York R D, Yao H, Dillon T, Ellig C L, Eckert S P, McCleskey E W, Stork P J
The Vollum Institute for Advanced Biomedical Research, Oregon Health Sciences University, Portland 97201, USA.
Nature. 1998 Apr 9;392(6676):622-6. doi: 10.1038/33451.
Activation of mitogen-activated protein (MAP) kinase (also known as extracellular-signal-regulated kinase, or ERK) by growth factors can trigger either cell growth or differentiation. The intracellular signals that couple growth factors to MAP kinase may determine the different effects of growth factors: for example, transient activation of MAP kinase by epidermal growth factor stimulates proliferation of PC12 cells, whereas they differentiate in response to nerve growth factor, which acts partly by inducing a sustained activation of MAP kinase. Here we show that activation of MAP kinase by nerve growth factor involves two distinct pathways: the initial activation of MAP kinase requires the small G protein Ras, but its activation is sustained by the small G protein Rap1. Rap1 is activated by CRK adaptor proteins and the guanine-nucleotide-exchange factor C3G, and forms a stable complex with B-Raf, an activator of MAP kinase. Rap1 is required for at least two indices of neuronal differentiation by nerve growth factor: electrical excitability and the induction of neuron-specific genes. We propose that the activation of Rap1 by C3G represents a common mechanism to induce sustained activation of the MAP kinase cascade in cells that express B-Raf.
生长因子对丝裂原活化蛋白（MAP）激酶（也称为细胞外信号调节激酶，即ERK）的激活可引发细胞生长或分化。将生长因子与MAP激酶偶联的细胞内信号可能决定了生长因子的不同作用：例如，表皮生长因子对MAP激酶的短暂激活会刺激PC12细胞增殖，而它们会对神经生长因子作出反应而分化，神经生长因子部分通过诱导MAP激酶的持续激活发挥作用。我们在此表明，神经生长因子对MAP激酶的激活涉及两条不同的途径：MAP激酶的初始激活需要小G蛋白Ras，但其激活由小G蛋白Rap1维持。Rap1由CRK衔接蛋白和鸟嘌呤核苷酸交换因子C3G激活，并与MAP激酶的激活剂B-Raf形成稳定复合物。Rap1是神经生长因子诱导神经元分化的至少两个指标所必需的：电兴奋性和神经元特异性基因的诱导。我们提出，C3G对Rap1的激活代表了一种在表达B-Raf的细胞中诱导MAP激酶级联持续激活的常见机制。
