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Emerging evidence on the role of the Hippo/YAP pathway in liver physiology and cancer

  • Dean Yimlamai
    Correspondence
    Corresponding author. Address: Department of Medicine, Boston Children’s Hospital, Boston, MA 02115, United States. Tel.: +1 6173556058.
    Affiliations
    The Stem Cell Program, Department of Medicine, Boston Children’s Hospital, Boston, MA 02115, United States

    Division of Gastroenterology and Nutrition, Department of Medicine, Boston Children’s Hospital, Boston, MA 02115, United States
    Search for articles by this author
  • Brendan H. Fowl
    Affiliations
    The Stem Cell Program, Department of Medicine, Boston Children’s Hospital, Boston, MA 02115, United States

    Division of Gastroenterology and Nutrition, Department of Medicine, Boston Children’s Hospital, Boston, MA 02115, United States
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  • Fernando D. Camargo
    Affiliations
    The Stem Cell Program, Department of Medicine, Boston Children’s Hospital, Boston, MA 02115, United States

    Harvard Stem Cell Institute, Cambridge, MA 02138, United States

    Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, United States
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      Summary

      The Hippo pathway and its regulatory target, YAP, has recently emerged as an important biochemical signaling pathway that tightly governs epithelial tissue growth. Initially defined in Drosophilia, this pathway has shown remarkable conservation in vertebrate systems with many components of the Hippo/YAP pathway showing biochemical and functional conservation. The liver is particularly sensitive to changes in Hippo/YAP signaling with rapid increases in liver size becoming manifest on the order of days to weeks after perturbation. The first identified direct targets of Hippo/YAP signaling were pro-proliferative and anti-apoptotic gene programs, but recent work has now implicated this pathway in cell fate choice, stem cell maintenance/renewal, epithelial to mesenchymal transition, and oncogenesis. The mechanisms by which Hippo/YAP signaling is changed endogenously are beginning to come to light as well as how this pathway interacts with other signaling pathways, and important details for designing new therapeutic interventions. This review focuses on the known roles for Hippo/YAP signaling in the liver and promising avenues for future study.

      Keywords

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      References

        • Wu S.
        • Huang J.
        • Dong J.
        • Pan D.
        Hippo encodes a Ste-20 family protein kinase that restricts cell proliferation and promotes apoptosis in conjunction with salvador and warts.
        Cell. 2003; 114: 445-456
        • Justice R.W.
        • Zilian O.
        • Woods D.F.
        • Noll M.
        • Bryant P.J.
        The Drosophila tumor suppressor gene warts encodes a homolog of human myotonic dystrophy kinase and is required for the control of cell shape and proliferation.
        Genes Dev. 1995; 9: 534-546
        • Tapon N.
        • Harvey K.F.
        • Bell D.W.
        • Wahrer D.C.
        • Schiripo T.A.
        • Haber D.
        • et al.
        Salvador Promotes both cell cycle exit and apoptosis in Drosophila and is mutated in human cancer cell lines.
        Cell. 2002; 110: 467-478
        • Pan D.
        The Hippo Signaling Pathway in Development and Cancer.
        Dev Cell. 2010; 19: 491-505
        • Zhao B.
        • Lei Q.-Y.
        • Guan K.-L.
        The Hippo–YAP pathway: new connections between regulation of organ size and cancer.
        Curr Opin Cell Biol. 2008; 20: 638-646
        • Zeng Q.
        • Hong W.
        The emerging role of the hippo pathway in cell contact inhibition, organ size control, and cancer development in mammals.
        Cancer Cell. 2008; 13: 188-192
        • Dong J.
        • Feldmann G.
        • Huang J.
        • Wu S.
        • Zhang N.
        • Comerford S.A.
        • et al.
        Elucidation of a universal size-control mechanism in Drosophila and mammals.
        Cell. 2007; 130: 1120-1133
        • Kanai F.
        • Marignani P.A.
        • Sarbassova D.
        • Yagi R.
        • Hall R.A.
        • Donowitz M.
        • et al.
        TAZ: a novel transcriptional co-activator regulated by interactions with 14-3-3 and PDZ domain proteins.
