The expanding functional roles and signaling mechanisms of adhesion G protein-coupled receptors

Abstract

The adhesion class of G protein-coupled receptors (GPCRs) is the second largest family of GPCRs (33 members in humans). Adhesion GPCRs (aGPCRs) are defined by a large extracellular N-terminal region that is linked to a C-terminal seven transmembrane (7TM) domain via a GPCR-autoproteolysis inducing (GAIN) domain containing a GPCR proteolytic site (GPS). Most aGPCRs undergo autoproteolysis at the GPS motif, but the cleaved fragments stay closely associated, with the N-terminal fragment (NTF) bound to the 7TM of the C-terminal fragment (CTF). The NTFs of most aGPCRs contain domains known to be involved in cell-cell adhesion, while the CTFs are involved in classical G protein signaling, as well as other intracellular signaling. In this workshop report, we review the most recent findings on the biology, signaling mechanisms, and physiological functions of aGPCRs.

Keywords: adhesion G protein-coupled receptor; cancer; development; immunology; mechanosensation; neurobiology; signal transduction; structural biology.

Figure 1.

Latrophilin function in pancreatic beta cells. ADGRL3 (LPHN3) coupling to G_αi proteins and reducing intracellular cAMP levels reduces glucose-induced insulin secretion in pancreatic beta cells upon activation with Stachel-derived peptides.

Figure 2.

Ligand-activated ADGRF1 (GPR110) signaling with neurodevelopmental and neuroprotective implications.

Figure 3.

Working model for ADGRB1 (BAI1) protective effect on p53. When BAI1 is expressed (left), it binds to MDM2 and prevents MDM2-mediated polyubiquitination of p53. P53 target proteins that restrict cell proliferation (p21, GADD45) are induced. When BAI1 expression is lost due to ADGRB1 gene silencing (right), p53 is degraded by the proteasome and cells are more prone to transformation. This mechanism suggests that MDM2 inhibitors or epigenetic reactivation of ADGRB1 with a new MBD2 inhibitor has therapeutic potential. Modified from Ref. 78.

Figure 4.

Model for the regulation of ADGRL1 (latrophilin)/teneurin interaction in an alternative splice–dependent manner. The model depicts how alternative splicing acts as a molecular switch to determine which adhesion partner teneurin 2 binds to, and, accordingly, which cellular functions teneurin 2 mediates. Left: the teneurin 2 variant lacking the β-propeller splice insert (−) interacts with ADGRL1 and modulates cAMP levels in the neighboring cell. Right: teneurin 2 variant including the splice insert (+) is unable to interact with ADGRL1, but it induces inhibitory synapses by interacting with unknown ligands. The left and right sides of the teneurin 2 dimer represent various cell–cell junctions and inhibitory synapses, respectively. The teneurin structure (PDB ID: 6CMX), membranes, and distance between synaptic membranes are drawn to scale. The molecules on the postsynaptic side are drawn schematically and are not to scale. The alternative splice site is shown by a red star. From Ref. 93.