文章基本信息

标题：BRCA1/BARD1-dependent ubiquitination of NF2 regulates Hippo-YAP1 signaling
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作者：Sachin Verma ; Narayana Yeddula ; Yasushi Soda 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2019
卷号：116
期号：15
页码：7363-7370
DOI：10.1073/pnas.1822155116
出版社：The National Academy of Sciences of the United States of America
摘要：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.
关键词：Hippo ; BRCA1 ; NF2 ; ubiquitination ; cancer