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J. Biol. Chem., Vol. 279, Issue 40, 41734-41743, October 1, 2004

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Identification of Novel ₁ Integrin Binding Sites in the Type 1 and Type 2 Repeats of Thrombospondin-1^*

Maria J. Calzada, Douglas S. Annis, Bixi Zeng, Cezary Marcinkiewicz¶, Bernhard Banas||, Jack Lawler**, Deane F. Mosher, and David D. Roberts

From the Laboratory of Pathology, NCI, National Institutes of Health, Bethesda, Maryland 20892-1500, Department of Medicine, University of Wisconsin, Madison, Wisconsin 53706, ^¶Temple University, Department of Biology, College of Science and Technology, Philadelphia, Pennsylvania 19122, ^||Medizinische Klinik II, Universität Regensburg, Franz Josef Strauss Allee 11, 93053 Regensburg, Germany, and ^**Beth Israel Deaconess Medical Center and Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115

In addition to the three known ₁ integrin recognition sites in the N-module of thrombospondin-1 (TSP1), we found that ₁ integrins mediate cell adhesion to the type 1 and type 2 repeats. The type 1 repeats of TSP1 differ from typical integrin ligands in that recognition is pan-₁-specific. Adhesion of cells that express one dominant ₁ integrin on immobilized type 1 repeats is specifically inhibited by antagonists of that integrin, whereas adhesion of cells that express several ₁ integrins is partially inhibited by each -subunit-specific antagonist and completely inhibited by combining the antagonists. ₁ integrins recognize both the second and third type 1 repeats, and each type 1 repeat shows pan-₁ specificity and divalent cation dependence for promoting cell adhesion. Adhesion to the type 2 repeats is less sensitive to -subunit antagonists, but a ₁ blocking antibody and two disintegrins inhibit adhesion to immobilized type 2 repeats. ₁ integrin expression is necessary for cell adhesion to the type 1 or type 2 repeats, and ₁ integrins bind in a divalent cation-dependent manner to a type 1 repeat affinity column. The widely used TSP1 function blocking antibody A4.1 binds to a site in the third type 2 repeat. A4.1 proximally inhibits ₁ integrin-dependent adhesion to the type 2 repeats and indirectly inhibits integrin-dependent adhesion mediated by the TSP1 type 1 repeats. Although antibody A4.1 is also an antagonist of CD36 binding to TSP1, these data suggest that some biological activities of A4.1 result from antagonism of these novel ₁ integrin binding sites.

Received for publication, June 4, 2004 , and in revised form, August 3, 2004.

^* 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: NIH, Bldg. 10, Rm. 2A33, 10 Center Dr. MSC1500, Bethesda, MD 20892-1500. Tel.: 301-496-6264; Fax: 301-402-0043; E-mail: droberts{at}helix.nih.gov.

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