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J. Biol. Chem., Vol. 283, Issue 16, 10919-10929, April 18, 2008

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Protein-tyrosine Phosphatase PTPD1 Regulates Focal Adhesion Kinase Autophosphorylation and Cell Migration^*

Annalisa Carlucci¹, Chiara Gedressi, Luca Lignitto, Luigi Nezi, Emma Villa-Moruzzi, Enrico V. Avvedimento, Max Gottesman^¶, Corrado Garbi, and Antonio Feliciello²

From the Dipartimento di Biologia e Patologia Molecolare e Cellulare, Istituto di Endocrinologia ed Oncologia Sperimentale, CNR, Facoltà di Medicina, Università "Federico II", via s. Pansini, 5 80131 Napoli, Italy, Dipartimento di Patologia Sperimentale, Università di Pisa, 56126 Pisa, Italy, and ^¶Institute of Cancer Research, Columbia University, New York, New York 10032

PTPD1 is a cytosolic nonreceptor tyrosine phosphatase and a positive regulator of the Src-epidermal growth factor transduction pathway. We show that PTPD1 localizes along actin filaments and at adhesion plaques. PTPD1 forms a stable complex via distinct molecular modules with actin, Src tyrosine kinase, and focal adhesion kinase (FAK), a scaffold protein kinase enriched at adhesion plaques. Overexpression of PTPD1 promoted cell scattering and migration, short hairpin RNA-mediated silencing of endogenous PTPD1, or expression of PTPD1 mutants lacking either catalytic activity (PTPD1_C1108S) or the FERM domain (PTPD1_1-325) significantly reduced cell motility. PTPD1 and Src catalytic activities were both required for epidermal growth factor-induced FAK autophosphorylation at its active site and for downstream propagation of ERK1/2 signaling. Our findings demonstrate that PTPD1 is a component of a multivalent scaffold complex nucleated by FAK at specific intracellular sites. By modulating Src-FAK signaling at adhesion sites, PTPD1 promotes the cytoskeleton events that induce cell adhesion and migration.

Received for publication, August 29, 2007 , and in revised form, January 11, 2008.

^* This work was supported by the "Associazione Italiana per la Ricerca sul Cancro." 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 Supported by a fellowship from "MoMa project, ASI-Rome, Italy."

² To whom correspondence should be addressed. Fax: 39-081-7463252; Tel.: 39-081-7463615; E-mail: feliciel{at}unina.it.

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