Activation of glycogen synthase kinase-3 inhibits protein phosphatase-2A and the underlying mechanisms
Activation of glycogen synthase kinase-3 inhibits protein phosphatase-2A and the underlying mechanisms
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DOI：
10.1016/j.neurobiolaging.2007.03.012
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发表时间：
2008-09-01
影响因子：
4.2
通讯作者：
Wang, Jian-Zhi
中科院分区：
文献类型：
--
作者：
Liu, Gong-Ping;Zhang, Yao;Wang, Jian-Zhi
阿尔茨海默病（AD）患者大脑中蛋白磷酸酶-2A（PP-2A）的活性显着受到抑制，但其机制尚不清楚。在这里，我们发现糖原合酶激酶 30 (GSK-3 beta) 与 PP-2A 抑制剂 2 (I-2(PP-2A)) 的体内关联。在 HEK293、N2a 和 PC12 细胞中，GSK-3 的激活导致 I-2(PP-IA) 积累，同时抑制 PP-2A 活性和 tau 磷酸化增加，而 GSK-3 的抑制导致 I-2(PP-2A) 减少，同时 PP-2A 活性增加和 tau 磷酸化减少。检测到 GSK-3 β 和 I-2(PP-2A) 之间呈正相关 (R = 0.9158)，而 GSK3 β 和 PP-2A 之间呈负相关 (R = -0.9166)。 GSK-3 激活不影响 I-2(PP-2A) mRNA 水平，但增加异源核糖核蛋白 A18 (hnRNP A18) 的 mRNA 水平。 GSK-3的激活增加了蛋白酶体系统的表达和活性。这表明GSK-3的激活通过hnRNP A18参与的机制上调I-2(PP-2A)来抑制PP-2A。 (c) 2007 Elsevier Inc. 保留所有权利。
The activity of protein phosphatase-2A (PP-2A) is significantly suppressed in the brain of Alzheimer's disease (AD) patients, but the mechanism is not understood. Here, we found an in vivo association of glycogen synthase kinase 30 (GSK-3 beta) with inhibitor-2 of PP-2A (I-2(PP-2A)). The activation of GSK-3 resulted in accumulation of I-2(PP-IA) with concomitant suppression of PP-2A activity and increases of tau phosphorylation in HEK293, N2a and PC12 cells, while inhibition of GSK-3 caused decreases of I-2(PP-2A) with increased PP-2A activity and decreased tau phosphorylation. A positive correlation between GSK-3 beta and I-2(PP-2A) (R = 0.9158) and a negative correlation between GSK3 beta and PP-2A (R = -0.9166) were detected. GSK-3 activation did not affect I-2(PP-2A) mRNA level, while it increased the mRNA level of a heterogeneous ribonucleoprotein A18 (hnRNP A18). The activation of GSK-3 increased the expression and the activity of proteasome system. It suggests that activation of GSK-3 inhibits PP-2A through up-regulation of I-2(PP-2A) with hnRNP A18-involved mechanism. (c) 2007 Elsevier Inc. All rights reserved.