Function and mechanism of LGR4 and LGR5 in Modulation of Wnt Signaling

LGR4和LGR5在Wnt信号传导调节中的功能和机制

• 批准号: 9762122
• 负责人: Qingyun Liu
• 金额: $ 30.03万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9762122
• 关键词: Ablation; Actins; Affinity; Architecture; Arrestins; Binding; Biology; Cancer cell line; Cell Adhesion; Cell Line; Cell Survival; Cell physiology; Cell-Cell Adhesion; Cells; Cessation of life; Chemosensitization; Colon Carcinoma; Complement; Complex; Cytoskeleton; Defect; Development; Disease; Embryo; Enzymes; Epithelial; Extracellular Domain; Family; Foundations; Funding; G-Protein-Coupled Receptors; GPR4 gene; Gastrointestinal tract structure; Gene Fusion; Genes; Goals; Growth Factor; Heterotrimeric GTP-Binding Proteins; Human; IQ motif containing GTPase activating protein 1; In Vitro; Intestines; Knock-out; Knowledge; LGR5 gene; LRRC17 gene; Laboratories; Leucine-Rich Repeat; Ligands; Maintenance; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Mediator of activation protein; Mitogen-Activated Protein Kinases; Molecular; Mus; Mutation; Normal tissue morphology; Organ; Organ Survival; Organoids; Pathway interactions; Phosphoric Monoester Hydrolases; Phosphorylation; Physiological; Play; Protein Dephosphorylation; Proteins; Receptor Signaling; Recurrence; Regenerative Medicine; Regulation; Reporting; Research; Rhodopsin; Role; Scaffolding Protein; Signal Transduction; Stem Cell Factor; Stem cells; Structure; System; Testing; Tissues; Transducers; Translating; WNT Signaling Pathway; Work; adult stem cell; bench to bedside; beta catenin; cancer cell; cancer therapy; cell motility; design; fitness; human disease; in vivo; insight; intestinal crypt; knock-down; new therapeutic target; novel therapeutics; null mutation; organ growth; overexpression; public health relevance; receptor; receptor binding; recruit; repaired; self-renewal; simulation; therapeutic development; tumorigenesis; ubiquitin ligase; ubiquitin-protein ligase

Project title: Function and mechanism of LGR4 and LGR5 in modulation of Wnt signaling Abstract LGR4 and LGR5 (leucine-rich repeat containing G protein-coupled receptor 4 and 5) are two related receptors of the rhodopsin-like 7TM receptor superfamily with critical roles in development and oncogenesis. Heterozygous mutation of LGR4 is associated with several human diseases while complete knockout of LGR4 in mice leads to embryonic lethality with hypoplasia and defective tubulogenesis in several organs. LGR5 is now the most recognized marker of adult stem cells in the gastrointestinal tract and other epithelial tissues, although it is not essential for the self-renewal of LGR5-positive stem cells. We and others discovered that LGR4/5 function as receptors of R-spondins (RSPOs) to potentiate Wnt signaling. RSPOs are a group of four related secreted proteins (RSPO1-4) with distinct roles in organ development and survival of stem cells. Recently, recurrent gene fusions of RSPO2 and RSPO3 were identified in a subset of colon and prostate cancers. The discovery of RSPOs as ligand of LGR4/5 provides a molecular basis for stem cell-specific effect of the Wnt signaling and for the pleiotropic functions that LGR4/5 and R-spondins have in development, stem cell survival, and oncogenesis. Despite containing a 7TM domain typical of the rhodopsin family of GPCRs, simulation of LGR4/5 by RSPOs does not lead to activation of heterotrimeric G proteins or - arrestin. Instead, RSPO-LGR4 potentiates Wnt signaling via two pathways, inhibition of ubiquitin ligases that degrade Wnt receptors and recruitment of the scaffold protein IQGAP1 that coordinate Wnt signaling. However, the exact roles and signaling mechanisms of the RSPO- LGR4/5 system in the regulation of stem cell fitness and Wnt signaling remain poorly understood. In this proposal, we will carry out three aims to dissect how RSPO, LGR4/5, and IQGAP1 interact to regulate their downstream mediators, to identify and characterize the function and mechanism of LGR5 in the regulation of cell-cell adhesion and stem cell fitness, and to delineate the mechanisms of RSPO-LGR4 activation in potentiation of Wnt signaling. The results and conclusions will provide important insights not only into the governing principles of Wnt signaling and stem cell survival but also the discovery and development of novel therapeutics in regenerative medicine and cancer treatment.

项目名称：LGR4和LGR5在Wnt信号调制中的作用和机制 摘要 LGR4和LGR5(富含亮氨酸重复序列，包含G蛋白偶联受体4和5)是两个 视紫红质样7TM受体超家族相关受体在细胞周期调控中的作用 发育和肿瘤发生。LGR4杂合突变与几个 人类疾病，而在小鼠中完全敲除LGR4会导致胚胎死亡 几个器官的发育不全和小管生成缺陷。LG5现在是最受认可的 胃肠道和其他上皮组织中的成体干细胞的标记，尽管它是 对LGR5阳性干细胞的自我更新不是必需的。我们和其他人发现 LGR4/5作为R-Spin(RSPO)的受体，增强Wnt信号转导。RSPO是一个 四组相关的分泌蛋白(Rspo1-4)，在器官发育和 干细胞的存活。最近，rspO2和rsp3的复发基因融合被鉴定出来。 在结肠癌和前列腺癌的子集中。作为LGR4/5配体的RSPO的发现 为Wnt信号转导的干细胞特异性效应提供了分子基础 LGR4/5和R-Spinins在发育、干细胞存活和 致癌作用。尽管含有典型的GPCR视紫红质家族的7TM结构域， RSPOS对LGR4/5的模拟不会导致异源三聚体G蛋白或- 阿瑞斯汀。相反，RSPO-LGR4通过两条途径增强Wnt信号，抑制 降解Wnt受体的泛素连接酶和支架蛋白IQGAP1的募集 协调WNT信令。然而，RSPO的确切作用和信号机制- LGR4/5系统在调节干细胞适合性和Wnt信号中的作用仍然很差 明白了。在这项提案中，我们将实现三个目标，以剖析RSPO、LGR4/5和 IQGAP1相互作用以调节其下游介体，以识别和表征 LGR5在调节细胞间黏附和干细胞适合性中的作用和机制 并探讨RSPO-LGR4激活在Wnt信号增强中的作用机制。 结果和结论不仅将为指导原则提供重要的见解 研究Wnt信号与干细胞存活的同时也发现和发展了新的 再生医学和癌症治疗的治疗学。