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Annual Review of Pathology: Mechanisms of Disease

Volume 16, 2021

The Hippo Pathway in Liver Homeostasis and Pathophysiology

Abstract

Studies of the regenerative capacity of the liver have converged on the Hippo pathway, a serine/threonine kinase cascade discovered in and conserved from unicellular organisms to mammals. Genetic studies of mouse and rat livers have revealed that the Hippo pathway is a key regulator of liver size, regeneration, development, metabolism, and homeostasis and that perturbations in the Hippo pathway can lead to the development of common liver diseases, such as fatty liver disease and liver cancer. In turn, pharmacological targeting of the Hippo pathway may be utilized to boost regeneration and to prevent the development and progression of liver diseases. We review current insights provided by the Hippo pathway into liver pathophysiology. Furthermore, we present a path forward for future studies to understand how newly identified components of the Hippo pathway may control liver physiology and how the Hippo pathway is regulated in the liver.

Keyword(s): fatty liver disease, Hippo pathway, liver cancer, metabolism, regeneration, YAP/TAZ
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/content/journals/10.1146/annurev-pathol-030420-105050
2021-01-24
2024-04-16
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Literature Cited

  1. 1. 
    Schuppan D, Afdhal NH. 2008. Liver cirrhosis. Lancet 371:838–51
     [Google Scholar]
  2. 2. 
    Mokdad AA, Lopez AD, Shahraz S, Lozano R, Mokdad AH et al. 2014. Liver cirrhosis mortality in 187 countries between 1980 and 2010: a systematic analysis. BMC Med 12:145
     [Google Scholar]
  3. 3. 
    Michalopoulos GK, DeFrances MC. 1997. Liver regeneration. Science 276:60–66
     [Google Scholar]
  4. 4. 
    Higgins GM, Anderson RM. 1931. Experimental pathology of liver: restoration of liver in the white rat following partial surgical removal. Arch. Pathol. 12:186–202
     [Google Scholar]
  5. 5. 
    Emre S, Umman V. 2011. Split liver transplantation: an overview. Transplant. Proc. 43:884–87
     [Google Scholar]
  6. 6. 
    Starzl TE, Fung J, Tzakis A, Todo S, Demetris AJ et al. 1993. Baboon-to-human liver transplantation. Lancet 341:65–71
     [Google Scholar]
  7. 7. 
    Kawasaki S, Makuuchi M, Ishizone S, Matsunami H, Terada M, Kawarazaki H 1992. Liver regeneration in recipients and donors after transplantation. Lancet 339:580–81
     [Google Scholar]
  8. 8. 
    Dong J, Feldmann G, Huang J, Wu S, Zhang N et al. 2007. Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell 130:1120–33
     [Google Scholar]
  9. 9. 
    Pan D. 2010. The Hippo signaling pathway in development and cancer. Dev. Cell 19:491–505
     [Google Scholar]
  10. 10. 
    Machado MV, Michelotti GA, Pereira TA, Xie G, Premont R et al. 2015. Accumulation of duct cells with activated YAP parallels fibrosis progression in non-alcoholic fatty liver disease. J. Hepatol. 63:962–70
     [Google Scholar]
  11. 11. 
    Justice RW, Zilian O, Woods DF, Noll M, Bryant PJ 1995. 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 9:534–46
     [Google Scholar]
  12. 12. 
    Xu T, Wang W, Zhang S, Stewart RA, Yu W 1995. Identifying tumor suppressors in genetic mosaics: The Drosophila lats gene encodes a putative protein kinase. Development 121:1053–63
     [Google Scholar]
  13. 13. 
    Kango-Singh M, Nolo R, Tao C, Verstreken P, Hiesinger PR et al. 2002. Shar-pei mediates cell proliferation arrest during imaginal disc growth in Drosophila. . Development 129:5719–30
     [Google Scholar]
  14. 14. 
    Tapon N, Harvey KF, Bell DW, Wahrer DC, Schiripo TA et al. 2002. salvador promotes both cell cycle exit and apoptosis in Drosophila and is mutated in human cancer cell lines. Cell 110:467–78
     [Google Scholar]
  15. 15. 
    Lai Z-C, Wei X, Shimizu T, Ramos E, Rohrbaugh M et al. 2005. Control of cell proliferation and apoptosis by Mob as tumor suppressor, Mats. Cell 120:675–85
     [Google Scholar]
  16. 16. 
    Harvey KF, Pfleger CM, Hariharan IK 2003. The Drosophila Mst ortholog, hippo, restricts growth and cell proliferation and promotes apoptosis. Cell 114:457–67
     [Google Scholar]
  17. 17. 
    Jia J, Zhang W, Wang B, Trinko R, Jiang J 2003. The Drosophila Ste20 family kinase dMST functions as a tumor suppressor by restricting cell proliferation and promoting apoptosis. Genes Dev 17:2514–19
     [Google Scholar]
  18. 18. 
    Pantalacci S, Tapon N, Léopold P 2003. The Salvador partner Hippo promotes apoptosis and cell-cycle exit in Drosophila. Nat. Cell Biol 5:921–27
     [Google Scholar]
  19. 19. 
    Udan RS, Kango-Singh M, Nolo R, Tao C, Halder G 2003. Hippo promotes proliferation arrest and apoptosis in the Salvador/Warts pathway. Nat. Cell Biol. 5:914–20
     [Google Scholar]
  20. 20. 
    Wu S, Huang J, Dong J, Pan D 2003. hippo encodes a Ste-20 family protein kinase that restricts cell proliferation and promotes apoptosis in conjunction with salvador and warts. . Cell 114:445–56
     [Google Scholar]
  21. 21. 
