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Open Access Research article

Mechanism of PP2A-mediated IKKβ dephosphorylation: a systems biological approach

Johannes Witt1*, Sandra Barisic2, Eva Schumann2, Frank Allgöwer3, Oliver Sawodny1, Thomas Sauter14 and Dagmar Kulms2*

Author affiliations

1 Institute for System Dynamics, Universität Stuttgart, Pfaffenwaldring 9, 70569 Stuttgart, Germany

2 Institute of Cell Biology and Immunology, Universität Stuttgart, Allmandring 31, 70569 Stuttgart, Germany

3 Institute for Systems Theory and Automatic Control, Universität Stuttgart, Pfaffenwaldring 9, 70569 Stuttgart, Germany

4 Life Sciences Research Unit, University of Luxembourg, 162 A, avenue de la Faïencerie, 1511 Luxembourg, Luxembourg

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Citation and License

BMC Systems Biology 2009, 3:71  doi:10.1186/1752-0509-3-71

Published: 16 July 2009

Abstract

Background

Biological effects of nuclear factor-κB (NFκB) can differ tremendously depending on the cellular context. For example, NFκB induced by interleukin-1 (IL-1) is converted from an inhibitor of death receptor induced apoptosis into a promoter of ultraviolet-B radiation (UVB)-induced apoptosis. This conversion requires prolonged NFκB activation and is facilitated by IL-1 + UVB-induced abrogation of the negative feedback loop for NFκB, involving a lack of inhibitor of κB (IκBα) protein reappearance. Permanent activation of the upstream kinase IKKβ results from UVB-induced inhibition of the catalytic subunit of Ser-Thr phosphatase PP2A (PP2Ac), leading to immediate phosphorylation and degradation of newly synthesized IκBα.

Results

To investigate the mechanism underlying the general PP2A-mediated tuning of IKKβ phosphorylation upon IL-1 stimulation, we have developed a strictly reduced mathematical model based on ordinary differential equations which includes the essential processes concerning the IL-1 receptor, IKKβ and PP2A. Combining experimental and modelling approaches we demonstrate that constitutively active, but not post-stimulation activated PP2A, tunes out IKKβ phosphorylation thus allowing for IκBα resynthesis in response to IL-1. Identifiability analysis and determination of confidence intervals reveal that the model allows reliable predictions regarding the dynamics of PP2A deactivation and IKKβ phosphorylation. Additionally, scenario analysis is used to scrutinize several hypotheses regarding the mode of UVB-induced PP2Ac inhibition. The model suggests that down regulation of PP2Ac activity, which results in prevention of IκBα reappearance, is not a direct UVB action but requires instrumentality.

Conclusion

The model developed here can be used as a reliable building block of larger NFκB models and offers comprehensive simplification potential for future modeling of NFκB signaling. It gives more insight into the newly discovered mechanisms for IKK deactivation and allows for substantiated predictions and investigation of different hypotheses. The evidence of constitutive activity of PP2Ac at the IKK complex provides new insights into the feedback regulation of NFκB, which is crucial for the development of new anti-cancer strategies.