平面细胞极化蛋白Frizzled6在早期分泌转运途中运输的分子机制

平面细胞极化（PCP）在生长发育过程中有很重要的作用。PCP受一组PCP核心蛋白调控。新合成的跨膜的PCP蛋白沿着分泌转运途径被传递至质膜，而后在质膜上执行其生理功能。但是其运输机制仍然大部分未知。此外，许多PCP蛋白彼此相互作用。然而这些相互作用是否调控PCP蛋白的运输未知。本课题研究PCP蛋白Frizzled6(Fzd6)从内质网运输到高尔基体的分子机制（目标1），探索与Fzd6有相互作用的PCP蛋白Celsr1在调节Fzd6的表面运输中的功能（目标2），并且揭示调节Fzd6从内质网向高尔基体转运的其他因子（目标3）。最后，我们将验证这些因子是否参与平面细胞极化介导的生理过程（目标4）。 我们的研究将为Fzd6早期分泌转运途径的机制提供新的见解。此外，我们的分析将指导通过阻断PCP蛋白的胞内运输来下调PCP信号传导的抑制剂的合理设计，为治疗平面细胞极化失调导致的疾病提供一条新途径。

Planar cell polarity (PCP), a process in which cells are polarized along the plane of the epithelium, plays important roles in developmental processes and defects of PCP are associated with a variety of human diseases including cancer metastasis. The establishment of PCP is regulated by a group of evolutionary conserved transmembrane core PCP components including Frizzled (Fzd) and members in the family of cadherin EGF LAG seven-pass G-type receptor (Celsr). After their synthesis, these PCP proteins are delivered along the secretory transport pathway to the plasma membrane, where they perform their physiological functions. Currently, the molecular mechanism regulating delivery of PCP proteins along the secretory transport pathway remains unclear. Moreover, many PCP proteins interact with each other. However, it remains unclear as to how these interactions also regulate the surface delivery process of PCP proteins. . Here, we propose to investigate how a PCP core protein, Fizzled6, is delivered from the endoplasmic reticulum (ER) to the Golgi in the early secretory transport pathway. We will elucidate coat protein complex II (COPII)-mediated ER export of Frizzled6 (Aim 1), analyze the functional roles of Celsr1, another PCP protein that interacts with Fzd6, in regulating the surface delivery of Frizzled6 (Aim 2), reveal and characterize additional factors that regulate ER-to-Golgi delivery of Frizzled6 (Aim 3), and test whether the identified protein factors are important for the propagation of PCP in Drosophila wing (Aim 4). Our study will provide novel insight into the molecular machinery that regulates transport of Fzd6 in the early secretory transport pathway. The stoichiometry of PCP proteins on cell boundaries are important for establishing the asymmetric localization of PCP proteins. Our study also provides analysis to test whether that the association of Celsr1 with Frizzled6 is important to allow Frizzled6 to be efficiently delivered to the cell surface, providing a novel quality control mechanism to ensure the stoichiometry of these two PCP proteins on cell boundaries. Moreover, these studies will aid in the design of mechanism-based inhibitors to down-regulate PCP signaling by inhibiting biosynthetic trafficking of PCP proteins, which will provide a novel therapeutic strategy.