylation Thr568 SPGVPMQtPCFTLQY 9606 BTO:0000567 10806207 t llicata "Rskb, a 90-kda ribosomal s6 protein kinase family (rsk) member with two complete catalytic domains connected by a linker, is activated through p38- and erk-mitogen-activated protein kinases. unlike other rsks, the activation loop phosphorylation sites of both catalytic domains of rskb, ser(196) and thr(568), were required for activity. Rskb activation depended on phosphorylation of linker ser(343) and ser(360) and associated with phosphorylation of nonconserved ser(347), but ser(347)-deficient rskb retained partial activity." SIGNOR-77220 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 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 FOXO proteinfamily SIGNOR-PF27 SIGNOR 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-252946 CDK5 protein Q00535 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-249318 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 MAPK14 protein Q16539 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-179912 CORT protein O00230 UNIPROT MRGPRX2 protein Q96LB1 UNIPROT up-regulates binding 9606 BTO:0000938 16111673 t gcesareni "The mrgx2 receptor has been shown to be activated by the peptides cortistatin and proadrenomedullin n-terminal peptides (pamp)" SIGNOR-139855 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 CSNK2A1 protein P68400 UNIPROT NFKBIA protein P25963 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser32 LLDDRHDsGLDSMKD 10398585 t lperfetto "Serine 32 and serine 36 of IkappaBalpha are directly phosphorylated by protein kinase CKII in vitro|Phosphorylation of IkappaBalpha at serine 32 (S32) and serine 36 (S36) is necessary for this stimuli-induced degradation" SIGNOR-249332 CSNK2A1 protein P68400 UNIPROT NFKBIA protein P25963 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser36 RHDSGLDsMKDEEYE 10398585 t lperfetto "Serine 32 and serine 36 of IkappaBalpha are directly phosphorylated by protein kinase CKII in vitro|Phosphorylation of IkappaBalpha at serine 32 (S32) and serine 36 (S36) is necessary for this stimuli-induced degradation" SIGNOR-249333 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 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 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 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 AURKB protein Q96GD4 UNIPROT PLEKHG6 protein Q3KR16 UNIPROT up-regulates phosphorylation Thr544 SPSTRPStPSLEGSQ 9606 24482237 t lperfetto "In this study we report that aurora b-mediated phosphorylation of myogef at thr-544 creates a docking site for plk1, leading to the localization and activation of myogef at the central spindle." SIGNOR-204534 DUSP9 protein Q99956 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 21908610 t gcesareni "In addition, although mutation of ser-58 to either alanine or glutamic acid does not affect the intrinsic catalytic activity of dusp9/mkp-4, phospho-mimetic (ser-58 to glu) substitution inhibits both the interaction of dusp9/mkp-4 with erk2 and p38? In vivo and its ability to dephosphorylate and inactivate these map kinases." SIGNOR-176586 MAPK3 protein P27361 UNIPROT ETV6 protein P41212 UNIPROT down-regulates phosphorylation Ser213 DNMIRRLsPAERAQG 9606 15060146 t tpavlidou "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 GSK3B protein P49841 UNIPROT MAFA protein Q8NHW3 UNIPROT up-regulates 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 IL17A protein Q16552 UNIPROT KLF3 protein P57682 UNIPROT up-regulates "transcriptional regulation" 9606 23332504 f fspada "Specifically, il-17 suppresses klf15, a pro-adipogenic tf, and enhances expression of klf2 and klf3, which are anti-adipogenic. " SIGNOR-210114 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 AURKA protein O14965 UNIPROT PLK1 protein P53350 UNIPROT up-regulates phosphorylation Thr210 YDGERKKtLCGTPNY 9606 18615013 t gcesareni "We find that aurora a (aurka) can directly phosphorylate plk1 on thr 210;activation of plk1 requires phosphorylation of a conserved threonine residue (thr 210)." SIGNOR-179422 CD19 protein P15391 UNIPROT VAV1 protein P15498 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-242897 CDK5 protein Q00535 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. The kinases involved in phosphorylating stmn ser-16 and ser-63 include camp-dependent protein kinase (pka) and pak1, whereas stmn ser-25 and ser-38 have been shown to be targets for proline-directed serine/threonine kinases such as cyclin-dependent kinases, erk1/2, and members of the p38 mapk subfamily." SIGNOR-166682 CSNK2A1 protein P68400 UNIPROT IGF2R protein P11717 UNIPROT unknown phosphorylation Ser2484 LVSFHDDsDEDLLHI 9606 8318012 t lperfetto "The two sites phosphorylated by ck ii in vivo and in vitro are ser82 and ser157." SIGNOR-37835 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 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 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 ACVR1 protein Q04771 UNIPROT SMAD5 protein Q99717 UNIPROT up-regulates phosphorylation 9606 9748228 t fspada "Bmp7 stimulated phosphorylation of endogenous smad1 and 5, formation of complexes with smad4 and induced the promoter for the homeobox gene, tlx2" SIGNOR-60171 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 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 LPAR3 protein Q9UBY5 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 BTO:0000938 12531543 t gcesareni "Lpa3couples to gq" SIGNOR-97400 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1889 SPTTPKYsPTSPTYS 9606 22012619 t miannu "Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna" SIGNOR-176813 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1896 SPTSPTYsPTSPVYT 9606 22012619 t miannu "Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna" SIGNOR-176817 ELL protein P55199 UNIPROT ELL/ICE2 complex SIGNOR-C49 SIGNOR "form complex" binding 9606 BTO:0001271 22195968 t miannu "The ell-ice complex is called lec for its proposed role in transcriptional regulation of the littlesnrna genes." SIGNOR-193461 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 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 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 TOP2B protein Q02880 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR down-regulates 9606 24463367 f lperfetto "Topoisomerase IIbeta is required for proper retinal development and survival of postmitotic cells" SIGNOR-242533 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 CDK4 protein P11802 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Ser4 sPRRPLIL 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-177251 FOXP3 protein Q9BZS1 UNIPROT IL10 protein P22301 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 24315995 f alessandro "FoxP3, a lineage-specification factor, executes its multiple activities mostly through transcriptional regulation of target genes. We identified an interleukin-10 (IL-10)-producing FoxP3(+) T regulatory cell population that contributes to IL-10-dependent type 2 cytokine bias in breast-cancer patients. Although genetic ablation of FOXP3 inhibited IL10 transcription, genome-wide analysis ruled out its role as a transcription factor for IL10" SIGNOR-254525 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 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 CHEK1 protein O14757 UNIPROT H3F3A protein P84243 UNIPROT up-regulates phosphorylation Thr12 KQTARKStGGKAPRK 9606 18243098 t gcesareni "We identify chk1 as the kinase responsible for h3-t11 phosphorylation. H3-t11 phosphorylation occurs throughout the cell cycle and is chk1 dependent in vivo.Phosphorylation at thr-12 (h3t11ph) by pkn1 is a specific tag for epigenetic transcriptional activation that promotes demethylation of lys-10 (h3k9me) by kdm4c/jmjd2c." SIGNOR-160557 IRF3 protein Q14653 UNIPROT Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 12692549 f lperfetto "The transcription factors interferon regulatory factor 3 (IRF3) and NF-B are required for the expression of many genes involved in the innate immune response." SIGNOR-216316 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 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 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 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 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 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 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 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 ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT "down-regulates activity" phosphorylation Ser429 KEESVESsLPLNAIE 9606 BTO:0000007 19816404 t lperfetto "These data indicate that atm is responsible for directly phosphorylating s386 and s429 after dna damagemdm2 phosphorylation inhibits p53 poly ubiquitination" SIGNOR-188412 ATR protein Q13535 UNIPROT MDM2 protein Q00987 UNIPROT "down-regulates activity" phosphorylation Ser407 SSSIIYSsQEDVKEF 9606 BTO:0002552 14654783 t lperfetto "We found that a major kinase responsible for s407 phosphorylation is atrs407 phosphorylation of mdm2 by atr reduces mdm2-dependent export of p53 from nuclei to cytoplasm." SIGNOR-119546 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 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 17beta-estradiol smallmolecule CHEBI:16469 ChEBI GPER1 protein Q99527 UNIPROT up-regulates binding 9606 18262661 t gcesareni "Recent studies have revealed the contribution of a novel estrogen receptor gpr30, which belongs to the family of seven-transmembrane g-protein-coupled receptors, to many of the rapid biological responses to estrogen." SIGNOR-160778 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 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 MAPK8 protein P45983 UNIPROT BCL2 protein P10415 UNIPROT down-regulates phosphorylation 9606 10567572 t amattioni "Jnk was capable of phosphorylating bcl-2. Phosphorylation of bcl-2 inactivates the molecule" SIGNOR-72364 EIF4G1 protein Q04637 UNIPROT EIF4A2/EIF4E/EIF4G1 complex SIGNOR-C44 SIGNOR "form complex" binding 9606 BTO:0000671 11408474 t miannu "Eif4a interacts with a scaffold protein, eif4g, to form complexes that also contain the cap-binding protein eif4e, which binds the cap structure (m7gpppn_) at the 5_-end of the mrna. These complexes are termed eif4f." SIGNOR-108518 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 GNAS protein Q5JWF2 UNIPROT ADCY1 protein Q08828 UNIPROT up-regulates binding 9606 17652154 t gcesareni "Thus, gs-coupled gpcr can induce yap phosphorylation mainly via camp and pka;gs_? But not any other g_? Directly activates adenylyl cyclases." SIGNOR-157014 CAMK2A protein Q9UQM7 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Thr548 KKVAVVRtPPKSPSS 9606 BTO:0000590 10090741 t lperfetto "We found that when tau was first phosphorylated by A-kinase, C-kinase, cdk5, or CaM kinase II and then by GSK-3, its binding to microtubules was inhibited by 45, 61, 78, and 79%, respectively. Further, the kinase combinations cdk5/GSK-3 and CaM kinase II/GSK-3 rapidly phosphorylated the sites Thr 231 and Ser 235. When these sites were individually replaced by Ala and the phosphorylation experiments repeated, tau binding to microtubules was inhibited by 54 and 71%, respectively. By comparison, when Ser 262 was replaced by Ala, tau binding to microtubules was inhibited by only 8% after phosphorylation by CaM kinase II." SIGNOR-249315 CAMK2G protein Q13555 UNIPROT GRIA4 protein P48058 UNIPROT unknown phosphorylation Ser862 IRNKARLsITGSVGE 10366608 t llicata "We found that GluR4 is phosphorylated on serine 842 within the C-terminal domain in vitro and in vivo. Serine 842 is phosphorylated by PKA, PKC, and CaMKII in vitro and is phosphorylated in transfected cells by PKA." SIGNOR-250699 "Caspase 8 complex" complex SIGNOR-C231 SIGNOR Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 14585074 f amattioni "Downstream of caspase-8 activation, apoptosis induction takes place" SIGNOR-256641 CCND1 protein P24385 UNIPROT CDK6/CCND1 complex SIGNOR-C143 SIGNOR "form complex" binding 9606 8114739 t lperfetto "Here, we show that the human PLSTIRE gene product is a novel cyclin-dependent kinase, cdk6. The cdk6 kinase is associated with cyclins D1, D2, and D3 in lysates of human cells and is activated by coexpression with D-type cyclins in Sf9 insect cells." SIGNOR-250680 APH1A protein Q96BI3 UNIPROT g-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-209714 CAMK2A protein Q9UQM7 UNIPROT ETS2 protein P15036 UNIPROT down-regulates phosphorylation Ser313 QRVPSFEsFEDDCSQ 9606 19182667 t lperfetto "Camkii caused ets-2 phosphorylation.Serine 246, 310, and 313 were the targets. Camkii to phosphorylates ets-2, thus altering ets-2 binding to its downstream promoters" SIGNOR-183604 CAMK2G protein Q13555 UNIPROT PEA15 protein Q15121 UNIPROT unknown phosphorylation Ser116 KDIIRQPsEEEIIKL BTO:0000099 9721757 t llicata "Partly purified PEA-15 was a substrate in vitro for CaMKII, but not for casein kinase II. Two-dimensional phosphopeptide mapping demonstrated that the site phosphorylated in vitro by CaMKII was also phosphorylated in intact astrocytes in response to endothelin. CaMKII phosphorylated selectively Ser116 and had no effect on Ser104, but in vitro phosphorylation by CaMKII appeared to facilitate further phosphorylation by protein kinase C. " SIGNOR-250701 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 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 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 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 CRBN protein Q96SW2 UNIPROT CRL4(CRBN) complex SIGNOR-C119 SIGNOR "form complex" binding 9606 22649780 t gcesareni "The CUL4 family employs the structurally distinct triple WD40 ²-propeller domain-containing DDB1 adaptor to recruit members of the DDB1€“CUL4 associated factors (DCAF) family of substrate receptors" SIGNOR-234805 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 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 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 CSNK2A1 protein P68400 UNIPROT EGR1 protein P18146 UNIPROT "down-regulates activity" phosphorylation Thr526 TNSFSAStGLSDMTA 10090 BTO:0000944 8662759 t llicata "Casein kinase II associates with Egr-1 and acts as a negative modulator of its DNA binding and transcription activities in NIH 3T3 cells. | There are three CKII recognition sites (S376XXD, T389XE, and T516XXXD) in fragment 10." SIGNOR-250858 GNAI1 protein P63096 UNIPROT HCK protein P08631 UNIPROT "up-regulates activity" binding -1 11007482 t "Galphas and Galphai similarly modulate Hck, another member of Src-family tyrosine kinases." SIGNOR-256528 CAMK1 protein Q14012 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser498 RPLSRTQsSPLPQSP 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-85022 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 CSNK2A1 protein P68400 UNIPROT F5 protein P12259 UNIPROT "down-regulates activity" phosphorylation Ser692 IPDDDEDsYEIFEPP -1 9525959 t llicata "Factor Va, the essential cofactor for prothrombinase, is phosphorylated on the acidic COOH terminus of the heavy chain of the cofactor, at Ser692, by a platelet membrane-associated casein kinase II (CKII). | The phosphorylated cofactor has increased susceptibility to inactivation by activated protein C, since phosphorylated factor Va was found to be inactivated approximately 3-fold faster than its native counterpart." SIGNOR-250862 CSNK2A1 protein P68400 UNIPROT HCLS1 protein P14317 UNIPROT unknown phosphorylation Thr23 TQGDDWDtDPDFVND 9606 BTO:0000132 10806407 t llicata "The in vivo Ser/Thr phosphorylation of HS1 is enhanced by okadaic acid and reduced by specific inhibitors of casein kinase (CK)2. In vitro, HS1 is an excellent substrate for either CK2 alpha subunit alone (Km = 47 nM) or CK2 holoenzyme | It is likely therefore that Thr16 and/or Thr23 account for the phosphate incorporated into HS1 threonyl residue(s) upon incubation with CK2." SIGNOR-250886 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 CSNK2A1 protein P68400 UNIPROT HMOX2 protein P30519 UNIPROT "up-regulates activity" phosphorylation Ser79 TALYFTYsALEEEME 10116 BTO:0003036 14527438 t llicata "Carbon monoxide neurotransmission activated by CK2 phosphorylation of heme oxygenase-2. | CK2 activation is abolished by the S79A mutation but preserved in S179A and T248A mutations, indicating that S79 is the target of CK2-dependent activation of HO2" SIGNOR-250895 CSNK2A1 protein P68400 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-250901 CD27 protein P26842 UNIPROT BCL2 protein P10415 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-93317 CREB5 protein Q02930 UNIPROT JUN protein P05412 UNIPROT "up-regulates activity" binding 9534 BTO:0000318 8378084 t miannu "CRE-BPa specifically binds to CRE as a homodimer or heterodimer with c-Jun or CRE-BP1. In CAT cotransfection experiments using CV-1 cells, transient expression of each of four CRE-BPa proteins caused a 1.6- to 3.4-fold increase of CRE-dependent transcription" SIGNOR-219634 CSNK2A1 protein P68400 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-250952 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 NGFR protein P08138 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 14699954 f amattioni "Neurotrophin binding to p75ntr has also been shown to induce apoptosis" SIGNOR-256655 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 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 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 JNK proteinfamily SIGNOR-PF15 SIGNOR BCL2L1 protein Q07817 UNIPROT down-regulates phosphorylation Ser62 PSWHLADsPAVNGAT 9606 BTO:0001130 12633850 t lperfetto "We have identified that serine 62 is the necessary site for taxol- or 2-me-induced bcl-xl phosphorylation 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" SIGNOR-99215 MAPK8IP2 protein Q13387 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates binding 9606 10490659 t "These data demonstrated that JIP2 increases JNK activation by the MLK signaling pathway" gcesareni "These experiments demonstrated that 10 different jnk isoforms bound to both jip proteins." SIGNOR-70860 PAK1 protein Q13153 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser338 RPRGQRDsSYYWEIE 9606 18775988 t gcesareni "P21-activated protein kinases (paks) are serine/threonine protein kinases that phosphorylate raf-1 at ser-338 and ser-339." SIGNOR-180808 CDK5 protein Q00535 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-197945 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 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 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 CDK2 protein P24941 UNIPROT MCM4 protein P33991 UNIPROT "down-regulates activity" phosphorylation Ser54 ELQPMPTsPGVDLQS 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-100885 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 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 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 NTRK2 protein Q16620 UNIPROT FRS3 protein O43559 UNIPROT "up-regulates activity" phosphorylation Tyr417 EPPRQLNyIQVELKG 9606 BTO:0000007 11432792 t miannu "The tyrosine phosphoryla tion of FRS2/SNT2 was stimulated dependently on the TrkB activation. to explore the possibility that tyrosine residues 417 and 455 on FRS2/SNT2 function as the binding sites for Shp2, we coexpressed Y417F or Y455F phenylalanine mutants and the Y417/455F double phenylalanine mutant of Myc/Histagged FRS2/SNT2 with TrkB. The active TrkB induced somewhat reduced tyrosine phosphorylation of all of the phenylalanine mutants of FRS2/SNT2 in comparison with tyrosine phosphorylation of the wild type" SIGNOR-250202 MAPK13 protein O15264 UNIPROT EEF2K protein O00418 UNIPROT "down-regulates activity" phosphorylation Ser359 GTEEKCGsPQVRTLS 9606 BTO:0000887;BTO:0001103 11500363 t lperfetto "Sapk4/p38delta phosphorylated eef2k at ser359 in vitro, causing its inactivation." SIGNOR-109703 MAPK9 protein P45984 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-188168 CSNK2A1 protein P68400 UNIPROT TOP2A protein P11388 UNIPROT up-regulates phosphorylation Ser1525 PIKYLEEsDEDDLF 9606 19098900 t gcesareni "Here we report that when phosphorylated, ser 1524 of topo iialpha acts as a binding site for the brct domain of mdc1 (mediator of dna damage checkpoint protein-1), thereby recruiting mdc1 to chromatin" SIGNOR-182840 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 HIPK2 protein Q9H2X6 UNIPROT PML protein P29590 UNIPROT up-regulates phosphorylation Ser8 MEPAPARsPRPQQDP 9606 19015637 t llicata "In response to dna damage, hipk2 phosphorylates pml at serines 8 and 38. he n-terminal phosphorylation sites contribute to the dna damage-induced pml sumoylation and are required for the ability of pml to cooperate with hipk2 for the induction of cell death." SIGNOR-182432 CDK1 protein P06493 UNIPROT ESCO1 protein Q5FWF5 UNIPROT down-regulates phosphorylation 9606 23314252 t gcesareni "We show here that eco1 degradation requires the sequential actions of cdk1 and two additional kinases , cdc7-dbf4 and the gsk-3 homolog mck1." SIGNOR-200400 CSNK2A1 protein P68400 UNIPROT TELO2 protein Q9Y4R8 UNIPROT down-regulates phosphorylation Ser487 AQLAGSDsDLDSDDE 9606 23263282 t lperfetto "Here we report that tel2 and tti1 are targeted for degradation within mtorc1 by the scffbxo9 ubiquitin ligase to adjust mtor signalling to growth factor availability. This process is primed by ck2, which translocates to the cytoplasm to mediate mtorc1-specific phosphorylation of tel2/tti1. ere, we show that tel2 is constitutively phosphorylated on conserved serines 487 and 491 by casein kinase 2 (ck2)" SIGNOR-200202 MAPK1 protein P28482 UNIPROT FGFR1 protein P11362 UNIPROT down-regulates phosphorylation Ser777 SMPLDQYsPSFPDTR 9606 23405013 t lperfetto "Erk-mediated phosphorylation of fibroblast growth factor receptor 1 on ser777 inhibits signaling" SIGNOR-200880 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 AMOT protein Q4VCS5 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates relocalization 9606 23431053 t "AMOT proteins, a family of proteins including AMOT, AMOTL1, and AMOTL2, interact extensively with multiple TJ components and are important for maintaining TJ integrity and epithelial cell polarity." gcesareni "Yap/taz and angiomotin (amot) family proteins were shown to interact, resulting in yap/taz localization to tight junctions and inhibition through phosphorylation-dependent and -independent mechanisms." SIGNOR-201132 AURKA protein O14965 UNIPROT FAF1 protein Q9UNN5 UNIPROT down-regulates phosphorylation Ser291 DVHMVSDsDGDDFED 9606 18790738 t llicata "This study reports that aurora-a (aur-a) phosphorylates fas-associated factor-1 (faf1) at ser-289 and ser-29 our findings support the negative feedback regulation of aur-a via phosphorylation of the death-promoting protein, faf1" SIGNOR-180891 F-actin_assembly phenotype SIGNOR-PH18 SIGNOR LATS1 protein O95835 UNIPROT down-regulates 9606 23450633 f gcesareni "Ga12/13 recruitment of rho-gefs causes rhoa activation and f-actin assembly, which promotes lats1/lat2 inactivation by an unknown, but myosin-independent mechanism." SIGNOR-201522 HLF protein Q16534 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 23415677 f miannu "Ectopic hlf expression inhibits apoptosis in murine and human cells, suggesting that hlf is regulating a conserved transcriptional program that inhibits cell death." SIGNOR-201034 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 CSNK2A1 protein P68400 UNIPROT EXOSC9 protein Q06265 UNIPROT up-regulates phosphorylation Ser394 APIILSDsEEEEMII 9606 19217413 t lperfetto "Indeed recombinant pmscl1 undergoes ck2-mediated phosphorylation in vitro at various serine residues, including serines 409 and 411, which reside within the phosphosim region. the exchange of hydrophobic core residues or serines 409 and 411 to alanine attenuates binding of sumo to the phosphosim-containing fragment of pmscl1 in a yeast two-hybrid assay" SIGNOR-184035 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 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 AKT proteinfamily SIGNOR-PF24 SIGNOR MTOR protein P42345 UNIPROT "down-regulates activity" 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-244311 CAMK2A protein Q9UQM7 UNIPROT CACNA1B protein Q00975 UNIPROT down-regulates phosphorylation Ser2120 ERRQPSSsSSEKQRF 9606 BTO:0000938 16982421 t gcesareni "Here, we report a direct modulation of ca(v)2.2 channel inactivation properties by 14-3-3, a family of signaling proteins involved in a wide range of biological processes.Wild-type gst fusion proteins containing the putative 14-3-3-binding motif (aa 2076__?2140) werein vitro phosphorylated at s2126 by either camkii or pka, as detected by thesequence- and phosphorylation-specific antibody, anti-ps2126 (middle panel). Phosphorylation of s2126 significantly increases its binding to recombinant 14-3-3?" SIGNOR-149684 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 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 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser1080 IFYYFSNsPSKRLRE 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-104671 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 CDC25C protein P30307 UNIPROT CDK1 protein P06493 UNIPROT up-regulates dephosphorylation Thr14 IEKIGEGtYGVVYKG 9606 19574738 t gcesareni "Cdk1/cdc2 activation involves tyr15/thr14 dephosphorylation by cdc25c" SIGNOR-186617 CDK6 protein Q00534 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser672 TLYDRYSsPPASTTR 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. all three residues selectively targeted by cdk4(6), t401 (n-terminus), s672 (spacer region) and s1035 (c-terminus)" SIGNOR-104715 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 FOXL2 protein P58012 UNIPROT SIRT1 protein Q96EB6 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19010791 f miannu "Foxl2 can directly activate the transcription of sirt1" SIGNOR-182300 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-244326 CD40 protein P25942 UNIPROT TRAF3 protein Q13114 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-250560 GNB2 protein P62879 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates 9606 23074268 f gcesareni "Furthermore, this work suggested that the gbetagamma subunits released upon gi activation activated phospholipase c-gamma (plc-gamma) to produce inositol 3 phosphate (ip3) which would subsequently increase intracellular ca2+ abundance." SIGNOR-199132 AKT proteinfamily SIGNOR-PF24 SIGNOR STK3 protein Q13188 UNIPROT down-regulates phosphorylation Thr117 IIRLRNKtLIEDEIA 9606 20086174 t lperfetto "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-244345 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 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser5 sESFTMAS 9606 19647517 t lperfetto "Phosphorylation of mcm2 by cdc7 promotes pre-replication complex assembly during cell-cycle re-entry" SIGNOR-187396 FGFR2 protein P21802 UNIPROT PTEN protein P60484 UNIPROT unknown phosphorylation Tyr240 RREDKFMyFEFPQPL 9606 BTO:0000527 22891331 t llicata "Fgfrs phosphorylate pten at tyrosine 240" SIGNOR-191793 ATXN2L protein Q8WWM7 UNIPROT DDX6 protein P26196 UNIPROT unknown binding 9606 23209657 t miannu "Ataxin-2-like associates with known interaction partners of ataxin-2, the rna helicase ddx6" SIGNOR-199948 BRSK1 protein Q8TDC3 UNIPROT TUBG1 protein P23258 UNIPROT up-regulates phosphorylation Ser131 READGSDsLEGFVLC 9606 19648910 t "The effect has been demonstrated using Q8TDC3-2" llicata "Sadb kinases associate and phosphorylate gamma-tubulin on ser 131 s131d gamma-tubulin expression amplifies centrosome duplication" SIGNOR-187405 CAMK2G protein Q13555 UNIPROT EGFR protein P00533 UNIPROT "down-regulates activity" phosphorylation Ser1070 DSFLQRYsSDPTGAL BTO:0000017 1309762 t llicata "The mechanism of desensitization of kinase activity can be accounted for, in part, by the EGF-stimulated phosphorylation of the receptor at Ser1046/7, a substrate for the multifunctional calmodulin-dependent protein kinase II in vitro. Mutation of Ser1046/7 by replacement with Ala residues blocks desensitization of the EGF receptor protein-tyrosine kinase activity. " SIGNOR-250694 UPR stimulus SIGNOR-ST6 SIGNOR HERPUD1 protein Q15011 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10922362 f miannu "We demonstrate a new target gene for upr-induced transcription, herp." SIGNOR-80156 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 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 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 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 CDK2 protein P24941 UNIPROT CDX2 protein Q99626 UNIPROT down-regulates phosphorylation Ser283 RSVPEPLsPVSSLQA 9606 16027724 t llicata "Using site-specific mutagenesis, we identified serine 281 as a new key residue for cdx2 phosphorylation. a nonphosphorylated mutant cdx2 lacking the 4s motif (4s>a) exhibited reduced polyubiquitination upon proteasome inhibition and increased stability compared to wild-type cdx2." SIGNOR-138825 CDC42BPA protein Q5VT25 UNIPROT LIMK1 protein P53667 UNIPROT "up-regulates activity" phosphorylation Thr508 PDRKKRYtVVGNPYW BTO:0000567 11340065 t llicata "Activation of LIM kinases by myotonic dystrophy kinase-related Cdc42-binding kinase alpha. \ In vitro, MRCKalpha phosphorylated the protein kinase domain of LIM kinases, and the site in LIMK2 phosphorylated by MRCKalpha proved to be threonine 505 within the activation segment." SIGNOR-250721 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 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 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 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CABLES1 protein Q8TDN4 UNIPROT unknown phosphorylation Ser273 PGQGGSTsAFEQLQR -1 11733001 t llicata "Here, we report that Ser274 of p70ik3-1 is phosphorylated by cdk2 or cdk3 bound to cyclin A and to cyclin E in vitro. We also found that in COS7 cells in which cyclin E and cdk3 were ectopically overexpressed, the phosphorylation level of Ser274 in coexpressed p70ik3-1 is upregulated. We therefore conclude that p70ik3-1 is a substrate for cdk3-mediated phosphorylation." SIGNOR-250756 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR TP53 protein P04637 UNIPROT unknown phosphorylation Ser392 FKTEGPDsD -1 10884347 t llicata "Our previous data has shown that cyclin A-cdk2 is the major enzyme responsible for modifying p53 at Ser315 in vivo after irradiation damage and in this report we dissect the mechanism of cyclinA-cdk2 binding to and phosphorylation of p53." SIGNOR-250751 ATM protein Q13315 UNIPROT ATM protein Q13315 UNIPROT "up-regulates activity" phosphorylation Ser367 DTRSLEIsQSYTTTQ 9606 21149446 t gcesareni "In human cells, the activation process involves autophosphorylation on three sites (ser367, ser1893, and ser1981) and acetylation on lys3016. We now describe the identification of a new atm phosphorylation site, thr(p)1885 and an additional autophosphorylation site, ser(p)2996, that is highly dna damage-inducible." SIGNOR-170477 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 SMAD9 protein O15198 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-195567 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 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 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 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 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 ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates phosphorylation Ser1219 DDTESLHsQGEEEFD 9606 22621922 t gcesareni "Here we report phosphorylation of 53bp1 at several novel residues, using mass spectrometry and phospho-specific antibodies, and show that ionising radiation-stimulated phosphorylation of these residues requires atm." SIGNOR-197611 CSNK1D protein P48730 UNIPROT DVL2 protein O14641 UNIPROT up-regulates phosphorylation Ser143 FHPNVSSsHENLEPE 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-197547 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 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 FLI1 protein Q01543 UNIPROT COL1A2 protein P08123 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 24058639 f miannu "Fli1 functions as a potent transcriptional repressor of the col1a2 gene" SIGNOR-202685 CSNK1G1 protein Q9HCP0 UNIPROT FOXO1 protein Q12778 UNIPROT "down-regulates activity" phosphorylation Ser322 PRTSSNAsTISGRLS -1 11980723 t llicata "Phosphorylation of Ser319 forms a consensus sequence for phosphorylation by CK1, allowing it to phosphorylate Ser322, which in turn primes the CK1-catalysed phosphorylation of Ser325 | Multisite phosphorylation of the region containing Ser319, Ser322, Ser325 and Ser329 provides a signal for the nuclear exclusion of FKHR" SIGNOR-250822 DYRK1A protein Q13627 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser519 SGYSSPGsPGTPGSR 9606 21215781 t "The effect has been demonstrated using P10636-8" lperfetto "Dyrk1a phosphorylates tau at least at s202, t212 and s404, but t212 phosphorylation is known to initiate tau hyperphosphorylation by gsk3b (ryoo et al., 2007;woods et al., 2001) and has been demonstrated to have a role in alternative splicing of taumrna" SIGNOR-171030 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 CYLD protein Q9NQC7 UNIPROT CCND1 protein P24385 UNIPROT up-regulates 9606 BTO:0001286 16713561 f gcesareni "Cyld was also recently shown to deubiquitylate the p50 and p52 co-activator bcl-3, leading to both cyclin d1 expression and proliferation in keratinocytes" SIGNOR-146777 ITCH protein Q96J02 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates ubiquitination 9606 BTO:0001253 10940313 t gcesareni "Itch binds to the n-terminal portion of the notch intracellular domain via its ww domains and promotes ubiquitination of notch through its hect ubiquitin ligase domain." SIGNOR-80702 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 BMX protein P51813 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr577 YMEDSTYyKASKGKL 9606 23716717 t llicata "Bmx phosphorylated focal adhesion kinase (fak) at tyr577 subsequent to its src-mediated phosphorylation at tyr576. Loss of bmx by rna interference or by genetic deletion in mouse embryonic fibroblasts (mefs) markedly impaired fak activity." SIGNOR-202139 CDK2 protein P24941 UNIPROT ATRIP protein Q8WXE1 UNIPROT up-regulates phosphorylation Ser224 APSVSHVsPRKNPSV 9606 17638878 t lperfetto "Atrip is a cdk2 substrate, and cdk2-dependent phosphorylation of s224 regulates the ability of atr-atrip to promote cell cycle arrest in response to dna damage./ One possibility is s224 phosphorylation creates a binding site for another protein involved in the g2-m checkpoint response" SIGNOR-156928 CSNK2A1 protein P68400 UNIPROT GAP43 protein P17677 UNIPROT unknown phosphorylation Ser202 PPTETGEsSQAEENI -1 1828073 t llicata "Two serines located in the C-terminal end of neuromodulin, Ser-192 and Ser-193, were identified as the major casein kinase II phosphorylation sites." SIGNOR-250866 lapatinib chemical CHEBI:49603 ChEBI KIT protein P10721 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001949 21443688 t Luana "YN968D1 potently suppressed the kinase activities of VEGFR-2, c-kit and c-src, and inhibited cellular phosphorylation of VEGFR-2, c-kit and PDGFRβ." SIGNOR-257901 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 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 CDK1 protein P06493 UNIPROT USP16 protein Q9Y5T5 UNIPROT up-regulates phosphorylation Ser552 DLEVLTSsPTRNLNG 9606 24013421 t llicata "Here, we report that cyclin-dependent kinase 1 (cdk1) phosphorylates the histone h2a deubiquitinase ubp-m at serine 552 (s552p), and, importantly, this phosphorylation is required for cell cycle progression." SIGNOR-202678 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 CREBBP protein Q92793 UNIPROT CBP/p300 complex SIGNOR-C6 SIGNOR "form complex" binding 9606 11559745 t lperfetto "P300/cbp proteins: hats for transcriptional bridges and scaffolds" SIGNOR-110559 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 DLL4 protein Q9NR61 UNIPROT NRP1 protein O14786 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 18339870 f gcesareni "Dll4 down-regulates vascular endothelial growth factor (vegf)_ receptor_ 2 and nrp1 expression and inhibits vegf function" SIGNOR-178029 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 EXT1 protein Q16394 UNIPROT EXT1/EXT2 complex SIGNOR-C51 SIGNOR "form complex" binding 9606 11518722 t miannu "Biochemical analysis shows that ext1 and ext2 are type ii transmembrane glycoproteins and form a golgi-localized hetero-oligomeric complex that catalyzes the polymerization of hs" SIGNOR-109938 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 FOXO1 protein Q12778 UNIPROT GK protein P32189 UNIPROT "down-regulates quantity by repression" "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 foxo1 localizes to the nucleus, where it represses hnf-4-dependent activity of the gk promoter as a corepressor." SIGNOR-181268 HDAC3 protein O15379 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates 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-199961 HDAC3 protein O15379 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates binding 9606 SIGNOR-C12 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-199964 CCND1 protein P24385 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR "form complex" 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-32298 CSNK1D protein P48730 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation Ser166 SSRRRAIsETEENSD 9606 20708156 t gcesareni "Phosphorylation by casein kinase i promotes the turnover of the mdm2 oncoprotein via the scf(beta-trcp) ubiquitin ligase." SIGNOR-167505 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 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 CPSF1 protein Q10570 UNIPROT FIP1L1/CPSF1 complex SIGNOR-C53 SIGNOR "form complex" binding 9606 14749727 t miannu "Recombinant hfip1 is sufficient to stimulate the in vitro polyadenylation activity of pap in a u-rich element-dependent manner. hfip1, cpsf160 and pap form a ternary complex in vitro, suggesting that hfip1 and cpsf160 act together in poly(a) site recognition and in cooperative recruitment of pap to the rna." SIGNOR-121646 RFWD2 protein Q8NHY2 UNIPROT "DCX DET1-COP1" complex SIGNOR-C24 SIGNOR "form complex" binding 9606 17452440 t lperfetto "Mammalian det1 regulates cul4a activity and forms stable complexes with e2 ubiquitin-conjugating enzymes" SIGNOR-154514 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1931 SPTSPTYsPTSPKGS 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-203600 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 CSNK2A1 protein P68400 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT "up-regulates activity" phosphorylation Ser59 SETNQNSsSDSEAER -1 11711551 t llicata "We show here that Tcf-4 can be phosphorylated in vitro by protein kinase CK2 stoichiometrically in amino acids Ser-58-Ser-59-Ser-60. Phosphorylation of these residues does not modify the interaction of Tcf-4 with beta-catenin but reduces its association to plakoglobin. | Experiments performed using a Tcf-4 mutant with decreased interaction to plakoglobin demonstrated that binding to this protein negatively affected the transcriptional activity of Tcf-4." SIGNOR-250963 BTK protein Q06187 UNIPROT PLCG2 protein P16885 UNIPROT "up-regulates activity" phosphorylation Tyr1217 LNNQLFLyDTHQNLR 9606 BTO:0000776 11507089 t lperfetto "These findings indicate that the phosphorylations of the tyrosine residues 753, 759, 1197, and 1217, which have been identified as btk-dependent phosphorylation sites in vitro, coordinately contribute to bcr-induced activation of plcgamma2." SIGNOR-109750 BTK protein Q06187 UNIPROT PLCG2 protein P16885 UNIPROT "up-regulates activity" phosphorylation Tyr753 ERDINSLyDVSRMYV 9606 BTO:0000776 11507089 t lperfetto "These findings indicate that the phosphorylations of the tyrosine residues 753, 759, 1197, and 1217, which have been identified as btk-dependent phosphorylation sites in vitro, coordinately contribute to bcr-induced activation of plcgamma2." SIGNOR-109754 MDC1 protein Q14676 UNIPROT RNF8 protein O76064 UNIPROT up-regulates relocalization 9606 18678647 t gcesareni "Rnf8 relocalizes to dna damage sites via a phospho-dependent interaction with mdc1" SIGNOR-179820 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 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 CSNK2A1 protein P68400 UNIPROT IGF2R protein P11717 UNIPROT unknown phosphorylation Ser2409 LHGDDQDsEDEVLTI 9606 8318012 t lperfetto "The two sites phosphorylated by ck ii in vivo and in vitro are ser82 and ser157." SIGNOR-37831 LRRK2 protein Q5S007 UNIPROT SNAPIN protein O95295 UNIPROT down-regulates phosphorylation Thr117 NHSVAKEtARRRAML 9606 BTO:0000938 BTO:0000142 23949442 t lperfetto "Lrrk2 phosphorylates snapin and inhibits interaction of snapin with snap-25. these data suggest that lrrk2 may regulate neurotransmitter release via control of snapin function by inhibitory phosphorylation. hreonine 117 of snapin is one of the sites phosphorylated by lrrk2" SIGNOR-202436 MAP3K11 protein Q16584 UNIPROT PIN1 protein Q13526 UNIPROT up-regulates phosphorylation Ser138 QKPFEDAsFALRTGE 9606 25519816 t llicata "Here we demonstrate that mixed-lineage kinase 3 (mlk3), a map3k family member, phosphorylates pin1 on a ser138 site to increase its catalytic activity and nuclear translocation." SIGNOR-205586 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 ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT unknown phosphorylation Ser29 IEDSQPEsQVLEDDS 9606 12697768 t llicata "To examine whether the respective sq sites become phosphorylated in vivo, we raised polyclonal antibodies against phosphorylated ser-6 (anti-s6p), phosphorylated ser-25 and ser-29 (anti-s25p/29p), and phosphorylated ser-784 (anti-s784p). All affinity-purified antisera recognized 53bp1" SIGNOR-100645 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 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 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 NLK protein Q9UBE8 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates phosphorylation 9606 20118921 t gcesareni "Nlk-phosphorylated notch1icd is impaired in its ability to form a transcriptionally_ active_ ternary_ complex." SIGNOR-163697 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 CDK2 protein P24941 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-232134 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 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 CHUK protein O15111 UNIPROT CREBBP protein Q92793 UNIPROT up-regulates phosphorylation Ser1382 MKSRFVDsGEMSESF 9606 BTO:0000551 17434128 t lperfetto "Phosphorylation of cbp by ikkalpha promotes cell growth by switching the binding preference of cbp from p53 to nf-kappabhere, we show that ikkalpha phosphorylates cbp at serine 1382 and serine 1386 and consequently increases cbp's hat and transcriptional activities" SIGNOR-154329 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 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 CAMK2A protein Q9UQM7 UNIPROT RIMS1 protein Q86UR5 UNIPROT up-regulates phosphorylation Ser242 PSAPPDRsKGAEPSQ 9606 BTO:0000938 BTO:0000142 12871946 t gcesareni "Two serine residues in rim1 (ser-241 and ser-287) and one serine residue in rim2 (ser-335) were required for 14-3-3 binding. Incubation with ca2+/calmodulin-dependent protein kinase ii greatly stimulated the interaction of recombinant n-terminal rim but not the s241/287a mutant with 14-3-3," SIGNOR-103886 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 EGFR protein P00533 UNIPROT CALM1 protein P62158 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 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 CSNK2A1 protein P68400 UNIPROT ACACA protein Q13085 UNIPROT unknown phosphorylation Ser29 GSVSEDNsEDEISNL -1 2900140 t llicata "These results show that casein kinase-2 phosphorylates site 6 exclusively" SIGNOR-250823 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 CSNK2A1 protein P68400 UNIPROT FKBP4 protein Q02790 UNIPROT "down-regulates activity" phosphorylation Thr143 EFKGEDLtEEEDGGI -1 9405642 t llicata "Thr-143 in the hinge I region was identified as the major phosphorylation site for CK2. | Most importantly, CK2-phosphorylated FKBP52 did not bind to HSP90" SIGNOR-250865 CSNK2A1 protein P68400 UNIPROT MAX protein P61244 UNIPROT down-regulates phosphorylation Ser11 NDDIEVEsDEEQPRF 9606 8018564 t gcesareni "Max activity is affected by phosphorylation at two nh2-terminal sites, ser2 and ser11." SIGNOR-35768 CYCS protein P99999 UNIPROT APAF1 protein O14727 UNIPROT "up-regulates activity" binding 9606 15907471 t lperfetto "Cytochrome c (Cyt c) is then released from the intermembrane space of the mitochondrion into the cytosol, where it binds to apoptotic protease-activating factor 1 (Apaf-1) in the presence of ATP/dATP to form the apoptosome." SIGNOR-137295 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 CDK1 protein P06493 UNIPROT PPP1CA protein P62136 UNIPROT down-regulates phosphorylation Thr320 NPGGRPItPPRNSAK 9606 BTO:0000938 BTO:0000142 17202132 t gcesareni "In this study, we observed that phosphorylation of protein phosphatase 1 (pp1) on thr(320) is reduced in brain extracts from egr-1(-/-) mice, indicating that a kinase downstream of egr-1 phosphorylates pp1. 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 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 AKT3 protein Q9Y243 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-61565 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 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 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 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 AURKB protein Q96GD4 UNIPROT MYBBP1A protein Q9BQG0 UNIPROT unknown phosphorylation Ser1303 ARKKARLsLVIRSPS 9606 20177074 t lperfetto "We identified mybbp1a as a novel aurora b substrate and serine 1303 as the major phosphorylation site" SIGNOR-163903 CSNK2A1 protein P68400 UNIPROT MAPK9 protein P45984 UNIPROT unknown phosphorylation Ser407 STEQTLAsDTDSSLD 9606 11062067 t lperfetto "The phosphorylation of thr-404 and ser-407 is not increased in response to other agonists that activate mkk7 and sapk1/jnk, suggesting that phosphorylation of these residues is catalysed by another protein kinase, such as ck2, which also phosphorylates thr-404 and ser-407 in vitro." SIGNOR-83711 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 IKBKB protein O14920 UNIPROT NFKBIB protein Q15653 UNIPROT down-regulates phosphorylation 9606 9346241 t gcesareni "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-52932 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR CEBPA protein P49715 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000011 12270934 f lperfetto "We further show that activation of mek1 significantly enhances the transactivation of the c/ebpalpha minimal promoter during the early phase of the differentiation process." SIGNOR-244773 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR 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-244776 PAK1 protein Q13153 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 10913145 t gcesareni "We find that, in vitro, pak1 phosphorylates op18/stathmin specifically at serine 16 and inactivates its catastrophe promoting activity in biochemical and time lapse microscopy microtubule assembly assays." SIGNOR-79955 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NPM1 protein P06748 UNIPROT "down-regulates activity" phosphorylation Thr237 KQEKTPKtPKGPSSV 9606 12058066 t lperfetto "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-216749 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 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 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 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 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 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PPARG protein P37231 UNIPROT "up-regulates activity" phosphorylation Ser112 AIKVEPAsPPYYSEK 9606 8943212 t fspada "The GST fusion protein containing full-length PPAR_2 was phosphorylated by purified P42MAP kinase in vitro. In contrast, protein containing the 300-residue PPAR_ ligand binding domain (and lacking Ser112) was a poor substrate for MAP kinase." SIGNOR-232236 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 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 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 LRRK2 protein Q5S007 UNIPROT LRRK2 protein Q5S007 UNIPROT unknown phosphorylation Ser1403 AGREEFYsTHPHFMT 9606 BTO:0000938 19824698 t lperfetto "We identified ser1403, thr1404, thr1410, thr1491 located within the roc domain, as well as thr1967 and thr1969 in the kinase domain, as the autophosphorylation sites." SIGNOR-188429 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 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 CSNK2B protein P67870 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" phosphorylation Thr112 EGMQIPStQFDAAHP 9606 BTO:0000007 12432063 t llicata "We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin" SIGNOR-251067 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 CSNK2B protein P67870 UNIPROT MME protein P08473 UNIPROT unknown phosphorylation Ser6 sQMDITDI 9606 BTO:0003288 8943850 t llicata "Taken together, these data indicate that CD10/NEP is itself phosphorylated by CKII and that CD10/NEP co-associates with additional tyrosine phosphoproteins including lyn." SIGNOR-251078 CSNK2B protein P67870 UNIPROT RNF7 protein Q9UBF6 UNIPROT "up-regulates activity" phosphorylation Thr10 DVEDGEEtCALASHS 9606 BTO:0000567 12748192 t llicata "In the present study, we show the evidence that CKBBP1 is phosphorylated on threonine residue at position 10 by CKII in vitro and in vivo. Most importantly, disruption of this phosphorylation in CKBBP1 results in accumulation of IκBα and p27Kip1 in HeLa cells and inhibits cell proliferation that appears to be linked to defects in G1/S transition." SIGNOR-251081 CSNK2A1 protein P68400 UNIPROT PML protein P29590 UNIPROT down-regulates phosphorylation Ser518 PSTSKAVsPPHLDGP 9606 BTO:0000551 16873060 t gcesareni "Here we show that ck2 regulates pml protein levels by promoting its ubiquitin-mediated degradation dependent on direct phosphorylation at ser517." SIGNOR-148306 CSNK2A1 protein P68400 UNIPROT PML protein P29590 UNIPROT down-regulates phosphorylation Ser565 VISSSEDsDAENSSS 9606 BTO:0000551 16873060 t llicata "Here we show that ck2 regulates pml protein levels by promoting its ubiquitin-mediated degradation dependent on direct phosphorylation at ser517." SIGNOR-148310 DYRK1A protein Q13627 UNIPROT CCNL2 protein Q96S94 UNIPROT unknown phosphorylation Ser369 AKKAKADsPVNGLPK 9534 BTO:0000298 14623875 t llicata "DYRK1A interacted with cyclin L2 in pull-down assays, and overexpression of DYRK1A stimulated phosphorylation of cyclin L2 in COS-7 cells. | Three phosphoserines were identified in the slower migrating bands (Fig. 9; Ser-330, Ser-338, and Ser-369). All of these serine residues are located N-terminal of proline residues, consistent with our previous classification of DYRK1A as a “proline-directed” kinase." SIGNOR-251089 PTPN12 protein Q05209 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 10734133 t gcesareni "Autophosphorylated on tyrosine residues in response to insulin. Dephosphorylated by ptpreand ptpn1 at tyr-999, tyr-1185, tyr-1189 and tyr-1190." SIGNOR-75902 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 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 EGFR protein P00533 UNIPROT CTNND1 protein O60716 UNIPROT unknown phosphorylation Tyr228 YPGGSDNyGSLSRVT 9606 BTO:0000017 14996911 t llicata "In A431 cells, epidermal growth factor induced striking p120 phosphorylation at Y228. Y228-phosphorylated p120 localized to adherens junctions and lamellipodia, and was significantly enhanced in cells around the colony periphery." SIGNOR-251092 DNER protein Q8NFT8 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 BTO:0000938 15965470 t gcesareni "Dner binds to notch1 at cell-cell contacts and activates notch signaling in vitro." SIGNOR-138346 DYRK1A protein Q13627 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser721 PVVSGDTsPRHLSNV 9606 21215781 t "The effect has been demonstrated using P10636-8" lperfetto "Dyrk1a phosphorylates tau at least at s202, t212 and s404, but t212 phosphorylation is known to initiate tau hyperphosphorylation by gsk3b (ryoo et al., 2007;woods et al., 2001) and has been demonstrated to have a role in alternative splicing of taumrna" SIGNOR-171034 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 FGFR2 protein P21802 UNIPROT GRB2 protein P62993 UNIPROT up-regulates phosphorylation 9606 22726438 t gcesareni "Inhibition of basal fgf receptor signaling by dimeric grb2." SIGNOR-197980 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 BTRC protein Q9Y297 UNIPROT EZH2 protein Q15910 UNIPROT down-regulates ubiquitination 9606 BTO:0000785 24469040 t lperfetto "_-trcp ubiquitinates ezh2 and jak2-mediated phosphorylation on y641 directs _-trcp-mediated ezh2 degradation." SIGNOR-204481 CDK3 protein Q00526 UNIPROT CABLES1 protein Q8TDN4 UNIPROT unknown phosphorylation Ser313 RCRTLSGsPRPKNFK 9606 11733001 t lperfetto "Here, we report that ser274 of p70ik3-1 is phosphorylated by cdk2 or cdk3 bound to cyclin a and to cyclin e in vitro. Currently, however, the question of how ik3-1 function is modified by its cdk3-mediated phosphorylation of ser274 remains to be adressed." SIGNOR-112418 CDK9 protein P50750 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser315 LPNNTSSsPQPKKKP 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-201931 CSNK2A1 protein P68400 UNIPROT XRCC1 protein P18887 UNIPROT up-regulates phosphorylation Ser485 QDNGAEDsGDTEDEL 9606 20471329 t lperfetto "Xrcc1 phosphorylation by ck2 is required for its stability and efficient dna repair" SIGNOR-165419 PRKCD protein Q05655 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates phosphorylation 9606 17183360 t gcesareni "By contrast, after uv stimulation, rela directly induces the expression of pkcdelta, which in turn activates jnk." SIGNOR-151428 CSNK2A1 protein P68400 UNIPROT KLF1 protein Q13351 UNIPROT "up-regulates activity" phosphorylation Thr23 ALGPFPDtQDDFLKW 10090 BTO:0004475 9722526 t 2 miannu "Regulation of erythroid Krƒppel-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-241361 CSNK2A1 protein P68400 UNIPROT SMC3 protein Q9UQE7 UNIPROT unknown phosphorylation Ser1067 GDVEGSQsQDEGEGS 9606 18442975 t gcesareni "Our data provide evidence that phosphorylation of a core cohesin subunit smc3 by atm plays an important role in dna damage response and suggest that a constitutive phosphorylation by ck2 may affect intra-s phase checkpoint by modulating smc3 phosphorylation by atm." SIGNOR-178483 FER protein P16591 UNIPROT CTTN protein Q14247 UNIPROT "up-regulates activity" phosphorylation Tyr421 RLPSSPVyEDAASFK 10029 BTO:0000246 10921917 t "FER kinase was implicated in the direct phosphorylation of cortactin. tyrosine residues (421, 466, and 482) were required for the hypertonicity-induced responses that were predominantly targeted upon FER overexpression." SIGNOR-251132 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 BAX protein Q07812 UNIPROT BAX protein Q07812 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 10629050 t "Following Bid-induced conformational change" lperfetto "Following bid-induced conformational change, bax oligomerizes and inserts tightly within the outer mitochondrial membrane. The integration of bax in the outer mitochondrial membrane is followed by cytochrome crelease" SIGNOR-73895 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 GRK2 protein P25098 UNIPROT FPR1 protein P21462 UNIPROT "down-regulates activity" phosphorylation Thr329 RALTEDStQTSDTAT -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-249664 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 FGR protein P09769 UNIPROT FGR protein P09769 UNIPROT "up-regulates activity" phosphorylation Tyr412 RLIKDDEyNPCQGSK -1 8612628 t "Autophosphorylation of c-Fgr under basal conditions involves Tyr-400 (homologous of c-Src Tyr-416) but not, to any appreciable extent, Tyr-511. Both Tyr-511 and Tyr-400, however, incorporate phosphate if autophosphorylation is performed in the presence of polycationic peptides, such as polylysine, histones H1 and protamines. Such a double phosphorylation induced by polylysine gives rise to an upshifted form of c-Fgr on SDS-PAGE and correlates with a stimulation of catalytic activity instead of a down-regulation" SIGNOR-251143 CDK1 protein P06493 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%." SIGNOR-87097 CSNK2A1 protein P68400 UNIPROT IKZF1 protein Q13422 UNIPROT down-regulates phosphorylation Ser101 GSHRDQGsSALSGVG 9606 BTO:0001271 21750978 t miannu "We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway / these results suggest that ck2 kinase directly phosphorylates amino acids 13, 23, 63, 101 and 294 in vivo" SIGNOR-174820 CSNK2A1 protein P68400 UNIPROT IKZF1 protein Q13422 UNIPROT down-regulates phosphorylation Ser13 GQDMSQVsGKESPPV 9606 BTO:0001271 21750978 t miannu "We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway / these results suggest that ck2 kinase directly phosphorylates amino acids 13, 23, 63, 101 and 294 in vivo" SIGNOR-174824 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 CSNK2A1 protein P68400 UNIPROT FOSB protein P53539 UNIPROT up-regulates phosphorylation Ser27 SAESQYLsSVDSFGS 9606 BTO:0000142 17241283 t lperfetto "Our findings indicate that ck2 activation increases deltafosb's transactivation potential, while ck2 inhibition decreases it. Further, we show that preventing ser27 phosphorylation by mutating the site to ala results in a significant decrease in deltafosb transactivation" SIGNOR-152403 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOX9 protein P48436 UNIPROT up-regulates "transcriptional regulation" 9606 20457810 f lperfetto "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-244750 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SREBF1 protein P36956 UNIPROT up-regulates phosphorylation Ser117 YPSMPAFsPGPGIKE 9606 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-244754 EGFR protein P00533 UNIPROT PIK3C2B protein O00750 UNIPROT up-regulates phosphorylation 9606 BTO:0000017 10805725 t gcesareni "The n-terminal region of pi3k-c2beta was found to selectively interact with the egf receptor in vitro, suggesting that it mediates the association of this pi3k with the receptor." SIGNOR-77195 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 CSNK2B protein P67870 UNIPROT IKZF1 protein Q13422 UNIPROT down-regulates phosphorylation Ser295 LSDTPYDsSASYEKE 9606 BTO:0001271 21750978 t miannu "We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway / these results suggest that ck2 kinase directly phosphorylates amino acids 13, 23, 63, 101 and 294 in vivo" SIGNOR-174848 CSNK2B protein P67870 UNIPROT IKZF1 protein Q13422 UNIPROT down-regulates phosphorylation Ser63 NVKVETQsDEENGRA 9606 BTO:0001271 21750978 t miannu "We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway / these results suggest that ck2 kinase directly phosphorylates amino acids 13, 23, 63, 101 and 294 in vivo" SIGNOR-174852 GRK2 protein P25098 UNIPROT SNCG protein O76070 UNIPROT "down-regulates activity" phosphorylation Ser124 EVAEEAQsGGD -1 10852916 t "GRK-mediated phosphorylation inhibits synuclein's interaction with both phospholipids and PLD2. Mutation of Ser124 dramatically inhibits γ-synuclein phosphorylation by GRK2" SIGNOR-251204 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 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 INSR protein P06213 UNIPROT CBL protein P22681 UNIPROT "up-regulates activity" phosphorylation Tyr700 EGEEDTEyMTPSSRP 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-251305 BAX protein Q07812 UNIPROT CYCS protein P99999 UNIPROT up-regulates relocalization 9606 10629050 t "Translocation from Mitochondria to Cytosol" amattioni "The integration of bax oligomers in the outer mitochondrial membrane is followed by cytochrome crelease" SIGNOR-73898 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 TOP2A protein P11388 UNIPROT unknown phosphorylation Ser1393 GSVPLSSsPPATHFP 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. phosphopeptide 1 was eliminated by replacement of ser1392" SIGNOR-30256 DAXX protein Q9UER7 UNIPROT AIRE protein O43918 UNIPROT "down-regulates activity" binding 9606 BTO:0000567 20185822 t 1 miannu "The interaction between AIRE and DAXX has been validated by in vivo coimmunoprecipitation analysis and colocalization study in mammalian cells. The interaction has been further confirmed by showing in transactivation assays that DAXX exerts a strong repressive role on the transcriptional activity of AIRE." SIGNOR-239287 ATM protein Q13315 UNIPROT RNF20 protein Q5VTR2 UNIPROT up-regulates phosphorylation 9606 21763684 t gcesareni "E3 ubiquitin ligase, a heterodimeric complex of the ringfinger rfn20/rfn40 is phosphorylated by atm." SIGNOR-174949 CDK2 protein P24941 UNIPROT SF3B1 protein O75533 UNIPROT up-regulates phosphorylation Thr244 GRAKGSEtPGATPGS 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 phosphopeptide). Three phosphorylation sites were identified as thr244, thr248, and thr313" SIGNOR-90434 AMER1 protein Q5JTC6 UNIPROT APC protein P25054 UNIPROT up-regulates relocalization 9606 23151663 t gcesareni "Apc membrane recruitment protein 1 (amer1;alsoknownas wtx)" SIGNOR-199375 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 MAP2K1 protein Q02750 UNIPROT MAP2K1 protein Q02750 UNIPROT "up-regulates activity" phosphorylation Ser304 LSSYGMDsRPPMAIF -1 8226933 t "MEK1 and MEK2 can also be activated by autophosphorylation. Tyrosine 304 may be a candidate for the autophosphorylation site in MEK1." SIGNOR-251415 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 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 ATM protein Q13315 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Ser498 QIVMAPSsQSQPSGS 9606 15916964 t lperfetto "Here, we demonstrate that the protein kinase atm phosphorylates atf2 on serines 490 and 498 following ionizing radiation (ir). dose- and time-dependent phosphorylation of atf2 by atm that results in its rapid colocalization with gamma-h2ax and mrn components into ir-induced foci (irif)" SIGNOR-137623 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 AURKB protein Q96GD4 UNIPROT KIF2C protein Q99661 UNIPROT down-regulates phosphorylation Ser192 VNSVRRKsCLVKEVE 9606 17567953 t lperfetto "Here, we show that the binding of mcak to chromosome arms is also regulated by aurora b and that aurora b-dependent chromosome arm and centromere localization is regulated by distinct two-site phosphoregulatory mechanisms. Mcak association with chromosome arms is promoted by phosphorylation of t95 on mcak, whereas phosphorylation of s196 on mcak promotes dissociation from the arms. Although targeting of mcak to centromeres requires phosphorylation of s110 on mcak, dephosphorylation of t95 on mcak increases the binding of mcak to centromeres." SIGNOR-155898 BIRC5 protein O15392 UNIPROT DIABLO protein Q9NR28 UNIPROT down-regulates binding 9606 17546047 t gcesareni "Mitochondrial survivin associated with smac/diablo, delaying its release." SIGNOR-155361 CAMK2A protein Q9UQM7 UNIPROT RCHY1 protein Q96PM5 UNIPROT down-regulates phosphorylation Ser155 CLEDIHTsRVVAHVL 9606 17568776 t lperfetto "Phosphorylation of pirh2 by calmodulin-dependent kinase ii impairs its ability to ubiquitinate p53" SIGNOR-156064 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 BORA protein Q6PGQ7 UNIPROT down-regulates phosphorylation 9606 18521620 t gcesareni "Our data additionally identify the cdk1 site s252 as critical for the recruitment of plk1 to hbora. collectively, our findings lead us to propose that hbora contributes to integrate the functions of three major mitotic kinases, cdk1, plk1, and aurora a." SIGNOR-178799 HIF1AN protein Q9NWT6 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates hydroxylation Asn1955 LEASADAnIQDNMGR 9606 18299578 t gcesareni "We show that fih-1 hydroxylates notch icd at two residues (n(1945) and n(2012)) that are critical for the function of notch icd as a transactivator within cells and during neurogenesis and myogenesis in vivo. Fih-1 negatively regulates notch activity and accelerates myogenic differentiation." SIGNOR-161057 MK-2461 chemical CID:44137946 PUBCHEM FLT3 protein P36888 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194378 AKT3 protein Q9Y243 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-201129 CSNK2A1 protein P68400 UNIPROT MDC1 protein Q14676 UNIPROT up-regulates phosphorylation Thr301 PPGEDSDtDVDDDSR 9606 18678890 t gcesareni "The mdc1-nbs1 interaction occurs through a specific region (residues 200-420) of mdc1, which contains multiple consensus casein kinase 2 (ck2) phosphorylation sites." SIGNOR-179883 CSNK2A1 protein P68400 UNIPROT XRCC1 protein P18887 UNIPROT up-regulates phosphorylation Thr488 GAEDSGDtEDELRRV 9606 20471329 t lperfetto "Xrcc1 phosphorylation by ck2 is required for its stability and efficient dna repair" SIGNOR-165427 ATM protein Q13315 UNIPROT DAXX protein Q9UER7 UNIPROT down-regulates phosphorylation Ser564 LEEESPVsQLFELEI 9606 23405218 t gcesareni "The main phosphorylation site of daxx is identified to be ser564, which is a direct target of atm. Phosphorylation of endogenous daxx at ser564 occurs rapidly during the dna damage response and precedes p53 activation. Blockage of this phosphorylation event prevents the separation of daxx from mdm2, stabilizes mdm2, and inhibits dna damage-induced p53 activation." SIGNOR-200889 CDK1 protein P06493 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates phosphorylation Ser5 sPPLRDVD 9606 BTO:0000222 SIGNOR-C17 14749395 t lperfetto "Myod is phosphorylated on ser5 and ser200 by cyclin b-cdc2, resulting in a decrease of its stability and down-regulation of both myod and p21." SIGNOR-121605 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser413 VRYIKENsPCVTPVS 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-104675 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser639 DEICIAGsPLTPRRV 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-104679 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 CAMK1 protein Q14012 UNIPROT NUMB protein P49757 UNIPROT down-regulates phosphorylation Ser276 EQLARQGsFRGFPAL 9606 17022975 t esanto "Based on experiments using numb mutants, both the initial phosphorylation of ser(264) and the subsequent phosphorylation of ser(283) are sufficient to abolish the binding of numb to ap-2." SIGNOR-149993 ATM protein Q13315 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-187591 CDK1 protein P06493 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates phosphorylation Thr269 GGKRSRLtPVSPESS 9606 BTO:0000551 SIGNOR-C17 20974803 t gcesareni "Here we show that cdk1 phosphorylates p62 in vitro and in vivo at t269 and s272, which is necessary for the maintenance of appropriate cyclin b1 levels and the levels of cdk1 activity necessary to allow cells to properly enter and exit mitosis." SIGNOR-169016 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 CDK5 protein Q00535 UNIPROT AR protein P10275 UNIPROT up-regulates phosphorylation Ser83 QQQQQETsPRQQQQQ 9606 BTO:0001130 21799006 t gcesareni "Cdk5 enables phosphorylation of ar at ser-81 site through direct biochemical interaction and, therefore, results in the stabilization of ar proteins" SIGNOR-175696 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 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 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 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 HCRT protein O43612 UNIPROT HCRTR2 protein O43614 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-55848 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 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 CSNK2A1 protein P68400 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser214 LVRSREVsVDEGRAC -1 9677319 t llicata "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." SIGNOR-250944 AKT1 protein P31749 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Thr198 PGLRRRQt 9606 12042314 t miannu "Identification of p27kip1phosphorylation sites revealed that akt phosphorylated p27kip1at ser10(fig.4). Therefore, akt might participate in nuclear export of p27kip1as well as p27kip1degradation. Moreover, akt might be one of the unidentified ser10kinases." SIGNOR-88294 ATR protein Q13535 UNIPROT RBBP8 protein Q99708 UNIPROT up-regulates phosphorylation Thr859 WEVGFPStQTCMERG 9606 23273981 t llicata "Characterization of this site using phospho-specific antibodies and mutational analysis reveals that it is phosphorylated by atr and is required for binding of ctip to chromatin and subsequent processive resection." SIGNOR-200245 CDK2 protein P24941 UNIPROT CDC6 protein Q99741 UNIPROT down-regulates 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 EGFR protein P00533 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates binding 9606 14967450 t lperfetto "The egf-r coimmunoprecipitated with p85 alpha" SIGNOR-121959 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 BAK1 protein Q16611 UNIPROT HTRA2 protein O43464 UNIPROT up-regulates relocalization 9606 14585074 t "Translocation from Mitochondria to Cytosol" amattioni "Bax and/or bak-mediated release of pro-apoptotic mediators including smac/diablo and omi" SIGNOR-118908 ATM protein Q13315 UNIPROT MDM4 protein O15151 UNIPROT down-regulates phosphorylation Ser342 SKLTHSLsTSDITAI 9606 16943424 t lperfetto "Recently we showed that atm- and hdm2-dependent ubiquitination and subsequent degradation of hdmx following dsb induction are mediated by phosphorylation of hdmx on s403, s367, and s342, with s403 being targeted directly by atm." SIGNOR-149292 "DNA damage" stimulus SIGNOR-ST1 SIGNOR ATM protein Q13315 UNIPROT up-regulates 9606 21034966 f lperfetto "the ATM-Chk2 and ATR-Chk1 pathways, which are activated by DNA double-strand breaks (DSBs) and single-stranded DNA respectively." SIGNOR-242612 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 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 BRCA1 protein P38398 UNIPROT Cell_cycle_block phenotype SIGNOR-PH10 SIGNOR up-regulates 15549093 f lperfetto "The BRCA1 protein also contributes to cell-cycle arrest and DNA repair by homologous recombination" SIGNOR-251499 AKT3 protein Q9Y243 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-245424 ATM protein Q13315 UNIPROT MDM4 protein O15151 UNIPROT down-regulates phosphorylation Ser403 DLAHSSEsQETISSM 9606 16943424 t lperfetto "Recently we showed that atm- and hdm2-dependent ubiquitination and subsequent degradation of hdmx following dsb induction are mediated by phosphorylation of hdmx on s403, s367, and s342, with s403 being targeted directly by atm." SIGNOR-149300 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 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 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-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 CHEK1 protein O14757 UNIPROT CDC7 protein O00311 UNIPROT up-regulates phosphorylation 9606 20068082 t gcesareni "Chk1 directly phosphorylates essential s-phase kinases cdc7." SIGNOR-163161 CSNK2A1 protein P68400 UNIPROT CDC34 protein P49427 UNIPROT "down-regulates activity" phosphorylation Thr233 DDEDDSGtEES 9606 BTO:0000567 11546811 t lperfetto "The ubiquitin-conjugating enzyme, cdc34, has been implicated in the ubiquitination of a number of vertebrate substrates, including p27(kip1), ikappabalpha, wee1, and myod. We show that mammalian cdc34 is a phosphoprotein that is phosphorylated in proliferating cells. Phosphorylation of cdc34 by the associated kinase maps predominantly to residues 203 and 222. Mutation of cdc34 at ck2-targeted residues, ser-203, ser-222, ser-231, thr-233, and ser-236, abolishes the phosphorylation of cdc34 observed in vivo and markedly shifts nuclearly localized cdc34 to the cytoplasm." SIGNOR-110407 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 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 DUSP6 protein Q16828 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates dephosphorylation 9606 12840032 t gcesareni "P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3)." SIGNOR-103149 CAMK2A protein Q9UQM7 UNIPROT HRH1 protein P35367 UNIPROT down-regulates phosphorylation Thr140 LRYLKYRtKTRASAT 9606 BTO:0000975 15107581 t "Translocation from Endosome to Lysosome" gcesareni "As we have shown previously, human h1r can be phosphorylated in vitro by several kinases includingpka, pkc, pkg, and camk ii in summary, these data suggest that thr140, thr142, ser396, ser398, and thr478 can be phosphorylated by the kinases described above (table 2)." SIGNOR-124348 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 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 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 ARPC2 protein O15144 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-251514 ARPC3 protein O15145 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-251516 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 ARPC5 protein O15511 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-251518 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 ATM protein Q13315 UNIPROT IKBKG protein Q9Y6K9 UNIPROT down-regulates phosphorylation Ser85 ELLHFQAsQREEKEF 9606 16497931 t lperfetto "Atm phosphorylates serine-85 of nemo to promote its ubiquitin-dependent nuclear export." SIGNOR-144813 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 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT up-regulates phosphorylation Tyr771 ADIESSNyMAPYDNY 9606 1314164 t llicata "Mutagenesis studies show that tyr740 and 751 are involved in the pdgf-stimulated binding of phosphatidylinositol (pi) 3 kinase, and tyr771 is required for efficient binding of gap, the gtpase activator of ras." SIGNOR-16892 ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT "up-regulates activity" phosphorylation Ser33 TQSQGSSsQSQGISS 9606 BTO:0000007 10973490 t lperfetto "Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to ir" SIGNOR-81399 ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT "up-regulates activity" phosphorylation Thr26 SQPHGSVtQSQGSSS 9606 BTO:0000007 12024051 t gcesareni "We show here that autophosphorylation of chk2 produced in a cell-free system requires trans phosphorylation by a wortmannin-sensitive kinase, probably atm or atr" SIGNOR-87850 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 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 4-(2-methyl-3-propan-2-yl-4-imidazolyl)-N-(4-methylsulfonylphenyl)-2-pyrimidinamine chemical CHEBI:91419 ChEBI CDK9 protein P50750 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190182 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-251526 ATM protein Q13315 UNIPROT ATM protein Q13315 UNIPROT unknown phosphorylation Ser440 SPLLMILsQLLPQQR -1 10608806 t llicata "Putative ATM in vitro targets include p95/nibrin, Mre11, Brca1, Rad17, PTS, WRN, and ATM (S440) itself." SIGNOR-250576 BIRC5 protein O15392 UNIPROT CASP3 protein P42574 UNIPROT down-regulates binding 9606 10587640 t gcesareni "Use of a dominant-negative survivin mutant or antisense survivin complementary dna disrupts a supramolecular assembly of survivin, caspase-3 and the cyclin-dependent-kinase inhibitor p21waf1/cip1 within centrosomes, and results in caspase-dependent cleavage of p21." SIGNOR-72882 SOX17 protein Q9H6I2 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-72006 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 MAP2K1 protein Q02750 UNIPROT "up-regulates activity" phosphorylation Ser248 SVQSDIWsMGLSLVE -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-39058 PTPRH protein Q9HD43 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 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-76080 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 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 AKT1 protein P31749 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates phosphorylation Ser166 SSRRRAIsETEENSD 9606 BTO:0000671 15169778 t gcesareni "Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylation." SIGNOR-124949 BMPR1A protein P36894 UNIPROT BMPR1B protein O00238 UNIPROT up-regulates binding 9606 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-75649 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 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 CHUK protein O15111 UNIPROT NFKB2 protein Q00653 UNIPROT "up-regulates activity" phosphorylation Ser866 TAEVKEDsAYGSQSV 10090 BTO:0000785 15084608 t lperfetto "Ikkalfa phosphorylates p100, leading to its proteasomal processing to p52." SIGNOR-124226 CDK1 protein P06493 UNIPROT BCL2 protein P10415 UNIPROT down-regulates 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 CSNK2A1 protein P68400 UNIPROT LEF1 protein Q9UJU2 UNIPROT up-regulates phosphorylation 9606 2861485 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-23958 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 AKT3 protein Q9Y243 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 aminoterminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity." SIGNOR-78697 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 FYN protein P06241 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-78702 HAND2 protein P61296 UNIPROT HAND2 protein P61296 UNIPROT "up-regulates activity" binding -1 11812799 t miannu "The basic helix-loop-helix factor, HAND2, functions as a transcriptional activator by binding to E-boxes as a heterodimer" SIGNOR-223476 AURKB protein Q96GD4 UNIPROT DES protein P17661 UNIPROT down-regulates phosphorylation Ser60 VYQVSRTsGGAGGLG -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. In the present study, we found aurora-b phosphorylates desmin at ser-11, thr-16, and ser-59, in vitro." SIGNOR-100111 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 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 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 ISL1 protein P61371 UNIPROT NLI/Lmx1.1/Isl1 complex SIGNOR-C103 SIGNOR "form complex" binding 9606 BTO:0000007 9452425 t miannu "Interactions between LIM transcription factors were also evaluated in vivo. Cotransfected FLAG-Lmx1.1 and HA-Isl1 were capable of interacting. the NLI-dependent interaction observed between Isl1 and Lmx1.1 is likely to represent a physiologically significant complex found in the endocrine cells of the pancreas." SIGNOR-220131 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 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 AKT3 protein Q9Y243 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-81122 BTG1 protein P62324 UNIPROT HOXB9 protein P17482 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 10617598 t miannu "The leukemia-associated protein Btg1 and the p53-regulated protein Btg2 interact with the homeoprotein Hoxb9 and enhance its transcriptional activation." SIGNOR-221019 CAMK2A protein Q9UQM7 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates phosphorylation Ser110 SFSEQTRsLDGRLQV 9606 SIGNOR-C8 11027280 t gcesareni "Smad2 is a target substrate for cam kinase ii in vitro at serine-110, -240, and -260. furthermore, cam kinase ii blocked nuclear accumulation of a smad2 and induced smad2-smad4 hetero-oligomerization independently of tgfbeta receptor activation, while preventing tgf-beta-dependent smad2-smad3 interactions." SIGNOR-82966 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 MAPK1 protein P28482 UNIPROT SOS1 protein Q07889 UNIPROT "down-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" SIGNOR-236242 CASP7 protein P55210 UNIPROT 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-83703 EIF2AK1 protein Q9BQI3 UNIPROT EIF2S1 protein P05198 UNIPROT down-regulates phosphorylation Ser52 MILLSELsRRRIRSI 9606 11041858 t lperfetto "The wild-type and ser-48 mutant proteins became extensively phosphorylated by eif-2 kinases . The ser-51 mutant showed little covalent modification by the endogenous enzymes. Phosphorylation of the serine 51 residue in the alpha-subunit of translational initiation factor 2 in eukaryotes (eif2 alpha) impairs protein synthesis presumably by sequestering eif2b, a rate-limiting pentameric guanine nucleotide exchange protein which catalyzes the exchange of gtp for gdp in the eif2-gdp binary complex" SIGNOR-83226 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 CSNK2A1 protein P68400 UNIPROT WASF2 protein Q9Y6W5 UNIPROT down-regulates phosphorylation Ser497 EFDEDDWsD 9606 19012317 t gcesareni "Here we identify five casein kinase 2 (ck2) phosphorylation sites within the vca domain of wave2, serines 482, 484, 488, 489, and 497. Phosphorylation of these sites is required for a high affinity interaction with the arp2/3 complex;we and show that their mutation to non-phosphorylatable alanine residues inhibits wave2 function in vivo." SIGNOR-182362 ATM protein Q13315 UNIPROT WRN protein Q14191 UNIPROT unknown phosphorylation Ser1292 MTIGMHLsQAVKAGC -1 10608806 t llicata "We determined a general phosphorylation consensus sequence for ATM and identified putative in vitro targets by using glutathione S-transferase peptides as substrates. Putative ATM in vitro targets include p95/nibrin, Mre11, Brca1, Rad17, PTS, WRN, and ATM (S440) itself." SIGNOR-250578 ATM protein Q13315 UNIPROT XPA protein P23025 UNIPROT unknown phosphorylation Ser173 VKKNPHHsQWGDMKL -1 16540648 t llicata "Kinase phosphorylation assays were done with synthesized short peptides (20-mer) with the sequences at Ser173 and Ser196 of XPA, respectively. Both peptides seemed to be good substrates for DNA-PK, ATR ( Fig. 2D), and ATM (data not shown)." SIGNOR-250579 MAP3K10 protein Q02779 UNIPROT NEUROD1 protein Q13562 UNIPROT "up-regulates activity" binding -1 12881483 t lperfetto "we identified two proteins that interact with ND, huntingtin-associated protein 1 (HAP1) and mixed-lineage kinase 2 (MLK2). Stimulation of NeuroD activity by huntingtin and huntingtin-associated proteins HAP1 and MLK2" SIGNOR-234599 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 PPP2CA protein P67775 UNIPROT EEF2 protein P13639 UNIPROT up-regulates dephosphorylation Thr59 GETRFTDtRKDEQER 9606 phosphorylation:Thr59 GETRFTDtRKDEQER 8386634 t gcesareni "Protein phosphatases-2a and -2c (pp-2a and pp-2c) can each efficiently dephosphorylate phosphorylated eef-2" SIGNOR-38566 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 MAPK3 protein P27361 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser324 RDLELPLsPSLLGGP 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-34653 MAPK3 protein P27361 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser389 LSPIAPRsPAKLSFQ 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-34661 MRGPRX2 protein Q96LB1 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-257434 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 ATXN7 protein O15265 UNIPROT CRX protein O43186 UNIPROT "down-regulates activity" binding 10090 11580893 t miannu "We found that ataxin-7 and CRX colocalize and coimmunoprecipitate. We observed that polyglutamine-expanded ataxin-7 can dramatically suppress CRX transactivation." SIGNOR-223226 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NPM1 protein P06748 UNIPROT "down-regulates activity" phosphorylation Thr199 VKKSIRDtPAKNAQK 9606 12058066 t lperfetto "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-216845 IRF1 protein P10914 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-222841 IRF8 protein Q02556 UNIPROT CYBB protein P04839 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001412 11483597 f 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-222710 ARAF protein P10398 UNIPROT MAP2K2 protein P36507 UNIPROT up-regulates phosphorylation 9606 21779497 t gcesareni "Active raf phosphorylates mek." SIGNOR-175142 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 IL22 protein Q9GZX6 UNIPROT IL10RB protein Q08334 UNIPROT up-regulates binding 9606 17208301 t gcesareni "See table 2" SIGNOR-151880 MAP3K3 protein Q99759 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates 9606 BTO:0000007 10347227 f gcesareni "However, the autocatalytic activities of both mkk6 and mkk7 were enhanced by their coexpression with either mekk3 or mekk2." SIGNOR-68020 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 PPP2CA protein P67775 UNIPROT ELF1 protein P32519 UNIPROT "down-regulates activity" dephosphorylation Thr231 CPKYIKWtQREKGIF 9606 18714041 t "Elf-1 enhances the expression of CD3zeta, whereas it suppresses the expression of FcRgamma gene and lupus T cells have decreased amounts of DNA-binding 98 kDa form of Elf-1. We show that the aberrantly increased PP2A in lupus T cells dephosphorylates Elf-1 at Thr-231. Dephosphorylation results in limited expression and binding of the 98 kDa Elf-1 form to the CD3zeta and FcRgamma promoters. Suppression of the expression of the PP2A leads to increased expression of CD3zeta and decreased expression of FcRgamma genes and correction of the early signaling response" SIGNOR-248634 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 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 SP3 protein Q02447 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-255197 SPRY4 protein Q9C004 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002058 20501643 f miannu "When Spry4 was stably transfected into H157 and H2122 NSCLC cell lines, decreased migration and invasion were observed. Matrix metalloproteinase-9 activity was decreased, and the expression of matrix metalloproteinase inhibitors TIMP1 and CD82 were increased. Stable expression of Spry4 led to reduced cell growth and reduced anchorage-independent growth in NSCLC cell lines, along with upregulation of tumor suppressors p53 and p21." SIGNOR-253040 AKT1 protein P31749 UNIPROT MAP3K8 protein P41279 UNIPROT "down-regulates activity" phosphorylation Ser413 LERKRLLsRKELELP 9606 BTO:0000661 12138205 t gcesareni "The regulation of NF-kappa B-dependent transcription by Cot requires Akt-dependent phosphorylation of serine 400 (S400)," SIGNOR-252560 IL15RA protein Q13261 UNIPROT IL2RB protein P14784 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103 17709786 t milica "The il-15 receptor comprises a heterotrimeric complex consisting of the common ?cytokine Receptor (?c), the il-2 ? Receptor subunit (il-2r?), And an il-15-specific ? Receptor (il-15r?)" SIGNOR-157418 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 PRKCI protein P41743 UNIPROT up-regulates phosphorylation Tyr334 RLFFVIEyVNGGDLM 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-111928 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 TOP2B protein Q02880 UNIPROT PBX3 protein P40426 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24463367 f lperfetto "While Top2a is essential in proliferating cells and has been linked to DNA replication and chromosome condensation/segregation, Top2b has been clearly indicated in regulating gene expression (e.g. Reln, Dab1, Catna2, Cdh13, Sst, Pbx3, and Epha7) during brain development" SIGNOR-242308 TOP2B protein Q02880 UNIPROT SST protein P61278 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24463367 f lperfetto "While Top2a is essential in proliferating cells and has been linked to DNA replication and chromosome condensation/segregation, Top2b has been clearly indicated in regulating gene expression (e.g. Reln, Dab1, Catna2, Cdh13, Sst, Pbx3, and Epha7) during brain development" SIGNOR-242305 TWIST2 protein Q8WVJ9 UNIPROT ICAM1 protein P05362 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002590 17487558 f miannu "Immunoblot analysis showed that HEY/si-TWIST cells exhibited decreased expression levels of CD29, CD44 and CD54 compared to those of HEY/si-scrambled cells" SIGNOR-255514 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA1A protein P35348 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-257450 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA1D protein P25100 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-257452 "A6/b1 integrin" complex SIGNOR-C164 SIGNOR SOX2 protein P48431 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001086 18757303 f lperfetto "Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1." SIGNOR-253279 "A6/b1 integrin" complex SIGNOR-C164 SIGNOR TERT protein O14746 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001086 18757303 f lperfetto "Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1." SIGNOR-253280 "A6/b1 integrin" complex SIGNOR-C164 SIGNOR UTF1 protein Q5T230 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001086 18757303 f lperfetto "Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1." SIGNOR-253281 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 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 "AEP complex" complex SIGNOR-C117 SIGNOR HOXA9 protein P31269 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0001271 20854876 f irozzo "Inhibition of EAP components pTEFb and Dot1l show that both contribute significantly to activation of Hoxa9 and Meis1 expression. EAP is dynamically associated with the Hoxa9 and Meis1 loci in hematopoietic cells and rapidly dissociates during induction of differentiation. In the presence of MLL fusion proteins, its dissociation is prevented." SIGNOR-255879 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 AKT proteinfamily SIGNOR-PF24 SIGNOR CHEK1 protein O14757 UNIPROT down-regulates phosphorylation Ser280 AKRPRVTsGGVSESP 9606 15107605 t lperfetto "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-244206 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-244214 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-251481 AKT proteinfamily SIGNOR-PF24 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR "up-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-252817 AKT proteinfamily SIGNOR-PF24 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR "up-regulates activity" 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-217586 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-72137 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 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 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 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 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 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 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 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 AKT3 protein Q9Y243 UNIPROT NOS3 protein P29474 UNIPROT "up-regulates activity" binding 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-251625 AMPK complex SIGNOR-C15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR "up-regulates activity" phosphorylation 9606 17900900 t lperfetto "The energy sensor amp-activated protein kinase (ampk) has been shown to directly phosphorylate foxo factors at six regulatory sites that are distinct from the akt." SIGNOR-252889 APH1B protein Q8WW43 UNIPROT NCSTN protein Q92542 UNIPROT up-regulates binding 9606 BTO:0000142 12297508 t gcesareni "By using co-immunoprecipitation and nickel affinity pull-down approaches, we now show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain.These data indicate that maph-1 is probably a functional component of the gamma-secretase complex" SIGNOR-93307 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 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 APOB protein P04114 UNIPROT LDL_assembly phenotype SIGNOR-PH63 SIGNOR up-regulates 9606 BTO:0000575 23721961 f miannu "Apolipoprotein B is a structural protein that is an integral component of chylomicrons, as well as very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and low density lipoprotein (LDL) particles." SIGNOR-252116 AR protein P10275 UNIPROT SEPT7 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 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK4 protein P11802 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189990 ARVCF protein O00192 UNIPROT ERBIN protein Q96RT1 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 11821434 t miannu "We characterized the interactions between the Erbin PDZ domain and both ARVCF and δ-catenin in vitro and in vivo. endogenous δ-catenin and Erbin co-localized in and co-immunoprecipitated from neurons. These results suggest that δ-catenin and ARVCF may function to mediate the association of Erbin with the junctional cadherin-catenin complex." SIGNOR-252119 AS-605240 chemical CID:5289247 PUBCHEM PIK3CG protein P48736 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189921 ASXL1 protein Q8IXJ9 UNIPROT NCOA1 protein Q15788 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 16606617 t irozzo "We also show that ASXL1 associates specifically with SRC-1 and cooperates synergistically in the transcriptional activation. Further data indicated that the transactivation domain (AD; amino acids 300–655) of ASXL1, newly defined in this study, interacts with the C-terminal AD2 (amino acids 1217–1441) of SRC-1, suggesting that one AD cooperates with the other AD in transcriptional activation by RAR." SIGNOR-255931 ASXL1 protein Q8IXJ9 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 10090 26470845 f lperfetto "Consistently, our results show that ASXL1 mutations are associated with lower expression levels of p15INK4B and a proliferative advantage of hematopoietic progenitors in primary bone marrow cells, and that depletion of ASXL1 in multiple cell lines results in resistance to growth inhibitory signals." SIGNOR-241614 AT9283 chemical CID:11696609 PUBCHEM AURKA protein O14965 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190011 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 ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1524 LQNRNYPsQEELIKV 9606 BTO:0000150 10550055 t lperfetto "The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. phosphorylation of brca1 by the checkpoint kinase atm may be critical for proper responses to dna double-strand breaks. Phosphorylation of brca1 on ser1423 and ser1524 by atm" SIGNOR-72068 ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1542 EEQQLEEsGPHDLTE 9606 BTO:0000150 10550055 t lperfetto "The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. phosphorylation of brca1 by the checkpoint kinase atm may be critical for proper responses to dna double-strand breaks. Phosphorylation of brca1 on ser1423 and ser1524 by atm" SIGNOR-72072 AURKB protein Q96GD4 UNIPROT DES protein P17661 UNIPROT down-regulates phosphorylation Thr17 RVSSYRRtFGGAPGF -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. In the present study, we found aurora-b phosphorylates desmin at ser-11, thr-16, and ser-59, in vitro." SIGNOR-100115 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 BCOR protein Q6W2J9 UNIPROT HDAC3 protein O15379 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 10898795 t miannu "BCoR can interact w Because HDACs appear to be involved in repression by an increasing number of transcriptional repressors, we tested whether BCoR can associate with HDACs. BCoR can interact with HDAC1, HDAC3, and HDAC-B/5 more strongly than with HDAC-A/4, HDAC-C, HDAC-D, and HDAC-E." SIGNOR-252237 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 BHLHE40 protein O14503 UNIPROT PER2 protein O15055 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000944 14672706 f lperfetto "Forced expression of Clock/Bmal increased endogenous Dec1 mRNA level, and overexpression of Dec1 resulted in suppression of Dec2, Per2, and Dbp expression" SIGNOR-253717 BHLHE41 protein Q9C0J9 UNIPROT BHLHE40 protein O14503 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000944 14672706 f lperfetto "We show here an autofeedback loop of Dec1 encoding a basic helix–loop–helix transcription factor: CLOCK/BMAL increased the promoter activity of Dec1, and DEC1 and DEC2 as well as PERs and CRYs suppressed the induced expression." SIGNOR-253714 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 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 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 CAMK2A protein Q9UQM7 UNIPROT EGFR protein P00533 UNIPROT "down-regulates activity" phosphorylation Ser1120 QPLNPAPsRDPHYQD 9606 BTO:0000007 10347170 t llicata " We show that serines 1046/1047 are sites for CaM kinase II phosphorylation, although there is a preference for serine 1047, which resides within the consensus -R-X-X-S-. In addition, we have identified major phosphorylation sites at serine 1142 and serine 1057, which lie within a novel -S-X-D- consensus. Mutation of serines 1046/1047 in full-length EGFR enhanced both fibroblast transformation and tyrosine autokinase activity that was significantly potentiated by additional mutation of serines 1057 and 1142. A single CaM kinase II site was also identified at serine 744 within sub-kinase domain III, and autokinase activity was significantly affected by mutation of this serine to an aspartic acid making this site appear constitutively phosphorylated. We have addressed the mechanism by which CaM kinase II phosphorylation of the EGFR might regulate receptor autokinase activity and show that this modification can hinder association of the cytoplasmic tail with the kinase domain to prevent an enzyme-substrate interaction. " SIGNOR-250623 CAMK2B protein Q13554 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-250689 CAMK2B protein Q13554 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation Ser727 TDNLLPMsPEEFDEV 9606 17502367 t gcesareni "All stats are phosphorylated on at least one serine residue in their tad specifically, ser727 in stats 1 and 3 and ser721 in stat4. Stat serine kinases have been identified through the use of inhibitors, dominant-negative alleles, and in vitro kinase assays. They include mapk (p38mapk: stats 1, 3, 4;erk: stat3, 5;jnk: stat3), pkc_ (stat1, stat3), mtor (stat3), nlk (stat3 (42)), and camkii and ikk_ (stat1 (39, 40, 43)).STAT Serine phosphorylation regulates transcriptional activity (see below)." SIGNOR-154771 CAMK2B protein Q13554 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser16 KELEKRAsGQAFELI 9606 BTO:0000661 9686569 t gcesareni "Stimulation via cd2 activated multiple signal transduction pathways, resulting in phosphorylation of distinct sites of stathmin. Ser16 of recombinant human stathmin was phosphorylated also by purified cam kinase ii, and in vivo, cam kinase ii activity was indeed stimulated in cd2-triggered jurkat cells." SIGNOR-59358 CAMKK2 protein Q96RR4 UNIPROT CAMK1 protein Q14012 UNIPROT "up-regulates activity" phosphorylation Thr177 DPGSVLStACGTPGY 7641687 t llicata "Human calcium-calmodulin dependent protein kinase I: cDNA cloning, domain structure and activation by phosphorylation at threonine-177 by calcium-calmodulin dependent protein kinase I kinase." SIGNOR-250716 CAMKK2 protein Q96RR4 UNIPROT CAMK4 protein Q16566 UNIPROT "up-regulates activity" phosphorylation Thr200 EHQVLMKtVCGTPGY 7615569 t llicata "Phosphorylation and activation of Ca(2+)-calmodulin-dependent protein kinase IV by Ca(2+)-calmodulin-dependent protein kinase Ia kinase. Phosphorylation of threonine 196 is essential for activation." SIGNOR-250718 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 CASP2 protein P42575 UNIPROT "Caspase 2 complex" complex SIGNOR-C227 SIGNOR "form complex" binding cleavage:Asp347 SPGCEESdAGKEKLP 21828056 t lperfetto "Like other caspases, caspase-2 is synthesized as an inactive zymogen. The zymogen sequence includes a long prodomain containing a CARD followed by a large domain, a linker, and a small domain. Caspase-2 undergoes autocatalytic activation to remove the prodomain and linker region to generate a stable dimer consisting of the large subunit (p19) and the small subunit (p12). This p19/p12 dimer self-associates to form the active caspase-2" SIGNOR-256389 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 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR 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-256435 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR 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-256434 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 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 CCL7 protein P80098 UNIPROT CCR1 protein P32246 UNIPROT up-regulates binding 9606 14991608 t "For example, 11 chemokines are reported to bind to CC chemokine receptor (CCR) 1, including macrophage inflammatory protein (MIP)‐1α , MIP‐1β, MIP‐1δ, regulated upon activation, normal T cell‐expressed and secreted (RANTES), monocyte chemotactic peptide (MCP)‐1, MCP‐2, MCP‐3, MCP‐4, leukotactin‐1 (Lkn‐1), myeloid progenitor inhibitory factor (MPIF)‐1, and hemofiltrate CC chemokine (HCC)‐1" SIGNOR-254368 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 CD3E protein P07766 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-255294 CDC42BPA protein Q5VT25 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-188785 CDK1 protein P06493 UNIPROT RAD9A protein Q99638 UNIPROT "up-regulates activity" phosphorylation Thr292 PQLQAHStPHPDDFA 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-101055 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 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 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 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 SF3B1 protein O75533 UNIPROT unknown phosphorylation Thr313 HGSGWAEtPRTDRGG 9606 SIGNOR-C16 12105215 t llicata "We indeed found that sap155-(223_322) and sap155-(1_491) are excellent substrates for in vitrophosphorylation by cyclin e-cdk2 as well as cyclin b-cdk1" SIGNOR-90442 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 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR 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-251598 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR 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-251588 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr548 KKVAVVRtPPKSPSS 9606 21215781 t "The effect has been demonstrated using P10636-8" lperfetto "However, other kinases, such as cdk5, p38 and pka, also phosphorylate tau at t231tau phosphorylation at t231, s235 and s262 also contributes to the dissociation of tau from microtubules" SIGNOR-251601 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 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 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 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 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 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 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 CHRM3 protein P20309 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-256882 CHUK protein O15111 UNIPROT CREBBP protein Q92793 UNIPROT up-regulates phosphorylation Ser1386 FVDSGEMsESFPYRT 9606 BTO:0000551 17434128 t lperfetto "Phosphorylation of cbp by ikkalpha promotes cell growth by switching the binding preference of cbp from p53 to nf-kappabhere, we show that ikkalpha phosphorylates cbp at serine 1382 and serine 1386 and consequently increases cbp's hat and transcriptional activities" SIGNOR-154333 CHUK protein O15111 UNIPROT NFKB1 protein P19838 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser927 DSDSVCDsGVETSFR 9606 BTO:0000567 SIGNOR-C13 10469655 t lperfetto "All residues of p105 phosphorylated by ikka are c-terminal; the major phosphorylation region contains three serines (ser923; ser927;ser932) and two threonines (thr927 and thr391)." SIGNOR-70453 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 COL6A3 protein P12111 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 BTO:0001103;BTO:0002319 21949456 t "Muscle basement membrane consists primarily of a type IV collagen network, however types VI, XV, and XVIII are also present." SIGNOR-254675 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 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 CRTC2 protein Q53ET0 UNIPROT NR3C1 protein P04150 UNIPROT "up-regulates activity" binding 9600 BTO:0000567 26652733 t "We show here that CRTC2 also functions as a coactivator for the glucocorticoid receptor (GR)." SIGNOR-256101 CRTC2 protein Q53ET0 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-256106 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 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 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 LRRK2 protein Q5S007 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000938 24916379 t lperfetto "Expression of wild-type LRRK2 promoted neuronal survival against apoptosis through activation of the downstream effector, Akt by phosphorylation of Ser473. Phosphorylated Akt in turn inhibited FOXO 1 signaling" SIGNOR-205115 CSNK2A1 protein P68400 UNIPROT CAV1 protein Q03135 UNIPROT unknown phosphorylation Ser88 FDGIWKAsFTTFTVT -1 8058322 t llicata "Here, we have identified this serine kinase activity as a casein kinase II-like enzyme, since the phosphorylation of caveolin-rich membrane domains is stimulated and inhibited by known effectors of casein kinase II (poly-L-lysine, endogenous polyamines, and a casein kinase II inhibitor peptide), but is unaffected by modulators of other known kinases. In support of these observations, caveolin contains a consensus sequence for casein kinase II phosphorylation in its cytoplasmic N-terminal domain (Ser-88)" SIGNOR-250835 CSNK2A1 protein P68400 UNIPROT GTF2A1L protein Q9UNN4 UNIPROT "up-regulates activity" phosphorylation Ser423 LNSGDDVsEQDVPDL -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-250873 CSNK2A1 protein P68400 UNIPROT GYS1 protein P13807 UNIPROT unknown phosphorylation Ser10 LNRTLSMsSLPGLED -1 2117608 t llicata "With all four peptides, prior phosphorylation significantly stimulated phosphorylation by casein kinase I. From these results, we propose that there are substrates for casein kinase I for which prior phosphorylation is a critical determinant of protein kinase action. | From analysis of 32P release during Edman degradation, no radioactively labeled phosphate was associated with Thr3 or Ser7, but could be accounted for by phosphorylation at Ser10" SIGNOR-250878 CSNK2A1 protein P68400 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-250915 CSNK2A1 protein P68400 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 erine threonine phosphorylation and may stimulate CKII activity in B cells." SIGNOR-250916 CSNK2A1 protein P68400 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 erine threonine phosphorylation and may stimulate CKII activity in B cells." SIGNOR-250917 CSNK2A1 protein P68400 UNIPROT RELA protein Q04206 UNIPROT "up-regulates activity" phosphorylation Ser543 SIADMDFsALLSQIS 9606 BTO:0000567 10938077 t llicata "We demonstrate that casein kinase II (CKII) interacts with p65 in vivo and can phosphorylate p65 at serine 529 in vitro. A CKII inhibitor (PD144795) inhibited TNFalpha-induced p65 phosphorylation in vivo. Furthermore, our results indicate that the association between IkappaBalpha and p65 inhibits p65 phosphorylation by CKII and that degradation of IkappaBalpha allows CKII to phosphorylate p65 to increase NF-kappaB transactivation potential. " SIGNOR-250942 CSNK2A1 protein P68400 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-250943 CSNK2A1 protein P68400 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" phosphorylation Ser392 FKTEGPDsD 9606 BTO:0000568 10747897 t llicata "Furthermore, we demonstrate that anisomycin- and tumor necrosis factor-alpha-induced phosphorylation of p53 at Ser-392, which is important for the transcriptional activity of this growth suppressor protein, requires p38 MAP kinase and CK2 activities." SIGNOR-250967 CSNK2A1 protein P68400 UNIPROT TSPY1 protein Q01534 UNIPROT "up-regulates activity" phosphorylation Thr300 PPEEGTEtSGDSQLL -1 16426576 t llicata "CK2-dependent C-terminal phosphorylation at T300 directs the nuclear transport of TSPY protein" SIGNOR-250969 CSNK2A1 protein P68400 UNIPROT XRCC1 protein P18887 UNIPROT "up-regulates activity" phosphorylation Ser475 IDIEGVQsEGQDNGA 10029 BTO:0002640 15066279 t llicata "We show that inhibiting XRCC1 phosphorylation by mutation of the CK2 phosphorylation sites or preventing CK2 activity using a highly specific inhibitor ablates the rapid repair of cellular DNA single-strand breaks by XRCC1. |" SIGNOR-250972 CSNK2A2 protein P19784 UNIPROT GTF2A1L protein Q9UNN4 UNIPROT "up-regulates activity" phosphorylation Ser423 LNSGDDVsEQDVPDL -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-250994 CSNK2A2 protein P19784 UNIPROT PTPRC protein P08575 UNIPROT "up-regulates activity" phosphorylation Ser999 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 CSNK2B protein P67870 UNIPROT BRCA1 protein P38398 UNIPROT unknown phosphorylation Ser1572 ESGISLFsDDPESDP -1 10403822 t llicata "Subsequent studies showed that BRCA1 was phosphorylated in vitro by CK2. An analysis by site directed mutagenesis of BRCA1 showed that in vitro phosphorylation by CK2 required a serine at aa1572. These data implicate CK2 as a potential mediator of BRCA1 activity." SIGNOR-251055 CSNK2B protein P67870 UNIPROT HOXB6 protein P17509 UNIPROT unknown phosphorylation Ser214 LLSASQLsAEEEEEK -1 10327653 t llicata "Using two-dimensional tryptic phosphopeptide mapping and purified protein kinases, we demonstrate that Hoxb-6 is phosphorylated in vitro by casein kinase II and cAMP-dependent protein kinase. The casein kinase II phosphorylation site was mapped to serine-214. " SIGNOR-251071 CSNK2B protein P67870 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Ser24 GYLRKPKsMHKRFFV -1 8349691 t llicata "These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1." SIGNOR-251072 CSNK2B protein P67870 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Ser330 SFRVRASsDGEGTMS -1 8349691 t llicata "These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1." SIGNOR-251073 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 CTDSPL protein O15194 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-248308 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 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 IKK-complex complex SIGNOR-C14 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 BTO:0000150 15084260 t lperfetto "Ikappab kinase promotes tumorigenesis through inhibition of forkhead foxo3a. The tnf treatment of ht-29 cells increased ikk-dependent foxo3 ser644 phosphorylation." SIGNOR-252950 KAT6A/KAT6B complex SIGNOR-C54 SIGNOR RUNX2 protein Q13950 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271;BTO:0000785 11965546 t lperfetto "Moz and morf both interact with runx2 / while morf does not acetylate runx2, its sm domain potentiates runx2-dependent transcriptional activation." SIGNOR-217204 KAT6A/KAT6B complex SIGNOR-C54 SIGNOR TP53 protein P04637 UNIPROT up-regulates acetylation Lys382 QSTSRHKkLMFKTEG 9606 BTO:0001271 23431171 t lperfetto "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-217198 KAT6A protein Q92794 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271;BTO:0000785 SIGNOR-C54 11965546 t miannu "Moz and morf both interact with runx2 / while morf does not acetylate runx2, its sm domain potentiates runx2-dependent transcriptional activation." SIGNOR-117332 KAT6B protein Q8WYB5 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271;BTO:0000785 SIGNOR-C54 11965546 t miannu "Moz and morf both interact with runx2 / while morf does not acetylate runx2, its sm domain potentiates runx2-dependent transcriptional activation." SIGNOR-117335 KCNIP3 protein Q9Y2W7 UNIPROT PDYN protein P01213 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 12667101 f miannu "As a transcriptional repressor, DREAM may control the expression of the endogenous opioid gene prodynorphin amongst others, and itself is exquisitely regulated by second messenger molecules, protein kinases and other transcription factors." SIGNOR-254540 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 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 PIK3R1 protein P27986 UNIPROT "up-regulates activity" binding 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-255948 LAMA4 protein Q16363 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-253226 LEF1 protein Q9UJU2 UNIPROT ALX4 protein Q9H161 UNIPROT "up-regulates quantity by expression" binding 10090 BTO:0003952 11696550 t miannu "Alx4 Stably Interacts with LEF-1. LEF-1 enhances Alx4 binding to DNA, suggesting that both interaction with LEF-1 and DNA binding are required to mediate its effects on the N-CAM promoter." SIGNOR-254547 "LE-TGN SNARE" complex SIGNOR-C157 SIGNOR IGF2R protein P11717 UNIPROT "up-regulates activity" relocalization 9606 18195106 t lperfetto "These findings place the retromer complex upstream of both STX10 function and the GCC185 tethering complex in MPR transport. Together, our data suggest that STX10, STX16, Vti1a, and VAMP3 are important for the trafficking of both CD- and CI-MPRs.|Thus, MPRs must pass through a compartment of pH ≤ 5.5 before returning to the Golgi to carry out their biological function." SIGNOR-253083 LPAR1 protein Q92633 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-257282 LPAR1 protein Q92633 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-257091 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 LPAR3 protein Q9UBY5 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-257406 LRRK2 protein Q5S007 UNIPROT ARFGAP1 protein Q8N6T3 UNIPROT down-regulates phosphorylation 9606 BTO:0000938 BTO:0000142 22363216 t gcesareni "Arfgap1 is an lrrk2 kinase substrate whose gap activity is inhibited by lrrk2. The phosphorylation of arfgap1 by lrrk2 was subjected to mass spectrometry to determine the sites of phosphorylation. There was 95.3% coverage and serines(s155, s246, s284) and threonine (t189, t216, t292) are phosphorylated by lrrk2. Mutational analysis of these serine and threonine amino acids to alanine reveals that no single amino acid is the predominant phospho-amino acid." SIGNOR-196267 LRRK2 protein Q5S007 UNIPROT DVL3 protein Q92997 UNIPROT up-regulates binding 9606 23754980 t gcesareni "Subsequent assays confirmed a direct interaction between the lrrk2 roccor domain and all three human dvl proteins, these data are consistent with a role for lrrk2 in the activation of canonical wnt signaling bringing dvl proteins to cellular membranes." SIGNOR-202187 LY2784544 chemical CID:46213929 PUBCHEM JAK2 protein O60674 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193796 LY2940680 chemical CID:49848070 PUBCHEM SMO protein Q99835 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193805 "lysophosphatidylserine 14:0(1-)" chemical CHEBI:72402 ChEBI GPR34 protein Q9UPC5 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-257505 MAP3K11 protein Q16584 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates 9606 9003778 f gcesareni "The kinase-inactive mlk-3 failed to activate sapk, demonstraiting that mlk-3 catalytic activity is necessary for the induction of the sapk pathway." SIGNOR-45791 MAP3K11 protein Q16584 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates 9606 9733513 f gcesareni "This scaffold protein selectively enhanced jnk activation by the mlk signaling pathway." SIGNOR-59884 MAP3K14 protein Q99558 UNIPROT CHUK protein O15111 UNIPROT "up-regulates activity" phosphorylation 9606 20651737 t lperfetto "Once activated by autophosphorylation, nik activates ikkalpha, which in turn phosphorylates nf-kb2. This stimulates limited proteasome-mediated proteolysis of nf-kb2 to p52. Removal of the carboxy-terminal ankyrin repeats from nf-kb2 releases the p52/RELB heterodimer, allowing its translocation to the nucleus where it instigates the expression of nf-kb target genes." SIGNOR-167060 MAPK1 protein P28482 UNIPROT DAPK1 protein P53355 UNIPROT up-regulates phosphorylation Ser734 NSSRFPPsPLASKPT 9606 15616583 t gcesareni "Dapk interacts with erk through a docking sequence within its death domain and is a substrate of erk. Phosphorylation of dapk at ser 735 by erk increases the catalytic activity of dapk both in vitro and in vivo" SIGNOR-132614 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 PDE4D protein Q08499-2 UNIPROT down-regulates phosphorylation Ser579 YQSTIPQsPSPAPDD 9606 10828059 t "The effect has been demonstrated using Q08499-5" llicata "The pde4d2 isoform is inhibited by erk2 phosphorylation" SIGNOR-77563 MAPK1 protein P28482 UNIPROT RUNX1 protein Q01196 UNIPROT down-regulates phosphorylation Ser276 VHPATPIsPGRASGM 9606 BTO:0000887 17015473 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-149983 MAPK13 protein O15264 UNIPROT EEF2K protein O00418 UNIPROT down-regulates phosphorylation Ser359 GTEEKCGsPQVRTLS 9606 18337751 t gcesareni "The phosphorylation of eef2k at ser359 is of particular interest. First, the phosphorylation of this site strongly decreases the activity of eef2k even at high calcium concentrations (knebel et al, 2001), that is, desensitizes eef2k to the activating effects of elevated ca2+ levels. third, although p38 map kinase (also termed sapk4 can phosphorylate ser359 in vitro (knebel et al, 2001), this enzyme is not known to be active basally or to be regulated by amino acids." SIGNOR-177986 MAPK14 protein Q16539 UNIPROT CDX2 protein Q99626 UNIPROT "up-regulates activity" phosphorylation Ser291 PVSSLQAsVPGSVPG 9606 BTO:0001111 16027724 t miannu "ERK2, p38alpha and GSK-3beta can phosphorylate Cdx2 in vitro and that the 4S motif is required for phosphorylation by GSK-3beta and p38alpha but dispensable for phosphorylation by ERK2. phosphorylation of Cdx2 by the kinase p38 accompanies cell differentiation and enhances its transcriptional activity" SIGNOR-250094 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 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 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 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 MKL1 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 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 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 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-120240 MAPK3 protein P27361 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-120244 MAPK3 protein P27361 UNIPROT RPS6KA1 protein Q15418 UNIPROT "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-102648 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 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 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 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 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 BCL2L11 protein O43521 UNIPROT "up-regulates activity" phosphorylation Ser69 GPLAPPAsPGPFATR 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-250132 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 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 MC1R protein Q01726 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-256813 MCL1 protein Q07820 UNIPROT BAK1 protein Q16611 UNIPROT down-regulates binding 9606 17289999 t gcesareni "Bax is held in check by mcl1, bcl-2, and either bcl2l1 or bcl2l2, or by all four. They bind a primed conformer of bak or bax" SIGNOR-149774 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 MCHR1 protein Q99705 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-257235 MCHR2 protein Q969V1 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-257334 MCM2 protein P49736 UNIPROT ATR protein Q13535 UNIPROT up-regulates 9606 21070963 f gcesareni "Additional activation of mec1 could be mediated by replication intermediates derived from type (ii) ddk driven initiation or checkpoint signaling." SIGNOR-169509 MEF2A protein Q02078 UNIPROT MYOD1 protein P15172 UNIPROT "up-regulates activity" binding 9606 BTO:0000887;BTO:0001103 9418854 t lperfetto "Myod-e protein heterodimers interact with mef2 proteins to synergistically activate myogenesis." SIGNOR-54086 MEIS1 protein O00470 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 BTO:0001271 19109563 f irozzo "To discern the mechanisms by which Meis1 inhibition leads to reduced cell growth, we performed cell-cycle and apoptosis analyses.Meis1 knockdown also resulted in increased apoptosis, as evidenced by increased uptake of PI and a stain for activated caspases (CaspaTag) by M26-transduced cells compared with control cells. These results indicate that Meis1 is required for proliferation and survival of 4166 leukemia cells." SIGNOR-256648 miR-29b mirna MI0000105 miRBase DNMT3B protein Q9UBC3 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 25477897 t miannu "The down-regulation of miR-29b is thought to promote DNA hypermethylation in AML since miR-29b can directly target DNMT3A, DNMT3B, and Sp1 (a transcriptional regulator of DNMT2" SIGNOR-255794 miR-29b mirna MI0000105 miRBase SP1 protein P08047 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 25477897 t miannu "The down-regulation of miR-29b is thought to promote DNA hypermethylation in AML since miR-29b can directly target DNMT3A, DNMT3B, and Sp1 (a transcriptional regulator of DNMT3" SIGNOR-255795 miR-29b mirna MI0000105 miRBase TET2 protein Q6N021 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 10090 BTO:0004850 25477897 t miannu "The three miR-29 family members in mouse bone marrow cells reduced the level of TET2 as well as its metabolic by-product, 5hmC" SIGNOR-255796 MN1 protein Q10571 UNIPROT MYBBP1A protein Q9BQG0 UNIPROT "up-regulates activity" binding -1 12569362 t irozzo "Taken together, our results indicate that MN1 is a transcription coactivator rather than a sequence-specific transcription factor, and that it may stimulate RAR/RXR-mediated transcription through interaction with p160 and p300." SIGNOR-256021 MN1 protein Q10571 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 BTO:0004850 17494859 f irozzo "MN1 is a unique oncogene in hematopoiesis that both promotes proliferation/self-renewal and blocks differentiation, and may become useful as a predictive marker in AML treatment." SIGNOR-256015 Mob1 proteinfamily SIGNOR-PF42 SIGNOR LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR "up-regulates activity" binding 9606 21084559 t miannu "Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1." SIGNOR-256186 MS4A2 protein Q01362 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-254960 "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 MSC protein O60682 UNIPROT TCF3 protein P15923 UNIPROT "down-regulates activity" binding 9606 BTO:0000776 9584154 t 2 miannu "ABF-1 contains a transcriptional repression domain and is capable of inhibiting the transactivation capability of E47 in mammalian cells." SIGNOR-241315 "MTA1/DJ1 complex" complex SIGNOR-C123 SIGNOR TH protein P07101 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000793 21368136 f 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-239773 MTCP1 protein P56278 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-81677 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 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 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 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Ser65 FLMECRNsPVTKTPP 9606 BTO:0000007 12747827 t lperfetto "Phosphorylated on serine and threonine residues in response to insulin, egf and pdgf. Phosphorylation at thr-37, thr-46, ser-65 and thr-70, corresponding to the hyperphosphorylated form, is regulated by mtorc1 and abolishes binding to eif4e." SIGNOR-236690 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr46 GGTLFSTtPGGTRII 9606 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-217114 mTORC1 complex SIGNOR-C3 SIGNOR RPS6KB2 protein Q9UBS0 UNIPROT up-regulates phosphorylation 9606 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-217074 mTORC1 complex SIGNOR-C3 SIGNOR 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-248274 mTORC1 complex SIGNOR-C3 SIGNOR ULK1 protein O75385 UNIPROT down-regulates phosphorylation 9606 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-217133 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 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 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 CDKN2A protein P42771 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 12835716 f gcesareni "C-myc also directly represses transcription of cdk kinase inhibitors including p27kip1, p21cip1, p15ink4b and p16ink4a" SIGNOR-102743 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 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 HLA-A protein P30443 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-254603 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 MYD88 protein Q99836 UNIPROT IRAK4 protein Q9NWZ3 UNIPROT "up-regulates activity" binding 9606 BTO:0000776 17548806 t lperfetto "St2825 interfered with recruitment of irak1 and irak4 by myd88, causing inhibition of il-1beta-mediated activation of nf-kappab transcriptional activity." SIGNOR-155385 MYF6 protein P23409 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-241497 MYF6 protein P23409 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR "up-regulates activity" BTO:0001103 7532173 f "Simone Vumbaca" "Finally, MRF4 may be responsible for the final myogenic events of the fully differentiated myofiber" SIGNOR-255645 MYOD1 protein P15172 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103;BTO:0001760 7791789 f lperfetto "The upregulation of p21 occurred at the levels of mrna and protein," SIGNOR-235831 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 SMARCD3 protein Q6STE5 UNIPROT up-regulates binding 9606 BTO:0000887 15870273 t lperfetto "This suggests a novel mechanism by which myod interacts with the promoter indirectly via pbx-1 and recruits chromatin-remodeling enzymes, which then facilitate the binding of myod and other regulators. Demonstration of physical interactions between brg1 and myod and brg1 and pbx support this conclusion" SIGNOR-136130 MYOD1 protein P15172 UNIPROT SP1 protein P08047 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0004058 9148896 t lperfetto "these data suggest a regulatory model in which MyoD activation during myogenesis causes the down-regulation of Sp1, which contributes to the repression of GLUT1 gene transcription and, therefore, leads to the reduction in GLUT1 expression and glucose transport." SIGNOR-241765 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/SWI/SNF complex" complex SIGNOR-C93 SIGNOR DYSF protein O75923 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887 15870273 f miannu "Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material)" SIGNOR-136497 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 mir-133a2 mirna MI0000452 miRBase "up-regulates quantity" 10090 BTO:0000165 16731620 t "Moreover, both loci encoding miR-1, miR-1-1, and miR-1-2, and two of the three encoding miR-133, miR-133a-1 and miR-133a-2, are strongly induced during myogenesis.[…]By using CHIP analysis, we demonstrate that the myogenic factors Myogenin and MyoD bind to regions upstream of these microRNAs and, therefore, are likely to regulate their expression." SIGNOR-255917 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 "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 4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexenyl]methyl]-1-piperazinyl]-N-[4-[[(2R)-4-(4-morpholinyl)-1-(phenylthio)butan-2-yl]amino]-3-(trifluoromethylsulfonyl)phenyl]sulfonylbenzamide chemical CHEBI:94128 ChEBI BCL2L1 protein Q07817 UNIPROT down-regulates "chemical inhibition" 9606 Other t "The effect has been demonstrated using Q07817-1" gcesareni SIGNOR-189153 NANOG protein Q9H9S0 UNIPROT DNMT1 protein P26358 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003298 22795133 t lperfetto "Oct4 and Nanog upregulate Dnmt1 through direct binding to its promoter, thereby leading to the repressed expression of p16 and p21 and genes associated with development and lineage differentiation" SIGNOR-253157 NANOG protein Q9H9S0 UNIPROT FOXA2 protein Q9Y261 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0003298 22795133 f lperfetto "Knockdown of Oct4 or Nanog induced an increase in the expression of Pax6, Gata4, Gata6, Sox17, and FoxA2 in E, H, and p21KD MSCs ( Figure 3F and Figure S2D)" SIGNOR-253166 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 NCOA1 protein Q15788 UNIPROT RARA protein P10276 UNIPROT "up-regulates quantity" "transcriptional activation" 9606 BTO:0000567 16606617 f irozzo "We also show that ASXL1 associates specifically with SRC-1 and cooperates synergistically in the transcriptional activation. Further data indicated that the transactivation domain (AD; amino acids 300–655) of ASXL1, newly defined in this study, interacts with the C-terminal AD2 (amino acids 1217–1441) of SRC-1, suggesting that one AD cooperates with the other AD in transcriptional activation by RAR." SIGNOR-255932 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 NCOA2 protein Q15596 UNIPROT NR3C1 protein P04150 UNIPROT "up-regulates activity" binding 10090 BTO:0000801 29170386 t "Here we report that GRIP1 loss in macrophages attenuates glucocorticoid induction of several anti-inflammatory targets, and that GC treatment of quiescent macrophages globally directs GRIP1 toward GR binding sites dominated by palindromic GC response elements (GRE), suggesting a non-redundant GRIP1 function as a GR coactivator." SIGNOR-256095 NME1 protein P15531 UNIPROT L1CAM protein P32004 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-255161 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 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 PDK2 protein Q15119 UNIPROT PDHA1 protein P08559 UNIPROT "down-regulates activity" phosphorylation Ser232 NRYGMGTsVERAAAS -1 11485553 t lperfetto "Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293." SIGNOR-109559 PDK2 protein Q15119 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates phosphorylation Ser293 TYRYHGHsMSDPGVS -1 7782287 t gcesareni "Mammalian pyruvate dehydrogenase (?2_2) (e1) is regulated by phosphorylation-dephosphorylation, catalyzed by the e1-kinase and the phospho-e1-phosphatase." SIGNOR-33137 PDK4 protein Q16654 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates phosphorylation Ser293 TYRYHGHsMSDPGVS -1 7782287 t gcesareni "Mammalian pyruvate dehydrogenase (?2_2) (e1) is regulated by phosphorylation-dephosphorylation, catalyzed by the e1-kinase and the phospho-e1-phosphatase." SIGNOR-33197 PAX3-FOXO1 "fusion protein" SIGNOR-FP12 SIGNOR MET protein P08581 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25211658 t miannu "Several deregulated signalling pathways enhance cell growth by modulating cell-cycle regulatory factors in RMS. The most frequently affected signalling pathways include the insulin-like growth factor (IGF), fibroblast growth factor (FGF), hepatocyte growth factor, and platelet-derived growth factor. In ARMS, PAX-FOXO1 activates these pathways by transcriptional activation of receptor genes including IGFR1, FGFR4, MET (c-Met), and PDGFRA." SIGNOR-251570 PEX6 protein Q13608 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-253619 PEX6 protein Q13608 UNIPROT Protein_localization_to_peroxisome phenotype SIGNOR-PH86 SIGNOR up-regulates 9606 26476099 f "The Pex1 and Pex6 proteins are members of the AAA family of ATPases and are involved in peroxisome biogenesis." SIGNOR-253617 PITX1 protein P78337 UNIPROT GNRH1 protein P01148 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0004467 19106114 f miannu "Knockdown of PITX1 or PITX2 isoforms impaired GNRH1 induction, and endogenous PITX1 bound to the candidate PITX binding site on the LHB promoter." SIGNOR-254921 PITX1 protein P78337 UNIPROT LHB protein P01229 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0004467 19106114 f miannu "GNRH1 induces expression of early growth response 1 (EGR1), which interacts with steroidogenic factor 1 (SF1) and paired-like homeodomain transcription factor 1 (PITX1) to regulate Lhb promoter activity." SIGNOR-254920 PITX2 protein Q99697 UNIPROT GNRH1 protein P01148 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0004467 19106114 f miannu "Knockdown of PITX1 or PITX2 isoforms impaired GNRH1 induction, and endogenous PITX1 bound to the candidate PITX binding site on the LHB promoter." SIGNOR-254922 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 POU5F1 protein Q01860 UNIPROT DKK1 protein O94907 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001086 17068183 f miannu "To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG." SIGNOR-254934 POU5F1 protein Q01860 UNIPROT NANOG protein Q9H9S0 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001086 17068183 f miannu "To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG." SIGNOR-254939 PPP1CA protein P62136 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-248553 PPP1CA protein P62136 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-248554 PPP2CA protein P67775 UNIPROT AKT1 protein P31749 UNIPROT "down-regulates activity" dephosphorylation Ser473 RPHFPQFsYSASGTA 10090 BTO:0000944 15367694 t "Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes" SIGNOR-252606 PPP2CA protein P67775 UNIPROT AKT1 protein P31749 UNIPROT "down-regulates activity" dephosphorylation Thr308 KDGATMKtFCGTPEY 10090 BTO:0000944 15367694 t "Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes" SIGNOR-252614 PPP2CA protein P67775 UNIPROT TFCP2 protein Q12800 UNIPROT up-regulates dephosphorylation Ser309 SLGEGNGsPNHQPEP 9606 20682773 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. This predominant cis conformation would also limit dephosphorylation of ser-291 and ser-309 by phosphatases such as pp2a" SIGNOR-167389 PPP3CA protein Q08209 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-248686 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 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 PRKCA protein P17252 UNIPROT HAND1 protein O96004 UNIPROT unknown phosphorylation Ser98 RLGRRKGsGPKKERR 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-249243 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 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 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 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 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 EWSR1 protein Q01844 UNIPROT up-regulates phosphorylation Ser266 SSYGQQSsFRQDHPS 9606 19076070 t lperfetto "Ews was reported to be phosphorylated in vitro by pkc (protein kinase c). The site of phosphorylation was not identified, but was suggested to be ser266 . The mutation of ser266 to alanine suppressed phosphorylation and binding to dna and reduced the transcriptional activity of the ews-fli1 fusion protein by 40%" SIGNOR-182786 PRKCD protein Q05655 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-249028 PRKCD protein Q05655 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-249287 PRKCQ protein Q04759 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-251636 PRKG1 protein Q13976 UNIPROT VASP protein P50552 UNIPROT down-regulates phosphorylation Ser239 GAKLRKVsKQEEASG 9606 14679200 t lperfetto "Vasodilator-stimulated phosphoprotein activation of serum-response element-dependent transcription occurs downstream of rhoa and is inhibited by cgmp-dependent protein kinase phosphorylation. G-kinase phosphorylation of vasp on ser(239) at the carboxyl-terminal end of the g-actin binding site, with some contribution by phosphorylation of ser(157)" SIGNOR-120351 PSENEN protein Q9NZ42 UNIPROT g-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-209708 PTCH1 protein Q13635 UNIPROT CCNB1 protein P14635 UNIPROT up-regulates binding 9606 BTO:0000007 11331587 t "Type I noncanonical;P-cyclina B (CCNB)." gcesareni "In addition, we demonstrate that endogenous ptc1 and endogenous cyclin B1 interact in vivo. The findings reported here demonstrate that ptc1 participates in determining the subcellular localization of cyclin B1 and suggest a link between the tumor suppressor activity of ptc1 and the regulation of cell division. Thus, we propose that ptc1 participates in a G2/M checkpoint by regulating the localization of MPF." SIGNOR-199147 PTPN12 protein Q05209 UNIPROT BCAR1 protein P56945 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 11432829 t gcesareni "Ptp-pest is an efficient negative regulator of lymphocyte activation. This function correlated with the ability of ptp-pest to induce dephosphorylation of shc, pyk2, fak and cas, and inactivate the ras pathway." SIGNOR-109032 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 STAT3 protein P40763 UNIPROT "down-regulates activity" dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 15821101 t "PTP1B was able to dephosphorylate activated JAK2 and STAT3 in vitro, whereas either no or a minimal effect was observed with cluster of differentiation 45 (CD45), PTPalpha and leukocyte antigen-related (LAR). By utilisation of a selective PTP1B inhibitor, the leptin-induced STAT3 activation was enhanced in cells. In conclusion, these results suggested that the negative regulatory role of PTP1B on leptin signalling is mediated through a direct and selective dephosphorylation of the two signalling molecules, JAK2 and STAT3." SIGNOR-248427 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 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 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 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 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 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 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 KIT protein P10721 UNIPROT "down-regulates activity" dephosphorylation Tyr703 DHAEAALyKNLLHSK -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-254709 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 PRKCD protein Q05655 UNIPROT "up-regulates activity" dephosphorylation Tyr313 SSEPVGIyQGFEKKT -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-254716 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 "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 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 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 PTPRJ protein Q12913 UNIPROT MET protein P08581 UNIPROT "down-regulates activity" dephosphorylation Tyr1349 STFIGEHyVHVNATY 9606 BTO:0000007 12475979 t "When co-expressed in 293 cells, the full-length substrate-trapping mutant form of DEP-1 formed a stable complex with the chimeric receptor colony stimulating factor 1 (CSF)-Met and wild type DEP-1 dephosphorylated CSF-Met. Furthermore, we observed that DEP-1 preferentially dephosphorylated a Gab1 binding site (Tyr(1349)) and a COOH-terminal tyrosine implicated in morphogenesis (Tyr(1365))," SIGNOR-248702 RAC1 protein P63000 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR "up-regulates activity" 23290138 f "Simone Vumbaca" "This result strongly supports the assertion that Wnt7a and FN stimulate PCP signaling to drive the symmetric expansion of satellite stem cells during regenerative myogenesis." SIGNOR-255648 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11486031 t lperfetto "Using this inducible system, we show that Notchic activates transcription of the cyclin D1 gene with rapid kinetics." SIGNOR-209753 RELA protein Q04206 UNIPROT JUN protein P05412 UNIPROT up-regulates binding 9606 SIGNOR-C13 18174238 t gcesareni "Chromatin immunoprecipitation (chip) analysis confirmed the serum-induced recruitment of jund to the promoter in vivo and showed that the presence of jund was dependent on the presence of p65 and p50, indicating a protein-protein-dependent mechanism of jund recruitment" SIGNOR-160330 "RFX complex" complex SIGNOR-C104 SIGNOR HLA-DRA protein P01903 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" -1 11258423 f "The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex" SIGNOR-253998 "RFX complex" complex SIGNOR-C104 SIGNOR HLA-DRB3 protein P79483 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" -1 11258423 f "The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex" SIGNOR-254001 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1693 SPTSPSYsPTSPSYS 9606 BTO:0000567 22137580 t "In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator" SIGNOR-248752 RPS6K proteinfamily SIGNOR-PF26 SIGNOR ETV1 protein P50549 UNIPROT "up-regulates activity" phosphorylation Ser216 PMYQRQMsEPNIPFP 9606 BTO:0002181 12213813 t lperfetto "Here we describe that the 90-kDa ribosomal S6 kinase 1 (RSK1), a protein kinase downstream of the extracellular signal-regulated kinase (ERK) subclass of MAPKs, binds to ER81, phosphorylates it, and enhances ER81-dependent transcription. Two in vivo RSK1 phosphorylation sites within ER81, Ser(191) and Ser(216), were identified, whose mutation to alanine reduces ER81 activity upon ERK-MAPK stimulation." SIGNOR-252769 RPS6K proteinfamily SIGNOR-PF26 SIGNOR FLNA protein P21333 UNIPROT up-regulates phosphorylation Ser2152 TRRRRAPsVANVGSH 9606 BTO:0000848 15024089 t gcesareni "We show that the n-terminal kinase domain of rsk phosphorylates flna on ser(2152) in response to mitogens" SIGNOR-252790 RPS6K proteinfamily SIGNOR-PF26 SIGNOR GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser9 SGRPRTTsFAESCKP 9606 11584304 t lperfetto "S6k then phosphorylates the same serine residue on gsk3 that is targeted by pkb/akt (fig. 1), thereby inhibiting its activity." SIGNOR-252788 RRAGC protein Q9HB90 UNIPROT RAGBC complex SIGNOR-C115 SIGNOR "form complex" binding 9606 20381137 t gcesareni "Mammals express four Rag proteins€”RagA, RagB, RagC, and RagD€”that form heterodimers consisting of RagA or RagB with RagC or RagD. RagA and RagB, like RagC and RagD, are highly similar to each other and are functionally redundant" SIGNOR-228173 RRAGD protein Q9NQL2 UNIPROT RAGAD complex SIGNOR-C114 SIGNOR "form complex" binding 9606 20381137 t gcesareni "Mammals express four Rag proteins€”RagA, RagB, RagC, and RagD€”that form heterodimers consisting of RagA or RagB with RagC or RagD. RagA and RagB, like RagC and RagD, are highly similar to each other and are functionally redundant" SIGNOR-228170 SCN3A protein Q9NY46 UNIPROT "sodium ion" smallmolecule "CID: 923" PUBCHEM "up-regulates quantity" relocalization 9606 BTO:0000938 27262167 t miannu "Voltage-gated Na1 channels (NaV channels) drive the rapid upstroke of action potentials in cardiac and skeletal muscle and in most neurons, thereby serving as initiators of electrical activity in excitable tissue. Nine genes encode a family of homologous of NaV channel pore-forming a subunits. While channels are open, Na1 ions flux through the central pore down an electrochemical gradient, further depolarizing the membrane and triggering an action potential." SIGNOR-253409 SCN4A protein P35499 UNIPROT "sodium ion" smallmolecule "CID: 923" PUBCHEM "up-regulates quantity" relocalization 9606 BTO:0001103 27262167 t miannu "Voltage-gated Na1 channels (NaV channels) drive the rapid upstroke of action potentials in cardiac and skeletal muscle and in most neurons, thereby serving as initiators of electrical activity in excitable tissue. Nine genes encode a family of homologous of NaV channel pore-forming a subunits. While channels are open, Na1 ions flux through the central pore down an electrochemical gradient, further depolarizing the membrane and triggering an action potential." SIGNOR-253405 SCN5A protein Q14524 UNIPROT "sodium ion" smallmolecule "CID: 923" PUBCHEM "up-regulates quantity" relocalization 9606 BTO:0000199 27262167 t miannu "Voltage-gated Na1 channels (NaV channels) drive the rapid upstroke of action potentials in cardiac and skeletal muscle and in most neurons, thereby serving as initiators of electrical activity in excitable tissue. Nine genes encode a family of homologous of NaV channel pore-forming a subunits. While channels are open, Na1 ions flux through the central pore down an electrochemical gradient, further depolarizing the membrane and triggering an action potential." SIGNOR-253401 SCN9A protein Q15858 UNIPROT "sodium ion" smallmolecule "CID: 923" PUBCHEM "up-regulates quantity" relocalization 9606 27262167 t miannu "Voltage-gated Na1 channels (NaV channels) drive the rapid upstroke of action potentials in cardiac and skeletal muscle and in most neurons, thereby serving as initiators of electrical activity in excitable tissue. Nine genes encode a family of homologous of NaV channel pore-forming a subunits. While channels are open, Na1 ions flux through the central pore down an electrochemical gradient, further depolarizing the membrane and triggering an action potential." SIGNOR-253403 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 SGK2 protein Q9HBY8 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-252991 SGK3 protein Q96BR1 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-252992 SNW1 protein Q13573 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 BTO:0000222 BTO:0000887 10713164 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-75788 SOCS1 protein O15524 UNIPROT IFNG protein P01579 UNIPROT down-regulates 9606 BTO:0000801 21628332 f lperfetto "SOCS1 inhibits macrophage responses to IFN-g, and SOCS1-deficient mice develop symptoms of severe systemic autoimmune and inflammatory disease." SIGNOR-249571 SOS1 protein Q07889 UNIPROT KRAS protein P01116 UNIPROT up-regulates "guanine nucleotide exchange factor" 9606 25624485 t "Ras proteins bind GDP/GTP and possess intrinsic GTPase activity." gcesareni "Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts" SIGNOR-122075 somatostatin smallmolecule CHEBI:64628 ChEBI SSTR2 protein P30874 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-257582 SRC protein P12931 UNIPROT STAP2 protein Q9UGK3 UNIPROT "up-regulates activity" phosphorylation Tyr322 GDGPAVDyENQDVAS 9606 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 Tyr-22 and Tyr-322 are the major tyrosine phosphorylation sites by v-Src." SIGNOR-247337 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 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1784 TPTSPNYsPTSPSYS -1 15125841 t "Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro" SIGNOR-248826 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 TFDP1 protein Q14186 UNIPROT MYBL2 protein P10244 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000972 14618416 f miannu "To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells." SIGNOR-253862 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 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 TWIST2 protein Q8WVJ9 UNIPROT CTPS1 protein P17812 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004828 19051271 f miannu "we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion" SIGNOR-255500 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 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 CSNK2A1 protein P68400 UNIPROT TERF1 protein P54274 UNIPROT up-regulates phosphorylation Thr122 LTACQLRtIYICQFL 9606 18347021 t lperfetto "Regulation of telomeric repeat binding factor 1 binding to telomeres by casein kinase 2-mediated phosphorylation. Mapping of the ck2 target site identified threonine 122 as a substrate in trf1. A threonine to alanine change at this position led to a diminished dna binding due to reduced dimerization of trf1." SIGNOR-178034 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 IL4R protein P24394 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR "up-regulates activity" 10090 23582327 f "Activation of IL-4/IL-13 signaling promotes proliferation of FAPs to support myogenesis while inhibiting their differentiation into adipocytes" SIGNOR-256482 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 GNAI2 protein P04899 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-256492 mTORC1 complex SIGNOR-C3 SIGNOR Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR "up-regulates activity" 10090 BTO:0002314 25047835 f "Knockdown (KD) of either mTORC or its subunit Raptor delayed SC activation without influencing the differentiation program." SIGNOR-256273 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 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 CDK2 protein P24941 UNIPROT ZC3HC1 protein Q86WB0 UNIPROT down-regulates phosphorylation Ser395 PGLEVPSsPLRKAKR 9606 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-154051 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 MZF1 protein P28698 UNIPROT CTGF 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 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 GSTA1 protein P08263 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0000018 29928434 f irozzo "In addition, the downregulation of GSTA1 in A549 cells significantly induced cell apoptosis in vitro. In conclusion, GSTA1 plays an important role in regulation of cell proliferation and cell apoptosis in A549 cell line." SIGNOR-256297 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 GNAI1 protein P63096 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-256498 GNAI2 protein P04899 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-256499 midostaurin chemical CHEBI:63452 ChEBI FLT3 protein P36888 UNIPROT "down-regulates activity" "chemical inhibition" -1 12124173 t "PKC412 is a potent inhibitor of mutant FLT3 and is a candidate for testing as an antileukemia agent in AML patients with mutant FLT3 receptors." SIGNOR-256308 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 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 DOK1 protein Q99704 UNIPROT "A1/b1 integrin" complex SIGNOR-C159 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-257670 AMPK complex SIGNOR-C15 SIGNOR 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-251618 DOK1 protein Q99704 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-257679 DOK1 protein Q99704 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-257685 DOK1 protein Q99704 UNIPROT "A6/b4 integrin" complex SIGNOR-C174 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-257690 DOK1 protein Q99704 UNIPROT "AE/b7 integrin" complex SIGNOR-C186 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-257696 DOK1 protein Q99704 UNIPROT "Av/b5 integrin" complex SIGNOR-C178 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-257692 DOK1 protein Q99704 UNIPROT "Av/b6 integrin" complex SIGNOR-C179 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-257694 DOK1 protein Q99704 UNIPROT "Av/b8 integrin" complex SIGNOR-C185 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-257699 DOK1 protein Q99704 UNIPROT ITGB5 protein P18084 UNIPROT "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-257691 DOK1 protein Q99704 UNIPROT ITGB6 protein P18564 UNIPROT "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-257693 "A1/b1 integrin" complex SIGNOR-C159 SIGNOR 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-257701 "A2/b1 integrin" complex SIGNOR-C160 SIGNOR 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-257702 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 "A5/b1 integrin" complex SIGNOR-C163 SIGNOR 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-257705 "A11/b1 integrin" complex SIGNOR-C168 SIGNOR 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-257710 "AL/b2 integrin" complex SIGNOR-C169 SIGNOR 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-257712 "Av/b2 integrin" complex SIGNOR-C176 SIGNOR 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-257715 "Av/b3 integrin" complex SIGNOR-C177 SIGNOR 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-257719 4-[4-(2-fluorophenyl)phenyl]-N-(4-hydroxyphenyl)butanamide chemical CHEBI:92949 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates "chemical inhibition" 9606 15362850 t gcesareni "In steady-state kinetics experiments, cmpd1 was observed to prevent the p38alpha-dependent phosphorylation (k(i)(app) = 330 nm) of the splice variant of mitogen-activated protein kinase-activated protein kinase 2 (mk2a) that contains a docking domain for p38alpha and p38beta" SIGNOR-128864 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 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 MLF1 protein P58340 UNIPROT TP53 protein P04637 UNIPROT up-regulates 9606 BTO:0001271 15861129 f miannu "Mlf1 induces p53-dependent cell cycle arrest" SIGNOR-135943 (-)-anisomycin chemical CHEBI:338412 ChEBI JUN protein P05412 UNIPROT up-regulates "chemical activation" 9606 Other t CellSignaling gcesareni SIGNOR-189632 "Av/b8 integrin" complex SIGNOR-C185 SIGNOR 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-257730 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 NLRC4 protein Q9NPP4 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-256404 belinostat chemical CHEBI:61076 ChEBI HDAC4 protein P56524 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-257743 GSDMD protein P57764 UNIPROT Pyroptosis phenotype SIGNOR-PH105 SIGNOR up-regulates cleavage:Asp275 CLHNFLTdGVPAEGA 26375003 f lperfetto "These results establish that proteolytic cleavage at Asp275 in GSDMDis sufficient to instructmammalian cells to undergo pyroptosis" SIGNOR-256416 belinostat chemical CHEBI:61076 ChEBI HDAC3 protein O15379 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-257746 belinostat chemical CHEBI:61076 ChEBI HDAC6 protein Q9UBN7 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-257745 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 CSNK2A2 protein P19784 UNIPROT CDC37 protein Q16543 UNIPROT "up-regulates activity" phosphorylation Ser13 VWDHIEVsDDEDETH -1 12930845 t llicata "Phosphorylation of serine 13 is required for the proper function of the Hsp90 co-chaperone, Cdc37. | In this report, we demonstrate that mammalian Cdc37 is phosphorylated on Ser13 in situ in rabbit reticulocyte lysate and in cultured K562 cells and that casein kinase II is capable of quantitatively phosphorylating recombinant Cdc37 at this site." SIGNOR-250982 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 CSNK2A1 protein P68400 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-250844 "2-(Decan-2-ylamino)ethyl 4-aminobenzoate" chemical CID:50729 PUBCHEM TOP2A protein P11388 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000664 18258442 t Luana "As shown in Table 1 all of the bisanthrapyrazoles inhibited the decatenation activity of human topoisomerase IIα in the low micromolar concentration range" SIGNOR-257768 aliskiren chemical CHEBI:601027 ChEBI REN protein P00797 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000131 18307734 t Luana "Aliskiren has a low bioavailality (between 2.6 and 5.0%) compensated by its high potency to inhibit renin (IC50: 0.6 nmol/L) and a long plasma half-life (23–36 h)" SIGNOR-257771 azelastine chemical CHEBI:2950 ChEBI HRH1 protein P35367 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0002126 18446005 t Luana "We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells" SIGNOR-257790 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR CASP6 protein P55212 UNIPROT up-regulates cleavage 9606 9922454 t amattioni "Caspase-3 is required for the activation of caspases 6" SIGNOR-256467 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 BTO:0000142 10200555 f amattioni "Caspase-3 is required for blebbing, chromatin condensation and dna fragmentation" SIGNOR-256477 HMOX1 protein P09601 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0000356 26722274 f irozzo "Heme oxygenase-1 (HO-1) protects endothelial cells (EC) from undergoing apoptosis. These results indicated that HMOX-1 may be involved in conferring the chemoresistance of breast cancer cells, by preventing apoptosis and autophagy." SIGNOR-256559 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 GNAI1 protein P63096 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-256538 NANOG protein Q9H9S0 UNIPROT GATA6 protein Q92908 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0003298 22795133 f lperfetto "Knockdown of Oct4 or Nanog induced an increase in the expression of Pax6, Gata4, Gata6, Sox17, and FoxA2 in E, H, and p21KD MSCs ( Figure 3F and Figure S2D)" SIGNOR-253160 lurasidone chemical CHEBI:70735 ChEBI ADRA2A protein P08913 UNIPROT "down-regulates activity" "chemical inhibition" 10030 BTO:0000246 20404009 t Luana "Lurasidone was found to have potent binding affinity for dopamine D2, 5-hydroxytryptamine 2A (5-HT2A), 5-HT7, 5-HT1A, and noradrenaline 2C receptors." SIGNOR-257842 lurasidone chemical CHEBI:70735 ChEBI DRD2 protein P14416 UNIPROT "down-regulates activity" "chemical inhibition" 10030 20404009 t Luana "In vitro functional assays demonstrated that lurasidone acts as an antagonist at D2 and 5-HT7 receptors and as a partial agonist at the 5-HT1A receptor subtype." SIGNOR-257838 8-hydroxy-5-[1-hydroxy-2-(propan-2-ylamino)butyl]-1H-quinolin-2-one chemical CHEBI:91585 ChEBI ADRB2 protein P07550 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000457 20590599 t Luana "Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy. " SIGNOR-257857 CASP8 protein Q14790 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 14585074 f amattioni "Downstream of caspase-8 activation, apoptosis induction takes place" SIGNOR-256639 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 PLAG1 protein Q6DJT9 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 11888928 f miannu "Plagl1 has been shown to prevent the proliferation of tumor cells by inducing cell cycle arrest and apoptosis" SIGNOR-256658 azelastine chemical CHEBI:2950 ChEBI HRH3 protein Q9Y5N1 UNIPROT "down-regulates activity" "chemical inhibition" 10030 BTO:0000246 21381763 t Luana "Azelastine was used as a standard, with affinities (pKi) for H1 and H3 8.9 and 6.8, respectively. " SIGNOR-257895 bufexamac chemical CHEBI:31317 ChEBI HDAC10 protein Q969S8 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000664 21258344 t Luana " We also identified the anti-inflammatory drug bufexamac as a class IIb (HDAC6, HDAC10) HDAC inhibitor." SIGNOR-257891 bufexamac chemical CHEBI:31317 ChEBI HDAC6 protein Q9UBN7 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000664 21258344 t Luana " We also identified the anti-inflammatory drug bufexamac as a class IIb (HDAC6, HDAC10) HDAC inhibitor." SIGNOR-257892 chlorphenamine chemical CHEBI:52010 ChEBI HRH1 protein P35367 UNIPROT "down-regulates activity" "chemical inhibition" -1 12781173 t Luana "Identification of a dual histamine H1/H3 receptor ligand based on the H1 antagonist chlorpheniramine." SIGNOR-257896 chlorphenamine chemical CHEBI:52010 ChEBI HRH3 protein Q9Y5N1 UNIPROT "down-regulates activity" "chemical inhibition" -1 12781173 t Luana "Identification of a dual histamine H1/H3 receptor ligand based on the H1 antagonist chlorpheniramine." SIGNOR-257897 entinostat chemical CHEBI:132082 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-257902 entinostat chemical CHEBI:132082 ChEBI HDAC2 protein Q92769 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-257904 entinostat chemical CHEBI:132082 ChEBI HDAC3 protein O15379 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-257903 JWOGUUIOCYMBPV-GMFLJSBRSA-N chemical CID:6918328 PUBCHEM HDAC2 protein Q92769 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-257914 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 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC6 protein Q9UBN7 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-257926 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC9 protein Q9UKV0 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-257925 vorinostat chemical CHEBI:45716 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-257921 levomilnacipran chemical CHEBI:136040 ChEBI SLC6A2 protein P23975 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 18468895 t Luana "Studies on a series of milnacipran analogs containing a heteroaromatic group as potent norepinephrine and serotonin transporter inhibitors" SIGNOR-257946 N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide chemical CHEBI:94525 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-257933 LRRK2 protein Q5S007 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000938 21658387 t lperfetto "A knockdown experiment using intact cells also demonstrated LRRK2-mediated phosphorylation of Akt1 (Ser473), suggesting that Akt1 is a convincing candidate for the physiological substrate of LRRK2." SIGNOR-174044 N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide chemical CHEBI:94525 ChEBI HDAC2 protein Q92769 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-257934 belinostat chemical CHEBI:61076 ChEBI HDAC7 protein Q8WUI4 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257954 belinostat chemical CHEBI:61076 ChEBI HDAC8 protein Q9BY41 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257958 PRKAA1 protein Q13131 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "up-regulates activity" phosphorylation Ser626 SLECDMEsIIRSELM 9606 BTO:0000007 17711846 t gcesareni "Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization." SIGNOR-252979 "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI RXRA protein P19793 UNIPROT "up-regulates activity" binding 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-256192 "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI RXRB protein P28702 UNIPROT "up-regulates activity" binding 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-256191 ALPL protein P05186 UNIPROT Bone_mineralization phenotype SIGNOR-PH69 SIGNOR up-regulates 9606 BTO:0004473 19049325 f miannu "PC-1 and Tnap work together to produce normally mineralized bone matrix through the generation and hydrolysis of pyrophosphate." SIGNOR-252196 AMOT protein Q4VCS5 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates relocalization 9606 BTO:0000567 21205866 t "AMOT proteins, a family of proteins including