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

Azadeh Arabi1, Karim Ullah, Rui M M Branca

  • 1Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden. azadeh.arabi@ki.se

Nature Communications
|August 7, 2012
PubMed

Insights

F-box protein 7 (Fbw7) targets disease-associated proteins for degradation. This study identifies 89 new Fbw7 targets, including NF-κB2 (p100/p52), revealing Fbw7

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • F-box protein 7 (Fbw7) is a key ubiquitin ligase targeting oncoproteins for proteolysis.
  • The complete substrate repertoire of Fbw7 remains incompletely defined.
  • Identifying novel Fbw7 substrates is crucial for understanding its role in disease.

Purpose of the Study:

  • To comprehensively identify Fbw7 substrates using quantitative proteomics and degron motif analysis.
  • To investigate the role of Fbw7 in the regulation of NF-κB2 (p100/p52).

Main Methods:

  • Quantitative proteomics screening for Fbw7 targets.
  • Degron motif analysis to identify substrate recognition sites.
  • Biochemical assays to confirm Fbw7-p100 interaction and degradation.
  • Analysis of NF-κB pathway activation and apoptosis in Fbw7-deficient cells.

Main Results:

  • Identification of 89 putative Fbw7 substrates, including disease-associated proteins.
  • Demonstration of Fbw7 interaction with NF-κB2 (p100) via a conserved degron.
  • GSK3β phosphorylation-dependent degradation of p100 mediated by Fbw7.
  • Fbw7 inactivation leads to increased p100/p52 levels and enhanced NF-κB2 pathway activity.
  • Loss of Fbw7 increases the apoptotic threshold in a p100-dependent manner.

Conclusions:

  • Fbw7-mediated degradation of p100 is a critical regulatory mechanism for the NF-κB2 pathway.
  • Fbw7 acts as a tumor suppressor by restricting NF-κB2 pathway activation.
  • This study expands the known functions of Fbw7 in cellular signaling and disease.

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