title: Quantitative analysis of transient and sustained transforming growth factor-β signaling dynamics.
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.
authors: BIOSS Centre for Biological Signalling Studies and Center for Biological Systems Analysis (ZBSA), University of Freiburg, Freiburg, Germany. zhike.zi@bioss.uni-freiburg.de
authors: Zhike
authors: Z
authors: Zi
authors: Zipei
authors: Z
authors: Feng
authors: Douglas A
authors: DA
authors: Chapnick
authors: Markus
authors: M
authors: Dahl
authors: Difan
authors: D
authors: Deng
authors: Edda
authors: E
authors: Klipp
authors: Aristidis
authors: A
authors: Moustakas
authors: Xuedong
authors: X
authors: Liu
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