Adhesion GPCR-induced ectocytosis mediates intercellular GPCR signal propagation

  • Nat Chem Biol. 2026 Feb 13. doi: 10.1038/s41589-026-02148-7.
Guobing Huang  #  1  2 ,  Ni Li  #  1  2 ,  Yiyang Chen  1  2 ,  Xingrun Li  1  2 ,  X Z Shawn Xu  3 ,  Chanjuan Xu  4  5  6 ,  Jianfeng Liu  7  8  9  10
Affiliations
  • 1. Cellular Signaling Laboratory, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
  • 2. Hubei Provincial Research Center for Basic Biological Sciences, Wuhan, China.
  • 3. Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA.
  • 4. Cellular Signaling Laboratory, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China. [email protected].
  • 5. Hubei Provincial Research Center for Basic Biological Sciences, Wuhan, China. [email protected].
  • 6. Bioland Laboratory, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, China. [email protected].
  • 7. Cellular Signaling Laboratory, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China. [email protected].
  • 8. Hubei Provincial Research Center for Basic Biological Sciences, Wuhan, China. [email protected].
  • 9. Bioland Laboratory, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, China. [email protected].
  • 10. Hubei Jiangxia Laboratory, Wuhan, China. [email protected].
  • # Contributed equally.
PMID: 41688711 DOI: 10.1038/s41589-026-02148-7
Abstract

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 G12/13-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.

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