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J. Biol. Chem., Vol. 281, Issue 46, 34816-34825, November 17, 2006

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Identification of the Heparin-binding Determinants within Fibronectin Repeat III₁

ROLE IN CELL SPREADING AND GROWTH^*

Liqiong Gui¹, Katherine Wojciechowski¹, Candace D. Gildner, Hristina Nedelkovska, and Denise C. Hocking²

From the Departments of Biomedical Engineering and Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York 14642

Fibronectins are high molecular mass glycoproteins that circulate as soluble molecules in the blood, and are also found in an insoluble, multimeric form in extracellular matrices throughout the body. Soluble fibronectins are polymerized into insoluble extracellular matrix (ECM) fibrils via a cell-dependent process. Recent studies indicate that the interaction of cells with the ECM form of fibronectin promotes actin organization and cell contractility, increases cell growth and migration, and enhances the tensile strength of artificial tissue constructs; ligation of integrins alone is insufficient to trigger these responses. Evidence suggests that the effect of ECM fibronectin on cell function is mediated in part by a matricryptic heparin-binding site within the first III₁ repeat (FNIII₁). In this study, we localized the heparin-binding activity of FNIII₁ to a cluster of basic amino acids, Arg⁶¹³, Trp⁶¹⁴, Arg⁶¹⁵, and Lys⁶¹⁷. Site-directed mutagenesis of a recombinant fibronectin construct engineered to mimic the ECM form of fibronectin demonstrates that these residues are also critical for stimulating cell spreading and increasing cell proliferation. Cell proliferation has been tightly correlated with cell area. Using integrin- and heparin-binding fibronectin mutants, we found a positive correlation between cell spreading and growth when cells were submaximally spread on ECM protein-coated surfaces at the time of treatment. However, cells maximally spread on vitronectin or fibronectin still responded to the fibronectin matrix mimetic with an increase in growth, indicating that an absolute change in cell area is not required for the increase in cell proliferation induced by the matricryptic site of FNIII₁.

Received for publication, September 6, 2006

^* This work was supported by Grants EB00986 and HL64074 from the National Institutes of Health. 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.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Box 711, 601 Elmwood Ave., Rochester, NY 14642. Tel.: 585-273-1770; Fax: 585-273-2652; E-mail: denise_hocking{at}urmc.rochester.edu.

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