Fotiadou Poppy P, Takahashi Chiaki, Rajabi Hasan N, Ewen Mark E
Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
Mol Cell Biol. 2007 Oct;27(19):6742-55. doi: 10.1128/MCB.00234-07. Epub 2007 Jul 16.
The ras proto-oncogenes, of which there are four isoforms, are molecular switches that function in signal transduction pathways to control cell differentiation, proliferation, and survival. How the Ras isoforms orchestrate cellular processes that affect behavior is poorly understood. Further, why cells express two or more Ras isoforms is unknown. Here, using a genetically defined system, we show that the presence of both wild-type KRas and NRas isoforms is required for transformation because they perform distinct nonoverlapping functions: wild-type NRas regulates adhesion, and KRas coordinates motility. Remarkably, we find that Ras isoforms achieve functional specificity by engaging different signaling pathways to affect the same cellular processes, thereby coordinating cellular outcome. Although we find that signaling from both isoforms intersects in actin and microtubule cytoskeletons, our results suggest that KRas signals through Akt and Cdc42 while NRas signals through Raf and RhoA. Our analyses suggest a previously unappreciated convergence of different Ras isoforms on the dynamics of the processes involved in transformation.
原癌基因ras有四种亚型，是在信号转导通路中发挥作用以控制细胞分化、增殖和存活的分子开关。Ras亚型如何协调影响行为的细胞过程仍知之甚少。此外，细胞为何表达两种或更多种Ras亚型也尚不清楚。在此，我们利用一个基因定义系统表明，野生型KRas和NRas亚型同时存在是细胞转化所必需的，因为它们执行不同的非重叠功能：野生型NRas调节黏附，而KRas协调运动性。值得注意的是，我们发现Ras亚型通过参与不同的信号通路来影响相同的细胞过程，从而实现功能特异性，进而协调细胞结果。虽然我们发现两种亚型的信号在肌动蛋白和微管细胞骨架中相交，但我们的结果表明KRas通过Akt和Cdc42发出信号，而NRas通过Raf和RhoA发出信号。我们的分析表明，不同Ras亚型在转化过程的动力学上存在一种此前未被认识到的趋同现象。
