Specific Cross-talk between Epidermal Growth Factor Receptor and Integrin _v5 Promotes Carcinoma Cell Invasion and Metastasis

¹Moores UCSD Cancer Center and ²Department of Pathology, University of California, San Diego, La Jolla, California and ³Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee

^* To whom correspondence should be addressed. E-mail: dcheresh{at}ucsd.edu.

	Abstract

Tyrosine kinase receptors and integrins play essential roles in tumor cell invasion and metastasis. Previously, we showed that epidermal growth factor (EGF) stimulation of pancreatic carcinoma cells led to invasion and metastasis that was blocked by antagonists of integrin _v5. Here, we show that EGF stimulates metastasis of carcinoma cells via a Src-dependent phosphorylation of p130 CAS leading to activation of Rap1, a small GTPase involved in integrin activation. Specifically, EGF receptor (EGFR)–induced Src activity leads to phosphorylation of a region within the CAS substrate domain, which is essential for Rap1 and _v5 activation. This pathway induces _v5-mediated invasion and metastasis in vivo yet does not influence primary tumor growth or activation of other integrins on these cells. These findings show cross-talk between a tyrosine kinase receptor and an integrin involved in carcinoma cell invasion and metastasis and may explain in part how inhibitors of EGFR affect malignant disease. [Cancer Res 2009;69(4):1383–91]

Key Words: EGF, integrin, Src, CAS, Rap1