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 0.498 KSR1 protein Q8IVT5 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 BTO:0000007 29433126 t miannu In mammals, RAF family kinases include three catalytically competent enzymes (ARAF, BRAF and CRAF) and two pseudokinases (KSR1 and KSR2) that have been described as scaffolds owing to their apparent ability to bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK).Kinase suppressor of Ras (KSR) pseudokinases were also shown to dimerize with kinase-competent RAFs to stimulate catalysis allosterically. SIGNOR-273878 0.628 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 0.68 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 0.672 PPP1CA protein P62136 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity dephosphorylation 9606 29335436 t miannu To address whether PP1\u03b1 activates B-Raf through these inhibitory sites, we made use of B-Raf protein mutants in which an individual inhibitory site, as well as all four sites (4A), were mutated to alanine.|We confirmed that GST-B-Raf was phosphorylated by ERK2 in vitro  xref  , mainly on S151 and T753 (Fig.\u00a0 xref ), and found that PP1\u03b1 dephosphorylated B-Raf on both ERK phosphorylation sites (Fig.\u00a0 xref ). SIGNOR-277160 0.295 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 0.788 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MAPK3 protein P27361 UNIPROT up-regulates activity phosphorylation 10090 11730323 t Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs SIGNOR-258991 0.2 MAPK1 protein P28482 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser289 RSHSESAsPSALSSS 10090 15664191 t lperfetto Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2 SIGNOR-249440 0.63 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 0.788 JAK2 protein O60674 UNIPROT PTPN11 protein Q06124 UNIPROT up-regulates activity phosphorylation Tyr304 PNEPVSDyINANIIM 9534 BTO:0004055 8995399 t lperfetto Tyrosine residues 304 and 327 in shp-2 are phosphorylated by jaks, and phosphorylated shp-2 can associate with the downstream adapter protein grb2 SIGNOR-236266 0.793 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 0.636 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 0.616 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 0.2 BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation -1 8413257 t lperfetto Raf-1 phosphorylation of MEK activated it, as judged by its ability to stimulate the phosphorylation of myelin basic protein by glutathione S-transferase-ERK1. SIGNOR-244831 0.788 PPP1CA protein P62136 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates dephosphorylation 9606 12840032 t inferred from 70% of family members 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-269927 0.448 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MAPK1 protein P28482 UNIPROT up-regulates activity phosphorylation 10090 11730323 t Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs SIGNOR-258990 0.2 BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 9606 21900390 t miannu BRAFV600E has been shown to initiate thyroid follicular cell transformation. The BRAFV600E mutation disrupts the hydrophobic interaction, enabling the BRAF kinase to fold into a catalytically active formation, resulting in an almost 500-fold increase in kinase activity. Mutant BRAF can dimerize and activate MEK without Ras activation. SIGNOR-251988 0.788 PDGFRB protein P09619 UNIPROT PTPN11 protein Q06124 UNIPROT up-regulates activity phosphorylation Tyr542 SKRKGHEyTNIKYSL 10090 BTO:0000944 8041791 t miannu Upon PDGF stimulation, SHPTP2 binds to the PDGFR and becomes tyrosine-phosphorylated. We have identified tyrosine-542 (pY542TNI) as the major in vivo site of SHPTP2 tyrosine phosphorylation. phosphorylation of SHPTP2 couples Grb2 to PDGFR in vivo, providing a mechanism for Ras activation by PDGFR and for positive signaling via SHPTP2 and Csw. SIGNOR-250260 0.749 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR 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-244862 0.757 JAK2 protein O60674 UNIPROT RAF1 protein P04049 UNIPROT up-regulates activity phosphorylation Tyr341 GQRDSSYyWEIEASE 10090 BTO:0001482 8876196 t  JAK2 phosphorylated Raf-1. e sites at 340/341 are indeed phosphorylated by JAK2 and that this phosphorylation represents a major component of the activation process. SIGNOR-251362 0.616 MAP2K1 protein Q02750 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates phosphorylation 9606 12270934 t lbriganti Mek1 as indicated by extensive phosphorylation of erk1 and erk2 during the initial 2 h of adipogenesis. SIGNOR-210176 0.751 MAP2K2 protein P36507 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity phosphorylation 10090 11730323 t Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs SIGNOR-258995 0.746 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 0.749 PRKACA protein P17612 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser233 VSSQHRYsTPHAFTF 9534 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 0.498 SRC protein P12931 