Evidence for a Ras-dependent extracellular signal-regulated protein kinase (ERK) cascade.

The small GTP-binding protein Ras appears to be required for transformation and differentiation induced by tyrosine kinases. The Ras requirement may be limited to a few tyrosine kinase-regulated signaling pathways or may be universal for all tyrosine kinase actions. Because both Ras and the microtubule-associated protein 2 kinases ERK1 and ERK2 have been implicated in events that lead to neurite outgrowth, we explored the possibility that Ras and ERKs may lie on the same signaling pathway. Utilizing PC-12 rat adrenal pheochromocytoma cell lines that contain a dominant inhibitory Ras mutant (S17N-Ras(H)), we found that Ras was required for stimulation of the ERK cascade by nerve growth factor but apparently not by the heterotrimeric G protein activator AlF4-. Within this cascade, Ras appears to be upstream of an ERK activator, raising the intriguing possibility that Ras may directly regulate a serine/threonine protein kinase. IMAGES:

小GTP结合蛋白Ras（small GTP-binding protein Ras）似乎是酪氨酸激酶（tyrosine kinases）诱导细胞转化与分化的必需因子。Ras的必需性可能仅局限于少数受酪氨酸激酶调控的信号通路，亦或是所有酪氨酸激酶介导的生物学活动均需其参与。由于Ras与微管相关蛋白2激酶ERK1、ERK2（microtubule-associated protein 2 kinases ERK1 and ERK2）均被证实与神经突生长的调控事件相关，我们探究了Ras与ERKs可能处于同一信号通路的可能性。通过使用携带显性负性突变体Ras（S17N-Ras(H)）的大鼠肾上腺嗜铬细胞瘤PC-12细胞系（PC-12 rat adrenal pheochromocytoma cell lines），我们发现：神经生长因子（nerve growth factor）激活ERK级联反应（ERK cascade）的过程依赖于Ras，但异三聚体G蛋白激活剂AlF4-（heterotrimeric G protein activator AlF4-）的刺激则无此要求。在该级联反应中，Ras似乎位于ERK激活因子的上游，这一发现引出了一个颇具吸引力的可能性：Ras可直接调控丝氨酸/苏氨酸蛋白激酶（serine/threonine protein kinase）。图像：