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Phosphorylated Caveolin-1 Regulates Rho/ROCK-Dependent Focal Adhesion Dynamics and Tumor Cell Migration and Invasion

¹ Department of Cellular and Physiological Sciences, Life Sciences Institute, ² Prostate Research Center, British Columbia Cancer Agency, ³ Department of Medical Genetics, University of British Columbia, British Columbia Cancer Agency and Michael Smith Genome Sciences Center, ⁴ Department of Surgery, St. Paul's Hospital, ⁵ Department of Pathology, and ⁶ Genetic Pathology Evaluation Center, Vancouver General Hospital, British Columbia Cancer Agency, University of British Columbia, Vancouver, British Columbia, Canada

Requests for reprints: Ivan R. Nabi, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada. Phone: 604-822-7000; Fax: 604-822-2316; E-mail: irnabi{at}interchange.ubc.ca.

Key Words: Rho/ROCK signaling • Caveolin-1 • Focal adhesions

Rho/ROCK signaling and caveolin-1 (Cav1) are implicated in tumor cell migration and metastasis; however, the underlying molecular mechanisms remain poorly defined. Cav1 was found here to be an independent predictor of decreased survival in breast and rectal cancer and significantly associated with the presence of distant metastasis for colon cancer patients. Rho/ROCK signaling promotes tumor cell migration by regulating focal adhesion (FA) dynamics through tyrosine (Y14) phosphorylation of Cav1. Phosphorylated Cav1 is localized to protrusive domains of tumor cells and Cav1 tyrosine phosphorylation is dependent on Src kinase and Rho/ROCK signaling. Increased levels of phosphorylated Cav1 were associated with elevated GTP-RhoA levels in metastatic tumor cells of various tissue origins. Stable expression and knockdown studies of Cav1 in tumor cells showed that phosphorylated Cav1 expression stimulates Rho activation, stabilizes FAK association with FAs, and promotes cell migration and invasion in a ROCK-dependent and Src-dependent manner. Tyrosine-phosphorylated Cav1, therefore, functions as an effector of Rho/ROCK signaling in the regulation of FA turnover and, thereby, tumor cell migration and invasion. These studies define a feedback loop between Rho/ROCK, Src, and phosphorylated Cav1 in tumor cell protrusions, identifying a novel function for Cav1 in tumor metastasis that may contribute to the poor prognosis of some Cav1-expressing tumors. [Cancer Res 2008;68(20):8210–20]