Insulin-like growth factor-I-mediated neurite outgrowth in vitro requires mitogen-activated protein kinase activation
Insulin-like growth factor-I-mediated neurite outgrowth in vitro requires mitogen-activated protein kinase activation
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DOI：
10.1074/jbc.272.34.21268
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发表时间：
1997-08-22
影响因子：
4.8
通讯作者：
Feldman, EL
中科院分区：
文献类型：
--
作者：
Kim, B;Leventhal, PS;Feldman, EL
胰岛素样生长因子- i （IGF-I）在体外诱导神经元分化。在本研究中，我们研究了igf - i介导的神经突生长的信号通路。在SH-SY5Y人神经母细胞瘤细胞中，用IGF-I治疗可诱导I型IGF受体（IGF- ir）和细胞外信号调节蛋白激酶（ERK） 1和2的浓度和时间依赖性酪氨酸磷酸化。IGF-I的这些作用被抗IGF-IR的中和抗体阻断。IGF-IR的磷酸化在1分钟内被观察到，而ERKs的最大磷酸化在30分钟内未达到。IGF-IR和ERK磷酸化都维持了至少24小时。此外，igf - i刺激的IGF-IR和ERK酪氨酸磷酸化的浓度依赖性与igf - i介导的神经突生长的浓度依赖性相似。我们使用丝裂原活化蛋白激酶- erk激酶抑制剂PD98059进一步研究了丝裂原活化蛋白激酶在igf - i刺激的神经元分化中的作用。虽然PD98059对IGF-IR磷酸化没有影响，但PD98059降低了igf - i介导的ER酪氨酸磷酸化和底物Elk-1的ERK磷酸化。PD98059也能平行减少igf - i刺激的神经突生长。最后，与其阻断神经元分化的能力一致，PD98059抑制了igf - i依赖性的GAp-43和c-myc基因表达的变化。综上所述，这些结果表明，ERKs的激活对于igf - i刺激的神经元分化至关重要。
Insulin-like growth factor-I (IGF-I) induces neuronal differentiation in vitro. In the present study, we examined the signaling pathway underlying IGF-I-mediated neurite outgrowth. In SH-SY5Y human neuroblastoma cells, treatment with IGF-I induced concentration- and time-dependent tyrosine phosphorylation of the type I IGF receptor (IGF-IR) and extracellular signal-regulated protein kinases (ERK) 1 and 2. These effects of IGF-I were blocked by a neutralizing antibody against IGF-IR. Whereas IGF-IR phosphorylation was observed within 1 min, maximal phosphorylation of ERKs was not reached for 30 min. Both IGF-IR and ERK phosphorlyation were maintained for at least 24 h. Also, the concentration dependence of IGF-I-stimulated IGF-IR and ERK tyrosine phosphorylation paralleled that of IGF-I-mediated neurite outgrowth. We further examined the role of mitogen-activated protein kinase activation in IGF-I-stimulated neuronal differentiation using the mitogen-activated protein kinase-ERK kinase inhibitor PD98059. Whereas PD98059 had no effect on IGF-IR phosphorylation, PD98059 reduced IGF-I-mediated ER tyrosine phosphorylation and ERK phosphorylation of the substrate Elk-1. PD98059 also produced a parallel reduction of IGF-I-stimulated neurite outgrowth. Finally, consistence with its ability to block neuronal differentiation, PD98059 inhibited IGF-I-dependent changes of GAp-43 and c-myc gene expression. Together these results suggest that activation of ERKs is essential for IGF-I-stimulated neuronal differentiation.