        EMBO J. 2000; 19: 6778-6791
        • Yagi R.
        • Chen L.F.
        • Shigesada K.
        • Murakami Y.
        • Ito Y.
        A WW domain-containing yes-associated protein (YAP) is a novel transcriptional co-activator.
        EMBO J. 1999; 18: 2551-2562
        • Cui C.B.
        • Cooper L.F.
        • Yang X.
        • Karsenty G.
        • Aukhil I.
        Transcriptional coactivation of bone-specific transcription factor Cbfa1 by TAZ.
        Mol Cell Biol. 2003; 23: 1004-1013
        • Camargo F.D.
        • Gokhale S.
        • Johnnidis J.B.
        • Fu D.
        • Bell G.W.
        • Jaenisch R.
        • et al.
        YAP1 increases organ size and expands undifferentiated progenitor cells.
        Curr Biol. 2007; 17: 2054-2060
        • Basu S.
        • Totty N.
        • Irwin M.
        • Sudol M.
        • Downward J.
        Akt phosphorylates the Yes-associated protein, YAP, to induce interaction with 14-3-3 and attenuation of p73-mediated apoptosis.
        Mol Cell. 2003; 11: 11-23
        • Oka T.
        • Mazack V.
        • Sudol M.
        Mst2 and Lats kinases regulate apoptotic function of Yes kinase-associated protein (YAP).
        J Biol Chem. 2008; 283: 27534-27546
        • Zhao B.
        • Li L.
        • Tumaneng K.
        • Wang C.-Y.
        • Guan K.-L.
        A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF -TRCP.
        Genes Dev. 2010; 24: 72-85
        • Ribeiro P.S.
        • Josué F.
        • Wepf A.
        • Wehr M.C.
        • Rinner O.
        • Kelly G.
        • et al.
        Combined functional genomic and proteomic approaches identify a PP2A complex as a negative regulator of Hippo signaling.
        Mol Cell. 2010; 39: 521-534
        • Zhou D.
        • Conrad C.
        • Xia F.
        • Park J.-S.
        • Payer B.
        • Yin Y.
        • et al.
        Mst1 and Mst2 maintain hepatocyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yap1 oncogene.
        Cancer Cell. 2009; 16: 425-438
        • Song H.
        • Mak K.K.
        • Topol L.
        • Yun K.
        • Hu J.
        • Garrett L.
        • et al.
        Mammalian Mst1 and Mst2 kinases play essential roles in organ size control and tumor suppression.
        Proc Natl Acad Sci. 2010; 107: 1431-1436
        • Lu L.
        • Li Y.
        • Kim S.M.
        • Bossuyt W.
        • Liu P.
        • Qiu Q.
        • et al.
        Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver.
        Proc Natl Acad Sci. 2010; 107: 1437-1442
        • Zhang N.
        • Bai H.
        • David K.K.
        • Dong J.
        • Zheng Y.
        • Cai J.
        • et al.
        The Merlin/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals.
        Dev Cell. 2010; 19: 27-38
        • Benhamouche S.
        • Curto M.
        • Saotome I.
        • Gladden A.B.
        • Liu C.-H.
        • Giovannini M.
        • et al.
        Nf2/Merlin controls progenitor homeostasis and tumorigenesis in the liver.
        Genes Dev. 2010; 24: 1718-1730
        • Lee K.-P.
        • Lee J.-H.
        • Kim T.-S.
        • Kim T.-H.
        • Park H.-D.
        • Byun J.-S.
        • et al.
        The Hippo–Salvador pathway restrains hepatic oval cell proliferation, liver size, and liver tumorigenesis.
        Proc Natl Acad Sci. 2010; 107: 8248-8253
        • Yin F.
        • Yu J.
        • Zheng Y.
        • Chen Q.
        • Zhang N.
        • Pan D.
        Spatial organization of Hippo signaling at the plasma membrane mediated by the tumor suppressor Merlin/NF2.
        Cell. 2013; 154: 1342-1355
        • Yimlamai D.
        • Christodoulou C.
        • Galli G.G.
        • Yanger K.
        • Pepe-Mooney B.
