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

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 si...

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Main Authors:	Shindo, Yuki, Iwamoto, Kazunari, Mouri, Kazunari, Hibino, Kayo, Tomita, Masaru, Kosako, Hidetaka, Sako, Yasushi, Takahashi, Koichi
Format:	Online
Language:	English
Published:	Nature Publishing Group 2016
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4736105/

id	pubmed-4736105
recordtype	oai_dc
spelling	pubmed-47361052016-03-04 Conversion of graded phosphorylation into switch-like nuclear translocation via autoregulatory mechanisms in ERK signalling Shindo, Yuki Iwamoto, Kazunari Mouri, Kazunari Hibino, Kayo Tomita, Masaru Kosako, Hidetaka Sako, Yasushi Takahashi, Koichi Article 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. Nature Publishing Group 2016-01-20 /pmc/articles/PMC4736105/ /pubmed/26786866 http://dx.doi.org/10.1038/ncomms10485 Text en Copyright © 2016, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Shindo, Yuki Iwamoto, Kazunari Mouri, Kazunari Hibino, Kayo Tomita, Masaru Kosako, Hidetaka Sako, Yasushi Takahashi, Koichi
spellingShingle	Shindo, Yuki Iwamoto, Kazunari Mouri, Kazunari Hibino, Kayo Tomita, Masaru Kosako, Hidetaka Sako, Yasushi Takahashi, Koichi Conversion of graded phosphorylation into switch-like nuclear translocation via autoregulatory mechanisms in ERK signalling
author_facet	Shindo, Yuki Iwamoto, Kazunari Mouri, Kazunari Hibino, Kayo Tomita, Masaru Kosako, Hidetaka Sako, Yasushi Takahashi, Koichi
author_sort	Shindo, Yuki
title	Conversion of graded phosphorylation into switch-like nuclear translocation via autoregulatory mechanisms in ERK signalling
title_short	Conversion of graded phosphorylation into switch-like nuclear translocation via autoregulatory mechanisms in ERK signalling
title_full	Conversion of graded phosphorylation into switch-like nuclear translocation via autoregulatory mechanisms in ERK signalling
title_fullStr	Conversion of graded phosphorylation into switch-like nuclear translocation via autoregulatory mechanisms in ERK signalling
title_full_unstemmed	Conversion of graded phosphorylation into switch-like nuclear translocation via autoregulatory mechanisms in ERK signalling
title_sort	conversion of graded phosphorylation into switch-like nuclear translocation via autoregulatory mechanisms in erk signalling
description	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.
publisher	Nature Publishing Group
publishDate	2016
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4736105/
_version_	1613531746413838336

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

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