Adams Gregory, Zhou Jiajia, Wang Wenwen, Wu Huihui, Quan Jie, Liu Yingying, Xia Peng, Wang Zhikai, Zhou Shu, Jiang Jiying, Mo Fei, Zhuang Xiaoxuan, Thomas Kelwyn, Hill Donald L, Aikhionbare Felix O, He Ping, Liu Xing, Ding Xia, Yao Xuebiao
From the BUCM-MSM Joint Research Group for Cellular Dynamics, BUCM School of Basic Medical Sciences, and Anhui Key Laboratory for Cellular Dynamics and Chemical Biology, University of Science and Technology of China, Hefei, Anhui 230026, China, the Departments of Physiology and.
From the BUCM-MSM Joint Research Group for Cellular Dynamics, BUCM School of Basic Medical Sciences, and Anhui Key Laboratory for Cellular Dynamics and Chemical Biology, University of Science and Technology of China, Hefei, Anhui 230026, China.
J Biol Chem. 2016 Sep 23;291(39):20692-706. doi: 10.1074/jbc.M116.732719. Epub 2016 Jul 22.
Cell migration is orchestrated by dynamic interactions of microtubules with the plasma membrane cortex. How these interactions facilitate these dynamic processes is still being actively investigated. TIP150 is a newly characterized microtubule plus end tracking protein essential for mitosis and entosis (Ward, T., Wang, M., Liu, X., Wang, Z., Xia, P., Chu, Y., Wang, X., Liu, L., Jiang, K., Yu, H., Yan, M., Wang, J., Hill, D. L., Huang, Y., Zhu, T., and Yao, X. (2013) Regulation of a dynamic interaction between two microtubule-binding proteins, EB1 and TIP150, by the mitotic p300/CBP-associated factor (PCAF) orchestrates kinetochore microtubule plasticity and chromosome stability during mitosis. J. Biol. Chem. 288, 15771-15785; Xia, P., Zhou, J., Song, X., Wu, B., Liu, X., Li, D., Zhang, S., Wang, Z., Yu, H., Ward, T., Zhang, J., Li, Y., Wang, X., Chen, Y., Guo, Z., and Yao, X. (2014) Aurora A orchestrates entosis by regulating a dynamic MCAK-TIP150 interaction. J. Mol. Cell Biol. 6, 240-254). Here we show that TIP150 links dynamic microtubules to steer cell migration by interacting with cortactin. Mechanistically, TIP150 binds to cortactin via its C-terminal tail. Interestingly, the C-terminal TIP150 proline-rich region (CT150) binds to the Src homology 3 domain of cortactin specifically, and such an interaction is negatively regulated by EGF-elicited tyrosine phosphorylation of cortactin. Importantly, suppression of TIP150 or overexpression of phospho-mimicking cortactin inhibits polarized cell migration. In addition, CT150 disrupts the biochemical interaction between TIP150 and cortactin in vitro, and perturbation of the TIP150-cortactin interaction in vivo using a membrane-permeable TAT-CT150 peptide results in an inhibition of directional cell migration. We reason that a dynamic TIP150-cortactin interaction orchestrates directional cell migration via coupling dynamic microtubule plus ends to the cortical cytoskeleton.
细胞迁移是由微管与质膜皮质层的动态相互作用所调控的。这些相互作用如何促进这些动态过程仍在积极研究中。TIP150是一种新鉴定的微管正端追踪蛋白，对有丝分裂和细胞内吞作用至关重要（沃德，T.，王，M.，刘，X.，王，Z.，夏，P.，楚，Y.，王，X.，刘，L.，江，K.，于，H.，严，M.，王，J.，希尔，D.L.，黄，Y.，朱，T.，和姚，X.（2013年）有丝分裂p300/CBP相关因子（PCAF）对两种微管结合蛋白EB1和TIP150之间动态相互作用的调控在有丝分裂期间协调动粒微管可塑性和染色体稳定性。《生物化学杂志》288卷，15771 - 15785页；夏，P.，周，J.，宋，X.，吴，B.，刘，X.，李，D.，张，S.，王，Z.，于，H.，沃德，T.，张，J.，李，Y.，王，X.，陈，Y.，郭，Z.，和姚，X.（2014年）极光激酶A通过调控MCAK - TIP150的动态相互作用来协调细胞内吞作用。《分子细胞生物学杂志》6卷，240 - 254页）。在这里，我们表明TIP150通过与皮层肌动蛋白相互作用将动态微管连接起来以引导细胞迁移。从机制上讲，TIP150通过其C末端尾巴与皮层肌动蛋白结合。有趣的是，TIP150富含脯氨酸的C末端区域（CT150）特异性地与皮层肌动蛋白的Src同源3结构域结合，并且这种相互作用受到表皮生长因子诱导的皮层肌动蛋白酪氨酸磷酸化的负调控。重要的是，抑制TIP150或过表达模拟磷酸化的皮层肌动蛋白会抑制极化细胞迁移。此外，CT150在体外破坏了TIP150与皮层肌动蛋白之间的生化相互作用，并且使用膜通透性TAT - CT150肽在体内干扰TIP150 - 皮层肌动蛋白相互作用会导致定向细胞迁移受到抑制。我们推断，动态的TIP150 - 皮层肌动蛋白相互作用通过将动态微管正端与皮层细胞骨架偶联来协调定向细胞迁移。
