Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) (LGR5)

Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5), also commonly referred to as GPR49, is a member of the Class A G protein-coupled receptor superfamily and serves as a definitive marker for adult stem cells in various tissues, most notably the intestinal epithelium, stomach, and hair follicles. LGR5 functions as a receptor for R-spondin growth factors (RSPO1-4) and plays an essential role in the potentiation of the canonical Wnt/beta-catenin signaling pathway. Unlike traditional GPCRs that signal primarily through heterotrimeric G proteins, LGR5 operates by binding RSPOs and facilitating the internalization of the E3 ubiquitin ligases RNF43 and ZNRF3, which prevents the degradation of Frizzled receptors and enhances Wnt responsiveness. In the context of oncology, LGR5 is significantly overexpressed in several malignancies, including colorectal, gastric, and ovarian cancers, where it identifies a subpopulation of cancer stem cells (CSCs) responsible for tumor initiation, metastasis, and resistance to conventional chemotherapy. Therapeutic development targeting LGR5 includes monoclonal antibodies like BNC101, antibody-drug conjugates, and bispecific antibodies aimed at eradicating these chemoresistant CSC populations. However, the clinical advancement of these therapies is challenged by the receptor's critical role in normal tissue homeostasis, particularly in the gut, which can lead to severe on-target, off-tumor toxicities such as gastrointestinal mucosal damage.

Other names

G-protein coupled receptor 5G-protein coupled receptor 49G-protein coupled receptor 67G-protein coupled receptor HG38GPR49GPR67HG38FEX

LGR5 acts as a high-affinity receptor for R-spondin (RSPO1-4) ligands. Upon binding RSPO, the LGR5-RSPO complex internalizes the E3 ubiquitin ligases RNF43 and ZNRF3, which would otherwise ubiquitinate and degrade Frizzled receptors. This sequestration stabilizes Frizzled and LRP6 on the cell surface, thereby potentiating canonical Wnt/beta-catenin signaling and driving the expression of Wnt target genes involved in stemness and proliferation.