NUAK1介导LKB1信号通路与PTEN信号通路相互作用的分子机制

LKB1 and PTEN are both key cell signaling factors regulating cell proliferation, apoptosis, etc. Though reportedly LKB1 may regulate the activities of PTEN, how LKB1 pathway regualtes PTEN and interacts with PTEN pathway has long been a puzzle. Our previous study showed a possible direct interaction between NUAK1, the downstream kinase of LKB1, and PTEN. We thus hypothesize that LKB1 may regulate PTEN via the direct phosphorylation of PTEN by kinase NUAK1, which regulates the phosphatase activities and cellular localization of PTEN and triggers the crosstalk between LKB1 and PTEN pathways. The present study focuses on the novel functions of NUAK1 in LKB1 pathway and the crosstalk between LKB1 and PTEN pathways. By integrating Molecular and Cellular approaches, Biochemistry technologies, LC-MS/MS and protein crystallography, etc., we seek to answer the following questions: How does NUAK1, involved in the LKB1 pathway, regulate the activities and cellular localization of PTEN by direct interaction? How does the crosstalk between LKB1 and PTEN pathways affect multiple signaling factors regulated by PTEN? And what is the biological implication of these molecular regulations? Through this study we will elucidate the molecular mechanism of the regulation of PTEN signaling pathway, cell proliferation, apoptosis and migration by LKB1/NUAK1.

LKB1与PTEN均为调控细胞增殖与凋亡等的关键信号因子，尽管研究表明LKB1可能调控PTEN，对LKB1通路如何作用于PTEN并调控其下游信号通路仍未见报道。我们的前期研究发现LKB1的下游激酶NUAK1可能直接作用于PTEN，因此提出假说"NUAK1 可能通过直接磷酸化PTEN 介导LKB1对PTEN的调控，通过调节PTEN的磷酸酶活性和细胞定位而实现两条信号通路的交互"。本项目围绕NUAK1在LKB1通路中的新功能及LKB1通路与PTEN通路的相互作用展开研究，使用多种分子细胞生物学和生物化学研究手段及LC-MS/MS和蛋白晶体结构解析等技术回答以下科学问题：在LKB1的调控下NUAK1与PTEN是否存在直接相互作用及如何调节其磷酸酶活性和细胞定位？两条信号通路的相互作用对PTEN所调节的多个信号因子的功能有何影响及细胞生物学意义。从而揭示LKB1/NUAK1调控PTEN通路和调节细胞增殖、凋亡及迁移的分子机制。