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© Biologie structurale et chimie
Structure du domaine en doigt de zinc de la protéine NEMO, déterminée par Résonance magnétique nucléaire (RMN). Cette protéine jouant un rôle dans des maladies (cancer, inflammation), les connaissances acquises sur sa structure offrent de précieuses informations sur sa fonction.
Publication : Nature communications

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

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in Nature communications - 25 May 2021

Kastan N, Gnedeva K, Alisch T, Petelski AA, Huggins DJ, Chiaravalli J, Aharanov A, Shakked A, Tzahor E, Nagiel A, Segil N, Hudspeth AJ,

Link to Pubmed [PMID] – 34035288

Link to DOI – 10.1038/s41467-021-23395-3

Nat Commun 2021 05; 12(1): 3100

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.

https://pubmed.ncbi.nlm.nih.gov/34035288