    Huang J, Wu S, Barrera J, Matthews K, Pan D 2005. The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila homolog of YAP. Cell 122:421–34
     [Google Scholar]
  22. 22. 
    Zhang L, Ren F, Zhang Q, Chen Y, Wang B, Jiang J 2008. The TEAD/TEF family of transcription factor Scalloped mediates Hippo signaling in organ size control. Dev. Cell 14:377–87
     [Google Scholar]
  23. 23. 
    Wu S, Liu Y, Zheng Y, Dong J, Pan D 2008. The TEAD/TEF family protein Scalloped mediates transcriptional output of the Hippo growth-regulatory pathway. Dev. Cell 14:388–98
     [Google Scholar]
  24. 24. 
    Lei Q-Y, Zhang H, Zhao B, Zha Z-Y, Bai F et al. 2008. TAZ promotes cell proliferation and epithelial-mesenchymal transition and is inhibited by the hippo pathway. Mol. Cell. Biol. 28:2426–36
     [Google Scholar]
  25. 25. 
    Zhao B, Wei X, Li W, Udan RS, Yang Q et al. 2007. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev 21:2747–61
     [Google Scholar]
  26. 26. 
    Zheng Y, Pan D. 2019. The Hippo signaling pathway in development and disease. Dev. Cell 50:264–82
     [Google Scholar]
  27. 27. 
    Liu C-Y, Zha Z-Y, Zhou X, Zhang H, Huang W et al. 2010. The hippo tumor pathway promotes TAZ degradation by phosphorylating a phosphodegron and recruiting the SCFβ-TrCP E3 ligase. J. Biol. Chem. 285:37159–69
     [Google Scholar]
  28. 28. 
    Zhao B, Li L, Tumaneng K, Wang C-Y, Guan K-L 2010. A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCFβ-TrCP. Genes Dev 24:72–85
     [Google Scholar]
  29. 29. 
    Zhao B, Ye X, Yu J, Li L, Li W et al. 2008. TEAD mediates YAP-dependent gene induction and growth control. Genes Dev 22:1962–71
     [Google Scholar]
  30. 30. 
    Zanconato F, Forcato M, Battilana G, Azzolin L, Quaranta E et al. 2015. Genome-wide association between YAP/TAZ/TEAD and AP-1 at enhancers drives oncogenic growth. Nat. Cell Biol. 17:1218–27
     [Google Scholar]
  31. 31. 
    Galli GG, Carrara M, Yuan WC, Valdes-Quezada C, Gurung B et al. 2015. YAP drives growth by controlling transcriptional pause release from dynamic enhancers. Mol. Cell 60:328–37
     [Google Scholar]
  32. 32. 
    Kitagawa M. 2007. A Sveinsson's chorioretinal atrophy-associated missense mutation in mouse Tead1 affects its interaction with the co-factors YAP and TAZ. Biochem. Biophys. Res. Commun. 361:1022–26
     [Google Scholar]
  33. 33. 
    Koontz LM, Liu-Chittenden Y, Yin F, Zheng Y, Yu J et al. 2013. The Hippo effector Yorkie controls normal tissue growth by antagonizing scalloped-mediated default repression. Dev. Cell 25:388–401
     [Google Scholar]
  34. 34. 
    Kalamarides M, Acosta MT, Babovic-Vuksanovic D, Carpen O, Cichowski K et al. 2012. Neurofibromatosis 2011: a report of the Children's Tumor Foundation annual meeting. Acta Neuropathol 123:369–80
     [Google Scholar]
  35. 35. 
    Zhang N, Bai H, David KK, Dong J, Zheng Y et al. 2010. The Merlin/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals. Dev. Cell 19:27–38
     [Google Scholar]
  36. 36. 
    Hamaratoglu F, Willecke M, Kango-Singh M, Nolo R, Hyun E et al. 2006. The tumour-suppressor genes NF2/Merlin and Expanded act through Hippo signalling to regulate cell proliferation and apoptosis. Nat. Cell Biol. 8:27–36
     [Google Scholar]
  37. 37. 
    Yin F, Yu J, Zheng Y, Chen Q, Zhang N, Pan D 2013. Spatial organization of Hippo signaling at the plasma membrane mediated by the tumor suppressor Merlin/NF2. Cell 154:1342–55
     [Google Scholar]
  38. 38. 
    Genevet A, Wehr MC, Brain R, Thompson BJ, Tapon N 2010. Kibra is a regulator of the Salvador/Warts/Hippo signaling network. Dev. Cell 18:300–8
     [Google Scholar]
  39. 39. 
    Kapoor A, Yao W, Ying H, Hua S, Liewen A et al. 2014. Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer. Cell 158:185–97
     [Google Scholar]
  40. 40. 
    Oh H, Slattery M, Ma L, Crofts A, White KP et al. 2013. Genome-wide association of Yorkie with chromatin and chromatin-remodeling complexes. Cell Rep 3:309–18
     [Google Scholar]
  41. 41. 
    Cordenonsi M, Zanconato F, Azzolin L, Forcato M, Rosato A et al. 2011. The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells. Cell 147:759–72
     [Google Scholar]
  42. 42. 
    Janse van Rensburg HJ, Azad T, Ling M, Hao Y, Snetsinger B et al. 2018. The Hippo pathway component TAZ promotes immune evasion in human cancer through PD-L1. Cancer Res 78:1457–70
     [Google Scholar]
  43. 43. 
    Zhao Y, Yang X. 2015. The Hippo pathway in chemotherapeutic drug resistance. Int. J. Cancer 137:2767–73
     [Google Scholar]
  44. 44. 
