ABNORMAL ALZHEIMER-LIKE PHOSPHORYLATION OF TAU-PROTEIN BY CYCLIN-DEPENDENT KINASES CDK2 AND CDK5
ABNORMAL ALZHEIMER-LIKE PHOSPHORYLATION OF TAU-PROTEIN BY CYCLIN-DEPENDENT KINASES CDK2 AND CDK5
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DOI：
10.1016/0014-5793(93)80849-p
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发表时间：
1993-12-28
期刊：
影响因子：
3.5
通讯作者：
MANDELKOW, E
中科院分区：
文献类型：
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作者：
BAUMANN, K;MANDELKOW, EM;MANDELKOW, E
我们之前已经证明，某些脯氨酸导向的激酶，如MAP激酶或GSK-3，可以以一种异常的方式磷酸化tau蛋白，使人想起阿尔茨海默氏症配对螺旋细丝中的tau蛋白[Drewes等人（1992）]；Mandelkow et al.(1992)]。这两种激酶在脑组织中丰富，并通过几个组装和拆卸循环与微管物理关联。在本报告中，我们发现cdk2/cyclinA将大约5个P-i整合到重组tau中，并且它还诱导了阿尔茨海默氏tau典型的M(R)移位和抗体反应性。然而，由于大脑中没有cdk2 [Meyerson等人（1992）]，我们寻找了该激酶家族的其他成员。利用一种针对保守n端的抗体，我们从大脑中分离出一种cdk样激酶，该激酶能够通过磷酸化诱导tan的阿尔茨海默样特征。它的大小（31 kDa）、靶特异性（脯氨酸导向）、色谱行为和在大脑中的丰度表明，该激酶与神经元cdc2样激酶nclk（又称PSSARLE或cdk5）相似或相同[Hellmich et al. (1992)]；Meyerson等人（1992）；Xiong等人(1992);Tsai et al.（1993）。cdk5特异性抗体证实了这一点。与MAP激酶和GSK-3一样，该激酶与微管有物理关联，并可通过微管组装和拆卸的循环而富集。因此，cdk5应被视为在阿尔茨海默病进展过程中可能负责tau蛋白变化的另一种激酶。
We have shown earlier that certain proline-directed kinases such as MAP kinase or GSK-3 can phosphorylate tau protein in an abnormal manner reminiscent of tau from Alzheimer paired helical filaments [Drewes et al. (1992); Mandelkow et al. (1992)]. Both kinases are abundant in brain tissue and associate physically with microtubules through several cycles of assembly and disassembly. In this report we show that cdk2/cyclinA incorporates approximate to 5 P-i into recombinant tau, and that it also induces the M(R) shift and antibody reactivity typical of Alzheimer tau. However, since there is no cdk2 in brain [Meyerson et al. (1992)] we looked for other members of this family of kinases. Using an antibody against the conserved N-terminus we isolated a cdk-like kinase from brain which was capable of inducing the Alzheimer-like characteristics in tan by phosphorylation. Its size (31 kDa), target specificity (proline-directed), chromatographic behavior, and abundance in brain suggest that this kinase is similar or identical to the neuronal cdc2-like kinase nclk alias PSSARLE or cdk5 [Hellmich et al. (1992); Meyerson et al. (1992); Xiong et al. (1992); Tsai et al. (1993)]. This was confirmed by an antibody specific for cdk5. Like MAP kinase and GSK-3, this kinase is physically associated with microtubules and can be enriched by cycles of microtubule assembly and disassembly. Thus, cdk5 should be regarded as another kinase that could be held responsible for the changes in tau protein during Alzheimer disease progression.