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Small-molecule inhibition of Lats kinases may promote Yap-dependent proliferation in postmitotic mammalian tissues

Author

Listed:
  • Nathaniel Kastan

    (The Rockefeller University
    The Rockefeller University)

  • Ksenia Gnedeva

    (University of Southern California)

  • Theresa Alisch

    (The Rockefeller University
    The Rockefeller University)

  • Aleksandra A. Petelski

    (The Rockefeller University
    The Rockefeller University
    Northeastern University)

  • David J. Huggins

    (Tri-Institutional Therapeutics Discovery Institute
    Weill Cornell Medical College of Cornell University)

  • Jeanne Chiaravalli

    (The Rockefeller University
    Institut Pasteur)

  • Alla Aharanov

    (Weizmann Institute of Science)

  • Avraham Shakked

    (Weizmann Institute of Science)

  • Eldad Tzahor

    (Weizmann Institute of Science)

  • Aaron Nagiel

    (Vision Center
    Children’s Hospital Los Angeles
    University of Southern California)

  • Neil Segil

    (University of Southern California
    University of Southern California)

  • A. J. Hudspeth

    (The Rockefeller University
    The Rockefeller University)

Abstract

Hippo signaling is an evolutionarily conserved pathway that restricts growth and regeneration predominantly by suppressing the activity of the transcriptional coactivator Yap. Using a high-throughput phenotypic screen, we identified a potent and non-toxic activator of Yap. In vitro kinase assays show that the compound acts as an ATP-competitive inhibitor of Lats kinases—the core enzymes in Hippo signaling. The substance prevents Yap phosphorylation and induces proliferation of supporting cells in the murine inner ear, murine cardiomyocytes, and human Müller glia in retinal organoids. RNA sequencing indicates that the inhibitor reversibly activates the expression of transcriptional Yap targets: upon withdrawal, a subset of supporting-cell progeny exits the cell cycle and upregulates genes characteristic of sensory hair cells. Our results suggest that the pharmacological inhibition of Lats kinases may promote initial stages of the proliferative regeneration of hair cells, a process thought to be permanently suppressed in the adult mammalian inner ear.

Suggested Citation

  • Nathaniel Kastan & Ksenia Gnedeva & Theresa Alisch & Aleksandra A. Petelski & David J. Huggins & Jeanne Chiaravalli & Alla Aharanov & Avraham Shakked & Eldad Tzahor & Aaron Nagiel & Neil Segil & A. J., 2021. "Small-molecule inhibition of Lats kinases may promote Yap-dependent proliferation in postmitotic mammalian tissues," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23395-3
    DOI: 10.1038/s41467-021-23395-3
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    Cited by:

    1. Gustavo Medeiros & Raphael Ortiz & Petr Strnad & Andrea Boni & Franziska Moos & Nicole Repina & Ludivine Challet Meylan & Francisca Maurer & Prisca Liberali, 2022. "Multiscale light-sheet organoid imaging framework," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Marc A. Vittoria & Nathan Kingston & Kristyna Kotynkova & Eric Xia & Rui Hong & Lee Huang & Shayna McDonald & Andrew Tilston-Lunel & Revati Darp & Joshua D. Campbell & Deborah Lang & Xiaowei Xu & Crai, 2022. "Inactivation of the Hippo tumor suppressor pathway promotes melanoma," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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