Nature Cell Biology
3, 460 - 465 (2001)
Published online: 6 April 2001; | doi:10.1038/35074525
Tyrosine-phosphorylated SOCS-3 inhibits STAT activation but binds to p120 RasGAP and activates RasNicholas A. Cacalano1, David Sanden1
& James A. Johnston21
DNAX Research Institute, 901 California Avenue, Palo Alto, California 94304, USA
2
Current address: Department of Immunology, Whitla Medical Building, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK
Correspondence should be addressed to James A. Johnston jim.johnston@qub.ac.ukSuppressors 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.
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