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Regulation of the Hippo pathway in cancer biology

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Abstract

The Hippo tumor suppressor pathway, which is well conserved from Drosophila to humans, has emerged as the master regulator of organ size, as well as major cellular properties, such as cell proliferation, survival, stemness, and tissue homeostasis. The biological significance and deregulation of the Hippo pathway in tumorigenesis have received a surge of interest in the past decade. In the current review, we present the major discoveries that made substantial contributions to our understanding of the Hippo pathway and discuss how Hippo pathway components contribute to cellular signaling, physiology, and their potential implications in anticancer therapeutics.

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References

  1. Gonzalez C (2013) Drosophila melanogaster: a model and a tool to investigate malignancy and identify new therapeutics. Nat Rev Cancer 13(3):172–183. https://doi.org/10.1038/nrc3461

    Article  PubMed  CAS  Google Scholar 

  2. St Johnston D (2002) The art and design of genetic screens: drosophila melanogaster. Nat Rev Genet 3(3):176–188. https://doi.org/10.1038/nrg751

    Article  PubMed  CAS  Google Scholar 

  3. 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(5):534–546

    Article  PubMed  CAS  Google Scholar 

  4. 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(4):1053–1063

    PubMed  CAS  Google Scholar 

  5. Tapon N, Harvey KF, Bell DW, Wahrer DC, Schiripo TA, Haber D, Hariharan IK (2002) Salvador promotes both cell cycle exit and apoptosis in Drosophila and is mutated in human cancer cell lines. Cell 110(4):467–478

    Article  PubMed  CAS  Google Scholar 

  6. Kango-Singh M, Nolo R, Tao C, Verstreken P, Hiesinger PR, Bellen HJ, Halder G (2002) Shar-pei mediates cell proliferation arrest during imaginal disc growth in Drosophila. Development 129(24):5719–5730

    Article  PubMed  CAS  Google Scholar 

  7. Harvey KF, Pfleger CM, Hariharan IK (2003) The Drosophila Mst ortholog, hippo, restricts growth and cell proliferation and promotes apoptosis. Cell 114(4):457–467

    Article  PubMed  CAS  Google Scholar 

  8. 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(20):2514–2519. https://doi.org/10.1101/gad.1134003

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Pantalacci S, Tapon N, Leopold P (2003) The Salvador partner Hippo promotes apoptosis and cell-cycle exit in Drosophila. Nat Cell Biol 5(10):921–927. https://doi.org/10.1038/ncb1051

    Article  PubMed  CAS  Google Scholar 

  10. 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(10):914–920. https://doi.org/10.1038/ncb1050

    Article  PubMed  CAS  Google Scholar 

  11. 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(4):445–456

    Article  PubMed  CAS  Google Scholar 

  12. Richardson HE, O’Keefe LV, Reed SI, Saint R (1993) A Drosophila G1-specific cyclin E homolog exhibits different modes of expression during embryogenesis. Development 119(3):673–690

    PubMed  CAS  Google Scholar 

  13. Richardson H, O’Keefe LV, Marty T, Saint R (1995) Ectopic cyclin E expression induces premature entry into S phase and disrupts pattern formation in the Drosophila eye imaginal disc. Development 121(10):3371–3379

    PubMed  CAS  Google Scholar 

  14. Knoblich JA, Sauer K, Jones L, Richardson H, Saint R, Lehner CF (1994) Cyclin E controls S phase progression and its down-regulation during Drosophila embryogenesis is required for the arrest of cell proliferation. Cell 77(1):107–120

    Article  PubMed  CAS  Google Scholar 

  15. Wang SL, Hawkins CJ, Yoo SJ, Muller HA, Hay BA (1999) The Drosophila caspase inhibitor DIAP1 is essential for cell survival and is negatively regulated by HID. Cell 98(4):453–463

    Article  PubMed  CAS  Google Scholar 

  16. Ryoo HD, Steller H (2003) Hippo and its mission for growth control. Nat Cell Biol 5(10):853–855. https://doi.org/10.1038/ncb1003-853

    Article  PubMed  CAS  Google Scholar 

  17. Lai ZC, Wei X, Shimizu T, Ramos E, Rohrbaugh M, Nikolaidis N, Ho LL, Li Y (2005) Control of cell proliferation and apoptosis by mob as tumor suppressor, mats. Cell 120(5):675–685. https://doi.org/10.1016/j.cell.2004.12.036

    Article  PubMed  CAS  Google Scholar 

  18. 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(3):421–434. https://doi.org/10.1016/j.cell.2005.06.007

    Article  PubMed  CAS  Google Scholar 

  19. Dong J, Feldmann G, Huang J, Wu S, Zhang N, Comerford SA, Gayyed MF, Anders RA, Maitra A, Pan D (2007) Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell 130(6):1120–1133. https://doi.org/10.1016/j.cell.2007.07.019

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Sudol M (1994) Yes-associated protein (YAP65) is a proline-rich phosphoprotein that binds to the SH3 domain of the Yes proto-oncogene product. Oncogene 9(8):2145–2152

    PubMed  CAS  Google Scholar 

  21. Zhao B, Ye X, Yu J, Li L, Li W, Li S, Yu J, Lin JD, Wang CY, Chinnaiyan AM, Lai ZC, Guan KL (2008) TEAD mediates YAP-dependent gene induction and growth control. Genes Dev 22(14):1962–1971. https://doi.org/10.1101/gad.1664408

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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(3):377–387. https://doi.org/10.1016/j.devcel.2008.01.006

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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(3):388–398. https://doi.org/10.1016/j.devcel.2008.01.007

    Article  PubMed  CAS  Google Scholar 

  24. Goulev Y, Fauny JD, Gonzalez-Marti B, Flagiello D, Silber J, Zider A (2008) SCALLOPED interacts with YORKIE, the nuclear effector of the hippo tumor-suppressor pathway in Drosophila. Curr Biol 18(6):435–441. https://doi.org/10.1016/j.cub.2008.02.034