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Tyr340 RGQRDSSyYWEIEAS 9606 10998357 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-82150 0.603 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 0.878 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 0.749 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 0.498 PRKCA protein P17252 UNIPROT PTPN11 protein Q06124 UNIPROT unknown phosphorylation Ser595 GLMQQQKsFR 9606 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-249138 0.324 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 0.556 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 0.749 PRKACA protein P17612 UNIPROT BRAF protein P15056 UNIPROT down-regulates activity phosphorylation Ser429 PQRERKSsSSSEDRN 10116 BTO:0001009 11510412 t The in vitro phosphorylation of a site unique to B-Raf (Ser429) has been proposed to be responsible for the negative regulation of the isoenzyme by Akt. Using phosphopetide mapping and site-directed mutagenesis we showed that Ser429 is phosphorylated upon cAMP elevation in PC12 cells and proposed that PKA is a major kinase phosphorylating the B-Raf-specific site in vivo SIGNOR-259922 0.634 KRAS protein P01116 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 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 0.847 AKT2 protein P31751 UNIPROT BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr440 EDRNRMKtLGRRDSS 9606 10869359 t gcesareni We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf SIGNOR-78689 0.272 AKT1 protein P31749 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser259 SQRQRSTsTPNVHMV 9606 BTO:0000150;BTO:0001130 16854453 t gcesareni Akt and protein kinase a (pka) phosphorylate s259 on raf-1 and inhibit its activity. SIGNOR-147963 0.699 PRKACA protein P17612 UNIPROT PTPN11 protein Q06124 UNIPROT down-regulates activity phosphorylation Thr73 YGGEKFAtLAELVQY 9606 BTO:0002181 25802336 t miannu  We identified two key amino acids in Shp2 that are phosphorylated by PKA. Thr-73 contributes a helix cap to helix αB within the N-terminal SH2 domain of Shp2, whereas Ser-189 occupies an equivalent position within the C-terminal SH2 domain. Utilizing double mutant PKA phosphodeficient (T73A/S189A) and phosphomimetic (T73D/S189D) constructs, in vitro binding assays, and phosphatase activity assays, we demonstrate that phosphorylation of these residues disrupts Shp2 interaction with tyrosine-phosphorylated ligands and inhibits its protein-tyrosine phosphatase activity.  SIGNOR-276891 0.449 MAP2K2 protein P36507 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates phosphorylation Thr202 HDHTGFLtEYVATRW 9606 BTO:0000142 1411546 t gcesareni The primary structure of mek, a protein kinase that phosphorylates the erk gene product SIGNOR-19240 0.741 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 0.446 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser289 RSHSESAsPSALSSS 10090 15664191 t lperfetto Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2 SIGNOR-244677 0.2 MAP2K2 protein P36507 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates activity phosphorylation 10090 11730323 t Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs SIGNOR-258996 0.744 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 0.676 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RAF1 protein P04049 UNIPROT down-regulates phosphorylation 9606 9922370 t lperfetto 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-244688 0.2 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 0.757 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 0.699 KSR2 protein Q6VAB6 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 BTO:0000007 29433126 t miannu In mammals, RAF family kinases include three catalytically competent enzymes (ARAF, BRAF and CRAF) and two pseudokinases (KSR1 and KSR2) that have been described as scaffolds owing to their apparent ability to bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK).Kinase suppressor of Ras (KSR) pseudokinases were also shown to dimerize with kinase-competent RAFs to stimulate catalysis allosterically. SIGNOR-273877 0.616 JAK2 protein O60674 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr718 IPERDSRySQPLHEE 9606 BTO:0001963 19287004 t miannu Furthermore, JAK2, but not JAK1, directly bound to and phosphorylated ASK1 at Tyr-718, leading to an enhanced association of ASK1 with SOCS1 and subsequent ASK1 degradation.  SIGNOR-276145 0.368 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 0.627 PRKACA protein P17612 UNIPROT PTPN11 protein Q06124 UNIPROT down-regulates activity phosphorylation Ser189 GGGERFDsLTDLVEH 9606 BTO:0002181 25802336 t miannu  We identified two key amino acids in Shp2 that are phosphorylated by PKA. Thr-73 contributes a helix cap to helix αB within the N-terminal SH2 domain of Shp2, whereas Ser-189 occupies an equivalent position within the C-terminal SH2 domain. Utilizing double mutant PKA phosphodeficient (T73A/S189A) and phosphomimetic (T73D/S189D) constructs, in vitro binding assays, and phosphatase activity assays, we demonstrate that phosphorylation of these residues disrupts Shp2 interaction with tyrosine-phosphorylated ligands and inhibits its protein-tyrosine phosphatase activity.  