Conversion of graded phosphorylation into switch-like nuclear translocation via autoregulatory mechanisms in ERK signalling.
Conversion of graded phosphorylation into switch-like nuclear translocation via autoregulatory mechanisms in ERK signalling.
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DOI：
10.1038/ncomms10485
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发表时间：
2016-01-20
影响因子：
16.6
通讯作者：
Takahashi K
中科院分区：
文献类型：
--
作者：
Shindo Y;Iwamoto K;Mouri K;Hibino K;Tomita M;Kosako H;Sako Y;Takahashi K
细胞外信号调节激酶（ERK）通路中的磷酸化级联是一个多功能的反应网络基序，可以潜在地作为开关，振荡器或记忆。然而，越来越多的证据表明，在哺乳动物细胞中，磷酸化反应主要与细胞外信号呈线性关系。在这里，我们发现随后的核易位引起核ERK浓度响应于信号输入的开关式增加。在ERK抑制剂的存在下，开关样反应消失，这表明ERK核易位的自动调节机制参与了从分级到开关样反应的转化。体外重建ERK核易位表明，ERK介导的核孔蛋白磷酸化调节ERK易位。数学模型和敲除实验表明核孔蛋白对ERK核易位反应的调节有贡献。综上所述，本研究提供了具有自调节机制的核易位作为ERK信号传导开关的证据。虽然ERK信号可以产生类似开关的细胞行为，但ERK的磷酸化随着细胞外信号的增加而线性增加。在这里，作者通过表明ERK的核易位以一种类似开关的方式进行，并由ERK活性控制，解决了这个看似矛盾的问题。
The phosphorylation cascade in the extracellular signal-regulated kinase (ERK) pathway is a versatile reaction network motif that can potentially act as a switch, oscillator or memory. Nevertheless, there is accumulating evidence that the phosphorylation response is mostly linear to extracellular signals in mammalian cells. Here we find that subsequent nuclear translocation gives rise to a switch-like increase in nuclear ERK concentration in response to signal input. The switch-like response disappears in the presence of ERK inhibitor, suggesting the existence of autoregulatory mechanisms for ERK nuclear translocation involved in conversion from a graded to a switch-like response. In vitro reconstruction of ERK nuclear translocation indicates that ERK-mediated phosphorylation of nucleoporins regulates ERK translocation. A mathematical model and knockdown experiments suggest a contribution of nucleoporins to regulation of the ERK nuclear translocation response. Taken together, this study provides evidence that nuclear translocation with autoregulatory mechanisms acts as a switch in ERK signalling. While ERK signalling can produce switch-like cell behaviour, phosphorylation of ERK increases linearly with extracellular signals. Here, the authors solve this seeming contradiction by showing that nuclear translocation of ERK behaves in a switch-like manner and is controlled by ERK activity.