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J. Biol. Chem., Vol. 279, Issue 10, 8848-8855, March 5, 2004

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Connective Tissue Growth Factor (CCN2) Induces Adhesion of Rat Activated Hepatic Stellate Cells by Binding of Its C-terminal Domain to Integrin _v3 and Heparan Sulfate Proteoglycan^*

Runping Gao and David R. Brigstock¶||

From the Departments of Surgery and ^¶Molecular and Cellular Biochemistry, The Ohio State University, Columbus, Ohio 43212 and the Center for Cell and Vascular Biology, Children's Research Institute, Columbus, Ohio 43205

Connective tissue growth factor (CCN2, also known as CTGF) is a matricellular protein that appears to play an important role in hepatic stellate cell (HSC)-mediated fibrogenesis. After signal peptide cleavage, the full-length CCN2 molecule comprises four structural modules (CCN2_1–4) and is susceptible to proteolysis by HSC yielding isoforms comprising essentially modules 3 and 4 (CCN2_3–4) or module 4 alone (CCN2₄). In this study we show that rat activated HSC are capable of adhesion to all three CCN2 isoforms via the binding of module 4 to integrin _v3, a process that is dependent on interactions between module 4 and cell surface heparan sulfate proteoglycans (HSPGs). These findings are based on several lines of evidence. First, integrin _v3 was detected in HSC lysates by immunoprecipitation and Western blot, and CCN2₄-mediated HSC adhesion was blocked by anti-integrin _v3 antibody. Second, as assessed by immunoprecipitation and solid phase binding assay, CCN2₄ bound directly to integrin _v3 in cell-free systems. Third, destruction or inhibition of synthesis of cell surface HSPGs with, respectively, heparinase or sodium chlorate abrogated HSC adhesion to CCN2₄. Fourth, prior occupancy of heparin-binding sites on CCN2₄ with soluble heparin completely blocked HSC adhesion. These findings indicate that integrin _v3 functions as a co-receptor with HSPGs for CCN2₄-mediated HSC adhesion. Furthermore, by peptide mapping and site-directed mutagenesis we demonstrated that the sequence IRTPKISKPIKFELSG within CCN2₄ is a unique binding domain for integrin _v3 that is sufficient to mediate integrin _v3- and HSPG-dependent HSC adhesion. These findings offer the possibility of developing novel antifibrotic therapies that target the integrin-binding domain.

Received for publication, December 3, 2003

^* This work was supported by National Institutes of Health Grant R01 AA12817 (to D. R. B.). 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.

^|| To whom correspondence should be addressed: Children's Research Inst., Rm. WA 2022, 700 Children's Dr., Columbus, OH 43205. Tel.: 614-722-2840; Fax: 614-722-2716; E-mail: brigstod{at}pediatrics.ohio-state.edu.

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