Augmented AMPK activity inhibits cell migration by phosphorylating the novel substrate Pdlim5.
Augmented AMPK activity inhibits cell migration by phosphorylating the novel substrate Pdlim5.
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DOI：
10.1038/ncomms7137
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发表时间：
2015-01-30
影响因子：
16.6
通讯作者：
Takashima S
中科院分区：
文献类型：
--
作者：
Yan Y;Tsukamoto O;Nakano A;Kato H;Kioka H;Ito N;Higo S;Yamazaki S;Shintani Y;Matsuoka K;Liao Y;Asanuma H;Asakura M;Takafuji K;Minamino T;Asano Y;Kitakaze M;Takashima S
增强的AMP活化蛋白激酶（AMPK）活性抑制细胞迁移，可能有助于化学AMPK活化剂在预防动脉粥样硬化、血管重塑和癌症转移中的临床益处。然而，其潜在机制在很大程度上仍然未知。在这里，我们确定PDZ和LIM结构域5（Pdlim 5）作为一种新的AMPK底物，并表明它在抑制细胞迁移中起着关键作用。AMPK直接在Ser 177磷酸化Pdlim 5。外源性表达拟磷酸化S177 D-Pdlim 5抑制细胞迁移并减弱板状伪足形成。与这一观察结果一致，S177 D-Pdlim 5抑制细胞周边的Rac 1活性，并从前缘置换Arp 2/3复合物。值得注意的是，S177 D-Pdlim 5，而不是WT-Pdlim 5，减弱与Rac 1特异性鸟嘌呤核苷酸交换因子在细胞周边的关联。总之，我们的研究结果表明，Pdlim 5的Ser 177磷酸化AMPK介导的抑制细胞迁移抑制Rac 1-Arp 2/3信号通路。 增强的AMP活化蛋白激酶（AMPK）活性通过一种未知的机制抑制细胞迁移。在这里，Yan等人表明AMPK磷酸化新底物PDZ和LIM结构域5（Pdlim 5），并且磷酸模拟物Pdlim 5通过破坏Rac 1-Arp 2/3信号传导途径来损害细胞迁移。
Augmented AMP-activated protein kinase (AMPK) activity inhibits cell migration, possibly contributing to the clinical benefits of chemical AMPK activators in preventing atherosclerosis, vascular remodelling and cancer metastasis. However, the underlying mechanisms remain largely unknown. Here we identify PDZ and LIM domain 5 (Pdlim5) as a novel AMPK substrate and show that it plays a critical role in the inhibition of cell migration. AMPK directly phosphorylates Pdlim5 at Ser177. Exogenous expression of phosphomimetic S177D-Pdlim5 inhibits cell migration and attenuates lamellipodia formation. Consistent with this observation, S177D-Pdlim5 suppresses Rac1 activity at the cell periphery and displaces the Arp2/3 complex from the leading edge. Notably, S177D-Pdlim5, but not WT-Pdlim5, attenuates the association with Rac1-specific guanine nucleotide exchange factors at the cell periphery. Taken together, our findings indicate that phosphorylation of Pdlim5 on Ser177 by AMPK mediates inhibition of cell migration by suppressing the Rac1-Arp2/3 signalling pathway. Augmented AMP-activated protein kinase (AMPK) activity inhibits cell migration through an unknown mechanism. Here, Yan et al. show that AMPK phosphorylates the novel substrate PDZ and LIM domain 5 (Pdlim5), and that phosphomimetic Pdlim5 impairs cell migration by disrupting the Rac1-Arp2/3 signalling pathway.
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DOI：
10.1038/nrm2957
发表时间：
2010-09
期刊：
Nature reviews. Molecular cell biology
影响因子：
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作者：
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DOI：
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发表时间：
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期刊：
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影响因子：
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发表时间：
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期刊：
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影响因子：
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作者：
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影响因子：
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作者：
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