sig_id path_name coalesce path_curator SIGNOR-MM Malignant Melanoma Melanoma is a skin cancer. It might exist as distinct subtypes associated with the activation of the MAPK and the PI3K pathways even if there is an association between distinct melanoma subtypes and molecular somatic events. Mucosal, acral, and to a lesser extent, lentigo malignant melanomas, can have increased copies of CDK4, and CCND1 (cyclinD), as well as mutations in KIT receptor. NRAS is mutated in about 18% of melanomas, and seems to be more frequently activated in nodular melanomas and melanomas due to chronic sun damage. BRAF has a recurrent V600E mutation (Gain of function) in about 50–70% of melanomas, however, this mutational event is frequently reported in benign pigmented naevi, and is not fully sufficient to induce a malignant transformation. MEK1 and MEK2 are downstream from RAS and RAF, on the same MAPK pathway. Activating mutations of MEK1 and MEK2 are found in 8% of melanomas. The PI3K pathway is activated through a PTEN loss-of-function mutation (most often deletion) in 20–40% of melanomas. Activating mutations or amplifications of PI3K or of AKT1 can also be found in some melanomas. Livia Perfetto pathway_id pathway_name entitya regulator_location typea ida databasea entityb target_location 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 score SIGNOR-MM Malignant Melanoma UV stress extracellular stimulus SIGNOR-ST7 SIGNOR CDKN2A protein P42771 UNIPROT up-regulates 9606 11830546 f miannu The expression of the melanoma susceptibility gene product p16 is increased after UVR both in epidermally derived cell lines and in human skin. The increased expression of p16 after exposure to suberythemal doses of UVR is potentiated by α-MSH, a ligand for MC1R, and this effect is mimicked by cAMP, the intracellular mediator of α-MSH signaling via the MC1 receptor. SIGNOR-252376 0.7 SIGNOR-MM Malignant Melanoma 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 0.857 SIGNOR-MM Malignant Melanoma 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 0.857 SIGNOR-MM Malignant Melanoma 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 0.857 SIGNOR-MM Malignant Melanoma 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 0.857 SIGNOR-MM Malignant Melanoma 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 0.857 SIGNOR-MM Malignant Melanoma 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 0.857 SIGNOR-MM Malignant Melanoma 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 0.2 SIGNOR-MM Malignant Melanoma 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 0.2 SIGNOR-MM Malignant Melanoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000763;BTO:0000149 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-244591 0.2 SIGNOR-MM Malignant Melanoma 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 0.2 SIGNOR-MM Malignant Melanoma 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 0.2 SIGNOR-MM Malignant Melanoma 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 0.2 SIGNOR-MM Malignant Melanoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation -1 8929531 t lperfetto The rapid phosphorylation of bad following il-3 connects a proximal survival signal with the bcl-2 family, modulating this checkpoint for apoptosis.phosphorylatedBAD is bound to 14-3-3 within the cytosol, while only nonphosphorylated BAD is heterodimerized with membrane-bound BCL-XL. SIGNOR-244497 0.2 SIGNOR-MM Malignant Melanoma 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 SIGNOR-MM Malignant Melanoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR E2F1 factor protein Q01094 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-233526 0.2 SIGNOR-MM Malignant Melanoma 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 0.2 SIGNOR-MM Malignant Melanoma 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 0.2 SIGNOR-MM Malignant Melanoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization 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. SIGNOR-244610 0.2 SIGNOR-MM Malignant Melanoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Ser70 RDPVARTsPLQTPAA 9534 BTO:0004055 10677502 t lperfetto Erk1 and erk2 directly phosphorylate bcl2 exclusively at ser-70. SIGNOR-244501 0.2 SIGNOR-MM Malignant Melanoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Ser360 TEMDPTYsPAALPQS 9606 18267068 t lperfetto 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-249572 0.2 SIGNOR-MM Malignant Melanoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Thr581 PDNQPLKtPCFTLHY 9606 18267068 t lperfetto 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-249573 0.2 SIGNOR-MM Malignant Melanoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA5 protein O75582 UNIPROT up-regulates activity phosphorylation Ser376 EKLFQGYsFVAPSIL 9606 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-249574 