TRPM8 Inhibits Endothelial Cell Migration Via A Non-Channel Function By Trapping Small Gtpase Rap1

Here we reveal a novel non-channel function for TRPM8 which unexpectedly acts as a Rap1 GTPase inhibitor, thereby inhibiting EC motility, independently from the pore function. TRPM8 retains Rap1 intracellularly through direct protein-protein interaction preventing thus its cytoplasm-plasma membrane trafficking. In turn, this mechanism impairs the activation of a major inside-out signaling pathway that trigger the conformational activation of integrins and, consequently, cell adhesion, migration, in vitro endothelial tube formation and spheroid sprouting.