FCHo2, instead of talin, enables inside-out activation of integrin αvβ5 in curved adhesions

Abstract

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 {beta} 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 v{beta}5 and selectively formed at curved membranes. Instead, a curvature-sensing protein FCHo2 binds to the HDRRE motif in the cytoplasmic tail of integrin {beta}5 (ITG{beta}5) and inside-out activates integrin v{beta}5 in curved adhesions. Intriguingly, FCHo2 does not bind to a similar motif in the homologous integrin {beta}3 tail. Through truncations and mutations, we identified a pivotal tryptophan (W) in the {beta}3 tail, which is conserved in all homologous integrin {beta} isoforms except {beta}5, where it is replaced by a tyrosine (Y766). This tyrosine substitution is crucial for integrin {beta}5s unique capability in forming curved adhesions. A Y766W mutation abolishes integrin {beta}5s capacity to form curved adhesions, without affecting its ability to form focal adhesions. Furthermore, our studies suggest that the phosphorylation state of Y766 regulates whether integrin v{beta}5 forms curved adhesions or focal adhesions, providing a cellular mechanism governing different adhesion types. Overall, our work unveils distinct molecular interactions and regulatory mechanisms between curved adhesions and focal adhesions, and establishes a molecular basis for the formation of curved adhesions by integrin v{beta}5. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=108 SRC="FIGDIR/small/691229v2_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@eb4addorg.highwire.dtl.DTLVardef@1802a01org.highwire.dtl.DTLVardef@145e805org.highwire.dtl.DTLVardef@83d641_HPS_FORMAT_FIGEXP M_FIG C_FIG