title: Proteomic screen reveals Fbw7 as a modulator of the NF-κB pathway.
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.
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden. azadeh.arabi@ki.se
authors.forename: Azadeh
authors.initials: A
authors.lastname: Arabi
authors.forename: Karim
authors.initials: K
authors.lastname: Ullah
authors.forename: Rui M M
authors.initials: RM
authors.lastname: Branca
authors.forename: Johan
authors.initials: J
authors.lastname: Johansson
authors.forename: Daniel
authors.initials: D
authors.lastname: Bandarra
authors.forename: Moritz
authors.initials: M
authors.lastname: Haneklaus
authors.forename: Jing
authors.initials: J
authors.lastname: Fu
authors.forename: Ingrid
authors.initials: I
authors.lastname: Ariës
authors.forename: Peter
authors.initials: P
authors.lastname: Nilsson
authors.forename: Monique L
authors.initials: ML
authors.lastname: Den Boer
authors.forename: Katja
authors.initials: K
authors.lastname: Pokrovskaja
authors.forename: Dan
authors.initials: D
authors.lastname: Grandér
authors.forename: Gutian
authors.initials: G
authors.lastname: Xiao
authors.forename: Sonia
authors.initials: S
authors.lastname: Rocha
authors.forename: Janne
authors.initials: J
authors.lastname: Lehtiö
authors.forename: Olle
authors.initials: O
authors.lastname: Sangfelt
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D019295:Computational Biology; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D052003:NF-kappa B p52 Subunit / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics / Q000502:physiology; D040901:Proteomics; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D053719:Tandem Mass Spectrometry; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D052003:NF-kappa B p52 Subunit; D044767:Ubiquitin-Protein Ligases; D038362:Glycogen Synthase Kinase 3