Dynamics and feedback loops in the transforming growth factor β signaling pathway

Transforming growth factor β (TGF-β) ligands activate a signaling cascade with multiple cell context dependent outcomes. Disruption or disturbance leads to variant clinical disorders. To develop strategies for disease intervention, delineation of the pathway in further detail is required. Current theoretical models of this pathway describe production and degradation of signal mediating proteins and signal transduction from the cell surface into the nucleus, whereas feedback loops have not exhaustively been included.In this study we present a mathematical model to determine the relevance of feedback regulators (Arkadia, Smad7, Smurf1, Smurf2, SnoN and Ski) on TGF-β target gene expression and the potential to initiate stable oscillations within a realistic parameter space. We employed massive sampling of the parameters space to pinpoint crucial players for potential oscillations as well as transcriptional product levels. We identified Smad7 and Smurf2 with the highest impact on the dynamics. Based on these findings, we conducted preliminary time course experiments.

Highlights► We present a mathematical model to determine the relevance of feedback loops in the TGF-β signaling. ► Our computational analysis indicated that oscillations are possible under realistic conditions. ► Smad7 and Smurf1/2 have the strongest potential to act as negative feedback regulators. ► Ski, SnoN, SARA, Arkadia have a high potential to also act as positive feedback mechanisms. ► Preliminary experimental data revealed a more dynamic behavior than the simple on-off mechanism.