AMOT, AMOTL1, and AMOTL2, interact extensively with multiple TJ components and are important for maintaining TJ integrity and epithelial cell polarity." gcesareni "Our results indicate a potential tumor-suppressing role of AMOT family proteins as components of the Hippo pathway, and demonstrate a novel mechanism of YAP and TAZ inhibition by AMOT-mediated tight junction localization. These observations provide a potential link between the Hippo pathway and cell contact inhibition." SIGNOR-175776 AMOT protein Q4VCS5 UNIPROT YAP1 protein P46937 UNIPROT down-regulates relocalization 9606 BTO:0000567 21205866 t gcesareni "Our results indicate a potential tumor-suppressing role of AMOT family proteins as components of the Hippo pathway, and demonstrate a novel mechanism of YAP and TAZ inhibition by AMOT-mediated tight junction localization. These observations provide a potential link between the Hippo pathway and cell contact inhibition." SIGNOR-201135 entinostat chemical CHEBI:132082 ChEBI HDAC1 protein Q13547 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257963 entinostat chemical CHEBI:132082 ChEBI HDAC2 protein Q92769 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257962 entinostat chemical CHEBI:132082 ChEBI HDAC3 protein O15379 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257961 PRKCA protein P17252 UNIPROT CTPS1 protein P17812 UNIPROT down-regulates phosphorylation Thr455 MRLGKRRtLFQTKNS 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-154621 JWOGUUIOCYMBPV-GMFLJSBRSA-N chemical CID:6918328 PUBCHEM HDAC2 protein Q92769 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257979 JWOGUUIOCYMBPV-GMFLJSBRSA-N chemical CID:6918328 PUBCHEM HDAC3 protein O15379 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257978 AMPK complex SIGNOR-C15 SIGNOR RRN3 protein Q9NYV6 UNIPROT down-regulates phosphorylation Ser635 DTHFRSPsSSVGSPP 9606 19815529 t lperfetto "We show that ampk down-regulates rrna synthesis under glucose restriction by phosphorylating the rna polymerase i (pol i)-associated transcription factor tif-ia at a single serine residue (ser-635)." SIGNOR-216592 AMPK complex SIGNOR-C15 SIGNOR TSC2 protein P49815 UNIPROT up-regulates phosphorylation Ser1387 QPLSKSSsSPELQTL 9606 16959574 t lperfetto "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. Phosphorylation of tsc2 by ampk is required for translation regulation and cell size control in response to energy deprivation." SIGNOR-216438 MAP2K1 protein Q02750 UNIPROT ARRB2 protein P32121 UNIPROT "up-regulates activity" phosphorylation Thr382 EFDTNYAtDDDIVFE 9606 BTO:0000007 28169830 t "Here, we show that activation of serotonin 5-HT2C receptors, which engage Erk1/2 pathway via a _-arrestin-dependent mechanism, promotes MEK-dependent _-arrestin2 phosphorylation at Thr383" SIGNOR-252027 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC1 protein Q13547 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257984 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC4 protein P56524 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257986 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC5 protein Q9UQL6 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257987 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC6 protein Q9UBN7 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257988 6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide chemical CHEBI:92401 ChEBI HDAC6 protein Q9UBN7 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257999 PDK4 protein Q16654 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates phosphorylation Ser300 SMSDPGVsYRTREEI -1 7782287 t gcesareni "Mammalian pyruvate dehydrogenase (?2_2) (e1) is regulated by phosphorylation-dephosphorylation, catalyzed by the e1-kinase and the phospho-e1-phosphatase." SIGNOR-33201 6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide chemical CHEBI:92401 ChEBI HDAC2 protein Q92769 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-258006 6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide chemical CHEBI:92401 ChEBI HDAC5 protein Q9UQL6 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-258005 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT "up-regulates activity" phosphorylation Thr402 PEQSKRStMVGTPYW -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-250230 "trichostatin A" chemical CHEBI:46024 ChEBI HDAC2 protein Q92769 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-258015 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 Naphtho[1,2-d]thiazol-2-amine chemical CID:94880 PUBCHEM KCNN3 protein Q9UGI6 UNIPROT "up-regulates activity" "chemical activation" 9534 BTO:0000298 18955585 t Luana "Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM. " SIGNOR-258024 PTK2 protein Q05397 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr576 RYMEDSTyYKASKGK 9606 BTO:0000671 15694384 t llicata "Once stimulated, fak undergoes autophosphorylation at tyrosine (y) 397, followed by phosphorylation of several sites including y576/y577 which increases fak's kinase activity, as well as at y407, y861, and y925." SIGNOR-133841 STK4 protein Q13043 UNIPROT MOB1B protein Q7L9L4 UNIPROT up-regulates phosphorylation Thr35 LLKHAEAtLGSGNLR 9606 23431053 t milica "Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity" SIGNOR-201318 "[5-fluoro-1-(4-isopropylbenzylidene)-2-methylinden-3-yl]acetic acid" chemical CHEBI:59660 ChEBI RXRA protein P19793 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001109 20541701 t Luana "NSAID Sulindac and Its Analogs Bind RXRα and Inhibit RXRα-dependent AKT Signaling" SIGNOR-258031 "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI RARG protein P13631 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-258030 "dasatinib (anhydrous)" chemical CHEBI:49375 ChEBI ABL1 protein P00519 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-258063 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 tazarotene chemical CHEBI:32184 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-258028 "4-{[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]amino}benzoic acid" chemical CHEBI:64210 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-258035 AURKB protein Q96GD4 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT "up-regulates activity" phosphorylation Thr145 AGNKRLStIDESGSI 9606 BTO:0000567 14744859 t llicata "It was found that the 5A fragment in which five Ser/Thr residues were substituted with Ala (S144A/T145A/S185A/T186A/S187A) fully prevented phosphorylation (Fig. 5B), confirming that Aurora B primarily phosphorylates five Ser/Thr residues in the basic region of MgcRacGAP. | the strong phosphorylation of the basic region of MgcRacGAP by Aurora B kinase was demonstrated, and this phosphorylation prevents the inhibition of MgcRacGAP GAP activity by PRC1" SIGNOR-250589 CSNK2A1 protein P68400 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-250933 PTPN11 protein Q06124 UNIPROT HRAS protein P01112 UNIPROT "up-regulates activity" dephosphorylation Tyr32 QNHFVDEyDPTIEDS 9606 BTO:0000007 26617336 t "Here we identify SHP2 as the ubiquitously expressed tyrosine phosphatase that preferentially binds to and dephosphorylates Ras to increase its association with Raf and activate downstream proliferative Ras/ERK/MAPK signalling." SIGNOR-252094 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 aclidinium chemical CHEBI:65346 ChEBI CHRM2 protein P08172 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000131 19653626 t Luana "This compound is a potent muscarinic antagonist, with long duration of action in vivo, and was found to have a rapid hydrolysis in human plasma, minimizing the potential to induce class-related systemic side effects." SIGNOR-258049 Ast-487 chemical CID:11409972 PUBCHEM KIT protein P10721 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t llicata "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-258070 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 NCOA4 protein Q13772 UNIPROT PPARG protein P37231 UNIPROT up-regulates binding 9606 10347167 t miannu "Identification of ara70 as a ligand-enhanced coactivator for the peroxisome proliferator-activated receptor gamma. / ppargamma and ara70 interact in the absence of the ppargamma ligand 15-deoxy-delta12,14-prostaglandin j2, although the addition of exogenous ligand enhances this interaction." SIGNOR-67687 PRKACA protein P17612 UNIPROT CREB1 protein P16220 UNIPROT "up-regulates activity" phosphorylation Ser133 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 4-{[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl]amino}-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide chemical CHEBI:49868 ChEBI PLK1 protein P53350 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-258078 L-thyroxine(1-) chemical CHEBI:60302 ChEBI UGT1A1 protein P22309 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 21030469 t Luana "Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation." SIGNOR-258051 4-methylumbelliferone chemical CHEBI:17224 ChEBI UGT1A1 protein P22309 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 21030469 t Luana "Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation." SIGNOR-258057 AMPK complex SIGNOR-C15 SIGNOR ULK1 protein O75385 UNIPROT up-regulates phosphorylation 9606 21460634 t lperfetto "Ampk and ulk1 interact and that the latter is phosphorylated by ampk. This phosphorylation leads to the direct activation of ulk1 by ampk bypassing mtor-inhibition." SIGNOR-216464 AMPK complex SIGNOR-C15 SIGNOR VASP protein P50552 UNIPROT down-regulates phosphorylation Thr278 LARRRKAtQVGEKTP 9606 17082196 t lperfetto "Pharmacological ampk inhibitors and activators and ampk mutants revealed that the kinase specifically targets residue thr-278 but not ser-157 or ser-239. Quantitative fluorescence-activated cell sorter analysis and serum response factor transcriptional reporter assays, which quantify the cellular f-/g-actin equilibrium, indicated that ampk-mediated vasp phosphorylation impaired actin stress fiber formation and altered cell morphology." SIGNOR-216515 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation 9606 21880741 t miannu "Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat." SIGNOR-255463 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 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 afatinib chemical CHEBI:61390 ChEBI ERBB2 protein P04626 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-258066 CDK1 protein P06493 UNIPROT PBK protein Q96KB5 UNIPROT unknown phosphorylation Thr9 EGISNFKtPSKLSEK 9606 SIGNOR-C17 15541388 t llicata "Topk-thr-9 was phosphorylated by cdk1/cyclin b and topk significantly associates with mitotic spindles." SIGNOR-130439 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 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 axitinib chemical CHEBI:66910 ChEBI KIT protein P10721 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-258073 axitinib chemical CHEBI:66910 ChEBI PDGFRA protein P16234 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-258074 axitinib chemical CHEBI:66910 ChEBI PDGFRB protein P09619 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-258075 mTORC2 complex SIGNOR-C2 SIGNOR AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation Thr450 TAQMITItPPDQDDS 10090 BTO:0002572 18566586 t gcesareni "MTORC2 phosphorylates newly synthesized Akt at the TM (Thr450) site to facilitate carboxyl-terminal folding and to stabilize Akt" SIGNOR-252438 "2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid" chemical CID:135461425 PUBCHEM FGFR2 protein P21802 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t llicata "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-258080 "2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid" chemical CID:135461425 PUBCHEM FGFR3 protein P22607 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t llicata "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-258081 (2R)-1-[[4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-5-methyl-6-pyrrolo[2,1-f][1,2,4]triazinyl]oxy]-2-propanol chemical CHEBI:94562 ChEBI FGFR1 protein P11362 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-258090 (2R)-1-[[4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-5-methyl-6-pyrrolo[2,1-f][1,2,4]triazinyl]oxy]-2-propanol chemical CHEBI:94562 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-258091 canertinib chemical CHEBI:61399 ChEBI ERBB2 protein P04626 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-258093 canertinib chemical CHEBI:61399 ChEBI PDGFRA protein P16234 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-258094 TRAF6 protein Q9Y4K3 UNIPROT MAP3K8 protein P41279 UNIPROT "up-regulates activity" 9606 BTO:0000007 16371247 f "The activation of Cot-MKK1-ERK1/ERK2 signalling pathway by IL-1 is dependent on the activity of the transducer protein TRAF6." SIGNOR-252254 1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-2-benzimidazolamine chemical CHEBI:91451 ChEBI BRAF protein P15056 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-258097 BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR BCR protein P11274 UNIPROT down-regulates phosphorylation Tyr360 VSPSPTTyRMFRDKS 9606 BTO:0001271 8622703 t lperfetto "We have previously demonstrated that the bcr protein is tyrosine phosphorylated within first-exon sequences by the bcr-abl oncoprotein. Here we report that in addition to tyrose 177 (y-177), y-360 and y283 are phosphorylated in bcr-abl proteins in vitro. Tyrosine-phosphorylated bcr, phosphorylated in vitro by bcr-abl, was greatly inhibited in its serine/threonine kinase activity, impairing both auto- and transkinase activities of bcr." SIGNOR-40619 canertinib chemical CHEBI:61399 ChEBI PDGFRB protein P09619 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-258095 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 1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-2-benzimidazolamine chemical CHEBI:91451 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-258098 4-amino-5-fluoro-3-[5-(4-methyl-1-piperazinyl)-1,3-dihydrobenzimidazol-2-ylidene]-2-quinolinone chemical CHEBI:91395 ChEBI FGFR3 protein P22607 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-258105 crizotinib chemical CHEBI:64310 ChEBI ALK protein Q9UM73 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-258101 crizotinib chemical CHEBI:64310 ChEBI MET protein P08581 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-258102 PTPRH protein Q9HD43 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 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-76072 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 BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR CRKL protein P46109 UNIPROT up-regulates phosphorylation Tyr207 IPEPAHAyAQPQTTT 9606 BTO:0001271 9053848 t lperfetto "Tyrosine 207 in crkl is the bcr/abl phosphorylation sitephosphorylation of y207 provides a binding site for the crkl sh2 domain and potentially for other sh2-containing proteins." SIGNOR-46893 "5-[1-(2-hydroxyethyl)-3-pyridin-4-yl-4-pyrazolyl]-2,3-dihydroinden-1-one oxime" chemical CHEBI:91434 ChEBI BRAF protein P15056 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-258112 AKT proteinfamily SIGNOR-PF24 SIGNOR GATA1 protein P15976 UNIPROT up-regulates phosphorylation Ser310 QTRNRKAsGKGKKKR 9606 16107690 t lperfetto "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-244267 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 2-[[2-[[1-[2-(dimethylamino)-1-oxoethyl]-5-methoxy-2,3-dihydroindol-6-yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-6-fluoro-N-methylbenzamide chemical CHEBI:93768 ChEBI IGF1R protein P08069 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-258116 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 ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT unknown phosphorylation Ser784 GVEKCSDsQSWEDIA 9606 12697768 t llicata "To examine whether the respective sq sites become phosphorylated in vivo, we raised polyclonal antibodies against phosphorylated ser-6 (anti-s6p), phosphorylated ser-25 and ser-29 (anti-s25p/29p), and phosphorylated ser-784 (anti-s784p). All affinity-purified antisera recognized 53bp1" SIGNOR-100653 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 AURKB protein Q96GD4 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser278 QKVAERRsSPLLRRK 9606 22865920 t lperfetto "We define the precise site of aurb-mediated phosphorylation as a conserved serine within the nuclear localization signals of hdac4, hdac5, and hdac9 at ser265, ser278, and ser242, respectivelyduring mitosis, aurb-mediated phosphorylation may localize class iia hdacs to a phosphorylation gradient at the spindle midzone, permitting temporal and spatial regulatory mechanisms altering hdac protein interactions" SIGNOR-198650 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR miR-155 mirna MI0000681 miRBase "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004479 25092144 f miannu "We showed a strong induction of miR-155 promoter activity by p65. We demonstrate that NF-κB (p65) directly binds to the miR-155 promoter in FLT3-ITD-associated MV4;11 cells." SIGNOR-255816 (2S)-3-(4-acetamidophenoxy)-2-hydroxy-2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]propanamide chemical CHEBI:94760 ChEBI AR protein P10275 UNIPROT up-regulates "chemical activation" 9606 Other t Selleck gcesareni SIGNOR-189623 ANAPC5 protein Q9UJX4 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-252005 ANAPC7 protein Q9UJX3 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-252007 APC-c complex SIGNOR-C150 SIGNOR CDR2 protein Q01850 UNIPROT "down-regulates quantity by destabilization" ubiquitination 20383333 t lperfetto "Here we find that cdr2 is cell cycle regulated in tumor cells with protein levels peaking in mitosis. As cells exit mitosis, cdr2 is ubiquitinated by the anaphase promoting complex/cyclosome (APC/C) and rapidly degraded by the proteasome. Previously we showed that cdr2 binds to the oncogene c-myc, and here we extend this observation to show that cdr2 and c-myc interact to synergistically regulate c-myc-dependent transcription during passage through mitosis." SIGNOR-252024 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 ARFGAP1 protein Q8N6T3 UNIPROT LRRK2 protein Q5S007 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 22363216 t "The effect has been demonstrated using Q8N6T3-2" flangone "The gtp hydrolysis activity of lrrk2 is markedly enhanced by arfgap1 supporting a role for arfgap1 as a gtpase-activating protein for lrrk2.Lrrk2 and arfgap1 interact in vitro in mammalian cells and in vivo in brain, and co-localize in the cytoplasm and at golgi membranes" SIGNOR-196264 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-244243 CSNK2A1 protein P68400 UNIPROT MAX protein P61244 UNIPROT down-regulates phosphorylation Ser2 sDNDDIEV 9606 8018564 t gcesareni "Here, we have mapped the nh2-terminal in vivo phosphorylation sites of max to ser2 and ser11[...]" SIGNOR-35772 "4-{[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]amino}benzoic acid" chemical CHEBI:64210 ChEBI RARG protein P13631 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-258140 AMPK complex SIGNOR-C15 SIGNOR ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser317 SHLASPPsLGEMQQL 9606 19584320 t lperfetto "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-216491 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 NCOR2 protein Q9Y618 UNIPROT BHLHE41 protein Q9C0J9 UNIPROT up-regulates binding 9606 12897056 t gcesareni "The spen protein, sharp (smrt/hdac1-associated repressor protein), was identified as a component of transcriptional repression complexes in both nuclear receptor and notch/rbp-jkappa signaling pathways." SIGNOR-104489 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 hydromorphone chemical CHEBI:5790 ChEBI OPRD1 protein P41143 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000246 19282177 t Luana "A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ." SIGNOR-258143 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol chemical CHEBI:75722 ChEBI OPRM1 protein P35372 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000246 19282177 t Luana "A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ." SIGNOR-258149 PRMT1 protein Q99873 UNIPROT CNBP protein P62633 UNIPROT down-regulates methylation Arg27 PTGGGRGrGMRSRGR 9606 24726729 t miannu "Cnbp interacts with protein arginine methyltransferase prmt1 / r25 or r27 appear to be the major methylation sites in cnbp /arginine methylation of cnbp impedes rna binding" SIGNOR-204962 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 FYN protein P06241 UNIPROT CBL protein P22681 UNIPROT "up-regulates activity" phosphorylation Tyr731 QQIDSCTyEAMYNIQ 9606 BTO:0001454 9890970 t lperfetto "Fyn associates with cbl and phosphorylates tyrosine 731 in cbl, a binding site for phosphatidylinositol 3-kinasecbl represents a substrate for src-like kinases that are activated in response to the engagement of cell surface receptors, and that src-like kinases are responsible for the phosphorylation of a tyrosine residue in cbl that may regulate activation of phosphatidylinositol 3-kinase" SIGNOR-63968 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 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-135105 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-130920 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 MAPK14 protein Q16539 UNIPROT SLC9A1 protein P19634 UNIPROT up-regulates phosphorylation Ser726 IDPASPQsPESVDLV 9606 11604491 t llicata "Trophic factor withdrawal: p38 mitogen-activated protein kinase activates nhe1, which induces intracellular alkalinization. activated p38 mapk directly phosphorylated the c terminus of nhe1 within a 40-amino-acid region. Analysis by mass spectroscopy identified four phosphorylation sites on nhe1, thr 717, ser 722, ser 725, and ser 728." SIGNOR-111043 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 PAK5 protein Q9P286 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser75 EIRSRHSsYPAGTED 9534 BTO:0000298 12897128 t miannu "P21-Activated kinase 5 (Pak5) localizes to mitochondria and inhibits apoptosis by phosphorylating BAD. Pak5 phosphorylates BAD Ser-112" SIGNOR-250247 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 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 NPFFR1 protein Q9GZQ6 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-256987 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-137430 carvedilol chemical CHEBI:3441 ChEBI UGT1A1 protein P22309 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 21030469 t Luana "Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation." SIGNOR-258165 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 afatinib chemical CHEBI:61390 ChEBI EGFR protein P00533 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-258169 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-139391 alvocidib chemical CHEBI:47344 ChEBI CDK2 protein P24941 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-258171 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK2 protein P24941 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-258176 4-[[5-amino-1-[(2,6-difluorophenyl)-oxomethyl]-1,2,4-triazol-3-yl]amino]benzenesulfonamide chemical CHEBI:94506 ChEBI AURKB protein Q96GD4 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193534 ATM protein Q13315 UNIPROT H2AFX 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 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 CDK2 protein P24941 UNIPROT COIL protein P38432 UNIPROT up-regulates phosphorylation Ser184 NEEAKRKsPKKKEKC 9606 BTO:0000567;BTO:0000938 SIGNOR-C16 11102515 t lperfetto "In particular, we have recently found that the cdk2/cyclin e complex can phosphorylate coilin in vitro . there is but a single consensus cdk2/cyclin e phosphorylation site in coilin, located at serine 184. when serine 184 was mutated to an alanine (s184a), mimicking a dephosphorylated state, a nucleolar mislocalization similar to that of gfp-coilin(1_248) was observed" SIGNOR-84949 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser15 PSVEPPLsQETFSDL 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-153463 2-[3-[[7-[3-[ethyl(2-hydroxyethyl)amino]propoxy]-4-quinazolinyl]amino]-1H-pyrazol-5-yl]-N-(3-fluorophenyl)acetamide chemical CHEBI:91367 ChEBI AURKB protein Q96GD4 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-258181 "2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid" chemical CID:135461425 PUBCHEM FGFR1 protein P11362 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t llicata "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-258183 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-141424 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-143098 "2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid" chemical CID:135461425 PUBCHEM KDR protein P35968 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t llicata "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-258188 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 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 PDK1 protein Q15118 UNIPROT PDHA1 protein P08559 UNIPROT "down-regulates activity" phosphorylation Ser232 NRYGMGTsVERAAAS -1 11485553 t lperfetto "Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293." SIGNOR-109547 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-145284 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-145288 ATM protein Q13315 UNIPROT ATM protein Q13315 UNIPROT "up-regulates activity" phosphorylation Ser2996 QECKRNLsDIDQSFN 9606 21149446 t gcesareni "In human cells, the activation process involves autophosphorylation on three sites (ser367, ser1893, and ser1981) and acetylation on lys3016. We now describe the identification of a new atm phosphorylation site, thr(p)1885 and an additional autophosphorylation site, ser(p)2996, that is highly dna damage-inducible." SIGNOR-170473 CSNK1A1 protein P48729 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser111 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 ATM protein Q13315 UNIPROT XPA protein P23025 UNIPROT unknown phosphorylation Ser196 RSLEVWGsQEALEEA -1 16540648 t llicata "Kinase phosphorylation assays were done with synthesized short peptides (20-mer) with the sequences at Ser173 and Ser196 of XPA, respectively. Both peptides seemed to be good substrates for DNA-PK, ATR ( Fig. 2D), and ATM (data not shown)." SIGNOR-250580 canertinib chemical CHEBI:61399 ChEBI EGFR protein P00533 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-258196 CDC7 protein O00311 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-143984 CDK3 protein Q00526 UNIPROT LIN9 protein Q5TKA1 UNIPROT up-regulates phosphorylation Thr96 KFTATMStPDKKASQ 9606 BTO:0002181 24475316 t lperfetto "In this report, we demonstrate that cyclin e1/cdk3 phosphorylates lin-9 on thr-96. Mutating thr-96 to alanine inhibits activation of cyclins a2 and b1 promoters, whereas a phosphomimetic asp mutant strongly activates their promoters and triggers accelerated entry into g2/m phase in 293t cells." SIGNOR-204529 canertinib chemical CHEBI:61399 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-258200 CSNK2A1 protein P68400 UNIPROT CDC34 protein P49427 UNIPROT "down-regulates activity" phosphorylation Ser222 EVEEEADsCFGDDED 9606 BTO:0000567 11546811 t lperfetto "The ubiquitin-conjugating enzyme, cdc34, has been implicated in the ubiquitination of a number of vertebrate substrates, including p27(kip1), ikappabalpha, wee1, and myod. We show that mammalian cdc34 is a phosphoprotein that is phosphorylated in proliferating cells. Phosphorylation of cdc34 by the associated kinase maps predominantly to residues 203 and 222. Mutation of cdc34 at ck2-targeted residues, ser-203, ser-222, ser-231, thr-233, and ser-236, abolishes the phosphorylation of cdc34 observed in vivo and markedly shifts nuclearly localized cdc34 to the cytoplasm." SIGNOR-110395 MAPK9 protein P45984 UNIPROT BCL2L11 protein O43521 UNIPROT "up-regulates activity" phosphorylation Ser69 GPLAPPAsPGPFATR 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." SIGNOR-250136 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-151216 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 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 doramapimod chemical CHEBI:40953 ChEBI MAPK14 protein Q16539 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-258208 EGFR protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr307 MRHVSISyDIPPTPG -1 10734310 t lperfetto "Gab1 is also phosphorylated in response to epidermal growth factor (egf) but is unable to induce tubule formation. nine tyrosines are phosphorylated by both receptors. Three of them (y307, y373, y407) bind phospholipase c-gamma (plc-gamma)." SIGNOR-233233 AKT proteinfamily SIGNOR-PF24 SIGNOR RANBP3 protein Q9H6Z4 UNIPROT unknown phosphorylation Ser126 VKRERTSsLTQFPPS 9606 18280241 t llicata "Akt regulates ranbp3 phosphorylation in vitro and in vivo" SIGNOR-160900 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-157467 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 CSNK2A1 protein P68400 UNIPROT HMGN1 protein P05114 UNIPROT down-regulates phosphorylation Ser7 sSAEGAAK 9606 10739259 t gcesareni "Peptide mass and sequence analysis showed major and minor phosphorylation sites, respectively, at ser24 and ser28 in hmg-17, and ser20 and ser24 in hmg-14 a third phosphorylation site in hmg-14 was located at either ser6 or ser7phosphorylation of ser6 and ser7 may compromise the binding of hmgn1 protein to the binding domain of importin proteins, which in turn affects the nuclear transport and sub-cellular localization of hmgn1 protein. Protein kinase ck2 could potentially be an enzyme that regulates this process." SIGNOR-76266 2-[[2-[[1-[2-(dimethylamino)-1-oxoethyl]-5-methoxy-2,3-dihydroindol-6-yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-6-fluoro-N-methylbenzamide chemical CHEBI:93768 ChEBI ALK protein Q9UM73 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-258219 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-161829 5-[6-[(4-methyl-1-piperazinyl)methyl]-1-benzimidazolyl]-3-[(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy]-2-thiophenecarboxamide chemical CHEBI:91333 ChEBI PLK1 protein P53350 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-258221 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-162984 AKT proteinfamily SIGNOR-PF24 SIGNOR VIM protein P08670 UNIPROT up-regulates 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-167971 CDK1 protein P06493 UNIPROT DDX3X protein O00571 UNIPROT down-regulates phosphorylation Thr204 LTRYTRPtPVQKHAI 9606 SIGNOR-C17 16280325 t lperfetto "Thr204 to glu204 ddx3 mutant protein lost its function, suggesting that phosphorylation at thr204 affects ddx3 function. Thr204 was phosphorylated by cyclin b/cdc2. Thr323 in motif ib was also phosphorylated by cyclin b/cdc2 kinase. We propose a novel function of cyclin b/cdc2 kinase in mitosis, which is to cause a loss of ddx3 function to repress cyclin a expression and to decrease ribosome biogenesis and translation during mitosis." SIGNOR-141565 imatinib chemical CHEBI:45783 ChEBI KIT protein P10721 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-258225 imatinib chemical CHEBI:45783 ChEBI PDGFRA protein P16234 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-258226 imatinib chemical CHEBI:45783 ChEBI PDGFRB protein P09619 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-258227 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 [4-[2-(1H-indazol-3-yl)ethenyl]phenyl]-(1-piperazinyl)methanone chemical CHEBI:91441 ChEBI AURKA protein O14965 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-258232 [4-[2-(1H-indazol-3-yl)ethenyl]phenyl]-(1-piperazinyl)methanone chemical CHEBI:91441 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-258233 AKT3 protein Q9Y243 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni "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-183644 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 AURKA protein O14965 UNIPROT TP53 protein P04637 UNIPROT down-regulates phosphorylation Ser315 LPNNTSSsPQPKKKP 9606 14702041 t gcesareni "Aurora kinase a phosphorylates p53 at ser315, leading to its ubiquitination by mdm2 and proteolysis" SIGNOR-120836 CAMK4 protein Q16566 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser498 RPLSRTQsSPLPQSP 9606 BTO:0000887;BTO:0001103 12058061 t lperfetto "Recently, camkiv, a calcium-calmodulindependent protein kinase, was also shown to activate mef2s by dissociating class ii histone deacetylases (e.g., Hdac5) from mef2s, thus relieving the transcriptional repressive effect of hdacs." SIGNOR-236575 DUSP3 protein P51452 UNIPROT EGFR protein P00533 UNIPROT "down-regulates activity" dephosphorylation Tyr1016 DVVDADEyLIPQQGF 9606 BTO:0002552 21262974 t "We found that EGF receptor (EGFR) was a direct substrate of VHR and that overexpression of VHR down-regulated EGFR phosphorylation, particularly at Tyr-992 residue. Expression of VHR inhibited the activation of phospholipase Cγ and protein kinase C, both downstream effectors of Tyr-992 phosphorylation of EGFR." SIGNOR-248532 CAMK2A protein Q9UQM7 UNIPROT NCOR2 protein Q9Y618 UNIPROT down-regulates phosphorylation Ser2437 ASGDRPPsVSSVHSE 9606 22888005 t lperfetto "We demonstrated that camkii directly bound and phosphorylated smrt at ser-1407, thereby facilitating smrt translocation from the nucleus to the cytoplasm and proteasome-dependent degradation." SIGNOR-191773 linifanib chemical CHEBI:91435 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-258243 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 CSNK2A1 protein P68400 UNIPROT IGFBP3 protein P17936 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser140 APGNASEsEEDRSAG 9606 BTO:0000093 10650937 t llicata "The importance of Ser111 and Ser113 as targets for CK2 has also been shown in our laboratory, as mutation of either residue to alanine caused a major decrease in IGFBP-3 phosphorylation by this enzyme in vitro | These results indicate that IGFBP-3 interaction with acid-labile subunit and with the cell surface, both of which involve basic carboxyl-terminal residues, may be modulated by phosphorylation. Relative resistance to proteolysis and poor binding to cells suggest that CK2-phospho-IGFBP-3 may be a significant inhibitor of IGF activity in the extracellular environment." SIGNOR-250904 CSNK2B protein P67870 UNIPROT OCLN protein Q16625 UNIPROT unknown phosphorylation Thr404 HYETDYTtGGESCDE 9606 BTO:0002043 12804768 t llicata "Mutagenesis of serine 407 to alanine resulted in reduced ability of the kinase to phosphorylate occludin. The threonine 403 to alanine mutant had a smaller effect but the double mutant (T403/S407A) was even less phosphorylated than either of the single mutants. These data are consistent with the claim that CK2 is the kinase in brain extracts responsible for phosphorylation of occludin." SIGNOR-251080 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 CDK1 protein P06493 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-161801 CDK2 protein P24941 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser263 CKLFDSPsLCSSSTR 9606 17110335 t gcesareni "We show here that dna-responsive checkpoints activate pp2a/b56delta phosphatase complexes to dephosphorylate cdc25 at a site distinct from ser287 (t138), the phosphorylation of which is required for 14-3-3 release." SIGNOR-150839 nilotinib chemical CHEBI:52172 ChEBI ABL1 protein P00519 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-258256 PLK1 protein P53350 UNIPROT CDC6 protein Q99741 UNIPROT up-regulates phosphorylation Thr37 SDAKLEPtNVQTVTC 9606 21041660 t lperfetto "Binding between cdc6 and plk1 occurs through the polo-box domain of plk1, and cdc6 is phosphorylated by plk1 on t37. These results suggest that plk1-mediated phosphorylation of cdc6 promotes the interaction of cdc6 and cdk1, leading to the attenuation of cdk1 activity, release of separase, and subsequent anaphase progression." SIGNOR-169184 PLX-4720 chemical CHEBI:90295 ChEBI BRAF protein P15056 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-258267 SATB1 protein Q01826 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000725 23563689 f miannu "Satb1 simultaneously repressed sets of genes encoding molecules involved in HSC activation and cellular polarity, including Numb and Myc" SIGNOR-224831 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-179059 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 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR NPM1 protein P06748 UNIPROT "down-regulates activity" phosphorylation Thr234 SFKKQEKtPKTPKGP 9606 14670079 t lperfetto "We have recently found that nucleophosmin (npm/b23), a phosphoprotein primarily found in nucleolus, associates with unduplicated centrosomes and is a direct substrate of cdk2-cyclin e in centrosome duplication." SIGNOR-216690 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 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 5-[(Z)-(5-Fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-3H-pyrrole-3-carboxamide chemical CID:73755145 PUBCHEM PDGFRB protein P09619 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t llicata "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-258288 7-[4-[4-(2,3-Dichlorophenyl)-1,4-diazepan-1-yl]butoxy]-3,4-dihydro-1H-quinolin-2-one chemical CID:56597938 PUBCHEM DRD2 protein P14416 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002181 22025698 t Luana "Through a robust diversity-oriented modification of the scaffold represented by aripiprazole (1), we discovered UNC9975 (2), UNC0006 (3), and UNC9994 (4) as unprecedented β-arrestin–biased D2R ligands. " SIGNOR-258320 6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)-4-pyrimidinyl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one chemical CHEBI:91348 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-258294 7-[4-[4-(2,3-Dichlorophenyl)-1,4-diazepan-1-yl]butoxy]-3,4-dihydro-1H-1,8-naphthyridin-2-one chemical CID:56593482 PUBCHEM DRD2 protein P14416 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002181 22025698 t Luana "Through a robust diversity-oriented modification of the scaffold represented by aripiprazole (1), we discovered UNC9975 (2), UNC0006 (3), and UNC9994 (4) as unprecedented β-arrestin–biased D2R ligands. " SIGNOR-258321 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-199776 PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT "down-regulates activity" phosphorylation Ser241 SKQARANsFVGTAQY -1 12177059 t miannu "PDK1 kinase activity is negatively regulated by binding to 14-3-3 through the PDK1 autophosphorylation site Ser-241. PDK1 binds to 14-3-3 in vivo and in vitro through the residues surrounding the autophosphorylation site Ser-241 and that the association is achieved only when Ser-241 has been phosphorylated" SIGNOR-250077 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-201046 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-201121 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 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 gemfibrozil chemical CHEBI:5296 ChEBI PPARA protein Q07869 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000599 21889235 t Luana " The combination of stilbene scaffold and gemfibrozil enhances the PPARα agonistic activity." SIGNOR-258318 5-{3-[4-(2,3-Dichlorophenyl)piperidin-1-yl]propoxy}-1,3-benzothiazole chemical CID:56599142 PUBCHEM DRD2 protein P14416 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002181 22025698 t Luana "Through a robust diversity-oriented modification of the scaffold represented by aripiprazole (1), we discovered UNC9975 (2), UNC0006 (3), and UNC9994 (4) as unprecedented β-arrestin–biased D2R ligands. " SIGNOR-258322 "5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid" chemical CHEBI:76223 ChEBI PTGS1 protein P23219 UNIPROT "down-regulates activity" "chemical inhibition" -1 22091869 t Luana " Here we report the application of STD-NMR to characterize the binding of the anti-inflammatory drugs ibuprofen, diclofenac, and ketorolac to COX-1 and COX-2. " SIGNOR-258323 "5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid" chemical CHEBI:76223 ChEBI PTGS2 protein P35354 UNIPROT "down-regulates activity" "chemical inhibition" -1 22091869 t Luana " Here we report the application of STD-NMR to characterize the binding of the anti-inflammatory drugs ibuprofen, diclofenac, and ketorolac to COX-1 and COX-2. " SIGNOR-258324 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 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-83217 CSNK2A1 protein P68400 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation Ser129 SGSPSDNsGAEEMEV 9606 BTO:0000007 21735093 t gcesareni "CK2 hyperactivates AKT by phosphorylation at Ser129" SIGNOR-174691 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine smallmolecule CHEBI:44811 ChEBI PTAFR protein P25105 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-257567 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 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 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 AKT1 protein P31749 UNIPROT ACAP1 protein Q15027 UNIPROT unknown phosphorylation Ser554 SIRPRPGsLRSKPEP 9606 16256741 t llicata "Akt phosphorylates s554 in acap1" SIGNOR-252483 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-209651 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-141581 AKT1 protein P31749 UNIPROT COPS6 protein Q7L5N1 UNIPROT up-regulates phosphorylation Ser60 DHWIRMRsQEGRPVQ 9606 23095642 t llicata "Mechanistic studies show that akt causes csn6 phosphorylation at ser 60, which, in turn, reduces ubiquitin-mediated protein degradation of csn6." SIGNOR-252532 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-96062 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 BRAF protein P15056 UNIPROT "down-regulates activity" phosphorylation Ser365 GQRDRSSsAPNVHIN 9606 BTO:0000007 10869359 t "Akt phosphorylates both S364 and S428. Akt downregulates B-Raf activity in vivo" SIGNOR-251471 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 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 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 AKT2 protein P31751 UNIPROT MDM2 protein Q00987 UNIPROT "up-regulates activity" phosphorylation Ser166 SSRRRAIsETEENSD 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-109732 PF-04691502 chemical CID:25033539 PUBCHEM AKT1 protein P31749 UNIPROT down-regulates "chemical inhibition" 9606 Other t "Selleck;inhibitor of phosphorylation of AktT308 and AktS473" gcesareni SIGNOR-252631 PPP2CA protein P67775 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation Thr450 TAQMITItPPDQDDS 9606 11839802 t gcesareni "Integrin alpha 2 beta 1 promotes activation of protein phosphatase 2a and dephosphorylation of akt and glycogen synthase kinase 3 beta" SIGNOR-252616 PPP2R5B protein Q15173 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation Thr308 KDGATMKtFCGTPEY 9606 16495456 t gcesareni "Activation of pp2a is the intermediate step between the abeta-ceramide cascade and the subsequent inactivation of akt." SIGNOR-252615 AMPK complex SIGNOR-C15 SIGNOR BAIAP2 protein Q9UQB8 UNIPROT down-regulates phosphorylation Ser366 KTLPRSSsMAAGLER 9606 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-216572 AMPK complex SIGNOR-C15 SIGNOR PAK2 protein Q13177 UNIPROT unknown phosphorylation Ser20 APPVRMSsTIFSTGG 9606 22137581 t lperfetto "Together, these results indicate that ampk phosphorylates endogenous ppp1r12c at s452 and pak2 at s20 in human cells." SIGNOR-216612 AMPK complex SIGNOR-C15 SIGNOR PPP1R12C protein Q9BZL4 UNIPROT down-regulates phosphorylation Ser452 AGLQRSAsSSWLEGT 9606 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-216600 Apoptosome complex SIGNOR-C230 SIGNOR CASP3 protein P42574 UNIPROT "up-regulates activity" cleavage 9606 BTO:0000567 9390557 t lperfetto "Activated caspase-9 in turn cleaves and activates caspase-3. Mutation of the active site of caspase-9 attenuated the activation of caspase-3 and cellular apoptotic response in vivo, indicating that caspase-9 is the most upstream member of the apoptotic protease cascade." SIGNOR-256472 APPL1 protein Q9UKG1 UNIPROT STK11 protein Q15831 UNIPROT up-regulates binding 9606 BTO:0000887 19520843 t milica "In this study, we identified lkb1 as a new binding partner of appl1 and showed that the bar domain of appl1 is involved in this interaction.Here we show that in muscle cells adiponectin and metformin induce ampk activation by promoting appl1-dependent lkb1 cytosolic translocation. Appl1 mediates adiponectin signaling by directly interacting with adiponectin receptors and enhances lkb1 cytosolic localization by anchoring this kinase in the cytosol." SIGNOR-186065 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 ARID5B protein Q14865 UNIPROT TAL1 protein P17542 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000661 29326336 f miannu "ARID5B positively regulates the expression of TAL1 and its regulatory partners. we also observed that ARID5B regulates the expression of four major components of the TAL1 complex (namely, TAL1,GATA3, RUNX1, and MYB) in Jurkat cells. Knockdown of ARID5B resulted in reductions of the H3K27ac signals at those enhancer loci (Supplemental Fig. S6E–H) and down-regulation of all four factors at the mRNA (Fig. 6E) and protein levels (Fig. 6F)." SIGNOR-256157 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 ATF3 protein P18847 UNIPROT GDF15 protein Q99988 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004743 15670751 t lperfetto "In addition, DIM increased the expression of NAG-1 as well as activating transcription factor 3 (ATF3), and the induction of ATF3 was earlier than that of NAG-1. The DIM treatment increased luciferase activity of NAG-1 in HCT-116 cells transfected with NAG-1 promoter construct. The results suggest that I3C represses cell proliferation through up-regulation of NAG-1 and that ATF3 may play a pivotal role in DIM-induced NAG-1 expression in human colorectal cancer cells." SIGNOR-253725 PRKCE protein Q02156 UNIPROT PRKCE protein Q02156 UNIPROT down-regulates phosphorylation Ser729 QEEFKGFsYFGEDLM 9606 11964154 t llicata "Protein kinase-inactive mutants of pkcepsilon were not phosphorylated at ser(729) in cells, and phosphorylation of this site leads to dephosphorylation of the activation-loop thr(566)" SIGNOR-117324 ATRX protein P46100 UNIPROT Immortality phenotype SIGNOR-PH47 SIGNOR down-regulates 9606 BTO:0000584 26428317 f "Telomere length must be maintained for the immortalization of malignant cells […] alternative lengthening of telomeres status was perfectly correlated with the loss of expression of either α-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated (DAXX) protein in pancreatic neuroendocrine tumors" SIGNOR-256595 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 BAD protein Q92934 UNIPROT BCL2 protein P10415 UNIPROT "down-regulates activity" relocalization 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-133756 BCL2 protein P10415 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 1286168 f lperfetto "Bcl-2 functions to inhibit apoptosis in a variety of in vitro and in vivo experiments, suggesting interference with a central mechanism of apoptosis" SIGNOR-256637 BMPR1A protein P36894 UNIPROT SMAD5/SMAD4 complex SIGNOR-C205 SIGNOR "up-regulates activity" phosphorylation 10090 BTO:0004058 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-255788 BTG2 protein P78543 UNIPROT CAT protein P04040 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000093 22493435 f miannu "BTG2 was found to up-regulate expression of antioxidant enzymes known to be regulated by NFE2L2, including catalase, SOD1, and SOD2" SIGNOR-254648 BTK protein Q06187 UNIPROT ITK protein Q08881 UNIPROT up-regulates phosphorylation Tyr180 ETVVIALyDYQTNDP 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 mechanismthe major phosphorylation sites were identified as conserved tyrosines, for itk y180" SIGNOR-98036 CAMK2A protein Q9UQM7 UNIPROT EGFR protein P00533 UNIPROT "down-regulates activity" phosphorylation Ser1081 TGALTEDsIDDTFLP 9606 BTO:0000007 10347170 t llicata " We show that serines 1046/1047 are sites for CaM kinase II phosphorylation, although there is a preference for serine 1047, which resides within the consensus -R-X-X-S-. In addition, we have identified major phosphorylation sites at serine 1142 and serine 1057, which lie within a novel -S-X-D- consensus. Mutation of serines 1046/1047 in full-length EGFR enhanced both fibroblast transformation and tyrosine autokinase activity that was significantly potentiated by additional mutation of serines 1057 and 1142. A single CaM kinase II site was also identified at serine 744 within sub-kinase domain III, and autokinase activity was significantly affected by mutation of this serine to an aspartic acid making this site appear constitutively phosphorylated. We have addressed the mechanism by which CaM kinase II phosphorylation of the EGFR might regulate receptor autokinase activity and show that this modification can hinder association of the cytoplasmic tail with the kinase domain to prevent an enzyme-substrate interaction. " SIGNOR-250622 CAMK4 protein Q16566 UNIPROT NOS1 protein P29475 UNIPROT "down-regulates activity" phosphorylation Ser852 SYKVRFNsVSSYSDS 10400690 t llicata "It was found that purified recombinant nNOS was phosphorylated by CaM-K Ialpha, CaM-K IIalpha, and CaM-K IV at Ser847 in vitro. Replacement of Ser847 with Ala (S847A) prevented phosphorylation by CaM kinases. Phosphorylated recombinant wild-type nNOS at Ser847 (approximately 0.5 mol of phosphate incorporation into nNOS) exhibited a 30% decrease of Vmax with little change of both the Km for L-arginine and Kact for CaM relative to unphosphorylated enzyme. The activity of mutant S847D was decreased to a level 50-60% as much as the wild-type enzyme. The decreased NOS enzyme activity of phosphorylated nNOS at Ser847 and mutant S847D was partially due to suppression of CaM binding, but not to impairment of dimer formation which is thought to be essential for enzyme activation." SIGNOR-250713 CARM1 protein Q86X55 UNIPROT SMARCC1 protein Q92922 UNIPROT "up-regulates activity" methylation Arg1064 PGNILGPrVPLTAPN 9606 BTO:0000007;BTO:0000356 24434208 t "CARM1-mediated BAF155 methylation affects gene expression by directing methylated BAF155 to unique chromatin regions (e.g., c-Myc pathway genes). Collectively, our studies uncover a mechanism by which BAF155 acquires tumorigenic functions via arginine methylation." SIGNOR-251708 RPS6K proteinfamily SIGNOR-PF26 SIGNOR CREB1 protein P16220 UNIPROT "up-regulates activity" phosphorylation Ser133 EILSRRPsYRKILND 9606 BTO:0000938 10558990 t lperfetto "The rsks phosphorylate the trascription factor creb at serine 133 to promote cell survival." SIGNOR-252782 CBP/p300 complex SIGNOR-C6 SIGNOR H3F3A protein P84243 UNIPROT up-regulates acetylation Lys28 LATKAARkSAPSTGG 9606 21131905 t lperfetto "These results highlight the substrate and site specificities of hats in cells, demonstrate the distinct roles of gcn5/pcaf- and cbp/p300-mediated histone acetylations in gene activation, and suggest an important role of cbp/p300-mediated h3k18/27ac in nr-dependent transcription." SIGNOR-217214 MMP14 protein P50281 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0005300 28709001 f "MMP14 Promotes Adipogenesis Downstream of or in Parallel to TIMP3" SIGNOR-255909 RPS6K proteinfamily SIGNOR-PF26 SIGNOR 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-252814 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 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-252827 "BMS 794833" chemical CID:44155856 PUBCHEM MET protein P08581 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190422 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 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 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 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 CDK1 protein P06493 UNIPROT CDC25A protein P30304 UNIPROT up-regulates phosphorylation Ser116 PQKLLGCsPALKRSH 9606 SIGNOR-C17 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-95256 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 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 CDK5 protein Q00535 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-173685 CHUK protein O15111 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 BTO:0000150 SIGNOR-C14 15084260 t gcesareni "Ikappab kinase promotes tumorigenesis through inhibition of forkhead foxo3a. The tnf treatment of ht-29 cells increased ikk-dependent foxo3 ser644 phosphorylation." SIGNOR-252893 CDK5 protein Q00535 UNIPROT EPRS protein P07814 UNIPROT down-regulates phosphorylation Ser886 LSQSSDSsPTRNSEP 9606 BTO:0000801 21220307 t lperfetto "Ser(886) phosphorylation is required for the interaction of nsap1, which blocks eprs binding to target mrnas. The same phosphorylation event induces subsequent binding of ribosomal protein l13a and gapdh and restores mrna binding. Ifn-_ activates cdk5 to phosphorylate ser(886) in the linker domain of glutamyl-prolyl trna synthetase (eprs), the initial event in assembly of the gait complex. Cdk5/p35 also induces, albeit indirectly via a distinct kinase, phosphorylation of ser(999), the second essential event in gait pathway activation" SIGNOR-171138 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr522 SSPGSPGtPGSRSRT 9606 BTO:0000590 12226093 t "The effect has been demonstrated using P10636-8" lperfetto "Phosphopeptide mapping revealed enhanced phosphorylation of ser(202)/thr(205) residues by p25-cdk5 considering the fact that phosphorylation of ser(202)/thr(205) antagonizes the tau-mediated nucleation of tubulin, p25-cdk5 may play a pivotal role in neuronal cell death in alzheimer's disease." SIGNOR-92607 MAPK12 protein P53778 UNIPROT CARM1 protein Q86X55 UNIPROT "down-regulates activity" phosphorylation Ser595 GPAISMAsPMSIPTN 10090 BTO:0002314 BTO:0001103 29681515 t apalma "Here, we identify a role for the mitogen-activated protein kinase (MAPK) p38g/MAPK12 as a critical regulator of satellite stem cell fate through phosphorylation of Carm1." SIGNOR-255897 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR DCX protein O43602 UNIPROT unknown phosphorylation Thr289 AGPKASPtPQKTSAK 9606 BTO:0000007 14741103 t llicata "In order to determine the sites of phosphorylation by Cdk5, serine or threonine in the nine potential sites were substituted with alanine by site-directed mutagenesis to create mutant Dcx proteins. hese were analyzed by co-transfection of 293T cells with cdk5/p35. All-sites-A mutant Dcx showed no slower migrating species on Western analysis, indicating that removal of all nine possible sites is sufficient to block the phosphorylation by Cdk5/p35. However, each single mutant Dcx retains the slower migrating species similar to the wild-type Dcx, suggesting that any single mutation is not sufficient to block phosphorylation by Cdk5/p35." SIGNOR-250656 CEBPB protein P17676 UNIPROT PPARG protein P37231 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 16431920 t fspada "These data suggest that c/CEBP beta activates a single unified pathway of adipogenesis involving its stimulation of PPARgamma expression, which then activates C/EBP alpha expression by dislodging HDAC1 from the promoter for degradation in the proteasome" SIGNOR-143952 PPP2CA protein P67775 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates dephosphorylation Ser253 APRRRAVsMDNSNKY 9606 18593906 t gcesareni "Pp2a-mediated dephosphorylation of t32/s253 is required for dissociation of 14-3-3, nuclear translocation, and transcriptional activation of foxo3a." SIGNOR-252971 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 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 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 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 BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR CSF2RB protein P32927 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0005248 8758906 t irozzo "We demonstrated that Bcr-Abl co-immunoprecipitates with, and constitutively phosphorylates, the common βc,subunit of the interleukin 3 and granulocyte/macrophage-colony stimulating factor receptors.We demonstrate that Bcr-Abl interacts with the common βc subunit of the IL-3 family of receptors and phosphorylates it on tyrosine." SIGNOR-255814 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 CSNK2A1 protein P68400 UNIPROT AQP4 protein P55087 UNIPROT "down-regulates activity" phosphorylation Ser316 EKKGKDQsGEVLSSV 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. AQP4 phosphorylation by CKII may thus provide a mechanism that regulates AQP4 cell surface expression. | 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-250828 CSNK2A1 protein P68400 UNIPROT CDC34 protein P49427 UNIPROT "down-regulates activity" phosphorylation Ser203 APAPDEGsDLFYDDY 9606 BTO:0000567 11546811 t lperfetto "The ubiquitin-conjugating enzyme, cdc34, has been implicated in the ubiquitination of a number of vertebrate substrates, including p27(kip1), ikappabalpha, wee1, and myod. We show that mammalian cdc34 is a phosphoprotein that is phosphorylated in proliferating cells. Phosphorylation of cdc34 by the associated kinase maps predominantly to residues 203 and 222. Mutation of cdc34 at ck2-targeted residues, ser-203, ser-222, ser-231, thr-233, and ser-236, abolishes the phosphorylation of cdc34 observed in vivo and markedly shifts nuclearly localized cdc34 to the cytoplasm." SIGNOR-110383 CSNK2A1 protein P68400 UNIPROT CLTB protein P09497 UNIPROT unknown phosphorylation Ser11 DFGFFSSsESGAPEA -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-250842 CSNK2A1 protein P68400 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-250953 CSNK2A1 protein P68400 UNIPROT SLK protein Q9H2G2 UNIPROT down-regulates phosphorylation Ser347 SSDLSIAsSEEDKLS 9606 16837460 t gcesareni "Slk down-regulation by v-src is indirect and is accompanied by slk hyperphosphorylation on serine residues. Deletion analysis revealed that casein kinase ii (ck2) sites at position 347/348 are critical for v-src-dependent modulation of slk activity." SIGNOR-147879 CSNK2B protein P67870 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-251064 NEDD4L protein Q96PU5 UNIPROT SCN2A protein Q99250 UNIPROT "down-regulates quantity by destabilization" ubiquitination 10090 BTO:0000938 23778145 t miannu "The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2)." SIGNOR-253459 CSNK2A1 protein P68400 UNIPROT VTN protein P04004 UNIPROT "up-regulates activity" phosphorylation Thr76 TMPEDEYtVYDDGEE 10090 BTO:0000944 9733784 t llicata " Therefore, we expressed Vn in a baculovirus system and show (i) that the CKII phosphorylation of wt-Vn enhances the adhesion of bovine aorta endothelial cells; (ii) that the double mutant T50E/T57E (in which the neutral Thr residues are replaced by the negatively charged Glu residues considered analogs of Thr-P) has a significantly enhanced capacity to promote cell adhesion and to accelerate cell spreading when compared with either wild-type Vn or to the neutral T50A/T57A mutant" SIGNOR-250971 Calcineurin complex SIGNOR-C155 SIGNOR FLNA protein P21333 UNIPROT down-regulates dephosphorylation Ser2152 TRRRRAPsVANVGSH 9606 16442073 t gcesareni "We report that a purified c-terminal recombinant region of filamin is a suitable substrate for calcineurin in vitro. Furthermore, 1 microm cyclosporin a (csa), a specific calcineurin inhibitor, reduced the dephosphorylation of the recombinant fragment in 293ft cells" SIGNOR-252339 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1644 SPTSPSYsPTSPSYS -1 22137580 t "Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat." SIGNOR-248781 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1672 SPTSPSYsPTSPSYS -1 22137580 t "Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat." SIGNOR-248784 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1766 SPSYSPTsPSYSPTS -1 22137580 t "Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat." SIGNOR-248778 CTDSP1 protein Q9GZU7 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-248800 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 CTDSP1 protein Q9GZU7 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" dephosphorylation Ser208 DAGSPNLsPNPMSPA 9606 BTO:0000007 17035229 t "SCP1 Dephosphorylates Smad2/3 in the Linkers|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-248792 CXCR4 protein P61073 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 9606 BTO:0005387 19584257 f lperfetto "However, we show that soluble factors secreted by SUM102 breast cancer cells stimulated the expression of MMP-1 and CXCR4 in HMFs. As a result, these stromal cells acquired an invasive and migratory phenotype" SIGNOR-252266 BCOR protein Q6W2J9 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 10090 BTO:0004850 26847029 f irozzo "Our results strongly suggest that BCOR plays an indispensable role in hematopoiesis by inhibiting myeloid cell proliferation and differentiation and offer a mechanistic explanation for how BCOR regulates gene expression such as Hox genes." SIGNOR-256011 BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0005248 8758906 t irozzo "We demonstrated that Bcr-Abl co-immunoprecipitates with, and constitutively phosphorylates, the common βc,subunit of the interleukin 3 and granulocyte/macrophage-colony stimulating factor receptors.We demonstrate that Bcr-Abl interacts with the common βc subunit of the IL-3 family of receptors and phosphorylates it on tyrosine." SIGNOR-255999 BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT "down-regulates activity" phosphorylation Tyr7 yDFKATAD 9606 BTO:0000007 20554525 t lperfetto "More recently, however, tyrosine phosphorylation of Grb2 in BCR-ABL-transformed cells on residues Tyr7, Tyr37, Tyr52, and Tyr209 in the SH3 domains has been reported and shown to negatively regulate the Ras/MAPK pathway." SIGNOR-246285 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MYOD1 protein P15172 UNIPROT down-regulates phosphorylation Ser200 YSGDSDAsSPRSNCS 9606 21902831 t lperfetto "Phosphorylation of myod at s200 is common to other cdks, such as the mitotic cyclin b/cdk1, which may prevent inappropriate myod accumulation during mitosis." SIGNOR-216860 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR NPM1 protein P06748 UNIPROT "up-regulates activity" phosphorylation Thr199 VKKSIRDtPAKNAQK BTO:0000567 11278991 t llicata "Upon phosphorylation by CDK2-cyclin E, NPM/B23 dissociates from centrosomes, which is a prerequisite step for centrosomes to initiate duplication. Here, we identified that threonine 199 (Thr(199)) of NPM/B23 is the major phosphorylation target site of CDK2-cyclin E in vitro, and the same site is phosphorylated in vivo. NPM/T199A, a nonphosphorylatable NPM/B23 substitution mutant (Thr(199) --> Ala) acts as dominant negative when expressed in cells, resulting in specific inhibition of centrosome duplication." SIGNOR-250744 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR RB1 protein P06400 UNIPROT "down-regulates activity" phosphorylation Ser608 TAADMYLsPVRSPKK BTO:0001968 10207050 t llicata "In the present assay, ΔP3,4HA repressed E2F-mediated transcription similarly to wild-type pRB, suggesting that phosphorylation at other sites on ΔP3,4HA can disrupt its interaction with E2F and that these two sites are not sufficient to regulate E2F binding on DNA. This result is consistent with another report which showed that mutation of the human sites 8 and 9 (human Ser608 and Ser612) repressed E2F-mediated transcription to the same level as wild-type pRB (2). | Surprisingly, no one CDK site regulated the interaction of pRB with E2F when E2F was bound to DNA. Instead, disruption of transcriptional repression resulted from accumulation of phosphate groups on the RB molecule." SIGNOR-250747 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR TP73 protein O15350 UNIPROT down-regulates phosphorylation Thr86 AASASPYtPEHAASV 9606 12676926 t lperfetto "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-216702 DAB2IP protein Q5VWQ8 UNIPROT ERN1 protein O75460 UNIPROT "up-regulates activity" binding 9606 BTO:0001176 27858941 t miannu "DAB2IP binds IRE1α, and was shown to be required for activation of this signaling cascade in endothelial cells. IRE1α can trigger pro-apoptotic JNK signaling through recruitment of the TRAF2–ASK1 complex. DAB2IP facilitates IRE1α activation, and participates in a signaling complex required to induce TRAF2-dependent ASK1 activation and JNK phosphorylation." SIGNOR-254749 CYSLTR1 protein Q9Y271 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-256740 DAB2IP protein Q5VWQ8 UNIPROT PP2Ca_R1A_Bd complex SIGNOR-C133 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 20080667 t miannu "DAB2IP interacts via its C2 domain with GSK3β, recruiting phosphatase PP2A for S9 de-phosphorylation and leading to GSK3β activation" SIGNOR-254753 DAB2IP protein Q5VWQ8 UNIPROT PROX1 protein Q92786 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9606 BTO:0001033 27476001 f miannu "DAB2IP regulates EMT and metastasis of prostate cancer through targeting PROX1 transcription and destabilizing HIF1α protein. In this study, based on different PCa cell lines and knockout mice, we showed that PROX1 could be suppressed by DAB2IP, a novel member of the Ras GTPase-activating protein family and a critical player in control of epithelial-mesenchymal transition (EMT) and PCa metastasis." SIGNOR-254764 DAB2IP protein Q5VWQ8 UNIPROT STAT3 protein P40763 UNIPROT "down-regulates activity" binding 9606 BTO:0001033 26512963 t 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-254761 DEF6 protein Q9H4E7 UNIPROT RAP1B protein P61224 UNIPROT "up-regulates activity" binding 9606 BTO:0000782 26483383 t lperfetto "Mechanistic studies revealed that SLAT interacts, through its PH domain, with a key component of inside-out signaling, namely the active form of the small GTPase Rap1 (which has two isoforms, Rap1A and Rap1B). This interaction has been further shown to facilitate the interdependent recruitment of Rap1 and SLAT to the T cell immunological synapse upon TCR engagement. Furthermore, a SLAT mutant lacking its PH domain drastically inhibited LFA-1 activation and CD4(+) T cell adhesion." SIGNOR-253366 DLL3 protein Q9NYJ7 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-254316 DNAJC3 protein Q13217 UNIPROT EIF2AK4 protein Q9P2K8 UNIPROT "down-regulates activity" binding 9606 BTO:0000567 25329545 t gcesareni "€ we show that p58IPK is a general inhibitor of the eIF2 kinases in that it also interacts with GCN2" SIGNOR-246204 DNMT3B protein Q9UBC3 UNIPROT HOXB13 protein Q92826 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001033 22808286 f miannu "EZH2 recruited DNMT3b to HOXB13 promoter to form a repression complex." SIGNOR-254145 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 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 dopamine smallmolecule CHEBI:18243 ChEBI DRD2 protein P14416 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-257478 dopamine smallmolecule CHEBI:18243 ChEBI DRD4 protein P21917 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-257480 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 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 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 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 DTNA protein Q9Y4J8 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-255989 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 DUSP9 protein Q99956 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates binding 9606 21908610 t gcesareni "Here we demonstrate that inactivation of both erk1/2 and p38_ by dusp9/mkp-4 is mediated by a conserved arginine-rich kinase interaction motif located within the amino-terminal non-catalytic domain of the protein." SIGNOR-176589 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 DYRK1A protein Q13627 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Thr310 VPPLPKVtPTKELQQ 9606 BTO:0000142 16733250 t lperfetto "Here we report that amphiphysin i (amph i) is also a mnb/dyrk1a substrate. This kinase phosphorylated native amph i in rodent brains and recombinant human amph i expressed in escherichia coli. Serine 293 (ser-293) was identified as the major site, whereas serine 295 and threonine 310 were found as minor kinase sitesamph i phosphorylated by mnb/dyrk1a decreased endophilin binding in vitro. From these results we conclude that amph i at ser-293 is phosphorylated by mnb/dyrk1a and that the phosphorylation has physiological significance in controlling the interaction of amphiphysin with endocytic accessory proteins." SIGNOR-146910 DYRK2 protein Q92630 UNIPROT JUN protein P05412 UNIPROT down-regulates phosphorylation Ser243 PGETPPLsPIDMESQ 9606 BTO:0000150 22307329 t lperfetto "Degradation of c-jun/c-myc is a critical process for the g(1)/s transition, which is initiated upon phosphorylation by glycogen synthase kinase 3 ? (gsk3?). However, a specific kinase or kinases responsible for priming phosphorylation events that precede this gsk3? Modification has not been definitively identified. Here, we found that the dual-specificity tyrosine phosphorylation-regulated kinase dyrk2 functions as a priming kinase of c-jun and c-myc.The finding that kinase-active dyrk2 phosphorylated gst_c-jun210_310-wt by detection with an anti_phospho_c-jun(ser243) antibody demonstrated that dyrk2 is a ser243 kinase in vitro" SIGNOR-195771 E2F1 protein Q01094 UNIPROT ABCB1 protein P08183 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 23542036 f miannu "We show here that EAPP stimulates the MDR1 promoter resulting in higher PGP levels. Independently of EAPP, E2F1 also increases the activity of the MDR1 promoter." SIGNOR-253841 E2F1 protein Q01094 UNIPROT BBC3 protein Q96PG8 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003476 17263886 f miannu "Up-regulation of the PUMA gene and protein by E2F-1 overexpression was detected by real-time PCR and Western blot analysis in the SK-MEL-2 melanoma cell line" SIGNOR-253843 E2F1 protein Q01094 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-245468 E2F1 protein Q01094 UNIPROT DHFR protein P00374 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000972 14618416 f miannu "To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells." SIGNOR-253853 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 ATR protein Q13535 UNIPROT CHEK2 protein O96017 UNIPROT "up-regulates activity" phosphorylation Thr68 SSLETVStQELYSIP 9606 BTO:0000007 10973490 t lperfetto "Atm- and rad3-related also phosphorylates thr68 in addition to thr26 and ser50, which are not phosphorylated to a significant extent by atm in vitro.Substitution of thr68 with ala reduced the extent of phosphorylation and activation of chk2 in response to ir" SIGNOR-81442 E2F1 protein Q01094 UNIPROT RRM1 protein P23921 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000972 14618416 f miannu "To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells." SIGNOR-253852 E2F4 protein Q16254 UNIPROT PPARG protein P37231 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 12110166 f fspada "We show here that e2f1 induces ppar gamma transcription during clonal expansion, whereas e2f4 represses pparg amma expression during terminal adipocyte differentiation" SIGNOR-90507 EDNRB protein P24530 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-257428 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 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 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 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 EFNA3 protein P52797 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-52381 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 adenosine smallmolecule CHEBI:16335 ChEBI ADORA1 protein P30542 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-257446 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT "down-regulates quantity by destabilization" phosphorylation Tyr1069 EDSFLQRySSDPTGA 9606 BTO:0000017 10635327 t llicata "Initially, an autophosphorylation reaction creates docking sites for several signaling proteins, including a Cbl binding site at tyrosine 1045 of EGFR. Second, EGFR trans-phosphorylates Cbl at a linker domain, which activates an associated ubiquitin ligase activity." SIGNOR-251093 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 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 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 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-254253 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 EGR3 protein Q06889 UNIPROT NAB2 protein Q15742 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000782 20506119 f miannu "In T lymphocytes EGR2 and EGR3 have been shown to inhibit NAB2 expression." SIGNOR-253884 EP300 protein Q09472 UNIPROT CPT1B protein Q92523 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9534 BTO:0001538 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-254260 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 EP300 protein Q09472 UNIPROT RUNX2 protein Q13950 UNIPROT "up-regulates quantity" acetylation 9606 BTO:0000007;BTO:0000165 20851880 t gcesareni "These results indicate that Erk signaling increases Runx2 stability and transcriptional activity, partly via increasing p300 protein levels and histone acetyltransferase activity and subsequently increasing Runx2 acetylation by p300" SIGNOR-167966 EP300 protein Q09472 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates binding 9606 SIGNOR-C6 12419246 t gcesareni "Thus, Ski/SnoN represses TGFβ signaling by multiple mechanisms. In addition to recruitment of a transcriptional repressor complex and dissociation of the transcriptional coactivator p300/CBP from the Smads" SIGNOR-95462 9-HODE chemical CHEBI:72651 ChEBI GPR132 protein Q9UNW8 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-257501 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-252833 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates quantity by destabilization" phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 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-252823 AKT proteinfamily SIGNOR-PF24 SIGNOR TBX3 protein O15119 UNIPROT "up-regulates activity" phosphorylation Ser719 AEKEAATsELQSIQR 9606 BTO:0000848 25595898 t lperfetto "We have identified TBX3 as a key substrate of AKT3 in melanomagenesis. we have identified the AKT3 target site at serine residue 720 in the TBX3 protein and show that this site is phosphorylated in vivo. the phosphorylation at S720 promotes TBX3 protein stability, nuclear localization, transcriptional repression of E-cadherin, and its role in cell migration and invasion." SIGNOR-244353 AKT proteinfamily SIGNOR-PF24 SIGNOR TERT protein O14746 UNIPROT up-regulates phosphorylation Ser227 GARRRGGsASRSLPL 9606 BTO:0000848 10224060 t lperfetto "Akt kinase enhances human telomerase activity through phosphorylation of htert subunit as one of its substrate proteins." SIGNOR-244361 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-155532 AKT proteinfamily SIGNOR-PF24 SIGNOR PPP1CA protein P62136 UNIPROT down-regulates phosphorylation Thr320 NPGGRPItPPRNSAK 9606 BTO:0000661 12202491 t lperfetto "Ir-induced pp1 activation in the nucleus may be a critical component in an atm-mediated pathway controlling checkpoint activation." SIGNOR-244330 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-174017 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-164298 AKT proteinfamily SIGNOR-PF24 SIGNOR STK3 protein Q13188 UNIPROT down-regulates phosphorylation Thr384 GTMKRNAtSPQVQRP 9606 20086174 t lperfetto "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-244349 BRCC3 protein P46736 UNIPROT HIST1H2AG 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 CAMKK1 protein Q8N5S9 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Thr308 KDGATMKtFCGTPEY 10833263 t llicata "Protein kinase B (PKB) was recently reported to be activated on the phosphorylation of Thr(308) by Ca(2+)/calmodulin-dependent protein kinase kinase alpha (CaM-kinase kinase alpha), suggesting that PKB was regulated through not only the phosphoinositide 3-kinase pathway but also the Ca(2+)/calmodulin protein kinase pathway." SIGNOR-250714 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser324 RDLELPLsPSLLGGP 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-252085 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR 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-244553 DET1 protein Q7L5Y6 UNIPROT "DCX DET1-COP1" complex SIGNOR-C24 SIGNOR "form complex" binding 9606 17452440 t lperfetto "Mammalian det1 regulates cul4a activity and forms stable complexes with e2 ubiquitin-conjugating enzymes" SIGNOR-154508 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR 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-252742 FOXO3 protein O43524 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000007 14976264 f lperfetto "Sirt1 inhibited foxo3's ability to induce cell death." SIGNOR-217887 TNFRSF17 protein Q02223 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates 9606 10903733 f miannu "Overexpression of bcma activates jnk" SIGNOR-79492 AMPK complex SIGNOR-C15 SIGNOR RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser259 SQRQRSTsTPNVHMV 9606 11971957 t lperfetto "Mutation of serine 259 increased the basal raf-1 activity and rendered it largely resistant to inhibition by pka." SIGNOR-216523 AMPK complex SIGNOR-C15 SIGNOR ZNF692 protein Q9BU19 UNIPROT down-regulates phosphorylation Ser470 VAAHRSKsHPALLLA 9606 17097062 t lperfetto "Arebp is phosphorylated at ser(470) by ampk. Phosphorylation reduces the dna-binding activity of arebp." SIGNOR-216519 MAPK10 protein P53779 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. is regulated by jnk3 via phosphorylation of app at thr668" SIGNOR-204671 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 ELOC protein Q15369 UNIPROT HIST1H1A protein Q02539 UNIPROT up-regulates phosphorylation Ser183 KPKKVAKsPAKAKAV 9606 BTO:0000567 20551309 t lperfetto "Our results also show the potential function of p-tefb phosphorylation of h1, namely, to increase h1 dissociation from actively transcribed dna. P-tefb preferentially phosphorylates the ser-183 phosphorylation site of histone h1.1" SIGNOR-166120 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 2-[[3-[[2-(dimethylamino)phenyl]methyl]-2-pyridin-4-yl-1,3-diazinan-1-yl]methyl]-N,N-dimethylaniline smallmolecule CHEBI:94276 ChEBI GLI1 protein P08151 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-154753 CAMK2B protein Q13554 UNIPROT CYLD protein Q9NQC7 UNIPROT up-regulates phosphorylation Ser418 TTENRFHsLPFSLTK 9606 24614225 t lperfetto "Purified camkii phosphorylates cyld on at least three residues (s-362, s-418, and s-772 on the human cyld protein q9nqc7-1) and promotes its deubiquitinase activity." SIGNOR-25329 CSNK2A1 protein P68400 UNIPROT SSB protein P05455 UNIPROT up-regulates phosphorylation Ser366 GKKTKFAsDDEHDEH 9606 18257391 t gcesareni "Prior studies indicate that hla is activated by phosphorylation of serine-366 by protein kinase ck2, neutralizing a negative effect of a short basic motif (sbm)" SIGNOR-160761 DFFA protein O00273 UNIPROT DFFB protein O76075 UNIPROT down-regulates binding 9606 BTO:0000567 9108473 t amattioni "Dff is a heterodimer of 40 kda and 45 kda subunits." SIGNOR-29729 EFNA5 protein P52803 UNIPROT EPHA8 protein P29322 UNIPROT up-regulates binding 9606 9330863 t gcesareni "Efna5 are able to activate epha8" SIGNOR-52479 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR 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-250557 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Thr8 MSSILPFtPPVVKRL 9606 BTO:0000763 12193595 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-244735 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 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 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 PRKDC protein P78527 UNIPROT GOLPH3 protein Q9H4A6 UNIPROT "up-regulates activity" phosphorylation Thr143 ALKHVKEtQPPETVQ -1 BTO:0000567 24485452 t "In response to DNA damage, DNA-PK phosphorylates GOLPH3, resulting in increased interaction with MYO18A, which applies a tensile force to the Golgi. Interference with the Golgi DNA damage response by depletion of DNA-PK, GOLPH3, or MYO18A reduces survival after DNA damage, whereas overexpression of GOLPH3, as is observed frequently in human cancers, confers resistance to killing by DNA-damaging agents" SIGNOR-253557 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 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 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 ETS1 protein P14921 UNIPROT ABCB1 protein P08183 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000093 20392592 f miannu "High ETS1 expression levels in all resistant MCF-7 sublines may lead to the upregulation of the transcription of MDR1 gene." SIGNOR-254077 AMPK complex SIGNOR-C15 SIGNOR PFKFB2 protein O60825 UNIPROT "up-regulates activity" phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000562 11069105 t lperfetto "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-216623 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 AKT proteinfamily SIGNOR-PF24 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24743741 f "Activation of PDGFRα stimulates proliferation of PDGFRα(+) cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFRα(+) cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases." SIGNOR-257606 AMPK complex SIGNOR-C15 SIGNOR NR2C2 protein P49116 UNIPROT down-regulates phosphorylation Ser351 HVISRDQsTPIIEVE 9606 21478464 t lperfetto "Tr4 transactivation is inhibited via phosphorylation bymetformin-induced amp-activated protein kinase (ampk) at the amino acid serine 351, which results in the suppression of scd1 gene expression" SIGNOR-216537 3-isobutyl-1-methyl-7H-xanthine smallmolecule CHEBI:34795 ChEBI PDE1A protein P54750 UNIPROT "down-regulates activity" "chemical inhibition" 9606 22014080 t "Until now, very few inhibitors of PDE1 were available for evaluating the contribution of PDE1 in tissue and cell function. Vinpocetine (Ahn et al., 1989) and 8-methoxymethyl-IBMX (Ahn et al., 1997) are common PDE1 inhibitors." SIGNOR-256274 471905-41-6 chemical CID:9803433 PUBCHEM APP protein P05067 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194358 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 TAK-960 chemical CID:53357478 PUBCHEM PLK1 protein P53350 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207200 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 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 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 F2RL1 protein P55085 UNIPROT AREG protein P15514 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007 21072196 f miannu "PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15)." SIGNOR-254855 F2RL1 protein P55085 UNIPROT DUSP6 protein Q16828 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007 21072196 f miannu "PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15)." SIGNOR-254853 F2RL1 protein P55085 UNIPROT F2RL1 protein P55085 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007 21072196 f miannu "PAR2 expression is up-regulated following PAR2 activation. This is logical for PAR2, as endogenous activators for the receptor are serine proteases, which irreversibly activate PAR2 through N-terminal cleavage." SIGNOR-254840 F2RL1 protein P55085 UNIPROT FOSL1 protein P15407 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-254839 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 THBS1 protein P07996 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-254850 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 ELL protein P55199 UNIPROT ELL/ICE1 complex SIGNOR-C48 SIGNOR "form complex" binding 9606 BTO:0001271 22195968 t miannu "The ell-ice complex is called lec for its proposed role in transcriptional regulation of the littlesnrna genes." SIGNOR-193458 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 BTRC protein Q9Y297 UNIPROT PER1 protein O15534 UNIPROT down-regulates ubiquitination 9606 BTO:0000671 15917223 t miannu "We have found that per1 interacts with both _-trcp1 and _-trcp2 in a manner that depends on casein kinase 1 activity, and depletion of both _-trcp1 and _-trcp2 by rnai leads to dramatic stabilization of per1" SIGNOR-137755 F2RL2 protein O00254 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-257360 FBXO32 protein Q969P5 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR "up-regulates activity" 10090 25549588 f areggio "Muscle-specific ubiq- uitin ligases, muscle-specific RING-finger 1 (MURF1; also known as TRIM63)12 and atrogin 1 (also known as MAFBX)8, are markedly induced in almost all types of atrophy." SIGNOR-254994 F2RL3 protein Q96RI0 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-257370 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 CDK5 protein Q00535 UNIPROT PPP1CA protein P62136 UNIPROT down-regulates phosphorylation Thr320 NPGGRPItPPRNSAK 9606 BTO:0000938 BTO:0000142 17202132 t gcesareni "We observed that phosphorylation of protein phosphatase 1 (PP1) on Thr320 is reduced in brain extracts from Egr-1-/- mice, indicating that a kinase downstream of Egr-1 phosphorylates PP1. In HEK 293 cells co-transfected with PP1 and Cdk5, Cdk5 phosphorylates PP1. In vitro, Cdk5 purified from bovine brain phosphorylates bacterially expressed recombinant PP1" SIGNOR-151803 FER protein P16591 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-251131 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 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 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 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 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-200875 FFAR4 protein Q5NUL3 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-257371 FGF12 protein P61328 UNIPROT SCN4A protein P35499 UNIPROT "down-regulates activity" binding 9606 BTO:0001103 20679355 t miannu "Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels." SIGNOR-253432 FGF13 protein Q92913 UNIPROT SCN11A protein Q9UI33 UNIPROT "down-regulates activity" binding 9606 BTO:0000938 20679355 t miannu "Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels." SIGNOR-253435 AMPK complex SIGNOR-C15 SIGNOR CTBP1 protein Q13363 UNIPROT down-regulates phosphorylation Ser158 REGTRVQsVEQIREV 9606 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-216604 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 FGFR1 protein P11362 UNIPROT PDK1 protein Q15118 UNIPROT up-regulates phosphorylation Tyr244 RRLCDLYyINSPELE 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-193454 FLCN protein Q8NFG4 UNIPROT RRAGD protein Q9NQL2 UNIPROT "up-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 24095279 t "The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1 [..} RagC/D is a key regulator of the interaction of mTORC1 with the Rag heterodimer and that, unexpectedly, RagC/D must be GDP-bound for the interaction to occur" SIGNOR-256504 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 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 AKT3 protein Q9Y243 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-249643 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 AMPK complex SIGNOR-C15 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR "down-regulates activity" phosphorylation 10090 BTO:0002572 21460634 t miannu "AMP-activated protein kinase (AMPK), which is activated by LKB1/Strad/Mo25 upon high AMP levels, stimulates autophagy by inhibiting mTORC1." SIGNOR-216418 FYN protein P06241 UNIPROT LAT protein O43561 UNIPROT up-regulates phosphorylation Tyr220 SLDGSREyVNVSQEL 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-148931 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 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 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 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 GNAS protein P63092 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR "down-regulates activity" binding -1 10224115 f "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-256524 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 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 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 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 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 PIK-90 chemical CID:6857685 PUBCHEM PIK3CG protein P48736 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206232 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 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 "2-methylpropanethioic acid S-[2-[[[1-(2-ethylbutyl)cyclohexyl]-oxomethyl]amino]phenyl] ester" chemical CHEBI:95001 ChEBI CETP protein P11597 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191265 AURKA protein O14965 UNIPROT MBD3 protein O95983 UNIPROT up-regulates phosphorylation Ser85 RQRVRYDsSNQVKGK 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-93697 FLT3 protein P36888 UNIPROT CEBPA protein P49715 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 16146838 t lperfetto "Oncogenic mutations of Flt3 also result in the activation of aberrant signaling pathways, including strong activation of STAT5, induction of STAT target genes, and repression of myeloid transcription factors c/EBP-3 and Pu.1." SIGNOR-249635 RET protein P07949 UNIPROT GRB7 protein Q14451 UNIPROT up-regulates binding 9606 8631863 t gcesareni "Grb7 and grb10, likely relay signals emanating from ret to other, as yet, unidentified targets within the cell" SIGNOR-41765 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 SALL4 protein Q9UJQ4 UNIPROT ZEB1 protein P37275 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000356 23954296 f miannu "Our shRNA-mediated SALL4 knockdown system and SALL4 overexpression system revealed that SALL4 suppresses the expression of adhesion gene CDH1, and positively regulates the CDH1 suppressor ZEB1." SIGNOR-255123 GHSR protein Q92847 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-257054 GHSR protein Q92847 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-257322 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 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 AMPK complex SIGNOR-C15 SIGNOR PFKFB3 protein Q16875 UNIPROT up-regulates phosphorylation Ser461 NPLMRRNsVTPLASP 9606 BTO:0000876 BTO:0000671 12065600 t lperfetto "Ipfk-2 was phosphorylated on the homologous serine (ser-461) and activated by ampk in vitro." SIGNOR-216639 BCL11A protein Q9H165 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-251800 BCL2L1 protein Q07817 UNIPROT VDAC1 protein P21796 UNIPROT "down-regulates activity" binding 10365962 t lperfetto "The anti-apoptotic protein Bcl-x(L) closes VDAC by binding to it directly" SIGNOR-249614 BCL2 protein P10415 UNIPROT BECN1 protein Q14457 UNIPROT down-regulates binding 9606 17643073 t gcesareni "In mammalian cells, the antiapoptotic protein, bcl-2, binds to beclin 1 during nonstarvation conditions and inhibits its autophagy function." SIGNOR-156941 BCL2 protein P10415 UNIPROT BECN1 protein Q14457 UNIPROT down-regulates binding 9606 18570871 t gcesareni "In mammalian cells, the antiapoptotic protein, bcl-2, binds to beclin 1 during nonstarvation conditions and inhibits its autophagy function." SIGNOR-179084 AMPK complex SIGNOR-C15 SIGNOR PPARGC1A protein Q9UBK2 UNIPROT up-regulates phosphorylation Ser539 SLFNVSPsCSSFNSP 9606 BTO:0000887;BTO:0001103 17609368 t lperfetto "Ampk phosphorylates pgc-1alpha directly both in vitro and in cells. These direct phosphorylations of the pgc-1alpha protein at threonine-177 and serine-538." SIGNOR-216647 AMPK complex SIGNOR-C15 SIGNOR PPARGC1A protein Q9UBK2 UNIPROT up-regulates phosphorylation Thr178 NHNHRIRtNPAIVKT 9606 BTO:0000887;BTO:0001103 17609368 t lperfetto "Ampk phosphorylates pgc-1alpha directly both in vitro and in cells. These direct phosphorylations of the pgc-1alpha protein at threonine-177 and serine-538." SIGNOR-216651 BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT down-regulates 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-112354 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 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione chemical CHEBI:92539 ChEBI ADRA1A protein P35348 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190604 BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates phosphorylation 9606 18756288 t lperfetto "Bmp ligands bind to the bmp receptors bmpr1 and bmpr2, and bmpr2 then phosphorylates and activates bmpr1." SIGNOR-217029 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR CDC25C protein P30307 UNIPROT up-regulates phosphorylation Ser214 SRSGLYRsPSMPENL 9606 BTO:0000150 20530684 t lperfetto "The cyclin e/cdk2 complex phosphorylates cdc25c on ser(214), leading to its premature activation, which coincides with higher cyclin b/cdk1 and polo-like kinase 1 (plk1) activities in an s-phase-enriched population that result in faster mitotic entry." SIGNOR-216721 MAPK8IP1 protein Q9UQF2 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates binding 9606 9922370 t gcesareni "The jip proteins function by aggregating components of a map kinase module (including mlk, mkk7, and jnk) and facilitate signal transmission by the protein kinase cascade. Overexpression of jip1 deactivates the jnk pathway selectively by cytoplasmic retention of jnk and thereby inhibits gene expression mediated by jnk, which occurs in the nucleus" SIGNOR-64175 (2R)-1-[[4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-5-methyl-6-pyrrolo[2,1-f][1,2,4]triazinyl]oxy]-2-propanol chemical CHEBI:94562 ChEBI KDR protein P35968 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190708 CAMK2B protein Q13554 UNIPROT CYLD protein Q9NQC7 UNIPROT up-regulates phosphorylation Ser772 LFKKIFPsLELNITD 9606 24614225 t lperfetto "Purified camkii phosphorylates cyld on at least three residues (s-362, s-418, and s-772 on the human cyld protein q9nqc7-1) and promotes its deubiquitinase activity." SIGNOR-91403 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR PRKAR1A protein P10644 UNIPROT up-regulates phosphorylation Ser83 DSREDEIsPPPPNPV 9606 BTO:0000093 16582606 t lperfetto "In this context, we have identified rialpha as a novel substrate for the g(1)/s-cyclin-dependent kinase, cdk2/cyclin e, and found that rialpha is specifically phosphorylated at the serine residue." SIGNOR-216729 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR SIRT2 protein Q8IXJ6 UNIPROT down-regulates phosphorylation Ser368 PNPSTSAsPKKSPPP 9606 BTO:0000938 18332217 t lperfetto "We define ser-331 as the site phosphorylated by cyclin e-cdk2, cyclin a-cdk2, and p35-cdk5 both in vitro and in cells. Importantly, phosphorylation at ser-331 inhibits the catalytic activity of sirt2." SIGNOR-216725 BTG2 protein P78543 UNIPROT SOD2 protein P04179 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000093 22493435 f miannu "BTG2 was found to up-regulate expression of antioxidant enzymes known to be regulated by NFE2L2, including catalase, SOD1, and SOD2" SIGNOR-254649 BTRC protein Q9Y297 UNIPROT WEE1 protein P30291 UNIPROT down-regulates binding 9606 SIGNOR-C5 15340381 t gcesareni "Scfb-trcp continues to have a role in this phase, however, through its induced degradation of the cdk1 inhibitor, wee1." SIGNOR-128439 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 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 GPR84 protein Q9NQS5 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-256847 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 CDK2 protein P24941 UNIPROT CCNE1 protein P24864 UNIPROT down-regulates phosphorylation Thr395 PLPSGLLtPPQSGKK 9606 BTO:0000150 BTO:0000149 19561641 t gcesareni "Phosphorylation of threonine 395 has been linked to the proteasome-mediated degradation of full length cyclin e" SIGNOR-186418 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 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 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 β-synuclein phosphorylation by both GRK2 and GRK5" SIGNOR-251203 BMPR2 protein Q13873 UNIPROT ACVR1/BMPR2 complex SIGNOR-C30 SIGNOR "form complex" binding 9606 7791754 t lperfetto "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-33437 BMPR2 protein Q13873 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-33443 GSK2126458 chemical CID:25167777 PUBCHEM PI3K complex SIGNOR-C156 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-252645 GSK3A protein P49840 UNIPROT MAFA protein Q8NHW3 UNIPROT down-regulates 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 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 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates 10090 25787076 f miannu "The UPS by itself degrades actomyosin and myofibrillar proteins slowly, but when caspase-3 is activated, it cleaves actomyosin and the myofibrillar proteins to provide substrates for degradation in the UPS . Caspase-3 also can cleave specific subunits of the 19 S proteasome particle, which stimulates the proteolytic activity of the 26S proteasome[...] These results indicate that caspase-3 participates in the muscle proteolysis that is present in tumor-bearing mice" SIGNOR-256475 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR 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-256460 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 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 MYC protein P01106 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr58 KKFELLPtPPLSPSR 9606 BTO:0000938 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 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 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 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 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CDC25A protein P30304 UNIPROT up-regulates phosphorylation Ser116 PQKLLGCsPALKRSH 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-216761 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 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 HDAC1 protein Q13547 UNIPROT ABCB1 protein P08183 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0005192 20037778 f miannu "we find UHRF1 plays an important role in inhibiting MDR1 promoter activity by directly binding to the MDR1 promoter. Overexpression of UHRF1 in NCI/ADR-RES cells can induce deacetylation of histones H3 and H4 on the MDR1 promoter, which is facilitated by recruitment of HDAC1 to the MDR1 promoter." SIGNOR-254223 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 HDAC2 protein Q92769 UNIPROT SNAI2 protein O43623 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001939 23836662 f miannu "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-254156 HERC2 protein O95714 UNIPROT XPA protein P23025 UNIPROT down-regulates ubiquitination 9606 20304803 t miannu "Herc2 may ubiquitinate xpa and thus target it for proteolytic degradation" SIGNOR-164595 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CDC25C protein P30307 UNIPROT up-regulates phosphorylation Thr130 PAQLLCStPNGLDRG 9606 10864927 t lperfetto "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-216769 HIF1A protein Q16665 UNIPROT Metabolism phenotype SIGNOR-PH77 SIGNOR up-regulates 9606 17415528 f "HIF-1 has been known as a major transcription factor for the induction of virtually all genes encoding glucose transporters and glycolytic enzymes, which allows hypoxic tumor cells to take up glucose more efficiently and metabolize pyruvate to lactate" SIGNOR-256591 HIF1A protein Q16665 UNIPROT VEGFA protein P15692 UNIPROT "up-regulates quantity" "transcriptional activation" 9606 BTO:0000972 8387214 t "Transcription of the human erythropoietin (EPO) gene is activated in Hep3B cells exposed to hypoxia. Hypoxia-inducible factor 1 (HIF-1) is a nuclear factor whose DNA binding activity is induced by hypoxia in Hep3B cells, and HIF-1 binds at a site in the EPO gene enhancer that is required for hypoxic activation of transcription." SIGNOR-256592 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 HIPK2 protein Q9H2X6 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-158620 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 GLI3 protein P10071 UNIPROT MED12 protein Q93074 UNIPROT down-regulates binding 9606 17000779 t gcesareni "We propose that activated gli3 physically targets med12 in mediator to reverse mediator-dependent suppression of shh target gene (i.e., Gli1 or cyclin d1) transcription." SIGNOR-149876 HMOX1 protein P09601 UNIPROT BAD protein Q92934 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000356 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-256304 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 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 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 CEP350 protein Q5VT06 UNIPROT FGFR1OP/CEP350 complex SIGNOR-C52 SIGNOR "form complex" binding 9606 16314388 t miannu "Here we show that cap350 and fop (fgfr1 oncogene partner) form a centrosomal complex required for mt anchoring." SIGNOR-142355 CSNK2A1 protein P68400 UNIPROT SNAI1 protein O95863 UNIPROT up-regulates phosphorylation Ser11 SFLVRKPsDPNRKPN 9606 19923321 t lperfetto "Serines 11 and 92 participate in the control of snail1 stability and positively regulate snail1 repressive function and its interaction with msin3a corepressor. Furthermore, serines 11 and 92 are required for snail1-mediated emt and cell viability, respectively. Pka and ck2 have been characterized as the main kinases responsible for in vitro snail1 phosphorylation at serine 11 and 92, respectively." SIGNOR-161771 HRH4 protein Q9H3N8 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-256672 HRH4 protein Q9H3N8 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-256815 CHUK protein O15111 UNIPROT NFKB1 protein P19838 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser923 DELRDSDsVCDSGVE 9606 BTO:0000567 SIGNOR-C13 10469655 t lperfetto "All residues of p105 phosphorylated by ikka are c-terminal; the major phosphorylation region contains three serines (ser923; ser927;ser932) and two threonines (thr927 and thr391)." SIGNOR-70449 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 CLOCK protein O15516 UNIPROT PER2 protein O15055 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-253634 PPP2CA protein P67775 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 20626350 t gcesareni "In particular, p38 mapk activity stimulates the physical association between ppa2 and mkk1/2- erk1/2 complex, leading to mkk1/2 dephosphorilation by pp2a . p38 mapks activity stimulates the physical association between pp2a and erk complex, leading to mkk1/2 dephosphorylation by pp2a." SIGNOR-166655 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 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 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 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 COL6A1 protein P12109 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 BTO:0001103;BTO:0002319 21949456 t "Muscle basement membrane consists primarily of a type IV collagen network, however types VI, XV, and XVIII are also present." SIGNOR-254673 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 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 HTR4 protein Q13639 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-257154 CellCont stimulus SIGNOR-ST13 SIGNOR TJP2 protein Q9UDY2 UNIPROT up-regulates 9606 21529719 f milica "Another junction protein, the tight junction protein ZO-2, binds to YAP/TAZ, facilitating their nuclear translocation." SIGNOR-230703 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 CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000876 BTO:0001103 19436055 t miannu "As a consequence of Jak2 activation and tyrosine phosphorylation of the cytoplasmic tail of Œ≤c, Src homology 2 and phosphotyrosine binding domain proteins are recruited to the active receptor and initiate the major tyrosine phosphorylation-dependent signaling pathways, including the Jak/signal transducer and activator of transcription, Ras/mitogen-activated protein kinase, and phosphatidylinositol 3 (PI-3) kinase pathways" SIGNOR-255585 CSNK1A1 protein P48729 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-183667 CTTN protein Q14247 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR "up-regulates activity" binding 9606 11231575 t "Cortactin binds directly to the Arp2/3 complex and activates it to promote nucleation of actin filaments." SIGNOR-251519 DUSP10 protein Q9Y6W6 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates dephosphorylation 9606 10391943 t gcesareni "Mkp-5 binds to p38 and sapk/jnk, but not to mapk/erk, and inactivates p38 and sapk/jnk, but not mapk/erk. p38 is a preferred substrate" SIGNOR-68983 DUSP10 protein Q9Y6W6 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates dephosphorylation 9606 10391943 t gcesareni "Mkp-5 directly dephosphorylates sapk/jnk and p38 in vitromkp-5 binds to p38 and sapk/jnk, but not to mapk/erk, and inactivates p38 and sapk/jnk" SIGNOR-68986 FBXW11 protein Q9UKB1 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 10074433 t gcesareni "We conclude that beta-trcp is a component of an e3 ubiquitin ligase that is responsible for the targeted degradation of phosphorylated beta-catenin. we found that the binding of beta-trcp to beta-catenin was direct." SIGNOR-65429 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 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 MAP2K1 protein Q02750 UNIPROT MAPK1 protein P28482 UNIPROT "up-regulates activity" phosphorylation Tyr187 HTGFLTEyVATRWYR 9606 BTO:0003807 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-235937 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 HTRA2 protein O43464 UNIPROT PEA15 protein Q15121 UNIPROT down-regulates binding 9606 BTO:0000567 15328349 t gcesareni "Htra2 promotes cell death by binding and degrading the anti-apoptotic protein pea15" SIGNOR-126966 PRKACA protein P17612 UNIPROT CAMKK1 protein Q8N5S9 UNIPROT "down-regulates activity" phosphorylation Thr108 SPRAWRRPtIESHHVAI 10116 BTO:0001009 10187789 t "In vitro, CaMKK is phosphorylated by PKA and this is associated with inhibition of enzyme activity. The major site of phosphorylation is threonine 108, although additional sites are phosphorylated with lower efficiency." SIGNOR-256115 SMAD7 protein O15105 UNIPROT MAP3K1 protein Q13233 UNIPROT down-regulates 9606 10085121 f lperfetto "Overexpression of smad7 can inhibit the mekk-1-mediated stimulation of smad2 transcriptional activity" SIGNOR-65572 ZFPM2 protein Q8WW38 UNIPROT GATA4 protein P43694 UNIPROT "down-regulates activity" binding 10090 BTO:0000944 9927675 t miannu "FOG-2 associates physically with the N-terminal zinc finger of GATA-4 both in vitro and in vivo. This interaction appears to modulate specifically the transcriptional activity of GATA-4 because overexpression of FOG-2 in both NIH 3T3 cells and primary rat cardiomyocytes represses GATA-4-dependent transcription from multiple cardiac-restricted promoters." SIGNOR-236959 CRYGD protein P07320 UNIPROT Maintenance_of_lens_transparency phenotype SIGNOR-PH65 SIGNOR up-regulates 9606 BTO:0001874 10521291 f "The γ-crystallin proteins are tightly folded in two domains with no free loops. It is possible that the R58H mutation destabilizes the contact between lens-fiber cells, which is critical for the maintenance of lens transparency. Improper folding of CRYGD, the most abundantly expressed γ-crystallin in the lens, could well cause protein aggregation and lens opacification." SIGNOR-253620 ICK protein Q9UPZ9 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates phosphorylation 9606 22356909 t lperfetto "Our findings demonstrate an important role for ick in modulating the activity of mtorc1 through phosphorylation of raptor thr-908 and thus implicate a potential signaling mechanism by which ick regulates cell proliferation and division." SIGNOR-217562 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 CSNK2A1 protein P68400 UNIPROT XRCC1 protein P18887 UNIPROT up-regulates phosphorylation Ser518 GEDPYAGsTDENTDS 9606 20471329 t lperfetto "Xrcc1 phosphorylation by ck2 is required for its stability and efficient dna repair. Rcc1 is phosphorylated in vivo and in vitro by ck2, and ck2 phosphorylation of xrcc1 on s518, t519, and t523" SIGNOR-165423 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 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 AMPK complex SIGNOR-C15 SIGNOR SREBF1 protein P36956 UNIPROT down-regulates phosphorylation 9606 21892142 t lperfetto "Ampk was recently found to phosphorylate a conserved serine near the cleavage site within srebp1, suppressing its activation" SIGNOR-216564 CSNK2A1 protein P68400 UNIPROT BRCA1 protein P38398 UNIPROT unknown phosphorylation Ser1572 ESGISLFsDDPESDP -1 10403822 t llicata " Subsequent studies showed that BRCA1 was phosphorylated in vitro by CK2. An analysis by site directed mutagenesis of BRCA1 showed that in vitro phosphorylation by CK2 required a serine at aa1572. These data implicate CK2 as a potential mediator of BRCA1 activity." SIGNOR-250832 CTNNBIP1 protein Q9NSA3 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 10898789 t gcesareni "We identify a novel beta-catenin-interacting protein, icat, that was found to inhibit the interaction of beta-catenin with tcf-4 and represses beta-catenin-tcf-4-mediated transactivation." SIGNOR-79399 HES1 protein Q14469 UNIPROT RBPJ protein Q06330 UNIPROT down-regulates binding 9606 16682003 t gcesareni "Here we show that hrt2 and hes1 interact with rbp-jkappa to negatively regulate notch-dependent activation of hrt and hes expression." SIGNOR-146684 IKBKB protein O14920 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser307 TRRSRTEsITATSPA -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-251292 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 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 CASP8 protein Q14790 UNIPROT CASP8AP2 protein Q9UKL3 UNIPROT up-regulates binding 9606 17245429 t gcesareni "The caspase-8-binding protein flice-associated huge protein (flash) would form a molecular complex with caspase-8, thereby presumably activating the mitochondrial apoptosis pathway by regulating caspase-8 activity." SIGNOR-152473 DIABLO protein Q9NR28 UNIPROT BIRC5 protein O15392 UNIPROT down-regulates binding 9606 10929711 t gcesareni "Diablo seem to function as a general iaps neutralizer by binding to these protein. Diablo promotes casp9 activation by binding to inhibitor of apoptosis proteins, iaps, and removing their inhibitory activity. mitochondrial survivin associated with smac/diablo, delaying its release." SIGNOR-80212 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 IKBKE protein Q14164 UNIPROT REL/RELA complex SIGNOR-C68 SIGNOR up-regulates phosphorylation 9606 16888014 t lperfetto "The present results demonstrate that ikkepsilon- and tbk1-mediated phosphorylation of crel in the c-terminal td leads to cytoplasmic dissociation of a crel-ikb_ complex and nuclear accumulation of crel." SIGNOR-217664 IKBKG protein Q9Y6K9 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR "up-regulates activity" binding 10090 BTO:0002572 19666475 t lperfetto "Proinflammatory NF-kappaB activation requires the IkappaB (inhibitor of NF-kappaB) kinase (IKK) complex that contains two catalytic subunits named IKKalpha and IKKbeta and a regulatory subunit named NF-kappaB essential modulator (NEMO)." SIGNOR-209762 IKZF4 protein Q9H2S9 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-255406 IKZF5 protein Q9H5V7 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-255407 IL10RA protein Q13651 UNIPROT JAK1 protein P23458 UNIPROT "up-regulates activity" binding 9606 BTO:0000801;BTO:0000776 10347215 t miannu "Specifically, il-10 effects the activation of jak1 (associated with the il-10 receptor alpha Chain) and tyk2 (associated with the il-10 receptor beta Chain) and induces the activation of stat1, stat3, and, in some cells, stat5." SIGNOR-68010 IL10RA protein Q13651 UNIPROT Phagocytosis phenotype SIGNOR-PH97 SIGNOR up-regulates BTO:0000801 19837374 f apalma "Treatment of monocytes with IL-10 as compared to IL-15 resulted in a two-fold greater level of phagocytosis and binding of latex beads. In summary, IL-10, in comparison to IL-15, induces greater macrophage endocytic function" SIGNOR-255442 FOXA2 protein Q9Y261 UNIPROT OTX2 protein P32243 UNIPROT "down-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-221164 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 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 CENPK protein Q9BS16 UNIPROT SOX6 protein P35712 UNIPROT "up-regulates activity" binding 10029 BTO:0000246 10996314 t miannu "Here we report the cloning of a novel cDNA, termed Solt, from a mouse testis cDNA library. Its gene product, Solt, interacts with the leucine zipper region of SoxLZ/Sox6. In transient transfection assays with SoxLZ/Sox6 containing the transactivation domain of herpes simplex virus VP16, the expression of a luciferase reporter gene under the control of a promoter containing a synthetic cis element that is bound by the HMG box of SoxLZ/Sox6 was poorly enhanced in the presence of Solt." SIGNOR-221820 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 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 IL20RA protein Q9UHF4 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 15120645 t gcesareni "Each r1-type chain (il-10r1, il-20r1, il-22r1, ifn-_r1 and ifn-_r1) is associated with jak1 tyrosine kinase and mediates recruitment of a variety of signaling molecules after being phosphorylated on its intracellular domain." SIGNOR-124486 IL20RA protein Q9UHF4 UNIPROT STAT3 protein P40763 UNIPROT up-regulates 9606 BTO:0000782;BTO:0000876 12941475 f gcesareni "Il-20 induces cheratin proliferation and stat-3 signal transduction pathway" SIGNOR-86269 IL21 protein Q9HBE4 UNIPROT BCL6 protein P41182 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782;BTO:0000785 22486304 f miannu "Interleukin-21 inhibits humoral response to an hiv dna vaccine by enhancing bcl-6 andpax-5expression." SIGNOR-196918 IL2 protein P60568 UNIPROT TNFSF10 protein P50591 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000782 22128144 f miannu "We observe that the CD8(+) T-cell autocrine growth factor IL-2 coordinately increases Nab2 expression and decreases TRAIL expression." SIGNOR-253895 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 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 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 AES protein Q08117 UNIPROT SIX6 protein O95475 UNIPROT "down-regulates activity" binding -1 12441302 t lperfetto "Biochemical and mutational analysis shows that the Six domain of both SIX3 and SIX6 strongly interact with the QD domain of TLE1 and AES. AES abrogates SIX3- and SIX6-induced phenotypes" SIGNOR-234589 CHRM2 protein P08172 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates 9606 BTO:0000007 12665513 f lperfetto "Here we show that m2 muscarinic receptors and go require taos and mek3/6 as the primary intermediates activating p38 mapk in 293 cells" SIGNOR-235536 ILK protein Q13418 UNIPROT PPP1R14A protein Q96A00 UNIPROT down-regulates phosphorylation Thr38 QKRHARVtVKYDRRE 9606 BTO:0000887;BTO:0001260 12144526 t miannu "Phosphopeptide mapping, phospho amino acid analysis and immunoblotting using phospho-specific antibodies indicated that ilk predominantly phosphorylated the site critical for potent inhibition, i.e. Thr(38) of cpi-17" SIGNOR-90828 CTDSP1 protein Q9GZU7 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" dephosphorylation Ser213 NLSPNPMsPAHNNLD 9606 BTO:0000007 17035229 t "SCP1 Dephosphorylates Smad2/3 in the Linkers|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-248793 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 "1D-myo-inositol 1,4,5-trisphosphate" smallmolecule CHEBI:16595 ChEBI ITPR1 protein Q14643 UNIPROT "up-regulates activity" "chemical activation" 9606 24646566 t miannu "The key event in activation of fluid secretion is an increase in intracellular [ca2+] ([ca2+]i) triggered by ip3-induced release of ca2+ from er via the ip3r. ip3rs determine the site of initiation and the pattern of [ca2+]i signal in the cell." SIGNOR-256239 INHBA protein P08476 UNIPROT ACVR2B protein Q13705 UNIPROT "up-regulates activity" binding 9606 8622651 t gcesareni "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-235142 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 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 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MYOD1 protein P15172 UNIPROT down-regulates phosphorylation Ser200 YSGDSDAsSPRSNCS 9606 BTO:0000222 14749395 t lperfetto "Myod is phosphorylated on ser5 and ser200 by cyclin b-cdc2, resulting in a decrease of its stability and down-regulation of both myod and p21." SIGNOR-216920 DUSP16 protein Q9BY84 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates dephosphorylation 9606 11359773 t gcesareni "Mkp-7 binds to and inactivates p38 mapk and jnk/sapk, but not erk inhibited by dual specificity phosphatases, such as dusp1, dusp10, and dusp16(uniprot)" SIGNOR-108233 GNG12 protein Q9UBI6 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-152615 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 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 MAPK14 protein Q16539 UNIPROT FGFR1 protein P11362 UNIPROT down-regulates phosphorylation Ser777 SMPLDQYsPSFPDTR 9606 20626350 t gcesareni "Fgfr1 translocation requires p38 mapk activation which phosphorylates the c-term tail of fgfr1 on ser777" SIGNOR-166598 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR TSC1 protein Q92574 UNIPROT down-regulates phosphorylation Ser584 ETSIFTPsPCKIPPP 9606 BTO:0000680;BTO:0001573;BTO:0001286 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-216944 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR BRCA1 protein P38398 UNIPROT down-regulates phosphorylation Ser632 LVVSRNLsPPNCTEL 9606 BTO:0000150 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-216984 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR MYOG protein P15173 UNIPROT down-regulates binding 9606 21902831 t lperfetto "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-216972 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 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 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR HIRA protein P54198 UNIPROT up-regulates phosphorylation Thr555 LSPSVLTtPSKIEPM 9606 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-216670 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 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 AR protein P10275 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 15861399 f miannu "AR homodimers recruit a panoply of factors including coactivators and mediator proteins whose enzymatic activities promote chromatin remodeling and transcriptional regulation of target genes leading to cell differentiation, survival, and proliferation" SIGNOR-251539 COL1A1 protein P02452 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 BTO:0001103;BTO:0002319 21949456 t "Collagen is the major structural protein in skeletal muscle ECM;...Several studies suggest that perimysial collagen is predominantly type I" SIGNOR-254662 EZH2 protein Q15910 UNIPROT AR protein P10275 UNIPROT "up-regulates activity" binding 9606 23239736 t miannu "This study demonstrates that phosphorylation of EZH2 at Ser21, mediated directly or indirectly by the PI3K-Akt pathway, can switch its function from a Polycomb repressor to a transcriptional coactivator of AR (and potentially other factors)." SIGNOR-251542 NEK2 protein P51955 UNIPROT NEK2 protein P51955 UNIPROT up-regulates phosphorylation Thr175 HDTSFAKtFVGTPYY 9606 17197699 t gcesareni "Enzymatic activity, induced;" SIGNOR-151763 IRF5 protein Q13568 UNIPROT IL10 protein P22301 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000801 22025054 f lperfetto "IRF5 is directly recruited to gene promoters associated with the M1 phenotype (including Il12b), but it represses Il10, probably also by binding to an ISRE in the gene promoter" SIGNOR-249509 IRF5 protein Q13568 UNIPROT IL1B protein P01584 UNIPROT up-regulates "transcriptional regulation" 9606 BTO:0000801 21240265 f "Among the genes with differences in expression in the M1 and M2 subsets are those regulated by IRF5, including IL12A, IL12B, IL23A, IL1B, TNF, CCL3(encoding MIP-1α), RANTES, CD1A, CD40, CD86 and CCR7" SIGNOR-254510 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-252695 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR SQSTM1 protein Q13501 UNIPROT up-regulates phosphorylation Ser272 RSRLTPVsPESSSTE 9606 BTO:0000551 20974803 t lperfetto "Here we show that cdk1 phosphorylates p62 in vitro and in vivo at t269 and s272, which is necessary for the maintenance of appropriate cyclin b1 levels and the levels of cdk1 activity necessary to allow cells to properly enter and exit mitosis." SIGNOR-216932 NKX3-1 protein Q99801 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" 9606 16697957 t miannu "NKX3.1 negatively regulates AKT activity in an AR-dependent manner" SIGNOR-251552 ITGA6 protein P23229 UNIPROT PMP22 protein Q01453 UNIPROT "up-regulates activity" binding 10090 BTO:0000938 16436605 t Regulation miannu "PMP22 is in a complex with α6β4 integrin and laminin. PMP22 and β4 integrin are in a complex in a variety of cell types. The interaction with the integrins provides PMP22 with the ability to modulate the cell–ECM communications, as well as intracellular events. Signaling between the ECM and the intracellular compartment is essential for SC myelination, as well as cellular differentiation and motility, in general. The identification of PMP22 as a binding partner for an integrin signaling complex provides a major step toward understanding the role of this disease-linked molecule in the nervous system and in non-neural cell types." SIGNOR-251895 ITGAV protein P06756 UNIPROT "Av/b5 integrin" complex SIGNOR-C178 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-253207 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 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 CDK2 protein P24941 UNIPROT CCNE1 protein P24864 UNIPROT down-regulates phosphorylation Ser399 GLLTPPQsGKKQSSG 9606 14536078 t amattioni "Phosphorylation-triggered ubiquitination has been proposed to be the major pathway regulating cyclin e protein abundance. Cdk2 activity is required for cyclin e turnover in vivo because it phosphorylates s384. Mutation of ser384 to alanine also rendered cyclin e resistant to degradation" SIGNOR-118555 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 FOXP3 protein Q9BZS1 UNIPROT T-reg_differentiation phenotype SIGNOR-PH91 SIGNOR up-regulates 9606 15785758 t mrosina "Viewed as a whole, the available data demonstrate essential involvement of Foxp3 in the development and function of CD4 + CD25 + T reg cells." SIGNOR-254970 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 DAB2IP protein Q5VWQ8 UNIPROT GSK3B protein P49841 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 20080667 t miannu "DAB2IP activates GSK-3β and antagonizes Wnt-mediated EMT. GSK-3β appears to directly associate with DAB2IP. Because DAB2IP is not a phosphatase, the mechanism of GSK-3β activation by DAB2IP is likely mediated by a separate phosphatase associated within this complex. PP2A is critical for DAB2IP-mediated GSK-3β activation and MET responses." SIGNOR-254752 Diacylglycerol smallmolecule CID:6026790 PUBCHEM 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 Diacylglycerol smallmolecule CID:6026790 PUBCHEM PRKCQ protein Q04759 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-242596 CDON protein Q4KMG0 UNIPROT MAP3K7 protein O43318 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-235554 CDON/SPAG9 complex SIGNOR-C21 SIGNOR MAP3K5 protein Q99683 UNIPROT unknown binding 10090 BTO:0000165;BTO:0000222;BTO:0002181 22337877 t lperfetto "Cdo and jlp interacted with ask1 or tak1 in 293t cells and c2c12 myoblasts" SIGNOR-235557 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 CDON/SPAG9 complex SIGNOR-C21 SIGNOR MAP3K7 protein O43318 UNIPROT unknown binding 10090 BTO:0000165;BTO:0000222;BTO:0002181 22337877 t lperfetto "Cdo and jlp interacted with ask1 or tak1 in 293t cells and c2c12 myoblasts" SIGNOR-235560 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 Frizzled proteinfamily SIGNOR-PF11 SIGNOR CTNNB1 protein P35222 UNIPROT up-regulates BTO:0001103 23209147 f apalma "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-255687 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 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RUNX3 protein Q13761 UNIPROT down-regulates phosphorylation Ser356 SSSGGDRsPTRMLAS 9606 19351720 t lperfetto "Our findings demonstrate that the cell cycle proteins cyclin d1 and cdk4 induce runx2 and runx3 phosphorylation, ubiquitylation and proteasomal degradation." SIGNOR-216980 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 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 ITPRIPL1 protein Q6GPH6 UNIPROT ITPR1 protein Q14643 UNIPROT up-regulates binding 9606 BTO:0000938 21368195 t "Induces Ca2+ release that increases the binding affinity of Shh for Boc." 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-172497 JAG1 protein P78504 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 10551863 t "Binding Calcium-dependent." gcesareni "Here we report the first x-ray structure of a functional fragment of a notch ligand, the dsl-egf3 domains of human jagged-1 (j-1dsl-egf3). The structure identifies a highly conserved face of the dsl domain and we show, by functional analysis of drosophila ligand mutants, that this surface is required for both cis- and trans-regulatory interactions with notch." SIGNOR-72112 mTORC1 complex SIGNOR-C3 SIGNOR GRB10 protein Q13322 UNIPROT up-regulates phosphorylation 9606 21659604 t lperfetto "The adaptor protein grb10 was identified as an mtorc1 substrate that mediates the phosphoinositide 3-kinase." SIGNOR-217063 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 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 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 DYRK2 protein Q92630 UNIPROT SIAH2 protein O43255 UNIPROT up-regulates phosphorylation Ser28 PQPQHTPsPAAPPAA 9606 22878263 t llicata "In the present study, we identify the serine/threonine kinase dyrk2 as siah2 interaction partner that phosphorylates siah2 at five residues (ser16, thr26, ser28, ser68, and thr119). accordingly, phosphorylated siah2 is more active than the wild-type e3 ligase and shows an increased ability to trigger the hif-1?-Mediated transcriptional response and angiogenesis." SIGNOR-198725 DYRK2 protein Q92630 UNIPROT SIAH2 protein O43255 UNIPROT up-regulates phosphorylation Thr26 PPPQPQHtPSPAAPP 9606 22878263 t llicata "In the present study, we identify the serine/threonine kinase dyrk2 as siah2 interaction partner that phosphorylates siah2 at five residues (ser16, thr26, ser28, ser68, and thr119). accordingly, phosphorylated siah2 is more active than the wild-type e3 ligase and shows an increased ability to trigger the hif-1?-Mediated transcriptional response and angiogenesis." SIGNOR-198737 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 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 CAPN3 protein P20807 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-251606 JAK2 protein O60674 UNIPROT ITGAL protein P20701 UNIPROT "up-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-254739 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 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 AML1-ETO "fusion protein" SIGNOR-FP1 SIGNOR KIT protein P10721 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000567 29236325 f irozzo "We report here that AML1/ETO transactivates c-KIT expression through directly binding to and mediating the long-range interaction between the promoter and intronic enhancer regions of c-KIT." SIGNOR-255699 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1878 SPKYSPTsPTYSPTT 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 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 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 IL17A protein Q16552 UNIPROT KLF3 protein P57682 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 23332504 f fspada "Specifically, il-17 suppresses klf15, a pro-adipogenic tf, and enhances expression of klf2 and klf3, which are anti-adipogenic." SIGNOR-192610 ELF2 protein Q15723 UNIPROT VCP protein P55072 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000093 18544453 f "These findings indicate that ELF2 transactivates VCP promoter through binding to two motifs, with a predominant contribution of the upstream one." SIGNOR-254283 EPHA3 protein P29320 UNIPROT EPHA3 protein P29320 UNIPROT "up-regulates activity" phosphorylation Tyr779 EDDPEAAyTTRGGKI 9606 BTO:0000007 11870224 t "Eph receptor activation leads to tyrosine phosphorylation of three major autophosphorylation sites. these residues function to regulate kinase activity, their phosphorylation being required for full intrinsic enzyme activity. these tyrosines (EphA3 Y596, Y602 and Y779) as the prominent autophosphorylation sites of EphA3" SIGNOR-251117 ARP2/3 complex SIGNOR-C146 SIGNOR F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 9606 12479800 f lperfetto "The Arp2/3 complex concentrates at leading edges, where it catalyzes the growth of branched actin networks that are believed to provide the protrusive force for leading edge extension." SIGNOR-251511 BAK1 protein Q16611 UNIPROT AIFM1 protein O95831 UNIPROT up-regulates relocalization 9606 23003569 t gcesareni "First, bax/bak-mediated momp leads to the release of a significant part of the cyt c, smac/diablo and htra2/omi proteins. in a third step, cyt c, smac/diablo and htra2/omi, which were released into the cytosol, trigger caspase activation. This is necessary to alter the physical association of aif and endog with the im to enable their relocation to the cytosol." SIGNOR-192092 "Raf265 derivative" chemical CID:23654923 PUBCHEM RAF1 protein P04049 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206394 CSNK2A1 protein P68400 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-200798 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 CSNK2B protein P67870 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-200806 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 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 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT up-regulates phosphorylation Thr56 FSSQPGHtPHPAASR 9606 10669763 t lperfetto "The results of this study reveal the following novel findings: destruction of the three putative MAP kinase sites at positions 56, 74, and 87 results in ubiquitination and subsequent degradation of the protein. Progressive inactivation of these MAP kinase sites revealed that Bcl-2 stability is mainly regulated by phosphorylation at Thr74 and Ser87, with Ser87 phosphorylation playing a predominant role. TNF-α or the MAP kinase-specific inhibitor PD98059 diminishes Ser87 phosphorylation of Bcl-2 in vivo, while activated ERK2 induces phosphorylation of Bcl-2 in vivo and in vitro." SIGNOR-244610 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr74 ARTSPLQtPAAPGAA 9606 BTO:0000567 10669763 t lperfetto "The results of this study reveal the following novel findings: destruction of the three putative MAP kinase sites at positions 56, 74, and 87 results in ubiquitination and subsequent degradation of the protein. Progressive inactivation of these MAP kinase sites revealed that Bcl-2 stability is mainly regulated by phosphorylation at Thr74 and Ser87, with Ser87 phosphorylation playing a predominant role. TNF-α or the MAP kinase-specific inhibitor PD98059 diminishes Ser87 phosphorylation of Bcl-2 in vivo, while activated ERK2 induces phosphorylation of Bcl-2 in vivo and in vitro." SIGNOR-244494 LTB4R2 protein Q9NPC1 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-256674 BAX protein Q07812 UNIPROT CYCS protein P99999 UNIPROT up-regulates 9606 18097445 f gcesareni "This process of mitochondrial outer membrane permeabilization (momp) results in the release of cycs.it is commonly thought that bax and bak form pores in membranes" SIGNOR-160039 CASP8 protein Q14790 UNIPROT CYCS protein P99999 UNIPROT "up-regulates activity" 9606 BTO:0000661 10364179 f "Translocation from Mitochondria to Cytosol" lperfetto "Caspase-8 triggered rapid cytochrome c release from mitochondria. The effect was indirect." SIGNOR-68225 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR 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-244584 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR 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-244588 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1193 QPTSKAYsPRYSISD 9606 20724475 t lperfetto "ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process." SIGNOR-244747 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR MYBL2 protein P10244 UNIPROT up-regulates phosphorylation Thr487 SQKVVVTtPLHRDKT 9606 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-217260 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR MYBL2 protein P10244 UNIPROT up-regulates phosphorylation Thr494 TPLHRDKtPLHQKHA 9606 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-217264 ESR2 protein Q92731 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-253472 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR RAD9A protein Q99638 UNIPROT unknown phosphorylation Ser328 VLPSISLsPGPQPPK 9606 23028682 t lperfetto "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-217268 ETS1 protein P14921 UNIPROT MMP9 protein P14780 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-254083 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 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-253915 EZH2 protein Q15910 UNIPROT SSTR1 protein P30872 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004094 22144423 f miannu "For three selected genes (ALDH1A1, SSTR1, and DACT3), we validated their upregulation upon EZH2 knockdown and confirmed the binding of EZH2/H3K27Me3 to their genomic loci." SIGNOR-254143 EZH2 protein Q15910 UNIPROT TWIST1 protein Q15672 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001939 23836662 f miannu "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-254151 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 MAPK14 protein Q16539 UNIPROT ZNHIT1 protein O43257 UNIPROT up-regulates phosphorylation 9606 BTO:0000222 BTO:0000887 20473270 t gcesareni "We show that the srcap subunit named znhit1 or p18(hamlet), which is a substrate of p38 mapk, is recruited to the myogenin promoter at the onset of muscle differentiation, in a p38 mapk-dependent manner. Furthermore, p18hamlet was phosphorylated during myoblast differentiation in a p38 mapk-dependent manner (dal testo pmc)" SIGNOR-165571 cabazitaxel chemical CHEBI:63584 ChEBI TUBA4A protein P68366 UNIPROT "down-regulates activity" binding 9606 21770474 t miannu "Among these, larotaxel (XRP9881, formerly RPR109881A)[3,4] and cabazitaxel (XRP6258, TXD258, RPR116258A)[5] share a mechanism of action unique to taxanes, promoting tubulin assembly and stabilizing microtubules against cold-induced depolymerization" SIGNOR-259340 cabazitaxel chemical CHEBI:63584 ChEBI TUBB1 protein Q9H4B7 UNIPROT "down-regulates activity" binding 9606 21770474 t miannu "Among these, larotaxel (XRP9881, formerly RPR109881A)[3,4] and cabazitaxel (XRP6258, TXD258, RPR116258A)[5] share a mechanism of action unique to taxanes, promoting tubulin assembly and stabilizing microtubules against cold-induced depolymerization" SIGNOR-259341 CDK19 protein Q9BWU1 UNIPROT PAK1 protein Q13153 UNIPROT unknown phosphorylation Ser174 TPAVPPVsEDEDDDD 9606 19520772 t llicata "Here, we identified p21 activated kinase 1 (pak1) as a new cdk11(p58) substrate and we mapped a new phosphorylation site of ser174 on pak1" SIGNOR-185000 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 "docetaxel anhydrous" chemical CHEBI:4672 ChEBI TUBA4A protein P68366 UNIPROT "down-regulates activity" binding 9606 BTO:0001033 23337758 t miannu "Tubulin exists in the cell as dimers of α and β subunits, which complexes with a variety of regulatory proteins. There is a dynamic equilibrium between free and polymerized tubulin causing a state called ""dynamic instability,"" which is a target of anticancer drugs, which inhibit tubulin through polymerization (taxanes, epothilones) or depolymerization (vinca alkaloids). Docetaxel-based therapy was the first such treatment to demonstrate a survival benefit in men with castration-resistant prostate cancer." SIGNOR-259342 "docetaxel anhydrous" chemical CHEBI:4672 ChEBI TUBB1 protein Q9H4B7 UNIPROT "down-regulates activity" binding 9606 BTO:0001033 23337758 t miannu "Tubulin exists in the cell as dimers of α and β subunits, which complexes with a variety of regulatory proteins. There is a dynamic equilibrium between free and polymerized tubulin causing a state called ""dynamic instability,"" which is a target of anticancer drugs, which inhibit tubulin through polymerization (taxanes, epothilones) or depolymerization (vinca alkaloids). Docetaxel-based therapy was the first such treatment to demonstrate a survival benefit in men with castration-resistant prostate cancer." SIGNOR-259343 "eribulin mesylate" chemical CHEBI:70710 ChEBI TUBA4A protein P68366 UNIPROT "down-regulates activity" binding 9606 16940412 t miannu "The complex marine natural product halichondrin B was compared with NSC 707389 (E7389), a structurally simplified, synthetic macrocyclic ketone analog, which has been selected for clinical trials in human patients. NSC 707389 was invariably more potent than halichondrin B in its interactions with tubulin. Both compounds inhibited tubulin assembly, inhibited nucleotide exchange on beta-tubulin, and were noncompetitive inhibitors of the binding of radiolabeled vinblastine and dolastatin 10 to tubulin." SIGNOR-259344 "eribulin mesylate" chemical CHEBI:70710 ChEBI TUBB1 protein Q9H4B7 UNIPROT "down-regulates activity" binding 9606 16940412 t miannu "The complex marine natural product halichondrin B was compared with NSC 707389 (E7389), a structurally simplified, synthetic macrocyclic ketone analog, which has been selected for clinical trials in human patients. NSC 707389 was invariably more potent than halichondrin B in its interactions with tubulin. Both compounds inhibited tubulin assembly, inhibited nucleotide exchange on beta-tubulin, and were noncompetitive inhibitors of the binding of radiolabeled vinblastine and dolastatin 10 to tubulin." SIGNOR-259345 ixabepilone chemical CHEBI:63605 ChEBI TUBB3 protein Q13509 UNIPROT "down-regulates activity" binding 9606 BTO:0000356 18945860 t miannu "Ixabepilone, the first drug in a new class of microtubule-stabilizing agents called epothilones, offers a new treatment option for patients with metastatic or locally advanced breast cancer who are refractory to standard chemotherapy." SIGNOR-259349 paclitaxel chemical CHEBI:45863 ChEBI TUBA4A protein P68366 UNIPROT "down-regulates activity" binding 9606 28298489 t miannu "Here we integrate a computational model for microtubule assembly with nanometer-scale fluorescence microscopy measurements to identify the kinetic and thermodynamic basis of kinetic stabilization by the MTAs paclitaxel, an assembly promoter, and vinblastine, a disassembly promoter. We identify two distinct modes of kinetic stabilization in live cells, one that truly suppresses on-off kinetics, characteristic of vinblastine, and the other a ""pseudo"" kinetic stabilization, characteristic of paclitaxel, that nearly eliminates the energy difference between the GTP- and GDP-tubulin thermodynamic states. By either mechanism, the main effect of both MTAs is to effectively stabilize the microtubule against disassembly in the absence of a robust GTP cap." SIGNOR-259346 paclitaxel chemical CHEBI:45863 ChEBI TUBB1 protein Q9H4B7 UNIPROT "down-regulates activity" binding 9606 28298489 t miannu "Here we integrate a computational model for microtubule assembly with nanometer-scale fluorescence microscopy measurements to identify the kinetic and thermodynamic basis of kinetic stabilization by the MTAs paclitaxel, an assembly promoter, and vinblastine, a disassembly promoter. We identify two distinct modes of kinetic stabilization in live cells, one that truly suppresses on-off kinetics, characteristic of vinblastine, and the other a ""pseudo"" kinetic stabilization, characteristic of paclitaxel, that nearly eliminates the energy difference between the GTP- and GDP-tubulin thermodynamic states. By either mechanism, the main effect of both MTAs is to effectively stabilize the microtubule against disassembly in the absence of a robust GTP cap." SIGNOR-259347 "vinorelbine L-tartrate" chemical CHEBI:32296 ChEBI TUBB protein P07437 UNIPROT "down-regulates activity" binding 9606 BTO:0000356;BTO:0000762 7740336 t miannu "Vinorelbine (Navelbine; Burroughs Wellcome Co, Research Triangle Park, NC; Pierre Fabre Médicament, Paris, France) and paclitaxel (Taxol; Bristol-Myers Oncology, Princeton, NJ) as single-agent therapy exhibit good activity in breast and lung cancers. Because these agents bind to distinct sites on tubulin and affect microtubules in opposite ways, a pilot study was conducted of the combination of vinorelbine and paclitaxel in patients with metastatic breast cancer or lung cancer who were refractory to first-line chemotherapy." SIGNOR-259348 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 2',2'-difluoro-2'-deoxyuridine chemical CHEBI:83486 ChEBI TYMS protein P04818 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0003207 25562513 t miannu "2',2'-Difluoro-2'-deoxycytidine (dFdC, gemcitabine) is a cytidine analogue active against several solid tumor types, such as ovarian, pancreatic and non-small cell lung cancer. The compound has a complex mechanism of action. Because of the structural similarity of one metabolite of dFdC, dFdUMP, with the natural substrate for thymidylate synthase (TS) dUMP, we investigated whether dFdC and its deamination product 2',2'-difluoro-2'-deoxyuridine (dFdU) would inhibit TS. This study was performed using two solid tumor cell lines: the human ovarian carcinoma cell line A2780 and its dFdC-resistant variant AG6000. The specific TS inhibitor Raltitrexed (RTX) was included as a positive control. Using the in situ TS activity assay measuring the intracellular conversion of [5-(3)H]-2'-deoxyuridine or [5-(3)H]-2'-deoxycytidine to dTMP and tritiated water, it was observed that dFdC and dFdU inhibited TS." SIGNOR-259351 capecitabine chemical CHEBI:31348 ChEBI TYMS protein P04818 UNIPROT "down-regulates activity" "chemical inhibition" 9606 15866500 t miannu "These findings suggest that the mechanism of antiproliferative toxicity of capecitabine is at least partly due to TS inhibitory activity of its active metabolite 5-fluoro-2'-deoxyuridine monophosphate (FdUMP)." SIGNOR-259354 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 gemcitabine chemical CHEBI:175901 ChEBI TYMS protein P04818 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0003207 25562513 t miannu "2',2'-Difluoro-2'-deoxycytidine (dFdC, gemcitabine) is a cytidine analogue active against several solid tumor types, such as ovarian, pancreatic and non-small cell lung cancer. The compound has a complex mechanism of action. Because of the structural similarity of one metabolite of dFdC, dFdUMP, with the natural substrate for thymidylate synthase (TS) dUMP, we investigated whether dFdC and its deamination product 2',2'-difluoro-2'-deoxyuridine (dFdU) would inhibit TS. This study was performed using two solid tumor cell lines: the human ovarian carcinoma cell line A2780 and its dFdC-resistant variant AG6000. The specific TS inhibitor Raltitrexed (RTX) was included as a positive control. Using the in situ TS activity assay measuring the intracellular conversion of [5-(3)H]-2'-deoxyuridine or [5-(3)H]-2'-deoxycytidine to dTMP and tritiated water, it was observed that dFdC and dFdU inhibited TS." SIGNOR-259350 pralatrexate chemical CHEBI:71223 ChEBI DHFR protein P00374 UNIPROT "down-regulates activity" "chemical inhibition" 9606 23409799 t miannu "Pralatrexate is a small molecule with a chemical formula C23H23N7O5 and a molecular weight of 477.48 g/mol (Box 1). It competitively inhibits dihydrofolate reductase (DHFR) and thymidylate synthase." SIGNOR-259353 pralatrexate chemical CHEBI:71223 ChEBI TYMS protein P04818 UNIPROT "down-regulates activity" "chemical inhibition" 9606 23409799 t miannu "Pralatrexate is a small molecule with a chemical formula C23H23N7O5 and a molecular weight of 477.48 g/mol (Box 1). It competitively inhibits dihydrofolate reductase (DHFR) and thymidylate synthase." SIGNOR-259352 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 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 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 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 TGFB1 protein P01137 UNIPROT SLC5A5 protein Q92911 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9606 BTO:0003873 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 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 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 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 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 CDKN2A protein P42771 UNIPROT CDK4 protein P11802 UNIPROT down-regulates binding 9606 16161044 t gcesareni "The cdk-inhibitor p16 is a tumor suppressor gene that is inactivated in many forms of cancer. In addition, cytoplasmic p16 bound cyclin dependent kinase (cdk)4/6, potentially indicating that p16 could have a function in the cytoplasm." SIGNOR-140409 DNMT3A protein Q9Y6K1 UNIPROT CDKN2A protein Q8N726 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9606 19786833 f 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-259361 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 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 hydroxyurea chemical CHEBI:44423 ChEBI RRM2 protein P31350 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001061 14583450 t miannu "In PC3 cells, hydroxyurea inhibited hRRM2 and resulted in increased sensitivity to UV irradiation." SIGNOR-259355 "imatinib methanesulfonate" chemical CHEBI:31690 ChEBI BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR "down-regulates activity" "chemical inhibition" 9606 BTO:0000740 15206509 t miannu "Imatinib mesylate (Gleevec/Glivec, Novartis, Basel, Switzerland), formerly called STI571, is a specific and potent inhibitor of the BCR-ABL tyrosine kinase, the molecular hallmark of chronic myeloid leukaemia." SIGNOR-259357 Kindlin proteinfamily SIGNOR-PF48 SIGNOR "A1/b1 integrin" complex SIGNOR-C159 SIGNOR "up-regulates activity" binding 9606 29544897 t miannu "Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival." SIGNOR-259000 MYC protein P01106 UNIPROT LDHA protein P00338 UNIPROT "up-regulates quantity" "transcriptional activation" 10116 BTO:0000452 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 PRC2 complex SIGNOR-C130 SIGNOR CDKN2A protein Q8N726 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9606 BTO:0001271 22469984 t irozzo "The requirement for PRC2 in leukemia is partly because of its role in direct transcriptional repression of genes that limit the self-renewal potential of hematopoietic cells, including Cdkn2a" SIGNOR-259360 "Ribonucleotide reductase" complex SIGNOR-C233 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 14583450 f 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-259365 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 RRM2B protein Q7LG56 UNIPROT RRM1 protein P23921 UNIPROT "up-regulates activity" binding 9606 BTO:0001061 14583450 t miannu "Taken together, we conclude that UV-induced activation of p53R2 transcription and binding of p53R2 to hRRM1 to form RR holoenzyme are impaired in the p53-mutant cell line PC3." SIGNOR-259366 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 SARS 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 "SWI/SNF complex" complex SIGNOR-C92 SIGNOR CDKN2A protein P42771 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 18332116 f irozzo "HSNF5 reexpression in MRT cells caused SWI/SNF recruitment and activation of p15INK4b and p16INK4a, but not of p14ARF.Reexpression of hSNF5 in MRT cells overcomes epigenetic silencing and mediates transcriptional activation of p15INK4b and p16INK4a" SIGNOR-256299 "UV stress" stimulus SIGNOR-ST7 SIGNOR RRM2B protein Q7LG56 UNIPROT up-regulates 9606 BTO:0001061 14583450 f miannu "Taken together, we conclude that UV-induced activation of p53R2 transcription and binding of p53R2 to hRRM1 to form RR holoenzyme are impaired in the p53-mutant cell line PC3." SIGNOR-259362 BRAF protein P15056 UNIPROT Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates 9606 BTO:0000797 27340238 f "These alterations corresponded to mutant KRAS and BRAF-dependent increases in glucose uptake and lactate production. Metabolic reprogramming and glucose conversion to lactate in RKO cells were proportional to levels of BRAF V600E protein." SIGNOR-259373 CRABP2 protein P29373 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-regulates 9606 BTO:0000551 30696915 f "Analysis of clinical samples revealed that high CRABP2 levels were correlated with lymph node metastases, poor overall survival, and increased recurrence. Knockdown of Crabp2 decreased migration, invasion, anoikis resistance, and in vivo metastasis." SIGNOR-259371 KRAS protein P01116 UNIPROT Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates 9606 BTO:0000797 27340238 f "These alterations corresponded to mutant KRAS and BRAF-dependent increases in glucose uptake and lactate production. Metabolic reprogramming and glucose conversion to lactate in RKO cells were proportional to levels of BRAF V600E protein." SIGNOR-259372 LDHA protein P00338 UNIPROT Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates 9606 BTO:0000164 9192621 f "The lactate dehydrogenase-A gene (LDH-A), whose product participates in normal anaerobic glycolysis and is frequently increased in human cancers, was identified as a c-Myc-responsive gene." SIGNOR-259370 MAPK11 protein Q15759 UNIPROT EGFR protein P00533 UNIPROT down-regulates phosphorylation 9606 16932740 t gcesareni "P38 map kinase mediates stress-induced internalization of egfrthe underlying mechanism entails phosphorylation of egfr at a short segment (amino acids 1002-1022) containing multiple serines and threonines, as well as phosphorylation of two rab5 effectors, eea1 and gdi." SIGNOR-149086 MYC protein P01106 UNIPROT VEGFA protein P15692 UNIPROT "up-regulates quantity" "transcriptional activation" 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 P2RY12 protein Q9H244 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-256712 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 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 S1PR1 protein P21453 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-256713 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 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 F2RL1 protein P55085 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-256752 "125-L-serine-2-133-interleukin 2 (human reduced)" smallmolecule SID:46508054 ChEBI IL2RB protein P14784 UNIPROT "up-regulates activity" binding 9606 18031103 t miannu "Aldesleukin (recombinant IL-2) has similar pharmacodynamic properties to endogenous IL-2 and, when administered to patients with cancer, stimulates the antitumour immune response." SIGNOR-259389 "125-L-serine-2-133-interleukin 2 (human reduced)" smallmolecule SID:46508054 ChEBI IL2RG protein P31785 UNIPROT "up-regulates activity" binding 9606 18031103 t miannu "Aldesleukin (recombinant IL-2) has similar pharmacodynamic properties to endogenous IL-2 and, when administered to patients with cancer, stimulates the antitumour immune response." SIGNOR-259390 Aflibercept smallmolecule SID:134445687 ChEBI PGF protein P49763 UNIPROT "down-regulates activity" binding 9606 22813448 t miannu "Aflibercept, a fusion protein with binding domains from native VEGF receptors, binds VEGF-A, VEGF-B, and placental growth factors 1 and 2 with high affinity.This soluble decoy receptor is produced by fusing all-human DNA sequences of the second immunoglobulin (Ig) domain of human VEGF receptor (VEGFR) 1 to the third Ig domain of human VEGFR-2, which then is fused to the Fc region of human IgG-1.2 Aflibercept binds to all VEGF-A and VEGF-B isoforms, as well as the highly related placental growth factor." SIGNOR-259385 Aflibercept smallmolecule SID:134445687 ChEBI VEGFA protein P15692 UNIPROT "down-regulates activity" binding 9606 22813448 t miannu "Aflibercept, a fusion protein with binding domains from native VEGF receptors, binds VEGF-A, VEGF-B, and placental growth factors 1 and 2 with high affinity.This soluble decoy receptor is produced by fusing all-human DNA sequences of the second immunoglobulin (Ig) domain of human VEGF receptor (VEGFR) 1 to the third Ig domain of human VEGFR-2, which then is fused to the Fc region of human IgG-1.2 Aflibercept binds to all VEGF-A and VEGF-B isoforms, as well as the highly related placental growth factor." SIGNOR-259386 Aflibercept smallmolecule SID:134445687 ChEBI VEGFB protein P49765 UNIPROT "down-regulates activity" binding 9606 22813448 t miannu "Aflibercept, a fusion protein with binding domains from native VEGF receptors, binds VEGF-A, VEGF-B, and placental growth factors 1 and 2 with high affinity.This soluble decoy receptor is produced by fusing all-human DNA sequences of the second immunoglobulin (Ig) domain of human VEGF receptor (VEGFR) 1 to the third Ig domain of human VEGFR-2, which then is fused to the Fc region of human IgG-1.2 Aflibercept binds to all VEGF-A and VEGF-B isoforms, as well as the highly related placental growth factor." SIGNOR-259387 EZR protein P15311 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-regulates 9606 BTO:0001802 16488997 f "Ezrin is indispensable for Six1-induced metastasis and highly expressed in a panel of representative pediatric cancers." SIGNOR-259375 FOXO3 protein O43524 UNIPROT TSC1 protein Q92574 UNIPROT "up-regulates quantity" "transcriptional activation" 10090 BTO:0003328 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 G8RGG88B68 smallmolecule SID:135317436 ChEBI IFNAR2 protein P48551 UNIPROT "up-regulates activity" binding -1 15898717 t miannu "To significantly improve the pharmacological properties of the drug, a pegylated form of IFNalpha(2a) was developed (PEGASYS). This 40 kDa PEG-conjugated IFNalpha(2a) ((40)PEG-IFNalpha(2a)) is obtained by the covalent binding of one 40 kDa branched PEG-polymer to a lysine side-chain of IFNalpha(2a). Here, we report the detailed structural, kinetic, and thermodynamic analysis of the binding to the extracellular domain of the receptor IFNAR2 of (40)PEG-IFNalpha(2a) and its isolated positional isomers modified at K31, K134, K131, K121, K164, and K70, respectively, in comparison with unmodified IFNalpha(2a)." SIGNOR-259391 HIF1A protein Q16665 UNIPROT Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates 9606 17415528 f "HIF-1 has been known as a major transcription factor for the induction of virtually all genes encoding glucose transporters and glycolytic enzymes, which allows hypoxic tumor cells to take up glucose more efficiently and metabolize pyruvate to lactate" SIGNOR-259381 HIF1A protein Q16665 UNIPROT Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates 9606 BTO:0001336 28623342 f "Our results demonstrate that SF(synovial fibroblasts) are highly dependent on glycolytic metabolism and that HIF-1α plays a regulatory role in glycolysis even under aerobic conditions." SIGNOR-259380 MLL-AF9 "fusion protein" SIGNOR-FP5 SIGNOR CBFB protein Q13951 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9606 BTO:0001412 24449215 f irozzo "However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. We found that MLL-BP and the 3 MLL fusion proteins all decreased RUNX1 levels, and MLL-eleven nineteen leukemia (ENL) caused a greater decrease in RUNX1 compared with MLL-AF9 and MLL-AF4 fusion proteins." SIGNOR-255852 PLK1 protein P53350 UNIPROT TPT1 protein P13693 UNIPROT down-regulates phosphorylation Ser64 PEGEGTEsTVITGVD 9606 12167714 t lperfetto "Plk phosphorylates tctp on two serine residues. These results suggest that phosphorylation decreases the microtubule-stabilizing activity of tctp and promotes the increase in microtubule dynamics that occurs after metaphase" SIGNOR-91348 SIX1 protein Q15475 UNIPROT EZR protein P15311 UNIPROT "up-regulates quantity" "transcriptional activation" 9606 BTO:0001802 16488997 t "We now show that the gene encoding Ezrin is a direct transcriptional target of Six1." SIGNOR-259374 valrubicin chemical CHEBI:135876 ChEBI TOP2A protein P11388 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000096 16019763 t miannu "Valrubicin (N-trifluoroacetyladriamycin-14-valerate) is a semi-synthetic derivative of the anthracycline doxorubicin. Valrubicin inhibits the incorporation of nucleosides into nucleic acids, causing extensive chromosomal damage and cell-cycle arrest in the G2 phase. Its principal metabolites inhibit topoisomerase II, thus arresting DNA synthesis." SIGNOR-259383 valrubicin chemical CHEBI:135876 ChEBI TOP2B protein Q02880 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000096 16019763 t miannu "Valrubicin (N-trifluoroacetyladriamycin-14-valerate) is a semi-synthetic derivative of the anthracycline doxorubicin. Valrubicin inhibits the incorporation of nucleosides into nucleic acids, causing extensive chromosomal damage and cell-cycle arrest in the G2 phase. Its principal metabolites inhibit topoisomerase II, thus arresting DNA synthesis." SIGNOR-259384 "denileukin diftitox" smallmolecule SID:125240988 ChEBI IL2RA protein P01589 UNIPROT "up-regulates activity" binding 9606 BTO:0001825 15757436 t miannu "Denileukin diftitox (DAB389IL-2; Ontak) is a novel recombinant fusion protein approved by the US Food and Drug Administration for the treatment of relapsed or refractory cutaneous T-cell lymphoma. It consists of fragments of diphtheria toxin linked to human interleukin-2 and works by targeting the high-affinity interleukin-2 receptor expressed on malignant cells. " SIGNOR-259392 "denileukin diftitox" smallmolecule SID:125240988 ChEBI IL2RB protein P14784 UNIPROT "up-regulates activity" binding 9606 BTO:0001825 15757436 t miannu "Denileukin diftitox (DAB389IL-2; Ontak) is a novel recombinant fusion protein approved by the US Food and Drug Administration for the treatment of relapsed or refractory cutaneous T-cell lymphoma. It consists of fragments of diphtheria toxin linked to human interleukin-2 and works by targeting the high-affinity interleukin-2 receptor expressed on malignant cells. " SIGNOR-259393 "denileukin diftitox" smallmolecule SID:125240988 ChEBI IL2RG protein P31785 UNIPROT "up-regulates activity" binding 9606 BTO:0001825 15757436 t miannu "Denileukin diftitox (DAB389IL-2; Ontak) is a novel recombinant fusion protein approved by the US Food and Drug Administration for the treatment of relapsed or refractory cutaneous T-cell lymphoma. It consists of fragments of diphtheria toxin linked to human interleukin-2 and works by targeting the high-affinity interleukin-2 receptor expressed on malignant cells. " SIGNOR-259394 RIPK1 protein Q13546 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT "up-regulates activity" binding 9606 20404851 t lperfetto "Collectively, TRIF forms a multiprotein signaling complex along with TRAF6, TRADD, Pellino-1 and RIP1 for the activation of TAK1, which in turn activates the NF-_B and MAPK pathways." SIGNOR-216325 NMUR1 protein Q9HB89 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-256751 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 TBXA2R protein P21731 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-256744 P2RY13 protein Q9BPV8 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-256749 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 PTGDR protein Q13258 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-256755 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 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 S1PR3 protein Q99500 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-256790 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 P2RY6 protein Q15077 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-256804 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 NR4A3 protein Q92570 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 30455429 f miannu "Over-expression of NR4A3 attenuated proliferation of cancer cells and promoted apoptosis by augmenting the expression of pro-apoptotic genes, PUMA and Bax." SIGNOR-259398 NR4A3 protein Q92570 UNIPROT BAX protein Q07812 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000150;BTO:0000551 30455429 t miannu "Over-expression of NR4A3 attenuated proliferation of cancer cells and promoted apoptosis by augmenting the expression of pro-apoptotic genes, PUMA and Bax." SIGNOR-259397 NR4A3 protein Q92570 UNIPROT BBC3 protein Q9BXH1 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000150;BTO:0000551 30455429 t miannu "Over-expression of NR4A3 attenuated proliferation of cancer cells and promoted apoptosis by augmenting the expression of pro-apoptotic genes, PUMA and Bax." SIGNOR-259396 NR4A3 protein Q92570 UNIPROT BCL2 protein P10415 UNIPROT "down-regulates activity" binding 9606 30455429 t miannu "NR4A3 physically interacted with