Cells Interpret Temporal Information From TGF-β Through A Nested Relay Mechanism

The detection and transmission of the strength and temporal quality of intracellular and extracellullar signals is an essential cellular mechanism. While TGF-β signaling is one of the most thoroughly studied signaling pathways, the mechanisms by which cells translate TGF-β signals remain unclear. 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. This nested relay mechanism places SNAIL1 as a key integrator of information from TGF-β signaling subsequently distributed through divergent pathways; essentially cells generate a transient or sustained expression of SNAIL1 depending on TGF-β duration. Our results provide a mechanistic understanding of a long-standing paradox that TGF-β can both suppress and promote cancer development.