Inhibitory signalling to the Arp2/3 complex steers cell migration
Inhibitory signalling to the Arp2/3 complex steers cell migration
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DOI：
10.1038/nature12611
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发表时间：
2013-11-14
期刊：
影响因子：
64.8
通讯作者：
Gautreau, Alexis
中科院分区：
文献类型：
--
作者：
Dang, Irene;Gorelik, Roman;Gautreau, Alexis
细胞迁移需要产生分支肌动蛋白网络，为片状伪足中质膜的突出提供动力（1，2）。肌动蛋白相关蛋白2和3（Arp 2/3）复合物是使这些分支肌动蛋白网络成核的分子机器（3）。该机器在迁移细胞的前沿被Wiskott-Aldrich综合征蛋白（WASP）-家族维脯氨酸同源蛋白（WAVE，也称为SCAR）激活。WAVE复合物本身直接被小的GTd-Rac激活，其诱导板状伪足（4-6）。然而，细胞如何调节迁移的方向性却知之甚少。在这里，我们确定了一种新的蛋白质，Arpin，抑制Arp 2/3复合体在体外，并显示Rac信号招募和激活Arpin在板状脂质体尖端，像波。一致地，在抑制性Arpin耗尽后，板状伪足突出得更快，细胞迁移得更快。然而，这种抑制回路的一个主要作用是控制迁移的方向性持续。事实上，Arpin耗尽在哺乳动物细胞和Dictyosteobacterdiscoideum变形虫导致更直的轨迹，而Arpin显微注射在鱼类角膜细胞，最持久的系统之一的细胞迁移，诱导这些细胞转向。Rac-Arpin-Arp 2/3抑制回路与Rac-WAVE-Arp 2/3激活回路的共存可以解释Arpin在操纵细胞迁移中的这种保守作用。
Cell migration requires the generation of branched actin networks that power the protrusion of the plasma membrane inlamellipodia(1,2). The actin-related proteins 2 and 3 (Arp2/3) complex is the molecular machine that nucleates these branched actin networks(3). This machine is activated at the leading edge of migrating cells by Wiskott-Aldrich syndrome protein (WASP)-family verprolin-homologous protein (WAVE, also known as SCAR). The WAVE complex is itself directly activated by the small GTPase Rac, which induces lamellipodia(4-6). However, how cells regulate the directionality of migration is poorly understood. Here we identify a new protein, Arpin, that inhibits the Arp2/3 complex in vitro, and show that Rac signalling recruits and activates Arpin at the lamellipodial tip, like WAVE. Consistently, after depletion of the inhibitory Arpin, lamellipodia protrude faster and cells migrate faster. A major role of this inhibitory circuit, however, is to control directional persistence of migration. Indeed, Arpin depletion in both mammalian cells and Dictyostelium discoideum amoeba resulted in straighter trajectories, whereas Arpin microinjection in fish keratocytes, one of the most persistent systems of cell migration, induced these cells to turn. The coexistence of the Rac-Arpin-Arp2/3 inhibitory circuit with the Rac-WAVE-Arp2/3 activatory circuit can account for this conserved role of Arpin in steering cell migration.