Quantitative analysis of transient and sustained transforming growth factor-β signaling dynamics

Mammalian cells can decode the concentration of extracellular transforming growth factor-beta (TGF-beta) and transduce this cue into appropriate cell fate decisions. How variable TGF-beta ligand doses quantitatively control intracellular signaling dynamics and how continuous ligand doses are translated into discontinuous cellular fate decisions remain poorly understood. Using a combined experimental and mathematical modeling approach, we discovered that cells respond differently to continuous and pulsating TGF-beta stimulation. The TGF-beta pathway elicits a transient signaling response to a single pulse of TGF-beta stimulation, whereas it is capable of integrating repeated pulses of ligand stimulation at short time interval, resulting in sustained phospho-Smad2 and transcriptional responses. Additionally, the TGF-beta pathway displays different sensitivities to ligand doses at different time scales. While ligand-induced short-term Smad2 phosphorylation is graded, long-term Smad2 phosphorylation is switch-like to a small change in TGF-beta levels. Correspondingly, the short-term Smad7 gene expression is graded, while long-term PAI-1 gene expression is switch-like, as is the long-term growth inhibitory response. Our results suggest that long-term switch-like signaling responses in the TGF-beta pathway might be critical for cell fate determination. Molecular Systems Biology 7: 492; published online 24 May 2011; doi: 10.1038/msb.2011.22