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

项目名称：LGR 4和LGR 5在Wnt信号转导中的功能和机制 摘要 LGR 4和LGR 5（富含亮氨酸重复的G蛋白偶联受体4和5）是两种 视紫红质样7 TM受体超家族的相关受体，在 发育和肿瘤发生。LGR 4的杂合突变与几种 而在小鼠中完全敲除LGR 4导致胚胎致死， 几个器官发育不全和小管发育缺陷。LGR 5是目前最受认可的 胃肠道和其他上皮组织中成体干细胞的标志物，尽管它是 对LGR 5阳性干细胞的自我更新不是必需的。我们和其他人发现， LGR 4/5作为R-脊椎蛋白（RSPO）的受体发挥作用以增强Wnt信号传导。RSPO是一个 一组四种相关的分泌蛋白（RSPO 1 -4），在器官发育中具有不同的作用， 干细胞的存活最近，鉴定了RSPO 2和RSPO 3的复发性基因融合 在结肠癌和前列腺癌的一个子集中。RSPO作为LGR 4/5配体的发现 为Wnt信号传导的干细胞特异性作用和Wnt信号传导的细胞周期调控提供了分子基础。 LGR 4/5和R-spondin在发育、干细胞存活和分化中具有多效性功能 肿瘤发生尽管含有GPCR的视紫红质家族典型的7 TM结构域， RSPO对LGR 4/5的模拟不会导致异源三聚体G蛋白或β-半乳糖苷酶的激活。 抑制素。相反，RSPO-LGR 4通过两种途径增强Wnt信号传导，抑制Wnt信号传导。 泛素连接酶降解Wnt受体和募集支架蛋白IQGAP 1， 协调Wnt信号传导。然而，RSPO的确切作用和信号传导机制- LGR 4/5系统在调节干细胞适应性和Wnt信号转导方面仍然很差 明白在本提案中，我们将实现三个目标，剖析RSPO、LGR 4/5和 IQGAP 1相互作用调节其下游介质，以识别和表征 LGR 5在调节细胞-细胞粘附和干细胞适应性中的功能和机制， 并阐明RSPO-LGR 4激活增强Wnt信号传导的机制。 结果和结论不仅将为指导原则提供重要的见解， Wnt信号传导和干细胞存活的研究，而且还发现和开发了新的 再生医学和癌症治疗的治疗方法。

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.