Duan Biao, Cui Jie, Sun Shixiu, Zheng Jianchao, Zhang Yujie, Ye Bixing, Chen Yan, Deng Wenjie, Du Jun, Zhu Yichao, Chen Yongchang, Gu Luo
Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu 210029, China; Department of Physiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
Cancer Lett. 2016 Aug 28;379(1):70-83. doi: 10.1016/j.canlet.2016.05.027. Epub 2016 May 26.
Non-small cell lung cancer (NSCLC) remains one of the most metastasizing tumors, and directional cell migration is critical for targeting tumor metastasis. GIT2 has been known to bind to Paxillin to control cell polarization and directional migration. However, the molecular mechanisms underlying roles of GIT2 in controlling cell polarization and directional migration remain elusive. Here we demonstrated GIT2 control cell polarization and direction dependent on the regulation of Golgi through RUSC2. RUSC2 interacts with SHD of GIT2 in various lung cancer cells, and stabilizes GIT2 (Mazaki et al., 2006; Yu et al., 2009) by decreasing degradation and increasing its phosphorylation. Silencing of RUSC2 showed reduced stability of GIT2, defective Golgi reorientation toward the wound edge and decreased directional migration. Moreover, short-term EGF stimulation can increase the interaction between RUSC2 and GIT2, prolonged stimulation leads to a decrease of their interaction through activating Rab35. Silencing of Rab35 also reduced stability and phosphorylation of GIT2 and decreased cell migration. Taken together, our study indicated that RUSC2 participates in EGFR signaling and regulates lung cancer progression, and may be a new therapeutic target against lung cancer metastasis.
非小细胞肺癌（NSCLC）仍然是最易发生转移的肿瘤之一，细胞定向迁移对于靶向肿瘤转移至关重要。已知GIT2与桩蛋白结合以控制细胞极化和定向迁移。然而，GIT2在控制细胞极化和定向迁移中作用的分子机制仍不清楚。在这里，我们证明GIT2通过RUSC2对高尔基体的调节来控制细胞极化和方向。RUSC2在各种肺癌细胞中与GIT2的SHD相互作用，并通过减少降解和增加其磷酸化来稳定GIT2（Mazaki等人，2006年；Yu等人，2009年）。RUSC2的沉默显示GIT2的稳定性降低，高尔基体向伤口边缘的重新定向缺陷以及定向迁移减少。此外，短期表皮生长因子（EGF）刺激可增加RUSC2与GIT2之间的相互作用，长期刺激通过激活Rab35导致它们的相互作用减少。Rab35的沉默也降低了GIT2的稳定性和磷酸化，并减少了细胞迁移。综上所述，我们的研究表明RUSC2参与表皮生长因子受体（EGFR）信号传导并调节肺癌进展，可能是对抗肺癌转移的新治疗靶点。
