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

Nathaniel Kastan, Ksenia Gnedeva (), Theresa Alisch, Aleksandra A. Petelski, David J. Huggins, Jeanne Chiaravalli, Alla Aharanov, Avraham Shakked, Eldad Tzahor, Aaron Nagiel, Neil Segil and A. J. Hudspeth
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Nathaniel Kastan: The Rockefeller University
Ksenia Gnedeva: University of Southern California
Theresa Alisch: The Rockefeller University
Aleksandra A. Petelski: The Rockefeller University
David J. Huggins: Tri-Institutional Therapeutics Discovery Institute
Jeanne Chiaravalli: The Rockefeller University
Alla Aharanov: Weizmann Institute of Science
Avraham Shakked: Weizmann Institute of Science
Eldad Tzahor: Weizmann Institute of Science
Aaron Nagiel: Vision Center
Neil Segil: University of Southern California
A. J. Hudspeth: The Rockefeller University

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-23395-3

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