        • Gurung B.
        • et al.
        Hippo pathway activity influences liver cell fate.
        Cell. 2014; 157: 1324-1338
        • Hong J.H.
        • Hwang E.S.
        • McManus M.T.
        • Amsterdam A.
        • Tian Y.
        • Kalmukova R.
        • et al.
        TAZ, a transcriptional modulator of mesenchymal stem cell differentiation.
        Science. 2005; 309: 1074-1078
        • Boulter L.
        • Lu W.Y.
        • Forbes S.J.
        Differentiation of progenitors in the liver: a matter of local choice.
        J Clin Invest. 2013; 123: 1867-1873
        • Kordes C.
        • Haussinger D.
        Hepatic stem cell niches.
        J Clin Invest. 2013; 123: 1874-1880
        • Li H.
        • Wolfe A.
        • Septer S.
        • Edwards G.
        • Zhong X.
        • Bashar Abdulkarim A.
        • et al.
        Deregulation of Hippo kinase signalling in Human hepatic malignancies.
        Liver Int. 2012; 32: 38-47
        • Bai H.
        • Gayyed M.F.
        • Lam-Himlin D.M.
        • Klein A.P.
        • Nayar S.K.
        • Xu Y.
        • et al.
        Expression of Yes-associated protein modulates Survivin expression in primary liver malignancies.
        Hum Pathol. 2012; 43: 1376-1385
        • Bai H.
        • Zhang N.
        • Xu Y.
        • Chen Q.
        • Khan M.
        • Potter J.J.
        • et al.
        Yes-associated protein regulates the hepatic response after bile duct ligation.
        Hepatology. 2012; 56: 1097-1107
        • Oertel M.
        • Shafritz D.
        Stem cells, cell transplantation and liver repopulation.
        Biochim Biophys Acta. 2008; 1782: 61-74
        • Yanger K.
        • Zong Y.
        • Maggs L.R.
        • Shapira S.N.
        • Maddipati R.
        • Aiello N.M.
        • et al.
        Robust cellular reprogramming occurs spontaneously during liver regeneration.
        Genes Dev. 2013; 27: 719-724
        • Fan B.
        • Malato Y.
        • Calvisi D.F.
        • Naqvi S.
        • Razumilava N.
        • Ribback S.
        • et al.
        Cholangiocarcinomas can originate from hepatocytes in mice.
        J Clin Invest. 2012; 122: 2911-2915
        • Tarlow B.D.
        • Pelz C.
        • Naugler W.E.
        • Wakefield L.
        • Wilson E.M.
        • Finegold M.J.
        • et al.
        Bipotential adult liver progenitors are derived from chronically injured mature hepatocytes.
        Cell Stem Cell. 2014; 15: 605-618
        • Gurda G.T.
        • Zhu Q.
        • Bai H.
        • Pan D.
        • Schwarz K.B.
        • Anders R.A.
        The use of Yes-associated protein expression in the diagnosis of persistent neonatal cholestatic liver disease.
        Hum Pathol. 2014; 45: 1057-1064
        • Wang C.
        • Zhang L.
        • He Q.
        • Feng X.
        • Zhu J.
        • Xu Z.
        • et al.
        Differences in Yes-associated protein and mRNA levels in regenerating liver and hepatocellular carcinoma.
        Mol Med Rep. 2012; 5: 410-414
        • Wu H.
        • Xiao Y.
        • Zhang S.
        • Ji S.
        • Wei L.
        • Fan F.
        • et al.
        The Ets transcription factor GABP is a component of the hippo pathway essential for growth and antioxidant defense.
        Cell Rep. 2013; 3: 1663-1677
        • Grijalva J.L.
        • Huizenga M.
        • Mueller K.
        • Rodriguez S.
        • Brazzo J.
        • Camargo F.
        • et al.
        Dynamic alterations in Hippo signaling pathway and YAP activation during liver regeneration.
        Am J Physiol Gastrointest Liver Physiol. 2014; 307: G196-G204
        • Sato Y.
        • Koyama S.
        • Tsukada K.
        • Hatakeyama K.
        Acute portal hypertension reflecting shear stress as a trigger of liver regeneration following partial hepatectomy.
