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Nat Commun. 2016 Jan 20;7:10485. doi: 10.1038/ncomms10485.

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

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Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan.
Laboratory for Biochemical Simulation, RIKEN Quantitative Biology Center, Suita, Osaka 565-0874, Japan.
Cellular Informatics Laboratory, RIKEN, Wako, Saitama 351-0198, Japan.
Laboratory for Cell Signaling Dynamics, RIKEN Quantitative Biology Center, Suita, Osaka 565-0874, Japan.
Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0017, Japan.
Division of Cell Signaling, Fujii Memorial Institute of Medical Sciences, Tokushima University, Tokushima 770-8503, Japan.


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.

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