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

Research output: Contribution to journalArticle

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.

Details

Authors
  • Pontus Melke
  • Henrik Jönsson
  • Evangelia Pardali
  • Peter ten Dijke
  • Carsten Peterson
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Biophysics
Original languageEnglish
Pages (from-to)4368-4380
JournalBiophysical Journal
Volume91
Issue number12
Publication statusPublished - 2006
Publication categoryResearch
Peer-reviewedYes

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