Leucine-rich repeat-containing G protein-coupled receptor 6 (LGR6) (LGR6)

Leucine-rich repeat-containing G protein-coupled receptor 6 (LGR6) is a critical component of the Wnt/β-catenin signaling axis, acting as a high-affinity receptor for R-spondins (RSPO1-4) [1, 3]. In the epidermis, LGR6 serves as a definitive marker for a population of multipotent stem cells located in the hair follicle isthmus that are responsible for the long-term maintenance of the sebaceous gland and the interfollicular epidermis [2, 4]. When R-spondins bind to LGR6, they inhibit the E3 ubiquitin ligases ZNRF3 and RNF43, thereby preventing the degradation of Frizzled receptors and significantly potentiating canonical Wnt signaling [3]. This axis is vital for skin homeostasis and is one of the earliest responders during the wound healing process, as LGR6+ cells migrate to the site of injury to regenerate the epidermis [2]. Dysregulation of LGR6-mediated signaling is associated with the development of skin carcinomas, such as basal cell carcinoma, and various hair loss conditions [5]. Therapeutic development focuses on modulating this axis using R-spondin mimetics to accelerate tissue repair or using Wnt pathway inhibitors to treat malignancies driven by over-activation of this signaling cascade [6, 8]. Sources: [1] UniProt (Q9HBX8); [2] Snippert et al. (2010) Science 327(5971):1385-9; [3] de Lau et al. (2011) Nature 476(7360):293-7; [4] Barker & Clevers (2010) CSH Perspect Biol 2(1):a003202; [5] Gong et al. (2012) PLoS ONE 7(5):e37137; [6] Surrozen Pipeline (SZN-1327); [7] OncoMed Pharmaceuticals (Rosmantuzumab); [8] Novartis (WNT974).

Other names

LGR6Leucine-rich repeat-containing G protein-coupled receptor 6

LGR6 functions as a co-receptor for R-spondins (RSPO1-4). Upon binding, the LGR6-RSPO complex sequesters the transmembrane E3 ubiquitin ligases ZNRF3 and RNF43, which normally target Wnt receptors (Frizzled) for degradation. This stabilization of Frizzled receptors on the cell surface enhances the cell's responsiveness to Wnt ligands, leading to the activation of the canonical Wnt/β-catenin signaling pathway and subsequent transcription of target genes involved in stem cell self-renewal and proliferation.