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

Mol Syst Biol. 2007:3:111. doi: 10.1038/msb4100148. Epub 2007 May 8.


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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Blotting, Western
  • Cells, Cultured / metabolism
  • Computer Simulation*
  • Electrophoretic Mobility Shift Assay
  • Fibroblasts / metabolism
  • Half-Life
  • Homeostasis / physiology*
  • I-kappa B Kinase / deficiency
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / physiology
  • I-kappa B Proteins / genetics
  • I-kappa B Proteins / metabolism*
  • Kinetics
  • Leupeptins / pharmacology
  • Mice
  • Mice, Knockout
  • Models, Biological*
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism*
  • Phosphorylation
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Binding
  • Protein Interaction Mapping
  • Protein Processing, Post-Translational
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Signal Transduction / physiology*
  • Tumor Necrosis Factor-alpha / pharmacology


  • I kappa B beta protein
  • I-kappa B Proteins
  • Leupeptins
  • NF-kappa B
  • Nfkbia protein, mouse
  • Nfkbie protein, mouse
  • Proto-Oncogene Proteins
  • Tumor Necrosis Factor-alpha
  • NF-KappaB Inhibitor alpha
  • I-kappa B Kinase
  • Proteasome Endopeptidase Complex
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde