Prediction and validation of the distinct dynamics of transient and sustained ERK activation

Nat Cell Biol. 2005 Apr;7(4):365-73. doi: 10.1038/ncb1233. Epub 2005 Mar 27.


To elucidate the hidden dynamics of extracellular-signal-regulated kinase (ERK) signalling networks, we developed a simulation model of ERK signalling networks by constraining in silico dynamics based on in vivo dynamics in PC12 cells. We predicted and validated that transient ERK activation depends on rapid increases of epidermal growth factor and nerve growth factor (NGF) but not on their final concentrations, whereas sustained ERK activation depends on the final concentration of NGF but not on the temporal rate of increase. These ERK dynamics depend on Ras and Rap1 dynamics, the inactivation processes of which are growth-factor-dependent and -independent, respectively. Therefore, the Ras and Rap1 systems capture the temporal rate and concentration of growth factors, and encode these distinct physical properties into transient and sustained ERK activation, respectively.

Publication types

  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Animals
  • Computer Simulation*
  • Enzyme Activation / physiology
  • Epidermal Growth Factor / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Kinetics
  • Models, Biological*
  • Nerve Growth Factor / metabolism
  • PC12 Cells
  • Rats
  • Signal Transduction / physiology
  • Time Factors
  • rap1 GTP-Binding Proteins / metabolism*
  • ras Proteins / metabolism


  • Epidermal Growth Factor
  • Nerve Growth Factor
  • Extracellular Signal-Regulated MAP Kinases
  • rap1 GTP-Binding Proteins
  • ras Proteins