Tyrosine-phosphorylated SOCS-3 inhibits STAT activation but binds to p120 RasGAP and activates Ras

Nat Cell Biol. 2001 May;3(5):460-5. doi: 10.1038/35074525.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Amino Acid Motifs
  • Animals
  • Blotting, Western
  • Cell Division
  • Cell Line
  • DNA-Binding Proteins / antagonists & inhibitors*
  • Electrophoresis, Polyacrylamide Gel
  • Enzyme Activation
  • Epidermal Growth Factor / metabolism
  • Erythropoietin / metabolism
  • Humans
  • Interleukin-2 / metabolism
  • Mice
  • Milk Proteins*
  • Mitogen-Activated Protein Kinases / metabolism
  • Mutation
  • Phosphorylation
  • Platelet-Derived Growth Factor / metabolism
  • Precipitin Tests
  • Protein Binding
  • Protein Structure, Tertiary
  • Proteins / metabolism*
  • Repressor Proteins*
  • STAT5 Transcription Factor
  • Signal Transduction
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Thymidine / metabolism
  • Trans-Activators / antagonists & inhibitors*
  • Transcription Factors*
  • Transfection
  • Tyrosine / chemistry
  • Tyrosine / metabolism*
  • p120 GTPase Activating Protein / metabolism*
  • ras Proteins / metabolism*
  • src Homology Domains

Substances

  • DNA-Binding Proteins
  • Interleukin-2
  • Milk Proteins
  • Platelet-Derived Growth Factor
  • Proteins
  • Repressor Proteins
  • SOCS3 protein, human
  • STAT5 Transcription Factor
  • Socs3 protein, mouse
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Trans-Activators
  • Transcription Factors
  • p120 GTPase Activating Protein
  • Erythropoietin
  • Tyrosine
  • Epidermal Growth Factor
  • Mitogen-Activated Protein Kinases
  • ras Proteins
  • Thymidine