The Merlin/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals

By Nailing Zhang, Haibo Bai, K. David, Jixin Dong, Yonggang Zheng, Jing Cai, M. Giovannini, Pentao Liu, R. Anders, Duojia Pan. Developmental Cell, 2010

784 citations recorded by the source corpus.

The conserved Hippo signaling pathway regulates organ size in both Drosophila and mammals. While a core kinase cascade leading from the protein kinase Hippo (Hpo) (Mst1 and Mst2 in mammals) to the transcription coactivator Yorkie (Yki) (YAP in mammals) has been established, upstream regulators of the Hippo kinase cascade are less well defined, especially in mammals. Using liver-specific conditional knockout mice, we demonstrate that the Merlin/NF2 tumor suppressor and the YAP oncoprotein function antagonistically to regulate liver development. While inactivation of Yap led to loss of hepatocytes and biliary epithelial cells, inactivation of Nf2 led to hepatocellular carcinoma and bile duct hamartoma. Strikingly, the Nf2-deficient phenotype was largely suppressed by heterozygous deletion of Yap, suggesting that YAP is a major effector of Merlin/NF2 in growth regulation. Our studies link Merlin/NF2 to mammalian Hippo signaling and implicate YAP activation as a mediator of pathologies relevant to Neurofibromatosis 2.

Subfields: Cell Biology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/9b66281e50b4ad0a00641c68c235625c8c414f44

How researchers see this paper

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In Cell Biology

1. K. Guan
2. S. Piccolo
3. Fa-Xing Yu
4. G. Halder
5. Bin Zhao
6. M. Cordenonsi
7. Randy L. Johnson
8. H. Park

In Molecular Biology

1. K. Guan
2. Fa-Xing Yu
3. Bin Zhao
4. S. Piccolo
5. Duojia Pan
6. G. Halder
7. Randy L. Johnson
8. M. Cordenonsi

Citations in the corpus

• Regulation of the Hippo-YAP pathway by G-protein coupled receptor signaling (2012, background): “Genetic ablation of Hippo pathway components in mice also leads to tumor formation (Benhamouche et al., 2010; Cai et al., 2010; Lee et al., 2010; Lu et al., 2010; Xu et al., 2009; Zhang et al., 2010; Zhou et al., 2009).”
• Hippo Pathway in Organ Size Control, Tissue Homeostasis, and Cancer. (2015, positive): “In mammalian cells, Neurofibromin 2 (NF2, Mer ortholog) appears to play a more direct role in regulating LATS1/2 activity: it can directly interact with LATS1/2 and recruit LATS1/2 to the plasma membrane for activation by MST1/2 (Yin et al., 2013; Zhang et al., 2010) (Figures 2 and 3).”
• YAP/TAZ at the roots of cancer (2016, background): “…Hippo pathway components causes some dramatic overgrowth phenotypes ultimately leading, at least in liver and intestine, to tumor development (Chen et al., 2015; Heallen et al., 2011; Lee et al., 2010; Lu et al., 2010; Song et al., 2010; Zhang et al., 2010; Zhou et al., 2009; Zhou et al., 2011a).”
• The Hippo signaling pathway in stem cell biology and cancer (2014, positive): “Zhang et al [98] reported that NF2 and YAP act antagonistically to each other in the Hippo pathway to regulate liver development and physiology.”
• The Hippo pathway effectors TAZ and YAP in development, homeostasis and disease (2014, background): “A similar onset of hepatocellular carcinoma is associated with liver-specific deletions of Sav1, Nf2 or both Mst1 and Mst2, all of which result in elevated nuclear YAP levels (Lee et al., 2010; Lu et al., 2010; Song et al., 2010; Zhang et al., 2010; Zhou et al., 2009).”
• The Hippo signalling pathway and its implications in human health and diseases (2022, background): “64 In another study, the connection between NF2 and YAP was evaluated in the mouse myocardium.”
• The Hippo Signaling Pathway in Development and Disease (2019, background): “Conversely, mice with liver-specific deletion of Nf2 or Lats1/2 displayed a significant increase of biliary epithelial cells at the expense of hepatocytes (Chen et al., 2015b; Yi et al., 2016; Zhang et al., 2010).”
• YAP/TAZ-Dependent Reprogramming of Colonic Epithelium Links ECM Remodeling to Tissue Regeneration (2018, background): “…Models: Organisms/Strains Rosa26mT/mG A.G. Botton Muzumdar et al., 2007 tetO-YAP S127A F. Camargo Camargo et al., 2007 Yap1fl/fl D.J. Pan Zhang et al., 2010 Villin-CreERT2 S. Robine el Marjou et al., 2004 Tazfl/fl S. Piccolo Azzolin et al., 2014 RAG2 / Taconic C57BL/6NTac Rosa26-rtTAM2…”
• Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP. (2012, methodology): “…YAP's oncogenic activity, we first used genetic approaches to inactivate the TEAD proteins in the mouse liver, an organ that is exquisitely sensitive to Hippo signaling (Camargo et al. 2007; Dong et al. 2007; Zhou et al. 2009; Lee et al. 2010; Lu et al. 2010; Song et al. 2010; Zhang et al. 2010).”
• Hippo signaling: growth control and beyond (2011, background): “2B) (Chan et al., 2005; Dong et al., 2007; Hao et al., 2008; Hirabayashi et al., 2008; Lei et al., 2008; Oka et al., 2008; Praskova et al., 2008; Zhang et al., 2008a; Zhao et al., 2010b; Zhao et al., 2007).”