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

Veronika Reiterer, Cristina Figueras-Puig, Francois Le Guerroue, Stefano Confalonieri, Manuela Vecchi, Dasaradha Jalapothu, Sandip M Kanse, Raymond J Deshaies, Pier Paolo Di Fiore, Christian Behrends, Hesso Farhan

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)260-273
Number of pages14
JournalEMBO Journal
Volume36
Issue number3
DOIs
Publication statusPublished - Feb 1 2017

Keywords

  • Breast Neoplasms/diagnosis
  • Cell Cycle Proteins/antagonists & inhibitors
  • F-Box Proteins/antagonists & inhibitors
  • F-Box-WD Repeat-Containing Protein 7
  • Humans
  • Intracellular Signaling Peptides and Proteins/metabolism
  • Nuclear Proteins/metabolism
  • SKP Cullin F-Box Protein Ligases/antagonists & inhibitors
  • Ubiquitin-Protein Ligases/antagonists & inhibitors

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    Reiterer, V., Figueras-Puig, C., Le Guerroue, F., Confalonieri, S., Vecchi, M., Jalapothu, D., Kanse, S. M., Deshaies, R. J., Di Fiore, P. P., Behrends, C., & Farhan, H. (2017). The pseudophosphatase STYX targets the F-box of FBXW7 and inhibits SCFFBXW7 function. EMBO Journal, 36(3), 260-273. https://doi.org/10.15252/embj.201694795