Small-molecule inhibition of Lats kinases may promote Yap-dependent proliferation in postmitotic mammalian tissues. Academic Article uri icon

Overview

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.

publication date

  • May 25, 2021

Research

keywords

  • Adaptor Proteins, Signal Transducing
  • Cell Proliferation
  • Protein Serine-Threonine Kinases
  • Small Molecule Libraries
  • Tumor Suppressor Proteins

Identity

PubMed Central ID

  • PMC8149661

Scopus Document Identifier

  • 85106857746

Digital Object Identifier (DOI)

  • 10.1186/s12859-019-2879-1

PubMed ID

  • 34035288

Additional Document Info

volume

  • 12

issue

  • 1