β-arrestin1/YAP/mutant p53 complexes orchestrate the endothelin A receptor signaling in high-grade serous ovarian cancer.
Adaptor Proteins, Signal Transducing
/ metabolism
Animals
Antineoplastic Agents
Cell Line, Tumor
Cell Survival
/ drug effects
Cystadenocarcinoma, Serous
/ drug therapy
Disease Models, Animal
Endothelin-1
/ metabolism
Female
Gene Expression Regulation, Neoplastic
Guanine Nucleotide Exchange Factors
/ metabolism
Humans
Mice, Nude
Mutation
Ovarian Neoplasms
/ drug therapy
Protein Serine-Threonine Kinases
/ metabolism
Pyrimidines
/ pharmacology
Receptor, Endothelin A
/ drug effects
Signal Transduction
Sulfonamides
/ pharmacology
Transcription Factors
/ metabolism
Tumor Suppressor Protein p53
/ genetics
Xenograft Model Antitumor Assays
YAP-Signaling Proteins
beta-Arrestin 1
/ drug effects
rho GTP-Binding Proteins
/ metabolism
rhoA GTP-Binding Protein
/ metabolism
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
19 07 2019
19 07 2019
Historique:
received:
14
09
2018
accepted:
19
06
2019
entrez:
21
7
2019
pubmed:
22
7
2019
medline:
18
12
2019
Statut:
epublish
Résumé
The limited clinical response observed in high-grade serous ovarian cancer (HG-SOC) with high frequency of TP53 mutations (mutp53) might be related to mutp53-driven oncogenic pathway network. Here we show that β-arrestin1 (β-arr1), interacts with YAP, triggering its cytoplasmic-nuclear shuttling. This interaction allows β-arr1 to recruit mutp53 to the YAP-TEAD transcriptional complex upon activation of endothelin-1 receptors (ET-1R) in patient-derived HG-SOC cells and in cell lines bearing mutp53. In parallel, β-arr1 mediates the ET-1R-induced Trio/RhoA-dependent YAP nuclear accumulation. In the nucleus, ET-1 through β-arr1 orchestrates the tethering of YAP and mutp53 to YAP/mutp53 target gene promoters, including EDN1 that ensures persistent signals. Treatment of patient-derived xenografts reveals synergistic antitumoral and antimetastatic effects of the dual ET-1R antagonist macitentan in combination with cisplatinum, shutting-down the β-arr1-mediated YAP/mutp53 transcriptional programme. Furthermore, ET
Identifiants
pubmed: 31324767
doi: 10.1038/s41467-019-11045-8
pii: 10.1038/s41467-019-11045-8
pmc: PMC6642155
doi:
Substances chimiques
ARRB1 protein, human
0
Adaptor Proteins, Signal Transducing
0
Antineoplastic Agents
0
Endothelin-1
0
Guanine Nucleotide Exchange Factors
0
Pyrimidines
0
Receptor, Endothelin A
0
RhoH protein, human
0
Sulfonamides
0
Transcription Factors
0
Tumor Suppressor Protein p53
0
YAP-Signaling Proteins
0
YAP1 protein, human
0
beta-Arrestin 1
0
Protein Serine-Threonine Kinases
EC 2.7.11.1
TRIO protein, human
EC 2.7.11.1
rho GTP-Binding Proteins
EC 3.6.5.2
rhoA GTP-Binding Protein
EC 3.6.5.2
macitentan
Z9K9Y9WMVL
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3196Références
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