0.2 SIGNOR-MM Malignant Melanoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MITF factor 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 0.2 SIGNOR-MM Malignant Melanoma 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 0.743 SIGNOR-MM Malignant Melanoma 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 0.743 SIGNOR-MM Malignant Melanoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Survival phenotypesList phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 BTO:0000830 15526160 f Numerous studies have implicated the critical importance of the Ras/Erk pathway in cell division and survival SIGNOR-254948 0.7 SIGNOR-MM Malignant Melanoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Survival phenotypesList phenotype SIGNOR-PH13 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-255579 0.7 SIGNOR-MM Malignant Melanoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList 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 0.7 SIGNOR-MM Malignant Melanoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 19819937 f In addition to the JAK2–STAT5 pathway, the Ras GTPase–extracellular signal-regulated kinase (Ras–ERK) pathway has also been implicated in signaling of IL-5 and is important for IL-5-dependent cell survival, proliferation and differentiation of eosinophils. SIGNOR-254354 0.7 SIGNOR-MM Malignant Melanoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList 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 0.7 SIGNOR-MM Malignant Melanoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 20219869 f areggio Furthermore, stimulation of myoblasts with CCL2, CCL3, or CCL4 was sufficient to induce phosphorylation and activation of ERK1/2. This outcome may be functionally important because ERK1/2 activation is a component of the pathway through which many mitogenic growth factors can stimulate cell proliferation. SIGNOR-255120 0.7 SIGNOR-MM Malignant Melanoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList 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 0.7 SIGNOR-MM Malignant Melanoma AKT proteinfamily SIGNOR-PF24 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000938 9346240 t lperfetto Experiments in this study reveal that akt phosphorylates bad both in vitro and in vivo and that akt-mediated phosphorylation of bad effectively blocks bad induced cell death.[...] In addition, these findings implicate a particular phosphorylation site on bad, serine 136, in the suppression of bad-mediated death by akt.[...]The Phosphorylation of bad may lead to the prevention of cell death via a mechanism that involves the selective association of the phosphorylated forms of bad with 14-3-3 protein isoforms. Akt phosphorylates bad in vitro and in vivo we show that growth factor activation of the pi3'k/akt signaling pathway culminates in the phosphorylation of the bcl-2 family member bad, thereby suppressing apoptosis and promoting cell survival. Akt phosphorylates bad in vitro and in vivo erbb-mediated phosphorylation of bad by akt promotes survival by blocking the interaction of this pro-apoptotic molecule with bcl-2 and bcl-x proteins SIGNOR-244144 0.2 SIGNOR-MM Malignant Melanoma AKT proteinfamily SIGNOR-PF24 SIGNOR 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-244148 0.2 SIGNOR-MM Malignant Melanoma AKT proteinfamily SIGNOR-PF24 SIGNOR 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-251469 0.2 SIGNOR-MM Malignant Melanoma AKT proteinfamily SIGNOR-PF24 SIGNOR 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-251470 0.2 SIGNOR-MM Malignant Melanoma 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 SIGNOR-MM Malignant Melanoma 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 SIGNOR-MM Malignant Melanoma AKT proteinfamily SIGNOR-PF24 SIGNOR CREB1 factor protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 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 0.2 SIGNOR-MM Malignant Melanoma AKT proteinfamily SIGNOR-PF24 SIGNOR CREB1 factor protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 9606 9829964 t The nuclear factor CREB stimulates the expression of cellular genes following its protein kinase A-mediated phosphorylation at Ser-133. Ser-133 phosphorylation, in turn, activates target gene expression by promoting recruitment of the co-activator CBP. |When overexpressed in serum-stimulated cells, Akt/PKB potently induced Ser-133 phosphorylation of CREB and promoted recruitment of CBP. SIGNOR-251474 0.2 SIGNOR-MM Malignant Melanoma AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Ser188 RKRHKSDsISLSFDE 9606 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-244300 0.2 SIGNOR-MM Malignant Melanoma 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 0.2 SIGNOR-MM Malignant Melanoma AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Ser166 