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Negative feedback regulation of the ERK1/2 MAPK pathway
Lake, D. Corrêa, Sonia A.L. Muller, Jurgen
Lake, D.
Corrêa, Sonia A.L.
Muller, Jurgen
Publication Date
2016
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© The Author(s) 2016. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
This article is published with open access at Springerlink.com
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openAccess
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2016-06-17
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Abstract
The extracellular signal-regulated kinase 1/2
(ERK1/2) mitogen-activated protein kinase (MAPK) signalling
pathway regulates many cellular functions,
including proliferation, differentiation, and transformation.
To reliably convert external stimuli into specific cellular
responses and to adapt to environmental circumstances, the
pathway must be integrated into the overall signalling
activity of the cell. Multiple mechanisms have evolved to
perform this role. In this review, we will focus on negative
feedback mechanisms and examine how they shape ERK1/
2 MAPK signalling. We will first discuss the extensive
number of negative feedback loops targeting the different
components of the ERK1/2 MAPK cascade, specifically
the direct posttranslational modification of pathway components
by downstream protein kinases and the induction
of de novo gene synthesis of specific pathway inhibitors.
We will then evaluate how negative feedback modulates
the spatiotemporal signalling dynamics of the ERK1/2
pathway regarding signalling amplitude and duration as
well as subcellular localisation. Aberrant ERK1/2 activation
results in deregulated proliferation and malignant
transformation in model systems and is commonly
observed in human tumours. Inhibition of the ERK1/2
pathway thus represents an attractive target for the treatment
of malignant tumours with increased ERK1/2
activity. We will, therefore, discuss the effect of ERK1/2
MAPK feedback regulation on cancer treatment and how it
contributes to reduced clinical efficacy of therapeutic
agents and the development of drug resistance.
Version
Published version
Citation
Lake D, Correa SAL and Müller J (2016) Negative feedback regulation of the ERK1/2
MAPK pathway. Cellular and Molecular Life Sciences. 73(23): 4397-4413.
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