    Neto-Silva RM, de Beco S, Johnston LA 2010. Evidence for a growth-stabilizing regulatory feedback mechanism between Myc and Yorkie, the Drosophila homolog of Yap. Dev. Cell 19:507–20
     [Google Scholar]
  45. 45. 
    Park HW, Kim YC, Yu B, Moroishi T, Mo J-S et al. 2015. Alternative Wnt signaling activates YAP/TAZ. Cell 162:780–94
     [Google Scholar]
  46. 46. 
    Azzolin L, Panciera T, Soligo S, Enzo E, Bicciato S et al. 2014. YAP/TAZ incorporation in the β-catenin destruction complex orchestrates the Wnt response. Cell 158:157–70
     [Google Scholar]
  47. 47. 
    Yimlamai D, Christodoulou C, Galli GG, Yanger K, Pepe-Mooney B et al. 2014. Hippo pathway activity influences liver cell fate. Cell 157:1324–38
     [Google Scholar]
  48. 48. 
    Camargo FD, Gokhale S, Johnnidis JB, Fu D, Bell GW et al. 2007. YAP1 increases organ size and expands undifferentiated progenitor cells. Curr. Biol. 17:2054–60
     [Google Scholar]
  49. 49. 
    Chen Q, Zhang N, Xie R, Wang W, Cai J et al. 2015. Homeostatic control of Hippo signaling activity revealed by an endogenous activating mutation in YAP. Genes Dev 29:1285–97
     [Google Scholar]
  50. 50. 
    Yi J, Lu L, Yanger K, Wang W, Sohn BH et al. 2016. Large tumor suppressor homologs 1 and 2 regulate mouse liver progenitor cell proliferation and maturation through antagonism of the coactivators YAP and TAZ. Hepatology 64:1757–72
     [Google Scholar]
  51. 51. 
    Lu L, Li Y, Kim SM, Bossuyt W, Liu P et al. 2010. Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver. PNAS 107:1437–42
     [Google Scholar]
  52. 52. 
    Song H, Mak KK, Topol L, Yun K, Hu J et al. 2010. Mammalian Mst1 and Mst2 kinases play essential roles in organ size control and tumor suppression. PNAS 107:1431–36
     [Google Scholar]
  53. 53. 
    Zhou D, Conrad C, Xia F, Park J-S, Payer B et al. 2009. Mst1 and Mst2 maintain hepatocyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yap1 oncogene. Cancer Cell 16:425–38
     [Google Scholar]
  54. 54. 
    Lee K-P, Lee J-H, Kim T-S, Kim T-H, Park H-D et al. 2010. The Hippo-Salvador pathway restrains hepatic oval cell proliferation, liver size, and liver tumorigenesis. PNAS 107:8248–53
     [Google Scholar]
  55. 55. 
    Nishio M, Sugimachi K, Goto H, Wang J, Morikawa T et al. 2016. Dysregulated YAP1/TAZ and TGF-β signaling mediate hepatocarcinogenesis in Mob1a/1b-deficient mice. PNAS 113:E71–80
     [Google Scholar]
  56. 56. 
    Hermann A, Wennmann DO, Gromnitza S, Edeling M, Van Marck V et al. 2018. WW and C2 domain-containing proteins regulate hepatic cell differentiation and tumorigenesis through the hippo signaling pathway. Hepatology 67:1546–59
     [Google Scholar]
  57. 57. 
    Liu-Chittenden Y, Huang B, Shim JS, Chen Q, Lee S-J et al. 2012. Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP. Genes Dev 26:1300–5
     [Google Scholar]
  58. 58. 
    Grijalva JL, Huizenga M, Mueller K, Rodriguez S, Brazzo J et al. 2014. Dynamic alterations in Hippo signaling pathway and YAP activation during liver regeneration. Am. J. Physiol. Gastrointest. Liver Physiol. 307:G196–204
     [Google Scholar]
  59. 59. 
    Lu L, Finegold MJ, Johnson RL 2018. Hippo pathway coactivators Yap and Taz are required to coordinate mammalian liver regeneration. Exp. Mol. Med. 50:e423
     [Google Scholar]
  60. 60. 
    Sato K, Marzioni M, Meng F, Francis H, Glaser S, Alpini G 2019. Ductular reaction in liver diseases: pathological mechanisms and translational significances. Hepatology 69:420–30
     [Google Scholar]
  61. 61. 
    Gurda GT, Zhu Q, Bai H, Pan D, Schwarz KB, Anders RA 2014. The use of Yes-associated protein expression in the diagnosis of persistent neonatal cholestatic liver disease. Hum. Pathol. 45:1057–64
     [Google Scholar]
  62. 62. 
    Bai H, Zhang N, Xu Y, Chen Q, Khan M et al. 2012. Yes-associated protein regulates the hepatic response after bile duct ligation. Hepatology 56:1097–107
     [Google Scholar]
  63. 63. 
    Pepe-Mooney BJ, Dill MT, Alemany A, Ordovas-Montanes J, Matsushita Y et al. 2019. Single-cell analysis of the liver epithelium reveals dynamic heterogeneity and an essential role for YAP in homeostasis and regeneration. Cell Stem Cell 25:23–38.e8
     [Google Scholar]
  64. 64. 
    Planas-Paz L, Sun T, Pikiolek M, Cochran NR, Bergling S et al. 2019. YAP, but not RSPO-LGR4/5, signaling in biliary epithelial cells promotes a ductular reaction in response to liver injury. Cell Stem Cell 25:39–53.e10
     [Google Scholar]
  65. 65. 
