Endothelial FAT1 inhibits angiogenesis by controlling YAP/TAZ protein degradation via E3 ligase MIB2.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
08 04 2023
08 04 2023
Historique:
received:
05
09
2022
accepted:
27
03
2023
medline:
11
4
2023
entrez:
8
4
2023
pubmed:
9
4
2023
Statut:
epublish
Résumé
Activation of endothelial YAP/TAZ signaling is crucial for physiological and pathological angiogenesis. The mechanisms of endothelial YAP/TAZ regulation are, however, incompletely understood. Here we report that the protocadherin FAT1 acts as a critical upstream regulator of endothelial YAP/TAZ which limits the activity of these transcriptional cofactors during developmental and tumor angiogenesis by promoting their degradation. We show that loss of endothelial FAT1 results in increased endothelial cell proliferation in vitro and in various angiogenesis models in vivo. This effect is due to perturbed YAP/TAZ protein degradation, leading to increased YAP/TAZ protein levels and expression of canonical YAP/TAZ target genes. We identify the E3 ubiquitin ligase Mind Bomb-2 (MIB2) as a FAT1-interacting protein mediating FAT1-induced YAP/TAZ ubiquitination and degradation. Loss of MIB2 expression in endothelial cells in vitro and in vivo recapitulates the effects of FAT1 depletion and causes decreased YAP/TAZ degradation and increased YAP/TAZ signaling. Our data identify a pivotal mechanism of YAP/TAZ regulation involving FAT1 and its associated E3 ligase MIB2, which is essential for YAP/TAZ-dependent angiogenesis.
Identifiants
pubmed: 37031213
doi: 10.1038/s41467-023-37671-x
pii: 10.1038/s41467-023-37671-x
pmc: PMC10082778
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Trans-Activators
0
YAP-Signaling Proteins
0
Ubiquitin-Protein Ligases
EC 2.3.2.27
Phosphoproteins
0
MIB2 protein, human
EC 2.3.2.27
FAT1 protein, human
0
Cadherins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1980Informations de copyright
© 2023. The Author(s).
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