Schilling2009 - ERK distributive
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This model is described in the article:
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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Theoretical and experimental analysis links isoform-specific ERK signalling to cell fate decisions.
- Marcel Schilling, Thomas Maiwald, Stefan Hengl, Dominic Winter, Clemens Kreutz, Walter Kolch, Wolf D Lehmann, Jens Timmer, Ursula Klingmüller
- Molecular systems biology , 0/ 2009 , Volume 5 , pages: 334 , PubMed ID: 20029368
Submitter of this revision: Lucian Smith
Curator: Lucian Smith
Modellers: administrator, Marcel Schilling
Metadata information
isDescribedBy (1 statement)
hasTaxon (1 statement)
hasVersion (5 statements)
Gene Ontology erythropoietin receptor activity
Gene Ontology cytokine-mediated signaling pathway
KEGG Pathway MAPK signaling pathway - Mus musculus (mouse)
KEGG Pathway Jak-STAT signaling pathway - Mus musculus (mouse)
occursIn (1 statement)
hasProperty (1 statement)
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