Department of Chemical Engineering and Ilse Kats Institute for Nanoscale Science and Technology, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
Curr Biol. 2011 Dec 20;21(24):2092-7. doi: 10.1016/j.cub.2011.11.010. Epub 2011 Dec 8.
Cortactin is involved in invadopodia and podosome formation [1], pathogens and endosome motility [2], and persistent lamellipodia protrusion [3, 4]; its overexpression enhances cellular motility and metastatic activity [5-8]. Several mechanisms have been proposed to explain cortactin's role in Arp2/3-driven actin polymerization [9, 10], yet its direct role in cell movement remains unclear. We use a biomimetic system to study the mechanism of cortactin-mediated regulation of actin-driven motility [11]. We tested the role of different cortactin variants that interact with Arp2/3 complex and actin filaments distinctively. We show that wild-type cortactin significantly enhances the bead velocity at low concentrations. Single filament experiments show that cortactin has no significant effect on actin polymerization and branch stability, whereas it strongly affects the branching rate driven by Wiskott-Aldrich syndrome protein (WASP)-VCA fragment and Arp2/3 complex. These results lead us to propose that cortactin plays a critical role in translating actin polymerization at a bead surface into motion, by releasing WASP-VCA from the new branching site. This enhanced release has two major effects: it increases the turnover rate of branching per WASP molecule, and it decreases the friction-like force caused by the binding of the moving surface with respect to the growing actin network.
Cortactin 参与了侵袭伪足和足突的形成 [1]、病原体和内体的运动 [2]，以及持续的片状伪足伸出 [3,4]；其过表达增强了细胞的迁移能力和转移活性 [5-8]。已经提出了几种机制来解释 cortactin 在 Arp2/3 驱动的肌动蛋白聚合中的作用 [9,10]，但其在细胞运动中的直接作用仍不清楚。我们使用生物仿生系统来研究 cortactin 介导的肌动蛋白驱动的运动调节的机制 [11]。我们测试了与 Arp2/3 复合物和肌动蛋白丝不同相互作用的不同 cortactin 变体的作用。我们表明野生型 cortactin 在低浓度下显著提高了珠粒的速度。单丝实验表明 cortactin 对肌动蛋白聚合和分支稳定性没有显著影响，而对 Wiskott-Aldrich 综合征蛋白 (WASP)-VCA 片段和 Arp2/3 复合物驱动的分支速率有强烈影响。这些结果使我们提出，cortactin 通过将 WASP-VCA 从新的分支位点释放出来，在将珠粒表面的肌动蛋白聚合转化为运动方面发挥关键作用。这种增强的释放有两个主要作用：它增加了每个 WASP 分子分支的周转率，并且降低了由于运动表面与生长中的肌动蛋白网络的结合而引起的摩擦样力。