    Article  PubMed  CAS  Google Scholar 

  25. Thompson BJ, Cohen SM (2006) The Hippo pathway regulates the bantam microRNA to control cell proliferation and apoptosis in Drosophila. Cell 126(4):767–774. https://doi.org/10.1016/j.cell.2006.07.013

    Article  PubMed  CAS  Google Scholar 

  26. Nolo R, Morrison CM, Tao C, Zhang X, Halder G (2006) The bantam microRNA is a target of the hippo tumor-suppressor pathway. Curr Biol 16(19):1895–1904. https://doi.org/10.1016/j.cub.2006.08.057

    Article  PubMed  CAS  Google Scholar 

  27. Herranz H, Hong X, Cohen SM (2012) Mutual repression by bantam miRNA and Capicua links the EGFR/MAPK and Hippo pathways in growth control. Curr Biol 22(8):651–657. https://doi.org/10.1016/j.cub.2012.02.050

    Article  PubMed  CAS  Google Scholar 

  28. 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(4):507–520. https://doi.org/10.1016/j.devcel.2010.09.009

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Ziosi M, Baena-Lopez LA, Grifoni D, Froldi F, Pession A, Garoia F, Trotta V, Bellosta P, Cavicchi S, Pession A (2010) dMyc functions downstream of Yorkie to promote the supercompetitive behavior of hippo pathway mutant cells. PLoS Genet 6(9):e1001140. https://doi.org/10.1371/journal.pgen.1001140

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Peng HW, Slattery M, Mann RS (2009) Transcription factor choice in the Hippo signaling pathway: homothorax and yorkie regulation of the microRNA bantam in the progenitor domain of the Drosophila eye imaginal disc. Genes Dev 23(19):2307–2319. https://doi.org/10.1101/gad.1820009

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Ota M, Sasaki H (2008) Mammalian Tead proteins regulate cell proliferation and contact inhibition as transcriptional mediators of Hippo signaling. Development 135(24):4059–4069. https://doi.org/10.1242/dev.027151

    Article  PubMed  CAS  Google Scholar 

  32. Nishioka N, Inoue K, Adachi K, Kiyonari H, Ota M, Ralston A, Yabuta N, Hirahara S, Stephenson RO, Ogonuki N, Makita R, Kurihara H, Morin-Kensicki EM, Nojima H, Rossant J, Nakao K, Niwa H, Sasaki H (2009) The Hippo signaling pathway components Lats and Yap pattern Tead4 activity to distinguish mouse trophectoderm from inner cell mass. Dev Cell 16(3):398–410. https://doi.org/10.1016/j.devcel.2009.02.003

    Article  PubMed  CAS  Google Scholar 

  33. Vassilev A, Kaneko KJ, Shu H, Zhao Y, DePamphilis ML (2001) TEAD/TEF transcription factors utilize the activation domain of YAP65, a Src/Yes-associated protein localized in the cytoplasm. Genes Dev 15(10):1229–1241. https://doi.org/10.1101/gad.888601

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Zhang W, Gao Y, Li P, Shi Z, Guo T, Li F, Han X, Feng Y, Zheng C, Wang Z, Li F, Chen H, Zhou Z, Zhang L, Ji H (2014) VGLL4 functions as a new tumor suppressor in lung cancer by negatively regulating the YAP–TEAD transcriptional complex. Cell Res 24(3):331–343. https://doi.org/10.1038/cr.2014.10

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Jiao S, Wang H, Shi Z, Dong A, Zhang W, Song X, He F, Wang Y, Zhang Z, Wang W, Wang X, Guo T, Li P, Zhao Y, Ji H, Zhang L, Zhou Z (2014) A peptide mimicking VGLL4 function acts as a YAP antagonist therapy against gastric cancer. Cancer Cell 25(2):166–180. https://doi.org/10.1016/j.ccr.2014.01.010

    Article  PubMed  CAS  Google Scholar 

  36. Koontz LM, Liu-Chittenden Y, Yin F, Zheng Y, Yu J, Huang B, Chen Q, Wu S, Pan D (2013) The Hippo effector Yorkie controls normal tissue growth by antagonizing scalloped-mediated default repression. Dev Cell 25(4):388–401. https://doi.org/10.1016/j.devcel.2013.04.021

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Guo T, Lu Y, Li P, Yin MX, Lv D, Zhang W, Wang H, Zhou Z, Ji H, Zhao Y, Zhang L (2013) A novel partner of Scalloped regulates Hippo signaling via antagonizing Scalloped-Yorkie activity. Cell Res 23(10):1201–1214. https://doi.org/10.1038/cr.2013.120

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Moroishi T, Hansen CG, Guan KL (2015) The emerging roles of YAP and TAZ in cancer. Nat Rev Cancer 15(2):73–79. https://doi.org/10.1038/nrc3876

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Lai D, Ho KC, Hao Y, Yang X (2011) Taxol resistance in breast cancer cells is mediated by the hippo pathway component TAZ and its downstream transcriptional targets Cyr61 and CTGF. Cancer Res 71(7):2728–2738. https://doi.org/10.1158/0008-5472.CAN-10-2711

    Article  PubMed  CAS  Google Scholar 

  40. Park HW, Kim YC, Yu B, Moroishi T, Mo JS, Plouffe SW, Meng Z, Lin KC, Yu FX, Alexander CM, Wang CY, Guan KL (2015) Alternative Wnt Signaling Activates YAP/TAZ. Cell 162(4):780–794. https://doi.org/10.1016/j.cell.2015.07.013

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Seo E, Kim WY, Hur J, Kim H, Nam SA, Choi A, Kim YM, Park SH, Chung C, Kim J, Min S, Myung SJ, Lim DS, Kim YK (2016) The Hippo-Salvador signaling pathway regulates renal tubulointerstitial fibrosis. Sci Rep 6:31931. https://doi.org/10.1038/srep31931

