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Proteomic screen reveals Fbw7 as a modulator of the NF-kappa B pathway
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2012 (English)In: Nature Communications, ISSN 2041-1723, Vol. 3, 976- p.Article in journal (Refereed) Published
Abstract [en]

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 GSK3 2 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.

Place, publisher, year, edition, pages
2012. Vol. 3, 976- p.
Keyword [en]
F-Box Protein, Tumor-Suppressor, Cyclin-E, Multiple-Myeloma, Nf-Kappa-B2 P100, Ubiquitin Ligase, Human Cancer, Degradation, Phosphorylation, Activation
National Category
Cell and Molecular Biology
URN: urn:nbn:se:kth:diva-101502DOI: 10.1038/ncomms1975ISI: 000306995000048ScopusID: 2-s2.0-84864837496OAI: diva2:549178
Swedish Research CouncilSwedish e‐Science Research CenterScience for Life Laboratory - a national resource center for high-throughput molecular bioscience

QC 20120903

Available from: 2012-09-03 Created: 2012-08-30 Last updated: 2013-04-19Bibliographically approved

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Nilsson, Peter
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Proteomics (closed 20130101)Science for Life Laboratory, SciLifeLab
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