A homeostatic model of IkappaB metabolism to control constitutive NF-kappaB activity.

TitleA homeostatic model of IkappaB metabolism to control constitutive NF-kappaB activity.
Publication TypeJournal Article
Year of Publication2007
AuthorsO'Dea EL, Barken D, Peralta RQ, Tran KT, Werner SL, Kearns JD, Levchenko A, Hoffmann A
JournalMol Syst Biol
Date Published2007
KeywordsAnimals, Blotting, Western, Cells, Cultured, Computer Simulation, Electrophoretic Mobility Shift Assay, Fibroblasts, Half-Life, Homeostasis, I-kappa B Kinase, I-kappa B Proteins, Kinetics, Leupeptins, Mice, Mice, Knockout, Models, Biological, NF-kappa B, Phosphorylation, Proteasome Endopeptidase Complex, Protein Binding, Protein Interaction Mapping, Protein Processing, Post-Translational, Proto-Oncogene Proteins, Signal Transduction, Tumor Necrosis Factor-alpha

Cellular signal transduction pathways are usually studied following administration of an external stimulus. However, disease-associated aberrant activity of the pathway is often due to misregulation of the equilibrium state. The transcription factor NF-kappaB is typically described as being held inactive in the cytoplasm by binding its inhibitor, IkappaB, until an external stimulus triggers IkappaB degradation through an IkappaB kinase-dependent degradation pathway. Combining genetic, biochemical, and computational tools, we investigate steady-state regulation of the NF-kappaB signaling module and its impact on stimulus responsiveness. We present newly measured in vivo degradation rate constants for NF-kappaB-bound and -unbound IkappaB proteins that are critical for accurate computational predictions of steady-state IkappaB protein levels and basal NF-kappaB activity. Simulations reveal a homeostatic NF-kappaB signaling module in which differential degradation rates of free and bound pools of IkappaB represent a novel cross-regulation mechanism that imparts functional robustness to the signaling module.

PubMed URLhttp://www.ncbi.nlm.nih.gov/pubmed/17486138?dopt=Abstract
Alternate TitleMol. Syst. Biol.
PubMed ID17486138