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Tschaharganeh DF, Chen X, Latzko P, Malz M, Gaida MM, Felix K, Ladu S, Singer S, Pinna F, Gretz N, Sticht C, Tomasi ML, Delogu S, Evert M, Fan B, Ribback S, Jiang LJ, Brozzetti S, Bergmann F, Dombrowski F, Schirmacher P, Calvisi DF, Breuhahn K (2013) Yes-associated protein up-regulates jagged-1 and activates the NOTCH pathway in human hepatocellular carcinoma. Gastroenterology 144(7):1530-U1368. https://doi.org/10.1053/j.gastro.2013.02.009

    Article  CAS  Google Scholar 

  43. Kim T, Yang SJ, Hwang D, Song J, Kim M, Kyum Kim S, Kang K, Ahn J, Lee D, Kim MY, Kim S, Seung Koo J, Seok Koh S, Kim SY, Lim DS (2015) A basal-like breast cancer-specific role for SRF-IL6 in YAP-induced cancer stemness. Nat Commun 6:10186. https://doi.org/10.1038/ncomms10186

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Zhang J, Ji JY, Yu M, Overholtzer M, Smolen GA, Wang R, Brugge JS, Dyson NJ, Haber DA (2009) YAP-dependent induction of amphiregulin identifies a non-cell-autonomous component of the Hippo pathway. Nat Cell Biol 11(12):1444–1450. https://doi.org/10.1038/ncb1993

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Kwon Y, Vinayagam A, Sun X, Dephoure N, Gygi SP, Hong P, Perrimon N (2013) The Hippo signaling pathway interactome. Science 342(6159):737–740. https://doi.org/10.1126/science.1243971

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Zhao B, Li L, Tumaneng K, Wang CY, Guan KL (2010) A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP). Genes Dev 24(1):72–85. https://doi.org/10.1101/gad.1843810

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Lei QY, Zhang H, Zhao B, Zha ZY, Bai F, Pei XH, Zhao S, Xiong Y, Guan KL (2008) TAZ promotes cell proliferation and epithelial-mesenchymal transition and is inhibited by the hippo pathway. Mol Cell Biol 28(7):2426–2436. https://doi.org/10.1128/MCB.01874-07

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Liu CY, Zha ZY, Zhou X, Zhang H, Huang W, Zhao D, Li T, Chan SW, Lim CJ, Hong W, Zhao S, Xiong Y, Lei QY, Guan KL (2010) The hippo tumor pathway promotes TAZ degradation by phosphorylating a phosphodegron and recruiting the SCF{beta}-TrCP E3 ligase. J Biol Chem 285(48):37159–37169. https://doi.org/10.1074/jbc.M110.152942

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Kanai F, Marignani PA, Sarbassova D, Yagi R, Hall RA, Donowitz M, Hisaminato A, Fujiwara T, Ito Y, Cantley LC, Yaffe MB (2000) TAZ: a novel transcriptional co-activator regulated by interactions with 14-3-3 and PDZ domain proteins. EMBO J 19(24):6778–6791. https://doi.org/10.1093/emboj/19.24.6778

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Meng Z, Moroishi T, Guan KL (2016) Mechanisms of Hippo pathway regulation. Genes Dev 30(1):1–17. https://doi.org/10.1101/gad.274027.115

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. He M, Zhou Z, Shah AA, Hong Y, Chen Q, Wan Y (2016) New insights into posttranslational modifications of Hippo pathway in carcinogenesis and therapeutics. Cell Div 11:4. https://doi.org/10.1186/s13008-016-0013-6

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. 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(5):888–895. https://doi.org/10.1016/j.devcel.2011.08.028

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. 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(5):896–906. https://doi.org/10.1016/j.devcel.2011.09.012

    Article  PubMed  CAS  Google Scholar 

  54. Plouffe SW, Meng Z, Lin KC, Lin B, Hong AW, Chun JV, Guan KL (2016) Characterization of Hippo pathway components by gene inactivation. Mol Cell 64(5):993–1008. https://doi.org/10.1016/j.molcel.2016.10.034

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Li Q, Li S, Mana-Capelli S, Roth Flach RJ, Danai LV, Amcheslavsky A, Nie Y, Kaneko S, Yao X, Chen X, Cotton JL, Mao J, McCollum D, Jiang J, Czech MP, Xu L, Ip YT (2014) The conserved misshapen-warts-Yorkie pathway acts in enteroblasts to regulate intestinal stem cells in Drosophila. Dev Cell 31(3):291–304. https://doi.org/10.1016/j.devcel.2014.09.012

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Mohseni M, Sun J, Lau A, Curtis S, Goldsmith J, Fox VL, Wei C, Frazier M, Samson O, Wong KK, Kim C, Camargo FD (2014) A genetic screen identifies an LKB1-MARK signalling axis controlling the Hippo-YAP pathway. Nat Cell Biol 16(1):108–117. https://doi.org/10.1038/ncb2884

    Article  PubMed  CAS  Google Scholar 

  57. 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(6):642–655. https://doi.org/10.1016/j.devcel.2015.08.014

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Meng Z, Moroishi T, Mottier-Pavie V, Plouffe SW, Hansen CG, Hong AW, Park HW, Mo JS, Lu W, Lu S, Flores F, Yu FX, Halder G, Guan KL (2015) MAP4K family kinases act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway. Nat Commun 6:8357. https://doi.org/10.1038/ncomms9357

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Rodriguez-Boulan E, Macara IG (2014) Organization and execution of the epithelial polarity programme. Nat Rev Mol Cell Biol 15(4):225–242. https://doi.org/10.1038/nrm3775

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Zecca M, Struhl G (2010) A feed-forward circuit linking wingless, fat-dachsous signaling, and the warts-hippo pathway to Drosophila wing growth. PLoS Biol 8(6):e1000386. https://doi.org/10.1371/journal.pbio.1000386

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Vrabioiu AM, Struhl G (2015) Fat/Dachsous signaling promotes drosophila wing growth by regulating the conformational state of the NDR kinase warts. Dev Cell 35(6):737–749. https://doi.org/10.1016/j.devcel.2015.11.027

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Renfranz PJ, Siegrist SE, Stronach BE, Macalma T, Beckerle MC (2003) Molecular and phylogenetic characterization of Zyx102, a Drosophila orthologue of the zyxin family that interacts with Drosophila Enabled. Gene 305(1):13–26

