Mst1 and Mst2 maintain hepatocyte quiescence and suppress the development of hepatocellular carcinoma through inactivation of the Yap1 oncogene

By Dawang Zhou, C. Conrad, Fan Xia, Ji-Sun park, B. Payer, Yi Yin, G. Lauwers, W. Thasler, Jeannie T. Lee, J. Avruch and 1 more. Cancer Cell, 2009

921 citations recorded by the source corpus.

Hippo-Lats-Yorkie signaling regulates tissue overgrowth and tumorigenesis in Drosophila. We show that the Mst1 and Mst2 protein kinases, the mammalian Hippo orthologs, are cleaved and constitutively activated in the mouse liver. Combined Mst1/2 deficiency in the liver results in loss of inhibitory Ser127 phosphorylation of the Yorkie ortholog, Yap1, massive overgrowth, and hepatocellular carcinoma (HCC). Reexpression of Mst1 in HCC-derived cell lines promotes Yap1 Ser127 phosphorylation and inactivation, and abrogates their tumorigenicity. Notably, Mst1/2 inactivates Yap1 in liver through an intermediary kinase distinct from Lats1/2. Approximately 30% of human HCCs show low Yap1(Ser127) phosphorylation and a majority exhibit loss of cleaved, activated Mst1. Mst1/2 inhibition of Yap1 is an important pathway for tumor suppression in liver relevant to human HCC. Significance The pathways that regulate quiescence and tumor suppression in the liver have not been fully elucidated. We show that the Mst1 and Mst2 kinases are tumor suppressors and regulators of liver size in adults and that negative regulation of the transcriptional coactivator, Yap1, is central to Mst1/2 tumor suppressor function. Loss of both Mst1 and Mst2 is sufficient to initiate hepatocyte proliferation, resulting in dramatic liver overgrowth, resistance to pro-apoptotic stimuli, and the development of HCC. Mst1 and Mst2 promote phosphorylation of Yap1 and thereby suppress its oncogenic activity. Mst1/2 regulation of Yap1 is tissue-specific and, in the liver, involves an Mst1/2-regulated Yap1 kinase distinct from Lats1/2. Significantly, the Mst-Yap1 pathway is disrupted in a substantial fraction of human HCCs.

Subfields: Cell Biology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/796ccb6fddc4b1187498ee102d67620573d6b3e0

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In Cell Biology

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

In Molecular Biology

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

Citations in the corpus

• 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 Development and Cancer (2010, background): “Hippo Pathway Components in Drosophila and Human Drosophila Human Conserved Domains and Motifs The Core Pathway Hippo Mst1-2 Ste20 Ser/Thr kinase and SARAH domains Salvador Sav1/WW45 WW and SARAH domain Warts Lats1-2 NDR Ser/Thr kinase domain, PPXY motif Mats MOBKL1A-B Mob1/phocein domain Yorkie YAP”
• The Hippo Signaling Pathway in Development and Disease (2019, background): “Echoing the growth-regulatory function of Hippo signaling in Drosophila, mouse models with targeted deletion of Mst1/2 (Lu et al., 2010; Song et al., 2010; Zhou et al., 2009), Sav1 (Cai et al.”
• The biology of YAP/TAZ: hippo signaling and beyond. (2014, methodology): “Germ line mutants of NF2, MST1/2, and LATS2 were not particularly informative as death occurred at relatively early embryonic stages: in NF2 / and MST1/2 / caused by defective development of the extraembryonic tissues, and in LATS2 / by multiple defects (139, 141, 269).”
• A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factors. (2013, neutral): “For example, recent data show that, at least in MEFs or keratinocytes, the mammalian Hippo homologs MST1/2 and LATS1/2 are dispensable for CIP (Schlegelmilch et al., 2011; Zhou et al., 2009).”
• The two faces of Hippo: targeting the Hippo pathway for regenerative medicine and cancer treatment (2013, positive): “For example, while the MST kinases are essential to inhibit YAP and TAZ in the liver 135–138 , intestine 139 , pancreas 140, 141 , and heart 142 , they appear to be dispensable in the skin 106 .”
• 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).”
• E-cadherin mediates contact inhibition of proliferation through Hippo signaling-pathway components (2011, background): “S1B), suggesting that it may not be involved, similar to other recent findings for mouse embryonic fibroblasts (MEFs) using knockout mice (29, 30).”
• Hippo Pathway in Organ Size Control, Tissue Homeostasis, and Cancer. (2015, positive): “It has been observed that, in mouse embryonic fibroblast (MEF) cells, MST1/2 double knockout did not abolish YAP phosphorylation, suggesting the existence of additional Hippo-like activity (Zhou et al., 2009).”
• 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).”
• Hippo signaling: growth control and beyond (2011, background): “…of Yap (Camargo et al., 2007; Dong et al., 2007) and targeted deletion of Mst1/2 in the mouse liver (Lu et al., 2010; Song et al., 2010; Zhou et al., 2009) provide evidence that Hippo signaling has a pivotal role in regulating organ size, suggesting that Hippo signaling is a universal…”
• The Hippo-YAP pathway in organ size control and tumorigenesis: an updated version. (2010, background): “Moreover, tissuespecific ablation of both Mst1 and Mst2 in liver leads to massive HCC (Zhou et al. 2009; Lu et al. 2010; Song et al. 2010).”
• The Merlin/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals (2010, background): “The importance of Hippo signaling in mammalian growth control is supported by reports that YAP is amplified in certain tumors and can transform immortalizedmammary epithelial cells in vitro (Zender et al., 2006; Overholtzer et al., 2006) and that transgenic overexpression of YAP, or loss of Mst1/2, ”