FMNL2 regulates dynamics of fascin in filopodia
FMNL2 regulates dynamics of fascin in filopodia
复制标题
DOI：
10.1083/jcb.201906111
复制
发表时间：
2020-05-04
影响因子：
7.8
通讯作者：
Parsons, Maddy
中科院分区：
文献类型：
--
作者：
Pfisterer, Karin;Levitt, James;Parsons, Maddy
丝状伪足是外周富含F-肌动蛋白的结构，使细胞能够感知微环境。Fascin是一种F-肌动蛋白捆绑蛋白，在稳定丝状伪足以支持有效粘附和迁移中起关键作用。Fascin在人类癌症中也高度上调，它增加了侵袭性细胞行为，并与患者预后不良相关。以前的研究表明，肌成束蛋白磷酸化可以调节F-肌动蛋白捆绑，这种修饰可以有助于亚细胞肌成束蛋白的定位和功能。然而，在丝状伪足内调节肌束蛋白动力学的因素仍然知之甚少。在当前的研究中，我们使用先进的活细胞成像技术和肌成束蛋白生物传感器来证明肌成束蛋白磷酸化、定位和与F-肌动蛋白的结合是高度动态的，并且依赖于2D和3D环境中细胞中的局部细胞骨架结构。丝状伪足内的肌成束蛋白动力学受formins，特别是FMNL 2的控制，其直接结合去磷酸化肌成束蛋白。我们的数据提供了新的见解，在纳米级的肌成束蛋白动力学的控制，并进入管理快速细胞骨架适应环境变化的机制。这种丝状伪足驱动的探索阶段可能代表了从静止到迁移癌细胞过渡的重要调控步骤。
Filopodia are peripheral F-actin-rich structures that enable cell sensing of the microenvironment. Fascin is an F-actin-bundling protein that plays a key role in stabilizing filopodia to support efficient adhesion and migration. Fascin is also highly up-regulated in human cancers, where it increases invasive cell behavior and correlates with poor patient prognosis. Previous studies have shown that fascin phosphorylation can regulate F-actin bundling, and that this modification can contribute to subcellular fascin localization and function. However, the factors that regulate fascin dynamics within filopodia remain poorly understood. In the current study, we used advanced live-cell imaging techniques and a fascin biosensor to demonstrate that fascin phosphorylation, localization, and binding to F-actin are highly dynamic and dependent on local cytoskeletal architecture in cells in both 2D and 3D environments. Fascin dynamics within filopodia are under the control of formins, and in particular FMNL2, that binds directly to dephosphorylated fascin. Our data provide new insight into control of fascin dynamics at the nanoscale and into the mechanisms governing rapid cytoskeletal adaptation to environmental changes. This filopodia-driven exploration stage may represent an essential regulatory step in the transition from static to migrating cancer cells.