    Mannaerts I, Leite SB, Verhulst S, Claerhout S, Eysackers N et al. 2015. The Hippo pathway effector YAP controls mouse hepatic stellate cell activation. J. Hepatol. 63:679–88
     [Google Scholar]
  66. 66. 
    Konishi T, Schuster RM, Lentsch AB 2018. Proliferation of hepatic stellate cells, mediated by YAP and TAZ, contributes to liver repair and regeneration after liver ischemia-reperfusion injury. Am. J. Physiol. Gastrointest. Liver Physiol. 314:G471–82
     [Google Scholar]
  67. 67. 
    Swiderska-Syn M, Xie G, Michelotti GA, Jewell ML, Premont RT et al. 2016. Hedgehog regulates yes-associated protein 1 in regenerating mouse liver. Hepatology 64:232–44
     [Google Scholar]
  68. 68. 
    Sherman MH. 2018. Stellate cells in tissue repair, inflammation, and cancer. Annu. Rev. Cell Dev. Biol. 34:333–55
     [Google Scholar]
  69. 69. 
    Su T, Bondar T, Zhou X, Zhang C, He H, Medzhitov R 2015. Two-signal requirement for growth-promoting function of Yap in hepatocytes. eLife 4:e02948
     [Google Scholar]
  70. 70. 
    Wang X, Zheng Z, Caviglia JM, Corey KE, Herfel TM et al. 2016. Hepatocyte TAZ/WWTR1 promotes inflammation and fibrosis in nonalcoholic steatohepatitis. Cell Metab 24:848–62
     [Google Scholar]
  71. 71. 
    Kodama T, Yi J, Newberg JY, Tien JC, Wu H et al. 2018. Molecular profiling of nonalcoholic fatty liver disease-associated hepatocellular carcinoma using SB transposon mutagenesis. PNAS 115:E10417–26
     [Google Scholar]
  72. 72. 
    Plouffe SW, Lin KC, Moore JL 3rd, Tan FE, Ma S et al. 2018. The Hippo pathway effector proteins YAP and TAZ have both distinct and overlapping functions in the cell. J. Biol. Chem. 293:11230–40
     [Google Scholar]
  73. 73. 
    Hagenbeek TJ, Webster JD, Kljavin NM, Chang MT, Pham T et al. 2018. The Hippo pathway effector TAZ induces TEAD-dependent liver inflammation and tumors. Sci. Signal. 11:eaaj1757
     [Google Scholar]
  74. 74. 
    Kim W, Khan SK, Liu Y, Xu R, Park O et al. 2018. Hepatic Hippo signaling inhibits protumoural microenvironment to suppress hepatocellular carcinoma. Gut 67:1692–703
     [Google Scholar]
  75. 75. 
    Lee D-H, Park JO, Kim T-S, Kim S-K, Kim T-h et al. 2016. LATS-YAP/TAZ controls lineage specification by regulating TGFβ signaling and Hnf4α expression during liver development. Nat. Commun. 7:11961
     [Google Scholar]
  76. 76. 
    Wang X, Freire Valls A, Schermann G, Shen Y, Moya IM et al. 2017. YAP/TAZ orchestrate VEGF signaling during developmental angiogenesis. Dev. Cell 42:462–78.e7
     [Google Scholar]
  77. 77. 
    Azad T, Janse van Rensburg HJ, Lightbody ED, Neveu B, Champagne A et al. 2018. A LATS biosensor screen identifies VEGFR as a regulator of the Hippo pathway in angiogenesis. Nat. Commun. 9:1061
     [Google Scholar]
  78. 78. 
    Neto F, Klaus-Bergmann A, Ong YT, Alt S, Vion A-C et al. 2018. YAP and TAZ regulate adherens junction dynamics and endothelial cell distribution during vascular development. eLife 7:e31037
     [Google Scholar]
  79. 79. 
    Kim J, Kim YH, Kim J, Park DY, Bae H et al. 2017. YAP/TAZ regulates sprouting angiogenesis and vascular barrier maturation. J. Clin. Investig. 127:3441–61
     [Google Scholar]
  80. 80. 
    Sakabe M, Fan J, Odaka Y, Liu N, Hassan A et al. 2017. YAP/TAZ-CDC42 signaling regulates vascular tip cell migration. PNAS 114:10918–23
     [Google Scholar]
  81. 81. 
    Sun P, Zhang G, Su X, Jin C, Yu B et al. 2019. Maintenance of primary hepatocyte functions in vitro by inhibiting mechanical tension-induced YAP activation. Cell Rep 29:3212–22.e4
     [Google Scholar]
  82. 82. 
    Zender L, Spector MS, Xue W, Flemming P, Cordon-Cardo C et al. 2006. Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach. Cell 125:1253–67
     [Google Scholar]
  83. 83. 
    Shen S, Guo X, Yan H, Lu Y, Ji X et al. 2015. A miR-130a-YAP positive feedback loop promotes organ size and tumorigenesis. Cell Res 25:997–1012
     [Google Scholar]
  84. 84. 
    Perra A, Kowalik MA, Ghiso E, Ledda-Columbano GM, Di Tommaso L et al. 2014. YAP activation is an early event and a potential therapeutic target in liver cancer development. J. Hepatol. 61:1088–96
     [Google Scholar]
  85. 85. 
    Tao J, Calvisi DF, Ranganathan S, Cigliano A, Zhou L et al. 2014. Activation of β-catenin and Yap1 in human hepatoblastoma and induction of hepatocarcinogenesis in mice. Gastroenterology 147:690–701
     [Google Scholar]
  86. 86. 
