Adhesion G protein-coupled receptor gluing action guides tissue development and disease

Phylogenetic analysis of human G protein-coupled receptors (GPCRs) divides these transmembrane signaling proteins into five groups: glutamate, rhodopsin, adhesion, frizzled, and secretin families, commonly abbreviated as the GRAFS classification system. The adhesion GPCR (aGPCR) sub-family comprises 33 different receptors in humans. Majority of the aGPCRs are orphan receptors with unknown ligands, structures, and tissue expression profiles. They have a long N-terminal extracellular domain (ECD) with several adhesion sites similar to integrin receptors. Many aGPCRs undergo autoproteolysis at the GPCR proteolysis site (GPS), enclosed within the larger GPCR autoproteolysis inducing (GAIN) domain. Recent breakthroughs in aGPCR research have created new paradigms for understanding their roles in organogenesis. They play crucial roles in multiple aspects of organ development through cell signaling, intercellular adhesion, and cell-matrix associations. They are involved in essential physiological processes like regulation of cell polarity, mitotic spindle orientation, cell adhesion, and migration. Multiple aGPCRs have been associated with the development of the brain, musculoskeletal system, kidneys, cardiovascular system, hormone secretion, and regulation of immune functions. Since aGPCRs have crucial roles in tissue patterning and organogenesis, mutations in these receptors are often associated with diseases with loss of tissue integrity. Thus, aGPCRs include a group of enigmatic receptors with untapped potential for elucidating novel signaling pathways leading to drug discovery. We summarized the current knowledge on how aGPCRs play critical roles in organ development and discussed how aGPCR mutations/genetic variants cause diseases.