        Surg Today. 1997; 27: 518-526
        • Dupont S.
        • Morsut L.
        • Aragona M.
        • Enzo E.
        • Giulitti S.
        • Cordenonsi M.
        • et al.
        Role of YAP/TAZ in mechanotransduction.
        Nature. 2011; 474: 179-183
        • Aragona M.
        • Panciera T.
        • Manfrin A.
        • Giulitti S.
        • Michielin F.
        • Elvassore N.
        • et al.
        A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factors.
        Cell. 2013; 154: 1047-1059
        • Porazinski S.
        • Wang H.
        • Asaoka Y.
        • Behrndt M.
        • Miyamoto T.
        • Morita H.
        • et al.
        YAP is essential for tissue tension to ensure vertebrate 3D body shape.
        Nature. 2015; 521: 217-221
        • Schlegelmilch K.
        • Mohseni M.
        • Kirak O.
        • Pruszak J.
        • Rodriguez J.R.
        • Zhou D.
        • et al.
        Yap1 acts downstream of alpha-catenin to control epidermal proliferation.
        Cell. 2011; 144: 782-795
        • Herr K.J.
        • Tsang Y.H.
        • Ong J.W.
        • Li Q.
        • Yap L.L.
        • Yu W.
        • et al.
        Loss of alpha-catenin elicits a cholestatic response and impairs liver regeneration.
        Sci Rep. 2014; 4: 1-11
        • Mohseni M.
        • Sun J.
        • Lau A.
        • Curtis S.
        • Goldsmith J.
        • Fox V.L.
        • et al.
        A genetic screen identifies an LKB1-MARK signalling axis controlling the Hippo–YAP pathway.
        Nat Cell Biol. 2014; 16: 108-117
        • Baas A.F.
        • Smit L.
        • Clevers H.
        LKB1 tumor suppressor protein: PARtaker in cell polarity.
        Trends Cell Biol. 2004; 14: 312-319
        • Yamanaka T.
        • Ohno S.
        Role of Lgl/Dlg/Scribble in the regulation of epithelial junction, polarity and growth.
        Front Biosci. 2008; 13: 6693-6707
        • Nguyen H.B.
        • Babcock J.T.
        • Wells C.D.
        • Quilliam L.A.
        LKB1 tumor suppressor regulates AMP kinase/mTOR-independent cell growth and proliferation via the phosphorylation of Yap.
        Oncogene. 2013; 32: 4100-4109
        • Chan S.W.
        • Lim C.J.
        • Chong Y.F.
        • Pobbati A.V.
        • Huang C.
        • Hong W.
        Hippo pathway-independent restriction of TAZ and YAP by angiomotin.
        J Biol Chem. 2011; 286: 7018-7026
        • Zhao B.
        • Li L.
        • Lu Q.
        • Wang L.H.
        • Liu C.Y.
        • Lei Q.
        • et al.
        Angiomotin is a novel Hippo pathway component that inhibits YAP oncoprotein.
        Genes Dev. 2011; 25: 51-63
        • Wang W.
        • Huang J.
        • Chen J.
        Angiomotin-like proteins associate with and negatively regulate YAP1.
        J Biol Chem. 2011; 286: 4364-4370
        • Yi C.
        • Shen Z.
        • Stemmer-Rachamimov A.
        • Dawany N.
        • Troutman S.
        • Showe L.C.
        • et al.
        The p130 isoform of angiomotin is required for Yap-mediated hepatic epithelial cell proliferation and tumorigenesis.
        Sci Signal. 2013; 6: 1-12
        • Hohmann N.
        • Weiwei W.
        • Dahmen U.
        • Dirsch O.
        • Deutsch A.
        • Voss-Bohme A.
        How does a single cell know when the liver has reached its correct size?.
        PLoS One. 2014; 9: 1-15
        • Miller E.
        • Yang J.
        • DeRan M.
        • Wu C.
        • Su A.I.
        • Bonamy G.M.
        • et al.
        Identification of serum-derived sphingosine-1-phosphate as a small molecule regulator of YAP.
        Chem Biol. 2012; 19: 955-962
        • Yu F.X.
