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J. Biol. Chem., Vol. 280, Issue 8, 7080-7087, February 25, 2005

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BMP-1/Tolloid-like Metalloproteases Process Endorepellin, the Angiostatic C-terminal Fragment of Perlecan^*

Eva M. Gonzalez, Charles C. Reed, Gregory Bix, Jian Fu, Yue Zhang¶, Bagavathi Gopalakrishnan¶, Daniel S. Greenspan¶, and Renato V. Iozzo||**

From the Department of Pathology, Anatomy and Cell Biology and the ^||Cellular Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107 and the ^¶Department of Pathology and Laboratory Medicine, and Program in Cellular and Molecular Biology, University of Wisconsin Medical School, Madison, Wisconsin 53706

Endorepellin, the C-terminal domain of the heparan sulfate proteoglycan perlecan, possesses angiostatic activity. The terminal laminin-like globular (LG3) domain of endorepellin appears to possess most of the biological activity on endothelial cells. LG3 protein has been detected in the urine of patients with end-stage renal disease and in the amniotic fluid of pregnant women with premature rupture of fetal membranes. These findings suggest that proteolytic processing of endorepellin and the generation of LG3 might have biological significance. In this study, we have identified specific enzymes of the bone morphogenetic protein-1 (BMP-1)/Tolloid family of metalloproteases that cleave LG3 from recombinant endorepellin at the physiologically relevant site and that cleave LG3 from endogenous perlecan in cultured mouse and human cells. The BMP-1/Tolloid family of metalloproteases is thereby implicated in the processing of a major basement membrane proteoglycan and in the liberation of an anti-angiogenic factor. Using molecular modeling, site-directed mutagenesis and angiogenic assays, we further demonstrate that LG3 activity requires specific amino acids involved in Ca²⁺ coordination.

Received for publication, August 26, 2004 , and in revised form, December 9, 2004.

^* This work was supported by National Institutes of Health Grants RO1 CA39481 and RO1 CA47282 and Department of the Army grant DAMD17-00-1-0425 (to R. V. I.) and by National Institutes of Health Grants RO1 GM63471 and RO1 AR47746 (to D. S. G.). 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.

Both authors contributed equally to this work.

^** To whom correspondence should be addressed: Dept. of Pathology, Anatomy and Cell Biology, Rm. 249 JAH, Thomas Jefferson University, 1020 Locust St., Philadelphia, PA 19107. E-mail: iozzo{at}mail.jci.tju.edu.

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