SIGNOR-276892 0.449 NRAS protein P01111 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 21779497 t lperfetto The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. SIGNOR-175219 0.854 Gbeta proteinfamily SIGNOR-PF4 SIGNOR JAK2 protein O60674 UNIPROT down-regulates phosphorylation 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-270046 0.2 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 0.63 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 0.728 PRKCA protein P17252 UNIPROT RAF1 protein P04049 UNIPROT unknown phosphorylation Ser497 ATVKSRWsGSQQVEQ 9606 12551925 t gcesareni For example, PKCα phosphorylates Raf-1 at serine 499 (13), but mutation of this residue did not impede activation of Raf-1 by the physiological stimulators Ras and Lck. Similarly, both v-Src and phorbol esters were able to activate Raf-1 even though the PKC phosphorylation sites at serine 497 and serine 499 were mutated to alanine (14). Thus, although some PKC phosphorylation sites on Raf-1 have been identified, these sites do not appear to be required for activation of Raf-1. SIGNOR-37844 0.556 RAF1 protein P04049 UNIPROT MAP2K2 protein P36507 UNIPROT up-regulates phosphorylation Ser226 LIDSMANsFVGTRSY 9606 8157000 t Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. gcesareni To understand the mechanism of activation of MAPKK, we have identified Ser217 and Ser221 of MAPKK1 as the sites phosphorylated by p74raf-1. SIGNOR-36553 0.732 KRAS protein P01116 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 21779497 t miannu The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. SIGNOR-156906 0.876 SRC protein P12931 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Tyr315 TFCGTPEyLAPEVLE 9534 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 0.676 MAPK1 protein P28482 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser29 FDGSSCIsPTIVQQF 10090 BTO:0000944 15664191 t lperfetto Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2 SIGNOR-249441 0.63 MAPK3 protein P27361 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser296 SPSALSSsPNNLSPT 10090 15664191 t lperfetto Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2 SIGNOR-143692 0.636 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 0.2 PDGFRB protein P09619 UNIPROT SRC protein P12931 UNIPROT up-regulates activity phosphorylation Tyr419 RLIEDNEyTARQGAK 9606 BTO:0002057 15489898 t gcesareni The increased Src activity is mainly due to the phosphorylation of Tyr-419, rather than the dephosphorylation of Tyr-530 of Src protein. PDGFR, not FAK or EGFR, appears to be the upstream protein tyrosine kinase responsible for the detachment-induced Src activation in the lung tumor cells. SIGNOR-247979 0.603 MAP2K2 protein P36507 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates activity phosphorylation 10090 11730323 t Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs SIGNOR-258997 0.741 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MAPK3 protein P27361 UNIPROT up-regulates phosphorylation Thr202 HDHTGFLtEYVATRW 9606 9677429 t MAPK3/ERK1 is a MAPK which plays an important role in the MAPK/ERK cascade. lperfetto The mek1 proline-rich insert is required for efficient activation of the mitogen-activated protein kinases erk1 and erk2 in mammalian cells. SIGNOR-244802 0.2 Gbeta proteinfamily SIGNOR-PF4 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation 9606 16508002 t inferred from 70% family members 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-270043 0.2 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 0.746 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 0.775 BRAF protein P15056 UNIPROT EEF1A2 protein Q05639 UNIPROT down-regulates quantity by destabilization phosphorylation Ser21 GHVDSGKsTTTGHLI -1 22378069 t miannu Mass spectrometry identified in vitro S21 and T88 as phosphorylation sites mediated by B-Raf but not C-Raf on eEF1A1 whereas S21 was phosphorylated on eEF1A2 by both B- and C-Raf.  SIGNOR-276406 0.327 AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr440 EDRNRMKtLGRRDSS 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-244156 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR RAF1 protein P04049 UNIPROT down-regulates phosphorylation 9606 14967450 t lperfetto Akt negatively regulates the raf and gsk-3 kinases and the cell cycle regulatory transcription factor fkhr. SIGNOR-244333 0.2 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 0.361 PRKACA protein P17612 UNIPROT SRC protein P12931 UNIPROT up-regulates phosphorylation Ser17 DASQRRRsLEPAENV 9606 11804588 t llicata Pka activated src both in vitro and in vivo by phosphorylating src on serine 17 SIGNOR-114277 0.361 MAP2K1 protein Q02750 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates activity phosphorylation 10090 11730323 t Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs SIGNOR-258994 0.751 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 0.603 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 