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Cited by 90NF-κB Signaling PathwaysUbiquitin and proteasome pathwaysSignaling Pathways in Disease

Proteomic screen reveals Fbw7 as a modulator of the NF-κB pathway

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Arabi, Azadeh, Ullah, Karim, Branca, Rui M.M., Johansson, Johan, Bandarra, Daniel, Haneklaus, Moritz, Fu, Jing, Ariës, Ingrid +8 more·2012·Nature Communications
DOI 10.1038/ncomms1975PMC PMC4354031
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Abstract

Fbw7 is a ubiquitin-ligase that targets several oncoproteins for proteolysis, but the full range of Fbw7 substrates is not known. Here we show that by performing quantitative proteomics combined with degron motif searches, we effectively screened for a more complete set of Fbw7 targets. We identify 89 putative Fbw7 substrates, including several disease-associated proteins. The transcription factor NF-κB2 (p100/p52) is one of the candidate Fbw7 substrates. We show that Fbw7 interacts with p100 via a conserved degron and that it promotes degradation of p100 in a GSK3β phosphorylation-dependent manner. Fbw7 inactivation increases p100 levels, which in the presence of NF-κB pathway stimuli, leads to increased p52 levels and activity. Accordingly, the apoptotic threshold can be increased by loss of Fbw7 in a p100-dependent manner. In conclusion, Fbw7-mediated destruction of p100 is a regulatory component restricting the response to NF-κB2 pathway stimulation. Fbw7 is a ubiquitin-ligase, which targets several oncoproteins for proteolysis, and is therefore important for the control and prevention of tumorigenesis. In this study, Arabi and colleagues carry out a proteomic screen of the targets of Fbw7, and identify Nuclear Factor of κ-B2 as a substrate.

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Cited by

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Authors
Arabi, A., Ullah, K., Branca, R. M. M., Johansson, J., Bandarra, D., Haneklaus, M., Fu, J., Ariës, I., Nilsson, P., Den Boer, M. L., Pokrovskaja, K., Grandér, D., Xiao, G., Rocha, S., Lehtiö, J., & Sangfelt, O.
Affiliations
  • Karolinska Institutet (SE)
  • Science for Life Laboratory (SE)
  • University of Dundee (GB)
  • University of Pittsburgh (US)
Corresponding author
  • Arabi, Azadeh
  • Sangfelt, Olle
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2012-07-31
Volume
3
Issue
1
Pages
976-976
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/ncomms1975
PMC
PMC4354031
OpenAlex
W2021056570
Cited by
90
References
3
Citations by year
2026: 1 · 2025: 2 · 2024: 1 · 2023: 4 · 2022: 6 · 2021: 6 · 2020: 11 · 2019: 11 · 2018: 5 · 2017: 6 · 2016: 8 · 2015: 6 · 2014: 9 · 2013: 12 · 2012: 2
FWCI
3.08
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Discovery Research Portal (University of Dundee) (submittedVersion)
Funders
  • Swedish Cancer Foundation
  • Cancer Research UK (A12918, 12918)
  • Cancerfonden
  • Karolinska Institutet
  • Vetenskapsrådet
  • National Institutes of Health
  • National Cancer Institute (R01CA116616)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
Keywords
FBXW7, NF-κB2, P100, p52, ubiquitin ligase, protein degradation, GSK3β phosphorylation, proteomic screen, apoptosis, tumor suppression
MeSH terms
F-Box-WD Repeat-Containing Protein 7, Cell Line, Humans, Phosphorylation, Immunoblotting, Signal Transduction, Cell Cycle Proteins, Computational Biology, Glycogen Synthase Kinase 3, Proteomics, Ubiquitin-Protein Ligases, F-Box Proteins, Cell Line, Tumor, Immunoprecipitation, NF-kappa B p52 Subunit, Tandem Mass Spectrometry

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