Pathway crosstalk enables cells to interpret TGF-β duration

The detection and transmission of the temporal quality of intracellular and extracellular signals is an essential cellular mechanism. It remains largely unexplored how cells interpret the duration information of a stimulus. In this paper, through an integrated quantitative and computational approach we demonstrate that crosstalk among multiple TGF-β activated pathways forms a relay from SMAD to GLI1 that initializes and maintains SNAILl expression, respectively. This transaction is smoothed and accelerated by another temporal switch from elevated cytosolic GSK3 enzymatic activity to reduced nuclear GSK3 enzymatic activity. The intertwined network places SNAIL1 as a key integrator of information from TGF-β signaling subsequently distributed through upstream divergent pathways; essentially cells generate a transient or sustained expression of SNAIL1 depending on TGF-β duration. Other signaling pathways may use similar network structure to encode duration information.