GSK-3β directly phosphorylates and activates MARK2/PAR-1
GSK-3β directly phosphorylates and activates MARK2/PAR-1
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DOI：
10.1074/jbc.m507941200
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发表时间：
2005-12-30
影响因子：
4.8
通讯作者：
Imoto, M
中科院分区：
文献类型：
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作者：
Kosuga, S;Tashiro, E;Imoto, M
在阿尔茨海默病(AD)中，微管相关蛋白tau在成对的螺旋细丝中被发现过度磷酸化。在tau蛋白的众多磷酸化位点中，Ser-262是AD脑内tau蛋白异常磷酸化的主要位点。已知的使这一特定位点磷酸化的激酶是Mark2，其激活机制尚不清楚。我们的第一个发现是用LiCl处理细胞，LiCl是另一种主要的tau激酶-糖原合成酶激酶-3β(GSK-3β)的选择性抑制剂，它抑制了tau的Ser-262的磷酸化，这促使我们研究了GSK-3β可能参与Mark2的激活。体外激酶反应表明，重组GSK-3β确实能磷酸化Mark2，而不能磷酸化tau的Ser-262。我们的进一步发现使我们得出结论，GSK-3β使Mark2在Ser-212上磷酸化，Ser-212是已报道的在Mark2激活环中发现的两个磷酸化位点之一(Thr-208和Ser-212)。小干扰RNA对GSK-3β或Mark2的下调抑制了Ser-262的磷酸化水平。这些结果分别表明GSK-3β通过MARK2的磷酸化和激活负责对tau的Ser-262进行磷酸化，并且该特定位点的tau的磷酸化主要是由GSK-3β-Mark2途径介导的。这些发现对阿尔茨海默病的发病机制很有意义。
In Alzheimer disease (AD), the microtubule-associated protein tau is found hyperphosphorylated in paired helical filaments. Among many phosphorylated sites in tau, Ser-262 is the major site for abnormal phosphorylation of tau in AD brain. The kinase known to phosphorylate this particular site is MARK2, whose activation mechanism is yet to be studied. Our first finding that treatment of cells with LiCl, a selective inhibitor of another major tau kinase, glycogen synthase kinase-3 beta(GSK-3 beta), inhibits phosphorylation of Ser-262 of tau led us to investigate the possible involvement of GSK-3 beta in MARK2 activation. In vitro kinase reaction revealed that recombinant GSK-3 beta indeed phosphorylates MARK2, whereas it failed to phosphorylate Ser-262 of tau. Our further findings led us to conclude that GSK-3 beta phosphorylates MARK2 on Ser-212, one of the two reported phosphorylation sites (Thr-208 and Ser-212) found in the activation loop of MARK2. Down-regulation of either GSK-3 beta or MARK2 by small interfering RNAs suppressed the level of phosphorylation on Ser-262. These results, respectively, indicated that GSK-3 beta is responsible for phosphorylating Ser-262 of tau through phosphorylation and activation of MARK2 and that the phosphorylation of tau at this particular site is predominantly mediated by a GSK-3 beta-MARK2 pathway. These findings are of interest in the context of the pathogenesis of AD.