Cited by 337NF-κB Signaling PathwaysSignaling Pathways in DiseaseImmune Response and Inflammation

Phosphorylation of IκBα Precedes but Is Not Sufficient for Its Dissociation from NF-κB

Open access
DiDonato, Joseph A., Mercurio, Frank, Karin, Michael·1995·Molecular and Cellular Biology

Abstract

NF-kappa B is an important activator of immune and inflammatory response genes. NF-kappa B is sequestered in the cytoplasm of nonstimulated cells through interaction with the I kappa B inhibitors. These inactive complexes are dissociated in response to a variety of extracellular signals, thereby allowing free NF-kappa B dimers to translocate to the nucleus and active transcription of specific target genes. The current dogma is that phosphorylation of the I kappa Bs is responsible for dissociation of the inactive complexes, an event that is rendered irreversible by rapid I kappa B degradation. Here, we show that inducers of NF-kappa B activity stimulate the hyperphosphorylation of one of the I kappa Bs, I kappa B alpha. However, contrary to the present dogma the hyperphosphorylated form of I kappa B alpha remains associated with NF-kappa B components such as RelA (p65). Thus, phosphorylation of I kappa B alpha is not sufficient to cause dissociation of the inactive NF-kappa B:I kappa B alpha complex. However, that complex is disrupted through the selective degradation of phosphorylated I kappa B alpha in response to extracellular signals. Using a variety of protease inhibitors, some of which have specificity towards the multicatalytic proteinase complex, we demonstrate that degradation of I kappa B alpha is required for NF-kappa B activation. The results of these experiments are more consistent with a new model according to which phosphorylation of I kappa B alpha associated with NF-kappa B marks it for proteolytic degradation. I kappa B alpha is degraded while bound to NF-kappa B. The selective degradation of I kappa B alpha releases active NF-kappa B dimers which can translocate to the nucleus to activate specific target genes.

Integrity signals

Registry

Crossref · 10.1128/mcb.15.3.1302

Cites

63 of 63 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

The text we found for this paper looks like another document, so its claims and self-check weren’t run. The registry and citation checks still apply.

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The text we found for this paper looks like another document, so the self-check wasn’t run.

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Authors
DiDonato, J. A., Mercurio, F., & Karin, M.
Affiliations
  • University of California San Diego (US)
  • SignalRx Pharmaceuticals (United States) (US)
Venue
Molecular and Cellular Biology
Published
1995-03-01
Volume
15
Issue
3
Pages
1302-1311
ISSN
  • 0270-7306 (ISSN-L)
  • 1098-5549
OpenAlex
W2169053713
Cited by
337
References
63
Citations by year
2026: 2 · 2025: 1 · 2023: 2 · 2022: 1 · 2021: 1 · 2020: 3 · 2019: 4 · 2017: 5 · 2016: 7 · 2015: 2 · 2014: 4 · 2013: 5 · 2012: 5
FWCI
18.79
Type
journal article
Language
en
Open access
Locations
  • Molecular and Cellular Biology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5p01ca050528-07)
  • Laboratório Nacional de Luz Síncrotron
  • National Heart, Lung, and Blood Institute (HL 35018, P01HL035018)
  • National Cancer Institute (CA50528)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK-085401)
  • Lawrence Livermore National Laboratory
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords
IκBα, NF-κB activation, protein phosphorylation, IκB degradation, RelA/p65, NF-κB inhibitors, proteasome, proteolysis, nuclear translocation
MeSH terms
NF-KappaB Inhibitor alpha, Amino Acid Sequence, Cysteine Endopeptidases, DNA-Binding Proteins, Electrophoresis, Polyacrylamide Gel, HeLa Cells, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Models, Biological, Molecular Sequence Data, Multienzyme Complexes, Oligopeptides, Phosphorylation, Protease Inhibitors, Transfection, Tumor Cells, Cultured, Signal Transduction, NF-kappa B, I-kappa B Proteins, Macromolecular Substances, Proteasome Endopeptidase Complex, Transcription Factor RelA

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review