Prediction and validation of the distinct dynamics of transient and sustained ERK activation.
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.
Sasagawa
Satoru
S
Undergraduate Program for Bioinformatics and Systems Biology, Graduate School of Information Science and Technology, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Ozaki
Yu-ichi
Y
Fujita
Kazuhiro
K
Kuroda
Shinya
S
D000818:Animals; D003198:Computer Simulation; D004789:Enzyme Activation / Q000502:physiology; D004815:Epidermal Growth Factor / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D007700:Kinetics; D008954:Models, Biological; D020932:Nerve Growth Factor / Q000378:metabolism; D016716:PC12 Cells; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D013997:Time Factors; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism
D004815:Epidermal Growth Factor; D020932:Nerve Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D020827:rap1 GTP-Binding Proteins; D018631:ras Proteins