Proteomic screen reveals Fbw7 as a modulatorof the nF-κB pathway

摘要

Fbw7 is a ubiquitin-ligase that targets several oncoproteins for proteolysis, but the full rangeof Fbw7 substrates is not known. Here we show that by performing quantitative proteomicscombined with degron motif searches, we effectively screened for a more complete set of Fbw7targets. 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 showthat Fbw7 interacts with p100 via a conserved degron and that it promotes degradation ofp100 in a GsK3 beta 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-dependentmanner. In conclusion, Fbw7-mediated destruction of p100 is a regulatory componentrestricting the response to nF-kapp B2 pathway stimulation.