Abstract
SHP-1, an src homology 2 (SH2) domain containing protein tyrosine phosphatase, functions as a negative regulator of signaling downstream of cytokine receptors, receptor tyrosine kinases and receptor complexes of the immune system. Dephosphorylation of receptors and/or receptor-associated kinases has been described as the mechanism for the function of SHP-1. Here we demonstrate a novel mechanism by which SHP-1 down-regulates the Janus kinase-2 (Jak2)/signal transducer and activator of transcription-5 (Stat5) pathway downstream of the prolactin receptor (PRLR) and the erythropoietin receptor (EPOR) in a catalytic activity-independent manner. Structural/functional analysis of SHP-1 defined the C-terminal tyrosine residues (Y278, Y303, Y538, Y566) within growth factor receptor-bound protein 2 (Grb-2) binding motif to be responsible for delivering the inhibitory effects. Our results further indicate that these tyrosine residues, via recruitment of the adaptor protein Grb-2, are required for targeting the inhibitory protein suppressor of cytokine signaling-1 (SOCS-1) to Jak2 kinase. Finally, loss of SOCS-1 expression in SOCS-1(-/-) mouse embryonic fibroblast (MEF) cells led to attenuation in SHP-1 function to down-regulate PRL-induced Stat5 activation. All together, our results indicate that SHP-1 inhibits PRLR and EPOR signaling by recruitment and targeting of SOCS-1 to Jak2, highlighting a new mechanism of SHP-1 regulation of cytokine-receptor signaling.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing*
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Animals
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Carrier Proteins / metabolism
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Catalysis
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Cell Line, Tumor
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DNA-Binding Proteins / metabolism
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Epithelial Cells / cytology
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GRB2 Adaptor Protein
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Humans
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Intracellular Signaling Peptides and Proteins*
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Janus Kinase 2
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Kidney / cytology
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Luciferases / genetics
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Lymphoma, T-Cell
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Mice
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Milk Proteins*
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Protein Structure, Tertiary
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Protein Tyrosine Phosphatases / chemistry
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Protein Tyrosine Phosphatases / genetics
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Protein Tyrosine Phosphatases / metabolism*
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Protein-Tyrosine Kinases / metabolism
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Proteins / metabolism*
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Proto-Oncogene Proteins*
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Rats
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Receptors, Cytokine / metabolism*
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Receptors, Erythropoietin / metabolism
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Receptors, Prolactin / metabolism
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Repressor Proteins / metabolism
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STAT5 Transcription Factor
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Signal Transduction / physiology*
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling Proteins
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Trans-Activators / metabolism
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Tyrosine / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Carrier Proteins
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DNA-Binding Proteins
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GRB2 Adaptor Protein
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GRB2 protein, human
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Grb2 protein, mouse
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Grb2 protein, rat
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Intracellular Signaling Peptides and Proteins
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Milk Proteins
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Proteins
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Proto-Oncogene Proteins
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Receptors, Cytokine
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Receptors, Erythropoietin
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Receptors, Prolactin
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Repressor Proteins
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SOCS1 protein, human
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STAT5 Transcription Factor
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Socs1 protein, mouse
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Socs1 protein, rat
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling Proteins
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Trans-Activators
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Tyrosine
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Luciferases
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Protein-Tyrosine Kinases
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JAK2 protein, human
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Jak2 protein, mouse
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Jak2 protein, rat
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Janus Kinase 2
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PTPN6 protein, human
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Protein Tyrosine Phosphatases
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Ptpn6 protein, mouse
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Ptpn6 protein, rat