Abstract
Male "viable motheaten" (me(v)) mice, with a naturally occurring mutation in the gene of the SH2 domain protein tyrosine phosphatase SHP-1, are sterile. Known defects in sperm maturation in these mice correlate with an impaired differentiation of the epididymis, which has similarities to the phenotype of mice with a targeted inactivation of the Ros receptor tyrosine kinase. Ros and SHP-1 are coexpressed in epididymal epithelium, and elevated phosphorylation of Ros in the epididymis of me(v) mice suggests that Ros signaling is under control of SHP-1 in vivo. Phosphorylated Ros strongly and directly associates with SHP-1 in yeast two-hybrid, glutathione S-transferase pull-down, and coimmunoprecipitation experiments. Strong binding of SHP-1 to Ros is selective compared to six other receptor tyrosine kinases. The interaction is mediated by the SHP-1 NH(2)-terminal SH2 domain and Ros phosphotyrosine 2267. Overexpression of SHP-1 results in Ros dephosphorylation and effectively downregulates Ros-dependent proliferation and transformation. We propose that SHP-1 is an important downstream regulator of Ros signaling.
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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Animals
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Cell Line
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Epididymis / cytology
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Epithelial Cells / cytology
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Epithelial Cells / physiology*
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Humans
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Intracellular Signaling Peptides and Proteins
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Male
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Mice
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Mice, Knockout
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Mice, Mutant Strains
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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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Proto-Oncogene Proteins / deficiency
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Receptor Protein-Tyrosine Kinases*
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Receptor, trkA / genetics
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Receptor, trkA / physiology*
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Recombinant Fusion Proteins / metabolism
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Signal Transduction / physiology*
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Transfection
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src Homology Domains
Substances
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Intracellular Signaling Peptides and Proteins
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Proto-Oncogene Proteins
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Recombinant Fusion Proteins
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Protein-Tyrosine Kinases
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ROS1 protein, human
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Receptor Protein-Tyrosine Kinases
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Receptor, trkA
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Ros1 protein, mouse
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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