Dishevelled相分离对Wnt信号通路转导及功能影响的研究

Wnt信号调控发育及组织自稳态，其信号失调导致多种恶性疾病的发生。尽管Wnt信号转导的基本框架已搭建完成，但一些关键问题如Wnt信号刺激如何介导膜相关信号复合体的形成以及降解复合体的解聚，需要进一步探讨。Dishevelled (Dvl)蛋白是Wnt信号通路的关键成分，介导Wnt信号复合体的组装及降解复合体的解聚，但其机制并不清楚。我们前期研究结果表明Dvl2蛋白存在多段固有无序区，它在体内外均能够发生相分离，且阻碍Axin1相分离对降解复合体组装的促进作用。在本项目中，通过结合多领域的研究方法，我们将继续探讨Dvl2相分离的驱动机制，探究Dvl2相分离对Wnt信号复合体组装及破坏复合体解聚的影响及机制，并深入了解Dvl2相分离在Wnt信号转导中的调控作用及这种调控作用在胚胎发育中的功能。本项目将从新的层面（相分离）阐明Dvl在Wnt信号转导中重要功能，希望为相关的疾病治疗提供新的思路。

Wnt signaling controls embryonic development and tissue homeostasis. Its deregulation results in various diseases. Although the basic scheme of the Wnt signaling pathway has been established, some critical questions await further investigation, for instance, how Wnt stimulates the formation of the signalosome complex and causes dissociation of the degradation complex. Dishevelled (Dvl) functions as a principal component in the Wnt signaling pathway by mediating both the assembly of the signalosome complex and the disassembly of the degradation complex, but the mechanisms remain unclear. Our preliminary results suggest that Dvl2 undergoes phase separation both in vivo and in vitro, accompanied by suppressing assembly of degradation complex promoted by Axin phase separation. In this project, by combining multi-discipline approaches, we will continue to explore the detailed mechanism underlying the phase separation of Dvl2, determine the influence of Dvl2 phase separation in the assembly of the signalosome complex and the disassembly of the degradation complex, and gain a deep insight into the regulatory function of Dvl2 phase separation in Wnt signaling and its roles in embryonic development. The project will demonstrate the important function of Dvl2 in Wnt signaling transduction from a new perspective (phase separation), and hope to offer new insights for disease treatment.