Phosphorylation of tau by glycogen synthase kinase-3 beta in intact mammalian cells: The effects on the organization and stability of microtubules
Phosphorylation of tau by glycogen synthase kinase-3 beta in intact mammalian cells: The effects on the organization and stability of microtubules
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DOI：
10.1016/0306-4522(96)00126-1
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发表时间：
1996-08-01
期刊：
影响因子：
3.3
通讯作者：
Anderton, BH
中科院分区：
文献类型：
--
作者：
Lovestone, S;Hartley, CL;Anderton, BH
tau蛋白的磷酸化状态在神经发育过程中发生变化，高度磷酸化的tau蛋白在阿尔茨海默病中发现的成对螺旋细丝中积累。在非神经元哺乳动物细胞中，瞬时表达的tau蛋白在已知成对螺旋丝中磷酸化的位点上主要不被磷酸化。然而，这种磷酸化模式是由糖原合成酶激酶-3和-3诱导的，这里我们表明这导致tau细胞内特性的改变。在细胞内，tau与细胞骨架结构结合，通过诱导厚而稳定的微管束引起细胞结构的变化。当tau蛋白与糖原合成酶激酶-3 β共表达时，这种形态就消失了；微管变得不那么稳定，不受tau蛋白的束缚。独立于对tau的任何直接或间接影响，糖原合成酶激酶-3 β诱导微管组织的一些但相对轻微的变化，失去一个突出的中心体微管起源。细胞骨架对细胞功能至关重要，在有丝分裂后神经元内具有高度特化的结构，部分由神经元特异性微管相关蛋白（如tau）诱导。体外研究表明，tau蛋白的特性受磷酸化调控，因为高度磷酸化的tau蛋白不会促进微管蛋白聚合物的组装。我们已经证明，在完整细胞中，糖原合酶激酶-3 β存在时，tau高度磷酸化失去了微管结合和稳定的特性，这表明该酶对tau磷酸化的调节可能是神经发育期间细胞骨架功能调节和神经退行性变中细胞骨架功能丧失的重要机制。版权所有IBRO。Elsevier Science Ltd.出版。
The phosphorylation state of tau changes during neurodevelopment and highly phosphorylated tau accumulates in the paired helical filaments found in Alzheimer's disease. In non-neuronal mammalian cells transiently expressed tau is predominantly not phosphorylated at sites known to be phosphorylated in paired helical filaments. However this pattern of phosphorylation is induced by both glycogen synthase kinase-3 alpha and -3 beta and here we show that this results in a change in the intracellular properties of tau. Within cells tau is bound to cytoskeletal structures and causes changes in cellular cytoarchitecture with the induction of thick and stable microtubule bundles. This morphology is lost when tau is co-expressed with glycogen synthase kinase-3 beta; microtubules become less stable and are not bound by tau. Independently of any direct or indirect effects on tau, glycogen synthase kinase-3 beta induces some but relatively slight changes in microtubule organization with the loss of a prominent centrosomal microtubular origin. The cytoskeleton is critical to cell function and within post-mitotic neurons has a highly specialized structure induced, in part, by the neuronal-specific microtubule-associated proteins such as tau. In vitro studies have suggested that the properties of tau are regulated by phosphorylation as highly phosphorylated tau does not promote tubulin polymer assembly.We have demonstrated, in intact cells, that tau highly phosphorylated in the presence of glycogen synthase kinase-3 beta loses the properties of microtubule binding and stabilization, suggesting that regulation of tau phosphorylation by this enzyme might be an important mechanism whereby cytoskeletal function is modulated during neurodevelopment and lost in neurodegeneration. Copyright (C) 1996 IBRO. Published by Elsevier Science Ltd.