Constraint-based modeling and kinetic analysis of the Smad dependent TGF-beta signaling pathway.
BACKGROUND
Investigation of dynamics and regulation of the TGF-beta signaling pathway is central to the understanding of complex cellular processes such as growth, apoptosis, and differentiation. In this study, we aim at using systems biology approach to provide dynamic analysis on this pathway.


RESULTS
We proposed a constraint-based modeling method to build a comprehensive mathematical model for the Smad dependent TGF-beta signaling pathway by fitting the experimental data and incorporating the qualitative constraints from the experimental analysis. The performance of the model generated by constraint-based modeling method is significantly improved compared to the model obtained by only fitting the quantitative data. The model agrees well with the experimental analysis of TGF-beta pathway, such as the time course of nuclear phosphorylated Smad, the subcellular location of Smad and signal response of Smad phosphorylation to different doses of TGF-beta.


CONCLUSIONS
The simulation results indicate that the signal response to TGF-beta is regulated by the balance between clathrin dependent endocytosis and non-clathrin mediated endocytosis. This model is useful to be built upon as new precise experimental data are emerging. The constraint-based modeling method can also be applied to quantitative modeling of other signaling pathways.
Zi
Zhike
Z
Computational Systems Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany.
Klipp
Edda
E
D007700:Kinetics; D008962:Models, Theoretical; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000502:physiology*; D051785:Smad Proteins / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology
D051785:Smad Proteins; D016212:Transforming Growth Factor beta