biostudies-literatureUnknownLu CHNHLBI NIH HHSNINDS NIH HHSNIGMS NIH HHSInside-out activation of integrins is crucial for transducing mechanical forces through the extracellular ligand-integrin-talin-F-actin axis. Extensive studies have shown that talin is the essential player in this process 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 that is exclusively mediated by integrin αvβ5 and selectively formed at curved membranes. Instead, a curvature-sensing protein FCHo2 binds to the HDRRE motif in the cytoplasmic tail of integrin β5 (ITGβ5) and inside-out activates integrin αvβ5 in curved adhesions. Intriguingly, FCHo2 does not bind to a similar motif in the homologous integrinbioRxiv : the preprint server for biology2025.11.28.691229https://www.ebi.ac.uk/biostudies/studies/S-EPMC12694587biostudies-literatureFCHo2, instead of talin, enables inside-out activation of integrin ɑvβ5 in curved adhesions.PMC12694587T32 GM139791R35 GM141598R01 NS121934T32 GM136568R01 HL165491Zhang WYang YTsai CTLu CHValencia LALee CEYou HCui BfalseFCHo2, instead of talin, enables inside-out activation of integrin ɑvβ5 in curved adhesions.Inside-out activation of integrins is crucial for transducing mechanical forces through the extracellular ligand-integrin-talin-F-actin axis. Extensive studies have shown that talin is the essential player in this process 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 that is exclusively mediated by integrin αvβ5 and selectively formed at curved membranes. Instead, a curvature-sensing protein FCHo2 binds to the HDRRE motif in the cytoplasmic tail of integrin β5 (ITGβ5) and inside-out activates integrin αvβ5 in curved adhesions. Intriguingly, FCHo2 does not bind to a similar motif in the homologous integrin2025-01-01T00:00:00Z2025 Dec2026-06-04T03:18:36.045Z2026-06-04T03:12:08.461ZS-EPMC126945874138375710.1101/2025.11.28.691229