SSRRRAIsETEENSD 9606 15169778 t lperfetto Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylation. SIGNOR-244296 0.2 SIGNOR-MM Malignant Melanoma 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 0.743 SIGNOR-MM Malignant Melanoma PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity chemical activation 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 0.8 SIGNOR-MM Malignant Melanoma PIP3 receptor 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 0.8 SIGNOR-MM Malignant Melanoma PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9534 9637919 t lperfetto In response to PDGF, binding of ptdlns (3,4,5)p3 and/or ptdlns(3,4)p2 to the PH domain of PDK-1 causes its translocation to the plasma membrane where it co-localises with PKB, significantly contributing to the scale of PKB activation. SIGNOR-58313 0.8 SIGNOR-MM Malignant Melanoma PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity chemical activation -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 0.8 SIGNOR-MM Malignant Melanoma PIK3CA protein P42336 UNIPROT PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 24367090 t AKT is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates (PIPs) with phosphate s at positions 3, 4 and 3,4,5 on the inositol ring miannu Insulin activation of phosphoinositide 3-kinase (pi3k) signaling regulates glucose homeostasis through the production of phosphatidylinositol 3,4,5-trisphosphate (pip3). The dual-specificity phosphatase and tensin homolog deleted on chromosome 10 (pten) blocks pi3k signaling by dephosphorylating pip3, and is inhibited through its interaction with phosphatidylinositol 3,4,5-trisphosphate-dependent rac exchanger 2 SIGNOR-147948 0.8 SIGNOR-MM Malignant Melanoma PIK3CA protein P42336 UNIPROT PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 24647478 t AKT is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates (PIPs) with phosphate s at positions 3, 4 and 3,4,5 on the inositol ring miannu Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, which recruit akt to the plasma membrane through its pleckstrin homology (ph) domain, permitting its activation by pdks. SIGNOR-65409 0.8 SIGNOR-MM Malignant Melanoma PIK3CA protein P42336 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 12167717 t lperfetto PKB induction requires phosphorylation of two critical residues, threonine 308 in the activation loop and serine 473 near the carboxyl terminus. Membrane localization of PKB was found to be a primary determinant of serine 473 phosphorylation. PI3K activity was equally important for promoting phosphorylation of serine 473, SIGNOR-244429 0.812 SIGNOR-MM Malignant Melanoma 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 0.812 SIGNOR-MM Malignant Melanoma 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 0.848 SIGNOR-MM Malignant Melanoma NRAS protein P01111 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates activity binding 9606 21779497 t lperfetto Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k SIGNOR-175222 0.835 SIGNOR-MM Malignant Melanoma PDPK1 protein O15530 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000007 15175348 t lperfetto In vitro kinase assay revealed that the direct targets of pdk1 in the mapk pathway were the upstream mapk kinases mek1 and mek2. The identified pdk1 phosphorylation sites in mek1 and mek2 are ser222 and ser226, respectively, and are known to be essential for full activation SIGNOR-244934 0.277 SIGNOR-MM Malignant Melanoma PDPK1 protein O15530 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 15175348 t lperfetto The identified pdk1 phosphorylation sites in mek1 and mek2 are ser222 and ser226, respectively, and are known to be essential for full activation. SIGNOR-244938 0.277 SIGNOR-MM Malignant Melanoma 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 0.73 SIGNOR-MM Malignant Melanoma PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 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 0.73 SIGNOR-MM Malignant Melanoma 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 0.73 SIGNOR-MM Malignant Melanoma PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0000887;BTO:0001103;BTO:0001760 9512493 t lperfetto The activation of PKBbeta and PKBamma by PDK11 was accompanied by the phosphorylation of the residues equivalent to Thr308 in PKBalpha, namely Thr309 (PKBbeta) and Thr305 (PKBgamma) SIGNOR-244480 0.73 SIGNOR-MM Malignant Melanoma 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 0.73 SIGNOR-MM Malignant Melanoma RB1 protein P06400 UNIPROT E2F1 factor protein Q01094 UNIPROT down-regulates activity binding 9606 8255752 t amattioni E2f binds rb. E2f activation domain is the target for rb-induced repression. Rb can silence the 57 residue e2f activation domain. Rb can mask e2f residues involved in the activation process, possibly