    Article  PubMed  CAS  Google Scholar 

  63. Rauskolb C, Pan G, Reddy BV, Oh H, Irvine KD (2011) Zyxin links fat signaling to the hippo pathway. PLoS Biol 9(6):e1000624. https://doi.org/10.1371/journal.pbio.1000624

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Chen CL, Gajewski KM, Hamaratoglu F, Bossuyt W, Sansores-Garcia L, Tao C, Halder G (2010) The apical-basal cell polarity determinant Crumbs regulates Hippo signaling in Drosophila. Proc Natl Acad Sci USA 107(36):15810–15815. https://doi.org/10.1073/pnas.1004060107

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Grzeschik NA, Parsons LM, Allott ML, Harvey KF, Richardson HE (2010) Lgl, aPKC, and Crumbs regulate the Salvador/Warts/Hippo pathway through two distinct mechanisms. Curr Biol 20(7):573–581. https://doi.org/10.1016/j.cub.2010.01.055

    Article  PubMed  CAS  Google Scholar 

  66. Ling C, Zheng Y, Yin F, Yu J, Huang J, Hong Y, Wu S, Pan D (2010) The apical transmembrane protein Crumbs functions as a tumor suppressor that regulates Hippo signaling by binding to Expanded. Proc Natl Acad Sci USA 107(23):10532–10537. https://doi.org/10.1073/pnas.1004279107

    Article  PubMed  PubMed Central  Google Scholar 

  67. Robinson BS, Huang J, Hong Y, Moberg KH (2010) Crumbs regulates Salvador/Warts/Hippo signaling in Drosophila via the FERM-domain protein Expanded. Curr Biol 20(7):582–590. https://doi.org/10.1016/j.cub.2010.03.019

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. McCartney BM, Kulikauskas RM, LaJeunesse DR, Fehon RG (2000) The neurofibromatosis-2 homologue, Merlin, and the tumor suppressor expanded function together in Drosophila to regulate cell proliferation and differentiation. Development 127(6):1315–1324

    PubMed  CAS  Google Scholar 

  69. Badouel C, Gardano L, Amin N, Garg A, Rosenfeld R, Le Bihan T, McNeill H (2009) The FERM-domain protein Expanded regulates Hippo pathway activity via direct interactions with the transcriptional activator Yorkie. Dev Cell 16(3):411–420. https://doi.org/10.1016/j.devcel.2009.01.010

    Article  PubMed  CAS  Google Scholar 

  70. Ribeiro P, Holder M, Frith D, Snijders AP, Tapon N (2014) Crumbs promotes expanded recognition and degradation by the SCF(Slimb/beta-TrCP) ubiquitin ligase. Proc Natl Acad Sci USA 111(19):E1980–1989. https://doi.org/10.1073/pnas.1315508111

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Baumgartner R, Poernbacher I, Buser N, Hafen E, Stocker H (2010) The WW domain protein Kibra acts upstream of Hippo in Drosophila. Dev Cell 18(2):309–316. https://doi.org/10.1016/j.devcel.2009.12.013

    Article  PubMed  CAS  Google Scholar 

  72. 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(2):300–308. https://doi.org/10.1016/j.devcel.2009.12.011

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Yu J, Zheng Y, Dong J, Klusza S, Deng WM, Pan D (2010) Kibra functions as a tumor suppressor protein that regulates Hippo signaling in conjunction with Merlin and Expanded. Dev Cell 18(2):288–299. https://doi.org/10.1016/j.devcel.2009.12.012

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Zhou PJ, Xue W, Peng J, Wang Y, Wei L, Yang Z, Zhu HH, Fang YX, Gao WQ (2017) Elevated expression of Par3 promotes prostate cancer metastasis by forming a Par3/aPKC/KIBRA complex and inactivating the hippo pathway. J Exp Clin Cancer Res 36(1):139. https://doi.org/10.1186/s13046-017-0609-y

    Article  PubMed  PubMed Central  Google Scholar 

  75. Bratt A, Wilson WJ, Troyanovsky B, Aase K, Kessler R, Van Meir EG, Holmgren L (2002) Angiomotin belongs to a novel protein family with conserved coiled-coil and PDZ binding domains. Gene 298(1):69–77

    Article  PubMed  CAS  Google Scholar 

  76. Sugihara-Mizuno Y, Adachi M, Kobayashi Y, Hamazaki Y, Nishimura M, Imai T, Furuse M, Tsukita S (2007) Molecular characterization of angiomotin/JEAP family proteins: interaction with MUPP1/Patj and their endogenous properties. Genes Cells 12(4):473–486. https://doi.org/10.1111/j.1365-2443.2007.01066.x

    Article  PubMed  CAS  Google Scholar 

  77. Wells CD, Fawcett JP, Traweger A, Yamanaka Y, Goudreault M, Elder K, Kulkarni S, Gish G, Virag C, Lim C, Colwill K, Starostine A, Metalnikov P, Pawson T (2006) A Rich1/Amot complex regulates the Cdc42 GTPase and apical-polarity proteins in epithelial cells. Cell 125(3):535–548. https://doi.org/10.1016/j.cell.2006.02.045

    Article  PubMed  CAS  Google Scholar 

  78. Zhao B, Li L, Lu Q, Wang LH, Liu CY, Lei Q, Guan KL (2011) Angiomotin is a novel Hippo pathway component that inhibits YAP oncoprotein. Genes Dev 25(1):51–63. https://doi.org/10.1101/gad.2000111

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Chan SW, Lim CJ, Chong YF, Pobbati AV, Huang C, Hong W (2011) Hippo pathway-independent restriction of TAZ and YAP by angiomotin. J Biol Chem 286(9):7018–7026. https://doi.org/10.1074/jbc.C110.212621

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Wang W, Huang J, Chen J (2011) Angiomotin-like proteins associate with and negatively regulate YAP1. J Biol Chem 286(6):4364–4370. https://doi.org/10.1074/jbc.C110.205401

