Schilling2009 - ERK distributive

Schilling2009 - ERK distributive

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This model is described in the article:

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

Schilling M, Maiwald T, Hengl S,
Winter D, Kreutz C, Kolch W, Lehmann WD, Timmer J,
Klingmüller U.
Mol. Syst. Biol. 2009; 5: 334
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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