The Rho-mDia1 pathway regulates cell polarity and focal adhesion turnover in migrating cells through mobilizing Apc and c-Src
The Rho-mDia1 pathway regulates cell polarity and focal adhesion turnover in migrating cells through mobilizing Apc and c-Src
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DOI：
10.1128/mcb.00283-06
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发表时间：
2006-09-01
影响因子：
5.3
通讯作者：
Narumiya, Shuh
中科院分区：
文献类型：
--
作者：
Yamana, Norikazu;Arakawa, Yoshiki;Narumiya, Shuh
细胞定向迁移需要细胞极化和黏附转换，其中肌动蛋白细胞骨架和微管起关键作用。Rho GTP酶诱导特定类型的肌动蛋白细胞骨架，调节微管动力学。在迁移细胞中，CDC42调节细胞的极性，RAC在膜突起中起作用。然而，Rho在迁徙中的作用鲜为人知。Rho作用于ROCK和mDia1两个主要效应器，其中mDia1产生直的肌动蛋白细丝并排列微管。在这里，我们通过RNA干扰耗尽mDial，并发现mDial耗尽通过抑制细胞极化和黏附转换来损害大鼠C6胶质瘤细胞的定向迁移。共同起细胞极化作用的APE和活性CDC42定位于迁移细胞的前部，而调节黏附周转的活性c-Src定位于局灶性粘连。MDia1缺失会损害这些分子在各自位置的定位。相反，活性mDia1的表达促进了APC和活性CDC42在细胞极端的微管依赖的聚集，以及c-Src在粘连中的肌动蛋白依赖的募集。因此，Rho-mDia1通路通过排列微管和肌动蛋白细丝并将APC/CDC42和c-Src运送到各自的作用部位来调节极化和黏附翻转。
Directed cell migration requires cell polarization and adhesion turnover, in which the actin cytoskeleton and microtubules work critically. The Rho GTPases induce specific types of actin cytoskeleton and regulate microtubule dynamics. In migrating cells, Cdc42 regulates cell polarity and Rac works in membrane protrusion. However, the role of Rho in migration is little known. Rho acts on two major effectors, ROCK and mDia1, among which mDia1 produces straight actin filaments and aligns microtubules. Here we depleted mDial by RNA interference and found that mDial depletion impaired directed migration of rat C6 glioma cells by inhibiting both cell polarization and adhesion turnover. Ape and active Cdc42, which work together for cell polarization, localized in the front of migrating cells, while active c-Src, which regulates adhesion turnover, localized in focal adhesions. mDia1 depletion impaired localization of these molecules at their respective sites. Conversely, expression of active mDia1 facilitated microtubule-dependent accumulation of Apc and active Cdc42 in the polar ends of the cells and actin-dependent recruitment of c-Src in adhesions. Thus, the Rho-mDia1 pathway regulates polarization and adhesion turnover by aligning microtubules and actin filaments and delivering Apc/Cdc42 and c-Src to their respective sites of action.