Endocytic trafficking of Rac is required for the spatial restriction of signaling in cell migration
Endocytic trafficking of Rac is required for the spatial restriction of signaling in cell migration
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DOI：
10.1016/j.cell.2008.05.034
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发表时间：
2008-07-11
期刊：
影响因子：
64.5
通讯作者：
Di Fiore, Pier Paolo
中科院分区：
文献类型：
--
作者：
Palamidessi, Andrea;Frittoli, Emanuela;Di Fiore, Pier Paolo
小的GTP酶Rab5和Rac分别是内吞作用和肌动蛋白重塑所必需的。这些过程的协调对于实现细胞内信号的空间限制至关重要，而细胞内信号对各种极化功能是必不可少的。在这里，我们表明，网状蛋白和Rab5介导的内吞作用是运动刺激诱导的Rac激活所必需的。RAC激活发生在早期的内小体上，在那里也招募了racgef Tiam1。随后，RAC循环到质膜上，确保了局部信号传递，导致了基于肌动蛋白的迁移突起的形成。因此，RAC的膜运输对于RAC依赖的运动发生信号的空间分辨是必要的。我们进一步证明，在斑马鱼发育过程中，Rab5-to-Rac回路控制着可移动的哺乳动物肿瘤细胞和原始生发细胞的形态，表明该回路与体外环境和整个生物体中各种细胞的迁移计划的调节有关。
The small GTPases, Rab5 and Rac, are essential for endocytosis and actin remodeling, respectively. Coordination of these processes is critical to achieve spatial restriction of intracellular signaling, which is essential for a variety of polarized functions. Here, we show that clathrin- and Rab5- mediated endocytosis are required for the activation of Rac induced by motogenic stimuli. Rac activation occurs on early endosomes, where the RacGEF Tiam1 is also recruited. Subsequent recycling of Rac to the plasma membrane ensures localized signaling, leading to the formation of actin- based migratory protrusions. Thus, membrane trafficking of Rac is required for the spatial resolution of Rac-dependent motogenic signals. We further demonstrate that a Rab5-to-Rac circuitry controls the morphology of motile mammalian tumor cells and primordial germinal cells during zebrafish development, suggesting that this circuitry is relevant for the regulation of migratory programs in various cells, in both in vitro settings and whole organisms.