Abstract
Several components in cytokine signaling remain unidentified. We report the cloning and initial characterization of one such component, p97, a widely expressed scaffolding protein distantly related to Drosophila DOS and mammalian Gab1. Upon cytokine, growth factor, or antigen receptor stimulation, p97 becomes tyrosyl phosphorylated and associates with several SH2 domain-containing proteins, including SHP2. Expression of p97 mutants unable to bind SHP2 blocks cytokine-induced c-fos promoter activation, inhibiting Elk1-mediated and STAT5-mediated transactivation. Surprisingly, such mutants do not inhibit MAPK activation. Our results identify p97 as an important regulator of receptor signaling that controls a novel pathway to immediate-early gene activation and suggest multiple functions for SHP2 in cytokine receptor signaling.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing*
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Adaptor Proteins, Vesicular Transport*
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Amino Acid Sequence
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Animals
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Cell Line
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Cloning, Molecular
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Cytokines / pharmacology*
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DNA, Complementary / chemistry
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DNA, Complementary / genetics
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DNA, Complementary / isolation & purification
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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DNA-Binding Proteins / physiology*
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GRB2 Adaptor Protein
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Gene Expression Regulation / drug effects
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Interleukin-3 / pharmacology
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Intracellular Signaling Peptides and Proteins
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Lymphocytes / cytology
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Lymphocytes / drug effects*
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Lymphocytes / physiology
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Molecular Sequence Data
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Phosphatidylinositol 3-Kinases / metabolism
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Protein Binding
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Protein Tyrosine Phosphatases / genetics
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Protein Tyrosine Phosphatases / metabolism
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Protein Tyrosine Phosphatases / physiology*
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Proteins / metabolism
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SH2 Domain-Containing Protein Tyrosine Phosphatases
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Sequence Homology, Amino Acid
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Shc Signaling Adaptor Proteins
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Signal Transduction
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Transcriptional Activation
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src Homology Domains
Substances
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Adaptor Proteins, Signal Transducing
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Adaptor Proteins, Vesicular Transport
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Cytokines
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DNA, Complementary
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DNA-Binding Proteins
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GRB2 Adaptor Protein
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Interleukin-3
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Intracellular Signaling Peptides and Proteins
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Proteins
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Shc Signaling Adaptor Proteins
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Phosphatidylinositol 3-Kinases
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Protein Tyrosine Phosphatases
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SH2 Domain-Containing Protein Tyrosine Phosphatases