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J. Biol. Chem., Vol. 280, Issue 36, 31906-31912, September 9, 2005
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-Catenin and Maintains the Cellular Mesenchymal State*
From the Moores Cancer Center, University of California at San Diego, La Jolla, California 92093
In several pathological conditions, epithelial cells demonstrate a breakdown of barrier function and acquire an invasive phenotype. Endothelial cells in particular are maintained in a mesenchymal state during the cell invasion phase of angiogenesis. We show here that tyrosine phosphorylation of the adherens junction protein VE-cadherin at two critical tyrosines, Tyr-658 and Tyr-731, via tyrosine kinase activation or phosphatase inactivation was sufficient to prevent the binding of p120- and 
-catenin, respectively, to the cytoplasmic tail of VE-cadherin. In fact, phosphorylation at either site led to the inhibition of cell barrier function. Cells expressing wild-type VE-cadherin showed decreased cell migration compared with cells lacking VE-cadherin, whereas expression of VE-cadherin with a simple phosphomimetic tyrosine-to-glutamic acid mutation of Y658E or Y731E was sufficient to restore the migratory response. These findings demonstrate that a single phosphorylation event within the VE-cadherin cytoplasmic tail is sufficient to maintain cells in a mesenchymal state.
Received for publication, May 20, 2005 , and in revised form, July 8, 2005.
* This work was supported in part by National Institutes of Health Grants CA50286, CA45726, CA95262, EY14174, CA78045, and HL57900 (to D. A. C.) and 5F32CA097885 (to M. D. P.). 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.
Recipient of an American-Italian Cancer Foundation fellowship.
To whom correspondence should be addressed: Moores Cancer Center, University of California at San Diego, 3855 Health Sciences Dr. #0803, La Jolla, CA 92093-0803. Tel.: 858-822-2232; Fax: 858-822-2630; E-mail: dcheresh{at}ucsd.edu.
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