Identification of the mechanisms regulating the differential activation of the MAPK cascade by epidermal growth factor and nerve growth factor in PC12 cells
Identification of the mechanisms regulating the differential activation of the MAPK cascade by epidermal growth factor and nerve growth factor in PC12 cells
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DOI：
10.1074/jbc.m008870200
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发表时间：
2001-05-25
影响因子：
4.8
通讯作者：
Landreth, GE
中科院分区：
文献类型：
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作者：
Kao, SC;Jaiswal, RK;Landreth, GE
在PC12细胞中，表皮生长因子(EGF)瞬时刺激丝裂原活化蛋白(MAP)激酶ERK1和ERK2，刺激细胞增殖。相反，神经生长因子(NGF)刺激导致MAPK的持续激活，进而导致神经元分化。已有研究表明，MAPK激活的大小和寿命决定了细胞反应的性质。MAPK的激活依赖于两个不同的小G蛋白，Has和Rap1，它们分别通过激活c-Raf和B-Raf将生长因子受体与MAPK级联联系起来。我们发现在EGF和NGF处理的PC12细胞中，RES都被瞬时地刺激。然而，EGF短暂激活Rap1，而NGF刺激延长Rap1的激活。ERKs的激活几乎完全(90%)是由于B-Raf的作用，EGF对MAPKs的瞬时激活是由Crk、C3G、Rap1和B-Raf组成的EGF受体本身形成的短暂复合体的结果，相反，NGF刺激细胞导致FRS2的磷酸化。FRS2支架组装了稳定的Crk、C3G、Rap1和B-Raf复合体，导致MAPK的激活时间延长。总之，这些数据提供了生长因子受体和MAPK激活之间的信号联系，并从机制上解释了这些生长因子表现出的不同MAPK动力学。
In PC12 cells, epidermal growth factor (EGF) transiently stimulates the mitogen-activated protein (MAP) kinases, ERK1 and ERK2, and provokes cellular proliferation. In contrast, nerve growth factor (NGF) stimulation leads to the sustained activation of the MAPKs and subsequently to neuronal differentiation. It has been shown that both the magnitude and longevity of MAPK activation governs the nature of the cellular response. The activations of MAPKs are dependent upon two distinct small G-proteins, Has and Rap1, that link the growth factor receptors to the MAPK cascade by activating c-Raf and B-Raf, respectively. We found that Res was transiently stimulated upon both EGF and NGF treatment of PC12 cells. However, EGF transiently activated Rap1, whereas NGF stimulated prolonged Rap1 activation. The activation of the ERKs was due almost exclusively (>90%) to the action of B-Raf, The transient activation of the MAPKs by EGF was a consequence of the formation of a short lived complex assembling on the EGF receptor itself, composed of Crk, C3G, Rap1, and B-Raf, In contrast, NGF stimulation of the cells resulted in the phosphorylation of FRS2. FRS2 scaffolded the assembly of a stable complex of Crk, C3G, Rap1, and B-Raf resulting in the prolonged activation of the MAPKs. Together, these data provide a signaling link between growth factor receptors and MAPK activation and a mechanistic explanation of the differential MAPK kinetics exhibited by these growth factors.