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J. Biol. Chem., Vol. 279, Issue 42, 44177-44187, October 15, 2004

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Targeted Mutagenesis of the Angiogenic Protein CCN1 (CYR61)

SELECTIVE INACTIVATION OF INTEGRIN ₆₁-HEPARAN SULFATE PROTEOGLYCAN CORECEPTOR-MEDIATED CELLULAR FUNCTIONS^*

Shr-Jeng Leu, Ningyu Chen, Chih-Chiun Chen, Viktor Todorovi, Tao Bai, Vladislava Juric, Ying Liu, Guoqiang Yan¶, Stephen C.-T. Lam¶, and Lester F. Lau||

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

The matricellular protein CCN1 (CYR61) regulates multiple cellular processes and plays essential roles in embryonic vascular development. A ligand of several integrin receptors, CCN1 acts through integrin ₆₁ and heparan sulfate proteoglycans (HSPGs) to promote specific functions in fibroblasts, smooth muscle cells, and endothelial cells. We have previously identified a novel ₆₁ binding site, T1, in domain III of CCN1. Here we uncover two novel 16-residue sequences, H1 and H2, in domain IV that can support ₆₁- and HSPGs-dependent cell adhesion, suggesting that these sequences contain closely juxtaposed or overlapping sites for interaction with ₆₁ and HSPGs. Furthermore, fibroblast adhesion to the H1 and H2 peptides is sufficient to induce prolonged MAPK activation, whereas adhesion to T1 induces transient MAPK activation. To dissect the roles of these sites in CCN1 function, we have created mutants disrupted in T1, H1, and H2 or in all three sites in the context of full-length CCN1. We show that the T1 and H1/H2 sites are functionally non-equivalent, and disruption of these sites differentially affected cell adhesion, migration, mitogen-activated protein kinase activation, and regulation of gene expression. Disruption of all three sites completely abolished ₆₁-HSPG-mediated cellular activities. All mutants disrupting T1, H1, and H2 fully retain _v3-mediated pro-angiogenic activities, indicating that these mutants are biologically active and are defective only in ₆₁-HSPG-mediated functions. Together, these findings identify and dissect the differential roles of the three sites (T1, H1, H2) required for ₆₁-HSPG-dependent CCN1 activities and provide a strategy to investigate these ₆₁-HSPG-specific activities in vivo.

Received for publication, July 12, 2004 , and in revised form, August 9, 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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