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J. Biol. Chem., Vol. 281, Issue 45, 34179-34188, November 10, 2006

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Proteolytically Processed Soluble Tumor Endothelial Marker (TEM) 5 Mediates Endothelial Cell Survival during Angiogenesis by Linking Integrin _v3 to Glycosaminoglycans^*

From the Technical University of Munich, Department of Nuclear Medicine, Ismaninger Strasse 22, Munich 81675, Germany

Tumor endothelial marker (TEM) 5 is a member of the adhesion family of G-protein-coupled receptors and up-regulated in endothelial cells during tumor and physiologic angiogenesis. Here, we report that TEM5 is expressed on the surface of endothelial cells. A soluble TEM5 (sTEM5) fragment is shed by endothelial cells during capillary-like network formation and upon growth factor stimulation. We found that sTEM5 binds to several glycosaminoglycans. Furthermore, sequence analysis and functional and biochemical studies revealed that sTEM5 contains a cryptic RGD-binding site for integrin _v3. Matrix metalloprotease 9-processed, but not full-length, sTEM5 mediated endothelial cell adhesion by direct interaction with integrin _v3. Adhesion to proteolytically processed sTEM5 (ppsTEM5) or glycosaminoglycan-bound ppsTEM5 promoted survival of growth factor deprived endothelial cells. ppsTEM5-mediated cell survival was inhibited by a function blocking integrin _v3 antibody. Based on our results we conclude that sTEM5 is shed by endothelial cells during angiogenesis and binds to glycosaminoglycans present on extracellular matrix and cell surface proteoglycans. Further proteolytic processing of sTEM5 leads to exposure of its RGD motif mediating endothelial cell survival by linking integrin _v3 to glycosaminoglycans.

Received for publication, June 2, 2006 , and in revised form, September 14, 2006.

^* This work was supported by grants from the "Deutsche Forschungsgemeinschaft" (GRK438 and ES 155 2/2) and the Technical University of Munich (Konto für Klinische Forschung). 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 This work is part of the Ph.D. thesis of the first author.

² To whom correspondence should be addressed. E-mail: markus.essler{at}gmx.de.

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