Glycogen Synthase Kinase (GSK) 3β Directly Phosphorylates Serine 212 in the Regulatory Loop and Inhibits Microtubule Affinity-regulating Kinase (MARK) 2*
Glycogen Synthase Kinase (GSK) 3β Directly Phosphorylates Serine 212 in the Regulatory Loop and Inhibits Microtubule Affinity-regulating Kinase (MARK) 2*
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DOI：
10.1074/jbc.m706596200
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发表时间：
2008-07
影响因子：
4.8
通讯作者：
T. Timm;Kiruthiga Balusamy;Xiao-yu Li;J. Biernat;E. Mandelkow;E. Mandelkow
中科院分区：
文献类型：
--
作者：
T. Timm;Kiruthiga Balusamy;Xiao-yu Li;J. Biernat;E. Mandelkow;E. Mandelkow
MARK/PAR-1是一个具有多种功能的激酶家族，尤其是在诱导细胞极性方面，它可以磷酸化重复结构域中的微管相关蛋白，导致它们与微管分离，从而使微管失稳。由于它在阿尔茨海默病中Tau蛋白异常磷酸化中的作用，我们寻找调节蛋白激酶。MARK家族的激酶可以通过保守的苏氨酸的磷酸化(Mark2中的Thr-208)激活，也可以通过丝氨酸的磷酸化失活(Ser-212)，两者都位于催化域的激活环中。激活是通过MARK/TAO1或LKB1实现的，但失活的激酶尚不清楚。我们在这里展示了GSK3β起到抑制激酶的作用。由于Gsk3β也可以在重复结构域之外的位置磷酸化Tau，因此Gsk3β的激活和伴随的MARK失活可以改变阿尔茨海默病中Tau蛋白的病理性磷酸化模式。
MARK/Par-1, a kinase family with diverse functions particularly in inducing cell polarity, can phosphorylate microtubule-associated proteins in their repeat domain and cause their detachment from microtubules, and thereby microtubule destabilization. Because of its role in abnormal phosphorylation of the Tau protein in Alzheimer disease, we searched for regulatory kinases. MARK family kinases can be activated by phosphorylation of a conserved threonine (Thr-208 in MARK2), and inactivated by phosphorylation of a serine (Ser-212), both in the activation loop of the catalytic domain. Activation is achieved by the kinases MARKK/TAO1 or LKB1, although the inactivating kinase was unknown. We show here that GSK3β serves the role of the inhibitory kinase. Because GSK3β can also phosphorylate Tau at sites outside the repeat domain, the activation of GSK3β, and concomitant inactivation of MARK can shift the pattern of pathological phosphorylation of Tau protein in Alzheimer disease.