0.636 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr401 STTGLSAtPPASLPG 9606 21135229 t lperfetto We show that b-raf is a calcineurin substrate;among calcineurin target residues on b-raf is t401, a site of negative feedback phosphorylation by erk1/2. Blocking calcineurin activity in _ cells prevents dephosphorylation of b-raf t401 and decreases b-raf and erk1/2 activities. SIGNOR-170339 0.2 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 0.556 BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 10090 8131746 t lperfetto Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf. SIGNOR-244827 0.788 Gbeta proteinfamily SIGNOR-PF4 SIGNOR RAF1 protein P04049 UNIPROT down-regulates phosphorylation 9606 16407412 t inferred from 70% family members 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-270010 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BRAF protein P15056 UNIPROT down-regulates activity phosphorylation Ser151 VARSNPKsPQKPIVR 9606 BTO:0000848 21478863 t We show that overactivation of the MAPK pathway, induced by the oncogenic Ras in melanoma, induces constitutive phosphorylation of BRAF on Ser151 by ERK, which inhibits NRAS-BRAF interaction SIGNOR-259919 0.2 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 0.272 PRKCB protein P05771 UNIPROT PTPN11 protein Q06124 UNIPROT unknown phosphorylation Ser595 GLMQQQKsFR 9606 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 0.331 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR 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-244561 0.2 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 0.2 AKT2 protein P31751 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates activity phosphorylation Ser83 ATRGRGSsVGGGSRR 9606 BTO:0000150 12697749 t lperfetto Akt2 interacts with and phosphorylates ask1 at ser-83 resulting in inhibition of its kinase activity SIGNOR-100588 0.645 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 0.442 PTPN11 protein Q06124 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-248670 0.652 BRAF protein P15056 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates activity phosphorylation Ser218 VSGQLIDsMANSFVG 10090 BTO:0000944 8131746 t lperfetto Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf. SIGNOR-235475 0.788 PTPN11 protein Q06124 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates activity dephosphorylation Tyr751 SKDESVDyVPMLDMK -1 7545675 t Upon activation, the βPDGFR is phosphorylated at multiple tyrosine residues and thereby becomes a docking site for SH2-domain-containing signal transduction proteins.|While all phosphotyrosine sites on the βPDGFR are equally good targets for rPTP1B, maps of the βPDGFR dephosphorylated by rSyp showed that rSyp had a distinct preference for certain sites (Fig. 4 D-F). The low dose of rSyp primarily dephosphorylated spots 1, 6, 7, 9, and to a lesser extent 8a|Spot 1 corresponds to tyrosine 751; spot 3 corresponds to tyrosine 1009; spot 6 corresponds to tyrosine 740; spot 8b corresponds to tyrosine 1021; spot 9 corresponds to tyrosine 771, and spots 2, 7, and 8a are as yet unidentified phosphopeptides SIGNOR-248668 0.749 KRAS protein P01116 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 16293107 t gcesareni Among other effectors, active ras binds and activates the raf kinase, iniziating a kinase cascade involving serine phosporylation of mek1/2 (mapkk) and tyrosine and threonine phosphorylation of erk1/2. the raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases.. Association of ras with the mapk kinase kinase, raf, initiates the raf mek erk map kinase cascade. SIGNOR-141641 0.847 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 0.748 KSR1 protein Q8IVT5 UNIPROT RAF1 protein P04049 UNIPROT up-regulates activity binding 9606 BTO:0000007 29433126 t miannu In mammals, RAF family kinases include three catalytically competent enzymes (ARAF, BRAF and CRAF) and two pseudokinases (KSR1 and KSR2) that have been described as scaffolds owing to their apparent ability to bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK).Kinase suppressor of Ras (KSR) pseudokinases were also shown to dimerize with kinase-competent RAFs to stimulate catalysis allosterically. SIGNOR-273880 0.652 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 0.2 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 0.603 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 0.676 PRKCA protein P17252 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Ser518 VFRTNGVsDVPTSPT -1 27368100 t miannu These results suggest that PKC activates JAK2 and thereby STAT3 by directly phosphorylating T174 and S518.  