Type IV collagen is an activating ligand for the adhesion G protein–coupled receptor GPR126

Abstract

GPR126 is an orphan heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptor (GPCR) that is essential for the development of diverse organs. We found that type IV collagen, a major constituent of the basement membrane, binds to Gpr126 and activates its signaling function. Type IV collagen stimulates the production of cyclic adenosine monophosphate in rodent Schwann cells, which require Gpr126 activity to differentiate, and in human embryonic kidney 293 (HEK 293) cells expressing exogenous Gpr126. Type IV collagen specifically bound to the extracellular N-terminal region of Gpr126 containing the CUB and pentraxin domains. Gpr126 derivatives lacking the entire N-terminal region were constitutively active, suggesting that this region inhibits signaling, and that ligand binding relieves this inhibition to stimulate receptor activity. A new zebrafish mutation that truncates Gpr126 after the CUB and pentraxin domains disrupted development of peripheral nerves and the inner ear. Thus, our findings identify type IV collagen as an activating ligand for GPR126, define its mechanism of activation, and highlight a previously unrecognized signaling function of type IV collagen in basement membranes.

Adhesion G protein-coupled receptors are activated by exposure of a cryptic tethered agonist

“…3 B and C), corroborating previous work and our finding that active urea-mediated ECD dissociation from full-length aGPCRs resulted in receptor activation ( Fig. 2 C and D) (11,12). Serial deletion of single amino acids from the GPR56 or GPR110 7TM domain N termini sequentially reduced the ability of the receptors to activate G proteins.…”

“…The means of ligand action resulting in aGPCR activation is unknown. Transfection of aGPCRs with deleted N-terminal ECDs (expressed 7TM domains only) enhanced cell-based signaling outputs (11,12). Therefore, aGPCR ECDs are suspected to impart an inhibitory influence upon the 7TM domains, and ligands are proposed to bind the ECD and alter its orientation with respect to the 7TM domain to relieve this inhibition.…”

Quantitative Profiling of the Activity of Protein Lysine Methyltransferase SMYD2 Using SILAC-Based Proteomics

“…For example, there are now multiple lines of evidence supporting an oncogenic role for FAM83B, in which we identified SMYD2-mediated monomethylation sites at K652 and K661 (51)(52)(53). We also identified a SMYD2-mediated mono-methylation site at K1304 in RICTOR, a component of the mTORC2 kinase complex (54) as well as in the intracellular domain of GPR126, an adhesion G-protein coupled receptor that bridges type-IV collagen in the extracellular matrix to intracellular cyclic AMP signaling (55). BTF3 is a component of the evolutionary-conserved nascent polypeptide-associated complex (NAC) that prevents the inappropriate recruitment of ribosomes to the endoplasmic reticulum (56,57).…”

Myelination and mTOR

“…Alternatively, different expression levels of the same NRG1 isoform, modulation of NRG1 by regulated proteolysis (Taveggia, 2016), and/or crosstalk interactions with other pathways affecting NRG1 downstream signaling may lead to diminished mTORC1 activation in SCs at the onset of myelination. In this respect, it was recently proposed that signals from the basal lamina, potentially via the receptor GPR126 (Paavola, Sidik, Zuchero, Eckart, & Talbot, 2014; Petersen et al, 2015), alter SC responsiveness to NRG1 (Ghidinelli et al, 2017). Despite all these hints, the question of how mTORC1 activity is affected by which signals in the various stages of SC myelination remains largely unanswered at this time.…”