    Article  PubMed  CAS  Google Scholar 

  81. Paramasivam M, Sarkeshik A, Yates JR 3rd, Fernandes MJ, McCollum D (2011) Angiomotin family proteins are novel activators of the LATS2 kinase tumor suppressor. Mol Biol Cell 22(19):3725–3733. https://doi.org/10.1091/mbc.E11-04-0300

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Cordenonsi M, Zanconato F, Azzolin L, Forcato M, Rosato A, Frasson C, Inui M, Montagner M, Parenti AR, Poletti A, Daidone MG, Dupont S, Basso G, Bicciato S, Piccolo S (2011) The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells. Cell 147(4):759–772. https://doi.org/10.1016/j.cell.2011.09.048

    Article  PubMed  CAS  Google Scholar 

  83. Oka T, Remue E, Meerschaert K, Vanloo B, Boucherie C, Gfeller D, Bader GD, Sidhu SS, Vandekerckhove J, Gettemans J, Sudol M (2010) Functional complexes between YAP2 and ZO-2 are PDZ domain-dependent, and regulate YAP2 nuclear localization and signalling. Biochem J 432(3):461–472. https://doi.org/10.1042/BJ20100870

    Article  PubMed  CAS  Google Scholar 

  84. Remue E, Meerschaert K, Oka T, Boucherie C, Vandekerckhove J, Sudol M, Gettemans J (2010) TAZ interacts with zonula occludens-1 and -2 proteins in a PDZ-1 dependent manner. FEBS Lett 584(19):4175–4180. https://doi.org/10.1016/j.febslet.2010.09.020

    Article  PubMed  CAS  Google Scholar 

  85. Kobielak A, Fuchs E (2004) Alpha-catenin: at the junction of intercellular adhesion and actin dynamics. Nat Rev Mol Cell Biol 5(8):614–625. https://doi.org/10.1038/nrm1433

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Schlegelmilch K, Mohseni M, Kirak O, Pruszak J, Rodriguez JR, Zhou D, Kreger BT, Vasioukhin V, Avruch J, Brummelkamp TR, Camargo FD (2011) Yap1 acts downstream of alpha-catenin to control epidermal proliferation. Cell 144(5):782–795. https://doi.org/10.1016/j.cell.2011.02.031

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Silvis MR, Kreger BT, Lien WH, Klezovitch O, Rudakova GM, Camargo FD, Lantz DM, Seykora JT, Vasioukhin V (2011) Alpha-catenin is a tumor suppressor that controls cell accumulation by regulating the localization and activity of the transcriptional coactivator Yap1. Sci Signal 4(174):ra33. https://doi.org/10.1126/scisignal.2001823

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Kim NG, Koh E, Chen X, Gumbiner BM (2011) E-cadherin mediates contact inhibition of proliferation through Hippo signaling-pathway components. Proc Natl Acad Sci USA 108(29):11930–11935. https://doi.org/10.1073/pnas.1103345108

    Article  PubMed  PubMed Central  Google Scholar 

  89. Huang JM, Nagatomo I, Suzuki E, Mizuno T, Kumagai T, Berezov A, Zhang H, Karlan B, Greene MI, Wang Q (2013) YAP modifies cancer cell sensitivity to EGFR and survivin inhibitors and is negatively regulated by the non-receptor type protein tyrosine phosphatase 14. Oncogene 32(17):2220–2229. https://doi.org/10.1038/onc.2012.231

    Article  PubMed  CAS  Google Scholar 

  90. Liu X, Yang N, Figel SA, Wilson KE, Morrison CD, Gelman IH, Zhang J (2013) PTPN14 interacts with and negatively regulates the oncogenic function of YAP. Oncogene 32(10):1266–1273. https://doi.org/10.1038/onc.2012.147

    Article  PubMed  CAS  Google Scholar 

  91. Michaloglou C, Lehmann W, Martin T, Delaunay C, Hueber A, Barys L, Niu H, Billy E, Wartmann M, Ito M, Wilson CJ, Digan ME, Bauer A, Voshol H, Christofori G, Sellers WR, Hofmann F, Schmelzle T (2013) The tyrosine phosphatase PTPN14 is a negative regulator of YAP activity. PLoS One 8(4):e61916. https://doi.org/10.1371/journal.pone.0061916

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Wang W, Huang J, Wang X, Yuan J, Li X, Feng L, Park JI, Chen J (2012) PTPN14 is required for the density-dependent control of YAP1. Genes Dev 26(17):1959–1971. https://doi.org/10.1101/gad.192955.112

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Hodge RG, Ridley AJ (2016) Regulating Rho GTPases and their regulators. Nat Rev Mol Cell Biol 17(8):496–510. https://doi.org/10.1038/nrm.2016.67

    Article  PubMed  CAS  Google Scholar 

  94. Zhao B, Li L, Wang L, Wang CY, Yu J, Guan KL (2012) Cell detachment activates the Hippo pathway via cytoskeleton reorganization to induce anoikis. Genes Dev 26(1):54–68. https://doi.org/10.1101/gad.173435.111

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Dupont S, Morsut L, Aragona M, Enzo E, Giulitti S, Cordenonsi M, Zanconato F, Le Digabel J, Forcato M, Bicciato S, Elvassore N, Piccolo S (2011) Role of YAP/TAZ in mechanotransduction. Nature 474(7350):179–183. https://doi.org/10.1038/nature10137

    Article  PubMed  CAS  Google Scholar 

  96. Yu FX, Zhao B, Panupinthu N, Jewell JL, Lian I, Wang LH, Zhao J, Yuan H, Tumaneng K, Li H, Fu XD, Mills GB, Guan KL (2012) Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling. Cell 150(4):780–791. https://doi.org/10.1016/j.cell.2012.06.037

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Wang Z, Liu P, Zhou X, Wang TX, Feng X, Sun YP, Xiong Y, Yuan HX, Guan KL (2017) Endothelin promotes colorectal tumorigenesis by activating YAP/TAZ. Cancer Res 77(9):2413–2423. https://doi.org/10.1158/0008-5472.Can-16-3229

