Chiang Tsai-Shin, Wu Hsu-Feng, Lee Fang-Jen S
Institute of Molecular Medicine, College of Medicine, National Taiwan University, 100 Taipei, Taiwan.
Institute of Molecular Medicine, College of Medicine, National Taiwan University, 100 Taipei, Taiwan
Mol Biol Cell. 2017 Nov 1;28(22):3013-3028. doi: 10.1091/mbc.E17-01-0059. Epub 2017 Aug 30.
Changes in cell morphology and the physical forces that occur during migration are generated by a dynamic filamentous actin cytoskeleton. The ADP-ribosylation factor-like 4C (Arl4C) small GTPase acts as a molecular switch to regulate morphological changes and cell migration, although the mechanism by which this occurs remains unclear. Here we report that Arl4C functions with the actin regulator filamin-A (FLNa) to modulate filopodium formation and cell migration. We found that Arl4C interacted with FLNa in a GTP-dependent manner and that FLNa IgG repeat 22 is both required and sufficient for this interaction. We also show that interaction between FLNa and Arl4C is essential for Arl4C-induced filopodium formation and increases the association of FLNa with Cdc42-GEF FGD6, promoting cell division cycle 42 (Cdc42) GTPase activation. Thus our study revealed a novel mechanism, whereby filopodium formation and cell migration are regulated through the Arl4C-FLNa-mediated activation of Cdc42.
细胞形态的变化以及迁移过程中产生的物理力是由动态的丝状肌动蛋白细胞骨架所引发的。ADP-核糖基化因子样4C（Arl4C）小GTP酶作为一种分子开关来调节形态变化和细胞迁移，尽管其具体发生机制尚不清楚。在此我们报告，Arl4C与肌动蛋白调节因子细丝蛋白-A（FLNa）共同作用来调节丝状伪足的形成和细胞迁移。我们发现Arl4C以GTP依赖的方式与FLNa相互作用，并且FLNa免疫球蛋白重复序列22对于这种相互作用既是必需的也是充分的。我们还表明，FLNa与Arl4C之间的相互作用对于Arl4C诱导的丝状伪足形成至关重要，并增加了FLNa与Cdc42鸟嘌呤核苷酸交换因子FGD6的结合，促进细胞分裂周期42（Cdc42）GTP酶的激活。因此，我们的研究揭示了一种新机制，即通过Arl4C-FLNa介导的Cdc42激活来调节丝状伪足的形成和细胞迁移。
