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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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Average fraction of dimerised phosphorylated STAT5 in the nucleus (DpSnc,osc) (norm. units) during oscillatory stimulation. The simulated data was averaged for several following periods. The behaviour of the system was analysed for oscillatory stimuli with an average period duration T ∈ [0.5, 1440] minutes, and an average concentration of Epoocs ∈ [10-6, 10] units/ml. In all the simulations, the signal was averaged for 12 periods of the oscillatory stimulus.
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Figure 8: Average fraction of dimerised phosphorylated STAT5 in the nucleus (DpSnc,osc) (norm. units) during oscillatory stimulation. The simulated data was averaged for several following periods. The behaviour of the system was analysed for oscillatory stimuli with an average period duration T ∈ [0.5, 1440] minutes, and an average concentration of Epoocs ∈ [10-6, 10] units/ml. In all the simulations, the signal was averaged for 12 periods of the oscillatory stimulus.

Mentions: The dynamics of the system with oscillatory Epo concentration were also considered. For simulations, we did not choose perfect sinusoidal oscillatory signals but a design based on truncated triangular signals (Sup. Mat. A5 includes further explanations [see Additional file 1]). In [27] a physiological daily oscillation of the Epo concentration in the blood is described in which Epo is maintained at an almost stable value during daytime but reduces to half its value during the night. Two periods of transition are described that we adopted to describe the oscillatory signals used in our simulations. The oscillations in the input signal were characterised by two properties: the period of the oscillatory signal (T) which is the time between two consecutive maxima, and the average value of Epo during the oscillation (Epoosc). The average value of pEpJ (pEpJosc) and DpSnc (DpSnc,osc) during the oscillation were defined and computed (Sup. Mat. A7 [see Additional file 1]). Our analysis suggested that the average of the signals for a number of periods between eight and twelve is sufficient to avoid the transient behaviour from the start of the simulations. We explored the performance of the system for oscillations with a period between half a minute and one day and with Epoosc in the interval studied in the previous cases ([10-6,10] units/ml). Figure 8 shows the results obtained for DpSnc,osc (Sup. Mat. A7 contains figures for pEpJosc [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, Klingmüller U, Wolkenhauer O - BMC Syst Biol (2008)

Average fraction of dimerised phosphorylated STAT5 in the nucleus (DpSnc,osc) (norm. units) during oscillatory stimulation. The simulated data was averaged for several following periods. The behaviour of the system was analysed for oscillatory stimuli with an average period duration T ∈ [0.5, 1440] minutes, and an average concentration of Epoocs ∈ [10-6, 10] units/ml. In all the simulations, the signal was averaged for 12 periods of the oscillatory stimulus.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 8: Average fraction of dimerised phosphorylated STAT5 in the nucleus (DpSnc,osc) (norm. units) during oscillatory stimulation. The simulated data was averaged for several following periods. The behaviour of the system was analysed for oscillatory stimuli with an average period duration T ∈ [0.5, 1440] minutes, and an average concentration of Epoocs ∈ [10-6, 10] units/ml. In all the simulations, the signal was averaged for 12 periods of the oscillatory stimulus.
Mentions: The dynamics of the system with oscillatory Epo concentration were also considered. For simulations, we did not choose perfect sinusoidal oscillatory signals but a design based on truncated triangular signals (Sup. Mat. A5 includes further explanations [see Additional file 1]). In [27] a physiological daily oscillation of the Epo concentration in the blood is described in which Epo is maintained at an almost stable value during daytime but reduces to half its value during the night. Two periods of transition are described that we adopted to describe the oscillatory signals used in our simulations. The oscillations in the input signal were characterised by two properties: the period of the oscillatory signal (T) which is the time between two consecutive maxima, and the average value of Epo during the oscillation (Epoosc). The average value of pEpJ (pEpJosc) and DpSnc (DpSnc,osc) during the oscillation were defined and computed (Sup. Mat. A7 [see Additional file 1]). Our analysis suggested that the average of the signals for a number of periods between eight and twelve is sufficient to avoid the transient behaviour from the start of the simulations. We explored the performance of the system for oscillations with a period between half a minute and one day and with Epoosc in the interval studied in the previous cases ([10-6,10] units/ml). Figure 8 shows the results obtained for DpSnc,osc (Sup. Mat. A7 contains figures for pEpJosc [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