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Originally published In Press as doi:10.1074/jbc.M111361200 on February 6, 2002

J. Biol. Chem., Vol. 277, Issue 16, 13650-13658, April 19, 2002
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Alternative Splicing of the IIICS Domain in Fibronectin Governs the Role of the Heparin II Domain in Fibrillogenesis and Cell Spreading*

Amy J. SantasDagger §, Jennifer A. PetersonDagger , Jennifer L. HalbleibDagger , Sue E. Craig, Martin J. Humphries, and Donna M. Pesciotta PetersDagger ||**

From the Departments of Dagger  Pathology and Laboratory Medicine and || Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisconsin 53706 and the  Wellcome Trust Centre for Cell-Matrix Research, School of Biological Sciences, University of Manchester, M13 9PT Manchester, United Kingdom

The Heparin (Hep) II-binding domain of fibronectin regulates the formation of focal adhesions and actin stress fibers and hence plays an important role in cell spreading, migration, and fibronectin fibrillogenesis. Using human skin fibroblast cultures, we demonstrate that alternative splicing of the neighboring IIICS domain may regulate the activities of the Hep II domain in cell spreading and fibronectin fibrillogenesis. Recombinant Hep II domains, adjacent to either the IIICS domain or the H89 splice variant that contains the amino-terminal sequence of the IIICS domain, blocked fibronectin fibrillogenesis and required sulfated proteoglycans to mediate cell spreading. If the Hep II domain was adjacent to either the H0 or H95 splice variants, which both lack the amino terminus of the IIICS domain, fibrillogenesis was not inhibited and cell spreading was independent of a sulfated proteoglycan-mediated mechanism. The effect of the splice variants on the Hep II domain could be mimicked using a Hep II domain that contained only 6 amino acids from the III15 repeat or 10 amino acids from the IIICS domain suggesting that sequences proximal to the III14 repeat determined the role of the Hep II domain in these processes. We propose that alternative splicing of the IIICS domain modulates interactions between heparan sulfate proteoglycans and the Hep II domain and that this serves as a mechanism to control the biological activities of fibronectin.

* This work was supported in part by National Institutes of Health Grant EY12515, the American Heart Association grant-in-aid, Wisconsin Affiliate, National Science Foundation Grant MCB9728382 (to D. M. P.), and the Wellcome Trust (to M. J. H.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Current address: Div. of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109.

** To whom correspondence should be addressed to: Dept. of Pathology and Laboratory Medicine, Rm 6590 MSC, 1300 University Ave., Madison, WI 53706. Tel.: 608-262-4626; Fax: 608-265-3301; E-mail: dmpeter2@facstaff.wisc.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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Copyright © 2002 by the American Society for Biochemistry and Molecular Biology.