an anti-apoptotic Bcl-2 protein hence sequestering it from blunting apoptosis." SIGNOR-259399 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 PELI1 protein Q96FA3 UNIPROT BIRC3 protein Q13489 UNIPROT "up-regulates quantity by stabilization" ubiquitination 9606 BTO:0002552 27248820 t miannu "Notably, Pellino-1 directly interacted with cIAP2 and stabilized cIAP2 through lysine63-mediated polyubiquitination via its E3 ligase activity." SIGNOR-259395 RPS6KA1 protein Q15418 UNIPROT RPS6KA1 protein Q15418 UNIPROT "up-regulates activity" phosphorylation Ser221 DHEKKAYsFCGTVEY 9606 BTO:0000007 20048145 t lperfetto "Herein, we demonstrate that the n-terminal kinase domain (ntk) of rsk1 is necessary for interactions with pkarialpha. Substitution of the activation loop phosphorylation site (ser-221) in the ntk with the negatively charged asp residue abrogated the association between rsk1 and pkarialpha." SIGNOR-162681 RPS6KB1 protein P23443 UNIPROT CCT2 protein P78371 UNIPROT unknown phosphorylation Ser260 GSRVRVDsTAKVAEI 9606 19332537 t llicata "Mass spectrometry and mutagenesis analysis revealed that rsk and s6k1 phosphorylate cct_ ser-260 in vitro and in intact cells" SIGNOR-184926 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 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 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 PRKACA protein P17612 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-259402 PRKACB protein P22694 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-259403 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 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 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 P2RY12 protein Q9H244 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-256855 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 S1PR1 protein P21453 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-256856 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 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 NMUR1 protein Q9HB89 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-256894 CDKN2A protein P42771 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000176 7972006 f "Transfection of the p16INK4 cDNA expression vector into carcinoma cells inhibits their colony-forming efficiency and the p16INK4 expressing cells are selected against with continued passage in vitro. These results are consistent with the hypothesis that p16INK4 is a tumor-suppressor protein and that genetic and epigenetic abnormalities in genes controlling the G1 checkpoint can lead to both escape from senescence and cancer formation." SIGNOR-259406 CDKN2B protein P42772 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 10090 BTO:0001056 14681685 f "The Ink4b gene (Cdkn2b) encodes p15Ink4b, a cyclin-dependent kinase inhibitor. It has been implicated in playing a role in the development of acute myeloid leukemia (AML) in man, since it is hypermethylated with high frequency. We provide evidence that the gene is a tumor suppressor for myeloid leukemia in mice." SIGNOR-259407 CSNK2A1 protein P68400 UNIPROT CDC34 protein P49427 UNIPROT "down-regulates activity" phosphorylation Ser236 DDSGTEEs 9606 BTO:0000567 11546811 t lperfetto "The ubiquitin-conjugating enzyme, cdc34, has been implicated in the ubiquitination of a number of vertebrate substrates, including p27(kip1), ikappabalpha, wee1, and myod. We show that mammalian cdc34 is a phosphoprotein that is phosphorylated in proliferating cells. Phosphorylation of cdc34 by the associated kinase maps predominantly to residues 203 and 222. Mutation of cdc34 at ck2-targeted residues, ser-203, ser-222, ser-231, thr-233, and ser-236, abolishes the phosphorylation of cdc34 observed in vivo and markedly shifts nuclearly localized cdc34 to the cytoplasm." SIGNOR-110403 ERG protein P11308 UNIPROT PIM proteinfamily SIGNOR-PF34 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002398 22140532 t miannu "ERG deregulation induces PIM1 over-expression and aneuploidy in prostate epithelial cells. The up-regulation of PIM1 induced by tERG over-expression significantly modified Cyclin B1 levels and increased the percentage of aneuploid cells in the RWPE-1 cell line after taxane-based treatment. Here we provide the first evidence for an ERG-mediated PIM1 up-regulation in prostate cells in vitro and in vivo, suggesting a direct effect of ERG transcriptional activity in the alteration of genetic stability." SIGNOR-259408 PIM proteinfamily SIGNOR-PF34 SIGNOR BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000007 16403219 t lperfetto "All three Pim kinase family members predominantly phosphorylate Bad on Ser112 and in addition are capable of phosphorylating Bad on multiple sites associated with the inhibition of the pro-apoptotic function of Bad in HEK-293 cells. This would be consistent with the proposed function of Pim kinases in promoting cell proliferation and preventing cell death." SIGNOR-259421 PIM proteinfamily SIGNOR-PF34 SIGNOR BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 10837473 t gcesareni "Similar to pim1, pim2 phosphorylates bad, which antagonizes the pro-apoptotic function of bax" SIGNOR-259418 PIM proteinfamily SIGNOR-PF34 SIGNOR HIST1H3A 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-259409 PIM proteinfamily SIGNOR-PF34 SIGNOR 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-259410 PIM proteinfamily SIGNOR-PF34 SIGNOR 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-259411 PIM proteinfamily SIGNOR-PF34 SIGNOR 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-259412 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 ACE2 protein Q9BYF1 UNIPROT APLN protein Q9ULZ1 UNIPROT "up-regulates activity" cleavage -1 11815627 t miannu "ACE2 hydrolyzes the hormone apelin-13 with high catalytic efficiency and cleaves apelin-36, whose C-terminal 13 amino acids are identical to those of apelin-13." SIGNOR-256316 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 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 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 CUL1 protein Q13616 UNIPROT SCF-betaTRCP complex SIGNOR-C5 SIGNOR "form complex" binding 9606 10023660 t gcesareni "The human f box protein beta-trcp associates with the cul1/skp1 complex and regulates the stability of beta-catenin." SIGNOR-64502 PIM proteinfamily SIGNOR-PF34 SIGNOR BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser118 GRELRRMsDEFVDSF 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-259423 PIM proteinfamily SIGNOR-PF34 SIGNOR 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-259422 PIM proteinfamily SIGNOR-PF34 SIGNOR CDKN1A protein P38936 UNIPROT up-regulates 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-259424 PIM proteinfamily SIGNOR-PF34 SIGNOR 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-259426 PIM proteinfamily SIGNOR-PF34 SIGNOR CDKN1B protein P46527 UNIPROT down-regulates 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." SIGNOR-259425 PIM proteinfamily SIGNOR-PF34 SIGNOR 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-259429 PIM proteinfamily SIGNOR-PF34 SIGNOR FOXO3 protein O43524 UNIPROT 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-259428 PIM proteinfamily SIGNOR-PF34 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 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-259427 PIM proteinfamily SIGNOR-PF34 SIGNOR MARK3 protein P27448 UNIPROT down-regulates phosphorylation Ser96 KTQLNPTsLQKLFRE 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-259432 PIM proteinfamily SIGNOR-PF34 SIGNOR MARK3 protein P27448 UNIPROT down-regulates phosphorylation Thr90 AIKIIDKtQLNPTSL 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-259431 PIM proteinfamily SIGNOR-PF34 SIGNOR 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-259430 PIM proteinfamily SIGNOR-PF34 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates phosphorylation Ser166 SSRRRAIsETEENSD 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-259433 PIM proteinfamily SIGNOR-PF34 SIGNOR 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-259434 SGI-1776 chemical CID:24795070 PUBCHEM PIM proteinfamily SIGNOR-PF34 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-259435 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 P2RY13 protein Q9BPV8 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-256892 afatinib chemical CHEBI:61390 ChEBI "ErbB receptor family" proteinfamily SIGNOR-PF36 SIGNOR "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-259441 afatinib chemical CHEBI:61390 ChEBI "ErbB receptor family" proteinfamily SIGNOR-PF36 SIGNOR "down-regulates activity" "chemical inhibition" 9606 BTO:0000150 22418700 t gcesareni "Afatinib is an oral, erbb family blocker, which covalently binds and irreversibly blocks all kinase-competent erbb family members." SIGNOR-259442 afatinib chemical CHEBI:61390 ChEBI "ErbB receptor family" proteinfamily SIGNOR-PF36 SIGNOR "down-regulates activity" "chemical inhibition" 9606 BTO:0000551 22452896 t "Like lapatinib and neratinib, afatinib is a next generation tyrosine kinase inhibitor (TKI) that irreversibly inhibits human epidermal growth factor receptor 2 (Her2) and epidermal growth factor receptor (EGFR) kinases." gcesareni "Afatinib, an irreversible erbb-family blocker, has shown preclinical activity when tested in egfr mutant models with mutations that confer resistance to egfr tyrosine-kinase inhibitors." SIGNOR-259440 cabazitaxel chemical CHEBI:63584 ChEBI Tubulin proteinfamily SIGNOR-PF46 SIGNOR "down-regulates activity" binding 9606 21770474 t miannu "Among these, larotaxel (XRP9881, formerly RPR109881A)[3,4] and cabazitaxel (XRP6258, TXD258, RPR116258A)[5] share a mechanism of action unique to taxanes, promoting tubulin assembly and stabilizing microtubules against cold-induced depolymerization" SIGNOR-259445 afatinib chemical CHEBI:61390 ChEBI "ErbB receptor family" proteinfamily SIGNOR-PF36 SIGNOR "down-regulates activity" "chemical inhibition" 9606 BTO:0002058 24643470 t miannu "This manuscript comprehensively reviews the preclinical data on afatinib, an irreversible inhibitor of the tyrosine kinase activity of members of the epidermal growth factor receptor family (ErbB) including EGFR, HER2 and ErbB4. Afatinib covalently binds to cysteine 797 of the EGFR and the corresponding cysteines 805 and 803 in HER2 and ErbB4, respectively." SIGNOR-259443 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 "eribulin mesylate" chemical CHEBI:70710 ChEBI Tubulin proteinfamily SIGNOR-PF46 SIGNOR "down-regulates activity" binding 9606 16940412 t miannu "The complex marine natural product halichondrin B was compared with NSC 707389 (E7389), a structurally simplified, synthetic macrocyclic ketone analog, which has been selected for clinical trials in human patients. NSC 707389 was invariably more potent than halichondrin B in its interactions with tubulin. Both compounds inhibited tubulin assembly, inhibited nucleotide exchange on beta-tubulin, and were noncompetitive inhibitors of the binding of radiolabeled vinblastine and dolastatin 10 to tubulin." SIGNOR-259444 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT "up-regulates activity" phosphorylation Tyr612 TLHTDDGyMPMSPGV 10116 BTO:0000443 11416002 t lperfetto "All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin re- ceptors Tyr(612) and Tyr(632) in human insulin receptor substrate-1 are important for full activation of insulin-stimulated phosphatidylinositol 3-kinase activity and translocation of GLUT4 in adipose cells" SIGNOR-235971 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 IRS1 protein P35568 UNIPROT PIK3CA protein P42336 UNIPROT "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-168985 ixabepilone chemical CHEBI:63605 ChEBI Tubulin proteinfamily SIGNOR-PF46 SIGNOR "down-regulates activity" binding 9606 BTO:0000356 18945860 t miannu "Ixabepilone, the first drug in a new class of microtubule-stabilizing agents called epothilones, offers a new treatment option for patients with metastatic or locally advanced breast cancer who are refractory to standard chemotherapy." SIGNOR-259450 paclitaxel chemical CHEBI:45863 ChEBI Tubulin proteinfamily SIGNOR-PF46 SIGNOR "down-regulates activity" binding 9606 28298489 t miannu "Here we integrate a computational model for microtubule assembly with nanometer-scale fluorescence microscopy measurements to identify the kinetic and thermodynamic basis of kinetic stabilization by the MTAs paclitaxel, an assembly promoter, and vinblastine, a disassembly promoter. We identify two distinct modes of kinetic stabilization in live cells, one that truly suppresses on-off kinetics, characteristic of vinblastine, and the other a ""pseudo"" kinetic stabilization, characteristic of paclitaxel, that nearly eliminates the energy difference between the GTP- and GDP-tubulin thermodynamic states. By either mechanism, the main effect of both MTAs is to effectively stabilize the microtubule against disassembly in the absence of a robust GTP cap." SIGNOR-259449 trametinib chemical CHEBI:75998 ChEBI MAP2K1 protein Q02750 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000848 26347206 t miannu "Trametinib (Mekinist™) is a reversible and highly selective allosteric inhibitor of MEK1 and MEK2 with anticancer activity against metastatic melanoma carrying the BRAF V600 mutation." SIGNOR-259447 trametinib chemical CHEBI:75998 ChEBI MAP2K2 protein P36507 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000848 26347206 t miannu "Trametinib (Mekinist™) is a reversible and highly selective allosteric inhibitor of MEK1 and MEK2 with anticancer activity against metastatic melanoma carrying the BRAF V600 mutation." SIGNOR-259448 trametinib chemical CHEBI:75998 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "down-regulates activity" "chemical inhibition" 9606 BTO:0000848 26347206 t miannu "Trametinib (Mekinist™) is a reversible and highly selective allosteric inhibitor of MEK1 and MEK2 with anticancer activity against metastatic melanoma carrying the BRAF V600 mutation." SIGNOR-259446 PTGDR protein Q13258 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-256898 MLL-AF9 "fusion protein" SIGNOR-FP5 SIGNOR DOT1L protein Q8TEK3 UNIPROT "up-regulates activity" binding 10090 BTO:0004052 23996074 t irozzo "In this work, we have identified and mapped the protein-protein interaction site between DOT1L and MLL fusion proteins, AF9 and ENL.The MLL fusion proteins, AF9 and ENL, activate target genes in part via recruitment of the histone methyltransferase DOT1L (disruptor of telomeric silencing 1-like). It is known that the recruitment of DOT1L results in hypermethylation of H3K79 on the prominent MLL fusion downstream target loci Hoxa9 and Meis1" SIGNOR-255869 "pazopanib hydrochloride" chemical CHEBI:71217 ChEBI RTKs proteinfamily SIGNOR-PF38 SIGNOR "down-regulates activity" "chemical inhibition" -1 17620431 t miannu "The present study describes an orally bioavailable, ATP-competitive, multitargeted kinase inhibitor, pazopanib (GW786034), and the drug concentration requirement for maximal in vivo activity. Pazopanib is a low nanomolar inhibitor of VEGFR, PDGFR, and c-Kit tyrosine kinases. Pazopanib inhibition of a number of kinases outside of the VEGFR family was also determined. These included Abl1; Akt3; activin-like kinase 6; cyclin-dependent kinase 1/cyclin A; cyclin-dependent kinase 2/cyclin A; c-fms; c-Kit; epidermal growth factor receptor; ErbB2; ErbB4; EphB4; focal adhesion kinase; FGF receptors (FGFR) 1, 2, and 3; Flt-3; glycogen synthase kinase 3; insulin-like growth factor type I receptor; insulin receptor; interleukin-2–inducible T-cell kinase; c-jun NH2-terminal kinases 1, 2, and 3; lymphocyte-specific protein tyrosine kinase (murine); Met; p38α; PDGFRα and PDGFRβ; protein kinase C-β1 and -β2; polo-like kinases 1 and 3; Ret; Src; Syk; Tie-2; and Wee1. All assays were conducted using purified, recombinantly expressed catalytic domains of the kinases." SIGNOR-259451 regorafenib chemical CHEBI:68647 ChEBI RTKs proteinfamily SIGNOR-PF38 SIGNOR "down-regulates activity" "chemical inhibition" 9606 24756792 t miannu "In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically." SIGNOR-259453 regorafenib chemical CHEBI:68647 ChEBI RTKs proteinfamily SIGNOR-PF38 SIGNOR "down-regulates activity" "chemical inhibition" 9606 26254357 t miannu "A novel multi-kinase inhibitor, regorafenib (Figure 1), inhibits vascular endothelial growth factor receptor (VEGFR) 1, VEGFR2, and VEGFR3, that play key roles in angiogenesis, and fibroblast growth factor receptor (FGFR) 1, platelet-derived growth factor receptor-β (PDGFR-β), tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 (TIE2) and the mutant oncogenic kinase KIT, RET, B-RAF" SIGNOR-259452 "sorafenib tosylate" chemical CHEBI:50928 ChEBI RTKs proteinfamily SIGNOR-PF38 SIGNOR "down-regulates activity" "chemical inhibition" -1 16757355 t miannu "Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. The in vitro and cellular profile of sorafenib is summarized in Table I." SIGNOR-259454 TACR2 protein P21452 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-256879 TBXA2R protein P21731 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-256887 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 MCHR1 protein Q99705 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-256905 NMBR protein P28336 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-256918 OXGR1 protein Q96P68 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-256913 atomoxetine chemical CHEBI:127342 ChEBI SLC6A3 protein Q01959 UNIPROT "down-regulates activity" "chemical inhibition" -1 9871604 t miannu "The gamma-amino alcohol/ether unit contained in venlafaxine, 2 fluoxetine, 3 and tomoxetine 3 has been prepared by a sequence of nitrile aldol reaction and nitrile reduction. Equilibrium dissociation constants KD for binding of (_+)-2 and (_+)-3 to hSERT, hNET, and hDAT are given in Table 2." SIGNOR-259070 atomoxetine chemical CHEBI:127342 ChEBI SLC6A4 protein P31645 UNIPROT "down-regulates activity" "chemical inhibition" -1 9871604 t miannu "The gamma-amino alcohol/ether unit contained in venlafaxine, 2 fluoxetine, 3 and tomoxetine 3 has been prepared by a sequence of nitrile aldol reaction and nitrile reduction. Equilibrium dissociation constants KD for binding of (_+)-2 and (_+)-3 to hSERT, hNET, and hDAT are given in Table 2." SIGNOR-259067 clotrimazole chemical CHEBI:3764 ChEBI NR1I2 protein O75469 UNIPROT "up-regulates activity" "chemical activation" 9606 9770465 t miannu "In addition to rifampicin, other known inducers of human CYP3A4 expression, including nifedipine and clotrimazole, also activated hPAR." SIGNOR-259065 frovatriptan chemical CHEBI:134991 ChEBI HTR1A protein P08908 UNIPROT "up-regulates activity" "chemical activation" -1 9986723 t miannu "As far as the selectivity against the 5-HT1A receptor, compound 10 shows similar selectivity as VML-251 (4) but has slightly lower selectivity as compared to sumatriptan (1), naratriptan (2), and rizatriptan (3). Although none of the 5-HT1D receptor agonists in the current study demonstrate as good selectivity versus the 5-HT1B receptor, the N-methyl-5-tert-butyltryptamine (10) remains the most selective (4-fold)." SIGNOR-259074 frovatriptan chemical CHEBI:134991 ChEBI HTR1D protein P28221 UNIPROT "up-regulates activity" "chemical activation" -1 9986723 t miannu "As far as the selectivity against the 5-HT1A receptor, compound 10 shows similar selectivity as VML-251 (4) but has slightly lower selectivity as compared to sumatriptan (1), naratriptan (2), and rizatriptan (3). Although none of the 5-HT1D receptor agonists in the current study demonstrate as good selectivity versus the 5-HT1B receptor, the N-methyl-5-tert-butyltryptamine (10) remains the most selective (4-fold)." SIGNOR-259073 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 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 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 Isradipine chemical CHEBI:6073 ChEBI CACNA1C protein Q13936 UNIPROT "down-regulates activity" "chemical inhibition" 9606 10072735 t miannu "The protein expression as measured by3H-(+)-PN 200-110-binding (Bmax) and Western Blot analysis withcalsequestrin as reference was similar in left ventricular failing and non-failing myocardium. However, both werereduced in atrial compared to ventricular tissue in failing and non-failing hearts. The KDremained unchanged." SIGNOR-259076 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 MLL-ENL "fusion protein" SIGNOR-FP7 SIGNOR "Core Binding Factor complex" complex SIGNOR-C214 SIGNOR "down-regulates quantity by repression" "transcriptional repression" 9606 BTO:0001412 24449215 f miannu "However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions." SIGNOR-255971 nefazodone chemical CHEBI:7494 ChEBI SLC6A2 protein P23975 UNIPROT "down-regulates activity" "chemical inhibition" -1 9871604 t miannu "Equilibrium dissociation constants KD for binding of (_+)-2 and (_+)-3 to hSERT, hNET, and hDAT are given in Table 2. Nefazodone has similar affinities at hSERT, hNET, and hDAT, but has low potency" SIGNOR-259069 nefazodone chemical CHEBI:7494 ChEBI SLC6A4 protein P31645 UNIPROT "down-regulates activity" "chemical inhibition" -1 9871604 t miannu "Equilibrium dissociation constants KD for binding of (_+)-2 and (_+)-3 to hSERT, hNET, and hDAT are given in Table 2. Nefazodone has similar affinities at hSERT, hNET, and hDAT, but has low potency" SIGNOR-259068 RASSF1 protein Q9NS23 UNIPROT CCND1 protein P24385 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0002552 12024041 f Luana "RASSF1A expression dramatically inhibits native cyclin D1 accumulation | Regulation of cyclin D1 accumulation by RASSF1A is independent of the cyclin D1 promoter and likely occurs through inhibition of mRNA translation." SIGNOR-259455 SGK1 protein O00141 UNIPROT NR3C1 protein P04150 UNIPROT "up-regulates activity" phosphorylation Ser226 IDENCLLsPLAGEDD 9606 23650397 t gcesareni "SGK1 also potentiated and maintained GR activation in the presence of cortisol, and even after cortisol withdrawal, by increasing GR phosphorylation and GR nuclear translocation|SGK1 mediates CORT effects on GR phosphorylation. After 12 h, CORT (100 ¬µM) increases GR phosphorylation at S203 (n = 6; A), S211 (n = 6; B), and S226 (n = 6; C)." SIGNOR-251671 STAT3 protein P40763 UNIPROT VEGFA protein P15692 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0003266 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 telmisartan chemical CHEBI:9434 ChEBI AGTR1 protein P30556 UNIPROT "down-regulates activity" "chemical inhibition" 9606 9878991 t miannu "Telmisartan is a nonpeptide angiotensin II receptor antagonist which selectively and insurmountably inhibits the angiotensin II AT1 receptor subtype without affecting other receptor systems involved in cardiovascular regulation." SIGNOR-259072 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 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 P2RY11 protein Q96G91 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-256931 PTAFR protein P25105 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-256932 S1PR3 protein Q99500 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-256933 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 UTS2R protein Q9UKP6 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-256922 lurasidone chemical CHEBI:70735 ChEBI Drd2 protein P61169 UNIPROT "down-regulates activity" "chemical inhibition" 10030 BTO:0000246 20404009 t Luana "In vitro functional assays demonstrated that lurasidone acts as an antagonist at D2 and 5-HT7 receptors and as a partial agonist at the 5-HT1A receptor subtype." SIGNOR-259462 lurasidone chemical CHEBI:70735 ChEBI Htr1a protein P19327 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000246 20404009 t Luana "In vitro functional assays demonstrated that lurasidone acts as an antagonist at D2 and 5-HT7 receptors and as a partial agonist at the 5-HT1A receptor subtype." SIGNOR-259463 lurasidone chemical CHEBI:70735 ChEBI Htr2a protein P14842 UNIPROT "down-regulates activity" "chemical inhibition" 10030 BTO:0000246 20404009 t Luana "Lurasidone was found to have potent binding affinity for dopamine D2, 5-hydroxytryptamine 2A (5-HT2A), 5-HT7, 5-HT1A, and noradrenaline 2C receptors." SIGNOR-259465 PRKAA2 protein P54646 UNIPROT PAK2 protein Q13177 UNIPROT unknown phosphorylation Ser20 APPVRMSsTIFSTGG 9606 SIGNOR-C15 22137581 t llicata "Together, these results indicate that ampk phosphorylates endogenous ppp1r12c at s452 and pak2 at s20 in human cells." SIGNOR-195110 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 PTGER1 protein P34995 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-256954 PTGFR protein P43088 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-256953 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 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 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 P2RY14 protein Q15391 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-257002 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 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 CDK1 protein P06493 UNIPROT RANBP2 protein P49792 UNIPROT "up-regulates activity" phosphorylation Ser2246 SSSVHASerPLASSP -1 26051540 t irozzo "Cdk1 phosphorylates conserved sites within RanBP2 and activates BicD2 binding and early dynein recruitment." SIGNOR-259118 PRKACA protein P17612 UNIPROT NFATC1 protein O95644 UNIPROT down-regulates phosphorylation Ser269 PCNKRKYsLNGRQPP 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-93535 OXGR1 protein Q96P68 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-257042 ADRA2A protein P08913 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-256698 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 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 TACR1 protein P25103 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-257048 S1PR3 protein Q99500 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-257062 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 TG protein P01266 UNIPROT "Thyroid hormonogenesis" phenotype SIGNOR-PH110 SIGNOR up-regulates 9606 BTO:0004710 30886364 f miannu "In humans, the thyroid hormones T3 and T4 are synthesized in the thyroid gland in a process that crucially involves the iodoglycoprotein thyroglobulin. The overall structure of thyroglobulin is conserved in all vertebrates. Upon thyroglobulin delivery from thyrocytes to the follicular lumen of the thyroid gland via the secretory pathway, multiple tyrosine residues can become iodinated to form mono-iodotyrosine (MIT) and/or di-iodotyrosine (DIT); however, selective tyrosine residues lead to preferential formation of T4 and T3 at distinct sites." SIGNOR-259915 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 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 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 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 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 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 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 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 P2RY12 protein Q9H244 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-257107 MAPK14 protein Q16539 UNIPROT PIP4K2B protein P78356 UNIPROT down-regulates phosphorylation Ser326 SYGTPPDsPGNLLSF 9606 16949365 t gcesareni "Inhibition of pip4kbeta activity occurs through the direct phosphorylation of pip4kbeta at ser326 by the p38 stress-activated protein kinase." SIGNOR-149359 MAPK3 protein P27361 UNIPROT KRT8 protein P05787 UNIPROT unknown phosphorylation Ser432 SAYGGLTsPGLSYSL 9606 22344252 t llicata "Our data suggested a close relationship between k8(s431) phosphorylation and keratin reorganization in epithelial tumor cells." SIGNOR-196141 MAPK3 protein P27361 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates phosphorylation Ser226 IDENCLLsPLAGEDD 9606 12351702 t gcesareni "Furthermore, we show that this gnrh-stimulated phosphorylation of the unliganded gr is mediated by a combination of the mapks jnk, p38, and erk as well as pkc in l t2 cells, because individual kinase inhibitors or combinations thereof inhibit this phosphorylation in intact cells." SIGNOR-93554 STK3/4 proteinfamily SIGNOR-PF41 SIGNOR SAV1 protein Q9H4B6 UNIPROT "up-regulates activity" phosphorylation 9606 21084559 t miannu "Mst is activated by binding of salvador (sav1, sav in drosophila), which is, in turn, also phosphorylated by mst." SIGNOR-256184 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 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 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 P2RY14 protein Q15391 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-257118 NMUR2 protein Q9GZQ4 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-257126 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 MAPK8 protein P45983 UNIPROT IRS1 protein P35568 UNIPROT down-regulates 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 PRKACA protein P17612 UNIPROT NFATC1 protein O95644 UNIPROT down-regulates phosphorylation Ser294 PHGSPRVsVTDDSWL 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-93539 PRKCE protein Q02156 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT down-regulates 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-97291 PTPN22 protein Q9Y2R2 UNIPROT LCK protein P06239 UNIPROT down-regulates dephosphorylation Tyr394 RLIEDNEyTAREGAK 9606 BTO:0000007 16461343 t gcesareni "Native ptpn22 dephosphorylated lck at its activating tyrosine residues tyr-394." SIGNOR-144341 RAD51 protein Q06609 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 27660832 f lperfetto "Rad51 is a key component of homologous recombination (HR) to repair DNA double-strand breaks and it forms Rad51 recombinase filaments of broken single-stranded DNA to promote HR. In addition to its role in DNA repair and cell cycle progression, Rad51 contributes to the reprogramming process during the generation of induced pluripotent stem cells" SIGNOR-251508 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 CYSLTR1 protein Q9Y271 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-257135 TBXA2R protein P21731 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-257139 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 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 P2RY6 protein Q15077 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-257189 FASN protein P49327 UNIPROT Lipogenesis phenotype SIGNOR-PH30 SIGNOR up-regulates 9606 20373869 f lperfetto "Fatty acid synthase (FASN) is a key enzyme involved in neoplastic lipogenesis" SIGNOR-242874 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 RBPJ protein Q06330 UNIPROT MAML2 protein Q8IZL2 UNIPROT up-regulates binding 9606 21873209 t gcesareni "When bound to the active intracellular domain of notch (nicd), rbpj recruits a coactivator complex, including a mastermind homologue (maml1-3 in mammals), and drives a complex transcriptional program with pervasive phenotypic effects" SIGNOR-176197 SPEN protein Q96T58 UNIPROT RBPJ protein Q06330 UNIPROT down-regulates binding 9606 12374742 t gcesareni "We identified sharp as an rbp-jkappa/cbf-1-interacting corepressor in a yeast two-hybrid screen." SIGNOR-94201 SRGAP3 protein O43295 UNIPROT RAC1 protein P63000 UNIPROT down-regulates 9606 12447388 f miannu "Wrp binds directly to wave-1 through its src homology domain 3 and specifically inhibits rac function in vivo." SIGNOR-95918 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 WDR5 protein P61964 UNIPROT KMT2A/WDR5 complex SIGNOR-C57 SIGNOR "form complex" binding 9606 15960975 t miannu "The mll1-wdr5 complex is enzymatically active" SIGNOR-138251 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 S1PR3 protein Q99500 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-257175 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 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 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 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 NMUR2 protein Q9GZQ4 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-257218 P2RY13 protein Q9BPV8 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-257231 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 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 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 UTS2R protein Q9UKP6 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-257252 TACR1 protein P25103 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-257249 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 P2RY6 protein Q15077 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-257277 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 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 NOG protein Q13253 UNIPROT BMP2 protein P12643 UNIPROT down-regulates binding 9606 12700180 t lperfetto "Noggin acts by binding bmps, thus preventing them from binding to their receptors (180). Noggin binds with various degrees of affinity bmp-2, -4, -5, -6, and -7, gdf-5, gdf-6, and vg1, but not other members of the tgf- family of peptides" SIGNOR-100657 NOG protein Q13253 UNIPROT BMP4 protein P12644 UNIPROT down-regulates binding 9606 12700180 t lperfetto "Noggin acts by binding bmps, thus preventing them from binding to their receptors (180). Noggin binds with various degrees of affinity bmp-2, -4, -5, -6, and -7, gdf-5, gdf-6, and vg1, but not other members of the tgf- family of peptides" SIGNOR-100660 NMUR2 protein Q9GZQ4 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-257292 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 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 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 P2RY6 protein Q15077 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-257343 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 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-256939 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 PAK1 protein Q13153 UNIPROT MAP2K1 protein Q02750 UNIPROT "up-regulates activity" phosphorylation Ser298 RTPGRPLsSYGMDSR 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-236002 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 NMUR2 protein Q9GZQ4 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-257352 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 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 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 GPR119 protein Q8TDV5 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-257366 PAK1 protein Q13153 UNIPROT MAP3K1 protein Q13233 UNIPROT "up-regulates activity" phosphorylation Ser67 RQLRKVRsVELDQLP 9606 BTO:0000007 12228228 t lperfetto "We found that pak1 phosphorylated mekk1 on serine 67 of its amino-terminal regulatory domain. mekk1 activity was increased modestly following pak phosphorylation." SIGNOR-236006 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 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 OXGR1 protein Q96P68 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-257368 NMBR protein P28336 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-257373 S1PR3 protein Q99500 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-257388 TACR1 protein P25103 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-257374 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 PTAFR protein P25105 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-257387 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 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 PRKCB protein P05771 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT down-regulates 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 PRKCD protein Q05655 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT down-regulates phosphorylation Ser473 PPSGTKKsKRGRGRP 9606 12529391 t gcesareni "Protein kinase c phosphorylates ribosomal protein s6 kinase betaii and regulates its subcellular localization." SIGNOR-97287 OXGR1 protein Q96P68 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-257417 P2RY11 protein Q96G91 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-257435 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 S1PR3 protein Q99500 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-257437 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 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 WKYMVm chemical CID:457933 PUBCHEM FPR2 protein P25090 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-257493 "lysophosphatidylserine 14:0(1-)" chemical CHEBI:72402 ChEBI P2RY10 protein O00398 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-257558 "1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate" smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT "up-regulates activity" binding 9606 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-249628 PRKG1 protein Q13976 UNIPROT VASP protein P50552 UNIPROT down-regulates phosphorylation Thr278 LARRRKAtQVGEKTP 9606 12576312 t lperfetto "Vasodilator-stimulated phosphoprotein activation of serum-response element-dependent transcription occurs downstream of rhoa and is inhibited by cgmp-dependent protein kinase phosphorylation. 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-98139 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 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 F2RL1 protein P55085 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-257144 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 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-257011 F2RL3 protein Q96RI0 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-257044 F2RL3 protein Q96RI0 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-257157 F2RL3 protein Q96RI0 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-256915 RBPJ protein Q06330 UNIPROT RBPJ/NOTCH complex SIGNOR-C97 SIGNOR "form complex" binding 9606 21873209 t lperfetto "When bound to the active intracellular domain of notch (nicd), rbpj recruits a coactivator complex, including a mastermind homologue (maml1-3 in mammals), and drives a complex transcriptional program with pervasive phenotypic effects." SIGNOR-209702 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 FFAR1 protein O14842 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-257071 FFAR1 protein O14842 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-256942 FFAR1 protein O14842 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-257272 FFAR2 protein O15552 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-257342 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 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 FFAR4 protein Q5NUL3 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-257313 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 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 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 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 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 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 GALR2 protein O43603 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-257296 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 GHSR protein Q92847 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-257255 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 GPR119 protein Q8TDV5 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-257415 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 GPR119 protein Q8TDV5 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-256768 GPR132 protein Q9UNW8 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-257074 GPR132 protein Q9UNW8 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-257187 GPR132 protein Q9UNW8 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-257341 GPR132 protein Q9UNW8 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-256802 GPR174 protein Q9BXC1 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-256900 GPR174 protein Q9BXC1 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-256757 GPR17 protein Q13304 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-256692 MIB1 protein Q86YT6 UNIPROT SMN1 protein Q16637 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 23615451 t lperfetto "The E3 ubiquitin ligase mind bomb 1 ubiquitinates and promotes the degradation of survival of motor neuron protein" SIGNOR-253112 MLL-ENL "fusion protein" SIGNOR-FP7 SIGNOR miR-495 mirna MI0003135 miRBase "down-regulates quantity by repression" "transcriptional repression" 9606 BTO:0000725 23132946 f irozzo "We then showed that ectopic expression of MLL fusion genes in both human and mouse normal hematopoietic stem/progenitor cells could significantly down-regulate endogenous expression of miR-495 and that the depletion of MLL fusions resulted in the up-regulation of miR-495. Thus, our data suggest that there is an MLL-fusion–mediated negative regulation of the production of miR-495 in hematopoietic cells." SIGNOR-255887 GPR17 protein Q13304 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-256971 GPR17 protein Q13304 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-257087 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 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 GPR34 protein Q9UPC5 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-256688 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 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CCL2 protein P13500 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001103 20219869 f apalma "Once in the nucleus, NF-kB can induce the transcription of iNOS, TNF-alpha, and IL-1, which may then promote further NF-kB activation, as well as elevate the expression of other inflammatory mediators such as CCL2 and IL-6." SIGNOR-255356 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CCL2 protein P13500 UNIPROT up-regulates "transcriptional regulation" 9606 BTO:0000801 20086235 f "Both NF-κBs bind to a conserved DNA motif (80) that is found in numerous IL-1–responsive genes, in particular the ones encoding IκBα (81), IL-6 (82), IL-8 (18, 83,84), monocyte chemoattractant protein 1 (MCP1) (28), and cyclooxygenase 2 (COX2)" SIGNOR-254509 GPR34 protein Q9UPC5 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-256831 GPR34 protein Q9UPC5 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-256967 GPR35 protein Q9HC97 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-257204 GPR35 protein Q9HC97 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-256717 GPR35 protein Q9HC97 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-256860 GPR35 protein Q9HC97 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-257112 GPR55 protein Q9Y2T6 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-256670 GPR84 protein Q9NQS5 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-256983 chemical CHEBI:11314340 ChEBI AKT1 protein P31749 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-259688 NR0B2 protein Q15466 UNIPROT NR1I2 protein O75469 UNIPROT down-regulates binding 9606 12805410 t gcesareni "Our results suggest that shp is a negative regulator of pxr transcriptional activity. This conclusion derives from_ in vitro, cell culture, and_ in vivo_ experiments." SIGNOR-101924 PAK2 protein Q13177 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Thr2 tAKMETTF 9606 BTO:0000848 21177766 t lperfetto "P21-activated protein kinase (pak2)-mediated c-jun phosphorylation at 5 threonine sites promotes cell transformationour data showed that pak2 binds and phosphorylates c-jun at five threonine sites (thr2, thr8, thr89, thr93 and thr286)" SIGNOR-170760 PPP1CA protein P62136 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 12840032 t gcesareni "P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3)" SIGNOR-103152 GPR84 protein Q9NQS5 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-257099 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 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 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 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 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 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 chemical CHEBI:11409972 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-259693 chemical CHEBI:11409972 ChEBI KIT protein P10721 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-259694 PRKCB protein P05771 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates phosphorylation Thr143 RGKFKRPtLRRVRIS 9606 17010989 t lperfetto "Pkc-betaii sensitizes cardiac myofilaments to ca2+ by phosphorylating troponin i on threonine-144." SIGNOR-149957 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 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 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 "BI 2536" chemical CID:11364421 PUBCHEM PLK1 protein P53350 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-259702 chemical CHEBI:135461425 ChEBI FGFR1 protein P11362 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-259703 chemical CHEBI:135461425 ChEBI FGFR2 protein P21802 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-259704 chemical CHEBI:135461425 ChEBI FGFR3 protein P22607 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-259705 chemical CHEBI:135461425 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-259708 chemical CHEBI:135461425 ChEBI PDGFRA protein P16234 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-259706 chemical CHEBI:135461425 ChEBI PDGFRB protein P09619 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-259707 PTPRJ protein Q12913 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 12771128 t gcesareni "A dominant-negative mutant of high cell density-enhanced 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-101279 PTPRJ protein Q12913 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates dephosphorylation 9606 12771128 t gcesareni "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-101282 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 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 HTR4 protein Q13639 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-256912 "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 "lysophosphatidic acid" smallmolecule CHEBI:132742 ChEBI LPAR4 protein Q99677 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-257531 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 F2R protein P25116 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-256732 F2R protein P25116 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-256875 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 GHSR protein Q92847 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-256782 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 histamine smallmolecule CHEBI:18295 ChEBI HRH2 protein P25021 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-257513 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 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 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 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 MAPK7 protein Q13164 UNIPROT MEF2D protein Q14814 UNIPROT up-regulates phosphorylation Ser180 LTDPRLLsPQQPALQ 9606 BTO:0000567 10849446 t lperfetto "Here, we demonstrate that, in addition to mef2c, bmk1 phosphorylates and activates mef2a and mef2d but not mef2b. the sites phosphorylated by activated bmk1 were mapped to ser-355, thr-312, and thr-319 of mef2a and ser-179 of mef2d both in vitro and in vivo." SIGNOR-236041 "MLL/SET subcomplex" complex SIGNOR-C87 SIGNOR "MLL2 complex" complex SIGNOR-C88 SIGNOR "form complex" binding 9606 24680668 t miannu "The mixed lineage leukemia-1 (mll1) enzyme is a histone h3 lysine 4 (h3k4) monomethyltransferase and has served as a paradigm for understanding the mechanism of action of the human set1 family of enzymes that include mll1_Mll4 and setd1a,b. Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal core complex that is required for multiple lysine methylation." SIGNOR-204822 HTR4 protein Q13639 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-257367 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 LPAR2 protein Q9HBW0 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-257056 LPAR2 protein Q9HBW0 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-256927 LPAR2 protein Q9HBW0 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-257382 LPAR2 protein Q9HBW0 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-257324 LPAR3 protein Q9UBY5 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-256890 chemical CHEBI:11617559 ChEBI CSF1R protein P07333 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-259743 "MLL1 complex" complex SIGNOR-C89 SIGNOR "PAX7/MLL1 complex" complex SIGNOR-C90 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-198620 "MLL2 complex" complex SIGNOR-C88 SIGNOR ESR1 protein P03372 UNIPROT up-regulates binding 9606 16603732 t miannu "Eralpha directly binds to the mll2 complex through two lxxll motifs in a region of mll2 near the c terminus in a ligand-dependent manner. Disrupting the interaction between eralpha and the mll2 complex with small interfering rnas specific against mll2 or an mll2 fragment representing the interacting region with eralpha significantly inhibited the eralpha transcription activity." SIGNOR-145868 LPAR5 protein Q9H1C0 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-257205 LPAR5 protein Q9H1C0 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-257113 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 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 "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 chemical CHEBI:11676971 ChEBI CSF1R protein P07333 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-259748 chemical CHEBI:11676971 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-259749 chemical CHEBI:9869779 ChEBI CSF1R protein P07333 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-259750 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 "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 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 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA2C protein P18825 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-257455 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 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-257365 ITCH protein Q96J02 UNIPROT DTX1 protein Q86Y01 UNIPROT down-regulates ubiquitination 9606 17028573 t gcesareni "Itch/aip4 mediates deltex degradation through the formation of k29-linked polyubiquitin chains." SIGNOR-150002 LSM-1231 chemical CHEBI:91471 ChEBI Ntrk2 protein P15209 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-259759 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 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 HIST1H3A protein P68431 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-138475 RPS6KA5 protein O75582 UNIPROT H3F3A 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 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 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 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 ADP chemical CHEBI:16761 ChEBI P2RY12 protein Q9H244 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-257560 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 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 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 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 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 1-[5-bromo-4-methyl-2-[[(2S)-2-morpholinyl]methoxy]phenyl]-3-(5-methyl-2-pyrazinyl)urea chemical CHEBI:124917 ChEBI CHEK1 protein O14757 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193787 3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-3-piperidinyl]-2-thiophenecarboxamide chemical CHEBI:131156 ChEBI CHEK2 protein O96017 UNIPROT down-regulates "chemical inhibition" 9606 20068082 t gcesareni "Azd7762 is equally potent against chk2 in vitro." SIGNOR-163119 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 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 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 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 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 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 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 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-257125 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 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 F2RL3 protein Q96RI0 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-257245 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 FFAR3 protein O14843 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-256821 FFAR4 protein Q5NUL3 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-257045 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 chemical CHEBI:6918852 ChEBI CDK1 protein P06493 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-259792 chemical CHEBI:6918852 ChEBI CDK2 protein P24941 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-259793 chemical CHEBI:6918852 ChEBI CDK4 protein P11802 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-259794 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 dabigatran chemical CHEBI:70752 ChEBI F2 protein P00734 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190314 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 HTR2A protein P28223 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-257021 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 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 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 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 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 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 "MLL2 complex" complex SIGNOR-C88 SIGNOR "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-198623 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103 10409765 f lperfetto "Nf-kappab regulation of cyclin d1 occurs at the transcriptional level and is mediated by direct binding of nf-kappab to multiple sites in the cyclin d1 promoter." SIGNOR-235648 HTR4 protein Q13639 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-257242 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 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 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 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 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 chemical CHEBI:73755145 ChEBI FLT1 protein P17948 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-259807 chemical CHEBI:73755145 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-259809 chemical CHEBI:73755145 ChEBI PDGFRB protein P09619 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-259808 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 PTK2 protein Q05397 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr407 IIDEEDTyTMPSTRD 9606 BTO:0000671 15694384 t llicata "Once stimulated, fak undergoes autophosphorylation at tyrosine (y) 397, followed by phosphorylation of several sites including y576/y577 which increases fak's kinase activity, as well as at y407, y861, and y925." SIGNOR-133837 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 LPAR4 protein Q99677 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-257432 LPAR4 protein Q99677 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-257383 LPAR5 protein Q9H1C0 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-256718 LTB4R protein Q15722 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-257196 LTB4R protein Q15722 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-256691 LTB4R protein Q15722 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-256834 2-(2-amino-3-methoxyphenyl)chromen-4-one chemical CHEBI:77954 ChEBI MAPK7 protein Q13164 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000142 11782488 t gcesareni "Bmk1 activation by h2o2 was inhibited by both pd98059 and u0126, which were reported to inhibit mek5 as well as mek1/2." SIGNOR-113773 PTPN12 protein Q05209 UNIPROT SHC1 protein P29353 UNIPROT down-regulates dephosphorylation Tyr350 EPPDHQYyNDFPGKE 9606 8939605 t gcesareni "The shc adaptor protein is highly phosphorylated at conserved, twin tyrosine residues (y239/240) that mediate protein-protein interactions." SIGNOR-44862 RPS6KA5 protein O75582 UNIPROT HIST1H3A protein P68431 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-138483 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 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 MCHR2 protein Q969V1 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-256938 "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 P2RY11 protein Q96G91 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-257060 P2RY11 protein Q96G91 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-256788 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 P2RY6 protein Q15077 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-257398 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 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR2A protein P28223 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-257521 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 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 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 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 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 FFAR4 protein Q5NUL3 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-257158 1-[2-chloro-4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-3-(5-methyl-3-isoxazolyl)urea chemical CHEBI:91327 ChEBI FLT1 protein P17948 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207296 (2S)-2-hydroxy-3-methyl-N-[(2S)-1-[[(5S)-3-methyl-4-oxo-2,5-dihydro-1H-3-benzazepin-5-yl]amino]-1-oxopropan-2-yl]butanamide chemical CHEBI:131158 ChEBI APP protein P05067 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206850 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 MRGPRX1 protein Q96LB2 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-257058 P2RY11 protein Q96G91 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-257173 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 PIAS3 protein Q9Y6X2 UNIPROT STAT3 protein P40763 UNIPROT down-regulates binding 9606 9388184 t gcesareni "Specific inhibition of stat3 signal transduction by pias3stat3 mediated signaling pathways can be inhibited by pias3 (protein inhibitor of activated stat3), which was recently found to regulate protein stability and function by its sumo (small-ubiquitin like modifiers) ligase activity in promoting sumoylation of important nuclear proteins." SIGNOR-53572 PRKAA1 protein Q13131 UNIPROT POU2F1 protein P14859 UNIPROT down-regulates phosphorylation Ser385 RRRKKRTsIETNIRV 9606 9368058 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-53254 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 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 P2RY11 protein Q96G91 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-257386 P2RY11 protein Q96G91 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-257328 "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 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 "125-L-serine-2-133-interleukin 2 (human reduced)" smallmolecule SID:46508054 ChEBI IL2RA protein P01589 UNIPROT "up-regulates activity" binding 9606 18031103 t miannu "Aldesleukin (recombinant IL-2) has similar pharmacodynamic properties to endogenous IL-2 and, when administered to patients with cancer, stimulates the antitumour immune response." SIGNOR-259388 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile chemical CHEBI:77397 ChEBI SLC6A4 protein P31645 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 18487050 t Luana "For [3H]paroxetine, [3H]citalopram, [3H]nisoxetine, and [3H]WIN35,428 the following KD values were obtained on the human monoamine transporters hSERT, hNET, and hDAT by homologous competition experiments: 0.69 nM [3H]paroxetine, 4.46 nM [3H]citalopram, 6.77 nM [3H]nisoxetine, and 24.1 [3H]WIN35,428. " SIGNOR-257794 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates binding 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni "In this study, we demonstrate that akt also regulates the activity of fkhrl1, a member of the forkhead family of transcription factors. In the presence of survival factors, akt phosphorylates fkhrl1, leading to fkhrl1's association with 14-3-3 proteins and fkhrl1's retention in the cytoplasm. 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-183608 1-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-2-methoxyphenyl)-3-(1-(thiazol-2-yl)ethyl)urea chemical CID:9869779 PUBCHEM CSF1R protein P07333 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t llicata "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-258126 1-naphthol chemical CHEBI:10319 ChEBI UGT1A1 protein P22309 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 21030469 t Luana "Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation." SIGNOR-258163 "1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate" smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT "up-regulates activity" binding -1 9094314 t gcesareni "We tested the kinase in the presence of several inositol phospholipids and found that only low micromolar concentrations of the D enantiomers of either phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) or PtdIns(3,4)P2 were effective in potently activating the kinase, which has been named PtdIns(3,4,5)P3-dependent protein kinase-1 (PDK1)" SIGNOR-243274 2-[4-[3-[2-(trifluoromethyl)-9-thioxanthenylidene]propyl]-1-piperazinyl]ethanol chemical CHEBI:93235 ChEBI DRD3 protein P35462 UNIPROT "down-regulates activity" "chemical inhibition" 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-258728 (2s)-1-{[5-(3-Methyl-1h-Indazol-5-Yl)pyridin-3-Yl]oxy}-3-Phenylpropan-2-Amine chemical CID:11314340 PUBCHEM AKT1 protein P31749 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t llicata "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-258064 "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 [4-[2-(1H-indazol-3-yl)ethenyl]phenyl]-(1-piperazinyl)methanone chemical CHEBI:91441 ChEBI ABL1 protein P00519 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-258127 CDKN2A protein P42771 UNIPROT CDK6/CCND1 complex SIGNOR-C143 SIGNOR down-regulates binding 9606 8891723 t luana "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-259810 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 4-[2-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]ethyl]aniline chemical CHEBI:92250 ChEBI HTR1A protein P08908 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9760039 t miannu "A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors" SIGNOR-258852 5-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine chemical CID:11617559 PUBCHEM CSF1R protein P07333 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t llicata "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-258119 5-azacytidine chemical CHEBI:2038 ChEBI DNMT1 protein P26358 UNIPROT "down-regulates activity" "chemical inhibition" 9606 14585280 t miannu "Both Azacitidine and Decitabine may also exert antitumor activity through induction of DNA hypomethylation, by forming a covalent complex with the major DNA methyltransferase (now termed DNMT1).Azacitidine and Decitabine effectively deplete the cell of functional DNA methylating activity, which results in profound hypomethylation after several rounds of DNA replication (Fig. 2). DNMT1 is considered a bona fide anticancer target at different levels" SIGNOR-259293 8-[4,4-bis(4-fluorophenyl)butyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one chemical CHEBI:93369 ChEBI HRH1 protein P35367 UNIPROT "down-regulates activity" "chemical inhibition" -1 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-258538 "9-cis-retinoic acid" chemical CHEBI:50648 ChEBI RARA protein P10276 UNIPROT "up-regulates activity" "chemical activation" 9606 18321241 t miannu "Alitretinoin (9-cis-retinoic acid) is a unique panagonist retinoid, capable of binding to all six known retinoid receptors (RAR-alpha, -beta, -gamma, and RXR-alpha, -beta, -gamma)." SIGNOR-259234 "A4/b7 integrin" complex SIGNOR-C187 SIGNOR 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-257728 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 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 RNF10 protein Q8N5U6 UNIPROT MEOX2 protein P50222 UNIPROT "up-regulates activity" binding 10090 BTO:0000944 16335786 t miannu "RFN10 co-immunoprecipitates with MEOX2. RNF10 potentiates MEOX2 transcriptional activation" SIGNOR-236968 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 afatinib chemical CHEBI:61390 ChEBI ERBB4 protein Q15303 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0002058 24643470 t miannu "This manuscript comprehensively reviews the preclinical data on afatinib, an irreversible inhibitor of the tyrosine kinase activity of members of the epidermal growth factor receptor family (ErbB) including EGFR, HER2 and ErbB4. Afatinib covalently binds to cysteine 797 of the EGFR and the corresponding cysteines 805 and 803 in HER2 and ErbB4, respectively." SIGNOR-259295 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 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 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 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 RPS6KA1 protein Q15418 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates quantity by destabilization" phosphorylation 9606 BTO:0001103 21798082 t lperfetto "Negative feedback involves s6k, which inactivates irs by phosphorylation at multiple sites, thus inducing its degradation and altered cell localization." SIGNOR-175687 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 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 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 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 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 AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser364 FGQRDRSsSAPNVHI 9606 10869359 t lperfetto "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-244152 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-252831 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-137241 alvimopan chemical CHEBI:135686 ChEBI OPRD1 protein P41143 UNIPROT "down-regulates activity" "chemical inhibition" -1 18313920 t Luana "A series of N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines, l opioid receptor antagonists, analogs of alvimopan, were prepared using solid phase methodology. This study led to the identification of a highly selective l opioid receptor antagonist, which interacts selectively with l peripheral receptors." SIGNOR-257772 AMPK complex SIGNOR-C15 SIGNOR GLI1 protein P08151 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr1074 QRGSSGHtPPPSGPP 26190112 t "Activation of AMPK reduces GLI1 protein levels and stability, thus blocking Sonic-hedgehog-induced transcriptional activity. AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency." SIGNOR-253543 "anthraflavic acid" chemical CHEBI:34250 ChEBI UGT1A1 protein P22309 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 21030469 t Luana "Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation." SIGNOR-258156 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 "1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate" smallmolecule CHEBI:16618 ChEBI AKT3 protein Q9Y243 UNIPROT up-regulates binding 9606 21779497 t gcesareni "When active, pi3k converts phosphatidylinositol (4,5)-bisphosphate (pip2) into phosphatidylinositol (3,4,5)-trisphosphate (pip3). Pip3, in turn, binds the pleckstrin homology (ph) domain of akt/pkb, stimulating its kinase activity, resulting in the phosphorylation of a host of other proteins that affect cell growth, cell cycle entry, and cell survival." SIGNOR-175250 "AP 23573" chemical CHEBI:79700 ChEBI MTOR protein P42345 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000887 20554235 t gcesareni "Deforolimus was well tolerated on the schedule tested in this trial with toxicity and pharmacokinetic profiles that were similar to that of other mtor inhibitors." SIGNOR-166186 ARVCF protein O00192 UNIPROT CDH2 protein P19022 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-252128 ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT unknown phosphorylation Ser1524 LQNRNYPsQEELIKV 9606 BTO:0000150 10550055 t lperfetto "The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. Results from this study indicate that the checkpoint protein kinase atm (mutated in ataxia telangiectasia) was required for phosphorylation of brca1 in response to ionizing radiation. Atm resides in a complex with brca1 and phosphorylated brca1 in vivo and in vitro in a region that contains clusters of serine-glutamine residues. Phosphorylation of this domain appears to be functionally important because a mutated brca1 protein lacking two phosphorylation sites failed to rescue the radiation hypersensitivity of a brca1-deficient cell line.Atm-dependent phosphorylation of ser1423 or ser1524 also occurred in vivo," SIGNOR-72079 ATM protein Q13315 UNIPROT E2F1 protein Q01094 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser31 ALRLLDSsQIVIISA 10090 BTO:0001372 11459832 t lperfetto "Selective induction of e2f1 in response to dna damage, mediated by atm-dependent phosphorylation. We identify a site for atm/atr phosphorylation in the amino terminus of e2f1 and we show that this site is required for atm-mediated stabilization of e2f1. Finally, we also show that e2f1 is required for dna damaged induced apoptosis in mouse thymocytes." SIGNOR-109416 ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT "down-regulates activity" phosphorylation Ser395 SQESEDYsQPSTSSS -1 12383858 t gcesareni "Dephosphorylation stabilizes mdm2 and increases its affinity for p53, inducing p53 degredation. ;phosphorylated s260 and s395 ands260d and s395d mutant peptides inhibited binding of binding of a specific monoclonal antibody raised to mdm2. Phosphorylation of mdm2 regulates p53 degradation." SIGNOR-94268 ATM protein Q13315 UNIPROT RIF1 protein Q5UIP0 UNIPROT "up-regulates activity" binding 9606 15342490 t miannu "Human Rif1, ortholog of a yeast telomeric protein, is regulated by ATM and 53BP1 and functions in the S-phase checkpoint. After induction of double-strand breaks (DSBs), Rif1 formed foci that colocalized with other DNA-damage-response factors. This response was strictly dependent on ATM (ataxia telangiectasia mutated) and 53BP1, but not affected by diminished function of ATR (ATM- and Rad3-related kinase), BRCA1, Chk2, Nbs1, and Mre11." SIGNOR-259059 ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser15 PSVEPPLsQETFSDL 9606 11875057 t gcesareni "In response to ionizing radiation (ir), atm, the gene product mutated in ataxia telangiectasia, stabilizes and activates p53 through phosphorylation of ser15 and (indirectly) ser20. Here we show that phosphorylation of p53 on ser46, a residue important for p53 apoptotic activity, as well as on ser9, in response to ir also is dependent on the atm protein kinase. one pathway involves the phosphorylation of p53 and its negative regulator mdm2 by ataxia telangiectasia mutated (atm) and chk2 causing p53 activation and stabilization." SIGNOR-115340 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 ATR protein Q13535 UNIPROT MCM4 protein P33991 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-169412 CSNK2A1 protein P68400 UNIPROT NPHP1 protein O15259 UNIPROT up-regulates phosphorylation Ser121 PTEEEEEsESEDSED 9606 BTO:0000671 16308564 t lperfetto "Casein kinase 2 (ck2)-mediated phosphorylation of three critical serine residues within a cluster of acidic amino acids in nephrocystin mediates pacs-1 binding, and is essential for colocalization of nephrocystin with pacs-1 at the base of cilia. Inhibition of ck2 activity abrogates this interaction and results in the loss of correct nephrocystin targeting." SIGNOR-142343 AURKB protein Q96GD4 UNIPROT GFAP protein P14136 UNIPROT "down-regulates activity" phosphorylation Ser38 LGPGTRLsLARMPPP -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-100169 AXIN2 protein Q9Y2T1 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "up-regulates activity" binding 9606 BTO:0000142;BTO:0000671;BTO:0000763 10911903 t lperfetto "It has been found that a multiprotein complex assembled by the cytoplasmic component conductin induces degradation of cytoplasmic beta-catenin. The complex includes apc, the serine/threonine kinase gsk3 beta, and beta-catenin, which bind to conductin at distinct domains." SIGNOR-228003 baicalein chemical CHEBI:2979 ChEBI UGT1A1 protein P22309 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 21030469 t Luana "Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation." SIGNOR-258158 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 BCOR protein Q6W2J9 UNIPROT RNF2 protein Q99496 UNIPROT "up-regulates activity" binding 9606 17296600 t miannu "BcoR and Fbxl10/Jhdm1B are among the most abundant Ring1B/Rnf2 interactors identified with the highest confidence, and their association has been validated by coimmunoprecipitation studies; hence we call this the Fbxl10-BcoR complex. In summary, we have widened the set of multiprotein complexes containing the Polycomb group protein Ring1B/Rnf2. The new interactors contain protein motifs whose enzymatic activities and binding properties would expand the regulatory potential and gene target diversity of Ring1B/Rnf2 complexes in terms of recruitment to and modification of chromatin" SIGNOR-252241 belinostat chemical CHEBI:61076 ChEBI HDAC4 protein P56524 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257957 BMP7 protein P18075 UNIPROT PRDM16 protein Q9HAZ2 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-180317 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 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 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 C1RL protein Q9NZP8 UNIPROT HP protein P00738 UNIPROT "up-regulates activity" cleavage Arg161 NPANPVQrILGGHLD 9534 BTO:0001538 15385675 t miannu "We demonstrate that coexpression of the proform of Hp (proHp) and C1r-LP in COS-1 cells effected cleavage of proHp in the endoplasmic reticulum. This cleavage depended on proteolytic activity of C1r-LP because mutation of the putative active-site Ser residue abolished the reaction. Furthermore, incubation of affinity-purified C1r-LP and proHp led to the cleavage of the latter protein. ProHp appeared to be cleaved at the expected site because substitution of Gly for Arg-161 blocked the reaction." SIGNOR-256358 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 CAMK2A protein Q9UQM7 UNIPROT EGFR protein P00533 UNIPROT "down-regulates activity" phosphorylation Ser1064 SCPIKEDsFLQRYSS 9606 BTO:0000007 10347170 t llicata " We show that serines 1046/1047 are sites for CaM kinase II phosphorylation, although there is a preference for serine 1047, which resides within the consensus -R-X-X-S-. In addition, we have identified major phosphorylation sites at serine 1142 and serine 1057, which lie within a novel -S-X-D- consensus. Mutation of serines 1046/1047 in full-length EGFR enhanced both fibroblast transformation and tyrosine autokinase activity that was significantly potentiated by additional mutation of serines 1057 and 1142. A single CaM kinase II site was also identified at serine 744 within sub-kinase domain III, and autokinase activity was significantly affected by mutation of this serine to an aspartic acid making this site appear constitutively phosphorylated. We have addressed the mechanism by which CaM kinase II phosphorylation of the EGFR might regulate receptor autokinase activity and show that this modification can hinder association of the cytoplasmic tail with the kinase domain to prevent an enzyme-substrate interaction. " SIGNOR-250619 CAMK2A protein Q9UQM7 UNIPROT EGFR protein P00533 UNIPROT "down-regulates activity" phosphorylation Ser1071 SFLQRYSsDPTGALT 9606 BTO:0000007 10347170 t llicata " We show that serines 1046/1047 are sites for CaM kinase II phosphorylation, although there is a preference for serine 1047, which resides within the consensus -R-X-X-S-. In addition, we have identified major phosphorylation sites at serine 1142 and serine 1057, which lie within a novel -S-X-D- consensus. Mutation of serines 1046/1047 in full-length EGFR enhanced both fibroblast transformation and tyrosine autokinase activity that was significantly potentiated by additional mutation of serines 1057 and 1142. A single CaM kinase II site was also identified at serine 744 within sub-kinase domain III, and autokinase activity was significantly affected by mutation of this serine to an aspartic acid making this site appear constitutively phosphorylated. We have addressed the mechanism by which CaM kinase II phosphorylation of the EGFR might regulate receptor autokinase activity and show that this modification can hinder association of the cytoplasmic tail with the kinase domain to prevent an enzyme-substrate interaction. " SIGNOR-250621 CAMK2A protein Q9UQM7 UNIPROT GFAP protein P14136 UNIPROT "down-regulates activity" phosphorylation Ser393 NLQIRETsLDTKSVS -1 7822264 t llicata "On the other hand, GFAP was phosphorylated to approximately 1.9 mol of phosphate/mol of GFAP by Ca(2+)-CaM-dependent protein kinase II, and this phosphorylation did induce disassembly of the filament. Sequential analysis of the purified phosphopeptides revealed that only Ser8 on GFAP was phosphorylated by cdc2 kinase, whereas Ser13, Ser17, Ser34, and Ser389 on GFAP were phosphorylated by Ca(2+)-CaM-dependent protein kinase II." SIGNOR-250629 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR 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-251525 CAMK2A protein Q9UQM7 UNIPROT HSF1 protein Q00613 UNIPROT "up-regulates activity" phosphorylation Ser230 PKYSRQFsLEHVHGS BTO:0000664 11447121 t llicata "Ser230 is located in the regulatory domain of HSF1, and promotes the magnitude of the inducible transcriptional activity. Ser230 lies within a consensus site for calcium/calmodulin-dependent protein kinase II (CaMKII), and CaMKII overexpression enhances both the level of in vivo Ser230 phosphorylation and transactivation of HSF1. The importance of Ser230 was further established by the S230A HSF1 mutant showing markedly reduced activity relative to wild-type HSF1 when expressed in hsf1(-/-) cells." SIGNOR-250631 CAMK2B protein Q13554 UNIPROT ETS1 protein P14921 UNIPROT "down-regulates activity" phosphorylation Ser257 DSFESIEsYDSCDRL BTO:0003637 12475968 t llicata "Increased Transactivation of the GM-CSF Promoter/Enhancer by Ets1 with Mutated CaMK II Sites | Significantly, phosphorylation of Ets1 by Ca2+-dependent pathways is thought to inhibit DNA binding in vitro. To analyze the role of these four serines, S251, S257, S282, and S285, in transcription, we constructed three mutant derivatives of human Ets1 " SIGNOR-250685 CAMK2B protein Q13554 UNIPROT GRIN2B protein Q13224 UNIPROT "up-regulates activity" phosphorylation Ser1303 NKLRRQHsYDTFVDL BTO:0003036 8940188 t llicata "By peptide mapping, automated sequencing, and mass spectrometry, we identified the major site of phosphorylation on the fusion protein as Ser-383, corresponding to Ser-1303 of full-length NR2B. The Km for phosphorylation of this site in the fusion protein was approximately 50 nM, much lower than that of other known substrates for CaM kinase II, suggesting that the receptor is a high affinity substrate. We show that serine 1303 in the full-length NR2B and/or the cognate site in NR2A is a major site of phosphorylation of the receptor both in the postsynaptic density fraction and in living hippocampal neurons." SIGNOR-250688 CAMK2G protein Q13555 UNIPROT ATF1 protein P18846 UNIPROT "up-regulates activity" phosphorylation Ser63 GILARRPsYRKILKD 8663317 t llicata "Phosphopeptide mapping analysis and Western blotting studies demonstrated that in vitro, CaMK II phosphorylates only Ser63 (corresponding to Ser133 of CREB), which is essential for the activation, and not Ser72 (corresponding to Ser142 of CREB), which is a negative regulation site." SIGNOR-250692 CAMK2G protein Q13555 UNIPROT FLNA protein P21333 UNIPROT unknown phosphorylation Ser2523 VTGPRLVsNHSLHET BTO:0001141 11290523 t llicata "Our TER experiments using a CaM peptide, which functions as a specific competitive inhibitor of nonmuscle filamin phosphorylation by CaM kinase II, strongly suggest that filamin phosphorylation is involved in endothelial cell barrier regulation, although the exact mechanism is not clear and consequent signaling events are not well understood. " SIGNOR-250696 carfilzomib chemical CHEBI:65347 ChEBI PSMB10 protein P40306 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000898 17591945 t miannu "Carfilzomib is a tetrapeptide epoxyketone related to epoxomicin (Figure 1A), the latter of which shows high specificity in vitro for the ChT-L proteasome activity. To evaluate the proteasomal inhibitory potential of carfilzomib in MM, extracts from ANBL-6 cells were exposed to increasing concentrations of carfilzomib. Extended exposure to carfilzomib for 5 hours saturated the β5 and β5i active sites in a dose-dependent manner and also led to increased binding to the β1, β1i, β2, and β2i subunits, with maximal binding observed at 50 nM." SIGNOR-259308 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 14585074 f amattioni "Caspase-3 is responsible for apoptosis execution" SIGNOR-256474 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 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR FOS protein P01100 UNIPROT up-regulates 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-251522 FLT3LG protein P49771 UNIPROT FLT3 protein P36888 UNIPROT up-regulates binding 9606 BTO:0000574 10080542 t gcesareni "Flt3 ligand (fl) is an early-acting potent co-stimulatory cytokine that regulates proliferation and differentiation of a number of blood cell lineages. Its receptor flt3/flk2 belongs to class iii receptor tyrosine kinases that also include the receptors for colony-stimulating factor 1" SIGNOR-65564 CCNY protein Q8ND76 UNIPROT CDK14 protein O94921 UNIPROT up-regulates binding 9606 20059949 t gcesareni "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-162920 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 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 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 CDC42BPA protein Q5VT25 UNIPROT MYL2 protein P10916 UNIPROT "up-regulates activity" phosphorylation Ser19 GANSNVFsMFEQTQI BTO:0000567 9418861 t llicata "These approximately 190-kDa myotonic dystrophy kinase-related Cdc42-binding kinases (MRCKs) preferentially phosphorylate nonmuscle myosin light chain at serine 19, which is known to be crucial for activating actin-myosin contractility." SIGNOR-250723 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 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 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 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 GRB2 protein P62993 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates binding 9606 BTO:0000007 12766170 t "Grb2-associated binding (Gab) scaffolding/adapter proteins are a family of three members including mammalian Gab1, Gab2, and Gab3 that are highly conserved." lperfetto "The gab1 docking protein forms a platform for the assembly of a multiprotein signaling complex downstream from receptor tyrosine kinases. In general, recruitment of gab1 occurs indirectly, via the adapter protein grb2" SIGNOR-235917 MAPKAPK5 protein Q8IW41 UNIPROT MAPK4 protein P31152 UNIPROT up-regulates phosphorylation Ser186 YSHKGYLsEGLVTKW 9606 1319925 t lperfetto "This is due to mk5-dependent phosphorylation and only this retarded erk4 species is both phosphorylated on ser(186) and co-immunoprecipitates with wild-type mk5. We conclude that binding between erk4 and mk5 facilitates phosphorylation of ser(186) and stabilization of the erk4-mk5 complex." SIGNOR-17069 4'-epidoxorubicin chemical CHEBI:47898 ChEBI TOP2A protein P11388 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0002058 17639997 t miannu "The combinatory use of low concentrations of SM with low-toxic topoisomerase II inhibitor epirubicin accelerated apoptotic cell death." SIGNOR-259282 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 RPA2 protein P15927 UNIPROT up-regulates 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 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 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 NR3C1 protein P04150 UNIPROT "up-regulates activity" phosphorylation Ser211 PGKETNEsPWRSDLL -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-249427 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 Ser1068 HKNETMLsPREKIFY 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-104667 CDK4 protein P11802 UNIPROT RBL1 protein P28749 UNIPROT "up-regulates activity" phosphorylation Ser650 SVHERYSsPTAGSAK 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-250763 CDK5 protein Q00535 UNIPROT DPYSL3 protein Q14195 UNIPROT up-regulates phosphorylation Thr514 TTTPKGGtPAGSARG 9606 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-145971 CDK5 protein Q00535 UNIPROT DRD2 protein P14416 UNIPROT "down-regulates activity" phosphorylation Ser321 GLHSTPDsPAKPEKN 9606 24391960 t miannu "These results indicate that Cdk5-mediated phosphorylation of S321 inhibits DRD2 function, providing a novel regulatory mechanism for dopamine signaling." SIGNOR-259401 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 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 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 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 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 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 cis-(z)-Flupenthixol chemical CHEBI:10454 ChEBI DRD3 protein P35462 UNIPROT "down-regulates activity" "chemical inhibition" 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-258715 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 PPARGC1A protein Q9UBK2 UNIPROT NFKB1 protein P19838 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0001103 SIGNOR-C13 20404331 f lperfetto "In mouse muscles, overexpression of PGC-1beta (like PGC-1alpha) inhibited denervation atrophy, ubiquitin ligase induction, and transcription by NFkappaB" SIGNOR-217969 PTPN11 protein Q06124 UNIPROT GAB1 protein Q13480 UNIPROT down-regulates dephosphorylation Tyr659 VADERVDyVVVDQQK 9606 BTO:0000782;BTO:0000776 10068651 t lperfetto "Tyrosine phosphorylation of gab2 was induced by stimulation through gp130, il-2r, il-3r, tpor, scfr, and tcr. Gab1 and gab2 were shown to be substrates for shp-2 in vitro." SIGNOR-236254 MCHR1 protein Q99705 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-257302 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 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 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 up-regulates phosphorylation Tyr699 DPEGGVDyKNIHLEK 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-127536 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 CSNK2A1 protein P68400 UNIPROT CDH1 protein P12830 UNIPROT "up-regulates activity" phosphorylation Ser838 LVFDYEGsGSEAASL 10090 BTO:0000944 10671552 t llicata "Casein kinase II phosphorylation of E-cadherin increases E-cadherin/beta-catenin interaction and strengthens cell-cell adhesion. | All mutants showed a clear reduction in phosphorylation. Phosphorylation was completely abolished in the single mutant S855A and the double mutant S853/855A, and phosphorylation in S840A and S853A mutants was reduced to 43 and 28% that of wt GST-ECT. | Expression of the E-cadherin double mutant S853A/S855A in NIH3T3 cells expressing Wnt-1 reduces cell-cell adhesion." SIGNOR-250839 CSNK2A1 protein P68400 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" phosphorylation Thr102 RAAMFPEtLDEGMQI 9606 BTO:0000007 12432063 t llicata "We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin" SIGNOR-250847 CSNK2A1 protein P68400 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-250859 PTPN11 protein Q06124 UNIPROT GAB1 protein Q13480 UNIPROT "down-regulates activity" dephosphorylation Tyr589 SHDSEENyVPMNPNL 9606 BTO:0000782;BTO:0000776 10068651 t lperfetto "Tyrosine phosphorylation of gab2 was induced by stimulation through gp130, il-2r, il-3r, tpor, scfr, and tcr. Gab1 and gab2 were shown to be substrates for shp-2 in vitro." SIGNOR-236258 SMO protein Q99835 UNIPROT SUFU protein Q9UMX1 UNIPROT "down-regulates activity" binding 9606 BTO:0000452 22114142 t lperfetto "In addition to activating g(i), smo signals through its c-terminal tail to inhibit suppressor of fused, resulting in stabilization and activation of the gli family of transcription factors, which execute a transcriptional response to so-called canonical hh signaling." SIGNOR-177656 MCHR1 protein Q99705 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-256762 bortezomib chemical CHEBI:52717 ChEBI PSMD2 protein Q13200 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000898 21504411 t miannu "Proteasome inhibition is a modern and surprisingly successful approach how to cancer treatment. Bortezomib (Velcade®) is a first-in-class proteasome inhibitor and has been approved for first-line treatment of multiple myeloma and second-line treatment of mantle cell lymphoma." SIGNOR-259313 CSNK2A1 protein P68400 UNIPROT HMGN1 protein P05114 UNIPROT down-regulates phosphorylation Ser99 AGEKEAKsD 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-76278 CSNK2A1 protein P68400 UNIPROT NPHP1 protein O15259 UNIPROT up-regulates phosphorylation Ser123 EEEEESEsEDSEDSG 9606 BTO:0000671 16308564 t lperfetto "Casein kinase 2 (ck2)-mediated phosphorylation of three critical serine residues within a cluster of acidic amino acids in nephrocystin mediates pacs-1 binding, and is essential for colocalization of nephrocystin with pacs-1 at the base of cilia. Inhibition of ck2 activity abrogates this interaction and results in the loss of correct nephrocystin targeting." SIGNOR-142347 CSNK2A1 protein P68400 UNIPROT PIAS1 protein O75925 UNIPROT up-regulates phosphorylation Ser466 VIDLTIDsSSDEEEE 9606 19217413 t llicata "Ck2 phosphorylates serine residues adjacent to the sim of pias1 these findings show that the phosphosim module mediates binding to free sumo and sumo conjugates in a phosphorylation-dependent mode, with ck2 being the critical kinase involvedin this process." SIGNOR-184039 CSNK2A1 protein P68400 UNIPROT SRF protein P11831 UNIPROT "up-regulates activity" phosphorylation Ser77 PTAGALYsGSEGDSE -1 2046671 t llicata "Casein kinase II (CKII) phosphorylates the mammalian transcription factor serum response factor (SRF) on a serine residue(s) located within a region of the protein spanning amino acids 70 to 92, thereby enhancing its DNA-binding activity in vitro.| Nevertheless, additional mutation of serines 77 and 79 was required before phosphorylation and enhanced binding were completely abolished. Thus, serines 77 and 79 could also be recognized by CKII if serines 83 and 85 were mutated." SIGNOR-250955 CSNK2A1 protein P68400 UNIPROT SSRP1 protein Q08945 UNIPROT "down-regulates activity" phosphorylation Ser688 KRRRSEDsEEEELAS 9606 BTO:0000007 15659405 t llicata "CK2 phosphorylates SSRP1 and inhibits its DNA-binding activity. | we identified serines 510, 657, and 688 as phosphorylation targets of CK2 in vitro. Mutagenesis of the three serines revealed that serine 510 was more important for the regulation of SSRP1 DNA-binding activity." SIGNOR-250961 CSNK2A1 protein P68400 UNIPROT TELO2 protein Q9Y4R8 UNIPROT down-regulates phosphorylation Ser487 AQLAGSDsDLDSDDE 9606 20864032 t lperfetto "Here we report that tel2 and tti1 are targeted for degradation within mtorc1 by the scffbxo9 ubiquitin ligase to adjust mtor signalling to growth factor availability. This process is primed by ck2, which translocates to the cytoplasm to mediate mtorc1-specific phosphorylation of tel2/tti1. ere, we show that tel2 is constitutively phosphorylated on conserved serines 487 and 491 by casein kinase 2 (ck2)" SIGNOR-168036 CSNK2A1 protein P68400 UNIPROT TELO2 protein Q9Y4R8 UNIPROT down-regulates phosphorylation Ser491 GSDSDLDsDDEFVPY 9606 23263282 t lperfetto "Here we report that tel2 and tti1 are targeted for degradation within mtorc1 by the scffbxo9 ubiquitin ligase to adjust mtor signalling to growth factor availability. This process is primed by ck2, which translocates to the cytoplasm to mediate mtorc1-specific phosphorylation of tel2/tti1. Here, we show that tel2 is constitutively phosphorylated on conserved serines 487 and 491 by casein kinase 2 (ck2)" SIGNOR-200206 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 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 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 GADD45A protein P24522 UNIPROT CDK1 protein P06493 UNIPROT down-regulates binding 9606 SIGNOR-C17 10362260 t gcesareni "Gadd45 has now been found to directly inhibit the activity of cdc2/cyclin b1 complex" SIGNOR-68221 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 ixazomib chemical CHEBI:90942 ChEBI PSMB5 protein P28074 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194509 5-(2-propoxyphenyl)-2,3-dihydrotriazolo[4,5-d]pyrimidin-7-one chemical CHEBI:92215 ChEBI GPR35 protein Q9HC97 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-257506 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 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 CTNND2 protein Q9UQB3 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-252130 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 CUL1 protein Q13616 UNIPROT SCF-SKP2 complex SIGNOR-C136 SIGNOR "form complex" binding 9606 15340381 t gcesareni "The F-box family of proteins €” which are the substrate-recognition components of the Skp1€“Cul1€“F-box-protein (SCF) ubiquitin ligase €” are important players in many mammalian functions." SIGNOR-243557 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 "dasatinib (anhydrous)" chemical CHEBI:49375 ChEBI BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR "down-regulates activity" "chemical inhibition" 9606 BTO:0001056 23409026 t miannu "Pre-existing BCR-ABL mutations can be detected in a substantial number of chronic-phase CML patients by sensitive allele-specific PCR technique using CD34+ cells. These mutations are associated with imatinib resistance if affecting drug binding directly or indirectly. After the recent approval of nilotinib, dasatinib, bosutinib and ponatinib for treatment of chronic myeloid leukemia along with imatinib, all of which vary in their effectiveness against mutated BCR-ABL forms, detection of pre-existing BCR-ABL mutations can help in selection of appropriate first-line drug therapy." SIGNOR-259270 Diacylglycerol smallmolecule CID:6026790 PUBCHEM PRKCZ protein Q05513 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-242599 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 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 PAXIP1 protein Q6ZW49 UNIPROT PAX2 protein Q02962 UNIPROT "up-regulates activity" binding 10090 BTO:0000944 10908331 t miannu "PTIP, a novel BRCT domain-containing protein interacts with Pax2 and is associated with active chromatin. The degree of interaction with the Pax2 C-terminal polypeptides correlates with their transcription transactivation potential and we have therefore designated this factor PTIP for Pax transactivation-domain interacting protein." SIGNOR-236965 PRKAA1 protein Q13131 UNIPROT EP300 protein Q09472 UNIPROT down-regulates phosphorylation Ser89 SELLRSGsSPNLNMG 9606 BTO:0000801;BTO:0001271;BTO:0000876 21940946 t gcesareni "The mechanism of ampk-mediated anti- inflammation involves the induction of p300 ser89 phosphor- ylation and subsequent inactivation of p300 hat activity." SIGNOR-176637 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 DUSP4 protein Q13115 UNIPROT MAPK3 protein P27361 UNIPROT "down-regulates activity" dephosphorylation Thr202 HDHTGFLtEYVATRW 10116 7535768 t "Dephosphorylation and Inactivation of ERKs|ERK1 phosphorylated on either threonine (ERK1*Y204F) or tyrosine alone (ERK1*T202A) was utilized as a substrate for HVH2. Threonine 202 and tyrosine 204 in ERK1 (53) correspond to threonine 183 and tyrosine 185 in ERK2 which are the activation-phosphorylation sites by MEK(14, 15, 16). ERK1*, a kinase-deficient mutant, was phosphorylated on both threonine and tyrosine by MEK2 (Fig. 3B). ERK1*T202A, having threonine 202 substituted by an alanine, was phosphorylated only on tyrosine while ERK1*Y204F, having tyrosine 204 substituted by a phenylalanine, was phosphorylated only on threonine (Fig. 3B). GST-HVH2 dephosphorylated all three ERK1* mutants (Fig. 3A), suggesting that double phosphorylations of adjacent threonine and tyrosine were not a prerequisite for HVH2 recognition. However, HVH2 dephosphorylated ERK1* and ERK1*T202A more efficiently than ERK1*Y204F (Fig. 3A), indicating that HVH2 preferred phosphotyrosine over phosphothreonine. Interestingly, MEK also phosphorylated tyrosine residues more efficiently than threonine residues of ERK" SIGNOR-248715 DUSP4 protein Q13115 UNIPROT MAPK3 protein P27361 UNIPROT "down-regulates activity" dephosphorylation Tyr204 HTGFLTEyVATRWYR 10116 7535768 t "Dephosphorylation and Inactivation of ERKs|ERK1 phosphorylated on either threonine (ERK1*Y204F) or tyrosine alone (ERK1*T202A) was utilized as a substrate for HVH2. Threonine 202 and tyrosine 204 in ERK1 (53) correspond to threonine 183 and tyrosine 185 in ERK2 which are the activation-phosphorylation sites by MEK(14, 15, 16). ERK1*, a kinase-deficient mutant, was phosphorylated on both threonine and tyrosine by MEK2 (Fig. 3B). ERK1*T202A, having threonine 202 substituted by an alanine, was phosphorylated only on tyrosine while ERK1*Y204F, having tyrosine 204 substituted by a phenylalanine, was phosphorylated only on threonine (Fig. 3B). GST-HVH2 dephosphorylated all three ERK1* mutants (Fig. 3A), suggesting that double phosphorylations of adjacent threonine and tyrosine were not a prerequisite for HVH2 recognition. However, HVH2 dephosphorylated ERK1* and ERK1*T202A more efficiently than ERK1*Y204F (Fig. 3A), indicating that HVH2 preferred phosphotyrosine over phosphothreonine. Interestingly, MEK also phosphorylated tyrosine residues more efficiently than threonine residues of ERK" SIGNOR-248716 DUSP5 protein Q16690 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 10224087 t gcesareni "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" SIGNOR-67355 DVL1P1 protein P54792 UNIPROT CCDC88C protein Q9P219 UNIPROT up-regulates binding 9606 23151663 t gcesareni "Daple binds to dvl and functions as a negative regulator of the wnt signalling pathway." SIGNOR-199448 DYRK2 protein Q92630 UNIPROT DPYSL3 protein Q14195 UNIPROT up-regulates phosphorylation Ser518 KGGTPAGsARGSPTR 9606 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-145975 ECM stimulus SIGNOR-ST20 SIGNOR "A11/b1 integrin" complex SIGNOR-C168 SIGNOR up-regulates 9606 30889378 t miannu "Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions" SIGNOR-259050 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 "(1R,4S,5S,6S)-4-amino-2,2-dioxo-2$l^{6}-thiabicyclo[3.1.0]hexane-4,6-dicarboxylic acid" chemical CHEBI:94640 ChEBI GRM3 protein Q14832 UNIPROT up-regulates "chemical activation" 9606 Other t Selleck gcesareni SIGNOR-193772 EFNB3 protein Q15768 UNIPROT EPHB3 protein P54753 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-52624 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 EIF2AK1 protein Q9BQI3 UNIPROT EIF2S1 protein P05198 UNIPROT down-regulates phosphorylation Ser52 MILLSELsRRRIRSI 9606 3352609 t lperfetto "The wild-type and ser-48 mutant proteins became extensively phosphorylated by eif-2 kinases . The ser-51 mutant showed little covalent modification by the endogenous enzymes. Phosphorylation of the serine 51 residue in the alpha-subunit of translational initiation factor 2 in eukaryotes (eif2 alpha) impairs protein synthesis presumably by sequestering eif2b, a rate-limiting pentameric guanine nucleotide exchange protein which catalyzes the exchange of gtp for gdp in the eif2-gdp binary complex" SIGNOR-24543 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 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser87 AAAGPALsPVPPVVH 9606 BTO:0000567 10669763 t lperfetto "The results of this study reveal the following novel findings: destruction of the three putative MAP kinase sites at positions 56, 74, and 87 results in ubiquitination and subsequent degradation of the protein. Progressive inactivation of these MAP kinase sites revealed that Bcl-2 stability is mainly regulated by phosphorylation at Thr74 and Ser87, with Ser87 phosphorylation playing a predominant role. TNF-α or the MAP kinase-specific inhibitor PD98059 diminishes Ser87 phosphorylation of Bcl-2 in vivo, while activated ERK2 induces phosphorylation of Bcl-2 in vivo and in vitro." SIGNOR-244505 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR 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-249575 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 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 (-)-selegiline chemical CHEBI:9086 ChEBI MAOB protein P27338 UNIPROT "down-regulates activity" "chemical inhibition" -1 21377879 t Luana "All the compounds were found as extremely potent and selective towards MAO-B, (Table 2) with at least 100 times more potent than the positive control selegiline. " SIGNOR-258136 [4-[2-(1H-indazol-3-yl)ethenyl]phenyl]-(1-piperazinyl)methanone chemical CHEBI:91441 ChEBI FLT3 protein P36888 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193615 FGF13 protein Q92913 UNIPROT SCN1A protein P35498 UNIPROT "down-regulates activity" binding 9606 BTO:0000938 20679355 t miannu "Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels." SIGNOR-253419 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 FGFR1 protein P11362 UNIPROT SYNCRIP protein O60506 UNIPROT down-regulates phosphorylation Tyr373 RVKKLKDyAFIHFDE 9606 12601080 t lperfetto "Novel in vivo tyrosine phosphorylation sites were found in the fgfr-1, phospholipase cgamma, p90 ribosomal s6 kinase, cortactin, and ns-1-associated protein-1. Syncrip, was very recently found to be phosphorylated in response to insulin treatment of 3t3-l1 adipocytes (32). Phosphorylation of syncrip was accommodated by the insulin receptor tyrosine kinase in vitro but was inhibited upon binding of rna. Tyrosine phosphorylation at tyr-373 in the third rna recognition motif domain of nsap1/syncrip can possibly influence its rna binding properties and thus link fgfr-1 signaling to mrna metabolism." SIGNOR-98704 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 FOXO1 protein Q12778 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 12530968 f "�The present data provide a direct link between insulin signaling through Irs _ PI 3-kinase _ Akt and adipogenesis through Foxo1 phosphorylation. Inhibition of Foxo1 via phosphorylation appears to be required during the clonal expansion phase, and our data show that unrestrained Foxo1 activity prevents terminal differentiation." SIGNOR-254977 frovatriptan chemical CHEBI:134991 ChEBI HTR1B protein P28222 UNIPROT "up-regulates activity" "chemical activation" -1 9986723 t miannu "As far as the selectivity against the 5-HT1A receptor, compound 10 shows similar selectivity as VML-251 (4) but has slightly lower selectivity as compared to sumatriptan (1), naratriptan (2), and rizatriptan (3). Although none of the 5-HT1D receptor agonists in the current study demonstrate as good selectivity versus the 5-HT1B receptor, the N-methyl-5-tert-butyltryptamine (10) remains the most selective (4-fold)." SIGNOR-259075 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 WIF1 protein Q9Y5W5 UNIPROT WNT8A protein Q9H1J5 UNIPROT down-regulates binding 9606 10201374 t gcesareni "Here we describe wnt-inhibitory factor-1 (wif-1), a secreted protein that binds to wnt proteins and inhibits their activities." SIGNOR-66892 acetylcholine smallmolecule CHEBI:15355 ChEBI CHRM1 protein P11229 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-257468 2-(2-amino-3-methoxyphenyl)chromen-4-one chemical CHEBI:77954 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205743 FYN protein P06241 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-249336 FYN protein P06241 UNIPROT SLAMF1 protein Q13291 UNIPROT "up-regulates activity" phosphorylation Tyr307 QDPCTTIyVAATEPV 9534 BTO:0000298 11806999 t "All 3 tyrosines of CD150 (Tyr281, Tyr307, Tyr327) are phosphorylated by the src kinase Fyn. CD150 is unique among its homologues in the immunoglobulin superfamily in that it is able to bind SAP, a floating SH2 domain, in the absence of tyrosine phosphorylation. In this study, using a detailed mutagenesis mapping approach we have shown that SAP binding to CD150 is in fact bimodal. Prior to tyrosine phosphorylation, SAP binds the membrane-proximal motif surrounding Tyr281. Following tyrosine phosphorylation by tyrosine kinases such as Fyn, SAP binds additionally to the distal motif surrounding Tyr327." SIGNOR-251182 GATA3 protein P23771 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-254089 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 GNAI1 protein P63096 UNIPROT ADCY1 protein Q08828 UNIPROT "down-regulates activity" binding 9606 15922020 t "Activation of receptors coupled to inhibitory G proteins (Galpha i/o) has opposing consequences for cyclic AMP accumulation and the activity of cyclic AMP-dependent protein kinase, depending on the duration of stimulation. Acute activation inhibits the activity of adenylate cyclase, thereby attenuating cyclic AMP accumulation; in contrast, persistent activation of Galpha i/o-coupled receptors produces a paradoxical enhancement of adenylate cyclase activity, thus increasing cyclic AMP accumulation when the action of the inhibitory receptor is terminated." SIGNOR-256532 GNAS protein P63092 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103;BTO:0001760 22179044 t gcesareni "Notably, the fzd7 receptor complex was associated with g_?(s) and pi(3)k and these components were required for wnt7a to activate the akt/mtor growth pathway in myotubes. These data led us to hypothesize that g_?s Mediates the activation of pi3kinase following wnt7a binding to fzd7." SIGNOR-191561 GNG2 protein P59768 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0000938 16537363 t gcesareni "Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt." SIGNOR-252683 IRAK1 protein P51617 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 12242293 t lperfetto "We now find that the phosphorylated IRAK in turn recruits TRAF6 to the receptor complex (complex I), which differs from the previous concept that IRAK interacts with TRAF6 after it leaves the receptor. IRAK then brings TRAF6 to TAK1" SIGNOR-92994 MYD88 protein Q99836 UNIPROT IRAK1 protein P51617 UNIPROT "up-regulates activity" binding 10090 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. Myd88 binds to both irak (il-1 receptor-associated kinase) and the heterocomplex (the signaling complex) of the two receptor chains and thereby mediates the association of irak with the receptor." SIGNOR-67143 4-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-[(5-nitro-2-thiazolyl)thio]-1H-1,2,4-triazol-5-one chemical CHEBI:94732 ChEBI MAPK8 protein P45983 UNIPROT down-regulates "chemical inhibition" 9606 18922779 t "BI-78D3 is substrate competitive." gcesareni "Bi-78d3, dose-dependently inhibits the phosphorylation of jnk substrates both in vitro and in cell." SIGNOR-181647 GPER1 protein Q99527 UNIPROT "1D-myo-inositol 1,4,5-trisphosphate" smallmolecule CHEBI:16595 ChEBI up-regulates 9606 19549922 f gcesareni "Gpr30 also stimulates the pi3k pathway, elevating cellular pip3 levels, which is also predicted to activate nr5a receptors by direct binding of pip3 to the ligand binding domain ." SIGNOR-186206 GRB2 protein P62993 UNIPROT CBL protein P22681 UNIPROT up-regulates relocalization 9606 11823423 t "GRB2 is an adapter protein that provides a critical link between cell surface growth factor receptors and the Ras signaling pathway." gcesareni "The underlying mechanism seems to involve recruitment of a grb2 c-cbl complex to grb2-specific docking sites of egfr, and concurrent acceleration of receptor ubiquitylation and desensitization." SIGNOR-114704 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 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 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 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser768 LQARRRQsVLNLMTH 9606 1377674 t lperfetto "Direct amino acid sequencing and peptide mapping of cf-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by pka and pkgcftr possesses a large cluster of strict dibasic consensus sites for phosphorylation by protein kinase a (pka) in the r-domain and an obligatory dependence on phosphorylation is a hallmark of cftr cl(-) channel function" SIGNOR-18141 PRKCG protein P05129 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation Ser21 SGRARTSsFAEPGGG 9606 BTO:0000007 11884598 t gcesareni "Convergence of multiple signaling cascades at glycogen synthase kinase 3: edg receptor-mediated phosphorylation and inactivation by lysophosphatidic acid through a protein kinase c-dependent intracellular pathway." SIGNOR-115726 PTPRF protein P10586 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 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-76005 RBCK1 protein Q9BYM8 UNIPROT BACH1 protein O14867 UNIPROT "down-regulates quantity by destabilization" ubiquitination 10090 BTO:0000944 17682061 t miannu "HOIL-1 bound Bach1 in vivo and thus stimulated its polyubiquitination in vitro. These results suggest that heme regulates the polyubiquitination of Bach1 and subsequent degradation and that HOIL-1 may function as an E3 ligase in this process." SIGNOR-236971 GSK3B protein P49841 UNIPROT MAFA protein Q8NHW3 UNIPROT up-regulates 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 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 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 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 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 GXYLT1 protein Q4G148 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 22117070 t 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-177694 HACE1 protein Q8IYU2 UNIPROT RAC1 protein P63000 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 22036506 t "The CNF1 toxin of pathogenic Escherichia coli addresses Rac1 to ubiquitin-proteasome system (UPS). We report the essential role of the tumor suppressor HACE1, a HECT-domain containing E3 ubiquitin-ligase, in the targeting of Rac1 to UPS. HACE1 binds preferentially GTP-bound Rac1 and catalyzes its polyubiquitylation" SIGNOR-255538 SFRP1 protein Q8N474 UNIPROT WNT1 protein P04628 UNIPROT down-regulates binding 9606 10523516 t gcesareni "Frp inhibits wnt signaling through interactions with wnt and/or formation of nonfunctional complexes with the frizzled receptor. here we demonstrate that frza, a sfrp that is highly expressed in vascular endothelium and a variety of epithelium, specifically binds to wnt-1 protein, but not wnt-5a protein, and modulates wnt-1 signaling." SIGNOR-71423 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 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 HEY2 protein Q9UBP5 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates binding 9606 16682003 t "The NotchIC-RBP-Jkappa complex activates target genes, such as those encoding the Hrt and Hes families. The interaction did not interfere with the formation or DNA-binding of the NotchIC-RBP-Jkappa complex, indicating direct inhibition by Hrt and Hes as co-repressors." gcesareni "Here we show that hrt2 and hes1 interact with rbp-jkappa to negatively regulate notch-dependent activation of hrt and hes expression." SIGNOR-146690 HNF1A protein P20823 UNIPROT ALDOB protein P05062 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 8383844 f miannu "Contransfection experiments of aldolase B/CAT constructs and of expression vectors for different transcription factors were carried out in human hepatoma Hep G2 cells. We found that DBP and HNF-1 are strong transactivators of the aldolase B promoter while C/EBP and vHNF-1 are only weak activators" SIGNOR-253834 HRAS protein P01112 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 8052307 t gcesareni "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-35878 IFNGR1 protein P15260 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-249505 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 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 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 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 IKK-complex complex SIGNOR-C14 SIGNOR IKBKG protein Q9Y6K9 UNIPROT "down-regulates activity" phosphorylation Ser85 ELLHFQAsQREEKEF 9606 BTO:0000007 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-209784 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 IL13RA1 protein P78552 UNIPROT TYK2 protein P29597 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000801;BTO:0000876 BTO:0000887;BTO:0000763;BTO:0001260 12704343 t milica "IL-4R, ?c, and IL-13R1 All contain proline-rich box-1 regions that bind jak1, jak3, and tyk2, respectivelyil-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-100756 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 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 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 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 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 TSC1/TSC2 complex SIGNOR-C101 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR "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-251527 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 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 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 ITGB5 protein P18084 UNIPROT "Av/b5 integrin" complex SIGNOR-C178 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-253208 JAG2 protein Q9Y219 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 10958687 t gcesareni "Binding of delta1, jagged1, and jagged2 to notch2 rapidly induces cleavage, nuclear translocation, and hyperphosphorylation of notch2" SIGNOR-81367 JWOGUUIOCYMBPV-GMFLJSBRSA-N chemical CID:6918328 PUBCHEM HDAC8 protein Q9BY41 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257976 lapatinib chemical CHEBI:49603 ChEBI EGFR protein P00533 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-258234 lofepramine chemical CHEBI:47782 ChEBI SLC6A2 protein P23975 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 9537821 t miannu "At the human norepinephrine transporter, among the antidepressants desipramine was the most potent with a KD=0.83±0.05 nM. All the tetracyclic antidepressants, except mirtazapine, which is a structural analog of mianserin, were more potent at the norepinephrine transporter than at the serotonin transporter. Tomoxetine, considered from animal data to be very selective for the norepinephrine transporter, had high affinity for the human norepinephrine transporter (KD=2.03±0.06 nM). However, at the human serotonin transporter, tomoxetine was nearly as potent and close to that for dothiepin and venlafaxine. Venlafaxine, considered a serotonin and norepinephrine re-uptake inhibitor based on animal data, was very weak at the human norepinephrine transporter. Its KD value was 5× less that than for norepinephrine. All of the serotonin selective re-uptake inhibitors, with the exception of paroxetine, were also weak at the human norepinephrine transporter. " SIGNOR-258881 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 LRRK2 protein Q5S007 UNIPROT SNCA protein P37840 UNIPROT "up-regulates activity" phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 BTO:0000938 19576176 t lperfetto "Here we show that full-length Lrrk2 or fragments containing its kinase domain have a significant capacity to phosphorylate recombinant alpha synuclein (Asyn) at serine 129. Such phosphorylated Asyn is the major component of pathological deposits in PD. We further show that the G2019S mutation in Lrrk2, which is the most common genetic determinant of PD, has a significantly greater capacity than wild-type Lrrk2 to phosphorylate Asyn. This suggests that the G2019S mutant protein may cause PD by generating pathological levels of phosphorylated Asyn." SIGNOR-249690 MACF1 protein Q9UPN3 UNIPROT GSK3B protein P49841 UNIPROT down-regulates 9606 BTO:0000938 16815997 f gcesareni "In the absence of wnt, macf1 associated with a complex that contained axin, betBeta-catenin, gsk3beta, and apc. Upon wnt stimulation, macf1 appeared to be involved in the translocation and subsequent binding of the axin complex to lrp6 at the cell membrane. Macf1 is involved in the translocation of the complex containing axin, Beta-catenin, and gsk3_ but not apc from the cytosol to the cell membrane, where axin and macf1 bind to lrp-5/6. Subsequently, gsk3_ is inactivated by phosphorylation, axin is degraded, and Beta-catenin is released and enters the nucleus, where it can activate the wnt-responsive genes." SIGNOR-147451 MAP1LC3A protein Q9H492 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates binding 9606 17580304 t gcesareni "Sqstm1/p62 (named a170 in the mouse;hereafter p62) is the first proposed example of such proteins (bj_?_?Rk_?_?Y et al.,2005). It binds polyubiquitinated protein aggregates via its uba domain and interacts with lc3 on the autophagosome/ this interaction is necessary for autophagic degradation of p62-positive cytoplasmic inclusion bodies containing ubiquitinated proteins. We also demonstrate that alis are indistinguishable from p62 inclusion bodies and that p62 is required for their formation." SIGNOR-156353 MAP3K11 protein Q16584 UNIPROT MAP3K11 protein Q16584 UNIPROT up-regulates phosphorylation Ser281 WHKTTQMsAAGTYAW 9606 11053428 t gcesareni "These residues within the activation loop are critical for mlk-3 autophosphorylation and activation. In addition, when the thr277 and ser281 residues were mutated to negatively charged glutamic acid to mimic phosphorylated serine/threonine residues, the resulting mutants were fully functional, implying that these two residues may serve as the autophosphorylation sites." SIGNOR-83407 MAPK14 protein Q16539 UNIPROT JDP2 protein Q8WYK2 UNIPROT unknown phosphorylation Thr148 VRTDSVKtPESEGNP -1 12225289 t miannu "Wild-type JDP2 exhibited efficient phosphorylation by the p38 kinase, the mutant JDP2 T%)A did not incorporate labelled Figure 5 JDP2 C-terminal domain is necessary but not sufficient for p38 phosphorylation (A) p38 phosphorylated JDP2 at Thr-148. Bacterially purified His-JDP2 (Wt) or His-JDP2 T148A (Ala) were incubated with bacterially purified activated p38 F327S [21] in the presence of [γ- 32P]ATP for 30 min. Proteins were resolved by SDS/PAGE (12 % gel), dried and exposed to autoradiography. (B) The JDP2 C-terminal domain is necessary but not sufficient for phosphorylation by p38 kinase. Bacterially purified GST fusion proteins with full-length JDP2 (Wt) C-terminally truncated JDP2 (∆C) and JDP2 C-terminal fragment (Dock) were used in an in vitro kinase assay as described in (A). A representative experiment is presented. (C) In vitro kinase assay using GST-JDP2 (JDP2wt), JDP2 ∆C and JDP2-Dock as substrates with either activated p38 or HA-JNK2 kinases. Protein mixtures were resolved by SDS/PAGE, fixed, dried and analysed by PhosphorImaging. The results represent meansS.E.M. from three independent experiments. phosphate in the presence of activated p38 kinase. This indicates that both p38 and JNK kinases are able to integrate stress signals to JDP2 Thr-148" SIGNOR-250100 MAPK14 protein Q16539 UNIPROT SLC9A1 protein P19634 UNIPROT up-regulates phosphorylation Thr718 KEDLPVItIDPASPQ 9606 11604491 t llicata "Trophic factor withdrawal: p38 mitogen-activated protein kinase activates nhe1, which induces intracellular alkalinization. activated p38 mapk directly phosphorylated the c terminus of nhe1 within a 40-amino-acid region. Analysis by mass spectroscopy identified four phosphorylation sites on nhe1, thr 717, ser 722, ser 725, and ser 728." SIGNOR-111051 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0000093 10581258 t lperfetto "P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site." SIGNOR-72695 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 acetylcholine smallmolecule CHEBI:15355 ChEBI CHRM3 protein P20309 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-257470 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 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 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 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 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 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 NUP50 protein Q9UKX7 UNIPROT down-regulates phosphorylation Ser221 KVAAETQsPSLFGST 9606 19767751 t gcesareni "Erk directly phosphorylated at least 13 proteins in vitro. Of these, nup50 was verified as a bona fide erk substrate. Notably, 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 PPARG protein P37231 UNIPROT down-regulates phosphorylation Ser112 AIKVEPAsPPYYSEK 9606 18596912 t "The effect has been demonstrated using P37231-1" 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-179397 MAPK1 protein P28482 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR "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-252752 MAPK1 protein P28482 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. The kinases involved in phosphorylating stmn ser-16 and ser-63 include camp-dependent protein kinase (pka) and pak1, whereas stmn ser-25 and ser-38 have been shown to be targets for proline-directed serine/threonine kinases such as cyclin-dependent kinases, erk1/2, and members of the p38 mapk subfamily." SIGNOR-166686 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 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 RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser289 RSHSESAsPSALSSS 9606 16407412 t llicata "Erk-induced raf-1 phosphorylation sustains raf-1 kinase activity furthermore, using direct in vitro phosphorylation we show that these sites are direct targets of erk-1 and using phosphospecific antibodies developed against one of the sites, s296, show that these sites are physiological phosphorylation sites induced in vivo after mitogen stimulation." SIGNOR-143688 MAPK3 protein P27361 UNIPROT RPS6KA1 protein Q15418 UNIPROT "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-219345 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 TAL1 protein P17542 UNIPROT down-regulates phosphorylation Ser122 DGRMVQLsPPALAAP 9606 BTO:0000782;BTO:0001271 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 MAPK9 protein P45984 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-102402 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 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 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR PPARG protein P37231 UNIPROT "down-regulates activity" phosphorylation Ser112 AIKVEPAsPPYYSEK 9606 18596912 t lperfetto "In conclusion, PPAR emerges as a tumor-type and tumor-stage-specific modulator that is regulated by at least three mechanisms through the ERK cascade. Downregulation is carried out through (1) MAPK-mediated Ser84/114 phosphorylation, (2) ERK cascade activation through PPAR ligands, and (3) cooperation of PPAR with tumor modulating proteins (such as MEK1)" SIGNOR-244968 PRKG1 protein Q13976 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser768 LQARRRQsVLNLMTH 9606 1377674 t lperfetto "Direct amino acid sequencing and peptide mapping of cf-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by pka and pkgcftr possesses a large cluster of strict dibasic consensus sites for phosphorylation by protein kinase a (pka) in the r-domain and an obligatory dependence on phosphorylation is a hallmark of cftr cl(-) channel function" SIGNOR-18245 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 MTA1 protein Q13330 UNIPROT EPHA2 protein P29317 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001211 22184117 f miannu "The receptor tyrosine kinase EphA2 is a direct target gene of hypermethylated in cancer 1 (HIC1). we observe that inactivation of endogenous HIC1 through RNA interference in normal breast epithelial cells results in the up-regulation of EphA2 and is correlated with increased cellular migration. chromatin immunoprecipitation (ChIP) and sequential ChIP experiments demonstrate that endogenous HIC1 proteins are bound, together with the MTA1 corepressor, to the EphA2 promoter in WI38 cells." SIGNOR-254242 NFE2 protein Q16621 UNIPROT HBG2 protein P69892 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000426 16287851 f "Regulation of expression" miannu "NF-E2 is a transcription activator for the regulation of a number of erythroid- and megakaryocytic lineage-specific genes. Here we present evidence that the large subunit of mammalian NF-E2, p45, is sumoylated in vivo in human erythroid K562 cells. we demonstrated by stable transfection assay that only the wild-type p45, but not its mutant form p45 (K368R), could efficiently rescue β-globin gene expression in the p45-null, erythroid cell line CB3. These data together point to a model of mammalian β-like globin gene activation by sumoylated p45/NF-E2 in erythroid cells." SIGNOR-251840 NME1 protein P15531 UNIPROT KSR1 protein Q8IVT5 UNIPROT down-regulates phosphorylation Ser406 TRLRRTEsVPSDINN 9606 BTO:0000007 12105213 t gcesareni "Autophosphorylated recombinant nm23-h1 phosphorylated ksr in vitro. Using site-directed mutagenesis, we found that nm23-h1 phosphorylated ksr serine 392, a 14-3-3-binding site, consistent with the recent identification of c-tak1 as a kinase for this site." SIGNOR-90390 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 NUDCD2 protein Q8WVJ2 UNIPROT PAFAH1B1 protein P43034 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000567 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-252167 PTPRH protein Q9HD43 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-76084 PTPRJ protein Q12913 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 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-76092 olanzapine chemical CHEBI:7735 ChEBI HTR1A protein P08908 UNIPROT "up-regulates activity" "chemical activation" 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-258509 olanzapine chemical CHEBI:7735 ChEBI HTR1F protein P30939 UNIPROT "up-regulates activity" "chemical activation" 9534 BTO:0000298 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-258512 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 paliperidone chemical CHEBI:82978 ChEBI HTR1D protein P28221 UNIPROT "down-regulates activity" "chemical inhibition" 10116 BTO:0000529 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-258562 PAMPs stimulus SIGNOR-ST11 SIGNOR AIM2 protein O14862 UNIPROT "up-regulates activity" 16037825 f lperfetto "Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage" SIGNOR-256423 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 PDPK1 protein O15530 UNIPROT PRKCB protein P05771 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-126069 PDPK1 protein O15530 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr252 HDGTVTHtFCGTIEY 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-55306 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 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 Pentostatin chemical CID:439693 PUBCHEM ADA protein P00813 UNIPROT "down-regulates activity" "chemical inhibition" 9606 2433905 t miannu "2'-Chloropentostatin is a new inhibitor of adenosine deaminase isolated from the fermentation broth of an unidentified actinomycete, ATCC 39365. It contains the aglycone of coformycin, i.e. 3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-o1, coupled to the unusual carbohydrate, 2'-chloro-2'-deoxyribose. 2'-Chloropentostatin is a slightly weaker inhibitor of rat and human adenosine deaminases than coformycin, and considerably weaker than pentostatin. Unlike pentostatin, which appears to undergo a two-stage interaction with adenosine deaminase, 2'-chloropentostatin forms a single enzyme-inhibitor complex. The enzyme-inhibitor complex between adenosine deaminase and 2'-chloropentostatin was much more rapidly dissociable than the complex with pentostatin." SIGNOR-259261 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 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 POU5F1 protein Q01860 UNIPROT BMP4 protein P12644 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001086 17068183 f miannu "To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG." SIGNOR-254932 POU5F1 protein Q01860 UNIPROT HLX protein Q14774 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001086 17068183 f miannu "To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG." SIGNOR-254936 PPP2CA protein P67775 UNIPROT HDAC7 protein Q8WUI4 UNIPROT "up-regulates activity" dephosphorylation Ser155 FPLRKTVsEPNLKLR 9606 18339811 t "Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. |Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs.|we demonstrate that PP2A constitutively dephosphorylates the class IIa member HDAC7 to control its biological functions as a regulator of T cell apoptosis and endothelial cell functions." SIGNOR-248646 PRKACA protein P17612 UNIPROT APC protein P25054 UNIPROT "down-regulates activity" phosphorylation Ser2054 MPKKKKPsRLKGDNE 9606 BTO:0000007 11050185 t miannu "Changing a serine residue (Ser(2054)) to aspartic acid mutated the potential protein kinase A site adjacent to NLS2(APC), resulting in both inhibition of the NLS2(APC)-mediated nuclear import of a chimeric beta-galactosidase fusion protein and a reduction of full-length APC nuclear localization." SIGNOR-250335 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 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 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 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 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 SH3GLB1 protein Q9Y371 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 BTO:0000567 16227588 t gcesareni "Here, we provide evidence that bif-1 plays a regulatory role in apoptotic activation of not only bax but also bak and appears to be involved in suppression of tumorigenesis. while bif-1 did not directly interact with bak, it heterodimerized with bax on mitochondria in intact cells, and this interaction was enhanced by apoptosis induction and preceded the bax conformational change." SIGNOR-141166 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR 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-250553 FGF6 protein P10767 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-18570 PRKCD protein Q05655 UNIPROT CYTH1 protein Q15438 UNIPROT unknown phosphorylation Thr395 RKKKVSStKRH 9606 BTO:0001948 11438522 t lperfetto "We show here that a serine/threonine motif within the short polybasic stretch of cytohesin-1 is phosphorylated by purified protein kinase C delta in vitro. Furthermore, the respective residues are also found to be phosphorylated after phorbol ester stimulation in vivo. Biochemical and functional analyses show that phosphorylated cytohesin-1 is able to tightly associate with the actin cytoskeleton, and we further demonstrate that phosphorylation of the protein is required for maximal leukocyte function antigen-1-mediated adhesion of Jurkat cells to intercellular adhesion molecule 1. " SIGNOR-249099 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 PRKG1 protein Q13976 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser737 EPLERRLsLVPDSEQ 9606 1377674 t lperfetto "Direct amino acid sequencing and peptide mapping of cf-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by pka and pkgcftr possesses a large cluster of strict dibasic consensus sites for phosphorylation by protein kinase a (pka) in the r-domain and an obligatory dependence on phosphorylation is a hallmark of cftr cl(-) channel function" SIGNOR-18241 PRKG1 protein Q13976 UNIPROT PLCB3 protein Q01970 UNIPROT "down-regulates activity" phosphorylation Ser26 VETLRRGsKFIKWDE 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-249079 protriptyline chemical CHEBI:8597 ChEBI SLC6A2 protein P23975 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 9537821 t miannu "At the human norepinephrine transporter, among the antidepressants desipramine was the most potent with a KD=0.83±0.05 nM. All the tetracyclic antidepressants, except mirtazapine, which is a structural analog of mianserin, were more potent at the norepinephrine transporter than at the serotonin transporter. Tomoxetine, considered from animal data to be very selective for the norepinephrine transporter, had high affinity for the human norepinephrine transporter (KD=2.03±0.06 nM). However, at the human serotonin transporter, tomoxetine was nearly as potent and close to that for dothiepin and venlafaxine. Venlafaxine, considered a serotonin and norepinephrine re-uptake inhibitor based on animal data, was very weak at the human norepinephrine transporter. Its KD value was 5× less that than for norepinephrine. All of the serotonin selective re-uptake inhibitors, with the exception of paroxetine, were also weak at the human norepinephrine transporter." SIGNOR-258736 PTK2 protein Q05397 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr861 PIGNQHIyQPVGKPD 9606 BTO:0000671 15694384 t llicata "Once stimulated, fak undergoes autophosphorylation at tyrosine (y) 397, followed by phosphorylation of several sites including y576/y577 which increases fak's kinase activity, as well as at y407, y861, and y925." SIGNOR-133849 ADRA1D protein P25100 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-257191 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 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 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 PTPRF protein P10586 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 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-76009 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 quetiapine chemical CHEBI:8707 ChEBI HTR1D protein P28221 UNIPROT "up-regulates activity" "chemical activation" 10116 BTO:0000529 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-258535 RAD52 protein P43351 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 27649245 f lperfetto "Homologous recombination (HR) plays an important role in maintaining genomic integrity. It is responsible for repair of the most harmful DNA lesions, DNA double-strand breaks and inter-strand DNA cross-links. HR function is also essential for proper segregation of homologous chromosomes in meiosis, maintenance of telomeres, and resolving stalled replication forks. Defects in HR often lead to genetic diseases and cancer. Rad52 is one of the key HR proteins, which is evolutionarily conserved from yeast to humans| in mammals, Rad52 knockouts showed no significant DNA repair or recombination phenotype. |These new findings indicate an important backup role for Rad52, which complements the main HR mechanism in mammals." SIGNOR-251507 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 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT "up-regulates activity" phosphorylation Ser391 RSSMNNGsPTALSGS 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-249309 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 EYA1 protein Q99502 UNIPROT H2AFX protein P16104 UNIPROT down-regulates dephosphorylation Tyr143 ATQASQEy 9606 20965415 t gcesareni "Tyr142 is dephosphorylated by the tyr phosphatases eya1 and eya3." SIGNOR-168879 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT "up-regulates activity" phosphorylation Thr86 YTLSRAQtVVVEYTH 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-96759 ITSN1 protein Q15811 UNIPROT CDC42 protein P60953 UNIPROT up-regulates binding 9606 15824104 t gcesareni "Full-length intersectin-l exhibited little ability to stimulate nucleotide exchange on cdc42" SIGNOR-135377 MAPK14 protein Q16539 UNIPROT NFATC4 protein Q14934 UNIPROT "down-regulates activity" phosphorylation Ser168 QGGGAFFsPSPGSSS 10029 BTO:0001131 11997522 t miannu "P38 MAP kinase phosphorylates Ser168 and Ser170 of NFATc4. Mutational replacement of Ser168,170 with Ala promotes NFATc4 nuclear localization and increases NFATc4-mediated transcription activity." SIGNOR-250107 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT "up-regulates activity" phosphorylation Ser574 NSNSCRSsTTTCPEQ 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-249303 RPS6KA1 protein Q15418 UNIPROT PPP1R3A protein Q16821 UNIPROT "up-regulates activity" phosphorylation Ser46 PQPSRRGsDSSEDIY -1 10648825 t lperfetto "The protein G(M), which targets protein phosphatase 1 (PP1) to the glycogen particles and sarcoplasmic reticulum (SR) of striated muscles, is known to be phosphorylated at Ser48 and Ser67 in vitro by adenosine 3',5' cyclic monophosphate-dependent protein kinase (PKA) and at Ser48 by MAP kinase-activated protein kinase-1 (MAPKAP-K1, also called p90 RSK). The phosphorylation of Ser48 increases the rate at which the glycogen-associated PP1.G(M) complex dephosphorylates (activates) glycogen synthase, but the phosphorylation of Ser67 has the opposite effect, suppressing the activity of PP1 toward glycogen-bound substrates. " SIGNOR-249036 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 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 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 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT up-regulates phosphorylation Tyr1009 LDTSSVLyTAVQPNE 9606 1396585 t llicata "These data show that tyrosine phosphorylation of plc-gamma is dependent on autophosphorylation of the pdgf beta-receptor at tyr1009 and tyr1021." SIGNOR-18575 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 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 SGK3 protein Q96BR1 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-249135 SRC protein P12931 UNIPROT AFAP1 protein Q8N556 UNIPROT unknown phosphorylation Tyr94 SSLPEGYyEEAVPLS 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-246363 SRC protein P12931 UNIPROT HNRNPK protein P61978 UNIPROT down-regulates phosphorylation Tyr380 YAGGRGSyGDLGGPI 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-88915 sufentanil chemical CHEBI:9316 ChEBI OPRM1 protein P35372 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000246 21215785 t Luana "Experiments were conducted to obtain K(i)'s for 19 approved opioid drugs using a single binding assay in a cell membrane preparation expressing recombinant human MOR. The K(i) values obtained ranged from 0.1380 nM (sufentanil) to 12.486 μM (tramadol). " SIGNOR-257890 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 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 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT up-regulates phosphorylation Tyr1021 PNEGDNDyIIPLPDP 9606 1396585 t llicata "These data show that tyrosine phosphorylation of plc-gamma is dependent on autophosphorylation of the pdgf beta-receptor at tyr1009 and tyr1021." SIGNOR-18579 SIRT1 protein Q96EB6 UNIPROT RELA protein Q04206 UNIPROT "down-regulates activity" deacetylation Lys310 KRTYETFkSIMKKSP 9606 BTO:0002207 15152190 t gcesareni "SIRT1 physically interacts with the RelA/p65 subunit of NF-kappaB and inhibits transcription by deacetylating RelA/p65 at lysine 310." SIGNOR-238817 TBX2 protein Q13207 UNIPROT CDKN2A protein Q8N726 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 25211658 t lperfetto "TBX2 and TBX3 function as transcriptional repressors and both have been shown to inhibit myogenesis (Carlson et al, 2002; Zhu et al, 2014). Abnormal expression of TBX2 has been reported in several cancers including breast, pancreas, and melanoma, where it has been shown to drive proliferation (reviewed in Abrahams et al (2010)). As has been previously shown in other cell types, TBX2 was found to induce a downregulation of p14/19ARF and function as a direct repressor of p21 in RMS" SIGNOR-249594 TEAD proteinfamily SIGNOR-PF22 SIGNOR WWTR1 protein Q9GZV5 UNIPROT "up-regulates activity" binding 9606 23431053 t miannu "YAP/TAZ do not contain intrinsic DNA-binding domains but instead bind to the promoters of target genes by interacting with DNA-binding transcription factors. YAP/TAZ mainly bind to the transcription factors TEAD1–4 to regulate genes involved in cell proliferation and cell death" SIGNOR-230722 TMOD1 protein P28289 UNIPROT TPM3 protein P06753 UNIPROT "down-regulates activity" binding 9606 BTO:0000516 8002995 t irozzo "Tropomodulin is a 40.6-kDa protein that binds to one end of the rod-like tropomyosin and inhibits its cooperativity and binding to actin. [.] we demonstrate that it is the N-terminus of tropomyosin that interacts with tropomodulin. Among several tropomyosin isoforms tested, hTM5 encoded by the human gamma-tropomyosin gene has the highest affinity toward human erythrocyte tropomodulin." SIGNOR-259111 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 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 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 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 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 zotepine chemical CHEBI:32316 ChEBI HRH1 protein P35367 UNIPROT "down-regulates activity" "chemical inhibition" -1 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-258551 zotepine chemical CHEBI:32316 ChEBI HTR1E protein P28566 UNIPROT "down-regulates activity" "chemical inhibition" 9534 BTO:0000298 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-258557 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 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 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-256735 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 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 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 MAPK3 protein P27361 UNIPROT JAK2 protein O60674 UNIPROT down-regulates phosphorylation Ser523 GVSDVPTsPTLQRPT 9606 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-146747 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 EDNRA protein P25101 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-257253 EDNRB protein P24530 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-256781 F2RL1 protein P55085 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-257232 F2RL3 protein Q96RI0 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-256772 FFAR4 protein Q5NUL3 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-257420 FPR2 protein P25090 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-256745 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CCR3 protein P51677 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16604092 f miannu "Rosmarinic acid also inhibited TNF-alpha-induced phosphorylation and degradation of IkappaB-alpha, as well as nuclear translocation of NF-kappaB heterodimer induced by TNF-alpha. This suggests that rosmarinic acid downregulates the expression of CCL11 and CCR3 via the inhibition of NF-kappaB activation signaling." SIGNOR-254660 PAK1 protein Q13153 UNIPROT ILK protein Q13418 UNIPROT up-regulates phosphorylation Ser246 CPRLRIFsHPNVLPV 9606 17420447 t lperfetto "We found that pak1 phosphorylates ilk at threonine-173 and serine-246 in vitro and in vivo. together, these results suggest that ilk is a pak1 substrate, undergoes phosphorylation-dependent shuttling between the cell nucleus and cytoplasm, and interacts with gene-regulatory chromatin." SIGNOR-154303 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 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 GHSR protein Q92847 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-257167 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 GPR119 protein Q8TDV5 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-257241 GPR132 protein Q9UNW8 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-257275 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 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 PHLPP2 protein Q6ZVD8 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-237039 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser660 FSAERRNsILTETLH 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-21312 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 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 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 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 HTR1A protein P08908 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-256972 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 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 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 PTPN9 protein P43378 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 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-146680 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 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 LPAR4 protein Q99677 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-257057 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 melatonin smallmolecule CHEBI:16796 ChEBI MTNR1A protein P48039 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-257545 "Neuropeptide W-30" smallmolecule CHEBI:80256 ChEBI NPBWR1 protein P48145 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-257548 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 "Orexin A" smallmolecule CHEBI:80319 ChEBI HCRTR2 protein O43614 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-257511 P2RY13 protein Q9BPV8 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-257299 ASH2L protein Q9UBL3 UNIPROT GATA3 protein P23771 UNIPROT up-regulates binding 9606 BTO:0000150 25258321 t miannu "We identifiedgata3as the binding protein of ash2l. Ash2l was shown to potentiate the transcriptional activity ofgata3." SIGNOR-205312 TNFRSF17 protein Q02223 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 10903733 f miannu "Overexpression of bcma activates the p38 mapk" SIGNOR-79504 P2RY13 protein Q9BPV8 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-257027 "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 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 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA1B protein P35368 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-257451 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 S1PR3 protein Q99500 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-257330 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 somatostatin smallmolecule CHEBI:64628 ChEBI SSTR4 protein P31391 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-257584 ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT "up-regulates activity" phosphorylation Ser19 SHGSSACsQPHGSVT 9606 BTO:0000007 10973490 t lperfetto "Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to ir" SIGNOR-81391 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 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT "down-regulates activity" phosphorylation Thr5 tPRKTAAT -1 9139732 t llicata "In summary, we have shown evidence that CDK4-cyclin D1 phosphorylates Thr5, Ser249, Thr252, Thr356, Thr373, Ser788, Ser795, Ser807, Ser811, and Thr826 of pRB." SIGNOR-250762 TACR1 protein P25103 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-257161 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 UTS2R protein Q9UKP6 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-257426 UTS2R protein Q9UKP6 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-256779 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 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 CHRM5 protein P08912 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-257291 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 FBXW7 protein Q969H0 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity" ubiquitination 9606 SIGNOR-C135 20852628 t gcesareni "We now show that the F-box protein Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1. Whereas wild-type Fbw7 promoted c-Myc turnover in cells, an Fbw7 mutant lacking the F-box domain delayed it." SIGNOR-243545 CHRM5 protein P08912 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-257351 CHRM5 protein P08912 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-257009 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 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 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 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 MCHR2 protein Q969V1 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-257390 MCHR2 protein Q969V1 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-256795 MRGPRX2 protein Q96LB1 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-256787 IKBKB protein O14920 UNIPROT CDKN2A protein P42771 UNIPROT down-regulates phosphorylation Ser8 MEPAAGSsMEPSADW 9606 20152798 t lperfetto "Ikkbeta specifically binds to p16 and phosphorylates ser8 of p16 phosphorylation at ser8 of p16 brings about a significant loss of its cyclin-dependent kinase (cdk) 4-inhibitory activity" SIGNOR-163801 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 "lysophosphatidic acids" smallmolecule CHEBI:32957 ChEBI LPAR2 protein Q9HBW0 UNIPROT up-regulates binding 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 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 MYC protein P01106 UNIPROT up-regulates phosphorylation Thr58 KKFELLPtPPLSPSR 9534 BTO:0004055 8386367 t "Recently, we have demonstrated that Myc is an in vitro substrate for phosphorylation by mitogen-activated protein kinase (MAP kinases) at Ser-62" lperfetto "Transactivation of gene expression by myc is inhibited by mutation at the phosphorylation sites thr-58 and ser-62." SIGNOR-236250 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CD40 protein P25942 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19164127 f miannu "We found that upon TLR7 and TLR8 activation, JNK and NF-kappaB positively regulated the expression of CCR7, CD86, CD83, and CD40 and the production of IL-6 and IL-12p40." SIGNOR-254785 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CD80 protein P33681 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12860928 f miannu "Upon CD40 signaling, transcription of the CD80 gene is induced by the nuclear factor (NF)-kappaB transcription factor." SIGNOR-254783 CDK5 protein Q00535 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT "down-regulates activity" phosphorylation Thr668 ENLDLKLTPYKVLAT 9606 BTO:0000007 20513426 t miannu "Phosphorylation of Vps34 on Thr159 inhibits its interaction with Beclin 1. two additional amino acids in Vps34, Thr159 and Thr668, were found to be phosphorylated only after co-transfection with Cdk5/p25" SIGNOR-259811 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 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 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 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 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-259816 PIM1 protein P11309 UNIPROT SKP2 protein Q13309 UNIPROT "up-regulates activity" phosphorylation Thr417 WGIKCRLTLQKPSCL 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-259817 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 SKP2 protein Q13309 UNIPROT "up-regulates activity" phosphorylation Ser72 PPRKRLKsKGSDKDF 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-259819 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 MAPK7 protein Q13164 UNIPROT MAPK7 protein Q13164 UNIPROT "up-regulates activity" phosphorylation Ser731 DPLPPVFSGTPKGSG 9606 BTO:0000567 20667468 t miannu "Activated ERK5 undergoes autophosphorylation on its C-terminal half, necessary for maximal activation of ERK5 transcriptional activation. The Ser731 and Thr733 sites were previously shown to be ERK5 autophosphorylation sites in vitro and also in ERK5-overexpressing cells.Our data coincide with a recent study examining whole protein phosphorylation in HeLa cells arrested in G1 and mitotic phases [37] reported that Ser731 and Thr733, as well as Ser720, are phosphorylated in ERK5 during mitosis. We also identified two unreported ERK5 phosphorylation sites, Ser567 and Ser803." SIGNOR-259821 ATR protein Q13535 UNIPROT RPA2 protein P15927 UNIPROT unknown phosphorylation Ser33 GFGSPAPsQAEKKSR 9606 19843584 t llicata "Atr phosphorylates s33 in response to replication stress" SIGNOR-188666 NFKB1 protein P19838 UNIPROT TRAF1 protein Q13077 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9733516 f gcesareni "Thus, our data indicate that nf-kb controls the expression of traf1 and traf2 and c-iap1 and c-iap2" SIGNOR-59954 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 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser795 TASTRKVsLAPQANL 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-21320 MAPK7 protein Q13164 UNIPROT MAPK7 protein Q13164 UNIPROT "up-regulates activity" phosphorylation Thr733 LPPVFSGtPKGSGAG 9606 BTO:0000567 20667468 t miannu "Activated ERK5 undergoes autophosphorylation on its C-terminal half, necessary for maximal activation of ERK5 transcriptional activation. The Ser731 and Thr733 sites were previously shown to be ERK5 autophosphorylation sites in vitro and also in ERK5-overexpressing cells.Our data coincide with a recent study examining whole protein phosphorylation in HeLa cells arrested in G1 and mitotic phases [37] reported that Ser731 and Thr733, as well as Ser720, are phosphorylated in ERK5 during mitosis. We also identified two unreported ERK5 phosphorylation sites, Ser567 and Ser803." SIGNOR-259822 MAPK7 protein Q13164 UNIPROT MAPK7 protein Q13164 UNIPROT "up-regulates activity" phosphorylation Ser567 VLSDNDRsLLERWTR 9606 BTO:0000567 20667468 t miannu "Activated ERK5 undergoes autophosphorylation on its C-terminal half, necessary for maximal activation of ERK5 transcriptional activation. The Ser731 and Thr733 sites were previously shown to be ERK5 autophosphorylation sites in vitro and also in ERK5-overexpressing cells.Our data coincide with a recent study examining whole protein phosphorylation in HeLa cells arrested in G1 and mitotic phases [37] reported that Ser731 and Thr733, as well as Ser720, are phosphorylated in ERK5 during mitosis. We also identified two unreported ERK5 phosphorylation sites, Ser567 and Ser803." SIGNOR-259823 MAP2K5 protein Q13163 UNIPROT MAPK7 protein Q13164 UNIPROT "up-regulates activity" phosphorylation Thr219 AEHQYFMtEYVATRW 9606 BTO:0000567 20667468 t miannu "ERK5 is a member of the mitogen-activated protein kinase (MAPK) family that, after stimulation, is activated selectively by dual phosphorylation in the TEY motif by MAPK kinase 5 (MEK5). ERK5 is activated selectively by dual phosphorylation on Thr218 and Tyr220 in the TEY motif by its only upstream kinase, MEK5, a member of the MEK" SIGNOR-259824 MAP2K5 protein Q13163 UNIPROT MAPK7 protein Q13164 UNIPROT "up-regulates activity" phosphorylation Tyr221 HQYFMTEyVATRWYR 9606 BTO:0000567 20667468 t miannu "ERK5 is a member of the mitogen-activated protein kinase (MAPK) family that, after stimulation, is activated selectively by dual phosphorylation in the TEY motif by MAPK kinase 5 (MEK5). ERK5 is activated selectively by dual phosphorylation on Thr218 and Tyr220 in the TEY motif by its only upstream kinase, MEK5, a member of the MEK" SIGNOR-259825 MAPK7 protein Q13164 UNIPROT MAPK7 protein Q13164 UNIPROT "up-regulates activity" phosphorylation Ser803 QREIQMDsPMLLADL 9606 BTO:0000567 20667468 t miannu "Activated ERK5 undergoes autophosphorylation on its C-terminal half, necessary for maximal activation of ERK5 transcriptional activation. The Ser731 and Thr733 sites were previously shown to be ERK5 autophosphorylation sites in vitro and also in ERK5-overexpressing cells.Our data coincide with a recent study examining whole protein phosphorylation in HeLa cells arrested in G1 and mitotic phases [37] reported that Ser731 and Thr733, as well as Ser720, are phosphorylated in ERK5 during mitosis. We also identified two unreported ERK5 phosphorylation sites, Ser567 and Ser803." SIGNOR-259826 AURKA protein O14965 UNIPROT AR protein P10275 UNIPROT "up-regulates activity" phosphorylation Thr282 VPPAVRPTPCAPLAE 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-259827 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 PRKD1 protein Q15139 UNIPROT PKD2 protein Q13563 UNIPROT "up-regulates activity" phosphorylation Ser801 SSLPRPMSSRSFPRS 9606 BTO:0000007 20881056 t miannu "Here, we report the identification of a previously unrecognized phosphorylation site within the polycystin-2 C terminus (Ser801), and we demonstrate that it is phosphorylated by protein kinase D. Phosphorylation at this site was significantly increased in response to serum and epidermal growth factor stimulation.We confirmed previous studies showing that PC2 mediated Ca2+ release from the ER can be stimulated by ATP.Phosphorylation at Ser801 seems to be permissive for this activity without altering the subcellular localization nor homophilic and heterophilic (with PC1) interactions of wild-type PC2." SIGNOR-259829 CDK1 protein P06493 UNIPROT NINL protein Q9Y2I6 UNIPROT "up-regulates activity" phosphorylation Ser185 NRHSPSWSPDGRRRQ 9606 BTO:0000567 20890132 t miannu "In this study, we show that Nlp can be phosphorylated by cell cycle protein kinase Cdc2/cyclin B1. The phosphorylation sites of Nlp are mapped at Ser185 and Ser589. Interestingly, the Cdc2/cyclin B1 phosphorylation site Ser185 of Nlp is required for its recognition by PLK1, which enable Nlp depart from centrosomes to allow the establishment of a mitotic scaffold at the onset of mitosis ." SIGNOR-259830 CDK1 protein P06493 UNIPROT NINL protein Q9Y2I6 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser589 NRHSPSWSPDGRRRQ 9606 BTO:0000567 20890132 t miannu "In this study, we show that Nlp can be phosphorylated by cell cycle protein kinase Cdc2/cyclin B1. The phosphorylation sites of Nlp are mapped at Ser185 and Ser589. the phosphorylation at the site Ser589 by Cdc2/cyclin B1 plays an important role in Nlp protein stability probably due to its effect on protein degradation." SIGNOR-259831 CDK1 protein P06493 UNIPROT KMT5A protein Q9NQR1 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser100 SKIYSYMSPNKCSGM 9606 BTO:0000567 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 PRKCB protein P05771 UNIPROT PRKCB protein P05771 UNIPROT down-regulates phosphorylation Ser661 QNEFAGFsYTNPEFV 9606 10828076 t "The effect has been demonstrated using P05771-2" llicata "We found in preliminary studies that autophosphorylation at ser660 was enhanced in response to angiotensin ii and phorbol esters.2 this raises the possibility that initial translocation and activation of pkc result in further autophosphorylation, which then provides a further force for reverse translocation and signal termination." SIGNOR-77583 TAB2 protein Q9NYJ8 UNIPROT MAP3K7 protein O43318 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 14633987 t lperfetto "These results suggest that TAB2 and TAB3 function redundantly as mediators of TAK1 activation in IL-1 and TNF signal transduction." SIGNOR-119370 TFAP4 protein Q01664 UNIPROT HDAC1 protein Q13547 UNIPROT "up-regulates activity" binding 9606 BTO:0001109 19505873 t miannu "We also observed moderately increased recruitment of CTCF, HDAC1, and SP1 by the full-length AP-4 onto the WT DNA beads." SIGNOR-226590 TEK protein Q02763 UNIPROT TEK protein Q02763 UNIPROT "up-regulates activity" phosphorylation Tyr1108 TYVNTTLYEKFTYAG 9606 BTO:0001176 20973951 t miannu "This phosphorylation requires a kinase competent Tie2 as well as intact tyrosines 1100 and 1106 (Y1100 and Y1106) on the receptor. This suggests that Y1100 and Y1106 on Tie2 play a role in Grb14 mediated signal transduction downstream of this receptor." SIGNOR-259833 TEK protein Q02763 UNIPROT TEK protein Q02763 UNIPROT "up-regulates activity" phosphorylation Tyr1102 MLEERKTyVNTTLYE 9606 BTO:0001176 20973951 t miannu "This phosphorylation requires a kinase competent Tie2 as well as intact tyrosines 1100 and 1106 (Y1100 and Y1106) on the receptor. This suggests that Y1100 and Y1106 on Tie2 play a role in Grb14 mediated signal transduction downstream of this receptor." SIGNOR-259834 PRKACA protein P17612 UNIPROT RGS13 protein O14921 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr41 SFENLMATKYGPVVY BTO:0000007 20974683 t miannu "Phosphorylation of RGS13 by the cyclic AMP-dependent protein kinase inhibits RGS13 degradation.we show that PKA activation also leads to increased steady-state RGS13 expression through RGS13 phosphorylation, which inhibits RGS13 protein degradation. RGS13 phosphorylation was diminished by mutation of an N-terminal Thr residue (T41) identified as a phosphorylation site by mass spectrometry." SIGNOR-259835 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT "down-regulates activity" phosphorylation Ser788 PIPHIPRsPYKFPSS -1 9139732 t llicata "In summary, we have shown evidence that CDK4-cyclin D1 phosphorylates Thr5, Ser249, Thr252, Thr356, Thr373, Ser788, Ser795, Ser807, Ser811, and Thr826 of pRB." SIGNOR-250759 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 UBE2N protein P61088 UNIPROT TRAF2 protein Q12933 UNIPROT "up-regulates activity" ubiquitination 9606 BTO:0000785 14713952 t lperfetto "Intact ring and