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Originally published In Press as doi:10.1074/jbc.M708822200 on December 19, 2007
J. Biol. Chem., Vol. 283, Issue 8, 4612-4621, February 22, 2008
Protein-tyrosine Phosphatase Regulates Shc Signaling in a Kinase-specific MannerINCREASING COHERENCE IN TYROSINE PHOSPHATASE SIGNALING*
Judith Kraut-Cohen ,
William J. Muller , and
Ari Elson 1
From the
Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel and the Molecular Oncology Group and Departments of Biochemistry and Medicine, McGill University, Montreal, Quebec H3A 1A1, Canada
Individual protein tyrosine kinases and phosphatases target multiple substrates; this may generate conflicting signals, possibly within a single pathway. Protein-tyrosine phosphatase (PTP ) performs two potentially opposing roles: in Neu-induced mammary tumors, PTP activates Src downstream of Neu, whereas in other systems PTP 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. PTP binds and dephosphorylates Shc in vivo, reducing the association of Shc with Grb2 and inhibiting downstream ERK activation. PTP binds Shc in a phosphotyrosine-independent manner mediated by the Shc PTB domain and aided by a sequence of 10 N-terminal residues in PTP . Surprisingly, PTP dephosphorylates Shc in a kinase-dependent manner; PTP 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 PTP for binding the same domain. In agreement, PTP 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 PTP from targeting Shc and from reducing its promitogenic signal while phosphorylating PTP and directing it to activate Src in support of mitogenesis. In so doing, Neu contributes to the coherence of the promitogenic role of PTP in this system.
Received for publication, October 25, 2007
, and in revised form, December 18, 2007.
* This work was supported by the Israel Cancer Research Fund and also by the David and Fela Shapell Family Center for Genetic Disorders Research and the Women's Health Research Center, both at the Weizmann Institute of Science. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 To whom correspondence should be addressed: Dept. of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel. Tel.: 972-8-934-2331; Fax: 972-8-934-4108; E-mail: ari.elson{at}weizmann.ac.il.

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Copyright © 2008 by the American Society for Biochemistry and Molecular Biology.
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