by mimicking a component of the transcriptional machinery SIGNOR-37305 0.917 SIGNOR-MM Malignant Melanoma RB1 protein P06400 UNIPROT G1/S_transition phenotypesList phenotype SIGNOR-PH50 SIGNOR down-regulates 9606 21524151 f lperfetto In its hypophosphorylated state, pRb binds transcription factors of the E2F family which are required for cell cycle progression. As the level of CyclinD/Cdk4/6 complexes increases, pRb becomes phosphorylated and progression through G1 occurs. At a critical level of phosphorylation, E2F is released from pRb. This activates the transcription of CyclinE which complexes with Cdk2 to fully release pRb repression by further phosphorylation, establishing a positive feedback loop. E2F further promotes the transcription of S-phase genes. Thus, CyclinD/Cdk4/6 and CyclinE/Cdk2 together regulate S-phase entry via phosphorylating pRb, which controls pRb binding to E2F SIGNOR-245483 0.7 SIGNOR-MM Malignant Melanoma MDM2 protein Q00987 UNIPROT TP53 factor 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 0.968 SIGNOR-MM Malignant Melanoma MDM2 protein Q00987 UNIPROT TP53 factor 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 0.968 SIGNOR-MM Malignant Melanoma MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 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 0.968 SIGNOR-MM Malignant Melanoma GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 10090 BTO:0000669 23452850 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Interaction domains of sos1/grb2 are finely tuned for cooperative control of embryonic stem cell fate. SIGNOR-235773 0.91 SIGNOR-MM Malignant Melanoma 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 0.91 SIGNOR-MM Malignant Melanoma 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 0.91 SIGNOR-MM Malignant Melanoma BAK1 protein Q16611 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 23567751 f miannu 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-261493 0.7 SIGNOR-MM Malignant Melanoma BAX protein Q07812 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 23567751 f miannu 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-261494 0.7 SIGNOR-MM Malignant Melanoma MITF factor 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 0.45 SIGNOR-MM Malignant Melanoma CREB1 factor protein P16220 UNIPROT BCL2L1 protein Q07817 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16205321 f gcesareni The results showed that the nuclear pkcalpha was significantly decreased in the liver during sepsis, which was accompanied by decreases in phospho-creb content, dna-binding activity of creb, and bcl-xl expression. SIGNOR-140911 0.373 SIGNOR-MM Malignant Melanoma CREB1 factor 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 0.434 SIGNOR-MM Malignant Melanoma CREB1 factor 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 0.434 SIGNOR-MM Malignant Melanoma CREB1 factor protein P16220 UNIPROT MITF factor protein O75030 UNIPROT up-regulates quantity by expression transcriptional regulation 10841026 t lperfetto Therefore, the molecular steps linking cAMPto melanogenesis up-regulation appear currently better elucidated. cAMP activates PKA, and PKA phosphorylates and activates CREB which, when activated, binds to the CRE domain present in the microphthalmia promoter,thereby up-regulating its transcription. SIGNOR-249619 0.621 SIGNOR-MM Malignant Melanoma CREB1 factor protein P16220 UNIPROT Survival phenotypesList phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 20660310 f amattioni beta-catenin/CBP-driven transcription is critical for maintenance of an undifferentiated/proliferative state SIGNOR-229777 0.7 SIGNOR-MM Malignant Melanoma RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT unknown phosphorylation Ser750 RRKMKKTsTSTETRS 9606 15568999 t lperfetto Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. ser-750, ser-752 and ser-758 are phosphorylated by the n-terminal kinase domain;however, their function is not known. SIGNOR-131399 0.2 SIGNOR-MM Malignant Melanoma RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT unknown phosphorylation Ser752 KMKKTSTsTETRSSS 9606 15568999 t lperfetto Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. ser-750, ser-752 and ser-758 are phosphorylated by the n-terminal kinase domain;however, their function is not known. SIGNOR-131403 0.2 SIGNOR-MM Malignant Melanoma RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT unknown phosphorylation Ser758 TSTETRSsSSESSHS 9606 15568999 t lperfetto Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. ser-750, ser-752 and ser-758 are phosphorylated by the n-terminal kinase domain;however, their function is not known. SIGNOR-131407 0.2 SIGNOR-MM Malignant Melanoma 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 0.2 SIGNOR-MM Malignant Melanoma 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 