title: Tyrosine-phosphorylated SOCS-3 inhibits STAT activation but binds to p120 RasGAP and activates Ras.
abstract: Suppressors of cytokine signalling (SOCS, also known as CIS and SSI) are encoded by immediate early genes that act in a feedback loop to inhibit cytokine responses and activation of 'signal transducer and activator of transcription' (STAT). Here we show that SOCS-3 is strongly tyrosine-phosphorylated in response to many growth factors, including interleukin-2 (IL-2), erythropoietin (EPO), epidermal growth factor (EGF) and platelet-derived growth factor (PDGF). The principal phosphorylation sites on SOCS-3 are residues 204 and 221 at the carboxy terminus, and upon phosphorylation tyrosine 221 interacts with the Ras inhibitor p120 RasGAP. After IL-2 stimulation, phosphorylated SOCS-3 strongly inhibits STAT5 activation but, by binding to RasGAP, maintains activation of extracellular-signal-regulated kinase (ERK). A tyrosine mutant of SOCS-3 still blocks STAT phosphorylation, but also strongly inhibits IL-2-dependent activation of ERK and cell proliferation. Moreover, it also inhibits EPO- and PDGF-induced proliferation and ERK activation. Therefore, although SOCS proteins inhibit growth-factor responses, tyrosine phosphorylation of SOCS-3 can ensure cell survival and proliferation through the Ras pathway.
authors.affiliation: DNAX Research Institute, 901 California Avenue, Palo Alto, California 94304, USA.
authors.forename: N A
authors.initials: NA
authors.lastname: Cacalano
authors.forename: D
authors.initials: D
authors.lastname: Sanden
authors.forename: J A
authors.initials: JA
authors.lastname: Johnston
mesh_terms: D016475:3T3 Cells; D020816:Amino Acid Motifs; D000818:Animals; D015153:Blotting, Western; D002455:Cell Division; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000378:metabolism; D004921:Erythropoietin / Q000378:metabolism; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D051379:Mice; D008894:Milk Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism*; D012097:Repressor Proteins; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D013936:Thymidine / Q000378:metabolism; D015534:Trans-Activators / Q000037:antagonists & inhibitors*; D014157:Transcription Factors; D014162:Transfection; D014443:Tyrosine / Q000737:chemistry / Q000378:metabolism*; D020729:p120 GTPase Activating Protein / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*; D018909:src Homology Domains
chemical_list: D004268:DNA-Binding Proteins; D007376:Interleukin-2; D008894:Milk Proteins; D010982:Platelet-Derived Growth Factor; D011506:Proteins; D012097:Repressor Proteins; C106644:SOCS3 protein, human; D050799:STAT5 Transcription Factor; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D020729:p120 GTPase Activating Protein; D004921:Erythropoietin; D014443:Tyrosine; D004815:Epidermal Growth Factor; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins; D013936:Thymidine