        • Zhao B.
        • Panupinthu N.
        • Jewell J.L.
        • Lian I.
        • Wang L.H.
        • et al.
        Regulation of the Hippo–YAP pathway by G-protein-coupled receptor signaling.
        Cell. 2012; 150: 780-791
        • Mo J.S.
        • Yu F.X.
        • Gong R.
        • Brown J.H.
        • Guan K.L.
        Regulation of the Hippo–YAP pathway by protease-activated receptors (PARs).
        Genes Dev. 2012; 26: 2138-2143
        • Huang W.
        • Ma K.
        • Zhang J.
        • Qatanani M.
        • Cuvillier J.
        • Liu J.
        • et al.
        Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration.
        Science. 2006; 312: 233-236
        • Anakk S.
        • Bhosale M.
        • Schmidt V.A.
        • Johnson R.L.
        • Finegold M.J.
        • Moore D.D.
        Bile acids activate YAP to promote liver carcinogenesis.
        Cell Rep. 2013; 5: 1060-1069
        • Vassilev A.
        • Kaneko K.J.
        • Shu H.
        • Zhao Y.
        • DePamphilis M.L.
        TEAD/TEF transcription factors utilize the activation domain of YAP65, a Src/Yes-associated protein localized in the cytoplasm.
        Genes Dev. 2001; 15: 1229-1241
        • Ota M.
        • Sasaki H.
        Mammalian Tead proteins regulate cell proliferation and contact inhibition as transcriptional mediators of Hippo signaling.
        Development. 2008; 135: 4059-4069
        • Wu S.
        • Liu Y.
        • Zheng Y.
        • Dong J.
        • Pan D.
        The TEAD/TEF family protein Scalloped mediates transcriptional output of the Hippo growth-regulatory pathway.
        Dev Cell. 2008; 14: 388-398
        • Zhang L.
        • Ren F.
        • Zhang Q.
        • Chen Y.
        • Wang B.
        • Jiang J.
        The TEAD/TEF family of transcription factor Scalloped mediates Hippo signaling in organ size control.
        Dev Cell. 2008; 14: 377-387
        • Zhao B.
        • Ye X.
        • Yu J.
        • Li L.
        • Li W.
        • Li S.
        • et al.
        TEAD mediates YAP-dependent gene induction and growth control.
        Genes Dev. 2008; 22: 1962-1971
        • Zhao B.
        • Kim J.
        • Ye X.
        • Lai Z.
        • Guan K.
        Both TEAD-binding and WW domains are required for the growth stimulation and oncogenic transformation activity of yes-associated protein.
        Cancer Res. 2009; 69: 1089-1098
        • Nishioka N.
        • Inoue K.
        • Adachi K.
        • Kiyonari H.
        • Ota M.
        The Hippo signaling pathway components Lats and Yap pattern Tead4 activity to distinguish mouse trophectoderm from inner cell mass.
        Dev Cell. 2009; 16: 398-410
        • Jiao S.
        • Wang H.
        • Shi Z.
        • Dong A.
        • Zhang W.
        • Song X.
        • et al.
        A peptide mimicking VGLL4 function acts as a YAP antagonist therapy against gastric cancer.
        Cancer Cell. 2014; 25: 166-180
        • Zhang W.
        • Gao Y.
        • Li P.
        • Shi Z.
        • Guo T.
        • Li F.
        • et al.
        VGLL4 functions as a new tumor suppressor in lung cancer by negatively regulating the YAP-TEAD transcriptional complex.
        Cell Res. 2014; 24: 331-343
        • Strano S.
        • Munarriz E.
        • Rossi M.
        • Castagnoli L.
        Physical interaction with Yes-associated protein enhances p73 transcriptional activity.
        J Biol Chem. 2001; 276: 15164-15173
        • Komuro A.
        • Nagai M.
        • Navin N.E.
        • Sudol M.
        WW domain-containing protein YAP associates with ErbB-4 and acts as a co-transcriptional activator for the carboxyl-terminal fragment of ErbB-4 that translocates to the nucleus.
        J Biol Chem. 2003; : 33334-33341
        • Imajo M.
