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

Azadeh Arabi; Karim Ullah; Rui M. M. Branca; Johan Johansson; Daniel Bandarra; Moritz Haneklaus; Jing Fu; Ingrid Ariës; Peter  Nilsson; Monique L. Den Boer; Katja Pokrovskaja; Dan Grandér; Gutian Xiao; Sonia Rocha; Janne Lehtiö; Olle Sangfelt

doi:10.1038/ncomms1975

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

Azadeh Arabi, Karim Ullah, Rui M. M. Branca, Johan Johansson, Daniel Bandarra, Moritz Haneklaus, Jing Fu, Ingrid Ariës, Peter Nilsson, Monique L. Den Boer, Katja Pokrovskaja, Dan Grandér, Gutian Xiao, Sonia Rocha, Janne Lehtiö, Olle Sangfelt

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77 Citations (Scopus)

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-?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 2 phosphorylation-dependent manner. Fbw7 inactivation increases p100 levels, which in the presence of NF-?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-?B2 pathway stimulation.

Original language	English
Article number	976
Journal	Nature Communications
Volume	3
DOIs	https://doi.org/10.1038/ncomms1975
Publication status	Published - 2012

Keywords

Cell Cycle Proteins
Cell Line
Cell Line, Tumor
Computational Biology
F-Box Proteins
Glycogen Synthase Kinase 3
Humans
Immunoblotting
Immunoprecipitation
NF-kappa B p52 Subunit
Phosphorylation
Proteomics
Signal Transduction
Tandem Mass Spectrometry
Ubiquitin-Protein Ligases

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10.1038/ncomms1975

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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-?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 2 phosphorylation-dependent manner. Fbw7 inactivation increases p100 levels, which in the presence of NF-?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-?B2 pathway stimulation.",

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author = "Azadeh Arabi and Karim Ullah and Branca, {Rui M. M.} and Johan Johansson and Daniel Bandarra and Moritz Haneklaus and Jing Fu and Ingrid Ari{\"e}s and Peter Nilsson and {Den Boer}, {Monique L.} and Katja Pokrovskaja and Dan Grand{\'e}r and Gutian Xiao and Sonia Rocha and Janne Lehti{\"o} and Olle Sangfelt",

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doi = "10.1038/ncomms1975",

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volume = "3",

journal = "Nature Communications",

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AU - Arabi, Azadeh

AU - Ullah, Karim

AU - Branca, Rui M. M.

AU - Johansson, Johan

AU - Bandarra, Daniel

AU - Haneklaus, Moritz

AU - Fu, Jing

AU - Ariës, Ingrid

AU - Nilsson, Peter

AU - Den Boer, Monique L.

AU - Pokrovskaja, Katja

AU - Grandér, Dan

AU - Xiao, Gutian

AU - Rocha, Sonia

AU - Lehtiö, Janne

AU - Sangfelt, Olle

PY - 2012

Y1 - 2012

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AB - 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-?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 2 phosphorylation-dependent manner. Fbw7 inactivation increases p100 levels, which in the presence of NF-?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-?B2 pathway stimulation.

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KW - Humans

KW - Immunoblotting

KW - Immunoprecipitation

KW - NF-kappa B p52 Subunit

KW - Phosphorylation

KW - Proteomics

KW - Signal Transduction

KW - Tandem Mass Spectrometry

KW - Ubiquitin-Protein Ligases

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SN - 2041-1723

VL - 3

JO - Nature Communications

JF - Nature Communications

M1 - 976

ER -

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

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Keywords

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