Sanz-Moreno Victoria, Gadea Gilles, Ahn Jessica, Paterson Hugh, Marra Pierfrancesco, Pinner Sophie, Sahai Erik, Marshall Christopher J
Institute of Cancer Research, Cancer Research UK Centre for Cell and Molecular Biology, 237 Fulham Road, London SW3 6JB, UK.
Cell. 2008 Oct 31;135(3):510-23. doi: 10.1016/j.cell.2008.09.043.
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, ARHGAP22, 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.
肿瘤细胞表现出两种不同的单个细胞运动模式。间充质型运动的特征是细胞形态拉长，需要细胞外蛋白水解作用。在阿米巴样运动中，细胞呈圆形，对蛋白酶的依赖性较小，需要高 Rho 激酶信号传导来驱动肌动球蛋白收缩水平升高。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充质型运动是由 GTP 酶 Rac 的激活驱动的，通过一个包含 NEDD9（一个最近鉴定出的黑色素瘤转移基因）和 DOCK3（一种 Rac 鸟嘌呤核苷酸交换因子）的复合物。Rac 通过 WAVE2 信号传导来指导间充质运动，并通过降低肌动球蛋白收缩性来抑制阿米巴样运动。相反，在阿米巴样运动中，Rho 激酶信号传导激活一种 Rac GAP（ARHGAP22），它通过使 Rac 失活来抑制间充质运动。我们证明了 Rho 和 Rac 在决定肿瘤细胞不同运动模式方面存在紧密的相互作用，揭示了肿瘤细胞如何在不同运动模式之间切换。