    Article  PubMed  CAS  Google Scholar 

  98. Zhou X, Wang SY, Wang Z, Feng X, Liu P, Lv XB, Li FL, Yu FX, Sun YP, Yuan HX, Zhu HG, Xiong Y, Lei QY, Guan KL (2015) Estrogen regulates Hippo signaling via GPER in breast cancer. J Clin Investig 125(5):2123–2135. https://doi.org/10.1172/Jci79573

    Article  PubMed  PubMed Central  Google Scholar 

  99. Yu FX, Luo J, Mo JS, Liu GB, Kim YC, Meng ZP, Zhao L, Peyman G, Ouyang H, Jiang W, Zhao JG, Chen X, Zhang LF, Wang CY, Bastian BC, Zhang K, Guan KL (2014) Mutant Gq/11 promote uveal melanoma tumorigenesis by activating YAP. Cancer Cell 25(6):822–830. https://doi.org/10.1016/j.ccr.2014.04.017

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Feng XD, Degese MS, Iglesias-Bartolome R, Vaque JP, Molinolo AA, Rodrigues M, Zaidi MR, Ksander BR, Merlino G, Sodhi A, Chen QM, Gutkind JS (2014) Hippo-independent activation of YAP by the GNAQ uveal melanoma oncogene through a trio-regulated Rho GTPase signaling circuitry. Cancer Cell 25(6):831–845. https://doi.org/10.1016/j.ccr.2014.04.016

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Yu FX, Zhang Y, Park HW, Jewell JL, Chen Q, Deng Y, Pan D, Taylor SS, Lai ZC, Guan KL (2013) Protein kinase A activates the Hippo pathway to modulate cell proliferation and differentiation. Genes Dev 27(11):1223–1232. https://doi.org/10.1101/gad.219402.113

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Kim M, Kim M, Lee S, Kuninaka S, Saya H, Lee H, Lee S, Lim DS (2013) cAMP/PKA signalling reinforces the LATS-YAP pathway to fully suppress YAP in response to actin cytoskeletal changes. EMBO J 32(11):1543–1555. https://doi.org/10.1038/emboj.2013.102

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Fernandez BG, Gaspar P, Bras-Pereira C, Jezowska B, Rebelo SR, Janody F (2011) Actin-capping protein and the Hippo pathway regulate F-actin and tissue growth in Drosophila. Development 138(11):2337–2346. https://doi.org/10.1242/dev.063545

    Article  PubMed  CAS  Google Scholar 

  104. Sansores-Garcia L, Bossuyt W, Wada K, Yonemura S, Tao C, Sasaki H, Halder G (2011) Modulating F-actin organization induces organ growth by affecting the Hippo pathway. EMBO J 30(12):2325–2335. https://doi.org/10.1038/emboj.2011.157

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Imajo M, Miyatake K, Iimura A, Miyamoto A, Nishida E (2012) A molecular mechanism that links Hippo signalling to the inhibition of Wnt/beta-catenin signalling. EMBO J 31(5):1109–1122. https://doi.org/10.1038/emboj.2011.487

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Azzolin L, Panciera T, Soligo S, Enzo E, Bicciato S, Dupont S, Bresolin S, Frasson C, Basso G, Guzzardo V, Fassina A, Cordenonsi M, Piccolo S (2014) YAP/TAZ incorporation in the beta-catenin destruction complex orchestrates the Wnt response. Cell 158(1):157–170. https://doi.org/10.1016/j.cell.2014.06.013

    Article  PubMed  CAS  Google Scholar 

  107. Azzolin L, Zanconato F, Bresolin S, Forcato M, Basso G, Bicciato S, Cordenonsi M, Piccolo S (2012) Role of TAZ as mediator of Wnt signaling. Cell 151(7):1443–1456. https://doi.org/10.1016/j.cell.2012.11.027

    Article  PubMed  CAS  Google Scholar 

  108. Liang N, Zhang C, Dill P, Panasyuk G, Pion D, Koka V, Gallazzini M, Olson EN, Lam H, Henske EP, Dong Z, Apte U, Pallet N, Johnson RL, Terzi F, Kwiatkowski DJ, Scoazec JY, Martignoni G, Pende M (2014) Regulation of YAP by mTOR and autophagy reveals a therapeutic target of tuberous sclerosis complex. J Exp Med 211(11):2249–2263. https://doi.org/10.1084/jem.20140341

    Article  PubMed  PubMed Central  Google Scholar 

  109. Tumaneng K, Schlegelmilch K, Russell RC, Yimlamai D, Basnet H, Mahadevan N, Fitamant J, Bardeesy N, Camargo FD, Guan KL (2012) YAP mediates crosstalk between the Hippo and PI(3)K-TOR pathways by suppressing PTEN via miR-29. Nat Cell Biol 14(12):1322–1329. https://doi.org/10.1038/ncb2615

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Hansen CG, Ng YL, Lam WL, Plouffe SW, Guan KL (2015) The Hippo pathway effectors YAP and TAZ promote cell growth by modulating amino acid signaling to mTORC1. Cell Res 25(12):1299–1313. https://doi.org/10.1038/cr.2015.140

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Strassburger K, Tiebe M, Pinna F, Breuhahn K, Teleman AA (2012) Insulin/IGF signaling drives cell proliferation in part via Yorkie/YAP. Dev Biol 367(2):187–196. https://doi.org/10.1016/j.ydbio.2012.05.008

    Article  PubMed  CAS  Google Scholar 

  112. Sun G, Irvine KD (2013) Ajuba family proteins link JNK to Hippo signaling. Sci Signal 6(292):ra81. https://doi.org/10.1126/scisignal.2004324

    Article  PubMed  CAS  Google Scholar 

  113. Tomlinson V, Gudmundsdottir K, Luong P, Leung KY, Knebel A, Basu S (2010) JNK phosphorylates Yes-associated protein (YAP) to regulate apoptosis. Cell Death Dis 1:e29. https://doi.org/10.1038/cddis.2010.7

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Lee KK, Yonehara S (2012) Identification of mechanism that couples multisite phosphorylation of Yes-associated protein (YAP) with transcriptional coactivation and regulation of apoptosis. J Biol Chem 287(12):9568–9578. https://doi.org/10.1074/jbc.M111.296954

