Tyrosine 394 is phosphorylated in Alzheimer's paired helical filament tau and in fetal tau with c-Abl as the candidate tyrosine kinase
Tyrosine 394 is phosphorylated in Alzheimer's paired helical filament tau and in fetal tau with c-Abl as the candidate tyrosine kinase
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DOI：
10.1523/jneurosci.1487-05.2005
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发表时间：
2005-07-13
影响因子：
5.3
通讯作者：
Anderton, BH
中科院分区：
文献类型：
--
作者：
Derkinderen, P;Scales, TME;Anderton, BH
Tau是轴突的主要微管相关蛋白，并且也是成对螺旋丝（PHF）的主要组分，所述成对螺旋丝（PHF）包括在阿尔茨海默病和其他Tau病中发现的神经元缠结。除了在正常tau和来自神经元缠结的tau中的丝氨酸和苏氨酸残基上的tau磷酸化之外，据报道Tyr-18是Src家族激酶Fyn的磷酸化位点。我们研究了tau蛋白中Tyr-18以外的酪氨酸残基是否磷酸化，以及其他酪氨酸激酶是否可能磷酸化tau蛋白。使用质谱法，我们在来自阿尔茨海默病脑的PHF-tau和人胎脑tau中阳性鉴定了磷酸化Tyr-394。当将野生型人tau转染到成纤维细胞或神经母细胞瘤细胞中时，用过钒酸盐处理导致tau通过内源性激酶在酪氨酸上磷酸化。通过用苯丙氨酸取代tau中的五个酪氨酸中的每一个，我们鉴定了Tyr-394为tau中酪氨酸磷酸化的主要位点。PP 2（4-amino-5-（4-chlorophenyl-7-（t-butyl）pyrazole [3，4-d] pyrimidine））抑制tau蛋白的酪氨酸磷酸化。PP 2抑制Src家族激酶和c-Abl。Abl可以与tau蛋白共沉淀，并存在于阿尔茨海默病患者脑切片中的pretangle神经元中。这些结果表明，tau蛋白在Tyr-394上的磷酸化是一种生理事件，可能是信号传递的一部分，并表明Abl可能在阿尔茨海默病中具有致病作用。
Tau is a major microtubule-associated protein of axons and is also the principal component of the paired helical filaments (PHFs) that comprise the neurofibrillary tangles found in Alzheimer's disease and other tauopathies. Besides phosphorylation of tau on serine and threonine residues in both normal tau and tau from neurofibrillary tangles, Tyr-18 was reported to be a site of phosphorylation by the Src-family kinase Fyn. We examined whether tyrosine residues other than Tyr-18 are phosphorylated in tau and whether other tyrosine kinases might phosphorylate tau. Using mass spectrometry, we positively identified phosphorylated Tyr-394 in PHF-tau from an Alzheimer brain and in human fetal brain tau. When wild-type human tau was transfected into fibroblasts or neuroblastoma cells, treatment with pervanadate caused tau to become phosphorylated on tyrosine by endogenous kinases. By replacing each of the five tyrosines in tau with phenylalanine, we identified Tyr-394 as the major site of tyrosine phosphorylation in tau. Tyrosine phosphorylation of tau was inhibited by PP2 (4-amino-5-(4-chlorophenyl-7-(t-butyl) pyrazolo[3,4-d] pyrimidine), which is known to inhibit Src-family kinases and c-Abl. Cotransfection of tau and kinases showed that Tyr-18 was the major site for Fyn phosphorylation, but Tyr-394 was the main residue for Abl. In vitro, Abl phosphorylated tau directly. Abl could be coprecipitated with tau and was present in pretangle neurons in brain sections from Alzheimer cases. These results show that phosphorylation of tau on Tyr-394 is a physiological event that is potentially part of a signal relay and suggest that Abl could have a pathogenic role in Alzheimer's disease.