zinc finger domains are required for tnfalfa-induced traf2 ubiquitination, which is also dependent on ubc13. Traf2 ubiquitination coincides with its translocation to the insoluble cellular fraction, resulting in selective activation of jnk. Ubc13 expression by rnai resulted in tnfalfa-induced traf2 translocation and impaired activation of jnk but not of ikk or p38." SIGNOR-121274 ADAM10 protein O14672 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR "up-regulates activity" cleavage 9606 28624438 t miannu "One of the most important and best characterized ADAM10 substrates is the Notch receptor [16]. After ligand binding to the Notch receptor, ADAM10 liberates the ectodomain and the membrane remaining part is processed by the γ-secretase complex, which releases a Notch Intracellular Domain (NICD)." SIGNOR-259836 USF1 protein P22415 UNIPROT ADAM10 protein O14672 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 28624438 t miannu "The promoter region of ADAM10 contains several transcription factor binding sites that can stimulate its transcription. These include binding sites for transcription factors SP1 and USF, and the spliced form of the X-box binding protein (XBP)-1 as well as a retinoic acid-responsive element" SIGNOR-259837 ADAM10 protein O14672 UNIPROT NOTCH1 protein P46531 UNIPROT "up-regulates activity" cleavage 9606 BTO:0000782 28624438 t miannu "ADAM10-mediated Notch1 cleavage is the rate limiting-step for release of the NICD and subsequent activation of Notch1 signaling. In T cells ADAM10-mediated Notch1 shedding controls T cell development" SIGNOR-259838 ADAM10 protein O14672 UNIPROT BTC protein P35070 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-259839 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 ADAM17 protein P78536 UNIPROT TGFA protein P01135 UNIPROT "up-regulates activity" cleavage 9606 26284334 t miannu "ADAM17 is involved in the release and activation of several growth factors and cytokine receptor ligands. Among the growth factors activated by ADAM17 are TGF-alpha, amphiregulin, epiregulin and HB-EGF" SIGNOR-259841 ADAM17 protein P78536 UNIPROT AREG protein P15514 UNIPROT "up-regulates activity" cleavage 9606 26284334 t miannu "ADAM17 is involved in the release and activation of several growth factors and cytokine receptor ligands. Among the growth factors activated by ADAM17 are TGF-alpha, amphiregulin, epiregulin and HB-EGF" SIGNOR-259842 ADAM17 protein P78536 UNIPROT EREG protein O14944 UNIPROT "up-regulates activity" cleavage 9606 26284334 t miannu "ADAM17 is involved in the release and activation of several growth factors and cytokine receptor ligands. Among the growth factors activated by ADAM17 are TGF-alpha, amphiregulin, epiregulin and HB-EGF" SIGNOR-259843 ADAM17 protein P78536 UNIPROT HBEGF protein Q99075 UNIPROT "up-regulates activity" cleavage 9606 26284334 t miannu "ADAM17 is involved in the release and activation of several growth factors and cytokine receptor ligands. Among the growth factors activated by ADAM17 are TGF-alpha, amphiregulin, epiregulin and HB-EGF" SIGNOR-259844 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 ADAM10 protein O14672 UNIPROT CD44 protein P16070 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-259847 CDK7 protein P50613 UNIPROT MCM2 protein P49736 UNIPROT "up-regulates activity" phosphorylation S27 GNDPLTSSPGRSSRR 9606 BTO:0000567 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 S41 RTDALTSSPGRDLPP 9606 BTO:0000567 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 MCM2 protein P49736 UNIPROT "up-regulates activity" phosphorylation S139 RRGLLYDSDEEDEER 9606 BTO:0000567 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 XRN2 protein Q9H0D6 UNIPROT "up-regulates activity" phosphorylation T439 FTPSGILTPHALGSR 9606 BTO:0001109 26728557 t Luana "CDKs and Xrn2 phosphorylation promote transcription termination. | Cdk7 phosphorylated Xrn2-Thr439 but was less efficient than Cdk9. |" SIGNOR-259851 CDK7 protein P50613 UNIPROT RARG protein P13631 UNIPROT "up-regulates activity" phosphorylation S79 EMVPSSPSPPPPPRV 9534 BTO:0001538 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 AKT proteinfamily SIGNOR-PF24 SIGNOR NR4A1 protein P22736 UNIPROT "down-regulates activity" phosphorylation Ser351 GRRGRLPsKPKQPPD 9606 BTO:0000782 11274386 t lperfetto "We show that akt interacts with nur77 and inactivates nur77 by phosphorylation at ser-350" SIGNOR-105927 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT "down-regulates activity" phosphorylation Thr356 DSFETQRtPRKSNLD -1 9139732 t llicata "In summary, we have shown evidence that CDK4-cyclin D1 phosphorylates Thr5, Ser249, Thr252, Thr356, Thr373, Ser788, Ser795, Ser807, Ser811, and Thr826 of pRB." SIGNOR-250760 CDK7 protein P50613 UNIPROT RARG protein P13631 UNIPROT "up-regulates activity" phosphorylation S77 SEEMVPSSPSPPPPP 9534 BTO:0001538 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 Ptk2 protein P34152 UNIPROT SHC1 protein P29353 UNIPROT "up-regulates activity" phosphorylation Y317 ELFDDPSYVNVQNLD 9606 9566877 t Luana " In vitro, FAK directly phosphorylated Shc Tyr-317 to promote Grb2 binding. FAK can associate and directly phosphorylate Shc at Tyr-317 to promote Grb2 binding and low-level signaling to ERK2." SIGNOR-259854 STK38 protein Q15208 UNIPROT YAP1 protein P46937 UNIPROT "down-regulates activity" phosphorylation S127 PQHVRAHSSPASLQL 9606 BTO:0000038 25601544 t Luana "We show that mammalian NDR1/2 kinases phosphorylate YAP1 on S127 and thereby negatively regulate YAP1 activity in tissue-cultured cells." SIGNOR-259855 STK38 protein Q15208 UNIPROT YAP1 protein P46937 UNIPROT "down-regulates activity" phosphorylation S109 KSHSRQASTDAGTAG 9606 BTO:0000038 25601544 t Luana "We performed mass spectrometry to determine additional sites on YAP1 targeted by NDR, identifying three additional serines, namely S61, S109, and S164, to also be phosphorylated by NDR in vitro " SIGNOR-259856 PRKAA1 protein Q13131 UNIPROT GAPDH protein P04406 UNIPROT "up-regulates activity" phosphorylation S122 GAKRVIISAPSADAP 10090 BTO:0002572 26626483 t Luana " Under glucose starvation, but not amino acid starvation, cytoplasmic GAPDH is phosphorylated on Ser122 by activated AMPK. This causes GAPDH to redistribute into the nucleus. Inside the nucleus, GAPDH interacts directly with Sirt1, displacing Sirt1's repressor and causing Sirt1 to become activated. " SIGNOR-259857 PRKAA1 protein Q13131 UNIPROT CFTR protein P13569 UNIPROT "down-regulates activity" phosphorylation S737 EPLERRLSLVPDSEQ 9606 19095655 t Luana " We demonstrate that CFTR normally remains closed at baseline, but nevertheless, opens after inhibition of AMPK. AMPK phosphorylates CFTR in vitro at two essential serines (Ser737and Ser768) in the R domain, formerly identified as “inhibitory” PKA sites. Replacement of both serines by alanines (i) reduced phosphorylation of the R domain, with Ser768 having dramatically greater impact, (ii) produced CFTR channels that were partially open in the absence of any stimulation, (iii) significantly augmented their activation by IBMX/forskolin, and (iv) eliminated CFTR inhibition post AMPK activation." SIGNOR-259858 PRKAA1 protein Q13131 UNIPROT CDKN1B protein P46527 UNIPROT "up-regulates activity" phosphorylation T198 PGLRRRQT 10090 BTO:0005300 30033086 t Luana "P27Kip1-Mediated Cell Survival Is Dependent on AMPK-Specific Thr198 Phosphorylation" SIGNOR-259859 PRKAA1 protein Q13131 UNIPROT GLI1 protein P08151 UNIPROT "down-regulates activity" phosphorylation S408 GPLPRAPSISTVEPK 9606 BTO:0002181 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-259860 PRKAA1 protein Q13131 UNIPROT GLI1 protein P08151 UNIPROT "down-regulates activity" phosphorylation S102 LQTVIRTSPSSLVAF 9606 BTO:0002181 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 PRKAA1 protein Q13131 UNIPROT GLI1 protein P08151 UNIPROT "down-regulates activity" phosphorylation T1074 QRGSSGHTPPPSGPP 9606 BTO:0002181 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-259862 PRKAA1 protein Q13131 UNIPROT GLI1 protein P08151 UNIPROT "down-regulates activity" phosphorylation S408 GPLPRAPSISTVEPK 9606 BTO:0004328 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-259863 PRKAA1 protein Q13131 UNIPROT DDIT3 protein P35638 UNIPROT "down-regulates activity" phosphorylation S30 EDLQEVLSSDENGGT 10090 BTO:0003292 27650555 t Luana "Here, we report that phosphorylation of CHOP at Ser30 by AMPKα1 triggers CHOP degradation resulting in reduced macrophage apoptosis and subsequent ameliorated plaque vulnerability in vivo." SIGNOR-259864 PRKACA protein P17612 UNIPROT PRKAA1 protein Q13131 UNIPROT "down-regulates activity" phosphorylation S496 ATPQRSGSVSNYRSC 9606 BTO:0001949 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 PRKAA1 protein Q13131 UNIPROT PIAS1 protein O75925 UNIPROT "up-regulates activity" phosphorylation S510 SPVSRTPSLPAVDTS 9606 BTO:0004577 27256105 t Luana "Mechanically, we found that AMPKα1 directly phosphorylated protein inhibitor of activated STAT-1 (PIAS1), the SUMO E3-ligase of Runx2, at serine 510, to promote its SUMO E3-ligase activity. Finally, mutation of protein inhibitor of activated STAT-1 at serine 510 suppressed m" SIGNOR-259866 PRKAA1 protein Q13131 UNIPROT CFTR protein P13569 UNIPROT "down-regulates activity" phosphorylation S768 LQARRRQSVLNLMTH 9606 19095655 t Luana " We demonstrate that CFTR normally remains closed at baseline, but nevertheless, opens after inhibition of AMPK. AMPK phosphorylates CFTR in vitro at two essential serines (Ser737and Ser768) in the R domain, formerly identified as “inhibitory” PKA sites. Replacement of both serines by alanines (i) reduced phosphorylation of the R domain, with Ser768 having dramatically greater impact, (ii) produced CFTR channels that were partially open in the absence of any stimulation, (iii) significantly augmented their activation by IBMX/forskolin, and (iv) eliminated CFTR inhibition post AMPK activation." SIGNOR-259867 BCORL1 protein Q5H9F3 UNIPROT HDAC4 protein P56524 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 17379597 t irozzo "BCoR-L1 interacts with Class II HDACs, HDAC4, HDAC5, and HDAC7, suggesting that they are involved in its function as transcriptional corepressor." SIGNOR-259112 EIF2AK1 protein Q9BQI3 UNIPROT EIF2S1 protein P05198 UNIPROT up-regulates phosphorylation Ser49 IEGMILLsELSRRRI 9606 3352609 t lperfetto "The wild-type and ser-48 mutant proteins became extensively phosphorylated by eif-2 kinases present in the reticulocyte lysate. These findings support the hypothesis that the serine 48 residue is required for high-affinity interaction between eif2 alpha(p) and eif2b." SIGNOR-24539 IKBKB protein O14920 UNIPROT IKBKG protein Q9Y6K9 UNIPROT "down-regulates activity" phosphorylation Ser43 PAMLHLPsEQGAPET 9606 BTO:0000007 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 TLR5 protein O60602 UNIPROT IL6 protein P05231 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000727 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 ETS1 protein P14921 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 11175361 f miannu "Ets1 and Ets2 seem to play opposing roles in apoptosis. While Ets1 seems to activate pro-apoptotic pathways, Ets2 seems to inhibit apoptosis" SIGNOR-259869 ETS2 protein P15036 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 11175361 f miannu "Ets1 and Ets2 seem to play opposing roles in apoptosis. While Ets1 seems to activate pro-apoptotic pathways, Ets2 seems to inhibit apoptosis" SIGNOR-259870 ETS2 protein P15036 UNIPROT Macrophage_differentiation phenotype SIGNOR-PH99 SIGNOR up-regulates 9606 BTO:0004178 11175361 f miannu "the constitutive expression of ets2 in myeloblast leukemic cells induces their differentiation to macrophages" SIGNOR-259871 ETS2 protein P15036 UNIPROT SPP1 protein P10451 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 10090 BTO:0001957 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 activation" 10090 BTO:0001957 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 ETS2 protein P15036 UNIPROT SPARC protein P09486 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 10090 BTO:0001957 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 BGLAP protein P02818 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 10090 BTO:0001957 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 OPTN protein Q96CV9 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 10090 BTO:0005118 22194658 f "same result in PC12 cell" miannu "SiRNA effectively downregulated optineurin expression in RGC-5 and PC12 stable transfected cells. Optineurin siRNA significantly inhibited cell growth and increased apoptosis in RGC-5 and PC12 cells. Microarray analysis identified 112 differentially expressed genes in optineurin siRNA transfected RGC-5 cells. Quantitative real-time PCR and western blot confirmed that the expression of brain-derived neurotrophic factor (Bdnf), neurotrophin-3(Ntf3), synaptosomal-associated protein 25(Snap25), and neurofilament, light polypeptide(Nefl) was significantly downregulated in RGC-5 and PC12 cells transfected with optineurin siRNA." SIGNOR-259876 OPTN protein Q96CV9 UNIPROT Cell_growth phenotype SIGNOR-PH33 SIGNOR up-regulates 10090 BTO:0005118 22194658 f "same result in PC12 cell" miannu "SiRNA effectively downregulated optineurin expression in RGC-5 and PC12 stable transfected cells. Optineurin siRNA significantly inhibited cell growth and increased apoptosis in RGC-5 and PC12 cells. Microarray analysis identified 112 differentially expressed genes in optineurin siRNA transfected RGC-5 cells. Quantitative real-time PCR and western blot confirmed that the expression of brain-derived neurotrophic factor (Bdnf), neurotrophin-3(Ntf3), synaptosomal-associated protein 25(Snap25), and neurofilament, light polypeptide(Nefl) was significantly downregulated in RGC-5 and PC12 cells transfected with optineurin siRNA." SIGNOR-259877 OPTN protein Q96CV9 UNIPROT BDNF protein P23560 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 10090 BTO:0005118 22194658 f "same result in PC12 cell" miannu "SiRNA effectively downregulated optineurin expression in RGC-5 and PC12 stable transfected cells. Optineurin siRNA significantly inhibited cell growth and increased apoptosis in RGC-5 and PC12 cells. Microarray analysis identified 112 differentially expressed genes in optineurin siRNA transfected RGC-5 cells. Quantitative real-time PCR and western blot confirmed that the expression of brain-derived neurotrophic factor (Bdnf), neurotrophin-3(Ntf3), synaptosomal-associated protein 25(Snap25), and neurofilament, light polypeptide(Nefl) was significantly downregulated in RGC-5 and PC12 cells transfected with optineurin siRNA." SIGNOR-259878 OPTN protein Q96CV9 UNIPROT NTF3 protein P20783 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 10090 BTO:0005118 22194658 f "same result in PC12 cell" miannu "SiRNA effectively downregulated optineurin expression in RGC-5 and PC12 stable transfected cells. Optineurin siRNA significantly inhibited cell growth and increased apoptosis in RGC-5 and PC12 cells. Microarray analysis identified 112 differentially expressed genes in optineurin siRNA transfected RGC-5 cells. Quantitative real-time PCR and western blot confirmed that the expression of brain-derived neurotrophic factor (Bdnf), neurotrophin-3(Ntf3), synaptosomal-associated protein 25(Snap25), and neurofilament, light polypeptide(Nefl) was significantly downregulated in RGC-5 and PC12 cells transfected with optineurin siRNA." SIGNOR-259879 WNT8A protein Q9H1J5 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-131984 OPTN protein Q96CV9 UNIPROT SNAP25 protein P60880 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 10090 BTO:0005118 22194658 f "same result in PC12 cell" miannu "SiRNA effectively downregulated optineurin expression in RGC-5 and PC12 stable transfected cells. Optineurin siRNA significantly inhibited cell growth and increased apoptosis in RGC-5 and PC12 cells. Microarray analysis identified 112 differentially expressed genes in optineurin siRNA transfected RGC-5 cells. Quantitative real-time PCR and western blot confirmed that the expression of brain-derived neurotrophic factor (Bdnf), neurotrophin-3(Ntf3), synaptosomal-associated protein 25(Snap25), and neurofilament, light polypeptide(Nefl) was significantly downregulated in RGC-5 and PC12 cells transfected with optineurin siRNA." SIGNOR-259880 OPTN protein Q96CV9 UNIPROT NEFL protein P07196 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 10090 BTO:0005118 22194658 f "same result in PC12 cell" miannu "SiRNA effectively downregulated optineurin expression in RGC-5 and PC12 stable transfected cells. Optineurin siRNA significantly inhibited cell growth and increased apoptosis in RGC-5 and PC12 cells. Microarray analysis identified 112 differentially expressed genes in optineurin siRNA transfected RGC-5 cells. Quantitative real-time PCR and western blot confirmed that the expression of brain-derived neurotrophic factor (Bdnf), neurotrophin-3(Ntf3), synaptosomal-associated protein 25(Snap25), and neurofilament, light polypeptide(Nefl) was significantly downregulated in RGC-5 and PC12 cells transfected with optineurin siRNA." SIGNOR-259881 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 IKBKB protein O14920 UNIPROT IKBKG protein Q9Y6K9 UNIPROT "down-regulates activity" phosphorylation Ser68 LRDAIRQsNQILRER 9606 BTO:0000007 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 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 "ado-trastuzumab emtansine" antibody DB05773 DRUGBANK ERBB2 protein P04626 UNIPROT "down-regulates activity" binding 9606 BTO:0000150 19010901 t miannu "The anatomy of an antibody–cytotoxic drug conjugate can be divided into three general components: the antibody, the linker, and the cytotoxic drug. The efficacy of any such conjugate is dictated in part by the differential expression of the target antigen in tumor versus normal tissue. HER2 is a clinically validated target for the treatment of breast cancer. Trastuzumab and, more recently, lapatinib are approved for clinical use in women whose breast cancer overexpresses HER2. a trastuzumab conjugate, which simply uses HER2 as an address for the delivery of a potent cytotoxic agent, may offer promise as an effective therapeutic modality." SIGNOR-259882 alemtuzumab antibody DB00087 DRUGBANK CD52 protein P31358 UNIPROT "down-regulates activity" binding 9606 BTO:0000782;BTO:0000776 15757437 t miannu "Alemtuzumab is a humanized monoclonal antibody against CD52, a small glycosylphosphatidylinositol-anchored glycoprotein that is highly expressed on normal T- and B-lymphocytes, and on a large proportion of malignant lymphoid cells, but not on hematopoietic progenitor cells." SIGNOR-259883 bevacizumab antibody DB00112 DRUGBANK VEGFA protein P15692 UNIPROT "down-regulates activity" binding 9606 BTO:0001615 15961063 t miannu "Clinical trials with VEGF inhibitors in a variety of malignancies are ongoing. Recently, a humanized anti-VEGF monoclonal antibody (bevacizumab; Avastin) has been approved by the FDA as a first-line treatment for metastatic colorectal cancer in combination with chemotherapy." SIGNOR-259884 bevacizumab antibody DB00112 DRUGBANK VEGFB protein P49765 UNIPROT "down-regulates activity" binding 9606 BTO:0001615 15961063 t miannu "Clinical trials with VEGF inhibitors in a variety of malignancies are ongoing. Recently, a humanized anti-VEGF monoclonal antibody (bevacizumab; Avastin) has been approved by the FDA as a first-line treatment for metastatic colorectal cancer in combination with chemotherapy." SIGNOR-259885 bevacizumab antibody DB00112 DRUGBANK VEGFC protein P49767 UNIPROT "down-regulates activity" binding 9606 BTO:0001615 15961063 t miannu "Clinical trials with VEGF inhibitors in a variety of malignancies are ongoing. Recently, a humanized anti-VEGF monoclonal antibody (bevacizumab; Avastin) has been approved by the FDA as a first-line treatment for metastatic colorectal cancer in combination with chemotherapy." SIGNOR-259886 bevacizumab antibody DB00112 DRUGBANK VEGFD protein O43915 UNIPROT "down-regulates activity" binding 9606 BTO:0001615 15961063 t miannu "Clinical trials with VEGF inhibitors in a variety of malignancies are ongoing. Recently, a humanized anti-VEGF monoclonal antibody (bevacizumab; Avastin) has been approved by the FDA as a first-line treatment for metastatic colorectal cancer in combination with chemotherapy." SIGNOR-259887 blinatumomab antibody DB09052 DRUGBANK CD19 protein P15391 UNIPROT "down-regulates activity" binding 9606 BTO:0000731 25883042 t miannu "Blinatumomab, a bispecific antibody construct targeting CD19, is the most advanced member of bispecific T-cell engager (BiTE®) molecules.Blinatumomab recently gained approval in the United States by the U.S. Food and Drug Administration for treatment of Philadelphia chromosome-negative B-precursor relapsed/refractory acute lymphoblastic leukemia." SIGNOR-259888 blinatumomab antibody DB09052 DRUGBANK CD33 protein P20138 UNIPROT "down-regulates activity" binding 9606 BTO:0001545 25883042 t miannu "Blinatumomab, a bispecific antibody construct targeting CD19, is the most advanced member of bispecific T-cell engager (BiTE®) molecules. all data strongly suggest CD33 as a suitable target antigen for BiTE® therapy in AML." SIGNOR-259889 cetuximab antibody DB00002 DRUGBANK EGFR protein P00533 UNIPROT "down-regulates activity" binding 9606 BTO:0001615 16336752 t miannu "Cetuximab binds to domain III of EGFR and hinders ligand binding. It is now approved by the US Food and Drug Administration for metastatic colorectal cancer treatment." SIGNOR-259890 denosumab antibody DB06643 DRUGBANK TNFSF11 protein O14788 UNIPROT "down-regulates activity" binding 9606 BTO:0000372 18685421 t miannu "Denosumab, a novel, fully human monoclonal antibody specific to RANKL, suppresses bone resorption markers in patients with a variety of metastatic tumors and is being investigated in multiple clinical trials for the prevention and treatment of bone metastases." SIGNOR-259891 "gemtuzumab ozogamicin" antibody DB00056 DRUGBANK CD33 protein P20138 UNIPROT "down-regulates activity" binding 9606 BTO:0001545 11410481 t miannu "Gemtuzumab ozogamicin (Mylotarg; Wyeth Laboratories, Philadelphia, PA) consists of a semisynthetic derivative of calicheamicin, a cytotoxic antibiotic linked to a recombinant monoclonal antibody directed against the CD33 antigen present on leukemic myeloblasts in most patients with acute myeloid leukemia (AML)." SIGNOR-259892 "ibritumomab tiuxetan" antibody DB00078 DRUGBANK MS4A1 protein P11836 UNIPROT "down-regulates activity" binding 9606 BTO:0002846 27497027 t miannu "Zevalin® (ibritumomab tiuxetan) is a radioactive drug product, which is the combination of a β-emitting isotope, 90Y, linked to the anti-CD20 monoclonal antibody (mAb), rituximab. It has demonstrated therapeutic efficacy with durable responses and allows delivery of ionizing radiation directly to the tumor site, while minimizing toxicity to normal tissue. Ibritumomab tiuxetan is indicated for treatment of patients with relapsed or refractory low-grade, follicular NHL" SIGNOR-259893 ipilimumab antibody DB06186 DRUGBANK CTLA4 protein P16410 UNIPROT "down-regulates activity" binding 9606 BTO:0005594 18049334 t miannu "The inhibitory receptor CTLA4 has a key role in peripheral tolerance of T cells for both normal and tumor-associated antigens. CTLA4 blockade with ipilimumab induces cancer regression in some patients with metastatic clear cell renal cancer, even if they have not responded to other immunotherapies." SIGNOR-259894 nivolumab antibody DB09035 DRUGBANK PDCD1 protein Q15116 UNIPROT "down-regulates activity" binding 9606 BTO:0001023 26351349 t miannu "Nivolumab is an anti-PD-1 antibody that blocks PD-1 signaling. We assessed the safety and antitumor activity of nivolumab in patients with platinum-resistant ovarian cancer." SIGNOR-259895 obinutuzumab antibody DB08935 DRUGBANK MS4A1 protein P11836 UNIPROT "down-regulates activity" binding 9606 BTO:0001546;BTO:0004656 28584136 t miannu "Obinutuzumab (OBZ) is a recombinant type II anti-CD20 and immunoglobulin G1 Fc-optimized monoclonal antibody (mAb), recently approved in chronic lymphocytic leukemia (CLL; B-cell CLL) and follicular lymphoma (FL)." SIGNOR-259896 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 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 PHLPP2 protein Q6ZVD8 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-237051 PIM2 protein Q9P1W9 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 10837473 t gcesareni "Similar to pim1, pim2 phosphorylates bad, which antagonizes the pro-apoptotic function of bax" SIGNOR-78015 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 ofatumumab antibody DB06650 DRUGBANK MS4A1 protein P11836 UNIPROT "down-regulates activity" binding 9606 BTO:0001546 28580841 t miannu "Ofatumumab is a human IgG1κ monoclonal antibody that binds to a membrane-proximal epitope of CD20 molecule expressed on the surface of B lymphocytes. Ofatumumab, the second-generation anti-CD20 antibody, induces cell lysis through complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity. Ofatumumab is approved as monotherapy and in combination with chlorambucil for the treatment of fludarabine- and alemtuzumab-refractory CLL patients and previously untreated CLL patients, respectively." SIGNOR-259897 panitumumab antibody DB01269 DRUGBANK EGFR protein P00533 UNIPROT "down-regulates activity" binding 9606 BTO:0000176 11255078 t miannu "ABX-EGF binds EGFr with high affinity (5x10(-11) M), blocks the binding of both EGF and transforming growth factor-alpha (TGF-alpha) to various EGFr-expressing human carcinoma cell lines, and inhibits EGF-dependent tumor cell activation, including EGFr tyrosine phosphorylation, increased extracellular acidification rate, and cell proliferation. Being a fully human antibody, ABX-EGF is anticipated to exhibit a long serum half-life and minimal immunogenicity with repeated administration, even in immunocompetent patients. These results demonstrate the potent anti-tumor activity of ABX-EGF and its therapeutic potential for the treatment of multiple human solid tumors that overexpress EGFr." SIGNOR-259898 pembrolizumab antibody DB09037 DRUGBANK PDCD1 protein Q15116 UNIPROT "down-regulates activity" binding 9606 "BTO:0000848; BTO:0002058" 25685857 t miannu "Preclinical studies described PD-1 blockade resulting in tumor growth suppression and even decreased metastasis. This has led to the development of pembrolizumab (MK-3475), a highly selective, humanized monoclonal IgG4-kappa isotype antibody against PD-1. Early clinical trials have shown high tumor response rates and long duration of effect in previously treated advanced melanoma resulting in accelerated FDA approval for the drug in this situation. Pembrolizumab has also had success in non-small cell lung cancer and is being tested in multiple other tumor types." SIGNOR-259899 pertuzumab antibody DB06366 DRUGBANK ERBB2 protein P04626 UNIPROT "down-regulates activity" binding 9606 BTO:0000176 15093539 t miannu "Pertuzumab binds to ErbB2 near the center of domain II, sterically blocking a binding pocket necessary for receptor dimerization and signaling." SIGNOR-259900 ramucirumab antibody DB05578 DRUGBANK KDR protein P35968 UNIPROT "down-regulates activity" binding 27217518 9606 BTO:0002058 28395526 t miannu "Ramucirumab (Cyramza), an anti-angionenic agent was approved in 2014 for treatment of several malignancies, including second-line treatment of patients with NSCLC with disease progression on or after platinum-based chemotherapy. Ramucirumab, an anti-VEGFR2 agent, combined with docetaxel, was FDA-approved for NSCLC patients." SIGNOR-259901 rituximab antibody DB00073 DRUGBANK MS4A1 protein P11836 UNIPROT "down-regulates activity" binding 9606 BTO:0001546 20350663 t miannu "Rituximab is a class I chimeric anti-CD20 antibody that has shown efficacy in chronic lymphocytic leukemia (CLL), both as a single agent and in combination with traditional chemotherapies." SIGNOR-259902 "tositumomab and iodine i 131 tositumomab" antibody DB00081 DRUGBANK MS4A1 protein P11836 UNIPROT "down-regulates activity" binding 9606 BTO:0001690 14748653 t miannu "Tositumomab is an immunoglobulin G murine monoclonal antibody that binds to the CD20 antigen on the surface of normal and malignant human B-cells. Tositumomab is linked covalently with iodine-131 to produce the radioimmunoconjugate iodine-131 tositumomab (Bexxar). The iodine-131 tositumomab regimen was approved by the US Food and Drug Administration in June 2003 for the treatment of patients with CD20-positive, follicular non-Hodgkin's lymphoma, both with and without transformation, whose disease is refractory to rituximab (Rituxan) and has relapsed following chemotherapy." SIGNOR-259903 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 INS protein P01308 UNIPROT DUSP6 protein Q16828 UNIPROT down-regulates 9606 22521266 f gcesareni "In conclusion,insulinlikely promotes mkp-3 protein degradation" SIGNOR-197203 YBX1 protein P67809 UNIPROT ABCB1 protein P08183 UNIPROT "down-regulates quantity by repression" "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-255614 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 KTN1 protein Q86UP2 UNIPROT EGFR protein P00533 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0001289 30683916 f miannu "Collectively, our findings revealed a novel mechanism wherein MALAT1 interacts with c-MYC to transactivate KTN1 for enhancing EGFR protein expression, which finally contributes to the development of cSCC." SIGNOR-259906 ZNRD1 protein Q9P1U0 UNIPROT ABCB1 protein P08183 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 16373708 f miannu "ZNRD1 could significantly up-regulate the expression of P-gp, Bcl-2, and the transcription of the MDR1 gene but not alter the expression of MDR-associated protein, glutathione S-transferase activity, or intracellular glutathione content in leukemia cells." SIGNOR-259907 ZNRD1 protein Q9P1U0 UNIPROT BCL2 protein P10415 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 16373708 f miannu "ZNRD1 could significantly up-regulate the expression of P-gp, Bcl-2, and the transcription of the MDR1 gene but not alter the expression of MDR-associated protein, glutathione S-transferase activity, or intracellular glutathione content in leukemia cells." SIGNOR-259908 AHR protein P35869 UNIPROT CYP1A1 protein P04798 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 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 ARNT protein P27540 UNIPROT CYP1A1 protein P04798 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 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-259910 AIP protein O00170 UNIPROT TFF1 protein P04155 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9606 BTO:0000093 21984905 t miannu "We show that XAP2 is recruited to the promoter of ERα regulated genes like the breast cancer marker gene pS2 or GREB1 and negatively regulate the expression of these genes in MCF-7 cells." SIGNOR-259911 GAB1 protein Q13480 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 11043767 t lperfetto "We have shown that gab1 colocalizes pi3k with sh2 domain-containing inositol phosphatase (ship) and shp2, two enzymes that regulate pi3k-dependent signaling. The src homology 2 (sh2) domain of the phosphatidylinositol 3-kinase (pi3k) regulatory subunit binds gab1 in a phosphorylation-independent manner. Moreover, the regulatory subunit of pi3k can mediate the association of gab1 and receptor protein-tyrosine kinases including the insulin, egf, and ngf receptors, all of which phosphorylate gab1." SIGNOR-83343 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 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 RASSF1 protein Q9NS23 UNIPROT STK3 protein Q13188 UNIPROT up-regulates binding 9606 21808241 t "Mst1/2 are pro-apoptotic kinases that are activated by caspase cleavage" milica "Mst1/2 is also activated by binding to Ras association domain family (RASSF) proteins, possibly owing to alteration of Mst1/2 subcellular localization." SIGNOR-175790 "sphingosine 1-phosphate" smallmolecule CHEBI:37550 ChEBI S1PR1 protein P21453 UNIPROT up-regulates binding 9606 16794003 t gcesareni "The evidence suggests that s1p acting on s1p receptors coupled to gq" SIGNOR-147227 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 PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Tyr95 KFPECGFyGMYDKIL 9606 17804414 t llicata "Critical for the regulation of pkd1 activity in response to oxidative stress are src- and abl-mediated tyrosine phosphorylations that eventually lead to protein kinase cdelta (pkcdelta)-mediated activation of pkd1. our data suggest that pkd1 phosphorylation at tyr95 generates a binding motif for pkcdelta, and that oxidative stress-mediated pkcdelta/pkd interaction results in pkd1 activation loop phosphorylation and activation." SIGNOR-157716 STK11 protein Q15831 UNIPROT PTEN protein P60484 UNIPROT "down-regulates activity" phosphorylation Thr383 HYRYSDTtDSDPENE 9606 18321849 t gcesareni "The C-terminal tail of PTEN is also the target of mutations in tumors. As mentioned, this region contains the main phosphorylation sites mapped to residues Ser362, Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385, and the kinases involved are casein kinase 2 (CK2), GSK3_, LKB1, and MAST.84,97-101 The phosphorylation of the tail has been shown to enhance PTEN stability but at the same time decrease its phosphatase activity" SIGNOR-161126 CAMK2G protein Q13555 UNIPROT GRIA1 protein P42261 UNIPROT "up-regulates activity" phosphorylation Ser645 LTVERMVsPIESAED BTO:0000007 7877986 t llicata "In this study, CaM-kinase II enhanced kainate currents of expressed glutamate receptor 6 in 293 cells and of wild-type glutamate receptor 1, but not the Ser-627 to Ala mutant, in Xenopus oocytes. | This CaM-kinase II regulatory phosphorylation site is conserved in all AMPA/kainate-type glutamate receptors, and its phosphorylation may be important in enhancing postsynaptic responsiveness as occurs during synaptic plasticity." SIGNOR-250697 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 TRAF2 protein Q12933 UNIPROT UBE2N protein P61088 UNIPROT "up-regulates activity" binding 9606 BTO:0000459 18635759 t lperfetto "Traf2, ubc13, and ikkgamma were required for complex assembly and activation of mekk1 and mapk cascades." SIGNOR-179479 "imatinib methanesulfonate" chemical CHEBI:31690 ChEBI ABL1 protein P00519 UNIPROT down-regulates "chemical inhibition" 9606 Other t "Selleck;VIRAL ABL" gcesareni SIGNOR-193387 MMP2 protein P08253 UNIPROT LAMC2 protein Q13753 UNIPROT "up-regulates activity" cleavage 9211848 t lperfetto "Induction of Cell Migration by Matrix Metalloprotease-2 Cleavage of Laminin-5|MMP2 cleaved the Ln-5 gamma2 subunit at residue 587, exposing a putative cryptic promigratory site on Ln-5 that triggers cell motility. This altered form of Ln-5 is found in tumors and in tissues undergoing remodeling, but not in quiescent tissues. Cleavage of Ln-5 by MMP2 and the resulting activation of the Ln-5 cryptic site may provide new targets for modulation of tumor cell invasion and tissue remodeling." SIGNOR-253240 MMP2 protein P08253 UNIPROT TGFB1 protein P01137 UNIPROT up-regulates cleavage 9606 10652271 t gcesareni "We also demonstrate that mmp-9, as well as its relative, mmp-2, cleave latent transforming growth factor-beta (tgf-beta), which constitutes a novel mechanism of tgf-beta activation" SIGNOR-74384 MMP3 protein P08254 UNIPROT HBEGF protein Q99075 UNIPROT up-regulates cleavage 9606 BTO:0000150 11043579 t gcesareni "It was concluded that mmp-3 cleaves hb-egf at a specific site in the jm domain and that this enzyme might regulate the conversion of hb-egf from being a juxtacrine to a paracrine/autocrine growth factor." SIGNOR-83339 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 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR LTC4S protein Q16873 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001433 12574384 f miannu "activation of NF-kappaB and p50/p65 overexpression down-regulated the LTC(4) synthase gene. LPS down-regulates cysteinyl LT release and LTC(4) synthase gene expression in mononuclear phagocytes by an NF-kappaB-mediated mechanism." SIGNOR-254799 PTPRA protein P18433 UNIPROT KCNB1 protein Q14721 UNIPROT down-regulates dephosphorylation 9606 16870705 t gcesareni "Ptpalpha inhibits kv channels more strongly than ptpepsilon;this correlates with constitutive association of ptpalpha with kv2.1, driven by membranal localization of ptpalpha." SIGNOR-148301 ROCK1 protein Q13464 UNIPROT DES protein P17661 UNIPROT down-regulates phosphorylation Thr17 RVSSYRRtFGGAPGF -1 12686604 t lperfetto "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. Rho-kinase was found to phosphorylate desmin at Thr-16, Thr-75, and Thr-76" SIGNOR-100177 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 SNIP1 protein Q8TAD8 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates binding 9606 SIGNOR-C6 10887155 t gcesareni "In this study, we characterize a novel nuclear protein, termed snip1 its principal mechanism of action appears to be through transcription by binding to cbp/p300 and interfering with the ability of these coactivators to interact with smad4" SIGNOR-78984 STK3 protein Q13188 UNIPROT MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation Thr12 FSSRSSKtFKPKKNI 9606 23431053 t milica "Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity" SIGNOR-201282 STK4 protein Q13043 UNIPROT MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation Thr35 LLKHAEAtLGSGNLR 9606 23431053 t milica "Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity" SIGNOR-201310 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 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 LHX3 protein Q9UBR4 UNIPROT ISL1 protein P61371 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 9452425 t miannu "the Lhx3-Isl1 C terminus interaction was dependent on the LIM domains of Lhx3. The combinatorial expression of the LIM homeodomain proteins Isl1, Isl2, Lhx1, and Lhx3 in subsets of developing motor neurons correlates with the future organization of these neurons into motor columns with distinct innervation targets, implying a functional role for LIM homeodomain protein combinations in the specification of neuronal identity" SIGNOR-220169 ANKLE2 protein Q86XL3 UNIPROT VRK1 protein Q99986 UNIPROT down-regulates 9606 22770216 f miannu "Lem4 inhibits the activity of baf's kinase vrk-1 during mitotic exit" SIGNOR-198103 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 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 PELI2 protein Q9HAT8 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates ubiquitination 9606 17997719 t gcesareni "These studies suggest that pellino isoforms may be the e3 ubiquitin ligases that mediate the il-1-stimulated formation of k63-pub-irak1 in cells, which may contribute to the activation of ikkbeta and the transcription factor nf-kappab, as well as other pathways dependent on irak1/4." SIGNOR-159058 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 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 PSTPIP1 protein O43586 UNIPROT ABL1 protein P00519 UNIPROT down-regulates 9606 11163214 f lperfetto "Cytoskeletal protein pstpip1 directs the pest-type protein tyrosine phosphatase to the c-abl kinase to mediate abl dephosphorylationSeveral experiments suggest that the PEST-type PTPs negatively regulate c-Abl activity" SIGNOR-105035 PTK2 protein Q05397 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr577 YMEDSTYyKASKGKL 9606 7529876 t llicata "We found that maximal kinase activity of fak immune complexes requires phosphorylation of both tyrosines 576 and 577. Our results indicate that phosphorylation of fak by src (or other src family kinases) is an important step in the formation of an active signaling complex." SIGNOR-27879 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 STK3 protein Q13188 UNIPROT MOB1B protein Q7L9L4 UNIPROT up-regulates phosphorylation Thr12 FGSRSSKtFKPKKNI 9606 23431053 t milica "Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity" SIGNOR-201290 STK3 protein Q13188 UNIPROT MOB1B protein Q7L9L4 UNIPROT up-regulates phosphorylation Thr35 LLKHAEAtLGSGNLR 9606 23431053 t milica "Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity" SIGNOR-201294 STK4 protein Q13043 UNIPROT MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation Thr12 FSSRSSKtFKPKKNI 9606 23431053 t milica "Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity" SIGNOR-201306 STK4 protein Q13043 UNIPROT MOB1B protein Q7L9L4 UNIPROT up-regulates phosphorylation Thr12 FGSRSSKtFKPKKNI 9606 23431053 t milica "Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity" SIGNOR-201314 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA1 protein Q15418 UNIPROT "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-250556 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 VHL protein P40337 UNIPROT HIF1A protein Q16665 UNIPROT down-regulates ubiquitination 9606 10944113 t miannu "Here we show that the product of the von hippel-lindau (vhl) tumor suppressor gene mediated ubiquitylation and proteasomal degradation of hif-1 alpha under normoxic conditions via interaction with the core of the oxygen-dependent degradation domain of hif-1 alpha." SIGNOR-80969 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 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 LATS1 protein O95835 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates phosphorylation Ser89 AQHVRSHsSPASLQL 9606 22658639 t "Together,the YAP/TAZ-TEAD complex promotes proliferative and survival programs." 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-197643 LATS2 protein Q9NRM7 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser127 PQHVRAHsSPASLQL 9606 22658639 t "Uninhibited YAP/TAZ localize to the nucleus where they serve as coactivators for the TEA-domain family member (TEAD) of DNA-binding transcription factors." 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-197655 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser447 GSPRTPVsPVKFSPG 9606 7545671 t gcesareni "Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase" SIGNOR-28800 TAB3 protein Q8N5C8 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates binding 9606 25290089 t lperfetto "The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex." SIGNOR-205452 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 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 BTG2 protein P78543 UNIPROT HOXB9 protein P17482 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 10617598 t miannu "The leukemia-associated protein Btg1 and the p53-regulated protein Btg2 interact with the homeoprotein Hoxb9 and enhance its transcriptional activation." SIGNOR-220987 TRAF2 protein Q12933 UNIPROT MAP3K7 protein O43318 UNIPROT "up-regulates activity" ubiquitination Lys158 ALIHRDLkPPNLLLV 9606 BTO:0000007 20038579 t lperfetto "Tumor necrosis factor receptor-associated factors 2 and 6 (traf2 and -6) act as the ubiquitin e3 ligases to mediate lys63-linked tak1 polyubiquitination at the lys158 residue in vivo and in vitro. Lys(63)-linked TAK1 polyubiquitination at the Lys(158) residue is required for TAK1-mediated IKK complex recruitment." SIGNOR-162638 CDON protein Q4KMG0 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-235551 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 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 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 MAPK1 protein P28482 UNIPROT RPS3 protein P23396 UNIPROT unknown phosphorylation Thr42 SGVEVRVtPTRTEII 9606 15950189 t llicata "Erk phosphorylates threonine 42 residue of ribosomal protein s3." SIGNOR-136075 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 PP121 chemical CHEBI:50915 ChEBI MTOR protein P42345 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206289 MRAP protein Q8TCY5 UNIPROT MC4R protein P32245 UNIPROT "down-regulates activity" binding 10029 BTO:0000246 19329486 t miannu "We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members." SIGNOR-252362 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR MMP13 protein P45452 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003858 12734180 f miannu "The suppressive effect of IGF-1 and OP-1 on MMP-13 expression was due in part to down-regulation of the expression of pro-inflammatory cytokines and the activity of their intermediate molecules, including NF-kappaB and AP-1 factors." SIGNOR-254800 POU3F2 protein P20265 UNIPROT POU3F2 protein P20265 UNIPROT "up-regulates activity" binding 9606 BTO:0002269 11029584 t miannu "These experiments lead to the conclusion that the full-length Brn-2 protein can interact with full-length Brn-2. Assay of homodimerization properties of Brn-2 protein on the b2s1 dimer recognition sequence also demonstrated cooperativity, indicating that protein-protein contacts would be important for synergistic interactions between the Brn-2 subunits." SIGNOR-221824 PRKACG protein P22612 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. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo." SIGNOR-81157 SL-327 chemical CHEBI:92211 ChEBI MAP2K2 protein P36507 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000938 BTO:0000142 11160424 t gcesareni "The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity" SIGNOR-104930 PRKACG protein P22612 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-81161 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 TJP2 protein Q9UDY2 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates binding 9606 21808241 t milica "In addition, yap and taz interact with another tight junction protein zo-2, which was reported to increase nuclear localization of yap and tight-junction localization of taz." SIGNOR-175931 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 HCK protein P08631 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" phosphorylation Tyr705 DPGSAAPyLKTKFIC -1 12244095 t "Activation of STAT3 by the Src family kinase Hck requires a functional SH3 domain. Direct Phosphorylation of STAT3 on Tyr-705 by Src Family Kinases" SIGNOR-251267 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR MMP9 protein P14780 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15536164 f miannu "Biglycan, NGAL, and MMP-9 are transcriptionally up-regulated by NF-kappaB, a transcription factor that is activated in FAP nerves and SG." SIGNOR-254798 PLK1 protein P53350 UNIPROT CTNNB1 protein P35222 UNIPROT unknown phosphorylation Ser718 QDDPSYRsFHSGGYG 9606 19001871 t lperfetto "Ser-718 of beta-catenin was directly phosphorylated by recombinant plk1thus it may be possible that function of the additional phosphorylation site(s) in cooperation with the ser-718 is required for the regulation of _-catenin at m phase" SIGNOR-182150 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 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 CSNK2A1 protein P68400 UNIPROT C1R protein P00736 UNIPROT "down-regulates activity" phosphorylation Ser206 TEASGYIsSLEYPRS -1 8635594 t llicata "We provide evidence that this kinase phosphorylates Clr at the level of Ser189. | Accessibility of Ser189 was low in intact C1r, due in part to the presence of one of the oligosaccharides borne by the alpha region, further reduced in the presence of calcium, and abolished when C1r was incorporated into the C1s-C1r-C1r-C1s tetramer or the C1 complex." SIGNOR-250833 SPRY2 protein O43597 UNIPROT CBLB protein Q13191 UNIPROT down-regulates binding 9606 11053437 t gcesareni "One function of hspry2 in signaling processes downstream of rtks may be to modulate c-cbl physiological function such as that seen with receptor-mediated endocytosis." SIGNOR-83507 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 SRPK1 protein Q96SB4 UNIPROT RBM8A protein Q9Y5S9 UNIPROT down-regulates phosphorylation Ser168 GGRRRSRsPDRRRR 9606 16100109 t gcesareni "We demonstrate that y14 is phosphorylated at its repeated arginine/serine (rs) dipeptides, likely by sr protein-specific kinases. Phosphorylation of y14 abolished its interaction with ejc components as well as factors that function downstream of the ejc." SIGNOR-139555 RAB33B protein Q9H082 UNIPROT ATG16L1 protein Q676U5 UNIPROT up-regulates binding 9606 18448665 t gcesareni "Olgi-resident small gtpase rab33b interacts with atg16l and modulates autophagosome formation." SIGNOR-178542 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 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CASP9 protein P55211 UNIPROT down-regulates phosphorylation Thr125 PEVLRPEtPRPVDIG 9606 16287866 t lperfetto "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-216876 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 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 XPO1 protein O14980 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates relocalization 9606 11074002 t gcesareni "We demonstrate that inhibition of crm1-mediated nuclear export by treatment of cells with leptomycin b results in endogenous smad4 accumulating very rapidly in the nucleus." SIGNOR-84247 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 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 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 GAS6 protein Q14393 UNIPROT TYRO3 protein Q06418 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-34414 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 GNAS protein Q5JWF2 UNIPROT ADCY1 protein Q08828 UNIPROT up-regulates binding 9606 BTO:0000007 22863277 t milica "Thus, Gs-coupled GPCR can induce YAP phosphorylation mainly via cAMP and PKA." SIGNOR-198510 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 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 MAP3K1 protein Q13233 UNIPROT MAP2K1 protein Q02750 UNIPROT "up-regulates activity" phosphorylation Ser222 LIDSMANsFVGTRSY 10090 BTO:0000944 8131746 t lperfetto "Phosphorylation at ser-218 and ser-222 by map kinase kinase kinases (raf or mekk1) positively regulates mek1 kinase activity." SIGNOR-235564 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 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 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 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 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 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 PHKG1 protein Q16816 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser669 DFKDRVQsKIGSLDN -1 8999860 t miannu "Muscle phosphorylase kinase phosphorylates Ser237, Ser262, Ser285, Ser305, and Ser352 of human tau. in vitro phosphorylation of tau on Ser262 alone strongly reduced the ability of tau to bind microtubules whereas the phosphorylation of many Ser/Thr-Pro motif sites of tau showed moderate effects on the binding of tau to microtubules" SIGNOR-250287 SYK protein P43405 UNIPROT PLCG1 protein P19174 UNIPROT "up-regulates activity" phosphorylation Tyr783 EGRNPGFyVEANPMP 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-246576 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 YAP1 protein P46937 UNIPROT Apoptosis phenotype SIGNOR-PH2 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-199214 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 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 HAP1 protein P54257 UNIPROT NEUROD1 protein Q13562 UNIPROT "up-regulates activity" binding -1 12881483 t lperfetto "we identified two proteins that interact with ND, huntingtin-associated protein 1 (HAP1) and mixed-lineage kinase 2 (MLK2). Stimulation of NeuroD activity by huntingtin and huntingtin-associated proteins HAP1 and MLK2" SIGNOR-234602 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 MDM2 protein Q00987 UNIPROT TP53 protein P04637 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 10935507 t lperfetto "Many posttranslational modifications of p53, such as phosphorylation, dephosphorylation, acetylation and ribosylation, have been shown to occur following cellular stress. Some of these modifications may activate the p53 protein, interfere with MDM2 binding and/or dictate cellular localization of p53." SIGNOR-80528 MDM2 protein Q00987 UNIPROT TP53 protein P04637 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 23150757 t lperfetto "Dual Roles of MDM2 in the Regulation of p53: Ubiquitination Dependent and Ubiquitination Independent Mechanisms of MDM2 Repression of p53 Activity" SIGNOR-199371 MDM2 protein Q00987 UNIPROT TP53 protein P04637 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000093 22337874 t lperfetto "The E3 ubiquitin ligase, MDM2, uses a dual-site mechanism to ubiquitinate and degrade the tumor suppressor protein p53, involving interactions with the N-terminal hydrophobic pocket and the acidic domain of MDM2." SIGNOR-196116 MRAP2 protein Q96G30 UNIPROT MC4R protein P32245 UNIPROT "down-regulates activity" binding 10029 BTO:0000246 19329486 t miannu "We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members." SIGNOR-252363 ARAF protein P10398 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 21779497 t lperfetto "Active raf phosphorylates mek." SIGNOR-244809 MRAP2 protein Q96G30 UNIPROT MC5R protein P33032 UNIPROT "down-regulates activity" binding 10029 BTO:0000246 19329486 t miannu "We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members." SIGNOR-252369 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 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 PTPN11 protein Q06124 UNIPROT SPRY1 protein O43609 UNIPROT down-regulates dephosphorylation 9606 16481357 t gcesareni "These results identify sprouty proteins as in vivo targets of corkscrew/shp-2 tyrosine phosphatases and show how corkscrew/shp-2 proteins can promote rtk signaling by inactivating a feedback inhibitor." SIGNOR-144547 BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation Ser463 SPHNPISsVS 9606 9136927 t lperfetto "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-210079 MRGPRX1 protein Q96LB2 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-257171 MRGPRX1 protein Q96LB2 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-256929 ROS stimulus SIGNOR-ST2 SIGNOR FOXL2 protein P58012 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19010791 f miannu "Transcriptional upregulation of foxl2 during oxidative and heat stress" SIGNOR-182303 MRGPRX1 protein Q96LB2 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-257259 IGF1R protein P08069 UNIPROT AKT1 protein P31749 UNIPROT "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-235373 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 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 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 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 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 fenoterol chemical CHEBI:149226 ChEBI ADRB1 protein P08588 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000457 20590599 t Luana "Finally, comparisons of the rank order of ligands for the three different receptors provide information about relative intrinsic efficacies. Fenoterol is a full and efficacious agonist at the β1-adrenoceptor, ranking third out of the agonists studied. It was also a full agonist at the β2- and β3-adrenoceptors with the highest intrinsic efficacy (i.e. top of Tables 4 and ​and5,5, rank 1). " SIGNOR-257867 TAF1 protein P21675 UNIPROT GTF2A1 protein P52655 UNIPROT "up-regulates activity" phosphorylation Ser280 VDGTGDTsSEEDEDE 9606 11278496 t lperfetto "TAFII 250 Phosphorylates Human Transcription Factor IIA on Serine Residues Important for TBP Binding and Transcription ActivityAdditional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels" SIGNOR-246630 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 MRGPRX2 protein Q96LB1 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-257059 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 PIAS4 protein Q8N2W9 UNIPROT STAT1 protein P42224 UNIPROT down-regulates binding 9606 11248056 t gcesareni "First, piasy interacts with stat1 both in vitro and in vivo. The in vivo piasy__stat1 interaction is dependent on cytokine stimulation. Second, piasy can inhibit stat1-mediated gene activation without blocking the dna binding activity of stat1." SIGNOR-105723 PPP2CA protein P67775 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-150369 PTPN6 protein P29350 UNIPROT ROS1 protein P08922 UNIPROT down-regulates dephosphorylation Tyr2274 KNREGLNyMVLATEC 9606 11266449 t gcesareni "Phosphorylated ros strongly and directly associates with shp-1.Overexpression Of shp-1 results in ros dephosphorylation and effectively downregulates ros-dependent proliferation and transformation" SIGNOR-105919 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 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 TAF1 protein P21675 UNIPROT GTF2A1 protein P52655 UNIPROT "up-regulates activity" phosphorylation Ser281 DGTGDTSsEEDEDEE 9606 11278496 t lperfetto "TAFII 250 Phosphorylates Human Transcription Factor IIA on Serine Residues Important for TBP Binding and Transcription ActivityAdditional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels" SIGNOR-246634 TAOK2 protein Q9UL54 UNIPROT ELK1 protein P19419 UNIPROT "up-regulates activity" phosphorylation Ser383 IHFWSTLsPIAPRSP 9606 BTO:0000007 12665513 t lperfetto "Transfection studies demonstrated that TAO2 stimulates phosphorylation of the TCF Elk1 on the major activating site, Ser383, and that TAO2 stimulates transactivation of Elk1 and the related TCF, Sap1." SIGNOR-246638 MRGPRX1 protein Q96LB2 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-257326 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 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 CSNK2A1 protein P68400 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Ser129 SGSPSDNsGAEEMEV 9606 BTO:0000007 21735093 t gcesareni "CK2 hyperactivates AKT by phosphorylation at Ser129" SIGNOR-252595 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 KLF13 protein Q9Y2Y9 UNIPROT SIN3A protein Q96ST3 UNIPROT "up-regulates activity" binding 10029 BTO:0000246 11438660 t miannu "detailed biochemical and functional analyses have demonstrated that the TIEG2 _-HRM domain interacts specifically with the PAH2 domain of mSin3A to repress transcription. our data suggest the presence of a conserved _-helical repression motif (_-HRM) in the TIEG and BTEB subfamilies of Sp1-like proteins that mediates transcriptional repression activity through interaction with the corepressor mSin3A." SIGNOR-222437 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 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 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 MRGPRX2 protein Q96LB1 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-257172 MRGPRX2 protein Q96LB1 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-257260 Apoptosome complex SIGNOR-C230 SIGNOR CASP3 protein P42574 UNIPROT "up-regulates activity" cleavage 9606 15657060 t lperfetto "Following autoprocessing in the apoptosome, caspase-9 cleaves and activates caspase-3." SIGNOR-256471 IRF8 protein Q02556 UNIPROT NCF2 protein P19878 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001412 11483597 f 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-222789 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 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 SUZ12/EZH2 complex SIGNOR-C77 SIGNOR YY1 protein P25490 UNIPROT "up-regulates activity" 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-235574 TBK1 protein Q9UHD2 UNIPROT NFKBIA protein P25963 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 11815618 t lperfetto "Nuclear factor-kappaB activation depends on phosphorylation and degradation of its inhibitor protein, IkapapB. TBK-1 and IKK-i phosphorylate Ser36 of IkappaBalpha." SIGNOR-246643 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 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 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 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 MAPK3 protein P27361 UNIPROT POU5F1 protein Q01860 UNIPROT down-regulates phosphorylation Ser111 ESNSDGAsPEPCTVT 9606 23024368 t gcesareni "Phosphorylation of this site downregulates nanog, sox2, rex1 and upregulates bmp4, gata6, ddlx5." SIGNOR-192101 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 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 PRKAA2 protein P54646 UNIPROT VASP protein P50552 UNIPROT down-regulates phosphorylation Thr278 LARRRKAtQVGEKTP 9606 SIGNOR-C15 17082196 t lperfetto "Pharmacological ampk inhibitors and activators and ampk mutants revealed that the kinase specifically targets residue thr-278 but not ser-157 or ser-239. Quantitative fluorescence-activated cell sorter analysis and serum response factor transcriptional reporter assays, which quantify the cellular f-/g-actin equilibrium, indicated that ampk-mediated vasp phosphorylation impaired actin stress fiber formation and altered cell morphology." SIGNOR-150462 RPS6KA1 protein Q15418 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser9 SGRPRTTsFAESCKP 9606 11584304 t lperfetto "S6k then phosphorylates the same serine residue on gsk3 that is targeted by pkb/akt (fig. 1), thereby inhibiting its activity." SIGNOR-110917 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 MAPK7 protein Q13164 UNIPROT PML protein P29590 UNIPROT down-regulates phosphorylation 9606 BTO:0001271 20832753 t gcesareni "We found that bmk1 interacted with promyelocytic leukemia protein (pml), and inhibited its tumor-suppressor function through phosphorylation." SIGNOR-167947 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 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 USF2 protein Q15853 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-222608 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 MYCN protein P04198 UNIPROT CTSD protein P07339 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000931 18566016 f miannu "In primary neuroblastomas, high CTSD messenger RNA (mRNA) levels were associated with amplified MYCN, a strong predictive marker of adverse outcome. Chromatin immunoprecipitation and luciferase promoter assays revealed that MYCN protein binds to the CTSD promoter and activates its transcription, suggesting a direct link between deregulated MYCN and CTSD mRNA expression." SIGNOR-254618 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 "MYOD1/SWI/SNF complex" complex SIGNOR-C93 SIGNOR ENO3 protein P13929 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887 15870273 f miannu "Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material)" SIGNOR-136550 Calcineurin complex SIGNOR-C155 SIGNOR 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-252324 "MYOD1/SWI/SNF complex" complex SIGNOR-C93 SIGNOR GYS1 protein P13807 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887 15870273 f miannu "Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material)" SIGNOR-136553 "MYOD1/SWI/SNF complex" complex SIGNOR-C93 SIGNOR IGFBP5 protein P24593 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887 15870273 f miannu "Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material)" SIGNOR-136601 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 BBC3 protein Q9BXH1 UNIPROT BAK1 protein Q16611 UNIPROT up-regulates binding 9606 17289999 t gcesareni "Bh3-only proteins induce apoptosis at least primarily by engaging the multiple pro-survival relatives guarding bax and bak enabler bh3-only proteins such as puma promote momp more indirectly. They activate bax and bak by forming inhibitory complexes with the anti-apoptotic bh1-4 proteins such as bcl2, bclxl and mcl1 that normally stabilize the outer membrane." SIGNOR-152974 PPP2CA protein P67775 UNIPROT HDAC4 protein P56524 UNIPROT up-regulates dephosphorylation Ser298 ACSSAPGsGPSSPNN 9606 18045992 t lperfetto "Different signal-regulated serine/threonine kinases phosphorylate class ii histone deacetylases (hdacs) to promote nuclear export, cytosolic accumulation, and activation of gene transcriptionhere we show that hdac4 forms a complex with the pp2a holoenzyme c alpha, a alpha, b/pr55 alpha. In vitro and in vivo binding studies demonstrate that the n-terminus of hdac4 interacts with the catalytic subunit of pp2a. Hdac4 is dephosphorylated by pp2a" SIGNOR-159492 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 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 TRAF7 protein Q6Q0C0 UNIPROT MAP3K3 protein Q99759 UNIPROT up-regulates binding 9606 15001576 t miannu "Traf7 specifically interacts with and activates mekk3." SIGNOR-123221 PPP2CA protein P67775 UNIPROT HDAC7 protein Q8WUI4 UNIPROT "up-regulates activity" dephosphorylation Ser358 WPLSRTRsEPLPPSA 9606 18339811 t "Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. |Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs.|we demonstrate that PP2A constitutively dephosphorylates the class IIa member HDAC7 to control its biological functions as a regulator of T cell apoptosis and endothelial cell functions." SIGNOR-248648 PPP2CA protein P67775 UNIPROT HDAC7 protein Q8WUI4 UNIPROT "up-regulates activity" dephosphorylation Ser486 RPLSRAQsSPAAPAS 9606 18339811 t "Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. |Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs.|we demonstrate that PP2A constitutively dephosphorylates the class IIa member HDAC7 to control its biological functions as a regulator of T cell apoptosis and endothelial cell functions." SIGNOR-248649 MAML3 protein Q96JK9 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 12370315 t gcesareni "We report here the cloning and characterization of two new genes, maml2 and maml3, that also function as transcriptional coactivators for notch receptors." SIGNOR-94097 PPP2CA protein P67775 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-248645 PRKCB protein P05771 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser257 QIRLRRDsKEANARR -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-249003 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 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 JUN protein P05412 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" binding 9606 10871633 t irozzo "These results indicate that interaction between Smad3 and c-Jun may repress Smad3 transcriptional activity." SIGNOR-256284 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 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-255208 lapatinib chemical CHEBI:49603 ChEBI KDR protein P35968 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001949 21443688 t Luana "YN968D1 potently suppressed the kinase activities of VEGFR-2, c-kit and c-src, and inhibited cellular phosphorylation of VEGFR-2, c-kit and PDGFRβ." SIGNOR-257898 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 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-255216 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 SP3 protein Q02447 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-255203 SP3 protein Q02447 UNIPROT MAOB protein P27338 UNIPROT "down-regulates quantity by repression" "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-253870 IFNL2 protein Q8IZJ0 UNIPROT IFNLR1 protein Q8IU57 UNIPROT up-regulates binding 9606 12469119 t gcesareni "Il-28 and il-29 interacted with a heterodimeric class ii cytokine receptor that consisted of il-10 receptor beta (il-10rbeta) and an orphan class ii receptor chain, designated il-28ralpha." SIGNOR-96206 SP3 protein Q02447 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-255214 SP4 protein Q02446 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-253869 SPAG5 protein Q96R06 UNIPROT CENPF protein P49454 UNIPROT "up-regulates activity" 9606 BTO:0000567 17664331 f lperfetto "Furthermore, although both the core kinetochore protein Hec1 and the spindle checkpoint kinase Bub1 were unaffected (Fig. 3 C), the kinetochore resident motor protein CENP-E (Yen et al., 1992) and its interaction partner CENP-F (Chan et al., 1998) were delocalized from the kinetochore in the absence of astrin. These cells remained cyclin B1 positive (unpublished data), confirming that they were still in mitosis. These data suggest that the presence of astrin is required for the kinetochore recruitment or maintenance of CENP-E and CENP-F." SIGNOR-252042 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 SPI1 protein P17947 UNIPROT miR-338 mirna MI0000814 miRBase "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000725 21730352 f miannu "We provide evidence that PU.1 directly controls expression of at least 4 of these miRs (miR-146a, miR-342, miR-338, and miR-155) through temporally dynamic occupation of binding sites within regulatory chromatin regions adjacent to their genomic coding loci. We conclude that PU.1 bound to open chromatin near 4 of its induced miR loci with 2 types of kinetics: (1) permanent (miR-146a, miR-342, and miR-338) and (2) transient (miR-155) during myeloid differentiation." SIGNOR-256243 SPI1 protein P17947 UNIPROT miR-34 mirna MI0000268 miRBase "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000725 21730352 f miannu "We provide evidence that PU.1 directly controls expression of at least 4 of these miRs (miR-146a, miR-342, miR-338, and miR-155) through temporally dynamic occupation of binding sites within regulatory chromatin regions adjacent to their genomic coding loci. We conclude that PU.1 bound to open chromatin near 4 of its induced miR loci with 2 types of kinetics: (1) permanent (miR-146a, miR-342, and miR-338) and (2) transient (miR-155) during myeloid differentiation." SIGNOR-256242 SPRY4 protein Q9C004 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002058 20501643 f miannu "When Spry4 was stably transfected into H157 and H2122 NSCLC cell lines, decreased migration and invasion were observed. Matrix metalloproteinase-9 activity was decreased, and the expression of matrix metalloproteinase inhibitors TIMP1 and CD82 were increased. Stable expression of Spry4 led to reduced cell growth and reduced anchorage-independent growth in NSCLC cell lines, along with upregulation of tumor suppressors p53 and p21." SIGNOR-253041 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 AMPK complex SIGNOR-C15 SIGNOR LIPE protein Q05469 UNIPROT down-regulates phosphorylation Ser855 EPMRRSVsEAALAQP 9606 9636039 t lperfetto "Phosphorylation of bovine hormone-sensitive lipase by the amp-activated protein kinase." SIGNOR-216507 PI-103 chemical CHEBI:90524 ChEBI PIK3CD protein O00329 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206169 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 BCAR1 protein P56945 UNIPROT "down-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" SIGNOR-246405 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT "down-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" SIGNOR-246413 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 BCAR1 protein P56945 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates binding 9606 18321991 t gcesareni "In this study, we show that, after tyrosine phosphorylation of p130cas mediated by integrin signaling, the phosphorylated p130cas is able to interact with phosphorylated smad3 and in turn prevent transcriptional activation by smad3" SIGNOR-161265 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 CTNND1 protein O60716 UNIPROT "up-regulates activity" phosphorylation Tyr302 DYGMMSDyGTARRTG -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-246504 SRC protein P12931 UNIPROT CTNND1 protein O60716 UNIPROT "up-regulates activity" phosphorylation Tyr96 QDHSHLLySTIPRMQ -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-246508 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 MAPK1 protein P28482 UNIPROT RPTOR protein Q8N122 UNIPROT unknown phosphorylation Ser863 LTQSAPAsPTNKGVH 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-169522 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 CUDC-907 chemical CID:54575456 PUBCHEM HDAC3 protein O15379 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191209 SRC protein P12931 UNIPROT HNRNPK protein P61978 UNIPROT down-regulates phosphorylation Tyr236 FYDETYDyGGFTMMF 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-88911 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 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 SYK protein P43405 UNIPROT "up-regulates activity" phosphorylation Tyr352 TEVYESPyADPEEIR 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-246613 SYK protein P43405 UNIPROT SYK protein P43405 UNIPROT "up-regulates activity" phosphorylation Tyr525 ALRADENyYKAQTHG 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-246617 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 TACR2 protein P21452 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-257131 MCL1 protein Q07820 UNIPROT BAX protein Q07812 UNIPROT down-regulates binding 9606 17289999 t gcesareni "Which of the multiple pro-survival proteins that can bind Bax (fig. S15A) can functionally restrain it? Mcl-1 must, because neutralizing Mcl-1 by enforced Noxa expression rendered MEFs containing only Bax (Bak KO cells) sensitive to the Bad BH3 mimetic ABT-737 (Fig. 4A), which inactivates Bcl-2, Bcl-xL, and Bcl-w" SIGNOR-151787 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 PTPRK protein Q15262 UNIPROT EGFR protein P00533 UNIPROT unknown dephosphorylation Tyr1092 TFLPVPEyINQSVPK 10029 BTO:0000246 16263724 t "RPTP-kappa also reduced epidermal growth factor-dependent EGFR tyrosine phosphorylation in CHO cells. Purified RPTP-kappa preferentially dephosphorylated EGFR tyrosines 1068 and 1173 in vitro." SIGNOR-248722 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 PKA proteinfamily SIGNOR-PF17 SIGNOR "SMN complex" complex SIGNOR-C158 SIGNOR "up-regulates quantity by stabilization" phosphorylation 9606 BTO:0000007 19103745 t lperfetto "PKA increases SMN complex formation and SMN stability." SIGNOR-253122 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MASTL protein Q96GX5 UNIPROT "up-regulates activity" phosphorylation Thr194 NMMDILTtPSMAKPR 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-243403 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 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 TWIST2 protein Q8WVJ9 UNIPROT ERBB3 protein P21860 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004828 19051271 f miannu "we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion" SIGNOR-255501 TWIST2 protein Q8WVJ9 UNIPROT F2R protein P25116 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004828 19051271 f miannu "we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion" SIGNOR-255502 GADD45A protein P24522 UNIPROT CyclinB/CDK1 complex SIGNOR-C17 SIGNOR down-regulates binding 9606 10362260 t lperfetto "Gadd45 has now been found to directly inhibit the activity of cdc2/cyclin b1 complex" SIGNOR-217508 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 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 TWIST2 protein Q8WVJ9 UNIPROT FOS protein P01100 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004828 19051271 f miannu "we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion" SIGNOR-255503 TWIST2 protein Q8WVJ9 UNIPROT ILK protein Q13418 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004828 19051271 f miannu "we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion" SIGNOR-255504 TWIST2 protein Q8WVJ9 UNIPROT ITGB1 protein P05556 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002590 17487558 f miannu "Immunoblot analysis showed that HEY/si-TWIST cells exhibited decreased expression levels of CD29, CD44 and CD54 compared to those of HEY/si-scrambled cells" SIGNOR-255513 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR AKT1S1 protein Q96B36 UNIPROT down-regulates binding 9606 SIGNOR-C3 20006481 t gcesareni "Akt can phosphorylate pras40, a raptor binding protein that also acts as an inhibitor of torc1. Akt-mediated phosphorylation of pras40 again promotes 14-3-3 binding, in this case leading to relief from pras40-mediated inhibition." SIGNOR-162003 TWIST2 protein Q8WVJ9 UNIPROT NF1 protein P21359 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004828 19051271 f miannu "we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion" SIGNOR-255505 TWIST2 protein Q8WVJ9 UNIPROT NR2F1 protein P10589 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004828 19051271 f miannu "we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion" SIGNOR-255506 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates binding 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni "In this study, we demonstrate that akt also regulates the activity of fkhrl1, a member of the forkhead family of transcription factors. In the presence of survival factors, akt phosphorylates fkhrl1, leading to fkhrl1's association with 14-3-3 proteins and fkhrl1's retention in the cytoplasm. 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-252818 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates binding 9606 BTO:0001130 1010227 t gcesareni "Progressive increase in akt activation during prostate cancer progression led to increase phosphorylation of foxo3a and binding with 14-3-3, which potentially affected its transcriptional activity in age-specific manner." SIGNOR-252819 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR KHSRP protein Q92945 UNIPROT down-regulates binding 9606 17177604 t gcesareni "Akt phosphorylates ksrp at a unique serine residue, creating a functional binding site for the molecular chaperone 14-3-3. As a consequence, akt activation impairs ksrp ability to interact with the exoribonucleolytic complex exosome and, in turn, to promote rapid mrna decay." SIGNOR-151212 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 7-Hydroxystaurosporine chemical CID:72271 PUBCHEM CHEK1 protein O14757 UNIPROT down-regulates "chemical inhibition" 9606 20068082 t gcesareni "The clinical use of ucn-01, the first chk1 inhibitor evaluated in humans, is limited by its prolonged plasma half-life due to extensive plasma binding to alfa1 acidic glycoprotein" SIGNOR-163222 85375-15-1 chemical CID:6917797 PUBCHEM SLC6A12 protein P48065 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207031 ABCG1 protein P45844 UNIPROT HDL_assembly phenotype SIGNOR-PH61 SIGNOR up-regulates 9606 16054053 f miannu "ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation. cholesterol efflux to HDL specifically requires ABCG1, whereas efflux to apoA1 requires ABCA1. These studies identify Abcg1 as a key gene involved in both cholesterol efflux to HDL and in tissue lipid homeostasis." SIGNOR-252111 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 GSK690693 chemical CHEBI:90677 ChEBI AKT2 protein P31751 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193003 "3-(2-Carboxyethyl)-4,6-dichloro-1H-indole-2-carboxylic acid" chemical CID:446916 PUBCHEM GPR17 protein Q13304 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-257502 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 ACVR1 protein Q04771 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" 9606 18801898 f gcesareni "Akt/mTOR signaling is a key target that accounts for myostatin function during muscle atrophy, uncovering a novel role for myostatin in protein metabolism and more specifically in the regulation of translation in skeletal muscle." SIGNOR-243185 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 ADAM17 protein P78536 UNIPROT EGFR protein P00533 UNIPROT up-regulates 9606 20626350 f gcesareni "Such phosphorylation is required for tace mediated ectodomain shedding of tgfalfa family ligands, which results in the activation of egfr and cell proliferation." SIGNOR-166568 ADAM17 protein P78536 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR "up-regulates activity" cleavage 9606 BTO:0000567 10882063 t gcesareni "... here we show that an additional processing event occurs in the extracellular part of the receptor, preceding cleavage by the gamma-secretase-like activity. Purification of the activity accounting for this cleavage in vitro shows that it is due to tace (tnfalpha-converting enzyme), a member of the adam (a disintegrin and metalloprotease domain) family of metalloproteases." SIGNOR-254334 P2RY12 protein Q9H244 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-256991 adenosine smallmolecule CHEBI:16335 ChEBI ADORA2B protein P29275 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-257448 AMPK complex SIGNOR-C15 SIGNOR ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser556 GLGCRLHsAPNLSDL 9606 19584320 t lperfetto "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-216495 adenosine smallmolecule CHEBI:16335 ChEBI ADORA3 protein P0DMS8 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-257449 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 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 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-257364 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 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 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 TFAP4 protein Q01664 UNIPROT SP1 protein P08047 UNIPROT "up-regulates activity" binding 9606 BTO:0001109 19505873 t miannu "We also observed moderately increased recruitment of CTCF, HDAC1, and SP1 by the full-length AP-4 onto the WT DNA beads." SIGNOR-226593 ADP chemical CHEBI:16761 ChEBI P2RY13 protein Q9BPV8 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-257561 PRKCA protein P17252 UNIPROT GRM1 protein Q13255 UNIPROT "down-regulates activity" phosphorylation Thr695 GSKKKICtRKPRFMS 9606 BTO:0000007 10823959 t lperfetto "Furthermore, we demonstrate that the selectivity of PKC action on receptor signaling rests on phosphorylation of a threonine residue located in the G protein-interacting domain of the receptor. Modification at Thr(695) selectively disrupts mGluR1alpha-G(q/11) interaction without affecting signaling through G(s)." SIGNOR-249043 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 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 PRKCA protein P17252 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-134617 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 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 seliciclib chemical CHEBI:45307 ChEBI CCNA2 protein P20248 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206559 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 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 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 AMPK complex SIGNOR-C15 SIGNOR ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser638 FDFPKTPsSQNLLAL 9606 19584320 t lperfetto "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-216499 ADRA2B protein P18089 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-256857 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 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 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 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 "AEP complex" complex SIGNOR-C117 SIGNOR MEIS1 protein O00470 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0001271 20854876 f irozzo "Inhibition of EAP components pTEFb and Dot1l show that both contribute significantly to activation of Hoxa9 and Meis1 expression. EAP is dynamically associated with the Hoxa9 and Meis1 loci in hematopoietic cells and rapidly dissociates during induction of differentiation. In the presence of MLL fusion proteins, its dissociation is prevented." SIGNOR-256144 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 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 AKT proteinfamily SIGNOR-PF24 SIGNOR CREB1 protein P16220 UNIPROT "up-regulates activity" phosphorylation Ser133 EILSRRPsYRKILND 9606 BTO:0000007 9829964 t gcesareni "When overexpressed in serum-stimulated cells, Akt/PKB potently induced Ser-133 phosphorylation of CREB and promoted recruitment of CBP. Correspondingly, Akt/PKB stimulated target gene expression via CREB in a phospho(Ser-133)-dependent manner." SIGNOR-247992 NEDD4L protein Q96PU5 UNIPROT SMAD2 protein Q15796 UNIPROT "down-regulates activity" ubiquitination 9606 19917253 t lperfetto "Through its ww domain, nedd4l specifically recognizes a tgf-beta-induced phosphothr-protyr motif in the linker region, resulting in smad2/3 polyubiquitination and degradation" SIGNOR-217622 ADRB3 protein P13945 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-256753 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-244222 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-181536 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-244247 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-244255 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-244251 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-244259 AKT proteinfamily SIGNOR-PF24 SIGNOR EZR protein P15311 UNIPROT up-regulates phosphorylation Thr567 QGRDKYKtLRQIRQG 9606 15531580 t lperfetto "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-244263 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-251476 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-123239 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-252824 AKT proteinfamily SIGNOR-PF24 SIGNOR MAP3K8 protein P41279 UNIPROT "down-regulates activity" phosphorylation Ser400 EDQPRCQsLDSALLE 9606 BTO:0000661 12138205 t gcesareni "The regulation of NF-kappa B-dependent transcription by Cot requires Akt-dependent phosphorylation of serine 400 (S400)," SIGNOR-248019 AKT proteinfamily SIGNOR-PF24 SIGNOR MAP3K8 protein P41279 UNIPROT "down-regulates activity" phosphorylation Ser413 LERKRLLsRKELELP 9606 BTO:0000661 12138205 t gcesareni "The regulation of NF-kappa B-dependent transcription by Cot requires Akt-dependent phosphorylation of serine 400 (S400)," SIGNOR-249666 AKT proteinfamily SIGNOR-PF24 SIGNOR NOS3 protein P29474 UNIPROT "up-regulates activity" binding 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-251627 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-236216 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-165497 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-150140 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-70205 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR 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-256441 ULK2 protein Q8IYT8 UNIPROT ATG13 protein O75143 UNIPROT up-regulates phosphorylation 9606 19225151 t gcesareni "Ulks directly phosphorylates atg13." SIGNOR-184126 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 BAX protein Q07812 UNIPROT "up-regulates activity" phosphorylation Ser184 VAGVLTAsLTIWKKM -1 26763134 t lperfetto "We found that AKT activated Bax and increased its cellular content. Both effects were dependent on Ser184, but a phosphorylation of this residue did not fully explain the effects of AKT." SIGNOR-252547 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 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 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 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-251483 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-248027 alvocidib chemical CHEBI:47344 ChEBI CDK7 protein P50613 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192446 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 PPP1CA protein P62136 UNIPROT down-regulates phosphorylation Thr320 NPGGRPItPPRNSAK 9606 BTO:0000938 BTO:0000142 17202132 t gcesareni "Ir-induced pp1 activation in the nucleus may be a critical component in an atm-mediated pathway controlling checkpoint activation." SIGNOR-252498 AKT1 protein P31749 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation 9606 22798428 t gcesareni "Akt negatively regulates the raf and gsk-3 kinases and the cell cycle regulatory transcription factor fkhr." SIGNOR-252531 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "down-regulates activity" phosphorylation 9606 BTO:0000586 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-227952 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 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 AKT3 protein Q9Y243 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni "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-252877 AKT3 protein Q9Y243 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser315 DFRSRTNsNASTVSG 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni "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-252878 AKT3 protein Q9Y243 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni "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-252879 AKT3 protein Q9Y243 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-252874 AKT3 protein Q9Y243 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-252875 MAPK13 protein O15264 UNIPROT CDC25B protein P30305 UNIPROT down-regulates 9606 11333986 f gcesareni "P38 map k can also induce a g2/m checkpoint through the phosphorylation and the phosphatase cdc25b." SIGNOR-85999 AKT3 protein Q9Y243 UNIPROT TBX3 protein O15119 UNIPROT "up-regulates activity" phosphorylation Ser719 AEKEAATsELQSIQR 9606 BTO:0000848 25595898 t miannu "We have identified TBX3 as a key substrate of AKT3 in melanomagenesis. we have identified the AKT3 target site at serine residue 720 in the TBX3 protein and show that this site is phosphorylated in vivo. the phosphorylation at S720 promotes TBX3 protein stability, nuclear localization, transcriptional repression of E-cadherin, and its role in cell migration and invasion." SIGNOR-223534 AMPK complex SIGNOR-C15 SIGNOR CRTC2 protein Q53ET0 UNIPROT down-regulates phosphorylation Ser170 PSALNRTsSDSALHT 9606 21892142 t lperfetto "Collectively, these findings suggest ampk suppresses glucose production through two transcriptional effects:reduced expression of creb targets via crtc inactivation and reduced expression of foxo target genes via class iia hdac inactivation" SIGNOR-216541 AMPK complex SIGNOR-C15 SIGNOR CRY1 protein Q16526 UNIPROT down-regulates phosphorylation Ser71 ANLRKLNsRLFVIRG 9606 phosphorylation:Ser71 ANLRKLNsRLFVIRG 21892142 t lperfetto "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-216546 AMPK complex SIGNOR-C15 SIGNOR EEF2K protein O00418 UNIPROT up-regulates phosphorylation Ser398 DSLPSSPsSATPHSQ 9606 22669845 t lperfetto "In response to genotoxic stress, eef2k was activated by ampk (adenosine monophosphate-activated protein kinase)-mediated phosphorylation on serine 398. Activated eef2k phosphorylated eef2 and induced a temporary ribosomal slowdown at the stage of elongation" SIGNOR-216503 AMPK complex SIGNOR-C15 SIGNOR FOXO1 protein Q12778 UNIPROT up-regulates phosphorylation 9606 18394876 t lperfetto "The energy sensor AMP-activated protein kinase (AMPK) has been shown to directly phosphorylate FoxO factors at six regulatory sites that are distinct from the Akt phosphorylation sites, resulting in FoxO activation." SIGNOR-216478 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT "up-regulates activity" phosphorylation Ser626 SLECDMEsIIRSELM 9606 BTO:0000007 17711846 t gcesareni "Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization." SIGNOR-249688 AMPK complex SIGNOR-C15 SIGNOR FOXO4 protein P98177 UNIPROT up-regulates phosphorylation 9606 17900900 t lperfetto "The energy sensor amp-activated protein kinase (ampk) has been shown to directly phosphorylate foxo factors at six regulatory sites that are distinct from the akt phosphorylation sites, resulting in foxo activation" SIGNOR-216484 AMPK complex SIGNOR-C15 SIGNOR 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-252880 AMPK complex SIGNOR-C15 SIGNOR 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-252881 AMPK complex SIGNOR-C15 SIGNOR 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-252882 AMPK complex SIGNOR-C15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR "up-regulates activity" phosphorylation Ser626 SLECDMEsIIRSELM 9606 BTO:0000007 17711846 t gcesareni "Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization." SIGNOR-252884 AMPK complex SIGNOR-C15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR "up-regulates activity" phosphorylation Thr179 SSPDKRLtLSQIYEW 9606 BTO:0000007 17711846 t gcesareni "Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization." SIGNOR-252885 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 RHEB protein Q15382 UNIPROT MTOR protein P42345 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 15854902 t lperfetto "Rheb binds and regulates the mTOR kinase." SIGNOR-135770 AMPK complex SIGNOR-C15 SIGNOR GLI1 protein P08151 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser408 GPLPRAPsISTVEPK 26190112 t "Activation of AMPK reduces GLI1 protein levels and stability, thus blocking Sonic-hedgehog-induced transcriptional activity. AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency." SIGNOR-253541 AMPK complex SIGNOR-C15 SIGNOR GLI1 protein P08151 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser408 GPLPRAPsISTVEPK 26843621 t "Indeed we show that AMPK phosphorylates Gli1 at the unique residue Ser408, which is conserved only in primates but not in other species. Once phosphorylated, Gli1 is targeted for proteasomal degradation." SIGNOR-253540 AMPK complex SIGNOR-C15 SIGNOR HDAC4 protein P56524 UNIPROT down-regulates phosphorylation 9606 BTO:0000938 BTO:0000887 21565617 t lperfetto "We show here that in liver, class iia hdacs (hdac4, 5, and 7) are phosphorylated and excluded from the nucleus by ampk family kinases." SIGNOR-216658 AMPK complex SIGNOR-C15 SIGNOR NOS3 protein P29474 UNIPROT up-regulates phosphorylation Ser1177 TSRIRTQsFSLQERQ 9606 11729179 t lperfetto "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-216445 APH1A protein Q96BI3 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates binding 9606 BTO:0000142 12297508 t gcesareni "Gamma secretase subunit. Leads to ps1/ps2 eterodimer complex stabilisation. By using co-immunoprecipitation and nickel affinity pull-down approaches, we now show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain." SIGNOR-93265 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 APOB protein P04114 UNIPROT VLDL_assembly phenotype SIGNOR-PH62 SIGNOR up-regulates 9606 BTO:0000575 23721961 f miannu "Apolipoprotein B is a structural protein that is an integral component of chylomicrons, as well as very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and low density lipoprotein (LDL) particles. In man, VLDL contains only ApoB100, the full length protein" SIGNOR-252115 APP protein P05067 UNIPROT Amyloid_fibril_formation phenotype SIGNOR-PH59 SIGNOR up-regulates 9606 BTO:0000590 11578751 f lperfetto "Neurodegeneration in Alzheimer's disease is a pathologic condition of cells rather than an accelerated way of aging. The senile plaques are generated by a deposition in the human brain of fibrils of the β-amyloid peptide (Aβ), a fragment derived from the proteolytic processing of the amyloid precursor protein (APP). Tau protein is the major component of paired helical filaments (PHFs), which form a compact filamentous network described as neurofibrillary tangles (NFTs)." SIGNOR-251638 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 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 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 SERPINB5 protein P36952 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 16304843 f lperfetto "In addition, androgen receptor (AR) can recognize and bind to the ARE element, and then inhibit the activity of maspin promoter" SIGNOR-253685 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 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 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 PER1 protein O15534 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-253628 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 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 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 WEE1 protein P30291 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-253678 HIPK2 protein Q9H2X6 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates phosphorylation Ser10 NVRVSNGsPSLERMD 9606 21715331 t lperfetto "Homeodomain-interacting protein kinase-2 stabilizes p27(kip1) by its phosphorylation at serine 10 and contributes to cell motility" SIGNOR-174617 ARNTL protein O00327 UNIPROT PER2 protein O15055 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-253629 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 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 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 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 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 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 SIGMAR1 protein Q99720 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22079628 f miannu "we have demonstrated that Sig-1Rs were transcriptionally upregulated by ATF4 in ER stress." SIGNOR-253750 ATF5 protein Q9Y2D1 UNIPROT CYP2B6 protein P20813 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18332083 f miannu "We induced endoplasmic reticulum stress by means of amino acid limitation or selective chemicals, and assessed the time course response of ATF5 and CYP2B6. We found a post-transcriptional up-regulation of ATF5 and a parallel induction of CYP2B6 mRNA." SIGNOR-253751 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 AURKA protein O14965 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "down-regulates activity" phosphorylation 9606 BTO:0001225 19060929 t lperfetto "The recombinant human aurka protein phosphorylated the gsk-3beta protein at ser 9 in a concentration-dependent manner, in vitro. The phosphorylation of beta-catenin (ser33/37/thr41) by gsk-3beta is known to target beta-catenin towards degradation. In line with our findings, the increase in phospho-gsk-3beta level was accompanied by a significant decrease in beta-catenin phosphorylation (ser33/37/thr41) and accumulation of beta-catenin protein." SIGNOR-227923 AURKB protein Q96GD4 UNIPROT CENPA protein P49450 UNIPROT unknown phosphorylation Ser7 sRKPEAPR 9606 BTO:0000567 11756469 t llicata "CENP-A–GST constructs were prepared in which Ser7 was mutated to alanine or glutamic acid. Phosphorylation of these proteins by Aurora B was reduced by 50%, demonstrating that Ser7 is a kinase substrate | Therefore, under the short term induction conditions used in these experiments, we can conclude that CENP-A Ser7 mutations do not grossly interfere with kinetochore formation, spindle assembly, or cell cycle progression." SIGNOR-250585 AURKB protein Q96GD4 UNIPROT CHMP4C protein Q96CF2 UNIPROT up-regulates phosphorylation Ser214 ARRSRAAsSQRAEEE 9606 22724069 t lperfetto "Moreover, we find that the cpc's catalytic subunit, aurora b kinase, phosphorylates one of the three human snf7 paralogues-chmp4c-in its c-terminal tail, a region known to regulate its ability to form polymers and associate with membranes. Phosphorylation at these sites appears essential for chmp4c function because their mutation leads to cytokinesis defects. The introduction of the s214a and s215a mutations together with s210a almost completely abolished aurora b phosphorylation" SIGNOR-197971 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 AURKB protein Q96GD4 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-100165 AURKB protein Q96GD4 UNIPROT GFAP protein P14136 UNIPROT "down-regulates activity" phosphorylation Thr7 tSAARRSY -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-100173 AURKB protein Q96GD4 UNIPROT KIF2C protein Q99661 UNIPROT up-regulates phosphorylation Ser95 IQKQKRRsVNSKIPA 9606 17567953 t lperfetto "Here, we show that the binding of mcak to chromosome arms is also regulated by aurora b and that aurora b-dependent chromosome arm and centromere localization is regulated by distinct two-site phosphoregulatory mechanisms. Mcak association with chromosome arms is promoted by phosphorylation of t95 on mcak, whereas phosphorylation of s196 on mcak promotes dissociation from the arms. Although targeting of mcak to centromeres requires phosphorylation of s110 on mcak, dephosphorylation of t95 on mcak increases the binding of mcak to centromeres." SIGNOR-155890 AURKB protein Q96GD4 UNIPROT NDC80 protein O14777 UNIPROT down-regulates phosphorylation Ser44 KPTFGKLsINKPTSE 9606 20471944 t lperfetto "To determine whether the combinatorial regulation of the kmn network by aurora b observed in vitro is critical to controlling kinetochore-microtubule attachments in vivo, we next investigated the effect of the phosphomimetic (to aspartate) and nonphosphorylatable (to alanine) mutants of dsn1, knl1, and ndc80 in vertebrate cells. We predicted that both types of mutations in critical phosphorylation sites would affect chromosome segregation, since preventing the inactivation of inappropriately attached kinetochores by aurora b (in the nonphosphorylatable mutant) or constitutively inactivating this attachment (in the phosphomimetic mutant)." SIGNOR-165558 AURKB protein Q96GD4 UNIPROT NINL protein Q9Y2I6 UNIPROT up-regulates phosphorylation Ser585 RLPKNRHsPSWSPDG 9606 20864540 t lperfetto "Importantly, nlp is characterized as a novel substrate of aurora b and can be phosphorylated by aurora b. The specific phosphorylation sites are mapped at ser-185, ser-448, and ser-585. The phosphorylation at ser-448 and ser-585 is likely required for nlp association with aurora b and localization at midbody. Meanwhile, the phosphorylation at ser-185 is vital to nlp protein stability. Disruptions of these phosphorylation sites abolish cytokinesis and lead to chromosomal instability." SIGNOR-168053 AXIN1 protein O15169 UNIPROT SMAD7 protein O15105 UNIPROT down-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." SIGNOR-145851 AXIN2 protein Q9Y2T1 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates 9606 BTO:0000149 11940574 f gcesareni "Although wnts act to stabilize _-catenin levels in the cytosol and nucleus, a multiprotein complex containing adenomatous polyposis coli, glycogen synthase kinase 3_, and axin1 or its homolog axin2/axil/conductin promotes _-catenin phosphorylation and subsequent proteasomal degradation." SIGNOR-116480 BAG1 protein Q99933 UNIPROT PPP1R15A protein O75807 UNIPROT "down-regulates activity" 9606 BTO:0000038 12724406 t lperfetto "Human BAG-1 proteins bind to the cellular stress response protein GADD34 and interfere with GADD34 functions.|BAG-1 negatively modulates GADD34-bound PP1 activity, and the expression of BAG-1 isoforms can also mask GADD34-mediated inhibition of colony formation and suppression of transcription. Our findings suggest that BAG-1 may function to suppress the GADD34-mediated cellular stress response and support a role for BAG-1 in the survival of cells undergoing stress." SIGNOR-254117 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 BAK1 protein Q16611 UNIPROT ENDOG protein Q14249 UNIPROT up-regulates 9606 12941691 f gcesareni "We show that the mitochondrial outer-membrane permeabilization induced by bax-, tbid- or bax/bak-dependent pro-apoptotic drugs results in the release of cytochrome c, smac/diablo and htra2/omi, but that subsequent caspase activation is required to induce the translocation of endog in addition to aif into the cytosol." SIGNOR-86406 BAK/BAX complex SIGNOR-C96 SIGNOR Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 23567751 f lperfetto "The mitochondrial pathway of apoptosis proceeds when the outer mitochondrial membrane (OMM) is compromised by the pro-apoptotic BCL-2 family members, BAK and BAX. Once activated, BAK and BAX form proteolipid pores in the OMM leading to mitochondrial outer membrane permeabilization (MOMP), and the release of inner membrane space proteins, such as cytochrome c, which promotes caspase activation." SIGNOR-256636 BAX protein Q07812 UNIPROT BAK/BAX complex SIGNOR-C96 SIGNOR "form complex" binding 9606 21195116 t lperfetto "Bax and Bak are two nuclear-encoded proteins present in higher eukaryotes that are able to pierce the mitochondrial outer membrane to mediate cell death by apoptosisHere, we review how Bax and Bak change conformation and oligomerize, as well as how oligomers might form a pore" SIGNOR-209660 BAD protein Q92934 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 "BTO:0002418;BTO:0002552;BTO:0000018; BTO:0002207;BTO:0002203" 23725574 f irozzo "Our data suggested that increased expression of BAD enhance apoptosis and has negative influence on cell proliferation and tumor growth in NSCLC. Bad is a new potential target for tumor interventions." SIGNOR-256260 BAX protein Q07812 UNIPROT DIABLO protein Q9NR28 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-170969 BBC3 protein Q9BXH1 UNIPROT BCL2L1 protein Q07817 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 15694340 t lperfetto "Only bimbh3 and bbc3 had comparable strong affinities for all the prosurvival proteins. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1.Puma promotes bax translocation by both by directly interacting with bax and by competitive binding to bcl-x(l) in uv-induced apoptosis." SIGNOR-133811 BCL2L1 protein Q07817 UNIPROT APAF1 protein O14727 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 9539746 t lperfetto "These experiments demonstrate that bcl-xl associates with caspase-9 and apaf-1, and show that bcl-xl inhibits the maturation of caspase-9 mediated by apaf-1." SIGNOR-56399 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 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 BCL3 protein P20749 UNIPROT MDM2 protein Q00987 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000776;BTO:0000785 16384933 f gcesareni "One mechanism by which this inhibition occurs is through bcl-3-mediated induction of the p53 inhibitor hdm2. Both stable and transient overexpression of bcl-3 leads to increased hdm2 expression, and small interfering rna (sirna)-mediated knockdown of bcl-3 blocks expression of hdm2. ( articolo-abstract)" SIGNOR-143403 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 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 BID protein P55957 UNIPROT BAK1 protein Q16611 UNIPROT up-regulates binding 9606 17289999 t gcesareni "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 c. these data support a two-class model for bh3 domains: bid-like domains that activate bax, bak and bad-like domains that sensitize by occupying the pocket of antiapoptotic members." SIGNOR-152992 BIRC2 protein Q13490 UNIPROT RIPK1 protein Q13546 UNIPROT "up-regulates activity" ubiquitination 9606 BTO:0000459 18621737 t amattioni "c-IAPs are ubiquitin ligases capable of promoting polymerization of non-degradative Lys-63-linked polyubiquitin chains on the critical adapter in the canonical NF-_B signaling pathway, RIP1. c-IAPs are E3 ligases and RIP1 ubiquitination is critical for propagation of TNF_-induced NF-_B activation" SIGNOR-179439 BIRC3 protein Q13489 UNIPROT BIRC3 protein Q13489 UNIPROT "down-regulates activity" ubiquitination 9606 BTO:0000567 14960576 t amattioni "Ciap1 and ciap2 undergo autoubiquitination and degradation upon binding to the iap antagonist second mitochondrial activator of caspases (smac)/direct iap-binding protein with low pi (diablo), which is released from the mitochondria." SIGNOR-121880 BIRC3 protein Q13489 UNIPROT TRAF2 protein Q12933 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 18997794 t lperfetto "Traf3-binding receptors stabilize nik by activating ciap-dependent degradation of traf2 and traf3." SIGNOR-182131 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 MST1 protein P26927 UNIPROT MST1R protein Q04912 UNIPROT up-regulates binding 9606 BTO:0000801;BTO:0000876 8062829 t gcesareni "P185ron is a tyrosine kinase activated by msp" SIGNOR-31107 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-182493 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 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 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 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 BMPR1B protein O00238 UNIPROT SMAD9 protein O15198 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-255264 BMPR2 protein Q13873 UNIPROT BMPR1A protein P36894 UNIPROT "up-regulates activity" binding 10090 10712517 t ggiuliani "Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known BMP type I receptors (BR-Ia and BR-Ib) and the BMP type II receptor (BR-II). Coimmunoprecipitation studies detected the formation of heteromeric and homomeric complexes among all the BMP receptor types even in the absence of ligand." SIGNOR-255781 BRAF protein P15056 UNIPROT MAP2K1 protein Q02750 UNIPROT "up-regulates activity" phosphorylation Ser252 DIWSMGLsLVEMAVG -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-39062 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 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 Calcineurin complex SIGNOR-C155 SIGNOR 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-252343 CAMK4 protein Q16566 UNIPROT HNRNPL protein P14866 UNIPROT up-regulates phosphorylation Ser544 GKSERSSsGLLEWES 9606 22570490 t lperfetto "Here we show that the regulation of the stress axis-regulated exon of the slo1 potassium channel transcripts by membrane depolarization requires a highly conserved camkiv target serine (ser-513) of the heterogeneous ribonucleoprotein l. Ser-513 phosphorylation within the rna recognition motif 4 enhanced heterogeneous ribonucleoprotein l interaction with the camkiv-responsive rna element 1 of stress axis-regulated exon and inhibited binding of the large subunit of the u2 auxiliary factor u2af65." SIGNOR-197367 AFDN protein P55196 UNIPROT RIT1 protein Q92963 UNIPROT "up-regulates activity" binding 9606 10545207 t miannu "Rit and Rin were found to interact with the known Ras binding proteins RalGDS, Rlf, and AF-6/Canoe. These interactions were GTP and effector domain dependent and suggest that RalGDS, Rlf, and AF-6 are Rit and Rin effectors." SIGNOR-220917 ATP smallmolecule CHEBI:15422 ChEBI AMPK complex SIGNOR-C15 SIGNOR down-regulates binding 9606 21399626 t lperfetto "Atp promotes dephosphorylation of catalytic subunit, rendering the ampk enzyme inactive" SIGNOR-217481 Calcineurin complex SIGNOR-C155 SIGNOR 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-252325 Calcineurin complex SIGNOR-C155 SIGNOR 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-252327 Calcineurin complex SIGNOR-C155 SIGNOR 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-252329 Calcineurin complex SIGNOR-C155 SIGNOR 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-252330 Calcineurin complex SIGNOR-C155 SIGNOR 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-252331 Calcineurin complex SIGNOR-C155 SIGNOR 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-252342 CALM1 protein P62158 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 CAMK2A protein Q9UQM7 UNIPROT CD44 protein P16070 UNIPROT "up-regulates activity" phosphorylation Ser706 LNGEASKsQEMVHLV 9606 BTO:0000452 11463356 t lperfetto "In previous studies we have demonstrated that a key control point for this receptor is the phosphorylation of CD44 on a conserved cytoplasmic serine residue, Ser(325). This modification is not required for efficient ligand binding, but is an essential component of CD44-dependent cell migration on a hyaluronan substratum. We demonstrate here that cd44 is phosphorylated to high stoichiometry in resting cells and that ca(2+)/calmodulin-dependent protein kinase ii is a cd44 ser(325) kinase." SIGNOR-109502 CAMK2B protein Q13554 UNIPROT CYLD protein Q9NQC7 UNIPROT up-regulates phosphorylation Ser362 FYTLNGSsVDSQPQS 9606 24614225 t lperfetto "Purified camkii phosphorylates cyld on at least three residues (s-362, s-418, and s-772 on the human cyld protein q9nqc7-1) and promotes its deubiquitinase activity." SIGNOR-25334 IL15RA protein Q13261 UNIPROT JAK3 protein P52333 UNIPROT up-regulates 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-256226 CAMK2A protein Q9UQM7 UNIPROT EGFR protein P00533 UNIPROT "down-regulates activity" phosphorylation Ser1166 QKGSHQIsLDNPDYQ 9606 BTO:0000007 10347170 t llicata " We show that serines 1046/1047 are sites for CaM kinase II phosphorylation, although there is a preference for serine 1047, which resides within the consensus -R-X-X-S-. In addition, we have identified major phosphorylation sites at serine 1142 and serine 1057, which lie within a novel -S-X-D- consensus. Mutation of serines 1046/1047 in full-length EGFR enhanced both fibroblast transformation and tyrosine autokinase activity that was significantly potentiated by additional mutation of serines 1057 and 1142. A single CaM kinase II site was also identified at serine 744 within sub-kinase domain III, and autokinase activity was significantly affected by mutation of this serine to an aspartic acid making this site appear constitutively phosphorylated. We have addressed the mechanism by which CaM kinase II phosphorylation of the EGFR might regulate receptor autokinase activity and show that this modification can hinder association of the cytoplasmic tail with the kinase domain to prevent an enzyme-substrate interaction. " SIGNOR-250624 CAMK2A protein Q9UQM7 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser579 NVKSKIGsTENLKHQ 9606 BTO:0000590 10090741 t lperfetto "We found that when tau was first phosphorylated by A-kinase, C-kinase, cdk5, or CaM kinase II and then by GSK-3, its binding to microtubules was inhibited by 45, 61, 78, and 79%, respectively. Further, the kinase combinations cdk5/GSK-3 and CaM kinase II/GSK-3 rapidly phosphorylated the sites Thr 231 and Ser 235. When these sites were individually replaced by Ala and the phosphorylation experiments repeated, tau binding to microtubules was inhibited by 54 and 71%, respectively. By comparison, when Ser 262 was replaced by Ala, tau binding to microtubules was inhibited by only 8% after phosphorylation by CaM kinase II." SIGNOR-249314 CAMK2A protein Q9UQM7 UNIPROT OPRM1 protein P35372 UNIPROT down-regulates phosphorylation Ser270 SVRMLSGsKEKDRNL 9606 BTO:0000671 10908300 t gcesareni "The decrease in mu-opioid receptor activity after chronic agonist exposure (1 microm [d-ala(2),n-mephe(4),gly-ol(5)]-enkephalin) is largely due to kinase-mediated phosphorylation of intracellular receptor domains. We have recently shown that the substitution of two putative ca(2+)/calmodulin-dependent protein kinase ii (camk ii) phosphorylation sites, s261 and s266, by alanines in the third intracellular loop of the rat mu-opioid receptor (rmor1) confers resistance to camk ii-induced receptor desensitization." SIGNOR-79682 CAMK2A protein Q9UQM7 UNIPROT PDC protein P20941 UNIPROT unknown phosphorylation Ser54 KEILRQMsSPQSRNG 11331285 t llicata "In this study, we report that Pd was rapidly phosphorylated by Ca(2+)/calmodulin-dependent kinase II, resulting in 100-fold greater inhibition of Gbetagamma binding than cAMP-dependent protein kinase phosphorylation. Furthermore, Pd phosphorylation by Ca(2+)/calmodulin-dependent kinase II at Ser-54 and Ser-73 led to binding of the phosphoserine-binding protein 14-3-3." SIGNOR-250636 CAMK2A protein Q9UQM7 UNIPROT SRF protein P11831 UNIPROT "up-regulates activity" phosphorylation Ser103 RGLKRSLsEMEIGMV 10753652 t llicata "Skeletal muscle CaMKII enriches in nuclei and phosphorylates myogenic factor SRF at multiple sites. | Microsequencing of these phosphorylated peptides identified that both Ser-103 and a novel residue, Thr-160 in the MADS box of SRF, were sites of phosphorylation. | The location of Thr-160 in the 3-D structure of SRF suggests that its phosphorylation by nuclear CaMKII may directly influence DNA binding of SRF and other MADS box factors." SIGNOR-250638 CAMK2A protein Q9UQM7 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser16 KELEKRAsGQAFELI 9606 BTO:0000661 9686569 t gcesareni "Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. In vitro, ser16 of recombinant human stathmin was phosphorylated also by purified cam kinase ii, and in vivo, cam kinase ii activity was indeed stimulated in cd2-triggered jurkat cells. Altogether, our results favor an association of cam kinase ii activity with costimulatory signals of t lymphocyte activation and phosphorylation of stathmin on ser16." SIGNOR-59354 CAMK2B protein Q13554 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Thr472 ICALRHLtSRHQEAE 9606 BTO:0000938 24117889 t lperfetto "Camkii represses transcriptionally active _-catenin to mediate acute ethanol neurodegeneration and can phosphorylate _-catenincamkii can directly phosphorylate _-catenin. Using targeted mutagenesis we identified camkii phosphorylation sites within human _-catenin at t332, t472, and s552." SIGNOR-202833 CAMK2B protein Q13554 UNIPROT ETS1 protein P14921 UNIPROT "down-regulates activity" phosphorylation Ser282 NSLQRVPsYDSFDSE BTO:0003637 12475968 t llicata "Increased Transactivation of the GM-CSF Promoter/Enhancer by Ets1 with Mutated CaMK II Sites | Significantly, phosphorylation of Ets1 by Ca2+-dependent pathways is thought to inhibit DNA binding in vitro. To analyze the role of these four serines, S251, S257, S282, and S285, in transcription, we constructed three mutant derivatives of human Ets1 " SIGNOR-250686 CAMK2D protein Q13557 UNIPROT SCN5A protein Q14524 UNIPROT down-regulates phosphorylation Thr594 LHGKKNStVDCNGVV 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-197067 CAMK2G protein Q13555 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser498 RPLSRTQsSPLPQSP 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-85102 CAMK2G protein Q13555 UNIPROT NCOR2 protein Q9Y618 UNIPROT down-regulates phosphorylation Ser2418 AKVSGRPsSRKAKSP 9606 22888005 t gcesareni "The kinase activity of camkii was essential for the activation of notch signaling. We also determined that camkii could enhance the association between notch1-ic and rbp-jk. Furthermore, the physical association between rbp-jk and smrt was substantially suppressed by camkii. We demonstrated that camkii directly bound and phosphorylated smrt at ser-1407, thereby facilitating smrt translocation from the nucleus to the cytoplasm and proteasome-dependent degradation." SIGNOR-191777 CAMK2G protein Q13555 UNIPROT SPR protein P35270 UNIPROT unknown phosphorylation Ser213 QQLARETsVDPDMRK 11825621 t llicata "Phosphorylation sites of rat sepiapterin reductase (rSPR) by Ca2+/calmodulin-dependent protein kinase II were determined in the present study. Using specific monoclonal anti-phospho-Ser and -Thr antibodies, we found that only Ser residues of rSPR were phosphorylated. We constructed several point mutants of SPR by systematically replacing the three Ser residues by Ala ones. These mutants showed that all three Ser residues, i.e. S46, S196, and S214, of rSPR were phosphorylated. We also recognized that only Ser-213 of human SPR was phosphorylated. " SIGNOR-250705 CAMK2G protein Q13555 UNIPROT TH protein P07101 UNIPROT "up-regulates activity" phosphorylation Ser19 KGFRRAVsELDAKQA 1680128 t llicata " In both isoforms, Ser-40 was found to be phosphorylated by PKA, and Ser-19 and Ser-40 were found to be phosphorylated by CaM-PK II. The putative phosphorylation site generated by alternative splicing (Ser-31) was phosphorylated specifically by CaM-PK II in TH-2 only. | Unlike TH-1, phosphorylation of TH-2 by CaM-PK II resulted in an increase of the Ki value for dopamine." SIGNOR-250709 CAMK4 protein Q16566 UNIPROT CREBBP protein Q92793 UNIPROT "up-regulates activity" phosphorylation Ser302 PQLASKQsMVNSLPT BTO:0000938 11970865 t llicata "Ser301 of CBP was identified as a major target of CaMKIV phosphorylation in vitro and in vivo. CaM kinase inhibitors attenuated phosphorylation at Ser301 and blocked CBP-dependent transcription. Additionally, mutation of Ser301 impaired NMDA- and CaMKIV-stimulated transcription. These findings demonstrate that activity-induced CaMKIV signaling contributes to CREB/CBP-dependent transcription by phosphorylating CBP at Ser301." SIGNOR-250710 CAMK4 protein Q16566 UNIPROT HDAC4 protein P56524 UNIPROT "down-regulates activity" phosphorylation Ser467 RPLGRTQsAPLPQNA BTO:0001938 11470791 t llicata "CaMKIV phosphorylates HDAC4 in vitro and promotes its nuclear-cytoplasmic shuttling in vivo. | Thus, CaMKIV can phosphorylate HDAC4 at Ser-467 and/or Ser-632 in vitro. | Collectively, our results suggest that CaMKIV reverses the transcriptional repression activity of HDAC4 by stimulating the mobilization of HDAC4 out of the nucleus." SIGNOR-250711 CAMK4 protein Q16566 UNIPROT HDAC4 protein P56524 UNIPROT "down-regulates activity" phosphorylation Ser632 RPLSRAQsSPASATF BTO:0001938 11470791 t llicata "CaMKIV phosphorylates HDAC4 in vitro and promotes its nuclear-cytoplasmic shuttling in vivo. | Thus, CaMKIV can phosphorylate HDAC4 at Ser-467 and/or Ser-632 in vitro. | Collectively, our results suggest that CaMKIV reverses the transcriptional repression activity of HDAC4 by stimulating the mobilization of HDAC4 out of the nucleus." SIGNOR-250712 CAPN3 protein P20807 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-251602 CAPN3 protein P20807 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-251604 CAPN3 protein P20807 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-251607 CAPN3 protein P20807 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-251605 CARM1 protein Q86X55 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-255980 CARM1 protein Q86X55 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates methylation 10090 BTO:0001103 29163212 t FFerrentino "The first evidence alluding to a role of PRMTs in mediating skeletal muscle plasticity, specifically myogenesis, arose from the identification of CARM1 as a glucocorticoid receptor-interacting protein 1 (GRIP1) binding protein. (Chen et al., 2000). Here, GRIP1 and MEF2 were co-expressed in the nucleus during skeletal muscle differentiation. These initial findings led to an investigation that revealed that this methyltransferase was responsible for coactivating the transcription of myocyte enhancer factor-2C (MEF2C) via GRIP1 " SIGNOR-255964 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser255 ELSPTTLsPVNHSLD 9606 26194464 t "MARCO ROSINA" "Taken together, ERK-mediated Smad2 linker phosphorylation is responsible for TH17 differentiation" SIGNOR-255020 CASP12 protein Q6UXS9 UNIPROT CASP9 protein P55211 UNIPROT up-regulates cleavage 9606 BTO:0000222 12097332 t gcesareni "Caspase-12 specifically cleaves and activates procaspase-9 in cytosolic extracts. Results suggest that caspase-12 can activate caspase-9 without involvement of cytochromec." SIGNOR-90318 CASP1 protein P29466 UNIPROT "Caspase 1 complex" complex SIGNOR-C220 SIGNOR "form complex" binding cleavage:Asp119 PAPQAVQdNPAMPTS 7721861 t lperfetto "The interleukin-1 beta-converting enzyme is a heterodimeric cysteine protease that is produced as a 45-kDa precursor. The full-length precursor form of the enzyme was expressed in Escherichia coli as insoluble inclusion bodies. Following solubilization and refolding of the 45-kDa protein, autoproteolytic conversion to a heterodimeric form containing 10- and 20-kDa subunits was observed." SIGNOR-256386 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 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 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 CASP3 protein P42574 UNIPROT "Caspase 3 complex" complex SIGNOR-C221 SIGNOR "form complex" binding cleavage:Asp28 IHGSESMdSGISLDN 15115390 t lperfetto "Caspases are expressed as inactive proenzymes of 30−50 kDa that include an amino-terminal domain of variable length and sequence that is followed by two domains of conserved sequences:  a large subunit (approximately 20 kDa, designated p17 in caspase-3) and a small carboxy-terminal subunit (approximately 10 kDa, designated p12 in caspase-3). Activation is accomplished by proteolytic cleavage between these domains and subsequent assembly of heterotetramers that contain two copies each of the large and small subunits but lack the amino-terminal domains." SIGNOR-256387 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 Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates 10090 25787076 f miannu "The UPS by itself degrades actomyosin and myofibrillar proteins slowly, but when caspase-3 is activated, it cleaves actomyosin and the myofibrillar proteins to provide substrates for degradation in the UPS . Caspase-3 also can cleave specific subunits of the 19 S proteasome particle, which stimulates the proteolytic activity of the 26S proteasome[...] These results indicate that caspase-3 participates in the muscle proteolysis that is present in tumor-bearing mice" SIGNOR-255336 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 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 Protein_degradation phenotype SIGNOR-PH96 SIGNOR up-regulates 10090 25787076 f miannu "The UPS by itself degrades actomyosin and myofibrillar proteins slowly, but when caspase-3 is activated, it cleaves actomyosin and the myofibrillar proteins to provide substrates for degradation in the UPS . Caspase-3 also can cleave specific subunits of the 19 S proteasome particle, which stimulates the proteolytic activity of the 26S proteasome[...] These results indicate that caspase-3 participates in the muscle proteolysis that is present in tumor-bearing mice." SIGNOR-255337 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR 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-256453 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR 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-256440 "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 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR DNA_fragmentation phenotype SIGNOR-PH22 SIGNOR up-regulates 9606 BTO:0000142 10200555 f amattioni "Caspase-3 is required for blebbing, chromatin condensation and dna fragmentation" SIGNOR-256478 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR 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-256439 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR GSN protein A2A418 UNIPROT "up-regulates activity" cleavage Asp403 WRDPDQTdGLGLSYL 9606 BTO:0001374 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-256433 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR Membrane_blebbing phenotype SIGNOR-PH24 SIGNOR up-regulates 9606 BTO:0000142 10200555 f amattioni "Caspase-3 is required for blebbing, chromatin condensation and dna fragmentation" SIGNOR-256481 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR 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-256456 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR Protein_degradation phenotype SIGNOR-PH96 SIGNOR up-regulates 10090 25787076 f miannu "The UPS by itself degrades actomyosin and myofibrillar proteins slowly, but when caspase-3 is activated, it cleaves actomyosin and the myofibrillar proteins to provide substrates for degradation in the UPS . Caspase-3 also can cleave specific subunits of the 19 S proteasome particle, which stimulates the proteolytic activity of the 26S proteasome[...] These results indicate that caspase-3 participates in the muscle proteolysis that is present in tumor-bearing mice." SIGNOR-256476 "Caspase 8 complex" complex SIGNOR-C231 SIGNOR BID protein P55957 UNIPROT "up-regulates activity" cleavage Asp60 GYDELQTdGNRSSHS 9606 BTO:0000093 9727492 t amattioni "Caspase-8 cleaves bid at aspartic acid residue 60 (asp60) cleavage of bid by casp8 releases its potent proapoptotic activity" SIGNOR-256443 "Caspase 8 complex" complex SIGNOR-C231 SIGNOR CASP3 protein P42574 UNIPROT "up-regulates activity" cleavage 10090 BTO:0002572 10988287 t amattioni "The temporal pattern of caspase-8 cleavage is consistent with the possibility that it may function upstream of caspase-3 during p53-dependent apoptosis." SIGNOR-256451 "Caspase 8 complex" complex SIGNOR-C231 SIGNOR CASP3 protein P42574 UNIPROT "up-regulates activity" cleavage 9606 21295084 t amattioni "Triggering of the DISC leads to caspase-8 activation. Active caspase-8 cleaves caspase-3 which, in type I cells, leads to cell death induction." SIGNOR-256452 "Caspase 8 complex" complex SIGNOR-C231 SIGNOR CASP7 protein P55210 UNIPROT up-regulates cleavage 9606 18073771 t amattioni "Active caspase-8 then proteolytically processes and activates caspase-7" SIGNOR-256454 "Caspase 8 complex" complex SIGNOR-C231 SIGNOR 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-256459 "Caspase 8 complex" complex SIGNOR-C231 SIGNOR 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-256479 "Caspase 8 complex" complex SIGNOR-C231 SIGNOR CYCS protein P99999 UNIPROT "up-regulates activity" 9606 BTO:0000661 10364179 f "Translocation from Mitochondria to Cytosol" lperfetto "Caspase-8 triggered rapid cytochrome c release from mitochondria. The effect was indirect." SIGNOR-256473 "Caspase 8 complex" complex SIGNOR-C231 SIGNOR RIPK1 protein Q13546 UNIPROT "down-regulates activity" cleavage Asp324 RMQSLQLdCVAVPSS 9606 BTO:0000007;BTO:0000093;BTO:0000567 10521396 t amattioni "These results suggested that the aspartic acid at position 324 is the cleavage site of ripk1. In this study we found that receptor-interacting protein (ripk1) is cleaved by casp8 when cells undergo tnf-induced apoptosis. The cleavage of ripk1 abolished its nf-kb inducing ability." SIGNOR-256442 BTK protein Q06187 UNIPROT WAS protein P42768 UNIPROT unknown phosphorylation Tyr291 AETSKLIyDFIEDQG 9606 BTO:0000776 10068673 t llicata "These results indicate that btk phosphorylates wasp on its tyrosine 291" SIGNOR-86004 "Caspase 9 complex" complex SIGNOR-C229 SIGNOR CASP3 protein P42574 UNIPROT "up-regulates activity" cleavage 9606 15657060 t lperfetto "Following autoprocessing in the apoptosome, caspase-9 cleaves and activates caspase-3." SIGNOR-256448 "Caspase 9 complex" complex SIGNOR-C229 SIGNOR CASP3 protein P42574 UNIPROT "up-regulates activity" cleavage 9606 BTO:0000567 9390557 t lperfetto "Activated caspase-9 in turn cleaves and activates caspase-3. Mutation of the active site of caspase-9 attenuated the activation of caspase-3 and cellular apoptotic response in vivo, indicating that caspase-9 is the most upstream member of the apoptotic protease cascade." SIGNOR-256462 CBFA2T3/ZNF651 complex SIGNOR-C197 SIGNOR ZNF652 protein Q9Y2D9 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 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-253955 CBFbeta-MYH11 "fusion protein" SIGNOR-FP3 SIGNOR RUNX1 protein Q01196 UNIPROT "up-regulates quantity by stabilization" binding 10090 BTO:0000596  11179217 t "The present work further demonstrated that β/SMMHC is more potent in protecting RUNX1 from proteolysis. These observations collectively suggest that β/SMMHC may make an extra contact with the negative regulatory domains of RUNX1 in addition to the Runt domain, thereby gaining an increased ability to interact with RUNX1 than from direct contact with β/SMMHC." SIGNOR-255743 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 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 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 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 CCP110 protein O43303 UNIPROT Cilium_assembly phenotype SIGNOR-PH64 SIGNOR down-regulates 9606 18694559 f miannu "CEP290 cooperates with Rab8a to promote ciliogenesis and this function is antagonized by CP110. CP110 in this complex is to keep CEP290 inactive in growing cells until cells are ready to undergo ciliogenesis as they transit into the quiescent state" SIGNOR-252150 CCT137690 chemical CID:25154041 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190895 CCT137690 chemical CID:25154041 PUBCHEM AURKC protein Q9UQB9 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190898 CCT239065 chemical CID:44131523 PUBCHEM BRAF protein P15056 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190907 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 CDC14A protein Q9UNH5 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-164408 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 BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Tyr86 VADIDGQyAMTRAQR 9606 BTO:0001271 17318191 t lperfetto "Bcr_abl_mediated phosphorylation of y86 could induce a conformational change of __catenin impairing its binding to axin" SIGNOR-153435 CDC14A protein Q9UNH5 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-248832 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 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 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 CDH4 protein P55283 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" 10090 BTO:0000165 18701479 t lperfetto "Together, these data suggest that R-cadherin expression inhibits myogenesis and induces myoblast transformation through Rac1 activation. Therefore, the properties of R-cadherin make it an attractive target for therapeutic intervention in RMS." SIGNOR-253103 CDK1 protein P06493 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr70 RNSPVTKtPPRDLPT 9606 BTO:0000567 11553333 t lperfetto "Phosphorylation of 4e-bp1 is critical in causing its dissociation from eif-4e, leaving 4e available to form translationally active eif-4f complexes, switching on mrna translation. We show that the cyclin-dependent kinase, cdc2, phosphorylates 4e-bp1 at thr-70 and that phosphorylation of this site is permissive for ser-65 phosphorylation. Crucially, the increased phosphorylation of 4e-bp1 during mitosis results in its complete dissociation from eif-4e." SIGNOR-110416 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 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 PPP1CA protein P62136 UNIPROT down-regulates phosphorylation Thr320 NPGGRPItPPRNSAK 9606 BTO:0000661 12202491 t gcesareni "In this study, we observed that phosphorylation of protein phosphatase 1 (pp1) on thr(320) is reduced in brain extracts from egr-1(-/-) mice, indicating that a kinase downstream of egr-1 phosphorylates pp1. 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-92261 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1924 SPTSPKYsPTSPTYS 9606 22012619 t miannu "Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna" SIGNOR-176829 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 CDK1 protein P06493 UNIPROT MASTL protein Q96GX5 UNIPROT "up-regulates activity" phosphorylation Thr194 NMMDILTtPSMAKPR 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-243414 CDK1 protein P06493 UNIPROT MCL1 protein Q07820 UNIPROT up-regulates phosphorylation Thr92 EVPDVTAtPARLLFF 9606 BTO:0000150 SIGNOR-C17 18676833 t gcesareni "Mcl-1 is phosphorylated at two sites in mitosis, ser64 and thr92. Phosphorylation of thr92 by cyclin-dependent kinase 1 (cdk1)-cyclin b1 initiates degradation of mcl-1 in cells arrested in mitosis by microtubule poisons." SIGNOR-179804 CDK1 protein P06493 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates phosphorylation Ser200 YSGDSDAsSPRSNCS 9606 SIGNOR-C17 21902831 t gcesareni "Phosphorylation of myod at s200 is common to other cdks, such as the mitotic cyclin b/cdk1, which may prevent inappropriate myod accumulation during mitosis." SIGNOR-176505 CDK1 protein P06493 UNIPROT NPM1 protein P06748 UNIPROT "down-regulates activity" phosphorylation Thr237 KQEKTPKtPKGPSSV 9606 14670079 t gcesareni "We further demonstrate that phospho-mkk1/mkk2 antibodies recognize npm on the c-terminal region, which is phosphorylated by cdc2 (cell division control kinase-2) during g2/m-phase. biochemical and immunocytochemistry analyses verified that the phospho-mkk1/mkk2 antibodies cross-reacted with npm that was phosphorylated at thr234 and thr237 during g2/m-phase, which are the same sites that are targeted by cdc2 (cell division cycle protein-2) during mitosis." SIGNOR-120334 CDK1 protein P06493 UNIPROT NUP98 protein P52948 UNIPROT up-regulates phosphorylation Ser612 LNNSNLFsPVNRDSE 9606 21335236 t gcesareni "We show that npc disassembly is a phosphorylation-driven process, dependent on cdk1 activity and supported by members of the nima-related kinase (nek) family. mitotic hyperphosphorylation of nup98 is accomplished by multiple kinases, including cdk1 and neks." SIGNOR-172217 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 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 TK1 protein P04183 UNIPROT down-regulates phosphorylation Ser13 LPTVLPGsPSKTRGQ 9606 14697231 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-120368 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 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 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 unknown phosphorylation Thr694 DSPSDGGtPGRMPPQ 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-104707 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 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT "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-249668 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 FZR1 protein Q9UM11 UNIPROT "down-regulates activity" phosphorylation Ser163 KSQKLLRsPRKPTRK 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-250733 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT "up-regulates activity" phosphorylation Thr518 SMDNTPHtPTPFKNA 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-250740 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 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 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 PRKAR1A protein P10644 UNIPROT up-regulates phosphorylation Ser83 DSREDEIsPPPPNPV 9606 BTO:0000093 SIGNOR-C16 16582606 t gcesareni "In this context, we have identified rialpha as a novel substrate for the g(1)/s-cyclin-dependent kinase, cdk2/cyclin e, and found that rialpha is specifically phosphorylated at the serine residue." SIGNOR-145577 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 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 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 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 2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide chemical CHEBI:91353 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck lperfetto SIGNOR-244854 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 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 CDK5 protein Q00535 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-249321 CDK5 protein Q00535 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-249326 CDK5 protein Q00535 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-249322 CDK5 protein Q00535 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-249323 CDK5 protein Q00535 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-249324 CDK5 protein Q00535 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-249325 CDK5 protein Q00535 UNIPROT STXBP2 protein Q15833 UNIPROT down-regulates phosphorylation Thr572 IGSSHILtPTRFLDD 9606 BTO:0000938 17716669 t lperfetto "It was shown that munc18 inhibition of neuronal syntaxin 1 can be overcome by cdk5 phosphorylation, indicating that structural change disrupts the syntaxin-munc18 interaction." SIGNOR-157528 1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-2-benzimidazolamine chemical CHEBI:91451 ChEBI RAF1 protein P04049 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206385 canertinib chemical CHEBI:61399 ChEBI ERBB2 protein P04626 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191012 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR DCX protein O43602 UNIPROT unknown phosphorylation Ser28 SRMNGLPsPTHSAHC -1 14741103 t llicata "In order to determine the sites of phosphorylation by Cdk5, serine or threonine in the nine potential sites were substituted with alanine by site-directed mutagenesis to create mutant Dcx proteins. These were analyzed by co-transfection of 293T cells with cdk5/p35. All-sites-A mutant Dcx showed no slower migrating species on Western analysis, indicating that removal of all nine possible sites is sufficient to block the phosphorylation by Cdk5/p35 (Figure 3D). However, each single mutant Dcx retains the slower migrating species similar to the wild-type Dcx, suggesting that any single mutation is not sufficient to block phosphorylation by Cdk5/p35. | Therefore, S28 residue may be a substrate in vitro, but our best efforts failed to detect phosphorylation of S28 in vivo." SIGNOR-250654 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR 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-251589 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser552 VVRTPPKsPSSAKSR 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-251590 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR 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-251591 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR 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-251592 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR 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-251597 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR 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-251593 CDK5 protein Q00535 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser20 PLSQETFsDLWKLLP 9606 BTO:0000938 17591690 t gcesareni "Here, we demonstrate for the first time that cdk5 interacts with p53 and increases its stability through posttranslational regulation, leading to accumulation of p53, particularly in the nucleus. We show that cdk5 phosphorylates p53 on ser15, ser33 and ser46 in vitro," SIGNOR-156418 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 PLK1 protein P53350 UNIPROT WEE1 protein P30291 UNIPROT down-regulates phosphorylation Ser53 GHSTGEDsAFQEPDS 9606 BTO:0000567 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-139477 R547 chemical CID:6918852 PUBCHEM CCNE1 protein P24864 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206355 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR 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-251595 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 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 PRKCD protein Q05655 UNIPROT DAB2 protein P98082 UNIPROT down-regulates phosphorylation Ser24 QAAPKAPsKKEKKKG 9606 BTO:0000782 15280374 t gcesareni "Mutational analysis revealed that a dab2 ser(24) phosphorylation mutant (s24a) abrogated the inhibitory function of dab2." SIGNOR-127198 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 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 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 CDK9 protein P50750 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates 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 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 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 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 "PH 797804" chemical CHEBI:82715 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206079 CDK9 protein P50750 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Thr179 PQSNIPEtPPPGYLS 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-161682 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 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 CDON protein Q4KMG0 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-150276 CDR2 protein Q01850 UNIPROT NUF2 protein Q9BZD4 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 20383333 f lperfetto "Additionally, cdr2 knockdown lead to a decrease (Table 3) in four other transcripts (AURKA, CENPE, SPC25 and TTK), which are involved in kinetochore and spindle biology" SIGNOR-252022 CDR2 protein Q01850 UNIPROT TTK protein P33981 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 20383333 f lperfetto "Additionally, cdr2 knockdown lead to a decrease (Table 3) in four other transcripts (AURKA, CENPE, SPC25 and TTK), which are involved in kinetochore and spindle biology" SIGNOR-252021 CDX1 protein P47902 UNIPROT VIL1 protein P09327 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19371634 f miannu "We concluded that cdx2 regulates intestinal villin expression through recruiting brm-type swi/snf complex to the villin promoter." SIGNOR-185483 CDX2 protein Q99626 UNIPROT VIL1 protein P09327 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19371634 f miannu "We concluded that cdx2 regulates intestinal villin expression through recruiting brm-type swi/snf complex to the villin promoter." SIGNOR-185486 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 SLC19A1 protein P41440 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 15652157 t "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-254053 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 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 TNFAIP6 protein P98066 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 7876106 t "In cotransfection experiments, the C/EBP beta protein trans-activated 10-15-fold the cAspAT gene promoter in HepG2 cells." SIGNOR-254055 LDB1 protein Q86U70 UNIPROT LHX2 protein P50458 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 17005264 t miannu "Cofactor CLIM2 promotes the repressive action of LIM homeodomain transcription factor Lhx2 in the expression of porcine pituitary glycoprotein hormone alpha subunit gene." SIGNOR-223962 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 CEBPG protein P53567 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-254058 CENPE protein Q02224 UNIPROT Spindle_assembly phenotype SIGNOR-PH60 SIGNOR up-regulates 20383333 f lperfetto "Additionally, cdr2 knockdown lead to a decrease (Table 3) in four other transcripts (AURKA, CENPE, SPC25 and TTK), which are involved in kinetochore and spindle biology" SIGNOR-252013 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 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 TP53 protein P04637 UNIPROT "up-regulates activity" phosphorylation Ser378 SKKGQSTsRHKKLMF 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-217857 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 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 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 CHEK2 protein O96017 UNIPROT MDM4 protein O15151 UNIPROT down-regulates 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 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 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 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 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 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 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 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 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 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 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-DRB3 protein P79483 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-254011 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 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 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 CLOCK/ARNTL2 complex SIGNOR-C196 SIGNOR SERPINE1 protein P05121 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001615 22198637 t lperfetto "Both CLOCK:ARNTL and CLOCK:ARNTL2 heterodimers powerfully activate the promoter of the PAI-1 gene, officially called SERPINE1 and located on the seventh chromosome (7q21.3-q22), underlying the circadian variation in circulating PAI-1" SIGNOR-253713 CLOCK/ARNTL complex SIGNOR-C195 SIGNOR SERPINE1 protein P05121 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001615 22198637 t lperfetto "Both CLOCK:ARNTL and CLOCK:ARNTL2 heterodimers powerfully activate the promoter of the PAI-1 gene, officially called SERPINE1 and located on the seventh chromosome (7q21.3-q22), underlying the circadian variation in circulating PAI-1" SIGNOR-253712 CLOCK/ARNTL complex SIGNOR-C195 SIGNOR 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-253703 COX5B protein P10606 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR down-regulates 10090 BTO:0000165 18701479 f lperfetto "Together, these data suggest that R-cadherin expression inhibits myogenesis and induces myoblast transformation through Rac1 activation. Therefore, the properties of R-cadherin make it an attractive target for therapeutic intervention in RMS." SIGNOR-253104 dacomitinib chemical CHEBI:132268 ChEBI ERBB4 protein Q15303 UNIPROT down-regulates "chemical inhibition" 9606 23405260 t gcesareni "The goal of this study was to compare dacomitinib (pf-00299804), a next generation small molecule tyrosine kinase inhibitor that irreversibly blocks multiple her family receptors (her-1 (egfr), her-2 and her-4 tyrosine kinases), to cetuximab, the current fda approved anti-egfr medication for hnscc and erlotinib, an egfr specific small molecule tyrosine kinase inhibitor." SIGNOR-200908 AKT2 protein P31751 UNIPROT AKT1S1 protein Q96B36 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C3 17386266 t gcesareni "Insulin-stimulated phosphorylation of pras40 by akt/pkb suppresses its mtorc1 inhibitory activity." SIGNOR-153931 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 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 COL6A6 protein A6NMZ7 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 BTO:0001103;BTO:0002319 21949456 t "Muscle basement membrane consists primarily of a type IV collagen network, however types VI, XV, and XVIII are also present." SIGNOR-254677 COX5B protein P10606 UNIPROT Cell_cycle_exit phenotype SIGNOR-PH41 SIGNOR down-regulates 10090 BTO:0000165 18701479 f lperfetto "Together, these data suggest that R-cadherin expression inhibits myogenesis and induces myoblast transformation through Rac1 activation. Therefore, the properties of R-cadherin make it an attractive target for therapeutic intervention in RMS.|R-cadherin expression inhibits myoblast cell cycle exit" SIGNOR-253105 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 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 CRYAB protein P02511 UNIPROT CRYGD protein P07320 UNIPROT "up-regulates activity" binding -1 t "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 CSNK2A1 protein P68400 UNIPROT MDC1 protein Q14676 UNIPROT up-regulates phosphorylation Ser376 LQESQAGsDTDVEEG 9606 18678890 t gcesareni "The mdc1-nbs1 interaction occurs through a specific region (residues 200-420) of mdc1, which contains multiple consensus casein kinase 2 (ck2) phosphorylation sites." SIGNOR-179879 CNR1 protein P21554 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-256867 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 CRYAB protein P02511 UNIPROT CRYGS protein P22914 UNIPROT "up-regulates activity" binding -1 t "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 CRYBB2 protein P43320 UNIPROT Maintenance_of_lens_transparency phenotype SIGNOR-PH65 SIGNOR up-regulates 9606 16319073 f 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-252151 CRYGS protein P22914 UNIPROT Maintenance_of_lens_transparency phenotype SIGNOR-PH65 SIGNOR up-regulates 9606 BTO:0001874 10521291 f "The γ-crystallin proteins are tightly folded in two domains with no free loops. It is possible that the R58H mutation destabilizes the contact between lens-fiber cells, which is critical for the maintenance of lens transparency. Improper folding of CRYGD, the most abundantly expressed γ-crystallin in the lens, could well cause protein aggregation and lens opacification." SIGNOR-253625 CSK protein P41240 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 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 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 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 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 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 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 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 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 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 CSNK1G1 protein Q9HCP0 UNIPROT FOXO1 protein Q12778 UNIPROT "down-regulates activity" phosphorylation Ser325 SSNASTIsGRLSPIM -1 11980723 t llicata "Phosphorylation of Ser319 forms a consensus sequence for phosphorylation by CK1, allowing it to phosphorylate Ser322, which in turn primes the CK1-catalysed phosphorylation of Ser325 | Multisite phosphorylation of the region containing Ser319, Ser322, Ser325 and Ser329 provides a signal for the nuclear exclusion of FKHR" SIGNOR-250821 CSNK1G1 protein Q9HCP0 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Ser325 SSNASTIsGRLSPIM -1 11980723 t llicata "Phosphorylation of Ser319 forms a consensus sequence for phosphorylation by CK1, allowing it to phosphorylate Ser322, which in turn primes the CK1-catalysed phosphorylation of Ser325 | Multisite phosphorylation of the region containing Ser319, Ser322, Ser325 and Ser329 provides a signal for the nuclear exclusion of FKHR" SIGNOR-252902 CSNK2A1 protein P68400 UNIPROT AIP protein O00170 UNIPROT unknown phosphorylation Ser43 FHYRTLHsDDEGTVL 9534 BTO:0001538 12361709 t llicata "Protein kinase CK2 (CK2) was identified as the 45-kDa kinase from COS 1 cell or liver extracts that was responsible for phosphorylation of serine 43 in the XAP2 peptide 39-57. Loss of phosphorylation at any or all of the serine residues did not significantly affect the ability of XAP2-FLAG to bind to the murine AhR in rabbit reticulocyte lysate or Hsp90 in COS-1 cells." SIGNOR-250824 CSNK2A1 protein P68400 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Thr387 LPWDLWTtSTDLVQP 9606 BTO:0000567 16945112 t lperfetto "Amphiphysins interact directly with clathrin and have a function in clathrin-mediated synaptic vesicle recycling and clathrin-mediated endocytosis. The n-terminal domain of clathrin bound to unphosphorylated amphiphysin-1, but not to the phosphorylated protein. The assumption that casein kinase 2 phosphorylates amphiphysin-1 at t350 and t387 was corroborated by experiments showing that: casein kinase 2 phosphorylated these residues directly in vitro,. upon activation by nerve growth factor, casein kinase 2 phosphorylates amphiphysin-1 and thereby regulates the endocytosis of clathrin-coated vesicles via the interaction between clathrin and amphiphysin." SIGNOR-149318 CSNK2A1 protein P68400 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. AQP4 phosphorylation by CKII may thus provide a mechanism that regulates AQP4 cell surface expression. | 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-250827 CSNK2A1 protein P68400 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-250830 CSNK2A1 protein P68400 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-250831 CSNK2A1 protein P68400 UNIPROT CBX5 protein P45973 UNIPROT up-regulates phosphorylation Ser12 TKRTADSsSSEDEEE 9606 21245376 t gcesareni "Hp1_ was multiply phosphorylated at n-terminal serine residues (s11-14) in human and mouse cells and that this phosphorylation enhanced hp1_'s affinity for h3k9me. Unphosphorylatable mutant hp1_ exhibited severe heterochromatin localization defects in vivo, and its prolonged expression led to increased chromosomal instability." SIGNOR-171699 CSNK2A1 protein P68400 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" phosphorylation Thr393 RNLSDAAtKQEGMEG 9534 BTO:0000298 12700239 t llicata "The major CK2 phosphorylation site in this domain is Thr393, a solvent-accessible residue in a key hinge region of the molecule. Mutation of this single amino acid reduces beta-catenin phosphorylation, cotranscriptional activity, and stability." SIGNOR-250849 CSNK2A1 protein P68400 UNIPROT DDIT3 protein P35638 UNIPROT "down-regulates activity" phosphorylation Ser14 PFSFGTLsSWELEAW 9606 BTO:0000567 12876286 t llicata "CHOP transcription factor phosphorylation by casein kinase 2 inhibits transcriptional activation. | The serine to alanine substituted site CHOP mutant was not phosphorylated by CK2, indicating that serines 14–15 and 30–31 of CHOP are the CK2 phosphoacceptor sites" SIGNOR-250850 CSNK2A1 protein P68400 UNIPROT DDIT3 protein P35638 UNIPROT "down-regulates activity" phosphorylation Ser15 FSFGTLSsWELEAWY 9606 BTO:0000567 12876286 t llicata "CHOP transcription factor phosphorylation by casein kinase 2 inhibits transcriptional activation. | The serine to alanine substituted site CHOP mutant was not phosphorylated by CK2, indicating that serines 14–15 and 30–31 of CHOP are the CK2 phosphoacceptor sites" SIGNOR-250851 CSNK2A1 protein P68400 UNIPROT DDIT3 protein P35638 UNIPROT "down-regulates activity" phosphorylation Ser31 DLQEVLSsDENGGTY 9606 BTO:0000567 12876286 t llicata "CHOP transcription factor phosphorylation by casein kinase 2 inhibits transcriptional activation. | The serine to alanine substituted site CHOP mutant was not phosphorylated by CK2, indicating that serines 14–15 and 30–31 of CHOP are the CK2 phosphoacceptor sites" SIGNOR-250853 CSNK2A1 protein P68400 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-250854 CSNK2A1 protein P68400 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-250855 CSNK2A1 protein P68400 UNIPROT EGR1 protein P18146 UNIPROT "down-regulates activity" phosphorylation Thr391 TTHIRTHtGEKPFAC 10090 BTO:0000944 8662759 t llicata "Casein kinase II associates with Egr-1 and acts as a negative modulator of its DNA binding and transcription activities in NIH 3T3 cells. | There are three CKII recognition sites (S376XXD, T389XE, and T516XXXD) in fragment 10." SIGNOR-250857 CSNK2A1 protein P68400 UNIPROT ESR1 protein P03372 UNIPROT down-regulates phosphorylation Ser559 PTSRGGAsVEETDQS 9606 BTO:0000150;BTO:0000567 20043841 t lperfetto "Additionally protein kinase ck2 was identified as a kinase that phosphorylated eralpha at s282 and s559 s282 and s559 represent the second and third sites of er_ regulation by ck2. Remarkably, mutation of s282 or s559 to alanine resulted in near opposite functional effects on er_ as compared to mutation of s167 to alanine. Er_ ligand independent transcriptional activity was markedly enhanced upon mutation of s282 and s559 to alanine" SIGNOR-162657 CSNK2A1 protein P68400 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-250874 CSNK2A1 protein P68400 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-250875 CSNK2A1 protein P68400 UNIPROT GYS1 protein P13807 UNIPROT unknown phosphorylation Ser653 PSLSRHSsPHQSEDE -1 2117608 t llicata "With all four peptides, prior phosphorylation significantly stimulated phosphorylation by casein kinase I. From these results, we propose that there are substrates for casein kinase I for which prior phosphorylation is a critical determinant of protein kinase action." SIGNOR-250881 CSNK2A1 protein P68400 UNIPROT GYS1 protein P13807 UNIPROT unknown phosphorylation Ser698 PEWPRRAsCTSSTSG -1 2117608 t llicata "With all four peptides, prior phosphorylation significantly stimulated phosphorylation by casein kinase I. From these results, we propose that there are substrates for casein kinase I for which prior phosphorylation is a critical determinant of protein kinase action." SIGNOR-250883 CSNK2A1 protein P68400 UNIPROT GYS1 protein P13807 UNIPROT unknown phosphorylation Thr713 SKRNSVDtATSSSLS -1 2117608 t llicata "With all four peptides, prior phosphorylation significantly stimulated phosphorylation by casein kinase I. From these results, we propose that there are substrates for casein kinase I for which prior phosphorylation is a critical determinant of protein kinase action." SIGNOR-250884 CSNK2A1 protein P68400 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-250888 CSNK2A1 protein P68400 UNIPROT HES6 protein Q96HZ4 UNIPROT "up-regulates activity" phosphorylation Ser183 GPGDDLCsDLEEAPE -1 12972610 t llicata "Hes6 inhibits the interaction of Hes1 with its transcriptional corepressor Gro/TLE. Moreover, it promotes proteolytic degradation of Hes1. This effect is maximal when both Hes1 and Hes6 contain the WRPW motif and is reduced when Hes6 is mutated to eliminate a conserved site (Ser183) that can be phosphorylated by protein kinase CK2. " SIGNOR-250890 CSNK2A1 protein P68400 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-250892 CSNK2A1 protein P68400 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-250893 CSNK2A1 protein P68400 UNIPROT HOXB7 protein P09629 UNIPROT "down-regulates activity" phosphorylation Ser133 IYPWMRSsGTDRKRG 10090 BTO:0002882 11290787 t llicata "Thus, we concluded that CKII can phosphorylate HOXB7 in vitro and that this phosphorylation occurs at both of the CKII target sites, S133 and T204. | Wild-type HOXB7 inhibited the differentiation of 32D cells, whereas mutations in the Pbx-binding pentapeptide motif or the DNA-binding homeodomain, as well as internal deletions of the N-terminal unique region, blocked this effect. Interestingly, mutations eliminating two target sites for casein kinase II, the glutamate-rich C terminus, or the first 14 amino acids of HOXB7, led to enhanced 32D differentiation." SIGNOR-250896 CSNK2A1 protein P68400 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Ser24 GYLRKPKsMHKRFFV -1 8349691 t llicata "These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1." SIGNOR-250907 LRRK2 protein Q5S007 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000938 24916379 t lperfetto "Expression of wild-type LRRK2 promoted neuronal survival against apoptosis through activation of the downstream effector, Akt by phosphorylation of Ser473. Phosphorylated Akt in turn inhibited FOXO 1 signaling" SIGNOR-252598 CSNK2A1 protein P68400 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-250922 CSNK2A1 protein P68400 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-250923 CSNK2A1 protein P68400 UNIPROT MYH9 protein P35579 UNIPROT up-regulates phosphorylation Ser1943 RKGAGDGsDEEVDGK 9606 22123909 t gcesareni "In egf-stimulated cells, the myosin-iia heavy chain is phosphorylated on the casein kinase 2 site (s1943)" SIGNOR-177818 CSNK2A1 protein P68400 UNIPROT MYH9 protein P35579 UNIPROT up-regulates phosphorylation Ser1943 RKGAGDGsDEEVDGK 9606 BTO:0000150 17567956 t gcesareni "In egf-stimulated cells, the myosin-iia heavy chain is phosphorylated on the casein kinase 2 site (s1943)" SIGNOR-155987 CSNK2A1 protein P68400 UNIPROT MYH9 protein P35579 UNIPROT up-regulates phosphorylation Ser1943 RKGAGDGsDEEVDGK 9606 BTO:0000150 21316371 t gcesareni "In egf-stimulated cells, the myosin-iia heavy chain is phosphorylated on the casein kinase 2 site (s1943)" SIGNOR-171907 CSNK2A1 protein P68400 UNIPROT PACS1 protein Q6VY07 UNIPROT "up-regulates activity" phosphorylation Ser278 SPDIDNYsEEEEESF 10090 BTO:0003532 14633983 t llicata "Phosphorylation of Ser278 by CK2 or a Ser278-->Asp mutation increased the interaction between PACS-1 and cargo, whereas a Ser278-->Ala substitution decreased this interaction. Moreover, the Ser278-->Ala mutation yields a dominant-negative PACS-1 molecule that selectively blocks retrieval of PACS-1-regulated cargo molecules to the TGN." SIGNOR-250925 CSNK2A1 protein P68400 UNIPROT PIAS1 protein O75925 UNIPROT up-regulates phosphorylation Ser468 DLTIDSSsDEEEEEP 9606 19217413 t llicata "Ck2 phosphorylates serine residues adjacent to the sim of pias1 these findings show that the phosphosim module mediates binding to free sumo and sumo conjugates in a phosphorylation-dependent mode, with ck2 being the critical kinase involvedin this process." SIGNOR-184047 CSNK2A1 protein P68400 UNIPROT PPP1R1B protein Q9UD71 UNIPROT "up-regulates activity" phosphorylation Ser102 NLNENQAsEEEDELG -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-250927 CSNK2A1 protein P68400 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-250928 CSNK2A1 protein P68400 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-250929 CSNK2A1 protein P68400 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-250936 AGTR2 protein P50052 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-252268 CSNK2A1 protein P68400 UNIPROT PSMA3 protein P25788 UNIPROT unknown phosphorylation Ser250 SLKEEDEsDDDNM -1 8619999 t llicata "Several C8 protein constructs allow the location of the CKII phosphorylation sites to be the COOH terminal portion of the protein, and direct mutational analyses show that Ser-243 and Ser-250 are the residues of the C8 subunit phosphorylated by CKII. The in vitro phosphorylation of the proteasome by CKII does not affect its proteolytic activity (on proteins or fluorogenic synthetic peptides), therefore suggesting its involvement in the interaction of the proteasome with other cellular proteins, i.e. in the formation of the 26S complex and/or in the interaction with the nuclear translocation machinery." SIGNOR-250939 CSNK2A1 protein P68400 UNIPROT RNF7 protein Q9UBF6 UNIPROT up-regulates phosphorylation Thr10 DVEDGEEtCALASHS 9606 BTO:0000567 12748192 t lperfetto "Ckbbp1 is phosphorylated in vivo and threonine to alanine mutation at residue 10 abrogates the phosphorylation of ckbbp1 observed in vivo, indicating that ckii is a major kinase that is responsible for in vivo phosphorylation of ckbbp1. As compared with the wild-type ckbbp1 or ckbbp1t10e (in which threonine 10 is replaced by glutamate), overexpression of nonphosphorylatable ckbbp1 (ckbbp1t10a) results in accumulation of ikappabalpha and p27kip1." SIGNOR-101187 CSNK2A1 protein P68400 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser257 QIRLRRDsKEANARR -1 9677319 t llicata "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." SIGNOR-250945 CSNK2A1 protein P68400 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser273 AGTRRREsLGKKAKR -1 9677319 t llicata "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." SIGNOR-250947 CSNK2A1 protein P68400 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser290 GRIVARNsRKMAFRA -1 9677319 t llicata "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." SIGNOR-250948 CSNK2A1 protein P68400 UNIPROT SPIB protein Q01892 UNIPROT down-regulates phosphorylation Ser37 KHSSYPDsEGAPDSL 9606 10618498 t lperfetto "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. Mutations of the ckii phosphorylation sites increase the ability of spi-b to transactivate. Spi-b phosphorylation by ckii reduces its stability" SIGNOR-73891 CSNK2A1 protein P68400 UNIPROT SRF protein P11831 UNIPROT "up-regulates activity" phosphorylation Ser83 YSGSEGDsESGEEEE -1 2046671 t llicata "Casein kinase II (CKII) phosphorylates the mammalian transcription factor serum response factor (SRF) on a serine residue(s) located within a region of the protein spanning amino acids 70 to 92, thereby enhancing its DNA-binding activity in vitro. We report here that serine 83 appears to be the residue phosphorylated by CKII but that three other serines in this region can also be involved in phosphorylation and the enhancement of DNA-binding activity." SIGNOR-250958 CSNK2A1 protein P68400 UNIPROT SRF protein P11831 UNIPROT "up-regulates activity" phosphorylation Ser85 GSEGDSEsGEEEELG -1 2046671 t llicata "Casein kinase II (CKII) phosphorylates the mammalian transcription factor serum response factor (SRF) on a serine residue(s) located within a region of the protein spanning amino acids 70 to 92, thereby enhancing its DNA-binding activity in vitro.