Merck
  • Home
  • Search Results
  • Theoretical and experimental analysis links isoform-specific ERK signalling to cell fate decisions.

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

Molecular systems biology (2009-12-24)
Marcel Schilling, Thomas Maiwald, Stefan Hengl, Dominic Winter, Clemens Kreutz, Walter Kolch, Wolf D Lehmann, Jens Timmer, Ursula Klingmüller
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-MAP Kinase, Activated (Diphosphorylated ERK-1&2) antibody, Mouse monoclonal, clone MAPK-YT, purified from hybridoma cell culture
Sigma-Aldrich
Anti-Phosphotyrosine Antibody, clone 4G10®, clone 4G10®, Upstate®, from mouse