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

Mol Syst Biol. 2009:5:334. doi: 10.1038/msb.2009.91. Epub 2009 Dec 22.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation*
  • Cells, Cultured
  • Embryonic Stem Cells / enzymology*
  • Enzyme Activation
  • Erythroid Precursor Cells / enzymology*
  • Erythropoietin / metabolism
  • Extracellular Signal-Regulated MAP Kinases / genetics
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Feedback, Physiological
  • Female
  • Isoenzymes
  • Kinetics
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Models, Biological*
  • Phosphorylation
  • Receptors, Erythropoietin / metabolism
  • Reproducibility of Results
  • Signal Transduction*
  • Transfection

Substances

  • Isoenzymes
  • Receptors, Erythropoietin
  • Erythropoietin
  • Extracellular Signal-Regulated MAP Kinases