Rac Activation and Inactivation Control Plasticity of Tumor Cell Movement
Rac Activation and Inactivation Control Plasticity of Tumor Cell Movement
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DOI：
10.1016/j.cell.2008.09.043
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发表时间：
2008-10-31
期刊：
影响因子：
64.5
通讯作者：
Marshall, Christopher J.
中科院分区：
文献类型：
--
作者：
Sanz-Moreno, Victoria;Gadea, Gilles;Marshall, Christopher J.
肿瘤细胞表现出两种不同的个体细胞运动模式。间叶型运动的特点是细胞形态拉长，需要细胞外蛋白分解。在阿米巴运动中，细胞具有圆形的形态，对蛋白酶的依赖性较低，需要高水平的Rho-Kinase信号来驱动肌动蛋白收缩水平的升高。这两种细胞运动模式是可以相互转换的。我们发现，黑色素瘤细胞中的间叶型运动是由GTPase RAC通过包含最近发现的黑色素瘤转移基因NEDD9和RAC鸟嘌呤核苷酸交换因子DOCK3的复合体而激活的。RAC信号通过WAVE2引导间充质运动，并通过降低肌球蛋白的收缩能力来抑制阿米巴运动。相反，在阿米巴运动中，Rho-Kinase信号激活RAC间隙ARH-GAP22，该间隙通过失活RAC来抑制间充质运动。我们展示了Rho和Rac在确定不同的肿瘤细胞运动模式方面的紧密相互作用，揭示了肿瘤细胞如何在不同的运动模式之间切换。
Tumor cells exhibit two different modes of individual cell movement. Mesenchymal-type movement is characterized by an elongated cellular morphology and requires extracellular proteolysis. In amoeboid movement, cells have a rounded morphology, are less dependent on proteases, and require high Rho-kinase signaling to drive elevated levels of actomyosin contractility. These two modes of cell movement are interconvertible. We show that mesenchymal-type movement in melanoma cells is driven by activation of the GTPase Rac through a complex containing NEDD9, a recently identified melanoma metastasis gene, and DOCK3, a Rac guanine nucleotide exchange factor. Rac signals through WAVE2 to direct mesenchymal movement and suppress amoeboid movement through decreasing actomyosin contractility. Conversely, in amoeboid movement, Rho-kinase signaling activates a Rac GAP, ARH-GAP22, that suppresses mesenchymal movement by inactivating Rac. We demonstrate tight interplay between Rho and Rac in determining different modes of tumor cell movement, revealing how tumor cells switch between different modes of movement.