A systems biology approach to analyse amplification in the JAK2-STAT5 signalling pathway.
BACKGROUND
The amplification of signals, defined as an increase in the intensity of a signal through networks of intracellular reactions, is considered one of the essential properties in many cell signalling pathways. Despite of the apparent importance of signal amplification, there have been few attempts to formalise this concept.


RESULTS
In this work we investigate the amplification and responsiveness of the JAK2-STAT5 pathway using a kinetic model. The recruitment of EpoR to the plasma membrane, activation by Epo, and deactivation of the EpoR/JAK2 complex are considered as well as the activation and nucleocytoplasmic shuttling of STAT5. Using qualitative biological knowledge, we first establish the structure of a general power-law model. We then generate a family of models from which we select suitable candidates. The parameter values of the model are estimated from experimental quantitative time-course data. The final model, whether it is conventional model with fixed predefined integer kinetic orders or a model with variable non-integer kinetic orders, is selected on the basis of a good agreement between simulations and the experimental data. The model is used to analyse the responsiveness and amplification properties of the pathway with sustained, transient, and oscillatory stimulation.


CONCLUSIONS
The selected kinetic model predicts that the system acts as an amplifier with maximum amplification and sensitivity for input signals whose intensity match physiological values for Epo concentration and with duration in the range of one to 100 minutes. The response of the system reaches saturation for more intense and longer stimulation with Epo. We hypothesise that these properties of the system directly relate to the saturation of Epo receptor activation, its low recruitment to the plasma membrane and intense deactivation as predicted by the model.
Vera
Julio
J
Systems Biology and Bioinformatics Group, Department of Computer Science, University of Rostock, Rostock, Germany. jv030@informatik.uni-rostock.de
Bachmann
Julie
J
Pfeifer
Andrea C
AC
Becker
Verena
V
Hormiga
Jose A
JA
Darias
Nestor V Torres
NV
Timmer
Jens
J
Klingmüller
Ursula
U
Wolkenhauer
Olaf
O
D021581:Active Transport, Cell Nucleus; D000818:Animals; D001665:Binding Sites; D002461:Cell Line, Transformed; D002467:Cell Nucleus / Q000378:metabolism; D004921:Erythropoietin / Q000378:metabolism; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism*; D007700:Kinetics; D051379:Mice; D008954:Models, Biological; D011237:Predictive Value of Tests; D017467:Receptors, Erythropoietin / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D049490:Systems Biology / Q000379:methods; D013997:Time Factors
D017467:Receptors, Erythropoietin; D050799:STAT5 Transcription Factor; D004921:Erythropoietin; D053614:Janus Kinase 2