Pollock J D, Rane S G
Department of Biological Sciences, Purdue University, West Lafayette, Indiana 47907, USA.
J Biol Chem. 1996 Apr 5;271(14):8008-14. doi: 10.1074/jbc.271.14.8008.
Nerve growth factor and basic fibroblast growth factor bind to and activate receptor tyrosine kinases, causing sequential signaling via the p21ras/extracellular signal-regulated kinase pathway. The necessity and sufficiency of this signaling pathway in transducing neuronal differentiation have been tested in the PC12 cell model. Although necessary for morphological changes, the sufficiency of p21ras-mediated signaling in these events has come into question. We report that growth factor induction of voltage-gated calcium channels, a hallmark of physiological differentiation, also requires p21ras-mediated signaling, but cannot be driven by p21ras activation alone. Thus, constitutive expression of the dominant negative N17ras mutant blocks growth factor-induced increases in Omega-conotoxin GVIA-sensitive, nimodipine-sensitive, and Omega-conotoxin GVIA/nimodipine-resistant calcium currents, but it does not block sodium current induction. However, manipulations that produce sustained activation of the p21ras signaling pathway and the neurite extension characteristic of morphological differentiation fail to increase calcium channel current densities. These results indicate the existence of distinct signaling requirements for morphological and physiological differentiation and further emphasize the importance of p21ras-independent signaling pathways in growth factor-mediated neuronal development.
神经生长因子和碱性成纤维细胞生长因子与受体酪氨酸激酶结合并激活它们，通过p21ras/细胞外信号调节激酶途径引发级联信号传导。在PC12细胞模型中已对该信号通路在转导神经元分化中的必要性和充分性进行了测试。尽管对于形态变化是必需的，但p21ras介导的信号传导在这些事件中的充分性受到了质疑。我们报告，电压门控钙通道的生长因子诱导（生理分化的一个标志）也需要p21ras介导的信号传导，但不能仅由p21ras激活驱动。因此，显性负性N17ras突变体的组成型表达可阻断生长因子诱导的对ω-芋螺毒素GVIA敏感、尼莫地平敏感以及对ω-芋螺毒素GVIA/尼莫地平耐药的钙电流增加，但不阻断钠电流诱导。然而，产生p21ras信号通路持续激活以及形态分化特征性的神经突延伸的操作未能增加钙通道电流密度。这些结果表明形态和生理分化存在不同的信号传导需求，并进一步强调了p21ras非依赖性信号通路在生长因子介导的神经元发育中的重要性。