| Mutation of serine 85 alone had a smaller but significant effect on phosphorylation that may be due to alteration in the protein kinase recognition site." SIGNOR-250957 CSNK2A1 protein P68400 UNIPROT SSRP1 protein Q08945 UNIPROT "down-regulates activity" phosphorylation Ser510 SSSNEGDsDRDEKKR 9606 BTO:0000007 15659405 t llicata "CK2 phosphorylates SSRP1 and inhibits its DNA-binding activity. | we identified serines 510, 657, and 688 as phosphorylation targets of CK2 in vitro. Mutagenesis of the three serines revealed that serine 510 was more important for the regulation of SSRP1 DNA-binding activity." SIGNOR-250959 CSNK2A1 protein P68400 UNIPROT SSRP1 protein Q08945 UNIPROT "down-regulates activity" phosphorylation Ser657 KSSSRQLsESFKSKE 9606 BTO:0000007 15659405 t llicata "CK2 phosphorylates SSRP1 and inhibits its DNA-binding activity. | we identified serines 510, 657, and 688 as phosphorylation targets of CK2 in vitro. Mutagenesis of the three serines revealed that serine 510 was more important for the regulation of SSRP1 DNA-binding activity." SIGNOR-250960 CSNK2A1 protein P68400 UNIPROT STX1A protein Q16623 UNIPROT up-regulates phosphorylation Ser14 ELRTAKDsDDDDDVA 9606 11846792 t lperfetto "In this report, we show that syntaxin-1a is phosphorylated in vitro by cki on thr21. Casein kinase ii (ckii) has been shown previously to phosphorylate syntaxin-1a in vitro and we have identified ser14 as the ckii phosphorylation site. the phosphorylation of syntaxin-1a by ckii enhances its capacity to associate with synaptotagmin [21]. Therefore, phosphorylation of ser14 by ckii suggests an important role for this residue in regulating the interaction between syntaxin-1a and synaptotagmin" SIGNOR-114840 CSNK2A1 protein P68400 UNIPROT VTN protein P04004 UNIPROT "up-regulates activity" phosphorylation Thr69 VTRGDVFtMPEDEYT 10090 BTO:0000944 9733784 t llicata " Therefore, we expressed Vn in a baculovirus system and show (i) that the CKII phosphorylation of wt-Vn enhances the adhesion of bovine aorta endothelial cells; (ii) that the double mutant T50E/T57E (in which the neutral Thr residues are replaced by the negatively charged Glu residues considered analogs of Thr-P) has a significantly enhanced capacity to promote cell adhesion and to accelerate cell spreading when compared with either wild-type Vn or to the neutral T50A/T57A mutant" SIGNOR-250970 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 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 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-250978 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 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 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 PTPRC protein P08575 UNIPROT "up-regulates activity" phosphorylation Ser1003 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 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR JUN protein P05412 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000675 23616010 lperfetto "The results revealed that PAR2-AP and FVIIa could upregulate c-Jun expression and c-Jun phosphorylation in SW620 cells in a time-dependent manner. The effect of FVIIa was significantly blocked by anti-TF and anti-PAR2 antibodies. Protein kinase C_ (PKC_) inhibitor safingol and extracellular signal-regulated kinase 1 and 2 (ERK1/2) inhibitor U0126 abrogated the activation of c-Jun" SIGNOR-236767 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 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 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 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 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 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 MYCN protein P04198 UNIPROT unknown phosphorylation Ser261 TSGEDTLsDSDDEDD -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-251014 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 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 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 PTPRC protein P08575 UNIPROT "up-regulates activity" phosphorylation Ser1002 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 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 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 protein O43524 UNIPROT "down-regulates activity" phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 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-183612 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 WAS protein P42768 UNIPROT "up-regulates activity" phosphorylation Ser483 KRSRAIHsSDEGEDQ 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-251048 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 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 CSNK2B protein P67870 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-251053 CSNK2B protein P67870 UNIPROT CSNK2B protein P67870 UNIPROT unknown phosphorylation Ser2 sSSEEVSW 9606 1939094 t llicata "Phosphorylation of the beta subunit of casein kinase II in human A431 cells. Identification of the autophosphorylation site | Cleavage of the beta subunit, that had been autophosphorylated in vitro, at tryptophan 9 and tryptophan 12 using N-chlorosuccinimide demonstrated that the autophosphorylation site is located near the amino terminus of the protein, most likely at serine 2 and serine 3." SIGNOR-251062 CSNK2B protein P67870 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" phosphorylation Ser29 VSHWQQQsYLDSGIH 9606 BTO:0000007 12432063 t llicata "We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin" SIGNOR-251065 CSNK2B protein P67870 UNIPROT EIF5 protein P55010 UNIPROT "up-regulates activity" phosphorylation Ser174 DKENGSVsSSETPPP 9606 BTO:0001938 11861906 t llicata "Mass spectrometric analysis of maximally in vitro phosphorylated eIF5 localized the major phosphorylation sites at Ser-387 and Ser-388 near the C-terminus of eIF5. These serine residues are embedded within a cluster of acidic amino acid residues and account for nearly 90% of the total in vitro eIF5 phosphorylation. A minor phosphorylation site at Ser-174 was also observed. | The results suggest that phosphorylation of eIF5 may have a role in stimulating the rate of eIF5-promoted GTP hydrolysis." SIGNOR-251068 CSNK2B protein P67870 UNIPROT OCLN protein Q16625 UNIPROT unknown phosphorylation Ser408 DYTTGGEsCDELEED 9606 BTO:0002043 12804768 t llicata "Mutagenesis of serine 407 to alanine resulted in reduced ability of the kinase to phosphorylate occludin. The threonine 403 to alanine mutant had a smaller effect but the double mutant (T403/S407A) was even less phosphorylated than either of the single mutants. These data are consistent with the claim that CK2 is the kinase in brain extracts responsible for phosphorylation of occludin." SIGNOR-251079 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1714 SPTSPSYsPTSPSYS -1 22137580 t "Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat." SIGNOR-248786 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1724 SPSYSPTsPSYSPTS -1 22137580 t "Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat." SIGNOR-248776 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1735 SPTSPSYsPTSPSYS -1 22137580 t "Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat." SIGNOR-248788 "CHIR 99021" chemical CHEBI:91091 ChEBI GSK3A protein P49840 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190997 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1738 SPSYSPTsPSYSPTS -1 22137580 t "Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat." SIGNOR-248777 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1763 TPTSPSYsPTSPSYS -1 22137580 t "Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat." SIGNOR-248789 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1784 TPTSPNYsPTSPSYS -1 22137580 t "Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat." SIGNOR-248790 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1787 SPNYSPTsPSYSPTS -1 22137580 t "Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat." SIGNOR-248779 CTDSP1 protein Q9GZU7 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" dephosphorylation Ser204 NHSMDAGsPNLSPNP 9606 BTO:0000007 17035229 t "SCP1 Dephosphorylates Smad2/3 in the Linkers|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-248791 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 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 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 CTDSPL protein O15194 UNIPROT RB1 protein P06400 UNIPROT "up-regulates activity" dephosphorylation Ser807 PGGNIYIsPLKSPYK 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-248304 CTDSPL protein O15194 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-248315 CTDSPL protein O15194 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-248310 CTDSPL protein O15194 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-248309 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 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 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser21 TPPSTALsPGKMSEA 9606 BTO:0000007 21059642 t "The effect has been demonstrated using Q01196-8" lperfetto "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-216916 IL10RA protein Q13651 UNIPROT Phagocytosis phenotype SIGNOR-PH97 SIGNOR up-regulates BTO:0000801 BTO:0001103 22933625 f apalma "Recent findings have shown that IL-10 stimulation of macrophages isolated from skeletal muscles increases the phagocytic activity of macrophages" SIGNOR-255443 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 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 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 LOR 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 miR-155 mirna MI0000681 miRBase "up-regulates quantity by expression" "transcriptional regulation" 9606 26055960 f miannu "Our results suggest that activating mutation of FLT3 in AML can lead, through the induction of JUN, to an increased expression of miR-155, which then causes down-regulation of SPI1 and CEBPB and consequently may causes block of myeloid differentiation." SIGNOR-255801 JUN protein P05412 UNIPROT Monocyte_differentiation phenotype SIGNOR-PH101 SIGNOR up-regulates 10090 BTO:0000725 17041602 f miannu "These results show that restoration of c-Jun expression rescues the myelomonocytic differentiation block in preleukemic PU.1-knockdown bone marrow cells, suggesting that c-Jun is a critical downstream target in PU.1-knockdown HSCs." SIGNOR-256066 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 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 KDM2B protein Q8NHM5 UNIPROT RNF2 protein Q99496 UNIPROT "up-regulates activity" binding 9606 17296600 t miannu "BcoR and Fbxl10/Jhdm1B are among the most abundant Ring1B/Rnf2 interactors identified with the highest confidence, and their association has been validated by coimmunoprecipitation studies; hence we call this the Fbxl10-BcoR complex. The assembly of Fbxl10-BcoR complex(es), the associations among its various subunits, and its functional significance remain to be characterized but are presently under investigation." SIGNOR-252242 KDM5B protein Q9UGL1 UNIPROT CBX4 protein O00257 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 19336002 t miannu "Our results clearly showed that the PcG protein hPc2 interacted with the N-terminus of JARID1B both in vivo and in vitro. It is interesting that the C-terminus of hPc2 was essential for the interaction and transcriptional co-repression." SIGNOR-226447 KIT protein P10721 UNIPROT KIT protein P10721 UNIPROT "up-regulates activity" phosphorylation Tyr823 DIKNDSNyVVKGNAR 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-823 is the last tyrosine residue to be autophosphorylated" SIGNOR-102641 KLF10 protein Q13118 UNIPROT TGFBI protein Q15582 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007 18359287 t lperfetto "Analyzing the mechanism of TGFBI up-regulation in clear cell carcinoma, we identified a novel VHL target, a Kruppel-like transcriptional factor 10 (KLF10). The TGFBI promoter, which we isolated and studied in Luc-reporter assay, was induced by KLF10 but not hypoxia." SIGNOR-253212 KLF1 protein Q13351 UNIPROT FLI1 protein Q01543 UNIPROT "down-regulates activity" binding 10090 BTO:0004475 12556498 t irozzo "The present study also shows that EKLF itself inhibits FLI-1 activity. As suggested above for the inhibition of EKLF activity, the inhibition of FLI-1 activity most probably involves the indirect recruitment of EKLF to FLI-1 target promoters by protein-protein interaction." SIGNOR-256046 KMT2A protein Q03164 UNIPROT KAT8 protein Q9H7Z6 UNIPROT up-regulates binding 9606 15960975 t miannu "Mll1 and mof can form a stable complex in vivo / given that an interaction of dmof with msl1 through its zinc finger is essential for correct targeting of mof to the male x chromosome" SIGNOR-138245 MARK3 protein P27448 UNIPROT CDC25C protein P30307 UNIPROT "down-regulates activity" phosphorylation Ser216 SGLYRSPsMPENLNR 9534 BTO:0000298 9543386 t miannu "C-TAK1 protein kinase phosphorylates human Cdc25C on serine 216 and promotes 14-3-3 protein binding. Phosphorylation of serine 21 6 promotes 1 4-3-3 binding to Cdc25C and is inhibitory to Cdc25C function." SIGNOR-250176 KLF11 protein O14901 UNIPROT HBE1 protein P02100 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000664 10207080 f Regulation miannu "Transfection of K562 cells with FKLF cDNA enhanced the expression of the endogenous epsilon- and gamma-globin genes, suggesting an in vivo role of FKLF in fetal and embryonic globin gene expression." SIGNOR-251829 KLF15 protein Q9UIH9 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-253816 KLF15 protein Q9UIH9 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-253817 KLF2 protein Q9Y5W3 UNIPROT HBE1 protein P02100 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 15947087 f "Regulation of expression" miannu "Our results show that KLF2 positively regulates the human (ε) and murine (Ey and βh1) embryonic globin genes at both E10.5 and E12.5, in the yolk sac, which is the site of primitive erythropoiesis." SIGNOR-251830 KLF2 protein Q9Y5W3 UNIPROT mir-143 mirna MI0000459 miRBase "up-regulates quantity" "transcriptional regulation" 9606 BTO:0001949 22327366 t "In endothelial cells. KLF2 binds to the promoter and induces a signi cant upregulation of the miR-143/145 cluster" SIGNOR-255941 KLF2 protein Q9Y5W3 UNIPROT PPARG protein P37231 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 12426306 f fspada "Constitutive overexpression of klf2 but not klf15 potently inhibits peroxisome proliferator-activated receptor-gamma (ppargamma) expression with no effect on the upstream regulators c/ebpbeta and c/ebpdelta." SIGNOR-95519 KLF2 protein Q9Y5W3 UNIPROT PPARG protein P37231 UNIPROT down-regulates "transcriptional regulation" 9606 12426306 f fspada "Constitutive overexpression of klf2 but not klf15 potently inhibits peroxisome proliferator-activated receptor-gamma (ppargamma) expression with no effect on the upstream regulators c/ebpbeta and c/ebpdelta." SIGNOR-210019 KLF2 protein Q9Y5W3 UNIPROT THBD protein P07204 UNIPROT "up-regulates quantity by expression" "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-254543 KLF3 protein P57682 UNIPROT CEBPA protein P49715 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 18391014 f fspada "We find that c/ebpalpha is derepressed in klf3 and ctbp knockout fibroblasts and adipocytes from klf3 knockout mice." SIGNOR-161370 KLF3 protein P57682 UNIPROT CEBPA protein P49715 UNIPROT down-regulates "transcriptional regulation" 9606 18391014 f fspada "We find that c/ebpalpha is derepressed in klf3 and ctbp knockout fibroblasts and adipocytes from klf3 knockout mice." SIGNOR-210117 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 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 KLF9 protein Q13886 UNIPROT SIN3A protein Q96ST3 UNIPROT "up-regulates activity" binding 10029 BTO:0000246 11438660 t miannu "detailed biochemical and functional analyses have demonstrated that the TIEG2 _-HRM domain interacts specifically with the PAH2 domain of mSin3A to repress transcription. our data suggest the presence of a conserved _-helical repression motif (_-HRM) in the TIEG and BTEB subfamilies of Sp1-like proteins that mediates transcriptional repression activity through interaction with the corepressor mSin3A." SIGNOR-222434 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 LAMA4 protein Q16363 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-253223 LPAR1 protein Q92633 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 9606 20331961 t milica "The receptor, now called lpa1, is a gpcr that couples to heterotrimeric g proteins (gi, gq, g12/13alpha subunits)." SIGNOR-164679 Laminin-10 complex SIGNOR-C182 SIGNOR "A6/b1 integrin" complex SIGNOR-C164 SIGNOR "up-regulates activity" binding 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-253222 Laminin-1 complex SIGNOR-C183 SIGNOR "A1/b1 integrin" complex SIGNOR-C159 SIGNOR "up-regulates activity" binding 9361014 t lperfetto "Using integrin-specific antibodies, recognition sites for the alpha1beta1 and alpha2beta1 integrins were identified in the short arms of both laminin alpha1- and alpha2-chain isoforms. Comparisons with a beta-alpha chimeric short arm protein possessing beta1-chain domain VI further localized these activities to alpha-chain domain VI." SIGNOR-253254 Laminin-1 complex SIGNOR-C183 SIGNOR "A2/b1 integrin" complex SIGNOR-C160 SIGNOR "up-regulates activity" binding 9361014 t lperfetto "Using integrin-specific antibodies, recognition sites for the alpha1beta1 and alpha2beta1 integrins were identified in the short arms of both laminin alpha1- and alpha2-chain isoforms. Comparisons with a beta-alpha chimeric short arm protein possessing beta1-chain domain VI further localized these activities to alpha-chain domain VI." SIGNOR-253255 Laminin-1 complex SIGNOR-C183 SIGNOR "A6/b1 integrin" complex SIGNOR-C164 SIGNOR "up-regulates activity" binding 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-253221 Laminin-1 complex SIGNOR-C183 SIGNOR "A6/b1 integrin" complex SIGNOR-C164 SIGNOR "up-regulates activity" binding 2351695 t lperfetto "In combination, the anti-alpha 1- and anti-alpha 6-specific antibodies completely inhibited JAR cell attachment to LN and fragment E1. Thus, the alpha 1/beta 1 and alpha 6/beta 1 integrin heterodimers each function as LN receptors and act together to mediate the interactions of human JAR choriocarcinoma cells with LN." SIGNOR-253256 Laminin-1 complex SIGNOR-C183 SIGNOR "a7/b1 integrin" complex SIGNOR-C126 SIGNOR "up-regulates activity" binding 1839357 t lperfetto "By using specific proteolytically derived fragments of laminin, it was determined that the alpha 7 beta 1 complex binds selectively to the E8 region, which represents part of the long arm of laminin." SIGNOR-253257 Laminin-5 complex SIGNOR-C184 SIGNOR "A3/b1 integrin" complex SIGNOR-C161 SIGNOR "up-regulates activity" binding 2032285 t lperfetto "Epiligrin, a new cell adhesion ligand for integrin alpha 3 beta 1 in epithelial basement membranes." SIGNOR-253252 LAMTOR3 protein Q9UHA4 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates binding 9606 9733512 t gcesareni "A protein called mp1 (mek partner 1) was identified that bound specifically to mek1 and erk1 and facilitated their activation. When overexpressed in cultured cells, mp1 enhanced activation of erk1 and activation of a reporter driven by the transcription factor elk-1." SIGNOR-59877 LCK protein P06239 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-249373 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 NFKBIA protein P25963 UNIPROT "down-regulates quantity by destabilization" phosphorylation Tyr42 DSMKDEEyEQMVKEL BTO:0000661 14534291 t lperfetto "Loss of tyrosine kinase p56lck in Jurkat cells abolished NFkappaB activation and partially suppressed and delayed phosphorylation of Tyr-42 of IkappaB upon pervanadate treatment." SIGNOR-249374 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 AMPK complex SIGNOR-C15 SIGNOR CRTC1 protein Q6UUV9 UNIPROT down-regulates phosphorylation 9606 21331044 t lperfetto "Here we show that both ampk and calcineurin modulate longevity exclusively through post-translational modification of crtc-1, the sole c. elegans crtc. We demonstrate that crtc-1 is a direct ampk target." SIGNOR-216529 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" binding 9606 BTO:0000782 phosphorylation:Tyr319 TSVYESPySDPEELK 10318843 t lperfetto "Phosphopeptide encompassing the motif harboring tyr319, ysdp, interacted with lcksh2;tyr319-mediated binding of the sh2 domain of lck is crucial for zap-70 activation and consequently for the propagation of the signaling cascade leading to t-cell activation" SIGNOR-67443 LEF1 protein Q9UJU2 UNIPROT CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000304 19653274 f irozzo "Expression of Lef-1 FL, but not the newly identified Lef-1 Deltaexon VI, induced the expression of the cell cycle regulating proteins c-myc and cyclin D1 in cooperation with beta-catenin and it enhanced cell proliferation" SIGNOR-256281 LEF1 protein Q9UJU2 UNIPROT CEBPA protein P49715 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19620402 f miannu "We have identified LEF-1 as a decisive transcription factor in granulopoiesis controlling proliferation and granulocytic differentiation by direct activation of its target gene, C/EBPalpha." SIGNOR-254551 LEF1 protein Q9UJU2 UNIPROT PITX2 protein Q99697 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887 19850024 f gcesareni "These results suggest that wnt/lef1 signaling regulates epaxial myogenesis via pitx2 but that this link is uncoupled in other regions of the body, emphasizing the unique molecular networks that control the development of various muscles in vertebrates. The pitx2 promoter contains tcf/lef binding sites and expression can be induced by licl, which activates the canonical wnt signaling pathway" SIGNOR-188730 "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 LEF1 protein Q9UJU2 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 17081971 f amattioni "The interaction of beta-catenin with the N terminus of tcf/lef transiently converts it into an activator, translating the Wnt signal into the transient transcription of Tcf target genes. The Wnt pathway has distinct transcriptional outputs, which are determined by the identity of the responding cell, and range from cell proliferation and survival to the terminal differentiation of postmitotic cells." SIGNOR-229767 "LE-TGN SNARE" complex SIGNOR-C157 SIGNOR M6PR protein P20645 UNIPROT "up-regulates activity" relocalization 9606 18195106 t lperfetto "These findings place the retromer complex upstream of both STX10 function and the GCC185 tethering complex in MPR transport. Together, our data suggest that STX10, STX16, Vti1a, and VAMP3 are important for the trafficking of both CD- and CI-MPRs.|Thus, MPRs must pass through a compartment of pH ≤ 5.5 before returning to the Golgi to carry out their biological function." SIGNOR-253084 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 lipopolysaccharide smallmolecule CHEBI:16412 ChEBI TLR4 protein O00206 UNIPROT "up-regulates activity" binding 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 LMO3 protein Q8TAP4 UNIPROT NHLH2 protein Q02577 UNIPROT "up-regulates activity" binding 9606 21573214 t miannu "Here we found that LMO3 forms a complex with HEN2 and acts as an upstream mediator for transcription of Mash1 in neuroblastoma." SIGNOR-254827 LMX1A protein Q8TE12 UNIPROT NLI/Lmx1.1/Isl1 complex SIGNOR-C103 SIGNOR "form complex" binding 9606 BTO:0000007 9452425 t lperfetto "Interactions between LIM transcription factors were also evaluated in vivo. Cotransfected FLAG-Lmx1.1 and HA-Isl1 were capable of interacting. the NLI-dependent interaction observed between Isl1 and Lmx1.1 is likely to represent a physiologically significant complex found in the endocrine cells of the pancreas." SIGNOR-236812 LMX1B protein O60663 UNIPROT "LMX1B/SFPQ/PSPC1 complex" complex SIGNOR-C106 SIGNOR "form complex" binding 10090 BTO:0000669 23308148 t miannu "LMX1B is part of a transcriptional complex with PSPC1 and PSF. This complex was observed in vitro and in vivo." SIGNOR-223966 LNX1 protein Q8TBB1 UNIPROT NUMB protein P49757 UNIPROT down-regulates ubiquitination 9606 11782429 t esanto "Lnx functions as a ring type e3 ubiquitin ligase that targets the cell fate determinant numb for ubiquitin-dependent degradation." SIGNOR-112201 LPAR1 protein Q92633 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 10090 BTO:0000944 15856019 t milica "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-236988 LRRK2 protein Q5S007 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation 9606 BTO:0000938 21658387 t lperfetto "Lrrk2 directly phosphorylates akt1 as a possible physiological substrate. These data establish that lrrk2 can protect neurons from apoptotic insult through a survival pathway in which lrrk2 signals to activate akt. Lrrk2-mediated phosphorylation of akt1 (ser473)" SIGNOR-244410 NR1H3 protein Q13133 UNIPROT BHLHE40 protein O14503 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000575 19032342 f lperfetto "LXRα and LXRβ are potent positive regulators for hepatic Dec1" SIGNOR-253691 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 LY96 protein Q9Y6Y9 UNIPROT HMGB1 protein P09429 UNIPROT "up-regulates activity" binding 10090 BTO:0000801 25559892 t gcesareni "Here we demonstrate that the extracellular TLR4 adaptor, myeloid differentiation factor 2 (MD-2), binds specifically to the cytokine-inducing disulfide isoform of HMGB1, to the exclusion of other isoforms. Using MD-2-deficient mice, as well as MD-2 silencing in macrophages, we show a requirement for HMGB1-dependent TLR4 signaling." SIGNOR-252058 LYL1 protein P12980 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-253923 LYL1 protein P12980 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-254208 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 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 PTPN6 protein P29350 UNIPROT "up-regulates activity" phosphorylation Tyr564 SKHKEDVyENLHTKN 9606 BTO:0000007 10574931 t "Lyn phosphorylates SHPTP1 at the C-terminal Tyr-564 site. Lyn-mediated phosphorylation of SHPTP1 stimulates SHPTP1 tyrosine phosphatase activity." SIGNOR-251409 LYN protein P07948 UNIPROT RGS16 protein O15492 UNIPROT "up-regulates activity" phosphorylation Tyr168 TLMEKDSyPRFLKSP -1 12588871 t "Lyn kinase phosphorylated recombinant RGS16 in vitro. Induction of RGS16 tyrosine phosphorylation was associated with increased RGS16 protein levels and enhanced GAP activity in cell membranes." SIGNOR-251410 MAP1LC3A protein Q9H492 UNIPROT Autophagosome_formation phenotype SIGNOR-PH36 SIGNOR up-regulates 9606 BTO:0001623 20921139 f lperfetto "We assessed both conversion of LC3-I to its cleaved and lipidated form LC3-II and its translocation to autophagic structures, two steps in autophagosome formation" SIGNOR-219406 MAP1LC3B protein Q9GZQ8 UNIPROT Autophagosome_formation phenotype SIGNOR-PH36 SIGNOR up-regulates 9606 BTO:0001623 20921139 f lperfetto "We assessed both conversion of LC3-I to its cleaved and lipidated form LC3-II and its translocation to autophagic structures, two steps in autophagosome formation" SIGNOR-219403 LPAR3 protein Q9UBY5 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-256747 "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 M2_polarization phenotype SIGNOR-PH55 SIGNOR IL10 protein P22301 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" BTO:0000801 BTO:0001103 22933625 f apalma "P38 activation contributes to the macrophage phenotype switch in injured muscle, which could elevate production of IL-10 (63), creating positive feedback for the phenotype switch" SIGNOR-255448 MACF1 protein Q9UPN3 UNIPROT AXIN1 protein O15169 UNIPROT "down-regulates quantity by destabilization" 9606 BTO:0000938 16815997 f gcesareni "In the absence of wnt, macf1 associated with a complex that contained axin, betBeta-catenin, gsk3beta, and apc. Upon wnt stimulation, macf1 appeared to be involved in the translocation and subsequent binding of the axin complex to lrp6 at the cell membrane. Macf1 is involved in the translocation of the complex containing axin, Beta-catenin, and gsk3_ but not apc from the cytosol to the cell membrane, where axin and macf1 bind to lrp-5/6. Subsequently, gsk3_ is inactivated by phosphorylation, axin is degraded, and Beta-catenin is released and enters the nucleus, where it can activate the wnt-responsive genes." SIGNOR-147448 MACF1 protein Q9UPN3 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "down-regulates activity" 9606 BTO:0000938 16815997 f lperfetto "In the absence of wnt, macf1 associated with a complex that contained axin, betBeta-catenin, gsk3beta, and apc. Upon wnt stimulation, macf1 appeared to be involved in the translocation and subsequent binding of the axin complex to lrp6 at the cell membrane. Macf1 is involved in the translocation of the complex containing axin, Beta-catenin, and gsk3_ but not apc from the cytosol to the cell membrane, where axin and macf1 bind to lrp-5/6. Subsequently, gsk3_ is inactivated by phosphorylation, axin is degraded, and Beta-catenin is released and enters the nucleus, where it can activate the wnt-responsive genes." SIGNOR-228000 MAFA protein Q8NHW3 UNIPROT GLP1R protein P43220 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17149590 f miannu "the expression of important beta cell genes, e.g. those encoding solute carrier family 2 (facilitated glucose transporter), member 2 (formerly known as GLUT2), pancreatic and duodenal homeobox factor 1 (PDX1), NK6 transcription factor-related, locus 1 (NKX6-1), glucagon-like peptide 1 receptor (GLP1R), prohormone convertase 1/3 (PCSK1) and pyruvate carboxylase (PC), was regulated positively by MAFA and negatively by DN-MAFA." SIGNOR-254563 MAFA protein Q8NHW3 UNIPROT NKX6-1 protein P78426 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17149590 f miannu "the expression of important beta cell genes, e.g. those encoding solute carrier family 2 (facilitated glucose transporter), member 2 (formerly known as GLUT2), pancreatic and duodenal homeobox factor 1 (PDX1), NK6 transcription factor-related, locus 1 (NKX6-1), glucagon-like peptide 1 receptor (GLP1R), prohormone convertase 1/3 (PCSK1) and pyruvate carboxylase (PC), was regulated positively by MAFA and negatively by DN-MAFA." SIGNOR-254564 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 MAML3 protein Q96JK9 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates binding 9606 12370315 t gcesareni "We report here the cloning and characterization of two new genes, maml2 and maml3, that also function as transcriptional coactivators for notch receptors." SIGNOR-254323 MAP1LC3A protein Q9H492 UNIPROT ATG3 protein Q9NT62 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-191543 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 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 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 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 MAPK1 protein P28482 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-249396 MAP3K20 protein Q9NYL2 UNIPROT MAP2K7 protein O14733 UNIPROT "up-regulates activity" phosphorylation 9606 11416147 t gcesareni "We show here that members of the mixed-lineage kinase (MLK) family (including MLK1, MLK2, MLK3, and dual leucine zipper kinase [DLK]) are expressed in neuronal cells and are likely to act between Rac1/Cdc42 and MKK4 and -7 in death signaling." SIGNOR-243345 MAP3K5 protein Q99683 UNIPROT MAP2K4 protein P45985 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-45366 MAP3K5 protein Q99683 UNIPROT MAP2K6 protein P52564 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-45353 MAP3K5 protein Q99683 UNIPROT MAP3K5 protein Q99683 UNIPROT "up-regulates activity" phosphorylation Thr813 GDNVLINtYSGVLKI 9606 17937911 t lperfetto "Reporter gene assays showed that all three identified in vitro autophosphorylation sites (thr813, thr838, thr842) regulate ask1 signalingmutation of thr838 drastically reduced reporter gene activity when compared to unstimulated control levels. Interestingly, mutation of the other two sites also provided a significant reduction in ask1 function (figure 6a), suggesting that autophosphorylation at the residues thr842 and thr813 regulates ask1 signaling." SIGNOR-158423 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 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 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 MAP4K1 protein Q92918 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates 9606 BTO:0002181 10224067 f gcesareni "These studies establish that hpk1 acts as an upstream activator for the tak1-sek-jnk1 module in relaying the tgf-_ signal into the nuclei in 293t cells." SIGNOR-67321 MAP4K1 protein Q92918 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates 9606 8824585 f gcesareni "These results demonstrated that the observed jnk1 activation was from hpk1 and not from other hpkl-associated kinases or from cross-reactive kinases precipitated by anti-hpk1 antibody." SIGNOR-43999 MAP4K2 protein Q12851 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates binding 9606 9712898 t gcesareni "The mekk1 associated with the gck carboxyl terminus is catalytically active." SIGNOR-59682 MAP4K3 protein Q8IVH8 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates phosphorylation 9606 9820741 t gcesareni "With regard to at least mekk1, serine/threonine kinases such as nik,glkand hpk1 appear also to be important for regulation" SIGNOR-61814 MAP4K4 protein O95819 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates phosphorylation 9606 8824585 t gcesareni "Hpk1 binds and phosphorylates mekk1 directly" SIGNOR-44040 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 MAPK1 protein P28482 UNIPROT FOS protein P01100 UNIPROT "up-regulates activity" phosphorylation Ser374 PSSDSLSsPTLLAL 9606 BTO:0000007 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 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 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 MAST1 protein Q9Y2H9 UNIPROT PTEN protein P60484 UNIPROT down-regulates phosphorylation 9606 15951562 t gcesareni "Mast1 was found to associate to pten." SIGNOR-138003 MAPK1 protein P28482 UNIPROT IRS1 protein P35568 UNIPROT "up-regulates activity" phosphorylation Ser636 SGDYMPMsPKSVSAP 10090 BTO:0002662 14579029 t lperfetto "MAP kinases and mTOR mediate insulin-induced phosphorylation of insulin receptor substrate-1 on serine residues 307, 612 and 632.|The phosphorylation of Serine(612/632) required the activation of the MAP kinase pathway following short-term insulin stimulation and activation of the PI 3-kinase/mTOR pathway following prolonged insulin stimulation" SIGNOR-249407 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 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 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 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 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 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 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 MKL1 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-195153 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 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 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 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 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 "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 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 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 PPARG protein P37231 UNIPROT down-regulates 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 PPARG protein P37231 UNIPROT down-regulates phosphorylation Ser112 AIKVEPAsPPYYSEK 9606 16574647 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-145195 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 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 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 SMAD1 protein Q15797 UNIPROT down-regulates 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 SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser214 PTSSDPGsPFQMPAD 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-52691 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 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 SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser208 DAGSPNLsPNPMSPA 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-161702 MAPK14 protein Q16539 UNIPROT DDIT3 protein P35638 UNIPROT "up-regulates activity" phosphorylation Ser79 EVTSTSQsPHSPDSS 9606 8650547 t lperfetto "...undergoes inducible phosphorylation on two adjacent serine residues (78 and 81). In vitro, chop is phosphorylated on these residues by p38 mitogen-activated protein kinase (map kinase). phosphorylation of chop on these residues enhanced its ability to function as a transcriptional activator." SIGNOR-42200 MAPK14 protein Q16539 UNIPROT DDIT3 protein P35638 UNIPROT "up-regulates activity" phosphorylation Ser82 STSQSPHsPDSSQSS -1 8650547 t miannu "CHOP, a member of the C/EBP family of transcription factors, mediates effects of cellular stress on growth and differentiation. It accumulates under conditions of stress and undergoes inducible phosphorylation on two adjacent serine residues (78 and 81). In vitro, CHOP is phosphorylated on these residues by p38 mitogen-activated protein kinase (MAP kinase)." SIGNOR-250096 MAPK14 protein Q16539 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Thr311 NSLALSLtADQMVSA 9606 12138194 t gcesareni "P38 mitogen-activated protein kinase was involved in estrogen receptor activation by estrogens and mekk1. Here, we report estrogen receptor-dependent p38 activation by estrogens in endometrial adenocarcinoma cells and in vitro and in vivo phosphorylation of the estrogen receptor alpha mediated through p38. The phosphorylation site was identified as threonine-311 (thr(311)), located in helix 1 of the hormone-binding domain." SIGNOR-90823 MAPK14 protein Q16539 UNIPROT STAT4 protein Q14765 UNIPROT up-regulates phosphorylation Ser721 PSDLLPMsPSVYAVL 9606 17502367 t gcesareni "All stats are phosphorylated on at least one serine residue in their tad specifically, ser727 in stats 1 and 3 and ser721 in stat4. Stat serine kinases have been identified through the use of inhibitors, dominant-negative alleles, and in vitro kinase assays. They include mapk (p38mapk: stats 1, 3, 4;erk: stat3, 5;jnk: stat3), pkc_ (stat1, stat3), mtor (stat3), nlk (stat3 (42)), and camkii and ikk_ (stat1 (39, 40, 43)).STAT Serine phosphorylation regulates transcriptional activity (see below)." SIGNOR-154787 MAPK15 protein Q8TD08 UNIPROT MAPK15 protein Q8TD08 UNIPROT up-regulates phosphorylation 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.Our results suggest that the activity of erk8 in transfected hek-293 cells depends on the relative rates of erk8 autophosphorylation" SIGNOR-142973 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 STK11 protein Q15831 UNIPROT "down-regulates activity" phosphorylation Ser428 SSKIRRLsACKQQ 9606 BTO:0001271 25846811 t lperfetto "Negative regulation of the LKB1/AMPK pathway by ERK in human acute myeloid leukemia cellsBRAFV600E activates downstream molecules, including ERK and p90 ribosomal S6 kinase (RSK), and leads to the phosphorylation of LKB-1 at Ser428 by these kinases. This cascade results in the dissociation of LKB1 from AMPK." SIGNOR-209876 MAPK1 protein P28482 UNIPROT TH protein P07101 UNIPROT up-regulates phosphorylation Ser62 SYTPTPRsPRFIGRR 9606 7901013 t "The effect has been demonstrated using P07101-2" 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 hydroxylase in vitro at comparable rates to other proteins thought to be physiological substrates of these protein kinases.The effect on activity of phosphorylating both ser31 and ser40 was not additive. The possible roles of mapkap kinase-1, mapkap kinase-2 and map kinase in the regulation of tyrosine hydroxylase in vivo are discussed." SIGNOR-34674 MAPK3 protein P27361 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Ser293 PAPARPRsPSQTRKG 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-126867 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 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 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 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 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 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 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 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 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 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 FOXO proteinfamily SIGNOR-PF27 SIGNOR "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-252961 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 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 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 H3F3A 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 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 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 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 IL16 protein Q14005 UNIPROT up-regulates phosphorylation Ser845 SIRQRISsFETFGSS 9606 BTO:0000782 14768064 t lperfetto "The precursor form of the cytokine il-16 (proil-16) was shown to be phosphorylated on ser144 in antigen receptor-, sdf1alpha- and il-2-activated t cells. Genetic and pharmacological-inhibitor experiments showed that the phosphorylation of proil-16 is dependent on activation of the kinases erk1/2. Il-16 is secreted by mitogen-activated t cells, and the biochemical link between proil-16 and erk1/2, revealed by studies with pap-1, prompted analysis of the role of map kinases in this response." SIGNOR-121856 AMPK complex SIGNOR-C15 SIGNOR NOS3 protein P29474 UNIPROT up-regulates phosphorylation Ser1177 TSRIRTQsFSLQERQ 9606 BTO:0000567 18303014 t lperfetto "The central finding of this report is that rosiglitazone rapidly stimulates no production and enos ser-1177 phosphorylation in an ampk-dependent manner" SIGNOR-216627 MAPK3 protein P27361 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser616 DDGYMPMsPGVAPVP 9606 BTO:0000783 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 IRS1 protein P35568 UNIPROT "up-regulates activity" phosphorylation Ser616 DDGYMPMsPGVAPVP 10090 BTO:0002662 14579029 t lperfetto "MAP kinases and mTOR mediate insulin-induced phosphorylation of insulin receptor substrate-1 on serine residues 307, 612 and 632.|The phosphorylation of Serine(612/632) required the activation of the MAP kinase pathway following short-term insulin stimulation and activation of the PI 3-kinase/mTOR pathway following prolonged insulin stimulation" SIGNOR-249410 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 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 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 NR3C1 protein P04150 UNIPROT down-regulates phosphorylation Ser226 IDENCLLsPLAGEDD 9606 20047289 t gcesareni "Furthermore, we show that this gnrh-stimulated phosphorylation of the unliganded gr is mediated by a combination of the mapks jnk, p38, and erk as well as pkc in l t2 cells, because individual kinase inhibitors or combinations thereof inhibit this phosphorylation in intact cells." SIGNOR-162676 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 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 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 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 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 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 miR-155 mirna MI0000681 miRBase TRIB2 protein Q92519 UNIPROT "up-regulates quantity by expression" "post transcriptional regulation" 9606 BTO:0004620 24708856 t miannu "We found overexpression of miR-155 led to increase in cJUN, FOS and TRIB2, and decrease in MEIS1, GFI1, cMYC and JARID2." SIGNOR-255763 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 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-120248 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 PTTG1 protein O95997 UNIPROT up-regulates phosphorylation Ser165 LFQLGPPsPVKMPSP 9606 10906323 t gcesareni "Pttg is phosphorylated in vitro on ser(162) by map kinase and this phosphorylation site plays an essential role in pttg transactivation function." SIGNOR-79519 MAPK3 protein P27361 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation 9606 15664191 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-133345 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 RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser296 SPSALSSsPNNLSPT 9606 16407412 t gcesareni "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-143692 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 RPS6K proteinfamily SIGNOR-PF26 SIGNOR "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-252762 MAPK3 protein P27361 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR "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-252758 MAPK3 protein P27361 UNIPROT RPTOR protein Q8N122 UNIPROT "up-regulates activity" phosphorylation Ser863 LTQSAPAsPTNKGVH 9606 BTO:0000007 SIGNOR-C3 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-188916 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 miR-29a mirna MI0000087 miRBase TET2 protein Q6N021 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 10090 BTO:0004850 25477897 t miannu "The three miR-29 family members in mouse bone marrow cells reduced the level of TET2 as well as its metabolic by-product, 5hmC" SIGNOR-255797 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 MAPK3 protein P27361 UNIPROT RPS6KA1 protein Q15418 UNIPROT "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-219349 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 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 SP1 protein P08047 UNIPROT "up-regulates activity" phosphorylation Thr453 SGPIIIRtPTVGPNG 9606 BTO:0000552 14744793 t lperfetto "Transcriptional activation of p21(waf1/cip1) by alkylphospholipids: role of the mitogen-activated protein kinase pathway in the transactivation of the human p21(waf1/cip1) promoter by Sp1.|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-249480 MAPK3 protein P27361 UNIPROT SP1 protein P08047 UNIPROT "up-regulates activity" phosphorylation Thr739 SEGSGTAtPSALITT 9606 BTO:0000552 14744793 t lperfetto "Transcriptional activation of p21(waf1/cip1) by alkylphospholipids: role of the mitogen-activated protein kinase pathway in the transactivation of the human p21(waf1/cip1) promoter by Sp1.|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-249481 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 STK11 protein Q15831 UNIPROT "down-regulates activity" phosphorylation Ser428 SSKIRRLsACKQQ 9606 BTO:0001272 25846811 t lperfetto "Negative regulation of the LKB1/AMPK pathway by ERK in human acute myeloid leukemia cellsBRAFV600E activates downstream molecules, including ERK and p90 ribosomal S6 kinase (RSK), and leads to the phosphorylation of LKB-1 at Ser428 by these kinases. This cascade results in the dissociation of LKB1 from AMPK." SIGNOR-209880 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 TAL1 protein P17542 UNIPROT up-regulates phosphorylation Ser122 DGRMVQLsPPALAAP 9606 BTO:0000782;BTO:0001271 8423803 t lperfetto "Moreover, s122 is readily phosphorylated in vitro by the extracellular signal-regulated protein kinase erk1." SIGNOR-39133 MAPK7 protein Q13164 UNIPROT KLF4 protein O43474 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-255455 MAPK7 protein Q13164 UNIPROT MAP2K5 protein Q13163 UNIPROT up-regulates phosphorylation Ser129 VNTRAGPsQHSSPAV 9606 BTO:0000671 12628002 t lperfetto "Phosphorylation and activation of extracellular-signal-regulated protein kinase 5 (erk5) by mitogen-activated protein kinase kinase 5 (mkk5)activated erk5 also phosphorylated mitogen-activated protein kinase kinase 5 (mkk5) extensively at ser(129), ser(137), ser(142) and ser(149)" SIGNOR-99127 BCL2 protein P10415 UNIPROT BAK1 protein Q16611 UNIPROT down-regulates binding 9606 9463381 t amattioni "Bcl-2 bind to bax or five other pro-apoptotic relatives (bak, bad, bik, bid or bim)" SIGNOR-55546 MAPK7 protein Q13164 UNIPROT MAP2K5 protein Q13163 UNIPROT up-regulates phosphorylation Ser142 AVSDSLPsNSLKKSS 9606 BTO:0000671 12628002 t lperfetto "Phosphorylation and activation of extracellular-signal-regulated protein kinase 5 (erk5) by mitogen-activated protein kinase kinase 5 (mkk5)activated erk5 also phosphorylated mitogen-activated protein kinase kinase 5 (mkk5) extensively at ser(129), ser(137), ser(142) and ser(149)" SIGNOR-99135 MAPK7 protein Q13164 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates phosphorylation Ser355 SALQGFNsPGMLSLG 9606 BTO:0000567 10849446 t lperfetto "We have previously shown that bmk1 regulates c-jun gene expression through direct phosphorylation and activation of transcription factor mef2c.Here, we demonstrate that, in addition to mef2c, bmk1 phosphorylates and activates mef2a and mef2d but not mef2b.The sites phosphorylated by activated bmk1 were mapped to ser-355, thr-312, and thr-319 of mef2a and ser-179 of mef2d both in vitro and in vivo." SIGNOR-236587 MAPK7 protein Q13164 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates phosphorylation Thr312 QATQPLAtPVVSVTT 9606 BTO:0000567 10849446 t lperfetto "We have previously shown that bmk1 regulates c-jun gene expression through direct phosphorylation and activation of transcription factor mef2c.Here, we demonstrate that, in addition to mef2c, bmk1 phosphorylates and activates mef2a and mef2d but not mef2b.The sites phosphorylated by activated bmk1 were mapped to ser-355, thr-312, and thr-319 of mef2a and ser-179 of mef2d both in vitro and in vivo." SIGNOR-236583 MAPK7 protein Q13164 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates phosphorylation Thr319 TPVVSVTtPSLPPQG 9606 BTO:0000567 10849446 t lperfetto "We have previously shown that bmk1 regulates c-jun gene expression through direct phosphorylation and activation of transcription factor mef2c.Here, we demonstrate that, in addition to mef2c, bmk1 phosphorylates and activates mef2a and mef2d but not mef2b.The sites phosphorylated by activated bmk1 were mapped to ser-355, thr-312, and thr-319 of mef2a and ser-179 of mef2d both in vitro and in vivo." SIGNOR-236579 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 MAPK7 protein Q13164 UNIPROT SGK1 protein O00141 UNIPROT up-regulates phosphorylation Ser78 ANPSPPPsPSQQINL 9606 11254654 t lperfetto "Bmk1 mediates growth factor-induced cell proliferation through direct cellular activation of serum and glucocorticoid-inducible kinasebmk1 activates sgk by phosphorylation at serine 78." SIGNOR-105728 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 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 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 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 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 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 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 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 MAPK8IP1 protein Q9UQF2 UNIPROT MAP3K10 protein Q02779 UNIPROT up-regulates binding 9606 15767678 t gcesareni "The c-jun nh2-terminal kinase (jnk)-interacting protein (jip) group of scaffold proteins (jip1, jip2, and jip3) can interact with components of the jnk signaling pathway and potently activate jnk." SIGNOR-134552 MAPK8IP1 protein Q9UQF2 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates binding 9606 10490659 t "JNK bound to an NH2-terminal reagion of JIP1 (residues 283 to 660)." gcesareni "These experiments demonstrated that 10 different jnk isoforms bound to both jip proteins." SIGNOR-70851 MAPK8IP1 protein Q9UQF2 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates binding 9606 18486448 t gcesareni "The jip proteins function by aggregating components of a map kinase module (including mlk, mkk7, and jnk) and facilitate signal transmission by the protein kinase cascade. Overexpression of jip1 deactivates the jnk pathway selectively by cytoplasmic retention of jnk and thereby inhibits gene expression mediated by jnk, which occurs in the nucleus" SIGNOR-178655 MAPK8IP1 protein Q9UQF2 UNIPROT MAPK9 protein P45984 UNIPROT down-regulates binding 9606 10490659 t "JNK bound to an NH2-terminal reagion of JIP1 (residues 283 to 660)" gcesareni "These experiments demonstrated that 10 different jnk isoforms bound to both jip proteins." SIGNOR-70854 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 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 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 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 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 MAPK9 protein P45984 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 "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;these results strongly indicate that jnk regulates the activity of bax by phosphorylating 14-3-3 proteins." SIGNOR-124023 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 MAPKAPK5 protein Q8IW41 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-249708 MAPKAPK5 protein Q8IW41 UNIPROT PLA2G4A protein P47712 UNIPROT "up-regulates activity" phosphorylation Ser727 RQNPSRCsVSLSNVE 9606 BTO:0000007;BTO:0000567 10978317 t miannu "The p38-activated protein kinases MNK1, MSK1, and PRAK1 phosphorylate cPLA2 in vitro uniquely on Ser-727. By using Chinese hamster ovary, HeLa, and HEK293 cells stably transfected with wild type and phosphorylation site mutant forms of cPLA2, we show that phosphorylation of cPLA2 at both Ser-505 and Ser-727 and elevation of Ca(2+) leads to its activation in agonist-stimulated cells." SIGNOR-250162 MARK1 protein Q9P0L2 UNIPROT MAP2 protein P11137 UNIPROT "down-regulates activity" phosphorylation Ser1540 KSPEKRSsLPRPSSI -1 8631898 t miannu "Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability." SIGNOR-250163 MARK1 protein Q9P0L2 UNIPROT MAP2 protein P11137 UNIPROT "down-regulates activity" phosphorylation Ser1679 NVKSKIGsTDNIKYQ -1 8631898 t miannu "Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability." SIGNOR-250164 MARK1 protein Q9P0L2 UNIPROT MAP2 protein P11137 UNIPROT "down-regulates activity" phosphorylation Ser1710 HVTSKCGsLKNIRHR -1 8631898 t miannu "Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability." SIGNOR-250165 MARK1 protein Q9P0L2 UNIPROT MAP2 protein P11137 UNIPROT "down-regulates activity" phosphorylation Ser1795 VASPRRLsNVSSSGS -1 8631898 t miannu "Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability." SIGNOR-250166 MARK1 protein Q9P0L2 UNIPROT MAP2 protein P11137 UNIPROT "down-regulates activity" phosphorylation Ser1799 RRLSNVSsSGSINLL -1 8631898 t miannu "Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability." SIGNOR-250167 MARK1 protein Q9P0L2 UNIPROT MAP2 protein P11137 UNIPROT "down-regulates activity" phosphorylation Ser1802 SNVSSSGsINLLESP -1 8631898 t miannu "Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability." SIGNOR-250168 MC1R protein Q01726 UNIPROT TNF protein P01375 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000552 19656324 f miannu "Constitutive expression of MC1R in HaCaT keratinocytes inhibits basal and UVB-induced TNF-alpha production. the constitutive activity of MC1R results in elevated intracellular cAMP level, reduced NF-kappaB activity and decreased TNF-alpha transcription" SIGNOR-252375 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 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 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 DRAP1 protein Q14919 UNIPROT "NC2 complex" complex SIGNOR-C108 SIGNOR "form complex" binding 9606 BTO:0000567 18838386 t miannu "NC2_ co-fractionated with NC2_ only in the low molecular weight complex (fractions 86–94) and an NC2_ antibody co-immunoprecipitated NC2_ (but not GCN5) in these fractions, which thus contain the classical NC2 complex" SIGNOR-226402 MEIS1 protein O00470 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 BTO:0000725 14701735 f irozzo "Here we demonstrate that MLL-ENL immortalizes cells mainly through inducing a reversible block on myeloid differentiation that is dependent on upregulation of Hoxa9 and Meis1 and that enforced expression of these two genes is sufficient to substitute for MLL-ENL function." SIGNOR-255865 "Melanotan II" chemical CID:92432 PUBCHEM MC4R protein P32245 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-253066 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Ser391 GAATPRTsQFTKYWT 9606 16216881 t lperfetto "We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase." SIGNOR-141002 MERTK protein Q12866 UNIPROT MERTK protein Q12866 UNIPROT up-regulates phosphorylation Tyr753 KKIYSGDyYRQGRIA 9606 8702477 t gcesareni "By using a vaccinia virus expression system to express a constitutively activated form of nyk, we identified the major sites of nyk autophosphorylation in tryptic peptide iy749sgdy753y754r. Tyr-749, tyr-753, and tyr-754 in this peptide lie in the activation loop of the kinase domain." SIGNOR-42918 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 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Ser407 SNGVESKsLTPALCR 9606 16216881 t lperfetto "We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase." SIGNOR-141006 MERTK protein Q12866 UNIPROT MERTK protein Q12866 UNIPROT up-regulates phosphorylation Tyr749 FGLSKKIySGDYYRQ 9606 8702477 t gcesareni "By using a vaccinia virus expression system to express a constitutively activated form of nyk, we identified the major sites of nyk autophosphorylation in tryptic peptide iy749sgdy753y754r. Tyr-749, tyr-753, and tyr-754 in this peptide lie in the activation loop of the kinase domain." SIGNOR-42914 MIF protein P14174 UNIPROT HBB protein P68871 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-251831 MIOS protein Q9NXC5 UNIPROT GATOR2 complex SIGNOR-C193 SIGNOR "form complex" binding 9606 23723239 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-255301 MIR1-1 mirna MI0000651 miRBase PAX7 protein P23759 UNIPROT "down-regulates quantity" "post transcriptional regulation" 10090 BTO:0002314 20819939 t "We show that miR-1 and miR-206 facilitate satellite cell differentiation by restricting their proliferative potential. We identify Pax7 as one of the direct regulatory targets of miR-1 and miR-206. Inhibition of miR-1 and miR-206 substantially enhances satellite cell proliferation and increases Pax7 protein level in vivo" SIGNOR-255922 miR-130a mirna MI0000448 miRBase PPARG protein P37231 UNIPROT "down-regulates quantity" "post transcriptional regulation" 10090 BTO:0000011 21135128 t "MiR-130 reduces adipogenesis by repressing PPARγ biosynthesis and suggest that perturbations in this regulation is linked to human obesity." SIGNOR-255930 miR-155 mirna MI0000681 miRBase INPP5D protein Q92835 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 25477897 t miannu "Overexpression of miR-155 leads to the activation of the PI3K-Akt pathway through negative regulation of Src Homology 2 domain-containing Inositol-5-Phosphatase (SHIP1)." SIGNOR-255769 miR-155 mirna MI0000681 miRBase JARID2 protein Q92833 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0004620 24708856 t miannu "We found overexpression of miR-155 led to increase in cJUN, FOS and TRIB2, and decrease in MEIS1, GFI1, cMYC and JARID2." SIGNOR-255767 miR-155 mirna MI0000681 miRBase JUN protein P05412 UNIPROT "up-regulates quantity by expression" "post transcriptional regulation" 9606 BTO:0004620 24708856 t miannu "We found overexpression of miR-155 led to increase in cJUN, FOS and TRIB2, and decrease in MEIS1, GFI1, cMYC and JARID2." SIGNOR-255761 miR-155 mirna MI0000681 miRBase MEIS1 protein O00470 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0004620 24708856 t miannu "We found overexpression of miR-155 led to increase in cJUN, FOS and TRIB2, and decrease in MEIS1, GFI1, cMYC and JARID2." SIGNOR-255764 miR-155 mirna MI0000681 miRBase MYC protein P01106 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0004620 24708856 t miannu "We found overexpression of miR-155 led to increase in cJUN, FOS and TRIB2, and decrease in MEIS1, GFI1, cMYC and JARID2." SIGNOR-255766 miR-155 mirna MI0000681 miRBase SPI1 protein P17947 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 26055960 t miannu "Our results suggest that activating mutation of FLT3 in AML can lead, to increased expression of miR-155, which then causes down-regulation of SPI1 and CEBPB and consequently causes block of myeloid differentiation." SIGNOR-255803 miR-29c mirna MI0000735 miRBase TET2 protein Q6N021 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 10090 BTO:0004850 25477897 t miannu "The three miR-29 family members in mouse bone marrow cells reduced the level of TET2 as well as its metabolic by-product, 5hmC" SIGNOR-255798 miR-495 mirna MI0003135 miRBase Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 10090 BTO:0004730 23132946 f irozzo "In human leukemic cells with MLL rearrangements (e.g., MONOMAC-6 and THP-1 cells), we found that ectopic expression of miR-495 could significantly inhibit cell growth/proliferation and increase apoptosis while decreasing cell viability." SIGNOR-256649 miR-495 mirna MI0003135 miRBase Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 10090 BTO:0004730 23132946 f irozzo "In human leukemic cells with MLL rearrangements (e.g., MONOMAC-6 and THP-1 cells), we found that ectopic expression of miR-495 could significantly inhibit cell growth/proliferation and increase apoptosis while decreasing cell viability." SIGNOR-255883 MLL-ENL "fusion protein" SIGNOR-FP7 SIGNOR DOT1L protein Q8TEK3 UNIPROT "up-regulates activity" binding 10090 BTO:0004052 23996074 t irozzo "In this work, we have identified and mapped the protein-protein interaction site between DOT1L and MLL fusion proteins, AF9 and ENL. The MLL fusion proteins, AF9 and ENL, activate target genes in part via recruitment of the histone methyltransferase DOT1L (disruptor of telomeric silencing 1-like). It is known that the recruitment of DOT1L results in hypermethylation of H3K79 on the prominent MLL fusion downstream target loci Hoxa9 and Meis1" SIGNOR-255870 MLL-ENL "fusion protein" SIGNOR-FP7 SIGNOR HOXA9 protein P31269 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000725 14701735 f irozzo "Here we demonstrate that MLL-ENL immortalizes cells mainly through inducing a reversible block on myeloid differentiation that is dependent on upregulation of Hoxa9 and Meis1 and that enforced expression of these two genes is sufficient to substitute for MLL-ENL function." SIGNOR-255863 MLL-ENL "fusion protein" SIGNOR-FP7 SIGNOR MEIS1 protein O00470 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000725 14701735 f irozzo "Here we demonstrate that MLL-ENL immortalizes cells mainly through inducing a reversible block on myeloid differentiation that is dependent on upregulation of Hoxa9 and Meis1 and that enforced expression of these two genes is sufficient to substitute for MLL-ENL function." SIGNOR-255862 AMPK complex SIGNOR-C15 SIGNOR PPARGC1A protein Q9UBK2 UNIPROT "up-regulates activity" phosphorylation Thr178 NHNHRIRtNPAIVKT 9606 20640476 t lperfetto "AMPK can directly phosphorylate PGC-1a at Thr177 and Ser538 in in vitro assays PGC-1a phosphorylation might not directly affect its intrinsic coactivation activity, but, rather, release it from its repressor protein p160myb [79] and/or allow deacetylation and subsequent activation by SIRT1" SIGNOR-209936 "MLL/SET subcomplex" complex SIGNOR-C87 SIGNOR "MLL1 complex" complex SIGNOR-C89 SIGNOR "form complex" binding 9606 24680668 t miannu "The mixed lineage leukemia-1 (mll1) enzyme is a histone h3 lysine 4 (h3k4) monomethyltransferase and has served as a paradigm for understanding the mechanism of action of the human set1 family of enzymes that include mll1_Mll4 and setd1a,b. Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal core complex that is required for multiple lysine methylation." SIGNOR-204819 MOB1A protein Q9H8S9 UNIPROT LATS1 protein O95835 UNIPROT up-regulates binding 9606 21084559 t "Lats1 and Lats2 are nuclear Dbf2-related (NDR) family protein kinases." gcesareni "Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1" SIGNOR-169752 MOB1A protein Q9H8S9 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates binding 9606 21084559 t "Lats1 and Lats2 are nuclear Dbf2-related (NDR) family protein kinases." gcesareni "Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1" SIGNOR-169755 MOB1B protein Q7L9L4 UNIPROT LATS1 protein O95835 UNIPROT up-regulates binding 9606 21084559 t "Lats1 and Lats2 are nuclear Dbf2-related (NDR) family protein kinases." gcesareni "Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1." SIGNOR-169795 MOB1B protein Q7L9L4 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates binding 9606 21084559 t "Lats1 and Lats2 are nuclear Dbf2-related (NDR) family protein kinases." gcesareni "Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1." SIGNOR-169798 MRAP protein Q8TCY5 UNIPROT MC1R protein Q01726 UNIPROT "down-regulates activity" binding 10029 BTO:0000246 19329486 t miannu "We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members." SIGNOR-252364 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 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 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 MRAP protein Q8TCY5 UNIPROT MC3R protein P41968 UNIPROT "down-regulates activity" binding 10029 BTO:0000246 19329486 t miannu "We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members." SIGNOR-252366 MRAP protein Q8TCY5 UNIPROT MC5R protein P33032 UNIPROT "down-regulates activity" binding 10029 BTO:0000246 19329486 t miannu "We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members." SIGNOR-252368 MSI2 protein Q96DH6 UNIPROT NUMB protein P49757 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001271 21084860 f miannu "Msi2 was shown to be upregulated in blast crisis cml and to negatively regulate expression ofnumb." SIGNOR-169848 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 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 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 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 MTA1 protein Q13330 UNIPROT CDH1 protein P12830 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-254594 MTA1 protein Q13330 UNIPROT CXCL1 protein P09341 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000812 18719363 f miannu "Screening for the expression of angiogenic cytokines expressed by ovarian cancer cells revealed MTA1-mediated upregulation of the oncogenic and angiogenic cytokine GRO (growth-regulated oncogene, CXCL1)." SIGNOR-254598 MRGPRX1 protein Q96LB2 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-257384 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 MTF1 protein Q14872 UNIPROT SOD1 protein P00441 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15378601 f miannu "MRE-binding transcription factor-1 (MTF-1) is a highly conserved heavy metal-induced transcriptional activator. MTF-1 also activates transcription in response to oxidative stress and regulates the expression of several cytoprotective factor genes, including MT, gamma-glutamylcysteine synthetase, and Cu/Zn-superoxide dismutase." SIGNOR-254601 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 MTMR4 protein Q9NYA4 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates dephosphorylation 9606 20061380 t gcesareni "Here we demonstrate that myotubularin-related protein 4 (mtmr4), a fyve domain-containing dual-specificity protein phosphatase (dsp), attenuates tgfbeta signaling by reducing the phosphorylation level of r-smads in early endosomes." SIGNOR-163031 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 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 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 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 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 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 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 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 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 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 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 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 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-106582 MTOR protein P42345 UNIPROT Myotube_hypertrophy phenotype SIGNOR-PH20 SIGNOR up-regulates 9606 BTO:0000887;BTO:0001103;BTO:0001760 22179044 f gcesareni "In differentiated myofibres, we observed that wnt7a binding to fzd7 directly activates the akt/mtor growth pathway, thereby inducing myofibre hypertrophy." SIGNOR-191564 MTOR protein P42345 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000007 20508131 f "The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogen and nutrient signals to control cell proliferation and cell size." SIGNOR-255944 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 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 mTORC1 complex SIGNOR-C3 SIGNOR Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0000011 19593385 f lperfetto "Activation of mTORC1 causes a robust increase in the mRNA and protein expression of peroxisome proliferator-activated receptor gamma (PPARgamma), which is the master transcriptional regulator of adipocyte differentiation." SIGNOR-235349 mTORC1 complex SIGNOR-C3 SIGNOR Autophagy phenotype SIGNOR-PH31 SIGNOR down-regulates 9606 23863160 f lperfetto "Historically, it was known that autophagy was switched off when mTORC1 was active and that inhibition of mTORC1 was a potent autophagy inducer." SIGNOR-209922 mTORC1 complex SIGNOR-C3 SIGNOR Cell_growth phenotype SIGNOR-PH33 SIGNOR up-regulates 9606 23863160 f lperfetto "Cellular energy and nutrient status will dictate whether mTORC1 takes over and drives cell growth or conversely whether AMPK becomes active once again to drive consecutive waves of autophagy thorough ULK1." SIGNOR-209919 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation 10029 BTO:0000246 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-235748 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation 10090 BTO:0002572 20670887 t lperfetto "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)phosphorylation of the 4E-BPs leads to their inhibition and release from eIF4E at the 5_ cap of mRNAs" SIGNOR-235745 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr36 LPPGDYStTPGGTLF 9606 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-217086 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 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 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 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 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 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 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 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 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 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 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 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr70 RNSPVTKtPPRDLPT 9606 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-217141 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr70 RNSPVTKtPPRDLPT 9606 BTO:0000007 10942774 t lperfetto "Mammalian target of rapamycin-dependent phosphorylation of phas-i in four (s/t)p sites detected by phospho-specific antibodies." SIGNOR-236702 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr70 RNSPVTKtPPRDLPT 9606 BTO:0000007 12747827 t lperfetto "Phosphorylated on serine and threonine residues in response to insulin, egf and pdgf. Phosphorylation at thr-37, thr-46, ser-65 and thr-70, corresponding to the hyperphosphorylated form, is regulated by mtorc1 and abolishes binding to eif4e." SIGNOR-235964 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 mTORC1 complex SIGNOR-C3 SIGNOR ISCU protein Q9H1K1 UNIPROT up-regulates phosphorylation Ser14 FRLRRAAsALLLRSP 9606 23508953 t lperfetto "Here, we demonstrate that mtorc1 associates with iscu and phosphorylates iscu at serine 14. This phosphorylation stabilized iscu protein." SIGNOR-217082 mTORC1 complex SIGNOR-C3 SIGNOR MAF1 protein Q9H063 UNIPROT down-regulates phosphorylation Ser60 PHVLEALsPPQTSGL 9606 20516213 t lperfetto "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-217149 mTORC1 complex SIGNOR-C3 SIGNOR MAF1 protein Q9H063 UNIPROT down-regulates phosphorylation Ser68 PPQTSGLsPSRLSKS 9606 20516213 t lperfetto "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-217145 mTORC1 complex SIGNOR-C3 SIGNOR MAF1 protein Q9H063 UNIPROT down-regulates phosphorylation Ser75 SPSRLSKsQGGEEEG 9606 20516213 t lperfetto "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-217153 mTORC1 complex SIGNOR-C3 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR "up-regulates activity" phosphorylation 10090 BTO:0000944 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 competition. We also find that mutation of ser-221 to ala increases the inhibitory activity of pras40 toward mtorc1." SIGNOR-235518 mTORC1 complex SIGNOR-C3 SIGNOR MYC protein P01106 UNIPROT up-regulates 9606 24856037 f miannu "MTORC1 and mTORC2 converge on c-Myc to control metabolic reprogramming in cancer. mTORC1 and mTORC2 conspire to link growth factor receptor–PI3K signaling with c-Myc-dependent metabolic reprogramming by controlling both c-Myc levels and activity" SIGNOR-256172 mTORC1 complex SIGNOR-C3 SIGNOR PPARG protein P37231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000011 19593385 f lperfetto "Activation of mTORC1 causes a robust increase in the mRNA and protein expression of peroxisome proliferator-activated receptor gamma (PPARgamma), which is the master transcriptional regulator of adipocyte differentiation." SIGNOR-235343 mTORC1 complex SIGNOR-C3 SIGNOR RPS6K proteinfamily SIGNOR-PF26 SIGNOR "up-regulates activity" phosphorylation Thr390 DSKFTRQtPVDSPDD 9600 BTO:0000007 11914378 t azuccotti "Thr229 phosphorylation requires prior phosphorylation of the Ser/Thr-Pro sites in the autoinhibitory domain and Thr389 in the linker domain [..]. Moreover, in vitro mTOR directly phosphorylates Ser371, and this event modulates Thr389phosphorylation by mTOR, compatible with earlier in vivo findings." SIGNOR-255842 mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation 9606 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-251982 mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000132 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-251983 mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000182;BTO:0000018 15718470 t lperfetto "The rictor-mtor complex directly phosphorylated akt/pkb on ser473 in vitro and facilitated thr308 phosphorylation by pdk1" SIGNOR-217008 mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Ser477 PQFSYSAsGTA 9606 BTO:0000093 24670654 t gcesareni "Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation" SIGNOR-252451 MYB protein P10242 UNIPROT GSTM1 protein P09488 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000944 14576818 t "Functional analysis of the GSTM1 promoter using reporter assays indicated that both the DNA binding and transactivation domains of Myb were required for transcriptional activation" SIGNOR-253975 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 ITK protein Q08881 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates phosphorylation 9606 BTO:0000782 20519342 t gcesareni "In t cells, the predominant tec kinase is itk, which functions downstream of the t-cell receptor to regulate phospholipase c-gamma." SIGNOR-165803 mTORC2 complex SIGNOR-C2 SIGNOR AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation Ser473 RPHFPQFsYSASGTA 9606 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-217004 mTORC2 complex SIGNOR-C2 SIGNOR AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation Ser477 PQFSYSAsGTA 9606 BTO:0000093 24670654 t gcesareni "Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation" SIGNOR-252441 mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Thr479 FSYSASGtA 9606 BTO:0000093 24670654 t gcesareni "Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation" SIGNOR-252454 mTORC2 complex SIGNOR-C2 SIGNOR mTORC2 complex SIGNOR-C2 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000782 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-217000 mTORC2 complex SIGNOR-C2 SIGNOR MYC protein P01106 UNIPROT up-regulates 9606 24856037 f miannu "MTORC1 and mTORC2 converge on c-Myc to control metabolic reprogramming in cancer. mTORC1 and mTORC2 conspire to link growth factor receptor–PI3K signaling with c-Myc-dependent metabolic reprogramming by controlling both c-Myc levels and activity" SIGNOR-256171 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 RAC1 protein P63000 UNIPROT up-regulates binding 9606 16280553 t lperfetto "Mim-b binds and activates rac via its irsp53/mim domain" SIGNOR-141573 MUL1 protein Q969V5 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates quantity by destabilization" ubiquitination Lys284 LENLMLDkDGHIKIT 9606 BTO:0000007 22410793 t gcesareni "The results of the functional studies suggest that the degradation of Akt by MULAN suppresses cell proliferation and viability." SIGNOR-252460 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 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-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 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 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 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 "MYOD1/SWI/SNF complex" complex SIGNOR-C93 SIGNOR MYLPF protein Q96A32 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887 15870273 f miannu "Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material)" SIGNOR-136726 SMAD6 protein O43541 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates binding 9606 19352540 t gcesareni "Mad6-pellino-1 interaction abrogated signaling mediated by a complex of irak1." SIGNOR-185128 "MYOD1/SWI/SNF complex" complex SIGNOR-C93 SIGNOR TNNT2 protein P45379 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887 15870273 f miannu "Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material)" SIGNOR-136870 "MYOD1/SWI/SNF complex" complex SIGNOR-C93 SIGNOR TNNT3 protein P45378 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887 15870273 f miannu "Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material)" SIGNOR-136942 MYOG protein P15173 UNIPROT FBXO32 protein Q969P5 UNIPROT "down-regulates activity" binding 9534 BTO:0004055 19631210 t llicata "Myogenin had a MAFbx-recognition motif and interacted with MAFbx. MAFbx activated polyubiquitination of myogenin. The results of this study suggest that MAFbx functions as an F-box protein for ubiquitination of myogenin." SIGNOR-237854 MYOG protein P15173 UNIPROT ITGA7 protein Q13683 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165;BTO:0000222;BTO:0001760 8798472 t lperfetto "Only myogenin and MyoD were able to efficiently trans-activate the alpha7 promoter-CAT construct (Fig. 7). Myogenin trans-activated the promoter by _2-fold whereas MyoD was able to trans-activate by nearly 4-fold, indicating that both of these factors may play a role in alpha7 gene expression during muscle development." SIGNOR-241521 MYOG protein P15173 UNIPROT PAX7 protein P23759 UNIPROT "down-regulates quantity by destabilization" 10090 BTO:0004058 17548510 f "Simone Vumbaca" "Indeed, we observed a reduction in Pax7 protein levels upon ectopic myogenin expression in MM14 myoblasts, even under proliferation conditions" SIGNOR-255638 MYOG protein P15173 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 BTO:0001103 28163303 f apalma "During early stages of myogenesis, CIITA binds directly to myogenin (MYOG) and inactivates it, preventing MYOG-mediated induction of myogenic genes that are required for muscle differentiation and function" SIGNOR-255112 MYOG protein P15173 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR "up-regulates activity" BTO:0001103 7532173 f "Simone Vumbaca" "These results suggest that at least initially, the muscle-forming regions contained cells with myogenic potential, and that this potential is lost in the myogenin mutants as development proceeds." SIGNOR-255644 NAE complex SIGNOR-C131 SIGNOR CUL1 protein Q13616 UNIPROT "up-regulates activity" neddylation 9606 25504797 t lperfetto "The family of cullin proteins is the most established target for NEDD8. In humans, it is composed of seven cullins (Cul1, 2, 3, 4A, 4B, 5 and 7), whereas PARC (CUL9) and APC2 (component of the anaphase promoting complex APC) contain a cullin-homology domain. All cullins are modified with NEDD8The role of cullin NEDDylation is to enhance the activity of the CRLs and subsequent ubiquitination and degradation of the regulated substrates." SIGNOR-243151 NAE complex SIGNOR-C131 SIGNOR CUL3 protein Q13618 UNIPROT "up-regulates activity" neddylation 9606 25504797 t lperfetto "The family of cullin proteins is the most established target for NEDD8. In humans, it is composed of seven cullins (Cul1, 2, 3, 4A, 4B, 5 and 7), whereas PARC (CUL9) and APC2 (component of the anaphase promoting complex APC) contain a cullin-homology domain. All cullins are modified with NEDD8The role of cullin NEDDylation is to enhance the activity of the CRLs and subsequent ubiquitination and degradation of the regulated substrates." SIGNOR-243157 NAE complex SIGNOR-C131 SIGNOR CUL4A protein Q13619 UNIPROT "up-regulates activity" neddylation 9606 25504797 t lperfetto "The family of cullin proteins is the most established target for NEDD8. In humans, it is composed of seven cullins (Cul1, 2, 3, 4A, 4B, 5 and 7), whereas PARC (CUL9) and APC2 (component of the anaphase promoting complex APC) contain a cullin-homology domain. All cullins are modified with NEDD8The role of cullin NEDDylation is to enhance the activity of the CRLs and subsequent ubiquitination and degradation of the regulated substrates." SIGNOR-243160 NAE complex SIGNOR-C131 SIGNOR CUL4B protein Q13620 UNIPROT "up-regulates activity" neddylation 9606 25504797 t lperfetto "The family of cullin proteins is the most established target for NEDD8. In humans, it is composed of seven cullins (Cul1, 2, 3, 4A, 4B, 5 and 7), whereas PARC (CUL9) and APC2 (component of the anaphase promoting complex APC) contain a cullin-homology domain. All cullins are modified with NEDD8The role of cullin NEDDylation is to enhance the activity of the CRLs and subsequent ubiquitination and degradation of the regulated substrates." SIGNOR-243163 NAE complex SIGNOR-C131 SIGNOR CUL5 protein Q93034 UNIPROT "up-regulates activity" neddylation 9606 25504797 t lperfetto "The family of cullin proteins is the most established target for NEDD8. In humans, it is composed of seven cullins (Cul1, 2, 3, 4A, 4B, 5 and 7), whereas PARC (CUL9) and APC2 (component of the anaphase promoting complex APC) contain a cullin-homology domain. All cullins are modified with NEDD8The role of cullin NEDDylation is to enhance the activity of the CRLs and subsequent ubiquitination and degradation of the regulated substrates." SIGNOR-243166 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 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR ACIN1 protein Q9UKV3 UNIPROT up-regulates cleavage 9606 10490026 t amattioni "Induces apoptotic chromatin condensation after activation by casp3" SIGNOR-256449 NAE complex SIGNOR-C131 SIGNOR CUL7 protein Q14999 UNIPROT "up-regulates activity" neddylation 9606 25504797 t lperfetto "The family of cullin proteins is the most established target for NEDD8. In humans, it is composed of seven cullins (Cul1, 2, 3, 4A, 4B, 5 and 7), whereas PARC (CUL9) and APC2 (component of the anaphase promoting complex APC) contain a cullin-homology domain. All cullins are modified with NEDD8The role of cullin NEDDylation is to enhance the activity of the CRLs and subsequent ubiquitination and degradation of the regulated substrates." SIGNOR-243172 NAE complex SIGNOR-C131 SIGNOR CUL9 protein Q8IWT3 UNIPROT "up-regulates activity" neddylation 9606 25504797 t lperfetto "The family of cullin proteins is the most established target for NEDD8. In humans, it is composed of seven cullins (Cul1, 2, 3, 4A, 4B, 5 and 7), whereas PARC (CUL9) and APC2 (component of the anaphase promoting complex APC) contain a cullin-homology domain. All cullins are modified with NEDD8The role of cullin NEDDylation is to enhance the activity of the CRLs and subsequent ubiquitination and degradation of the regulated substrates." SIGNOR-243169 NANOG protein Q9H9S0 UNIPROT GATA2 protein P23769 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001086;BTO:0005511 15983365 f miannu "Transfection of NANOG-specific small interfering RNAs reduced levels of NANOG transcript and protein and induced activation of the extraembryonic endoderm-associated genes GATA4, GATA6, LAMININ B1, and AFP as well as upregulation of trophectoderm-associated genes CDX2, GATA2, hCG-alpha, and hCG-beta." SIGNOR-254625 NANOG protein Q9H9S0 UNIPROT GATA4 protein P43694 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001086;BTO:0005511 15983365 f miannu "Transfection of NANOG-specific small interfering RNAs reduced levels of NANOG transcript and protein and induced activation of the extraembryonic endoderm-associated genes GATA4, GATA6, LAMININ B1, and AFP as well as upregulation of trophectoderm-associated genes CDX2, GATA2, hCG-alpha, and hCG-beta." SIGNOR-254626 NANOG protein Q9H9S0 UNIPROT GATA4 protein P43694 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0003298 22795133 f lperfetto "Knockdown of Oct4 or Nanog induced an increase in the expression of Pax6, Gata4, Gata6, Sox17, and FoxA2 in E, H, and p21KD MSCs ( Figure 3F and Figure S2D)" SIGNOR-253162 NANOG protein Q9H9S0 UNIPROT SOX17 protein Q9H6I2 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0003298 22795133 f lperfetto "Knockdown of Oct4 or Nanog induced an increase in the expression of Pax6, Gata4, Gata6, Sox17, and FoxA2 in E, H, and p21KD MSCs ( Figure 3F and Figure S2D)" SIGNOR-253168 NBR1 protein Q14596 UNIPROT GABARAPL1 protein Q9H0R8 UNIPROT up-regulates binding 9606 BTO:0000007 19250911 t gcesareni "We performed glutathione s-transferase (gst) pull-down assays using extracts from hek293 cells overexpressing an ha-tagged nbr1(d50r) mutant, which lacks the ability to bind p62 (lamark et al., 2003) (figures s1a and s1b, available online), and gst fusions of six human atg8 homologs: gabarap, gabarapl1, gabarapl2, lc3a, lc3b, and lc3c. Indeed, nbr1 interacted with all these members of the mammalian atg8 protein family" SIGNOR-184264 NBR1 protein Q14596 UNIPROT GABARAPL2 protein P60520 UNIPROT up-regulates binding 9606 BTO:0000007 19250911 t gcesareni "We performed glutathione s-transferase (gst) pull-down assays using extracts from hek293 cells overexpressing an ha-tagged nbr1(d50r) mutant, which lacks the ability to bind p62 (lamark et al., 2003) (figures s1a and s1b, available online), and gst fusions of six human atg8 homologs: gabarap, gabarapl1, gabarapl2, lc3a, lc3b, and lc3c. Indeed, nbr1 interacted with all these members of the mammalian atg8 protein family." SIGNOR-184267 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 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 NCOA1 protein Q15788 UNIPROT APOA5 protein Q6Q788 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 16891307 f miannu "Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate." SIGNOR-255064 NCOA1 protein Q15788 UNIPROT CYP7A1 protein P22680 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 16891307 f miannu "Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate." SIGNOR-255063 NCOA1 protein Q15788 UNIPROT ESR1 protein P03372 UNIPROT up-regulates binding 9606 9427757 t miannu "Steroid receptor co-activator (src1) is one of a number of transcriptional co-activators that are capable of potentiating the activity of nuclear receptors including the oestrogen receptor (er)." SIGNOR-54442 NCOA1 protein Q15788 UNIPROT OTC protein P00480 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 16891307 f miannu "Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate." SIGNOR-255062 DUSP7 protein Q16829 UNIPROT GHR protein P10912 UNIPROT down-regulates dephosphorylation 9606 12907755 t gcesareni "Identification of protein tyrosine phosphatases with specificity for the ligand-activated growth hormone receptor." SIGNOR-104545 NEDD4L protein Q96PU5 UNIPROT SCNN1A protein P37088 UNIPROT "down-regulates quantity by destabilization" ubiquitination 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-251948 NPFFR2 protein Q9Y5X5 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-257104 NEDD4L protein Q96PU5 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates ubiquitination 9606 19917253 t gcesareni "Through its ww domain, nedd4l specifically recognizes a tgf-beta-induced phosphothr-protyr motif in the linker region, resulting in smad2/3 polyubiquitination and degradation" SIGNOR-161710 NEK11 protein Q8NG66 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser82 GSSESTDsGFCLDSP 9606 19734889 t lperfetto "Nek11 regulates cdc25a degradation and the ir-induced g2/m checkpointincubation of wild-type cdc25a with nek11 led to a marked increase in phosphorylation of ser 82 and 88 as detected with the phosphospecific antibody recognizing these sites" SIGNOR-187867 NEK11 protein Q8NG66 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser88 DSGFCLDsPGPLDSK 9606 19734889 t lperfetto "Nek11 regulates cdc25a degradation and the ir-induced g2/m checkpointincubation of wild-type cdc25a with nek11 led to a marked increase in phosphorylation of ser 82 and 88 as detected with the phosphospecific antibody recognizing these sites" SIGNOR-187871 NF1 protein P21359 UNIPROT ADCY10 protein Q96PN6 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-203921 NF1 protein P21359 UNIPROT ADCY2 protein Q08462 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-203983 NF1 protein P21359 UNIPROT ADCY4 protein Q8NFM4 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-204091 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 ADCY6 protein O43306 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-204195 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 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 ADCY9 protein O60503 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-204354 NF1 protein P21359 UNIPROT HRAS protein P01112 UNIPROT "down-regulates activity" 9606 BTO:0002373 19777070 t "NF1 negatively regulates Ras as an exchangefactor converting Ras-GTP to Ras-GDP by its GTPase-activating (Ras-GAP) domain." SIGNOR-256067 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 NOTCH proteinfamily SIGNOR-PF30 SIGNOR PIN1 protein Q13526 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150 19151708 f lperfetto "Previously, we have shown that commitment of the C2C12 cells to the osteoblastic lineage occurs around 24h after BMP treatment, when the osteoblast specific transcription factor Cbfa1 and the novel osteoblast related genes Tcf7 and Hey1 become regulated" SIGNOR-254342 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 NR0B2 protein Q15466 UNIPROT NR1H3 protein Q13133 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000195 12198243 f gcesareni "Here we show that shp can interact with the liver x receptors lxr? (nr1h3) and lxr? (nr1h2), as demonstrated by glutathione-s-transferase pull-down assays, mammalian two-hybrid, and coimmunoprecipitation experiments. In transfection assays, shp inhibits the expression of an artificial reporter driven by an lxr-response element and represses the transcriptional activation by lxr of the human atp-binding cassette transporter 1 (abca1) promoter. T" SIGNOR-91996 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 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 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 NRF1 protein Q16656 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-254881 NRG4 protein Q8WWG1 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 BTO:0000887 7477375 t "Does not bind to the ERBB1, ERBB2 and ERBB3 receptors" gcesareni "The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4." SIGNOR-26280 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 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 PDK3 protein Q15120 UNIPROT PDHA1 protein P08559 UNIPROT "down-regulates activity" phosphorylation Ser293 TYRYHGHsMSDPGVS -1 11486000 t lperfetto "Activity of the mammalian pyruvate dehydrogenase complex is regulated by phosphorylation-dephosphorylation of the alpha subunit of the pyruvate dehydrogenase (e1) component. Phosphorylation is carried out by four pyruvate dehydrogenase kinase (pdk) isoenzymes." SIGNOR-109647 PDK3 protein Q15120 UNIPROT PDHA1 protein P08559 UNIPROT "down-regulates activity" phosphorylation Ser300 SMSDPGVsYRTREEI -1 11486000 t lperfetto "Activity of the mammalian pyruvate dehydrogenase complex is regulated by phosphorylation-dephosphorylation of the alpha subunit of the pyruvate dehydrogenase (e1) component. Phosphorylation is carried out by four pyruvate dehydrogenase kinase (pdk) isoenzymes." SIGNOR-109651 PDK4 protein Q16654 UNIPROT PDHA1 protein P08559 UNIPROT "down-regulates activity" phosphorylation Ser232 NRYGMGTsVERAAAS -1 11485553 t lperfetto "Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293." SIGNOR-109621 PDK4 protein Q16654 UNIPROT PDHA1 protein P08559 UNIPROT "down-regulates activity" phosphorylation Ser293 TYRYHGHsMSDPGVS -1 11485553 t lperfetto "Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293." SIGNOR-109617 PDP2 protein Q9P2J9 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates dephosphorylation 9606 16510868 t lpetrilli "We show that the mammalian pdps are important in dephosphorylation of bmp-activated smad1 but not tgf-beta-activated smad2 or smad3. Thus, pdps specifically inactivate smads in the bmp/dpp pathway. [...] These observations suggest that pdp1 and pdp2 are important for dephosphorylation of smad1." SIGNOR-144909 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 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 PDK2 protein Q15119 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates phosphorylation Ser300 SMSDPGVsYRTREEI -1 7782287 t gcesareni "Mammalian pyruvate dehydrogenase (?2_2) (e1) is regulated by phosphorylation-dephosphorylation, catalyzed by the e1-kinase and the phospho-e1-phosphatase." SIGNOR-33141 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 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 PHLPP2 protein Q6ZVD8 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.[...] These data are consistent with phlpp terminating akt signaling by directly dephosphorylating and inactivating akt." SIGNOR-252602 PHLPP2 protein Q6ZVD8 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-248727 PI3K complex SIGNOR-C156 SIGNOR 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-252708 PI3K complex SIGNOR-C156 SIGNOR 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-252716 PI3K complex SIGNOR-C156 SIGNOR 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-252709 PIK3C3 protein Q8NEB9 UNIPROT AKT1 protein P31749 UNIPROT up-regulates relocalization 9606 10698680 t lperfetto "One of the best characterized targets of pi3k lipid products is the protein kinase akt or protein kinase b (pkb). In quiescent cells, pkb resides in the cytosol in a low-activity conformation. Upon cellular stimulation, pkb is activated through recruitment to cellular membranes by pi3k lipid products and phosphorylation by 3h-phosphoinositide-dependent kinase-1 (pdk1)." SIGNOR-252632 PIK3C3 protein Q8NEB9 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates relocalization 9606 10698680 t lperfetto "One of the best characterized targets of pi3k lipid products is the protein kinase akt or protein kinase b (pkb). In quiescent cells, pkb resides in the cytosol in a low-activity conformation. Upon cellular stimulation, pkb is activated through recruitment to cellular membranes by pi3k lipid products and phosphorylation by 3h-phosphoinositide-dependent kinase-1 (pdk1)." SIGNOR-75370 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 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 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 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 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 PKN1 protein Q16512 UNIPROT CDC25C protein P30307 UNIPROT unknown phosphorylation Ser216 SGLYRSPsMPENLNR 9606 BTO:0000567 15791647 t lperfetto "A role for PKN1 in mediating arsenite-induced G(2)/M delay was supported by the finding that expression of a constitutively active form of PKN1 (PKN1AF3) in HeLa cells delayed the mitotic entry of cell cycle. Further experiments indicate that PKN1 directly phosphorylated serine 216 (Ser216) in Cdc25C, which then facilitated association between Cdc25C and 14-3-3." SIGNOR-249277 CCL3 protein P10147 UNIPROT CCR1 protein P32246 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-255114 PKN1 protein Q16512 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser637 VDLSKVTsKCGSLGN 9606 BTO:0000938 BTO:0000975 11104762 t "The effect has been demonstrated using P10636-8" lperfetto "Phosphorylation of tau is regulated by pknthere is a pkn-specific phosphorylation site, ser-320, in mbdsthus pkn serves as a regulator of microtubules by specific phosphorylation of tau, which leads to disruption of tubulin assembly." SIGNOR-84958 PKNOX1 protein P55347 UNIPROT PTPN6 protein P29350 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 20864515 f miannu "Prep1 overexpression in HepG2 liver cells upregulated SYP and SHP1 and inhibited insulin-induced IR and IRS1/2 phosphorylation and was accompanied by reduced glycogen content." SIGNOR-254924 PKNOX1 protein P55347 UNIPROT SYP protein P08247 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 20864515 f miannu "Prep1 overexpression in HepG2 liver cells upregulated SYP and SHP1 and inhibited insulin-induced IR and IRS1/2 phosphorylation and was accompanied by reduced glycogen content." SIGNOR-254923 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 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 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 NINL protein Q9Y2I6 UNIPROT "down-regulates activity" phosphorylation Ser87 VRPSDEDsSSLESAA -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-103352 PLK1 protein P53350 UNIPROT NINL protein Q9Y2I6 UNIPROT "down-regulates activity" phosphorylation Thr161 SDEEAEStKEAQNEL -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-103364 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 POU5F1 protein Q01860 UNIPROT DPPA4 protein Q7L190 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001086 17068183 f miannu "To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG." SIGNOR-254941 POU5F1 protein Q01860 UNIPROT EOMES protein O95936 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001086 17068183 f miannu "To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG." SIGNOR-254930 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 POU5F1 protein Q01860 UNIPROT ID2 protein Q02363 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001086 17068183 f miannu "To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG." SIGNOR-254937 POU5F1 protein Q01860 UNIPROT LEFTY1 protein O75610 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001086 17068183 f miannu "To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG." SIGNOR-254938 POU5F1 protein Q01860 UNIPROT ZFP42 protein Q96MM3 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001086 17068183 f miannu "To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG." SIGNOR-254944 PPARA protein Q07869 UNIPROT AQP3 protein Q92482 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003204 17150915 f miannu "To investigate the intimate function of PPARalpha in the kidney, we analyzed the target gene expression in human metastatic renal cell carcinoma cell line, Caki-1, using small interfering RNA (siRNA) against PPARalpha and real-time RT-PCR methods. We found that some selected genes (long-chain fatty-acid-CoA ligase (FACL1), carnitine palmitoyltransferase 1A (CPT1A), adipose differentiation-related protein (ADRP) and aquaporin 3 (AQP3)) were down-regulated by PPARalpha siRNA." SIGNOR-255045 PPARA protein Q07869 UNIPROT CPT1A protein P50416 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003204 17150915 f miannu "To investigate the intimate function of PPARalpha in the kidney, we analyzed the target gene expression in human metastatic renal cell carcinoma cell line, Caki-1, using small interfering RNA (siRNA) against PPARalpha and real-time RT-PCR methods. We found that some selected genes (long-chain fatty-acid-CoA ligase (FACL1), carnitine palmitoyltransferase 1A (CPT1A), adipose differentiation-related protein (ADRP) and aquaporin 3 (AQP3)) were down-regulated by PPARalpha siRNA." SIGNOR-255047 PPARA protein Q07869 UNIPROT PLIN2 protein Q99541 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003204 17150915 f miannu "To investigate the intimate function of PPARalpha in the kidney, we analyzed the target gene expression in human metastatic renal cell carcinoma cell line, Caki-1, using small interfering RNA (siRNA) against PPARalpha and real-time RT-PCR methods. We found that some selected genes (long-chain fatty-acid-CoA ligase (FACL1), carnitine palmitoyltransferase 1A (CPT1A), adipose differentiation-related protein (ADRP) and aquaporin 3 (AQP3)) were down-regulated by PPARalpha siRNA." SIGNOR-255046 PPARA protein Q07869 UNIPROT SLC25A20 protein O43772 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000759 19577614 f miannu "CACT is upregulated by PPARalpha and PPARdelta, probably by binding to a functional PPRE at position +45 to +57 relative to the transcription start site. The upregulation of CACT by PPARalpha and PPARdelta, which are both important for the regulation of fatty acid oxidation in tissues during fasting, may increase the import of acylcarnitine into the mitochondrial matrix during fasting." SIGNOR-255049 PPARD protein Q03181 UNIPROT CAT protein P04040 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001949 18048767 f miannu "Activation of PPAR-delta upregulated the expression of antioxidant genes superoxide dismutase 1, catalase, and thioredoxin and decreased reactive oxygen species production in ECs." SIGNOR-255051 PPARD protein Q03181 UNIPROT HSD11B2 protein P80365 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001975 15591138 f miannu "Peroxisome proliferator-activated receptor delta suppresses 11beta-hydroxysteroid dehydrogenase type 2 gene expression in human placental trophoblast cells." SIGNOR-255050 PPP2CB protein P62714 UNIPROT HDAC7 protein Q8WUI4 UNIPROT "up-regulates activity" dephosphorylation Ser155 FPLRKTVsEPNLKLR 9606 18339811 t "Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. |Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs." SIGNOR-248603 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 PPARD protein Q03181 UNIPROT SLC25A20 protein O43772 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000759 19577614 f miannu "CACT is upregulated by PPARalpha and PPARdelta, probably by binding to a functional PPRE at position +45 to +57 relative to the transcription start site. The upregulation of CACT by PPARalpha and PPARdelta, which are both important for the regulation of fatty acid oxidation in tissues during fasting, may increase the import of acylcarnitine into the mitochondrial matrix during fasting." SIGNOR-255048 PPARGC1A protein Q9UBK2 UNIPROT CYP7A1 protein P22680 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 16891307 f miannu "Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate." SIGNOR-255057 PPARGC1A protein Q9UBK2 UNIPROT SOD2 protein P04179 UNIPROT up-regulates 10090 18074631 f lperfetto "In fact, experiments with either genetic knockouts or RNAi for the PGC1s show that the ability of ROS to induce a ROS scavenging programme depends entirely on the PGC1s. This includes genes encoding mitochondrial proteins like SOD2, but also includes cytoplasmic proteins such as catalase and GPX1. Cells lacking PGC1alpha are hypersensitive to death from oxidative stress caused by H2O2 or paraquat." SIGNOR-253395 PPP1CA protein P62136 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-248551 PPP1CA protein P62136 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-248552 PPP1CA protein P62136 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-248556 PPP1CA protein P62136 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-248557 PPP1CB protein P62140 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-248569 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 PPP2CB protein P62714 UNIPROT HDAC7 protein Q8WUI4 UNIPROT "up-regulates activity" dephosphorylation Ser181 NPLLRKEsAPPSLRR 9606 18339811 t "Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. |Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs." SIGNOR-248604 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 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 PPP2CA protein P67775 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates dephosphorylation Ser24 APIRRRSsNYRAYAT 9606 BTO:0000887 15769444 t lperfetto "The major phosphatase thought to dephosphorylate ctni and phospholamban is type 2a protein phosphatase (pp2a) [61]. Activation of pp2a and ensuing dephosphorylation of regulatory proteins is involved in the anti-adrenergic effects of adenosine and muscarinic receptor activation see also fig2." SIGNOR-134601 PPP2CA protein P67775 UNIPROT TP53 protein P04637 UNIPROT "down-regulates activity" dephosphorylation Ser37 NVLSPLPsQAMDDLM 9606 14712210 t "Phosphorylation of p53 at serine 37 is important for transcriptional activity and regulation in response to DNA damage| Furthermore, in vitro phosphatase assays show that PP2A dephosphorylates p53 at S37." SIGNOR-248619 PPP2CA protein P67775 UNIPROT TRAF2 protein Q12933 UNIPROT "down-regulates activity" dephosphorylation Thr117 DGCTWKGtLKEYESC 10090 BTO:0002572 17188031 t "We show that the Thr117 residue in TRAF2 is phosphorylated following TNFalpha stimulation. This phosphorylation process is modulated by PP2A and is required for TRAF2 functional activity." SIGNOR-248640 PPP2CB protein P62714 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" dephosphorylation 9606 18160256 t "Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A." SIGNOR-248614 PPP2CB protein P62714 UNIPROT PRKCB protein P05771-2 UNIPROT "down-regulates activity" dephosphorylation Ser660 QSEFEGFsFVNSEFL 10116 15880462 t "Inhibition of PP2A increased phosphorylation at Ser660 that determines calcium sensitivity and activity of PKCbetaII isoform" SIGNOR-248586 PPP2CB protein P62714 UNIPROT PRKCB protein P05771-2 UNIPROT "down-regulates activity" dephosphorylation Thr641 TRHPPVLtPPDQEVI 10116 8749392 t "Specifically, the threonine at position 500 (T500) on the activation loop, and T641 and S660 on the carboxyl terminus of protein kinase C beta II are phosphorylated in vivo. T500 and S660 are selectively dephosphorylated in vitro by protein phosphatase 2A to yield an enzyme that is still capable of lipid-dependent activation, whereas all three residues are dephosphorylated by protein phosphatase 1 to yield an inactive enzyme." SIGNOR-248587 PPP2CB protein P62714 UNIPROT PRKCB protein P05771 UNIPROT "down-regulates activity" dephosphorylation Thr500 WDGVTTKtFCGTPDY 10116 8749392 t "Specifically, the threonine at position 500 (T500) on the activation loop, and T641 and S660 on the carboxyl terminus of protein kinase C beta II are phosphorylated in vivo. T500 and S660 are selectively dephosphorylated in vitro by protein phosphatase 2A to yield an enzyme that is still capable of lipid-dependent activation, whereas all three residues are dephosphorylated by protein phosphatase 1 to yield an inactive enzyme." SIGNOR-248585 PPP2CB protein P62714 UNIPROT TP53 protein P04637 UNIPROT "down-regulates activity" dephosphorylation Ser37 NVLSPLPsQAMDDLM 9606 14712210 t "Phosphorylation of p53 at serine 37 is important for transcriptional activity and regulation in response to DNA damage| Furthermore, in vitro phosphatase assays show that PP2A dephosphorylates p53 at S37." SIGNOR-248584 PPP2R1A protein P30153 UNIPROT PP2Ca_R1A_Ba 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 PPP2R2A protein P63151 UNIPROT PP2Ca_R1A_Ba 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-243430 PPP2R5C protein Q13362 UNIPROT ATF1 protein P18846 UNIPROT up-regulates dephosphorylation Ser41 SLSESEEsQDSSDSI 9606 20730097 t lperfetto "We propose that constitutive hyperphosphorylation by ck1/ck2 maintains atf1 in an inactive state that promotes transcriptional repression. Pp2a/b56c antagonizes phosphorylation of atm sites in both creb and atf2" SIGNOR-167568 PPP3CA protein Q08209 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-248684 PPP3CA protein Q08209 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-248687 RPS6KA1 protein Q15418 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser118 GRELRRMsDEFVDSF 9606 BTO:0000007 10837486 t lperfetto "Rsk1, and survival factor signaling stimulate phosphorylation of bad at ser-155, blocking the binding of bad to bcl-xl." SIGNOR-78020 PPP3CA protein Q08209 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-248688 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 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-248366 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 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 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 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 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 PRKACA protein P17612 UNIPROT PDE3B protein Q13370 UNIPROT unknown phosphorylation Ser442 TPQLRRSsGTSGLLP -1 8163498 t miannu "Serine 427 is the target for cAMP-PK phosphorylation of the rat adipocyte cGI-PDE in vitro" SIGNOR-250023 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 PIM1 protein P11309 UNIPROT "up-regulates activity" phosphorylation Ser65 HSHSPRHsLRHSPGS 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-256153 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 STK11 protein Q15831 UNIPROT "up-regulates activity" phosphorylation Ser428 SSKIRRLsACKQQ 10116 BTO:0002874 11297520 t miannu "Phosphorylation of the protein kinase mutated in Peutz-Jeghers cancer syndrome, LKB1/STK11, at Ser431 by p90(RSK) and cAMP-dependent protein kinase, but not its farnesylation at Cys(433), is essential for LKB1 to suppress cell growth." SIGNOR-250055 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 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 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 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 TPH1 protein P17752 UNIPROT "up-regulates activity" phosphorylation Ser58 RKSKRRNsEFEIFVD -1 9109552 t miannu "The activation of tryptophan hydroxylase by protein kinase A is mediated by the phosphorylation of serine-58 within the regulatory domain of the enzyme." SIGNOR-250062 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 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-248931 PRKCA protein P17252 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser190 RGAPKRGsGKDSHHP -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-248871 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 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-89166 PRKCA protein P17252 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-249089 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 PTPN12 protein Q05209 UNIPROT down-regulates phosphorylation Ser435 KKLERNLsFEIKKVP 9606 BTO:0000567 7520867 t llicata "Ptp-pest is phosphorylated in vitro by both cyclic amp-dependent protein kinase (pka) and protein kinase c (pkc) at two major sites, which we have identified as ser39 and ser435. our results suggest that both pkc and pka are capable of phosphorylating, and therefore inhibiting, ptp-pest in vivo" SIGNOR-27304 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 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 ADAM17 protein P78536 UNIPROT MUC1 protein P15941 UNIPROT down-regulates cleavage 9606 12441351 t gcesareni "These characteristics along with studies conducted with cell lines genetically deficient in various adams (for a disintegrin and metalloprotease) identified tumor necrosis factor-alpha converting enzyme (tace)/adam 17 as a muc1 sheddase." SIGNOR-95630 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 TNNI3 protein P19429 UNIPROT "down-regulates activity" phosphorylation Ser166 LGARAKEsLDLRAHL -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-249069 PRKCA protein P17252 UNIPROT TNNI3 protein P19429 UNIPROT "down-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. | 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-249066 PRKCA protein P17252 UNIPROT TNNI3 protein P19429 UNIPROT "down-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. | 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-249067 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 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 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 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 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 PRKCZ protein Q05513 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr681 QRHKRTHtGEKKFAC 9606 BTO:0000887;BTO:0001260 18258854 t llicata "Here we have used a variety of approaches to identify 3 amino acids (thr668, ser670, and thr681) in the zinc finger domain of sp1 that are modified by pkc-zeta angiotensin ii, which activates pkc-? Phosphorylation (at thr410) via the angiotensin ii type 1 receptor, stimulates sp1 phosphorylation and increases sp1 binding to the platelet-derived growth factor-d promoter." SIGNOR-160774 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 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 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 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 PRKCD protein Q05655 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser328 QDAYRRNsVRFLQQR 9606 BTO:0000130 12056906 t esanto "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. The use of p47phox mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc?, ???, And ?." SIGNOR-89233 PRKCD protein Q05655 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser370 PAVPPRPsADLILNR 9606 BTO:0000130 12056906 t esanto "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. The use of p47phox mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc?, ???, And ?." SIGNOR-89241 PRKD1 protein Q15139 UNIPROT HDAC5 protein Q9UQL6 UNIPROT "down-regulates activity" phosphorylation Ser259 FPLRKTAsEPNLKVR 9534 BTO:0004055 15367659 t lperfetto "Here, we demonstrate that signaling by protein kinase C (PKC) is sufficient and, in some cases, necessary to drive nuclear export of class II HDAC5 in cardiomyocytes." SIGNOR-249270 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 PRKCD protein Q05655 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser379 DLILNRCsESTKRKL 9606 BTO:0000130 12056906 t esanto "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. The use of p47phox mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc?, ???, And ?." SIGNOR-89248 PRKCD protein Q05655 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-249063 PRKCD protein Q05655 UNIPROT PLD2 protein O14939 UNIPROT up-regulates phosphorylation Thr566 FIQRWNFtKTTKAKY 9606 20733000 t "Translocation from Cytoplasm to the Edge of Lamellipodia" gcesareni "Finally, we show that thr566 of pld2 is directly phosphorylated by pkc and that pld2 mutation in this region prevents pld2 activation, pld2 translocation to the edge of lamellipodia, rac translocation, and cell spreading after integrin activation" SIGNOR-167577 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates phosphorylation Thr141 EDEAKFPtMNRRGAI 9606 19366211 t llicata "This study identifies novel in vitro pkcdelta autophosphorylation sites at thr(141) adjacent to the pseudosubstrate domain, thr(218) in the c1a-c1b interdomain, ser(295), ser(302), and ser(304) in the hinge region, and ser(503) adjacent to thr(505) in the activation loop. a t141d substitution markedly increases basal lipid-independent pkcdelta activity;" SIGNOR-185279 PRKCE protein Q02156 UNIPROT CTNND1 protein O60716 UNIPROT down-regulates phosphorylation Ser268 PQVRVGGsSVDLHRF 9606 21251911 t lperfetto "We find that ctnnd1/p120ctn phosphorylation at serine 268 (p-s268) occurs in a strictly pkc_-dependent manner,serine/threonine phosphorylation of p120-ctn has been reported to affect the integrity of ajs [12], [24] and [25]. Xia et al. (2003) reported that several residues (ser122, ser252, ser268, ser288, thr310, ser312, ser873, and thr910) in p120ctn can be either phosphorylated or dephosphorylated upon pkc activation" SIGNOR-171712 PRKCE protein Q02156 UNIPROT TRPV1 protein Q8NER1 UNIPROT "up-regulates activity" phosphorylation Ser801 VPLLREAsARDRQSA 9534 BTO:0000298 14523239 t lperfetto "We found that mutation of S800 to alanine significantly reduced the PMA-induced enhancement of capsaicin-evoked currents and the direct activation of TRPV1 by PMA. Mutation of S502 to alanine reduced PMA enhancement of capsaicin-evoked currents, but had no effect on direct activation of TRPV1 by PMA. Conversely, mutation of T704 to alanine had no effect on PMA enhancement of capsaicin-evoked currents but dramatically reduced direct activation of TRPV1 by PMA." SIGNOR-249232 PRKCE protein Q02156 UNIPROT TRPV1 protein Q8NER1 UNIPROT "up-regulates activity" phosphorylation Ser821 YLRQFSGsLKPEDAE 9534 BTO:0000298 14523239 t lperfetto "We found that mutation of S800 to alanine significantly reduced the PMA-induced enhancement of capsaicin-evoked currents and the direct activation of TRPV1 by PMA. Mutation of S502 to alanine reduced PMA enhancement of capsaicin-evoked currents, but had no effect on direct activation of TRPV1 by PMA. Conversely, mutation of T704 to alanine had no effect on PMA enhancement of capsaicin-evoked currents but dramatically reduced direct activation of TRPV1 by PMA." SIGNOR-249233 PRKCE protein Q02156 UNIPROT TRPV1 protein Q8NER1 UNIPROT "up-regulates activity" phosphorylation Thr145 QKSKKHLtDNEFKDP -1 14523239 t lperfetto "We found that mutation of S800 to alanine significantly reduced the PMA-induced enhancement of capsaicin-evoked currents and the direct activation of TRPV1 by PMA. Mutation of S502 to alanine reduced PMA enhancement of capsaicin-evoked currents, but had no effect on direct activation of TRPV1 by PMA. Conversely, mutation of T704 to alanine had no effect on PMA enhancement of capsaicin-evoked currents but dramatically reduced direct activation of TRPV1 by PMA. | Edman sequencing and scintillation counting delineated T144 as the in vitro PKC phosphorylation site" SIGNOR-249234 PRKCZ protein Q05513 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-43834 PRKCZ protein Q05513 UNIPROT AKT2 protein P31751 UNIPROT "up-regulates activity" phosphorylation Thr309 SDGATMKtFCGTPEY -1 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). PKBgamma which had been activated by PDK1 possessed a substrate specificity identical with that of PKBalpha and PKBbeta towards a range of peptides. The activation of PKBgamma and its phosphorylation at Thr305 was triggered by insulin-like growth factor-1 in 293 cells." SIGNOR-248997 PRKCZ protein Q05513 UNIPROT AKT3 protein Q9Y243 UNIPROT "up-regulates activity" phosphorylation Thr305 TDAATMKtFCGTPEY 9606 BTO:0000007 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). PKBgamma which had been activated by PDK1 possessed a substrate specificity identical with that of PKBalpha and PKBbeta towards a range of peptides. The activation of PKBgamma and its phosphorylation at Thr305 was triggered by insulin-like growth factor-1 in 293 cells." SIGNOR-248996 PRKCZ protein Q05513 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-249284 PRKCZ protein Q05513 UNIPROT MARK3 protein P27448 UNIPROT down-regulates phosphorylation Thr564 RGTASRStFHGQPRE 9606 15084291 t lperfetto "Hpar-1a, t564, is phosphorylated in vivo and by apkc in vitro.This study establishes a novel functional link between two central determinants of cellular polarity, apkc and par-1, and suggests a model by which apkc may regulate par-1 in polarized cells" SIGNOR-124221 PRKCZ protein Q05513 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-89252 PRKCZ protein Q05513 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-251637 PRKCZ protein Q05513 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-249239 PRKD1 protein Q15139 UNIPROT HDAC7 protein Q8WUI4 UNIPROT unknown phosphorylation Ser486 RPLSRAQsSPAAPAS -1 15738054 t lperfetto "We demonstrate that protein kinase D (PKD; also known as PKCmi), which is activated upon engagement of the TCR, stimulates HDAC7 nuclear export by direct phosphorylation on four serine residues. Conversely, selective PKD inhibition blocks TCR-induced HDAC7 nuclear export and Nur77 expression. In addition, an HDAC7 mutant specifically deficient in phosphorylation by PKD blocks TCR-mediated apoptosis. | PKD1 phosphorylates S155, S181, S321, and S449 of HDAC7 in vitro." SIGNOR-249276 PRKD1 protein Q15139 UNIPROT PPP1R14A protein Q96A00 UNIPROT unknown phosphorylation Thr38 QKRHARVtVKYDRRE -1 15003508 t lperfetto "For that purpose, PKCa, e, l, and f were incubated with CPI-17 in the presence of 50 lM [c- 32P]ATP and kinase buffer. The results indicated that all PKC isoforms were able to phosphorylate CPI-17 in vitro (Table 1). PKCa phosphorylated CPI-17 to a similar extent to PKCe and to a much greater extent than f and l." SIGNOR-249260 PRKD1 protein Q15139 UNIPROT PRKD1 protein Q15139 UNIPROT unknown phosphorylation Ser742 GEKSFRRsVVGTPAY -1 10867018 t lperfetto "The last two autophosphorylation sites (Ser(744) and Ser(748)) are located in the activation loop but are only phosphorylated in the isolated PKD-catalytic domain and not in the full-length PKD; they may affect enzyme catalysis but are not involved in the activation of wild-type PKD by phorbol ester. | These results indicate that neither of the activation loop serines is involved in PDBu-induced activation but that they may be involved in catalysis or in maintaining the conformation of the enzyme prot" SIGNOR-249047 PRKDC protein P78527 UNIPROT RPA2 protein P15927 UNIPROT unknown phosphorylation Thr21 YGGAGGYtQSPGGFG -1 9139719 t lperfetto "In this study, we show that efficient phosphorylation of HSSB-p34 by DNA-PK requires Ku as well as DNA. The DNA-PK phosphorylation sites in HSSB-p34 have been mapped at Thr-21 and Ser-33. Kinetic studies demonstrated that a phosphate residue is first incorporated at Thr-21 followed by the incorporation of a second phosphate residue at Ser-33." SIGNOR-248972 PTK2 protein Q05397 UNIPROT ACTN4 protein O43707 UNIPROT up-regulates phosphorylation Tyr265 MTYVSSFyHAFSGAQ 9606 23454549 t lperfetto "Phosphorylation at y12 by fak reduces _-actinin1's affinity for actin [25] and [27]. _-actinin4 is phosphorylated at y4, y31, and y265. Phosphorylation at y4 or y31 decreases its binding to actin [28] while phosphorylation of y265 increases its affinity for actin" SIGNOR-192191 PTK6 protein Q13882 UNIPROT STAP2 protein Q9UGK3 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 10980601 t gcesareni "The phosphorylation of and association with bks by brk was also dependent on the sh2-like domain present within bks.bks is a substrate for the kinase activity of brk and has the characteristics of an adaptor protein." SIGNOR-81489 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 BAMBI protein Q13145 UNIPROT DVL2 protein O14641 UNIPROT up-regulates binding 9606 BTO:0000763 2662247 t gcesareni "Bmp-2 mediates phosphorylated smad1 (psmad1) or, with loss of bmprii, psmad3-dependent recruitment of disheveled (dvl) to promote rhoa-rac1 signaling necessary for motility." SIGNOR-23037 PTPN11 protein Q06124 UNIPROT STAT1 protein P42224 UNIPROT "down-regulates activity" dephosphorylation Tyr701 DGPKGTGyIKTELIS 9606 BTO:0000007 12270932 t "SHP-2 is a dual-specificity phosphatase involved in Stat1 dephosphorylation at both tyrosine and serine residues in nuclei|In SHP-2-/- mouse fibroblast cells, Stat1 phosphorylation at both the tyrosine residue Tyr(701) and the serine residue Ser(727) |Overexpression of SHP-2 in 293T cells inhibited IFNgamma-dependent Stat1 phosphorylation and suppressed Stat1-dependent induction of luciferase activity." SIGNOR-248672 PTPN13 protein Q12923 UNIPROT TRIP6 protein Q15654 UNIPROT "down-regulates activity" dephosphorylation Tyr55 PLPSEQCyQAPGGPE 10090 BTO:0002572 17591779 t "PTPL1/FAP-1 negatively regulates TRIP6 function in lysophosphatidic acid-induced cell migration.|Here we further demonstrate that a switch from c-Src-mediated phosphorylation to PTPL1/Fas-associated phosphatase-1-dependent dephosphorylation serves as an inhibitory feedback control mechanism of TRIP6 function in LPA-induced cell migration. PTPL1 dephosphorylates phosphotyrosine 55 of TRIP6 in vitro and inhibits LPA-induced tyrosine phosphorylation of TRIP6 in cells." SIGNOR-248713 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 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 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 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 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 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 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 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 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 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 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 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 PYCARD protein Q9ULZ3 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-256411 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 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 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 "RFX complex" complex SIGNOR-C104 SIGNOR HLA-DOA protein P06340 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" -1 11258423 f "The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex" SIGNOR-253994 "RFX complex" complex SIGNOR-C104 SIGNOR HLA-DOB protein P13765 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" -1 11258423 f "The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex" SIGNOR-254000 SF1 protein Q15637 UNIPROT LHB protein P01229 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0004467 19106114 f miannu "The human LHB promoter also contains low and high affinity SF1 binding sites. Mutation of these elements or depletion of endogenous SF1 impaired basal and ligand-induced transcription." SIGNOR-254915 "RFX complex" complex SIGNOR-C104 SIGNOR HLA-DPA1 protein P20036 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" -1 11258423 f "The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex" SIGNOR-253995 "RFX complex" complex SIGNOR-C104 SIGNOR HLA-DPB1 protein P04440 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" -1 11258423 f "The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex" SIGNOR-253990 "RFX complex" complex SIGNOR-C104 SIGNOR 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-254007 "RFX complex" complex SIGNOR-C104 SIGNOR HLA-DQA1 protein P01909 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" -1 11258423 f "The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex" SIGNOR-253991 "RFX complex" complex SIGNOR-C104 SIGNOR HLA-DQA2 protein P01906 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" -1 11258423 f "The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex" SIGNOR-253996 "RFX complex" complex SIGNOR-C104 SIGNOR HLA-DQB1 protein P01920 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" -1 11258423 f "The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex" SIGNOR-253992 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT "up-regulates activity" phosphorylation Thr577 SCRSSTTtCPEQDFF 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-249301 ROCK1 protein Q13464 UNIPROT GFAP protein P14136 UNIPROT "down-regulates activity" phosphorylation Ser38 LGPGTRLsLARMPPP -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-100188 ROCK1 protein Q13464 UNIPROT GFAP protein P14136 UNIPROT "down-regulates activity" phosphorylation Thr7 tSAARRSY -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-100192 ROCK1 protein Q13464 UNIPROT RDX protein P35241 UNIPROT unknown phosphorylation Thr573 RQIRQGNtKQRIDEF -1 9456324 t lperfetto " A peak of the phosphopeptide, in which only T573 was phosphorylated, was not detected. Quantitative analyses revealed that _100% of T564, but at most _40% of T573, was phosphorylated when C-rad was incubated with Rho-Kc for 1 h. Then we concluded that the major and primary phosphorylation site of radixin by Rho-kinase was T564 and referred to the Rho-Kc€“phosphorylated C-rad as T564-phosphorylated C-rad." SIGNOR-248995 ROCK1 protein Q13464 UNIPROT VIM protein P08670 UNIPROT "down-regulates activity" phosphorylation Ser72 SSAVRLRsSVPGVRL 9534 BTO:0000298 9565595 t lperfetto "We found that vimentin, the most widely expressed intermediate filament protein, served as an excellent substrate for Rho-associated kinase (Rho-kinase) and that vimentin phosphorylated by Rho-kinase lost its ability to form filaments in vitro. Two amino-terminal sites on vimentin, Ser38 and Ser71, were identified as the major phosphorylation sites for Rho-kinase, and Ser71 was the most favored and unique phosphorylation site for Rho-kinase in vitro. " SIGNOR-248998 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1651 SPTSPSYsPTSPSYS 9606 BTO:0000567 22137580 t "In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator" SIGNOR-248749 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1714 SPTSPSYsPTSPSYS 9606 BTO:0000567 22137580 t "In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator" SIGNOR-248753 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1717 SPSYSPTsPSYSPTS 9606 BTO:0000567 22137580 t "In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator" SIGNOR-248742 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1724 SPSYSPTsPSYSPTS 9606 BTO:0000567 22137580 t "In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator" SIGNOR-248743 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1735 SPTSPSYsPTSPSYS 9606 BTO:0000567 22137580 t "In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator" SIGNOR-248755 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1738 SPSYSPTsPSYSPTS 9606 BTO:0000567 22137580 t "In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator" SIGNOR-248744 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1766 SPSYSPTsPSYSPTS 9606 BTO:0000567 22137580 t "In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator" SIGNOR-248745 RPS6K proteinfamily SIGNOR-PF26 SIGNOR DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser291 CGSSGYFsSSPTLSS 9606 22017877 t lperfetto "We found that deptor was rapidly phosphorylated on three serines in a conserved degron, facilitating binding and ubiquitylation by the f box protein _trcp, with consequent proteasomal degradation of deptor. Phosphorylation of the _trcp degron in deptor is executed by ck1" SIGNOR-252799 RPS6K proteinfamily SIGNOR-PF26 SIGNOR EEF2K protein O00418 UNIPROT "down-regulates activity" phosphorylation Ser366 SPQVRTLsGSRPPLL 9606 BTO:0000669 11500364 t lperfetto "We show that two such kinases, p70 s6 kinase (regulated via mtor) and p90(rsk1) (activated by erk), phosphorylate eef2k at a conserved serine and inhibit its activity" SIGNOR-252775 RPS6K proteinfamily SIGNOR-PF26 SIGNOR 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-252783 SOS1 protein Q07889 UNIPROT KRAS protein P01116 UNIPROT up-regulates "guanine nucleotide exchange factor" 9606 25624485 t "Ras proteins bind GDP/GTP and possess intrinsic GTPase activity." gcesareni "Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts" SIGNOR-141647 ACTR3 protein P61158 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-251513 RPS6K proteinfamily SIGNOR-PF26 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser167 GGRERLAsTNDKGSM 9606 BTO:0000150 7838153 t gcesareni "Serine 167 is the major phosphorylation site on the human estrogen receptor. Phosphorylation is mediated by casein kinase ii." SIGNOR-252807 RPS6K proteinfamily SIGNOR-PF26 SIGNOR H3F3A 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-252808 RPS6K proteinfamily SIGNOR-PF26 SIGNOR H3F3A 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-252806 RPS6K proteinfamily SIGNOR-PF26 SIGNOR MITF protein O75030 UNIPROT down-regulates phosphorylation Ser409 HGLSLIPsTGLCSPD 9606 21749389 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 73, whereas serine 409 serves as a substrate for p90 rsk-1. An unphosphorylatable double mutant at these two residues is at once profoundly stable and transcriptionally inert." SIGNOR-252795 RPS6K proteinfamily SIGNOR-PF26 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000007 15342917 t lperfetto "The mitogen-activated protein kinase (mapk)-activated kinase, p90 ribosomal s6 kinase (rsk) 1, was found to interact with and phosphorylate tuberin at a regulatory site, ser-1798, located at the evolutionarily conserved c terminus of tuberin. Rsk1 phosphorylation of ser-1798 inhibits the tumor suppressor function of the tuberin/hamartin complex, resulting in increased mtor signaling to s6k1" SIGNOR-252796 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RANBP3 protein Q9H6Z4 UNIPROT unknown phosphorylation Ser126 VKRERTSsLTQFPPS 9606 18280241 t llicata "Rsk phosphorylates serine 58 of ranbp3 in vitro and in vivo" SIGNOR-252770 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RPS6K proteinfamily SIGNOR-PF26 SIGNOR "up-regulates activity" phosphorylation Ser221 DHEKKAYsFCGTVEY 9606 BTO:0000007 20048145 t lperfetto "Herein, we demonstrate that the n-terminal kinase domain (ntk) of rsk1 is necessary for interactions with pkarialpha. Substitution of the activation loop phosphorylation site (ser-221) in the ntk with the negatively charged asp residue abrogated the association between rsk1 and pkarialpha." SIGNOR-252785 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RPS6 protein P62753 UNIPROT up-regulates phosphorylation Ser235 IAKRRRLsSLRASTS 9606 17360704 t gcesareni "We demonstrate that while ribosomal s6 kinase 1 (s6k1) phosphorylates rps6 at all sites, rsk exclusively phosphorylates rps6 at ser(235/236) in vitro and in vivo using an mtor-independent mechanism." SIGNOR-252813 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RPS6 protein P62753 UNIPROT up-regulates phosphorylation Ser236 AKRRRLSsLRASTSK 9606 17360704 t gcesareni "We demonstrate that while ribosomal s6 kinase 1 (s6k1) phosphorylates rps6 at all sites, rsk exclusively phosphorylates rps6 at ser(235/236) in vitro and in vivo using an mtor-independent mechanism." SIGNOR-252812 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RPTOR protein Q8N122 UNIPROT up-regulates phosphorylation Ser719 PCTPRLRsVSSYGNI 9606 SIGNOR-C3 18722121 t llicata "Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity" SIGNOR-252772 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RPTOR protein Q8N122 UNIPROT up-regulates phosphorylation Ser721 TPRLRSVsSYGNIRA 9606 SIGNOR-C3 18722121 t llicata "Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity" SIGNOR-252774 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RPTOR protein Q8N122 UNIPROT up-regulates phosphorylation Ser722 PRLRSVSsYGNIRAV 9606 SIGNOR-C3 18722121 t llicata "Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity" SIGNOR-252773 RPS6K proteinfamily SIGNOR-PF26 SIGNOR SLC9A1 protein P19634 UNIPROT up-regulates phosphorylation Ser703 MSRARIGsDPLAYEP 9606 10400637 t gcesareni "The results indicate that p90rsk phosphorylates serine 703 of nhe-1, and this phosphorylation is required for growth factor stimulation of na+/h+ exchange." SIGNOR-252792 RPS6K proteinfamily SIGNOR-PF26 SIGNOR VASP protein P50552 UNIPROT down-regulates phosphorylation Thr278 LARRRKAtQVGEKTP 9606 BTO:0000551 21423205 t lperfetto "Rsk1 phosphorylated vasp on t278, a site regulating its binding to actin." SIGNOR-252802 RRAGD protein Q9NQL2 UNIPROT RAGBD complex SIGNOR-C116 SIGNOR "form complex" binding 9606 20381137 t gcesareni "Mammals express four Rag proteins€”RagA, RagB, RagC, and RagD€”that form heterodimers consisting of RagA or RagB with RagC or RagD. RagA and RagB, like RagC and RagD, are highly similar to each other and are functionally redundant" SIGNOR-228182 STAT1 protein P42224 UNIPROT NOS2 protein P35228 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-249497 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 AMPK complex SIGNOR-C15 SIGNOR 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-256113 RUNX2 protein Q13950 UNIPROT SNAI3 protein Q3KNW1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001610 22641097 f miannu "Effective silencing of Runx2 by short interfering RNA (siRNA) demonstrated downregulation of EMT-related molecules (SNAI2, SNAI3 and TWIST1), MMP2 and vasculogenic factors (VEGFA and VEGFC) in thyroid carcinoma cells." SIGNOR-255083 RUNX2 protein Q13950 UNIPROT TWIST1 protein Q15672 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001610 22641097 f miannu "Effective silencing of Runx2 by short interfering RNA (siRNA) demonstrated downregulation of EMT-related molecules (SNAI2, SNAI3 and TWIST1), MMP2 and vasculogenic factors (VEGFA and VEGFC) in thyroid carcinoma cells." SIGNOR-255085 RUNX2 protein Q13950 UNIPROT VEGFA protein P15692 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001610 22641097 f miannu "Effective silencing of Runx2 by short interfering RNA (siRNA) demonstrated downregulation of EMT-related molecules (SNAI2, SNAI3 and TWIST1), MMP2 and vasculogenic factors (VEGFA and VEGFC) in thyroid carcinoma cells." SIGNOR-255084 RUNX3 protein Q13761 UNIPROT CAPN10 protein Q9HC96 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002384 17956589 f miannu "Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells." SIGNOR-255091 RUNX3 protein Q13761 UNIPROT CASP2 protein P42575 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002384 17956589 f miannu "Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells." SIGNOR-255094 RUNX3 protein Q13761 UNIPROT CFLAR protein O15519 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002384 17956589 f miannu "Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells." SIGNOR-255087 RUNX3 protein Q13761 UNIPROT DNASE1 protein P24855 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002384 17956589 f miannu "Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells." SIGNOR-255092 RUNX3 protein Q13761 UNIPROT FADD protein Q13158 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002384 17956589 f miannu "Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells." SIGNOR-255095 RUNX3 protein Q13761 UNIPROT HSPD1 protein P10809 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002384 17956589 f miannu "Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells." SIGNOR-255086 RUNX3 protein Q13761 UNIPROT ING4 protein Q9UNL4 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002384 17956589 f miannu "Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells." SIGNOR-255096 RUNX3 protein Q13761 UNIPROT TIAL1 protein Q01085 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002384 17956589 f miannu "Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells." SIGNOR-255088 RUNX3 protein Q13761 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002384 17956589 f miannu "Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells." SIGNOR-255098 SOS1 protein Q07889 UNIPROT KRAS protein P01116 UNIPROT up-regulates "guanine nucleotide exchange factor" 9606 25624485 t "Ras proteins bind GDP/GTP and possess intrinsic GTPase activity." gcesareni "Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts" SIGNOR-175256 SIK2 protein Q9H0K1 UNIPROT CDK5R1 protein Q15078 UNIPROT down-regulates phosphorylation Ser91 ENLKKSLsCANLSTF 9606 24561619 t lperfetto "Sik2 phosphorylates p35 at ser 91, to trigger its ubiquitylation by pja2 and promote insulin secretion. _-cell knockout of sik2 leads to accumulation of p35 and impaired secretion" SIGNOR-204648 SIRT1 protein Q96EB6 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 BTO:0000007 14976264 f lperfetto "Sirt1 inhibited foxo3's ability to induce cell death." SIGNOR-256662 SIRT1 protein Q96EB6 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates activity" deacetylation 9606 BTO:0000007 14976264 t lperfetto "Sirt1 inhibited foxo3's ability to induce cell death." SIGNOR-122408 SOSTDC1 protein Q6X4U4 UNIPROT WNT3A protein P56704 UNIPROT "down-regulates activity" 9606 BTO:0000815 21113658 f lperfetto "In this context, SOSTDC1 leads to decreased cellular proliferation and inhibition of Wnt3a- and BMP-7-induced signaling" SIGNOR-242714 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR6 protein P50406 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-257525 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 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 MAP2K1 protein Q02750 UNIPROT MAPK1 protein P28482 UNIPROT "up-regulates activity" phosphorylation Thr185 HDHTGFLtEYVATRW 9606 BTO:0003807 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-236447 SIRT1 protein Q96EB6 UNIPROT FOXO3 protein O43524 UNIPROT "up-regulates activity" deacetylation 9606 BTO:0000007 14976264 t lperfetto "Sirt1 increased foxo3's ability to induce cell cycle arrest and resistance to oxidative stress" SIGNOR-122405 SIRT1 protein Q96EB6 UNIPROT HYOU1 protein Q9Y4L1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 22564731 f miannu "Our results indicate a novel mechanism by which SIRT1 regulates ER stress by overexpression of ORP150, and suggest that SIRT1 ameliorates palmitate-induced insulin resistance in HepG2 cells via regulation of ER stress." SIGNOR-255143 somatostatin smallmolecule CHEBI:64628 ChEBI SSTR3 protein P32745 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-257583 SOSTDC1 protein Q6X4U4 UNIPROT WNT5B protein Q9H1J7 UNIPROT "down-regulates activity" 10090 22829579 f lperfetto "Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells." SIGNOR-242727 SOSTDC1 protein Q6X4U4 UNIPROT WNT7A protein O00755 UNIPROT "down-regulates activity" 10090 22829579 f lperfetto "Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells." SIGNOR-242710 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 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 VIL1 protein P09327 UNIPROT "up-regulates activity" phosphorylation Tyr256 LKAALKLyHVSDSEG 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-247433 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 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1644 SPTSPSYsPTSPSYS -1 15125841 t "Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro" SIGNOR-248817 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1651 SPTSPSYsPTSPSYS -1 15125841 t "Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro" SIGNOR-248818 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1665 SPTSPSYsPTSPSYS -1 15125841 t "Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro" SIGNOR-248819 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1693 SPTSPSYsPTSPSYS -1 15125841 t "Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro" SIGNOR-248821 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1696 SPSYSPTsPSYSPTS -1 15125841 t "Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro" SIGNOR-248810 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1717 SPSYSPTsPSYSPTS -1 15125841 t "Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro" SIGNOR-248811 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1724 SPSYSPTsPSYSPTS -1 15125841 t "Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro" SIGNOR-248812 STK3 protein Q13188 UNIPROT MOB1B protein Q7L9L4 UNIPROT up-regulates phosphorylation Thr35 LLKHAEAtLGSGNLR 9606 21808241 t "The regulation of MOB1 and LATS1/2 by MST1/2 may be organ and disease-specific." gcesareni "Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2 mob1 interaction." SIGNOR-175817 STK3 protein Q13188 UNIPROT STK3 protein Q13188 UNIPROT up-regulates phosphorylation Thr180 DTMAKRNtVIGTPFW 9606 BTO:0000150 20231902 t gcesareni "Consistent with previous studies, sts alone induces mst2 cleavage and autophosphorylation of thr180, an indicator of mst2 activation, as well as apoptosis." SIGNOR-164310 STK4 protein Q13043 UNIPROT HIST1H2BB 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-171009 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 CREBBP protein Q92793 UNIPROT ALOX15 protein P16050 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000018 12517954 f 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-254093 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 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 STK4 protein Q13043 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Thr1041 EHAFYEFtFRRFFDD 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-201302 TBX5 protein Q99593 UNIPROT SNCG protein O76070 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 20802524 f miannu "TBX5 suppressed tumor cell proliferation and metastasis through the upregulation of cyclin-dependent kinase inhibitor 2A, metastasis suppressor 1 and downregulation of synuclein gamma and metastasis-associated protein 1 family member 2." SIGNOR-255255 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 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 TFAP2A protein P05549 UNIPROT ECM1 protein Q16610 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-255401 TFAP2B protein Q92481 UNIPROT CRYAB protein P02511 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 21556774 t "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-253637 TFAP2C protein Q92754 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-255398 TFAP2C protein Q92754 UNIPROT ECM1 protein Q16610 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-255396 TFDP1 protein Q14186 UNIPROT RRM1 protein P23921 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000972 14618416 f miannu "To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells." SIGNOR-253866 TFDP1 protein Q14186 UNIPROT TYMS protein P04818 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000972 14618416 f miannu "To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells." SIGNOR-253861 TGFB1 protein P01137 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 f lperfetto "More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor" SIGNOR-252282 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 TGFB2 protein P61812 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 f lperfetto "More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor" SIGNOR-252283 TGFB3 protein P10600 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 f lperfetto "More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor" SIGNOR-252284 TLR4 protein O00206 UNIPROT TIRAP protein P58753 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 11544529 t gcesareni "Here we describe a protein, Mal (MyD88-adapter-like), which joins MyD88 as a cytoplasmic TlR-domain-containing protein in the human genome. Mal activates NF-_B, Jun amino-terminal kinase and extracellular signal-regulated kinase-1 and -2." SIGNOR-252064 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 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 TNF protein P01375 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 f lperfetto "More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor" SIGNOR-252285 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 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 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 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 TRAF7 protein Q6Q0C0 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 15001576 f miannu "Overexpression of traf7 induced caspase-dependent apoptosis." SIGNOR-123218 TRAF7 protein Q6Q0C0 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 15001576 f miannu "Overexpression of traf7 induced caspase-dependent apoptosis." SIGNOR-256666 TRIM27 protein P14373 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 BTO:0000671 12807881 f miannu "Here we show that ectopic expression of rfp in human embryonic kidney 293 cells causes extensive apoptosis, as assessed by multiple criteria." SIGNOR-256667 CDK1 protein P06493 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr444 RFIGSPRtPVSPVKF 9606 15774499 t gcesareni "The principal target of rapamycin-induced p70s6k inactivation is a novel phosphorylation site within a conserved hydrophobic domain." SIGNOR-134654 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 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 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 TWIST1 protein Q15672 UNIPROT AKR1C2 protein P52895 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004828 19051271 f miannu "we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion" SIGNOR-255510 TWIST1 protein Q15672 UNIPROT ATM protein Q13315 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004828 19051271 f miannu "we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion" SIGNOR-255511 TWIST1 protein Q15672 UNIPROT CD44 protein P16070 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002590 17487558 f miannu "Immunoblot analysis showed that HEY/si-TWIST cells exhibited decreased expression levels of CD29, CD44 and CD54 compared to those of HEY/si-scrambled cells" SIGNOR-255512 TWIST1 protein Q15672 UNIPROT GDF15 protein Q99988 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004828 19051271 f miannu "we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion" SIGNOR-255527 TWIST1 protein Q15672 UNIPROT ICAM1 protein P05362 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002590 17487558 f miannu "Immunoblot analysis showed that HEY/si-TWIST cells exhibited decreased expression levels of CD29, CD44 and CD54 compared to those of HEY/si-scrambled cells" SIGNOR-255515 TWIST1 protein Q15672 UNIPROT ITGB1 protein P05556 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002590 17487558 f miannu "Immunoblot analysis showed that HEY/si-TWIST cells exhibited decreased expression levels of CD29, CD44 and CD54 compared to those of HEY/si-scrambled cells" SIGNOR-255516 TWIST1 protein Q15672 UNIPROT MMP2 protein P08253 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003879 20646316 f miannu "Individual genes upregulated by TWIST1 known to promote EMT and/or GBM invasion included SNAI2, MMP2, HGF, FAP and FN1." SIGNOR-255525 TWIST1 protein Q15672 UNIPROT RAP1A protein P62834 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004828 19051271 f miannu "we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion" SIGNOR-255533 USF2 protein Q15853 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-255594 VDR protein P11473 UNIPROT CYP3A4 protein P08684 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000195 12147248 f miannu "Expression of cytochrome P450 3A4 (CYP3A4) is induced by 1,25-dihydroxyvitamin D(3)(1,25(OH)(2)D(3)) in Caco-2 cells. However, since a typical vitamin D responsive element has not been found in the 5(')-flanking region of the CYP3A4 gene, the mechanism of 1,25(OH)(2)D(3)-induced CYP3A4 mRNA expression is poorly understood. In the present study, we demonstrated that vitamin D receptor (VDR) is a critical factor for the induction using the antisense oligonucleotide technique." SIGNOR-255600 CSF1R protein P07333 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 24890514 f apalma "The Erk1/2 pathway has a central role in CSF-1R-regulated myeloid differentiation. CSF-1 induces early (peaking at ‚àº5 min) and persistent (starting at 1 h) waves of MEK/Erk1/2 phosphorylation" SIGNOR-255572 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 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 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 "SWI/SNF complex" complex SIGNOR-C92 SIGNOR CCND1 protein P24385 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9606 12138206 f irozzo "INI1/hSNF5 is a component of the ATP-dependent chromatin remodeling hSWI/SNF complex [.]