0.2 SIGNOR-MM Malignant Melanoma 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 0.2 SIGNOR-MM Malignant Melanoma RPS6KA5 protein O75582 UNIPROT CREB1 factor protein P16220 UNIPROT up-regulates phosphorylation Ser119 EILSRRPsYRKILND 9606 BTO:0000567 9687510 t lperfetto Msk1 is localized in the nucleus of unstimulated or stimulated cells, and phosphorylates creb at ser133_ .MSK1 Is activated in vitro by mapk2/erk2 or sapk2/p38. Endogenous msk1 is activated in 293 cells by either growth factor/phorbol ester stimulation, or by exposure to uv radiation, and oxidative and chemical stres msk was the kinase responsible for phosphorylation of the transcription factor creb in response to tcr stimulation. Pka, ca2+-calmodulin-dependent kinase iv (camkiv), msk, p70s6k and rsk phosphorylate creb. SIGNOR-59458 0.721 SIGNOR-MM Malignant Melanoma PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT up-regulates activity dephosphorylation Thr383 HYRYSDTtDSDPENE 9606 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 0.2 SIGNOR-MM Malignant Melanoma PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT up-regulates activity dephosphorylation Thr382 DHYRYSDtTDSDPEN 9606 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 0.2 SIGNOR-MM Malignant Melanoma PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT up-regulates activity dephosphorylation Ser380 EPDHYRYsDTTDSDP 9606 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 0.2 SIGNOR-MM Malignant Melanoma PTEN protein P60484 UNIPROT CREB1 factor protein P16220 UNIPROT down-regulates activity dephosphorylation Ser119 EILSRRPsYRKILND 10090 BTO:0002572 21385900 t Our study demonstrates that PTEN can dephosphorylate CREB at Ser133 and that PTEN protein phosphatase activity is required for CREB dephosphoryation.|Moreover, we use both in vitro and in vivo experiments to show PTEN can dephosphorylate CREB in a phosphatase-dependent manner, suggesting that CREB is a substrate of PTEN nuclear phosphatase. Loss of Pten results in an elevated RNA level of multiple CREB transcriptional targets and increased cell proliferation, which can be reversed by a nonphosphorylatable CREB mutant or knockdown of CREB. These data reveal a mechanism for PTEN modulation of CREB-mediated gene transcription and cell growth. SIGNOR-248543 0.455 SIGNOR-MM Malignant Melanoma PTEN protein P60484 UNIPROT PIP3 receptor smallmolecule CHEBI:16618 ChEBI down-regulates quantity chemical modification 9606 11875759 t lperfetto PTEN dephosphorylates PI3P, lowering its cellular levels and resulting in the down-regulation of AKT. SIGNOR-228145 0.8 SIGNOR-MM Malignant Melanoma CDKN2A protein P42771 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR down-regulates activity binding 9606 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-245459 0.822 SIGNOR-MM Malignant Melanoma CDKN2A protein P42771 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR down-regulates activity binding 9606 8891723 t lperfetto 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-217514 0.822 SIGNOR-MM Malignant Melanoma BCL2 protein P10415 UNIPROT BAX protein Q07812 UNIPROT down-regulates activity binding 9606 BTO:0000776;BTO:0000785 8183370 t lperfetto Bcl-2 has the unique oncogenic role of extending cell survival by inhibiting a variety of apoptotic deaths. Bcl-2 exerts its action through heterodimerization with bax. SIGNOR-36898 0.615 SIGNOR-MM Malignant Melanoma BCL2 protein P10415 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 bax/bak are kept in check by the pro-survival bcl-2 family members and also proposes that for apoptotic death to occur, all pro-survival bcl-2-like proteins present within a given cell need to be neutralised by bh3-only proteins, thereby derepressing bax/bak SIGNOR-152980 0.656 SIGNOR-MM Malignant Melanoma BCL2 protein P10415 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 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-249611 0.7 SIGNOR-MM Malignant Melanoma E2F1 factor protein Q01094 UNIPROT G1/S_transition phenotypesList phenotype SIGNOR-PH50 SIGNOR up-regulates 9606 21524151 f lperfetto In its hypophosphorylated state, pRb binds transcription factors of the E2F family which are required for cell cycle progression. As the level of CyclinD/Cdk4/6 complexes increases, pRb becomes phosphorylated and progression through G1 occurs. At a critical level of phosphorylation, E2F is released from pRb. This activates the transcription of CyclinE which complexes with Cdk2 to fully release pRb repression by further phosphorylation, establishing a positive feedback loop. E2F further promotes the transcription of S-phase genes. Thus, CyclinD/Cdk4/6 and CyclinE/Cdk2 together regulate S-phase entry via phosphorylating pRb, which controls pRb binding to E2F SIGNOR-245477 0.7 SIGNOR-MM Malignant