Overcoming Amino-Nogo-induced Inhibition of Cell Spreading and Neurite Outgrowth by 12-O-Tetradecanoylphorbol-13-acetate-type Tumor Promoters
Overcoming Amino-Nogo-induced Inhibition of Cell Spreading and Neurite Outgrowth by 12-O-Tetradecanoylphorbol-13-acetate-type Tumor Promoters
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DOI：
10.1074/jbc.m109.071548
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发表时间：
2010-02-26
影响因子：
4.8
通讯作者：
Walsh, Frank S.
中科院分区：
文献类型：
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作者：
Deng, Kangwen;Gao, Ying;Walsh, Frank S.
NogoA的N-末端结构域，称为氨基-Nogo，通过一种很大程度上未知的机制抑制轴突生长和细胞扩散。在本研究中，我们表明，氨基Nogo降低Rac 1活性，抑制成纤维细胞的蔓延。12-O-十四酰基佛波醇-13-乙酸酯型肿瘤促进剂，如佛波醇12-肉豆蔻酸酯13-乙酸酯（PMA）和teleocidin，增加Rac 1活性并克服氨基-Nogo诱导的细胞扩散抑制。肿瘤促进剂对细胞扩散的刺激作用需要蛋白激酶D的激活和随后的Akt 1的激活。此外，我们确定Akt 1作为一个新的信号成分的amino-Nogo途径。Akt 1磷酸化被氨基-Nogo降低。用细胞渗透性肽TAT-TCL 1激活Akt 1可阻断氨基-Nogo抑制。最后，我们提供的证据表明，除了成纤维细胞，这些信号通路在神经元中运作。我们的研究结果表明，蛋白激酶D和Akt 1的激活是促进损伤后轴突再生的途径。
The N-terminal domain of NogoA, called amino-Nogo, inhibits axonal outgrowth and cell spreading via a largely unknown mechanism. In the present study, we show that amino-Nogo decreases Rac1 activity and inhibits fibroblast spreading. 12-O-Tetradecanoylphorbol-13-acetate-type tumor promoters, such as phorbol 12-myristate 13-acetate (PMA) and teleocidin, increase Rac1 activity and overcome the amino-Nogo-induced inhibition of cell spreading. The stimulating effect of tumor promoters on cell spreading requires activation of protein kinase D and the subsequent activation of Akt1. Furthermore, we identified Akt1 as a new signaling component of the amino-Nogo pathway. Akt1 phosphorylation is decreased by amino-Nogo. Activation of Akt1 with a cell-permeable peptide, TAT-TCL1, blocks the amino-Nogo inhibition. Finally, we provide evidence that these signaling pathways operate in neurons in addition to fibroblasts. Our results suggest that activation of protein kinase D and Akt1 are approaches to promote axonal regeneration after injury.