SIGNOR-277261 0.26 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 0.676 PPP1CA protein P62136 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates dephosphorylation 9606 20186153 t lperfetto Several stps have been reported to negatively regulate akt pathway. It has been shown that pp1 dephosphorylates akt and regulates cell survival. SIGNOR-244436 0.427 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 0.521 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 0.936 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 0.556 KSR2 protein Q6VAB6 UNIPROT RAF1 protein P04049 UNIPROT up-regulates activity binding 9606 BTO:0000007 29433126 t miannu In mammals, RAF family kinases include three catalytically competent enzymes (ARAF, BRAF and CRAF) and two pseudokinases (KSR1 and KSR2) that have been described as scaffolds owing to their apparent ability to bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK).Kinase suppressor of Ras (KSR) pseudokinases were also shown to dimerize with kinase-competent RAFs to stimulate catalysis allosterically. SIGNOR-273879 0.604 BRAF protein P15056 UNIPROT MAP2K2 protein P36507 UNIPROT up-regulates phosphorylation Ser226 LIDSMANsFVGTRSY 9606 BTO:0000142 8668348 t gcesareni We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l. SIGNOR-42668 0.75 PTPN11 protein Q06124 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity dephosphorylation Tyr570 VRREVGDyGQLHETE 9606 30108215 t miannu Consistently, JAK2/STAT3 signaling was enhanced by overexpression of SHP2   with decreased levels of pJAK2   and increased levels of pJAK2   and pSTAT3  , while it was found suppressed by overexpression of SHP2   (Fig.\u00a06b).|We demonstrate that SHP2 can dephosphorylate JAK2 at Y570 to promote TGF\u03b2-dependent activation of JAK2 and its downstream mediator STAT3 (Supplementary Fig.\u00a04a). SIGNOR-277037 0.793 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 0.659 PRKCB protein P05771 UNIPROT EEF1A2 protein Q05639 UNIPROT up-regulates activity phosphorylation Ser53 AAEMGKGsFKYAWVL 10090 20923971 t miannu PKCβI phosphorylates eEF1A at Ser53.our proteomics exploration of cPKC signaling in the nuclei of C2C12 cells demonstrated that the up-regulation of eEF1A intranuclear content, evoked by insulin, is associated with an increase in the phosphorylation of the Ser53 residue of the protein. SIGNOR-263166 0.2 PRKACA protein P17612 UNIPROT BRAF protein P15056 UNIPROT down-regulates activity phosphorylation Ser429 PQRERKSsSSSEDRN -1 11510412 t miannu Direct phosphorylation of B-Raf by PKA exerts a negative effect on its kinase activity, essentially via phosphorylation of Ser429 SIGNOR-250339 0.634 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 0.63 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 0.793 MAP2K1 protein Q02750 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates phosphorylation Thr202 HDHTGFLtEYVATRW 9606 9677429 t MAPK3/ERK1 is a MAPK which plays an important role in the MAPK/ERK cascade. gcesareni The mek1 proline-rich insert is required for efficient activation of the mitogen-activated protein kinases erk1 and erk2 in mammalian cells. SIGNOR-59153 0.751 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 0.676 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 0.46 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 0.788 PPP1CA protein P62136 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation Thr450 TAQMITItPPDQDDS 9606 20186153 t gcesareni Several stps have been reported to negatively regulate akt pathway. It has been shown that pp1 dephosphorylates akt and regulates cell survival. SIGNOR-163961 0.427 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 0.652 BRAF protein P15056 UNIPROT MAP2K2 protein P36507 UNIPROT up-regulates phosphorylation Ser222 VSGQLIDsMANSFVG 9606 BTO:0000142 8668348 t gcesareni We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l. SIGNOR-42664 0.75 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 0.657 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser301 SSSPNNLsPTGWSQP 9606 16407412 t lperfetto 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-244685 0.2 PRKCA protein P17252 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Thr174 KVPVTHEtQEECLGM -1 27368100 t miannu These results suggest that PKC activates JAK2 and thereby STAT3 by directly phosphorylating T174 and S518.  SIGNOR-277262 0.26 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 0.749 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 0.748 AKT proteinfamily SIGNOR-PF24 SIGNOR RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser259 SQRQRSTsTPNVHMV 9606 BTO:0000150;BTO:0001130 16854453 t lperfetto Akt and protein kinase a (pka) phosphorylate s259 on raf-1 and inhibit its activity. SIGNOR-244337 0.2 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 0.643 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 0.427 RAF1 protein P04049 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates activity phosphorylation Ser218 VSGQLIDsMANSFVG 9606 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 0.748 MAPK3 protein P27361 UNIPROT BRAF protein P15056 UNIPROT down-regulates activity phosphorylation Ser151 VARSNPKsPQKPIVR 9606 BTO:0000848 21478863 t We show that overactivation of the MAPK pathway, induced by the oncogenic Ras in melanoma, induces constitutive phosphorylation of BRAF on Ser151 by ERK, which inhibits NRAS-BRAF interaction SIGNOR-259921 0.643 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity phosphorylation 10090 