Cellière2011 - Plasticity of TGF-β Signalling

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Cellière2011 - Plasticity of TGF-β Signalling

Transforming growth factor beta (TGF-β) signalling has been implicated as an important regulator of almost all major cell behaviours, including proliferation, differentiation, cell death, and motility. It remains unclear that how the TGF-β signalling pathway accomplishes the flexibility in its responses. What and how many parameters have to be altered for cells to respond differently to perform complex tasks? This canonical response has been explored in this model, by considering the core signalling architecture of TGF-β pathway.

This model is described in the article:

Cellière G, Fengos G, Hervé M, Iber D.
BMC Syst Biol. 2011 Nov 3;5:184.

Abstract:

The family of TGF-β ligands is large and its members are involved in many different signaling processes. These signaling processes strongly differ in type with TGF-β ligands eliciting both sustained or transient responses. Members of the TGF-β family can also act as morphogen and cellular responses would then be expected to provide a direct read-out of the extracellular ligand concentration. A number of different models have been proposed to reconcile these different behaviours. We were interested to define the set of minimal modifications that are required to change the type of signal processing in the TGF-β signaling network. RESULTS: To define the key aspects for signaling plasticity we focused on the core of the TGF-β signaling network. With the help of a parameter screen we identified ranges of kinetic parameters and protein concentrations that give rise to transient, sustained, or oscillatory responses to constant stimuli, as well as those parameter ranges that enable a proportional response to time-varying ligand concentrations (as expected in the read-out of morphogens). A combination of a strong negative feedback and fast shuttling to the nucleus biases signaling to a transient rather than a sustained response, while oscillations were obtained if ligand binding to the receptor is weak and the turn-over of the I-Smad is fast. A proportional read-out required inefficient receptor activation in addition to a low affinity of receptor-ligand binding. We find that targeted modification of single parameters suffices to alter the response type. The intensity of a constant signal (i.e. the ligand concentration), on the other hand, affected only the strength but not the type of the response. CONCLUSIONS: The architecture of the TGF-β pathway enables the observed signaling plasticity. The observed range of signaling outputs to TGF-β ligand in different cell types and under different conditions can be explained with differences in cellular protein concentrations and with changes in effective rate constants due to cross-talk with other signaling pathways. It will be interesting to uncover the exact cellular differences as well as the details of the cross-talks in future work.

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Format
SBML (L2V4)
Related Publication
  • Plasticity of TGF-β signaling.
  • Cellière G, Fengos G, Hervé M, Iber D
  • BMC systems biology , 0/ 2011 , Volume 5 , pages: 184
  • Department of Biosystems Science and Engineering (D-BSSE), Eidgenöossische Technische Hochschule Zurich (ETHZ), Mattenstrasse 26, 4058 Basel, Switzerland.
  • BACKGROUND: The family of TGF-β ligands is large and its members are involved in many different signaling processes. These signaling processes strongly differ in type with TGF-β ligands eliciting both sustained or transient responses. Members of the TGF-β family can also act as morphogen and cellular responses would then be expected to provide a direct read-out of the extracellular ligand concentration. A number of different models have been proposed to reconcile these different behaviours. We were interested to define the set of minimal modifications that are required to change the type of signal processing in the TGF-β signaling network. RESULTS: To define the key aspects for signaling plasticity we focused on the core of the TGF-β signaling network. With the help of a parameter screen we identified ranges of kinetic parameters and protein concentrations that give rise to transient, sustained, or oscillatory responses to constant stimuli, as well as those parameter ranges that enable a proportional response to time-varying ligand concentrations (as expected in the read-out of morphogens). A combination of a strong negative feedback and fast shuttling to the nucleus biases signaling to a transient rather than a sustained response, while oscillations were obtained if ligand binding to the receptor is weak and the turn-over of the I-Smad is fast. A proportional read-out required inefficient receptor activation in addition to a low affinity of receptor-ligand binding. We find that targeted modification of single parameters suffices to alter the response type. The intensity of a constant signal (i.e. the ligand concentration), on the other hand, affected only the strength but not the type of the response. CONCLUSIONS: The architecture of the TGF-β pathway enables the observed signaling plasticity. The observed range of signaling outputs to TGF-β ligand in different cell types and under different conditions can be explained with differences in cellular protein concentrations and with changes in effective rate constants due to cross-talk with other signaling pathways. It will be interesting to uncover the exact cellular differences as well as the details of the cross-talks in future work.
Contributors
Georgios Fengos

Metadata information

is
BioModels Database MODEL1208280000
BioModels Database BIOMD0000000600
isDescribedBy
PubMed 22051045
PubMed 22051045
Curation status
Curated
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  • Model originally submitted by : Georgios Fengos
  • Submitted: Aug 28, 2012 5:56:01 PM
  • Last Modified: Apr 18, 2016 3:56:39 PM
Revisions
  • Version: 2 public model Download this version
    • Submitted on: Apr 18, 2016 3:56:39 PM
    • Submitted by: Georgios Fengos
    • With comment: Current version of Cellière2011 - Plasticity of TGF-β Signalling
  • Version: 1 public model Download this version
    • Submitted on: Aug 28, 2012 5:56:01 PM
    • Submitted by: Georgios Fengos
    • With comment: Original import of Simple Hill with inhibitor
Curator's comment:
(added: 18 Apr 2016, 14:42:22, updated: 18 Apr 2016, 14:42:22)
Figure S1 and S2 have from the reference publication have been reproduced in Copasi and Matlab SimBiology. (The "transcription factor" line corresponds to the species Smad_P_CoSmad_N.) The curation plot shown reproduces Figure S2 and was produced using Copasi for simulation and matplotlib for plotting. Python script added as additional file.