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The pseudophosphatase STYX targets the F‐box of FBXW7 and inhibits SCF^(FBXW7) function

Reiterer, Veronika and Figueras-Puig, Cristina and Le Guerroue, Francois and Confalonieri, Stefano and Vecchi, Manuela and Jalapothu, Dasaradha and Kanse, Sandip M. and Deshaies, Raymond J. and Di Fiore, Pier Paolo and Behrends, Christian and Farhan, Hesso (2017) The pseudophosphatase STYX targets the F‐box of FBXW7 and inhibits SCF^(FBXW7) function. EMBO Journal, 36 (3). pp. 260-273. ISSN 0261-4189. PMCID PMC5286380. https://resolver.caltech.edu/CaltechAUTHORS:20170104-144844772

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Abstract

The F‐box protein FBXW7 is the substrate‐recruiting subunit of an SCF ubiquitin ligase and a major tumor‐suppressor protein that is altered in several human malignancies. Loss of function of FBXW7 results in the stabilization of numerous proteins that orchestrate cell proliferation and survival. Little is known about proteins that directly regulate the function of this protein. In the current work, we have mapped the interactome of the enigmatic pseudophosphatase STYX. We reasoned that a catalytically inactive phosphatase might have adopted novel mechanisms of action. The STYX interactome contained several F‐box proteins, including FBXW7. We show that STYX binds to the F‐box domain of FBXW7 and disables its recruitment into the SCF complex. Therefore, STYX acts as a direct inhibitor of FBXW7, affecting the cellular levels of its substrates. Furthermore, we find that levels of STYX and FBXW7 are anti‐correlated in breast cancer patients, which affects disease prognosis. We propose the STYX–FBXW7 interaction as a promising drug target for future investigations.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.15252/embj.201694795DOIArticle
http://emboj.embopress.org/content/36/3/260PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5286380/PubMed CentralArticle
ORCID:
AuthorORCID
Deshaies, Raymond J.0000-0002-3671-9354
Behrends, Christian0000-0002-9184-7607
Farhan, Hesso0000-0002-0889-8463
Additional Information:© 2016 The Authors. Received 17 May 2016; Revised 11 November 2016; Accepted 17 November 2016. Published online 22.12.2016. We thank Markus Welcker, Bruce Clurman, Anne‐Claude Gingras, Melanie Cobb, and Nikita Popov for providing different plasmids for FBXW7, CUL1, SKP1. We thank Alexander Krämer, Alexander Keller and Nicola Catone and Annette Aichem for technical help. H.F. is supported by the German Science Foundation (DFG), by the Canton of Thurgau, by the Swiss Science Foundation and by the Young Scholar Fund of the University of Konstanz. C.B. is supported by the LOEWE Program (Ub‐Net) of the State of Hessen (Germany) and the European Research Council (282333‐XABA). P.P.D.F. is supported by Associazione Italiana per la Ricerca sul Cancro (AIRC—IG 14404 to PPDF and MCO 10.000), Italian Ministry of Health, Monzino Foundation. Funding: German Science Foundation (DFG) FA 961/6‐1FA 961/3‐2; Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (SNF) 31003A_156913; Canton of Thurgau; Young Scholar Fund of the University of Konstanz; Hessisches Ministerium für Wissenschaft und Kunst; European Research Council 282333‐XABA; Associazione Italiana per la Ricerca sul Cancro IG 14404MCO 10.000; Italian Ministry of Health; Fondazione Antonio Carlo Monzino. Author contributions: VR performed and analyzed experiments; CF‐P performed experiments; FLG performed mass spectrometry experiments; SC and MV performed Affymetrix and qPCR experiments and analyzed the data from breast cancer patients; PPDF analyzed breast cancer data; SMK and DJ performed and analyzed experiments; RJD analyzed data and provided reagents; CB analyzed mass spectrometry experiments and contributed to the overall study design; HF conceived the project, analyzed the data, and supervised the study; and VR, SC, MV, PPDF, RJD, CB, and HF wrote the manuscript. Conflict of interest: The authors declare that they have no conflict of interest.
Funders:
Funding AgencyGrant Number
Deutsche Forschungsgemeinschaft (DFG)FA 961/6‐1FA 961/3‐2
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (SNF)31003A_156913
Canton of ThurgauUNSPECIFIED
University of KonstanzUNSPECIFIED
Hessisches Ministerium für Wissenschaft und KunstUNSPECIFIED
European Research Council (ERC)282333-XABA
Associazione Italiana per la Ricerca sul CancroIG 14404MCO 10.000
Ministry of Health (Italy)UNSPECIFIED
Fondazione Antonio Carlo MonzinoUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Subject Keywords:breast cancer; Cullin–RING ubiquitin ligase; F-box protein; mass spectrometry; pseudophosphatase
Issue or Number:3
PubMed Central ID:PMC5286380
Record Number:CaltechAUTHORS:20170104-144844772
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20170104-144844772
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:73226
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:04 Jan 2017 23:02
Last Modified:03 Oct 2019 16:25

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