ERM proteins recruit Epac1 to the plasma membrane and facilitate Epac1-induced cell adhesion

Epac1 is a GEF for the small G-protein Rap and is directly activated by cAMP. Epac1-Rap signaling is involved in plasma membrane-localized processes such as integrin-mediated cell adhesion and cellcell junction formation. We previously showed that cAMP induces the translocation of Epac1 to the plasma membrane, thereby enhancing Rap-mediated cell adhesion. We here report an additional mechanism of Epac1 recruitment to the plasma membrane via an interaction with members of the Ezrin/Radixin/Moesin (ERM) family. In contrast to cAMP-dependent Epac1 translocation, this recruitment depends neither on the DEP domain nor on the conformational state of Epac1. Instead, it is regulated by conformational opening of the ERM proteins. Furthermore, whereas cAMP binding targets Epac1 uniformly along the plasma membrane, ERM proteins recruit Epac1 to polarized subcompartments. Finally, we show that the ERM-interaction contributes to Epac1mediated cell adhesion. Taken together, our data suggest that ERM proteins spatially confine Epac1 to subcompartments of the plasma membrane, thereby contributing to the efficiency of localized