The N-terminal domains of talin cooperate with the phosphotyrosine binding-like domain to activate β1 and β3 integrins

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 beta 3 integrin cytoplasmic tail is required for beta 3 activation, and the integrin-binding PTB-like F3 domain of talin is sufficient to activate beta 3 integrins. Here we report that, whereas the conserved talin-integrin interaction is also required for beta 1 activation, and talin F3 binds beta 1 and beta 3 integrins with comparable affinity, expression of the talin F3 domain is not sufficient to activate beta 1 integrins. beta 1 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 beta 1 activation. This effect is not due to increased affinity for the integrin beta 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 beta 3 integrin activation indicates that inclusion of the N-terminal and F1 domains also enhances F3-mediated beta 3 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 beta 1 and beta 3 integrins.