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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, Klingm├╝ller 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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Data fitting of the selected solution for the observables. A: activated EpoR, [pEpoR]. B: activated cytosolic STAT5, [pSTAT5cyt]. Data from two replicates were used as independent experiments. The quantitative data obtained from the two experiments (data points represented as crosses for experiment 1 and points for experiment 2) are compared with the solution of the model identification process (lines). Experimental data were obtained from BaF3-EpoR cells (proB cells exogenously expressing the murine EpoR) stimulated with 5 units/ml Epo and normalised as defined in Sup. Mat. A1 [see Additional file 1].
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Figure 2: Data fitting of the selected solution for the observables. A: activated EpoR, [pEpoR]. B: activated cytosolic STAT5, [pSTAT5cyt]. Data from two replicates were used as independent experiments. The quantitative data obtained from the two experiments (data points represented as crosses for experiment 1 and points for experiment 2) are compared with the solution of the model identification process (lines). Experimental data were obtained from BaF3-EpoR cells (proB cells exogenously expressing the murine EpoR) stimulated with 5 units/ml Epo and normalised as defined in Sup. Mat. A1 [see Additional file 1].

Mentions: The model trajectories obtained for the chosen solution are depicted in Figure 2. The general behaviour of the system is reproduced despite the fact that the differences between the data obtained in the two replicates of the experiment are significant for some time points. We notice that the dynamics of phosphorylated EpoR is much better delimited by the experimental data and therefore the fit of the data is much clearer. The fit is also quantified with the objective function described in Equation 2 in Table A3 in Sup. Mat. A2 [see Additional file 1].


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, Klingm├╝ller U, Wolkenhauer O - BMC Syst Biol (2008)

Data fitting of the selected solution for the observables. A: activated EpoR, [pEpoR]. B: activated cytosolic STAT5, [pSTAT5cyt]. Data from two replicates were used as independent experiments. The quantitative data obtained from the two experiments (data points represented as crosses for experiment 1 and points for experiment 2) are compared with the solution of the model identification process (lines). Experimental data were obtained from BaF3-EpoR cells (proB cells exogenously expressing the murine EpoR) stimulated with 5 units/ml Epo and normalised as defined in Sup. Mat. A1 [see Additional file 1].
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Data fitting of the selected solution for the observables. A: activated EpoR, [pEpoR]. B: activated cytosolic STAT5, [pSTAT5cyt]. Data from two replicates were used as independent experiments. The quantitative data obtained from the two experiments (data points represented as crosses for experiment 1 and points for experiment 2) are compared with the solution of the model identification process (lines). Experimental data were obtained from BaF3-EpoR cells (proB cells exogenously expressing the murine EpoR) stimulated with 5 units/ml Epo and normalised as defined in Sup. Mat. A1 [see Additional file 1].
Mentions: The model trajectories obtained for the chosen solution are depicted in Figure 2. The general behaviour of the system is reproduced despite the fact that the differences between the data obtained in the two replicates of the experiment are significant for some time points. We notice that the dynamics of phosphorylated EpoR is much better delimited by the experimental data and therefore the fit of the data is much clearer. The fit is also quantified with the objective function described in Equation 2 in Table A3 in Sup. Mat. A2 [see Additional file 1].

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