Leucine-rich repeat-containing G protein-coupled receptor 4, 5, and 6 (LGR4, LGR5, LGR6)

LGR4, LGR5, and LGR6 are closely related seven-transmembrane G protein-coupled receptors with large extracellular domains rich in leucine-rich repeats, making them key modulators of the Wnt/β-catenin pathway through their interaction with R-spondin family ligands. They are essential for tissue stem cell survival, proliferation, and organogenesis, functioning as critical components in development, homeostasis, and various diseases, particularly cancer. Distinct, but overlapping, physiologic roles exist: LGR4 dominates in metabolic and developmental settings; LGR5 and LGR6 are more specialized stem cell markers, especially in the intestine and skin. Modulation of these receptors is an area of intense research for regenerative medicine and oncology, but therapeutic translation is complicated by safety concerns related to Wnt pathway activation.

Other names

GPR48 (LGR4)GPR49 (LGR5)GPR8 (LGR6)Leucine-rich repeat-containing GPCR 4/5/6

Drugs or biologicals targeting these receptors typically aim to potentiate Wnt/β-catenin signaling by binding to LGR4/5/6 and enhancing the signal transduction that promotes stem cell survival, proliferation, and tissue regeneration. R-spondins bind LGR4/5/6, modulating activities of E3 ubiquitin ligases (RNF43/ZNRF3) and thus stabilizing Wnt receptors on the cell surface (notably for LGR4; LGR5 interacts with Wnt signalosome instead).