Adhesion GPCR-induced ectocytosis mediates intercellular GPCR signal propagation

Cell-cell communications involve signal transmission from sending cells to receiving cells expressing specific receptors. Extracellular vesicles (EVs) mediate this process by transporting diverse biomolecules. G-protein-coupled receptors (GPCRs) are canonical membrane receptors that integrate various extracellular signals into intracellular responses. However, whether and how GPCRs engage in EV-mediated communications remain elusive. Here, we report that adhesion GPCRs (aGPCRs) induce the formation of migrasomes and retractosomes, two newly identified EV subtypes, through their extracellular adhesion-like domains and G_12/13-protein signaling. Remarkably, activated receptors undergo ectocytosis into these EVs and are subsequently internalized by receiving cells, eliciting de novo G-protein activation. We further demonstrate that cancer-cell-derived migrasomes transfer aGPCRs such as GPR56 to endothelial cells in vitro and in vivo, thereby enhancing angiogenic potential. Together, our findings uncover that aGPCRs promote migrasome formation and provide a novel mechanism of cell-cell communications through EV-mediated intercellular spread of active GPCRs.