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Lin KC, Moroishi T, Meng Z, Jeong HS, Plouffe SW, Sekido Y, Han J, Park HW, Guan KL (2017) Regulation of Hippo pathway transcription factor TEAD by p38 MAPK-induced cytoplasmic translocation. Nat Cell Biol 19(8):996–1002. https://doi.org/10.1038/ncb3581

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Hong AW, Meng Z, Yuan HX, Plouffe SW, Moon S, Kim W, Jho EH, Guan KL (2017) Osmotic stress-induced phosphorylation by NLK at Ser128 activates YAP. EMBO Rep 18(1):72–86. https://doi.org/10.15252/embr.201642681

    Article  PubMed  CAS  Google Scholar 

  117. Moon S, Kim W, Kim S, Kim Y, Song Y, Bilousov O, Kim J, Lee T, Cha B, Kim M, Kim H, Katanaev VL, Jho EH (2017) Phosphorylation by NLK inhibits YAP-14-3-3-interactions and induces its nuclear localization. EMBO Rep 18(1):61–71. https://doi.org/10.15252/embr.201642683

    Article  PubMed  CAS  Google Scholar 

  118. Ganem NJ, Cornils H, Chiu SY, O’Rourke KP, Arnaud J, Yimlamai D, Thery M, Camargo FD, Pellman D (2014) Cytokinesis failure triggers hippo tumor suppressor pathway activation. Cell 158(4):833–848. https://doi.org/10.1016/j.cell.2014.06.029

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Zhao B, Wei X, Li W, Udan RS, Yang Q, Kim J, Xie J, Ikenoue T, Yu J, Li L, Zheng P, Ye K, Chinnaiyan A, Halder G, Lai ZC, Guan KL (2007) Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev 21(21):2747–2761. https://doi.org/10.1101/gad.1602907

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Driscoll TP, Cosgrove BD, Heo SJ, Shurden ZE, Mauck RL (2015) Cytoskeletal to nuclear strain transfer regulates YAP signaling in mesenchymal stem cells. Biophys J 108(12):2783–2793. https://doi.org/10.1016/j.bpj.2015.05.010

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Wada K, Itoga K, Okano T, Yonemura S, Sasaki H (2011) Hippo pathway regulation by cell morphology and stress fibers. Development 138(18):3907–3914. https://doi.org/10.1242/dev.070987

    Article  PubMed  CAS  Google Scholar 

  122. Aragona M, Panciera T, Manfrin A, Giulitti S, Michielin F, Elvassore N, Dupont S, Piccolo S (2013) A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factors. Cell 154(5):1047–1059. https://doi.org/10.1016/j.cell.2013.07.042

    Article  PubMed  CAS  Google Scholar 

  123. Codelia VA, Sun G, Irvine KD (2014) Regulation of YAP by mechanical strain through Jnk and Hippo signaling. Curr Biol 24(17):2012–2017. https://doi.org/10.1016/j.cub.2014.07.034

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Kim MH, Kim J (2017) Role of YAP/TAZ transcriptional regulators in resistance to anti-cancer therapies. Cell Mol Life Sci 74(8):1457–1474. https://doi.org/10.1007/s00018-016-2412-x

    Article  PubMed  CAS  Google Scholar 

  125. Zanconato F, Cordenonsi M, Piccolo S (2016) YAP/TAZ at the roots of cancer. Cancer Cell 29(6):783–803. https://doi.org/10.1016/j.ccell.2016.05.005

    Article  PubMed  CAS  Google Scholar 

  126. Camargo FD, Gokhale S, Johnnidis JB, Fu D, Bell GW, Jaenisch R, Brummelkamp TR (2007) YAP1 increases organ size and expands undifferentiated progenitor cells. Curr Biol 17(23):2054–2060. https://doi.org/10.1016/j.cub.2007.10.039

    Article  PubMed  CAS  Google Scholar 

  127. Lee JH, Kim TS, Yang TH, Koo BK, Oh SP, Lee KP, Oh HJ, Lee SH, Kong YY, Kim JM, Lim DS (2008) A crucial role of WW45 in developing epithelial tissues in the mouse. EMBO J 27(8):1231–1242. https://doi.org/10.1038/emboj.2008.63

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  128. Zhou D, Zhang Y, Wu H, Barry E, Yin Y, Lawrence E, Dawson D, Willis JE, Markowitz SD, Camargo FD, Avruch J (2011) Mst1 and Mst2 protein kinases restrain intestinal stem cell proliferation and colonic tumorigenesis by inhibition of Yes-associated protein (Yap) overabundance. Proc Natl Acad Sci USA 108(49):E1312–1320. https://doi.org/10.1073/pnas.1110428108

    Article  PubMed  PubMed Central  Google Scholar 

  129. Lee KP, Lee JH, Kim TS, Kim TH, Park HD, Byun JS, Kim MC, Jeong WI, Calvisi DF, Kim JM, Lim DS (2010) The Hippo-Salvador pathway restrains hepatic oval cell proliferation, liver size, and liver tumorigenesis. Proc Natl Acad Sci USA 107(18):8248–8253. https://doi.org/10.1073/pnas.0912203107

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Cai J, Maitra A, Anders RA, Taketo MM, Pan D (2015) beta-Catenin destruction complex-independent regulation of Hippo-YAP signaling by APC in intestinal tumorigenesis. Genes Dev 29(14):1493–1506. https://doi.org/10.1101/gad.264515.115

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Lin L, Sabnis AJ, Chan E, Olivas V, Cade L, Pazarentzos E, Asthana S, Neel D, Yan JJ, Lu X, Pham L, Wang MM, Karachaliou N, Cao MG, Manzano JL, Ramirez JL, Torres JM, Buttitta F, Rudin CM, Collisson EA, Algazi A, Robinson E, Osman I, Munoz-Couselo E, Cortes J, Frederick DT, Cooper ZA, McMahon M, Marchetti A, Rosell R, Flaherty KT, Wargo JA, Bivona TG (2015) The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies. Nat Genet 47(3):250–256. https://doi.org/10.1038/ng.3218

