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J. Biol. Chem., Vol. 282, Issue 37, 26646-26655, September 14, 2007

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Insulin-like Growth Factor-I Receptor Mediates the Prosurvival Effect of Fibronectin^*

Mouad Edderkaoui, Peggy Hong, Jong K. Lee, Stephen J. Pandol, and Anna S. Gukovskaya¹

From the Department of Medicine, Veterans Affairs Greater Los Angeles Healthcare System and University of California, Los Angeles, California 90073 and School of Medicine, Sungkyunkwan University, Seoul 135-710, Korea

We recently showed that extracellular matrix (ECM) proteins, which are abundant in desmoplastic pancreatic tumor, are as potent as growth factors in inhibiting apoptosis in pancreatic cancer (PaCa) cells. Here we show that fibronectin, a major ECM component, engages insulin-like growth factor-I receptor (IGF-IR) to inhibit PaCa cell death. We found that fibronectin-induced protection from apoptosis is fully mediated by IGF-IR and is independent of IGF-I. Pharmacologic and molecular inhibitions of IGF-IR stimulated apoptosis and prevented the prosurvival effect of fibronectin in PaCa cells. Our data indicate that fibronectin protects from apoptosis through trans-activation of IGF-IR. We showed that fibronectin stimulated complex formation between its receptor 3 integrin and protein-tyrosine phosphatase SHP-2. This process of complex formation, in turn, prevents SHP-2 from dephosphorylating IGF-IR resulting in sustained phosphorylation of IGF-IR and leading to the downstream activation of Akt kinase, up-regulation of antiapoptotic Bcl_xL, and inhibition of apoptosis. Among ECM proteins tested only fibronectin and laminin but not vitronectin and collagen I stimulated trans-activation of IGF-IR. Interaction of fibronectin with 3 but not 1 integrin receptors mediates the survival pathway. In contrast, fibronectin-induced adhesion is mediated through 1 integrin receptor and is IGF-IR-independent. Thus, our results indicate that the prosurvival effect of fibronectin in PaCa cells is mediated by trans-activation of IGF-IR induced by the 3 integrin receptor. The data suggest IGF-IR as a key target for prevention of the prosurvival effects of ECM proteins and growth factors in pancreatic cancer.

Received for publication, April 3, 2007 , and in revised form, June 28, 2007.

^* This work was supported by National Institutes of Health Grant R01-CA119025-01 and the Department of Veterans Affairs Merit Review (to A. S. G.). 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: Veterans Affairs Greater Los Angeles Healthcare System, West Los Angeles Veterans Affairs Healthcare Center, 11301 Wilshire Blvd., Bldg. 258, Rm. 340, Los Angeles, CA 90073. Tel.: 310-478-3711 (ext. 41525); Fax: 310-268-4578; E-mail: agukovsk{at}ucla.edu.

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