ELMO1/DOCK1复合体激活Rac1促进恶性肿瘤细胞侵袭和转移的分子机制研究

肿瘤细胞的侵袭和转移是肿瘤患者复发和死亡的最主要原因，前期的研究已表明ELMO1和DOCK1 与肿瘤细胞的侵袭转移高度相关。支架蛋白ELMO1通过与DOCK1相互作用，并激活DOCK1的鸟苷酸转换因子活性，促进下游Rac1的活化，从而增强肿瘤细胞侵袭转移的能力。但ELMO1和DOCK1在静息状态下都处于自抑制状态，两者如何通过相互作用诱导自抑制状态解开的分子机制及其复合物的组装模式还不清楚。申请人在获得分辨率为5.6Å的ELMO1自抑制三维结构的基础上，希望通过结构生物学、生物化学和细胞生物学的方法，进一步解析ELMO1和DOCK1的自抑制状态和复合物活性状态的精细三维结构，并利用肺癌和肝癌细胞株研究其促进肿瘤细胞侵袭转移的分子机制。项目成果将为进一步了解肿瘤细胞侵袭转移的分子机制提供结构信息，并为疾病诊疗提供潜在的靶点。

The invasion and metastasis of tumor cells are the main causes of tumor recurrence and death. Previous studies have shown that ELMO1 and DOCK1 are highly correlated with the the invasion and metastasis of tumor cells. The scaffold protein ELMO1, by interacting with DOCK1 and activating its GTP exchange factor activity, promotes the activation of Rac1, thus enhancing the ability of invasion and metastasis of tumor cells. However, both ELMO1 and DOCK1 are in auto-inhibition in the resting state. It is not clear how they interact with each other and then induce the change of auto-inhibition conformation. Here, we have determined the ELMO1 auto-inhibition structure in 5.6Å. We further aim to study the molecular details of ELMO1/DOCK1 complex and their three-dimensional structures in different conformations, combing biochemical and structural methods. In addition, we will explore the function of ELMO1/DOCK1 complex in regulating the invasion and metastasis of lung cancer and liver cancer cell. We hope that our structural and biochemical discoveries will largely improve our understanding the molecular basis of tumor cell invasion and metastasis, as well as new insight for the diagnosis and treatment of related diseases.