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J. Biol. Chem., Vol. 283, Issue 10, 6118-6125, March 7, 2008

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The N-terminal Domains of Talin Cooperate with the Phosphotyrosine Binding-like Domain to Activate β1 and β3 Integrins^*

From the Department of Pharmacology and Interdepartmental Program in Vascular Biology and Transplantation, Yale University School of Medicine, New Haven, Connecticut 06520

The activation of integrin adhesion receptors from low to high affinity in response to intracellular cues controls cell adhesion and signaling. Binding of the cytoskeletal protein talin to the β3 integrin cytoplasmic tail is required for β3 activation, and the integrin-binding PTB-like F3 domain of talin is sufficient to activate β3 integrins. Here we report that, whereas the conserved talin-integrin interaction is also required for β1 activation, and talin F3 binds β1 and β3 integrins with comparable affinity, expression of the talin F3 domain is not sufficient to activate β1 integrins. β1 integrin activation could, however, be detected following expression of larger talin fragments that included the N-terminal and F1 domains, and mutagenesis indicates that these domains cooperate with talin F3 to mediate β1 activation. This effect is not due to increased affinity for the integrin β tail and we hypothesize that the N-terminal domains function by targeting or orienting talin in such a way as to optimize the interaction with the integrin tail. Analysis of β3 integrin activation indicates that inclusion of the N-terminal and F1 domains also enhances F3-mediated β3 activation. Our results therefore reveal a role for the N-terminal and F1 domains of talin during integrin activation and highlight differences in talin-mediated activation of β1 and β3 integrins.

Received for publication, November 20, 2007 , and in revised form, December 14, 2007.

^* This work was supported by Grants GM068600 and HL089433 from the National Institutes of Health (to D. A. C.) and by a fellowship from the Fondation pour la Recherche Médicale (to M. B.). 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 To whom correspondence should be addressed: 333 Cedar St., P. O. Box 208066, New Haven, CT 06520-8066. Tel.: 203-737-2311; Fax: 203-785-7670; E-mail: david.calderwood{at}yale.edu.

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