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J. Biol. Chem., Vol. 280, Issue 40, 34008-34018, October 7, 2005

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EphrinA1 Repulsive Response Is Regulated by an EphA2 Tyrosine Phosphatase^*

Matteo Parri1, Francesca Buricchi1, Maria Letizia Taddei, Elisa Giannoni, Giovanni Raugei, Giampietro Ramponi, and Paola Chiarugi2

From the Department of Biochemical Sciences and Center for Research, Transfer and High Education Study at Molecular and Clinical Level of Chronic, Inflammatory, Degenerative and Neoplastic Disorders for the Development of Novel Therapies, University of Florence, Via le Morgagni 50, Florence 50134, Italy

Ephrin kinases and their ephrin ligands transduce repulsion of cells in axon guidance, migration, invasiveness, and tumor growth, exerting a negative signaling on cell proliferation and adhesion. A key role of their kinase activity has been confirmed by mutant kinase inactive receptors that shift the cellular response from repulsion to adhesion. Our present study aimed to investigate the role of low molecular weight protein-tyrosine phosphatase (LMW-PTP) in ephrinA1/EphA2 signaling. LMW-PTP, by means of dephosphorylation of EphA2 kinase, negatively regulates the ephrinA1-mediated repulsive response, cell proliferation, cell adhesion and spreading, and the formation of retraction fibers, thereby confirming the relevance of the net level of tyrosine phosphorylation of Eph receptors. LMW-PTP interferes with ephrin-mediated mitogen-activated protein kinase signaling likely through inhibition of p120RasGAP binding to the activated EphA2 kinase, thereby confirming the key role of mitogen-activated protein kinase inhibition by ephrinA1 repulsive signaling. We conclude that LMW-PTP acts as a terminator of EphA2 signaling causing an efficient negative feedback loop on the biological response mediated by ephrinA1 and pointing on tyrosine phosphorylation as the main event orchestrating the repulsive response.

Received for publication, March 16, 2005 , and in revised form, July 20, 2005.

^* This work was supported by the Italian Association for Cancer Research, by the Ministero della Università e Ricerca Scientifica e Tecnologica (MIUR-PRIN 2002), 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 Both authors contributed equally to this work.

² To whom correspondence should be addressed: Dipartimento di ScienzeBiochimiche, Viale Morgagni 50, 50134 Firenze, Italy. Tel.: 39-055-459-8343; Fax: 39-055-449-8905; E-mail: paola.chiarugi{at}unifi.it.

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