Computational modelling of Smad-mediated negative feedback and crosstalk in the TGF-β superfamily network

The transforming growth factor-β (TGF-β) signal transduction pathway controls many cellular processes, including differentiation, proliferation and apoptosis. It plays a fundamental role during development and it is dysregulated in many diseases. The factors that control the dynamics of the pathway, however, are not fully elucidated yet and so far computational approaches have been very limited in capturing the distinct types of behaviour observed under different cellular backgrounds and conditions into a single-model description. Here, we develop a detailed computational model for TGF-β signalling that incorporates elements of previous models together with crosstalking between Smad1/5/8 and Smad2/3 channels through a negative feedback loop dependent on Smad7. The resulting model accurately reproduces the diverse behaviour of experimental datasets for human keratinocytes, bovine aortic endothelial cells and mouse mesenchymal cells, capturing the dynamics of activation and nucleocytoplasmic shuttling of both R-Smad channels. The analysis of the model dynamics and its system properties revealed Smad7-mediated crosstalking between Smad1/5/8 and Smad2/3 channels as a major determinant in shaping the distinct responses to single and multiple ligand stimulation for different cell types.