        • Ebisuya M.
        • Nishida E.
        Dual role of YAP and TAZ in renewal of the intestinal epithelium.
        Nat Cell Biol. 2015; 17: 7-19
        • Kapoor A.
        • Yao W.
        • Ying H.
        • Hua S.
        • Liewen A.
        • Wang Q.
        • et al.
        Yap1 activation enables bypass of oncogenic kras addiction in pancreatic cancer.
        Cell. 2014; 158: 185-197
        • Rayon T.
        • Menchero S.
        • Nieto A.
        • Xenopoulos P.
        • Crespo M.
        • Cockburn K.
        • et al.
        Notch and hippo converge on Cdx2 to specify the trophectoderm lineage in the mouse blastocyst.
        Dev Cell. 2014; 30: 410-422
        • Shao D.D.
        • Xue W.
        • Krall E.B.
        • Bhutkar A.
        • Piccioni F.
        • Wang X.
        • et al.
        KRAS and YAP1 Converge to Regulate EMT and Tumor Survival.
        Cell. 2014; 158: 171-184
        • Hofmann J.J.
        • Zovein A.C.
        • Koh H.
        • Radtke F.
        • Weinmaster G.
        • Iruela-Arispe M.L.
        Jagged1 in the portal vein mesenchyme regulates intrahepatic bile duct development: insights into Alagille syndrome.
        Development. 2010; 137: 4061-4072
        • Zong Y.
        • Panikkar A.
        • Xu J.
        • Antoniou A.
        • Raynaud P.
        • Lemaigre F.
        • et al.
        Notch signaling controls liver development by regulating biliary differentiation.
        Development. 2009; 136: 1727-1739
        • Geisler F.
        • Strazzabosco M.
        Emerging roles of Notch signaling in liver disease.
        Hepatology. 2015; 61: 382-392
        • Tschaharganeh D.F.
        • Chen X.
        • Latzko P.
        • Malz M.
        • Gaida M.M.
        • Felix K.
        • et al.
        Yes-associated protein up-regulates Jagged-1 and activates the Notch pathway in human hepatocellular carcinoma.
        Gastroenterology. 2013; 144: e1512
        • Clevers H.
        • Loh K.M.
        • Nusse R.
        Stem cell signaling. An integral program for tissue renewal and regeneration: Wnt signaling and stem cell control.
        Science. 2014; 346: 1248012
        • Barry E.R.
        • Morikawa T.
        • Butler B.L.
        • Shrestha K.
        • de la Rosa R.
        • Yan K.S.
        • et al.
        Restriction of intestinal stem cell expansion and the regenerative response by YAP.
        Nature. 2013; 493: 106-110
        • Heallen T.
        • Zhang M.
        • Wang J.
        • Bonilla-Claudio M.
        • Klysik E.
        • Johnson R.L.
        • et al.
        Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size.
        Science. 2011; 332: 458-461
        • Rosenbluh J.
        • Nijhawan D.
        • Cox A.G.
        • Li X.
        • Neal J.T.
        • Schafer E.J.
        • et al.
        Beta-Catenin-driven cancers require a YAP1 transcriptional complex for survival and tumorigenesis.
        Cell. 2012; 151: 1457-1473
        • Azzolin L.
        • Panciera T.
        • Soligo S.
        • Enzo E.
        • Bicciato S.
        • Dupont S.
        • et al.
        YAP/TAZ incorporation in the beta-catenin destruction complex orchestrates the Wnt response.
        Cell. 2014; 158: 157-170
        • Overholtzer M.
        • Zhang J.
        • Smolen G.A.
        • Muir B.
        • Li W.
        • Sgroi D.C.
        • et al.
        Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon.
        Proc Natl Acad Sci USA. 2006; 103: 12405-12410
        • Zender L.
        • Spector M.S.
        • Xue W.
        • Flemming P.
        • Cordon-Cardo C.
        • Silke J.
        • et al.
        Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach.
        Cell. 2006; : 1253-1267
        • Overholtzer M.
        • Zhang J.
        • Smolen G.
        Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon.
        Proc Natl Acad Sci USA. 2006; 103: 12405-12410
        • Steinhardt A.A.
