The pseudophosphatase STYX targets the F-box of FBXW7 and inhibits SCFFBXW7 function

EMBO J. 2017 Feb 1;36(3):260-273. doi: 10.15252/embj.201694795.

Veronika Reiterer ¹ ², Cristina Figueras-Puig ², Francois Le Guerroue ³, Stefano Confalonieri ⁴ ⁵, Manuela Vecchi ⁶ ⁷, Dasaradha Jalapothu ¹, Sandip M Kanse ¹, Raymond J Deshaies ⁶ ⁷, Pier Paolo Di Fiore ⁴ ⁵ ⁸, Christian Behrends ⁹ ¹⁰, Hesso Farhan ¹¹ ² ¹²

Affiliations

1 Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
2 Biotechnology Institute Thurgau, Kreuzlingen, Switzerland.
3 Institute of Biochemistry II, Medical School Goethe University, Frankfurt, Germany.
4 The FIRC Institute for Molecular Oncology, IFOM, Milan, Italy.
5 Molecular Medicine Program, European Institute of Oncology, Milan, Italy.
6 Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
7 Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA, USA.
8 Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
9 Institute of Biochemistry II, Medical School Goethe University, Frankfurt, Germany christian.behrends@mail03.med.uni-muenchen.de hesso.farhan@medisin.uio.no.
10 Munich Cluster for Systems Neurology, Ludwig-Maximilians-University Munich, Munich, Germany.
11 Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway christian.behrends@mail03.med.uni-muenchen.de hesso.farhan@medisin.uio.no.
12 Department of Biology, University of Konstanz, Konstanz, Germany.

PMID: 28007894 DOI: 10.15252/embj.201694795

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.

Keywords

Cullin–RING ubiquitin ligase; F‐box protein; breast cancer; mass spectrometry; pseudophosphatase.

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