Comment on "Controlling long-term signaling: receptor dynamics determine attenuation and refractory behavior of the TGF-β pathway"-Smad2/3 activity does not predict the dynamics of transcription
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Updated: Apr 23, 2026

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
Published on: October 27, 2020
Aryeh Warmflash1, Qixiang Zhang2, Ali H Brivanlou2
1Center for Studies in Physics and Biology, The Rockefeller University, New York, NY 10065, USA. Laboratory of Molecular Vertebrate Embryology, The Rockefeller University, New York, NY 10065, USA. aryeh.warmflash@rice.edu.
Abstract:
The transforming growth factor-β (TGF-β) pathway plays a fundamental role in development and disease. Despite its importance, the dynamics of signaling activity downstream of ligand stimulation have remained largely unexplored. The recent study by Vizán et al. demonstrates that loss of signaling-capable receptors from the cell surface leads to a refractory period during which cells are incapable of responding to additional signals. In this letter and in our previous work, we show that although receptor dynamics determine Smad2/3 activity, signaling activity at the level of transcription terminates far earlier in a receptor- and Smad2/3-independent manner. Thus, Smad2/3 activity does not reveal the dynamics of transcription, and downstream measures must be examined directly.
Insights
The transforming growth factor-β (TGF-β) pathway
Area of Science:
- Cellular signaling pathways
- Molecular biology
- Developmental biology
Background:
- The transforming growth factor-β (TGF-β) pathway is crucial for development and disease.
- Signaling dynamics downstream of TGF-β ligand stimulation are not well understood.
- Receptor dynamics influence Smad2/3 activity following TGF-β stimulation.
Discussion:
- Cellular response to TGF-β involves a refractory period after receptor loss.
- Transcriptional activity terminates independently of receptors and Smad2/3.
- Smad2/3 activity does not accurately reflect transcriptional dynamics.
Key Insights:
- TGF-β receptor dynamics control Smad2/3 activation.
- Transcriptional signaling in the TGF-β pathway ends much earlier than Smad2/3 activity.
- Downstream transcriptional events must be directly measured to understand signaling dynamics.
Outlook:
- Further investigation into the mechanisms of receptor- and Smad2/3-independent transcriptional termination.
- Exploring the implications of these findings for understanding TGF-β-related diseases.
- Developing novel methods to directly measure transcriptional dynamics in real-time.
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