        • Gayyed M.F.
        • Klein A.P.
        • Dong J.
        • Maitra A.
        • Pan D.
        • et al.
        Expression of Yes-associated protein in common solid tumors.
        Hum Pathol. 2008; 39: 1582-1589
        • Kim J.M.
        • Kang D.W.
        • Long L.Z.
        • Huang S.M.
        • Yeo M.K.
        • Yi E.S.
        • et al.
        Differential expression of Yes-associated protein is correlated with expression of cell cycle markers and pathologic TNM staging in non-small-cell lung carcinoma.
        Hum Pathol. 2011; 42: 315-323
        • Zhang X.
        • George J.
        • Deb S.
        • Degoutin J.L.
        • Takano E.A.
        • Fox S.B.
        • et al.
        The Hippo pathway transcriptional co-activator, YAP, is an ovarian cancer oncogene.
        Oncogene. 2011; 30: 2810-2822
        • Hall C.A.
        • Wang R.
        • Miao J.
        • Oliva E.
        • Shen X.
        • Wheeler T.
        • et al.
        Hippo pathway effector Yap is an ovarian cancer oncogene.
        Cancer Res. 2010; 70: 8517-8525
        • Fernandez-L A.
        • Northcott P.A.
        • Dalton J.
        • Fraga C.
        • Ellison D.
        • Angers S.
        • et al.
        YAP1 is amplified and up-regulated in hedgehog-associated medulloblastomas and mediates Sonic hedgehog-driven neural precursor proliferation.
        Genes Dev. 2009; : 2729-2741
        • Zhang T.
        • Zhang J.
        • You X.
        • Liu Q.
        • Du Y.
        • Gao Y.
        • et al.
        Hepatitis B virus X protein modulates oncogene Yes-associated protein by CREB to promote growth of hepatoma cells.
        Hepatology. 2012; 56: 2051-2059
        • Xu M.Z.
        • Yao T.-J.
        • Lee N.P.Y.
        • Ng I.O.L.
        • Chan Y.-T.
        • Zender L.
        • et al.
        Yes-associated protein is an independent prognostic marker in hepatocellular carcinoma.
        Cancer. 2009; : 4576-4585
        • Steinhardt A.A.
        • Gayyed M.F.
        • Klein A.P.
        • Dong J.
        • Maitra A.
        • Pan D.
        • et al.
        Expression of Yes-associated protein in common solid tumors.
        Hum Pathol. 2008; : 1-8
        • Pei T.
        • Li Y.
        • Wang J.
        • Wang H.
        • Liang Y.
        • Shi H.
        • et al.
        YAP is a critical oncogene in human cholangiocarcinoma.
        Oncotarget. 2015; : 1-15
        • Perra A.
        • Kowalik M.A.
        • Ghiso E.
        • Ledda-Columbano G.M.
        • Di Tommaso L.
        • Angioni M.M.
        • et al.
        YAP activation is an early event and a potential therapeutic target in liver cancer development.
        J Hepatol. 2014; 61: 1088-1096
        • Ehmer U.
        • Zmoos A.F.
        • Auerbach R.K.
        • Vaka D.
        • Butte A.J.
        • Kay M.A.
        • et al.
        Organ size control is dominant over Rb family inactivation to restrict proliferation in vivo.
        Cell Rep. 2014; 8: 371-381
        • Chen H.
        • Mei L.
        • Zhou L.
        • Zhang X.
        • Guo C.
        • Li J.
        • et al.
        Moesin–ezrin–radixin-like protein (merlin) mediates protein interacting with the carboxyl terminus-1 (PICT-1)-induced growth inhibition of glioblastoma cells in the nucleus.
        Int J Biochem Cell Biol. 2011; 43: 545-555
        • Guo G.
        • Chmielecki J.
        • Goparaju C.
        • Heguy A.
        • Dolgalev I.
        • Carbone M.
        • et al.
        Whole-exome sequencing reveals frequent genetic alterations in BAP1, NF2, CDKN2A, and CUL1 in malignant pleural mesothelioma.
        Cancer Res. 2015; 75: 264-269
        • Dalgliesh G.L.
