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J. Biol. Chem., Vol. 280, Issue 4, 2405-2408, January 28, 2005

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VE-cadherin Links tRNA Synthetase Cytokine to Anti-angiogenic Function^*

Eleni Tzima, John S. Reader¶||, Mohamad Irani-Tehrani, Karla L. Ewalt¶, Martin A. Schwartz**, and Paul Schimmel¶

From the ^¶Skaggs Institute for Chemical Biology, Departments of Chemistry and Molecular Biology and Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037 and the ^**Departments of Microbiology and Biomedical Engineering, Cardiovascular Research Center, Mellon Prostate Cancer Research Center, University of Virginia, Charlottesville, Virginia 22908

A natural fragment of an enzyme that catalyzes the first step of protein synthesis—human tryptophanyl-tRNA synthetase (T2-TrpRS) has potent anti-angiogenic activity. A cellular receptor through which T2-TrpRS exerts its anti-angiogenic activity has not previously been identified. Here T2-TrpRS was shown to bind at intercellular junctions of endothelial cells (ECs). Using genetic knock-outs, binding was established to depend on VE-cadherin, a calcium-dependent adhesion molecule, which is selectively expressed in ECs, concentrated at adherens junctions, and is essential for normal vascular development. In contrast, T2-TrpRS binding to EC junctions was not dependent on platelet endothelial cell adhesion molecule type-1, another adhesion molecule found at EC junctions. Pull-down assays confirmed direct complex formation between T2-TrpRS and VE-cadherin. Binding of T2-TrpRS inhibited VEGF-induced ERK activation and EC migration. Thus, a VE-cadherin-dependent pathway is proposed to link T2-TrpRS to inhibition of new blood vessel formation.

Received for publication, September 14, 2004 , and in revised form, November 30, 2004.

^* This work was supported in part by National Institutes of Health Grant CA92577, a Fellowship from the National Foundation of Cancer Research, and United States Public Health Service Grant PO1 HL48728. 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.

^|| Skaggs Institute for Chemical Biology Fellow.

American Heart Association Western States Fellow 032514Y. To whom correspondence should be addressed. Tel.: 858-784-8973; Fax: 858-784-8990; E-mail: etzima{at}scripps.edu.

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