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J. Biol. Chem., Vol. 279, Issue 28, 28889-28895, July 9, 2004

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Competition for Talin Results in Trans-dominant Inhibition of Integrin Activation^*

David A. Calderwood¶, Vera Tai, Gilbert Di Paolo||, Pietro De Camilli||, and Mark H. Ginsberg**

From the Deptartment of Cell Biology, The Scripps Research Institute, La Jolla, California 92037, the Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, and the ^||Department of Cell Biology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06510

The ability of integrin adhesion receptors to undergo rapid changes in affinity for their extracellular ligands (integrin activation) is essential for the development and function of multicellular animals and is dependent on interactions between the integrin subunit-cytoplasmic tail and the cytoskeletal protein talin. Cross-talk among different integrins and between integrins and other receptors impacts many cellular processes including adhesion, spreading, migration, clot retraction, proliferation, and differentiation. One form of integrin cross-talk, transdominant inhibition of integrin activation, occurs when ligand binding to one integrin inhibits the activation of a second integrin. This may be relevant clinically in a number of settings such as during platelet adhesion, leukocyte trans-migration, and angiogenesis. Here we report that competition for talin underlies the trans-dominant inhibition of integrin activation. This conclusion is based on our observations that (i) tails selectively defective in talin binding are unable to mediate trans-dominant inhibition, (ii) trans-dominant inhibition can be reversed by overexpression of integrin binding and activating fragments of talin, and (iii) expression of another non-integrin talin-binding protein, phosphatidylinositol phosphate kinase type I-90, also inhibits integrin activation. Thus, the sequestration of talin by the suppressive species is both necessary and sufficient for trans-dominant inhibition of integrin activation.

Received for publication, February 26, 2004 , and in revised form, May 10, 2004.

^* This work was supported by Grants GM68600, HL31950, AR27214, NS36251, and CA46128 from the National Institutes of Health and a Scientist Development Award from the American Heart Association (to D. A. C.). This is publication number 16429-CB from The Scripps Research Institute. 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.

^** Present address: Dept. of Medicine, University of California, San Diego, La Jolla, CA 92037.

^¶ To whom correspondence should be addressed. E-mail: david.calderwood{at}yale.edu.

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