Morooka T, Nishida E
Department of Biophysics, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan.
J Biol Chem. 1998 Sep 18;273(38):24285-8. doi: 10.1074/jbc.273.38.24285.
Nerve growth factor (NGF) induces sustained activation of classical MAP kinase (MAPK, also known as ERK) and neuronal differentiation in PC12 cells, whereas epidermal growth factor (EGF) induces transient activation of ERK/MAPK and stimulates proliferation of the cells. Although previous studies showed that sustained activation of ERK/MAPK is important for neuronal differentiation of the cells, a recent report revealed that inhibition of the sustained phase of ERK/MAPK activation alone does not block neurite outgrowth caused by NGF. These results suggest requirement for an additional signaling pathway(s) triggered by NGF in neuronal differentiation. Here we show that NGF induces sustained activation of p38, a subfamily member of the MAPK superfamily, and that inhibition of the p38 pathway blocks neurite outgrowth in PC12 cells. Surprisingly, expression of constitutively active MAPK/ERK kinase (MAPKK, also known as MEK) results in p38 activation as well as ERK/MAPK activation, and a p38 inhibitor blocks neurite outgrowth caused by the constitutively active MAPKK/MEK. Moreover, constitutive activation of p38 is able to induce neurite outgrowth when combined with EGF treatment. These results reveal an essential role of p38 in neuronal differentiation in PC12 cells.
神经生长因子（NGF）可诱导PC12细胞中经典丝裂原活化蛋白激酶（MAPK，也称为ERK）的持续激活以及神经元分化，而表皮生长因子（EGF）则诱导ERK/MAPK的瞬时激活并刺激细胞增殖。尽管先前的研究表明ERK/MAPK的持续激活对细胞的神经元分化很重要，但最近的一份报告显示，仅抑制ERK/MAPK激活的持续阶段并不能阻断NGF引起的神经突生长。这些结果表明，在神经元分化过程中，NGF触发的额外信号通路是必需的。在此我们表明，NGF可诱导p38（MAPK超家族的一个亚家族成员）的持续激活，并且抑制p38通路可阻断PC12细胞中的神经突生长。令人惊讶的是，组成型活性丝裂原活化蛋白激酶/细胞外信号调节激酶激酶（MAPKK，也称为MEK）的表达会导致p38激活以及ERK/MAPK激活，并且p38抑制剂可阻断由组成型活性MAPKK/MEK引起的神经突生长。此外，p38的组成型激活与EGF处理相结合时能够诱导神经突生长。这些结果揭示了p38在PC12细胞神经元分化中的重要作用。
