Abstract
BackgroundInvestigation of dynamics and regulation of the TGF-β 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.Methodology/Principal FindingsWe proposed a constraint-based modeling method to build a comprehensive mathematical model for the Smad dependent TGF-β 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-β 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-β.Conclusions/SignificanceThe simulation results indicate that the signal response to TGF-β 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.
Highlights
The transforming growth factor b (TGF-b) superfamily consists of TGF-bs, bone morphogenetic proteins (BMPs), activins and related proteins
We first check whether the model obtained by constraint-based modeling method can reproduce the experimental data used for parameter estimation, which can give us the information about quality of ‘‘in-sample fit’’
The results are in agreement with previous reports that TGF-b causes a change in the overall Smad2 distribution from predominantly cytoplasmic to predominantly nuclear [6,7,8,29]
Summary
Investigation of dynamics and regulation of the TGF-b signaling pathway is central to the understanding of complex cellular processes such as growth, apoptosis, and differentiation. We proposed a constraint-based modeling method to build a comprehensive mathematical model for the Smad dependent TGF-b 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 simulation results indicate that the signal response to TGF-b 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 be applied to quantitative modeling of other signaling pathways
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