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

Mammalian cells can decode the concentration of extracellular transforming growth factor‐β (TGF‐β) and transduce this cue into appropriate cell fate decisions. How variable TGF‐β 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‐β stimulation. The TGF‐β pathway elicits a transient signaling response to a single pulse of TGF‐β 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‐β 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‐β 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‐β pathway might be critical for cell fate determination