Adhesion GPCRs-induced ectocytosis mediates the intercellular G protein-signaling propagation

Cell-cell communication involves signal transmission from signal-producing cells to receiving cells expressing specific receptors, such as G protein-coupled receptors (GPCRs). Extracellular vesicles (EVs) critically mediate this process by transporting diverse biomolecules. However, whether and how GPCRs engage in EV-mediated communication remain unclear. Here, we discover that adhesion GPCRs (aGPCRs) induce EV trails formation during cell migration via adhesion-like domains and G12/13 protein activation. Remarkably, activated receptors undergo ectocytosis into EVs and are subsequently internalized by adjacent cells, eliciting de novo G protein activation. We further demonstrate that cancer cell-derived EVs transport aGPCRs, such as GPR56, both in vitro and in vivo, thus modulating endothelial cells and enhancing angiogenesis. Together, our findings uncover the triple roles of aGPCRs as receptors for intracellular signaling, triggers for EV biogenesis, and messengers for intercellular signaling, thus providing a novel mechanism of cell-cell communication through aGPCRs and EV-driven signal propagation.