. Our data suggest that one of the mechanisms by which INI1/hSNF5 exerts its tumor suppressor function is by mediating the cell cycle arrest due to the direct recruitment of HDAC activity to the cyclin D1 promoter thereby causing its repression and G(0)-G(1) arrest. These results together indicate that cyclin D1 is a direct target for repression by INI1/hSNF5." SIGNOR-256293 VEGFC protein P49767 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 f lperfetto "More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor" SIGNOR-252277 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 WNK1 protein Q9H4A3 UNIPROT SLC12A6 protein Q9UHW9 UNIPROT down-regulates phosphorylation Thr991 SAYTYERtLMMEQRS 9606 BTO:0000938 BTO:0000142 19665974 t gcesareni "We have attempted to identify kinases and phosphatases involved in the modulation of phosphorylation at kcc3 t991 and t1048. the wnk kinases and spak/osr1 are strong candidates for kcc3 regulatory kinases." SIGNOR-187564 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 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 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-131631 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 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 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 NOG protein Q13253 UNIPROT BMP7 protein P18075 UNIPROT "down-regulates activity" binding -1 12478285 t "We report the crystal structure of the antagonist Noggin bound to BMP-7, which shows that Noggin inhibits BMP signalling by blocking the molecular interfaces of the binding epitopes for both type I and type II receptors." SIGNOR-256484 PI3K complex SIGNOR-C156 SIGNOR 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-252703 PRKCZ protein Q05513 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-89272 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 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 STK24 protein Q9Y6E0 UNIPROT STK38 protein Q15208 UNIPROT up-regulates phosphorylation Thr444 DWVFINYtYKRFEGL 9606 BTO:0000007 16314523 t lperfetto "Ndr1/ndr2 protein kinase is activated by phosphorylation on the activation loop phosphorylation site ser281/ser282 and the hydrophobic motif phosphorylation site thr444/thr442. Autophosphorylation of ndr is responsible for phosphorylation on ser281/ser282, whereas thr444/thr442 is targeted by an upstream kinase. Here we show that mst3, a mammalian ste20-like protein kinase, is able to phosphorylate ndr protein kinase at thr444/thr442. In vitro, mst3 selectively phosphorylated thr442 of ndr2, resulting in a 10-fold stimulation of ndr activity." SIGNOR-142467 TLN1 protein Q9Y490 UNIPROT "A1/b1 integrin" complex SIGNOR-C159 SIGNOR "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257608 TLN1 protein Q9Y490 UNIPROT "A2/b1 integrin" complex SIGNOR-C160 SIGNOR "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257609 TLN1 protein Q9Y490 UNIPROT ITGB1 protein P05556 UNIPROT "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257607 WNT3A protein P56704 UNIPROT FZD1 protein Q9UP38 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.All the frizzled genes studied have a complex and partially overlapping pattern of expression in different regions of the embryo, and many of them (fz1, 3, 7, 8 and 9) have specific expression in the epithelial somites as well as in the newly formed myotomes." SIGNOR-169651 WNT3A protein P56704 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.All the frizzled genes studied have" SIGNOR-169657 ERBB4 protein Q15303 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-146882 TLN1 protein Q9Y490 UNIPROT "A10/b1 integrin" complex SIGNOR-C167 SIGNOR "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257616 TLN1 protein Q9Y490 UNIPROT "A11/b1 integrin" complex SIGNOR-C168 SIGNOR "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257617 TLN1 protein Q9Y490 UNIPROT "A3/b1 integrin" complex SIGNOR-C161 SIGNOR "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257610 TLN1 protein Q9Y490 UNIPROT "A4/b1 integrin" complex SIGNOR-C162 SIGNOR "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257611 TLN1 protein Q9Y490 UNIPROT "A5/b1 integrin" complex SIGNOR-C163 SIGNOR "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257612 TLN1 protein Q9Y490 UNIPROT "A6/b1 integrin" complex SIGNOR-C164 SIGNOR "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257613 TLN1 protein Q9Y490 UNIPROT "A8/b1 integrin" complex SIGNOR-C165 SIGNOR "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257614 TLN1 protein Q9Y490 UNIPROT "A9/b1 integrin" complex SIGNOR-C166 SIGNOR "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257615 ERBB4 protein Q15303 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-146888 SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR FBXO30 protein Q8TB52 UNIPROT down-regulates 10090 BTO:0000887 24076600 f "BMP-Smad1/5/8 signaling negatively regulates a gene (Fbxo30) that encodes a ubiquitin ligase required for muscle loss, which we named muscle ubiquitin ligase of the SCF complex in atrophy-1 (MUSA1)" SIGNOR-256488 SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR CDKN2B protein P42772 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000552 11013220 f irozzo "Our data demonstrate the physical interactions and functional cooperativity of Sp1 with a complex of Smad2, Smad3 and Smad4 in the induction of the p15Ink4B gene. These findings explain the tumor suppressor roles of Smad2 and Smad4 in growth arrest signaling by TGF-β." SIGNOR-256287 SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR SP1 protein P08047 UNIPROT "up-regulates activity" binding 9606 BTO:0000552 11013220 t irozzo "TGF-β induces the formation and nuclear translocation of a trimeric Smad complex, which in this case is likely to consist of one monomer each of Smad2, Smad3 and Smad4. Smad2 and Smad4 associate directly with Sp1 and co-activate the transcriptional activity of Sp1." SIGNOR-256288 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR CDKN2B protein P42772 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000552 11013220 f irozzo "Our data demonstrate the physical interactions and functional cooperativity of Sp1 with a complex of Smad2, Smad3 and Smad4 in the induction of the p15Ink4B gene. These findings explain the tumor suppressor roles of Smad2 and Smad4 in growth arrest signaling by TGF-β." SIGNOR-256286 SP1 protein P08047 UNIPROT CDKN2B protein P42772 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000552 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 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 "SWI/SNF complex" complex SIGNOR-C92 SIGNOR MYC protein P01106 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 10090 BTO:0001957 16452181 f irozzo "C-myc is a direct target of SWI/SNF complex–dependent promoter repression. These results indicate that repression of c-myc is indeed dependent on the activity of SWI/SNF–related complexes and specifically on complexes that contain ARID1A." SIGNOR-256292 "SWI/SNF complex" complex SIGNOR-C92 SIGNOR TP53 protein P04637 UNIPROT "up-regulates activity" binding 9606 BTO:0002181 11950834 t irozzo "Using genetic and biochemical approaches, we show that several subunits of the human SWI/SNF complex bind to the tumor suppressor protein p53 in vivo and in vitro.Molecular connection between p53 and the SWI/SNF complex implicates that (i) the SWI/SNF complex is necessary for p53-driven transcriptional activation, and (ii) the SWI/SNF complex plays an important role in p53-mediated cell cycle control." SIGNOR-256285 TLN1 protein Q9Y490 UNIPROT "AL/b2 integrin" complex SIGNOR-C169 SIGNOR "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257619 TLN1 protein Q9Y490 UNIPROT "AM/b2 integrin" complex SIGNOR-C170 SIGNOR "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257620 TLN1 protein Q9Y490 UNIPROT "AX/b2 integrin" complex SIGNOR-C171 SIGNOR "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257621 TLN1 protein Q9Y490 UNIPROT ITGB2 protein P05107 UNIPROT "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257618 SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR "up-regulates activity" 10090 BTO:0000887 24145169 f "The BMP pathway is a positive regulator of muscle mass. Increasing the expression of BMP7 or the activity of BMP receptors in muscles induced hypertrophy that was dependent on Smad1/5-mediated activation of mTOR signaling" SIGNOR-256487 SMAD3 protein P84022 UNIPROT BCL2 protein P10415 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9606 "BTO:0000972; BTO:0003477" 16766264 f irozzo "This protection is conferred by Smad3’s ability to promote apoptosis by repressing Bcl-2 transcription in vivo through a GC-rich element in the Bcl-2 promoter." SIGNOR-256294 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR MYC protein P01106 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9606 BTO:0000552 11689553 f irozzo "To identify this pathway, we analyzed TGF-β-responsive elements in the human c-myc promoter and found that Smad proteins directly bound to an element in the c-myc promoter and suppressed c-myc promoter activity." SIGNOR-256290 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 TLN1 protein Q9Y490 UNIPROT "A6/b4 integrin" complex SIGNOR-C174 SIGNOR "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257628 TLN1 protein Q9Y490 UNIPROT "AD/b2 integrin" complex SIGNOR-C172 SIGNOR "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257623 TLN1 protein Q9Y490 UNIPROT "AIIB/b3 integrin" complex SIGNOR-C173 SIGNOR "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257624 TLN1 protein Q9Y490 UNIPROT "Av/b2 integrin" complex SIGNOR-C176 SIGNOR "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257622 TLN1 protein Q9Y490 UNIPROT "Av/b3 integrin" complex SIGNOR-C177 SIGNOR "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257626 TLN1 protein Q9Y490 UNIPROT "Av/b5 integrin" complex SIGNOR-C178 SIGNOR "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257630 TLN1 protein Q9Y490 UNIPROT ITGB4 protein P16144 UNIPROT "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257627 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 GSTA1 protein P08263 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000018 29928434 f irozzo "Accordingly, downregulation of GSTA1 suppressed tumor growth. In conclusion, GSTA1 plays an important role in regulation of cell proliferation and cell apoptosis in A549 cell line." SIGNOR-256296 PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT unknown phosphorylation Ser396 SSSSSSHsLSASDTG 9606 BTO:0000007 10455013 t lperfetto "3-phosphoinositide-dependent protein kinase-1 (pdk1) expressed in unstimulated 293 cells was phosphorylated at ser-25, ser-241, ser-393, ser-396 and ser-410 and the level of phosphorylation of each site was unaffected by stimulation with insulin-like growth factor-1. Mutation of ser-241 to ala abolished pdk1 activity, whereas mutation of the other phosphorylation sites individually to ala did not affect pdk1 activity" SIGNOR-236764 PLCB1 protein Q9NQ66 UNIPROT "1D-myo-inositol 1,4,5-trisphosphate" smallmolecule CHEBI:16595 ChEBI "up-regulates quantity" "Small molecule catalysis" -1 23880553 t "Phospholipase C (PLC) enzymes convert phosphatidylinositol-4,5-bisphosphate into the second messengers diacylglycerol and inositol-1,4,5-triphosphate." SIGNOR-256497 PLCB1 protein Q9NQ66 UNIPROT diglyceride smallmolecule CHEBI:18035 ChEBI "up-regulates quantity" "Small molecule catalysis" -1 23880553 t "Phospholipase C (PLC) enzymes convert phosphatidylinositol-4,5-bisphosphate into the second messengers diacylglycerol and inositol-1,4,5-triphosphate." SIGNOR-256496 RUNX1 protein Q01196 UNIPROT HHEX protein Q03014 UNIPROT "up-regulates quantity" "transcriptional activation" 9606 BTO:0004479 28213513 t "We identified Hhex as a direct target of RUNX1 and FLT3-ITD stimulation and confirmed high HHEX expression in FLT3-ITD AMLs. HHEX could replace RUNX1 in cooperating with FLT3-ITD to induce AML." SIGNOR-256305 "SWI/SNF complex" complex SIGNOR-C92 SIGNOR CDKN2B protein P42772 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0002586 18332116 f irozzo "HSNF5 reexpression in MRT cells caused SWI/SNF recruitment and activation of p15INK4b and p16INK4a, but not of p14ARF.Reexpression of hSNF5 in MRT cells overcomes epigenetic silencing and mediates transcriptional activation of p15INK4b and p16INK4a" SIGNOR-256300 "SWI/SNF complex" complex SIGNOR-C92 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0002586 12226744 f irozzo "The hSNF5/INI1 gene encodes a member of the SWI/SNF chromatin remodelling complexes.Here, we show that the ectopic expression of wild-type hSNF5/INI1, but not that of truncated versions, leads to a cell cycle arrest by inhibiting the entry into S phase of MRT cells." SIGNOR-256298 TLN1 protein Q9Y490 UNIPROT "A4/b7 integrin" complex SIGNOR-C187 SIGNOR "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257635 TLN1 protein Q9Y490 UNIPROT "AE/b7 integrin" complex SIGNOR-C186 SIGNOR "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257634 TLN1 protein Q9Y490 UNIPROT "Av/b6 integrin" complex SIGNOR-C179 SIGNOR "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257632 TLN1 protein Q9Y490 UNIPROT ITGB5 protein P18084 UNIPROT "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257629 TLN1 protein Q9Y490 UNIPROT ITGB7 protein P26010 UNIPROT "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257633 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 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 ITGB1BP1 protein O14713 UNIPROT "A10/b1 integrin" complex SIGNOR-C167 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-257647 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 "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 "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 ITGB1 protein P05556 UNIPROT "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-257638 miR-146a mirna MI0000477 miRBase CXCR4 protein P61073 UNIPROT "up-regulates quantity by expression" "post transcriptional regulation" 9606 BTO:0000565 18568019 t miannu "In leukaemic cell lines PLZF overexpression downmodulated miR-146a and upregulated CXCR4 protein, whereas PLZF knockdown induced the opposite effects. Our data indicate that megakaryopoiesis is controlled by a cascade pathway, in which PLZF suppresses miR-146a transcription and thereby activates CXCR4 translation." SIGNOR-256310 MZF1 protein P28698 UNIPROT PRKCA protein P17252 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 "BTO:0000599; BTO:0001950" 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 RPS6K proteinfamily SIGNOR-PF26 SIGNOR TSC1/TSC2 complex SIGNOR-C101 SIGNOR "down-regulates activity" phosphorylation 9606 BTO:0000007 15342917 t lperfetto "The mitogen-activated protein kinase (mapk)-activated kinase, p90 ribosomal s6 kinase (rsk) 1, was found to interact with and phosphorylate tuberin at a regulatory site, ser-1798, located at the evolutionarily conserved c terminus of tuberin. Rsk1 phosphorylation of ser-1798 inhibits the tumor suppressor function of the tuberin/hamartin complex, resulting in increased mtor signaling to s6k1" SIGNOR-256311 TLN1 protein Q9Y490 UNIPROT ITGB8 protein P26012 UNIPROT "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257636 CSNK2A1 protein P68400 UNIPROT NPHP1 protein O15259 UNIPROT up-regulates phosphorylation Ser126 EESESEDsEDSGGEE 9606 BTO:0000671 16308564 t lperfetto "Casein kinase 2 (ck2)-mediated phosphorylation of three critical serine residues within a cluster of acidic amino acids in nephrocystin mediates pacs-1 binding, and is essential for colocalization of nephrocystin with pacs-1 at the base of cilia. Inhibition of ck2 activity abrogates this interaction and results in the loss of correct nephrocystin targeting." SIGNOR-142351 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 DOK1 protein Q99704 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-257674 DOK1 protein Q99704 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-257675 DOK1 protein Q99704 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-257676 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 "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 "Av/b2 integrin" complex SIGNOR-C176 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-257653 ITGB1BP1 protein O14713 UNIPROT "Av/b3 integrin" complex SIGNOR-C177 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-257657 ITGB1BP1 protein O14713 UNIPROT "Av/b5 integrin" complex SIGNOR-C178 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-257661 ITGB1BP1 protein O14713 UNIPROT "Av/b6 integrin" complex SIGNOR-C179 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-257663 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 ITGB4 protein P16144 UNIPROT "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-257658 ITGB1BP1 protein O14713 UNIPROT ITGB5 protein P18084 UNIPROT "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-257660 ITGB1BP1 protein O14713 UNIPROT ITGB6 protein P18564 UNIPROT "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-257662 PDIA6 protein Q15084 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR "up-regulates activity" 10090 BTO:0004086 17420453 f "Overexpression of ERp5 promotes both in vitro migration and invasion and in vivo metastasis of breast cancer cells." SIGNOR-256533 ZBTB16 protein Q05516 UNIPROT miR-146a mirna MI0000477 miRBase "down-regulates quantity by repression" "transcriptional repression" 9606 BTO:0000565 18568019 t miannu "In leukaemic cell lines PLZF overexpression downmodulated miR-146a and upregulated CXCR4 protein, whereas PLZF knockdown induced the opposite effects. Our data indicate that megakaryopoiesis is controlled by a cascade pathway, in which PLZF suppresses miR-146a transcription and thereby activates CXCR4 translation." SIGNOR-256309 DOK1 protein Q99704 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-257677 DOK1 protein Q99704 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-257686 DOK1 protein Q99704 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-257681 DOK1 protein Q99704 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-257682 DOK1 protein Q99704 UNIPROT "Av/b2 integrin" complex SIGNOR-C176 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-257684 DOK1 protein Q99704 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-257683 DOK1 protein Q99704 UNIPROT ITGB1 protein P05556 UNIPROT "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-257669 DOK1 protein Q99704 UNIPROT ITGB2 protein P05107 UNIPROT "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-257680 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 ITGB1BP1 protein O14713 UNIPROT "AE/b7 integrin" complex SIGNOR-C186 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-257665 ITGB1BP1 protein O14713 UNIPROT "Av/b8 integrin" complex SIGNOR-C185 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-257668 ITGB1BP1 protein O14713 UNIPROT ITGB8 protein P26012 UNIPROT "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-257667 NAB2 protein Q15742 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-253889 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 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 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 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 DOK1 protein Q99704 UNIPROT ITGB7 protein P26010 UNIPROT "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-257695 DOK1 protein Q99704 UNIPROT ITGB8 protein P26012 UNIPROT "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-257698 ELK1 protein P19419 UNIPROT PRKCA protein P17252 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 "BTO:0000599; BTO:0001950" 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-256336 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 PRKCD protein Q05655 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-251631 PRKCE protein Q02156 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-251632 PRKCG protein P05129 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-251633 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 PTK2 protein Q05397 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr576 RYMEDSTyYKASKGK 9606 7529876 t llicata "We found that maximal kinase activity of fak immune complexes requires phosphorylation of both tyrosines 576 and 577. Our results indicate that phosphorylation of fak by src (or other src family kinases) is an important step in the formation of an active signaling complex." SIGNOR-27875 PTPN11 protein Q06124 UNIPROT IRS1 protein P35568 UNIPROT down-regulates dephosphorylation Tyr896 EPKSPGEyVNIEFGS 9606 7515062 t gcesareni "The specific activity of four candidate protein-tyrosine phosphatases (protein-tyrosine phosphatase 1b (ptp1b), sh2 domain-containing ptpase-2 (shp-2), leukocyte common antigen-related (lar), and leukocyte antigen-related phosphatase) (lrp) toward irs-1 dephosphorylation was studied using recombinant proteins in vitro. Ptp1b exhibited the highest specific activity these results provide new insight into novel molecular interactions involving ptp1b and grb2 that may influence the steady-state capacity of irs-1 to function as a phosphotyrosine scaffold and possibly affect the balance of postreceptor insulin signaling." SIGNOR-27028 PTPN1 protein P18031 UNIPROT INSR protein P06213 UNIPROT "down-regulates activity" dephosphorylation Tyr1190 DIYETDYyRKGGKGL 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-248410 PTPRJ protein Q12913 UNIPROT MET protein P08581 UNIPROT "down-regulates activity" dephosphorylation Tyr1365 NVKCVAPyPSLLSSE 9606 BTO:0000007 12475979 t "When co-expressed in 293 cells, the full-length substrate-trapping mutant form of DEP-1 formed a stable complex with the chimeric receptor colony stimulating factor 1 (CSF)-Met and wild type DEP-1 dephosphorylated CSF-Met. Furthermore, we observed that DEP-1 preferentially dephosphorylated a Gab1 binding site (Tyr(1349)) and a COOH-terminal tyrosine implicated in morphogenesis (Tyr(1365))," SIGNOR-248703 UBE2I protein P63279 UNIPROT CEBPA protein P49715 UNIPROT "down-regulates activity" sumoylation Lys161 ALRPLVIkQEPREED -1 12511558 t miannu "C/EBPalpha interacts directly with the E2 SUMO-conjugating enzyme Ubc9 and can be SUMOylated in vitro using purified recombinant components. Our results indicate that SUMO modification of SC motifs provides a means to rapidly control higher order interactions among transcription factors and suggests that SUMOylation may be a general mechanism to limit transcriptional synergy." SIGNOR-256334 "A6/b1 integrin" complex SIGNOR-C164 SIGNOR 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-257706 "A8/b1 integrin" complex SIGNOR-C165 SIGNOR 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-257707 "AM/b2 integrin" complex SIGNOR-C170 SIGNOR 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-257713 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 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 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 DNMT3A protein Q9Y6K1 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 27639498 f irozzo "The DNA methyltransferase 3 genes (DNMT3A and DNMT3B) encode methyltransferases that catalyze the addition of a methyl group to the cytosine residue of CpG dinucleotide; therefore they play an essential role in DNA methylation and gene silencing regulatory processes. DNMT3A function is involved in hematopoietic stem cells (HSCs) renewal and myeloid differentiation." SIGNOR-255714 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 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 STK3/4 proteinfamily SIGNOR-PF41 SIGNOR Mob1 proteinfamily SIGNOR-PF42 SIGNOR "up-regulates activity" phosphorylation 9606 23431053 t miannu "Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity" SIGNOR-256185 UBIAD1 protein Q9Y5Z9 UNIPROT HRAS protein P01112 UNIPROT "down-regulates activity" binding 9606 BTO:0000362 30518913 t miannu "This study show that UBIAD1 interacts with H-Ras, retains H-Ras in the Golgi apparatus, prevents H-Ras trafficking from the Golgi apparatus to the plasma membrane, blocks the aberrant activation of Ras/MAPK signaling, and inhibits the proliferation of bladder cancer cells." SIGNOR-256206 UBIAD1 protein Q9Y5Z9 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000362 30518913 f miannu "This study show that UBIAD1 interacts with H-Ras, retains H-Ras in the Golgi apparatus, prevents H-Ras trafficking from the Golgi apparatus to the plasma membrane, blocks the aberrant activation of Ras/MAPK signaling, and inhibits the proliferation of bladder cancer cells." SIGNOR-256205 Calcineurin complex SIGNOR-C155 SIGNOR 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-252333 Calcineurin complex SIGNOR-C155 SIGNOR 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-252336 Calcineurin complex SIGNOR-C155 SIGNOR 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-252335 CASP3 protein P42574 UNIPROT GSN protein A2A418 UNIPROT "up-regulates activity" cleavage Asp403 WRDPDQTdGLGLSYL 9606 BTO:0001374 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 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 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 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 CSNK2A1 protein P68400 UNIPROT WAS protein P42768 UNIPROT up-regulates phosphorylation Ser483 KRSRAIHsSDEGEDQ 9606 12769847 t gcesareni "Here 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-101264 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 LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR WWTR1 protein Q9GZV5 UNIPROT "down-regulates activity" phosphorylation Ser89 AQHVRSHsSPASLQL 9606 22658639 t miannu "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-256187 LRRK2 protein Q5S007 UNIPROT LRRK2 protein Q5S007 UNIPROT up-regulates phosphorylation Thr1967 QQDKASLtRTLQHRI 9606 BTO:0000938 19824698 t lperfetto "We identified ser1403, thr1404, thr1410, thr1491 located within the roc domain, as well as thr1967 and thr1969 in the kinase domain, as the autophosphorylation sites. substitution of thr1969 located in close proximity to thr1967 had little effect on its kinase activity" SIGNOR-188417 MMP25 protein Q9NPA2 UNIPROT MMP2 protein P08253 UNIPROT "up-regulates activity" cleavage Asn109 CGNPDVAnYNFFPRK -1 14583471 t miannu "Direct activation of pro-matrix metalloproteinase-2 by leukolysin/membrane-type 6 matrix metalloproteinase/matrix metalloproteinase 25 at the asn(109)-Tyr bond. Leukolysin Cleaves ProMMP-2 at Asn66-Leu and Asn109-Tyr." SIGNOR-256345 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 BTF3 protein P20290 UNIPROT MRVI1 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 BTF3 protein P20290 UNIPROT NFKB1 protein P19838 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-253950 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 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 "Caspase 1 complex" complex SIGNOR-C220 SIGNOR IL1B protein P01584 UNIPROT "up-regulates activity" cleavage Asp116 DNEAYVHDAPVRSLN -1 1919001 t lperfetto "IL-1 converting enzyme (ICE) specifically cleaves the human IL-1 beta precursor at two sequence-related sites: Asp27-Gly28 (site 1) and Asp116-Ala117 (site 2). Cleavage at Asp116-Ala117 results in the generation of mature, biologically active IL-1 beta. " SIGNOR-256376 EAPP protein Q56P03 UNIPROT ABCB1 protein P08183 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 23542036 f miannu "We show here that EAPP stimulates the MDR1 promoter resulting in higher PGP levels. Independently of EAPP, E2F1 also increases the activity of the MDR1 promoter." SIGNOR-253842 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 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 LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR YAP1 protein P46937 UNIPROT "down-regulates activity" phosphorylation Ser127 PQHVRAHsSPASLQL 9606 22658639 t miannu "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-256188 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 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 BTK protein Q06187 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-98086 BTRC protein Q9Y297 UNIPROT GLI1 protein P08151 UNIPROT "down-regulates quantity by destabilization" ubiquitination 10090 BTO:0000944 16421275 t lperfetto "Here we show that Gli is rapidly destroyed by the proteasome and that mouse basal cell carcinoma induction correlates with Gli protein accumulation. We identify two independent destruction signals in Gli1, D(N) and D(C), and show that removal of these signals stabilizes Gli1 protein and rapidly accelerates tumor formation in transgenic animals.Levels of _TrCP appeared to be limiting for Gli1 degradation, as increasing the levels of _TrCP protein significantly decreased steady-state levels of Gli1 protein" SIGNOR-235631 Calcineurin complex SIGNOR-C155 SIGNOR 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-252315 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 CASP9 protein P55211 UNIPROT "Caspase 9 complex" complex SIGNOR-C229 SIGNOR "form complex" binding 29500231 t lperfetto "The caspase-9 CARD has been thought to be principally involved in recruitment to the apoptosome, but its roles outside this interaction have yet to be uncovered. In this work, we show that the CARD is involved in physical interactions with the catalytic core of caspase-9 in the absence of the apoptosome; this interaction requires a properly formed caspase-9 active site. " SIGNOR-256397 "Caspase 1 complex" complex SIGNOR-C220 SIGNOR IL18 protein Q14116 UNIPROT "up-regulates activity" cleavage Asp36 DDENLESDYFGKLES 9606 BTO:0001370 9334240 t lperfetto "We also found two precursor hIL-18 (prohIL-18)-processing activities in the cytosol of THP.1 cells. These activities were blocked separately by the caspase inhibitors Ac-YVAD-CHO and Ac-DEVD-CHO. Further analyses of the partially purified enzymes revealed that one is caspase-1, which cleaves prohIL-18 at the Asp36-Tyr37 site to generate the mature hIL-18, and the other is caspase-3, which cleaves both precursor and mature hIL-18 at Asp71-Ser72 and Asp76-Asn77 to generate biologically inactive products." SIGNOR-256377 LRRK2 protein Q5S007 UNIPROT LRRK2 protein Q5S007 UNIPROT up-regulates phosphorylation Thr1969 DKASLTRtLQHRIAL 9606 BTO:0000938 19824698 t lperfetto "We identified ser1403, thr1404, thr1410, thr1491 located within the roc domain, as well as thr1967 and thr1969 in the kinase domain, as the autophosphorylation sites. Substitution of thr1967, an autophosphorylation site located within the kinase domain, to ala caused a significant decrease in the kinase activity" SIGNOR-188421 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 "NLRC4 inflammasome" complex SIGNOR-C223 SIGNOR "Caspase 1 complex" complex SIGNOR-C220 SIGNOR "up-regulates activity" cleavage 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-256384 PML-RARalpha "fusion protein" SIGNOR-FP2 SIGNOR MYC protein P01106 UNIPROT "up-regulates activity" 9606 19855079 t apalma "We demonstrate that in addition to blocking myeloid differentiation, PLZF-RARα also promotes proliferation/self-renewal via the aberrant regulation of cell cycle–associated genes such as c-Myc, providing a basis for studying the aberrant response of this leukemia subtype to retinoic acid." SIGNOR-256374 PTK2 protein Q05397 UNIPROT GRB2 protein P62993 UNIPROT "up-regulates activity" binding 15688067 t miannu "Src-mediated phosphorylation of FAK at Tyr925 creates an SH2 binding site for the growth-factor-receptor-bound protein 2 (GRB2) adaptor protein, which leads to the activation of Ras and the extracellular signal-regulated kinase-2 (ERK2) cascade." SIGNOR-257733 "Pyrin inflammasome" complex SIGNOR-C226 SIGNOR "Caspase 1 complex" complex SIGNOR-C220 SIGNOR "up-regulates activity" cleavage 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-256383 SPI1 protein P17947 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 20861919 f apalma "In the myeloid compartment, Gfi1 is part of a regulatory network that determines lineage fate decision between granulocyte and monocyte/macrophage development. In this compartment, Gfi1 antagonizes the function of the transcription factor Pu.1. Pu.1 promotes monocytic differentiation, whereas Gfi1 enhances granulocytic differentiation." SIGNOR-256372 BIRC2 protein Q13490 UNIPROT CASP2 protein P42575 UNIPROT down-regulates binding 9606 16701639 t gcesareni "However, among hiap1, hiap2 and xiap, only hiap2 binds and inhibits caspase-2." SIGNOR-146738 pazopanib chemical CHEBI:71219 ChEBI FGFR1 protein P11362 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001949 18620382 t Luana "Pyrimidine 13 showed good potency against all the human VEGFR receptors with an IC50 of 10, 30, and 47 nM for VEGFR-1, -2, and -3, respectively. Significant activity was also seen against the closely related tyrosine receptor kinases PDGFRβ, c-Kit, FGF-R1, and c-fms with IC50’s of 84, 74, 140, and 146 nM, respectively." SIGNOR-257735 pazopanib chemical CHEBI:71219 ChEBI KIT protein P10721 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001949 18620382 t Luana "Pyrimidine 13 showed good potency against all the human VEGFR receptors with an IC50 of 10, 30, and 47 nM for VEGFR-1, -2, and -3, respectively. Significant activity was also seen against the closely related tyrosine receptor kinases PDGFRβ, c-Kit, FGF-R1, and c-fms with IC50’s of 84, 74, 140, and 146 nM, respectively." SIGNOR-257736 pazopanib chemical CHEBI:71219 ChEBI PDGFRB protein P09619 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001949 18620382 t Luana "Pyrimidine 13 showed good potency against all the human VEGFR receptors with an IC50 of 10, 30, and 47 nM for VEGFR-1, -2, and -3, respectively. Significant activity was also seen against the closely related tyrosine receptor kinases PDGFRβ, c-Kit, FGF-R1, and c-fms with IC50’s of 84, 74, 140, and 146 nM, respectively." SIGNOR-257737 PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT "up-regulates activity" dephosphorylation Thr383 HYRYSDTtDSDPENE 9606 BTO:0000007 22413754 t miannu "Overall, our results suggest that PTEN autodephosphorylation may be a critical event in this process; thus a major protein substrate for PTEN may be PTEN itself.|Various studies have demonstrated that PTEN is itself a phosphoprotein, and that the major sites of phosphorylation are found in an acidic stretch (DHYRYSDTTDSDPENE) near the C-terminus [1]. This prompted us to consider whether PTEN may autodephosphorylate these sites" SIGNOR-248545 PTK2 protein Q05397 UNIPROT TLN1 protein Q9Y490 UNIPROT "up-regulates activity" binding 9606 15688067 t 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-257731 PTPRJ protein Q12913 UNIPROT PDGFRB protein P09619 UNIPROT "down-regulates activity" dephosphorylation Tyr1021 PNEGDNDyIIPLPDP 9606 12062403 t "Primary sequence determinants responsible for site-selective dephosphorylation of the PDGF beta-receptor by the receptor-like protein tyrosine phosphatase DEP-1|DEP-1 dephosphorylation of original and chimeric phospho-peptides spanning the preferred pY1021" SIGNOR-248704 PTPRJ protein Q12913 UNIPROT RET protein P07949 UNIPROT down-regulates dephosphorylation Tyr905 DVYEEDSyVKRSQGR 9606 16778204 t gcesareni "Ptprj expression induces dephosphorylation of the ret(c634r) and, probably via an indirect mechanism, ret/ptc1 oncoproteins on two key ret autophosphorylation sites (tyr1062 and tyr905). in line with this finding, adoptive ptprj expression reduced the oncogenic activity of ret" SIGNOR-147165 PTPRR protein Q15256 UNIPROT PXN protein P49023 UNIPROT "down-regulates activity" dephosphorylation Tyr88 PQSSSPVyGSSAKTS 9606 20133777 t "Here, we show that paxillin is a direct substrate of PTPRT and that PTPRT specifically regulates paxillin phosphorylation at tyrosine residue 88 (Y88) in colorectal cancer (CRC) cells. We engineered CRC cells homozygous for a paxillin Y88F knock-in mutant and found that these cells exhibit significantly reduced cell migration and impaired anchorage-independent growth," SIGNOR-248720 PYCARD protein Q9ULZ3 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-256401 PYCARD protein Q9ULZ3 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-256405 PYCARD protein Q9ULZ3 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-256408 RALA protein P11233 UNIPROT FOXO4 protein P98177 UNIPROT "up-regulates activity" phosphorylation Thr451 PIPKALGtPVLTPPT 10090 BTO:0000944 11689711 t gcesareni "We conclude that Ral-mediated phosphorylation of threonines 447 and 451 is required for proper activity of AFX-WT." SIGNOR-248003 RALA protein P11233 UNIPROT FOXO4 protein P98177 UNIPROT "up-regulates activity" phosphorylation Thr455 ALGTPVLtPPTEAAS 10090 BTO:0000944 11689711 t gcesareni "We conclude that Ral-mediated phosphorylation of threonines 447 and 451 is required for proper activity of AFX-WT." SIGNOR-249665 belinostat chemical CHEBI:61076 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-257741 CYCS protein P99999 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-256430 belinostat chemical CHEBI:61076 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-257744 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 PAMPs stimulus SIGNOR-ST11 SIGNOR MEFV protein O15553 UNIPROT "up-regulates activity" 16037825 f lperfetto "Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage" SIGNOR-256426 pazopanib chemical CHEBI:71219 ChEBI CSF1R protein P07333 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001949 18620382 t Luana "Pyrimidine 13 showed good potency against all the human VEGFR receptors with an IC50 of 10, 30, and 47 nM for VEGFR-1, -2, and -3, respectively. Significant activity was also seen against the closely related tyrosine receptor kinases PDGFRβ, c-Kit, FGF-R1, and c-fms with IC50’s of 84, 74, 140, and 146 nM, respectively." SIGNOR-257740 pazopanib chemical CHEBI:71219 ChEBI FLT4 protein P35916 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001949 18620382 t Luana "Pyrimidine 13 showed good potency against all the human VEGFR receptors with an IC50 of 10, 30, and 47 nM for VEGFR-1, -2, and -3, respectively. Significant activity was also seen against the closely related tyrosine receptor kinases PDGFRβ, c-Kit, FGF-R1, and c-fms with IC50’s of 84, 74, 140, and 146 nM, respectively." SIGNOR-257739 pazopanib chemical CHEBI:71219 ChEBI KDR protein P35968 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001949 18620382 t Luana "Pyrimidine 13 showed good potency against all the human VEGFR receptors with an IC50 of 10, 30, and 47 nM for VEGFR-1, -2, and -3, respectively. Significant activity was also seen against the closely related tyrosine receptor kinases PDGFRβ, c-Kit, FGF-R1, and c-fms with IC50’s of 84, 74, 140, and 146 nM, respectively." SIGNOR-257738 PDIA6 protein Q15084 UNIPROT ERN1 protein O75460 UNIPROT "down-regulates activity" 10090 BTO:0000944 24508390 t "A resident ER protein disulfide isomerase, PDIA6, limits the duration of IRE1α activity by direct binding to cysteine148 in the luminal domain of the sensor," SIGNOR-256536 PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT "up-regulates activity" dephosphorylation Thr382 DHYRYSDtTDSDPEN 9606 BTO:0000007 22413754 t miannu "Overall, our results suggest that PTEN autodephosphorylation may be a critical event in this process; thus a major protein substrate for PTEN may be PTEN itself.|Various studies have demonstrated that PTEN is itself a phosphoprotein, and that the major sites of phosphorylation are found in an acidic stretch (DHYRYSDTTDSDPENE) near the C-terminus [1]. This prompted us to consider whether PTEN may autodephosphorylate these sites" SIGNOR-248546 PTTG1 protein O95997 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR "up-regulates activity" 10090 BTO:0000093 22002306 f "Overexpressed hPTTG1 promotes breast cancer cell invasion and metastasis by regulating GEF-H1/RhoA signalling" SIGNOR-256535 PYCARD protein Q9ULZ3 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-256414 RAC1 protein P63000 UNIPROT PAK2 protein Q13177 UNIPROT "up-regulates activity" binding 10090 BTO:0000142 8107774 t gcesareni "A new brain serine/threonine protein kinase may be a target for the p21ras-related proteins Cdc42 and Rac1. The kinase sequence is related to that of the yeast protein STE20, implicated in pheromone-response pathways." SIGNOR-248250 ROS stimulus SIGNOR-ST2 SIGNOR NLRP3 protein Q96P20 UNIPROT "up-regulates activity" 28531279 f lperfetto "Different mechanisms have been proposed for NLRP3 activation, including potassium efflux, calcium influx, reactive oxygen species (ROS), oxidized mitochondrial DNA, translocation of cardiolipin from the inner mitochondrial membrane, phagosome destabilization, perturbation in cell volume and pore-formation mechanisms driven by the host or bacteria" SIGNOR-256427 TLRs proteinfamily SIGNOR-PF20 SIGNOR NLRP3 protein Q96P20 UNIPROT "up-regulates quantity by expression" 28531279 f lperfetto "The activation of NLRP3 inflammasomes in macrophages requires two stimuli. The first signal, called priming, is provided by an inflammatory stimulus such as TLRs and TNF-α receptor (TNFR) that leads to NF-κB-mediated NLRP3 expression and post-translational modifications of NLRP3" SIGNOR-256428 belinostat chemical CHEBI:61076 ChEBI HDAC9 protein Q9UKV0 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-257748 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 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 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 complex SIGNOR-C154 SIGNOR up-regulates 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-252357 MAPK3 protein P27361 UNIPROT STMN1 protein P16949 UNIPROT "down-regulates activity" phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 BTO:0000007 9731215 t lperfetto "Stress-induced stathmin phosphorylation is not de- pendent on ERK. Stathmin is also known to be phos- phorylated by ERK on Ser-25 and Ser-38 (17). Thus, it is possible that ERK phosphorylates stathmin in 293 cells|In subsequent reports (28, 29) it was shown that phosphorylation of stathmin blocks its ability to destabilize MTs." SIGNOR-249483 panobinostat chemical CHEBI:85990 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-257754 panobinostat chemical CHEBI:85990 ChEBI HDAC3 protein O15379 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-257749 PDIA6 protein Q15084 UNIPROT EIF2AK3 protein Q9NZJ5 UNIPROT "down-regulates activity" 10116 BTO:0003318 26487694 t "Protein disulfide isomerase A6 (PDIA6) interacts with protein kinase RNA-like endoplasmic reticulum kinase (PERK) and inositol requiring enzyme (IRE)-1 and inhibits their unfolded protein response signaling." SIGNOR-256537 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 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 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT "up-regulates activity" phosphorylation Thr2609 LTPMFVEtQASQGTL 9606 BTO:0000773 12186630 t lperfetto "We have identified seven in vitro autophosphorylation sites in DNA-PKcs. Six of these sites (Thr2609, Ser2612, Thr2620, Ser2624, Thr2638 and Thr2647) are clustered in a region of 38 amino acids in the central region of the protein. Five of these sites (Thr2609, Ser2612, Thr2638, Thr2647 and Ser3205) are conserved between six vertebrate species. Moreover, we show that DNA-PKcs is phosphorylated in vivo at Thr2609, Ser2612, Thr2638 and Thr2647 in okadaic acid-treated human cells. | Thus phosphorylation of DNA-PKcs at one or more of the autophosphorylation sites identified in this study is likely to be required for DNA-PKcs function." SIGNOR-249154 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 "alvocidib hydrochloride" chemical CHEBI:90998 ChEBI CDK5 protein Q00535 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192467 CSNK2A1 protein P68400 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-250845 CSNK2B protein P67870 UNIPROT CD163 protein Q86VB7 UNIPROT "up-regulates activity" phosphorylation Ser1085 RQRLAVSsRGENLVH -1 11298324 t llicata "Interaction of CD163 with the regulatory subunit of casein kinase II (CKII) and dependence of CD163 signaling on CKII and protein kinase C. | 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-251056 panobinostat chemical CHEBI:85990 ChEBI HDAC6 protein Q9UBN7 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-257751 panobinostat chemical CHEBI:85990 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-257752 panobinostat chemical CHEBI:85990 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-257753 panobinostat chemical CHEBI:85990 ChEBI HDAC9 protein Q9UKV0 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-257750 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 Ser146 RPSQRHGsKYLATAS -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-248870 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT "up-regulates activity" phosphorylation Ser2624 QTRTQEGsLSARWPV -1 12186630 t lperfetto "We have identified seven in vitro autophosphorylation sites in DNA-PKcs. Six of these sites (Thr2609, Ser2612, Thr2620, Ser2624, Thr2638 and Thr2647) are clustered in a region of 38 amino acids in the central region of the protein. Five of these sites (Thr2609, Ser2612, Thr2638, Thr2647 and Ser3205) are conserved between six vertebrate species. Moreover, we show that DNA-PKcs is phosphorylated in vivo at Thr2609, Ser2612, Thr2638 and Thr2647 in okadaic acid-treated human cells. | Thus phosphorylation of DNA-PKcs at one or more of the autophosphorylation sites identified in this study is likely to be required for DNA-PKcs function." SIGNOR-249156 alvimopan chemical CHEBI:135686 ChEBI OPRK1 protein P41145 UNIPROT "down-regulates activity" "chemical inhibition" -1 18313920 t Luana "A series of N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines, l opioid receptor antagonists, analogs of alvimopan, were prepared using solid phase methodology. This study led to the identification of a highly selective l opioid receptor antagonist, which interacts selectively with l peripheral receptors." SIGNOR-257774 alvimopan chemical CHEBI:135686 ChEBI OPRM1 protein P35372 UNIPROT "down-regulates activity" "chemical inhibition" -1 18313920 t Luana "A series of N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines, l opioid receptor antagonists, analogs of alvimopan, were prepared using solid phase methodology. This study led to the identification of a highly selective l opioid receptor antagonist, which interacts selectively with l peripheral receptors." SIGNOR-257773 bepotastine chemical CHEBI:71204 ChEBI HRH1 protein P35367 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0002126 18446005 t Luana "We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells" SIGNOR-257781 CSNK2B protein P67870 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-251063 eplerenone chemical CHEBI:31547 ChEBI NR3C2 protein P08235 UNIPROT "down-regulates activity" "chemical inhibition" -1 18038968 t Luana "Indeed, eplerenone, 1, also acts as a mineralocorticoid receptor antagonist and is used to treat numerous patients for hypertension and congestive heart failure." SIGNOR-257763 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 complex SIGNOR-C154 SIGNOR up-regulates 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-252358 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 20219869 f apalma "ERK1/2 activation is a component of the pathway through which many mitogenic growth factors can stimulate cell proliferation" SIGNOR-256216 linagliptin chemical CHEBI:68610 ChEBI DPP4 protein P27487 UNIPROT "down-regulates activity" "chemical inhibition" 9606 18052023 t Luana "Herein, we report the discovery of the novel, potent, and selective DPP-4 inhibitor 1 (BI 1356)9 originating from the class of xanthines (Chart 1)" SIGNOR-257764 neostigmine chemical CHEBI:7514 ChEBI ACHE protein P22303 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001239 17888667 t Luana "AChE inhibitory activity study was carried out by using Ellman colorimetric assay with neostigmine as a reference standard against targets from different species, such as pure electric eel AChE, human serum AChE, and rat brain AChE. Among the compounds synthesized, compounds 5a, 5b, 5j showed good inhibition against AChE." SIGNOR-257758 nimodipine chemical CHEBI:7575 ChEBI NR3C2 protein P08235 UNIPROT "down-regulates activity" "chemical inhibition" -1 18250364 t Luana "Here we report a surprising finding, that the dihydropyridine CCBs have MR antagonist activity. A number of dihydropyridine CCBs compete for aldosterone binding to the MR ligand binding domain (LBD), block aldosterone-induced recruitment of coactivators, and inhibit aldosterone-induced gene expression. " SIGNOR-257765 paracetamol chemical CHEBI:46195 ChEBI PTGS2 protein P35354 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000876 17884974 t Luana "Acetaminophen (paracetamol) is a selective cyclooxygenase-2 inhibitor in man" SIGNOR-257757 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT "up-regulates activity" phosphorylation Ser2612 MFVETQAsQGTLQTR 9606 BTO:0000773 12186630 t lperfetto "We have identified seven in vitro autophosphorylation sites in DNA-PKcs. Six of these sites (Thr2609, Ser2612, Thr2620, Ser2624, Thr2638 and Thr2647) are clustered in a region of 38 amino acids in the central region of the protein. Five of these sites (Thr2609, Ser2612, Thr2638, Thr2647 and Ser3205) are conserved between six vertebrate species. Moreover, we show that DNA-PKcs is phosphorylated in vivo at Thr2609, Ser2612, Thr2638 and Thr2647 in okadaic acid-treated human cells. | Thus phosphorylation of DNA-PKcs at one or more of the autophosphorylation sites identified in this study is likely to be required for DNA-PKcs function." SIGNOR-249155 spironolactone chemical CHEBI:9241 ChEBI NR3C2 protein P08235 UNIPROT "down-regulates activity" "chemical inhibition" -1 18038968 t Luana "Results of the RALES trial (Randomized Aldactone Evaluation Study) demonstrated that the published MR antagonist spironolactone, added to standard therapy, reduced mortality due to all causes by 30% as well as reduced hospitalizations and improved cardiac function in patients with severe heart failure.2" SIGNOR-257762 betrixaban chemical CHEBI:140421 ChEBI F10 protein P00742 UNIPROT "down-regulates activity" "chemical inhibition" -1 19297154 t Luana "Discovery of betrixaban (PRT054021), N-(5-chloropyridin-2-yl)-2-(4-(N,N-dimethylcarbamimidoyl)benzamido)-5-methoxybenzamide, a highly potent, selective, and orally efficacious factor Xa inhibitor." SIGNOR-257817 Olopatadine chemical CHEBI:7769 ChEBI HRH1 protein P35367 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0002126 18446005 t Luana "We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells" SIGNOR-257782 epinastine chemical CHEBI:51032 ChEBI HRH1 protein P35367 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0002126 18446005 t Luana "We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells" SIGNOR-257779 felodipine chemical CHEBI:585948 ChEBI NR3C2 protein P08235 UNIPROT "down-regulates activity" "chemical inhibition" -1 18250364 t Luana "Here we report a surprising finding, that the dihydropyridine CCBs have MR antagonist activity. A number of dihydropyridine CCBs compete for aldosterone binding to the MR ligand binding domain (LBD), block aldosterone-induced recruitment of coactivators, and inhibit aldosterone-induced gene expression. " SIGNOR-257766 GAB2 protein Q9UQC2 UNIPROT PIK3CA protein P42336 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-204966 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 Mequitazine chemical CHEBI:31821 ChEBI HRH1 protein P35367 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0002126 18446005 t Luana "We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells" SIGNOR-257780 Nitrendipine chemical CID:4507 PUBCHEM NR3C2 protein P08235 UNIPROT "down-regulates activity" "chemical inhibition" -1 18250364 t Luana "Here we report a surprising finding, that the dihydropyridine CCBs have MR antagonist activity. A number of dihydropyridine CCBs compete for aldosterone binding to the MR ligand binding domain (LBD), block aldosterone-induced recruitment of coactivators, and inhibit aldosterone-induced gene expression. " SIGNOR-257767 Phenelzine chemical CHEBI:8060 ChEBI MAOA protein P21397 UNIPROT "down-regulates activity" "chemical inhibition" -1 18426226 t Luana "Phenylethylhydrazine stoichiometrically reduces the covalent FAD moieties of MAO A and of MAO B. Molecular oxygen is required for the inhibition reactions, and the level of O2 consumption for phenylethylhydrazine is 6-7-fold higher with either MAO A or MAO B than for the corresponding reactions with benzylhydrazine or phenylhydrazine." SIGNOR-257777 Carebastine chemical CID:65820 PUBCHEM HRH1 protein P35367 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0002126 18446005 t Luana "We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells" SIGNOR-257783 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR DFFA protein O00273 UNIPROT "up-regulates activity" cleavage 9606 BTO:0000567 9108473 t lperfetto "DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. We have identified and purified from HeLa cytosol a protein that induces DNA fragmentation in coincubated nuclei after it is activated by caspase-3." SIGNOR-256464 chlorphenamine chemical CHEBI:52010 ChEBI HRH1 protein P35367 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0002126 18446005 t Luana "We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells" SIGNOR-257786 desloratadine chemical CHEBI:291342 ChEBI HRH1 protein P35367 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0002126 18446005 t Luana "We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells" SIGNOR-257784 diphenhydramine chemical CHEBI:4636 ChEBI HRH1 protein P35367 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0002126 18446005 t Luana "We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells" SIGNOR-257787 fexofenadine chemical CHEBI:5050 ChEBI HRH1 protein P35367 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0002126 18446005 t Luana "We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells" SIGNOR-257785 ketotifen chemical CHEBI:92511 ChEBI HRH1 protein P35367 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0002126 18446005 t Luana "We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells" SIGNOR-257789 Phenelzine chemical CHEBI:8060 ChEBI MAOB protein P27338 UNIPROT "down-regulates activity" "chemical inhibition" -1 18426226 t Luana "Phenylethylhydrazine stoichiometrically reduces the covalent FAD moieties of MAO A and of MAO B. Molecular oxygen is required for the inhibition reactions, and the level of O2 consumption for phenylethylhydrazine is 6-7-fold higher with either MAO A or MAO B than for the corresponding reactions with benzylhydrazine or phenylhydrazine." SIGNOR-257778 PRKACA protein P17612 UNIPROT FOS protein P01100 UNIPROT "down-regulates quantity by repression" phosphorylation Ser362 AAAHRKGsSSNEPSS 9534 BTO:0000298 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 ritonavir chemical CHEBI:45409 ChEBI CYP3A4 protein P08684 UNIPROT "down-regulates activity" "chemical inhibition" -1 18285471 t Luana "Ritonavir is the most potent and efficacious inhibitor of cytochrome P4503A (CYP3A" SIGNOR-257769 JUN protein P05412 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 10090 12553907 f "In contrast, c-Jun is required for the survival of liver tumor cells. Reduced tumor formation strictly correlated with high apoptotic indices in c-Jun-deficient tumors, suggesting that increased apoptosis in c-Jun-deficient liver tumors is the primary cause for impaired tumorigenesis." SIGNOR-256560 ketoprofen chemical CHEBI:6128 ChEBI PTGS1 protein P23219 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001061 18667313 t Luana "Profens, that is, Ketoprofen 1, Suprofen 2 (Fig. 1), were chosen because of their interesting inhibitory activity against cyclooxygenase and of their different selectivity versus the two isoforms COX-1/COX-2. " SIGNOR-257810 ketoprofen chemical CHEBI:6128 ChEBI PTGS2 protein P35354 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001061 18667313 t Luana "Profens, that is, Ketoprofen 1, Suprofen 2 (Fig. 1), were chosen because of their interesting inhibitory activity against cyclooxygenase and of their different selectivity versus the two isoforms COX-1/COX-2. " SIGNOR-257811 metaproterenol chemical CHEBI:6792 ChEBI ADRB2 protein P07550 UNIPROT "up-regulates activity" "chemical activation" -1 19168263 t Luana "Synthesis, pharmacological and in silico evaluation of 1-(4-di-hydroxy-3,5-dioxa-4-borabicyclo[4.4.0]deca-7,9,11-trien-9-yl)-2-(tert-butylamino)ethanol, a compound designed to act as a β2 adrenoceptor agonist | After that, in vitro assays were carried out and the Kd value obtained for BR-AEA was compared with reported in vitro data for salbutamol and other well-known ligands." SIGNOR-257814 nintedanib chemical CHEBI:85164 ChEBI FGFR1 protein P11362 UNIPROT "down-regulates activity" "chemical inhibition" -1 18559524 t Luana "In this report, we describe the preclinical profile of BIBF 1120, a combined VEGFR, FGFR, and PDGFR inhibitor currently entering phase III clinical studies in non–small cell lung carcinoma and other cancers." SIGNOR-257804 nintedanib chemical CHEBI:85164 ChEBI FGFR3 protein P22607 UNIPROT "down-regulates activity" "chemical inhibition" -1 18559524 t Luana "In this report, we describe the preclinical profile of BIBF 1120, a combined VEGFR, FGFR, and PDGFR inhibitor currently entering phase III clinical studies in non–small cell lung carcinoma and other cancers." SIGNOR-257798 nintedanib chemical CHEBI:85164 ChEBI FGFR4 protein P22455 UNIPROT "down-regulates activity" "chemical inhibition" -1 18559524 t Luana "In this report, we describe the preclinical profile of BIBF 1120, a combined VEGFR, FGFR, and PDGFR inhibitor currently entering phase III clinical studies in non–small cell lung carcinoma and other cancers." SIGNOR-257803 nintedanib chemical CHEBI:85164 ChEBI FLT1 protein P17948 UNIPROT "down-regulates activity" "chemical inhibition" -1 18559524 t Luana "In this report, we describe the preclinical profile of BIBF 1120, a combined VEGFR, FGFR, and PDGFR inhibitor currently entering phase III clinical studies in non–small cell lung carcinoma and other cancers." SIGNOR-257800 nintedanib chemical CHEBI:85164 ChEBI FLT4 protein P35916 UNIPROT "down-regulates activity" "chemical inhibition" -1 18559524 t Luana "In this report, we describe the preclinical profile of BIBF 1120, a combined VEGFR, FGFR, and PDGFR inhibitor currently entering phase III clinical studies in non–small cell lung carcinoma and other cancers." SIGNOR-257801 nintedanib chemical CHEBI:85164 ChEBI KDR protein P35968 UNIPROT "down-regulates activity" "chemical inhibition" -1 18559524 t Luana "In this report, we describe the preclinical profile of BIBF 1120, a combined VEGFR, FGFR, and PDGFR inhibitor currently entering phase III clinical studies in non–small cell lung carcinoma and other cancers." SIGNOR-257802 nintedanib chemical CHEBI:85164 ChEBI PDGFRB protein P09619 UNIPROT "down-regulates activity" "chemical inhibition" -1 18559524 t Luana "In this report, we describe the preclinical profile of BIBF 1120, a combined VEGFR, FGFR, and PDGFR inhibitor currently entering phase III clinical studies in non–small cell lung carcinoma and other cancers." SIGNOR-257799 nisoxetine chemical CHEBI:73410 ChEBI SLC6A2 protein P23975 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 18487050 t Luana "For [3H]paroxetine, [3H]citalopram, [3H]nisoxetine, and [3H]WIN35,428 the following KD values were obtained on the human monoamine transporters hSERT, hNET, and hDAT by homologous competition experiments: 0.69 nM [3H]paroxetine, 4.46 nM [3H]citalopram, 6.77 nM [3H]nisoxetine, and 24.1 [3H]WIN35,428. " SIGNOR-257797 Oxatomide chemical CHEBI:31943 ChEBI HRH1 protein P35367 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0002126 18446005 t Luana "We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells" SIGNOR-257791 paroxetine chemical CHEBI:7936 ChEBI SLC6A4 protein P31645 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 18487050 t Luana "For [3H]paroxetine, [3H]citalopram, [3H]nisoxetine, and [3H]WIN35,428 the following KD values were obtained on the human monoamine transporters hSERT, hNET, and hDAT by homologous competition experiments: 0.69 nM [3H]paroxetine, 4.46 nM [3H]citalopram, 6.77 nM [3H]nisoxetine, and 24.1 [3H]WIN35,428. " SIGNOR-257795 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 QOCYWLABLBUJOR-UHFFFAOYSA-N chemical CID:53299324 PUBCHEM SLC6A3 protein Q01959 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 18487050 t Luana "For [3H]paroxetine, [3H]citalopram, [3H]nisoxetine, and [3H]WIN35,428 the following KD values were obtained on the human monoamine transporters hSERT, hNET, and hDAT by homologous competition experiments: 0.69 nM [3H]paroxetine, 4.46 nM [3H]citalopram, 6.77 nM [3H]nisoxetine, and 24.1 [3H]WIN35,428. " SIGNOR-257796 NANOG protein Q9H9S0 UNIPROT GATA6 protein Q92908 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001086;BTO:0005511 15983365 f miannu "Transfection of NANOG-specific small interfering RNAs reduced levels of NANOG transcript and protein and induced activation of the extraembryonic endoderm-associated genes GATA4, GATA6, LAMININ B1, and AFP as well as upregulation of trophectoderm-associated genes CDX2, GATA2, hCG-alpha, and hCG-beta." SIGNOR-254627 NANOG protein Q9H9S0 UNIPROT LAMB1 protein P07942 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001086;BTO:0005511 15983365 f miannu "Transfection of NANOG-specific small interfering RNAs reduced levels of NANOG transcript and protein and induced activation of the extraembryonic endoderm-associated genes GATA4, GATA6, LAMININ B1, and AFP as well as upregulation of trophectoderm-associated genes CDX2, GATA2, hCG-alpha, and hCG-beta." SIGNOR-254628 NANOG protein Q9H9S0 UNIPROT PAX6 protein P26367 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0003298 22795133 f lperfetto "Knockdown of Oct4 or Nanog induced an increase in the expression of Pax6, Gata4, Gata6, Sox17, and FoxA2 in E, H, and p21KD MSCs ( Figure 3F and Figure S2D)" SIGNOR-253164 Norzotepine chemical CID:10041551 PUBCHEM 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-257831 Norzotepine chemical CID:10041551 PUBCHEM SLC6A4 protein P31645 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-257830 NUMA1 protein Q14980 UNIPROT Tubulin proteinfamily SIGNOR-PF46 SIGNOR up-regulates binding 9606 11956313 t "Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules." SIGNOR-256541 PIM2 protein Q9P1W9 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 16146838 f 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-256575 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR HIF1A protein Q16665 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567 19808903 t lperfetto "We report a Notch signal-induced pathway that leads to transcriptional activation of HIF1-alpha gene." SIGNOR-209720 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR MYC protein P01106 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000785 16847353 t lperfetto "C-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma" SIGNOR-209593 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR NRARP protein Q7Z6K4 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000222;BTO:0000782 11783997 t gcesareni "These observations demonstrate that the nrarp gene is an evolutionarily conserved transcriptional target of the notch signaling pathway." SIGNOR-113786 saxagliptin chemical CHEBI:71272 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-257813 suprofen chemical CHEBI:9362 ChEBI PTGS1 protein P23219 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001061 18667313 t Luana "Profens, that is, Ketoprofen 1, Suprofen 2 (Fig. 1), were chosen because of their interesting inhibitory activity against cyclooxygenase and of their different selectivity versus the two isoforms COX-1/COX-2. " SIGNOR-257809 suprofen chemical CHEBI:9362 ChEBI PTGS2 protein P35354 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001061 18667313 t Luana "Profens, that is, Ketoprofen 1, Suprofen 2 (Fig. 1), were chosen because of their interesting inhibitory activity against cyclooxygenase and of their different selectivity versus the two isoforms COX-1/COX-2. " SIGNOR-257808 Terfenadine chemical CHEBI:9453 ChEBI HRH1 protein P35367 UNIPROT "down-regulates activity" "chemical inhibition" -1 19660947 t Luana " hERG activity was initially determined in a high throughput patch clamp screening assay (Ionworks)5 while a human H1 binding assay was used to determine H1 binding affinity.6 Selected results were confirmed in vitro using an IonWorks Quattro patch clamp assay and in vivo in the guinea pig.7, 8 Histamine H1activity was confirmed in vivo in the guinea pig.7" SIGNOR-257825 tibolone chemical CHEBI:32223 ChEBI AR protein P10275 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000567 19464167 t Luana "In this study, we have assessed the potential hormonal profile of tibolone and its primary metabolites on all human steroid receptors (PR, AR, GR, MR, ERα and ERβ) using HeLa or PC3 cells stably transfected with a given receptor and a luciferase reporter gene. We show that tibolone and its ∆ 4 -isomer predominantly bind and activate PR and AR whereas 3α and 3β-OH-tibolone predominantly bind and activate ERα (Table 1)." SIGNOR-257823 tibolone chemical CHEBI:32223 ChEBI ESR1 protein P03372 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000567 19464167 t Luana "In this study, we have assessed the potential hormonal profile of tibolone and its primary metabolites on all human steroid receptors (PR, AR, GR, MR, ERα and ERβ) using HeLa or PC3 cells stably transfected with a given receptor and a luciferase reporter gene. We show that tibolone and its ∆ 4 -isomer predominantly bind and activate PR and AR whereas 3α and 3β-OH-tibolone predominantly bind and activate ERα (Table 1)." SIGNOR-257821 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 lurasidone chemical CHEBI:70735 ChEBI HTR1A protein P08908 UNIPROT "up-regulates activity" "chemical activation" 10030 20404009 t Luana "In vitro functional assays demonstrated that lurasidone acts as an antagonist at D2 and 5-HT7 receptors and as a partial agonist at the 5-HT1A receptor subtype." SIGNOR-257839 lurasidone chemical CHEBI:70735 ChEBI HTR2A protein P28223 UNIPROT "down-regulates activity" "chemical inhibition" 10030 20404009 t Luana "Lurasidone was found to have potent binding affinity for dopamine D2, 5-hydroxytryptamine 2A (5-HT2A), 5-HT7, 5-HT1A, and noradrenaline 2C receptors." SIGNOR-257841 lurasidone chemical CHEBI:70735 ChEBI HTR7 protein P34969 UNIPROT "down-regulates activity" "chemical inhibition" 10030 BTO:0000246 20404009 t Luana "In vitro functional assays demonstrated that lurasidone acts as an antagonist at D2 and 5-HT7 receptors and as a partial agonist at the 5-HT1A receptor subtype." SIGNOR-257840 NANOG protein Q9H9S0 UNIPROT Pluripotency phenotype SIGNOR-PH43 SIGNOR up-regulates 9606 BTO:0001086 25126380 f flangone "Sex determining region Y-box 2 (Sox2), a member of the SoxB1 transcription factor family, is an important transcriptional regulator in pluripotent stem cells (PSCs). Together with octamer-binding transcription factor 4 and Nanog, they co-operatively control gene expression in PSCs and maintain their pluripotency. " SIGNOR-242073 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 PORCN protein Q9H237 UNIPROT WNT3A protein P56704 UNIPROT "up-regulates activity" palmitoylation Ser209 KCKCHGLsGSCEVKTC 9606 BTO:0000007 20826466 t "And WNT3A binding to WLS requires PORCN-dependent lipid modification of WNT3A at serine 209. Inhibition of vacuolar acidification results in accumulation of the WNT3A-WLS complex both in cells and at the plasma membrane." SIGNOR-256598 SLC16A3 protein O15427 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 26384349 f lperfetto "Treatment with _-cyano-4-hydroxy cinnamate (CHC), a known inhibitor of MCT1, MCT2 and MCT4, dose-dependently induced cell death in MM cell lines and primary MM cells (Figure 1C). Thus, monocarboxylate transportation across membranes appears crucial for MM cell survival." SIGNOR-256581 SLC16A4 protein O15374 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 26384349 f lperfetto "Treatment with _-cyano-4-hydroxy cinnamate (CHC), a known inhibitor of MCT1, MCT2 and MCT4, dose-dependently induced cell death in MM cell lines and primary MM cells (Figure 1C). Thus, monocarboxylate transportation across membranes appears crucial for MM cell survival." SIGNOR-256582 STAT5A protein P42229 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0001096 14530308 f apalma "Specific inhibition of Stat5a/b promotes apoptosis of IL-2-responsive primary and tumor-derived lymphoid cells" SIGNOR-256583 tibolone chemical CHEBI:32223 ChEBI PGR protein P06401 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000567 19464167 t Luana "In this study, we have assessed the potential hormonal profile of tibolone and its primary metabolites on all human steroid receptors (PR, AR, GR, MR, ERα and ERβ) using HeLa or PC3 cells stably transfected with a given receptor and a luciferase reporter gene. We show that tibolone and its ∆ 4 -isomer predominantly bind and activate PR and AR whereas 3α and 3β-OH-tibolone predominantly bind and activate ERα (Table 1)." SIGNOR-257822 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 zotepine chemical CHEBI:32316 ChEBI SLC6A4 protein P31645 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-257829 clenbuterol chemical CHEBI:174690 ChEBI ADRB1 protein P08588 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000457 20590599 t Luana "Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy. " SIGNOR-257862 clenbuterol chemical CHEBI:174690 ChEBI ADRB2 protein P07550 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000457 20590599 t Luana "Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy. " SIGNOR-257861 "Cy3-bifunctional dye zwitterion" chemical CHEBI:37990 ChEBI ADRB1 protein P08588 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000457 20590599 t Luana "Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy. " SIGNOR-257859 "Cy3-bifunctional dye zwitterion" chemical CHEBI:37990 ChEBI ADRB2 protein P07550 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000457 20590599 t Luana "Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy. " SIGNOR-257858 sulindac chemical CHEBI:9352 ChEBI RXRA protein P19793 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001109 20541701 t Luana "NSAID Sulindac and Its Analogs Bind RXRα and Inhibit RXRα-dependent AKT Signaling" SIGNOR-257847 sunitinib chemical CHEBI:38940 ChEBI FLT3 protein P36888 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0004479 20570526 t Luana "Sunitinib [inhibits KDR, PDGFR2, PDGFRβ, c-KIT and FLT3; approved for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors]," SIGNOR-257849 sunitinib chemical CHEBI:38940 ChEBI FLT4 protein P35916 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0004479 20570526 t Luana "Sunitinib [inhibits KDR, PDGFR2, PDGFRβ, c-KIT and FLT3; approved for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors]," SIGNOR-257848 sunitinib chemical CHEBI:38940 ChEBI KDR protein P35968 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0004479 20570526 t Luana "Sunitinib [inhibits KDR, PDGFR2, PDGFRβ, c-KIT and FLT3; approved for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors]," SIGNOR-257850 sunitinib chemical CHEBI:38940 ChEBI KIT protein P10721 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0004479 20570526 t Luana "Sunitinib [inhibits KDR, PDGFR2, PDGFRβ, c-KIT and FLT3; approved for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors]," SIGNOR-257851 VEGFA protein P15692 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 9606 16301830 f "VEGF as a key mediator of angiogenesis in cancer." SIGNOR-256597 venlafaxine chemical CHEBI:9943 ChEBI SLC6A4 protein P31645 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001585 20378347 t Luana "The cycloalkanol ethylamine scaffold was successfully utilized in the discovery and development of dual serotonin (5-HT)/norepinephrine (NE) reuptake inhibitors (SNRIs).1 Drugs such as venlafaxine (1) and duloxetine (2) possessing norepinephrine reuptake inhibition, either selectively or in combination with serotonin reuptake inhibition were approved for major depressive disorder (MDD)." SIGNOR-257836 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 vilanterol chemical CHEBI:75037 ChEBI ADRB2 protein P07550 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000246 20462258 t Luana "A series of saligenin β2 adrenoceptor agonist antedrugs having high clearance were prepared by reacting a protected saligenin oxazolidinone with protected hydroxyethoxyalkoxyalkyl bromides, followed by removal of the hydroxy-protecting group, alkylation, and final deprotection. The compounds were screened for β2, β1, and β3 agonist activity in CHO cells. | Compound 13f had high potency, selectivity, fast onset, and long duration of action in vitro and was found to have long duration in vivo" SIGNOR-257843 WLS protein Q5T9L3 UNIPROT WNT3A protein P56704 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000007 20826466 t "WNT secretion requires its binding to the carrier protein wntless (WLS);" SIGNOR-256599 adrenaline smallmolecule CHEBI:33568 ChEBI ADRB3 protein P13945 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-257877 denopamine chemical CHEBI:135359 ChEBI ADRB1 protein P08588 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000457 20590599 t Luana "Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy. " SIGNOR-257860 fenoterol chemical CHEBI:149226 ChEBI ADRB2 protein P07550 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000457 20590599 t Luana "Finally, comparisons of the rank order of ligands for the three different receptors provide information about relative intrinsic efficacies. Fenoterol is a full and efficacious agonist at the β1-adrenoceptor, ranking third out of the agonists studied. It was also a full agonist at the β2- and β3-adrenoceptors with the highest intrinsic efficacy (i.e. top of Tables 4 and ​and5,5, rank 1). " SIGNOR-257869 N-[2-hydroxy-5-(1-hydroxy-2-{[1-(4-methoxyphenyl)propan-2-yl]amino}ethyl)phenyl]formamide chemical CHEBI:63082 ChEBI ADRB1 protein P08588 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000457 20590599 t Luana "Thus, overall, salmeterol is a highly selective β2-adrenoceptor agonist because of its higher β2-affinity and not because of higher β2-intrinsic efficacy. A similar reasoning can be applied to formoterol, although this agonist has higher intrinsic efficacy at all three receptors (rank 6, 8 and 5 at β1, β2 and β3)." SIGNOR-257854 N-[2-hydroxy-5-(1-hydroxy-2-{[1-(4-methoxyphenyl)propan-2-yl]amino}ethyl)phenyl]formamide chemical CHEBI:63082 ChEBI ADRB2 protein P07550 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000457 20590599 t Luana "Thus, overall, salmeterol is a highly selective β2-adrenoceptor agonist because of its higher β2-affinity and not because of higher β2-intrinsic efficacy. A similar reasoning can be applied to formoterol, although this agonist has higher intrinsic efficacy at all three receptors (rank 6, 8 and 5 at β1, β2 and β3)." SIGNOR-257853 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 NCK1 protein P16333 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates binding 9606 BTO:0000782 11157752 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-235947 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 WASL protein O00401 UNIPROT up-regulates binding 9606 11340081 t gcesareni "Nck and cdc42 activate n-wasp by redundant mechanisms." SIGNOR-107634 NCKAP1 protein Q9Y2A7 UNIPROT "WRC complex" complex SIGNOR-C191 SIGNOR "form complex" binding 9606 21107423 t miannu "WAVE proteins are constitutively associated with four additional proteins in cells: Sra1/Cyfip1, Nap1/Hem-2, Abi and HSPC300. The components of this ~400 kDa pentamer, termed the WAVE regulatory complex (WRC) have all been implicated in control of Arp2/3 complex-mediated actin assembly in a wide range of systems" SIGNOR-253569 NFIL3 protein Q16649 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 10090 BTO:0003104 10082541 f lperfetto "NFIL3 inhibits apoptosis without affecting Bcl-xL expression." SIGNOR-256618 NYYJKMXNVNFOFQ-MHZLTWQESA-N chemical CID:9829836 PUBCHEM ADRB3 protein P13945 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000457 20590599 t Luana "There were several β3-selective compounds (e.g. AZ 40140d, L 755507, L 748337 and TAK 677)" SIGNOR-257856 procaterol chemical CHEBI:135209 ChEBI ADRB1 protein P08588 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000457 20590599 t Luana "Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy. " SIGNOR-257864 procaterol chemical CHEBI:135209 ChEBI ADRB2 protein P07550 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000457 20590599 t Luana "Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy. " SIGNOR-257863 clemastine chemical CHEBI:3738 ChEBI P2RX7 protein Q99572 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000007 21262970 t Luana "Clemastine potentiates the human P2X7 receptor by sensitizing it to lower ATP concentrations." SIGNOR-257893 fenoterol chemical CHEBI:149226 ChEBI ADRB3 protein P13945 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000457 20590599 t Luana "Finally, comparisons of the rank order of ligands for the three different receptors provide information about relative intrinsic efficacies. Fenoterol is a full and efficacious agonist at the β1-adrenoceptor, ranking third out of the agonists studied. It was also a full agonist at the β2- and β3-adrenoceptors with the highest intrinsic efficacy (i.e. top of Tables 4 and ​and5,5, rank 1). " SIGNOR-257868 metaproterenol chemical CHEBI:6792 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-257873 metaproterenol chemical CHEBI:6792 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-257875 Pyridostigmine chemical CHEBI:8665 ChEBI BCHE protein P06276 UNIPROT "down-regulates activity" "chemical inhibition" -1 20627738 t Luana "The compounds 3-[(dimethylamino)carboxyl]oxy]-N,N,N-trimethylammonium methyl sulfate, better known as neostigmine methyl sulfate (3),1 and 3-[(dimethylcarbamoyl)oxy]-1-methylpyridinium bromide, pyridostigmine bromide (4)2 (Figure 1) are well known peripheral cholinesterase inhibitors " SIGNOR-257880 RIPK1 protein Q13546 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 14965271 f amattioni "Fas-induced necrosis requires rip" SIGNOR-256661 metaproterenol chemical CHEBI:6792 ChEBI ADRB3 protein P13945 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-257874 PIM1 protein P11309 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 16146838 f 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-256657 PML protein P29590 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 BTO:0001271 15093545 f gcesareni "The promyelocytic leukemia (pml) protein is a potent growth suppressor and proapototic factor" SIGNOR-256659 PRKCA protein P17252 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 BTO:0000599 15730925 f irozzo "PKC-alpha asODN (antisense oligonucleotides) could inhibit the growth and proliferation of HepG2 and induce its apoptosis by blocking the cell signal transduction related to PKC-alpha in vitro, and may be potentially used in the prevention and management of recurrent and metastatic HCC." SIGNOR-256660 PTGER3 protein P43115 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates binding 9606 BTO:0000938 12038972 t gcesareni "Ep3 receptor signals are primarily involved in adenylyl cyclase via g(i) activation, and in ca(2+)-mobilization through g(beta)(gamma) from g(i)" SIGNOR-88143 PTGER3 protein P43115 UNIPROT GNB3 protein P16520 UNIPROT up-regulates binding 9606 BTO:0000938 12038972 t gcesareni "Ep3 receptor signals are primarily involved in adenylyl cyclase via g(i) activation, and in ca(2+)-mobilization through g(beta)(gamma) from g(i)" SIGNOR-88192 Pyridostigmine chemical CHEBI:8665 ChEBI ACHE protein P22303 UNIPROT "down-regulates activity" "chemical inhibition" -1 20627738 t Luana "The compounds 3-[(dimethylamino)carboxyl]oxy]-N,N,N-trimethylammonium methyl sulfate, better known as neostigmine methyl sulfate (3),1 and 3-[(dimethylcarbamoyl)oxy]-1-methylpyridinium bromide, pyridostigmine bromide (4)2 (Figure 1) are well known peripheral cholinesterase inhibitors " SIGNOR-257879 terbutaline chemical CHEBI:9449 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-257870 terbutaline chemical CHEBI:9449 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-257872 terbutaline chemical CHEBI:9449 ChEBI ADRB3 protein P13945 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-257871 TP53 protein P04637 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 24212651 f miannu "P53 is a nuclear transcription factor with a pro-apoptotic function" SIGNOR-256664 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 entinostat chemical CHEBI:132082 ChEBI HDAC9 protein Q9UKV0 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-257905 "N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester" chemical CHEBI:94187 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-257910 tadalafil chemical CHEBI:71940 ChEBI PDE5A protein O76074 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000815 21189023 t Luana "All of the final compounds and intermediates synthesized were screened for in vitro tumor cell growth inhibition activity using the human MDA-MB-231 breast tumor cell line and for inhibition of recombinant human PDE5 at a single concentration of 10 μM. For compounds showing >60% inhibition, the IC50 was determined by testing a range of eight concentrations with quadruple replicates per concentration, tadalafil used as a positive control.| Conversely, tadalafil possessed a selectivity index of just 16.6 for PDE5 versus PDE11" SIGNOR-257887 S1PR5 protein Q9H228 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-256676 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 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 JWOGUUIOCYMBPV-GMFLJSBRSA-N chemical CID:6918328 PUBCHEM HDAC3 protein O15379 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-257913 JWOGUUIOCYMBPV-GMFLJSBRSA-N chemical CID:6918328 PUBCHEM 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-257915 "N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester" chemical CHEBI:94187 ChEBI HDAC2 protein Q92769 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-257909 "N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester" chemical CHEBI:94187 ChEBI HDAC3 protein O15379 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-257906 "N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester" chemical CHEBI:94187 ChEBI HDAC6 protein Q9UBN7 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-257908 "N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester" chemical CHEBI:94187 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-257907 NCOA2 protein Q15596 UNIPROT PPARG protein P37231 UNIPROT up-regulates binding 9606 18584035 t gcesareni "Collectively, our data provide the first evidence that erbeta-deficiency protects against diet-induced ir and glucose intolerance which involves an augmented ppargamma signaling in adipose tissue. Moreover, our data suggest that the coactivators src1 and tif2 are involved in this interaction." SIGNOR-179175 NCOA2 protein Q15596 UNIPROT RARA protein P10276 UNIPROT up-regulates binding 9606 12503607 t gcesareni "Transcriptional coactivator for steroid receptors and nuclear receptors.nteracts with casp8ap2 and ttll5/stamp. Interacts with esr1, rara and rxra." SIGNOR-96827 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 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-257927 PTPN11 protein Q06124 UNIPROT NRAS protein P01111 UNIPROT "up-regulates activity" dephosphorylation Tyr32 QNHFVDEyDPTIEDS 9606 BTO:0000007 26617336 t miannu "Here we identify SHP2 as the ubiquitously expressed tyrosine phosphatase that preferentially binds to and dephosphorylates Ras to increase its association with Raf and activate downstream proliferative Ras/ERK/MAPK signalling." SIGNOR-255754 DRD2 protein P14416 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-256701 AR protein P10275 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 15861399 f miannu "AR homodimers recruit a panoply of factors including coactivators and mediator proteins whose enzymatic activities promote chromatin remodeling and transcriptional regulation of target genes leading to cell differentiation, survival, and proliferation" SIGNOR-251538 "N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester" chemical CHEBI:94187 ChEBI HDAC4 protein P56524 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-257911 "trichostatin A" chemical CHEBI:46024 ChEBI HDAC2 protein Q92769 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-257942 vorinostat chemical CHEBI:45716 ChEBI HDAC2 protein Q92769 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-257923 vorinostat chemical CHEBI:45716 ChEBI HDAC3 protein O15379 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-257916 vorinostat chemical CHEBI:45716 ChEBI HDAC4 protein P56524 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-257922 vorinostat chemical CHEBI:45716 ChEBI HDAC6 protein Q9UBN7 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-257918 LPAR1 protein Q92633 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-256696 N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide chemical CHEBI:94525 ChEBI HDAC3 protein O15379 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-257932 NAE1 protein Q13564 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000938 25568892 f lperfetto "Overexpression of AppBp1 in primary neurons induces apoptosis through the neddylation pathway" SIGNOR-251579 NAE1 protein Q13564 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 BTO:0000938 25568892 f lperfetto "Overexpression of AppBp1 in primary neurons induces apoptosis through the neddylation pathway" SIGNOR-256651 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 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-257929 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC2 protein Q92769 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-257931 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC4 protein P56524 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-257930 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 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-257928 vorinostat chemical CHEBI:45716 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-257919 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 vorinostat chemical CHEBI:45716 ChEBI HDAC9 protein Q9UKV0 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-257917 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 P2RY14 protein Q15391 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-256723 NEK2 protein P51955 UNIPROT NEK2 protein P51955 UNIPROT down-regulates phosphorylation Ser241 RRIPYRYsDELNEII 9606 17197699 t gcesareni "Enzymatic activity, inhibited;" SIGNOR-151767 "trichostatin A" chemical CHEBI:46024 ChEBI HDAC3 protein O15379 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-257935 "trichostatin A" chemical CHEBI:46024 ChEBI HDAC6 protein Q9UBN7 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-257937 "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 NMUR2 protein Q9GZQ4 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-256731 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 "trichostatin A" chemical CHEBI:46024 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-257939 "trichostatin A" chemical CHEBI:46024 ChEBI HDAC9 protein Q9UKV0 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-257936 vorinostat chemical CHEBI:45716 ChEBI HDAC1 protein Q13547 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257950 vorinostat chemical CHEBI:45716 ChEBI HDAC2 protein Q92769 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257951 vorinostat chemical CHEBI:45716 ChEBI HDAC3 protein O15379 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257948 vorinostat chemical CHEBI:45716 ChEBI HDAC5 protein Q9UQL6 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257947 3,3',5'-triiodo-L-thyronine smallmolecule CHEBI:11684 ChEBI MYOD1 protein P15172 UNIPROT "up-regulates activity" binding 20978344 f "D2-mediated increases in T3 were essential for the enhanced transcription of myogenic differentiation 1 (MyoD) and for execution of the myogenic program." SIGNOR-256203 NCOA2 protein Q15596 UNIPROT RXRA protein P19793 UNIPROT up-regulates binding 9606 11851396 t gcesareni "Here, it is demonstrated that mutation of the h11 phenylalanine residues diminishes the ability of rxr to associate with the p160 coactivators tif2 and p/cip, but has little effect on ligand-dependent interactions of the receptor with the unrelated coactivator tif1." SIGNOR-114847 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 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 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 SRC protein P12931 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Tyr478 PPPPPPVyEPVSYHV 9606 BTO:0000671 15623525 t lperfetto "Src phosphorylates ezrin at tyrosine 477 and induces a phosphospecific association between ezrin and a kelch-repeat protein family member" SIGNOR-132907 vorinostat chemical CHEBI:45716 ChEBI HDAC6 protein Q9UBN7 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257949 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 OXGR1 protein Q96P68 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-256770 belinostat chemical CHEBI:61076 ChEBI HDAC5 protein Q9UQL6 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257960 CDKN2A protein Q8N726 UNIPROT NPM1 protein P06748 UNIPROT "down-regulates quantity by destabilization" binding 9606 14636574 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-245077 MAPK3 protein P27361 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates phosphorylation Ser312 SYLSQMTsPSIHSTT 9606 19801668 t llicata "In this study, we identified two phosphorylation sites in runx2 at ser301 and ser319 that are required for mapk-dependent activation of runx2 transcriptional activity and osteoblast differentiation." SIGNOR-188347 "N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester" chemical CHEBI:94187 ChEBI HDAC2 protein Q92769 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257965 "N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester" chemical CHEBI:94187 ChEBI HDAC3 protein O15379 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257966 "N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester" chemical CHEBI:94187 ChEBI HDAC6 protein Q9UBN7 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257967 "N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester" chemical CHEBI:94187 ChEBI HDAC7 protein Q8WUI4 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257964 "N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester" chemical CHEBI:94187 ChEBI HDAC9 protein Q9UKV0 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257970 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 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 MAP4K1 protein Q92918 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates phosphorylation 9606 8824585 t gcesareni "Hpk1 binds and phosphorylates mekk1 directly," SIGNOR-43996 N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide chemical CHEBI:94525 ChEBI HDAC2 protein Q92769 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257973 N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide chemical CHEBI:94525 ChEBI HDAC3 protein O15379 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257974 "N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester" chemical CHEBI:94187 ChEBI HDAC1 protein Q13547 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257971 "N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester" chemical CHEBI:94187 ChEBI HDAC8 protein Q9BY41 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257972 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC2 protein Q92769 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257981 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC3 protein O15379 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257982 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC7 protein Q8WUI4 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257980 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 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr739 SEGSGTAtPSALITT 9606 BTO:0000887;BTO:0001260 20150555 t lperfetto "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-216940 PLK1 protein P53350 UNIPROT KIF2B protein Q8N4N8 UNIPROT "up-regulates activity" phosphorylation Ser204 HLDSSKIsVLEPPQE 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-252050 romidepsin chemical CHEBI:61080 ChEBI HDAC2 protein Q92769 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257997 romidepsin chemical CHEBI:61080 ChEBI HDAC3 protein O15379 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257993 romidepsin chemical CHEBI:61080 ChEBI HDAC4 protein P56524 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257991 romidepsin chemical CHEBI:61080 ChEBI HDAC5 protein Q9UQL6 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257989 romidepsin chemical CHEBI:61080 ChEBI HDAC6 protein Q9UBN7 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257990 romidepsin chemical CHEBI:61080 ChEBI HDAC7 protein Q8WUI4 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257992 RPS6K proteinfamily SIGNOR-PF26 SIGNOR STK11 protein Q15831 UNIPROT "down-regulates activity" phosphorylation Ser428 SSKIRRLsACKQQ 9606 BTO:0001271 25846811 t lperfetto "Negative regulation of the LKB1/AMPK pathway by ERK in human acute myeloid leukemia cellsBRAFV600E activates downstream molecules, including ERK and p90 ribosomal S6 kinase (RSK), and leads to the phosphorylation of LKB-1 at Ser428 by these kinases. This cascade results in the dissociation of LKB1 from AMPK." SIGNOR-252805 RPS6K proteinfamily SIGNOR-PF26 SIGNOR TSC2 protein P49815 UNIPROT down-regulates phosphorylation Ser1798 GQRKRLIsSVEDFTE 9606 BTO:0000007 15342917 t lperfetto "The mitogen-activated protein kinase (mapk)-activated kinase, p90 ribosomal s6 kinase (rsk) 1, was found to interact with and phosphorylate tuberin at a regulatory site, ser-1798, located at the evolutionarily conserved c terminus of tuberin. Rsk1 phosphorylation of ser-1798 inhibits the tumor suppressor function of the tuberin/hamartin complex, resulting in increased mtor signaling to s6k1" SIGNOR-252801 6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide chemical CHEBI:92401 ChEBI HDAC8 protein Q9BY41 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-258001 ANAPC2 protein Q9UJX6 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-252002 LCK protein P06239 UNIPROT CD3E protein P07766 UNIPROT "up-regulates activity" phosphorylation Tyr199 RKGQRDLySGLNQRR 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-251369 PDK1 protein Q15118 UNIPROT PDHA1 protein P08559 UNIPROT "down-regulates activity" phosphorylation Ser300 SMSDPGVsYRTREEI -1 11485553 t lperfetto "Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293." SIGNOR-109555 PDP1 protein Q9P0J1 UNIPROT PDHA1 protein P08559 UNIPROT "up-regulates activity" dephosphorylation Ser232 NRYGMGTsVERAAAS -1 7782287 t "Sites 1, 2, and 3 were dephosphorylated either individually or in the presence of the other sites by the phospho-E1-phosphatase resulting in complete reactivation of the E1. The rates of dephosphorylation and reactivation were similar for sites 1, 2, and 3, indicating a random dephosphorylation mechanism" SIGNOR-252055 PPP1CA protein P62136 UNIPROT RAF1 protein P04049 UNIPROT "up-regulates activity" dephosphorylation Ser259 SQRQRSTsTPNVHMV 9606 BTO:0000007 16630891 t "We have identified a complex comprised of Shoc2/Sur-8 and the catalytic subunit of protein phosphatase 1 (PP1c) as a highly specific M-Ras effector. M-Ras targets Shoc2-PP1c to stimulate Raf activity by dephosphorylating the S259 inhibitory site of Raf proteins" SIGNOR-251649 PTPN6 protein P29350 UNIPROT KDR protein P35968 UNIPROT "down-regulates activity" dephosphorylation Tyr1175 AQQDGKDyIVLPISE 9606 18377662 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-248475 romidepsin chemical CHEBI:61080 ChEBI HDAC8 protein Q9BY41 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257994 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 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 6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide chemical CHEBI:92401 ChEBI HDAC7 protein Q8WUI4 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-258004 "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 PDP1 protein Q9P0J1 UNIPROT PDHA1 protein P08559 UNIPROT "up-regulates activity" dephosphorylation Ser293 TYRYHGHsMSDPGVS -1 7782287 t "Sites 1, 2, and 3 were dephosphorylated either individually or in the presence of the other sites by the phospho-E1-phosphatase resulting in complete reactivation of the E1. The rates of dephosphorylation and reactivation were similar for sites 1, 2, and 3, indicating a random dephosphorylation mechanism" SIGNOR-252054 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT "down-regulates activity" dephosphorylation Tyr1009 LDTSSVLyTAVQPNE -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-248416 PTPRJ protein Q12913 UNIPROT EGFR protein P00533 UNIPROT "up-regulates quantity by stabilization" dephosphorylation Tyr1197 STAENAEyLRVAPQS 9606 BTO:0000567 19836242 t "We report the identification of PTPRK and PTPRJ (density-enhanced phosphatase-1 [DEP-1]) as EGFR-targeting phosphatases. DEP-1 is a tumor suppressor that dephosphorylates and thereby stabilizes EGFR by hampering its ability to associate with the CBL-GRB2 ubiquitin ligase complex|By employing commercially available antibodies, which are supposed to recognize specific tyrosine phosphorylation sites of EGFR, we found that depletion of endogenous DEP-1 nonselectively increased receptor phosphorylation, affecting all three sites we analyzed (tyrosines 1045, 1068, and 1173" SIGNOR-248699 tacedinaline chemical CHEBI:90195 ChEBI HDAC1 protein Q13547 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-258009 tacedinaline chemical CHEBI:90195 ChEBI HDAC2 protein Q92769 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-258008 tacedinaline chemical CHEBI:90195 ChEBI HDAC3 protein O15379 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-258007 "trichostatin A" chemical CHEBI:46024 ChEBI HDAC5 protein Q9UQL6 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-258010 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 ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT "up-regulates activity" phosphorylation Ser28 PHGSVTQsQGSSSQS 9606 BTO:0000007 10973490 t lperfetto "Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to irser28 was also found to be phosphorylated in an atm-dependent manner" SIGNOR-81395 MLN protein P12872 UNIPROT MLNR protein O43193 UNIPROT up-regulates binding 9606 BTO:0000938 10381885 t gcesareni "A heterotrimeric guanosine triphosphate-binding protein (g protein)-coupled receptor for motilin was isolated from human stomach" SIGNOR-68721 Riluzole chemical CHEBI:8863 ChEBI KCNN1 protein Q92952 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000007 18955585 t Luana "Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM. " SIGNOR-258021 Riluzole chemical CHEBI:8863 ChEBI KCNN2 protein Q9H2S1 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000007 18955585 t Luana "Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM. " SIGNOR-258020 Riluzole chemical CHEBI:8863 ChEBI KCNN3 protein Q9UGI6 UNIPROT "up-regulates activity" "chemical activation" 9534 BTO:0000298 18955585 t Luana "Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM. " SIGNOR-258019 SRC protein P12931 UNIPROT PLSCR1 protein O15162 UNIPROT "up-regulates activity" phosphorylation Tyr69 PVPNQPVyNQPVYNQ 9606 BTO:0000671 12871937 t lperfetto "Cell stimulation by egf results in tyr phosphorylation of plscr1, its association with both shc and egf receptors, and rapid cycling of plscr1 between plasma membrane and endosomal compartments.We Now report evidence that upon egf stimulation, plscr1 is phosphorylated by c-src, within the tandem repeat sequence 68vynqpvynqp77. The in vivo interaction between plscr1 and shc requires the src-mediated phosphorylation on tyrosines 69 and 74. Furthermore, our data suggest that deletion of plscr1 from the plasma membrane results in marked reduction in egf-initiated activation of c-src kinase.\ We propose that PLSCR1, through its interaction with Shc, promotes Src kinase activation through the EGF receptor." SIGNOR-103769 "trichostatin A" chemical CHEBI:46024 ChEBI HDAC7 protein Q8WUI4 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-258014 "trichostatin A" chemical CHEBI:46024 ChEBI HDAC8 protein Q9BY41 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-258013 "trichostatin A" chemical CHEBI:46024 ChEBI HDAC9 protein Q9UKV0 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-258016 Naphtho[1,2-d]thiazol-2-amine chemical CID:94880 PUBCHEM KCNN1 protein Q92952 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000007 18955585 t Luana "Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM. " SIGNOR-258026 Naphtho[1,2-d]thiazol-2-amine chemical CID:94880 PUBCHEM KCNN2 protein Q9H2S1 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000007 18955585 t Luana "Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM. " SIGNOR-258027 Naphtho[1,2-d]thiazol-2-amine chemical CID:94880 PUBCHEM KCNN4 protein O15554 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000007 18955585 t Luana "Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM. " SIGNOR-258025 Riluzole chemical CHEBI:8863 ChEBI KCNN4 protein O15554 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000007 18955585 t Luana "Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM. " SIGNOR-258022 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 tazarotene chemical CHEBI:32184 ChEBI RARG protein P13631 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-258029 "trichostatin A" chemical CHEBI:46024 ChEBI HDAC4 protein P56524 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-258017 "trichostatin A" chemical CHEBI:46024 ChEBI HDAC6 protein Q9UBN7 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-258018 LPAR1 protein Q92633 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-256839 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 DYRK1B protein Q9Y463 UNIPROT DYRK1B protein Q9Y463 UNIPROT up-regulates phosphorylation Tyr273 LGQRIYQyIQSRFYR 9606 10910078 t lperfetto "Mirk kinase is activated by autophosphorylation on tyrosine at the y271/y273 site" SIGNOR-79810 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 NPFFR1 protein Q9GZQ6 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-256851 Amyloid_fibril_formation phenotype SIGNOR-PH59 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates 26721223 f "Excessive accumulation of Aβ protein in the AD brain may lead to a decrease in the levels of phosphatidylinositol-3 kinase (PI3K) and the serine/threonine protein kinase B (Akt) activity." SIGNOR-255493 Amyloid_fibril_formation phenotype SIGNOR-PH59 SIGNOR DKK1 protein O94907 UNIPROT "up-regulates activity" 15229249 f "Exposure of the cultures to beta-amyloid peptide (βAP) induced the expression of the secreted glycoprotein Dickkopf-1 (DKK1). " SIGNOR-255482 NMUR2 protein Q9GZQ4 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-256874 TBX2 protein Q13207 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24470334 f "TBX2 blocks myogenesis and promotes proliferation in rhabdomyosarcoma cells" SIGNOR-251562 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 P2RY14 protein Q15391 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-256866 AMPK complex SIGNOR-C15 SIGNOR VASP protein P50552 UNIPROT down-regulates phosphorylation Ser322 TTLPRMKsSSSVTTS 9606 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-216568 Amyloid_fibril_formation phenotype SIGNOR-PH59 SIGNOR PI3K complex SIGNOR-C156 SIGNOR down-regulates 26721223 f "Excessive accumulation of Aβ protein in the AD brain may lead to a decrease in the levels of phosphatidylinositol-3 kinase (PI3K) and the serine/threonine protein kinase B (Akt) activity." SIGNOR-255492 ketoconazole chemical CHEBI:47519 ChEBI UGT1A1 protein P22309 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 21030469 t Luana "Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation." SIGNOR-258060 CYSLTR1 protein Q9Y271 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-256883 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 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 F2RL1 protein P55085 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-256895 "2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid" chemical CID:135461425 PUBCHEM PDGFRA protein P16234 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t llicata "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-258082 ATR protein Q13535 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser15 PSVEPPLsQETFSDL 9606 11865061 t gcesareni "Nhibition of atr kinase activity substantially reduces hypoxia-induced phosphorylation of p53 protein on serine 15 as well as p53 protein accumulation." SIGNOR-115134 N'-(1,8-dimethyl-4-imidazo[1,2-a]quinoxalinyl)ethane-1,2-diamine chemical CHEBI:91340 ChEBI CHUK protein O15111 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-258085 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 bosutinib chemical CHEBI:39112 ChEBI ABL1 protein P00519 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-258088 bosutinib chemical CHEBI:39112 ChEBI SRC protein P12931 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-258089 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 N-(5-{[(5-tert-butyl-1,3-oxazol-2-yl)methyl]sulfanyl}-1,3-thiazol-2-yl)piperidine-4-carboxamide chemical CHEBI:91399 ChEBI CDK2 protein P24941 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-258087 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 PRKDC protein P78527 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0001949 18439899 t gcesareni "DNA-PK phosphorylates HM Ser473 of PKB. However, we also noted similar patterns in T loop Thr308 phosphorylation after _-IR []his function is apparently restricted to the PKBalpha isoform" SIGNOR-252431 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 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 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 TRAF6 protein Q9Y4K3 UNIPROT IRAK1 protein P51617 UNIPROT "up-regulates activity" ubiquitination Lys134;Lys180 AEAWSPRkLPSSAST;SPAPSSTkPGPESSV 9606 BTO:0000007 18347055 t "K63-linked polyubiquitination of proximal signaling proteins is a common mechanism used by diverse innate immune receptors for recruiting IKK and activating NF-_B" SIGNOR-252252 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 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 BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT "down-regulates activity" phosphorylation Tyr209 TGMFPRNyVTPVNRN 9606 BTO:0000007 20554525 t lperfetto "More recently, however, tyrosine phosphorylation of Grb2 in BCR-ABL-transformed cells on residues Tyr7, Tyr37, Tyr52, and Tyr209 in the SH3 domains has been reported and shown to negatively regulate the Ras/MAPK pathway." SIGNOR-246281 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 "dasatinib (anhydrous)" chemical CHEBI:49375 ChEBI SRC protein P12931 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-258103 EPHA2 protein P29317 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 9606 12400011 t gcesareni "We also show that the interaction of epha2 with grb2 is indirect and mediated by shc and that this complex is necessary for epha2-mediated activation of erk kinases." SIGNOR-94804 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 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. phosphorylation at Ser-78 may also decrease the activity of eEF2 kinase" SIGNOR-250321 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 FPR1 protein P21462 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-256961 SSTR2 protein P30874 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-256963 CSNK2A2 protein P19784 UNIPROT AQP4 protein P55087 UNIPROT "down-regulates activity" phosphorylation Ser316 EKKGKDQsGEVLSSV 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-250976 CSNK2A2 protein P19784 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT "up-regulates activity" phosphorylation Ser59 SETNQNSsSDSEAER -1 11711551 t llicata "We show here that Tcf-4 can be phosphorylated in vitro by protein kinase CK2 stoichiometrically in amino acids Ser-58-Ser-59-Ser-60. Phosphorylation of these residues does not modify the interaction of Tcf-4 with beta-catenin but reduces its association to plakoglobin. | Experiments performed using a Tcf-4 mutant with decreased interaction to plakoglobin demonstrated that binding to this protein negatively affected the transcriptional activity of Tcf-4." SIGNOR-251045 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 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 MAPK8 protein P45983 UNIPROT H2AFX 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 N1'-[3-fluoro-4-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinolinyl]oxy]phenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide chemical CHEBI:91418 ChEBI AXL protein P30530 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-258109 NTRK2 protein Q16620 UNIPROT NTRK2 protein Q16620 UNIPROT "up-regulates activity" phosphorylation Tyr702 FGMSRDVySTDYYRV 10090 BTO:0000944 10533983 t miannu "TrkB autophosphorylation occurs on five cytoplasmic tyrosines: Y484, Y670, Y674, Y675, and Y785. Mutagenesis of Y484 inhibits the interaction between Shc and TrkB, and also block the E3DNF-inducible tyrosine phoslphorylation of Shc" SIGNOR-250205 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 pictrelisib chemical CHEBI:65326 ChEBI PIK3CA protein P42336 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-258113 PRKAA1 protein Q13131 UNIPROT FOXO3 protein O43524 UNIPROT "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-249677 PRKACA protein P17612 UNIPROT GMFB protein P60983 UNIPROT "up-regulates activity" phosphorylation Ser83 QHDDGRVsYPLCFIF -1 9030586 t miannu "Protein kinase A (PKA)-phosphorylated GMF is a potent inhibitor of extracellular signal-regulated kinase (ERK) and enhancer of p38; both are subfamilies of mitogen-activated protein (MAP) kinase, suggesting GMF as a bifunctional regulator of the MAP kinase cascades. PKA is capable of phosphorylating threonine 26 and serine 82." SIGNOR-249983 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 PTK2 protein Q05397 UNIPROT TRIO protein O75962 UNIPROT "up-regulates activity" phosphorylation Tyr2796 KDNFDSFySEVAELG 9534 BTO:0000298 12551902 t lperfetto "A FAK phosphorylation site, tyrosine residue 2737, was identified in subdomain I of the Trio kinase domain. Additionally, in vitro phosphorylation assays and in vivo co-expression studies indicated that Trio enhances FAK kinase activity." SIGNOR-249188 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 Bafetinib chemical CID:24853523 PUBCHEM BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190224 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 CSNK2A1 protein P68400 UNIPROT PDCL protein Q13371 UNIPROT unknown phosphorylation Ser25 SSSEDEDsDHEDKDR 9606 16717095 t lperfetto "Together, these data make a strong case for ck2 phosphorylation events within the serines 18-20 and 25 sites in vivo. hey also show that phosphorylation of ser-25 and ser-296 plays no additional role in g__ expression." SIGNOR-146837 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 ELF3 protein P78545 UNIPROT SPRR2A protein P35326 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567 10773884 f "Interestingly, ELF3 suppressed basal keratin 4 promoter activity in both esophageal and cervical epithelial cancer cell lines, a novel result, while simultaneously activating the late-differentiation linked SPRR2A promoter." SIGNOR-254292 ELK1 protein P19419 UNIPROT PRKCA protein P17252 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000599 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-256282 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR 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-244557 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 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 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 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 PRKCD protein Q05655 UNIPROT C5AR1 protein P21730 UNIPROT down-regulates phosphorylation Ser334 SVVRESKsFTRSTVD 9606 10636859 t gcesareni "Whole cell phosphorylation assays with specific inhibitors as well as in vitro phosphorylation assays with recombinant enzymes and peptide substrates revealed that phosphorylation of ser-334 is regulated by protein kinase c-beta this study is among the first to analyze in a detailed manner, using a non-mutational approach, modifications of a defined phosphorylation site in a g protein-coupled receptor and to correlate these findings with functional parameters of receptor deactivation." SIGNOR-73967 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 RPS6KA1 protein Q15418 UNIPROT MITF protein O75030 UNIPROT down-regulates phosphorylation Ser409 HGLSLIPsTGLCSPD 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 73, whereas serine 409 serves as a substrate for p90 rsk-1. An unphosphorylatable double mutant at these two residues is at once profoundly stable and transcriptionally inert." SIGNOR-75034 CSNK2A1 protein P68400 UNIPROT EIF5 protein P55010 UNIPROT up-regulates phosphorylation Ser390 KEAEEESsGGEEEDE 9606 16227438 t gcesareni "We find that eif5 is associated with ck2 when the kinase activity is at the highest level in vivo, and is phosphorylated at ser389 and ser390 by ck2." SIGNOR-141159 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation Thr479 FSYSASGtA 9606 BTO:0000093 24670654 t gcesareni "Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation" SIGNOR-252443 imatinib chemical CHEBI:45783 ChEBI ABL1 protein P00519 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-258120 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 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 PRKACA protein P17612 UNIPROT HDAC5 protein Q9UQL6 UNIPROT up-regulates phosphorylation Ser279 KVAERRSsPLLRRKD 9606 BTO:0000007;BTO:0001938;BTO:0000938 22865920 t lperfetto "We showed that phosphorylation at ser279 is necessary for efficient nuclear import of hdac5 in kidney cells (hek293) and osteosarcoma cells (u2os) (15). The kinases responsible for ser279 phosphorylation have recently been identified to be pka in cos-7 cells (16) and cdk5 in neurons" SIGNOR-198658 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 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 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 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 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 STAT5A protein P42229 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000830 20535135 f miannu "Specifically, SCF-induced activation of JAK2 in human mast cells has been shown to activate STAT5 and STAT6. STAT5 contributes to mast cell homeostasis, by mediating proliferation, survival, and mediator release." SIGNOR-256233 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 ARID5B protein Q14865 UNIPROT MYB protein P10242 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000661 29326336 f miannu "We also observed that ARID5B regulates the expression of four major components of the TAL1 complex (namely, TAL1,GATA3, RUNX1, and MYB) in Jurkat cells. Knockdown of ARID5B resulted in reductions of the H3K27ac signals at those enhancer loci (Supplemental Fig. S6E–H) and down-regulation of all four factors at the mRNA (Fig. 6E) and protein levels (Fig. 6F)." SIGNOR-256160 ARID5B protein Q14865 UNIPROT RUNX1 protein Q01196 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000661 29326336 f miannu "We also observed that ARID5B regulates the expression of four major components of the TAL1 complex (namely, TAL1,GATA3, RUNX1, and MYB) in Jurkat cells. Knockdown of ARID5B resulted in reductions of the H3K27ac signals at those enhancer loci (Supplemental Fig. S6E–H) and down-regulation of all four factors at the mRNA (Fig. 6E) and protein levels (Fig. 6F)." SIGNOR-256159 AT-406 chemical CID:25022340 PUBCHEM BIRC2 protein Q13490 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189954 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 "JNJ-28312141 free base" chemical CID:11676971 PUBCHEM FLT3 protein P36888 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t llicata "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-258125 DYRK2 protein Q92630 UNIPROT CARHSP1 protein Q9Y2V2 UNIPROT unknown phosphorylation Ser32 RSRERSPsPLRGNVV 9606 BTO:0000671 15910284 t lperfetto "Dyrk2 (dual-specificity tyrosine-phosphorylated and -regulated protein kinase 2) phosphorylated crhsp24 at ser30, ser32 and ser41 in vitro, and ser41 was identified as a site phosphorylated in cells." SIGNOR-137478 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 MAP2K7 protein O14733 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates phosphorylation Tyr185 TNFMMTPyVVTRYYR 9606 11062067 t lperfetto "In the present study, we found that mkk7 phosphorylates sapk2a/p38 exclusively at tyr-182, albeit at a low rate. Therefore one possibility is that the interaction of mkk7 and/or sapk1/jnk with another cellular protein alters the conformation of one of these enzymes in such a way as to facilitate phosphorylation of tyr-185 by mkk7 in vivo." SIGNOR-83748 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 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 PRKX protein P51817 UNIPROT PKD1 protein P98161 UNIPROT up-regulates phosphorylation Ser4166 EPLPSRSsRGSKVSP 9606 BTO:0000671 17980165 t lperfetto "The possibility of functional interactions between pkd1-encoded polycystin-1 and prkx was suggested by the renal co-distribution of prkx and polycystin-1 and the binding and phosphorylation of the c-terminal of polycystin-1 by prkx at s4166 in vitro. Taken together these results suggest that prkx can reverse the abnormalities in epithelial adhesion, migration and morphogenesis associated with pkd1 inhibition and cyst formation in adpkd." SIGNOR-158852 TBK1 protein Q9UHD2 UNIPROT IRF5 protein Q13568 UNIPROT up-regulates phosphorylation Ser293 VELFGPIsLEQVRFP 9606 22412986 t lperfetto "Activation of interferon regulatory factor 5 by site specific phosphorylation. Although the gene induction by irf5 in the presence of tbk-1 was modest, phosphorylation by tbk-1 produced a significant shift in the mobility of irf5 in sds-page. For this reason we identified the residues that are phosphorylated on irf5 by tbk-1 with mass spectrometry. Ser-158 and ser-309 were found to be phosphorylated" SIGNOR-196532 TTBK1 protein Q5TCY1 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser516 GDRSGYSsPGSPGTP 9606 BTO:0000938 16923168 t "The effect has been demonstrated using P10636-8" lperfetto "Direct tau phosphorylation by ttbk1 at ser198, ser199, ser202 and ser422, which are also phosphorylated in phfs. Ttbk1 also induces tau aggregation in human neuronal cells in a dose-dependent manner. We conclude that ttbk1 is a neuron-specific dual kinase involved in tau phosphorylation at ad-related sites and is also associated with tau aggregation." SIGNOR-148970 lapatinib chemical CHEBI:49603 ChEBI ERBB2 protein P04626 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-258131 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 mTORC2 complex SIGNOR-C2 SIGNOR AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation Thr479 FSYSASGtA 9606 BTO:0000093 24670654 t gcesareni "Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation" SIGNOR-252444 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 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 PRKD1 protein Q15139 UNIPROT PTRH2 protein Q9Y3E5 UNIPROT up-regulates phosphorylation Ser5 sLVMEYLA 9606 18703509 t lperfetto "Overexpression of constitutively active pkd or pkd activation by treatment with phorbol 12-myristate 13-acetate results in phosphorylation of two serine residues (ser5 and ser87) in a form of bit1 that is confined to the cytoplasm and concomitantly increases the apoptotic activity of cytoplasmic bit1" SIGNOR-180085 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 ATF3 protein P18847 UNIPROT ASNS protein P08243 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12881527 f miannu "Transcription from the ASNS (asparagine synthetase) gene is increased in response to either amino acid (amino acid response) or glucose (endoplasmic reticulum stress response) deprivation. the results provide evidence for a potential role of multiple predicted ATF3 isoforms in the transcriptional regulation of the ASNS gene in response to nutrient deprivation." SIGNOR-253746 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 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 PAK2 protein Q13177 UNIPROT MKNK1 protein Q9BUB5 UNIPROT "down-regulates activity" phosphorylation Ser39 RRGRATDsLPGKFED 9606 BTO:0000007 15234964 t miannu "Phosphorylation of Mnk1 by caspase-activated Pak2/gamma-PAK inhibits phosphorylation and interaction of eIF4G with Mnk. When 293T cells are subjected to apoptotic induction by hydrogen peroxide, Mnk1 is phosphorylated at both Thr(22) and Ser(27). These results indicate a role for Pak2 in the down-regulation of translation initiation in apoptosis by phosphorylation of Mnk1." SIGNOR-250221 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT "up-regulates activity" phosphorylation Ser141 TVKQKYLsFTPPEKD -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. Autophosphorylation of γ-PAK with MgATP alone takes place at Ser-19, Ser-20, Ser-55, Ser-192, and Ser-197." SIGNOR-250228 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT "up-regulates activity" phosphorylation Ser20 APPVRMSsTIFSTGG -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. Autophosphorylation of γ-PAK with MgATP alone takes place at Ser-19, Ser-20, Ser-55, Ser-192, and Ser-197." SIGNOR-250227 PPP2CA protein P67775 UNIPROT CHEK1 protein O14757 UNIPROT "down-regulates activity" dephosphorylation Ser345 LVQGISFsQPTCPDH 9606 17015476 t "Phosphorylation of Chk1 by ATR is antagonized by a Chk1-regulated protein phosphatase 2A circuit|In response to genotoxic stress, Chk1 is phosphorylated on serines 317 (S317) and 345 (S345) by the ataxia-telangiectasia-related (ATR) protein kinase. Phosphorylation of Chk1 on these C-terminal serine residues is used as an indicator of Chk1 activation in vivo." SIGNOR-248615 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 RNF8 protein O76064 UNIPROT H2AFX protein P16104 UNIPROT up-regulates ubiquitination 9606 18001824 t gcesareni "Rnf8 can ubiquitylate histone h2a and h2ax," SIGNOR-159309 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 CSNK2A1 protein P68400 UNIPROT CBX5 protein P45973 UNIPROT up-regulates phosphorylation Ser13 KRTADSSsSEDEEEY 9606 21245376 t gcesareni "Hp1_ was multiply phosphorylated at n-terminal serine residues (s11-14) in human and mouse cells and that this phosphorylation enhanced hp1_'s affinity for h3k9me. Unphosphorylatable mutant hp1_ exhibited severe heterochromatin localization defects in vivo, and its prolonged expression led to increased chromosomal instability." SIGNOR-171703 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr1110 GSVQNPVyHNQPLNP 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-236483 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 PPP2CA protein P67775 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT down-regulates dephosphorylation Ser387 ETGLYRIsGCDRTVK 9606 18201571 t gcesareni "We report here that (i) mgcracgap is phosphorylated by aurora b and cdk1, (ii) pp2a dephosphorylates aurora b and cdk1 phosphorylated sites and (iii) inhibition of pp2a abrogates mgcracgap/ect2 interaction. Therefore, pp2a may regulate cytokinesis by dephosphorylating mgcracgap and its interacting partners." SIGNOR-160398 PLK1 protein P53350 UNIPROT NINL protein Q9Y2I6 UNIPROT "down-regulates activity" phosphorylation Ser88 RPSDEDSsSLESAAS -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-103356 PPP2CB protein P62714 UNIPROT AKT3 protein Q9Y243 UNIPROT "down-regulates activity" dephosphorylation Ser472 RPHFPQFsYSASGRE 9606 18160256 t "Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A." SIGNOR-248610 PRKAA1 protein Q13131 UNIPROT SYN1 protein P17600 UNIPROT down-regulates phosphorylation Ser9 NYLRRRLsDSNFMAN 9606 10880969 t lperfetto "It has been reported that site 1 of syn i can be phosphorylated by pka. Pka-mediated synapsin i ser9 phosphorylation occurs in response to cgs 21680 treatment. Results show that the adenosine a2a receptor agonist, cgs 21680, increases neurotransmitter release, in particular, glutamate and noradrenaline and such response is mediated by protein kinase a activation, which in turn increased synapsin i phosphorylation" SIGNOR-78891 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 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 RPS6KA1 protein Q15418 UNIPROT SLC9A1 protein P19634 UNIPROT up-regulates phosphorylation Ser703 MSRARIGsDPLAYEP 9606 10400637 t gcesareni "The results indicate that p90rsk phosphorylates serine 703 of nhe-1, and this phosphorylation is required for growth factor stimulation of na+/h+ exchange." SIGNOR-69171 SIRT1 protein Q96EB6 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" deacetylation Lys14 VKEGWLHkRGEYIKT 10090 BTO:0000562 21775285 t gcesareni "We show that Akt and PDK1 are acetylated at lysine residues in their pleckstrin homology domains, which mediate PIP(3) binding. Acetylation blocked binding of Akt and PDK1 to PIP(3), thereby preventing membrane localization and phosphorylation of Akt. Deacetylation by SIRT1 enhanced binding of Akt and PDK1 to PIP(3) and promoted their activation." SIGNOR-252445 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 TNK2 protein Q07912 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation Tyr176 EKATGRYyAMKILKK 10090 BTO:0002021 20333297 t gcesareni "Ack1 (also known as ACK or TNK2), which directly phosphorylates AKT at an evolutionarily conserved tyrosine 176 in the kinase domain. Tyr176-phosphorylated AKT localizes to the plasma membrane and promotes Thr308/Ser473-phosphorylation leading to AKT activation." SIGNOR-252446 UHMK1 protein Q8TAS1 UNIPROT MBP protein P02686 UNIPROT down-regulates phosphorylation Ser299 GRDSRSGsPMARR 9606 10880969 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. Mass spectrometry and peptide sequencing allowed us to identify serine 164 of mbp as the unique site phosphorylated by kis. Phosphorylation of synthetic peptides indicated the importance of the proline residue at position +1." SIGNOR-78895 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 methylnaltrexone chemical CHEBI:136007 ChEBI OPRD1 protein P41143 UNIPROT "down-regulates activity" "chemical inhibition" 10030 BTO:0000246 19282177 t Luana "A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ." SIGNOR-258147 methylnaltrexone chemical CHEBI:136007 ChEBI OPRM1 protein P35372 UNIPROT "down-regulates activity" "chemical inhibition" 10030 BTO:0000246 19282177 t Luana "A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ." SIGNOR-258148 nalbuphine chemical CHEBI:7454 ChEBI OPRD1 protein P41143 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000246 19282177 t Luana "A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ." SIGNOR-258144 NCOR2 protein Q9Y618 UNIPROT AR protein P10275 UNIPROT down-regulates acetylation 9606 BTO:0000150;BTO:0001130 12771131 t gcesareni "In this study we assessed the effect of smrt and dax-1 on ar and pr activity in the presence of both agonists and partial antagonists. We show that smrt and dax-1 repress agonist-dependent activity of both receptors, and the mechanism of repression includes disruption of the receptor dimer interactions rather than recruitment of histone deacetylases." SIGNOR-101286 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 PPP3CA protein Q08209 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-248682 PRKACA protein P17612 UNIPROT TPH2 protein Q8IWU9 UNIPROT up-regulates phosphorylation Ser19 YWARRGFsLDSAVPE 9606 BTO:0000142 18339632 t llicata "We also demonstrate that phosphorylation of serine 19, a protein kinase a consensus site located in this n-terminal domain, results in increased tph2 stability and consequent increases in enzyme output in cell culture systems" SIGNOR-178018 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 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 TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT "up-regulates activity" binding 10090 BTO:0002572;BTO:0000801 21232017 t gcesareni "Rip1 is known to directly interact with traf2" SIGNOR-245032 UHMK1 protein Q8TAS1 UNIPROT MBP protein P02686 UNIPROT down-regulates phosphorylation Ser299 GRDSRSGsPMARR 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. Mass spectrometry and peptide sequencing allowed us to identify serine 164 of mbp as the unique site phosphorylated by kis. Phosphorylation of synthetic peptides indicated the importance of the proline residue at position +1." SIGNOR-143485 aclidinium chemical CHEBI:65346 ChEBI CHRM1 protein P11229 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000131 19653626 t Luana "This compound is a potent muscarinic antagonist, with long duration of action in vivo, and was found to have a rapid hydrolysis in human plasma, minimizing the potential to induce class-related systemic side effects." SIGNOR-258152 aclidinium chemical CHEBI:65346 ChEBI CHRM3 protein P20309 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000131 19653626 t Luana "This compound is a potent muscarinic antagonist, with long duration of action in vivo, and was found to have a rapid hydrolysis in human plasma, minimizing the potential to induce class-related systemic side effects." SIGNOR-258151 AKT3 protein Q9Y243 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 aminoterminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity." SIGNOR-78693 CSNK2A1 protein P68400 UNIPROT STARD10 protein Q9Y365 UNIPROT down-regulates phosphorylation Ser284 GGAGGEGsDDDTSLT 9606 BTO:0002181 17561512 t gcesareni "Interestingly, hypotonic extracts prepared from hek293t cells expressing the serine to alanine mutant exhibited increased lipid transfer activity compared with those from wild-type stard10-expressing cells, suggesting that, in a cellular context, phosphorylation on serine 284 negatively regulates stard10 activity" SIGNOR-155740 CSNK2A1 protein P68400 UNIPROT VAMP4 protein O75379 UNIPROT up-regulates phosphorylation Ser30 RNLLEDDsDEEEDFF 9606 14608369 t gcesareni "The r-snare vamp4, which contains a dileucine motif, binds to the ap-1 or the ggas. Serine 20 and leucines 25,26 are essential for this binding. Ap-1 association with vamp4 is enhanced when serine 30 is phosphorylated by casein kinase 2. This phosphorylation-dependent modulation of ap-1 binding is mediated by pacs-1 (phosphofurin acidic cluster sorting protein). Ablation of both the dileucine motif and serine 30 results in a dramatic mislocalization of vamp4 in the regulated secretory pathway." SIGNOR-119090 FYN protein P06241 UNIPROT FYN protein P06241 UNIPROT up-regulates phosphorylation 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-177109 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 PPP1CA protein P62136 UNIPROT NEK2 protein P51955 UNIPROT down-regulates dephosphorylation 9606 17283141 t gcesareni "Nek2 is activated by autophosphorylation, and its dephosphorylation is catalyzed by pp1" SIGNOR-152949 PRKACA protein P17612 UNIPROT KCNK3 protein O14649 UNIPROT up-regulates phosphorylation Ser393 GLMKRRSsV 9606 BTO:0000007 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 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 RPS6KA1 protein Q15418 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser293 GSTKRRKsMSGASPK 9606 23708659 t lperfetto "Rsk promotes g2/m transition through activating phosphorylation of cdc25a and cdc25b rsk is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of t359/s363 in rsk. Together, these findings indicate that rsk promotes g2/m transition in mammalian cells through activating phosphorylation of cdc25a and cdc25b." SIGNOR-202113 4-[[5-amino-1-[(2,6-difluorophenyl)-oxomethyl]-1,2,4-triazol-3-yl]amino]benzenesulfonamide chemical CHEBI:94506 ChEBI CCNA2 protein P20248 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193537 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 PRKCB protein P05771 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-249119 PRKCE protein Q02156 UNIPROT ADAP1 protein O75689 UNIPROT unknown phosphorylation Ser87 AARARFEsKVPSFYY 12893243 t lperfetto "The sites of phosphorylation by PKCalpha on centaurin-alpha1‚ were identified as S87 (peptide ARFEK) and T276 (peptide WFMDDRR) (‚ Fig. 5).‚ | The phosphorylation site analysis was carried out twice after phosphorylation of centaurin-alpha1‚ with PKCalpha and once with PKC_. A similar pattern of phosphopeptides was obtained each time." SIGNOR-249224 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 PTPN12 protein Q05209 UNIPROT ABL1 protein P00519 UNIPROT "down-regulates activity" dephosphorylation Tyr393 RLMTGDTyTAHAGAK 9534 BTO:0004055 11163214 t lperfetto "Several experiments suggest that the pest-type ptps negatively regulate c-abl activity: c-abl was hyperphosphorylated in ptp-pest-deficient cells dephosphorylation of c-abl by pest-type ptp represents a novel mechanism by which c-abl activity is regulated." SIGNOR-235568 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 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 ritonavir chemical CHEBI:45409 ChEBI UGT1A1 protein P22309 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 21030469 t Luana "Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation." SIGNOR-258154 RPS6KA3 protein P51812 UNIPROT HIST1H3A 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 RPS6KB1 protein P23443 UNIPROT EEF2K protein O00418 UNIPROT "down-regulates activity" phosphorylation Ser366 SPQVRTLsGSRPPLL 9606 BTO:0000669 11500364 t lperfetto "We show that two such kinases, p70 s6 kinase (regulated via mtor) and p90(rsk1) (activated by erk), phosphorylate eef2k at a conserved serine and inhibit its activity" SIGNOR-109712 SOX6 protein P35712 UNIPROT CEBPA protein P49715 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003298 26893351 t "We found that SOX6 regulates adipogenesis in vertebrate species by activating adipogenic regulators including PPARγ, C/EBPα and MEST" SIGNOR-255824 SRC protein P12931 UNIPROT GJA1 protein P17302 UNIPROT down-regulates phosphorylation Tyr247 VKGKSDPyHATSGAL 9606 16916748 t lperfetto "The oncogenic tyrosine kinase, v-src, phosphorylates connexin43 (cx43) on y247 and y265 and inhibits cx43 gap junctional communication (gjc), the process of intercellular exchange of ions and metabolites." SIGNOR-148913 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-118053 CBFB protein Q13951 UNIPROT "Core Binding Factor complex" complex SIGNOR-C214 SIGNOR "form complex" binding 9606 12495904 t irozzo "The core binding factor (CBF) transcription complex, consisting of the interacting proteins RUNX1 and CBFβ, is essential for normal hematopoiesis" SIGNOR-255711 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR 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-251594 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR 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-251596 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 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MYC protein P01106 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser62 LLPTPPLsPSRRSGL 10116 BTO:0004725 11018017 t "Phosphorylation of Ser 62 is required for Ras-induced stabilization of Myc, likely mediated through the action of ERK." SIGNOR-252079 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 11602185 f apalma "The GM-CSF promoted cell survival and proliferation correlated with MEK-1 dependent ERK1/2, Elk-1 and CREB phosphorylation and Egr-1, c-Fos expression as well as with increased STAT-5, AP-1, c-Myb and NF-kappaB DNA-binding." SIGNOR-255580 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser289 RSHSESAsPSALSSS 9606 16407412 t lperfetto "Erk-induced raf-1 phosphorylation sustains raf-1 kinase activity furthermore, using direct in vitro phosphorylation we show that these sites are direct targets of erk-1 and using phosphospecific antibodies developed against one of the sites, s296, show that these sites are physiological phosphorylation sites induced in vivo after mitogen stimulation." SIGNOR-244677 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 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 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 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 PIP5K1C protein O60331 UNIPROT up-regulates phosphorylation Tyr649 TDERSWVySPLHYSA 9606 15738269 t lperfetto "Phosphorylation by src of the tyrosine adjacent to s650 (y649 in human pipki gamma) was shown to enhance pipki gamma targeting to focal adhesions. We find that y649 phosphorylation does not stimulate directly pipki gamma binding to talin, but may do so indirectly by inhibiting s650 phosphorylation." SIGNOR-134459 Calcineurin complex SIGNOR-C155 SIGNOR 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-252309 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 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 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 PTPN11 protein Q06124 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-248667 PTPN11 protein Q06124 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-248669 PTPN12 protein Q05209 UNIPROT PTK2B protein Q14289 UNIPROT "down-regulates activity" dephosphorylation Tyr402 CSIESDIyAEIPDET 10116 11337490 t "Inhibition of the catalytic activity of cell adhesion kinase beta by protein-tyrosine phosphatase-PEST-mediated dephosphorylation|CAKbeta was found to be a substrate for PTP-PEST. Both the major autophosphorylation site of CAKbeta (Tyr(402)) and activation loop tyrosine residues, Tyr(579) and Tyr(580), were targeted for dephosphorylation by PTP-PEST. Dephosphorylation of CAKbeta by PTP-PEST dramatically inhibited CAKbeta kinase activity." SIGNOR-248662 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 RPS6KB1 protein P23443 UNIPROT POLDIP3 protein Q9BY77 UNIPROT unknown phosphorylation Ser385 PRRVNSAsSSNPPAE 9606 15341740 t llicata "Here we identify skar as a novel and specific binding partner and substrate of s6k1 but not s6k2. We find that serines 383 and 385 of human skar are insulin-stimulated and rapamycin-sensitive s6k1 phosphorylation sites." SIGNOR-128499 RPS6K proteinfamily SIGNOR-PF26 SIGNOR 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. erk_rsk phosphorylation of kibra is required for proper cell proliferation and rsk-mediated phosphorylation also positively modulates kibra's migratory activity." SIGNOR-252809 STK4 protein Q13043 UNIPROT MOB1B protein Q7L9L4 UNIPROT up-regulates phosphorylation Thr35 LLKHAEAtLGSGNLR 9606 21808241 t "MOB1a and MOB1b are near identical to each other with protein sequence homology>90%, and more importantly, both of them are putative tumor suppressors." gcesareni "Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2mob1 interaction." SIGNOR-175841 WNK1 protein Q9H4A3 UNIPROT OXSR1 protein O95747 UNIPROT up-regulates phosphorylation Ser325 VRRVPGSsGRLHKTE 9606 17190791 t gcesareni "Activation of wnk1 coincides with the phosphorylation and activation of two wnk1 substrates, namely, the protein kinases ste20/sps1-related proline alanine-rich kinase (spak) and oxidative stress response kinase-1 (osr1)" SIGNOR-151659 CDK2 protein P24941 UNIPROT CDC6 protein Q99741 UNIPROT up-regulates phosphorylation Ser74 TPHLPPCsPPKQGKK 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-67548 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 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 PRKG1 protein Q13976 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-71680 PTPN11 protein Q06124 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates quantity by destabilization" dephosphorylation Tyr1007 VLPQDKEyYKVKEPG 9606 14522994 t "We report that SHP-2 dephosphorylates tyrosine (Tyr-1007) of Jak2 kinase, a critical recruitment site for the ubiquitin ligase-associated inhibitory protein suppressor of cytokine signaling-1 (SOCS-1), thereby contributing to Jak2 stability. Inactivation of SHP-2 function by blocking receptor/SHP-2 association or by using a catalytically inactive mutant of SHP-2 led to a marked increase in Jak2 ubiquitination/degradation, Jak2 phosphorylation on Tyr-1007, and Jak2/SOCS-1 association" SIGNOR-248665 PTPN1 protein P18031 UNIPROT STAM2 protein O75886 UNIPROT "up-regulates quantity by stabilization" dephosphorylation Tyr291 KSEPEPVyIDEDKMD 9606 20504764 t "Together, the results presented here demonstrate that PTP1B can influence RTK signaling in a previously unrecognized manner. We show that PTP1B directly targets STAM2, part of the ESCRT-0 endosomal sorting complex, and we provide the first evidence that tyrosine phosphorylation affects STAM localization and function. This regulatory mechanism could impact signaling downstream of numerous cell surface receptors that are ubiquitinated and recognized by this conserved sorting machinery." SIGNOR-248406 Raltegravir chemical CID:54671008 PUBCHEM UGT1A1 protein P22309 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 21030469 t Luana "Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation." SIGNOR-258162 SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR DLX5 protein P56178 UNIPROT up-regulates "transcriptional regulation" 10090 BTO:0000165 12815054 f ggiuliani "Over-expression of Smad1 or Smad5, mediators of BMP-signaling, also induced Dlx5 expression even in the absence of BMP-2 treatment concomitant with positive ALP staining" SIGNOR-255837 alvocidib chemical CHEBI:47344 ChEBI CDK4 protein P11802 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-258172 CSNK2A1 protein P68400 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation Ser18 SPADDSLsNSEEEPD 9606 21559372 t llicata "Further investigation revealed that il-6 stabilizes twist in scchn cell lines through casein kinase 2 (ck2) phosphorylation of twist residues s18 and s20, and that this phosphorylation inhibits degradation of twist." SIGNOR-173668 mTORC1 complex SIGNOR-C3 SIGNOR 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-255840 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 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 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 PRKCD protein Q05655 UNIPROT HNRNPK protein P61978 UNIPROT down-regulates phosphorylation Ser302 GRGGRGGsRARNLPL 9606 10329716 t lperfetto "Ser302 is a major k protein site phosphorylated by pkcdelta in vitrothe ability of pkc_ to inducibly bind and phosphorylate k protein may serve not only to alter the activity of k protein itself, but k protein may also provide an avenue for pkc_ to engage in a cross-talk with other k protein molecular partners in response to specific changes in the extracellular environment" SIGNOR-67515 PRKCH protein P24723 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates phosphorylation Ser706 ARIIGEKsFRRSVVG 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-89423 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 Ast-487 chemical CID:11409972 PUBCHEM FLT3 protein P36888 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t llicata "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-258173 CSNK2A1 protein P68400 UNIPROT HIF1A protein Q16665 UNIPROT unknown phosphorylation Thr796 ESGLPQLtSYDCEVN -1 17382325 t llicata "These results implied that only Thr-796 was phosphorylated CK2. " SIGNOR-250891 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 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR HNRNPK protein P61978 UNIPROT up-regulates phosphorylation Ser353 DSAIDTWsPSEWQMA 9606 11259409 t lperfetto "When subjected to phosphorylation by erk, the most efficient decrease in erk phosphorylation was observed with the s353a mutantamong the mechanisms underlying k protein ability to confer increased transcriptional output are interconversion of duplex and single-stranded dna (59) and association with the c/ebp_ (60), each of which could be better affected by the phosphorylated form of the k protein, which may increase affinity to associated proteins or dna." SIGNOR-105754 FES protein P07332 UNIPROT FES protein P07332 UNIPROT up-regulates phosphorylation Tyr811 RPSFSTIyQELQSIR 9606 BTO:0002181 8663427 t llicata "Substitution of kinase domain tyrosine residues 713 or 811 with phenylalanine resulted in a loss of the 10- and 4-kda phosphopeptides, respectively, identifying these tyrosines as in vitro autophosphorylation sites. Cnbr cleavage analysis of fes isolated from 32po4-labeled 293t cells showed that tyr-713 and tyr-811 are also autophosphorylated in vivo. . Mutagenesis of tyr-713 reduced both autophosphorylation of tyr-811 and transphosphorylation of bcr, a recently identified fes substrate, supporting a major regulatory role for tyr-713." SIGNOR-42659 GSK3A protein P49840 UNIPROT MAFA protein Q8NHW3 UNIPROT down-regulates 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 MAP4K1 protein Q92918 UNIPROT MAP4K1 protein Q92918 UNIPROT up-regulates phosphorylation Thr165 ISAQIGAtLARRLSF 9606 BTO:0000782 15743830 t gcesareni "Activation of hematopoietic progenitor kinase 1 involves relocation, autophosphorylation, and transphosphorylation by protein kinase d1." SIGNOR-134490 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 STK4 protein Q13043 UNIPROT LATS1 protein O95835 UNIPROT up-regulates phosphorylation Ser909 HQRCLAHsLVGTPNY 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-133551 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 BCL2 protein P10415 UNIPROT DIABLO protein Q9NR28 UNIPROT down-regulates 9606 14585074 f amattioni "Bcl- confers protection to apoptosis by interference with bax/bak-mediated release of the pro-apoptotic mitochodrial factors smac/diablo and htra2/omi" SIGNOR-88885 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 EIF2AK2 protein P19525 UNIPROT EIF2S1 protein P05198 UNIPROT down-regulates phosphorylation Ser52 MILLSELsRRRIRSI 9606 16179259 t lperfetto "The antiviral protein kinase pkr inhibits protein synthesis by phosphorylating the translation initiation factor eif2alpha on ser51the protein kinases pkr, hri, perk, and gcn2 specifically phosphorylate ser51 on the _ subunit of the translation initiation factor eif2, a gtp binding protein that delivers the initiator methionyl-trna to the small ribosomal subunit in the first step of translation initiation. Phosphorylation of eif2_ converts eif2 from a substrate to an inhibitor of its gdp-gtp exchange factor eif2b, thereby blocking protein synthesis" SIGNOR-140656 MAPK1 protein P28482 UNIPROT PTTG1 protein O95997 UNIPROT up-regulates phosphorylation Ser165 LFQLGPPsPVKMPSP 9606 10906323 t gcesareni "Pttg is phosphorylated in vitro on ser(162) by map kinase and this phosphorylation site plays an essential role in pttg transactivation function." SIGNOR-79515 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 PDK1 protein Q15118 UNIPROT PKN2 protein Q16513 UNIPROT "up-regulates activity" phosphorylation Thr816 GYGDRTStFCGTPEF 9606 BTO:0000007 10753910 t miannu "PDK1 phosphorylates the PRKs at their conserved activation loop threonines (Thr-774 and Thr-816 for PRK1 and PRK2, respectively) both in vitro and in vivo." SIGNOR-250265 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 PRKG1 protein Q13976 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser813 DIYSRRLsQETGLEI 9606 1377674 t lperfetto "Direct amino acid sequencing and peptide mapping of cf-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by pka and pkgcftr possesses a large cluster of strict dibasic consensus sites for phosphorylation by protein kinase a (pka) in the r-domain and an obligatory dependence on phosphorylation is a hallmark of cftr cl(-) channel function" SIGNOR-18253 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 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 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 AKT proteinfamily SIGNOR-PF24 SIGNOR ACAP1 protein Q15027 UNIPROT unknown phosphorylation Ser554 SIRPRPGsLRSKPEP 9606 16256741 t llicata "Akt phosphorylates s554 in acap1" SIGNOR-141343 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-140216 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-141420 CAMK2G protein Q13555 UNIPROT ADCY3 protein O60266 UNIPROT "down-regulates activity" phosphorylation Ser1076 NVASRMEsTGVMGNI 9606 BTO:0000007 8798667 t llicata "Phosphorylation and inhibition of type III adenylyl cyclase by calmodulin-dependent protein kinase II in vivo. | Site-directed mutagenesis of a CaM kinase II consensus site (Ser-1076 to Ala-1076) in III-AC greatly reduced Ca2+-stimulated phosphorylation and inhibition of III-AC in vivo." SIGNOR-250691 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 CSNK2A1 protein P68400 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-250894 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 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 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 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 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-163756 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 NOLC1 protein Q14978 UNIPROT "up-regulates activity" phosphorylation Ser623 KGEKRASsPFRRVRE -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-250020 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 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 CSNK2A1 protein P68400 UNIPROT PTEN protein P60484 UNIPROT "down-regulates activity" phosphorylation Thr382 DHYRYSDtTDSDPEN 9606 21779440 t gcesareni "The C-terminal tail of PTEN is also the target of mutations in tumors. As mentioned, this region contains the main phosphorylation sites mapped to residues Ser362, Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385, and the kinases involved are casein kinase 2 (CK2), GSK3_, LKB1, and MAST.84,97-101 The phosphorylation of the tail has been shown to enhance PTEN stability but at the same time decrease its phosphatase activity" SIGNOR-89826 FES protein P07332 UNIPROT FES protein P07332 UNIPROT up-regulates phosphorylation Tyr713 REEADGVyAASGGLR 9606 BTO:0002181 8663427 t llicata "Substitution of kinase domain tyrosine residues 713 or 811 with phenylalanine resulted in a loss of the 10- and 4-kda phosphopeptides, respectively, identifying these tyrosines as in vitro autophosphorylation sites. Cnbr cleavage analysis of fes isolated from 32po4-labeled 293t cells showed that tyr-713 and tyr-811 are also autophosphorylated in vivo. . Mutagenesis of tyr-713 reduced both autophosphorylation of tyr-811 and transphosphorylation of bcr, a recently identified fes substrate, supporting a major regulatory role for tyr-713." SIGNOR-42655 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 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 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 NCOR2 protein Q9Y618 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-253508 NCOR2 protein Q9Y618 UNIPROT SNW1 protein Q13573 UNIPROT up-regulates binding 9606 BTO:0000222 BTO:0000887 10713164 t "Ncor2 is a Skip corepressor" gcesareni "Protein-protein interaction assays demonstrated interaction between skip and the corepressor smrt." SIGNOR-74227 PAK1 protein Q13153 UNIPROT ARAF protein P10398 UNIPROT up-regulates phosphorylation Ser299 KNLGYRDsGYYWEVP 9606 BTO:0000848 15710605 t lperfetto "Phosphorylation of endogenous a-raf, b-raf and raf-1 on the homologous pak phosphorylation sites (serine 299, serine 445, or serine 338 respectively)we found that the phosphorylation of a-raf on serine 299 was also stimulated by egf, although the duration of phosphorylation on this site was much shorter than for raf-1. Thus, by analogy with raf-1, phosphorylation of this site may play an important role in the a-raf activation mechanism." SIGNOR-236342 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 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 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 N'-(1,8-dimethyl-4-imidazo[1,2-a]quinoxalinyl)ethane-1,2-diamine chemical CHEBI:91340 ChEBI IKBKB protein O14920 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-258190 PDK4 protein Q16654 UNIPROT PDHA2 protein P29803 UNIPROT down-regulates phosphorylation Ser291 TYRYHGHsMSDPGVS 9606 BTO:0000887;BTO:0001103 14966024 t gcesareni "Pyruvate dehydrogenase (pdh) activity (pdha) controls the entry of carbohydrate into the tricarboxylic cycle and is regulated by pdh kinase (pdk), which phosphorylates and inactivates the enzyme, and pdh phosphatase, which dephosphorylates the enzyme to the active form" SIGNOR-121936 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 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 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 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 PRKCE protein Q02156 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-129308 PRKCQ protein Q04759 UNIPROT MSN protein P26038 UNIPROT unknown phosphorylation Thr558 LGRDKYKtLRQIRQG 9606 BTO:0001545 9856983 t lperfetto "By using mass spectroscopy and direct microsequencing of CNBr fragments of phospho-moesin, the phosphorylation site was identified as KYKT*LRQIR (where * indicates the phosphorylation site) (Thr558), which is conserved in the ERM family | Thus, PKC-theta is identified as a major kinase within cells with specificity for moesin and with activation under non-classical PKC conditions. It appears likely that this activity corresponds to a specific intracellular pathway controlling the function of moesin as well as other ERM proteins." SIGNOR-249013 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 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 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 NSD1 protein Q96L73 UNIPROT RELA protein Q04206 UNIPROT up-regulates methylation Lys218 EIFLLCDkVQKEDIE 9606 SIGNOR-C13 20080798 t miannu "Fbxl11 and nsd1 have opposite effects on nf-kb; both bind to p65 subunit after activation of nf-kb. / nsd1 activates nf-kb and reverses the inhibitory effect of fbxl11 / these data confirm that fbxl11 and nsd1 constitute an enzyme pair that methylates and demethylates p65 on k218 and 221 in response to cytokine stimulation." SIGNOR-163454 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 PLK1 protein P53350 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Ser198 SDELMEFsLKDQEAK 9606 11897663 t lperfetto "The nuclear accumulation of active m-phase promoting factor (mpf) during prophase is thought to be essential for coordinating m-phase events in vertebrate cells. The protein phosphatase cdc25c, an activator of mpf, enters the nucleus to keep mpf active in the nucleus during prophase. these results suggest that plk1 phosphorylates cdc25c on ser198 and regulates nuclear translocation of cdc25c during prophase." SIGNOR-115993 PPP2CA protein P67775 UNIPROT EIF4E protein P06730 UNIPROT down-regulates dephosphorylation Ser209 DTATKSGsTTKNRFV 9606 20927323 t tpavlidou "A recent study using genetically engineered mouse models has clearly shown that mnk-mediated eif4e phosphorylation is absolutely required for eif4e's oncogenic action. Taken together, we conclude that pp2a negatively regulates eif4e phosphorylation and eif4f complex assembly through dephosphorylation of mnk and eif4e, thus suggesting a novel mechanism by which pp2a exerts its tumor-suppressive function." SIGNOR-168306 PPP2CB protein P62714 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-248602 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT "up-regulates activity" phosphorylation Thr2620 QGTLQTRtQEGSLSA -1 12186630 t lperfetto "We have identified seven in vitro autophosphorylation sites in DNA-PKcs. Six of these sites (Thr2609, Ser2612, Thr2620, Ser2624, Thr2638 and Thr2647) are clustered in a region of 38 amino acids in the central region of the protein. Five of these sites (Thr2609, Ser2612, Thr2638, Thr2647 and Ser3205) are conserved between six vertebrate species. Moreover, we show that DNA-PKcs is phosphorylated in vivo at Thr2609, Ser2612, Thr2638 and Thr2647 in okadaic acid-treated human cells. | Thus phosphorylation of DNA-PKcs at one or more of the autophosphorylation sites identified in this study is likely to be required for DNA-PKcs function." SIGNOR-249158 RPS6KA3 protein P51812 UNIPROT H3F3A 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 RPS6K proteinfamily SIGNOR-PF26 SIGNOR 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-252810 SRC protein P12931 UNIPROT CTNND1 protein O60716 UNIPROT "up-regulates activity" phosphorylation Tyr228 YPGGSDNyGSLSRVT -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-246484 SSH3 protein Q8TE77 UNIPROT CFL1 protein P23528 UNIPROT "up-regulates activity" dephosphorylation Ser3 sGVAVSDG 9606 14531860 t "Differential activities, subcellular distribution and tissue expression patterns of three members of Slingshot family phosphatases that dephosphorylate cofilin.