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Am J Physiol Lung Cell Mol Physiol (May 9, 2003). doi:10.1152/ajplung.00075.2003
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Submitted on March 14, 2003
Accepted on May 2, 2003

Protein Kinase C Modifications of VE-cadherin, p120, and {beta}-catenin Contribute to Endothelial Barrier Dysregulation Induced by Thrombin

Maria Konstantoulaki1, Panos Kouklis1*, and Asrar B. Malik1

1 Department of Pharmacology, University of Illinois, Chicago, IL, USA

* To whom correspondence should be addressed. E-mail: mkostan{at}uic.edu.

The adherens junction is a multi-protein complex consisting of the transmembrane VE-cadherin (VEC) and cytoplasmic catenins (p120, {beta}-catenin, plakoglobin, {alpha}-catenin) responsible for the maintenance of endothelial barrier function. Junctional disassembly and modifications in cadherin/catenin complex lead to increased paracellular permeability of the endothelial barrier. However, the mechanisms of junctional disassembly remain unclear. In this study, we used the pro-inflammatory mediator, thrombin, to compromise the barrier function and test the hypothesis that phosphorylation-induced alterations of VEC, {beta}-cat, and p120 regulate junction disassembly, and mediate the increased endothelial permeability response. The study showed that thrombin induces dephosphorylation of VEC, which is coupled to disassembly of cell-cell contacts, but VEC remains in aggegrates in the plasma membrane. The cytoplasmic catenins dissociate from the VEC cytoplasmic domain in thin membrane projections formed in inter-endothelial gaps. We also showed thrombin induced dephosphorylation of {beta}-cat and phosphorylation p120. Thrombin-induced interendothelial gap formation and increased endothelial permeability were blocked by protein kinase C (PKC) inhibition using chelerythrine and Go6976 but not by LY379196. Chelerythrine also prevented the thrombin-induced phosphorylation changes of the cadherin/catenin complex. Thus, the present study links post-translational modifications of VE-cadherin, {beta}-catenin and p120 to the mechanism of thrombin-induced increase in endothelial permeability.




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