Sensitivity analysis-based approach for identifying key steps in cell signaling for hepatocytes stimulated by II-6

Signal transduction pathways generally consist of dozens of individual components and have an even greater number of parameters describing their reaction kinetics. While the general structure of some signaling pathways can be found in the literature, it is usually required to adapt the model and re-estimate some of the parameters from experimental data. However, it is not feasible to re-estimate hundreds of parameters due to the complexity and cost of the experiments associated with the generation of the data. Parameter sensitivity analysis is a useful tool for addressing this situation as it identifies the most important parameters, which also are the parameters which are easiest to estimate, for a signal transduction pathway. This paper presents a detailed parameter sensitivity analysis of the JAK/STAT and MAPK signal transduction pathway for stimulation with IL-6. Based upon the sensitivity analysis of the parameters, the most important step is the recruitment of the transcription factor to the dimer of the phosphorylated receptor complex. Sensitivity analysis also reveals that several other mechanism play an important role: desphosphorylation of the nuclear STAT3 dimer by PP2 as well as feedback inhibition by SOCS3.

Sensitivity analysis-based approach for identifying key steps in cell signaling for hepatocytes stimulated by II-6 Conference Paper