Tyrosine-phosphorylated SOCS-3 inhibits STAT activation but binds to p120 RasGAP and activates Ras.
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.
Cacalano
N A
NA
DNAX Research Institute, 901 California Avenue, Palo Alto, California 94304, USA.
Sanden
D
D
Johnston
J A
JA
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
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