Emerging Roles for LGR4 in Organ Development, Energy Metabolism and Carcinogenesis.

Linlin Yang,Jing Wang,Yuhong Li,Xiaodi Gong,Lijuan Li,Xiaoyan Gao,Qiong Fan,Yudong Wang,Xiao Sun,Yunxia Cui,Xiaoming Yang

doi:10.3389/fgene.2021.728827

Abstract

The leucine-rich repeats containing G protein-coupled receptor 4 (LGR4) belonging to G protein-coupled receptors (GPCRs) family, had various regulatory roles at multiple cellular types and numerous targeting sites, and aberrant LGR4 signaling played crucial roles in diseases and carcinogenesis. On the basis of these facts, LGR4 may become an appealing therapeutic target for the treatment of diseases and tumors. However, a comprehensive investigation of its functions and applications was still lacking. Hence, this paper provided an overview of the molecular characteristics and signaling mechanisms of LGR4, its involvement in multiple organ development and participation in the modulation of immunology related diseases, metabolic diseases, and oxidative stress damage along with cancer progression. Given that GPCRs accounted for almost a third of current clinical drug targets, the in-depth understanding of the sophisticated connections of LGR4 and its ligands would not only enrich their regulatory networks, but also shed new light on designing novel molecular targeted drugs and small molecule blockers for revolutionizing the treatment of various diseases and tumors.

Highlights

The leucine-rich repeat-containing G protein-coupled receptors (LGRs) are highly conserved proteins of the G protein-coupled receptors (GPCRs) family, identified as multiple repeats of leucine-rich repeats (LRRs) in the extracellular domain (Luo and Hsueh, 2006)
leucine-rich repeats containing G protein-coupled receptor 4 (LGR4) is a transmembrane receptor of the GPCRs superfamily that is characterized by a large extracellular Leucine-rich domain that recognizes and interacts with its ligands (Van Loy et al, 2008), regulating numerous cellular processes (Figure 1)
LGR4 was believed to be a novel receptor for RANKL, it could induce the cyclic AMP (cAMP)-protein kinase A (PKA)-cre-binding protein (CREB) signaling to control the expression of Atf4 and its target genes Ocn, Bsp and collagen in osteoblasts

Summary

INTRODUCTION

The leucine-rich repeat-containing G protein-coupled receptors (LGRs) are highly conserved proteins of the G protein-coupled receptors (GPCRs) family, identified as multiple repeats of leucine-rich repeats (LRRs) in the extracellular domain (Luo and Hsueh, 2006). LGR4 signaling plays a functional role in self-renewal of stem cells by binding to R-spondin, potentiating Wnt signaling. LGR4, as a new RANKL receptor, could counteract RANKL-driven osteoclastogenesis and enhance osteoblast maturation, mineralization (Luo et al, 2016) and vascular calcifcation (Carrillo-López et al, 2020). It plays an oncogenic role in various human cancers, such as multiple myeloma (van Andel et al, 2017), thyroid carcinoma (Kang et al, 2017), and ovarian cancer (Wang Z. et al, 2020), etc. This paper will systematically summarize LGR4’s role in organ development, energy metabolism and tumor formation, which may provide the fundamental basis for the targeted gene therapy in the future

METHODS

DISCUSSION AND FUTURE