Adhesion GPCR-induced ectocytosis mediates intercellular GPCR signal propagation

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• Cell-cell communication relies on signal transmission via receptors.
• Extracellular vesicles (EVs) are key mediators of intercellular signaling.
• The role of G-protein-coupled receptors (GPCRs) in EV-mediated communication is largely unknown.

Purpose of the Study:

• To investigate the involvement of GPCRs in EV-mediated cell communication.
• To explore the function of adhesion GPCRs (aGPCRs) in EV formation and signaling.

Main Methods:

• Investigated aGPCRs' role in migrasome and retractosome formation.
• Utilized G12/13-protein signaling pathways.
• Examined the ectocytosis and intercellular transfer of activated aGPCRs.
• Assessed the impact of aGPCR transfer on endothelial cell angiogenic potential in vitro and in vivo.

Main Results:

• aGPCRs induce the formation of migrasomes and retractosomes via their extracellular domains and G12/13 signaling.
• Activated aGPCRs are released via ectocytosis into these EVs and internalized by recipient cells.
• Cancer-derived migrasomes transfer aGPCRs (e.g., GPR56) to endothelial cells, enhancing angiogenesis.

Conclusions:

• aGPCRs actively promote the formation of migrasomes and retractosomes.
• A novel mechanism of cell-cell communication involves the EV-mediated intercellular spread of active GPCRs.
• This pathway contributes to cancer angiogenesis by transferring functional aGPCRs.