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
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Research Support, Non-U.S. Gov't
MeSH terms
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3T3 Cells
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Amino Acid Motifs
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Animals
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Blotting, Western
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Cell Division
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Cell Line
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DNA-Binding Proteins / antagonists & inhibitors*
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Electrophoresis, Polyacrylamide Gel
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Enzyme Activation
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Epidermal Growth Factor / metabolism
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Erythropoietin / metabolism
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Humans
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Interleukin-2 / metabolism
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Mice
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Milk Proteins*
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Mitogen-Activated Protein Kinases / metabolism
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Mutation
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Phosphorylation
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Platelet-Derived Growth Factor / metabolism
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Precipitin Tests
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Protein Binding
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Protein Structure, Tertiary
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Proteins / metabolism*
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Repressor Proteins*
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STAT5 Transcription Factor
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Signal Transduction
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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Thymidine / metabolism
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Trans-Activators / antagonists & inhibitors*
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Transcription Factors*
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Transfection
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Tyrosine / chemistry
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Tyrosine / metabolism*
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p120 GTPase Activating Protein / metabolism*
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ras Proteins / metabolism*
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src Homology Domains
Substances
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DNA-Binding Proteins
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Interleukin-2
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Milk Proteins
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Platelet-Derived Growth Factor
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Proteins
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Repressor Proteins
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SOCS3 protein, human
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STAT5 Transcription Factor
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Socs3 protein, mouse
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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Trans-Activators
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Transcription Factors
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p120 GTPase Activating Protein
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Erythropoietin
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Tyrosine
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Epidermal Growth Factor
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Mitogen-Activated Protein Kinases
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ras Proteins
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Thymidine