Tumor suppressor PTEN affects tau phosphorylation: deficiency in the phosphatase activity of PTEN increases aggregation of an FTDP-17 mutant Tau.
Tumor suppressor PTEN affects tau phosphorylation: deficiency in the phosphatase activity of PTEN increases aggregation of an FTDP-17 mutant Tau.
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DOI：
10.1186/1750-1326-1-7
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发表时间：
2006-07-31
影响因子：
15.1
通讯作者：
Xu H
中科院分区：
文献类型：
--
作者：
Zhang X;Zhang YW;Liu S;Bulloj A;Tong GG;Zhang Z;Liao FF;Xu H
Tau蛋白异常过度磷酸化与多种神经退行性疾病有关。尽管在体外和体内都发现了一些蛋白激酶对tau的磷酸化作用，但是tau磷酸化的分子机制在很大程度上还不清楚。最近，越来越多的证据表明tau磷酸化和PI3K信号之间存在联系。在这项研究中，我们研究了突变型额叶痴呆和17号染色体连锁帕金森病(FTDP-17)tau在抑癌基因PTEN存在下的磷酸化、聚集和与微管的结合。PTEN是PI3K信号的主要调节成分。在人野生型或磷酸酶活性缺失突变体PTEN存在的情况下，用不同的磷酸化tau特异性抗体评价了人突变体FTDP-17 tau T40RW的磷酸化。在被评估的磷酸化位点中，Ser214和Thr212磷酸化tau蛋白的水平在野生型PTEN存在时显著降低，而当磷酸酶活性缺失突变体PTEN异位表达时显著增加。表达野生型PTEN后，突变型tau细胞胞浆中的可溶性tau含量显著增加，突变型PTEN存在时，胞浆中可溶tau聚集体的含量显著增加。此外，与野生型PTEN和对照DNA高表达的细胞相比，Filter/Trap检测到高表达突变PTEN的细胞中有更多的不溶于SDS的突变型tau聚集体。免疫细胞化学实验证实了这一观点，证明了磷酸酶活性缺失突变体PTEN的过表达导致突变体tau在COS-7细胞中形成聚集体。抑癌基因PTEN可抑制突变型FTDP-17 tau在特定位点的磷酸化，而磷酸酶活性为空的PTEN可增加突变型tau在这些位点的磷酸化。PTEN异位表达引起的tau蛋白磷酸化状态的改变与突变型tau蛋白细胞分布的改变有关。此外，突变型PTEN的过表达可以增加突变型tau聚集体的水平，并导致细胞内可见聚集体的形成。
Aberrant hyperphosphorylation of tau protein has been implicated in a variety of neurodegenerative disorders. Although a number of protein kinases have been shown to phosphorylate tau in vitro and in vivo, the molecular mechanisms by which tau phosphorylation is regulated pathophysiologically are largely unknown. Recently, a growing body of evidence suggests a link between tau phosphorylation and PI3K signaling. In this study, phosphorylation, aggregation and binding to the microtubule of a mutant frontal temporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) tau in the presence of tumor suppressor PTEN, a major regulatory component in PI3K signaling, were investigated. Phosphorylation of the human mutant FTDP-17 tau, T40RW, was evaluated using different phospho-tau specific antibodies in the presence of human wild-type or phosphatase activity null mutant PTEN. Among the evaluated phosphorylation sites, the levels of Ser214 and Thr212 phospho-tau proteins were significantly decreased in the presence of wild-type PTEN, and significantly increased when the phosphatase activity null mutant PTEN was ectopically expressed. Fractionation of the mutant tau transfected cells revealed a significantly increased level of soluble tau in cytosol when wild-type PTEN was expressed, and an elevated level of SDS-soluble tau aggregates in the presence of the mutant PTEN. In addition, the filter/trap assays detected more SDS-insoluble mutant tau aggregates in the cells overexpressing the mutant PTEN compared to those in the cells overexpressing wild-type PTEN and control DNA. This notion was confirmed by the immunocytochemical experiment which demonstrated that the overexpression of the phosphatase activity null mutant PTEN caused the mutant tau to form aggregates in the COS-7 cells. Tumor suppressor PTEN can alleviate the phosporylation of the mutant FTDP-17 tau at specific sites, and the phosphatase activity null PTEN increases the mutant tau phosphorylation at these sites. The changes of the tau phosphorylation status by ectopic expression of PTEN correlate to the alteration of the mutant tau's cellular distribution. In addition, the overexpression of the mutant PTEN can increase the level of the mutant tau aggregates and lead to the formation of visible aggregates in the cells.
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影响因子：
6
作者：
DeTure, M;Ko, LW;Yen, SH
通讯作者：
Yen, SH
DOI：
10.1073/pnas.121119298
发表时间：
2001-06-05
影响因子：
11.1
作者：
Alonso, AD;Zaidi, T;Iqbal, K
通讯作者：
Iqbal, K
DOI：
10.1073/pnas.242720499
发表时间：
2003-01-21
影响因子：
11.1
作者：
Dou, F;Netzer, WJ;Xu, HX
通讯作者：
Xu, HX
影响因子：
1.7
作者：
Li, X;An, WL;Pei, JJ
通讯作者：
Pei, JJ
影响因子：
3.5
作者：
BAUMANN, K;MANDELKOW, EM;MANDELKOW, E
通讯作者：
MANDELKOW, E