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First published online 15 January 2008
doi: 10.1242/jcs.017145

Journal of Cell Science 121, 358-368 (2008)
Published by The Company of Biologists 2008
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Research Article

Overexpression of EPHA2 receptor destabilizes adherens junctions via a RhoA-dependent mechanism

Wei Bin Fang1, Reneé C. Ireton1, Guanglei Zhuang1, Takamune Takahashi2, Al Reynolds1,3 and Jin Chen1,3,4,5,*

1 Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
2 Department of Medicine, Division of Nephrology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
3 Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
4 Division of Rheumatology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
5 Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA

* Author for correspondence (e-mail: jin.chen{at}vanderbilt.edu)

Accepted 4 November 2007

EPHA2 receptor tyrosine kinase is overexpressed in several human cancer types and promotes malignancy. However, the mechanisms by which EPHA2 promotes tumor progression are not completely understood. Here we report that overexpression of a wild-type EPHA2, but not a signaling-defective cytoplasmic truncation mutant ({Delta}C), in human mammary epithelial cells weakens E-cadherin-mediated cell-cell adhesion. Interestingly, the total level of cadherins and the composition of the adherens junction complexes were not affected, nor was the tyrosine phosphorylation of the cadherin complex components changed. By contrast, RhoA GTPase activity was significantly affected by modulating the EPHA2 activity in MCF-10A cells. Treatment with a ROCK kinase inhibitor rescued cell-cell adhesion defects in EPHA2-overexpressing cells, whereas expression of constitutively activated Rho disrupted adherens junctions in {Delta}C-expressing cells. EPHA2-dependent Rho activation and destabilization of adherens junctions appeared to be regulated via a signaling pathway involving Src kinase, low molecular weight phosphotyrosine phosphatase (LMW-PTP) and p190 RhoGAP. EPHA2 interacted with both Src and LMW-PTP, and the interactions increased in EPHA2-overexpressing cells. In addition, LMW-PTP phosphatase activity was elevated, and this elevation was accompanied by a decrease in tyrosine phosphorylation of p190 RhoGAP and destabilization of cell-cell adhesion. Expression of either a dominant negative LMW-PTP mutant, C12S, or a wild-type p190 RhoGAP rescued adhesion defects in EPHA2-overexpressing cells. Together, these data suggest that EPHA2 promotes tumor malignancy through a mechanism involving RhoA-dependent destabilization of adherens junctions.

Key words: EPHA2, RhoA, Adherens junction




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W. B. Fang, R. C. Ireton, G. Zhuang, T. Takahashi, A. Reynolds, and J. Chen
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