Katoh Hironori, Negishi Manabu
Laboratory of Molecular Neurobiology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan.
Nature. 2003 Jul 24;424(6947):461-4. doi: 10.1038/nature01817.
The small GTPase Rac has a central role in regulating the actin cytoskeleton during cell migration and axon guidance. Elmo has been identified as an upstream regulator of Rac1 that binds to and functionally cooperates with Dock180 (refs 2-4). Dock180 does not contain a conventional catalytic domain for guanine nucleotide exchange on Rac, but possesses a domain that directly binds to and specifically activates Rac1 (refs 5, 6). The small GTPase RhoG mediates several cellular morphological processes, such as neurite outgrowth in neuronal cells, through a signalling cascade that activates Rac1 (refs 7-12); however, the downstream target of RhoG and the mechanism by which RhoG regulates Rac1 activity remain unclear. Here we show that RhoG interacts directly with Elmo in a GTP-dependent manner and forms a ternary complex with Dock180 to induce activation of Rac1. The RhoG-Elmo-Dock180 pathway is required for activation of Rac1 and cell spreading mediated by integrin, as well as for neurite outgrowth induced by nerve growth factor. We conclude that RhoG activates Rac1 through Elmo and Dock180 to control cell morphology.
小GTP酶Rac在细胞迁移和轴突导向过程中对肌动蛋白细胞骨架的调节起着核心作用。Elmo已被确定为Rac1的上游调节因子，它与Dock180结合并在功能上与其协作（参考文献2 - 4）。Dock180不包含用于Rac上鸟嘌呤核苷酸交换的传统催化结构域，但拥有一个直接结合并特异性激活Rac1的结构域（参考文献5, 6）。小GTP酶RhoG通过激活Rac1的信号级联反应介导多种细胞形态学过程，如神经元细胞中的神经突生长（参考文献7 - 12）；然而，RhoG的下游靶点以及RhoG调节Rac1活性的机制仍不清楚。在这里，我们表明RhoG以GTP依赖的方式直接与Elmo相互作用，并与Dock180形成三元复合物以诱导Rac1的激活。RhoG - Elmo - Dock180途径对于整合素介导的Rac1激活和细胞铺展以及神经生长因子诱导的神经突生长是必需的。我们得出结论，RhoG通过Elmo和Dock180激活Rac1以控制细胞形态。
