Handling Complex Rule-Based Models of Mitogenic Cell Signaling (on the Example of ERK Activation upon EGF Stimulation)

To continue our research on systems biology of mitogenesis, we have developed and fitted according to the experimental data a highly-branched network model of ERK activation in response to EGF stimulation. To produce a network with full number of possible complexes and reactions that may emerge during signal propagation, we used the rule based software tool in systems biology, BioNetGen 2. Although our network model contains more than 650 complexes and 5500 reactions, we showed the ability the handle this complexity, even using the manual parameter fitting. Analyzing the results of model fitting, we discuss possible details of protein-protein interaction, such as preferable sites/domains for binding one another, sequestration of active enzymes via binding to huge protein complexes etc. Plans for experimental validation of modeling results are also considered.