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

Proc Natl Acad Sci U S A. 2019 Apr 9;116(15):7363-7370. doi: 10.1073/pnas.1822155116. Epub 2019 Mar 27.

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.

Keywords: BRCA1; Hippo; NF2; cancer; ubiquitination.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Amino Acid Substitution
  • BRCA1 Protein / genetics
  • BRCA1 Protein / metabolism*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Female
  • HEK293 Cells
  • Hippo Signaling Pathway
  • Humans
  • Mutation, Missense
  • Neurofibromin 2 / genetics
  • Neurofibromin 2 / metabolism*
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Signal Transduction*
  • Transcription Factors
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination*
  • YAP-Signaling Proteins

Substances

  • Adaptor Proteins, Signal Transducing
  • BRCA1 Protein
  • BRCA1 protein, human
  • Neurofibromin 2
  • Phosphoproteins
  • Transcription Factors
  • Tumor Suppressor Proteins
  • YAP-Signaling Proteins
  • YAP1 protein, human
  • BARD1 protein, human
  • Ubiquitin-Protein Ligases
  • LATS1 protein, human
  • Protein Serine-Threonine Kinases