Theoretical and experimental analysis links isoform- specific ERK signalling to cell fate decisions

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Title: Theoretical and experimental analysis links isoform- specific ERK signalling to cell fate decisions
Authors: Schilling, Marcel
Maiwald, Thomas
Hengl, Stefan
et al.
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Date: 22-Dec-2009
Online since: 2013-11-29T09:49:58Z
Abstract: Cell fate decisions are regulated by the coordinated activation of signalling pathways such as the extracellular signal-regulated kinase (ERK) cascade, but contributions of individual kinase isoforms are mostly unknown. By combining quantitative data from erythropoietin-induced pathway activation in primary erythroid progenitor (colony-forming unit erythroid stage, CFU-E) cells with mathematical modelling, we predicted and experimentally confirmed a distributive ERK phosphorylation mechanism in CFU-E cells. Model analysis showed bow-tie-shaped signal processing and inherently transient signalling for cytokine-induced ERK signalling. Sensitivity analysis predicted that, through a feedback-mediated process, increasing one ERK isoform reduces activation of the other isoform, which was verified by protein over-expression. We calculated ERK activation for biochemically not addressable but physiologically relevant ligand concentrations showing that double-phosphorylated ERK1 attenuates proliferation beyond a certain activation level, whereas activated ERK2 enhances proliferation with saturation kinetics. Thus, we provide a quantitative link between earlier unobservable signalling dynamics and cell fate decisions.
Type of material: Journal Article
Publisher: Nature Publishing Group
Journal: Molecular Systems Biology
Volume: 5
Issue: 334
Copyright (published version): 2009 Nature Publishing Group
Keywords: endothelializationcoronary artery stentsrestenosislate stent thrombosisliposome
DOI: 10.1038/msb.2009.91
Language: en
Status of Item: Peer reviewed
Appears in Collections:SBI Research Collection

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