Theoretical and experimental analysis links isoform- specific ERK signalling to cell fate decisions
|Title:||Theoretical and experimental analysis links isoform- specific ERK signalling to cell fate decisions||Authors:||Schilling, Marcel
|Permanent link:||http://hdl.handle.net/10197/5052||Date:||22-Dec-2009||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||Copyright (published version):||2009 Nature Publishing Group||Keywords:||endothelialization;coronary artery stents;restenosis;late stent thrombosis;liposome||DOI:||10.1038/msb.2009.91||Language:||en||Status of Item:||Peer reviewed|
|Appears in Collections:||SBI Research Collection|
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