Signal transduction pathways generally consist of a large number of individual components and have an even greater number of parameters describing their reaction kinetics. While the structure of some signaling pathways can be found in the literature, many of the parameters are poorly known and they would need to be re-estimated from experimental data for each specific case. However, it is not feasible to estimate hundreds of parameters due to the cost of the experiments associated with generation of the data. Parameter sensitivity analysis can address this situation as it investigates how the system behavior is changed by variations of parameters and the analysis identifies which parameters play a key role in signal transduction. Only these important parameters need then to be re-estimated using data from further experiments.
This paper presents a detailed parameter sensitivity analysis of the JAK/STAT and MAPK signal transduction pathway that is used for signaling by the cytokine IL-6. As no parameter sensitivity analysis technique is known to work best for all situations, a comparison of the results returned by four techniques is presented: differential analysis, the Morris method, a sampling-based approach, and the Fourier amplitude sensitivity test (FAST).
The recruitment of the transcription factor STAT3 to the dimer of the phosphorylated receptor complex is determined as the most important step by the sensitivity analysis. Additionally, the desphosphorylation of the nuclear STAT3 dimer by PP2 as well as feedback inhibition by SOCS3 are found to play an important role for signal transduction.
IET Systems Biology 1, No. 6, pp. 342-352 (2007)