Activation of the transcription factor NF-κB is central to control of immune and inflammatory responses. Cytokine induced activation through the classical or canonical pathway relies on degradation of the inhibitor, IκBα and regulation by the IKKβ kinase. In addition, the NF-κB is activated through the NF-κB-inducing kinase, NIK. Analysis of the IKK/NIK inter-relationship and its impact on NF-κB control, were analysed by mathematical modelling, using matrix formalism and stoichiometrically balanced reactions. The analysis considered a range of bio-reactions and core metabolites and their role in relation to kinase activation and in control of specific steps of the NF-κB pathway. The model predicts a growth-rate and time dependent transfer of the primary kinase activity from IKKβ to NIK. In addition, it suggests that NIK/IKKβ interdependence is controlled by intermediates of phosphoribosylpyrophosphate (PRPP) within the glycolysis pathway, and thus, identifies a link between specific metabolic events and kinase activation in inflammatory signal transduction. Subsequent in vitro experiments, carried out to validate the impact of IKK/NIK interdependence, confirmed signal amplification at the level of the NF-κB/IκBα complex control in the presence of both kinases. Further, they demonstrate that the induced potentiation is due to synergistic enhancement of relA-dependent activation.
%0 Journal Article
%1 Kim2009NIK
%A Kim, Hong-Bum
%A Evans, Iona
%A Smallwood, Rod
%A Holcombe, Mike
%A Qwarnstrom, Eva E.
%D 2009
%J Biosystems
%K flux-analysis signalling
%R 10.1016/j.biosystems.2009.10.009
%T NIK and IKK interdependence in NF-B signalling - Flux analysis of regulation through metabolites
%U http://dx.doi.org/10.1016/j.biosystems.2009.10.009
%X Activation of the transcription factor NF-κB is central to control of immune and inflammatory responses. Cytokine induced activation through the classical or canonical pathway relies on degradation of the inhibitor, IκBα and regulation by the IKKβ kinase. In addition, the NF-κB is activated through the NF-κB-inducing kinase, NIK. Analysis of the IKK/NIK inter-relationship and its impact on NF-κB control, were analysed by mathematical modelling, using matrix formalism and stoichiometrically balanced reactions. The analysis considered a range of bio-reactions and core metabolites and their role in relation to kinase activation and in control of specific steps of the NF-κB pathway. The model predicts a growth-rate and time dependent transfer of the primary kinase activity from IKKβ to NIK. In addition, it suggests that NIK/IKKβ interdependence is controlled by intermediates of phosphoribosylpyrophosphate (PRPP) within the glycolysis pathway, and thus, identifies a link between specific metabolic events and kinase activation in inflammatory signal transduction. Subsequent in vitro experiments, carried out to validate the impact of IKK/NIK interdependence, confirmed signal amplification at the level of the NF-κB/IκBα complex control in the presence of both kinases. Further, they demonstrate that the induced potentiation is due to synergistic enhancement of relA-dependent activation.
@article{Kim2009NIK,
abstract = {Activation of the transcription factor {NF}-{κB} is central to control of immune and inflammatory responses. Cytokine induced activation through the classical or canonical pathway relies on degradation of the inhibitor, {IκBα} and regulation by the {IKKβ} kinase. In addition, the {NF}-{κB} is activated through the {NF}-{κB}-inducing kinase, {NIK}. Analysis of the {IKK}/{NIK} inter-relationship and its impact on {NF}-{κB} control, were analysed by mathematical modelling, using matrix formalism and stoichiometrically balanced reactions. The analysis considered a range of bio-reactions and core metabolites and their role in relation to kinase activation and in control of specific steps of the {NF}-{κB} pathway. The model predicts a growth-rate and time dependent transfer of the primary kinase activity from {IKKβ} to {NIK}. In addition, it suggests that {NIK}/{IKKβ} interdependence is controlled by intermediates of phosphoribosylpyrophosphate ({PRPP}) within the glycolysis pathway, and thus, identifies a link between specific metabolic events and kinase activation in inflammatory signal transduction. Subsequent in vitro experiments, carried out to validate the impact of {IKK}/{NIK} interdependence, confirmed signal amplification at the level of the {NF}-{κB}/{IκBα} complex control in the presence of both kinases. Further, they demonstrate that the induced potentiation is due to synergistic enhancement of {relA}-dependent activation.},
added-at = {2018-12-02T16:09:07.000+0100},
author = {Kim, Hong-Bum and Evans, Iona and Smallwood, Rod and Holcombe, Mike and Qwarnstrom, Eva E.},
biburl = {https://www.bibsonomy.org/bibtex/2c630de8b381c7e612f02a741092f4877/karthikraman},
citeulike-article-id = {6129289},
citeulike-linkout-0 = {http://dx.doi.org/10.1016/j.biosystems.2009.10.009},
day = 10,
doi = {10.1016/j.biosystems.2009.10.009},
interhash = {08b14728c7cad0cc5da765558b468a18},
intrahash = {c630de8b381c7e612f02a741092f4877},
issn = {03032647},
journal = {Biosystems},
keywords = {flux-analysis signalling},
month = nov,
posted-at = {2009-11-17 10:51:25},
priority = {5},
timestamp = {2018-12-02T16:09:07.000+0100},
title = {{NIK} and {IKK} interdependence in {NF}-B signalling - Flux analysis of regulation through metabolites},
url = {http://dx.doi.org/10.1016/j.biosystems.2009.10.009},
year = 2009
}