Function and mechanism of LGR4 and LGR5 in modulation of Wnt signaling

LGR4和LGR5在Wnt信号传导中的功能和机制

• 批准号: 8519480
• 负责人: Qingyun Liu
• 金额: $ 28.24万
• 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 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8519480
• 关键词: Adult; Arrestins; Binding Proteins; Biological Assay; Biology; Cell Culture System; Cell Survival; Cell Therapy; Cell physiology; Cells; Chemosensitization; Coupled; Coupling; Defect; Degenerative Disorder; Deletion Mutation; Development; Embryo; Embryonic Development; Family; GTP-Binding Proteins; Gastrointestinal tract structure; Genes; Goals; Growth; Growth Factor; Hair follicle structure; Heterotrimeric GTP-Binding Proteins; Human; Human Activities; Intestines; Knock-out; Knowledge; Lactamase; Lead; Leucine-Rich Repeat; Ligand Binding; Ligands; Maintenance; Mammalian Cell; Maps; Membrane; Methods; Molecular; Monomeric GTP-Binding Proteins; Mus; Nail plate; Neonatal; Normal tissue morphology; Organ; Pathway interactions; Phosphorylation; Phosphotransferases; Play; Point Mutation; Population; Process; Proteins; Regenerative Medicine; Reporting; Research; Rhodopsin; Role; Sequence Homology; Series; Signal Pathway; Signal Transduction; Skin; Solid; Stem Cell Development; Stem cells; Structure-Activity Relationship; System; Testing; Therapeutic; Tissues; Transducers; Vertebrates; abstracting; adult stem cell; base; cell growth; design; human CCXCR1 receptor; insight; mutant; novel; protein protein interaction; receptor; repaired; screening; sex determination; stem; stem cell biology; success; therapeutic development

DESCRIPTION (provided by applicant): Function and mechanism of LGR4 and LGR5 in modulation of Wnt signaling Abstract LGR4 and LGR5 are two related receptors of the rhodopsin-like 7TM receptor superfamily. LGR5 is specifically expressed in the rapidly cycling crypt stem cells of the entire gastrointestinal tract and hair follicle stem cells in the bulge whie LGR4 is essential for survival of the crypt stem cells. Complete knockout of either LGR4 or LGR5 in the mouse leads total embryonic/neonatal lethality. Among the hundreds of 7TM receptors in the rhodopsin family, LGR4 and LGR5 are among the few that are essential for development. Just recently, we discovered that LGR4/5 function as ligands of R-spondins, a group of secreted proteins with vital functions in embryonic development, se determination, nail formation and growth of crypt stem cells. Activation of LGR4/5 by R-spondins were shown to robustly potentiate Wnt/b-catenin signaling, a system that is well known to be essential for development and for survival of stem cells. The discovery of R-spondins as ligand of LGR4/5 provides a molecular basis for stem cell-specific effect of the Wnt/b-catenin pathway and for the pleiotropic functions LGR4/5 and R- spondins has in development and stem cell survival. However, the exact functions and signaling mechanisms of the RSPO-LGR4/5 ligand-receptor system remain unknown. No evidence of LGR4/5 coupling to heterotrimeric G proteins or to b-arrestin was found. Thus LGR4/5 may have unique signal transducers and mechanisms that relay activation of LGR4/5 to increased Wnt/b-catenin signaling and thus differentiate them from hundreds of other rhodopsin-like receptors. In this proposal, we plan to identify and characterize the transducers and mechanisms of LGR4 and LGR5 using a variety of approaches. Understanding of the mechanism of LGR4 and LGR5 will provide important insights not only to the operating principles of stem cells, the molecular processes of sex determination and organ development but also to the general field of signal transduction.

描述(申请人提供)：LGR4和LGR5在Wnt信号调节中的功能和机制摘要LGR4和LGR5是视紫红质样7TM受体超家族的两个相关受体。LGR5特异性地表达于整个胃肠道快速循环的隐窝干细胞和隆起中的毛囊干细胞，而LGR4是隐窝干细胞生存所必需的。在小鼠中，完全敲除LGR4或LGR5会导致胚胎/新生儿的全部死亡。在视紫红质家族的数百种7TM受体中，LGR4和LGR5是为数不多的对发育至关重要的受体之一。就在最近，我们发现LGR4/5是R-Spinins的配体，R-Spinins是一组分泌蛋白，在胚胎发育、Se测定、指甲形成和隐窝干细胞的生长中具有重要功能。研究表明，R-Spaindins激活LGR4/5可以有力地增强Wnt/b-catenin信号转导，而Wnt/b-catenin信号转导系统对于干细胞的发育和存活至关重要。作为LGR4/5配体的R-Spinins的发现为Wnt/b-catenin途径的干细胞特异性作用以及LGR4/5和R-Spinins在发育和干细胞存活中所具有的多效性功能提供了分子基础。然而，RSPO-LGR4/5配体-受体系统的确切功能和信号机制仍不清楚。未发现LGR4/5与异三聚体G蛋白或b-arrestin偶联的证据。因此，LGR4/5可能具有独特的信号转导和机制，将LGR4/5的激活传递给增加的Wnt/b-catenin信号，从而将它们与数百种其他视紫红质样受体区分开来。在这项提案中，我们计划使用各种方法来鉴定和表征LGR4和LGR5的转导和机制。了解LGR4和LGR5的机制不仅对干细胞的工作原理、性别决定和器官发育的分子过程，而且对一般的信号转导领域都有重要的意义。