LGR4 and Its Role in Intestinal Protection and Energy Metabolism.

Michael W. Mulholland,Weizhen Zhang,Ziru Li

doi:10.3389/fendo.2015.00131

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.

Highlights

Leucine-rich repeat-containing G protein-coupled receptors (LGRs) are a distinct group of highly conserved proteins of the GPCRs family, characterized by a large extracellular domain that harbors multiple copies of leucine-rich repeats (LRRs) [1]
Xie et al reported that mutation of furin-like domain 1 (FU1) (R66A or Q71A) abolished the interaction between Rspo1 and ZNRF3, without affecting the interaction between Rspo1 and LGR4, while mutation of two residues of the furin-like domain 2 (FU2) (F106A or F110A) blocked the interaction between Rspo1 and LGR4, without affecting the interaction between Rspo1 and ZNRF3 [29]. These results suggest that Rspo1 binds to ZNRF3 and LGR4 through distinct domains: the FU1 domain is involved in ZNRF3 binding, whereas the FU2 domain is involved in LGR4 binding
Significant progress has been made in our understanding of how Rspo binds with LGR4 and regulates the Wnt signaling pathway at the molecular level, the following fundamental questions remain unanswered

Summary

Introduction

Leucine-rich repeat-containing G protein-coupled receptors (LGRs) are a distinct group of highly conserved proteins of the GPCRs family, characterized by a large extracellular domain (ectodomain) that harbors multiple copies of leucine-rich repeats (LRRs) [1]. In 2011, the secreted R-spondin proteins (Rspo1-4) were identified as the endogenous ligands for these receptors to regulate cell proliferation, differentiation, and adult stem cell maintenance through the activation of Wnt signaling pathways [13, 14]. In the presence of Rspos, simultaneous binding of LGR4 and ZNRF3 inhibits the ubiquitination of FZD receptor, 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. Human Rspo protein effectively increases survival and proliferation of LGR5+ intestinal stem cells in vitro through activation of Wnt/β-catenin signaling [63].

Maintenance of crypt stem cells

Findings

Conclusion