|Cofilin, a key regulator of actin filament dynamics, is inactivated by phosphorylation at Ser-3 by LIM-kinases and is reactivated by dephosphorylation by a family of protein phosphatases, termed Slingshot (SSH)." SIGNOR-248759 DYRK1A protein Q13627 UNIPROT DNM1 protein Q05193 UNIPROT down-regulates phosphorylation Ser795 VPPARPGsRGPAPGP 9606 BTO:0000142 15287745 t lperfetto "Mnb/dyrk1a was shown to phosphorylate dynamin 1 and alter its interactions with several sh3 domain-containing endocytic accessory proteins.Phosphorylation At s795 and s857 was confirmed in full-length dynamin 1, and s857 was subsequently determined to be the major mnb/dyrk1a phosphorylation site in vitro. Phosphorylation at s857 was demonstrated to be the basis for altering the binding of dynamin 1 to amphiphysin 1 and grb 2 by site-directed mutants mimicking phosphorylation." SIGNOR-127440 GSK3A protein P49840 UNIPROT MAFA protein Q8NHW3 UNIPROT up-regulates 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 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 PRKAA1 protein Q13131 UNIPROT EEF2K protein O00418 UNIPROT up-regulates phosphorylation Ser398 DSLPSSPsSATPHSQ 9606 SIGNOR-C15 22669845 t gcesareni "In response to genotoxic stress, eef2k was activated by ampk (adenosine monophosphate-activated protein kinase)-mediated phosphorylation on serine 398. Activated eef2k phosphorylated eef2 and induced a temporary ribosomal slowdown at the stage of elongation" SIGNOR-197734 PRKACA protein P17612 UNIPROT AANAT protein Q16613 UNIPROT "up-regulates activity" phosphorylation Thr31 PSCQRRHtLPASEFR -1 11336675 t miannu "AANAT1201 is phosphorylated at Thr-31 by PKA, it binds to 14-3-3. regulation is achieved by binding to 14-3-3, which structurally modulates the substrate binding sites, leading to measurable effects on the affinity of AANAT for its substrates with an accompanying increase in activity at low substrate concentrations. " SIGNOR-250325 PRKD1 protein Q15139 UNIPROT PRKD1 protein Q15139 UNIPROT unknown phosphorylation Ser738 ARIIGEKsFRRSVVG -1 10867018 t lperfetto "The last two autophosphorylation sites (Ser(744) and Ser(748)) are located in the activation loop but are only phosphorylated in the isolated PKD-catalytic domain and not in the full-length PKD; they may affect enzyme catalysis but are not involved in the activation of wild-type PKD by phorbol ester. | These results indicate that neither of the activation loop serines is involved in PDBu-induced activation but that they may be involved in catalysis or in maintaining the conformation of the enzyme prot" SIGNOR-249046 RPS6KA3 protein P51812 UNIPROT HIST1H3A 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 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 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 STK11 protein Q15831 UNIPROT BRSK2 protein Q8IWQ3 UNIPROT up-regulates phosphorylation Thr174 VGDSLLEtSCGSPHY 9606 14976552 t lperfetto "Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold" SIGNOR-122485 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 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 N1'-[3-fluoro-4-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinolinyl]oxy]phenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide chemical CHEBI:91418 ChEBI MET protein P08581 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-258214 NLK protein Q9UBE8 UNIPROT LEF1 protein Q9UJU2 UNIPROT down-regulates phosphorylation Thr155 SHAVHPLtPLITYSD 9606 12556497 t gcesareni "Regulation of lymphoid enhancer factor 1/t-cell factor by mitogen-activated protein kinase-related nemo-like kinase-dependent phosphorylation in wnt/beta-catenin signaling.Nlk phosphorylates lef-1/tcf on two serine/threonine residues located in its central region. Mutation of both residues to alanine enhanced lef-1 transcriptional activity and rendered it resistant to inhibition by nlk." SIGNOR-97812 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 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 PRKG1 protein Q13976 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser660 FSAERRNsILTETLH 9606 1377674 t lperfetto "Direct amino acid sequencing and peptide mapping of cf-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by pka and pkgcftr possesses a large cluster of strict dibasic consensus sites for phosphorylation by protein kinase a (pka) in the r-domain and an obligatory dependence on phosphorylation is a hallmark of cftr cl(-) channel function" SIGNOR-18237 PRKG1 protein Q13976 UNIPROT CREB1 protein P16220 UNIPROT unknown phosphorylation Ser133 EILSRRPsYRKILND -1 11175347 t lperfetto "G-kinase phosphorylated GST-CREB, albeit less efficiently than A-kinase, but GST was not phosphorylated by either kinase (Figure 5a). GST-CREB purified from bacteria was similarly phosphorylated by G-kinase, whereas GST-CREB containing a serine 133 to alanine mutation was not (Figure 5b). These results demonstrate that G-kinase can directly phosphorylate CREB on serine 133." SIGNOR-249076 RARA protein P10276 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates 9606 BTO:0000150 10607566 f gcesareni "We shown that retinoic acid (ra) decreases the activity of the beta-catenin-lef/tcf signaling pathway" SIGNOR-73274 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 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 HRAS protein P01112 UNIPROT "down-regulates activity" phosphorylation Tyr32 QNHFVDEyDPTIEDS 9606 BTO:0000007 25157176 t "Src binds to and phosphorylates GTP-, but not GDP-, loaded Ras on a conserved Y32 residue within the switch I region in vitro and that in vivo, Ras-Y32 phosphorylation markedly reduces the binding to effector Raf and concomitantly increases binding to GTPase-activating proteins and the rate of GTP hydrolysis" SIGNOR-252093 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 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 SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser208 DAGSPNLsPNPMSPA 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-161674 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 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 NHLH2 protein Q02577 UNIPROT ASCL1 protein P50553 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21573214 f miannu "Overexpression of both LMO3 and HEN2 induced expression of Mash1, suggesting that they might function as a transcriptional activator for Mash1." SIGNOR-254823 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 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 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 PRKCB protein P05771 UNIPROT PRKCB protein P05771 UNIPROT up-regulates phosphorylation Ser661 QNEFAGFsYTNPEFV 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-150861 RUNX3 protein Q13761 UNIPROT TXN2 protein Q99757 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002384 17956589 f miannu "Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells." SIGNOR-255093 TLK1 protein Q9UKI8 UNIPROT RAD9A protein Q99638 UNIPROT unknown phosphorylation Thr355 EPSTVPGtPPPKKFR 9606 24376897 t "The effect has been demonstrated using Q9UKI8-2" llicata "Here we show that rad9 is phosphorylated in a tlk-dependent manner in vitro and in vivo, and that t355 within the c-terminal tail is the primary targeted residue." SIGNOR-203503 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 GPR35 protein Q9HC97 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-256996 (-)-anisomycin chemical CHEBI:338412 ChEBI FOSB protein P53539 UNIPROT up-regulates "chemical activation" 9606 Other t CellSignaling gcesareni SIGNOR-189629 (-)-anisomycin chemical CHEBI:338412 ChEBI FOS protein P01100 UNIPROT up-regulates "chemical activation" 9606 Other t CellSignaling gcesareni SIGNOR-189626 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 PRKCA protein P17252 UNIPROT DLX3 protein O60479 UNIPROT "down-regulates activity" phosphorylation Ser138 KPRTIYSsYQLAALQ -1 11343707 t lperfetto "Dlx3 is primarily phosphorylated by PKC alpha. By deletion and mutational analysis, we show that the serine residue S(138), located in the homeodomain of Dlx3 protein, was specifically phosphorylated by PKC. The phosphorylation of purified Dlx3 proteins by PKC partially inhibited formation of complexes between Dlx3 protein and DNA. These results suggest that Dlx3 protein can be directly phosphorylated by PKC and this affects the DNA binding activity of Dlx3." SIGNOR-249096 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 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 PRKG2 protein Q13237 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Thr143 RCFTRKYtLPPGVDP 9606 19593530 t "11383510: to test the hypothesis that cGK could inhibit platelet aggregation by phosphorylating Hsp27 and interfering with the MAPKAP kinase phosphorylation of Hsp27, the known MAPKAP kinase 2-phosphorylation sites (Ser15, Ser78, and Ser82) as well as Thr143 were replaced by negatively charged amino acids, which are considered to mimic phosphate groups, and tested in actin polymerization experiments. Mimicry at the MAPKAP kinase 2 phosphorylation sites led to mutants with a stimulating effect on actin polymerization" 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-186947 PTPN22 protein Q9Y2R2 UNIPROT CBL protein P22681 UNIPROT down-regulates dephosphorylation Ser798 SDISNASsSFGWLSL 9606 BTO:0000782 10068674 t amattioni "The tyrosine phosphatase lyp1 was found to be constitutively associated with the proto-oncogene c-cbl in thymocytes and t cells. Overexpression of lyp1 reduces cbl tyrosine phosphorylation. It is known that cbl is heavily tyrosine phosphorylated after tcr stimulation and can associate with the syk and zap tyrosine kinases, negatively regulating their activities. Tyrosine phosphatases keep cbl in a basally dephosphorylated state." SIGNOR-65405 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 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT "down-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" SIGNOR-246409 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 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 linifanib chemical CHEBI:91435 ChEBI CSF1R protein P07333 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-258241 LSM-1231 chemical CHEBI:91471 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-258236 LSM-1231 chemical CHEBI:91471 ChEBI JAK2 protein O60674 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-258237 PRKG1 protein Q13976 UNIPROT HRH1 protein P35367 UNIPROT down-regulates phosphorylation Ser398 WKRLRSHsRQYVSGL 9606 BTO:0000975 10101032 t "Translocation from Endosome to Lysosome" fspada "Ser396 and ser398 are also potential phosphorylation sites for capk, cgmp-dependent protein kinase, and camk ii. Elevation of intracellular camp content has been shown to attenuate histamine-induced accumulation of ip in c6 glioma cells (peakman and hill, 1994) and in ddt1 mf-2 smooth muscle cells (sipma et al., 1995" SIGNOR-66019 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT "up-regulates activity" phosphorylation Ser402 LSGSKTNsPKNSVHK 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-249304 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 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 STAT3 protein P40763 UNIPROT SP1/STAT3 complex SIGNOR-C74 SIGNOR "form complex" binding 9606 19723038 t miannu "Sp1 and stat3 seem to synergistically augment renalase transcription." SIGNOR-187793 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 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR MYBL2 protein P10244 UNIPROT up-regulates phosphorylation Thr444 NSLTPKStPVKTLPF 9606 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-217256 LSM-1231 chemical CHEBI:91471 ChEBI NTRK3 protein Q16288 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-258240 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 masitinib chemical CHEBI:63450 ChEBI KIT protein P10721 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-258244 masitinib chemical CHEBI:63450 ChEBI PDGFRA protein P16234 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-258245 masitinib chemical CHEBI:63450 ChEBI PDGFRB protein P09619 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-258246 midostaurin chemical CHEBI:63452 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-258247 PLK1 protein P53350 UNIPROT IRS1 protein P35568 UNIPROT down-regulates 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 kinaseirs-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 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 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr548 KKVAVVRtPPKSPSS 9606 21215781 t "The effect has been demonstrated using P10636-8" lperfetto "However, other kinases, such as cdk5, p38 and pka, also phosphorylate tau at t231tau phosphorylation at t231, s235 and s262 also contributes to the dissociation of tau from microtubules" SIGNOR-171022 midostaurin chemical CHEBI:63452 ChEBI KIT protein P10721 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-258248 motesanib chemical CHEBI:51098 ChEBI FLT1 protein P17948 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-258251 N-(6-Chloro-7-methoxy-9H-pyrido[3,4-b]indol-8-yl)-2-methylnicotinamide chemical CID:9929127 PUBCHEM IKBKB protein O14920 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-258249 PLK4 protein O00444 UNIPROT PLK4 protein O00444 UNIPROT up-regulates phosphorylation Ser305 SSTSISGsLFDKRRL 9606 20032307 t llicata "Autophosphorylation probably plays a role in the process of centriole duplication, because mimicking s305 phosphorylation enhances the ability of overexpressed plk4 to induce centriole amplification. Importantly, we show that s305-phosphorylated plk4 is specifically sequestered at the centrosome contrary to the nonphosphorylated form." SIGNOR-162559 PPP1CB protein P62140 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-248567 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 PRKACA protein P17612 UNIPROT SLC2A2 protein P11168 UNIPROT "down-regulates activity" phosphorylation Ser491 VPETKGKsFEEIAAE 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-250049 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser159 KKKKKRFsFKKSFKL -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-248925 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 RPS6KA3 protein P51812 UNIPROT TH protein P07101 UNIPROT up-regulates phosphorylation Ser71 RFIGRRQsLIEDARK 9606 7901013 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-34686 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 4-[[5-amino-1-[(2,6-difluorophenyl)-oxomethyl]-1,2,4-triazol-3-yl]amino]benzenesulfonamide chemical CHEBI:94506 ChEBI CDK1 protein P06493 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193546 BCL2 protein P10415 UNIPROT HTRA2 protein O43464 UNIPROT down-regulates 9606 14585074 f amattioni "Bcl- confers protection to apoptosis by interference with bax/bak-mediated release of the pro-apoptotic mitochodrial factors smac/diablo and htra2/omi" SIGNOR-89189 motesanib chemical CHEBI:51098 ChEBI FLT4 protein P35916 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-258252 motesanib chemical CHEBI:51098 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-258253 neratinib chemical CHEBI:61397 ChEBI EGFR protein P00533 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-258254 nilotinib chemical CHEBI:52172 ChEBI KIT protein P10721 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-258257 nilotinib chemical CHEBI:52172 ChEBI PDGFRA protein P16234 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-258258 PPP1CB protein P62140 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-248571 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1721 SPTSPSYsPTSPSYS 9606 BTO:0000567 22137580 t "In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator" SIGNOR-248754 RPS6KA5 protein O75582 UNIPROT H3F3A 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 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 pazopanib chemical CHEBI:71219 ChEBI FLT1 protein P17948 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-258260 pazopanib chemical CHEBI:71219 ChEBI FLT4 protein P35916 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-258261 PD173955 chemical CHEBI:49791 ChEBI SRC protein P12931 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-258264 PPP2CB protein P62714 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-248598 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 PRKD1 protein Q15139 UNIPROT PPP1R14A protein Q96A00 UNIPROT up-regulates phosphorylation Thr38 QKRHARVtVKYDRRE 9606 BTO:0000142 15003508 t llicata "Cpi-17 is phosphorylated by several kinases on thr-38 in vitro, which increases the inhibitory potency of cpi-17 on pp1 by 1000-fold using affinity chromatography and western blot analysis, we found interaction with all pkc isotypes and casein kinase i isoforms, ckialpha and cki. By contrast, rock and pkn did not associate with cpi-17, suggesting that pkc may be the relevant kinase that phosphorylates thr-38 in vivo." SIGNOR-123226 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 NMUR2 protein Q9GZQ4 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-257010 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 PRKCD protein Q05655 UNIPROT ITGB2 protein P05107 UNIPROT "up-regulates activity" phosphorylation Thr758 NPLFKSAtTTVMNPK 9606 BTO:0000782 11700305 t lperfetto "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. Pkc-mediated phosphorylation of cd18 after cell stimulation could lead to the recruitment of 14-3-3 proteins to the activated integrin, which may play a role in regulating its adhesive state or ability to signal." SIGNOR-111495 PTPN13 protein Q12923 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 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-132559 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 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 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1619 SPSYSPTsPSYSPTS 9606 BTO:0000567 22137580 t "In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator" SIGNOR-248735 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT "down-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" SIGNOR-246393 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 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 (-)-anisomycin chemical CHEBI:338412 ChEBI JUNB protein P17275 UNIPROT up-regulates "chemical activation" 9606 Other t "CellSignaling;phospho-JunB (Thr102/Thr104) (D3C6) Rabbit mAb #8053" gcesareni SIGNOR-189644 PRKDC protein P78527 UNIPROT RPA2 protein P15927 UNIPROT "down-regulates activity" phosphorylation Ser13 FESYGSSsYGGAGGY -1 9295339 t lperfetto "We showed previously that UV irradiation increases phosphorylation of the p34 subunit of human replication protein A (RPA) and that this hyperphosphorylation correlated with loss of activity of the DNA replication complex. | we detected phosphorylation of the RPA complex by DNA-PK on RPA-p34 sites Ser-23, Ser-29, and Ser-11, -12, or -13" SIGNOR-248982 PTEN protein P60484 UNIPROT PTK2 protein Q05397 UNIPROT "down-regulates activity" dephosphorylation Tyr397 SVSETDDyAEIIDEE 9606 BTO:0000356 10400703 t "The tumor suppressor PTEN is a phosphatase with sequence homology to tensin. PTEN dephosphorylates phosphatidylinositol 3,4, 5-trisphosphate (PIP3) and focal adhesion kinase (FAK), and it can inhibit cell growth, invasion, migration, and focal adhesions. We investigated molecular interactions of PTEN and FAK in glioblastoma and breast cancer cells lacking PTEN. The PTEN trapping mutant D92A bound wild-type FAK, requiring FAK autophosphorylation site Tyr397" SIGNOR-248547 PTPN12 protein Q05209 UNIPROT PSTPIP1 protein O43586 UNIPROT "down-regulates activity" dephosphorylation Tyr345 PERNEGVyTAIAVQE 10090 11711533 t "We also demonstrate that PTP-PEST dephosphorylates PSTPIP at tyrosine 344. Importantly, we identified tyrosine 344 as the main phosphorylation site of PSTPIP by performing tryptic phosphopeptide maps. |The biological functions of the complexes formed between PSTPIP and SH2 domain-containing tyrosine kinases may be to transmit the signals from activated EGF and PDGF receptor.|Furthermore, we show that PSTPIP is phosphorylated downstream of the activated PDGF and EGF receptors. This phosphorylation of PSTPIP is most likely mediated by c-Abl" SIGNOR-248656 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 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 quizartinib smallmolecule CHEBI:90217 ChEBI KIT protein P10721 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-258271 R547 chemical CID:6918852 PUBCHEM CDK4 protein P11802 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t llicata "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-258274 Ruboxistaurin chemical CID:153999 PUBCHEM PRKACB protein P22694 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-258275 SATB1 protein Q01826 UNIPROT NUMB protein P49757 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000725 23563689 f miannu "Satb1 simultaneously repressed sets of genes encoding molecules involved in HSC activation and cellular polarity, including Numb and Myc" SIGNOR-224835 "SB 203580" chemical CHEBI:90705 ChEBI MAPK14 protein Q16539 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-258279 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 AKT proteinfamily SIGNOR-PF24 SIGNOR FAM129A 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-197053 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 protein O43524 UNIPROT "down-regulates activity" phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 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-183620 AKT proteinfamily SIGNOR-PF24 SIGNOR MXD1 protein Q05195 UNIPROT down-regulates phosphorylation Ser145 IERIRMDsIGSTVSS 9606 19526459 t llicata "Here, we present evidence that akt inhibits mad1-mediated transcription repression by physical interaction with and phosphorylation of mad1." SIGNOR-186130 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-192260 MAP3K3 protein Q99759 UNIPROT MAP3K3 protein Q99759 UNIPROT up-regulates phosphorylation Ser526 MSGTGMRsVTGTPYW 9606 BTO:0000007 16407301 t lperfetto "Phosphorylation of serine 526 is required for mekk3 activity, and association with 14-3-3 blocks dephosphorylationautophosphorylation of mekk3 at ser526" SIGNOR-143647 RPS6KA3 protein P51812 UNIPROT TH protein P07101 UNIPROT up-regulates phosphorylation Ser71 RFIGRRQsLIEDARK 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-95487 selumetinib chemical CHEBI:90227 ChEBI MAP2K1 protein Q02750 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-258280 SGX-523 chemical CHEBI:90624 ChEBI MET protein P08581 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-258282 sorafenib chemical CHEBI:50924 ChEBI BRAF protein P15056 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-258283 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 LPAR3 protein Q9UBY5 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-257025 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 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 PRKD2 protein Q9BZL6 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates phosphorylation Ser876 QGLAERIsVL 9606 11062248 t gcesareni "The addition of phorbol 12,13-dibutyrate in the presence of dioleoylphosphatidylserine stimulated the autophosphorylation of pkd2 in a synergistic fashion.In addition, we could identify the c-terminal ser(876) residue as an in vivo phosphorylation site within pkd2. Phosphorylation of ser(876) of pkd2 correlated with the activation status of the kinase." SIGNOR-83834 PTPRB protein P23467 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1356 YVHVNATyVNVKCVA 9606 16101282 t gcesareni "Ptp1b and shp-2 are bound to the c-met receptor to control its activity. Although the binding of ptp1b increases when there is a decrease in c-met activation and acts as a negative regulator of the receptor, the increased binding and phosphorylation of shp-2 coincide with maximal stimulation of c-met, acting as a positive regulator." SIGNOR-139560 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 sorafenib chemical CHEBI:50924 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-258284 sorafenib chemical CHEBI:50924 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-258285 SRC protein P12931 UNIPROT AFAP1 protein Q8N556 UNIPROT unknown phosphorylation Tyr453 PEALHYDyIDVEMSA 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-246355 SRC protein P12931 UNIPROT AFAP1 protein Q8N556 UNIPROT unknown phosphorylation Tyr93 TSSLPEGyYEEAVPL 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-246359 STK38L protein Q9Y2H1 UNIPROT STK38L protein Q9Y2H1 UNIPROT up-regulates phosphorylation Ser282 NRRQLAYsTVGTPDY 9606 BTO:0000007 16314523 t lperfetto "Ndr1/ndr2 protein kinase is activated by phosphorylation on the activation loop phosphorylation site ser281/ser282 and the hydrophobic motif phosphorylation site thr444/thr442. Autophosphorylation of ndr is responsible for phosphorylation on ser281/ser282, whereas thr444/thr442 is targeted by an upstream kinase. Here we show that mst3, a mammalian ste20-like protein kinase, is able to phosphorylate ndr protein kinase at thr444/thr442. In vitro, mst3 selectively phosphorylated thr442 of ndr2, resulting in a 10-fold stimulation of ndr activity." SIGNOR-142518 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR KAT5 protein Q92993 UNIPROT "up-regulates activity" phosphorylation Ser86 TKNGLPGsRPGSPER 9606 BTO:0000567 12468530 t llicata "Baculovirus-based expression and purification of Tip60 combined with mass spectrometry allowed the identification of serines 86 and 90 as two major sites of phosphorylation in vivo. The phosphorylation of Tip60 was found to modulate its histone acetyltransferase activity. One of the identified phosphorylated serines, Ser-90, was within a consensus cyclin B/Cdc2 site. Ser-90 was specifically phosphorylatedin vitro by the cyclin B/Cdc2 complex." SIGNOR-250641 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 MAP3K5 protein Q99683 UNIPROT DAXX protein Q9UER7 UNIPROT up-regulates phosphorylation Ser176 TNAENTAsQSPRTRG 9606 19789335 t gcesareni "Our data demonstrated that ask1 controls the cytoplasmic localization of daxx (fig.1). our results indicate that daxx not only activates ask1 but also is a downstream target of ask1 and that accumulated daxx further activates ask1. Thus, the daxx-ask1 positive feedback loop amplifying jnk/p38 signaling plays an important role in the cell-killing effects of stressors, such as tnfalpha." SIGNOR-188321 NCSTN protein Q92542 UNIPROT APH1A protein Q96BI3 UNIPROT up-regulates binding 9606 BTO:0000142 12471034 t gcesareni "We show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain. Similar to the loss of presenilin or nicastrin, the inactivation of endogenous maph-1 using small interfering rnas results in the decrease of presenilin levels, accumulation of gamma-secretase substrates (app carboxyl-terminal fragments), and reduction of gamma-secretase products (amyloid-beta peptides and the intracellular domains of app and notch)." SIGNOR-96250 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 PP2B proteinfamily SIGNOR-PF18 SIGNOR MAPT protein P10636 UNIPROT up-regulates dephosphorylation Ser516 GDRSGYSsPGSPGTP 9606 BTO:0000142 20308788 t "The effect has been demonstrated using P10636-8" lperfetto "Among the sites studied, thr205, thr212, ser214, and ser262 were the most favorable sites, and ser199 and ser404 were the least favorable sites for pp2a in vitro." SIGNOR-164659 PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT "up-regulates activity" dephosphorylation Ser380 EPDHYRYsDTTDSDP 9606 BTO:0000007 22413754 t miannu "Overall, our results suggest that PTEN autodephosphorylation may be a critical event in this process; thus a major protein substrate for PTEN may be PTEN itself.|Various studies have demonstrated that PTEN is itself a phosphoprotein, and that the major sites of phosphorylation are found in an acidic stretch (DHYRYSDTTDSDPENE) near the C-terminus [1]. This prompted us to consider whether PTEN may autodephosphorylate these sites" SIGNOR-248544 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 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 sunitinib chemical CHEBI:38940 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-258292 tandutinib chemical CHEBI:90237 ChEBI KIT protein P10721 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-258297 tandutinib chemical CHEBI:90237 ChEBI PDGFRA protein P16234 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-258298 tandutinib chemical CHEBI:90237 ChEBI PDGFRB protein P09619 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-258299 moclobemide chemical CHEBI:83531 ChEBI MAOA protein P21397 UNIPROT "down-regulates activity" "chemical inhibition" -1 21680183 t Luana "Twenty-two pyrazoline derivatives were synthesized and tested for their human MAO (hMAO) inhibitory activity. Twelve molecules with unsubstituted ring A and substituted ring C (5–16) were found to be potent inhibitors of hMAO-A isoform with SIMAO-A in the order 103 and 104. " SIGNOR-258314 moclobemide chemical CHEBI:83531 ChEBI MAOB protein P27338 UNIPROT "down-regulates activity" "chemical inhibition" -1 21680183 t Luana "Twenty-two pyrazoline derivatives were synthesized and tested for their human MAO (hMAO) inhibitory activity. Twelve molecules with unsubstituted ring A and substituted ring C (5–16) were found to be potent inhibitors of hMAO-A isoform with SIMAO-A in the order 103 and 104. " SIGNOR-258315 N-[4-[[4-(4-methyl-1-piperazinyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]thio]phenyl]cyclopropanecarboxamide chemical CHEBI:91336 ChEBI AURKA protein O14965 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-258303 N-[4-[[4-(4-methyl-1-piperazinyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]thio]phenyl]cyclopropanecarboxamide chemical CHEBI:91336 ChEBI AURKB protein Q96GD4 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-258304 N-[4-[[4-(4-methyl-1-piperazinyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]thio]phenyl]cyclopropanecarboxamide chemical CHEBI:91336 ChEBI AURKC protein Q9UQB9 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-258305 NCSTN protein Q92542 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates binding 9606 12471034 t "Gamma secretase subunit. Leads to PS1/PS2 eterodimer complex stabilisation" gcesareni "Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes with presenilin 1 and presenilin 2." SIGNOR-96253 N-tert-butyl-3-[[5-methyl-2-[4-[2-(1-pyrrolidinyl)ethoxy]anilino]-4-pyrimidinyl]amino]benzenesulfonamide chemical CHEBI:91408 ChEBI JAK2 protein O60674 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-258301 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 PRKDC protein P78527 UNIPROT PDX1 protein P52945 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr11 EEQYYAAtQLYKDPC 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-225542 STK11 protein Q15831 UNIPROT MARK2 protein Q7KZI7 UNIPROT up-regulates phosphorylation Thr208 TFGNKLDtFCGSPPY 9606 14976552 t lperfetto "Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold" SIGNOR-122628 STK11 protein Q15831 UNIPROT SIK3 protein Q9Y2K2 UNIPROT up-regulates phosphorylation Thr163 TPGQLLKtWCGSPPY 9606 14976552 t lperfetto "Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold" SIGNOR-122835 tofacitinib chemical CHEBI:71200 ChEBI JAK3 protein P52333 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-258302 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-247997 alogliptin chemical CHEBI:72323 ChEBI DPP4 protein P27487 UNIPROT "down-regulates activity" "chemical inhibition" -1 22475866 t Luana "Novel pyrrolopyrimidine analogues as potent dipeptidyl peptidase IV inhibitors based on pharmacokinetic property-driven optimization." SIGNOR-258333 ibuprofen chemical CHEBI:5855 ChEBI PTGS2 protein P35354 UNIPROT "down-regulates activity" "chemical inhibition" -1 22091869 t Luana " Here we report the application of STD-NMR to characterize the binding of the anti-inflammatory drugs ibuprofen, diclofenac, and ketorolac to COX-1 and COX-2. " SIGNOR-258325 lofexidine chemical CHEBI:51368 ChEBI ADRA2A protein P08913 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000246 22341244 t Luana "Lofexidine was selected because its scaffold is similar to that of the imidazolines of the present study and, as emerged from our functional study (Table 2), it displayed significant α2A- and α2C-AR agonism. " SIGNOR-258332 lofexidine chemical CHEBI:51368 ChEBI ADRA2B protein P18089 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000246 22341244 t Luana "Lofexidine was selected because its scaffold is similar to that of the imidazolines of the present study and, as emerged from our functional study (Table 2), it displayed significant α2A- and α2C-AR agonism. " SIGNOR-258331 NCSTN protein Q92542 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates binding 9606 12603837 t "Gamma secretase subunit. Leads to PS1/PS2 eterodimer complex stabilisation" gcesareni "Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes with presenilin 1 and presenilin 2." SIGNOR-98724 PDP1 protein Q9P0J1 UNIPROT PDHA1 protein P08559 UNIPROT "up-regulates activity" dephosphorylation Ser300 SMSDPGVsYRTREEI -1 7782287 t "Sites 1, 2, and 3 were dephosphorylated either individually or in the presence of the other sites by the phospho-E1-phosphatase resulting in complete reactivation of the E1. The rates of dephosphorylation and reactivation were similar for sites 1, 2, and 3, indicating a random dephosphorylation mechanism" SIGNOR-252056 PRKCD protein Q05655 UNIPROT ADRB2 protein P07550 UNIPROT "down-regulates activity" phosphorylation Ser261 TGHGLRRsSKFCLKE -1 1848190 t lperfetto "We investigate the role of the beta 2-adrenergic receptor phosphorylation by protein kinase C in this regulatory process. Mutation of the serine-261, -262, -344 and -345 of the beta 2-adrenergic receptor prevented the phorbol-ester-induced phosphorylation of the receptor. This mutation also abolished the phorbol-ester-induced decrease in high-affinity agonist binding and potency of the beta 2-adrenergic receptor. We suggest that protein kinase C mediated phosphorylation of the receptor promotes its functional uncoupling." SIGNOR-248854 solifenacin chemical CHEBI:135530 ChEBI CHRM1 protein P11229 UNIPROT "down-regulates activity" "chemical inhibition" -1 21524581 t Luana "The IC50 values for solifenacin, YM-46303, tiotropium bromide and ipratropium bromide were also determined for reference" SIGNOR-258312 solifenacin chemical CHEBI:135530 ChEBI CHRM2 protein P08172 UNIPROT "down-regulates activity" "chemical inhibition" -1 21524581 t Luana "The IC50 values for solifenacin, YM-46303, tiotropium bromide and ipratropium bromide were also determined for reference" SIGNOR-258311 solifenacin chemical CHEBI:135530 ChEBI CHRM3 protein P20309 UNIPROT "down-regulates activity" "chemical inhibition" -1 21524581 t Luana "The IC50 values for solifenacin, YM-46303, tiotropium bromide and ipratropium bromide were also determined for reference" SIGNOR-258313 SPI1 protein P17947 UNIPROT FCGR1A protein P12314 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 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 vandetanib chemical CHEBI:49960 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-258308 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 VX-745 chemical CHEBI:90528 ChEBI MAPK14 protein Q16539 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-258310 eletriptan chemical CHEBI:50922 ChEBI HTR1D protein P28221 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000567 10193663 t Luana "This study has demonstrated that the 5-HT receptor binding profile of eletriptan is qualitatively similar to the binding profile of sumatriptan, zolmitriptan, naratriptan and rizatriptan. As expected these compounds demonstrated high affinity for the human 5-HT1B and 5-HT1D receptors which is consistent with their known vasoconstrictor properties in isolated vascular tissues " SIGNOR-258339 ILK protein Q13418 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation Ser473 RPHFPQFsYSASGTA 9606 9736715 t acerquone "Ilk can phosphorylate pkb-akt on serine-473, whereas kinase-deficient ilk severely inhibits endogenous phosphorylation of pkb-akt on serine-473, demonstrating that ilk is involved in agonist stimulated, pi(3)k-dependent, pkb-akt activation." SIGNOR-60115 lofexidine chemical CHEBI:51368 ChEBI ADRA2C protein P18825 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000246 22341244 t Luana "Lofexidine was selected because its scaffold is similar to that of the imidazolines of the present study and, as emerged from our functional study (Table 2), it displayed significant α2A- and α2C-AR agonism. " SIGNOR-258330 metoprolol chemical CHEBI:6904 ChEBI ADRB1 protein P08588 UNIPROT "down-regulates activity" "chemical inhibition" 10030 BTO:0000246 10079020 t Luana "In our CHO cells transfected with the human β1- and β2-adrenoceptors, the binding affinities of atenolol, metoprolol, betaxolol and practolol correlate with previously published β1- (P=0.03) and β2-adrenoceptor (P=0.03) binding affinities in human lung tissue" SIGNOR-258337 naratriptan chemical CHEBI:7478 ChEBI HTR1D protein P28221 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000567 10193663 t Luana "This study has demonstrated that the 5-HT receptor binding profile of eletriptan is qualitatively similar to the binding profile of sumatriptan, zolmitriptan, naratriptan and rizatriptan. As expected these compounds demonstrated high affinity for the human 5-HT1B and 5-HT1D receptors which is consistent with their known vasoconstrictor properties in isolated vascular tissues " SIGNOR-258338 NCSTN protein Q92542 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates binding 9606 BTO:0000975 14572442 t "Gamma secretase subunit. Leads to PS1/PS2 eterodimer complex stabilisation" gcesareni "Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes with presenilin 1 and presenilin 2." SIGNOR-118852 NCSTN protein Q92542 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates binding 9606 10993067 t "Gamma secretase subunit. Leads to PS1/PS2 eterodimer complex stabilisation" gcesareni "Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes with presenilin 1 and presenilin 2." SIGNOR-81936 oxybutynin chemical CHEBI:7856 ChEBI CHRM1 protein P11229 UNIPROT "down-regulates activity" "chemical inhibition" 10030 BTO:0000246 22243489 t Luana " Compared to the reference compound oxybutynin, an antagonist used for the treatment of OAB,(5) the newly synthesized 1,4-dioxane derivatives exhibit a higher potency." SIGNOR-258328 oxybutynin chemical CHEBI:7856 ChEBI CHRM2 protein P08172 UNIPROT "down-regulates activity" "chemical inhibition" 10030 BTO:0000246 22243489 t Luana " Compared to the reference compound oxybutynin, an antagonist used for the treatment of OAB,(5) the newly synthesized 1,4-dioxane derivatives exhibit a higher potency." SIGNOR-258329 oxybutynin chemical CHEBI:7856 ChEBI CHRM3 protein P20309 UNIPROT "down-regulates activity" "chemical inhibition" 10030 BTO:0000246 22243489 t Luana " Interestingly, unlike the methiodide 5, the tertiary amine 17 and to a lesser extent its (S)-eutomer preferentially block the M3 receptor subtype with respect to the M2, with an M3/M2 selectivity ratio slightly higher than those of oxybutynin and the conventional M3selective antagonist 4-DAMP. " SIGNOR-258327 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 PHLPP2 protein Q6ZVD8 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.[...] These data are consistent with phlpp terminating akt signaling by directly dephosphorylating and inactivating akt." SIGNOR-135046 practolol chemical CHEBI:258351 ChEBI ADRB1 protein P08588 UNIPROT "down-regulates activity" "chemical inhibition" 10030 BTO:0000246 10079020 t Luana "In our CHO cells transfected with the human β1- and β2-adrenoceptors, the binding affinities of atenolol, metoprolol, betaxolol and practolol correlate with previously published β1- (P=0.03) and β2-adrenoceptor (P=0.03) binding affinities in human lung tissue" SIGNOR-258336 PRKCA protein P17252 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser497 ATVKSRWsGSQQVEQ 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-37470 propranolol chemical CHEBI:8499 ChEBI ADRB2 protein P07550 UNIPROT "down-regulates activity" "chemical inhibition" 10030 BTO:0000246 10079020 t Luana "Similarly, the binding affinities of ICI 118–551, CGP 20712A, propranolol, bupranolol and CGP 12177 for human β1-, β2- and β3-adrenoceptors correlate with their affinities at human β1- (P=0.04), β2- (P=0.01)" SIGNOR-258334 PPP1CA protein P62136 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-248559 ACE2 protein Q9BYF1 UNIPROT AGT protein P01019 UNIPROT "up-regulates activity" cleavage Pro40 GDRVYIHpFHLVIHN -1 11815627 t miannu "The ACE2 hydrolytic activity is dependent on the C terminus sequence of the substrate, which is evident from the data with the angiotensin peptides. After 2 h, ACE2 hydrolyzes Ang I partially and Ang II completely, although there is no hydrolysis of angiotensin 1–9, angiotensin 1–7, and angiotensin 1–5, which possess the same N terminus." SIGNOR-256315 NDN protein Q99608 UNIPROT BMI1 protein P35226 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," SIGNOR-253384 NDN protein Q99608 UNIPROT CDKN2A protein P42771 UNIPROT up-regulates 9606 24392140 f lperfetto "In HEK293A cells transfected with luciferase reporter constructs, necdin relieves Bmi1-dependent repression of p16 promoter activity," SIGNOR-253383 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 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 PPP2CA protein P67775 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" dephosphorylation Ser473 RPHFPQFsYSASGTA 10090 BTO:0000944 15367694 t "Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes" SIGNOR-248627 PRKCB protein P05771 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser497 ATVKSRWsGSQQVEQ 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-37474 PTPA protein Q15257 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 21159657 t gcesareni "Consistent with previous reports (2830), we found that expression of sv40st, suppression of either pp2a c or b resulted in elevated levels of akt phosphorylation (ser473)" SIGNOR-170699 rizatriptan chemical CHEBI:48273 ChEBI HTR1D protein P28221 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000567 10193663 t Luana "This study has demonstrated that the 5-HT receptor binding profile of eletriptan is qualitatively similar to the binding profile of sumatriptan, zolmitriptan, naratriptan and rizatriptan. As expected these compounds demonstrated high affinity for the human 5-HT1B and 5-HT1D receptors which is consistent with their known vasoconstrictor properties in isolated vascular tissues " SIGNOR-258342 sildenafil chemical CHEBI:9139 ChEBI PDE5A protein O76074 UNIPROT "down-regulates activity" "chemical inhibition" -1 10385692 t Luana "Inhibition of cyclic GMP-binding cyclic GMP-specific phosphodiesterase (Type 5) by sildenafil and related compounds." SIGNOR-258343 sumatriptan chemical CHEBI:10650 ChEBI HTR1D protein P28221 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000567 10193663 t Luana "This study has demonstrated that the 5-HT receptor binding profile of eletriptan is qualitatively similar to the binding profile of sumatriptan, zolmitriptan, naratriptan and rizatriptan. As expected these compounds demonstrated high affinity for the human 5-HT1B and 5-HT1D receptors which is consistent with their known vasoconstrictor properties in isolated vascular tissues " SIGNOR-258340 TBK1 protein Q9UHD2 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation Ser473 RPHFPQFsYSASGTA 9606 21329883 t lperfetto "Upon mitogen stimulation, triggering of the innate immune response, re-exposure to glucose, or oncogene activation, tbk1 is recruited to the exocyst, where it activates akt. Akt is a direct tbk1 substrate that connects tbk1 to prosurvival signaling." SIGNOR-172132 zolmitriptan chemical CHEBI:10124 ChEBI HTR1D protein P28221 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000567 10193663 t Luana "This study has demonstrated that the 5-HT receptor binding profile of eletriptan is qualitatively similar to the binding profile of sumatriptan, zolmitriptan, naratriptan and rizatriptan. As expected these compounds demonstrated high affinity for the human 5-HT1B and 5-HT1D receptors which is consistent with their known vasoconstrictor properties in isolated vascular tissues " SIGNOR-258341 CASP8AP2 protein Q9UKL3 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates binding 9606 22075988 t lperfetto "In addition, both cleavage products of c-flip turned out to be inducers of nf-kb activity by binding to the ikk complex." SIGNOR-217385 CBFbeta-MYH11 "fusion protein" SIGNOR-FP3 SIGNOR Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 10090 BTO:0004793 10508507 f "The data reported here indicate that Cbfb-MYH11 blocks myeloid differentiation and predisposes mice to leukaemia." SIGNOR-255736 PPP1CB protein P62140 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-248575 PPP2CA protein P67775 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" dephosphorylation Thr308 KDGATMKtFCGTPEY 10090 BTO:0000944 15367694 t "Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes" SIGNOR-248629 PPP2CA protein P67775 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates dephosphorylation Thr450 TAQMITItPPDQDDS 9606 11839802 t gcesareni "Integrin alpha 2 beta 1 promotes activation of protein phosphatase 2a and dephosphorylation of akt and glycogen synthase kinase 3 beta" SIGNOR-114767 PPP2R5B protein Q15173 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates dephosphorylation Thr308 KDGATMKtFCGTPEY 9606 16495456 t gcesareni "Activation of pp2a is the intermediate step between the abeta-ceramide cascade and the subsequent inactivation of akt." SIGNOR-144808 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 PTK6 protein Q13882 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation Tyr315 TFCGTPEyLAPEVLE 9606 15994200 t gcesareni "These observations suggest that RET/PTC is able to phosphorylate the Y315 residue of PKB, an event that results in maximal activation of PKB for RET/PTC-induced thyroid tumorigenesis." SIGNOR-138437 PTK6 protein Q13882 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation Tyr315 TFCGTPEyLAPEVLE 9606 BTO:0000150 BTO:0001129 20606012 t gcesareni "Here we demonstrate that AKT is a direct substrate of PTK6 and that AKT tyrosine residues 315 and 326 are phosphorylated by PTK6." SIGNOR-166506 PTK6 protein Q13882 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation Tyr326 EVLEDNDyGRAVDWW 9606 BTO:0000150 BTO:0001129 20606012 t gcesareni "Here we demonstrate that AKT is a direct substrate of PTK6 and that AKT tyrosine residues 315 and 326 are phosphorylated by PTK6." SIGNOR-166510 RET protein P07949 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR 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-166514 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 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 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 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-236929 CBFbeta-MYH11 "fusion protein" SIGNOR-FP3 SIGNOR "Core Binding Factor complex" complex SIGNOR-C214 SIGNOR "down-regulates activity" relocalization 9606 BTO:0000661 9632809 f "The polyomavirus enhancer binding protein 2 (PEBP2)/core binding factor (CBF) is a transcription factor composed of two subunits, α and β. The gene encoding the β subunit is disrupted by inv(16), resulting in the formation of a chimeric protein, β-SMMHC, which is associated with acute myelogenous leukemia.Thus, the result suggess that β-SMMHC inhibits PEBP2-mediated transcription via cytoplasmic sequestration of the α subunit." SIGNOR-255741 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Ser477 PQFSYSAsGTA 9606 BTO:0000093 24670654 t gcesareni "Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation" SIGNOR-252450 mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Thr450 TAQMITItPPDQDDS 10090 BTO:0002572 18566586 t gcesareni "MTORC2 phosphorylates newly synthesized Akt at the TM (Thr450) site to facilitate carboxyl-terminal folding and to stabilize Akt" SIGNOR-252448 NDN protein Q99608 UNIPROT EID1 protein Q9Y6B2 UNIPROT "up-regulates activity" binding 10090 BTO:0000165 18557765 t llicata "The Prader-Willi syndrome protein necdin interacts with the E1A-like inhibitor of differentiation EID-1 and promotes myoblast differentiation." SIGNOR-237614 PRKDC protein P78527 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0001949 18439899 t gcesareni "DNA-PK phosphorylates HM Ser473 of PKB. However, we also noted similar patterns in T loop Thr308 phosphorylation after _-IR []his function is apparently restricted to the PKBalpha isoform" SIGNOR-252447 ADORA2B protein P29275 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-256910 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 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 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 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Thr479 FSYSASGtA 9606 BTO:0000093 24670654 t gcesareni "Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation" SIGNOR-252453 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 SIRT1 protein Q96EB6 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" deacetylation Lys14 VKEGWLHkRGEYIKT 10090 BTO:0000562 21775285 t gcesareni "We show that Akt and PDK1 are acetylated at lysine residues in their pleckstrin homology domains, which mediate PIP(3) binding. Acetylation blocked binding of Akt and PDK1 to PIP(3), thereby preventing membrane localization and phosphorylation of Akt. Deacetylation by SIRT1 enhanced binding of Akt and PDK1 to PIP(3) and promoted their activation." SIGNOR-252456 TNK2 protein Q07912 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Tyr176 EKATGRYyAMKILKK 10090 BTO:0002021 20333297 t gcesareni "Ack1 (also known as ACK or TNK2), which directly phosphorylates AKT at an evolutionarily conserved tyrosine 176 in the kinase domain. Tyr176-phosphorylated AKT localizes to the plasma membrane and promotes Thr308/Ser473-phosphorylation leading to AKT activation." SIGNOR-252457 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 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 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 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 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 NR4A1 protein P22736 UNIPROT "down-regulates activity" phosphorylation Ser351 GRRGRLPsKPKQPPD 9606 BTO:0000782 11274386 t lperfetto "We show that akt interacts with nur77 and inactivates nur77 by phosphorylation at ser-350" SIGNOR-252466 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 AKT proteinfamily SIGNOR-PF24 SIGNOR COPS6 protein Q7L5N1 UNIPROT up-regulates phosphorylation Ser60 DHWIRMRsQEGRPVQ 9606 23095642 t llicata "Mechanistic studies show that akt causes csn6 phosphorylation at ser 60, which, in turn, reduces ubiquitin-mediated protein degradation of csn6." SIGNOR-199254 AKT proteinfamily SIGNOR-PF24 SIGNOR CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Ser552 QDTQRRTsMGGTQQQ 9606 12063252 t lperfetto "AKT can phosphorylate and inactivate GSK3, leading to stabilization and increased levels of BETA-catenin. 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-152954 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-252828 CDK2 protein P24941 UNIPROT NPM1 protein P06748 UNIPROT "down-regulates activity" phosphorylation Thr234 SFKKQEKtPKTPKGP 10090 BTO:0000944 SIGNOR-C16 11278991 t lperfetto "We have recently found that nucleophosmin (npm/b23), a phosphoprotein primarily found in nucleolus, associates with unduplicated centrosomes and is a direct substrate of cdk2-cyclin e in centrosome duplication. Upon phosphorylation by CDK2-cyclin E, NPM/B23 dissociates from centrosomes, which is a prerequisite step for centrosomes to initiate duplication." SIGNOR-235725 NHLH2 protein Q02577 UNIPROT MAOA protein P21397 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000142 22169038 f miannu "SIRT1 deacetylates the brain-specific helix-loop-helix transcription factor NHLH2 on lysine 49 to increase its activation of the MAO-A promoter" SIGNOR-254829 NHS protein Q6T4R5 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR "up-regulates activity" relocalization 9606 20332100 t miannu "NHS knockdown also resulted in the mislocalization of the Arp2/3 complex and disruption of the actin cytoskeleton. in the absence of NHS, Arp2/3 localization and F-actin distribution are disrupted, suggesting that Arp2/3 actin-nucleation activity is mediated, in part, by NHS providing an additional functional link between NHS and actin." SIGNOR-253566 ADRB3 protein P13945 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-256896 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 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 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 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 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 protein O43524 UNIPROT "down-regulates activity" phosphorylation Ser315 DFRSRTNsNASTVSG 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 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-183616 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-141416 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-161283 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-104646 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-251628 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-155229 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 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 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 CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Ser552 QDTQRRTsMGGTQQQ 9606 12063252 t lperfetto "AKT can phosphorylate and inactivate GSK3, leading to stabilization and increased levels of BETA-catenin. 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-252499 AKT1 protein P31749 UNIPROT FAM129A 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 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 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 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 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 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 LTB4R2 protein Q9NPC1 UNIPROT unknown phosphorylation Thr355 GGRSREGtMELRTTP 9606 22044535 t llicata "Blt2 phosphorylation at thr355 by akt is necessary for blt2-mediated chemotaxis." SIGNOR-252516 AKT1 protein P31749 UNIPROT MAP3K8 protein P41279 UNIPROT "down-regulates activity" phosphorylation Ser400 EDQPRCQsLDSALLE 9606 BTO:0000661 12138205 t gcesareni "The regulation of NF-kappa B-dependent transcription by Cot requires Akt-dependent phosphorylation of serine 400 (S400)," SIGNOR-252553 AKT1 protein P31749 UNIPROT MDM4 protein O15151 UNIPROT up-regulates 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 MXD1 protein Q05195 UNIPROT down-regulates phosphorylation Ser145 IERIRMDsIGSTVSS 9606 19526459 t llicata "Here, we present evidence that akt inhibits mad1-mediated transcription repression by physical interaction with and phosphorylation of mad1." SIGNOR-252525 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 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 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-137942 PTPRJ protein Q12913 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation Tyr205 IMLNSKGyTKSIDIW 9606 19494114 t gcesareni "In this study we show that one of these potential targets, the erk1/2, is indeed a direct dep-1 substrate in vivo." SIGNOR-161536 "3-[({4-[4-({[1-(2-chlorophenyl)ethoxy]carbonyl}amino)-3-methyl-1,2-oxazol-5-yl]phenyl}methyl)sulfanyl]propanoic acid" chemical CHEBI:91194 ChEBI LPAR1 protein Q92633 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193558 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 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 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 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 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 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 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 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 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 NDN protein Q99608 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000671 24349431 t lperfetto "Deletion mapping demonstrated that the C-terminus of cystin and both termini of necdin are required for their mutual interaction. Speculating that these two proteins may function to regulate gene expression, we developed a luciferase reporter assay and observed that necdin strongly activated the Myc P1 promoter, and cystin did so more modestly." SIGNOR-253381 PRKACA protein P17612 UNIPROT IGF2R protein P11717 UNIPROT unknown phosphorylation Ser2347 TTCCRRSsNVSYKYS 9606 8318012 t lperfetto "Pka phosphorylates the cytoplasmic mpr 300 domain at ser20 and at a non-identified site," SIGNOR-37839 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 SALL4 protein Q9UJQ4 UNIPROT ABCG2 protein Q9UNQ0 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21526180 f miannu "we demonstrated that SALL4 was able to bind to the promoter region of ABCA3 and activate its expression while regulating the expression of ABCG2 indirectly. SALL4 expression was positively correlated to those of ABCG2 and ABCA3 in primary leukemic patient samples" SIGNOR-255122 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 PPP1CA protein P62136 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-252603 PPP1CB protein P62140 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-252604 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 PTK6 protein Q13882 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Tyr315 TFCGTPEyLAPEVLE 9606 BTO:0000150 BTO:0001129 20606012 t gcesareni "Here we demonstrate that AKT is a direct substrate of PTK6 and that AKT tyrosine residues 315 and 326 are phosphorylated by PTK6." SIGNOR-252618 PTK6 protein Q13882 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Tyr326 EVLEDNDyGRAVDWW 9606 BTO:0000150 BTO:0001129 20606012 t gcesareni "Here we demonstrate that AKT is a direct substrate of PTK6 and that AKT tyrosine residues 315 and 326 are phosphorylated by PTK6." SIGNOR-252622 PTPA protein Q15257 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 21159657 t gcesareni "Consistent with previous reports (2830), we found that expression of sv40st, suppression of either pp2a c or b resulted in elevated levels of akt phosphorylation (ser473)" SIGNOR-252607 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 SRC protein P12931 UNIPROT AKT1 protein P31749 UNIPROT "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-252620 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 PTAFR protein P25105 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-257061 ANAPC2 protein Q9UJX6 UNIPROT DVL1 protein O14640 UNIPROT down-regulates binding 9606 19805045 t gcesareni "We now report that the anaphase-promoting complex (apc/c) recognizes a d-box motif of dvl and ubiquitylates dvl on a highly conserved lysine residue.We now report that expression of the apc/c subunit anapc2 activates the apc/c-dependent degradation of dvl by disrupting canonical wnt signaling." SIGNOR-188393 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 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 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 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 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 TBK1 protein Q9UHD2 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Ser473 RPHFPQFsYSASGTA 9606 21329883 t lperfetto "Upon mitogen stimulation, triggering of the innate immune response, re-exposure to glucose, or oncogene activation, tbk1 is recruited to the exocyst, where it activates akt. Akt is a direct tbk1 substrate that connects tbk1 to prosurvival signaling." SIGNOR-252608 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 "alvocidib hydrochloride" chemical CHEBI:90998 ChEBI CDK2 protein P24941 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192461 GNB1 protein P62873 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0000938 16537363 t gcesareni "Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt" SIGNOR-252679 INSR protein P06213 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "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-252692 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 PRKCD protein Q05655 UNIPROT C5AR1 protein P21730 UNIPROT down-regulates phosphorylation Ser334 SVVRESKsFTRSTVD 9606 17145764 t gcesareni "Whole cell phosphorylation assays with specific inhibitors as well as in vitro phosphorylation assays with recombinant enzymes and peptide substrates revealed that phosphorylation of ser-334 is regulated by protein kinase c-beta this study is among the first to analyze in a detailed manner, using a non-mutational approach, modifications of a defined phosphorylation site in a g protein-coupled receptor and to correlate these findings with functional parameters of receptor deactivation." SIGNOR-151015 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 P2RY6 protein Q15077 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-257076 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 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 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 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 NDN protein Q99608 UNIPROT PIAS1 protein O75925 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 24911587 f lperfetto "Necdin bound to PIAS1 central domains that are highly conserved among PIAS family proteins and suppressed PIAS1-dependent sumoylation of the substrates STAT1 and PML (promyelocytic leukemia protein). Remarkably, necdin promoted degradation of PIAS1 via the ubiquitin-proteasome pathway. In transfected HEK293A cells, amino- and carboxyl-terminally truncated mutants of PIAS1 bound to necdin but failed to undergo necdin-dependent ubiquitination." SIGNOR-253387 PRKACA protein P17612 UNIPROT WT1 protein P19544 UNIPROT down-regulates phosphorylation Ser365 KDCERRFsRSDQLKR 9606 9366517 t llicata "Pka phosphorylated wt1 at ser-365 and ser-393 in vitro, as well as at additional sites, and this phosphorylation abolished the dna-binding activity of wt1 in vitro. Using wt1 mutants in which ser-365 and ser-393 were mutated to ala individually and in combination, we showed that phosphorylation of these sites was critical for inhibition of dna binding in vivo." SIGNOR-53172 PRKACA protein P17612 UNIPROT WT1 protein P19544 UNIPROT down-regulates phosphorylation Ser393 KTCQRKFsRSDHLKT 9606 9366517 t llicata "Pka phosphorylated wt1 at ser-365 and ser-393 in vitro, as well as at additional sites, and this phosphorylation abolished the dna-binding activity of wt1 in vitro. Using wt1 mutants in which ser-365 and ser-393 were mutated to ala individually and in combination, we showed that phosphorylation of these sites was critical for inhibition of dna binding in vivo." SIGNOR-53176 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 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 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 ATM protein Q13315 UNIPROT PNKP protein Q96T60 UNIPROT up-regulates phosphorylation Ser126 PPGTPLVsQDEKRDA 9606 21824916 t lperfetto "We demonstrate that pnkp is phosphorylated by the dna-dependent protein kinase (dna-pk) and ataxia-telangiectasia mutated (atm) in vitro. The major phosphorylation site for both kinases was serine 114, with serine 126 being a minor site. Purified pnkp protein with mutation of serines 114 and 126 had decreased dna kinase and dna phosphatase activities and reduced affinity for dna in vitro." SIGNOR-176012 ATM protein Q13315 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-180747 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 PTPN13 protein Q12923 UNIPROT PDCD10 protein Q9BUL8 UNIPROT down-regulates dephosphorylation 9606 17657516 t gcesareni "We also show that ccm3 directly binds to serine/threonine kinase 25 (stk25, ysk1, sok1) and the phosphatase domain of fas-associated phosphatase-1 (fap-1, ptpn13, ptp-bas, ptp-bl)." SIGNOR-157076 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 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 AURKB protein Q96GD4 UNIPROT DSN1 protein Q9H410 UNIPROT down-regulates phosphorylation Ser109 KETNRRKsLHPIHQG 9606 20471944 t lperfetto "To determine whether the combinatorial regulation of the kmn network by aurora b observed in vitro is critical to controlling kinetochore-microtubule attachments in vivo, we next investigated the effect of the phosphomimetic (to aspartate) and nonphosphorylatable (to alanine) mutants of dsn1, knl1, and ndc80 in vertebrate cells. We predicted that both types of mutations in critical phosphorylation sites would affect chromosome segregation, since preventing the inactivation of inappropriately attached kinetochores by aurora b (in the nonphosphorylatable mutant) or constitutively inactivating this attachment (in the phosphomimetic mutant)." SIGNOR-165550 AURKB protein Q96GD4 UNIPROT KNL1 protein Q8NG31 UNIPROT down-regulates phosphorylation Ser60 KKNSRRVsFADTIKV 9606 20471944 t lperfetto "To determine whether the combinatorial regulation of the kmn network by aurora b observed in vitro is critical to controlling kinetochore-microtubule attachments in vivo, we next investigated the effect of the phosphomimetic (to aspartate) and nonphosphorylatable (to alanine) mutants of dsn1, knl1, and ndc80 in vertebrate cells. We predicted that both types of mutations in critical phosphorylation sites would affect chromosome segregation, since preventing the inactivation of inappropriately attached kinetochores by aurora b (in the nonphosphorylatable mutant) or constitutively inactivating this attachment (in the phosphomimetic mutant)." SIGNOR-165506 AURKB protein Q96GD4 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT "up-regulates activity" phosphorylation Ser144 NAGNKRLsTIDESGS 9606 BTO:0000567 14744859 t llicata "It was found that the 5A fragment in which five Ser/Thr residues were substituted with Ala (S144A/T145A/S185A/T186A/S187A) fully prevented phosphorylation (Fig. 5B), confirming that Aurora B primarily phosphorylates five Ser/Thr residues in the basic region of MgcRacGAP. | the strong phosphorylation of the basic region of MgcRacGAP by Aurora B kinase was demonstrated, and this phosphorylation prevents the inhibition of MgcRacGAP GAP activity by PRC1" SIGNOR-250586 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 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 CSNK2A1 protein P68400 UNIPROT ARNT protein P27540 UNIPROT down-regulates phosphorylation Ser77 DKERFARsDDEQSSA 9606 16129408 t gcesareni "Here, we show that arnt and alt arnt proteins are differentially phosphorylated by protein kinase ckii in vitro. Phosphorylation had an inhibitory effect on dna-binding to an e-box probe by alt arnt, but not arnt, homodimers. This inhibitory phosphorylation occurs through ser77." SIGNOR-140034 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 SENP1 protein Q9P0U3 UNIPROT AKT1 protein P31749 UNIPROT "down-regulates quantity by destabilization" desumoylation 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-252736 BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR BCR protein P11274 UNIPROT down-regulates phosphorylation Tyr177 ADAEKPFyVNVEFHH 9606 BTO:0001271 8622703 t lperfetto "We have previously demonstrated that the bcr protein is tyrosine phosphorylated within first-exon sequences by the bcr-abl oncoprotein. Here we report that in addition to tyrose 177 (y-177), y-360 and y283 are phosphorylated in bcr-abl proteins in vitro. Tyrosine-phosphorylated bcr, phosphorylated in vitro by bcr-abl, was greatly inhibited in its serine/threonine kinase activity, impairing both auto- and transkinase activities of bcr." SIGNOR-40611 BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR BCR protein P11274 UNIPROT down-regulates phosphorylation Tyr283 YQPYQSIyVGGMMEG 9606 BTO:0001271 8622703 t lperfetto "We have previously demonstrated that the bcr protein is tyrosine phosphorylated within first-exon sequences by the bcr-abl oncoprotein. Here we report that in addition to tyrose 177 (y-177), y-360 and y283 are phosphorylated in bcr-abl proteins in vitro. Tyrosine-phosphorylated bcr, phosphorylated in vitro by bcr-abl, was greatly inhibited in its serine/threonine kinase activity, impairing both auto- and transkinase activities of bcr." SIGNOR-40615 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 BTRC protein Q9Y297 UNIPROT GLI3 protein P10071 UNIPROT "down-regulates quantity by destabilization" ubiquitination Lys773 RRNPAGTkWMEHVKL 9606 BTO:0000938 17283082 t lperfetto "Third, we and others have recently shown that only phosphorylated Ci/Gli3 are able to directly bind Slimb/BetaTrCP, that Gli3 is polyubiquitinated in the cell, and that mutations of 4 lysine residues, the putative ubiquitination sites in the Gli3 C-terminal region, inhibit Gli3 processing These observations further support the notion that Ci/Gli3 processing is carried out by the proteasome because the deletion of the cleavage site is expected to often disrupt the protease-mediated site-specific cleavage." SIGNOR-145116 BTRC protein Q9Y297 UNIPROT GLI3 protein P10071 UNIPROT "down-regulates quantity by destabilization" ubiquitination Lys779 TKWMEHVkLERLKQV 9606 BTO:0000938 17283082 t lperfetto "Third, we and others have recently shown that only phosphorylated Ci/Gli3 are able to directly bind Slimb/BetaTrCP, that Gli3 is polyubiquitinated in the cell, and that mutations of 4 lysine residues, the putative ubiquitination sites in the Gli3 C-terminal region, inhibit Gli3 processing These observations further support the notion that Ci/Gli3 processing is carried out by the proteasome because the deletion of the cleavage site is expected to often disrupt the protease-mediated site-specific cleavage." SIGNOR-249576 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 SENP1 protein Q9P0U3 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates quantity by destabilization" desumoylation 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-252738 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 Calcineurin complex SIGNOR-C155 SIGNOR 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-252318 Calcineurin complex SIGNOR-C155 SIGNOR 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-252328 Calcineurin complex SIGNOR-C155 SIGNOR 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-252334 CAMK2A protein Q9UQM7 UNIPROT DLG1 protein Q12959 UNIPROT "down-regulates activity" phosphorylation Ser232 ITLERGNsGLGFSIA 9534 BTO:0000298 12933808 t llicata "Synapse-associated protein 97 (SAP97), a member of membrane-associated guanylate kinase protein family, has been implicated in the processes of targeting ionotropic glutamate receptors at postsynaptic sites. | We show here that SAP97 is directly associated with NR2A through its PDZ1 domain, and CaMKII-dependent phosphorylation of SAP97-Ser-232 disrupts NR2A interaction both in an in vitro pull-out assay and in transfected COS-7 cells. Moreover, expression of SAP97(S232D) mutant has effects similar to those observed upon constitutively activating CaMKII." SIGNOR-250618 CAMK2A protein Q9UQM7 UNIPROT NOS1 protein P29475 UNIPROT "down-regulates activity" phosphorylation Ser852 SYKVRFNsVSSYSDS 10400690 t llicata "It was found that purified recombinant nNOS was phosphorylated by CaM-K Ialpha, CaM-K IIalpha, and CaM-K IV at Ser847 in vitro. Replacement of Ser847 with Ala (S847A) prevented phosphorylation by CaM kinases. Phosphorylated recombinant wild-type nNOS at Ser847 (approximately 0.5 mol of phosphate incorporation into nNOS) exhibited a 30% decrease of Vmax with little change of both the Km for L-arginine and Kact for CaM relative to unphosphorylated enzyme. The activity of mutant S847D was decreased to a level 50-60% as much as the wild-type enzyme. The decreased NOS enzyme activity of phosphorylated nNOS at Ser847 and mutant S847D was partially due to suppression of CaM binding, but not to impairment of dimer formation which is thought to be essential for enzyme activation." SIGNOR-250635 CAMK2A protein Q9UQM7 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates phosphorylation Ser260 TLSPVNHsLDLQPVT 9606 SIGNOR-C8 11027280 t gcesareni "Smad2 is a target substrate for cam kinase ii in vitro at serine-110, -240, and -260. furthermore, cam kinase ii blocked nuclear accumulation of a smad2 and induced smad2-smad4 hetero-oligomerization independently of tgfbeta receptor activation, while preventing tgfbeta-dependent smad2-smad3 interactions." SIGNOR-82974 CAMK2G protein Q13555 UNIPROT CHAT protein P28329 UNIPROT "up-regulates activity" phosphorylation Thr574 VDNIRSAtPEALAFV BTO:0000932 12486117 t llicata "Using mass spectrometry, we identified threonine 456 as a new phosphorylation site in choline acetyltransferase from A beta-(1-42)-treated cells and in purified recombinant ChAT phosphorylated in vitro by calcium/calmodulin-dependent protein kinase II (CaM kinase II). | This phosphorylation combination was observed in choline acetyltransferase from A beta-(1-42)-treated cells. Treatment of cells with A beta-(1-42) resulted in two phases of activation of choline acetyltransferase, the first within 30 min and associated with phosphorylation by protein kinase C and the second by 10 h and associated with phosphorylation by both CaM kinase II and protein kinase C." SIGNOR-250693 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 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RPS6 protein P62753 UNIPROT up-regulates phosphorylation Ser240 RLSSLRAsTSKSESS 9606 21233202 t lperfetto "In response to mitogenic stimuli, rps6 undergoes ordered c-terminal phosphorylation by p70 s6 kinases and p90 ribosomal s6 kinases on four conserved ser residues (ser-235, ser-236, ser-240, and ser-244) whose modification potentiates rps6 cap binding activity" SIGNOR-252765 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RPS6 protein P62753 UNIPROT up-regulates phosphorylation Ser244 LRASTSKsESSQK 9606 21233202 t lperfetto "In response to mitogenic stimuli, rps6 undergoes ordered c-terminal phosphorylation by p70 s6 kinases and p90 ribosomal s6 kinases on four conserved ser residues (ser-235, ser-236, ser-240, and ser-244) whose modification potentiates rps6 cap binding activity" SIGNOR-252764 CAMK2A protein Q9UQM7 UNIPROT SRF protein P11831 UNIPROT "up-regulates activity" phosphorylation Thr160 NKLRRYTtFSKRKTG 10753652 t llicata "Skeletal muscle CaMKII enriches in nuclei and phosphorylates myogenic factor SRF at multiple sites. | Microsequencing of these phosphorylated peptides identified that both Ser-103 and a novel residue, Thr-160 in the MADS box of SRF, were sites of phosphorylation. | The location of Thr-160 in the 3-D structure of SRF suggests that its phosphorylation by nuclear CaMKII may directly influence DNA binding of SRF and other MADS box factors." SIGNOR-250639 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 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR 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-256446 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR IL18 protein Q14116 UNIPROT "up-regulates activity" cleavage Asp71 PLFEDMTdSDCRDNA 9606 BTO:0001370 9334240 t lperfetto "We also found two precursor hIL-18 (prohIL-18)-processing activities in the cytosol of THP.1 cells. These activities were blocked separately by the caspase inhibitors Ac-YVAD-CHO and Ac-DEVD-CHO. Further analyses of the partially purified enzymes revealed that one is caspase-1, which cleaves prohIL-18 at the Asp36-Tyr37 site to generate the mature hIL-18, and the other is caspase-3, which cleaves both precursor and mature hIL-18 at Asp71-Ser72 and Asp76-Asn77 to generate biologically inactive products." SIGNOR-256378 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR 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-256437 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR 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-256444 CAV3 protein P56539 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-255997 RPS6K proteinfamily SIGNOR-PF26 SIGNOR BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser118 GRELRRMsDEFVDSF 9606 BTO:0000007 10837486 t lperfetto "Rsk1, and survival factor signaling stimulate phosphorylation of bad at ser-155, blocking the binding of bad to bcl-xl." SIGNOR-252786 RPS6K proteinfamily SIGNOR-PF26 SIGNOR BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser153 SWTRVFQsWWDRNLG 9606 BTO:0000007 10837486 t lperfetto "We report here that the phosphorylation of BAD at Ser-155 within the BH3 domain is a second phosphorylation-dependent mechanism that inhibits the death-promoting activity of BAD. Protein kinase A, RSK1, and survival factor signaling stimulate phosphorylation of BAD at Ser-155, blocking the binding of BAD to Bcl-XL. RSK1 phosphorylates BAD at both Ser-112 and Ser-155 and rescues BAD-mediated cell death in a manner dependent upon phosphorylation at both sites." SIGNOR-252767 RPS6K proteinfamily SIGNOR-PF26 SIGNOR BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000848 18246127 t lperfetto "To understand the mechanisms underlying B-RAF effects on cell survival we initially analysed the Bcl-2 family protein, Bad, that is phosphorylated by RSK1 at the inhibitory serine-75 residue in a MEK-dependent manner in melanoma cells" SIGNOR-252784 RPS6K proteinfamily SIGNOR-PF26 SIGNOR CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser295 TKRRKSMsGASPKES 9606 23708659 t lperfetto "Rsk promotes g2/m transition through activating phosphorylation of cdc25a and cdc25b rsk is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of t359/s363 in rsk. Together, these findings indicate that rsk promotes g2/m transition in mammalian cells through activating phosphorylation of cdc25a and cdc25b." SIGNOR-252776 RPS6K proteinfamily SIGNOR-PF26 SIGNOR 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-252778 RPS6K proteinfamily SIGNOR-PF26 SIGNOR DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser286 SSMSSCGsSGYFSSS 9606 22017877 t lperfetto "We found that deptor was rapidly phosphorylated on three serines in a conserved degron, facilitating binding and ubiquitylation by the f box protein _trcp, with consequent proteasomal degradation of deptor. Phosphorylation of the _trcp degron in deptor is executed by ck1" SIGNOR-252797 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 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 RPS6K proteinfamily SIGNOR-PF26 SIGNOR CCT2 protein P78371 UNIPROT up-regulates phosphorylation Ser260 GSRVRVDsTAKVAEI 9606 21440620 t lperfetto "Furthermore, both the s260a and s260d mutants showed a decreased folding capacity as compared to cells expressing the wild-type cct_ subunit ( fig.?_5e), suggesting that a cyclic phosphorylation of the s260 site by s6k1 is likely to be important for chaperonin function and that mutation of this site interferes with this process." SIGNOR-252780 RPS6K proteinfamily SIGNOR-PF26 SIGNOR DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser287 SMSSCGSsGYFSSSP 9606 22017877 t lperfetto "We found that deptor was rapidly phosphorylated on three serines in a conserved degron, facilitating binding and ubiquitylation by the f box protein _trcp, with consequent proteasomal degradation of deptor. Phosphorylation of the _trcp degron in deptor is executed by ck1" SIGNOR-252798 RPS6K proteinfamily SIGNOR-PF26 SIGNOR H3F3A 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-252815 SALL4 protein Q9UJQ4 UNIPROT CDH1 protein P12830 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000356 23954296 f miannu "Our shRNA-mediated SALL4 knockdown system and SALL4 overexpression system revealed that SALL4 suppresses the expression of adhesion gene CDH1, and positively regulates the CDH1 suppressor ZEB1." SIGNOR-255124 HCRTR2 protein O43614 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-257124 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 ATG10 protein Q9H0Y0 UNIPROT ATG12/5/16L1 complex SIGNOR-C109 SIGNOR up-regulates binding 9606 18704115 t lperfetto "Analogous to ubiquitination, atg12 is conjugated to atg5 by atg7--an e1-like protein--and atg10--an e2-like protein." SIGNOR-226699 ATR protein Q13535 UNIPROT XPA protein P23025 UNIPROT "up-regulates activity" phosphorylation Ser173 VKKNPHHsQWGDMKL 9606 BTO:0000018 16540648 t llicata "Defects in ATR-dependent XPA phosphorylation increases the cell sensitivity to UV irradiation. | The XPA-deficient cells complemented with XPA-S196A mutant, in which Ser196 was substituted with an alanine, displayed significantly higher UV sensitivity compared with the XPA cells complemented with wild-type XPA. Moreover, substitution of Ser196 with aspartic acid for mimicking the phosphorylation of XPA increased the cell survival to UV irradiation." SIGNOR-250584 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 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 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 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 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 CDC42BPA protein Q5VT25 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-188781 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 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 NPM1 protein P06748 UNIPROT "down-regulates activity" phosphorylation Thr234 SFKKQEKtPKTPKGP 9606 14670079 t gcesareni "We have recently found that nucleophosmin (npm/b23), a phosphoprotein primarily found in nucleolus, associates with unduplicated centrosomes and is a direct substrate of cdk2-cyclin e in centrosome duplication." SIGNOR-120330 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 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 NEDD4L protein Q96PU5 UNIPROT SCN11A protein Q9UI33 UNIPROT "down-regulates quantity by destabilization" ubiquitination 10090 BTO:0000938 23778145 t miannu "The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2)." SIGNOR-253462 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 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 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 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 DYRK1A protein Q13627 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR 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-252907 MAPK14 protein Q16539 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Ser7 sPAPLSPL 9606 BTO:0000150 22128155 t gcesareni "Ogether, our results suggest that p38 phosphorylation of foxo3a on ser-7 is essential for its nuclear relocalization in response to doxorubicin" SIGNOR-252960 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 P2RY13 protein Q9BPV8 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-257143 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 CDK5 protein Q00535 UNIPROT NDEL1 protein Q9GZM8 UNIPROT "up-regulates activity" phosphorylation Ser242 IPNGFGTsPLTPSAR 10090 BTO:0000142 12796778 t llicata "Three specific phosphorylation sites (Ser198, Thr219 and Ser231) and two weak phosphorylation sites (Ser242 and Thr245) for CDK5/p35 are located in this region of NUDEL | Each single or double mutant compromised,and the triple mutant completely eliminated, interaction with 14-3-3ε. | 14-3-3ε sustains NUDEL phosphorylation and protects it from phosphatase.e dynein motor function." SIGNOR-250677 CDK6 protein Q00534 UNIPROT RUNX1 protein Q01196 UNIPROT down-regulates phosphorylation Ser276 VHPATPIsPGRASGM 9606 BTO:0000007 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-169334 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 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 PAK1 protein Q13153 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser16 KELEKRAsGQAFELI 9606 14645234 t gcesareni "Pak1 phosphorylates op18/stathmin specifically at serine 16 and inactivates its catastrophe promoting activity in biochemical and time lapse microscopy microtubule assembly assays. Furthermore, phosphorylation of either serine 16 or 63 is sufficient to inhibit op18/stathmin in vitro." SIGNOR-119483 PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT unknown phosphorylation Ser25 VVLCSCPsPSMVRTQ 9606 BTO:0000009 10455013 t lperfetto "3-phosphoinositide-dependent protein kinase-1 (pdk1) expressed in unstimulated 293 cells was phosphorylated at ser-25, ser-241, ser-393, ser-396 and ser-410 and the level of phosphorylation of each site was unaffected by stimulation with insulin-like growth factor-1. Mutation of ser-241 to ala abolished pdk1 activity, whereas mutation of the other phosphorylation sites individually to ala did not affect pdk1 activity" SIGNOR-236777 PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT unknown phosphorylation Ser393 MQVSSSSsSHSLSAS 9606 BTO:0000010 10455013 t lperfetto "3-phosphoinositide-dependent protein kinase-1 (pdk1) expressed in unstimulated 293 cells was phosphorylated at ser-25, ser-241, ser-393, ser-396 and ser-410 and the level of phosphorylation of each site was unaffected by stimulation with insulin-like growth factor-1. Mutation of ser-241 to ala abolished pdk1 activity, whereas mutation of the other phosphorylation sites individually to ala did not affect pdk1 activity" SIGNOR-235782 PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT unknown phosphorylation Ser410 GLPQRSGsNIEQYIH 9606 BTO:0000008 10455013 t lperfetto "3-phosphoinositide-dependent protein kinase-1 (pdk1) expressed in unstimulated 293 cells was phosphorylated at ser-25, ser-241, ser-393, ser-396 and ser-410 and the level of phosphorylation of each site was unaffected by stimulation with insulin-like growth factor-1. Mutation of ser-241 to ala abolished pdk1 activity, whereas mutation of the other phosphorylation sites individually to ala did not affect pdk1 activity" SIGNOR-236772 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 OXGR1 protein Q96P68 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-257155 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 GPR119 protein Q8TDV5 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-257153 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 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 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 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 JNK proteinfamily SIGNOR-PF15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Thr455 ALGTPVLtPPTEAAS 9606 BTO:0000848 BTO:0001253 20959475 t lperfetto "Braf(v600e) signaling through mitogen-activated protein kinase/extracellular signal-regulated kinase kinase resulted in increased reactive oxygen species levels and c-jun nh(2) terminal kinase-mediated activation of foxo4 via its phosphorylation on thr(223), ser(226), thr(447), and thr(451)." SIGNOR-252956 MAPK1 protein P28482 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates quantity by destabilization" phosphorylation Ser294 QLSKWPGsPTSRSSD 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-252957 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 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 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 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR UBTF protein P17480 UNIPROT "up-regulates activity" phosphorylation Ser484 ERGKLPEsPKRAEEI 10090 BTO:0000944 10202152 t llicata "We have identified Ser484 as a direct target for cyclin-dependent kinase 4 (cdk4)-cyclin D1- and cdk2-cyclin E-directed phosphorylation. Mutation of Ser484 impairs rDNA transcription in vivo and in vitro. " SIGNOR-250754 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 PPP2CA protein P67775 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates dephosphorylation Ser253 APRRRAVsMDNSNKY 9606 20110348 t gcesareni "Protein phosphatase 2a reactivates foxo3a through a dynamic interplay with 14-3-3 and aktpp2a-mediated dephosphorylation of t32/s253 is required for dissociation of 14-3-3, nuclear translocation, and transcriptional activation of foxo3a." SIGNOR-252973 PPP2CA protein P67775 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates dephosphorylation Thr32 QSRPRSCtWPLQRPE 9606 20110348 t gcesareni "Protein phosphatase 2a reactivates foxo3a through a dynamic interplay with 14-3-3 and aktpp2a-mediated dephosphorylation of t32/s253 is required for dissociation of 14-3-3, nuclear translocation, and transcriptional activation of foxo3a." SIGNOR-252974 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 RALA protein P11233 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "up-regulates activity" phosphorylation Thr451 PIPKALGtPVLTPPT 10090 BTO:0000944 11689711 t gcesareni "We conclude that Ral-mediated phosphorylation of threonines 447 and 451 is required for proper activity of AFX-WT." SIGNOR-252984 RALA protein P11233 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "up-regulates activity" phosphorylation Thr455 ALGTPVLtPPTEAAS 10090 BTO:0000944 11689711 t gcesareni "We conclude that Ral-mediated phosphorylation of threonines 447 and 451 is required for proper activity of AFX-WT." SIGNOR-252985 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 TEC protein P42680 UNIPROT BTK protein Q06187 UNIPROT "up-regulates activity" phosphorylation Tyr223 LKKVVALyDYMPMNA 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. Further activation occurs within the SH3 domain via a transphosphorylation mechanism, which for Bruton's tyrosine kinase (Btk) affects tyrosine 223." SIGNOR-246652 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 CBP/p300 complex SIGNOR-C6 SIGNOR KLF1 protein Q13351 UNIPROT "up-regulates activity" acetylation 9606 BTO:0002731 9707565 t Regulation miannu "CBP and p300, but Not P/CAF, Enhance EKLF Trans-activation in Erythroid Cells. We find that EKLF is an acetylated transcription factor, and that it interacts in vivo with CBP, p300, and P/CAF. However, its interactions with these histone acetyltransferases are not equivalent, as CBP and p300, but not P/CAF, utilize EKLF as a substrate for in vitro acetylation within its trans-activation region." SIGNOR-251789 STK4 protein Q13043 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Ser209 SSAGWKNsIRHNLSL 9606 18394876 t gcesareni "Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity." SIGNOR-253001 STK4 protein Q13043 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Ser209 SSAGWKNsIRHNLSL 9606 BTO:0000782 BTO:0001253 22898666 t gcesareni "Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity." SIGNOR-253000 STK4 protein Q13043 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Ser212 SSAGWKNsIRHNLSL 9606 18394876 t gcesareni "Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity. The other major signaling modules that directly regulate the activity of the foxo factors include the stress-activated jun-n-terminal kinase (jnk), the mammalian ortholog of the ste20-like protein kinase (mst1), and the deacetylase sirt1." SIGNOR-252999 STK4 protein Q13043 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Ser212 SSAGWKNsIRHNLSL 9606 BTO:0000782 BTO:0001253 22898666 t gcesareni "Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity. The other major signaling modules that directly regulate the activity of the foxo factors include the stress-activated jun-n-terminal kinase (jnk), the mammalian ortholog of the ste20-like protein kinase (mst1), and the deacetylase sirt1." SIGNOR-252998 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 ZSTK-474 chemical CHEBI:90545 ChEBI PIK3CA protein P42336 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207935 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 BCL11A protein Q9H165 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-251802 CSNK1A1L protein Q8N752 UNIPROT GLIS2 protein Q9BZE0 UNIPROT up-regulates 9606 17289029 f gcesareni "We decided to focus on the interaction between _-catenin and glis2. the critical role of the first zinc finger motif was confirmed by the observation that a point mutation in the first zinc finger motif, that destroys its tetrahedral configuration, abolished the interaction. _-catenin contains several functional domains, the amino terminus interacts with gsk3_ and casein kinase i_ (ck1) binding sites while its 12 armadillo repeats provides an interface for tcf/lefs, the co-activator cbp, and several other proteins" SIGNOR-152962 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 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 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 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 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 "down-regulates activity" phosphorylation Ser8 MPLNRTLsMSSLPGL -1 6263629 t "A reinvestigation of the phosphorylation of Rabbit Skeletal-muscle glycogen synthase by cyclic AMP dependent Protein Kinase: identification of the third site of phosphorylation at Serine-7" SIGNOR-253008 UTS2R protein Q9UKP6 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-257164 SPRY4 protein Q9C004 UNIPROT TESK1 protein Q15569 UNIPROT "down-regulates activity" binding 9606 15584898 t miannu "Spry4 negatively regulates the kinase activity of TESK1 by associating with it through the C-terminal cysteine-rich region of Spry4" SIGNOR-253032 TEK protein Q02763 UNIPROT TEK protein Q02763 UNIPROT "down-regulates activity" phosphorylation Tyr897 GACEHRGyLYLAIEY -1 11080633 t lperfetto "The Tie2 nucleotide binding loop is in an inhibitory conformation, which is not seen in other kinase structures, while its activation loop adopts an activated-like conformation in the absence of phosphorylation. Tyr-897, located in the N-terminal domain, may negatively regulate the activity of Tie2 by preventing dimerization of the kinase domains or by recruiting phosphatases when it is phosphorylated." SIGNOR-246662 HTR1A protein P08908 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-257197 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 CSNK2A1 protein P68400 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-250877 CSNK2A2 protein P19784 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT "up-regulates activity" phosphorylation Ser58 ESETNQNsSSDSEAE -1 11711551 t llicata "We show here that Tcf-4 can be phosphorylated in vitro by protein kinase CK2 stoichiometrically in amino acids Ser-58-Ser-59-Ser-60. Phosphorylation of these residues does not modify the interaction of Tcf-4 with beta-catenin but reduces its association to plakoglobin. | Experiments performed using a Tcf-4 mutant with decreased interaction to plakoglobin demonstrated that binding to this protein negatively affected the transcriptional activity of Tcf-4." SIGNOR-251044 NEDD4L protein Q96PU5 UNIPROT SCN1A protein P35498 UNIPROT "down-regulates quantity by destabilization" ubiquitination 10090 BTO:0000938 23778145 t miannu "The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2)." SIGNOR-253457 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 APOA5 protein Q6Q788 UNIPROT LPL protein P06858 UNIPROT "up-regulates activity" binding 9606 21773006 t Regulation miannu "Apo A5 binds to and enhances the activity of lipoprotein lipase (LPL) enzyme" SIGNOR-251845 APOC3 protein P02656 UNIPROT LPL protein P06858 UNIPROT "down-regulates activity" 9606 17315402 f Regulation miannu "Apolipoprotein CIII inhibits the lipoprotein lipase." SIGNOR-251850 CSNK2A1 protein P68400 UNIPROT WASF2 protein Q9Y6W5 UNIPROT down-regulates phosphorylation Ser484 IAVEYSDsEDDSSEF 9606 19012317 t gcesareni "Here we identify five casein kinase 2 (ck2) phosphorylation sites within the vca domain of wave2, serines 482, 484, 488, 489, and 497. Phosphorylation of these sites is required for a high affinity interaction with the arp2/3 complex;we and show that their mutation to non-phosphorylatable alanine residues inhibits wave2 function in vivo." SIGNOR-182354 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 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 CSNK2A2 protein P19784 UNIPROT PPP1R1B protein Q9UD71 UNIPROT "up-regulates activity" phosphorylation Ser102 NLNENQAsEEEDELG -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-251018 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 PTPN11 protein Q06124 UNIPROT PTK2 protein Q05397 UNIPROT down-regulates dephosphorylation Tyr577 YMEDSTYyKASKGKL 9606 16920701 t gcesareni "Dca concomitantly and significantly increased association of tyrosine phosphatase shp2 with fak. Incubation of immunoprecipitated fak, in vitro, with glutathione-s-transferase-shp2 fusion protein resulted in tyrosine dephosphorylation of fak in a concentration-dependent manner." SIGNOR-148926 P2RY14 protein Q15391 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-257210 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 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 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR SF3B1 protein O75533 UNIPROT up-regulates phosphorylation Thr248 GSETPGAtPGSKIWD 9606 12105215 t lperfetto "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-216666 MAPK14 protein Q16539 UNIPROT DLX5 protein P56178 UNIPROT "up-regulates activity" phosphorylation Ser34 MHHPSQEsPTLPESS 10090 BTO:0000165 18056716 t ggiuliani "We show that Dlx5 is a novel substrate for p38 MAPK in vitro and in vivo and that Ser-34 and Ser-217 are the sites phosphorylated by p38" SIGNOR-255792 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 F2R protein P25116 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-257219 AKT3 protein Q9Y243 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-249644 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-249645 CTDSPL protein O15194 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-248311 PI3K complex SIGNOR-C156 SIGNOR 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-252704 PI3K complex SIGNOR-C156 SIGNOR 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-252711 PI3K complex SIGNOR-C156 SIGNOR 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-252721 PIK3CA protein P42336 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9534 BTO:0004055 14665640 f 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-242649 SGK1 protein O00141 UNIPROT FOXO1 protein Q12778 UNIPROT "down-regulates activity" phosphorylation Thr24 LPRPRSCtWPLPRPE 10090 BTO:0000011 19965929 t "We demonstrate that SGK1 affects differentiation by direct phosphorylation of Foxo1, thereby changing its cellular localization from the nucleus to the cytosol. In addition we show that SGK1-/- cells are unable to relocalize Foxo1 to the cytosol in response to dexamethasone." SIGNOR-255925 SRC protein P12931 UNIPROT ENO1 protein P06733 UNIPROT up-regulates phosphorylation Tyr44 SGASTGIyEALELRD 9606 BTO:0000887 7629021 t lperfetto "The present finding suggested that the tyrosine residue at position 44 in chicken alpha-enolase is the phosphorylation site by the tyrosine kinase. Our data suggest that eno1 was upregulated by caga protein through activating the src and mek/erk signal pathways" SIGNOR-30126 OXGR1 protein Q96P68 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-257243 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 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 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR KAT5 protein Q92993 UNIPROT "up-regulates activity" phosphorylation Ser90 LPGSRPGsPEREVPA 9606 BTO:0000567 12468530 t llicata "Baculovirus-based expression and purification of Tip60 combined with mass spectrometry allowed the identification of serines 86 and 90 as two major sites of phosphorylation in vivo. The phosphorylation of Tip60 was found to modulate its histone acetyltransferase activity. One of the identified phosphorylated serines, Ser-90, was within a consensus cyclin B/Cdc2 site. Ser-90 was specifically phosphorylatedin vitro by the cyclin B/Cdc2 complex." SIGNOR-250642 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR KMT5A protein Q9NQR1 UNIPROT down-regulates phosphorylation Ser100 SKIYSYMsPNKCSGM 9606 20966048 t lperfetto "First, we found that pr-set7 is phosphorylated at ser 29 (s29) specifically by the cyclin-dependent kinase 1 (cdk1)/cyclinb complex, s29 phosphorylation also functions to stabilize pr-set7 by directly inhibiting its interaction with the anaphase-promoting complex (apc), an e3 ubiquitin ligase." SIGNOR-216856 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MAPK6 protein Q16659 UNIPROT up-regulates phosphorylation 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. 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-216797 DTX1 protein Q86Y01 UNIPROT NOTCH1 protein P46531 UNIPROT "up-regulates activity" ubiquitination 7227 22162134 t lperfetto "The expression of dx, which physically interacts with notch, favors a mono-ubiquitinated state of the receptor, which leads to a ligand-independent intracellular activation of notch" SIGNOR-219269 NMBR protein P28336 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-257248 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MYOD1 protein P15172 UNIPROT down-regulates phosphorylation Ser5 sPPLRDVD 9606 BTO:0000222 14749395 t lperfetto "Myod is phosphorylated on ser5 and ser200 by cyclin b-cdc2, resulting in a decrease of its stability and down-regulation of both myod and p21." SIGNOR-216924 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 P2RY11 protein Q96G91 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-257261 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 S1PR3 protein Q99500 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-257263 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 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR PLEC protein Q15149 UNIPROT down-regulates phosphorylation Thr4539 GGLIEPDtPGRVPLD 9606 BTO:0000567 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-216908 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR RANGAP1 protein P46060 UNIPROT up-regulates phosphorylation Ser428 EPAPVLSsPPPADVS 9606 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-216781 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser397 SMVGGERsPPRILPP 9606 BTO:0000007 21059642 t "The effect has been demonstrated using Q01196-8" lperfetto "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-216912 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR TP73 protein O15350 UNIPROT down-regulates phosphorylation Thr86 AASASPYtPEHAASV 9606 12676926 t lperfetto "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-216849 WNT10B protein O00744 UNIPROT FZD1 protein Q9UP38 UNIPROT "up-regulates activity" binding 9606 19008118 t FFerrentino "In mesenchymal precursor cells, Wnt10b (and Wnt10a) binding to frizzled (FZD1)" SIGNOR-253511 CYSLTR1 protein Q9Y271 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-257225 DAB2IP protein Q5VWQ8 UNIPROT HRAS protein P01112 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 27858941 t miannu "The GAP domain of DAB2IP is homologous to other Ras-GAPs, such as GAP120 and neurofibromin (NF1), and can stimulate the GTPase activity of RAS proteins both in vitro and in cancer cell lines. DAB2IP is able to stimulate in vitro and in vivo the GTPase activity of RAS proteins (H-Ras, K-Ras, and N-Ras) facilitating GTP hydrolysis to GDP." SIGNOR-254745 DAB2IP protein Q5VWQ8 UNIPROT KRAS protein P01116 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 27858941 t miannu "The GAP domain of DAB2IP is homologous to other Ras-GAPs, such as GAP120 and neurofibromin (NF1), and can stimulate the GTPase activity of RAS proteins both in vitro and in cancer cell lines. DAB2IP is able to stimulate in vitro and in vivo the GTPase activity of RAS proteins (H-Ras, K-Ras, and N-Ras) facilitating GTP hydrolysis to GDP." SIGNOR-254746 "SB 505124" chemical CHEBI:100922 ChEBI ACVR1B protein P36896 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206736 CYSLTR1 protein Q9Y271 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-257019 CYSLTR2 protein Q9NS75 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-257024 DAB2IP protein Q5VWQ8 UNIPROT MAP3K5 protein Q99683 UNIPROT "up-regulates activity" binding 9606 27858941 t miannu "DAB2IP also mediates recruitment of PP2A to ASK1, binding both proteins through its C2 domain; this favors removal of the inhibitory S967 phosphorylation and further activation of ASK1" SIGNOR-254748 DAB2IP protein Q5VWQ8 UNIPROT NRAS protein P01111 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 27858941 t miannu "The GAP domain of DAB2IP is homologous to other Ras-GAPs, such as GAP120 and neurofibromin (NF1), and can stimulate the GTPase activity of RAS proteins both in vitro and in cancer cell lines. DAB2IP is able to stimulate in vitro and in vivo the GTPase activity of RAS proteins (H-Ras, K-Ras, and N-Ras) facilitating GTP hydrolysis to GDP." SIGNOR-254747 DAB2IP protein Q5VWQ8 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR down-regulates 9606 27858941 f miannu "DAB2IP inactivation promotes tumor growth and survival, development, and proliferation of CSC, and resistance to chemo- and radiotherapy. It induces EMT, increases cell migration and invasion, and counteracts pro-apoptotic signaling." SIGNOR-254779 DAMPS stimulus SIGNOR-ST18 SIGNOR MEFV protein O15553 UNIPROT "up-regulates activity" 16037825 f lperfetto "Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage" SIGNOR-256422 DAMPS stimulus SIGNOR-ST18 SIGNOR NAIP protein Q13075 UNIPROT "up-regulates activity" 16037825 f lperfetto "Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage" SIGNOR-256420 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 PRKD1 protein Q15139 UNIPROT OSBP protein P22059 UNIPROT down-regulates phosphorylation Ser240 TALQRSLsELESLKL 9606 21285358 t gcesareni "Pkd attenuates the function of both cert and osbp by phosphorylation at their respective ser(132) and ser(240) residues (phosphorylation inhibition)" SIGNOR-171756 OXGR1 protein Q96P68 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-257310 AGO2 protein Q9UKV8 UNIPROT DICER1/hAgo2/PRKRA complex SIGNOR-C41 SIGNOR "form complex" binding 9606 23661684 t miannu SIGNOR-143102 DBP protein Q10586 UNIPROT CYP3A4 protein P08684 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 18004209 f miannu "The oscillation in the expression of the CYP3A4 gene seemed to be the underlying cause of the rhythmic change in its metabolic activity. Luciferase reporter gene analysis and electrophoretic mobility shift assay revealed that the circadian transcriptional factor, D-site-binding protein (DBP), activated the transcription of the CYP3A4 gene by binding to the DNA sequence near the upstream of the transcriptional start site. The transactivation of the CYP3A4 gene by DBP was repressed by the E4 promoter-binding protein-4 (E4BP4), a negative component of the circadian clock." SIGNOR-253835 DDB2 protein Q92466 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates binding 9606 BTO:0000567 9418871 t miannu "We show that ddb, a putative dna repair protein, associates with the activation domain of e2f1 / expression of ddb specifically stimulated e2f1-activated transcription" SIGNOR-54102 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 "SB 505124" chemical CHEBI:100922 ChEBI ACVR1C protein Q8NER5 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206739 Diacylglycerol smallmolecule CID:6026790 PUBCHEM 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 Diacylglycerol smallmolecule CID:6026790 PUBCHEM PRKCB protein P05771 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-242584 Diacylglycerol smallmolecule CID:6026790 PUBCHEM PRKCD protein Q05655 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-242587 Diacylglycerol smallmolecule CID:6026790 PUBCHEM 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 Diacylglycerol smallmolecule CID:6026790 PUBCHEM 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 PKN1 protein Q16512 UNIPROT PKN1 protein Q16512 UNIPROT "up-regulates activity" phosphorylation Thr64 ENLRRATtDLGRSLG -1 10467162 t lperfetto "Autophosphorylation of wild-type PKN increased the protein kinase activity, however, substitution of Thr64, Ser374, or Thr531 in the regulatory region of PKN with alanine, abolished this effect." SIGNOR-249019 PPP2CA protein P67775 UNIPROT EEF2 protein P13639 UNIPROT up-regulates dephosphorylation Thr57 RAGETRFtDTRKDEQ 9606 phosphorylation:Thr57 RAGETRFtDTRKDEQ 8386634 t gcesareni "Protein phosphatases-2a and -2c (pp-2a and pp-2c) can each efficiently dephosphorylate phosphorylated eef-2" SIGNOR-38561 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 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 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 22298955 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-195573 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 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 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 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 UTS2R protein Q9UKP6 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-257319 DNMT3A protein Q9Y6K1 UNIPROT TIMP2 protein P16035 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9606 BTO:0002126 19786833 f 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-255807 CRH protein P06850 UNIPROT KRT14 protein P02533 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000667 15468147 t Regulation miannu "CRH stimulated the expression of cytokeratin 1 and involucrin, and inhibited cytokeratin 14 on both mRNA and protein levels." SIGNOR-251899 DNMT3A protein Q9Y6K1 UNIPROT CDKN2A protein P42771 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9606 19786833 f 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-255809 DNMT3B protein Q9UBC3 UNIPROT BAG1 protein Q99933 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001109 18413740 f lperfetto "DNA methyltransferase 1 and 3B activate BAG-1 expression via recruitment of CTCFL/BORIS and modulation of promoter histone methylation" SIGNOR-254109 DNMT3B protein Q9UBC3 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-254111 DNMT3B protein Q9UBC3 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-254113 MAML1 protein Q92585 UNIPROT NOTCH1 protein P46531 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12370315 f gcesareni "It has been shown that maml1 binds directly to the ankyrin repeat region of notch1 and forms a dna-binding complex with icn and csl" SIGNOR-94029 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 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 PKN1 protein Q16512 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser163 KRFSFKKsFKLSGFS 9534 BTO:0000298 8557118 t lperfetto "PRK1 phosphorylates MARCKS at the PKC sites: serine 152, serine 156 and serine 163." SIGNOR-248938 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 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 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 GATA6 protein Q92908 UNIPROT RARB protein P10826 UNIPROT "up-regulates quantity by expression" 9606 BTO:0000195 24317510 f lperfetto "Many GATA6-dependent genes lacked nearby binding sites but several strongly dependent, synexpressed and GATA6-bound genes encode TFs such as MYC, HES1, RARB and CDX2." SIGNOR-253154 Laminin-10 complex SIGNOR-C182 SIGNOR Laminin-10 complex SIGNOR-C182 SIGNOR "up-regulates activity" binding 10090 BTO:0001086 18757303 t lperfetto "Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1." SIGNOR-253277 PKN1 protein Q16512 UNIPROT PKN1 protein Q16512 UNIPROT "up-regulates activity" phosphorylation Ser374 GLYSRSGsLSGRSSL -1 10467162 t lperfetto "Autophosphorylation of wild-type PKN increased the protein kinase activity, however, substitution of Thr64, Ser374, or Thr531 in the regulatory region of PKN with alanine, abolished this effect." SIGNOR-249021 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 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 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 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 TGFBR1 protein P36897 UNIPROT "up-regulates activity" phosphorylation Thr200 LPLLVQRtIARTIVL -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-255962 DRD5 protein P21918 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-257156 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 DYRK1A protein Q13627 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Ser329 STISGRLsPIMTEQD 9606 BTO:0000887;BTO:0001103 11311120 t lperfetto "The kinase dyrk1a phosphorylates the transcription factor fkhr at ser329 in vitro, a novel in vivo phosphorylation siteser(329) phosphorylation also decreases the ability of fkhr to stimulate gene transactivation and reduces the proportion of fkhr present in the nucleus" SIGNOR-252909 DYRK1A protein Q13627 UNIPROT SPRY2 protein O43597 UNIPROT down-regulates phosphorylation Thr75 KPAPRPStQHKHERL 9606 BTO:0000142 18678649 t gcesareni "We identify dyrk1a as one of the protein kinases of sprouty2. We show that dyrk1a interacts with and regulates the phosphorylation status of sprouty2. Moreover, we identify thr75 on sprouty2 as a dyrk1a phosphorylation site in vitro and in vivo." SIGNOR-179828 DYRK1B protein Q9Y463 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates phosphorylation Ser153 SMTDFYHsKRRLIFS 10090 BTO:0000165;BTO:0000222;BTO:0001946 BTO:0000887;BTO:0001760 15851482 t lperfetto "Mirk exerts its anti-apoptotic effects during muscle differentiation at least in part through effects on the cell cycle inhibitor and pro-survival molecule p21cip1. Overexpression and rna interference experiments demonstrated that mirk phosphorylates p21 within its nuclear localization domain at ser-153 causing a portion of the typically nuclear p21 to localize in the cytoplasm.Translocation to the cytoplasm enables p21 to block apoptosis through inhibitory interaction with pro-apoptotic molecules." SIGNOR-235635 DYRK1B protein Q9Y463 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser279 KVAERRSsPLLRRKD 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103 15546868 t lperfetto "Mirk activated mef2 not through direct phosphorylation of mef2 but by phosphorylation of its inhibitors, the class ii histone deacetylases (hdacs). Mef2 is sequestered by class ii hdacs such as hdac5 and mef2-interacting transcriptional repressor (mitr). Mirk antagonized the inhibition of mef2c by mitr, whereas kinase-inactive mirk was ineffective. Mirk phosphorylates class ii hdacs at a conserved site within the nuclear localization region, reducing their nuclear accumulation in a dose-dependent and kinase-dependent mannermirk phosphorylates hdac5 at ser-279" SIGNOR-235809 DYRK1B protein Q9Y463 UNIPROT HDAC9 protein Q9UKV0 UNIPROT down-regulates phosphorylation Ser240 KVAERRSsPLLRRKD 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103 15546868 t lperfetto "Mirk activated mef2 not through direct phosphorylation of mef2 but by phosphorylation of its inhibitors, the class ii histone deacetylases (hdacs). Mef2 is sequestered by class ii hdacs such as hdac5 and mef2-interacting transcriptional repressor (mitr). Mirk antagonized the inhibition of mef2c by mitr, whereas kinase-inactive mirk was ineffective. Mirk phosphorylates class ii hdacs at a conserved site within the nuclear localization region, reducing their nuclear accumulation in a dose-dependent and kinase-dependent manner" SIGNOR-235813 DYRK1B protein Q9Y463 UNIPROT HNF1A protein P20823 UNIPROT up-regulates phosphorylation Ser249 IQRGVSPsQAQGLGS 9606 BTO:0000887;BTO:0001103 11980910 t lperfetto "Mirk phosphorylates hnf1 at amino acid 249mkk3 enhanced mirk kinase activity and the transcriptional activation of hnf1alpha by mirk" SIGNOR-86728 gefitinib chemical CHEBI:49668 ChEBI EGFR protein P00533 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192623 IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser32 LLDDRHDsGLDSMKD 9606 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-216385 UTS2R protein Q9UKP6 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-257377 E2F1 protein Q01094 UNIPROT CCNE1 protein P24864 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000972 14618416 f miannu "To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells." SIGNOR-253854 E2F1 protein Q01094 UNIPROT HSPA5 protein P11021 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 18840615 f miannu "we show that E2F1 represses GRP78/BIP at the transcriptional level, and this requires its DNA binding domain." SIGNOR-253845 E2F1 protein Q01094 UNIPROT LRBA protein P50851 UNIPROT "up-regulates quantity by expression" "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-253846 NMUR2 protein Q9GZQ4 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-257402 E2F1 protein Q01094 UNIPROT MCPH1 protein Q8NEM0 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22136275 f miannu "Overexpression of E2F1 led to the upregulation of MCPH1 transcription, and knocking down the endogenous E2F1 resulted in the inhibition of the MCPH1 promoter activity." SIGNOR-253848 E2F1 protein Q01094 UNIPROT MYBL2 protein P10244 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000972 14618416 f miannu "To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells." SIGNOR-253855 E2F1 protein Q01094 UNIPROT NOX4 protein Q9NPH5 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0002195 18554521 f lperfetto "Positive regulation of the NADPH oxidase NOX4 promoter in vascular smooth muscle cells by E2F" SIGNOR-254134 E2F1 protein Q01094 UNIPROT PCNA protein P12004 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000972 14618416 f miannu "To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells." SIGNOR-253856 E2F1 protein Q01094 UNIPROT RASGEF1B protein Q0VAM2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18396012 f miannu "We demonstrate that E2F1 induces ERK activation via a transcriptional mechanism and upregulates the expression of two guanine nucleotide exchange factors, RASGRP1 and RASGEF1B, which promote Ras activation." SIGNOR-253851 E2F1 protein Q01094 UNIPROT RASGRP1 protein O95267 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18396012 f miannu "We demonstrate that E2F1 induces ERK activation via a transcriptional mechanism and upregulates the expression of two guanine nucleotide exchange factors, RASGRP1 and RASGEF1B, which promote Ras activation." SIGNOR-253850 E2F1 protein Q01094 UNIPROT SERPINB5 protein P36952 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001938 20197383 f lperfetto "Importantly, we show that E2F1-mediated upregulation of maspin is enhanced by chemotherapeutic drugs, and inhibition of maspin expression significantly impairs the ability of E2F1 to promote chemotherapy-induced apoptosis. Summarily, our data indicate that maspin is an important effector of E2F1-induced chemosensitization." SIGNOR-254135 E2F1 protein Q01094 UNIPROT TLR3 protein O15455 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0002572 22310660 f lperfetto "Together, these data indicated that E2F1 suppresses TLR3 transcription, but during immune stimulation, Rb is upregulated to block the inhibitory effect of E2F1 on TLR3, highlighting a role of Rb-E2F1 axis in the innate immune response in epithelial cells." SIGNOR-254136 E2F1 protein Q01094 UNIPROT TYMS protein P04818 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000972 14618416 f miannu "To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells." SIGNOR-253863 EGFR protein P00533 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates phosphorylation Tyr771 IGTAEPDyGALYEGR 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-20984 IKK-complex complex SIGNOR-C14 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 BTO:0000150 15084260 t lperfetto "Ikappab kinase promotes tumorigenesis through inhibition of forkhead foxo3a. The tnf treatment of ht-29 cells increased ikk-dependent foxo3 ser644 phosphorylation." SIGNOR-216407 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 F2RL1 protein P55085 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-257408 F2RL3 protein Q96RI0 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-257419 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1178 IMSKHLDsPPAIPPR 9606 20724475 t lperfetto "ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process." SIGNOR-244743 GNAO1 protein P09471 UNIPROT ADCY1 protein Q08828 UNIPROT down-regulates binding 9606 17419683 t gcesareni "Members of the gi family are linked with reductions in camp through adenylyl cyclase, but have many other actions as well" SIGNOR-153467 JAK3 protein P52333 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-256254 PPARGC1A protein Q9UBK2 UNIPROT GPX1 protein P07203 UNIPROT up-regulates 10090 18074631 f lperfetto "In fact, experiments with either genetic knockouts or RNAi for the PGC1s show that the ability of ROS to induce a ROS scavenging programme depends entirely on the PGC1s. This includes genes encoding mitochondrial proteins like SOD2, but also includes cytoplasmic proteins such as catalase and GPX1. Cells lacking PGC1alpha are hypersensitive to death from oxidative stress caused by H2O2 or paraquat." SIGNOR-253396 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 ROS stimulus SIGNOR-ST2 SIGNOR PPARGC1A protein Q9UBK2 UNIPROT up-regulates 10090 18074631 f lperfetto "In fact, experiments with either genetic knockouts or RNAi for the PGC1s show that the ability of ROS to induce a ROS scavenging programme depends entirely on the PGC1s. This includes genes encoding mitochondrial proteins like SOD2, but also includes cytoplasmic proteins such as catalase and GPX1. Cells lacking PGC1alpha are hypersensitive to death from oxidative stress caused by H2O2 or paraquat." SIGNOR-253397 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 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 adenosine smallmolecule CHEBI:16335 ChEBI ADORA2A protein P29274 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-257447 RAC1 protein P63000 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 21712438 f gcesareni "Hypertonicity activates p38 via a rac1-osm-mekk3-mkk3-p38 pathway." SIGNOR-174602 "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 PTAFR protein P25105 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-257436 AMPK complex SIGNOR-C15 SIGNOR KLC2 protein Q9H0B6 UNIPROT up-regulates phosphorylation Ser582 PRMKRASsLNFLNKS 9606 21725060 t lperfetto "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-216468 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 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 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 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 EFNA5 protein P52803 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-52476 EFNB1 protein P98172 UNIPROT EPHB3 protein P54753 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-52517 EFNB1 protein P98172 UNIPROT EPHB4 protein P54760 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-52580 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 PPARGC1A protein Q9UBK2 UNIPROT OTC protein P00480 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 16891307 f miannu "Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate." SIGNOR-255056 PPARGC1A protein Q9UBK2 UNIPROT PCK2 protein Q16822 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 16891307 f miannu "Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate." SIGNOR-255060 "Ile(5)-angiotensin II" smallmolecule CHEBI:2719 ChEBI AGTR1 protein P30556 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-257459 L-isoprenaline chemical CHEBI:6257 ChEBI ADRB2 protein P07550 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-257457 EGR3 protein Q06889 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-253882 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 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 EIF2S1 protein P05198 UNIPROT HBG1 protein P69891 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24714526 f miannu "Reduction of globin inclusions and induction of ATF4 and HbF by the HRI-eIF2αP signaling provide strong bases for targeting this pathway for novel pharmaceutical therapy of hemoglobinopathy." SIGNOR-251819 EIF2S1 protein P05198 UNIPROT HBG2 protein P69892 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24714526 f miannu "Reduction of globin inclusions and induction of ATF4 and HbF by the HRI-eIF2αP signaling provide strong bases for targeting this pathway for novel pharmaceutical therapy of hemoglobinopathy." SIGNOR-251818 ELANE protein P08246 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-256510 ERBB4 protein Q15303 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 16829981 t gcesareni "Egfr and erbb4 had several docking sites for grb2, while erbb3 was characterized by six binding sites for pi3k. Egfr has six binding sites for the adapter protein grb2, and erbb4 has five, each with different binding strength." SIGNOR-147847 ERCC1 protein P07992 UNIPROT ERCC4/ERCC1 complex SIGNOR-C50 SIGNOR "form complex" binding 9606 16338413 t miannu "Human ercc1/xpf interaction domains reveals a complementary role for the two proteins in nucleotide excision repair." SIGNOR-142989 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 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 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 CUDC-907 chemical CID:54575456 PUBCHEM HDAC1 protein Q13547 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191157 EP300 protein Q09472 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-253904 EP300 protein Q09472 UNIPROT RELA protein Q04206 UNIPROT up-regulates acetylation 9606 SIGNOR-C6 16382138 t gcesareni "Rela is also acetylated at several sites by p300 and cbp" SIGNOR-143399 PTPN11 protein Q06124 UNIPROT KRAS protein P01116 UNIPROT "up-regulates activity" dephosphorylation Tyr32 QNHFVDEyDPTIEDS 9606 BTO:0000007 26617336 t irozzo "Here we identify SHP2 as the ubiquitously expressed tyrosine phosphatase that preferentially binds to and dephosphorylates Ras to increase its association with Raf and activate downstream proliferative Ras/ERK/MAPK signalling." SIGNOR-255982 "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 "propionic acid" chemical CHEBI:30768 ChEBI FFAR3 protein O14843 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-257490 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 EP300 protein Q09472 UNIPROT SMAD7 protein O15105 UNIPROT up-regulates acetylation Lys64 RAGCCLGkAVRGAKG 9606 15831498 t gcesareni "Here we present evidence that smad7 interacts with the transcriptional coactivator p300, resulting in acetylation of smad7 on two lysine residues in its n terminus. Acetylation or mutation of these lysine residues stabilizes smad7 and protects it from tgfbeta-induced degradation. we have recently shown that smad7 is acetylated on lysine residues 64 and 70 by p300" SIGNOR-135469 EP300 protein Q09472 UNIPROT TBXAS1 protein P24557 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000018 14565864 f miannu "We also showed that forced expression of p300 upregulated TXAS gene in a dose-dependent manner. Mutation of NF-E2 site, but not TATA or initiator site, abolished the p300-mediated activation of TXAS gene." SIGNOR-253906 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 ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates phosphorylation Tyr1023 DLVDAEEyLVPQQGF 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-21207 ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT "up-regulates activity" phosphorylation Tyr1222 PAFDNLYyWDQDPPE -1 1706616 t " Y1023 and Y1248, Y1139 and Y1222 also serve as autophosphorylation sites of HER2." SIGNOR-251130 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 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 ERBB4 protein Q15303 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 9606 18793634 t gcesareni "Erbb4 might not be able to directly recruit cbl, and therefore downregulation of this receptor is slow." SIGNOR-180895 ERBB4 protein Q15303 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 16729043 t gcesareni "Egfr and erbb4 had several docking sites for grb2, while erbb3 was characterized by six binding sites for pi3k. Egfr has six binding sites for the adapter protein grb2, and erbb4 has five, each with different binding strength." SIGNOR-146876 TRIM27 protein P14373 UNIPROT WASHC1 protein A8K0Z3 UNIPROT "up-regulates activity" ubiquitination Lys220 DAPLSISkREQLEQQ 9606 23452853 t miannu "Our mechanistic studies uncovered that K63-linked ubiquitination of WASH K220 by MAGE-L2-TRIM27 is required for endosomal F-actin nucleation and retrograde transport. These results suggest that K63-linked ubiquitination of WASH K220 by TRIM27 is required for WASH function in retrograde transport." SIGNOR-253514 leuprolide chemical CHEBI:6427 ChEBI GNRHR protein P30968 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-257499 AKT proteinfamily SIGNOR-PF24 SIGNOR 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 of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation" SIGNOR-252350 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT "down-regulates activity" 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-252348 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT "down-regulates activity" 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-252352 AKT proteinfamily SIGNOR-PF24 SIGNOR 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. These results indicate that phosphorylation by PKB/Akt negatively regulates FKHR1 by promoting export from the nucleus." SIGNOR-252346 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-252347 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-252351 AKT proteinfamily SIGNOR-PF24 SIGNOR GATA2 protein P23769 UNIPROT "down-regulates activity" phosphorylation Ser401 QTRNRKMsNKSKKSK 9606 BTO:0000876 15837948 t "PI-3K/Akt-dependent manner." lperfetto "We show that insulin induces gata2 phosphorylation on serine 401 in a pi-3k/akt-dependent manner. Insulin-dependent phosphorylation of serine 401 impairs gata2 translocation to the nucleus and its dna binding activity" SIGNOR-244271 AKT proteinfamily SIGNOR-PF24 SIGNOR GSK3B protein P49841 UNIPROT "down-regulates activity" phosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000007 9373175 t gcesareni "Evidence that the inhibition of glycogen synthase kinase-3_ by IGF-1 is mediated by PDK1/PKB-induced phosphorylation of Ser-9" SIGNOR-242578 AKT proteinfamily SIGNOR-PF24 SIGNOR TERT protein O14746 UNIPROT up-regulates phosphorylation Ser824 AVRIRGKsYVQCQGI 9606 BTO:0000848 10224060 t lperfetto "Akt kinase enhances human telomerase activity through phosphorylation of htert subunit as one of its substrate proteins." SIGNOR-244357 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-244369 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 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 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 AKT proteinfamily SIGNOR-PF24 SIGNOR RAC1 protein P63000 UNIPROT "down-regulates activity" phosphorylation Ser71 YDRLRPLsYPQTDVF 9606 BTO:0003476 10617634 t gcesareni "The results suggest that Akt kinase of the phosphoinositide 3-kinase signal transduction pathway phosphorylates serine 71 of Rac1 as one of its authentic substrates and modulates the Rac1 signal transduction pathway through phosphorylation." SIGNOR-248036 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-143721 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-251487 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-244365 AKT proteinfamily SIGNOR-PF24 SIGNOR TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation Ser42 GGRKRRSsRRSAGGG 9606 20400976 t lperfetto "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-244373 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-145292 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-244377 AMPK complex SIGNOR-C15 SIGNOR HNF4A protein P41235 UNIPROT down-regulates phosphorylation Ser303 DPDAKGLsDPGKIKR 9606 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-216511 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 CXCR4 protein P61073 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-253911 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 "PAS complex" complex SIGNOR-C190 SIGNOR Multivesicular_body_assembly phenotype SIGNOR-PH83 SIGNOR up-regulates 9606 BTO:0000007 17556371 f miannu "Sac3 assembles with PIKfyve and ArPIKfyve in a stable ternary complex and controls PtdIns(3,5)P2 levels. We further demonstrate a key function for each of the three proteins in the biogenesis of ECV/MVB transport intermediates from early endosomes." SIGNOR-253532 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 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR4 protein Q13639 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-257524 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 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 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 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 CREB1 protein P16220 UNIPROT "up-regulates activity" phosphorylation Ser133 EILSRRPsYRKILND 9606 BTO:0000007 9829964 t gcesareni "When overexpressed in serum-stimulated cells, Akt/PKB potently induced Ser-133 phosphorylation of CREB and promoted recruitment of CBP. Correspondingly, Akt/PKB stimulated target gene expression via CREB in a phospho(Ser-133)-dependent manner." SIGNOR-252549 AKT proteinfamily SIGNOR-PF24 SIGNOR YWHAZ protein P63104 UNIPROT unknown phosphorylation Ser58 VVGARRSsWRVVSSI 9606 BTO:0000007 11956222 t lperfetto "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-244381 AMPK complex SIGNOR-C15 SIGNOR GLI1 protein P08151 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser102 LQTVIRTsPSSLVAF 26190112 t "Activation of AMPK reduces GLI1 protein levels and stability, thus blocking Sonic-hedgehog-induced transcriptional activity. AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency." SIGNOR-253542 EIF4A2 protein Q14240 UNIPROT EIF4A2/EIF4E/EIF4G1 complex SIGNOR-C44 SIGNOR "form complex" binding 9606 BTO:0000671 11408474 t miannu "Eif4a interacts with a scaffold protein, eif4g, to form complexes that also contain the cap-binding protein eif4e, which binds the cap structure (m7gpppn_) at the 5_-end of the mrna. These complexes are termed eif4f." SIGNOR-108512 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Thr331 CTPVVTCtPSCTAYT 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-252353 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 protein P19419 UNIPROT up-regulates phosphorylation 9606 7618106 t lperfetto "The tcf protein elk-1 is phosphorylated by the jnk and erk groups of mitogen-activated protein (map) kinases causing increased dna binding, ternary complex formation, and transcriptional activation" SIGNOR-252081 FBXW7 protein Q969H0 UNIPROT GATA2 protein P23769 UNIPROT "down-regulates quantity by destabilization" ubiquitination Thr176 HLFGFPPtPPKEVSP 9606 BTO:0000007 25670854 t irozzo "Here, we demonstrate that F-box/WD repeat-containing protein 7 (Fbw7/Fbxw7), a component of Skp1, Cullin 1, F-box-containing complex (SCF)-type E3 ligase, is an E3 ligase for GATA2. GATA2 contains a cell division control protein 4 (Cdc4) phosphodegron (CPD), a consensus motif for ubiquitylation by Fbw7, which includes Thr(176). Ectopic expression of Fbw7 destabilized GATA2 and promoted its proteasomal degradation." SIGNOR-256005 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 SUFU protein Q9UMX1 UNIPROT up-regulates 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-200496 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 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 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Macrophage_differentiation phenotype SIGNOR-PH99 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 24890514 f apalma "The Erk1/2 pathway has a central role in CSF-1R-regulated myeloid differentiation. CSF-1 induces early (peaking at ‚àº5 min) and persistent (starting at 1 h) waves of MEK/Erk1/2 phosphorylation" SIGNOR-255573 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MKNK1 protein Q9BUB5 UNIPROT "up-regulates activity" phosphorylation Thr350 NSCTPITtPELTTPC 9606 BTO:0000093 17130135 t "We generated a phosphospecific antibody to Thr(P)-214 in the T-loop of MNKs and found that phosphorylations of both Thr-209 and Thr-214 in human MNK1 are required for activation" SIGNOR-253014 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MKNK1 protein Q9BUB5 UNIPROT "up-regulates activity" phosphorylation Thr355 ITTPELTtPCGSAEY 9606 BTO:0000093 17130135 t "We generated a phosphospecific antibody to Thr(P)-214 in the T-loop of MNKs and found that phosphorylations of both Thr-209 and Thr-214 in human MNK1 are required for activation" SIGNOR-253015 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 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24743741 f "Activation of PDGFRα stimulates proliferation of PDGFRα(+) cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFRα(+) cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases." SIGNOR-254374 GRK1 protein Q15835 UNIPROT RHO protein P08100 UNIPROT "up-regulates activity" phosphorylation Ser338 DEASATVsKTETSQV -1 8617805 t "That light-dependent phosphorylation of Rho is mediated primarily by RK. Addition of an inhibitory antibody against rhodopsin kinase (RK) lowered phosphorylation at Ser334, Ser338, and Ser343, without changing the ratio between phosphorylation sites. upon illumination, Ser334c, Ser338, and Ser343 are phosphorylated." SIGNOR-251190 NEDD4L protein Q96PU5 UNIPROT SCN4A protein P35499 UNIPROT "down-regulates quantity by destabilization" ubiquitination 10090 BTO:0000938 23778145 t miannu "The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2)." SIGNOR-253460 NEDD4L protein Q96PU5 UNIPROT SCN5A protein Q14524 UNIPROT "down-regulates quantity by destabilization" ubiquitination 10090 BTO:0000938 23778145 t miannu "The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2)." SIGNOR-253456 NEDD4L protein Q96PU5 UNIPROT SCN8A protein Q9UQD0 UNIPROT "down-regulates quantity by destabilization" ubiquitination 10090 BTO:0000938 23778145 t miannu "The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2)." SIGNOR-253461 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 PTPRF protein P10586 UNIPROT PLCG1 protein P19174 UNIPROT down-regulates dephosphorylation 9606 11121408 t gcesareni "Here we show that lar reduces the constitutive tyrosine autophosphorylation and kinase activity of ret-men2a but not ret-men2b, accompanying a significant decrease of phosphorylation of phospholipase cgamma, akt, and erk1/2." SIGNOR-85166 SIAH1 protein Q8IUQ4 UNIPROT SNCAIP protein Q9Y6H5 UNIPROT down-regulates ubiquitination 9606 BTO:0000938 16174773 t lperfetto "Siah proteins ubiquitylate synphilin-1 and promote its degradation through the ubiquitin proteasome system" SIGNOR-140612 TET2 protein Q6N021 UNIPROT OGT protein O15294 UNIPROT up-regulates binding 9606 23353889 t miannu "Tet2 and tet3 associate with the o_glcnac transferase ogt / tet2 and tet3 promote ogt_mediated glcnacylation" SIGNOR-200695 UBE2N protein P61088 UNIPROT H2AFX protein P16104 UNIPROT up-regulates ubiquitination 9606 18077395 t gcesareni "In an h2ax- and mdc1-dependent manner , rnf8/ubc13 complexes go to sites of dna damage through their fha domain and initiate the synthesis of k63 polyubiquitin chains on chromatin that recruit the brca1 a complex through the uim domains of rap80." SIGNOR-159880 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 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR 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-244569 FOXO3 protein O43524 UNIPROT Cell_cycle_block phenotype SIGNOR-PH10 SIGNOR up-regulates 9606 BTO:0000007 14976264 f lperfetto "Sirt1 increased foxo3's ability to induce cell cycle arrest and resistance to oxidative stress" SIGNOR-217881 NEDD4L protein Q96PU5 UNIPROT SCN9A protein Q15858 UNIPROT "down-regulates quantity by destabilization" ubiquitination 10090 BTO:0000938 23778145 t miannu "The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2)." SIGNOR-253458 PP2Ca_R1A_Ba complex SIGNOR-C132 SIGNOR AKT1 protein P31749 UNIPROT "down-regulates activity" dephosphorylation Thr308 KDGATMKtFCGTPEY 10090 BTO:0000944 18042541 t gcesareni "Regulation of phosphorylation of Thr-308 of Akt, cell proliferation, and survival by the B55alpha regulatory subunit targeting of the protein phosphatase 2A holoenzyme to Akt.|Phosphorylation of Akt at regulatory residues Thr-308 and Ser-473 leads to its full activation. The protein phosphatase 2A (PP2A) has long been known to negatively regulate Akt activity. The PP2A holoenzyme consists of the structural subunit (A), catalytic subunit (C), and a variable regulatory subunit (B)." SIGNOR-252613 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 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR Quiescence phenotype SIGNOR-PH25 SIGNOR up-regulates 10090 BTO:0002314 22045613 f gcesareni "Notch signaling is active in quiescent SCs. SC-specific deletion of recombining binding protein-J (RBP-J), a nuclear factor required for Notch signaling, resulted in the depletion of the SC pool and muscles that lacked any ability to regenerate in response to injury." SIGNOR-244004 RPS6K proteinfamily SIGNOR-PF26 SIGNOR NR4A3 protein Q92570 UNIPROT "down-regulates activity" phosphorylation Ser376 GRRGRLPsKPKSPLQ 9606 BTO:0000007 16223362 t lperfetto "Phosphorylation of Nur77 on Ser354 has been suggested to reduce ability of Nur77 to bind DNA; however, the kinase responsible for this phosphorylation in cells has not been clearly established. In the present study, we show that Nur77 is phosphorylated on this site by RSK (ribosomal S6 kinase)" SIGNOR-252771 RPS6K proteinfamily SIGNOR-PF26 SIGNOR PPP1R3A protein Q16821 UNIPROT "up-regulates activity" phosphorylation Ser46 PQPSRRGsDSSEDIY -1 10648825 t lperfetto "The protein G(M), which targets protein phosphatase 1 (PP1) to the glycogen particles and sarcoplasmic reticulum (SR) of striated muscles, is known to be phosphorylated at Ser48 and Ser67 in vitro by adenosine 3',5' cyclic monophosphate-dependent protein kinase (PKA) and at Ser48 by MAP kinase-activated protein kinase-1 (MAPKAP-K1, also called p90 RSK). The phosphorylation of Ser48 increases the rate at which the glycogen-associated PP1.G(M) complex dephosphorylates (activates) glycogen synthase, but the phosphorylation of Ser67 has the opposite effect, suppressing the activity of PP1 toward glycogen-bound substrates." SIGNOR-252777 SGK1 protein O00141 UNIPROT NR3C1 protein P04150 UNIPROT "up-regulates activity" phosphorylation Ser203 DLEFSSGsPGKETNE 9606 23650397 t gcesareni "SGK1 also potentiated and maintained GR activation in the presence of cortisol, and even after cortisol withdrawal, by increasing GR phosphorylation and GR nuclear translocation|SGK1 mediates CORT effects on GR phosphorylation. After 12 h, CORT (100 ¬µM) increases GR phosphorylation at S203 (n = 6; A), S211 (n = 6; B), and S226 (n = 6; C)." SIGNOR-251669 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 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR 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-252746 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 NEDD4L protein Q96PU5 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates ubiquitination 9606 19917253 t gcesareni "Through its ww domain, nedd4l specifically recognizes a tgf-beta-induced phosphothr-protyr motif in the linker region, resulting in smad2/3 polyubiquitination and degradation" SIGNOR-161713 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 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 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates phosphorylation Ser141 TVKQKYLsFTPPEKD 9606 BTO:0000007 16204230 t gcesareni "Pak2 is autophosphorylated at eight sites;ser-141 and ser-165 in the regulatory domain and thr-402 in the activation loop are identified as key sites in activation of the protein kinase." SIGNOR-140907 PAK2 protein Q13177 UNIPROT PRL protein P01236 UNIPROT up-regulates phosphorylation Ser207 LHCLRRDsHKIDNYL 9606 19555049 t gcesareni "Phosphorylated form of prolactin has a higher affinity for heparin." SIGNOR-186211 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 SGK1 protein O00141 UNIPROT NR3C1 protein P04150 UNIPROT "up-regulates activity" phosphorylation Ser211 PGKETNEsPWRSDLL 9606 23650397 t gcesareni "SGK1 also potentiated and maintained GR activation in the presence of cortisol, and even after cortisol withdrawal, by increasing GR phosphorylation and GR nuclear translocation|SGK1 mediates CORT effects on GR phosphorylation. After 12 h, CORT (100 ¬µM) increases GR phosphorylation at S203 (n = 6; A), S211 (n = 6; B), and S226 (n = 6; C)." SIGNOR-251670 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 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR 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-252744 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR 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-252745 FOXL2 protein P58012 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000975 16153597 f miannu "We observed that foxl2 induces apoptosis in the ovarian cells unveiling a novel function of foxl2" SIGNOR-140391 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 N-(2-aminoethyl)-5-chloroisoquinoline-8-sulfonamide chemical CHEBI:47322 ChEBI CSNK1E protein P49674 UNIPROT down-regulates "chemical inhibition" 9606 11524435 t amattioni "Cki-7, an inhibitor of ck1epsilon" SIGNOR-110053 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 NEFH protein P12036 UNIPROT "Neurofilament bundle assembly" phenotype SIGNOR-PH72 SIGNOR up-regulates 9606 BTO:0000938 8376466 f miannu "Neurofilaments (NFs), composed of three distinct subunits NF-L, NF-M, and NF-H, are neuron-specific intermediate filaments present in most mature neurons." SIGNOR-252390 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 NODAL protein Q96S42 UNIPROT LIF protein P15018 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003879 20383200 f Regulation miannu "Nodal induced LIF and Cripto-1 expressions through Smad2 signaling pathway." SIGNOR-251941 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 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 UGT2B7 protein P16662 UNIPROT up-regulates phosphorylation Tyr438 RVINDPSyKENVMKL 9606 BTO:0000150 19289110 t gcesareni "Overexpression of regular or active src, but not dominant-negative src, in 2b7-transfected cos-1 cells increased 2b7 activity and phospho-y438-2b7 by 50%" SIGNOR-184613 "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 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 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 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 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 PRKACG protein P22612 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-67400 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 XIAP protein P98170 UNIPROT CASP9 protein P55211 UNIPROT "down-regulates quantity by destabilization" binding 9606 11242052 t lperfetto "A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis" SIGNOR-105702 "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 "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 "AMG 900" chemical CID:24856041 PUBCHEM AURKA protein O14965 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189492 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 MAPK13 protein O15264 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser25 QAFELILsPRSKESV 9606 BTO:0000782 8325880 t gcesareni "Serine 25 of oncoprotein 18 is a major cytosolic target for the mitogen-activated protein kinase|The present study shows that the MAP kinase has a 20-fold preference for Ser25 as opposed to Ser38 of Op18, while cdc2 kinases have a 5-fold preference for the Ser38 residue." SIGNOR-37848 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser75 EIRSRHSsYPAGTED 9606 10230394 t gcesareni "Phosphorylation and inactivation of BAD by mitochondria-anchored protein kinase A|Collectively, these results implicate PKA as the principal mitochondria-based S112 kinase." SIGNOR-67383 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 PRKDC protein P78527 UNIPROT GOLPH3 protein Q9H4A6 UNIPROT "up-regulates activity" phosphorylation Thr148 KETQPPEtVQNWIEL -1 BTO:0000567 24485452 t "In response to DNA damage, DNA-PK phosphorylates GOLPH3, resulting in increased interaction with MYO18A, which applies a tensile force to the Golgi. Interference with the Golgi DNA damage response by depletion of DNA-PK, GOLPH3, or MYO18A reduces survival after DNA damage, whereas overexpression of GOLPH3, as is observed frequently in human cancers, confers resistance to killing by DNA-damaging agents" SIGNOR-253558 "sphingosine 1-phosphate(1-)" smallmolecule CHEBI:60119 ChEBI S1PR2 protein O95136 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-257578 "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 "sphingosine 1-phosphate(1-)" smallmolecule CHEBI:60119 ChEBI S1PR5 protein Q9H228 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-257580 ATM protein Q13315 UNIPROT ABRAXAS1 protein Q6UWZ7 UNIPROT "up-regulates activity" phosphorylation Ser406 GPGEYSRsPTF 9606 BTO:0000007 26778126 t "IR-Induced Double Phosphorylation of Abraxas C Terminus S404 and S406 Is ATM Dependent" SIGNOR-255588 RAF1 protein P04049 UNIPROT MAP2K2 protein P36507 UNIPROT up-regulates phosphorylation Ser218;Ser222 VSGQLIDsMANSFVG;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 WNK1 protein Q9H4A3 UNIPROT STK39 protein Q9UEW8 UNIPROT up-regulates phosphorylation Ser371 VRRVPGSsGHLHKTE 9606 16083423 t gcesareni "Phosphorylation by WNK1 or WNK4 markedly increased SPAK and OSR1 activity. Phosphopeptide mapping studies demonstrated that WNK1 phosphorylated kinase-inactive SPAK and OSR1 at an equivalent residue located within the T-loop of the catalytic domain (Thr233 in SPAK, Thr185 in OSR1) and a serine residue located within a C-terminal non-catalytic region (Ser373 in SPAK, Ser325 in OSR1)" SIGNOR-253553 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 "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 "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 CREBBP protein Q92793 UNIPROT STAT2 protein P52630 UNIPROT "up-regulates activity" acetylation Lys390 QKTLTPEkGQSQGLI 9606 BTO:0000007 17923090 t lperfetto "STAT2 is another important component of ISGF3 complex, and its acetylation was similar to IFNaR2 and IRF9 acetylation in many respects: CBP downregulation largely abolished STAT2 acetylation induction by IFNa (Figure 6A), and CBP was more potent than transferases tested in catalyzing STAT2 acetylation (Figure 6B). [...] Figure 6 (I) STAT2-K390R substitution has reduced activity in ISGF3 complex formation." SIGNOR-217891 ESR2 protein Q92731 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-253475 GSK1059615 chemical CHEBI:71955 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-252667 JAK3 protein P52333 UNIPROT STAT5A protein P42229 UNIPROT up-regulates phosphorylation Tyr694 LAKAVDGyVKPQIKQ 9606 18250158 t gcesareni "For these assays, coexpression of wt jak3 with stat5a was found to result in tyrosine phosphorylation of stat5a (lane 2) mediated by jak3, since stat5a coexpressed with the kinase-inactive k855a mutant form of jak3 was not tyrosine phosphorylated." SIGNOR-160672 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 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser434 SFEPKIRsPRRFIGS 9606 7545671 t gcesareni "Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase" SIGNOR-28796 MLH1 protein P40692 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR "up-regulates activity" 10090 9500552 f "Germline mutations in the human MSH2, MLH1, PMS2 and PMS1 DNA mismatch repair (MMR) gene homologues appear to be responsible for most cases of hereditary non-polyposis colorectal cancer" SIGNOR-257595 MSH2 protein P43246 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR "up-regulates activity" 10090 9500552 f "Germline mutations in the human MSH2, MLH1, PMS2 and PMS1 DNA mismatch repair (MMR) gene homologues appear to be responsible for most cases of hereditary non-polyposis colorectal cancer" SIGNOR-257594 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 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 18378770 t gcesareni "Following cdk1-dependent recruitment, plk1 triggers hbora destruction by phosphorylating a recognition site for scf(beta-trcp)." SIGNOR-178154 PMS1 protein P54277 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR "up-regulates activity" 10090 9500552 f "Germline mutations in the human MSH2, MLH1, PMS2 and PMS1 DNA mismatch repair (MMR) gene homologues appear to be responsible for most cases of hereditary non-polyposis colorectal cancer" SIGNOR-257597 PMS2 protein P54278 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR "up-regulates activity" 10090 9500552 f "Germline mutations in the human MSH2, MLH1, PMS2 and PMS1 DNA mismatch repair (MMR) gene homologues appear to be responsible for most cases of hereditary non-polyposis colorectal cancer" SIGNOR-257596 RET protein P07949 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Thr180 RHTDDEMtGYVATRW 9606 17126298 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-150875 RET protein P07949 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Thr180 RHTDDEMtGYVATRW 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-155377 TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT "up-regulates activity" ubiquitination Lys377 NEPSLQSkLQDEANY 10090 BTO:0002572;BTO:0000801 21232017 t lperfetto "Following binding to tradd, traf2 was thought to mediate non-degradative lys-63-linked polyubiquitination of rip1 via its ring e3 ligase domain. Rip1 is known to directly interact with traf2." SIGNOR-235407 WNK1 protein Q9H4A3 UNIPROT STK39 protein Q9UEW8 UNIPROT up-regulates phosphorylation Thr231 TRNKVRKtFVGTPCW 9606 BTO:0000007 BTO:0000671 16083423 t gcesareni "Phosphorylation by WNK1 or WNK4 markedly increased SPAK and OSR1 activity. Phosphopeptide mapping studies demonstrated that WNK1 phosphorylated kinase-inactive SPAK and OSR1 at an equivalent residue located within the T-loop of the catalytic domain (Thr233 in SPAK, Thr185 in OSR1) and a serine residue located within a C-terminal non-catalytic region (Ser373 in SPAK, Ser325 in OSR1)" SIGNOR-160846 CARD9 protein Q9H257 UNIPROT BCL10 protein O95999 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000007 11053425 t "To identify upstream signaling partners of BCL10, we performed a mammalian two-hybrid analysis and identified CARD9 as a novel CARD-containing protein that interacts selectively with the CARD activation domain of BCL10. When expressed in cells, CARD9 binds to BCL10 and activates NF-kappaB." SIGNOR-257602 CDK5 protein Q00535 UNIPROT LMTK2 protein Q8IWU2 UNIPROT down-regulates phosphorylation 9606 BTO:0000938 BTO:0000887;BTO:0000142 12832520 t gcesareni "Cprk displays catalytic activity in in vitro kinase assays and is itself phosphorylated by cdk5/p35. Cdk5/p35 inhibits cprk activity." SIGNOR-102652 CSNK2A1 protein P68400 UNIPROT CARD9 protein Q9H257 UNIPROT "down-regulates activity" phosphorylation Thr531;Thr533 NTTGSDNtDTEGS;TGSDNTDtEGS 9606 BTO:0000567 17936701 t "PVHL Acts as an Adaptor to Promote the Inhibitory Phosphorylation of the NF-κB Agonist Card9 by CK2" SIGNOR-257601 ETS1 protein P14921 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-254078 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 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 NEFL protein P07196 UNIPROT "Neurofilament L/M" complex SIGNOR-C207 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-255270 NEFM protein P07197 UNIPROT "Neurofilament bundle assembly" phenotype SIGNOR-PH72 SIGNOR up-regulates 9606 BTO:0000938 8376466 f miannu "Neurofilaments (NFs), composed of three distinct subunits NF-L, NF-M, and NF-H, are neuron-specific intermediate filaments present in most mature neurons." SIGNOR-252391 progesterone smallmolecule CHEBI:17026 ChEBI COMT protein P21964 UNIPROT down-regulates 17138778 f "Regulation of expression" miannu "Catechol-O-methyltransferase expression was down-regulated by progesterone or estrogen." SIGNOR-251960 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 AURKB protein Q96GD4 UNIPROT HIST1H3A protein P68431 UNIPROT up-regulates phosphorylation Ser29 ATKAARKsAPATGGV 9606 11856369 t gcesareni "Histone code pathway involving h3 s28 phosphorylation and k27 acetylation activates transcription and antagonizes polycomb silencingaurora-b phosphorylates histone h3 at serine28 with regard to the mitotic chromosome condensation" SIGNOR-114852 AURKB protein Q96GD4 UNIPROT HIST1H3A protein P68431 UNIPROT up-regulates phosphorylation Ser29 ATKAARKsAPATGGV 9606 21282660 t gcesareni "Histone code pathway involving h3 s28 phosphorylation and k27 acetylation activates transcription and antagonizes polycomb silencingaurora-b phosphorylates histone h3 at serine28 with regard to the mitotic chromosome condensation" SIGNOR-171717 NEFM protein P07197 UNIPROT "Neurofilament L/M" complex SIGNOR-C207 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-255271 NEK1 protein Q96PY6 UNIPROT VDAC1 protein P21796 UNIPROT down-regulates phosphorylation Ser193 DGTEFGGsIYQKVNK 9606 20230784 t lperfetto "Nek1 phosphorylates vdac1 on ser193. Wild-type vdac1 assumes an open configuration, but closes and prevents cytochrome c efflux when phosphorylated by nek1. A vdac1-ser193ala mutant, which cannot be phosphorylated by nek1 under identical conditions, remains open and constitutively allows cytochrome c efflux." SIGNOR-164222 NR3C1 protein P04150 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR down-regulates 9606 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-257599 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 RPS6KB1 protein P23443 UNIPROT PFKFB2 protein O60825 UNIPROT "up-regulates activity" phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000562 2846551 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-23757 TP53 protein P04637 UNIPROT MLH1 protein P40692 UNIPROT "up-regulates quantity" "transcriptional activation" 9606 BTO:0000567 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 PMS2 protein P54278 UNIPROT "up-regulates quantity" "transcriptional activation" 9606 BTO:0000567 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 TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT "up-regulates activity" ubiquitination Lys377 NEPSLQSkLQDEANY 9606 BTO:0000007 8702708 t lperfetto "Following binding to tradd, traf2 was thought to mediate non-degradative lys-63-linked polyubiquitination of rip1 via its ring e3 ligase domain. Rip1 is known to directly interact with traf2." SIGNOR-42984 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 CAMKK1 protein Q8N5S9 UNIPROT CAMK1 protein Q14012 UNIPROT "up-regulates activity" phosphorylation Thr177 DPGSVLStACGTPGY 8253780 t llicata "Human calcium-calmodulin dependent protein kinase I: cDNA cloning, domain structure and activation by phosphorylation at threonine-177 by calcium-calmodulin dependent protein kinase I kinase." SIGNOR-250717 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 CSNK2A1 protein P68400 UNIPROT MYH9 protein P35579 UNIPROT up-regulates phosphorylation Ser1943 RKGAGDGsDEEVDGK 9606 18971378 t gcesareni "In egf-stimulated cells, the myosin-iia heavy chain is phosphorylated on the casein kinase 2 site (s1943)" SIGNOR-181811 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 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 EZH2 protein Q15910 UNIPROT ALDH1A1 protein P00352 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004094 22144423 f miannu "For three selected genes (ALDH1A1, SSTR1, and DACT3), we validated their upregulation upon EZH2 knockdown and confirmed the binding of EZH2/H3K27Me3 to their genomic loci." SIGNOR-254141 EZH2 protein Q15910 UNIPROT DACT3 protein Q96B18 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004094 22144423 f miannu "For three selected genes (ALDH1A1, SSTR1, and DACT3), we validated their upregulation upon EZH2 knockdown and confirmed the binding of EZH2/H3K27Me3 to their genomic loci." SIGNOR-254142 EZH2 protein Q15910 UNIPROT HOXB13 protein Q92826 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001033 22808286 f miannu "EZH2 recruited DNMT3b to HOXB13 promoter to form a repression complex." SIGNOR-254144 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 GSK3B protein P49841 UNIPROT CEBPB protein P17676 UNIPROT up-regulates phosphorylation Ser231 LSTSSSSsPPGTPSP 9606 phosphorylation:Thr188 T-->L 17601773 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-156514 GSK3B protein P49841 UNIPROT CEBPB protein P17676 UNIPROT up-regulates phosphorylation Ser231 LSTSSSSsPPGTPSP 9606 phosphorylation:Thr188 T-->L 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 PRKACA protein P17612 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates phosphorylation Ser857 PPYNRAVsLDSPVSV 9606 BTO:0000551 22505454 t gcesareni "Herein, we report the successful identification of six functional in vivo src-3 phosphorylation sites." SIGNOR-196961 PTPN6 protein P29350 UNIPROT CSF2RB protein P32927 UNIPROT down-regulates dephosphorylation Tyr628 PPPGSLEyLCLPAGG 9606 11812650 t gcesareni "However, inhibition of shp2 binding to betac, did not prevent tyrosine phosphorylation of shp2. Interestingly, this same phosphopeptide served as a substrate for the tyrosine phosphatase activity of both shp1 and shp2." SIGNOR-114597 AMPK complex SIGNOR-C15 SIGNOR HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser155 FPLRKTVsEPNLKLR 9606 21892142 t lperfetto "Another recently described set of transcriptional regulators targeted by ampk and its related family members across a range of eukaryotes are the class iia family of histone deacetylases (hdacs)." SIGNOR-216554 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 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CEBPB protein P17676 UNIPROT up-regulates phosphorylation Thr235 SSSSPPGtPSPADAK 9606 17601773 t lperfetto "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-217312 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 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 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 JAK2 protein O60674 UNIPROT STAT5A protein P42229 UNIPROT up-regulates phosphorylation Tyr694 LAKAVDGyVKPQIKQ 4932 9575217 t gcesareni "Jak2 kinase induces tyrosine phosphorylation, dimerization, nuclear translocation, and dna binding of a concomitantly expressed stat5 protein." SIGNOR-56827 JAK2 protein O60674 UNIPROT STAT5A protein P42229 UNIPROT up-regulates phosphorylation Tyr694 LAKAVDGyVKPQIKQ 9606 18250158 t gcesareni "Jak2 kinase induces tyrosine phosphorylation, dimerization, nuclear translocation, and dna binding of a concomitantly expressed stat5 protein." SIGNOR-160656 JAK2 protein O60674 UNIPROT STAT5A protein P42229 UNIPROT up-regulates phosphorylation Tyr694 LAKAVDGyVKPQIKQ 9606 BTO:0000007;BTO:0000567 19088846 t gcesareni "Jak2 kinase induces tyrosine phosphorylation, dimerization, nuclear translocation, and dna binding of a concomitantly expressed stat5 protein." SIGNOR-182813 MAPK8 protein P45983 UNIPROT BCL2 protein P10415 UNIPROT down-regulates 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 phosphorylation Ser87 AAAGPALsPVPPVVH 9606 18570871 t gcesareni "Jnk1-mediated phosphorylation of bcl-2 regulates starvation-induced autophagy." SIGNOR-179092 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 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 PTPN6 protein P29350 UNIPROT CSF2RB protein P32927 UNIPROT down-regulates dephosphorylation Tyr628 PPPGSLEyLCLPAGG 9606 9162089 t gcesareni "However, inhibition of shp2 binding to betac, did not prevent tyrosine phosphorylation of shp2. Interestingly, this same phosphopeptide served as a substrate for the tyrosine phosphatase activity of both shp1 and shp2." SIGNOR-48561 ZM447439 chemical CHEBI:91376 ChEBI AURKA protein O14965 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207920 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 CDK1 protein P06493 UNIPROT WEE1 protein P30291 UNIPROT down-regulates phosphorylation Ser123 EEGFGSSsPVKSPAA 9606 BTO:0000567 15070733 t gcesareni "We have found also that the major M-phase kinases polo-like kinase 1 (Plk1) and Cdc2 are responsible for the phosphorylation of S53 and S123, respectively, and that in each case phosphorylation generates an unconventional phospho-degron (signal for degradation) that can be recognized by beta-TrCP" SIGNOR-123824 F2RL1 protein P55085 UNIPROT CD44 protein P16070 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-254843 F2RL1 protein P55085 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-254838 F2RL1 protein P55085 UNIPROT ITGB4 protein P16144 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000007 21072196 f miannu "PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15)." SIGNOR-254859 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 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 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates phosphorylation 9606 16837009 t gcesareni "A dimeric kinase assembly underlying autophosphorylation in the p21 activated kinasesa key step in the activation process is the phosphorylation of the activation loop of one pak kinase domain by another, but little is known about the underlying recognition events that make this phosphorylation specific." SIGNOR-147874 PRKCD protein Q05655 UNIPROT DAB2 protein P98082 UNIPROT down-regulates phosphorylation Ser24 QAAPKAPsKKEKKKG 9606 BTO:0001130 10542228 t gcesareni "Mutational analysis revealed that a dab2 ser(24) phosphorylation mutant (s24a) abrogated the inhibitory function of dab2." SIGNOR-71764 F2RL1 protein P55085 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-257028 F2RL1 protein P55085 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-254844 F2RL1 protein P55085 UNIPROT SERPINB2 protein P05120 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007 21072196 f miannu "PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15)." SIGNOR-254856 F2RL1 protein P55085 UNIPROT THBS1 protein P07996 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-254842 F2RL1 protein P55085 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-254837 F2RL1 protein P55085 UNIPROT TSPAN15 protein O95858 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000007 21072196 f miannu "PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15)." SIGNOR-254862 F2RL1 protein P55085 UNIPROT TXNIP protein Q9H3M7 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000007 21072196 f miannu "PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15)." SIGNOR-254857 F2RL1 protein P55085 UNIPROT WWOX protein Q9NZC7 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007 21072196 f miannu "PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15)." SIGNOR-254854 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 PTPN12 protein Q05209 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation "Tyr1185; Tyr1190" FGMTRDIyETDYYRK;DIYETDYyRKGGKGL -1 10734133 t gcesareni "Interestingly, all PTPs that were tested could completely dephosphorylate the receptor, given sufficient time, including a negative control (PTP-PEST) that failed to bind IRK as a trapping mutant." SIGNOR-75894 RAP1GDS1 protein P52306 UNIPROT RHOA protein P61586 UNIPROT up-regulates binding 9606 21242305 t miannu "Smggds is a guanine nucleotide exchange factor that specifically activates rhoa and rhoc" SIGNOR-171347 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 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 F2RL3 protein Q96RI0 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-257312 FBXW11 protein Q9UKB1 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 9784611 t gcesareni "we conclude that beta-trcp is a component of an e3 ubiquitin ligase that is responsible for the targeted degradation of phosphorylated beta-catenin.We Found that the binding of beta-trcp to beta-catenin was direct" SIGNOR-60751 FBXW11 protein Q9UKB1 UNIPROT SUFU protein Q9UMX1 UNIPROT up-regulates binding 9606 BTO:0001130;BTO:0000848;BTO:0000527 10564661 t tpavlidou "We found that in vitro-translated 35s- labeled slimb indeed specifically bound to su(fu) in the gst pull-down assay. In our functional gli reporter assay, slimb alone did not alter gli-induced reporter expression;however, when cotransfected with hsu(fu), slimb significantly potentiated the inhibitory effect of su(fu) on gli activity." SIGNOR-72240 FBXW7 protein Q969H0 UNIPROT NOTCH4 protein Q99466 UNIPROT down-regulates ubiquitination 9606 11585921 t gcesareni "We show here that the f-box/wd40 repeat protein sel-10 negatively regulates notch receptor activity by targeting the intracellular domain of notch receptors for ubiquitin-mediated protein degradation. in conclusion, hsel-10 physically associates with mouse notch4(int-3) through the wd40 domain, whereas the f-box domain is not required for this interaction." SIGNOR-110955 FCER1G/FCER1G complex SIGNOR-C199 SIGNOR 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-254962 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 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 INVS protein Q9Y283 UNIPROT DVL1 protein O14640 UNIPROT down-regulates ubiquitination 9606 BTO:0000671 15852005 t gcesareni "Inversin inhibits the canonical wnt pathway by targeting cytoplasmic dishevelled (dsh or dvl1) for degradation" SIGNOR-135766 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 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-120184 PPP1CB protein P62140 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-248568 RELA protein Q04206 UNIPROT TRAF1 protein Q13077 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9733516 f gcesareni "Thus, our data indicate that nf-kb controls the expression of traf1 and traf2 and c-iap1 and c-iap2." SIGNOR-59957 RNF111 protein Q6ZNA4 UNIPROT SKIL protein P12757 UNIPROT down-regulates ubiquitination 9606 17591695 t gcesareni "Arkadia interacts with snon and induces its ubiquitination irrespective of tgf-beta/activin signaling, but snon is efficiently degraded only when it forms a complex with both arkadia and phosphorylated smad2 or smad3" SIGNOR-156430 SPI1 protein P17947 UNIPROT NAB2 protein Q15742 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 10090 BTO:0000801 16923394 f miannu "PU.1 Induces Egr-2 and Nab-2, which Repress Neutrophil Genes during Macrophage Differentiation" SIGNOR-256039 TGFB1 protein P01137 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates 9606 18586026 f gcesareni "These data show that tgf-beta-induced nf-kappab activation is through tak1/mek-mediated aktactivation, which is essential for tgf-beta to support of osteoclast survival" SIGNOR-179179 4-(2-methyl-3-propan-2-yl-4-imidazolyl)-N-(4-methylsulfonylphenyl)-2-pyrimidinamine chemical CHEBI:91419 ChEBI CDK2 protein P24941 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190179 "BMS 794833" chemical CID:44155856 PUBCHEM KDR protein P35968 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190419 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 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 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 PRKCB protein P05771 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-249093 PRKCB protein P05771 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-249237 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 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 ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser20 PLSQETFsDLWKLLP 9606 BTO:0002552 17967874 t gcesareni "The increased interaction between B56gamma and p53 after DNA damage requires ATM-dependent phosphorylation of p53 at Ser15." SIGNOR-158636 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 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 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 CDK8 protein P49336 UNIPROT E2F1 protein Q01094 UNIPROT down-regulates phosphorylation Ser375 PVDEDRLsPLVAADS 9606 22945643 t lperfetto "Cdk8 regulates e2f1 transcriptional activity through s375 phosphorylation." SIGNOR-198934 FGF11 protein Q92914 UNIPROT SCN9A protein Q15858 UNIPROT "down-regulates activity" binding 9606 BTO:0000938 20679355 t miannu "Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels." SIGNOR-253426 FHL2 protein Q14192 UNIPROT AR protein P10275 UNIPROT up-regulates binding 9606 BTO:0001129 10654935 t gcesareni "Fhl2 contains a strong, autonomous transactivation function and binds specifically to the ar in vitro and in vivo." SIGNOR-74703 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 PDGFRB protein P09619 UNIPROT CRK protein P46108 UNIPROT up-regulates binding 9606 19426560 t amattioni "Crk can interact directly with tyrosine kinase receptors and can transmit signals downstream" SIGNOR-185667 SMURF2 protein Q9HAU4 UNIPROT SMAD9 protein O15198 UNIPROT down-regulates ubiquitination 9606 22298955 t gcesareni "Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps" SIGNOR-193390 STMN1 protein P16949 UNIPROT TTL protein Q8NG68 UNIPROT down-regulates binding 9606 23624152 t miannu "Stathmin depresses ttl tubulin tyrosination activityin vitro." SIGNOR-193465 SYK protein P43405 UNIPROT SH3BP2 protein P78314 UNIPROT "up-regulates activity" phosphorylation Tyr174 YPTDNEDyEHDDEDD 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-246587 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 FFAR4 protein Q5NUL3 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-256773 FGF11 protein Q92914 UNIPROT SCN3A protein Q9NY46 UNIPROT "down-regulates activity" binding 9606 BTO:0000938 20679355 t miannu "Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels." SIGNOR-253446 FGF11 protein Q92914 UNIPROT SCN4A protein P35499 UNIPROT "down-regulates activity" binding 9606 BTO:0001103 20679355 t miannu "Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels." SIGNOR-253434 FGF11 protein Q92914 UNIPROT SCN8A protein Q9UQD0 UNIPROT "down-regulates activity" binding 9606 BTO:0000938 20679355 t miannu "Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels." SIGNOR-253414 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 FOXO1 protein Q12778 UNIPROT G6PC 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-166349 MAPK3 protein P27361 UNIPROT SOX9 protein P48436 UNIPROT "up-regulates quantity by expression" "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-165353 NFKB1 protein P19838 UNIPROT BIRC2 protein Q13490 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9733516 f gcesareni "Thus, our data indicate that nf-kb controls the expression of traf1 and traf2 and c-iap1 and c-iap2" SIGNOR-59948 NFKB1 protein P19838 UNIPROT BIRC3 protein Q13489 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9733516 f gcesareni "Thus, our data indicate that nf-kb controls the expression of traf1 and traf2 and c-iap1 and c-iap2" SIGNOR-59951 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 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR SOD2 protein P04179 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21357467 f gcesareni "The nfkb p65/p50 heterodimer increases sod2, and p50/p50 suppresses it nf-kb p65/p50 binds to the enhancer and is important for cytokine-induced sod2" SIGNOR-172392 PLAG1 protein Q6DJT9 UNIPROT IGF2 protein P01344 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 14695992 f miannu "Plag1 has been shown be a transcriptional activator of igf2" SIGNOR-120363 SHPRH protein Q149N8 UNIPROT PCNA protein P12004 UNIPROT up-regulates ubiquitination 9606 19706603 t gcesareni "We provide evidence that similar to rad5, shprh physically interacts with the human rad6rad18 and mms2ubc13 protein complexes, and importantly, we show that it exhibits an ubiquitin ligase activity and mediates mms2ubc13-dependent polyubiquitylation of pcna. Thus, shprh is a functional homolog of rad5." SIGNOR-187757 XXYLT1 protein Q8NBI6 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 22117070 t "Xylosylation in ER membrane" gcesareni "Xxylt1 acts on the xyl1,3glc-o-linked glycan of notch egf domains." SIGNOR-177745 FGF13 protein Q92913 UNIPROT SCN2A protein Q99250 UNIPROT "down-regulates activity" binding 9606 BTO:0000938 20679355 t miannu "Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels." SIGNOR-253427 FGF14 protein Q92915 UNIPROT SCN11A protein Q9UI33 UNIPROT "down-regulates activity" binding 9606 BTO:0000938 20679355 t miannu "Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels." SIGNOR-253437 FGF14 protein Q92915 UNIPROT SCN1A protein P35498 UNIPROT "down-regulates activity" binding 9606 BTO:0000938 20679355 t miannu "Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels." SIGNOR-253421 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 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 MAPK8 protein P45983 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-168998 FGF3 protein P11487 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates binding 9606 8663044 t gcesareni "Using fgf 1 as an internal standard we have determined the relative activity of all the other members of the fgf family. These data should serve as a biochemical foundation for determining developmental, physiological, and pathophysiological processes that involve fgf signaling pathways" SIGNOR-42374 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 FGFR1OP protein O95684 UNIPROT FGFR1OP/CEP350 complex SIGNOR-C52 SIGNOR "form complex" binding 9606 16314388 t miannu "Here we show that cap350 and fop (fgfr1 oncogene partner) form a centrosomal complex required for mt anchoring." SIGNOR-142358 FGFR1OP 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 FGFR1 protein P11362 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates phosphorylation Tyr249 APGPQDIyDVPPVRG 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-98492 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr280 VEFMCKVySDPQPHI 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-98626 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 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 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 FIZ1 protein Q96SL8 UNIPROT NRL protein P54845 UNIPROT "up-regulates activity" binding 9913 12566383 t miannu "Interaction of Fiz1 and NRL-leucine zipper was validated by GST pulldown assays and co-immunoprecipitation from bovine retinal nuclear extracts. Fiz1 suppressed NRL- but not CRX-mediated transactivation of rhodopsin promoter activity in transiently transfected CV1 cells." SIGNOR-223796 FLCN protein Q8NFG4 UNIPROT RRAGC protein Q9HB90 UNIPROT "up-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 24095279 t "The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1 [..