Model-based selection of the robust JAK-STAT activation mechanism

Mikołaj Rybiński, Anna Gambin
2012 Journal of Theoretical Biology  
JAK-STAT pathway family is a principal signaling mechanism in eukaryotic cells. Evolutionary conserved roles of this mechanism include control over fundamental processes such as cell growth or apoptosis. Deregulation of the JAK-STAT signaling is frequently associated with cancerogenesis. JAK-STAT pathways become hyper-activated in many human tumors. Therefore, components of these pathways are an attractive target for drugs, which design requires as adequate models as possible. Although, in
more » ... iple, JAK-STAT signaling is relatively simple, the ambiguities in a receptor activation prevent a clear explanation of the underlying molecular mechanism. Here, we compare four variants of a computational model of the JAK1/2-STAT1 signaling pathway. These variants capture known, basic discrepancies in the mechanism of activation of a cytokine receptor, in the context of all key components of the pathway. We carry out a comparative analysis using mass action kinetics. The investigated differences are so marginal that all models satisfy a goodness of fit criteria to the extent that the state of the art Bayesian model selection (BMS) method fails to significantly promote one model. Therefore, we comparatively investigate changes in a robustness of the JAK1/2-STAT1 pathway variants using the global sensitivity analysis method (GSA), complemented with the identifiability analysis (IA). Both BMS and GSA are used to analyze the models for the varying parameter values. We found out that, both BMS and GSA, nar- * tel.
doi:10.1016/j.jtbi.2012.04.031 pmid:22677400 fatcat:zgxnsz5mhzgmnjqvvwvcwqx3wa