RasGRF suppresses Cdc42-mediated tumour cell movement, cytoskeletal dynamics and transformation
RasGRF suppresses Cdc42-mediated tumour cell movement, cytoskeletal dynamics and transformation
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DOI：
10.1038/ncb2271
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发表时间：
2011-07-01
影响因子：
21.3
通讯作者：
Crespo, Piero
中科院分区：
文献类型：
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作者：
Calvo, Fernando;Sanz-Moreno, Victoria;Crespo, Piero
单个肿瘤细胞以圆形或细长的“间质”形态在三维环境中移动。这两种运动方式受到Rho家族GTP酶的严格调控：拉长运动需要激活rac1，而圆形/变形体运动涉及特定的CDC42和Rho信号通路。在针对鸟嘌呤核苷酸交换因子(GEF)编码基因的siRNA筛选中，我们发现Ras Global RASGRF2调节细长运动和圆形运动之间的转换。RASGRF2通过抑制CDC42的激活而抑制圆形运动，而不依赖于其激活RAS的能力。RASGRF2和RasGRF1直接与CDC42结合，与CDC42GEF竞争，从而阻止了CDC42的激活。通过这一机制，RasGRFs调控了其他由CDC42介导的细胞过程，如肌动蛋白尖峰的形成、转化和体内侵袭。这些结果证明了RASGRF GEF作为CDC42激活的负调节因子的作用。
Individual tumour cells move in three-dimensional environments with either a rounded or an elongated 'mesenchymal' morphology. These two modes of movement are tightly regulated by Rho family GTPases: elongated movement requires activation of Rac1, where as rounded/amoeboid movement engages specific Cdc42 and Rho signalling pathways. In siRNA screens targeting the genes encoding guanine nucleotide exchange factors (GEFs), we found that the Ras GEF RasGRF2 regulates conversion between elongated- and rounded-type movement. RasGRF2 suppresses rounded movement by inhibiting the activation of Cdc42 independently of its capacity to activate Ras. RasGRF2 and RasGRF1 directly bind to Cdc42, out competing Cdc42 GEFs,thereby preventing Cdc42 activation. By this mechanism, RasGRFs regulate other Cdc42-mediated cellular processes such as the formation of actin spikes, transformation and invasion in vitro and in vivo. These results demonstrate a role for RasGRF GEFs as negative regulators of Cdc42 activation.