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A rate equation approach to elucidate the kinetics and robustness of the TGF-beta pathway

Melke, Pontus LU ; Jönsson, Henrik LU ; Pardali, Evangelia LU ; ten Dijke, Peter and Peterson, Carsten LU (2006) In Biophysical Journal 91(12). p.4368-4380
Abstract
We present a rate equation model for the TGF-beta pathway in endothelial cells together with novel measurements. This pathway plays a prominent role in inter- and intracellular communication and subversion can lead to cancer, fibrosis vascular disorders, and immune diseases. The model successfully describes the kinetics of experimental data and also correctly predicts the behavior in experiments where the system is perturbed. A novel method in this context, simulated tempering, is used to fit the model parameters to the data. It provides an ensemble of high quality solutions, which are analyzed with clustering methods and display a hierarchical structure highlighting distinct parameter subspaces with biological interpretations. This... (More)
We present a rate equation model for the TGF-beta pathway in endothelial cells together with novel measurements. This pathway plays a prominent role in inter- and intracellular communication and subversion can lead to cancer, fibrosis vascular disorders, and immune diseases. The model successfully describes the kinetics of experimental data and also correctly predicts the behavior in experiments where the system is perturbed. A novel method in this context, simulated tempering, is used to fit the model parameters to the data. It provides an ensemble of high quality solutions, which are analyzed with clustering methods and display a hierarchical structure highlighting distinct parameter subspaces with biological interpretations. This analysis discriminates between different biological mechanisms to achieve a transient signal from a sustained TGF-beta input, where one mechanism is to use a negative feedback to turn the signal off. Further analysis in terms of parameter sensitivity reveals that this negative feedback loop in TGF-beta signaling renders the system global robustness. This sheds light upon the role of the Smad7 protein in this system. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Biophysical Journal
volume
91
issue
12
pages
4368 - 4380
publisher
Cell Press
external identifiers
  • wos:000242339600006
  • scopus:33845424529
ISSN
1542-0086
DOI
10.1529/biophysj.105.080408
language
English
LU publication?
yes
id
59e927a9-4f02-4464-8eda-ae57b8fe3a45 (old id 685725)
alternative location
http://dx.doi.org/10.1529/biophysj.105.080408
date added to LUP
2016-04-01 11:48:47
date last changed
2020-07-29 02:11:28
@article{59e927a9-4f02-4464-8eda-ae57b8fe3a45,
  abstract     = {We present a rate equation model for the TGF-beta pathway in endothelial cells together with novel measurements. This pathway plays a prominent role in inter- and intracellular communication and subversion can lead to cancer, fibrosis vascular disorders, and immune diseases. The model successfully describes the kinetics of experimental data and also correctly predicts the behavior in experiments where the system is perturbed. A novel method in this context, simulated tempering, is used to fit the model parameters to the data. It provides an ensemble of high quality solutions, which are analyzed with clustering methods and display a hierarchical structure highlighting distinct parameter subspaces with biological interpretations. This analysis discriminates between different biological mechanisms to achieve a transient signal from a sustained TGF-beta input, where one mechanism is to use a negative feedback to turn the signal off. Further analysis in terms of parameter sensitivity reveals that this negative feedback loop in TGF-beta signaling renders the system global robustness. This sheds light upon the role of the Smad7 protein in this system.},
  author       = {Melke, Pontus and Jönsson, Henrik and Pardali, Evangelia and ten Dijke, Peter and Peterson, Carsten},
  issn         = {1542-0086},
  language     = {eng},
  number       = {12},
  pages        = {4368--4380},
  publisher    = {Cell Press},
  series       = {Biophysical Journal},
  title        = {A rate equation approach to elucidate the kinetics and robustness of the TGF-beta pathway},
  url          = {https://lup.lub.lu.se/search/ws/files/2652984/1266238.pdf},
  doi          = {10.1529/biophysj.105.080408},
  volume       = {91},
  year         = {2006},
}