ACK1介导的受体酪氨酸激酶信号在肿瘤发生发展中的作用

Amplification and overexpression of the non-receptor tyrosine kinase ACK1 have been linked to progression and relapse of multiple cancers, including lung, breast and prostate cancers. However, the role of ACK1 in tumor genesis and progression remains elusive. Our recent studies have found that ACK1 stimulates tyrosine phosphorylation of EGFR by binding to EGFR kinase domain via the EGFR-binding domain (EBD) and mediates EGF-promoted cancer cell migration and scattering. The ACK1-interactive residues in EGFR kinase domain are conserved in many other receptor tyrosine kinases (RTKs), raising the possibility that ACK1 may interact with other RTKs as well and function as an universal regulator of RTK tyrosine phosphorylation and the RTK-promoted cell migration and scattering signaling. Thus, the role of ACK1 in tumor progression and relapse is likely to be supported through regulating the RTK tyrosine phosphorylation signaling, in particular the EGFR and c-Met tyrosine phosphorylation signaling. Based on the rationale, this project sets to investigate the molecular mechanism by which ACK1 regulates EGFR and c-Met tyrosine phosphorylation, determine the ACK1-mediated EGFR and c-Met down-stream signaling, particularly the cancer cell migration and scattering signaling pathways, and examine the effect of ACK1 on EGFR- and c-Met-dependent cancer cell metastasis in a tumor cell xenograft nude mouse model. Through these studies, we expect to define the role of ACK1 in the RTK-promoted tumor genesis and progression, forward our understanding of the molecular mechanism underlying cancer cell migration and scattering, and validate ACK1 as a new cancer therapeutic target molecule.

酪氨酸激酶ACK1的基因扩增和过表达与肿瘤的发展和复发有密切相关性。但其分子机理仍不清楚。我们发现ACK1与EGFR结合并激活EGFR的酪氨酸磷酸化。敲除ACK1抑制 EGFR介导的癌细胞迁移和扩散。EGFR与ACK1相互作用的基团亦保守存在于其它的受体酪氨酸激酶中，暗示ACK1很可能是一个受体酪氨酸激酶通用的磷酸化调节蛋白。我们的实验也证明ACK1能与c-Met、ErbB2等多个受体酪氨酸激酶结合。因此我们推测ACK1在肿瘤发展和复发中的作用是通过调节受体酪氨酸磷酸化来实现的。本项目将系统研究ACK1调节受体酪氨酸激酶EGFR和c-Met磷酸化的分子机制以及ACK1介导的EGFR和c-Met促癌细胞迁移、扩散和转移信号。通过这些研究，我们期望阐明ACK1对EGFR和c-Met磷酸化及其下游信号的调节机理和确定ACK1在EGFR和c-Met的促癌细胞迁移、扩散与转移信号中的作用。

本项目旨在通过非受体酪氨酸激酶ACK1（亦称TNK2）在肺癌细胞中对受体酪氨酸激酶EGFR（Epidermal growth factor receptor, 表面生长因子受体）磷酸化信号调节机理的研究，确定ACK1/EGFR磷酸化以及相关联的信号途径在肺癌发生发展中的作用。经过四年的努力探索，我们基本完成了设定目标和研究内容，并取得了突破性的研究成果。我们的研究突破主要包括以下五个方面：（1）发现了ACK1高度磷酸化EGFR突变体并促进EGFR突变体肺癌细胞的恶性生长。（2）揭示和确定了ACK1激活泛素连接酶WWP2的分子机理。（3）发现了新的EGFR促肺癌细胞迁移信号途径。（4）发现了与ACK1相互作用的泛素连接酶NEDD4在肺癌细胞自噬中的重要调节作用。（5）揭示和确定了应激反应诱导的EGFR内吞和降解的分子机理。另外，我们发现Hippo-YAP/TAZ信号途径的目标基因产物CYR61是贲门癌转移的重要驱动蛋白和标志分子。本项目共发表SCI学术论文7篇，获得发明专利授权一项、申请专利一项。同时本项目培养了研究生7名，其中博士研究生4名，硕士研究生3名。