LGR4 and Its Role in Intestinal Protection and Energy Metabolism

Abstract

Leucine-rich repeat-containing G protein-coupled receptors were identified by the unique nature of their long leucine-rich repeat extracellular domains. Distinct from classical G protein-coupled receptors which act via G proteins, LGR4 functions mainly through Wnt/β-catenin signaling to regulate cell proliferation, differentiation, and adult stem cell homeostasis. LGR4 is widely expressed in tissues ranging from the reproductive system, urinary system, sensory organs, digestive system, and the central nervous system, indicating LGR4 may have multiple functions in development. Here, we focus on the digestive system by reviewing its effects on crypt cells differentiation and stem cells maintenance, which are important for cell regeneration after injury. Through effects on Wnt/β-catenin signaling and cell proliferation, LGR4 and its endogenous ligands, R-spondins, are involved in colon tumorigenesis. LGR4 also contributes to regulation of energy metabolism, including food intake, energy expenditure, and lipid metabolism, as well as pancreatic β-cell proliferation and insulin secretion. This review summarizes the identification of LGR4, its endogenous ligand, ligand-receptor binding and intracellular signaling. Physiological functions include intestinal development and energy metabolism. The potential effects of LGR4 and its ligand in the treatment of inflammatory bowel disease, chemoradiotherapy-induced gut damage, colorectal cancer, and diabetes are also discussed.

Keywords: LGR4; R-spondin; colon cancer; diabetes; digestive system; energy metabolism.

Figure 1

Rspondin1-LGR4 linear sructure illustration. Linear structure of Rspondin1 and LGR4-ECD. Rspondin1 consists of a signal peptide (SP), two adjacent cysteine-rich furin-like domains (FU1/2), a common thrombospondin (TSP-1) motif and a basic amino acid-rich (BR) domain. LGR4 ectodomain (LGR4-ECD) are characterized by 17 leucine-rich repeats (LRRs) flanked by the N-terminal LRRNT region and the C-terminal LRRCT region. The main interacting residues of LGR4-ECD are LRR3-9 [refer to Ref. (4, 5) for detailed information].

Figure 2

LGR4-Wnt/β-catenin signaling pathway. In the absence of Rspos, membrane E3 ubiquitin ligases ZNRF3/RNF43 ubiquitinates the (Frizzled) FZD receptor for degradation, Wnt signaling activity is blunted. Cytoplasmic β-catenin is degradated by the β-catenin destruction complex, leading to no β-catenin complex formation with T-cell transcription factor (Tcf) and subsequent silence in active transcriptional response. In the presence of Rspos, simultaneous binding of LGR4 and ZNRF3 inhibits the ubiquitination of FZD receptor, meanwhile, LGR4 recruits IQGAP1 and increases its affinity to DVL, leading to the formation of supercomplex with Wnt signalosome. This allows β-catenin accumulation in cytoplasm, followed by translocation into the nucleus and activation of TCF target genes. LGR4, leucine-rich repeat-containing G protein-coupled receptors 4; ZNRF3, zinc and ring finger 3; FZD, Frizzled class receptor; Rspos, R-spondins; LRP5/6, low-density lipoprotein receptor-related protein 5/6; Ubi, ubiquitination; DVL, disheveled.