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

Mol Syst Biol. 2011 May 24;7:492. doi: 10.1038/msb.2011.22.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Differentiation
  • Cell Line
  • Cell Proliferation
  • Gene Expression
  • Humans
  • Keratinocytes / cytology
  • Keratinocytes / physiology*
  • Mathematical Computing
  • Models, Biological
  • Phosphorylation
  • Plasminogen Activator Inhibitor 1 / genetics
  • Plasminogen Activator Inhibitor 1 / metabolism*
  • Signal Transduction*
  • Smad2 Protein / genetics
  • Smad2 Protein / metabolism*
  • Smad7 Protein / genetics
  • Smad7 Protein / metabolism*
  • Systems Biology / methods*
  • Transfection
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*

Substances

  • Plasminogen Activator Inhibitor 1
  • SMAD2 protein, human
  • SMAD7 protein, human
  • Smad2 Protein
  • Smad7 Protein
  • Transforming Growth Factor beta