EGFR异常活化与许多肿瘤发生发展密切相关，一直令人关心和困惑。近年人们发现其原因可能与EGFR下调障碍有关。TBC1D3癌蛋白包含细胞信号转导方面重要的TBC区域，在多种肿瘤中高表达，提示其功能可能对肿瘤某些信号途径的调节十分重要。有结果表明，TBC1D3干扰肿瘤细胞内Cbl募集，从而抑制EGFR下调，但其干扰Cbl募集的机制尚不清楚。β微管蛋白参与构成分子马达的轨道，对细胞内物质运输必不可少；还能结合Cbl，参与EGFR下调。我们前期研究表明，TBC1D3特异性结合β微管蛋白，抑制肿瘤细胞EGFR下调，而其不结合微管蛋白的变异体无此作用，提示TBC1D3可能通过结合微管蛋白，影响Cbl募集。本项目拟进一步阐明TBC1D3与微管蛋白相互作用对Cbl募集和EGFR下调以及肿瘤发生发展的影响及机制。该项目完成既有助于阐明肿瘤细胞EGFR下调机制，又对TBC1D3及微管蛋白功能研究有重要意义。

Scientists have been baffled by the fact that excessive activation of EGFR is involved in the development and progression of different cancer types. Recently, the problem was found to be correlated with the inhibition of EGFR down-regulation. TBC1D3 oncogene contains a TBC domain important in some cell signaling and is over-expressed in a variety of cancers, suggesting that TBC1D3 may play a critical role in regulation of some signal-transduction pathways in tumor cells. Some studies demonstrated that TBC1D3 suppressed the recruitment of c-Cbl, thereby resulting in the reduced ubiquitination and the delayed down-regulation of EGFR. However, the mechanisms are not clear so far. Beta-tubulin is necessary for vesicle trafficking in cells because it is an element of microtubules, which are used as tracks by some motor proteins. Moreover, beta-tubulin directly associates with c-Cbl, leading to EGFR down-regulation in cells. Preliminary results of the present study have demonstrated for the first time that TBC1D3 specifically interacted with beta-tubulin and inhibited EGFR down-regulation in tumor cells. However, the TBC1D3 mutant, which did not associate with beta-tubulin, had no impact on the EGFR level, suggesting that TBC1D3 might regulate the recruitment of c-Cbl via its interaction with beta-tubulin. Therefore, under the basis of the preliminary experiments related to TBC1D3, the present study aims to investigate the effect of TBC1D3 interaction with c-Cbl on the recruitment of c-Cbl and the down-regulation of EGFR as well as tumor development and progression. The completion of the study will contribute to the clarification of TBC1D3 and beta-tubulin functions as well as the mechanisms of EGFR down-regulation in tumor cells.