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J. Biol. Chem., Vol. 283, Issue 4, 2335-2343, January 25, 2008

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Integrin 2β1 Is the Required Receptor for Endorepellin Angiostatic Activity^*

Benjamin P. Woodall¹, Alexander Nyström¹, Rex A. Iozzo, Johannes A. Eble, Stephan Niland, Thomas Krieg^¶, Beate Eckes^¶, Ambra Pozzi^||, and Renato V. Iozzo²

From the Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, the Institute for Physiological Chemistry, Muenster University Hospital, 48149 Muenster, Germany, the ^¶Department of Dermatology, University of Cologne, 50937 Cologne, Germany, and the ^||Department of Medicine, Division of Nephrology, Vanderbilt University, Nashville, Tennessee 37232

Endorepellin, the C-terminal module of perlecan, has angiostatic activity. Here we provide definitive genetic and biochemical evidence that the functional endorepellin receptor is the 2β1 integrin. Notably, the specific endorepellin binding to the receptor was cation-independent and was mediated by the 2I domain. We show that the anti-angiogenic effects of endorepellin cannot occur in the absence of 2β1. Microvascular endothelial cells from 2β1^-/- mice, but not those isolated from either wild-type or 1β1^-/- mice, did not respond to endorepellin. Moreover, syngeneic Lewis lung carcinoma xenografts in 2β1^-/- mice failed to respond to systemic delivery of endorepellin. In contrast, endorepellin inhibited tumor growth and angiogenesis in the wild-type mice expressing integrin 2β1. We conclude that the angiostatic effects of endorepellin in vivo are mediated by a specific interaction of endorepellin with the 2β1 integrin receptor.

Received for publication, October 9, 2007 , and in revised form, November 14, 2007.

^* This work was supported in part by National Institutes of Health Grants RO1 CA39481, RO1 CA47282, and RO1 CA120975 (to R. V. I.), and by Deutsche Forschungsgemeinschaft Grants Eb177/3-3 and Eb177/5-1 (to J. A. E.) and 589 (to B. E. and T. K.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S3.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Pathology, Anatomy and Cell Biology, Rm. 249 JAH, Thomas Jefferson University, Philadelphia, PA 19107. Tel.: 215-503-2208; Fax: 215-923-7969; E-mail: iozzo{at}mail.jci.tju.edu.

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