Mathematical modeling and experimental analyses reveal that TGF-β ligand depletion has an important role in converting short-term graded signaling responses to long-term switch-like responses

Abramoff MD

Aristidis Moustakas

Difan Deng

Douglas A Chapnick

Edda Klipp

Markus Dahl

Xuedong Liu

Zhike Zi

Zipei Feng

Molecular Systems Biology

English

PubMed

Crossref

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

Zi, Z.

Feng, Z.

Chapnick, D.

Dahl, M.

Deng, D.

Klipp, E.

Moustakas, A.

Liu, X.

MPG.PuRe

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

Physiol 166: 512–522

Quantitative analysis of TGF-b signaling dynamics

Speciﬁcity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80: 179–185 Massague J

TbetaRI phosphorylation of

https://pure.mpg.de/pubman/item/item_2161978_1/component/file_2161977/Zi.pdf

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

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