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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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Structure of the JAK2-STAT5 pathway model proposed. Legend: Epo: concentration of Epo in the extracellular medium; EJ: fraction of non-activated EpoR/JAK2 complex; pEpJ: fraction of activated EpoR/JAK2 complex; S: fraction of non-activated and non-dimerised STAT5 in the cytosol; DpS: fraction of activated and dimerised STAT5 in the cytosol; DpSnc: fraction of activated and dimerised STAT5 inside the nucleus.
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Figure 1: Structure of the JAK2-STAT5 pathway model proposed. Legend: Epo: concentration of Epo in the extracellular medium; EJ: fraction of non-activated EpoR/JAK2 complex; pEpJ: fraction of activated EpoR/JAK2 complex; S: fraction of non-activated and non-dimerised STAT5 in the cytosol; DpS: fraction of activated and dimerised STAT5 in the cytosol; DpSnc: fraction of activated and dimerised STAT5 inside the nucleus.

Mentions: The Janus kinase – signal transducer and activator of transcription (JAK-STAT) pathways are one of the best-studied cell signalling pathways [11,12]. The JAK2-STAT5 pathway is activated through various receptors, including the erythropoietin receptor (EpoR). Cytokine-activated phosphorylation of EpoR is mediated by the cytosolic kinase JAK2 which is associated with the cytoplasmic domain of EpoR. Upon binding of the hormone erythropoietin (Epo), JAK2 is activated and phosphorylates several tyrosine residues within the cytoplasmic domain of EpoR [13]. Subsequently, the transcription factor STAT5 is recruited to the activated receptor, becomes phosphorylated and thereby gets activated. Upon activation STAT5 homodimerises and migrates to the nucleus, where it initiates the transcription of target genes (see Figure 1 for a simplified representation of this pathway).


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)

Structure of the JAK2-STAT5 pathway model proposed. Legend: Epo: concentration of Epo in the extracellular medium; EJ: fraction of non-activated EpoR/JAK2 complex; pEpJ: fraction of activated EpoR/JAK2 complex; S: fraction of non-activated and non-dimerised STAT5 in the cytosol; DpS: fraction of activated and dimerised STAT5 in the cytosol; DpSnc: fraction of activated and dimerised STAT5 inside the nucleus.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Structure of the JAK2-STAT5 pathway model proposed. Legend: Epo: concentration of Epo in the extracellular medium; EJ: fraction of non-activated EpoR/JAK2 complex; pEpJ: fraction of activated EpoR/JAK2 complex; S: fraction of non-activated and non-dimerised STAT5 in the cytosol; DpS: fraction of activated and dimerised STAT5 in the cytosol; DpSnc: fraction of activated and dimerised STAT5 inside the nucleus.
Mentions: The Janus kinase – signal transducer and activator of transcription (JAK-STAT) pathways are one of the best-studied cell signalling pathways [11,12]. The JAK2-STAT5 pathway is activated through various receptors, including the erythropoietin receptor (EpoR). Cytokine-activated phosphorylation of EpoR is mediated by the cytosolic kinase JAK2 which is associated with the cytoplasmic domain of EpoR. Upon binding of the hormone erythropoietin (Epo), JAK2 is activated and phosphorylates several tyrosine residues within the cytoplasmic domain of EpoR [13]. Subsequently, the transcription factor STAT5 is recruited to the activated receptor, becomes phosphorylated and thereby gets activated. Upon activation STAT5 homodimerises and migrates to the nucleus, where it initiates the transcription of target genes (see Figure 1 for a simplified representation of this pathway).

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