Talin is a cytoskeletal protein that regulates the function of integrin adhesion receptors by interacting with both the integrin β3 cytoplasmic tail and Rap1-GTP, the active form of Ras-related protein (Rap1). Here (Liao and Shattil, 2025), the authors uncover an unexpected role for talin in directly regulating Rap1 activity. Using an optogenetic approach in endothelial cells, they show that talin recruitment to the plasma membrane activates both Rap1 and integrins by displacing SH3 and multiple ankyrin repeat domains 3 (SHANK3), which sequesters Rap1-GTP. This displacement enables downstream signalling and integrin activation. In addition, experiments with mutant protein expression confirm that talin-mediated Rap1 activation occurs independently of integrin activation and is specifically observed at cell edges in adherent cells, as well as within lamellipodia and pseudopodia. Overexpression of SHANK3 blocks this effect, supporting a competitive binding model. Taken together, these findings reveal a novel regulatory mechanism in which membrane-associated talin plays a dual role: facilitating integrin activation while simultaneously promoting Rap1 activation by disrupting its sequestration by SHANK3. This study not only provides new insights into integrin signalling in endothelial cells but also highlights the power of optogenetic tools in dissecting dynamic molecular interactions at the plasma membrane.
