Deactivation of Src family kinases: hypothesis testing using a Monte Carlo sensitivity analysis of systems-level properties.
Src family tyrosine kinases play a key role in many cellular signalling networks, but due to the high complexity of these networks their precise function remains elusive. Many factors involved in Src regulation, such as specific kinases and phosphatases, are still unknown. Mathematical models have been constructed to improve the understanding of the system and its dynamic behavior. Using a computational random parameter search, we characterized and compared the dynamics of three alternative models in order to assess their likelihoods. For this, we investigated how systems-level properties such as bistability and excitable behavior relate to kinetic and physiological parameters and how robust these properties were. Our results suggest the existence of a putative negative feedback loop in the Src system. A previously suggested role for PTPalpha in the deactivation of Src was not supported by the model.
Fuss
Hendrik
H
School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland. h.fuss@ulster.ac.uk
Dubitzky
Werner
W
Downes
C Stephen
CS
Kurth
Mary Jo
MJ
D000818:Animals; D004789:Enzyme Activation; D004795:Enzyme Stability; D025461:Feedback, Physiological; D006801:Humans; D008954:Models, Biological; D009010:Monte Carlo Method; D010766:Phosphorylation; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4 / Q000378:metabolism; D012680:Sensitivity and Specificity; D049490:Systems Biology; D019061:src-Family Kinases / Q000378:metabolism*
D019061:src-Family Kinases; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4