失巢凋亡抵抗特性是肿瘤细胞从原发部位向远处组织播散的先决条件和关键步骤，但是目前肿瘤细胞失巢凋亡抵抗的确切分子机制仍不清楚。申请人首次报道了EGFR通路活化促进TRAF6自身泛素化介导的肿瘤失巢凋亡抵抗新机制，并且发现TRAF6与XIAP的相互作用在此过程中发挥重要作用。在此基础上，申请人提出“EGFR信号引起TRAF6蛋白的卷曲螺管样结构域关键氨基酸的磷酸化修饰，促进TRAF6与XIAP的相互结合以及TRAF6自身泛素化水平增加，从而激活NF-κB，赋予肿瘤细胞规避失巢凋亡能力”的科学假说。本项目拟聚焦研究EGFR如何磷酸化TRAF6，引起其蛋白构象变化、促进TRAF6-XIAP结合和对凋亡抑制通路的影响，以期揭示EGFR-TRAF6/XIAP-NF-κB信号轴在肿瘤细胞逃避失巢凋亡过程中的作用规律和生物学效应，为新型肿瘤转移靶向治疗策略的研发提供关键实验证据。

Anoikis resistance is a key and prerequisite step for the dissemination of metastatic tumor cells from the primary site to the distant tissue. However, the molecular mechanism underlining anoikis resistance remains unclear. Previously, we reported a new regulatory mechanism by which EGFR signaling promotes TRAF6 autoubiquitination and mediates tumor anoikis resistance. The interaction of TRAF6 with XIAP plays an important role in this process. We therefore proposed a novel anoikis-resistance hypothesis that "EGFR signaling, which causes phosphorylation of key amino acid residues in the Coiled coil domain of TRAF6 protein, promotes the binding of TRAF6 and XIAP proteins, and increases the level of self-ubiquitination of TRAF6, thereby activating NF-κB signaling pathway”. In this study, we will focuse on the study of EGFR-catalyzed phosphorylation of TRAF6, causing its conformational changes, promoting TRAF6-XIAP protein binding, and its effects on apoptosis-inhibiting pathways. This study is capable to reveal the role of EGFR-TRAF6/XIAP-NF-κB signal axis in the process of tumor cell evasion and anoikis, and provid direct experimental evidence for the development of novel tumor metastasis targeted therapy strategy.