连接蛋白lrap35a调节Wnt信号通路和细胞运动的作用机理

项目名称： 连接蛋白lrap35a调节Wnt信号通路和细胞运动的作用机理

项目编号： No.31471360

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 生物科学

项目作者： 石德利

作者单位： 山东大学

项目金额： 88万元

中文摘要： 已有的体外研究显示连接蛋白lrap35a通过结合并激活MRCK参与调节细胞的运动，但它在胚胎发育过程中的功能还没有报道。我们的工作首次发现lrap35a能与Wnt通路重要成员Dishevelled相结合并能抑制其激活经典Wnt信号的活性。在斑马鱼中靶向敲除lrap35a显示突变体胚胎的下包运动延迟，说明它在早期发育中有重要作用。本项目将依据这些工作基础在斑马鱼中深入研究lrap35a在胚胎发育过程中调节经典和非经典Wnt信号的机制，确定它在原肠作用过程中调节各种细胞行为的作用。我们还将通过解决lrap35a与其结合蛋白的相互作用如何调节胚胎细胞的运动能力和极向这个关键问题，来达到进一步阐明形态发生运动调控网络和分子机制的目标。这项研究将有助于鉴别出在发育过程中调节不同Wnt信号通路和细胞定向运动的新成员以及新机理，其成果能为了解人类疾病的病因和采取干预手段等方面提供有价值的线索。

中文关键词： lrap35a；细胞运动；Dishevelled；Wnt信号；斑马鱼

英文摘要： It was shown that leucine repeat adaptor protein 35a (lrap35a) regulates cell protrusion and migration through binding to and activation of MRCKα and MRCK? (Myotonic dystrophy Kinase-related Cdc42-binding Kinase αand ?). However, whether and how it plays a role during early development is actually not known. We have recently made the interesting finding that lrap35a physically interacts with Dishevelled (Dsh or DVL), a key component of both canonical and non-canonical Wnt signaling pathways. In addition, it is also able to modulate the activity of Dsh in canonical Wnt signaling. Talen-mediated disruption of lrap35a gene in zebrafish indicates that mutation of lrap35a affects epiboly movement, suggesting that it may be required for cell movements during gastrulation in zebrafish embryo. Based on these observations, we plan first to determine how lrap35a regulates the activation of canonical and non-canonical Wnt pathways, we will also analyze how it is involved in the regulation of different cell behaviors during gastrulation, such as epiboly, cell adhesion and migration, and convergence and extension. The main objective of our study is to understand how the interaction between lrap35a and its partners, such as Dsh and MRCK, as well as other novel proteins that we plan to identify in this project, regulates the ability and polarity of movement cells in the whole embryo. Furthermore, our results should help to provide insight into the regulatory network operating in morphogenesis. We also expect to uncover novel regulators of Wnt signaling pathway, and novel mechanism that controls cell movements. Since the protein partners of lrap35a, such as Dsh and MRCK, are implicated in tumorigenesis and cancer cell invasion, our results may be also potentially important for a better understanding of human diseases and should have a broad impact on developmental biology and medicine.

英文关键词： lrap35a;cell movement;Dishevelled;Wnt signaling;zebrafish