Journal
NATURE COMMUNICATIONS
Volume 3, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms1975
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Funding
- Swedish Cancer Society Radiumhemmets forsknongsfonder
- Swedish Cancer Foundation
- Swedish Research Council
- Swedish Children's Cancer Foundation
- Karolinska Institute Foundations
- Cancer Research UK
- Portuguese Science Foundation
- GABBA
- National Institute of Health (NIH)/National Cancer Institute (NCI) [R01 CA116616]
- American Cancer Society (ACS) [RSG-06-066-01-MGO]
- Cancer Research UK [12918] Funding Source: researchfish
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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-kappa B2 (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 beta phosphorylation-dependent manner. Fbw7 inactivation increases p100 levels, which in the presence of NF-kappa B 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-kappa B2 pathway stimulation.
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