} RagC/D is a key regulator of the interaction of mTORC1 with the Rag heterodimer and that, unexpectedly, RagC/D must be GDP-bound for the interaction to occur" SIGNOR-256503 FLT3 protein P36888 UNIPROT RUNX1 protein Q01196 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0004479 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 SPI1 protein P17947 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 16146838 t lperfetto "Oncogenic mutations of Flt3 also result in the activation of aberrant signaling pathways, including strong activation of STAT5, induction of STAT target genes, and repression of myeloid transcription factors c/EBP-3 and Pu.1." SIGNOR-249634 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 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 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 9606 25875593 t irozzo "C-Fos dimerizes with c-Jun to form the transcription activator protein-1 (AP-1) which binds to the specific recognition site." SIGNOR-256368 FOXA1 protein P55317 UNIPROT BCL2 protein P10415 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 19127412 f miannu "Foxa1 overexpression decreased the expression of bcl2, while foxa1 depletion increased the expression of bcl2" SIGNOR-161448 FOXL2 protein P58012 UNIPROT CYP11A1 protein P05108 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 21862621 f miannu "We previously demonstrated that FOXL2 is a transcriptional repressor of the steroidogenic acute regulatory (StAR), P450SCC (CYP11A), P450aromatase (CYP19), and cyclin D2 (CCND2) genes, markers of ovarian follicle proliferation and differentiation." SIGNOR-254177 FOXO proteinfamily SIGNOR-PF27 SIGNOR CDKN2D protein P55273 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17873901 f gcesareni "Foxo1a strongly activated p15ink4b transcription and p19ink4d transcription, while foxo3a showed higher p19ink4d transcription activity than p15ink4b transcription activity" SIGNOR-252918 FOXO proteinfamily SIGNOR-PF27 SIGNOR Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 BTO:0000007 14976264 f lperfetto "Sirt1 inhibited foxo3's ability to induce cell death." SIGNOR-256644 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 SALL4 protein Q9UJQ4 UNIPROT HOXA9 protein P31269 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001883 24051379 f miannu "In primary human AML cells, downregulation of SALL4 led to decreased HOXA9 expression and enhanced apoptosis. We found that SALL4 bound a specific region of the HOXA9 promoter in leukemic cells. SALL4 overexpression led to enhanced binding of histone activation markers at the HOXA9 promoter region, as well as increased HOXA9 expression in these cells." SIGNOR-255125 TESK1 protein Q15569 UNIPROT CFL2 protein Q9Y281 UNIPROT "down-regulates activity" phosphorylation Ser3 sGVTVNDE 9606 BTO:0001363 11418599 t lperfetto "Like TESK1, TESK2 phosphorylated cofilin specifically at Ser-3 and induced formation of actin stress fibers and focal adhesionsExpression of cofilin or S3A-cofilin into HeLa cells induced marked decreases in rhodamine-phalloidin staining due to the actin binding and -depolymerizing activity of cofilin" SIGNOR-246719 FOXO1 protein Q12778 UNIPROT G6PC 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-142147 FOXO1 protein Q12778 UNIPROT G6PC 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-181195 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 FOXO1 protein Q12778 UNIPROT Metabolism phenotype SIGNOR-PH77 SIGNOR up-regulates 18391974 f "Forkhead proteins, and FoxO1 in particular, play a significant role in regulating whole body energy metabolism." SIGNOR-253010 FOXO1 protein Q12778 UNIPROT PCK1 protein P35558 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22521266 f gcesareni "Phosphorylated foxo1 is inactive and retained in the cytosol. Mkp-3 mediated dephosphorylation activates foxo1 and subsequentially promotes its nuclear translocation and binding to the promoters of gluconeogenic genes, such as phosphoenolpyruvate carboxykinase (pepck) and glucose-6-phosphatase (g6pase)." SIGNOR-197200 FOXO3 protein O43524 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 BTO:0000007 14976264 f lperfetto "Sirt1 inhibited foxo3's ability to induce cell death." SIGNOR-256645 FOXO3 protein O43524 UNIPROT NOTCH3 protein Q9UM47 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-244079 FOXO proteinfamily SIGNOR-PF27 SIGNOR TRIM63 protein Q969Q1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165 18612045 f lperfetto "Transcriptional reporter assays performed in both HepG2 and C2C12 cells demonstrate that the MuRF1 promoter is highly responsive to dexamethasone-activated glucocorticoid receptor (GR) and FoxO1 individually, while co-overexpression of GR and FoxO1 leads to a dramatic synergistic increase in reporter activity" SIGNOR-252927 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR 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-253667 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 RASSF1 protein Q9NS23 UNIPROT STK4 protein Q13043 UNIPROT up-regulates binding 9606 22683405 t "Mst1/2 are pro-apoptotic kinases that are activated by caspase cleavage" gcesareni "Rassf1a and mst1 co-exist as a complex localizing at microtubules throughout the cell cycle, of which the rassf1a mst1 interaction is stimulatory to the mst1 kinase activity." SIGNOR-197744 SH2B3 protein Q9UQQ2 UNIPROT BCL2L1 protein Q07817 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 22101255 f miannu "Our results indicated that lnk/sh2b3 constrains expression of bcl-xl and participates in the regulation of hsc homeostasis by maintaining proper responses against various proapoptotic stimuli." SIGNOR-177485 SMARCB1 protein Q12824 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-132930 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 TESK1 protein Q15569 UNIPROT CFL1 protein P23528 UNIPROT "down-regulates activity" phosphorylation Ser3 sGVAVSDG 9606 BTO:0001363 11418599 t lperfetto "Like TESK1, TESK2 phosphorylated cofilin specifically at Ser-3 and induced formation of actin stress fibers and focal adhesionsExpression of cofilin or S3A-cofilin into HeLa cells induced marked decreases in rhodamine-phalloidin staining due to the actin binding and -depolymerizing activity of cofilin" SIGNOR-246723 TP53INP1 protein Q96A56 UNIPROT GABARAPL2 protein P60520 UNIPROT up-regulates binding 9606 22421968 t gcesareni "In this work, we show that tp53inp1 is also able to interact with atg8-family proteins and to induce autophagy-dependent cell death. mammalian cells contain multiple atg8 orthologs belonging to three subfamilies: microtubule-associated protein 1 light chain 3, -aminobutyric acid receptor-associated protein (gabarap) and -aminobutyric acid receptor-associated protein like 2 (gabarapl2)." SIGNOR-196667 UPR stimulus SIGNOR-ST6 SIGNOR CREB3L1 protein Q96BA8 UNIPROT up-regulates 9606 16417584 f miannu "Oasis (old astrocyte specifically induced substance) is an er stress transducer in astrocytes, a membrane-bound transcription factor that activates genes in the er stress response / when unfolded proteins accumulate in the er, oasis is cleaved at the membrane to release its cytoplasmic domain, which then enters the nucleus and activates target genes." SIGNOR-143823 FYN protein P06241 UNIPROT CNN1 protein P51911 UNIPROT "down-regulates activity" phosphorylation Tyr182 SQQGMTAyGTRRHLY 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-251157 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 CNN3 protein Q15417 UNIPROT "down-regulates activity" phosphorylation Tyr261 SQKGMSVyGLGRQVY 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-251159 FYN protein P06241 UNIPROT CTLA4 protein P16410 UNIPROT unknown phosphorylation Tyr218 CEKQFQPyFIPIN 9606 BTO:0000661 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-251160 FYN protein P06241 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-247159 FYN protein P06241 UNIPROT ITPR1 protein Q14643 UNIPROT up-regulates phosphorylation Tyr353 NAQEKMVySLVSVPE 9606 BTO:0000782 14761954 t lperfetto "We have identified tyrosine 353 (tyr353) in the ip3-binding domain of type 1 ip3r (ip3r1) as a phosphorylation site for fyntyrosine phosphorylation of ip3r1 increased ip3 binding at low ip3 concentrations (<10 nm)." SIGNOR-121795 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 PTPRF protein P10586 UNIPROT "up-regulates activity" phosphorylation 9534 BTO:0000298 12496362 t "LAR PTPase domain 2 was tyrosine phosphorylated by Fyn tyrosine kinase. we confirmed that LAR dephosphorylated the phosphorylated tyrosine residues of Lck and Fyn, and tyrosine residue(s) in LAR PTPase D2 was phosphorylated by Fyn to supply Fyn SH2 binding site." SIGNOR-251180 FYN protein P06241 UNIPROT SCN5A protein Q14524 UNIPROT down-regulates phosphorylation Tyr1495 TEEQKKYyNAMKKLG 9606 15831816 t llicata "This study addresses the effects of the src family tyrosine kinase fyn on na(v)1.5 cardiac sodium channels. Sodium currents were acquired by whole cell recording on hek-293 cells transiently expressing na(v)1.5. Acute treatment of cells with insulin caused a depolarizing shift in steady-state inactivation, an effect eliminated by the src-specific tyrosine kinase inhibitor pp2 we provide evidence that this linker is a substrate for fyn in vitro, and that y1495 is a preferred phosphorylation site." SIGNOR-135600 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 SALL4 protein Q9UJQ4 UNIPROT PTEN protein P60484 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 19440552 f miannu "Stem cell factor SALL4 represses the transcriptions of PTEN and SALL1 through an epigenetic repressor complex." SIGNOR-255126 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 BMS-740808 chemical CID:6914623 PUBCHEM F10 protein P00742 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190488 FYN protein P06241 UNIPROT SLAMF1 protein Q13291 UNIPROT "up-regulates activity" phosphorylation Tyr327 ETNSITVyASVTLPE 9534 BTO:0000298 11806999 t "All 3 tyrosines of CD150 (Tyr281, Tyr307, Tyr327) are phosphorylated by the src kinase Fyn. CD150 is unique among its homologues in the immunoglobulin superfamily in that it is able to bind SAP, a floating SH2 domain, in the absence of tyrosine phosphorylation. In this study, using a detailed mutagenesis mapping approach we have shown that SAP binding to CD150 is in fact bimodal. Prior to tyrosine phosphorylation, SAP binds the membrane-proximal motif surrounding Tyr281. Following tyrosine phosphorylation by tyrosine kinases such as Fyn, SAP binds additionally to the distal motif surrounding Tyr327." SIGNOR-251183 FZD2 protein Q14332 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-80604 FZD3 protein Q9NPG1 UNIPROT CXCL1 protein P09341 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 gpcrs signal through four relatively small families of galfa proteins (galfas, galfai/o, galfaq, and galfa12/13), and if fzd receptors are classic gpcrs, they should signal through one of these four galfa families." SIGNOR-152597 FZD3 protein Q9NPG1 UNIPROT GNB1 protein P62873 UNIPROT up-regulates binding 9606 17251915 t gcesareni "In the non-canonical wnt signalling pathway, frizzled uses galphaq or galphai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat." SIGNOR-152600 g-secretase complex SIGNOR-C98 SIGNOR NOTCH proteinfamily SIGNOR-PF30 SIGNOR "up-regulates activity" cleavage 9606 25610395 t lperfetto "The membrane-bound Notch segment that results from this cleavage, known as Notch Intracellular Truncation domain (NEXT), is a -secretase substrate (Kopan and Ilagan, 2009). -Secretase performs the subsequent cleavage at S3 (De Strooper et al., 1999), releasing Notch intracellular domain (NICD) from the membrane and allowing for signal transduction through binding with the CBL-1, Su(H), Lag-1 (CSL; Schroeter et al., 1998; Struhl and Adachi, 1998) family of DNA binding proteins." SIGNOR-254328 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 GATA1 protein P15976 UNIPROT AGGF1 protein Q8N302 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001176 19556247 f miannu "Overexpression of GATA1 increased expression of AGGF1. Knockdown of GATA1 expression by siRNA reduced expression of AGGF1, and resulted in endothelial cell apoptosis and inhibition of endothelial capillary vessel formation and cell migration, which was rescued by purified recombinant human AGGF1 protein." SIGNOR-254188 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 GATA2 protein P23769 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 11021798 f fspada "Constitutive gata-2 and gata-3 expression suppressed adipocyte differentiation and trapped cells at the preadipocyte stage." SIGNOR-78659 GATA2 protein P23769 UNIPROT KLF1 protein Q13351 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 10090 BTO:0000944 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 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 GATA3 protein P23771 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 11021798 f fspada "Constitutive gata-2 and gata-3 expression suppressed adipocyte differentiation and trapped cells at the preadipocyte stage." SIGNOR-78830 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 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-253920 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 ROS stimulus SIGNOR-ST2 SIGNOR ATF4 protein P18848 UNIPROT up-regulates "transcriptional regulation" 9606 19439225 f lperfetto "Oxidative and ER stress conditions induce rapid and significant activation of ATF4 downstream of eIF2alpha phosphorylation, which is responsible for Redd1 expression" SIGNOR-253729 GATA3 protein P23771 UNIPROT GATA3 protein P23771 UNIPROT up-regulates 9606 16386358 t "Experimental data indeed supports the existence of a positive circuit involvingGATA-3 that excludes IL-4 and STAT-6, specifically in mouse cells" SIGNOR-254297 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 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 GATA6 protein Q92908 UNIPROT CYP11A1 protein P05108 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002850 15284005 f miannu "The transcription factor GATA6, which regulates the promoter activity of CYP17 and CYP11A, was increased in the PCOS compared to normal theca cells." SIGNOR-254197 GATA6 protein Q92908 UNIPROT CYP17A1 protein P05093 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002850 BTO:0000975 15284005 f miannu "The transcription factor GATA6, which regulates the promoter activity of CYP17 and CYP11A, was increased in the PCOS compared to normal theca cells." SIGNOR-254198 GATA6 protein Q92908 UNIPROT HES1 protein Q14469 UNIPROT "up-regulates quantity by expression" 9606 BTO:0000195 24317510 f lperfetto "Many GATA6-dependent genes lacked nearby binding sites but several strongly dependent, synexpressed and GATA6-bound genes encode TFs such as MYC, HES1, RARB and CDX2." SIGNOR-253153 GATA6 protein Q92908 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity by expression" 9606 BTO:0000195 24317510 f lperfetto "Many GATA6-dependent genes lacked nearby binding sites but several strongly dependent, synexpressed and GATA6-bound genes encode TFs such as MYC, HES1, RARB and CDX2." SIGNOR-253152 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 GDF6 protein Q6KF10 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates binding 9606 16049014 t lperfetto "We found that transfection of small hairpin rna for bmprii and actriia in mc3t3 cells suppressed the signaling of gdf6, gdf7, and bmp10. Thus, the present approach provides a genomic paradigm for matching paralogous polypeptide ligands with a limited number of evolutionarily related receptors capable of activating specific downstream smad proteins." SIGNOR-217526 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 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 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 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 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 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 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 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 GEMIN7 protein Q9H840 UNIPROT "SMN complex" complex SIGNOR-C158 SIGNOR "form complex" binding 12065586 t lperfetto "SMN is part of a large macromolecular complex that also contains Gemin2, Gemin3, Gemin4, Gemin5, and Gemin6. The SMN complex functions in the assembly of spliceosomal small nuclear ribonucleoproteins and probably other ribonucleoprotein particles. We have identified a novel protein component of the SMN complex termed Gemin7 using native purified SMN complexes and peptide sequencing by mass spectrometry." SIGNOR-253121 GFI1B protein Q5VTD9 UNIPROT MEF2C protein Q06413 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000661 21261500 f miannu "Here, we analyzed the MEF2C 5'-region, thus identifying potential regulatory binding sites for GFI1B, basic helix-loop-helix proteins, STAT5, and HOXA9/HOXA10. Chromatin immunoprecipitation and overexpression analyses demonstrated direct activation by GFI1B and LYL1 and inhibition by STAT5." SIGNOR-254206 GFI1 protein Q99684 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-254203 GFI1 protein Q99684 UNIPROT CYP27B1 protein O15528 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001033 15947108 f miannu "Identification of growth factor independent-1 (GFI1) as a repressor of 25-hydroxyvitamin D 1-alpha hydroxylase (CYP27B1) gene expression in human prostate cancer cells." SIGNOR-254205 GFI1 protein Q99684 UNIPROT ETS1 protein P14921 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-254201 GFI1 protein Q99684 UNIPROT SPI1 protein P17947 UNIPROT "down-regulates activity" binding 10090 BTO:0000725 17197705 t miannu "Our data demonstrate that GFI-1 physically interacts with PU.1, repressing PU.1-dependent transcription. This repression is functionally significant, as GFI-1 blocked PU.1-induced macrophage differentiation of a multipotential hematopoietic progenitor cell line." SIGNOR-256043 GFs stimulus SIGNOR-ST12 SIGNOR AKT2 protein P31751 UNIPROT "up-regulates activity" 9606 23300340 f lperfetto "Akt normally resides in the cytosol under serum-starved conditions, but translocates to the plasma membrane where it is subsequently phosphorylated and activated in response to growth factor treatment. Phosphorylation of Akt at Thr308 by phosphoinositide-dependent kinase-1 (PDK1) and at Ser473 by mammalian target of rapamycin (mTOR) complex 2 (mTORC2) is required for full Akt activation" SIGNOR-245405 GFs stimulus SIGNOR-ST12 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR up-regulates 9606 23863153 f lperfetto "Growth factors and nutrients regulate the mTORC1 [mammalian (or mechanistic) target of rapamycin complex 1] by different mechanisms. The players that link growth factors and mTORC1 activation have been known for several years and mouse models have validated its relevance for human physiology and disease." SIGNOR-219382 GFs stimulus SIGNOR-ST12 SIGNOR RTKs proteinfamily SIGNOR-PF38 SIGNOR up-regulates 9606 17306385 t miannu "Multiple growth- and differentiation-inducing polypeptide factors bind to and activate transmembrane receptors tyrosine kinases (RTKs), to instigate a plethora of biochemical cascades culminating in regulation of cell fate." SIGNOR-256169 MAPK1 protein P28482 UNIPROT NUP50 protein Q9UKX7 UNIPROT up-regulates phosphorylation Ser221 KVAAETQsPSLFGST 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-188131 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 RPS6KA1 protein Q15418 UNIPROT METTL1 protein Q9UBP6 UNIPROT down-regulates phosphorylation Ser27 YYRQRAHsNPMADHT 9606 BTO:0000007;BTO:0000567 15861136 t gcesareni "Pkb and ribosomal s6 kinase (rsk) both phosphorylated mettl1 at ser27 in vitro." SIGNOR-135948 GHSR protein Q92847 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-256925 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 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 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 GNA12 protein Q03113 UNIPROT ARHGEF11 protein O15085 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 11799111 t "This RGS-like (RGL) domain provides a structural motif by which heterotrimeric G protein alpha subunits of the Galpha(12) family can bind and regulate the activity of RhoGEFs. Hence, these newly discovered RGL domain-containing RhoGEFs provide a direct link from Galpha(12) and Galpha(13) to Rho" SIGNOR-256516 GNA12 protein Q03113 UNIPROT ARHGEF12 protein Q9NZN5 UNIPROT "up-regulates activity" binding 10090 BTO:0000944 12024019 t "P115 RhoGEF stimulates the intrinsic GTP hydrolysis activity of G alpha 12/13 subunits and acts as an effector for G13-coupled receptors by linking receptor activation to RhoA activation." SIGNOR-256522 GNA13 protein Q14344 UNIPROT ARHGEF1 protein Q92888 UNIPROT "up-regulates activity" binding 9606 14607242 t "It turned out that RGS domain of p115RhoGEF is specific for Gα12 and Gα13, and does not bind Gαi, Gαs and Gαq (Kozasa et al., 1998). The binding of Gα13 but not Gα12 stimulated GEF activity for Rho" SIGNOR-256521 GNAI2 protein P04899 UNIPROT ADCY1 protein Q08828 UNIPROT down-regulates binding 9606 17419683 t gcesareni "Evidence suggests that both alpha and beta gamma subunits of heterotrimeric guanine nucleotide-binding regulatory proteins (g proteins) inhibit adenylyl cyclase." SIGNOR-154243 SATB1 protein Q01826 UNIPROT IGFBP2 protein P18065 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000664 17343824 f miannu "We found 59 up-regulated and 75 down-regulated genes in the K562-SATB1 cells that were not observed in the K562 cells. Partial genes that have special biological functions are listed in Table 1." SIGNOR-255129 SATB1 protein Q01826 UNIPROT IL23A protein Q9NPF7 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000664 17343824 f miannu "We found 59 up-regulated and 75 down-regulated genes in the K562-SATB1 cells that were not observed in the K562 cells. Partial genes that have special biological functions are listed in Table 1." SIGNOR-255132 SATB1 protein Q01826 UNIPROT MYB protein P10242 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000664 17343824 f miannu "We found 59 up-regulated and 75 down-regulated genes in the K562-SATB1 cells that were not observed in the K562 cells. Partial genes that have special biological functions are listed in Table 1." SIGNOR-255135 SATB1 protein Q01826 UNIPROT SPARC protein P09486 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000664 17343824 f miannu "In this study, a SATB1 eukaryotic expression plasmid was transfected into the human erythroleukemia K562 cell line and individual clones that stably over-expressed the SATB1 protein were isolated. Microarray analysis revealed that hundreds of genes were either up- or down-regulated in the SATB1 over-expressing K562 cell lines. One of these was the extra-cellular matrix glycoprotein, SPARC (human secreted protein acidic and rich in cysteine). siRNA knock-down of SATB1 also reduced SPARC expression, which was consistent with elevated SPARC levels in the SATB1 over-expressing cell line." SIGNOR-255128 SATB1 protein Q01826 UNIPROT TAF11 protein Q15544 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000664 17343824 f miannu "We found 59 up-regulated and 75 down-regulated genes in the K562-SATB1 cells that were not observed in the K562 cells. Partial genes that have special biological functions are listed in Table 1." SIGNOR-255130 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 BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Tyr654 RNEGVATyAAAVLFR 9606 BTO:0001271 17318191 t lperfetto "Bcr-abl stabilizes beta-catenin in chronic myeloid leukemia through its tyrosine phosphorylationthe notion that y86 and y654 are located respectively within the n_ and c_terminal transcriptional domains of __catenin suggests that one or both residues might regulate the transactivating function of __catenin. In this regard, phosphorylation of y654 was reported to strengthen __catenin association with the basal transcription factor tata_binding protein (tbp)" SIGNOR-153431 EAPP protein Q56P03 UNIPROT MAOB protein P27338 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 20980443 f miannu "we identified two novel transcriptional repressors of MAO B, E2F-associated phosphoprotein (EAPP) and R1 (RAM2/CDCA7L/JPO2), that down-regulate MAO B via MAO B core promoter, which contains Sp1 sites." SIGNOR-253867 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 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 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 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 GNAS protein P63092 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0000887;BTO:0001103;BTO:0001760 22179044 t gcesareni "Notably, the fzd7 receptor complex was associated with g_?(s) and pi(3)k and these components were required for wnt7a to activate the akt/mtor growth pathway in myotubes. These data led us to hypothesize that g_?s Mediates the activation of pi3kinase following wnt7a binding to fzd7." SIGNOR-252678 GNAS protein P63092 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-256539 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 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 GNG12 protein Q9UBI6 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0000586 16293724 t 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-252681 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT down-regulates phosphorylation Thr3950 GHAFGSAtQFLPVPE 9606 17189255 t gcesareni "Ir-induced dna-pkcs phosphorylation at thr-2609 and ser-2056, however, exhibits distinct kinetics indicating that they are differentially regulated. Although dna-pkcs autophosphorylates itself at ser-2056 after ir, we have reported here that atm mediates dna-pkcs phosphorylation at thr-2609 as well as at the adjacent (s/t)q motifs within the thr-2609 cluster." SIGNOR-151453 PURB protein Q96QR8 UNIPROT MYH6 protein P13533 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 12933792 f miannu "In functional assays, PURalpha and PURbeta repressed alpha-myosin heavy chain (alpha-MHC) gene expression in the presence of upstream regulatory sequences of the gene." SIGNOR-253901 SATB2 protein Q9UPW6 UNIPROT UPF3B protein Q9BZI7 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007 23925499 f miannu "chromatin immunoprecipitation demonstrates that SATB2 binds to the UPF3B promoter, and a luciferase reporter assay confirmed that SATB2 expression significantly activates gene transcription using the UPF3B promoter." SIGNOR-255137 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 GNG2 protein P59768 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 17419683 t gcesareni "Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt." SIGNOR-154255 GNG2 protein P59768 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 BTO:0000938 16537363 t gcesareni "Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt." SIGNOR-145122 GNG2 protein P59768 UNIPROT SRC protein P12931 UNIPROT "up-regulates activity" 15345719 f "In this study, we investigated the possible role of the Gβγ heterodimer in signaling Gi-induced Src activation" SIGNOR-251108 GNG3 protein P63215 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 17419683 t gcesareni "Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt" SIGNOR-252685 GNG3 protein P63215 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0000938 16537363 t gcesareni "Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt" SIGNOR-252684 GNG3 protein P63215 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 17419683 t gcesareni "Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt" SIGNOR-154258 GNG3 protein P63215 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates binding 9606 23074268 t gcesareni "Furthermore, this work suggested that the gbetagamma subunits released upon gi activation activated phospholipase c-gamma (plc-gamma) to produce inositol 3 phosphate (ip3) which would subsequently increase intracellular ca2+ abundance." SIGNOR-199141 GNGT1 protein P63211 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 17419683 t gcesareni "Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt" SIGNOR-252686 GNGT1 protein P63211 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0000938 16537363 t gcesareni "Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt" SIGNOR-252687 GNGT1 protein P63211 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 17419683 t gcesareni "Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt" SIGNOR-154261 GPHA2 protein Q96T91 UNIPROT TSHR protein P16473 UNIPROT up-regulates binding 9606 12045258 t gcesareni "Recombinant a2/b5 heterodimeric glycoproteins, purified using cation exchange and size fractionation chromatography, activated human tsh receptors, but not lh and fsh receptors, and showed high affinity to tsh receptors in a radioligand receptor assay" SIGNOR-88614 GPI protein P06744 UNIPROT AMFR protein Q9UKV5 UNIPROT up-regulates binding 9606 12527360 t gcesareni "Pgi is a housekeeping gene encoding phosphoglucose isomerase (pgi) a glycolytic enzyme that also functions as a cytokine (autocrine motility factor (amf)/neuroleukin/maturation factor) upon secretion from the cell and binding to its 78 kda seven-transmembrane domain receptor (gp78/amf-r)" SIGNOR-97270 SMURF2 protein Q9HAU4 UNIPROT SMAD5 protein Q99717 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0001593 BTO:0000140 22298955 t lperfetto "Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps" SIGNOR-153420 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 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 TAF1 protein P21675 UNIPROT TP53 protein P04637 UNIPROT down-regulates phosphorylation Thr55 DDIEQWFtEDPGPDE 9606 15053879 t llicata "Phosphorylation on thr-55 by taf1 mediates degradation of p53" SIGNOR-123651 GPR119 protein Q8TDV5 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-257040 GPR174 protein Q9BXC1 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-257029 Calcineurin complex SIGNOR-C155 SIGNOR 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-252332 BVES protein Q8NE79 UNIPROT VAMP3 protein Q15836 UNIPROT "up-regulates activity" binding -1 20057356 t llicata "Taken together, these data demonstrate that Bves interacts with VAMP3 and facilitates receptor recycling both in vitro and during early development." SIGNOR-237771 Calcineurin complex SIGNOR-C155 SIGNOR 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-252319 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 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 GRB2 protein P62993 UNIPROT ABL1 protein P00519 UNIPROT up-regulates binding 9606 BTO:0001271 8402896 t "GRB2 binds BCR-ABL with SH2 domain" gcesareni "We demonstrate that bcr-abl exists in a complex with grb-2 in vivo. Binding of grb-2 to bcr-abl is mediated by the direct interaction of the grb-2 sh2 domain with a phosphorylated tyrosine, y177, within the bcr first exon." SIGNOR-39049 GPR35 protein Q9HC97 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-257283 GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT "up-regulates activity" relocalization 9606 BTO:0001412 10570290 t "GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP" lperfetto "Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85." SIGNOR-236792 GRB7 protein Q14451 UNIPROT RND1 protein Q92730 UNIPROT up-regulates binding 9606 BTO:0000150 10664463 t gcesareni "We would like to propose that when cells are driven to divide by growth factor stimulation, grb7 relocalizes at the membrane, in the same subcellular compartment as rnd1, where they could interact in vivo." SIGNOR-74914 GRHL2 protein Q6ISB3 UNIPROT ZEB1 protein P37275 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-255624 GRK1 protein Q15835 UNIPROT GRK1 protein Q15835 UNIPROT "down-regulates activity" phosphorylation Thr492 QDVGAFStVKGVAFD -1 1527025 t "The major autophosphorylation site yielded the following sequence: DVGAFS488T489VKGVAFEK, where Ser488 and Thr489 are phosphorylated. Additionally, a minor autophosphorylation site was identified at Ser21. we speculate that autophosphorylation of RK may lower the affinity of the enzyme for Rho* via repulsion between phosphorylated sites on Rho* and the kinase." SIGNOR-251188 GRK2 protein P25098 UNIPROT ADRA2A protein P08913 UNIPROT "down-regulates activity" phosphorylation Ser299 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 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 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 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 Thr331 LTEDSTQtSDTATNS -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-249676 GRK2 protein P25098 UNIPROT FPR1 protein P21462 UNIPROT "down-regulates activity" phosphorylation Thr334 DSTQTSDtATNSTLP -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-251451 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 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 PKN1 protein Q16512 UNIPROT MARCKS protein P29966 UNIPROT "down-regulates activity" phosphorylation Ser163 KRFSFKKsFKLSGFS -1 8557118 t gcesareni "PRK1 phosphorylates MARCKS at the PKC sites: serine 152, serine 156 and serine 163." SIGNOR-249651 PTPN2 protein P17706 UNIPROT EGFR protein P00533 UNIPROT down-regulates dephosphorylation 9606 15592458 t gcesareni "Here, we report that the 45-kda variant of the protein tyrosine phosphatase tcptp (tc45) can recognize delta egfr as a cellular substrate" SIGNOR-132316 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 SNCA protein P37840 UNIPROT down-regulates phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 BTO:0000142 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 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 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 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 HIF1A protein Q16665 UNIPROT EPO protein P01588 UNIPROT "up-regulates quantity" "transcriptional activation" 9606 BTO:0000972 8756616 t "We demonstrate the involvement of HIF-1 in the activation of VEGF transcription. VEGF 5'-flanking sequences mediated transcriptional activation of reporter gene expression in hypoxic Hep3B cells" SIGNOR-256593 RAD50 protein Q92878 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-251506 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 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 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 GSK1016790A chemical CID:23630211 PUBCHEM TRPV4 protein Q9HBA0 UNIPROT "up-regulates activity" binding 23021218 t lperfetto "We next examined whether chemical activation of TRPV4 would have the opposite impact on these pathways. When added to 3T3-F442A adipocytes, the TRPV4 agonist GSK1016790A repressed the expression of mRNAs encoding Pgc1a, Ucp1, and Cox8b in a TRPV4-dependent manner (Fig- ure 2I). Taken together, these data strongly suggest that TRPV4 functions as a negative regulator of PGC1a and oxidative metabolism in white adipocytes." SIGNOR-253094 GSK2126458 chemical CID:25167777 PUBCHEM PIK3CA protein P42336 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192892 GSK2126458 chemical CID:25167777 PUBCHEM PIK3CG protein P48736 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192904 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 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 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 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 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 GSK3A protein P49840 UNIPROT MAFA protein Q8NHW3 UNIPROT up-regulates 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 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 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 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 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 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 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 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 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 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 MRE11/RAD50/NBS1 complex SIGNOR-C147 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 17713585 f lperfetto "The mre11_rad50_nbs1 (mrn) complex is among the earliest respondents to dna double-strand breaks (dsbs).|Current emerging structural and biological evidence suggests that MRN has 3 coupled critical roles in DSB sensing, stabilization, signaling, and effector scaffolding: (1) expeditious establishment of protein--nucleic acid tethering scaffolds for the recognition and stabilization of DSBs; (2) initiation of DSB sensing, cell-cycle checkpoint signaling cascades, and establishment of epigenetic marks via the ATM kinase; and (3) functional regulation of chromatin remodeling in the vicinity of a DSB." SIGNOR-251502 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 "Caspase 8 complex" complex SIGNOR-C231 SIGNOR CASP3 protein P42574 UNIPROT "up-regulates activity" cleavage 9606 BTO:0000007 16964285 t amattioni "Casp8 induces apoptosis by directly activating casp3." SIGNOR-256458 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 CDK1 protein P06493 UNIPROT RPTOR protein Q8N122 UNIPROT unknown phosphorylation Ser696 EKNYALPsPATTEGG 9606 20169205 t llicata "Cdc2 is the raptor ser696, thr706 kinase" SIGNOR-163849 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 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 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 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 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 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 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 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 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 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 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 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 MYC protein P01106 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr58 KKFELLPtPPLSPSR 10116 BTO:0004725 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 PPP2CA protein P67775 UNIPROT PRKCD protein Q05655 UNIPROT "down-regulates activity" dephosphorylation Ser645 LNEKARLsYSDKNLI 9606 11959144 t "PP2A(c) displayed the highest specific activity towards PKCdelta. The role of PP2A(c) in the dephosphorylation of PKCdelta in cells was supported by the demonstration that these proteins could be co-immunoprecipitated from NIH3T3 cells.|In conclusion, the evidence here indicates that PKCdelta de-phosphorylation and hence inactivation is effected by PP2A with which it forms a complex" SIGNOR-248638 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 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Thr41 GIHSGATtTAPSLSG 9606 BTO:0000938 BTO:0000142 19303846 t lperfetto "GSK3β regulates β-catenin stability by phosphorylating serine and threonine residues (Ser33/37 and Thr41) important for targeting β-catenin for ubiquitin-dependent proteasomal degradation" SIGNOR-227878 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 MAFA protein Q8NHW3 UNIPROT down-regulates 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 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 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 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 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 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 GUCA2A protein Q02747 UNIPROT GUCY2C protein P25092 UNIPROT up-regulates binding 9606 BTO:0000672 10845107 t gcesareni "Guanylins activate two receptors, gc-c and ok-gc, which are expressed in intestine and/or kidney" SIGNOR-78096 GUCA2B protein Q16661 UNIPROT GUCY2C protein P25092 UNIPROT up-regulates binding 9606 BTO:0000672 10845107 t gcesareni "Guanylins activate two receptors, gc-c and ok-gc, which are expressed in intestine and/or kidney." SIGNOR-78120 GYS1 protein P13807 UNIPROT Glycogen_synthesis phenotype SIGNOR-PH39 SIGNOR up-regulates 9534 BTO:0004055 14593110 f lperfetto "Glycogen synthase, a key enzyme in the regulation of glycogen synthesis by insulin, is controlled by multisite phosphorylation." SIGNOR-235751 HBA1 protein P69905 UNIPROT AHSP protein Q9NZD4 UNIPROT "down-regulates activity" 9606 2545495 f Regulation miannu "EDRF is rapidly inactivated by hemoglobin and superoxide." SIGNOR-251751 HBA1 protein P69905 UNIPROT APOB protein P04114 UNIPROT "up-regulates quantity by stabilization" 9606 8611031 f "Regulation of binding" miannu "Hemoglobin induced apolipoprotein B crosslinking in low-density lipoprotein peroxidation. Crosslinked apo B was shown to resist lysosomal degradation, thereby causing accumulation of oxidized LDL in macrophages" SIGNOR-251755 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 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 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 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 HAX1 protein O00165 UNIPROT ATP2A2 protein P16615 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 18971376 f miannu "HAX-1 overexpression was associated with down-regulation of SERCA2 expression levels, resulting in significant reduction of apparent ER Ca(2+) levels." SIGNOR-254222 HBA1 protein P69905 UNIPROT TNF protein P01375 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000876 11901318 f "Regulation of expression" miannu "Free hemoglobin enhances tumor necrosis factor-alpha production in isolated human monocytes." SIGNOR-251753 HBB protein P68871 UNIPROT ADAMTS13 protein Q76LX8 UNIPROT "down-regulates activity" 9606 15367436 f "Regulation of binding" miannu "Incubation of hemoglobin, recombinant and from lysed erythrocytes, with normal plasma revealed an ADAMTS13 inhibitory effect at hemoglobin concentrations of 2 g/L or higher." SIGNOR-251748 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 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 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 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 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-254029 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 GLI1 protein P08151 UNIPROT "up-regulates activity" deacetylation 20081843 t "Here, we identify a mechanism whereby Hh signalling is regulated, in which acetylation of Gli1 at Lys 518 represents a transcriptional inhibitory switch, while its HDAC1-mediated deacetylation is responsible for transcriptional activation." SIGNOR-253544 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 HDAC2 protein Q92769 UNIPROT CIITA protein P33076 UNIPROT "down-regulates quantity by repression" deacetylation 9606 BTO:0000801;BTO:0004576 19041327 t miannu "We report that CIITA and histone deacetylase 2 (HDAC2) interact in smooth muscle cells and macrophages as assayed by co-immunoprecipitations. HDAC2 deacetylates CIITA whereas both the HDAC inhibitor trichostatin A (TSA) and over-expression of HDAC2 interfering RNA increase CIITA acetylation. HDAC2 down-regulates CIITA recruitment to target promoters as evidenced by chromatin immunoprecipitation assays, and suppresses MHC II activation and collagen repression mediated by CIITA in luciferase reporter assays." SIGNOR-254231 HDAC2 protein Q92769 UNIPROT HPGD protein P15428 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 19010907 f miannu "We show an interaction between Snail and HDAC2 and the binding of HDAC2 to the 15-PGDH promoter. These data suggest that class I HDACs, specifically HDAC2, and the transcriptional repressor Snail play a central role in the suppression of 15-PGDH expression." SIGNOR-254236 HDAC2 protein Q92769 UNIPROT TWIST1 protein Q15672 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001939 23836662 f miannu "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-254154 HDAC3 protein O15379 UNIPROT SMAD7/HDAC1/E2F-1 complex SIGNOR-C12 SIGNOR up-regulates binding 9606 23213415 t lperfetto "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-217358 HDAC4 protein P56524 UNIPROT MEF2A protein Q02078 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-76231 HDAC4 protein P56524 UNIPROT MEF2D protein Q14814 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-76237 HES1 protein Q14469 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 BTO:0000011 16282371 f "Notch signaling blocks differentiation of 3T3-L1 preadipocytes, and this can be mimicked by constitutive expression of the Notch target gene Hes-1" SIGNOR-253058 HES1 protein Q14469 UNIPROT CTNND2 protein Q9UQB3 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0001033 21106062 f miannu "Coordinated regulation of δ-catenin expression by both the activating transcription factor E2F1 and repressive transcription factor Hes1 in prostate cancer progression." SIGNOR-251877 HES1 protein Q14469 UNIPROT NR3C1 protein P04150 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 19129776 t gcesareni "HES1 binding to the promoter of the NC3C1 gene inhibits its expression and results in insufficient production of the encoded glucocorticoid receptor- rendering these cells resistant to treatment with dexamethasone" SIGNOR-251674 HES1 protein Q14469 UNIPROT PTGDS protein P41222 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002605 15743775 f miannu "knock-down of Hes-1 mRNA by RNA interference significantly enhanced the L-PGDS mRNA level, indicating that the L-PGDS gene expression is repressed by the Notch-Hes signaling." SIGNOR-255424 HEY1 protein Q9Y5J3 UNIPROT MEF2C protein Q06413 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103 19917614 f lperfetto "Our results indicate instead that hey1 is recruited to the promoter regions of myogenin and mef2c, two genes whose induction is critical for myogenesis." SIGNOR-235819 1-[4-[[2-(2-amino-5-pyrimidinyl)-7-methyl-4-(4-morpholinyl)-6-thieno[3,2-d]pyrimidinyl]methyl]-1-piperazinyl]-2-hydroxy-1-propanone chemical CHEBI:93753 ChEBI PIK3CD protein O00329 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192617 HEY1 protein Q9Y5J3 UNIPROT MYOG protein P15173 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103 19917614 f lperfetto "Our results indicate instead that hey1 is recruited to the promoter regions of myogenin and mef2c, two genes whose induction is critical for myogenesis." SIGNOR-235822 HHAT protein Q5VTY9 UNIPROT SHH protein Q15465 UNIPROT up-regulates palmitoylation 9606 15075292 t gcesareni "Our molecular analysis of knockout mice deficient in skn, the murine homolog of the drosophila ski gene, which catalyzes hh palmitoylation, and gene-targeted mice producting a non palmitoylated form of shh indicates that hh palmitoylation is essential for its activity as well as the generation of a protein gradient in the developing embryos" SIGNOR-124118 HHEX protein Q03014 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR "up-regulates activity" 10090 BTO:0000089 26728554 f "Hhex is a potential therapeutic target that is specifically required for AML stem cells to repress tumor suppressor pathways and enable continued self-renewal." SIGNOR-256306 HHIP protein Q96QV1 UNIPROT IHH protein Q14623 UNIPROT "down-regulates activity" binding 10090 10050855 t lperfetto "Hip encodes a membrane glycoprotein that binds to all three mammalian hedgehog proteins with an affinity comparable to that of ptc-1. our findings support a model in which hip attenuates hedgehog signalling as a result of binding to hedgehog proteins: a negative regulatory feedback loop established in this way could thus modulate the responses to any hedgehog signal." SIGNOR-65075 HHIP protein Q96QV1 UNIPROT SHH protein Q15465 UNIPROT "down-regulates activity" binding 10090 10050855 t lperfetto "Hip encodes a membrane glycoprotein that binds to all three mammalian hedgehog proteins with an affinity comparable to that of ptc-1. our findings support a model in which hip attenuates hedgehog signalling as a result of binding to hedgehog proteins: a negative regulatory feedback loop established in this way could thus modulate the responses to any hedgehog signal." SIGNOR-65078 HIC1 protein Q14526 UNIPROT EPHA2 protein P29317 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001211 22184117 f miannu "The receptor tyrosine kinase EphA2 is a direct target gene of hypermethylated in cancer 1 (HIC1). we observe that inactivation of endogenous HIC1 through RNA interference in normal breast epithelial cells results in the up-regulation of EphA2 and is correlated with increased cellular migration. chromatin immunoprecipitation (ChIP) and sequential ChIP experiments demonstrate that endogenous HIC1 proteins are bound, together with the MTA1 corepressor, to the EphA2 promoter in WI38 cells." SIGNOR-254241 HLTF protein Q14527 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-254425 HMGB1 protein P09429 UNIPROT HOXB1 protein P14653 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-219853 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 HMGB2 protein P26583 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-254429 HMGB2 protein P26583 UNIPROT POU2F2 protein P09086 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-240108 HMOX1 protein P09601 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0004296 21037234 f irozzo "In conclusion, AMPK stimulates HO-1 gene expression in human ECs via the Nrf2/antioxidant responsive element signaling pathway. The induction of HO-1 mediates the antiapoptotic effect of AMPK, and this may provide an important adaptive response to preserve EC viability during periods of metabolic stress." SIGNOR-256302 HMOX1 protein P09601 UNIPROT BCL2 protein P10415 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000356 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 Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000848 17148680 f irozzo "Here we investigated the effects of HO-1 overexpression in murine and human melanoma cells. The most important findings of our study are that 1) overexpression of HO-1 augments the proliferation [.]" SIGNOR-256295 HNF1A protein P20823 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-251720 HOOK3 protein Q86VS8 UNIPROT MSR1 protein P21757 UNIPROT down-regulates binding 9606 BTO:0000801 17237231 t miannu "We have identified a microtubule-binding protein, hook3, as a novel interacting partner of sr-a. / by transfecting small interfering rna targeting hook3, total and surface expression, receptor-mediated ligand uptake and protein stability of sr-a were significantly promoted, whereas the protein synthesis and maturation were not altered. We propose for the first time that hook3 may participate in the turnover of the endocytosed scavenger receptor" SIGNOR-152314 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 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 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 HOXB13 protein Q92826 UNIPROT TCF4 protein P15884 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001033 15928669 f miannu "In prostate cancers, HOXB13 negatively regulates beta-catenin/TCF4-mediated transactivation and subsequently inhibits cell growth. " SIGNOR-254476 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 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 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 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 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 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 PIK3CB protein P42338 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." SIGNOR-175189 PRKG1 protein Q13976 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser795 TASTRKVsLAPQANL 9606 1377674 t lperfetto "Direct amino acid sequencing and peptide mapping of cf-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by pka and pkgcftr possesses a large cluster of strict dibasic consensus sites for phosphorylation by protein kinase a (pka) in the r-domain and an obligatory dependence on phosphorylation is a hallmark of cftr cl(-) channel function" SIGNOR-18249 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 TRADD protein Q15628 UNIPROT RIPK1 protein Q13546 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 8612133 t lperfetto "We show that tradd interacts strongly with rip;rip is a serinethreonine kinase that is recruited by tradd to tnfr1 in a tnf-dependent process." SIGNOR-40043 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 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 IGF1 protein P05019 UNIPROT PPP3CB protein P16298 UNIPROT up-regulates 10090 BTO:0000165;BTO:0002314 BTO:0000887;BTO:0001103;BTO:0001760 10448861 f 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-235825 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 BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR VAV1 protein P15498 UNIPROT up-regulates phosphorylation 9606 BTO:0001271 11790798 t lperfetto "Thus, the c-terminal tail of vav serves as a direct substrate of bcr-abl in vitro." SIGNOR-114094 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 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 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 TGFBR1 protein P36897 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-179268 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 HSP90AB1 protein P08238 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-252415 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 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 HSPB1 protein P04792 UNIPROT CASP3 protein P42574 UNIPROT down-regulates 9606 10544189 f gcesareni "Hsp27 overexpression delays poly(adp-ribose)polymerase cleavage and procaspase-3 activation." SIGNOR-71869 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 PRKCA protein P17252 UNIPROT RHO protein P08100 UNIPROT unknown phosphorylation Ser343 TVSKTETsQVAPA -1 9099669 t lperfetto "Thus, the primary protein kinase C sites are Ser334 and Ser338, with minor phosphorylation of Thr335/336 and Ser343." SIGNOR-248968 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 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 SRC protein P12931 UNIPROT PTPRA protein P18433 UNIPROT "up-regulates activity" phosphorylation Tyr798 YIDAFSDyANFK 9606 BTO:0000007 7518772 t "The effect has been demonstrated using P18433-2" lperfetto "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." SIGNOR-111306 HTR1D protein P28221 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-256721 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 IFNAR1 protein P17181 UNIPROT up-regulates binding 9606 1834641 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-21700 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 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 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 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 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 TAOK proteinfamily SIGNOR-PF21 SIGNOR STK4 protein Q13043 UNIPROT up-regulates phosphorylation 9606 23431053 t milica "In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2." SIGNOR-230710 TGFB2 protein P61812 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates binding 9606 1310899 t gcesareni "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-16690 HES1 protein Q14469 UNIPROT MYOD1 protein P15172 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000165 BTO:0000887 10066785 f lperfetto "Notch signaling up-regulated hes1 mrna expression within 1 h and subsequently reduced expression of myod mrna." SIGNOR-235596 IFNGR1 protein P15260 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 15864272 t gcesareni "The only type ii ifn, ifn-g, binds a distinct cell-surface receptor, which is known as the type ii ifn receptor. This receptor is also composed of two subunits, ifngr1 and ifngr2, which are associated with jak1 and jak2, respectively. Activation of the jaks that are associated with the type i ifn receptor results in tyrosine phosphorylation of stat2" SIGNOR-135952 IFNGR2/INFGR1 complex SIGNOR-C142 SIGNOR 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-249506 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 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 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 PIK3C2A protein O00443 UNIPROT up-regulates phosphorylation 9606 7692086 t gcesareni "Analysis of the ability of the full-length igfr and its mutant receptors described above to associate with phosphatidylinositol 3 kinase indicated that the association required ptk activity and tyrosine [?] Phosphorylation of the receptors and correlated well with their transforming activities" SIGNOR-32076 IGF1R protein P08069 UNIPROT PIK3R1 protein P27986 UNIPROT 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-179386 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 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 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT "down-regulates activity" phosphorylation Ser682 SMNASRLsQPGQLMS 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-251278 JNK proteinfamily SIGNOR-PF15 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Thr41 GIHSGATtTAPSLSG 9606 19667122 t lperfetto "Specifically, we provide evidence that jnk binds to e-cadherin/beta-catenin complex and phosphorylates beta-catenin at serine 37 and threonine 41, the sites also phosphorylated by gsk-3beta." SIGNOR-187582 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 PRKACA protein P17612 UNIPROT CBX3 protein Q13185 UNIPROT up-regulates phosphorylation Ser93 KDGTKRKsLSDSESD 9606 16531993 t gcesareni "We demonstrate that p-ser 83-hp1gamma has an exclusively euchromatic localization, interacts with ku70 (a regulatory protein involved in multiple nuclear procesess), has impaired silencing activity and serves as a marker for transcription elongation." SIGNOR-145109 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 CSNK1G1 protein Q9HCP0 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Ser322 PRTSSNAsTISGRLS -1 11980723 t llicata "Phosphorylation of Ser319 forms a consensus sequence for phosphorylation by CK1, allowing it to phosphorylate Ser322, which in turn primes the CK1-catalysed phosphorylation of Ser325 | Multisite phosphorylation of the region containing Ser319, Ser322, Ser325 and Ser329 provides a signal for the nuclear exclusion of FKHR" SIGNOR-252901 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MAPK6 protein Q16659 UNIPROT up-regulates phosphorylation 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. 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-216809 EIF2AK3 protein Q9NZJ5 UNIPROT EIF2S1 protein P05198 UNIPROT down-regulates phosphorylation Ser52 MILLSELsRRRIRSI 9606 17998206 t lperfetto "The endoplasmic reticulum (er)-resident protein kinase perk attenuates protein synthesis in response to er stress through the phosphorylation of translation initiation factor eif2_ at serine 51 / a modification that blocks initiation" SIGNOR-159160 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 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 IKBKB protein O14920 UNIPROT "down-regulates activity" phosphorylation Ser670 SKVRGPVsGSPDSMN 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-251274 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT "down-regulates activity" phosphorylation Ser679 SPDSMNAsRLSQPGQ 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-251277 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 PRKCD protein Q05655 UNIPROT PA2G4 protein Q9UQ80 UNIPROT up-regulates phosphorylation Ser360 ELKALLQsSASRKTQ 9606 BTO:0000938 21145366 t gcesareni "Trk receptor activation by both ngf and bdnf induced phosphorylation of ebp1 at the s360 upon the activation of protein kinase c (pkc ) and triggered dissociation of p48 from retinoblastoma (rb" SIGNOR-170348 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 RPS6KA5 protein O75582 UNIPROT HIST1H3A 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 SRC protein P12931 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Tyr340 RGQRDSSyYWEIEAS 9606 12551923 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-97635 STK3 protein Q13188 UNIPROT SAV1 protein Q9H4B6 UNIPROT up-regulates phosphorylation -1 BTO:0000007 16930133 t milica "In vitro phosphorylation experiments indicate that the phosphorylation of Sav by Mst is direct. The stabilizing effect of Mst was much greater on N-terminally truncated hSav mutants, as long as they retained the ability to bind Mst. Mst mutants that lacked the C-terminal coiled-coil domain and were unable to bind to hSav, also failed to stabilize or phosphorylate hSav" SIGNOR-230716 TBK1 protein Q9UHD2 UNIPROT IKBKE protein Q14164 UNIPROT "up-regulates activity" binding 9606 18353649 t lperfetto "Whereas nemo assembles some but not all ikk complexes [12,13], recent reports provide strong experimental evidence for a role of tank [also called traf-interacting protein (i-traf)], nak-associated protein (nap1) and similar to nap1 tbk1 adaptor (sintbad) in the assembly of tbk1 and ikk-e kinase complexes that phosphorylate irf3 and irf7 and promote type i ifn gene induction" SIGNOR-178053 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 WNT9B protein O14905 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 20093360 t gcesareni "We find that wnt9b binds to a different part of the lrp6 extracellular domain" SIGNOR-163552 6-{4-[(4-ethylpiperazin-1-yl)methyl]phenyl}-N-[(1R)-1-phenylethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine chemical CHEBI:40629 ChEBI ERBB2 protein P04626 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189347 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 IKBKG protein Q9Y6K9 UNIPROT "up-regulates activity" phosphorylation Ser31 QDVLGEEsPLGKPAM 9606 BTO:0000007 12657630 t "IKKbeta phosphorylates human IKKgamma at Ser-31, Ser-43, and Ser-376. IKKβ mediates IKKγ phosphorylation under physiologic signaling conditions. IKKγ is chronically phosphorylated in cells expressing the HTLV1 Tax oncoprotein, which interfaces directly with the IκB kinase complex.both Tax and TNF induce phosphorylation of human IKKγ at Ser-31, Ser-43, and Ser-376." SIGNOR-251285 IKBKB protein O14920 UNIPROT IKBKG protein Q9Y6K9 UNIPROT "up-regulates activity" phosphorylation Ser43 PAMLHLPsEQGAPET 9606 BTO:0000007 12657630 t "IKKbeta phosphorylates human IKKgamma at Ser-31, Ser-43, and Ser-376. IKKβ mediates IKKγ phosphorylation under physiologic signaling conditions. IKKγ is chronically phosphorylated in cells expressing the HTLV1 Tax oncoprotein, which interfaces directly with the IκB kinase complex.both Tax and TNF induce phosphorylation of human IKKγ at Ser-31, Ser-43, and Ser-376." SIGNOR-251287 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 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates phosphorylation 9606 10469655 t lperfetto "Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway." SIGNOR-217400 IKBKB protein O14920 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 BTO:0000150;BTO:0000782 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-217427 NFKB1 protein P19838 UNIPROT RELA protein Q04206 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 9450761 t lperfetto "Here we report the crystal structure at 2.9 a resolution of the p50/p65 heterodimer bound to the kappab dna" SIGNOR-55378 PCSK7 protein Q16549 UNIPROT RELA protein Q04206 UNIPROT up-regulates 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103 14767066 f lperfetto "Treatment with sb203580 significantly reduced this cooperation, consistent with the idea that p38 indirectly stimulates the transactivating activity of p65 through a mechanism involving cbp." SIGNOR-235734 RELA protein Q04206 UNIPROT TRAF2 protein Q12933 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9733516 f lperfetto "Thus, our data indicate that nf-kb controls the expression of traf1 and traf2 and c-iap1 and c-iap2" SIGNOR-59960 RHEB protein Q15382 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR "up-regulates activity" 9606 19222999 t lperfetto "Recent studies document that Rheb activates mTORC1 via direct, GTP-dependent interaction with the peptidyl-prolyl-cis/trans-isomerase FKBP38, which is proposed to act as an inhibitor of mTORC1." SIGNOR-232208 SRC protein P12931 UNIPROT SPTAN1 protein Q13813 UNIPROT up-regulates phosphorylation Tyr1176 AVQQQEVyGMMPRDE 9606 BTO:0000671 11971983 t llicata "Using mutagenesis on recombinant peptides, we identified the residue y1176 located in the calpain cleavage site of alpha ii-spectrin, near the sh3 domain, as an in vitro substrate for src kinase and lmw-ptp a. phosphorylation of this residue decreases spectrin sensitivity to calpain in vitro." SIGNOR-86718 TBX3 protein O15119 UNIPROT CDH1 protein P12830 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000848 25595898 f miannu "AKT phosphorylation potentiates the ability of TBX3 to repress the transcription of the E-cadherin gene" SIGNOR-223537 TRAF6 protein Q9Y4K3 UNIPROT TAB2 protein Q9NYJ8 UNIPROT "up-regulates activity" binding 9606 25290089 t lperfetto "The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex." SIGNOR-205458 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 SOX6 protein P35712 UNIPROT "down-regulates activity" sumoylation Lys417 TSPVTQkVkDEAAAQP 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-256130 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 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 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 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 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 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 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 IKBKE protein Q14164 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 BTO:0000150;BTO:0000551 23691078 t lperfetto "Ikbke phosphorylation and inhibition of foxo3a: a mechanism of ikbke oncogenic functionhere we report that ikbke regulates foxo3a through phosphorylation of foxo3a-ser644. The phosphorylation of foxo3a resulted in its degradation and nuclear-cytoplasmic translocation." SIGNOR-202054 IKBKE protein Q14164 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 BTO:0000150;BTO:0000551 23691078 t lperfetto "Ikbke phosphorylation and inhibition of foxo3a: a mechanism of ikbke oncogenic functionhere we report that ikbke regulates foxo3a through phosphorylation of foxo3a-ser644. The phosphorylation of foxo3a resulted in its degradation and nuclear-cytoplasmic translocation." SIGNOR-252949 IKBKE protein Q14164 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. |TBK-1 and IKK-i phosphorylate Ser36 of IkappaBalpha." SIGNOR-249367 NLK protein Q9UBE8 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT down-regulates phosphorylation Thr212 TYSNEHFtPGNPPPH 9606 12556497 t llicata "Nlk phosphorylates lef-1/tcf on two serine/threonine residues located in its central region. Mutation of both residues to alanine enhanced lef-1 transcriptional activity and rendered it resistant to inhibition by nlk." SIGNOR-97873 PKNOX1 protein P55347 UNIPROT HOXA1 protein P49639 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 9582372 t miannu "Our results are consistent with a primary interaction of the YPWM motif of HOXA1 with the homeodomain of PBX. HOX proteins are dependent upon cofactors of the PBX family for specificity of DNA binding." SIGNOR-220242 IKK-complex complex SIGNOR-C14 SIGNOR FOXO3 protein O43524 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser644 GLDFNFDsLISTQNV 9606 19188143 t lperfetto "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-209769 IKK-complex complex SIGNOR-C14 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates quantity by destabilization" phosphorylation Ser644 GLDFNFDsLISTQNV 9606 19188143 t lperfetto "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-252951 IKK-complex complex SIGNOR-C14 SIGNOR HES1 protein Q14469 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000584 22056382 f "Tnf-α enhanced the transcriptional activity of a classical Notch target gene via Ikk2 by inducing histone H3 phosphorylation" SIGNOR-253586 IKK-complex complex SIGNOR-C14 SIGNOR IKBKG protein Q9Y6K9 UNIPROT down-regulates phosphorylation Ser43 PAMLHLPsEQGAPET 9606 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-216403 IKK-complex complex SIGNOR-C14 SIGNOR IKBKG protein Q9Y6K9 UNIPROT down-regulates phosphorylation Ser85 ELLHFQAsQREEKEF 9606 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-216353 IKK-complex complex SIGNOR-C14 SIGNOR NCOR2 protein Q9Y618 UNIPROT down-regulates phosphorylation Ser2418 AKVSGRPsSRKAKSP 9606 15494311 t "Translocation from Nucleus to Cytoplasm" lperfetto "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-216393 IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 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-216389 IKK-complex complex SIGNOR-C14 SIGNOR 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-216341 IKZF1 protein Q13422 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-255403 IKZF2 protein Q9UKS7 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-255404 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 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 PRKCD protein Q05655 UNIPROT EP300 protein Q09472 UNIPROT down-regulates phosphorylation Ser89 SELLRSGsSPNLNMG 9606 12379484 t lperfetto "Inhibition of histone acetyltransferase function of p300 by pkcdeltawe found that pkcdelta but not classical pkc, specifically phosphorylates p300 at serine 89 in vitro and in vivo. This phosphorylation causes inhibition of p300 intrinsic hat activity." SIGNOR-94263 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT up-regulates phosphorylation Tyr1165 RDIYETDyYRKGGKG 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-45126 940929-33-9 chemical CID:49867937 PUBCHEM KIF11 protein P52732 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206724 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 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 IL10 protein P22301 UNIPROT SCN11A protein Q9UI33 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-253502 IL10 protein P22301 UNIPROT SCN1A protein P35498 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-253497 IL10 protein P22301 UNIPROT SCN2A protein Q99250 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-253499 IL10 protein P22301 UNIPROT SCN3A protein Q9NY46 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-253504 IL10 protein P22301 UNIPROT SCN4A protein P35499 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-253500 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 SCN9A protein Q15858 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-253498 IL10RA protein Q13651 UNIPROT JAK2 protein O60674 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000801 26260587 t lperfetto "IL10R2 recruits cytoplasmic protein Jak1 followed by phosphorylation of tyrosine at position 705 in the STAT3 (705Y-STAT3) molecule. Phosphorylated STAT3 forms a homodimer, which is then translocated to the nucleus to facilitate transcriptional regulation of target genes." SIGNOR-249545 IL10RB protein Q08334 UNIPROT TYK2 protein P29597 UNIPROT up-regulates binding 9606 BTO:0000801;BTO:0000776 10347215 t milica "Specifically, il-10 effects the activation of jak1 (associated with the il-10 receptor ? Chain) and tyk2 (associated with the il-10 receptor ? Chain) and induces the activation of stat1, stat3, and, in some cells, stat5." SIGNOR-68013 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 IL15RA protein Q13261 UNIPROT JAK3 protein P52333 UNIPROT up-regulates phosphorylation 9606 30029643 t areggio "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-256225 IL15RA protein Q13261 UNIPROT PPARG protein P37231 UNIPROT "down-regulates activity" 9606 30029643 f areggio "In addition, level of mRNAs encoding C/EBPa, PPARg and FABP4, the classic adipogenic markers, was significantly lower in samples administrated with IL-15" SIGNOR-256228 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-234441 IL15RA protein Q13261 UNIPROT TYK2 protein P29597 UNIPROT up-regulates 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-256253 IL17A protein Q16552 UNIPROT IL17RA protein Q96F46 UNIPROT up-regulates binding 9606 BTO:0000782 9367539 t gcesareni "Binding studies suggest that recombinant hil-17 binds to the hil-17r with low affinity. Monoclonal antibodies (mabs) generated against the hil-17r were able to block the il-17-induced production of cytokine from human foreskin fibroblast (hff) cells." SIGNOR-53249 IL17A protein Q16552 UNIPROT KLF15 protein Q9UIH9 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 23332504 f fspada "Specifically, il-17 suppresses klf15, a pro-adipogenic tf, and enhances expression of klf2 and klf3, which are anti-adipogenic." SIGNOR-192474 IL17A protein Q16552 UNIPROT KLF2 protein Q9Y5W3 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 23332504 f fspada "Specifically, il-17 suppresses klf15, a pro-adipogenic tf, and enhances expression of klf2 and klf3, which are anti-adipogenic." SIGNOR-192477 IL17A protein Q16552 UNIPROT KLF2 protein Q9Y5W3 UNIPROT up-regulates "transcriptional regulation" 9606 23332504 f fspada "Specifically, il-17 suppresses klf15, a pro-adipogenic tf, and enhances expression of klf2 and klf3, which are anti-adipogenic. " SIGNOR-210111 IL17A protein Q16552 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-255232 IL17B protein Q9UHF5 UNIPROT IL17RB protein Q9NRM6 UNIPROT up-regulates binding 9606 BTO:0000130 BTO:0000975;BTO:0000142;BTO:0000671 10749887 t gcesareni "Here we report on the discovery of a novel il-17 homolog (il-17b), together with the identification of a novel cell surface receptor that specifically binds to it. We detail the molecular cloning, tissue distribution, and expression of both il-17b and il-17br, describe thein vivo activity of il-17b, and demonstrate binding to il-17br." SIGNOR-76544 IL19 protein Q9UHD0 UNIPROT IL20RB protein Q6UXL0 UNIPROT up-regulates binding 9606 17208301 t gcesareni "Il-19 signals only through the type i il-20r complex." SIGNOR-151820 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 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 IL1B protein P01584 UNIPROT ENPP1 protein P22413 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000249 7479785 f miannu "Interleukin 1 beta suppresses transforming growth factor-induced inorganic pyrophosphate (PPi) production and expression of the PPi-generating enzyme PC-1 in human chondrocytes. IL-1 beta may be an important regulator of mineralization in chondrocytes by inhibiting TGF beta-induced PPi production and PC-1 expression." SIGNOR-252199 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 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 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 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 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 SMAD2 protein Q15796 UNIPROT SMURF2 protein Q9HAU4 UNIPROT "up-regulates activity" binding 9606 11389444 t lperfetto "We show that in the presence of TGF-beta signalling, Smad2 interacts through its proline-rich PPXY motif with the tryptophan-rich WW domains of Smurf2, a recently identified E3 ubiquitin ligases.Thus, stimulation by TGF-beta can induce the assembly of a Smad2-Smurf2 ubiquitin ligase complex that functions to target substrates for degradation." SIGNOR-108490 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-66032 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 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 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 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 IL1RAP protein Q9NPH3 UNIPROT IL1R1 protein P14778 UNIPROT up-regulates binding 9606 12530978 t gcesareni "Here we report that the soluble form of the il-1 receptor accessory protein (acp) increases the affinity of binding of human il-1alpha and il-1beta to the soluble human type ii il-1 receptor by approximately 100-fold," SIGNOR-97396 IL1RAP protein Q9NPH3 UNIPROT TOLLIP protein Q9H0E2 UNIPROT "down-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-251979 IL2 protein P60568 UNIPROT IL2RB protein P14784 UNIPROT up-regulates binding 9606 16477002 t miannu "Il-2 is a cytokine that functions as a growth factor and central regulator in the immune system and mediates its effects through ligand-induced hetero-trimerization of the receptor subunits il-2r alpha, il-2r beta, and gamma(c)." SIGNOR-144540 IL2 protein P60568 UNIPROT IL2RG protein P31785 UNIPROT up-regulates binding 9606 16477002 t miannu "Il-2 is a cytokine that functions as a growth factor and central regulator in the immune system and mediates its effects through ligand-induced hetero-trimerization of the receptor subunits il-2r alpha, il-2r beta, and gamma(c)." SIGNOR-144543 IL2 protein P60568 UNIPROT NAB2 protein Q15742 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 22128144 f miannu "We observe that the CD8(+) T-cell autocrine growth factor IL-2 coordinately increases Nab2 expression and decreases TRAIL expression." SIGNOR-253894 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 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-221893 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 RFXANK protein O14593 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-221571 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 TFAP4 protein Q01664 UNIPROT MDM2 protein Q00987 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001109 19505873 f miannu "AP-4 Mediates E-box-dependent Complex Formation for Transcriptional Repression of HDM2" SIGNOR-226596 IL21 protein Q9HBE4 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-108858 IL21 protein Q9HBE4 UNIPROT PAX5 protein Q02548 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782;BTO:0000785 22486304 f miannu "Interleukin-21 inhibits humoral response to an hiv dna vaccine by enhancing bcl-6 andpax-5expression." SIGNOR-196921 IL21R protein Q9HBE5 UNIPROT JAK3 protein P52333 UNIPROT up-regulates binding 9606 BTO:0000776 12093291 t gcesareni "Retroviral-mediated transduction of wild-type gamma c into xscid jt cells restored function to the il-21r, as shown by il-21-induced tyrosine phosphorylation of jak1 and jak3, and downstream activation of stat5" SIGNOR-90269 IL21R protein Q9HBE5 UNIPROT STAT3 protein P40763 UNIPROT up-regulates 9606 BTO:0000876 BTO:0000763;BTO:0001253 15667561 f gcesareni "Interleukin 24 (il-24) is a new member of the il-10 family of cytokines and it signals through two heterodimeric receptors: il-20r1/il-20r2 and il-22r1/il-20r2. Upon binding to its receptors, il-24 induces rapid activation of stat-1 and stat-3 transcription factors," SIGNOR-133379 IL23A protein Q9NPF7 UNIPROT IL23R protein Q5VWK5 UNIPROT up-regulates binding 9606 BTO:0000782 12023369 t gcesareni "We identify a novel member of the hemopoietin receptor family as a subunit of the receptor for il-23, il-23r." SIGNOR-87805 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 IL23R protein Q5VWK5 UNIPROT JAK2 protein O60674 UNIPROT up-regulates binding 9606 BTO:0000782 12023369 t gcesareni "Il-23 activates the same jak-stat signaling molecules as il-12: jak2, tyk2, and stat1, -3, -4, and -5, but stat4 activation is substantially weaker and different dna-binding stat complexes form in response to il-23 compared with il-12." SIGNOR-87808 IL23R protein Q5VWK5 UNIPROT STAT4 protein Q14765 UNIPROT up-regulates 9606 BTO:0000782 12023369 f gcesareni "Il-23 activates the same jak-stat signaling molecules as il-12: jak2, tyk2, and stat1, -3, -4, and -5, but stat4 activation is substantially weaker and different dna-binding stat complexes form in response to il-23 compared with il-12." SIGNOR-87838 IL27 protein Q8NEV9 UNIPROT IL27RA protein Q6UWB1 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000876 14764690 t gcesareni "Wsx-1 and glycoprotein 130 constitute a signal-transducing receptor for il-27." SIGNOR-121799 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 IL34 protein Q6ZMJ4 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-255569 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 IL3 protein P08700 UNIPROT IL3RA protein P26951 UNIPROT up-regulates binding 9606 BTO:0000876 1465408 t fspada "These results show the generation of an il-3 analog with increased biological and binding activities and support a model where the c terminus of il-3 interacts with the alpha chain of the il-3 receptor, making this region a useful focus for the development of more potent il-3 agonists or antagonists" SIGNOR-19538 IL3 protein P08700 UNIPROT NFIL3 protein Q16649 UNIPROT up-regulates 10090 BTO:0003104 10082541 f lperfetto "We previously reported that NFIL3 is an IL-3-responsive gene in Baf-3 cells" SIGNOR-242763 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 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 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 IL5 protein P05113 UNIPROT AKT1 protein P31749 UNIPROT up-regulates 9606 21106848 f "It has been reported that IL-5 family members and selected chemotactic factors can activate the PI3K-Akt pathway in human blood eosinophils" SIGNOR-254351 IL5 protein P05113 UNIPROT IL5RA protein Q01344 UNIPROT up-regulates binding -1 8567620 t fspada "Single chain and wt il5 also had similar binding affinity for soluble il5 receptor alpha chain, the specificity subunit of the il5 receptor, as measured kinetically with an optical biosensor." SIGNOR-40039 PF-04691502 chemical CID:25033539 PUBCHEM AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates "chemical inhibition" 9606 Other t "Selleck;inhibitor of phosphorylation of AktT308 and AktS473" gcesareni SIGNOR-205977 GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT "up-regulates activity" relocalization 9606 8479541 t "GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP" lperfetto "Furthermore, our results indicate that the interaction domains of sos1 and grb2 have evolved so as to bind ligands not with maximal strength but with specificities and affinities that maintain cooperativity. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85." SIGNOR-39163 IL5RA protein Q01344 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 21106848 f "Human blood eosinophils exhibit a hyperactive phenotype in response to chemotactic factors after cell priming with IL-5 family cytokines. Earlier work has identified ERK1/2 as molecular markers for IL-5 priming" SIGNOR-254350 IL5RA protein Q01344 UNIPROT JAK2 protein O60674 UNIPROT "up-regulates activity" phosphorylation 9606 7602114 t "Jak 2 is physically associated with the IL-5b receptor. The binding of IL-5 to its receptor results in tyrosine phosphorylation and activation of Jak 2 tyrosine kinase within 1 to 3 min." SIGNOR-254352 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 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 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 IL6ST protein P40189 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 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 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 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 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 ILK protein Q13418 UNIPROT MYL12B protein O14950 UNIPROT "up-regulates activity" phosphorylation Thr19 KKRPQRAtSNVFAMF 9606 BTO:0000887;BTO:0001260 11278951 t lperfetto "Integrin-linked kinase cdna was cloned, sequenced, expressed in e. coli, and shown to phosphorylate myosin light chain in the absence of ca(2+) at ser(19) and thr(18). Smooth muscle contraction follows an increase in cytosolic Ca(2+) concentration, activation of myosin light chain kinase, and phosphorylation of the 20-kDa light chain of myosin at Ser(19).Smooth muscle contraction follows an increase in cytosolic Ca(2+) concentration, activa" SIGNOR-106427 "Immune complexes" stimulus SIGNOR-ST15 SIGNOR FCGR1A protein P12314 UNIPROT "up-regulates activity" 9606 BTO:0000801 18064051 f lperfetto "Immune complexes bind to activating Fc receptors (FcR) and inhibitory FcRs that are expressed by innate immune effector cells such as basophils, mast cells, neutrophils, monocytes and macrophages, in which they trigger the indicated effector responses." SIGNOR-249521 IRF3 protein Q14653 UNIPROT ABCC2 protein Q92887 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15185298 f miannu "Expression of recombinant human IRF3 increased MRP2 promoter activity. " SIGNOR-254533 iloprost chemical CHEBI:63916 ChEBI PTGIR protein P43119 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-257574 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 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CASP9 protein P55211 UNIPROT down-regulates phosphorylation Thr125 PEVLRPEtPRPVDIG 9606 17466630 t lperfetto "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-216884 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR DDX3X protein O00571 UNIPROT down-regulates phosphorylation Thr204 LTRYTRPtPVQKHAI 9606 16280325 t lperfetto "Thr204 to glu204 ddx3 mutant protein lost its function, suggesting that phosphorylation at thr204 affects ddx3 function. Thr204 was phosphorylated by cyclin b/cdc2. Thr323 in motif ib was also phosphorylated by cyclin b/cdc2 kinase. We propose a novel function of cyclin b/cdc2 kinase in mitosis, which is to cause a loss of ddx3 function to repress cyclin a expression and to decrease ribosome biogenesis and translation during mitosis." SIGNOR-216868 "Immune complexes" stimulus SIGNOR-ST15 SIGNOR FCGR3A protein P08637 UNIPROT "up-regulates activity" 9606 BTO:0000801 17558411 f lperfetto "After binding their antibody ligands, FcgRI and FcgRIII deliver activating signals through an association with the FcRg-chain (FcRg), a transmembrane adaptor protein with an immuno-receptor tyrosine-based activation motif in its cytoplasmic domain." SIGNOR-249523 Inflammation phenotype SIGNOR-PH12 SIGNOR IL4 protein P05112 UNIPROT up-regulates 9606 BTO:0000399 11290754 f apalma "Our findings indicate that chemokines acting via CCR3-initiated signaling pathways can very rapidly mobilize preformed stores of IL-4 from within human eosinophils. The means of extracellular release was by noncytotoxic, vesicular transport" SIGNOR-255494 ING1 protein Q9UK53 UNIPROT AFP protein P02771 UNIPROT "down-regulates quantity by repression" "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-254480 ING1 protein Q9UK53 UNIPROT BAX protein Q07812 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001938 15662138 f miannu "Ectopic expression of p33ING1b could obviously upregulate p53, p21WAF1 and bax protein levels and activate caspase-3 in taxol-treated U2OS cells. Taken together, our data demonstrate that p33ING1b enhances taxol-induced apoptosis through p53-dependent pathway in human osteosarcoma cells." SIGNOR-254488 ING1 protein Q9UK53 UNIPROT CASP3 protein P42574 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001938 15662138 f miannu "Ectopic expression of p33ING1b could obviously upregulate p53, p21WAF1 and bax protein levels and activate caspase-3 in taxol-treated U2OS cells. Taken together, our data demonstrate that p33ING1b enhances taxol-induced apoptosis through p53-dependent pathway in human osteosarcoma cells." SIGNOR-254489 ING1 protein Q9UK53 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-254483 ING1 protein Q9UK53 UNIPROT SIRT2 protein Q8IXJ6 UNIPROT "down-regulates activity" binding 9606 BTO:0000599 14522900 f miannu "We found that p33(ING1b) physically interacts with hSIR2, reverses its ability to induce the AFP promoter, and induces acetylation of p53 residues at Lys(373) and/or Lys(382)." SIGNOR-254486 ING1 protein Q9UK53 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001938 15662138 f miannu "Ectopic expression of p33ING1b could obviously upregulate p53, p21WAF1 and bax protein levels and activate caspase-3 in taxol-treated U2OS cells. Taken together, our data demonstrate that p33ING1b enhances taxol-induced apoptosis through p53-dependent pathway in human osteosarcoma cells." SIGNOR-254490 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 RNF111 protein Q6ZNA4 UNIPROT SMAD2 protein Q15796 UNIPROT "down-regulates activity" ubiquitination 10090 BTO:0000165;BTO:0000222 17341133 t lperfetto "Arkadia represses the expression of myoblast differentiation markers through degradation of ski and the ski-bound smad complex in c2c12 myoblasts. Arkadia bound smad2/3 via ski to induce the ubiquitination of smad2/3. These results suggest that arkadia targets ski-bound, inactive phospho-smad2/3 to regulate positively myostatin/tgf-beta signaling." SIGNOR-235394 ING2 protein Q9H160 UNIPROT AFP protein P02771 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000599 14522900 f miannu "ING1b and ING2 also repressed the AFP promoter in Hep3B p53-null cell lines, and p53 coexpression enhanced this transcriptional repression. Suppression of AFP gene transcription by ING was strongly dependent on AT-motifs that bind to the hepatocyte nuclear factor 1 (HNF1) transcription factor." SIGNOR-254485 ING2 protein Q9H160 UNIPROT MMP13 protein P45452 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001913 19437536 f miannu "ING2 is upregulated in colon cancer and increases invasion by enhanced MMP13 expression." SIGNOR-254491 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 INSIG2 protein Q9Y5U4 UNIPROT SCAP protein Q12770 UNIPROT "down-regulates activity" binding 10029 BTO:0000246 12242332 t "insig-2, a second protein of the endoplasmic reticulum that blocks the processing of sterol regulatory element-binding proteins (SREBPs) by binding to SCAP (SREBP cleavage-activating protein) in a sterol-regulated fashion, thus preventing it from escorting SREBPs to the Golgi." SIGNOR-256209 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 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 IRS1 protein P35568 UNIPROT "down-regulates quantity by destabilization" 9606 17360977 f lperfetto "Research has focused on insulin receptor substrate (IRS)-1 as a locus for insulin resistance. Tyrosine phosphorylation of IRS-1 initiates insulin signaling, whereas serine/threonine phosphorylation alters the ability of IRS-1 to transduce the insulin signal. Insulin increased the phosphorylation of Ser312, Ser616, Ser636, Ser892, Ser1101, and Ser1223" SIGNOR-236737 INS protein P01308 UNIPROT LPL protein P06858 UNIPROT "up-regulates activity" 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-251858 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 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 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 IRF5 protein Q13568 UNIPROT IL10 protein P22301 UNIPROT down-regulates "transcriptional regulation" 9606 BTO:0000801 21240265 f "The role of IRF5 in inhibiting the transcription of the gene encoding IL-10 that we have identified here is important given its well- documented immunosuppressive activity." SIGNOR-254514 PRRX1 protein P54821 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-221961 PTPN6 protein P29350 UNIPROT ROS1 protein P08922 UNIPROT down-regulates dephosphorylation 9606 11266449 t lperfetto "Overexpression of shp-1 results in ros dephosphorylation and effectively downregulates ros-dependent proliferation and transformation. We propose that shp-1 is an important downstream regulator of ros signaling." SIGNOR-105922 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 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 BKM120 chemical CHEBI:71954 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-252656 CH5132799 chemical CID:49784945 PUBCHEM PI3K complex SIGNOR-C156 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-252648 INSR protein P06213 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr373 ASDTDSSyCIPTAGM 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-251312 INSR protein P06213 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr447 SEELDENyVPMNPNS 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-251313 INSR protein P06213 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr472 EPIQEANyVPMTPGT 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-251314 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 INSR protein P06213 UNIPROT "up-regulates activity" phosphorylation Tyr1190 DIYETDYyRKGGKGL -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-106518 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT "up-regulates activity" phosphorylation Tyr465 GEEELSNyICMGGKG 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-236713 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 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-236725 INSR protein P06213 UNIPROT IRS2 protein Q9Y4H2 UNIPROT "down-regulates activity" phosphorylation Tyr628 PKVAYHPyPEDYGDI -1 9195949 t "Tyr624 and Tyr628 are involved in the interaction between the IR and the KRLB domain of IRS-2, including tyrosine phosphorylation, and Tyr628 seems to be more important than Tyr624 in this process. the binding between the insulin receptor and the KRLB domain of IRS-2 results in tyrosine phosphorylation of the KRLB domain, and this leads to decreased binding of IRS-2 to the insulin receptor." SIGNOR-251318 INSR protein P06213 UNIPROT IRS2 protein Q9Y4H2 UNIPROT "down-regulates activity" phosphorylation Tyr632 YHPYPEDyGDIEIGS -1 9195949 t "Tyr624 and Tyr628 are involved in the interaction between the IR and the KRLB domain of IRS-2, including tyrosine phosphorylation, and Tyr628 seems to be more important than Tyr624 in this process. the binding between the insulin receptor and the KRLB domain of IRS-2 results in tyrosine phosphorylation of the KRLB domain, and this leads to decreased binding of IRS-2 to the insulin receptor." SIGNOR-251319 DIO2 protein Q92813 UNIPROT 3,3',5'-triiodo-L-thyronine smallmolecule CHEBI:11684 ChEBI "up-regulates quantity" "small molecule catalysis" 20978344 t "The deiodinase family of enzymes controls the tissue-specific activation and inactivation of the prohormone thyroxine (T4)" SIGNOR-256202 DTX1 protein Q86Y01 UNIPROT ASCL1 protein P50553 UNIPROT down-regulates binding 9606 11564735 t gcesareni "Through its binding to p300, dtx1 inhibited transcriptional activation by the neural-specific helix-loop-helix-type transcription factor mash1" SIGNOR-110626 GZMA protein P12544 UNIPROT SET protein Q01105 UNIPROT down-regulates cleavage 9606 11555662 t miannu "Gzma cleaved the nucleosome assembly protein set after lys176 and disrupted its nucleosome assembly activity." SIGNOR-110462 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 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 PIK3R1 protein P27986 UNIPROT "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-251322 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 PTPN1 protein P18031 UNIPROT "up-regulates activity" phosphorylation Tyr66 LHQEDNDyINASLIK -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-249370 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 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 KLF11 protein O14901 UNIPROT SIN3A protein Q96ST3 UNIPROT "up-regulates activity" binding 10029 BTO:0000246 11438660 t miannu "detailed biochemical and functional analyses have demonstrated that the TIEG2 _-HRM domain interacts specifically with the PAH2 domain of mSin3A to repress transcription. our data suggest the presence of a conserved _-helical repression motif (_-HRM) in the TIEG and BTEB subfamilies of Sp1-like proteins that mediates transcriptional repression activity through interaction with the corepressor mSin3A." SIGNOR-222344 KLF16 protein Q9BXK1 UNIPROT SIN3A protein Q96ST3 UNIPROT "up-regulates activity" binding 10029 BTO:0000246 11438660 t miannu "detailed biochemical and functional analyses have demonstrated that the TIEG2 _-HRM domain interacts specifically with the PAH2 domain of mSin3A to repress transcription. our data suggest the presence of a conserved _-helical repression motif (_-HRM) in the TIEG and BTEB subfamilies of Sp1-like proteins that mediates transcriptional repression activity through interaction with the corepressor mSin3A." SIGNOR-222460 "lysophosphatidic acids" smallmolecule CHEBI:32957 ChEBI LPAR3 protein Q9UBY5 UNIPROT up-regulates binding 9606 8276865 t gcesareni "Lpa activates its own g protein-coupled receptor(s)." SIGNOR-36389 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 PCSK7 protein Q16549 UNIPROT CDC25B protein P30305 UNIPROT down-regulates phosphorylation 9606 11333986 t gcesareni "We propose that regulation of cdc25b phosphorylation by p38 is a critical event for initiating the g2/m checkpoint after ultraviolet radiation" SIGNOR-107423 PPP1CA protein P62136 UNIPROT AURKA protein O14965 UNIPROT down-regulates dephosphorylation 9606 11551964 t gcesareni "Pp1 is shown to dephosphorylate active stk15 and abolish its activity in vitro." SIGNOR-110411 SUZ12/EZH2 complex SIGNOR-C77 SIGNOR 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-235577 SUZ12/EZH2/YY1 complex SIGNOR-C102 SIGNOR PAX7 protein P23759 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 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-235583 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 RAF1 protein P04049 UNIPROT STK3 protein Q13188 UNIPROT down-regulates binding 9606 15618521 t gcesareni "Raf-1 prevents dimerization and phosphorylation of the activation loop of mst2 independently of its protein kinase activity.Raf-1 counteracts apoptosis by suppressing the activation of mammalian sterile 20-like kinase (mst2)" SIGNOR-132824 AR protein P10275 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-251537 CDKN2A protein Q8N726 UNIPROT ATR protein Q13535 UNIPROT "up-regulates activity" phosphorylation 9606 15775976 t gcesareni "Regulation of NF-kappaB and p53 through activation of ATR and Chk1 by the ARF tumour suppressorInduction of ATR activity in Hs68 E2F1ER cells by endogenous ARF." SIGNOR-134781 CDKN2A protein Q8N726 UNIPROT MDM2 protein Q00987 UNIPROT "down-regulates activity" relocalization 9606 23416275 t fstefani "We propose that p14(arf) increases the binding of p53-mdm2 complexes to chromatin, thereby limiting the access of protein deacetylases to p53." SIGNOR-192697 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 CH5132799 chemical CID:49784945 PUBCHEM MTOR protein P42345 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190937 RASGEF1A protein Q8N9B8 UNIPROT NRAS protein P01111 UNIPROT up-regulates binding 9606 19201597 t gcesareni "Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras." SIGNOR-183829 RB1 protein P06400 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates binding 9606 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-176563 RFX4 protein Q33E94 UNIPROT IFT172 protein Q9UG01 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19887680 f miannu "We find that Ift172, which encodes an intraflagellar transport protein necessary for ciliogenesis, is a direct transcriptional target of Rfx4" SIGNOR-223319 SIRT1 protein Q96EB6 UNIPROT MYOD1 protein P15172 UNIPROT "down-regulates activity" 10090 BTO:0000165 12887892 t gcesareni "Sir2 forms a complex with the acetyltransferase PCAF and MyoD and, when overexpressed, retards muscle differentiation" SIGNOR-241963 SOX4 protein Q06945 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 BTO:0001271 24183681 f apalma "Collectively, our experiments identified the oncogene Sox4 as a factor mediating increased serial-replating ability and blocked differentiation of Cebpa-deficient progenitors." SIGNOR-255676 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 TBX3 protein O15119 UNIPROT CDKN2A protein Q8N726 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 25211658 t lperfetto "TBX2 and TBX3 function as transcriptional repressors and both have been shown to inhibit myogenesis (Carlson et al, 2002; Zhu et al, 2014). Abnormal expression of TBX2 has been reported in several cancers including breast, pancreas, and melanoma, where it has been shown to drive proliferation (reviewed in Abrahams et al (2010)). As has been previously shown in other cell types, TBX2 was found to induce a downregulation of p14/19ARF and function as a direct repressor of p21 in RMS" SIGNOR-249603 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 UHMK1 protein Q8TAS1 UNIPROT PAM protein P19021 UNIPROT unknown phosphorylation Ser946 DRLSTEGsDQEKEDD 9606 BTO:0004055 10574929 t lperfetto "Although P-CIP2 interacts with stathmin, it does not phosphorylate stathmin. Site-directed mutagenesis, phosphoamino acid analysis, and use of synthetic peptides demonstrate that PAM-Ser(949) is the major site phosphorylated by P-CIP2. B" SIGNOR-247009 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 YES1 protein P07947 UNIPROT YES1 protein P07947 UNIPROT "up-regulates activity" phosphorylation Tyr426 RLIEDNEyTARQGAK 9606 9794236 t lperfetto "Autophosphorylation of Src and Yes blocks their inactivation by Csk phosphorylation" SIGNOR-247014 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 IRAK4 protein Q9NWZ3 UNIPROT IRAK1 protein P51617 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0000801 17337443 t lperfetto "Analyses of embryonic fibroblasts and macrophages obtained from IRAK-4 KD mice demonstrate lack of cellular responsiveness to stimulation with IL-1beta or a Toll-like receptor 7 (TLR7) agonist. IRAK-4 kinase deficiency prevents the recruitment of IRAK-1 to the IL-1 receptor complex and its subsequent phosphorylation and degradation." SIGNOR-153458 IRAK4 protein Q9NWZ3 UNIPROT IRAK1 protein P51617 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007 11960013 t lperfetto "In addition, IRAK-4 is able to phosphorylate IRAK-1, and overexpression of dominant-negative IRAK-4 is blocking the IL-1-induced activation and modification of IRAK-1, suggesting a role of IRAK-4 as a central element in the early signal transduction of Toll/IL-1 receptors, upstream of IRAK-1." SIGNOR-117315 IRAK4 protein Q9NWZ3 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-251328 IRAK4 protein Q9NWZ3 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-251329 IRAK4 protein Q9NWZ3 UNIPROT IRAK4 protein Q9NWZ3 UNIPROT "up-regulates activity" phosphorylation Thr342 ASEKFAQtVMTSRIV 9606 BTO:0000007 17141195 t lperfetto "The present data indicate that the kinase activity of irak-4 is dependent on the autophosphorylations at t342" SIGNOR-151006 IRAK4 protein Q9NWZ3 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser288 QKSGQDVsQAQRQIK 9606 BTO:0000130 17217339 t lperfetto "Phosphorylation of the cytosolic factor p47phox is essential for activation of the nadph oxidase.We found that thr133, ser288 and thr356, targets for irak-4 phosphorylation in vitro, are also phosphorylated in endogenous p47phox after lps stimulation. We conclude that irak-4 phosphorylates p47phox and regulates nadph oxidase activation after lps stimulation." SIGNOR-152011 IRAK4 protein Q9NWZ3 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Thr133 KLPTDNQtKKPETYL 9606 BTO:0000130 17217339 t lperfetto "Phosphorylation of the cytosolic factor p47phox is essential for activation of the nadph oxidase.We found that thr133, ser288 and thr356, targets for irak-4 phosphorylation in vitro, are also phosphorylated in endogenous p47phox after lps stimulation. We conclude that irak-4 phosphorylates p47phox and regulates nadph oxidase activation after lps stimulation." SIGNOR-152023 IRAK4 protein Q9NWZ3 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Thr356 PLEEERQtQRSKPQP 9606 BTO:0000130 17217339 t lperfetto "Phosphorylation of the cytosolic factor p47phox is essential for activation of the nadph oxidase.We found that thr133, ser288 and thr356, targets for irak-4 phosphorylation in vitro, are also phosphorylated in endogenous p47phox after lps stimulation. We conclude that irak-4 phosphorylates p47phox and regulates nadph oxidase activation after lps stimulation." SIGNOR-152027 IRF1 protein P10914 UNIPROT SOCS2 protein O14508 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22291912 f miannu "SOCS2 induction by LPS was dependent on the type I IFN regulated transcription factors IRF1 and IRF3 as shown by using silencing RNAs for IRFs." SIGNOR-254494 IRF2BP1 protein Q8IU81 UNIPROT IRF2 protein P14316 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 12799427 t miannu "We have identified two novel proteins that interact specifically with the C-terminal repression domain of Interferon Regulatory Factor-2 (IRF-2). These proteins, which we term IRF-2 binding proteins 1 and 2 (IRF-2BP1 and IRF-2BP2, the latter having two splicing isoforms, A and B), are nuclear proteins, and have the properties of IRF-2-dependent transcriptional co-repressors that can inhibit both enhancer-activated and basal transcription in a manner that is not dependent upon histone deacetylation." SIGNOR-224045 NEK2 protein P51955 UNIPROT NEK2 protein P51955 UNIPROT up-regulates phosphorylation Thr170 ARILNHDtSFAKTFV 9606 17197699 t gcesareni "Thus, it appears that autophosphorylation of thr-170 and/or ser-171 in nek2 may fine-tune overall activity of nek2 in vivo. regardless, the importance of thr-175 suggested by its conservation in many other kinases is underlined by the t175a mutant that shows reduced kinase activity and a significant reduction in efficiency of cs." SIGNOR-151759 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 CYSLTR2 protein Q9NS75 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-256746 IRF2BP2 protein Q7Z5L9 UNIPROT IRF2 protein P14316 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 12799427 t miannu "We have identified two novel proteins that interact specifically with the C-terminal repression domain of Interferon Regulatory Factor-2 (IRF-2). These proteins, which we term IRF-2 binding proteins 1 and 2 (IRF-2BP1 and IRF-2BP2, the latter having two splicing isoforms, A and B), are nuclear proteins, and have the properties of IRF-2-dependent transcriptional co-repressors that can inhibit both enhancer-activated and basal transcription in a manner that is not dependent upon histone deacetylation." SIGNOR-224073 IRF3 protein Q14653 UNIPROT IFNB1 protein P01574 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007 16699525 t lperfetto "Similarly, exogenous expression of wild-type Pin1 suppressed TLR3-mediated, IRF3-dependent activation of the IFN-beta promoter and reduced IFN-beta secretion in culture supernatants" SIGNOR-252257 IRF3 protein Q14653 UNIPROT SOCS2 protein O14508 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22291912 f miannu "SOCS2 induction by LPS was dependent on the type I IFN regulated transcription factors IRF1 and IRF3 as shown by using silencing RNAs for IRFs." SIGNOR-254495 IRF4 protein Q15306 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-254284 IRF4 protein Q15306 UNIPROT FCER2 protein P06734 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000776 11342629 f "IFN-regulatory factor 4 (IRF-4) plays a critical role in mature B cell function. Using the transcriptional regulation of the human B cell activation marker CD23 as a model system, we have previously demonstrated that IRF-4 is induced in response to B cell-activating stimuli and that it acts as a transactivator of CD23 gene expression." SIGNOR-253933 IRF4 protein Q15306 UNIPROT IRF5 protein Q13568 UNIPROT "down-regulates activity" 9606 BTO:0000801 22378047 t lperfetto "IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing JMJD3-IRF4 axis to inhibit IRF5-mediated M1 polarization." SIGNOR-249560 IRF4 protein Q15306 UNIPROT M1_polarization phenotype SIGNOR-PH54 SIGNOR down-regulates 9606 BTO:0000801 22378047 f lperfetto "IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing JMJD3-IRF4 axis to inhibit IRF5-mediated M1 polarization." SIGNOR-249561 IRF5 protein Q13568 UNIPROT M1_polarization phenotype SIGNOR-PH54 SIGNOR up-regulates 9606 BTO:0000801 22378047 f lperfetto "IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing JMJD3-IRF4 axis to inhibit IRF5-mediated M1 polarization." SIGNOR-249562 IRF7 protein Q92985 UNIPROT IFNA1 protein P01562 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16612387 f gcesareni "Ikkalfa can also phosphorylate and activate interferon regulatory factor-7 (irf7), which is required for interferon-alfa (ifnalfa) production." SIGNOR-146119 IRF8 protein Q02556 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-254285 IRF9 protein Q00978 UNIPROT IFNAR2 protein P48551 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 17923090 t lperfetto "By binding to IFNalphaR2 within the region where two adjacent proline boxes bear phospho-Ser364 and phospho-Ser384, CBP acetylates IFNalphaR2 on Lys399, which in turn serves as the docking site for interferon regulatory factor 9 (IRF9)RF9 interacts with the acetyl-Lys399 motif by means of its IRF homology2 (IH2) domain, leading to formation of the ISGF3 complex that includes IRF9, STAT1, and STAT2." SIGNOR-217779 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 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 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 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 ITCH protein Q96J02 UNIPROT GLI1 protein P08151 UNIPROT down-regulates ubiquitination 9606 BTO:0001573 17115028 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. we demonstrate that the hedgehog transcription factor gli1 is targeted by numb for itch-dependent ubiquitination, which suppresses hedgehog signals, thus arresting growth and promoting cell differentiation" SIGNOR-150847 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 NKX3-1 protein Q99801 UNIPROT AR protein P10275 UNIPROT "down-regulates quantity by repression" "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-251547 ITCH protein Q96J02 UNIPROT SMAD7 protein O15105 UNIPROT down-regulates ubiquitination 9606 15946939 t gcesareni "We identified atrophin 1-interacting protein 4 (aip4) as an e3 ubiquitin ligase that specifically targets smad7 for ubiquitin-dependent degradation without affecting the turnover of the activated tbetari. Surprisingly, we found that despite the ability to degrade smad7, aip4 can inhibit tgf-beta signaling, presumably by enhancing the association of smad7 with the activated tbetari." SIGNOR-137951 ITCH protein Q96J02 UNIPROT TNIP2 protein Q8NFZ5 UNIPROT down-regulates ubiquitination 9606 16469705 t gcesareni "Here we show that tnfa-mediated jnk activation accelerates turnover of the NF-kappaBinduced 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 activationof the e3ubiquitin ligaseitch, which speci?cally Ubiquitinates c-flip and induces its proteasomal degradation." SIGNOR-144453 ITGA11 protein Q9UKX5 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-253187 ITGA1 protein P56199 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-253169 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 ITGA2 protein P17301 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-253171 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 ITGA4 protein P13612 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-253175 ITGA4 protein P13612 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-253293 NEK2 protein P51955 UNIPROT SGO1 protein Q5FBB7 UNIPROT up-regulates phosphorylation Ser14 LKKSFQDsLEDIKKR 9606 17621308 t lperfetto "Here we show that nek2a phosphorylates human sgo1 and such phosphorylation is essential for faithful chromosome congression in mitosis. phosphorylation sites were mapped to ser(14) and ser(507)" SIGNOR-156878 NKX3-1 protein Q99801 UNIPROT HDAC1 protein Q13547 UNIPROT "down-regulates activity" binding 9606 16697957 t miannu "NKX3.1 also binds HDAC1 and releases p53 from p53-MDM2-HDAC1 complex, promoting p53 acetylation and activity." SIGNOR-251549 ITGA6 protein P23229 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-253179 ITGA7 protein Q13683 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-241508 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 ITGA9 protein Q13797 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-253183 ITGAD protein Q13349 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-253195 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 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 ITGAM protein P11215 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-253191 RASSF5 protein Q8WWW0 UNIPROT KRAS protein P01116 UNIPROT "up-regulates activity" binding 9606 22195963 t lperfetto "NORE1A can bind K-Ras.GTP through its RA domain and regulate the proapoptotic activity of MST1/2 kinases" SIGNOR-249586 SMO protein Q99835 UNIPROT TIMP3 protein P35625 UNIPROT "up-regulates quantity" "transcriptional activation" 10090 BTO:0005300 28709001 f "We identified that ciliary Hh signaling in FAPs regulates expression of Timp3. Future experiments will determine whether Timp3 is a direct or indirect target of Hh signaling." SIGNOR-255907 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 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-252834 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/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 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 NEK2 protein P51955 UNIPROT SGO1 protein Q5FBB7 UNIPROT up-regulates phosphorylation Ser507 TDLCFLNsPIFKQKK 9606 17621308 t lperfetto "Here we show that nek2a phosphorylates human sgo1 and such phosphorylation is essential for faithful chromosome congression in mitosis. phosphorylation sites were mapped to ser(14) and ser(507)" SIGNOR-156882 NEK6 protein Q9HC98 UNIPROT SGK1 protein O00141 UNIPROT "up-regulates activity" phosphorylation Ser377 PPFNPNVsGPNDLRH -1 12023960 t miannu "The present study is the first report of a protein kinase (NEK6) capable of phosphorylating the hydrophobic motif of SGK1, although our data suggest that NEK6 may not mediate this reaction in cells. Nevertheless, the phosphorylation of the hydrophobic motif of SGK1in vitro, coupled with the phosphorylation of the T-loop with PDK1, may be a useful way of generating fully active wild type SGK1. Ser377 and Ser422of SGK1, and the CDK7 T-loop peptide, which are phosphorylated by NEK6." SIGNOR-250296 PRKD1 protein Q15139 UNIPROT RIN1 protein Q13671 UNIPROT down-regulates phosphorylation Ser351 RPLLRSMsAAFCSLL 9606 11784866 t gcesareni "Rin1 also binds to 14-3-3 proteins through a sequence including serine 351. Mutation of this residue abolished the 14-3-3 binding capacity of rin1 and led to more efficient blockade of ras-mediated transformation. The mutant protein, rin1(s351a), showed a shift in localization to the plasma membrane. Serine 351 is a substrate for protein kinase d (pkd [also known as pkcmu]) in vitro and in vivo. These data suggest that the normal localization and function of rin1, as well as its ability to compete with raf, are regulated in part by 14-3-3 binding, which in turn is controlled by pkd phosphorylation." SIGNOR-113960 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 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 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 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 CYSLTR2 protein Q9NS75 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-256889 DAB2IP protein Q5VWQ8 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" binding 9606 27858941 t miannu "DAB2IP inhibits the PI3K–AKT axis by directly interacting with both proteins, reducing phosphorylation and activation of AKT. The GAP activity of DAB2IP can further enforce inhibition of the PI3K–AKT axis by reducing Ras-dependent activation of PI3K p110α subunit." SIGNOR-254751 DAB2IP protein Q5VWQ8 UNIPROT AR protein P10275 UNIPROT "down-regulates activity" binding 9606 27858941 t miannu "DAB2IP acts as a scaffold protein for PP2A to suppress DHT-elicited S81 phosphorylation of the AR, preventing its nuclear translocation and binding to androgen response elements. In addition, DAB2IP can compete with the AR for binding to c-Src, thus blocking the non-genomic AR pathway" SIGNOR-254758 DAB2IP protein Q5VWQ8 UNIPROT GATA1 protein P15976 UNIPROT "up-regulates activity" binding 9606 27858941 t miannu "DAB2IP suppresses transcription of stem cell factor receptor CD117, by interacting with GATA-1 on a silencer element on its gene" SIGNOR-254770 DAB2IP protein Q5VWQ8 UNIPROT HIF1A protein Q16665 UNIPROT "down-regulates quantity by destabilization" 9606 27476001 f miannu "DAB2IP destabilizes HIF1Œ± protein to inhibit EMT in PCa cells. DAB2IP may destabilize HIF1Œ± protein in PCa cells via an ubiquitin-proteasome system." SIGNOR-254765 DAB2IP protein Q5VWQ8 UNIPROT KIT protein P10721 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 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-254769 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 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 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 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 DLX5 protein P56178 UNIPROT RUNX2 protein Q13950 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22298955 f gcesareni "Dlx5 can drive runx2 expression and osteogenic differentiation in developing cranial suture mesenchyme , indicat-ing that dlx5 can work as an upstream gene of runx2." SIGNOR-195576 "DNA damage" stimulus SIGNOR-ST1 SIGNOR TAOK2 protein Q9UL54 UNIPROT up-regulates 9606 17396146 f lperfetto "These findings indicate that TAO kinases are regulators of p38-mediated responses to DNA damage and are intermediates in the activation of p38 by ATM." SIGNOR-226602 DNAJC3 protein Q13217 UNIPROT EIF2AK3 protein Q9NZJ5 UNIPROT "down-regulates activity" binding 9606 BTO:0000567 25329545 t gcesareni "The protein p58IPK {also known asDnaJ3C [DnaJ heat-shock protein (hsp) 40 homologue, subfamily C, member 3]} is known to inhibit the eIF2 kinases PKR (dsRNA-dependent protein kinase/eIF2 kinase 2) and PERK" SIGNOR-246201 DNMT1 protein P26358 UNIPROT BAG1 protein Q99933 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001109 18413740 f lperfetto "DNA methyltransferase 1 and 3B activate BAG-1 expression via recruitment of CTCFL/BORIS and modulation of promoter histone methylation" SIGNOR-254108 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 "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-253178 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 "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 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 "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 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 PP2Ca_R1A_Bd complex SIGNOR-C133 SIGNOR AR protein P10275 UNIPROT "down-regulates activity" dephosphorylation Ser83 QQQQQETsPRQQQQQ 9606 27858941 t miannu "DAB2IP acts as a scaffold protein for PP2A to suppress DHT-elicited S81 phosphorylation of the AR, preventing its nuclear translocation and binding to androgen response elements. In addition, DAB2IP can compete with the AR for binding to c-Src, thus blocking the non-genomic AR pathway" SIGNOR-254759 PAX3-FOXO1 "fusion protein" SIGNOR-FP12 SIGNOR IGF2 protein P01344 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25211658 t miannu "Insulin-like growth factor is required for RMS cell growth and IGF2 is expressed in an autocrine manner by the tumour cells. The IGF2 locus shows a loss of imprinting in both ERMS and ARMS tumours and expression of PAX3-FOXO1 can induce the upregulation of IGF2, thus enhancing the activation of IGF signalling pathway in ARMS" SIGNOR-251573 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 PAX3-FOXO1 "fusion protein" SIGNOR-FP12 SIGNOR PDGFA protein P04085 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25211658 t miannu "Several deregulated signalling pathways enhance cell growth by modulating cell-cycle regulatory factors in RMS. The most frequently affected signalling pathways include the insulin-like growth factor (IGF), fibroblast growth factor (FGF), hepatocyte growth factor, and platelet-derived growth factor. In ARMS, PAX-FOXO1 activates these pathways by transcriptional activation of receptor genes including IGFR1, FGFR4, MET (c-Met), and PDGFRA." SIGNOR-251571 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 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 ITGB4 protein P16144 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-253200 ITGB4 protein P16144 UNIPROT PI3K complex SIGNOR-C156 SIGNOR 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-252697 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 RNF111 protein Q6ZNA4 UNIPROT SMAD7 protein O15105 UNIPROT down-regulates ubiquitination 9606 14657019 t gcesareni "Axin is a scaffold protein in tgf-beta signaling that promotes degradation of smad7 by arkadia" SIGNOR-119666 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 FOXO3 protein O43524 UNIPROT DIO2 protein Q92813 UNIPROT "up-regulates quantity" "transcriptional activation" 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 ITGB4 protein P16144 UNIPROT PIK3CD protein O00329 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-54700 RUNX1 protein Q01196 UNIPROT "Core Binding Factor complex" complex SIGNOR-C214 SIGNOR "form complex" binding 9606 12495904 t irozzo "The core binding factor (CBF) transcription complex, consisting of the interacting proteins RUNX1 and CBFβ, is essential for normal hematopoiesis" SIGNOR-255710 ITGB6 protein P18564 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-253210 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 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 ITGB8 protein P26012 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-253290 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 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 PRKAA1 protein Q13131 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR 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 phosphorylation sites, resulting in foxo activation" SIGNOR-252981 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 MAP3K7 protein O43318 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-235548 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 ITK protein Q08881 UNIPROT BMX protein P51813 UNIPROT "up-regulates activity" phosphorylation Tyr216 SSTSLAQyDSNSKKI -1 12573241 t "Itk phosphorylated Bmx-SH3 to a low extent. pY positions correspond to the residues Y215 and Y223 in Bmx. 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." SIGNOR-251331 ITK protein Q08881 UNIPROT BMX protein P51813 UNIPROT "up-regulates activity" phosphorylation Tyr224 DSNSKKIyGSQPNFN -1 12573241 t "Itk phosphorylated Bmx-SH3 to a low extent. pY positions correspond to the residues Y215 and Y223 in Bmx. 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." SIGNOR-251332 ITK protein Q08881 UNIPROT BTK protein Q06187 UNIPROT "up-regulates activity" phosphorylation Tyr223 LKKVVALyDYMPMNA -1 12573241 t "Btk-SH3 mutant Y223A was not phosphorylated by Itk. 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." SIGNOR-251333 ITK protein Q08881 UNIPROT CD28 protein P10747 UNIPROT "up-regulates activity" phosphorylation Tyr191 SRLLHSDyMNMTPRR 8992971 t "EMT can phosphorylate all four tyrosines of the CD28 tail. 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-251336 ITK protein Q08881 UNIPROT CD28 protein P10747 UNIPROT "up-regulates activity" phosphorylation Tyr206 PGPTRKHyQPYAPPR 8992971 t "EMT can phosphorylate all four tyrosines of the CD28 tail. 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-251334 ITK protein Q08881 UNIPROT CD28 protein P10747 UNIPROT "up-regulates activity" phosphorylation Tyr218 PPRDFAAyRS 8992971 t "EMT can phosphorylate all four tyrosines of the CD28 tail. 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-251337 ITK protein Q08881 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-198747 ITK protein Q08881 UNIPROT SIGLEC10 protein Q96LC7 UNIPROT up-regulates phosphorylation Tyr667 ESQEELHyATLNFPG 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. Phosphorylation of the tyrosine located at position 667 in an itim motif appears to be necessary for the recruitment of shp-1 and partial recruitment of shp-2" SIGNOR-112475 JAG1 protein P78504 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 10958687 t "Binding Calcium-dependent." gcesareni "Here we report the first x-ray structure of a functional fragment of a notch ligand, the dsl-egf3 domains of human jagged-1 (j-1dsl-egf3). The structure identifies a highly conserved face of the dsl domain and we show, by functional analysis of drosophila ligand mutants, that this surface is required for both cis- and trans-regulatory interactions with notch." SIGNOR-81364 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 JAK1 protein P23458 UNIPROT IFNGR2 protein P38484 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-249491 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 SOSTDC1 protein Q6X4U4 UNIPROT WNT2B protein Q93097 UNIPROT "down-regulates activity" 10090 22829579 f lperfetto "Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells." SIGNOR-242701 SOSTDC1 protein Q6X4U4 UNIPROT WNT2 protein P09544 UNIPROT "down-regulates activity" 10090 22829579 f lperfetto "Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells." SIGNOR-242724 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 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 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-256247 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 JAK2 protein O60674 UNIPROT CCR2 protein P41597 UNIPROT "up-regulates activity" phosphorylation Tyr139 ILLTIDRyLAIVHAV 9606 BTO:0000876 9670957 t "JAK2 phosphorylates CCR2 at the Tyr139 position and promotes JAK2/STAT3 complex association to the receptor. " SIGNOR-251345 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 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 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 NRF1 protein Q16656 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-254885 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT "up-regulates activity" phosphorylation Ser55 KPRHKIIsIFSGTEK -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. Autophosphorylation of γ-PAK with MgATP alone takes place at Ser-19, Ser-20, Ser-55, Ser-192, and Ser-197." SIGNOR-250229 PPP2CA protein P67775 UNIPROT PRKCD protein Q05655 UNIPROT "down-regulates activity" dephosphorylation Ser664 QSAFAGFsFVNPKFE 9606 11959144 t "PP2A(c) displayed the highest specific activity towards PKCdelta. The role of PP2A(c) in the dephosphorylation of PKCdelta in cells was supported by the demonstration that these proteins could be co-immunoprecipitated from NIH3T3 cells.|In conclusion, the evidence here indicates that PKCdelta de-phosphorylation and hence inactivation is effected by PP2A with which it forms a complex" SIGNOR-248639 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 RUNX1 protein Q01196 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR "down-regulates activity" binding 9606 22021368 t apalma "We found that AML1 inhibits NF-κB signaling through interaction with IκB kinase complex in the cytoplasm. Remarkably, AML1 mutants found in myeloid tumors lack the ability to inhibit NF-κB signaling, and human cases with AML1-related leukemia exhibits distinctly activated NF-κB signaling" SIGNOR-255690 SAV1 protein Q9H4B6 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR "up-regulates activity" binding 9606 21084559 t miannu "Mst is activated by binding of salvador (sav1, sav in drosophila), which is, in turn, also phosphorylated by mst." SIGNOR-256183 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 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 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 ITGB2 protein P05107 UNIPROT "up-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-254738 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 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 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 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 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 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 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 NEK8 protein Q86SG6 UNIPROT NEK8 protein Q86SG6 UNIPROT "up-regulates activity" phosphorylation Thr162 SSKSKAYtVVGTPCY -1 11864968 t miannu "Multimerization and autophosphorylation of Nek8 are important for its activation.Our data suggests that one site for Nek8 autophosphorylation may be Thr-210 within the activation loop." SIGNOR-250298 NEK9 protein Q8TD19 UNIPROT NEK7 protein Q8TDX7 UNIPROT "up-regulates activity" phosphorylation Ser195 SKTTAAHsLVGTPYY 9606 BTO:0000007 12840024 t lperfetto "Nercc1 catalyzes the phosphorylation of nek6 (ser206) and the equivalent site on nek7 (ser195), resulting in a 20-25-fold activation of nek6/7 kinase activity" SIGNOR-103030 NEK9 protein Q8TD19 UNIPROT NEK9 protein Q8TD19 UNIPROT up-regulates phosphorylation Ser944 GQQVGMHsKGTQTAK 9606 21454704 t lperfetto "We find that the interaction of lc8 with nek9 depends on a (k/r)xtqt motif adjacent to the nek9 c-terminal coiled coil motif, results in nek9 multimerization, and increases the rate of nek9 autoactivation. Lc8 binding to nek9 is regulated by nek9 activity through the autophosphorylation of ser(944), a residue immediately n-terminal to the (k/r)xtqt motif." SIGNOR-173026 CSNK2A1 protein P68400 UNIPROT ABCC1 protein P33527 UNIPROT up-regulates phosphorylation Thr249 WSLNKEDtSEQVVPV 9606 22695718 t lperfetto "Casein kinase 2_ regulates multidrug resistance-associated protein 1 function via phosphorylation of thr249. This study supports a model in which ck2_ potentiates mrp1 function via direct phosphorylation of thr249." SIGNOR-197844 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 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 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 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 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 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 JAK3 protein P52333 UNIPROT up-regulates phosphorylation Tyr904 SLRLVMEyLPSGCLR 9606 18250158 t lperfetto "Y904 and y939 are required for optimal jak3 autophosphorylation and kinase activity in vitro" SIGNOR-160664 JAK3 protein P52333 UNIPROT JAK3 protein P52333 UNIPROT up-regulates phosphorylation Tyr939 QICKGMEyLGSRRCV 9606 18250158 t lperfetto "Y904 and y939 are required for optimal jak3 autophosphorylation and kinase activity in vitro" SIGNOR-160668 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 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-112479 JAK3 protein P52333 UNIPROT STAT5A protein P42229 UNIPROT up-regulates phosphorylation Tyr694 LAKAVDGyVKPQIKQ 9606 BTO:0000007;BTO:0000567 19088846 t gcesareni "For these assays, coexpression of wt jak3 with stat5a was found to result in tyrosine phosphorylation of stat5a (lane 2) mediated by jak3, since stat5a coexpressed with the kinase-inactive k855a mutant form of jak3 was not tyrosine phosphorylated." SIGNOR-182817 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 22021368 f apalma "Once genetic mutation of AML1 occurs in hematopoietic cells, aberrant activation of NF-κB signaling exerts antiapoptotic and proliferation-promoting effects via activation of BCL-XL or JUNB." SIGNOR-255693 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 22021368 f apalma "In normal hematopoiesis, AML1 suppresses NF-κB signaling and thus may contribute to inhibition of excessive proliferation of hematopoietic cells." SIGNOR-255692 TAOK proteinfamily SIGNOR-PF21 SIGNOR STK3/4 proteinfamily SIGNOR-PF41 SIGNOR "up-regulates activity" phosphorylation 9606 23431053 t miannu "The thousand-and-one (TAO) amino acids kinase or TAOK1 – 3 has been shown to directly phosphorylate and activate Hpo or MST1/2." SIGNOR-256182 CCL3 protein P10147 UNIPROT CCR1 protein P32246 UNIPROT up-regulates binding 9606 10734056 t "CCR1 is also activated by MIP-1α, MCP-2, and MCP-3, although maximum responses are only obtained with RANTES and MIP-1α." SIGNOR-254366 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 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 EPO protein P01588 UNIPROT EPOR protein P19235 UNIPROT up-regulates binding 10090 BTO:0002882 9442088 t gcesareni "Binding of erythropoietin (epo) to the epo receptor (epor) initiates a signaling cascade resulting in tyrosine phosphorylation of several proteins and induction of ap-1 transcription factor(s)." SIGNOR-55300 GNG2 protein P59768 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates binding 9606 23074268 t gcesareni "Furthermore, this work suggested that the gbetagamma subunits released upon gi activation activated phospholipase c-gamma (plc-gamma) to produce inositol 3 phosphate (ip3) which would subsequently increase intracellular ca2+ abundance." SIGNOR-199138 JDP2 protein Q8WYK2 UNIPROT ATF2 protein P15336 UNIPROT "down-regulates activity" binding 9606 18671972 t miannu "JDP2 dimerizes with other AP-1 proteins such as activating transcription factor-2 (ATF2) and Jun to repress transcription from promoters that contain a cyclic AMP-responsive element (CRE)." SIGNOR-226395 JDP2 protein Q8WYK2 UNIPROT JUN protein P05412 UNIPROT "down-regulates activity" binding 9606 18671972 t miannu "JDP2 dimerizes with other AP-1 proteins such as activating transcription factor-2 (ATF2) and Jun to repress transcription from promoters that contain a cyclic AMP-responsive element (CRE)." SIGNOR-226398 JNK proteinfamily SIGNOR-PF15 SIGNOR JUN protein P05412 UNIPROT "up-regulates activity" phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 BTO:0000938 12040039 t lperfetto "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-236130 JNK proteinfamily SIGNOR-PF15 SIGNOR JUN protein P05412 UNIPROT "up-regulates activity" phosphorylation Ser73 VGLLKLAsPELERLI 9606 17158707 t lperfetto "The JNK-mediated phosphorylation of both Ser63 and Ser73 within the transactivation domain of c-Jun (Table _(Table1)1) potentiates its transcriptional activity" SIGNOR-36466 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 PRKACA protein P17612 UNIPROT LATS1 protein O95835 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-236991 SOSTDC1 protein Q6X4U4 UNIPROT WNT3 protein P56703 UNIPROT "down-regulates activity" 10090 22829579 f lperfetto "Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells." SIGNOR-242730 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 SP1 protein P08047 UNIPROT CYP1B1 protein Q16678 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12801909 f miannu "It was suggested that mutual interaction of XRE2 and XRE3 is important for transcriptional regulation, and that the Sp1 binding to the Sp1-like motif (-824) enhances both the constitutive and inducible transcriptional activities of the human CYP1B1 gene." SIGNOR-255196 SP1 protein P08047 UNIPROT DHCR24 protein Q15392 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22431021 f miannu "activation of Sp1 by oxidative stress is involved in the promotion of expression of DHCR24 by HCV." SIGNOR-255200 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 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 TET2 protein Q6N021 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000738 25601757 f irozzo "Cell proliferation was stimulated by the knockdown of either TET2 or WT1 gene in KG-1 cells, but not additively by the co-depletion of both genes. Collectively, these results suggest that TET2 and WT1 function in the same pathway to inhibit leukemia cell proliferation and colony formation." SIGNOR-255704 USF1 protein P22415 UNIPROT CEBPA protein P49715 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0004116 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 AKT proteinfamily SIGNOR-PF24 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 16982699 f "Protein kinase B (PKB/Akt) is an important modulator of insulin signaling, cell proliferation, and survival. Using small interfering RNA duplexes in nontransformed mammalian cells, we show that only Akt1 is essential for cell proliferation" SIGNOR-254353 CAMK2G protein Q13555 UNIPROT EGFR protein P00533 UNIPROT "down-regulates activity" phosphorylation Ser1071 SFLQRYSsDPTGALT 9606 BTO:0000017 1309762 t llicata "The mechanism of desensitization of kinase activity can be accounted for, in part, by the EGF-stimulated phosphorylation of the receptor at Ser1046/7, a substrate for the multifunctional calmodulin-dependent protein kinase II in vitro. Mutation of Ser1046/7 by replacement with Ala residues blocks desensitization of the EGF receptor protein-tyrosine kinase activity. " SIGNOR-250695 CDK1 protein P06493 UNIPROT PTTG1 protein O95997 UNIPROT up-regulates phosphorylation Ser165 LFQLGPPsPVKMPSP 9606 10656688 t llicata "Hpttg is phosphorylated by cdc2 at ser165 these results suggest that hpttg is induced by, and may have a role in, regulatory pathways involved in the control of cell proliferation." SIGNOR-74619 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 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 "ER stress" stimulus SIGNOR-ST9 SIGNOR PRNP protein F7VJQ1 UNIPROT up-regulates 9606 BTO:0000007 21478263 f "ER stress specifically increases the synthesis of AltPrP from PrP cDNA." SIGNOR-253609 INPPL1 protein O15357 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates 9606 BTO:0000776 10942391 f lperfetto "Taken together, the data presented here demonstrate that ship inhibits akt primarily through regulation of akt membrane localization." SIGNOR-244406 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 KDM2A protein Q9Y2K7 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates demethylation 9606 20080798 t lperfetto "Fbxl11 and nsd1 have opposite effects on nf-kb; both bind to p65 subunit after activation of nf-kb. / nsd1 activates nf-kb and reverses the inhibitory effect of fbxl11 / these data confirm that fbxl11 and nsd1 constitute an enzyme pair that methylates and demethylates p65 on k218 and 221 in response to cytokine stimulation." SIGNOR-217415 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 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 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 RCAN1 protein P53805 UNIPROT Calcineurin complex SIGNOR-C155 SIGNOR "down-regulates activity" binding 9606 12554096 t "MCIP proteins can bind to and inhibit calcineurin, a calcium/calmodulin-regulated serine/threonine protein phosphatase that is activated during cardiac hypertrophy and failure" SIGNOR-252341 RUNX1 protein Q01196 UNIPROT MECOM protein Q03112 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000565 22689058 f irozzo "Our results suggest that RUNX1 and EVI1 could be regulating each other. RUNX1 would activate EVI1 transcription, and when highly expressed, EVI1 could bind to RUNX1 at protein level, inhibiting its activity as a transcription factor, acting in a negative feedback." SIGNOR-255715 STK3 protein Q13188 UNIPROT MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation Thr35 LLKHAEAtLGSGNLR 9606 23431053 t milica "Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity" SIGNOR-201286 UNII-XH2662798I chemical CID:16156006 PUBCHEM H3F3A protein P84243 UNIPROT down-regulates 9606 20068082 f gcesareni "Pf-00477736 also significantly enhances docetaxel efficacy in vitro and in vivo, in association with decreased cdc25c cytoplasmic phosphorylation (ser216) and histone h3 phosphorylation (ser10)(42)." SIGNOR-163130 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 ERG protein P11308 UNIPROT ICAM2 protein P13598 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001949 10574717 f miannu "The Ets family member Erg was found to be constitutively expressed in HUVEC, and TNF-(alpha) down-regulated Erg protein levels. Furthermore, an Erg cDNA transactivated the ICAM-2 promoter when transiently transfected into both HeLa cells and HUVEC." SIGNOR-253913 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 L-isoprenaline chemical CHEBI:6257 ChEBI ADRB1 protein P08588 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-257456 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 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 KMT2A protein Q03164 UNIPROT "MLL1 complex" complex SIGNOR-C89 SIGNOR "form complex" binding 9606 24680668 t miannu "The mixed lineage leukemia-1 (mll1) enzyme is a histone h3 lysine 4 (h3k4) monomethyltransferase and has served as a paradigm for understanding the mechanism of action of the human set1 family of enzymes that include mll1_Mll4 and setd1a,b. Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal core complex that is required for multiple lysine methylation." SIGNOR-204813 Laminin-5 complex SIGNOR-C184 SIGNOR "A6/b1 integrin" complex SIGNOR-C164 SIGNOR "up-regulates activity" binding 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-253219 LCK protein P06239 UNIPROT DEF6 protein Q9H4E7 UNIPROT "up-regulates activity" phosphorylation Tyr133 NFLSEDKyPLIMVPD 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-253367 PRKG1 protein Q13976 UNIPROT TRPC3 protein Q13507-3 UNIPROT down-regulates phosphorylation Thr11 SPSLRRMtVMREKGR 9606 BTO:0000007 16331690 t "The effect has been demonstrated using Q13507-3" llicata "The present study demonstrates that human trpc3 expressed in hek293 cells forms store-operated ca2+ influx channels, the activity of which is inhibited by pkg. The inhibition is due to a direct phosphorylation of pkg on trpc3 channels at position t11 and s263." SIGNOR-142957 PTEN protein P60484 UNIPROT AKT1 protein P31749 UNIPROT "down-regulates activity" 9606 BTO:0001332 19903340 f lperfetto "PTEN-mediated suppression of the PI3K/AKT pathway is well established, accumulating evidence suggests that nuclear PTEN also plays a critical role in tumor suppression" SIGNOR-189105 PTEN protein P60484 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" 9606 BTO:0001332 19903340 f lperfetto "PTEN-mediated suppression of the PI3K/AKT pathway is well established, accumulating evidence suggests that nuclear PTEN also plays a critical role in tumor suppression" SIGNOR-244439 PTK6 protein Q13882 UNIPROT STAP2 protein Q9UGK3 UNIPROT "up-regulates activity" phosphorylation Tyr250 PFLLDEDyEKVLGYV 9606 19393627 t lperfetto "Our previous studies revealed that STAP-2 binds to signal transducer and activator of transcription 3 (STAT3) and STAT5, and regulates the signaling pathways downstream of them. In the present study, we identified tyrosine-250 (Tyr250) in STAP-2 as a major site of phosphorylation by Brk, using a series of STAP-2 YF mutants and anti-phospho-STAP-2 Tyr250 antibody. Furthermore, overexpression of the STAP-2 Y250F mutant protein affected Brk-mediated STAT3 activation." SIGNOR-247067 UBE2C protein O00762 UNIPROT Mitotic_checkpoint phenotype SIGNOR-PH28 SIGNOR down-regulates 9606 19632176 f 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-251544 EZH2 protein Q15910 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR "down-regulates activity" "transcriptional repression" 10090 BTO:0002314 15520282 f "We report that Ezh2 expression was developmentally regulated in the myotome compartment of mouse somites and that its down-regulation coincided with activation of muscle gene expression and differentiation of satellite-cell-derived myoblasts" SIGNOR-255719 "lysophosphatidic acid" smallmolecule CHEBI:132742 ChEBI LPAR1 protein Q92633 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-257528 KAT6A/KAT6B complex SIGNOR-C54 SIGNOR TP53 protein P04637 UNIPROT up-regulates acetylation Lys120 FLHSGTAkSVTCTYS 9606 BTO:0001271 23431171 t lperfetto "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-217194 LEF1 protein Q9UJU2 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-254183 PRKG1 protein Q13976 UNIPROT TRPC3 protein Q13507 UNIPROT down-regulates phosphorylation Ser263 KNDYRKLsMQCKDFV 9606 BTO:0000007 16331690 t "The effect has been demonstrated using Q13507-3" llicata "The present study demonstrates that human trpc3 expressed in hek293 cells forms store-operated ca2+ influx channels, the activity of which is inhibited by pkg. The inhibition is due to a direct phosphorylation of pkg on trpc3 channels at position t11 and s263." SIGNOR-142961 RIPK1 protein Q13546 UNIPROT DAB2IP protein Q5VWQ8 UNIPROT "up-regulates activity" phosphorylation Ser728 PSPARSSsYSEANEP 9606 27858941 t miannu "Upon TNF stimulation, RIP1 phosphorylates DAB2IP on Serine 604, inducing a conformational switch that allows formation of the complex." SIGNOR-254763 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 BTO:0000801 22703233 f lperfetto "Our results establish a novel biological role for TGFbeta signaling in controlling expression of genes characteristic for alternatively activated macrophages. We speculate that lack of TbetaRII signaling reduces the anti-inflammatory M2 phenotype of macrophages because of reduced expression of these products." SIGNOR-249551 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 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 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR 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-244580 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 LRIG1 protein Q96JA1 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates 9606 23723069 f miannu "Lrig1 is a negative regulator of oncogenic receptor tyrosine kinases, including erbb and met receptors, and promotes receptor degradation." SIGNOR-202143 MAP1LC3B protein Q9GZQ8 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates binding 9606 17580304 t gcesareni "Sqstm1/p62 (named a170 in the mouse;hereafter p62) is the first proposed example of such proteins (bj_?_?Rk_?_?Y et al.,2005). It binds polyubiquitinated protein aggregates via its uba domain and interacts with lc3 on the autophagosome/ this interaction is necessary for autophagic degradation of p62-positive cytoplasmic inclusion bodies containing ubiquitinated proteins. We also demonstrate that alis are indistinguishable from p62 inclusion bodies and that p62 is required for their formation." SIGNOR-156356 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 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 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 EIF4EBP1 protein Q13541 UNIPROT down-regulates phosphorylation Thr45 PGGTLFStTPGGTRI 9606 11777913 t gcesareni "Phosphorylation of 4e-bp1 is mediated by the p38/msk1 pathway in response to uvb irradiation. In the present study we demonstrated that uvb induced 4e-bp1 phosphorylation at multiple sites, thr-36, thr-45, ser-64, and thr-69, leading to dissociation of 4e-bp1 from eif-4e. Uvb-induced phosphorylation of 4e-bp1 was blocked by p38 kinase inhibitors, pd169316 and sb202190, and msk1 inhibitor, h89, but not by mitogen-activated protein kinase kinase inhibitors, pd98059 or u0126." SIGNOR-113563 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 SIRT1 protein Q96EB6 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates quantity" deacetylation 10090 BTO:0002572 27776347 t "SIRT1 deacetylates β-catenin to promote its accumulation in the nucleus and thus induces the transcription of genes that block MSC adipogenesis." SIGNOR-256208 ZIC1 protein Q15915 UNIPROT GLI1 protein P08151 UNIPROT up-regulates 9606 BTO:0002181 11238441 f fspada "Moreover, gli proteins were translocated to cell nuclei by coexpressed zic proteins, and both proteins regulated each others transcriptional activity.In Nih3t3 and 293t cells, both gli1 and gli3 proteins were located predominantly in the cytoplasm (fig. 2, c, d, h, k, l, and p). Coexpression of zic1 resulted in gli1 and gli3 proteins being translocated to the nucleus in varying levels (fig. 2, e and m)." SIGNOR-105494 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 ESR2 protein Q92731 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-253473 EZH2 protein Q15910 UNIPROT SNAI2 protein O43623 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001939 23836662 f miannu "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-254146 LATS2 protein Q9NRM7 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates phosphorylation Ser89 AQHVRSHsSPASLQL 9606 22658639 t "Together the YAP/TAZ-TEAD complex promotes proliferative and survival programs." 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-197651 MAPK14 protein Q16539 UNIPROT AKT2 protein P31751 UNIPROT "up-regulates activity" Ser474 RTHFPQFsYSASIRE 9606 12181443 t lperfetto "We show [] that the kinase activity and s473 phosphorylation of akt induced by lpa and s1p requires both mitogen-activated protein (map) kinase kinase (mek) and p38 map kinase. [] among different stimuli tested, platelet-derived growth factor stimulates s473 phosphorylation of akt in a mek- and p38-dependent manner. However, epidermal growth factor, thrombin, and endothelin-1?stimulated Akt s473 phosphorylation require p38 but not mek." SIGNOR-91408 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 MAPK1 protein P28482 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR "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-252750 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 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 SMAD3 protein P84022 UNIPROT down-regulates 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 PML-RARalpha "fusion protein" SIGNOR-FP2 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001412 8394219 f "We expressed the PML-RARa protein in U937 myeloid precursor cells and showed that they lost the capacity to differentiate under the action of different stimuli (vitamin Ds and transforming growth factor pl), acquired enhanced sensitivity to retinoic acid, and exhibited a higher growth rate consequent to diminished apoptotic cell death." SIGNOR-255722 ZIC1 protein Q15915 UNIPROT GLI3 protein P10071 UNIPROT up-regulates 9606 BTO:0002181 11238441 f fspada "Moreover, gli proteins were translocated to cell nuclei by coexpressed zic proteins, and both proteins regulated each others transcriptional activity.In Nih3t3 and 293t cells, both gli1 and gli3 proteins were located predominantly in the cytoplasm (fig. 2, c, d, h, k, l, and p). Coexpression of zic1 resulted in gli1 and gli3 proteins being translocated to the nucleus in varying levels (fig. 2, e and m)." SIGNOR-105500 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 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 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 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 PML-RARalpha "fusion protein" SIGNOR-FP2 SIGNOR CCNA1 protein P78396 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0001412 11090075 f "Overexpression of cyclin A1 observed in APL cells is caused by the expression of the aberrant fusion proteins, PML-RARα and PLZF-RARα. PML-RARα itself can lead to activation of the cyclin A1 promoter.Since both fusion proteins disrupt the normal RARα function, our results strongly suggested that the RARα pathway negatively regulates the expression of cyclin A1 and that this negative regulation is disrupted by the aberrant fusion proteins." SIGNOR-255725 PML-RARalpha "fusion protein" SIGNOR-FP2 SIGNOR Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 20966922 f "APL cells closely resemble normal promyelocytes, a specific stage of the granulocytic differentiation pathway, suggesting that PML–RARα blocks the normal myeloid differentiation programme." SIGNOR-255724 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 RUNX3 protein Q13761 UNIPROT PEA15 protein Q15121 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002384 17956589 f miannu "Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells." SIGNOR-255097 sirolimus chemical CHEBI:9168 ChEBI IRS1 protein P35568 UNIPROT up-regulates 9606 16452206 f gcesareni "The mtor inhibitory drug rapamycin up-regulates irs-1 protein levels and induces akt phosphorylation, protein kinase activity, and downstream signaling." SIGNOR-144159 SRC protein P12931 UNIPROT DAB1 protein O75553 UNIPROT "up-regulates activity" phosphorylation Tyr220 PETEENIyQVPTSQK 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-247080 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 DNM1 protein Q05193 UNIPROT "up-regulates activ