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J. Biol. Chem., Vol. 282, Issue 36, 26077-26088, September 7, 2007

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Role of c-Abl in Directing Metabolic versus Mitogenic Effects in Insulin Receptor Signaling^*

Francesco Frasca¹, Giuseppe Pandini², Roberta Malaguarnera, Angelo Mandarino, Rosa Linda Messina, Laura Sciacca, Antonino Belfiore, and Riccardo Vigneri

From the Endocrinologia, Dipartimento di Medicina Interna e di Medicina Specialistica, Università di Catania, Ospedale Garibaldi, Nesima, 95122 Catania and the Endocrinologia, Dipartimento di Medicina Sperimentale e Clinica, Università Magna Graecia, Policlinico Mater Domini, 88100 Catanzaro, Italy

c-Abl is a cytoplasmic tyrosine kinase involved in several signal transduction pathways. Here we report that c-Abl is involved also in insulin receptor signaling. Indeed, c-Abl tyrosine kinase is activated upon insulin stimulation. Inhibition of c-Abl tyrosine kinase by STI571 attenuates the effect of insulin on Akt/GSK-3 phosphorylation and glycogen synthesis, and at the same time, it enhances the effect of insulin on ERK activation, cell proliferation, and migration. This effect of STI571 is specific to c-Abl inhibition, because it does not occur in Abl-null cells and is restored in c-Abl-reconstituted cells. Numerous evidences suggest that focal adhesion kinase (FAK) is involved in mediating this c-Abl effect. First, anti-phosphotyrosine blots indicate that c-Abl tyrosine kinase activation is concomitant with FAK dephosphorylation in response to insulin, whereas c-Abl inhibition is accompanied by FAK phosphorylation in response to insulin, a response similar to that observed with IGF-I. Second, the c-Abl effects on insulin signaling are not observed in cells devoid of FAK (FAK^–/– cells). Taken together these results suggest that c-Abl activation by insulin, via a modification of FAK response, may play an important role in directing mitogenic versus metabolic insulin receptor signaling.

Received for publication, June 18, 2007

^* This work was supported by grants from Associazione Italiana Ricerca sul Cancro and Ministero dell'Università e della Ricerca Scientifica e Tecnologica (and Cofin 2005, Italy) (to R. V. and A. B.). 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.

² Recipient of a fellowship from the American Italian Cancer Foundation.

¹ To whom correspondence should be addressed: Dipartimento di Medicina Interna e di Medicina Specialistica, Endocrinologia, PO Garibaldi Nesima, Via Palermo 636, 95122 Catania, Italy. Tel.: 39-095-759-8827; Fax: 39-095-715-8072; E-mail: f.frasca{at}unict.it.

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