可逆磷酸化修饰是信号调控基础，但靶向激酶TKI耐药的磷酸酶调控方式缺乏认识。SHP2是EGFR下游关键信号分子，也是酪氨酸磷酸酶家族最明确的原癌基因。临床研究显示SHP2在肺癌中高表达，抑制SHP2活化可促进肺癌的TKI增敏，但分子机制与生化基础不明确。我们新近鉴定了锚定蛋白Hook1，可与SHP2活化基团直接结合, 形成自抑制SHP2-Hook1复合物；TGFβ1刺激可导致该复合物解聚，促进上皮间质转化形成耐药。上述体外证据表明SHP2-Hook1在EGFR-TKI耐药进程中可能具重要价值。基于此，本课题首先确立SHP2-Hook1与TKI临床耐药的相关性，同时运用已构建SHP2E76K转基因小鼠和Hook1敲除动物模型，明确SHP2-Hook1参与EMT、EGFR内化及其耐药调控的生理学意义。预期成果有助于理解EGFR-TKI耐药的磷酸酶作用新途径，为肺癌精准化疗提供新思路和实验依据。

Reversible protein phosphorylation is the foundation of signaling regulation, but the mechanism of TKI resistance regulated by phosphatase still remains unknown. SHP2 is an important signaling molecular in the downstream of EGFR, and it is also the best studied oncogene in tyrosine phosphatase family. Clinical studies have showed that SHP2 is over-expressed in lung cancer, and the sensitivity to TKI can be increased by inhibiting the activation of SHP2, but its molecular mechanism and biochemical basis are not clear. Our previous studies have just identified an ankyrin--Hook1, which can directly bind to SHP2 activation group to form SHP2-Hook1 complex that is autoinhibitory. TGFβ1 can stimulate the disaggregation of this complex, induce epithelial-mesenchymal transition and contribute to drug resistance. These in vitro studies suggest that SHP2-Hook1 plays an important role in EGFR-TKI resistance. Therefore, the task of this study is to explore the correlation between SHP2-Hook1 and EGFR-TKI resistance, and then to explicit the physiological significance of SHP2-Hook1 in EMT and EGFR internalization using SHP2E76K transgenic mouse model and Hook1 knockout model. Our research will help to clarify how phosphatase regulating EGFR-TKI resistance, which will bring new idea and experimental data for cancer targeting therapy.