scholarly journals CRB3 regulates contact inhibition by activating the Hippo pathway in mammary epithelial cells

2017 ◽  
Vol 8 (1) ◽  
pp. e2546-e2546 ◽  
Author(s):  
Xiaona Mao ◽  
Pingping Li ◽  
Yaochun Wang ◽  
Zheyong Liang ◽  
Jie Liu ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Mammary Epithelial Cells ◽  
Hippo Pathway ◽  
Mammary Epithelial ◽  
Contact Inhibition ◽  
The Hippo Pathway

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

2019 ◽  
Vol 116 (15) ◽  
pp. 7363-7370 ◽  
Author(s):  
Sachin Verma ◽  
Narayana Yeddula ◽  
Yasushi Soda ◽  
Quan Zhu ◽  
Gerald Pao ◽  
...  
Keyword(s):  
Transcriptional Activity ◽  
Mammary Epithelial Cells ◽  
Hippo Pathway ◽  
Ectopic Expression ◽  
Genomic Stability ◽  
Mammary Epithelial ◽  
Cell Physiology ◽  
The Hippo Pathway ◽  
Signaling Process

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.

scholarly journals p190 RhoGAP promotes contact inhibition in epithelial cells by repressing YAP activity

2018 ◽  
Vol 217 (9) ◽  
pp. 3183-3201 ◽  
Author(s):  
Scott R. Frank ◽  
Clemens P. Köllmann ◽  
Phi Luong ◽  
Giorgio G. Galli ◽  
Lihua Zou ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Epithelial Cells ◽  
Nuclear Translocation ◽  
Hippo Pathway ◽  
Contact Inhibition ◽  
Tumor Suppressor Function ◽  
Suppressor Function ◽  
Expression Of Genes ◽  
P190 Rhogap ◽  
The Hippo Pathway

ARHGAP35 encoding p190A RhoGAP is a cancer-associated gene with a mutation spectrum suggestive of a tumor-suppressor function. In this study, we demonstrate that loss of heterozygosity for ARHGAP35 occurs in human tumors. We sought to identify tumor-suppressor capacities for p190A RhoGAP (p190A) and its paralog p190B in epithelial cells. We reveal an essential role for p190A and p190B to promote contact inhibition of cell proliferation (CIP), a function that relies on RhoGAP activity. Unbiased mRNA sequencing analyses establish that p190A and p190B modulate expression of genes associated with the Hippo pathway. Accordingly, we determine that p190A and p190B induce CIP by repressing YAP–TEAD-regulated gene transcription through activation of LATS kinases and inhibition of the Rho–ROCK pathway. Finally, we demonstrate that loss of a single p190 paralog is sufficient to elicit nuclear translocation of YAP and perturb CIP in epithelial cells cultured in Matrigel. Collectively, our data reveal a novel mechanism consistent with a tumor-suppressor function for ARHGAP35.

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