title: Theoretical and experimental analysis links isoform-specific ERK signalling to cell fate decisions.
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.
authors.affiliation: Division Systems Biology of Signal Transduction, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Schilling
authors.forename: Thomas
authors.initials: T
authors.lastname: Maiwald
authors.forename: Stefan
authors.initials: S
authors.lastname: Hengl
authors.forename: Dominic
authors.initials: D
authors.lastname: Winter
authors.forename: Clemens
authors.initials: C
authors.lastname: Kreutz
authors.forename: Walter
authors.initials: W
authors.lastname: Kolch
authors.forename: Wolf D
authors.initials: WD
authors.lastname: Lehmann
authors.forename: Jens
authors.initials: J
authors.lastname: Timmer
authors.forename: Ursula
authors.initials: U
authors.lastname: Klingmüller
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000201:enzymology*; D004789:Enzyme Activation; D015672:Erythroid Precursor Cells / Q000201:enzymology*; D004921:Erythropoietin / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D025461:Feedback, Physiological; D005260:Female; D007527:Isoenzymes; D007700:Kinetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D010766:Phosphorylation; D017467:Receptors, Erythropoietin / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction; D014162:Transfection
chemical_list: D007527:Isoenzymes; D017467:Receptors, Erythropoietin; D004921:Erythropoietin; D048049:Extracellular Signal-Regulated MAP Kinases