MECHANISMS OF SIGNAL TRANSDUCTION
The Phosphotyrosine Binding-like Domain of Talin Activates Integrins*

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Cellular regulation of the ligand binding affinity of integrin adhesion receptors (integrin activation) depends on the integrin β cytoplasmic domains (tails). The head domain of talin binds to several integrin β tails and activates integrins. This head domain contains a predicted FERM domain composed of three subdomains (F1, F2, and F3). An integrin-activating talin fragment was predicted to contain the F2 and F3 subdomains. Both isolated subdomains bound specifically to the integrin β3 tail. However, talin F3 bound the β3 tail with a 4-fold higher affinity than talin F2. Furthermore, expression of talin F3 (but not F2) in cells led to activation of integrin αIIbβ3. A molecular model of talin F3 indicated that it resembles a phosphotyrosine-binding (PTB) domain. PTB domains recognize peptide ligands containing β turns, often formed by NPXY motifs. NPX(Y/F) motifs are highly conserved in integrin β tails, and mutations that disrupt this motif interfere with both integrin activation and talin binding. Thus, integrin binding to talin resembles the interactions of PTB domains with peptide ligands. These resemblances suggest that the activation of integrins requires the presence of a β turn at NPX(Y/F) motifs conserved in integrin β cytoplasmic domains.

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Published, JBC Papers in Press, April 3, 2002, DOI 10.1074/jbc.M111996200

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This work was supported by Grants HL-48728, HL-30915, and AR-27214 from the National Institutes of Health, and by the Susan G. Komen Breast Cancer Foundation, and the American Heart Association. This is Publication 13988-VB from the Scripps Research Institute.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.