Yan J, Roy S, Apolloni A, Lane A, Hancock J F
Queensland Cancer Fund Laboratory of Experimental Oncology, Department of Pathology, University of Queensland Medical School, Herston Road, Brisbane 4006, Australia.
J Biol Chem. 1998 Sep 11;273(37):24052-6. doi: 10.1074/jbc.273.37.24052.
Ha-, N-, and Ki-Ras are ubiquitously expressed in mammalian cells and can all interact with the same set of effector proteins. We show here, however, that in vivo there are marked quantitative differences in the ability of Ki- and Ha-Ras to activate Raf-1 and phosphoinositide 3-kinase. Thus, Ki-Ras both recruits Raf-1 to the plasma membrane more efficiently than Ha-Ras and is a more potent activator of membrane-recruited Raf-1 than Ha-Ras. In contrast, Ha-Ras is a more potent activator of phosphoinositide 3-kinase than Ki-Ras. Interestingly, the ability of Ha-Ras to recruit Raf-1 to the plasma membrane is significantly increased when the Ha-Ras hypervariable region is shortened so that the spacing of the Ha-Ras GTPase domains from the inner surface of the plasma membrane mimicks that of Ki-Ras. Importantly, these data show for the first time that the activation of different Ras isoforms can have distinct biochemical consequences for the cell. The mutation of specific Ras isoforms in different human tumors can, therefore, also be rationalized.
哈-、N-和Ki-Ras在哺乳动物细胞中普遍表达，并且都能与同一组效应蛋白相互作用。然而，我们在此表明，在体内，Ki-Ras和哈- Ras激活Raf-1和磷酸肌醇3激酶的能力存在显著的数量差异。因此，与哈- Ras相比，Ki-Ras能更有效地将Raf-1募集到质膜，并且是比哈- Ras更强效的膜募集Raf-1激活剂。相反，哈- Ras是比Ki-Ras更强效的磷酸肌醇3激酶激活剂。有趣的是，当哈- Ras高变区缩短，使得哈- Ras GTPase结构域与质膜内表面的间距模拟Ki-Ras时，哈- Ras将Raf-1募集到质膜的能力显著增加。重要的是，这些数据首次表明，不同Ras异构体的激活对细胞可能产生不同的生化后果。因此，不同人类肿瘤中特定Ras异构体的突变也可以得到合理的解释。