    Zhang J, Liu P, Tao J, Wang P, Zhang Y et al. 2019. TEA domain transcription factor 4 is the major mediator of Yes-associated protein oncogenic activity in mouse and human hepatoblastoma. Am. J. Pathol 189:1077–90
     [Google Scholar]
  87. 87. 
    Smith JL, Rodríguez TC, Mou H, Kwan S-Y, Pratt H et al. 2020. YAP1 withdrawal in hepatoblastoma drives therapeutic differentiation of tumor cells to functional hepatocyte-like cells. Hepatology In press. https://doi.org/10.1002/hep.31389
    [Crossref] [Google Scholar]
  88. 88. 
    Tomlinson GE, Kappler R. 2012. Genetics and epigenetics of hepatoblastoma. Pediatr. Blood Cancer 59:785–92
     [Google Scholar]
  89. 89. 
    Cai J, Maitra A, Anders RA, Taketo MM, Pan D 2015. β-Catenin destruction complex-independent regulation of Hippo-YAP signaling by APC in intestinal tumorigenesis. Genes Dev 29:1493–506
     [Google Scholar]
  90. 90. 
    Tanas MR, Sboner A, Oliveira AM, Erickson-Johnson MR, Hespelt J et al. 2011. Identification of a disease-defining gene fusion in epithelioid hemangioendothelioma. Sci. Transl. Med. 3:98ra82
     [Google Scholar]
  91. 91. 
    Errani C, Zhang L, Sung YS, Hajdu M, Singer S et al. 2011. A novel WWTR1-CAMTA1 gene fusion is a consistent abnormality in epithelioid hemangioendothelioma of different anatomic sites. Genes Chromosomes Cancer 50:644–53
     [Google Scholar]
  92. 92. 
    Antonescu CR, Le Loarer F, Mosquera JM, Sboner A, Zhang L et al. 2013. Novel YAP1-TFE3 fusion defines a distinct subset of epithelioid hemangioendothelioma. Genes Chromosomes Cancer 52:775–84
     [Google Scholar]
  93. 93. 
    Tanas MR, Ma S, Jadaan FO, Ng CK, Weigelt B et al. 2016. Mechanism of action of a WWTR1(TAZ)-CAMTA1 fusion oncoprotein. Oncogene 35:929–38
     [Google Scholar]
  94. 94. 
    Yuan W-C, Pepe-Mooney B, Galli GG, Dill MT, Huang H-T et al. 2018. NUAK2 is a critical YAP target in liver cancer. Nat. Commun. 9:4834
     [Google Scholar]
  95. 95. 
    Sohn BH, Shim JJ, Kim SB, Jang KY, Kim SM et al. 2016. Inactivation of Hippo pathway is significantly associated with poor prognosis in hepatocellular carcinoma. Clin. Cancer Res. 22:1256–64
     [Google Scholar]
  96. 96. 
    Guo Y, Pan Q, Zhang J, Xu X, Liu X et al. 2015. Functional and clinical evidence that TAZ is a candidate oncogene in hepatocellular carcinoma. J. Cell Biochem. 116:2465–75
     [Google Scholar]
  97. 97. 
    Han S-x, Bai E, Jin G-h, He C-c, Guo X-j et al. 2014. Expression and clinical significance of YAP, TAZ, and AREG in hepatocellular carcinoma. J. Immunol. Res. 2014:261365
     [Google Scholar]
  98. 98. 
    Kim GJ, Kim H, Park YN 2013. Increased expression of Yes-associated protein 1 in hepatocellular carcinoma with stemness and combined hepatocellular-cholangiocarcinoma. PLOS ONE 8:e75449
     [Google Scholar]
  99. 99. 
    Xiao H, Jiang N, Zhou B, Liu Q, Du C 2015. TAZ regulates cell proliferation and epithelial-mesenchymal transition of human hepatocellular carcinoma. Cancer Sci 106:151–59
     [Google Scholar]
  100. 100. 
    Xu MZ, Yao TJ, Lee NP, Ng IO, Chan YT et al. 2009. Yes-associated protein is an independent prognostic marker in hepatocellular carcinoma. Cancer 115:4576–85
     [Google Scholar]
  101. 101. 
    Sia D, Hoshida Y, Villanueva A, Roayaie S, Ferrer J et al. 2013. Integrative molecular analysis of intrahepatic cholangiocarcinoma reveals 2 classes that have different outcomes. Gastroenterology 144:829–40
     [Google Scholar]
  102. 102. 
    Zhang N, Zhao Z, Long J, Li H, Zhang B et al. 2017. Molecular alterations of the NF2 gene in hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Oncol. Rep. 38:3650–58
     [Google Scholar]
  103. 103. 
    Xue R, Chen L, Zhang C, Fujita M, Li R et al. 2019. Genomic and transcriptomic profiling of combined hepatocellular and intrahepatic cholangiocarcinoma reveals distinct molecular subtypes. Cancer Cell 35:932–47.e8
     [Google Scholar]
  104. 104. 
    Fujimoto A, Totoki Y, Abe T, Boroevich KA, Hosoda F et al. 2012. Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators. Nat. Genet. 44:760–64
     [Google Scholar]
  105. 105. 
    Guichard C, Amaddeo G, Imbeaud S, Ladeiro Y, Pelletier L et al. 2012. Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat. Genet. 44:694–98
     [Google Scholar]
  106. 106. 
    Chang L, Azzolin L, Di Biagio D, Zanconato F, Battilana G et al. 2018. The SWI/SNF complex is a mechanoregulated inhibitor of YAP and TAZ. Nature 563:265–69
     [Google Scholar]
  107. 107. 
