Microtubule Affinity-regulating Kinase 2 (MARK2) Turns on Phosphatase and Tensin Homolog (PTEN)-induced Kinase 1 (PINK1) at Thr-313, a Mutation Site in Parkinson Disease EFFECTS ON MITOCHONDRIAL TRANSPORT
Microtubule Affinity-regulating Kinase 2 (MARK2) Turns on Phosphatase and Tensin Homolog (PTEN)-induced Kinase 1 (PINK1) at Thr-313, a Mutation Site in Parkinson Disease EFFECTS ON MITOCHONDRIAL TRANSPORT
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DOI：
10.1074/jbc.m111.262287
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发表时间：
2012-03-09
影响因子：
4.8
通讯作者：
Mandelkow, Eva-Maria
中科院分区：
文献类型：
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作者：
Matenia, Dorthe;Hempp, Cindy;Mandelkow, Eva-Maria
激酶MARK2/Par-1在几个细胞过程中发挥关键作用，包括神经退行性疾病，如阿尔茨海默病，通过磷酸化tau并将其从微管中分离。为了寻找MARK2的相互作用伙伴，我们确定了磷酸酶和紧张素同源物（PTEN）诱导的激酶1 (PINK1)，这对神经元的存活很重要，其突变与家族性帕金森病（PD）有关。MARK2磷酸化并激活了PINK1的裂解形式（Delta N-PINK1；氨基酸156-581）。Thr-313是主要的磷酸化位点，在一种常见的PD变体中，一个残基突变为不可磷酸化的形式（T313M）。PINK1中Thr-313突变为Met或Glu，显示出毒性作用，神经元中线粒体分布异常。发现MARK2和PINK1与线粒体共定位并调节其运输。Delta N-PINK1促进顺行运输，增加固定线粒体的比例，而全长PINK1促进逆行运输。在这两种情况下，MARK2都增强了效果。结果发现MARK2是PINK1和Delta N-PINK1的上游调节因子，并为帕金森病神经元线粒体运输和神经退行性变的调控提供了见解。
The kinase MARK2/Par-1 plays key roles in several cell processes, including neurodegeneration such as Alzheimer disease by phosphorylating tau and detaching it from microtubules. In search of interaction partners of MARK2, we identified phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1), which is important for the survival of neurons and whose mutations are linked to familial Parkinson disease (PD). MARK2 phosphorylated and activated the cleaved form of PINK1 (Delta N-PINK1; amino acids 156-581). Thr-313 was the primary phosphorylation site, a residue mutated to a non-phosphorylatable form (T313M) in a frequent variant of PD. Mutation of Thr-313 to Met or Glu in PINK1 showed toxic effects with abnormal mitochondrial distribution in neurons. MARK2 and PINK1 were found to colocalize with mitochondria and regulate their transport. Delta N-PINK1 promoted anterograde transport and increased the fraction of stationary mitochondria, whereas full-length PINK1 promoted retrograde transport. In both cases, MARK2 enhanced the effects. The results identify MARK2 as an upstream regulator of PINK1 and Delta N-PINK1 and provide insights into the regulation of mitochondrial trafficking in neurons and neurodegeneration in PD.