Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas-IDICAN-Universidad de Cantabria, Departamento de Biología Molecular, Facultad de Medicina, Santander, 39011, Cantabria, Spain.
Nat Cell Biol. 2011 Jun 19;13(7):819-26. doi: 10.1038/ncb2271.
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, whereas 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, outcompeting 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.
肿瘤细胞在三维环境中移动，具有圆形或拉长的“间质”形态。这两种运动模式受 Rho 家族 GTPases 严格调控：拉长运动需要 Rac1 的激活，而圆形/阿米巴样运动则涉及特定的 Cdc42 和 Rho 信号通路。在针对编码鸟嘌呤核苷酸交换因子 (GEFs) 的基因的 siRNA 筛选中，我们发现 Ras GEF RasGRF2 调节伸长型和圆形型运动之间的转换。RasGRF2 通过抑制 Cdc42 的激活来抑制圆形运动，而不依赖于其激活 Ras 的能力。RasGRF2 和 RasGRF1 直接与 Cdc42 结合，与 Cdc42 GEF 竞争，从而防止 Cdc42 激活。通过这种机制，RasGRFs 调节其他 Cdc42 介导的细胞过程，如体外和体内的肌动蛋白刺的形成、转化和侵袭。这些结果表明 RasGRF GEFs 作为 Cdc42 激活的负调节剂的作用。