    Mello SS, Valente LJ, Raj N, Seoane JA, Flowers BM et al. 2017. A p53 super-tumor suppressor reveals a tumor suppressive p53-Ptpn14-Yap axis in pancreatic cancer. Cancer Cell 32:460–73.e6
     [Google Scholar]
  108. 108. 
    Hill MA, Alexander WB, Guo B, Kato Y, Patra K et al. 2018. Kras and Tp53 mutations cause cholangiocyte- and hepatocyte-derived cholangiocarcinoma. Cancer Res 78:4445–51
     [Google Scholar]
  109. 109. 
    Shao DD, Xue W, Krall EB, Bhutkar A, Piccioni F et al. 2014. KRAS and YAP1 converge to regulate EMT and tumor survival. Cell 158:171–84
     [Google Scholar]
  110. 110. 
    Fang L, Teng H, Wang Y, Liao G, Weng L et al. 2018. SET1A-mediated mono-methylation at K342 regulates YAP activation by blocking its nuclear export and promotes tumorigenesis. Cancer Cell 34:103–18.e9
     [Google Scholar]
  111. 111. 
    Ziosi M, Baena-López LA, Grifoni D, Froldi F, Pession A et al. 2010. dMyc functions downstream of Yorkie to promote the supercompetitive behavior of hippo pathway mutant cells. PLOS Genet 6:e1001140
     [Google Scholar]
  112. 112. 
    Moya IM, Castaldo SA, Van den Mooter L, Soheily S, Sansores-Garcia L et al. 2019. Peritumoral activation of the Hippo pathway effectors YAP and TAZ suppresses liver cancer in mice. Science 366:1029–34
     [Google Scholar]
  113. 113. 
    DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB 2008. The biology of cancer: Metabolic reprogramming fuels cell growth and proliferation. Cell Metab 7:11–20
     [Google Scholar]
  114. 114. 
    Wang W, Xiao ZD, Li X, Aziz KE, Gan B et al. 2015. AMPK modulates Hippo pathway activity to regulate energy homeostasis. Nat. Cell Biol. 17:490–99
     [Google Scholar]
  115. 115. 
    Zheng X, Han H, Liu G-P, Ma Y-X, Pan R-L et al. 2017. LncRNA wires up Hippo and Hedgehog signaling to reprogramme glucose metabolism. EMBO J 36:3325–35
     [Google Scholar]
  116. 116. 
    Hu Y, Shin D-J, Pan H, Lin Z, Dreyfuss JM et al. 2017. YAP suppresses gluconeogenic gene expression through PGC1α. Hepatology 66:2029–41
     [Google Scholar]
  117. 117. 
    Jeong SH, Kim HB, Kim MC, Lee JM, Lee J-H et al. 2018. Hippo-mediated suppression of IRS2/AKT signaling prevents hepatic steatosis and liver cancer. J. Clin. Investig. 128:1010–25
     [Google Scholar]
  118. 118. 
    Aylon Y, Gershoni A, Rotkopf R, Biton IE, Porat Z et al. 2016. The LATS2 tumor suppressor inhibits SREBP and suppresses hepatic cholesterol accumulation. Genes Dev 30:786–97
     [Google Scholar]
  119. 119. 
    Geng C, Zhang Y, Gao Y, Tao W, Zhang H et al. 2016. Mst1 regulates hepatic lipid metabolism by inhibiting Sirt1 ubiquitination in mice. Biochem. Biophys. Res. Commun. 471:444–49
     [Google Scholar]
  120. 120. 
    Cox AG, Hwang KL, Brown KK, Evason K, Beltz S et al. 2016. Yap reprograms glutamine metabolism to increase nucleotide biosynthesis and enable liver growth. Nat. Cell Biol. 18:886–96
     [Google Scholar]
  121. 121. 
    Liu P, Calvisi DF, Kiss A, Cigliano A, Schaff Z et al. 2017. Central role of mTORC1 downstream of YAP/TAZ in hepatoblastoma development. Oncotarget 8:73433–47
     [Google Scholar]
  122. 122. 
    Hensley CT, Wasti AT, DeBerardinis RJ 2013. Glutamine and cancer: cell biology, physiology, and clinical opportunities. J. Clin. Investig. 123:3678–84
     [Google Scholar]
  123. 123. 
    Du K, Hyun J, Premont RT, Choi SS, Michelotti GA et al. 2018. Hedgehog-YAP signaling pathway regulates glutaminolysis to control activation of hepatic stellate cells. Gastroenterology 154:1465–79.e13
     [Google Scholar]
  124. 124. 
    Yang C-S, Stampouloglou E, Kingston NM, Zhang L, Monti S, Varelas X 2018. Glutamine-utilizing transaminases are a metabolic vulnerability of TAZ/YAP-activated cancer cells. EMBO Rep 19:e43577
     [Google Scholar]
  125. 125. 
    DeRan M, Yang J, Shen CH, Peters EC, Fitamant J et al. 2014. Energy stress regulates hippo-YAP signaling involving AMPK-mediated regulation of angiomotin-like 1 protein. Cell Rep 9:495–503
     [Google Scholar]
  126. 126. 
    Enzo E, Santinon G, Pocaterra A, Aragona M, Bresolin S et al. 2015. Aerobic glycolysis tunes YAP/TAZ transcriptional activity. EMBO J 34:1349–70
     [Google Scholar]
  127. 127. 
    Mo J-S, Meng Z, Kim YC, Park HW, Hansen CG et al. 2015. Cellular energy stress induces AMPK-mediated regulation of YAP and the Hippo pathway. Nat. Cell Biol. 17:500–10
     [Google Scholar]
  128. 128. 
