Microtubule affinity-regulating kinase 2 functions downstream of the PAR-3/PAR-6/atypical PKC complex in regulating hippocampal neuronal polarity
Microtubule affinity-regulating kinase 2 functions downstream of the PAR-3/PAR-6/atypical PKC complex in regulating hippocampal neuronal polarity
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DOI：
10.1073/pnas.0509955103
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发表时间：
2006-05-30
影响因子：
11.1
通讯作者：
Luo, Z. G.
中科院分区：
文献类型：
--
作者：
Chen, Y. M.;Wang, Q. J.;Luo, Z. G.
PAR-3/PAR-6/非典型PKC（aPKC）复合物是海马神经元轴突-树突特化所必需的。然而，该复合物的下游效应物并没有很好地定义。在这篇文章中，我们报告了微管亲和力调节激酶（MARK）/PAR-1在轴突树突特化中的作用。用小干扰RNA敲低MARK 2表达诱导多个轴突样神经突的形成并促进轴突生长。MARK 2的异位表达引起tau蛋白磷酸化（S262）并导致轴突损失，并且这种表型通过PAR-3、PAR-6和aPKC的表达而被挽救。相反，由MARK 2突变体（T595 A）引起的极性缺陷，其对aPKC不响应，不能被PAR-3/PAR-6/aPKC复合物拯救。此外，极性废除在过度表达的突变体的MARK 2与删除激酶结构域，但一个完整的aPKC结合域的神经元。最后，MARK 2的抑制挽救了显性负性aPKC突变体诱导的极性缺陷。这些结果表明，MARK 2参与神经元极化和PAR-3/PAR-6/aPKC复合物下游的功能。我们认为aPKC与PAR-3/PAR-6复合后负性调节MARK，进而导致微管相关蛋白（如tau）的去磷酸化，导致微管组装和轴突伸长。
The PAR-3/PAR-6/atypical PKC (aPKC) complex is required for axon-dendrite specification of hippocampal neurons. However, the downstream effectors of this complex are not well defined. In this article, we report a role for microtubule affinity-regulating kinase (MARK)/PAR-1 in axon-dendrite specification. Knocking down MARK2 expression with small interfering RNAs induced formation of multiple axon-like neurites and promoted axon outgrowth. Ectopic expression of MARK2 caused phosphorylation of tau (S262) and led to loss of axons, and this phenotype was rescued by expression of PAR-3, PAR-6, and aPKC. In contrast, the polarity defects caused by an MARK2 mutant (T595A), which is not responsive to aPKC, were not rescued by the PAR-3/PAR-6/aPKC complex. Moreover, polarity was abrogated in neurons overexpressing a mutant of MARK2 with a deleted kinase domain but an intact aPKC-binding domain. Finally, suppression of MARK2 rescued the polarity defects induced by a dominant-negative aPKC mutant. These results suggest that MARK2 is involved in neuronal polarization and functions downstream of the PAR-3/PAR-6/aPKC complex. We propose that aPKC in complex with PAR-3/PAR-6 negatively regulates MARK(s), which in turn causes dephosphorylation of microtubule-associated proteins, such as tau, leading to the assembly of microtubules and elongation of axons.