11730323 t Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs SIGNOR-258989 0.757 MAPK3 protein P27361 UNIPROT BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr753 YACASPKtPIQAGGY 9606 19933846 t gcesareni Erk-induced phosphorylation of b-raf on t753 promoted the disassembly of raf heterodimers, and the mutation of t753 prolonged growth factor-induced heterodimerization. The b-raf t753a mutant enhanced differentiation of pc12 cells, which was previously shown to be dependent on sustained erk signaling. Site is critical for v-src dependent modulation of slk kinase activity. SIGNOR-161819 0.643 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 0.427 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 0.2 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 0.636 HRAS protein P01112 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 21779497 t lperfetto The first RAS effector pathway to be identified was the RAF-MEK-ERK pathway. This pathway is an essential, shared element of mitogenic signaling involving tyrosine kinase receptors, leading to a wide range of cellular responses, including growth, differentiation, inflammation, and apoptosis.23 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. SIGNOR-236656 0.936 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MAPK3 protein P27361 UNIPROT up-regulates activity phosphorylation Thr207 FLTEYVAtRWYRAPE 9606 BTO:0000562 19060905 t lperfetto Here we show that autophosphorylation of erk1/2 on thr188 directs erk1/2 to phosphorylate nuclear targets known to cause cardiac hypertrophy. SIGNOR-244565 0.2 PRKACA protein P17612 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser621 PKINRSAsEPSLHRA 9606 11971957 t gcesareni We have mapped all camp-induced phosphorylation sites in raf-1, showing that serines 43, 259, and 621 are phosphorylated by pka in vitro and induced by camp in vivo SIGNOR-86137 0.498 MAP2K1 protein Q02750 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity phosphorylation 10090 11730323 t Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs SIGNOR-258992 0.751 PRKCA protein P17252 UNIPROT SRC protein P12931 UNIPROT unknown phosphorylation Ser12 KSKPKDAsQRRRSLE -1 2996780 t lperfetto We propose that protein kinase C is responsible for this modification based on the following evidence. First, the tumor promoters, 12-O-tetradecanoylphorbol-13-acetate and teleocidin, and synthetic diacylglycerol, known activators of protein kinase C in vivo, cause nearly complete phosphorylation of pp60src at serine 12. Second, among five purified serine/threonine-specific protein kinases tested, only protein kinase C phosphorylates pp60c-src and pp60v-src in vitro at serine 12. Third, purified protein kinase C phosphorylates a synthetic peptide corresponding to the N-terminal 20 amino acids of pp60c-src at serine 12. The physiological significance of this novel phosphorylation is discussed. SIGNOR-248893 0.598 PPP1CA protein P62136 UNIPROT RAF1 protein P04049 UNIPROT up-regulates activity dephosphorylation Ser259 SQRQRSTsTPNVHMV 9606 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 0.271 PTPN11 protein Q06124 UNIPROT JAK2 protein O60674 UNIPROT up-regulates quantity by stabilization 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 0.793 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 0.676 MAPK1 protein P28482 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser296 SPSALSSsPNNLSPT 10090 15664191 t lperfetto Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2 SIGNOR-249442 0.63 PRKCB protein P05771 UNIPROT PTPN11 protein Q06124 UNIPROT unknown phosphorylation Ser576 CAEMREDsARVYENV 9606 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 0.331 MAPK1 protein P28482 UNIPROT JAK2 protein O60674 UNIPROT down-regulates phosphorylation Ser523 GVSDVPTsPTLQRPT 9534 BTO:0004055 16705159 t 16705160:the phosphorylation of Jak2 on Ser523 inhibits Jak2 activity and represents a novel mechanism for the regulation of Jak2-dependent cytokine signaling. lperfetto We hypothesize that phosphorylation of ser523 in jak2 by erks 1 and/or 2 or other as-yet-unidentified kinases acts in a negative feedback manner SIGNOR-236331 0.51 MAP2K1 protein Q02750 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates activity phosphorylation 10090 11730323 t Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs SIGNOR-258993 0.749 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 0.652 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 0.63 RAF1 protein P04049 UNIPROT EEF1A2 protein Q05639 UNIPROT down-regulates quantity by destabilization phosphorylation Ser21 GHVDSGKsTTTGHLI -1 22378069 t miannu Mass spectrometry identified in vitro S21 and T88 as phosphorylation sites mediated by B-Raf but not C-Raf on eEF1A1 whereas S21 was phosphorylated on eEF1A2 by both B- and C-Raf.  