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

Azadeh Arabi, Karim Ullah, Rui M M Branca, Johan Johansson, Daniel Bandarra, Moritz Haneklaus, Jing Fu, Ingrid Ariës, Peter Nilsson, Monique L Den Boer, Katja Pokrovskaja, Dan Grandér, Gutian Xiao, Sonia Rocha, Janne Lehtiö, Olle Sangfelt

Research output: Contribution to journalArticlepeer-review

69 Citations (Scopus)

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.

Original languageEnglish
Article number976
Pages (from-to)976
JournalNature communications
Volume3
DOIs
Publication statusPublished - 2012
Externally publishedYes

Keywords

  • Cell Cycle Proteins/genetics
  • Cell Line
  • Cell Line, Tumor
  • Computational Biology
  • F-Box Proteins/genetics
  • F-Box-WD Repeat-Containing Protein 7
  • Glycogen Synthase Kinase 3/genetics
  • Humans
  • Immunoblotting
  • Immunoprecipitation
  • NF-kappa B p52 Subunit/genetics
  • Phosphorylation/genetics
  • Proteomics
  • Signal Transduction/genetics
  • Tandem Mass Spectrometry
  • Ubiquitin-Protein Ligases/genetics

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