BRCA1/BARD1-dependent ubiquitination of NF2 regulates Hippo-YAP1 signaling.
Adaptor Proteins, Signal Transducing
/ genetics
Amino Acid Substitution
BRCA1 Protein
/ genetics
Breast Neoplasms
/ genetics
Cell Line, Tumor
Cell Proliferation
Female
HEK293 Cells
Hippo Signaling Pathway
Humans
Mutation, Missense
Neurofibromin 2
/ genetics
Phosphoproteins
/ genetics
Protein Serine-Threonine Kinases
/ genetics
Signal Transduction
Transcription Factors
Tumor Suppressor Proteins
/ genetics
Ubiquitin-Protein Ligases
/ genetics
Ubiquitination
YAP-Signaling Proteins
BRCA1
Hippo
NF2
cancer
ubiquitination
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
09 04 2019
09 04 2019
Historique:
pubmed:
29
3
2019
medline:
23
5
2019
entrez:
29
3
2019
Statut:
ppublish
Résumé
Coordination of growth and genomic stability is critical for normal cell physiology. Although the E3 ubiquitin ligase BRCA1 is a key player in maintenance of genomic stability, its role in growth signaling remains elusive. Here, we show that BRCA1 facilitates stabilization of YAP1 protein and turning "off" the Hippo pathway through ubiquitination of NF2. In BRCA1-deficient cells Hippo pathway is "turned On." Phosphorylation of YAP1 is crucial for this signaling process because a YAP1 mutant harboring alanine substitutions (Mt-YAP5SA) in LATS1 kinase recognition sites not only resists degradation but also rescues YAP1 transcriptional activity in BRCA1-deficient cells. Furthermore, an ectopic expression of the active Mt-YAP5SA, but not inactive Mt-YAP6SA, promotes EGF-independent proliferation and tumorigenesis in BRCA1
Identifiants
pubmed: 30918126
pii: 1822155116
doi: 10.1073/pnas.1822155116
pmc: PMC6462108
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
BRCA1 Protein
0
BRCA1 protein, human
0
Neurofibromin 2
0
Phosphoproteins
0
Transcription Factors
0
Tumor Suppressor Proteins
0
YAP-Signaling Proteins
0
YAP1 protein, human
0
BARD1 protein, human
EC 2.3.2.27
Ubiquitin-Protein Ligases
EC 2.3.2.27
LATS1 protein, human
EC 2.7.1.-
Protein Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
7363-7370Subventions
Organisme : NCI NIH HHS
ID : P30 CA014195
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM051586
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA196878
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007752
Pays : United States
Déclaration de conflit d'intérêts
Conflict of interest statement: K.-L.G. is a cofounder and has equity interest in Vivace Therapeutics, Inc. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies.
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