SIGNOR-276407 0.2 MAP2K1 protein Q02750 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates phosphorylation Tyr204 HTGFLTEyVATRWYR 9606 9677429 t MAPK3/ERK1 is a MAPK which plays an important role in the MAPK/ERK cascade. gcesareni The mek1 proline-rich insert is required for efficient activation of the mitogen-activated protein kinases erk1 and erk2 in mammalian cells. SIGNOR-59157 0.751 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 0.754 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 0.754 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 0.603 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 0.448 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 0.744 AKT proteinfamily SIGNOR-PF24 SIGNOR PRKACA protein P17612 UNIPROT up-regulates 9606 BTO:0000938 16537363 f gcesareni Indicating that akt positively regulates shh signaling by controlling pka-mediated gli inactivation. SIGNOR-145113 0.2 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 0.498 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 0.556 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 0.368 PTPN11 protein Q06124 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates quantity by stabilization dephosphorylation 9606 BTO:0001963 19287004 t miannu In this study, we identified JAK2 and SHP2 as a Tyr-718-specific kinase and phosphatase, respectively. SIGNOR-276144 0.368 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser296 SPSALSSsPNNLSPT 10090 15664191 t lperfetto Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2 SIGNOR-244681 0.2 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 0.63 BRAF protein P15056 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 9606 21900390 f miannu RAF, a cytoplasmic serine-threonine protein kinase, is a member of the RAS-RAF-MEK-ERK cell-signaling pathway [also known as the MAP kinase (MAPK) pathway], and it plays an essential role in mediating cellular differentiation, proliferation, senescence, and survival in response to extracellular cues. Raf phosphorylates and activates MAP-ERK kinase (MEK), which phosphorylates and activates extracellular signal-regulated kinase (ERK). SIGNOR-260082 0.659 RAF1 protein P04049 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 11018021 t Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. lperfetto The best characterized Raf substrates are MEK1 and MEK2. The activation of MEK1/2 by Raf is required to mediate many of the cellular responses to Raf activation, suggesting that MEK1/2 are the dominant Raf effector proteins. SIGNOR-244952 0.748 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MAPK3 protein P27361 UNIPROT up-regulates phosphorylation Tyr204 HTGFLTEyVATRWYR 9606 9677429 t MAPK3/ERK1 is a MAPK which plays an important role in the MAPK/ERK cascade. lperfetto The mek1 proline-rich insert is required for efficient activation of the mitogen-activated protein kinases erk1 and erk2 in mammalian cells. SIGNOR-244806 0.2 RAF1 protein P04049 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates binding 9606 11427728 t gcesareni Raf-1 interacts with the proapoptotic, stress-activated protein kinase ask1 (apoptosis signal-regulating kinase 1) in vitro and in vivo. SIGNOR-109023 0.396 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR 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-244858 0.757 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR Gbeta proteinfamily SIGNOR-PF4 SIGNOR up-regulates phosphorylation 9606 12270934 t inferred from 70% of family members lperfetto Mek1 as indicated by extensive phosphorylation of erk1 and erk2 during the initial 2 h of adipogenesis. SIGNOR-269913 0.2 MAPK1 protein P28482 UNIPROT MAP2K1 protein Q02750 UNIPROT down-regulates activity phosphorylation Thr386 IGLNQPStPTHAAGV 9606 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 0.749 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 0.2 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 0.442 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 0.699 SRC protein P12931 UNIPROT EPHA2 protein P29317 UNIPROT up-regulates activity phosphorylation Tyr594 TYVDPHTyEDPNQAV 9606 24457997 t gcesareni SRC phosphorylates EPHA2 on Tyr594|. It is therefore likely that this phosphorylation site is included in the binding motif of an additional signalling molecule required for cell transformation. SIGNOR-246104 0.451 RAF1 protein P04049 UNIPROT MAP2K2 protein P36507 UNIPROT up-regulates phosphorylation Ser222 VSGQLIDsMANSFVG 9606 8157000 t gcesareni To understand the mechanism of activation of MAPKK, we have identified Ser217 and Ser221 of MAPKK1 as the sites phosphorylated by p74raf-1. SIGNOR-262292 0.732 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 0.498 PTPN11 protein Q06124 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 9606 11085989 f miannu We show here that leptin can activate ERK signaling in thehypothalamus and that this stimulation is likely to occur viatwo pathways, both involving SHP-2.We have shown above that SHP-2 is a positive mediator of ERK activation by ObRb and that this requires both the phosphatase activity and tyrosine phosphorylation of SHP-2. Furthermore,Tyr-985 is required for maximal ERK phosphorylation. SIGNOR-263500 0.866 NRAS protein P01111 UNIPROT RAF1 protein P04049 UNIPROT up-regulates relocalization 9606 21779497 t Translocation