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Originally published In Press as doi:10.1074/jbc.M500898200 on March 18, 2005

J. Biol. Chem., Vol. 280, Issue 22, 21129-21136, June 3, 2005
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Proline-rich Tyrosine Kinase 2 (Pyk2) Mediates Vascular Endothelial-Cadherin-based Cell-Cell Adhesion by Regulating {beta}-Catenin Tyrosine Phosphorylation*{boxs}

Jaap D. van Buul{ddagger}§||, Eloise C. Anthony{ddagger}, Mar Fernandez-Borja{ddagger}**, Keith Burridge§, and Peter L. Hordijk {ddagger}{ddagger}{ddagger}

From the {ddagger}Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, 1066 CX Amsterdam, The Netherlands and §Department of Cell and Developmental Biology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599

Vascular endothelial-cadherin (VE-cadherin) controls endothelial cell-cell adhesion and preserves endothelial integrity. In order to maintain endothelial barrier function, VE-cadherin function is tightly regulated through mechanisms that involve protein phosphorylation and cytoskeletal dynamics. Here, we show that loss of VE-cadherin function results in intercellular gap formation and a drop in electrical resistance of monolayers of primary human endothelial cells. Detailed analysis revealed that loss of endothelial cell-cell adhesion, induced by VE-cadherin-blocking antibodies, is preceded by and dependent on a rapid activation of Rac1 and increased production of reactive oxygen species. Moreover, VE-cadherin-associated {beta}-catenin is tyrosine-phosphorylated upon loss of cell-cell contact. Finally, the redox-sensitive proline-rich tyrosine kinase 2 (Pyk2) is activated and recruited to cell-cell junctions following the loss of VE-cadherin homotypic adhesion. Conversely, the inhibition of Pyk2 activity in endothelial cells by the expression of CRNK (CADTK/CAK{beta}-related non-kinase), an N-terminal deletion mutant that acts in a dominant negative fashion, not only abolishes the increase in {beta}-catenin tyrosine phosphorylation but also prevents the loss of endothelial cell-cell contact. These results implicate Pyk2 in the reduced cell-cell adhesion induced by the Rac-mediated production of ROS through the tyrosine phosphorylation of {beta}-catenin. This signaling is initiated upon loss of VE-cadherin function and is important for our insight in the modulation of endothelial integrity.

Received for publication, January 25, 2005 , and in revised form, March 15, 2005.

* This work was supported in part by National Institutes of Health Grant HL45100. 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.

{boxs} The on-line version of this article (available at http://www.ibc.org) contains supplemental movies.

Supported by Grant 99-2000 from the Dutch Cancer Society.

|| Supported by the Ter Meulen Fund, Royal Netherlands Academy of Arts and Sciences.

** Supported by Grant 1249 from the Land Steiner Foundation for Blood Transfusion Research.

{ddagger}{ddagger} Fellow of the Landsteiner Foundation for Blood Transfusion Research (Grant 9910). To whom correspondence should be addressed: Dept. of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Plesmanlaan 125, 1066 CX, Amsterdam, The Netherlands. Tel.: 31205123263; Fax: 31205123474; E-mail: p.hordijk{at}sanquin.nl.


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