    Zhang X, Qiao Y, Wu Q, Chen Y, Zou S et al. 2017. The essential role of YAP O-GlcNAcylation in high-glucose-stimulated liver tumorigenesis. Nat. Commun. 8:15280
     [Google Scholar]
  129. 129. 
    Peng C, Zhu Y, Zhang W, Liao Q, Chen Y et al. 2017. Regulation of the Hippo-YAP pathway by glucose sensor O-GlcNAcylation. Mol. Cell 68:591–604.e5
     [Google Scholar]
  130. 130. 
    Koo JH, Guan K-L. 2018. Interplay between YAP/TAZ and metabolism. Cell Metab 28:196–206
     [Google Scholar]
  131. 131. 
    Sorrentino G, Ruggeri N, Specchia V, Cordenonsi M, Mano M et al. 2014. Metabolic control of YAP and TAZ by the mevalonate pathway. Nat. Cell Biol. 16:357–66
     [Google Scholar]
  132. 132. 
    Wang Z, Wu Y, Wang H, Zhang Y, Mei L et al. 2014. Interplay of mevalonate and Hippo pathways regulates RHAMM transcription via YAP to modulate breast cancer cell motility. PNAS 111:E89–98
     [Google Scholar]
  133. 133. 
    Mi W, Lin Q, Childress C, Sudol M, Robishaw J et al. 2015. Geranylgeranylation signals to the Hippo pathway for breast cancer cell proliferation and migration. Oncogene 34:3095–106
     [Google Scholar]
  134. 134. 
    Luo J, Yu F-X. 2019. GPCR-Hippo signaling in cancer. Cells 8:426
     [Google Scholar]
  135. 135. 
    Yu F-X, Zhao B, Panupinthu N, Jewell JL, Lian I et al. 2012. Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling. Cell 150:780–91
     [Google Scholar]
  136. 136. 
    Feng X, Degese MS, Iglesias-Bartolome R, Vaque JP, Molinolo AA et al. 2014. Hippo-independent activation of YAP by the GNAQ uveal melanoma oncogene through a trio-regulated Rho GTPase signaling circuitry. Cancer Cell 25:831–45
     [Google Scholar]
  137. 137. 
    Yu F-X, Luo J, Mo J-S, Liu G, Kim YC et al. 2014. Mutant Gq/11 promote uveal melanoma tumorigenesis by activating YAP. Cancer Cell 25:822–30
     [Google Scholar]
  138. 138. 
    Li H, Li Q, Dang K, Ma S, Cotton JL et al. 2019. YAP/TAZ activation drives uveal melanoma initiation and progression. Cell Rep 29:3200–11.e4
     [Google Scholar]
  139. 139. 
    Saikawa S, Kaji K, Nishimura N, Seki K, Sato S et al. 2018. Angiotensin receptor blockade attenuates cholangiocarcinoma cell growth by inhibiting the oncogenic activity of Yes-associated protein. Cancer Lett 434:120–29
     [Google Scholar]
  140. 140. 
    Cheng JC, Wang EY, Yi Y, Thakur A, Tsai SH, Hoodless PA 2018. S1P stimulates proliferation by upregulating CTGF expression through S1PR2-mediated YAP activation. Mol. Cancer Res. 16:1543–55
     [Google Scholar]
  141. 141. 
    Xu G, Wang Y, Li W, Cao Y, Xu J et al. 2018. COX-2 forms regulatory loop with YAP to promote proliferation and tumorigenesis of hepatocellular carcinoma cells. Neoplasia 20:324–34
     [Google Scholar]
  142. 142. 
    Yu F-X, Zhang Y, Park HW, Jewell JL, Chen Q et al. 2013. Protein kinase A activates the Hippo pathway to modulate cell proliferation and differentiation. Genes Dev 27:1223–32
     [Google Scholar]
  143. 143. 
    Anakk S, Bhosale M, Schmidt VA, Johnson RL, Finegold MJ, Moore DD 2013. Bile acids activate YAP to promote liver carcinogenesis. Cell Rep 5:1060–69
     [Google Scholar]
  144. 144. 
    Ji S, Liu Q, Zhang S, Chen Q, Wang C et al. 2019. FGF15 activates Hippo signaling to suppress bile acid metabolism and liver tumorigenesis. Dev. Cell 48:460–74.e9
     [Google Scholar]
  145. 145. 
    Naugler WE, Tarlow BD, Fedorov LM, Taylor M, Pelz C et al. 2015. Fibroblast growth factor signaling controls liver size in mice with humanized livers. Gastroenterology 149:728–40.e15
     [Google Scholar]
  146. 146. 
    Dupont S, Morsut L, Aragona M, Enzo E, Giulitti S et al. 2011. Role of YAP/TAZ in mechanotransduction. Nature 474:179–83
     [Google Scholar]
  147. 147. 
    Codelia VA, Sun G, Irvine KD 2014. Regulation of YAP by mechanical strain through Jnk and Hippo signaling. Curr. Biol. 24:2012–17
     [Google Scholar]
  148. 148. 
    Elosegui-Artola A, Andreu I, Beedle AEM, Lezamiz A, Uroz M et al. 2017. Force triggers YAP nuclear entry by regulating transport across nuclear pores. Cell 171:1397–410.e14
     [Google Scholar]
  149. 149. 
    Nakajima H, Yamamoto K, Agarwala S, Terai K, Fukui H et al. 2017. Flow-dependent endothelial YAP regulation contributes to vessel maintenance. Dev. Cell 40:523–36.e6
     [Google Scholar]
  150. 150. 
