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J. Biol. Chem., Vol. 283, Issue 20, 13714-13724, May 16, 2008

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Caveolin-1 Up-regulation during Epithelial to Mesenchymal Transition Is Mediated by Focal Adhesion Kinase^*

Kelly M. Bailey and Jun Liu¹

From the Mary Babb Randolph Cancer Center and the Department of Physiology and Pharmacology, West Virginia University, Morgantown, West Virginia 26506

Emerging evidence has shown that caveolin-1 is up-regulated in a number of metastatic cancers and can influence various aspects of cell migration. However, in general, the role of caveolin-1 in cancer progression is poorly understood. In the present study, we examined alterations in caveolin-1 expression during epithelial-to-mesenchymal transition (EMT) and the ability of caveolin-1 to alter cancer cell adhesion, an aspect of cell motility. We employed two EMT cell models, the human embryonic carcinoma cell line NT2/D1, and TGF-β1-treated NMuMG cells, which are derived from normal mouse mammary epithelia. Caveolin-1 expression was substantially up-regulated in both cell lines following the induction of EMT and was preceded by increased activation of focal adhesion kinase (FAK) and Src, two known tyrosine kinases involved in EMT. We hypothesized that caveolin-1 expression could be influenced by increased FAK phosphorylation, to which Src is a known contributor. Examination of FAK^+/+ and FAK^-/- mouse embryonic fibroblasts revealed that in cells devoid of FAK, caveolin-1 expression is strikingly diminished. Using FAK and superFAK constructs and the novel FAK inhibitor PF-228, we were able to demonstrate that indeed, FAK can regulate caveolin-1 expression. We also found that Src can contribute to increases in caveolin-1 expression, however, only in the presence of FAK. From the culmination of this data and our functional analyses, we conclude that caveolin-1 expression can be up-regulated during EMT, and further, once expressed, caveolin-1 can greatly influence cancer cell adhesion.

Received for publication, November 13, 2007 , and in revised form, February 4, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant RR016440. This work was also supported by the Sara and James Allen Lung Cancer Funds. 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: WV University, Health Science Center, Dept. of Physiology and Pharmacology, PO Box 9229, Morgantown, WV 26506-9229. Tel.: 304-293-1503; Fax: 304-293-3850; E-mail: junliu{at}hsc.wvu.edu.

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