AMPK controls the speed of microtubule polymerization and directional cell migration through CLIP-170 phosphorylation
AMPK controls the speed of microtubule polymerization and directional cell migration through CLIP-170 phosphorylation
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DOI：
10.1038/ncb2060
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发表时间：
2010-06-01
影响因子：
21.3
通讯作者：
Takashima, Seiji
中科院分区：
文献类型：
--
作者：
Nakano, Atsushi;Kato, Hisakazu;Takashima, Seiji
AMP活化蛋白激酶（AMPK）是一种能量敏感的Ser/Thr蛋白激酶，最初被证明受AMP调节（1）。AMPK被抑制ATP产生或刺激ATP消耗的各种细胞应激激活（2）。除了其在代谢中的作用之外，最近还报道AMPK通过调节细胞极性和分裂来重塑细胞（3-6）。然而，参与这些功能的AMPK下游靶点尚未完全确定。在这里，我们表明，磷酸化的微管加上端蛋白CLIP-170的AMPK是必需的微管动力学和定向细胞迁移的调节。AMPK的抑制和不可磷酸化的CLIP-170突变体的表达都导致CLIP-170在微管尖端的积累延长和增强，以及微管蛋白聚合减慢。此外，AMPK的抑制损害微管的稳定性和干扰定向细胞迁移。所有这些表型都通过磷酸化模拟物CLIP-170突变体的表达来拯救。因此，我们的研究结果表明，AMPK通过CLIP-170磷酸化调节微管动力学来控制基本的细胞功能。
AMP-activated protein kinase ( AMPK) is an energy-sensing Ser/Thr protein kinase originally shown to be regulated by AMP(1). AMPK is activated by various cellular stresses that inhibit ATP production or stimulate ATP consumption(2). In addition to its role in metabolism, AMPK has recently been reported to reshape cells by regulating cell polarity and division(3-6). However, the downstream targets of AMPK that participate in these functions have not been fully identified. Here, we show that phosphorylation of the microtubule plus end protein CLIP-170 by AMPK is required for microtubule dynamics and the regulation of directional cell migration. Both inhibition of AMPK and expression of a non-phosphorylatable CLIP-170 mutant resulted in prolonged and enhanced accumulation of CLIP-170 at microtubule tips, and slower tubulin polymerization. Furthermore, inhibition of AMPK impaired microtubule stabilization and perturbed directional cell migration. All of these phenotypes were rescued by expression of a phosphomimetic CLIP-170 mutant. Our results demonstrate, therefore, that AMPK controls basic cellular functions by regulating microtubule dynamics through CLIP-170 phosphorylation.