BRCA1/BARD1-dependent ubiquitination of NF2 regulates Hippo-YAP1 signaling

Sachin Verma, Narayana Yeddula, Yasushi Soda, Quan Zhu, Gerald Pao, James Moresco, Jolene K. Diedrich, Audrey Hong, Steve Plouffe, Toshiro Moroishi, Kun Liang Guan, Inder M. Verma

Research output: Contribution to journalArticle

Abstract

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/ mammary epithelial cells. These findings establish an important role of BRCA1 in regulating stability of YAP1 protein that correlates positively with cell proliferation.

Original languageEnglish (US)
Pages (from-to)7363-7370
Number of pages8
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number15
DOIs
StatePublished - Apr 9 2019
Externally publishedYes

Fingerprint

Genomic Instability
Ubiquitination
Cell Physiological Phenomena
Ubiquitin-Protein Ligases
Protein Stability
Growth
Epidermal Growth Factor
Alanine
Carcinogenesis
Breast
Phosphotransferases
Epithelial Cells
Maintenance
Phosphorylation
Cell Proliferation
Proteins
Ectopic Gene Expression

Keywords

  • BRCA1
  • Cancer
  • Hippo
  • NF2
  • Ubiquitination

ASJC Scopus subject areas

  • General

Cite this

BRCA1/BARD1-dependent ubiquitination of NF2 regulates Hippo-YAP1 signaling. / Verma, Sachin; Yeddula, Narayana; Soda, Yasushi; Zhu, Quan; Pao, Gerald; Moresco, James; Diedrich, Jolene K.; Hong, Audrey; Plouffe, Steve; Moroishi, Toshiro; Guan, Kun Liang; Verma, Inder M.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 15, 09.04.2019, p. 7363-7370.

Research output: Contribution to journalArticle

Verma, S, Yeddula, N, Soda, Y, Zhu, Q, Pao, G, Moresco, J, Diedrich, JK, Hong, A, Plouffe, S, Moroishi, T, Guan, KL & Verma, IM 2019, 'BRCA1/BARD1-dependent ubiquitination of NF2 regulates Hippo-YAP1 signaling', Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 15, pp. 7363-7370. https://doi.org/10.1073/pnas.1822155116
Verma, Sachin ; Yeddula, Narayana ; Soda, Yasushi ; Zhu, Quan ; Pao, Gerald ; Moresco, James ; Diedrich, Jolene K. ; Hong, Audrey ; Plouffe, Steve ; Moroishi, Toshiro ; Guan, Kun Liang ; Verma, Inder M. / BRCA1/BARD1-dependent ubiquitination of NF2 regulates Hippo-YAP1 signaling. In: Proceedings of the National Academy of Sciences of the United States of America. 2019 ; Vol. 116, No. 15. pp. 7363-7370.
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