A systems biology view of IL-6-induced signal transduction

Abstract:
A central part of systems biology is to develop computational models of biological pathways based on experimental data. These models can, for example, be used to quickly test experimental scenarios in silico before starting time-consuming laboratory work. In this work models are used to help discriminate between different postulated biological mechanisms. Specifically, different models were generated to elucidate the precise role of the phosphatase SHP2 in IL-6 signalling. Effects of transcriptionally regulated feedback inhibitors, e.g. SOCS3, were excluded by restricting simulations and experiments to the first 15 minutes of IL-6-induced signal transduction. Special attention was paid to balancing model complexity and the amount and precision of experimental data, thus avoiding model over-parameterisation(1). To determine values of unknown model parameters, highly standardised experiments were performed in HEK cells. Receptor numbers were determined by quantitative FACS using directly labelled antibodies. Molar concentrations of JAK/STAT pathway components were analysed by Western blotting using recombinant proteins as standard. Furthermore, highly time resolved data on the activation kinetics of the analysed signalling molecules were generated. It is the aim of this study to discriminate between mutually exclusive models of IL-6- induced signal transduction and to select the hypothesis among some candidates that explains the dynamics of the signal transduction best.