Proteomic screen reveals Fbw7 as a modulator of the NF-κB pathway

被引：79

作者：

Arabi, Azadeh ^{[1
]}

Ullah, Karim ^{[1
]}

Branca, Rui M. M. ^{[2
,3
]}

Johansson, Johan ^{[4
]}

Bandarra, Daniel ^{[5
]}

Haneklaus, Moritz ^{[3
]}

Fu, Jing ^{[6
]}

Aries, Ingrid ^{[7
]}

Nilsson, Peter ^{[8
]}

Den Boer, Monique L. ^{[7
]}

Pokrovskaja, Katja ^{[3
]}

Grander, Dan ^{[3
]}

Xiao, Gutian ^{[6
]}

Rocha, Sonia ^{[5
]}

Lehtio, Janne ^{[2
,3
]}

Sangfelt, Olle ^{[1
]}

机构：

[1] Karolinska Inst, Dept Cell & Mol Biol, S-17177 Stockholm, Sweden

[2] Sci Life Lab, S-17121 Solna, Sweden

[3] Karolinska Inst, Dept Oncol & Pathol, S-17176 Stockholm, Sweden

[4] Swedish Def, S-10251 Stockholm, Sweden

[5] Univ Dundee, Wellcome Trust Ctr Gene Regulat & Express, Dundee DD1 5EH, Scotland

[6] Univ Pittsburgh, Sch Med, Dept Microbiol & Mol Genet, Inst Canc, Pittsburgh, PA 15213 USA

[7] Erasmus MC Sophia Childrens Hosp, Dept Pediat Oncol & Hematol, NL-3000 CB Rotterdam, Netherlands

[8] Royal Inst Technol, Sch Biotechnol KTH, Sci Life Lab, S-17121 Stockholm, Sweden

来源：

NATURE COMMUNICATIONS | 2012年 / 3卷

基金：

瑞典研究理事会;

关键词：

TUMOR-SUPPRESSOR; CYCLIN-E; PROTEIN; PHOSPHORYLATION; DEGRADATION; ACTIVATION; COMPLEX; CANCER; HCDC4; P100;

D O I：

10.1038/ncomms1975

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页数：11

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