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J. Biol. Chem., Vol. 283, Issue 23, 15740-15746, June 6, 2008

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PTP1B Regulates Cortactin Tyrosine Phosphorylation by Targeting Tyr^446*

From the McGill Cancer Centre and Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada

The emergence of protein-tyrosine phosphatase 1B (PTP1B) as a potential drug target for treatment of diabetes, obesity, and cancer underlies the importance of understanding its full range of cellular functions. Here, we have identified cortactin, a central regulator of actin cytoskeletal dynamics, as a substrate of PTP1B. A trapping mutant of PTP1B binds cortactin at the phosphorylation site Tyr⁴⁴⁶, the regulation and function of which have not previously been characterized. We show that phosphorylation of cortactin Tyr⁴⁴⁶ is induced by hyperosmolarity and potentiates apoptotic signaling during prolonged hyperosmotic stress. This study advances the importance of Tyr⁴⁴⁶ in the regulation of cortactin and provides a potential mechanism to explain the effects of PTP1B on processes including cell adhesion, migration, and tumorigenesis.

Received for publication, December 26, 2007 , and in revised form, March 10, 2008.

^* This work was supported in part by Operating Grant MOP-62887 from the Canadian Institutes of Health Research (to M. L. T.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ Recipient of a Fonds de la Recherche en Santé du Québec doctoral award.

² Present address: Dept. of Physiological Chemistry, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.

³ Jeanne and Jean-Louis Lévesque Chair in Cancer Research. To whom correspondence should be addressed: McGill Cancer Centre, 3655 Prom. Sir-William-Osler, Montreal, Quebec H3G 1Y6, Canada. Tel.: 514-398-7290; Fax: 514-398-6769; E-mail: michel.tremblay{at}mcgill.ca.

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