A homeostatic model of IkappaB metabolism to control constitutive NF-kappaB activity.
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.
O'Dea
Ellen L
EL
Signaling Systems Laboratory, Department of Chemistry and Biochemistry, UCSD, La Jolla, CA 92037, USA.
Barken
Derren
D
Peralta
Raechel Q
RQ
Tran
Kim T
KT
Werner
Shannon L
SL
Kearns
Jeffrey D
JD
Levchenko
Andre
A
Hoffmann
Alexander
A
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured / Q000378:metabolism; D003198:Computer Simulation; D024202:Electrophoretic Mobility Shift Assay; D005347:Fibroblasts / Q000378:metabolism; D006207:Half-Life; D006706:Homeostasis / Q000502:physiology*; D051550:I-kappa B Kinase / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism*; D007700:Kinetics; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011499:Protein Processing, Post-Translational; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D007976:Leupeptins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; C491366:Nfkbie protein, mouse; D011518:Proto-Oncogene Proteins; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D051550:I-kappa B Kinase; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde