RACK1调控Dishevelled蛋白和Wnt信号的分子机制与生理意义研究

项目名称： RACK1调控Dishevelled蛋白和Wnt信号的分子机制与生理意义研究

项目编号： No.31501144

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 生物科学

项目作者： 薛华

作者单位： 北京林业大学

项目金额： 21万元

中文摘要： Wnt信号通路在细胞增殖、器官发生、组织稳态维持中发挥着关键作用。作为Wnt通路的核心蛋白，Dishevelled (Dvl)的稳定性受到严格调控。在筛选与Dvl2相互作用的蛋白时，我们发现了一种多功能支架蛋白RACK1。前期结果显示，RACK1能促进Dvl2蛋白降解，且该现象在自噬条件下尤为显著。在本项目中，我们将综合运用多种生物学方法研究RACK1对Dvl2蛋白稳定性和Wnt信号的调控，并深入探讨分子机制和生理意义。研究内容包括：(1) 证实RACK1与Dvl2互作并促进Dvl2蛋白降解的现象，明确降解途径；(2) 基本阐明细胞自噬在RACK1降解Dvl2蛋白过程中的作用与分子机制；(3) 在结肠癌细胞和组织中探究RACK1调控Dvl2蛋白与Wnt信号的生理意义。我们希望本项目能丰富人们对Dvl蛋白和Wnt信号调控网络的认识，尤其对理解自噬条件下或肿瘤细胞中Wnt信号的调控有所帮助。

中文关键词： Wnt信号转导；信号分子Dishevelled；接头蛋白RACK1；蛋白质稳定性；蛋白质降解

英文摘要： Wnt signaling plays a crucial role in cell proliferation, organ morphogenesis and tissue homeostasis maintenance. As a key component of Wnt signalling pathway, the stability of Dishevelled(Dvl) protein is stringently regulated. In screening of Dvl2 interaction proteins, receptor for activated C kinase 1 (RACK1), a kind of multifunctional adaptor protein, was identified. Our previous data showed that RACK1 could promote Dvl2 degradation, and this phenomenon was much more obvious upon autophagy induction. In this project, we will investigate the regulation of Dvl2 stability and Wnt signaling by RACK1, and explore the underlying molecular mechanisms as well as physiological significance, with combinational use of multiple biology methods. Firstly, we will confirm that RACK1 interacts with Dvl2 and promotes Dvl2 degradation, and also distinguish the degradation pathway. Then more intrinsic evidance should be provided on how the stability of Dvl2 is regulated by RACK1 under autophagy condition. Finally, with the use of colon cancer cell lines and tumor tissues, we will investigate the physiological significance of regulation on Dvl stability and Wnt signalling by RACK1. The results of this project are expected to enrich our understanding on the regulation networks of Dvl proteins and Wnt signaling, especially to provide new insights into Wnt signalling modulation in autophagy condition or cancer cells.

英文关键词： Wnt signaling transduction;signaling molecule Dishevelled;adaptor protein RACK1;protein stability;protein degredation