Theoretical and Experimental Analysis Links Isoform-specific ERK Signalling to Cell Fate Decisions

Overview

Journal Mol Syst Biol

Specialty Molecular Biology

Date 2009 Dec 24

PMID 20029368

Citations 34

Authors

Marcel Schilling

Thomas Maiwald

Stefan Hengl

Dominic Winter

Clemens Kreutz

Walter Kolch

Wolf D Lehmann

Jens Timmer

Ursula Klingmuller

Affiliations

Soon will be listed here.

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.

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