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Published 8 July 2002. doi:10.1083/jcb.200112015
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© The Rockefeller University Press, 0021-9525/2002/7/165 $5.00
The Journal of Cell Biology, Volume 158, Number 1, July 8, 2002 165-174

Article

 Integrin ({alpha}6ß4) regulation of eIF-4E activity and VEGF translation : a survival mechanism for carcinoma cells



Jun Chung, Robin E. Bachelder, Elizabeth A. Lipscomb, Leslie M. Shaw and Arthur M. Mercurio

Division of Cancer Biology and Angiogenesis, Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215

Address correspondence to Arthur M. Mercurio, Beth Israel Deaconess Medical Center, Research North, 330 Brookline Ave., Boston, MA 02215. Tel.: (617) 667-7714. Fax: (617) 667-5531. E-mail: amercuri{at}caregroup.harvard.edu

We define a novel mechanism by which integrins regulate growth factor expression and the survival of carcinoma cells. Specifically, we demonstrate that the {alpha}6ß4 integrin enhances vascular endothelial growth factor (VEGF) translation in breast carcinoma cells. The mechanism involves the ability of this integrin to stimulate the phosphorylation and inactivation of 4E-binding protein (4E-BP1), a translational repressor that inhibits the function of eukaryotic translation initiation factor 4E (eIF-4E). The regulation of 4E-BP1 phosphorylation by {alpha}6ß4 derives from the ability of this integrin to activate the PI-3K–Akt pathway and, consequently, the rapamycin-sensitive kinase mTOR that can phosphorylate 4E-BP1. Importantly, we show that this {alpha}6ß4-dependent regulation of VEGF translation plays an important role in the survival of metastatic breast carcinoma cells by sustaining a VEGF autocrine signaling pathway that involves activation of PI-3K and Akt. These findings reveal that integrin-mediated activation of PI-3K–Akt is amplified by integrin-stimulated VEGF expression and they provide a mechanism that substantiates the reported role of {alpha}6ß4 in carcinoma progression.

Key Words: integrin; VEGF; translation; carcinoma; eIF-4E


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