Journal
MOLECULAR SYSTEMS BIOLOGY
Volume 5, Issue -, Pages -Publisher
WILEY
DOI: 10.1038/msb.2009.91
Keywords
cytokine receptor; ERK; information processing; proliferation; sensitivity analysis
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Funding
- EU [LSHG-CT-2004-512060]
- SBCancer network in the Helmholtz Alliance on Systems Biology
- Cancer Research UK
- German Cancer Research Center (DKFZ)
- Israel's Ministry of Science and Technology (MOST)
- Excellence Initiative of the German Federal and State Governments
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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. Molecular Systems Biology 5: 334; published online 22 December 2009; doi:10.1038/msb.2009.91
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