Baumann K, Mandelkow E M, Biernat J, Piwnica-Worms H, Mandelkow E
Max-Planck Unit for Structural Molecular Biology, Hamburg, Germany.
FEBS Lett. 1993 Dec 28;336(3):417-24. doi: 10.1016/0014-5793(93)80849-p.
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/cyclin A incorporates = 5 Pi into recombinant tau, and that it also induces the MR 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 tau 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.
我们之前已经表明，某些脯氨酸定向激酶，如丝裂原活化蛋白激酶（MAP激酶）或糖原合成酶激酶-3（GSK-3），能够以异常方式磷酸化tau蛋白，这种方式让人联想到阿尔茨海默病配对螺旋丝中的tau蛋白[德鲁斯等人（1992年）；曼德科夫等人（1992年）]。这两种激酶在脑组织中含量丰富，并通过几个组装和拆卸循环与微管发生物理关联。在本报告中，我们表明细胞周期蛋白依赖性激酶2（cdk2）/细胞周期蛋白A能将约5个磷酸基团掺入重组tau蛋白中，并且它还能诱导出阿尔茨海默病tau蛋白典型的磁共振（MR）位移和抗体反应性。然而，由于脑组织中不存在cdk2[迈耶森等人（1992年）]，我们寻找了该激酶家族的其他成员。使用针对保守N端的抗体，我们从脑组织中分离出一种类似cdk样激酶，它能够通过磷酸化诱导tau蛋白出现类似阿尔茨海默病的特征。它的大小（31 kDa）、靶标特异性（脯氨酸定向）、色谱行为以及在脑组织中的丰度表明，这种激酶与神经元细胞周期蛋白依赖性激酶2样激酶（nclk，别名PSSARLE或cdk5）相似或相同[赫尔米奇等人（1992年）；迈耶森等人（1992年）；熊等人（1992年）；蔡等人（1993年）]。这一点通过一种对cdk5特异的抗体得到了证实。与MAP激酶和GSK-3一样，这种激酶与微管发生物理关联，并且可以通过微管组装和拆卸循环得到富集。因此，cdk5应被视为另一种可能导致阿尔茨海默病进展过程中tau蛋白变化的激酶。
