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A systems biology approach to analyse amplification in the JAK2-STAT5 signalling pathway.

Vera J, Bachmann J, Pfeifer AC, Becker V, Hormiga JA, Darias NV, Timmer J, Klingmüller U, Wolkenhauer O - BMC Syst Biol (2008)

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Systems Biology and Bioinformatics Group, Department of Computer Science, University of Rostock, Rostock, Germany. jv030@informatik.uni-rostock.de

ABSTRACT

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.

Conclusion: 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.

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Steady-state values of DpSnc (DpSnc,ss) for different values of sustained stimulation on Epo (Eposs). The dashed black line indicates the physiological value for serum concentration of Epo (aprox. 7.9·10-3 units/ml), while the finely dashed line indicates the concentration of Epo used in the experiments performed (5 units/ml).
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Figure 3: Steady-state values of DpSnc (DpSnc,ss) for different values of sustained stimulation on Epo (Eposs). The dashed black line indicates the physiological value for serum concentration of Epo (aprox. 7.9·10-3 units/ml), while the finely dashed line indicates the concentration of Epo used in the experiments performed (5 units/ml).

Mentions: In order to analyse the responsiveness and the ability of the system to amplify signals, the performance of the system was analysed via mathematical simulation assuming three different conditions: sustained stimulation, transient stimulation and oscillatory stimulation by Epo. In case of a sustained stimulus, we analysed the response of the system in terms of the steady-state induced in the system for different values of constant Epo concentration in the extracellular medium, Eposs, from very low concentrations, Eposs = 10-8 units/ml, to concentrations up to tenfold the initial concentration used in the experiments performed, Eposs = 50.0 units/ml. Under normal conditions, the physiological serum concentration of Epo in mice is 7.9·10-3 units/ml [26]. We have computed the steady-state values of DpSnc and they are shown in Figure 3. The logarithmic scale was used for the values of Eposs.


A systems biology approach to analyse amplification in the JAK2-STAT5 signalling pathway.

Vera J, Bachmann J, Pfeifer AC, Becker V, Hormiga JA, Darias NV, Timmer J, Klingmüller U, Wolkenhauer O - BMC Syst Biol (2008)

Steady-state values of DpSnc (DpSnc,ss) for different values of sustained stimulation on Epo (Eposs). The dashed black line indicates the physiological value for serum concentration of Epo (aprox. 7.9·10-3 units/ml), while the finely dashed line indicates the concentration of Epo used in the experiments performed (5 units/ml).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2386439&req=5

Figure 3: Steady-state values of DpSnc (DpSnc,ss) for different values of sustained stimulation on Epo (Eposs). The dashed black line indicates the physiological value for serum concentration of Epo (aprox. 7.9·10-3 units/ml), while the finely dashed line indicates the concentration of Epo used in the experiments performed (5 units/ml).
Mentions: In order to analyse the responsiveness and the ability of the system to amplify signals, the performance of the system was analysed via mathematical simulation assuming three different conditions: sustained stimulation, transient stimulation and oscillatory stimulation by Epo. In case of a sustained stimulus, we analysed the response of the system in terms of the steady-state induced in the system for different values of constant Epo concentration in the extracellular medium, Eposs, from very low concentrations, Eposs = 10-8 units/ml, to concentrations up to tenfold the initial concentration used in the experiments performed, Eposs = 50.0 units/ml. Under normal conditions, the physiological serum concentration of Epo in mice is 7.9·10-3 units/ml [26]. We have computed the steady-state values of DpSnc and they are shown in Figure 3. The logarithmic scale was used for the values of Eposs.

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Systems Biology and Bioinformatics Group, Department of Computer Science, University of Rostock, Rostock, Germany. jv030@informatik.uni-rostock.de

ABSTRACT

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.

Conclusion: 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.

Show MeSH