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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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Logarithmic amplification, LA (log. units, see Equation 7.1), for different values of sustained stimulation with Epo (Eposs). LA measures the signal amplification between pEpJ and DpSnc. 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 4: Logarithmic amplification, LA (log. units, see Equation 7.1), for different values of sustained stimulation with Epo (Eposs). LA measures the signal amplification between pEpJ and DpSnc. 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: Figure 4 shows the results obtained for the considered interval of sustained stimulus. The logarithmic amplification factor has a value slightly higher than two (LA = 2) for all different values of sustained stimulation simulated, which implies an intense amplification of the signal. Thus, our model predicts that an activated receptor can on average activate and induce the nuclear translocation of up to 125 units of STAT5 before its deactivation. In addition, the maximal increase in amplification is in the interval 10-4-10-1; smaller stimuli produce a higher amplification, which implies that the system reacts sensitively to weak stimulation.


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)

Logarithmic amplification, LA (log. units, see Equation 7.1), for different values of sustained stimulation with Epo (Eposs). LA measures the signal amplification between pEpJ and DpSnc. 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 4: Logarithmic amplification, LA (log. units, see Equation 7.1), for different values of sustained stimulation with Epo (Eposs). LA measures the signal amplification between pEpJ and DpSnc. 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: Figure 4 shows the results obtained for the considered interval of sustained stimulus. The logarithmic amplification factor has a value slightly higher than two (LA = 2) for all different values of sustained stimulation simulated, which implies an intense amplification of the signal. Thus, our model predicts that an activated receptor can on average activate and induce the nuclear translocation of up to 125 units of STAT5 before its deactivation. In addition, the maximal increase in amplification is in the interval 10-4-10-1; smaller stimuli produce a higher amplification, which implies that the system reacts sensitively to weak stimulation.

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