from Cytosol to Membrane gcesareni The raf family of proteins (raf-1, a-raf, and b-raf) bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. SIGNOR-175231 0.87 PPP1CA protein P62136 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR down-regulates dephosphorylation 9606 12840032 t inferred from 70% of family members 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-269906 0.2 MAPK1 protein P28482 UNIPROT BRAF protein P15056 UNIPROT down-regulates activity phosphorylation Ser151 VARSNPKsPQKPIVR 9606 BTO:0000848 21478863 t We show that overactivation of the MAPK pathway, induced by the oncogenic Ras in melanoma, induces constitutive phosphorylation of BRAF on Ser151 by ERK, which inhibits NRAS-BRAF interaction SIGNOR-259920 0.627 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 0.449 MAPK1 protein P28482 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates 9606 BTO:0000130 16709866 f gcesareni The role of members of the arrestin family to mediate kinase activation is also a well-established phenomenon, including activation of members of the src family, erk1/2, and jnk3. Activation often includes the recruitment and interaction of arrestins with upstream mapks (ask1, mek3, mkk3, and mek kinase-2). SIGNOR-146751 0.321 AKT proteinfamily SIGNOR-PF24 SIGNOR RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser259 SQRQRSTsTPNVHMV 9606 BTO:0000222 BTO:0000887;BTO:0001760 10576741 t gcesareni The stage-specific inhibitory action of Akt correlated with its stage-specific ability to form a complex with Raf, suggesting the existence of differentially expressed mediators of an inhibitory Akt-Raf complex. SIGNOR-72669 0.2 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 0.749 HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates binding 10090 BTO:0000944 7706312 t lperfetto Association of B-Raf with immobilized Ras occurred independently of prior stimulation of cells with serum, suggesting that primarily the production of GTP-Ras by mitogen stimulation is critical for the formation of B-Raf_GTP-Ras complexes. SIGNOR-235478 0.878 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 0.556 AKT1 protein P31749 UNIPROT BRAF protein P15056 UNIPROT down-regulates activity phosphorylation Ser365 GQRDRSSsAPNVHIN 9606 10869359 t Akt phosphorylates both S364 and S428. Akt downregulates B-Raf activity in vivo SIGNOR-251471 0.46 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 0.2 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 0.272 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 0.2 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 0.368 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR 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-244795 0.2 MAP2K2 protein P36507 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates phosphorylation Tyr204 HTGFLTEyVATRWYR 9606 BTO:0000142 1411546 t gcesareni The primary structure of mek, a protein kinase that phosphorylates the erk gene product SIGNOR-19244 0.741 MAP2K1 protein Q02750 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates activity phosphorylation 9606 12270934 t lperfetto Mek1 as indicated by extensive phosphorylation of erk1 and erk2 during the initial 2 h of adipogenesis. SIGNOR-235940 0.749 MAP2K2 protein P36507 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR up-regulates phosphorylation 9606 BTO:0000142 1411546 t inferred from 70% of family members gcesareni The primary structure of mek, a protein kinase that phosphorylates the erk gene product SIGNOR-269895 0.2 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 0.878 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 0.744 PTPN11 protein Q06124 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 9606 11085989 f miannu We show here that leptin can activate ERK signaling in thehypothalamus and that this stimulation is likely to occur viatwo pathways, both involving SHP-2.We have shown above that SHP-2 is a positive mediator of ERK activation by ObRb and that this requires both the phosphatase activity and tyrosine phosphorylation of SHP-2. Furthermore,Tyr-985 is required for maximal ERK phosphorylation. SIGNOR-263499 0.866 BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 8668348 t lperfetto We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l. SIGNOR-244843 0.788 MAPK3 protein P27361 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser289 RSHSESAsPSALSSS 10090 15664191 t lperfetto Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2 SIGNOR-143688 0.636 MAP2K1 protein Q02750 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR up-regulates phosphorylation 9606 12270934 t inferred from 70% of family members lbriganti Mek1 as indicated by extensive phosphorylation of erk1 and erk2 during the initial 2 h of adipogenesis. SIGNOR-269909 0.2 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 0.751 AKT1 protein P31749 UNIPROT PRKACA protein P17612 UNIPROT up-regulates 9606 BTO:0000938 16537363 f gcesareni Indicating that akt positively regulates shh signaling by controlling pka-mediated gli inactivation. SIGNOR-252490 0.252