    Wang L, Luo J-Y, Li B, Tian XY, Chen L-J et al. 2016. Integrin-YAP/TAZ-JNK cascade mediates atheroprotective effect of unidirectional shear flow. Nature 540:579–82
     [Google Scholar]
  151. 151. 
    Apte U, Gkretsi V, Bowen WC, Mars WM, Luo J-H et al. 2009. Enhanced liver regeneration following changes induced by hepatocyte-specific genetic ablation of integrin-linked kinase. Hepatology 50:844–51
     [Google Scholar]
  152. 152. 
    Serrano I, McDonald PC, Lock F, Muller WJ, Dedhar S 2013. Inactivation of the Hippo tumour suppressor pathway by integrin-linked kinase. Nat. Commun. 4:2976
     [Google Scholar]
  153. 153. 
    Wang W, Li N, Li X, Tran MK, Han X, Chen J 2015. Tankyrase inhibitors target YAP by stabilizing angiomotin family proteins. Cell Rep 13:524–32
     [Google Scholar]
  154. 154. 
    Fan F, He Z, Kong LL, Chen Q, Yuan Q et al. 2016. Pharmacological targeting of kinases MST1 and MST2 augments tissue repair and regeneration. Sci. Transl. Med. 8:352ra108
     [Google Scholar]
  155. 155. 
    Loforese G, Malinka T, Keogh A, Baier F, Simillion C et al. 2017. Impaired liver regeneration in aged mice can be rescued by silencing Hippo core kinases MST1 and MST2. EMBO Mol. Med. 9:46–60
     [Google Scholar]
  156. 156. 
    Jiao S, Wang H, Shi Z, Dong A, Zhang W et al. 2014. A peptide mimicking VGLL4 function acts as a YAP antagonist therapy against gastric cancer. Cancer Cell 25:166–80
     [Google Scholar]
  157. 157. 
    Kurppa KJ, Liu Y, To C, Zhang T, Fan M et al. 2020. Treatment-induced tumor dormancy through YAP-mediated transcriptional reprogramming of the apoptotic pathway. Cancer Cell 37:104–22.e12
     [Google Scholar]
  158. 158. 
    Boggiano JC, Vanderzalm PJ, Fehon RG 2011. Tao-1 phosphorylates Hippo/MST kinases to regulate the Hippo-Salvador-Warts tumor suppressor pathway. Dev. Cell 21:888–95
     [Google Scholar]
  159. 159. 
    Poon CL, Lin JI, Zhang X, Harvey KF 2011. The sterile 20-like kinase Tao-1 controls tissue growth by regulating the Salvador-Warts-Hippo pathway. Dev. Cell 21:896–906
     [Google Scholar]
  160. 160. 
    Zheng Y, Liu B, Wang L, Lei H, Pulgar Prieto KD, Pan D 2017. Homeostatic control of Hpo/MST kinase activity through autophosphorylation-dependent recruitment of the STRIPAK PP2A phosphatase complex. Cell Rep 21:3612–23
     [Google Scholar]
  161. 161. 
    Bae SJ, Ni L, Osinski A, Tomchick DR, Brautigam CA, Luo X 2017. SAV1 promotes Hippo kinase activation through antagonizing the PP2A phosphatase STRIPAK. eLife 6:e30278
     [Google Scholar]
  162. 162. 
    Li Q, Li S, Mana-Capelli S, Roth Flach RJ, Danai LV et al. 2014. The conserved Misshapen-Warts-Yorkie pathway acts in enteroblasts to regulate intestinal stem cells in Drosophila. Dev. Cell 31:291–304
     [Google Scholar]
  163. 163. 
    Meng Z, Moroishi T, Mottier-Pavie V, Plouffe SW, Hansen CG et al. 2015. MAP4K family kinases act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway. Nat. Commun. 6:8357
     [Google Scholar]
  164. 164. 
    Zheng Y, Wang W, Liu B, Deng H, Uster E, Pan D 2015. Identification of Happyhour/MAP4K as alternative Hpo/Mst-like kinases in the Hippo kinase cascade. Dev. Cell 34:642–55
     [Google Scholar]
  165. 165. 
    Cai J, Song X, Wang W, Watnick T, Pei Y et al. 2018. A RhoA-YAP-c-Myc signaling axis promotes the development of polycystic kidney disease. Genes Dev 32:781–93
     [Google Scholar]
  166. 166. 
    Zhao B, Li L, Wang L, Wang C-Y, Yu J, Guan K-L 2012. Cell detachment activates the Hippo pathway via cytoskeleton reorganization to induce anoikis. Genes Dev 26:54–68
     [Google Scholar]
  167. 167. 
    Kim M, Kim M, Lee S, Kuninaka S, Saya H et al. 2013. cAMP/PKA signalling reinforces the LATS-YAP pathway to fully suppress YAP in response to actin cytoskeletal changes. EMBO J 32:1543–55
     [Google Scholar]
  168. 168. 
    Grise F, Bidaud A, Moreau V 2009. Rho GTPases in hepatocellular carcinoma. Biochim. Biophys. Acta Rev. Cancer 1795:137–51
     [Google Scholar]
/content/journals/10.1146/annurev-pathol-030420-105050
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The Hippo Pathway in Liver Homeostasis and Pathophysiology
Annual Review of Pathology: Mechanisms of Disease 16, 299 (2021); https://doi.org/10.1146/annurev-pathol-030420-105050
/content/journals/10.1146/annurev-pathol-030420-105050
/content/journals/10.1146/annurev-pathol-030420-105050
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