Control of Adhesion GPCR Function Through Proteolytic Processing

Proteolytic processing events in adhesion GPCRs. aGPCRs can undergo multiple autoproteolytic (red asterisks) and proteolytic processing events by exogenous proteases (yellow asterisks) that may be involved in signaling events of the receptors. Proteolytic processing is an unusual property of adhesion family G protein-coupled receptors (aGPCRs) that was observed upon their cloning and biochemical characterization.Ever since, much effort has been dedicated to delineate the mechanisms and requirements for cleavage events in the control of aGPCR function. Most notably, all aGPCRs possess a juxtamembrane protein fold, the GPCR autoproteolysis-inducing (GAIN) domain, which operates as an autoprotease for many aGPCR homologs investigated thus far. Analysis of its autoproteolytic reaction, the consequences for receptor fate and function, and the allocation of physiological effects to this peculiar feature of aGPCRs has occupied the experimental agenda of the aGPCR field and shaped our current understanding of the signaling properties and cell biological effects of aGPCRs. Interestingly, individual aGPCRs may undergo additional proteolytic steps, one of them resulting in shedding of the entire ectodomain that is secreted and can function independently. Here, we summarize the current state of knowledge on GAIN domain-mediated and GAIN domain-independent aGPCR cleavage events and their significance for the pharmacological and cellular actions of aGPCRs. Further, we compare and contrast the proteolytic profile of aGPCRs with known signaling routes that are governed through proteolysis of surface molecules such as the Notch and ephrin pathways.