This Article Full Text Full Text (PDF) Supplement All Versions of this Article: biophysj.105.080408v1 91/12/4368    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Melke, P. Articles by Peterson, C. Search for Related Content PubMed PubMed Citation Articles by Melke, P. Articles by Peterson, C.

A Rate Equation Approach to Elucidate the Kinetics and Robustness of the TGF-ß Pathway

Pontus Melke ^*, Henrik Jönsson ^*, Evangelia Pardali , Peter ten Dijke  and Carsten Peterson ^*

^* Computational Biology & Biological Physics, Department of Theoretical Physics, Lund University, Lund, Sweden; and Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands

Correspondence: Address reprint requests to C. Peterson, E-mail: carsen{at}thep.lu.se.

We present a rate equation model for the TGF-ß 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-ß 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-ß signaling renders the system global robustness. This sheds light upon the role of the Smad7 protein in this system.