果蝇FRMD5调节Hippo信号通路活性与组织生长的分子机制研究

Hippo信号通路协同调控细胞增殖、生长、分化与凋亡，在组织器官发育以及稳态维持过程中发挥关键作用。Wts和Yki是Hippo信号通路的核心组分，其活性异常与肿瘤等疾病的发生发展密切相关。申请人实验室通过质谱分析，发现一个新的功能未知蛋白因子dFRMD5与Wts和Yki存在高信度潜在相互作用。前期免疫共沉淀实验验证了dFRMD5通过不同区域与Wts和Yki互作，并可形成dFRMD5/Wts/Yki三元复合体；而dFRMD5过表达则显著调节Wts和Yki的功能活性。本申请项目将以果蝇为模型，在体内体外确定dFRMD5/Wts/Yki三元复合体存在，阐明dFRMD5调节Wts/Yki活性参与组织生长的功能与分子机制。我们的研究将对阐明FRMD5的生理功能具有重要意义；同时，dFRMD5通过三元复合体调节Wts/Yki活性的全新机制亦将丰富人们对Hippo信号通路在动物发育与疾病发生过程的理解。

The Hippo signaling pathway plays key roles in organ size control and homeostasis through coordinating cell proliferation, cell growth, cell differentiation as well as cell death. As core components, the activities of Wts and Yki must be tightly regulated, and their dysfunction is implicated in human diseases such as cancers. Our IP-MS analysis in Drosophila S2 cells indicated that dFRMD5, a function unknown protein homologue to human FRMD5, was turned out to be a candidate associated with Wts and Yki. Our preliminary data from immunoprecipitation assays confirmed that dFRMD5 binds to Wts and Yki via different regions, and these 3 proteins may form a ternary complex. Genetic evidence further showed that dFRMD5 expression dramatically represses Wts and enhances Yki activity. Here we aim to demonstrate the complex assembly of dFRMD5/Wts/Yki in vitro and in vivo using Drosophila model, and elucidate the functional mechanism of this complex that regulates the Hippo pathway in animal development and human diseases. The expression of human FRMD5 is correlated to tumorigenesis but its molecular mechanism is unclear. Our studies will supply important implications to understand dFRMD5 and Hippo signaling under physiological and pathophysiological conditions.