Conversion of graded phosphorylation into switch-like nuclear translocation via autoregulatory mechanisms in ERK signalling

Yuki Shindo (), Kazunari Iwamoto, Kazunari Mouri, Kayo Hibino, Masaru Tomita, Hidetaka Kosako, Yasushi Sako and Koichi Takahashi ()
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Yuki Shindo: Graduate School of Frontier Biosciences, Osaka University
Kazunari Iwamoto: Laboratory for Biochemical Simulation, RIKEN Quantitative Biology Center
Kazunari Mouri: Cellular Informatics Laboratory, RIKEN
Kayo Hibino: Cellular Informatics Laboratory, RIKEN
Masaru Tomita: Institute for Advanced Biosciences, Keio University
Hidetaka Kosako: Fujii Memorial Institute of Medical Sciences, Tokushima University
Yasushi Sako: Cellular Informatics Laboratory, RIKEN
Koichi Takahashi: Laboratory for Biochemical Simulation, RIKEN Quantitative Biology Center

Nature Communications, 2016, vol. 7, issue 1, 1-10

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms10485

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