Melanoma BCL2L1 protein Q07817 UNIPROT BAD protein Q92934 UNIPROT up-regulates activity binding -1 10949026 t lperfetto Bad dimerizes with bcl-xl at the mitochondrial membrane where it exert its killing effects. Phosphorylation of bad promotes its binding to 14-3-3 protein, which may sequester bad from bcl-xl, thus promoting cell cells survival. SIGNOR-81125 0.838 SIGNOR-MM Malignant Melanoma 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 0.774 SIGNOR-MM Malignant Melanoma 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 0.774 SIGNOR-MM Malignant Melanoma 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 0.774 SIGNOR-MM Malignant Melanoma 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 0.774 SIGNOR-MM Malignant Melanoma BAD protein Q92934 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates activity binding 9606 BTO:0002552 17000778 t lperfetto We also demonstrate that bad physically interacts with cytoplasmic p53. bad is able to direct p53 to the mitochondria and forms a p53/bad complex at the mitochondria. the mitochondrial p53/bad complex promotes apoptosis SIGNOR-149815 0.338 SIGNOR-MM Malignant Melanoma BAD protein Q92934 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates activity binding 7834748 t lperfetto Bad binds more strongly to Bcl-x, than Bcl-2 in mammalian cells, and it reversed the death repressor activity of Bcl-x,, but not that of Bcl-2. When Bad dimerized with Bcl-x,, Bax was displaced and apoptosis was restored. SIGNOR-249617 0.838 SIGNOR-MM Malignant Melanoma BAD protein Q92934 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates activity binding 9606 BTO:0000007 15694340 t lperfetto Bad, however, bound tightly to bcl-2, bcl2l1, and bcl2l2 SIGNOR-133759 0.838 SIGNOR-MM Malignant Melanoma 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 0.789 SIGNOR-MM Malignant Melanoma BAD protein Q92934 UNIPROT Survival phenotypesList phenotype SIGNOR-PH13 SIGNOR down-regulates 9606 BTO:0000830 15526160 f miannu C-Kit promotes survival via PI3-kinase-dependent activation of Akt and phosphorylation of Bad, a pro-apoptotic molecule, at S136 in vivo. SIGNOR-254953 0.7 SIGNOR-MM Malignant Melanoma BAD protein Q92934 UNIPROT Proliferation phenotypesList 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 0.7 SIGNOR-MM Malignant Melanoma SOS1 protein Q07889 UNIPROT NRAS protein P01111 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 21779497 t lperfetto Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-175259 0.769 SIGNOR-MM Malignant Melanoma 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 0.769 SIGNOR-MM Malignant Melanoma KITLG extracellular protein P21583 UNIPROT KIT receptor protein P10721 UNIPROT up-regulates activity binding 9606 17259966 t miannu The most relevant and still unique mast-cell growth factor is SCF, which is the ligand of KIT, a receptor with tyrosine-kinase activity that is expressed on the surface of all human and murine mast cells SIGNOR-254946 0.933 SIGNOR-MM Malignant Melanoma KITLG extracellular protein P21583 UNIPROT KIT receptor 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 0.933 SIGNOR-MM Malignant Melanoma KIT receptor protein P10721 UNIPROT KIT receptor 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 0.2 SIGNOR-MM Malignant Melanoma KIT receptor protein P10721 UNIPROT KIT receptor protein P10721 UNIPROT up-regulates activity phosphorylation Tyr570 INGNNYVyIDPTQLP 9606 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-102637 0.2 SIGNOR-MM Malignant Melanoma KIT receptor protein P10721 UNIPROT KIT receptor protein P10721 UNIPROT up-regulates activity phosphorylation Tyr823 DIKNDSNyVVKGNAR 9606 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 0.2 SIGNOR-MM Malignant Melanoma KIT receptor protein P10721 UNIPROT KIT receptor 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 0.2 SIGNOR-MM Malignant Melanoma KIT receptor protein P10721 UNIPROT KIT receptor 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 0.2 SIGNOR-MM Malignant Melanoma KIT receptor protein P10721 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 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 0.632 SIGNOR-MM Malignant Melanoma TP53 factor 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 0.738 SIGNOR-MM Malignant Melanoma TP53 factor 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 0.968 SIGNOR-MM Malignant Melanoma TP53 factor protein P04637 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000452 7667317 f P53 controls both the G2/M and the G1 cell cycle checkpoints and mediates reversible growth arrest in human fibroblasts SIGNOR-255669 0.7 SIGNOR-MM Malignant Melanoma TP53 factor protein P04637 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 24212651 f miannu P53 is a nuclear transcription factor with a pro-apoptotic function SIGNOR-255678 0.7