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Specific Cross-talk between Epidermal Growth Factor Receptor and Integrin _vβ₅ Promotes Carcinoma Cell Invasion and Metastasis

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

Requests for reprints: David A. Cheresh, Moores UCSD Cancer Center, University of California, San Diego, 3855 Health Sciences Drive 0803, La Jolla, CA 92093-0803. Phone: 858-822-2232; Fax: 858-822-2630; E-mail: dcheresh{at}ucsd.edu.

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

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 _vβ₅. 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 _vβ₅ activation. This pathway induces _vβ₅-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]