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J. Biol. Chem., Vol. 279, Issue 42, 44166-44176, October 15, 2004

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Identification of a Novel Integrin _v3 Binding Site in CCN1 (CYR61) Critical for Pro-angiogenic Activities in Vascular Endothelial Cells^*

Ningyu Chen, Shr-Jeng Leu, Viktor Todorovi, Stephen C.-T. Lam¶, and Lester F. Lau||

From the Department of Biochemistry and Molecular Genetics and ^¶Department of Pharmacology, University of Illinois College of Medicine, Chicago, Illinois 60607-7170

CCN1 (CYR61) is a matricellular inducer of angiogenesis essential for successful vascular development. Though devoid of the canonical RGD sequence motif recognized by some integrins, CCN1 binds to, and functions through integrin _v3 to promote pro-angiogenic activities in activated endothelial cells. In this study we identify a 20-residue sequence, V2 (NCKHQCTCIDGAVGCIPLCP), in domain II of CCN1 as a novel binding site for integrin _v3. Immobilized synthetic V2 peptide supports _v3-mediated cell adhesion; soluble V2 peptide inhibits endothelial cell adhesion to CCN1 and the homologous family members CCN2 (connective tissue growth factor, CTGF) or CCN3 (NOV) but not to collagen. These activities are obliterated by mutation of the aspartate residue in the V2 peptide to alanine. The corresponding D125A mutation in the context of the N-terminal half of CCN1 (domains I and II) greatly diminished direct solid phase binding to purified integrin _v3 and abolished _v3-mediated cell adhesion activity. Likewise, soluble full-length CCN1 with the D125A mutation is defective in binding purified _v3 and impaired in _v3-mediated pro-angiogenic activities in vascular endothelial cells, including stimulation of cell migration and enhancement of DNA synthesis. In contrast, immobilized full-length CCN1-D125A mutant binds _v3 and supports _v3-mediated cell adhesion similar to wild type CCN1. These results indicate that V2 is the primary _v3 binding site in soluble CCN1, whereas additional cryptic _v3 binding site(s) in the C-terminal half of CCN1 becomes exposed when the protein is immobilized. Together, these results identify a novel and functionally important binding site for integrin _v3 and provide a new approach for dissecting _v3-specific CCN1 functions both in cultured cells and in the organism.

Received for publication, June 18, 2004

^* This work was supported by National Institutes of Health Grants CA46565 and CA80080 (to L. F. L.) and HL41793 (to S. C.-T. L.). 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.

Present address: Dept. of Microbiology and Immunology, Vanderbilt University, Nashville, TN 37232.

^|| To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Genetics, University of Illinois, College of Medicine, 900 South Ashland Ave., Chicago IL 60607. Tel.: 312-996-6978; Fax: 312-996-7034; E-mail: lflau{at}uic.edu.

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