Cross talk between PI3K-AKT-GSK-3β and PP2A pathways determines tau hyperphosphorylation
Cross talk between PI3K-AKT-GSK-3β and PP2A pathways determines tau hyperphosphorylation
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DOI：
10.1016/j.neurobiolaging.2014.07.035
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发表时间：
2015-01
影响因子：
4.2
通讯作者：
Yixuan Wang;Riyun Yang;Jianlan Gu;Xiaomin Yin;Nana Jin;Shutao Xie;Yifan Wang;Huanhuan Chang
中科院分区：
文献类型：
--
作者：
Yixuan Wang;Riyun Yang;Jianlan Gu;Xiaomin Yin;Nana Jin;Shutao Xie;Yifan Wang;Huanhuan Chang
糖原合成酶激酶-3β (GSK-3β)和蛋白磷酸酶2A （PP2A）是控制tau过度磷酸化的重要酶。这两种酶之间的关系及其对tau过度磷酸化的影响尚不清楚。在本研究中，我们确定了PI3K-AKT-GSK-3β与PP2A信号通路之间的串音，发现前者通过GSK-3β调控PP2Ac的甲基化。GSK-3β的上调通过抑制蛋白磷酸酶甲基酯酶-1的表达和亮氨酸羧甲基转移酶1的磷酸化，导致PP2Ac的甲基化和活性增加。PP2A也调节GSK-3β磷酸化。下调PP2A可增强GSK-3β的Ser9磷酸化，抑制其激酶活性。因此，GSK-3β和PP2A相互调节，并通过彼此直接或间接地控制tau磷酸化。抑制GSK-3β导致的tau磷酸化减少可能被抑制PP2A通过改变磷酸酶甲基化酯酶-1/亮氨酸羧基甲基转移酶1平衡所抵消；PP2A调节tau蛋白在Ser262/356位点的磷酸化，这是tau蛋白病理所必需的位点。这些发现表明靶向PP2A而不是GSK-3β抑制tau病理。
Glycogen synthase kinase-3β (GSK-3β) and protein phosphatase 2A (PP2A) are the important enzymes controlling tau hyperphosphorylation. The relationship between these two enzymes and its impact on tau hyperphosphorylation are not well understood. In the present study, we determined the cross talk between PI3K-AKT-GSK-3β and PP2A pathways and found that the former regulated the methylation of PP2Ac via GSK-3β. Upregulation of GSK-3β led to an increase in the methylation and activity of PP2Ac through suppression of protein phosphatase methylesterase-1 expression and phosphorylation of leucine carboxyl methyltransferase 1. PP2A also regulated GSK-3β phosphorylation. Downregulation of PP2A enhanced Ser9 phosphorylation of GSK-3β and inhibited its kinase activity. Thus, GSK-3β and PP2A regulate each other and control tau phosphorylation both directly and indirectly through each other. Reduction of tau phosphorylation by inhibition of GSK-3β may be more than offset by inhibition of PP2A through a shift in phosphatase methylesterase-1/leucine carboxyl methyltransferase 1 balance; PP2A regulates phosphorylation of tau at Ser262/356, a required site for tau pathology. These findings suggest targeting PP2A rather than GSK-3β to inhibit tau pathology.