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The USP46 deubiquitylase complex increases Wingless/Wnt signaling strength by stabilizing Arrow/LRP6

Author

Listed:
  • Zachary T. Spencer

    (Dartmouth College)

  • Victoria H. Ng

    (Vanderbilt University)

  • Hassina Benchabane

    (Dartmouth College)

  • Ghalia Saad Siddiqui

    (Dartmouth College)

  • Deepesh Duwadi

    (Dartmouth College)

  • Ben Maines

    (Dartmouth College)

  • Jamal M. Bryant

    (Vanderbilt University)

  • Anna Schwarzkopf

    (Vanderbilt University)

  • Kai Yuan

    (Dartmouth College)

  • Sara N. Kassel

    (Vanderbilt University)

  • Anant Mishra

    (Dartmouth College)

  • Ashley Pimentel

    (Dartmouth College)

  • Andres M. Lebensohn

    (Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health)

  • Rajat Rohatgi

    (Stanford University School of Medicine)

  • Scott A. Gerber

    (Geisel School of Medicine at Dartmouth)

  • David J. Robbins

    (Georgetown University)

  • Ethan Lee

    (Vanderbilt University)

  • Yashi Ahmed

    (Dartmouth College)

Abstract

The control of Wnt receptor abundance is critical for animal development and to prevent tumorigenesis, but the mechanisms that mediate receptor stabilization remain uncertain. We demonstrate that stabilization of the essential Wingless/Wnt receptor Arrow/LRP6 by the evolutionarily conserved Usp46-Uaf1-Wdr20 deubiquitylase complex controls signaling strength in Drosophila. By reducing Arrow ubiquitylation and turnover, the Usp46 complex increases cell surface levels of Arrow and enhances the sensitivity of target cells to stimulation by the Wingless morphogen, thereby increasing the amplitude and spatial range of signaling responses. Usp46 inactivation in Wingless-responding cells destabilizes Arrow, reduces cytoplasmic accumulation of the transcriptional coactivator Armadillo/β-catenin, and attenuates or abolishes Wingless target gene activation, which prevents the concentration-dependent regulation of signaling strength. Consequently, Wingless-dependent developmental patterning and tissue homeostasis are disrupted. These results reveal an evolutionarily conserved mechanism that mediates Wnt/Wingless receptor stabilization and underlies the precise activation of signaling throughout the spatial range of the morphogen gradient.

Suggested Citation

  • Zachary T. Spencer & Victoria H. Ng & Hassina Benchabane & Ghalia Saad Siddiqui & Deepesh Duwadi & Ben Maines & Jamal M. Bryant & Anna Schwarzkopf & Kai Yuan & Sara N. Kassel & Anant Mishra & Ashley P, 2023. "The USP46 deubiquitylase complex increases Wingless/Wnt signaling strength by stabilizing Arrow/LRP6," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41843-0
    DOI: 10.1038/s41467-023-41843-0
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