Proteomic screen reveals Fbw7 as a modulator of the NF-kappa B pathway
2012 (English)In: Nature Communications, ISSN 2041-1723, Vol. 3, 976- p.Article in journal (Refereed) Published
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-ÎºB2 (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-ÎºB 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-ÎºB2 pathway stimulation.
Place, publisher, year, edition, pages
2012. Vol. 3, 976- p.
F-Box Protein, Tumor-Suppressor, Cyclin-E, Multiple-Myeloma, Nf-Kappa-B2 P100, Ubiquitin Ligase, Human Cancer, Degradation, Phosphorylation, Activation
Cell and Molecular Biology
IdentifiersURN: urn:nbn:se:kth:diva-101502DOI: 10.1038/ncomms1975ISI: 000306995000048ScopusID: 2-s2.0-84864837496OAI: oai:DiVA.org:kth-101502DiVA: diva2:549178
FunderSwedish Research CouncilSwedish e‐Science Research CenterScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
QC 201209032012-09-032012-08-302013-04-19Bibliographically approved