Goedert M, Hasegawa M, Jakes R, Lawler S, Cuenda A, Cohen P
MRC Laboratory of Molecular Biology, Cambridge, UK.
FEBS Lett. 1997 Jun 2;409(1):57-62. doi: 10.1016/s0014-5793(97)00483-3.
The paired helical filament, which comprises the major fibrous element of the neurofibrillary lesions of Alzheimer's disease, is composed of hyperphosphorylated microtubule-associated protein tau. Many of the hyperphosphorylated sites in tau are serine/threonine-prolines. Here we show that the stress-activated protein (SAP) kinases SAPK1gamma (also called JNK1), SAPK2a (also called p38, RK, CSBPs, Mpk2 and Mxi2), SAPK2b (also called p38beta), SAPK3 (also called ERK6 and p38gamma) and SAPK4 phosphorylate tau at many serine/threonine-prolines, as assessed by the generation of the epitopes of phosphorylation-dependent anti-tau antibodies. Based on initial rates of phosphorylation, tau was found to be a good substrate for SAPK4 and SAPK3, a reasonable substrate for SAPK2b and a relatively poor substrate for SAPK2a and SAPK1gamma. Phosphorylation of tau by SAPK3 and SAPK4 resulted in a marked reduction in its ability to promote microtubule assembly. These findings double the number of candidate protein kinases for the hyperphosphorylation of tau in Alzheimer's disease and other neurodegenerative disorders.
成对螺旋丝构成了阿尔茨海默病神经原纤维病变的主要纤维成分，它由高度磷酸化的微管相关蛋白tau组成。tau蛋白中的许多高度磷酸化位点是丝氨酸/苏氨酸 - 脯氨酸。我们在此表明，应激激活蛋白（SAP）激酶SAPK1γ（也称为JNK1）、SAPK2a（也称为p38、RK、CSBPs、Mpk2和Mxi2）、SAPK2b（也称为p38β）、SAPK3（也称为ERK6和p38γ）和SAPK4会在许多丝氨酸/苏氨酸 - 脯氨酸处使tau蛋白磷酸化，这是通过磷酸化依赖性抗tau抗体表位的产生来评估的。根据磷酸化的初始速率，发现tau是SAPK4和SAPK3的良好底物，是SAPK2b的合理底物，而对于SAPK2a和SAPK1γ则是相对较差的底物。SAPK3和SAPK4对tau的磷酸化导致其促进微管组装的能力显著降低。这些发现使阿尔茨海默病和其他神经退行性疾病中tau蛋白过度磷酸化的候选蛋白激酶数量增加了一倍。
