The phosphatidylinositol-3 kinase (PI3K)-Akt pathway suppresses neurite branch formation in NGF-treated PC12 cells
The phosphatidylinositol-3 kinase (PI3K)-Akt pathway suppresses neurite branch formation in NGF-treated PC12 cells
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DOI：
10.1046/j.1365-2443.2003.00663.x
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发表时间：
2003-08-01
期刊：
影响因子：
2.1
通讯作者：
Gotoh, Y
中科院分区：
文献类型：
--
作者：
Higuchi, M;Onishi, K;Gotoh, Y
背景：已有研究表明，磷脂酰肌醇-3激酶(PI3K)在神经生长因子(NGF)诱导的神经突起延长中起重要作用。然而，PI3K通路在神经突起分支形成中的作用尚不完全清楚。结果：用PI3K抑制剂LY294002处理PC12细胞后，突起分支点明显增多，提示PI3K在突起分枝形成中起抑制作用。PI3K下游效应子Akt的表达减少了分支点的数量，而显性-负性Akt的表达增加了分支点的数量。相反，抑制PI3K的其他效应物RAC、mTOR和GSK3都不能促进分支的形成。重要的是，内源性Akt的磷酸化形式定位于生长锥体的顶端，但在NGF处理的PC12细胞中没有小分支。结论：PI3K-Akt通路在抑制神经生长因子诱导的PC12细胞突起分支形成中起关键作用。
Background: Previous studies have shown that phosphatidylinositol-3 kinase (PI3K) plays an important role in NGF (nerve growth factor)-induced neurite elongation. However, the roles of the PI3K pathway in neurite branch formation were not fully understood. Also, it was not clear where the PI3K pathway is activated during branch formation.Results:We found that the treatment of PC12 cells with the PI3K inhibitor LY294002 resulted in a marked increase in the number of neurite branch points, suggesting a suppressive role of PI3K in neurite branch formation. Expression of a constitutively active form of Akt, a downstream effector of PI3K, decreased the number of branch points, whereas that of a dominant-negative form of Akt increased it. In contrast, inhibition of neither Rac, mTOR nor GSK3, other effectors of PI3K, promoted branch formation. Importantly, the phosphorylated form of endogenous Akt was localized at the tips of growth cones, but devoid of small branches in NGF-treated PC12 cells. A GFP-fusion protein of the plekstrin-homology (PH) domain of Akt was also localized at the tips of growth cones.Conclusions: The PI3K-Akt pathway thus plays a key role in suppression of neurite branch formation in NGF-treated PC12 cells.