        • Furge K.
        • Greenman C.
        • Chen L.
        • Bignell G.
        • Butler A.
        • et al.
        Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes.
        Nature. 2010; 463: 360-363
        • Morrow K.A.
        • Das S.
        • Metge B.J.
        • Ye K.
        • Mulekar M.S.
        • Tucker J.A.
        • et al.
        Loss of tumor suppressor Merlin in advanced breast cancer is due to post-translational regulation.
        J Biol Chem. 2011; 286: 40376-40385
        • Armengol C.
        • Cairo S.
        • Fabre M.
        • Buendia M.A.
        Wnt signaling and hepatocarcinogenesis: the hepatoblastoma model.
        Int J Biochem Cell Biol. 2011; 43: 265-270
        • Nejak-Bowen K.N.
        • Monga S.P.
        Beta-catenin signaling, liver regeneration and hepatocellular cancer: sorting the good from the bad.
        Semin Cancer Biol. 2011; 21: 44-58
        • Wang J.
        • Park J.S.
        • Wei Y.
        • Rajurkar M.
        • Cotton J.L.
        • Fan Q.
        • et al.
        TRIB2 acts downstream of Wnt/TCF in liver cancer cells to regulate YAP and C/EBPalpha function.
        Mol Cell. 2013; 51: 211-225
        • Tao J.
        • Calvisi D.F.
        • Ranganathan S.
        • Cigliano A.
        • Zhou L.
        • Singh S.
        • et al.
        Activation of beta-catenin and Yap1 in human hepatoblastoma and induction of hepatocarcinogenesis in mice.
        Gastroenterology. 2014; 147: 690-701
        • Yamada D.
        • Rizvi S.
        • Razumilava N.
        • Bronk S.F.
        • Davila J.I.
        • Champion M.D.
        • et al.
        IL-33 facilitates oncogene-induced cholangiocarcinoma in mice by an interleukin-6-sensitive mechanism.
        Hepatology. 2015; 61: 1627-1642
        • Nishio M.
        • Hamada K.
        • Kawahara K.
        • Sasaki M.
        • Noguchi F.
        • Chiba S.
        • et al.
        Cancer susceptibility and embryonic lethality in Mob1a/1b double-mutant mice.
        J Clin Invest. 2012; 122: 4505-4518
        • Li S.
        • Mao M.
        Next generation sequencing reveals genetic landscape of hepatocellular carcinomas.
        Cancer Lett. 2013; 340: 247-253
        • Shibata T.
        • Aburatani H.
        Exploration of liver cancer genomes.
        Nat Rev Gastroenterol Hepatol. 2014; 11: 340-349
        • Liu-Chittenden Y.
        • Huang B.
        • Shim J.S.
        • Chen Q.
        • Lee S.J.
        • Anders R.A.
        • et al.
        Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP.
        Genes Dev. 2012; 26: 1300-1305
        • Fitamant J.
        • Kottakis F.
        • Benhamouche S.
        • Tian H.S.
        • Chuvin N.
        • Parachoniak C.A.
        • et al.
        YAP inhibition restores hepatocyte differentiation in advanced HCC, leading to tumor regression.
        Cell Rep. 2015; 10: 1692-1707
        • Guo T.
        • Lu Y.
        • Li P.
        • Yin M.X.
        • Lv D.
        • Zhang W.
        • et al.
        A novel partner of Scalloped regulates Hippo signaling via antagonizing Scalloped–Yorkie activity.
        Cell Res. 2013; 23: 1201-1214
        • Koontz L.M.
        • Liu-Chittenden Y.
        • Yin F.
        • Zheng Y.
        • Yu J.
        • Huang B.
        • et al.
        The Hippo effector Yorkie controls normal tissue growth by antagonizing scalloped-mediated default repression.
        Dev Cell. 2013; 25: 388-401
        • Ganem N.J.
        • Cornils H.
        • Chiu S.Y.
        • O’Rourke K.P.
        • Arnaud J.
        • Yimlamai D.
        • et al.
        Cytokinesis failure triggers hippo tumor suppressor pathway activation.
        Cell. 2014; 158: 833-848