title: The pseudophosphatase STYX targets the F-box of FBXW7 and inhibits SCFFBXW7 function.
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.
authors.affiliation: Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.|Biotechnology Institute Thurgau, Kreuzlingen, Switzerland.
authors.forename: Veronika
authors.initials: V
authors.lastname: Reiterer
authors.affiliation: Biotechnology Institute Thurgau, Kreuzlingen, Switzerland.
authors.forename: Cristina
authors.initials: C
authors.lastname: Figueras-Puig
authors.affiliation: Institute of Biochemistry II, Medical School Goethe University, Frankfurt, Germany.
authors.forename: Francois
authors.initials: F
authors.lastname: Le Guerroue
authors.affiliation: The FIRC Institute for Molecular Oncology, IFOM, Milan, Italy.|Molecular Medicine Program, European Institute of Oncology, Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Confalonieri
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.|Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA, USA.
authors.forename: Manuela
authors.initials: M
authors.lastname: Vecchi
authors.affiliation: Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
authors.forename: Dasaradha
authors.initials: D
authors.lastname: Jalapothu
authors.affiliation: Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
authors.forename: Sandip M
authors.initials: SM
authors.lastname: Kanse
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.|Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA, USA.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Deshaies
authors.affiliation: The FIRC Institute for Molecular Oncology, IFOM, Milan, Italy.|Molecular Medicine Program, European Institute of Oncology, Milan, Italy.|Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Di Fiore
authors.affiliation: Institute of Biochemistry II, Medical School Goethe University, Frankfurt, Germany christian.behrends@mail03.med.uni-muenchen.de hesso.farhan@medisin.uio.no.|Munich Cluster for Systems Neurology, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Christian
authors.identifier: 0000-0002-9184-7607
authors.initials: C
authors.lastname: Behrends
authors.affiliation: Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway christian.behrends@mail03.med.uni-muenchen.de hesso.farhan@medisin.uio.no.|Biotechnology Institute Thurgau, Kreuzlingen, Switzerland.|Department of Biology, University of Konstanz, Konstanz, Germany.
authors.forename: Hesso
authors.identifier: 0000-0002-0889-8463
authors.initials: H
authors.lastname: Farhan
mesh_terms: D001943:Breast Neoplasms / Q000175:diagnosis / Q000473:pathology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D044783:F-Box Proteins / Q000037:antagonists & inhibitors*; D000073979:F-Box-WD Repeat-Containing Protein 7; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D044843:SKP Cullin F-Box Protein Ligases / Q000037:antagonists & inhibitors*; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors*
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C584541:STYX protein, human; D044843:SKP Cullin F-Box Protein Ligases; D044767:Ubiquitin-Protein Ligases
keywords: Cullin–RING ubiquitin ligase; F‐box protein; breast cancer; mass spectrometry; pseudophosphatase