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J. Biol. Chem., Vol. 283, Issue 11, 7261-7270, March 14, 2008

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A Novel Role of Vascular Endothelial Cadherin in Modulating c-Src Activation and Downstream Signaling of Vascular Endothelial Growth Factor^*

Chang Hoon Ha, Anton M. Bennett, and Zheng-Gen Jin¹

From the Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, New York 14586 and the Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520

Vascular endothelial growth factor (VEGF) is a potent mediator of angiogenesis and vascular permeability, in which c-Src tyrosine kinase plays an essential role. However, the mechanisms by which VEGF stimulates c-Src activation have remained unclear. Here, we demonstrate that vascular endothelial cadherin (VE-cadherin) plays a critical role in regulating c-Src activation in response to VEGF. In vascular endothelial cells, VE-cadherin was basally associated with c-Src and Csk (C-terminal Src kinase), a negative regulator of Src activation. VEGF stimulated Csk release from VE-cadherin by recruiting the protein tyrosine phosphatase SHP2 to VE-cadherin signaling complex, leading to an increase in c-Src activation. Silencing VE-cadherin with small interference RNA significantly reduced VEGF-stimulated c-Src activation. Disrupting the association of VE-cadherin and Csk through the reconstitution of Csk binding-defective mutant of VE-cadherin also diminished Src activation. Moreover, inhibiting SHP2 by small interference RNA and adenovirus-mediated expression of a catalytically inactive mutant of SHP2 attenuated c-Src activation by blocking the disassociation of Csk from VE-cadherin. Furthermore, VE-cadherin and SHP2 differentially regulates VEGF downstream signaling. The inhibition of c-Src, VE-cadherin, and SHP2 diminished VEGF-mediated activation of Akt and endothelial nitric-oxide synthase. In contrast, inhibiting VE-cadherin and SHP2 enhanced ERK1/2 activation in response to VEGF. These findings reveal a novel role for VE-cadherin in modulating c-Src activation in VEGF signaling, thus providing new insights into the importance of VE-cadherin in VEGF signaling and vascular function.

Received for publication, April 4, 2007 , and in revised form, December 13, 2007.

^* This work was supported by National Institutes of Health Grants RO1 HL080611 (to Z. G. J.) and R01 AR046524-01 (to A. M. B.), American Diabetes Association Thomas R. Lee Award 1-06-CD-13 (to Z. G. J.) and, American Heart Association Grant-in-aid 0755916T (to Z. G. J.). 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: Aab Cardiovascular Research Institute of the University of Rochester School of Medicine and Dentistry, 211 Bailey Rd., W. Henrietta, Rochester, NY 14586. Tel.: 585-276-9783; Fax: 585-276-9829; E-mail: zheng-gen_jin{at}urmc.rochester.edu.

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