Lim Kian-Huat, Baines Antonio T, Fiordalisi James J, Shipitsin Michail, Feig Larry A, Cox Adrienne D, Der Channing J, Counter Christopher M
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
Cancer Cell. 2005 Jun;7(6):533-45. doi: 10.1016/j.ccr.2005.04.030.
RalGEFs were recently shown to be critical for Ras-mediated transformed and tumorigenic growth of human cells. We now show that the oncogenic activity of these proteins is propagated by activation of one RalGEF substrate, RalA, but blunted by another closely related substrate, RalB, and that the oncogenic signaling requires binding of the RalBP1 and exocyst subunit effector proteins. Knockdown of RalA expression impeded, if not abolished, the ability of human cancer cells to form tumors. RalA was also commonly activated in a panel of cell lines from pancreatic cancers, a disease characterized by activation of Ras. Activation of RalA signaling thus appears to be a critical step in Ras-induced transformation and tumorigenesis of human cells.
Ral鸟嘌呤核苷酸交换因子(RalGEFs)最近被证明对于Ras介导的人类细胞转化和致瘤生长至关重要。我们现在发现,这些蛋白质的致癌活性是通过激活一种RalGEF底物RalA来传播的,但会被另一种密切相关的底物RalB减弱,并且致癌信号传导需要RalBP1和外排体亚基效应蛋白结合。敲低RalA的表达即使没有完全消除,也会阻碍人类癌细胞形成肿瘤的能力。RalA在一组来自胰腺癌的细胞系中也普遍被激活,胰腺癌是一种以Ras激活为特征的疾病。因此,RalA信号的激活似乎是Ras诱导人类细胞转化和肿瘤发生的关键步骤。