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 and Olle Sangfelt ()
Additional contact information
Azadeh Arabi: Karolinska Institutet, 171 77 Stockholm, Sweden.
Karim Ullah: Karolinska Institutet, 171 77 Stockholm, Sweden.
Rui M.M. Branca: Clinical Proteomics Mass Spectrometry, Science for Life Laboratory, Solna 171 21, Sweden.
Johan Johansson: Swedish Defence, Stockholm 10251, Sweden.
Daniel Bandarra: Wellcome Trust Centre for Gene Regulation and Expression, University of Dundee, Dundee DD1 5EH, United Kingdom.
Moritz Haneklaus: Karolinska Institutet, Stockholm 17176, Sweden.
Jing Fu: University of Pittsburgh Cancer Institute, School of Medicine
Ingrid Ariës: Rotterdam 3000 CB, The Netherlands.
Peter Nilsson: Science for Life Laboratory, School of Biotechnology KTH, Royal Institute of Technology, Stockholm 171 21, Sweden.
Monique L. Den Boer: Rotterdam 3000 CB, The Netherlands.
Katja Pokrovskaja: Karolinska Institutet, Stockholm 17176, Sweden.
Dan Grandér: Karolinska Institutet, Stockholm 17176, Sweden.
Gutian Xiao: University of Pittsburgh Cancer Institute, School of Medicine
Sonia Rocha: Wellcome Trust Centre for Gene Regulation and Expression, University of Dundee, Dundee DD1 5EH, United Kingdom.
Janne Lehtiö: Clinical Proteomics Mass Spectrometry, Science for Life Laboratory, Solna 171 21, Sweden.
Olle Sangfelt: Karolinska Institutet, 171 77 Stockholm, Sweden.

Nature Communications, 2012, vol. 3, issue 1, 1-11

Abstract: 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.

Date: 2012
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DOI: 10.1038/ncomms1975

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