חיפוש מתקדם
Journal of Biological Chemistry
Kraut-Cohen, J., Dept. of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel
Muller, W.J., Molecular Oncology Group, Departments of Biochemistry and Medicine, McGill University, Montreal, QC H3A 1A1, Canada
Elson, A., Dept. of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel
Individual protein tyrosine kinases and phosphatases target multiple substrates; this may generate conflicting signals, possibly within a single pathway. Protein-tyrosine phosphatase ε (PTPε) performs two potentially opposing roles: in Neu-induced mammary tumors, PTPε activates Src downstream of Neu, whereas in other systems PTPε can indirectly down-regulate MAP kinase signaling. We now show that the latter effect is mediated at least in part via the adaptor protein Shc. PTPε binds and dephosphorylates Shc in vivo, reducing the association of Shc with Grb2 and inhibiting downstream ERK activation. PTPε binds Shc in a phosphotyrosine-independent manner mediated by the Shc PTB domain and aided by a sequence of 10 N-terminal residues in PTPε. Surprisingly, PTPε dephosphorylates Shc in a kinase-dependent manner; PTPε targets Shc in the presence of Src but not in the presence of Neu. Using a series of point mutants of Shc and Neu, we show that Neu protects Shc from dephosphorylation by binding the PTB domain of Shc, most likely competing against PTPε for binding the same domain. In agreement, PTPε dephosphorylates Shc in mouse embryo fibroblasts but not in Neu-induced mammary tumor cells. We conclude that in the context of Neu-induced mammary tumor cells, Neu prevents PTPε from targeting Shc and from reducing its promitogenic signal while phosphorylating PTPε and directing it to activate Src in support of mitogenesis. In so doing, Neu contributes to the coherence of the promitogenic role of PTPε in this system. © 2008 by The American Society for Biochemistry and Molecular Biology, Inc.
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הספר "אוצר וולקני"
אודות
תנאי שימוש
Protein-tyrosine phosphatase ε regulates Shc signaling in a kinase-specific manner: Increasing coherence in tyrosine phosphatase signaling
283
Kraut-Cohen, J., Dept. of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel
Muller, W.J., Molecular Oncology Group, Departments of Biochemistry and Medicine, McGill University, Montreal, QC H3A 1A1, Canada
Elson, A., Dept. of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel
Protein-tyrosine phosphatase ε regulates Shc signaling in a kinase-specific manner: Increasing coherence in tyrosine phosphatase signaling
Individual protein tyrosine kinases and phosphatases target multiple substrates; this may generate conflicting signals, possibly within a single pathway. Protein-tyrosine phosphatase ε (PTPε) performs two potentially opposing roles: in Neu-induced mammary tumors, PTPε activates Src downstream of Neu, whereas in other systems PTPε can indirectly down-regulate MAP kinase signaling. We now show that the latter effect is mediated at least in part via the adaptor protein Shc. PTPε binds and dephosphorylates Shc in vivo, reducing the association of Shc with Grb2 and inhibiting downstream ERK activation. PTPε binds Shc in a phosphotyrosine-independent manner mediated by the Shc PTB domain and aided by a sequence of 10 N-terminal residues in PTPε. Surprisingly, PTPε dephosphorylates Shc in a kinase-dependent manner; PTPε targets Shc in the presence of Src but not in the presence of Neu. Using a series of point mutants of Shc and Neu, we show that Neu protects Shc from dephosphorylation by binding the PTB domain of Shc, most likely competing against PTPε for binding the same domain. In agreement, PTPε dephosphorylates Shc in mouse embryo fibroblasts but not in Neu-induced mammary tumor cells. We conclude that in the context of Neu-induced mammary tumor cells, Neu prevents PTPε from targeting Shc and from reducing its promitogenic signal while phosphorylating PTPε and directing it to activate Src in support of mitogenesis. In so doing, Neu contributes to the coherence of the promitogenic role of PTPε in this system. © 2008 by The American Society for Biochemistry and Molecular Biology, Inc.
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