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Originally published In Press as doi:10.1074/jbc.M009518200 on May 17, 2001

J. Biol. Chem., Vol. 276, Issue 30, 27913-27922, July 27, 2001
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Conformational Regulation of the Fibronectin Binding and alpha 3beta 1 Integrin-mediated Adhesive Activities of Thrombospondin-1*

Rui G. RodriguesDagger , Neng-hua GuoDagger , Longen ZhouDagger , John M. SipesDagger , Sybil B. Williams§, Nancy Smyth Templeton, Harvey R. Gralnick§, and David D. RobertsDagger ||

From the Dagger  Laboratory of Pathology, NCI, National Institutes of Health and § Hematology Service, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892 and the  Center for Cell and Gene Therapy and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030

The recognition of extracellular matrix components can be regulated by conformational changes that alter the activity of cell surface integrins. We now demonstrate that conformational regulation of the matrix glycoprotein thrombospondin-1 (TSP1) can also modulate its binding to an integrin receptor. F18 1G8 is a conformation-sensitive TSP1 antibody that binds weakly to soluble TSP1 in the presence of divalent cations. However, binding of the antibody to melanoma cells was strongly stimulated by adding exogenous TSP1 in the presence of calcium, suggesting that TSP1 undergoes a conformational change following its binding to the cell surface. This conformation was not induced by known cell surface TSP1 receptors, whereas binding of F18 was stimulated when TSP1 bound to fibronectin but not to heparin or fibrinogen. Conversely, binding of F18 to TSP1 enhanced TSP1 binding to fibronectin. Exogenous fibronectin also stimulated TSP1-dependent binding of F18 to melanoma cells. Binding of the fibronectin-TSP1 complex to melanoma cells was mediated by alpha 4beta 1 and alpha 5beta 1 integrins. Furthermore, binding to F18 or fibronectin strongly enhanced the adhesive activity of immobilized TSP1 for some cell types. This enhancement of adhesion was mediated by alpha 3beta 1 integrin and required that the alpha 3beta 1 integrin be in an active state. Fibronectin also enhanced TSP1 binding to purified alpha 3beta 1 integrin. Therefore, both fibronectin and the F18 antibody induce conformational changes in TSP1 that enhance the ability of TSP1 to be recognized by alpha 3beta 1 integrin. The conformational and functional regulation of TSP1 activity by fibronectin represents a novel mechanism for extracellular signal transduction.

* 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.

|| To whom correspondence should be addressed: Bldg. 10, Rm. 2A33, 10 Center DR. MSC 1500, National Institutes of Health, Bethesda, MD 20892-1500. Tel.: 301-496-6264; Fax: 301-402-0043; E-mail: droberts@helix.nih.gov.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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