肝癌是目前严重威胁国人健康的恶性肿瘤，其转移则是影响肝癌患者预后的重要因素。肝细胞极性与动力学调控与肝癌细胞的浸润和转移密切相关，ARF6分子可塑性与功能在调控细胞极性运动力中作用关键，其相关分子机制研究意义重大。我们前期研究发现一个新的ARF6特异性GTP酶激活蛋白ACAP4。ACAP4在肝癌尤其是癌栓组织中的表达异常，但ARF6-ACAP4信号轴在调控肝癌细胞极性与迁移能力中的分子机制却不明了。本课题拟在我们前期工作基础上从肝癌细胞极性与动力学调控机制入手，利用化学生物学及生物光子学等研究手段，评估ACAP4的蛋白修饰与ARF6激酶相关功能，揭示ACAP4磷酸化如何促进肝癌细胞的极性改变和侵染性，阐明 ARF6-ACAP4信号轴调控在肝癌细胞浸润和转移中作用的分子机制，发现干预肝癌细胞转移的新靶点，为临床通过干预ACAP4修饰与活性抑制肝癌转移的治疗新策略提供理论和实验支撑。

Cell polarity (asymmetry) and motility has close relation with liver cancer cell invesion and metastasis.ARF6 ,a small GTPase,palys an critical role in in regulating cell polarity and motility. However, the underlying molecular mechaisms have remained elusive. We have identified a novel ARF6 specific regulating protien:ACAP4. ACAP4 is a specific GTPase activating protein for ARF6 GTPase and was identified as transcript that highly expressed in hepatocellular carcinoma (HCC). Further research revealed that ACAP4 played an important role in growth factor stimulated cytoskeleton regulation, cell polarity ,migration and invasion via EGF dependent phosphorylation and ARF6 plasticity modulation..The objectiive of this proposal is to delineate molecular mechanisms underlying ARF6 plasticity and function modulation in liver cancer cell polarity and metastasis. To this aim, we plan to identify the protein kinases that orchestrates ARF6-ACAP4 signaling and the underlying structural features. Successful accomplishment of the proposed studies will not only illustrate molecular mechanisms underlying HCC metastasis but also provide a novel niche for early intervention of HCC pogression and necessary platform technology for translation studies.