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快乐十分骗局真实经历:BRCA1/BARD1-dependent ubiquitination of NF2 regulates Hippo-YAP1 signaling
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Normal cells harbor protective mechanisms to sense DNA damage, halt cell growth, and repair chromatin lesions to maintain genomic stability. How mitogen signaling in proliferating cells is affected upon BRCA1 loss as part of these protective checkpoints is an intriguing question. This study reveals a unique finding of linking BRCA1 to Hippo signaling pathway to explain this conundrum. Our work shows that serum-responsive expression of BRCA1 is required for YAP1 stability. Ubiquitination of NF2 by BRCA1/BARD1 in proliferating cells inhibits NF2/LATS association and Hippo signaling. These findings suggest Hippo signaling activation as a protective barrier in BRCA1-deficient cells, which upon inactivation, promotes cell proliferation and tumorigenesis.
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.
?1Present address: Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037.
?2Present address: Project Division of ALA Advanced Medical Research, Institute of Medical Science, University of Tokyo, 108-8639 Tokyo, Japan.
?3Present address: Ludwig Institute for Cancer Research, La Jolla, CA 92093.
- ?4To whom correspondence may be addressed. Email: or .
Author contributions: S.V., K.-L.G., and I.M.V. designed research; S.V., N.Y., Y.S., J.M., J.K.D., and A.H. performed research; Q.Z., G.P., J.M., J.K.D., S.P., and T.M. contributed new reagents/analytic tools; S.V., N.Y., Y.S., K.-L.G., and I.M.V. analyzed data; and S.V., Q.Z., A.H., K.-L.G., and I.M.V. wrote the paper.
Reviewers: J.D., University of Nebraska Medical Center; and D.M.L., Dana Farber Cancer Institute.
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.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1822155116/-/DCSupplemental.
Published under the PNAS license.