FCHo2, not talin, enables inside-out activation of integrin ɑvβ5 in curved adhesions.

Extensive studies have shown that talin is the essential player for inside-out activation of integrins by binding to the intracellular tail of β integrins. Here we show that, while talin binding is essential for inside-out integrin activation in focal adhesions, it is dispensable in curved adhesions - a distinct adhesion architecture exclusively mediated by integrin αvβ5 and selectively formed at curved membranes. Instead, a curvature-sensing protein FCHo2 binds to the HDRRE motif in integrin β5's cytoplasmic tail and inside-out activates integrin αvβ5 in curved adhesions. FCHo2 does not bind to a similar motif in the homologous integrin β3. We identify a pivotal tryptophan (W), which is conserved in all homologous β integrins except β5, where it is replaced by a tyrosine (Y766). This tyrosine substitution is crucial for integrin β5's unique capability in forming curved adhesions. Furthermore, our studies suggest that the phosphorylation state of Y766 regulates whether integrin ɑvβ5 forms curved adhesions or focal adhesions. Overall, our work unveils distinct molecular interactions and regulatory mechanisms between curved adhesions and focal adhesions.