Fig. 3. Potential mechanisms regulating talin-mediated integrin activation. Talin binding to integrin ß tails induces conformational changes in the extracellular domain, increasing their affinity for ligands (the nature of the conformational changes remains controversial and the model shown represents only one of several possibilities). Mechanisms that regulate talin binding may therefore control integrin activation. The putative salt bridge stabilizing the interaction between membrane-proximal regions of the and ß tails in the inactive conformation is illustrated as a black bar. The three-lobed FERM domain within the talin head is indicated. (A) Stimulation of talin binding. Two hypothetical models of inactive talin are shown, where regions of the rod mask the ß tail-binding site in the F3 subdomain. Calpain cleavage or PtdIns(4,5)P₂ binding unmasks the binding site, potentially activating integrins. (B) Inhibition of talin binding. Src-mediated tyrosine phosphorylation (P) of integrin NPxY motifs, and competition with other ß tail-binding proteins (e.g. PTB domain proteins), or other talin-binding proteins (e.g. PIPKI-90), may prevent integrin-talin interactions, so inhibiting integrin activation. Hence, dynamic interplay between the stimulatory and inhibitory pathways might determine the integrin activation state.