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J. Biol. Chem., Vol. 282, Issue 27, 19619-19628, July 6, 2007

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EphrinA1 Activates a Src/Focal Adhesion Kinase-mediated Motility Response Leading to Rho-dependent Actino/Myosin Contractility^*

Matteo Parri, Francesca Buricchi, Elisa Giannoni, Giovanna Grimaldi, Tommaso Mello, Giovanni Raugei^¶, Giampietro Ramponi^¶, and Paola Chiarugi^¶1

From the Department of Biochemical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy, ^¶Center for Research, Transfer, and High Education Viale Morgagni 50, 50134 Florence, Italy, and Farmacogenomic Foundation FiorGen, Polo Scientifico Sesto Fiorentino, 50019 Florence, Italy

Eph receptors and ephrin ligands are widely expressed in epithelial cells and mediate cell repulsive motility through heterotypic cell-cell interactions. Several Ephs, including EphA2, are greatly overexpressed in certain tumors, in correlation with poor prognosis and high vascularity in cancer tissues. The ability of several Eph receptors to regulate cell migration and invasion likely contribute to tumor progression and metastasis. We report here that in prostatic carcinoma cells ephrinA1 elicits a repulsive response that is executed through a Rho-dependent actino/myosin contractility activation, ultimately leading to retraction of the cell body. This appears to occur through assembly of an EphA2-associated complex involving the two kinases Src and focal adhesion kinase (FAK). EphrinA1-mediated repulsion leads to the selective phosphorylation of Tyr-576/577 of FAK, enhancing FAK kinase activity. The repulsive response elicited by ephrinA1 in prostatic carcinoma cells is mainly driven by a Rho-mediated phosphorylation of myosin light chain II, in which Src and FAK activation are required steps. Consequently, Src and FAK are upstream regulators of the overall response induced by ephrinA1/EphA2, instructing cells to retract the cell body and to move away, probably facilitating dissemination and tissue invasion of ephrin-sensitive carcinomas.

Received for publication, February 15, 2007 , and in revised form, April 19, 2007.

^* This work was supported by the Italian Association for Cancer Research, by the Ministero della Università e Ricerca Scientifica e Tecnologica (MIUR-PRIN 2004), by Consorzio Interuniversitario Biotecnologie, and by Cassa di Risparmio di Firenze. 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 Biochemical Sciences, University of Florence, Viale Morgani 50, 50134 Florence, Italy. Tel.: 39-055-4598343; Fax: 39-055-4598905; E-mail: paola.chiarugi{at}unifi.it.

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