An essential role of the aPKC-Aurora A-NDEL1 pathway in neurite elongation by modulation of microtubule dynamics
An essential role of the aPKC-Aurora A-NDEL1 pathway in neurite elongation by modulation of microtubule dynamics
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DOI：
10.1038/ncb1919
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发表时间：
2009-09-01
影响因子：
21.3
通讯作者：
Hirotsune, Shinji
中科院分区：
文献类型：
--
作者：
Mori, Daisuke;Yamada, Masami;Hirotsune, Shinji
在轴突延伸过程中，细胞酮的协调重塑是突出的。与肌动蛋白细丝调控的广泛表征相比，微管在轴突伸展过程中的动态变化知之甚少。在这里，我们确定了一个非典型的蛋白激酶C(APKC)-Aurora A-NDEL1通路，它在轴突延伸过程中对微管组织的调节至关重要。APKC在Thr 287(T287)处使Aurora A磷酸化，从而增强与TPX2的相互作用，并促进Aurora A在突起丘处的激活，随后在S251处磷酸化NDEL1并重新招募。APKC、Aurora A或TPX2的抑制，或Well的破坏，都会导致轴突延伸的严重损害。用微管+末端标记对微管动力学的分析表明，抑制aPKC-Aurora A-NDEL1通路导致微管组织中心(MTOC)发出微管的频率显著降低，提示Aurora A作用于aPKC下游。这些发现表明，在轴突延伸过程中，aPKC-Aurora A-NDEL1通路在微管重塑中扮演着令人惊讶的角色。
Orchestrated remodelling of the cytoskeketon is prominent during neurite extension. In contrast with the extensive characterization of actin filament regulation, little is known about the dynamics of microtubules during neurite extension. Here we identify an atypical protein kinase C (aPKC)-Aurora A-NDEL1 pathway that is crucial for the regulation of microtubule organization during neurite extension. aPKC phosphorylates Aurora A at Thr 287 (T287), which augments interaction with TPX2 and facilitates activation of Aurora A at the neurite hillock, followed by phosphorylation of NDEL1 at S251 and recruitment. Suppression of aPKC, Aurora A or TPX2, or disruption of Well, results in severe impairment of neurite extension. Analysis of microtubule dynamics with a microtubule plus-end marker revealed that suppression of the aPKC-Aurora A-NDEL1 pathway resulted in a significant decrease in the frequency of microtubule emanation from the microtubule organizing centre (MTOC), suggesting that Aurora A acts downstream of aPKC. These findings demonstrate a surprising role of aPKC-Aurora A-NDEL1 pathway in microtubule remodelling during neurite extension.