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Lin KC, Park HW, Guan KL (2017) Regulation of the Hippo pathway transcription factor TEAD. Trends Biochem Sci 42(11):862–872. https://doi.org/10.1016/j.tibs.2017.09.003

    Article  PubMed  CAS  Google Scholar 

  133. Hirabayashi S, Cagan RL (2015) Salt-inducible kinases mediate nutrient-sensing to link dietary sugar and tumorigenesis in Drosophila. Elife 4:e08501. https://doi.org/10.7554/eLife.08501

    Article  PubMed  PubMed Central  Google Scholar 

  134. Ohsawa S, Sato Y, Enomoto M, Nakamura M, Betsumiya A, Igaki T (2012) Mitochondrial defect drives non-autonomous tumour progression through Hippo signalling in Drosophila. Nature 490(7421):547–551. https://doi.org/10.1038/nature11452

    Article  PubMed  CAS  Google Scholar 

  135. Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324(5930):1029–1033. https://doi.org/10.1126/science.1160809

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  136. Pavlova NN, Thompson CB (2016) The emerging hallmarks of cancer metabolism. Cell Metab 23(1):27–47. https://doi.org/10.1016/j.cmet.2015.12.006

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. DeRan M, Yang J, Shen CH, Peters EC, Fitamant J, Chan P, Hsieh M, Zhu S, Asara JM, Zheng B, Bardeesy N, Liu J, Wu X (2014) Energy stress regulates hippo-YAP signaling involving AMPK-mediated regulation of angiomotin-like 1 protein. Cell Rep 9(2):495–503. https://doi.org/10.1016/j.celrep.2014.09.036

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  138. Mo JS, Meng Z, Kim YC, Park HW, Hansen CG, Kim S, Lim DS, Guan KL (2015) Cellular energy stress induces AMPK-mediated regulation of YAP and the Hippo pathway. Nat Cell Biol 17(4):500–510. https://doi.org/10.1038/ncb3111

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  139. Wang W, Xiao ZD, Li X, Aziz KE, Gan B, Johnson RL, Chen J (2015) AMPK modulates Hippo pathway activity to regulate energy homeostasis. Nat Cell Biol 17(4):490–499. https://doi.org/10.1038/ncb3113

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  140. Enzo E, Santinon G, Pocaterra A, Aragona M, Bresolin S, Forcato M, Grifoni D, Pession A, Zanconato F, Guzzo G, Bicciato S, Dupont S (2015) Aerobic glycolysis tunes YAP/TAZ transcriptional activity. EMBO J 34(10):1349–1370. https://doi.org/10.15252/embj.201490379

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Gailite I, Aerne BL, Tapon N (2015) Differential control of Yorkie activity by LKB1/AMPK and the Hippo/Warts cascade in the central nervous system. Proc Natl Acad Sci USA 112(37):E5169–5178. https://doi.org/10.1073/pnas.1505512112

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  142. Wehr MC, Holder MV, Gailite I, Saunders RE, Maile TM, Ciirdaeva E, Instrell R, Jiang M, Howell M, Rossner MJ, Tapon N (2013) Salt-inducible kinases regulate growth through the Hippo signalling pathway in Drosophila. Nat Cell Biol 15(1):61–71. https://doi.org/10.1038/ncb2658

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  143. Peng C, Zhu Y, Zhang W, Liao Q, Chen Y, Zhao X, Guo Q, Shen P, Zhen B, Qian X, Yang D, Zhang JS, Xiao D, Qin W, Pei H (2017) Regulation of the Hippo-YAP pathway by glucose sensor O-GlcNAcylation. Mol Cell 68(3):591–604 e595. https://doi.org/10.1016/j.molcel.2017.10.010

    Article  PubMed  CAS  Google Scholar 

  144. Zhang X, Qiao Y, Wu Q, Chen Y, Zou S, Liu X, Zhu G, Zhao Y, Chen Y, Yu Y, Pan Q, Wang J, Sun F (2017) The essential role of YAP O-GlcNAcylation in high-glucose-stimulated liver tumorigenesis. Nat Commun 8:15280. https://doi.org/10.1038/ncomms15280

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Sorrentino G, Ruggeri N, Specchia V, Cordenonsi M, Mano M, Dupont S, Manfrin A, Ingallina E, Sommaggio R, Piazza S, Rosato A, Piccolo S, Del Sal G (2014) Metabolic control of YAP and TAZ by the mevalonate pathway. Nat Cell Biol 16(4):357–366. https://doi.org/10.1038/ncb2936

    Article  PubMed  CAS  Google Scholar 

  146. Wang Z, Wu Y, Wang H, Zhang Y, Mei L, Fang X, Zhang X, Zhang F, Chen H, Liu Y, Jiang Y, Sun S, Zheng Y, Li N, Huang L (2014) Interplay of mevalonate and Hippo pathways regulates RHAMM transcription via YAP to modulate breast cancer cell motility. Proc Natl Acad Sci USA 111(1):E89–98. https://doi.org/10.1073/pnas.1319190110

    Article  PubMed  CAS  Google Scholar 

  147. Cox AG, Hwang KL, Brown KK, Evason K, Beltz S, Tsomides A, O’Connor K, Galli GG, Yimlamai D, Chhangawala S, Yuan M, Lien EC, Wucherpfennig J, Nissim S, Minami A, Cohen DE, Camargo FD, Asara JM, Houvras Y, Stainier DYR, Goessling W (2016) Yap reprograms glutamine metabolism to increase nucleotide biosynthesis and enable liver growth. Nat Cell Biol 18(8):886–896. https://doi.org/10.1038/ncb3389

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  148. Guo X, Zhao Y, Yan H, Yang Y, Shen S, Dai X, Ji X, Ji F, Gong XG, Li L, Bai X, Feng XH, Liang T, Ji J, Chen L, Wang H, Zhao B (2017) Single tumor-initiating cells evade immune clearance by recruiting type II macrophages. Genes Dev 31(3):247–259. https://doi.org/10.1101/gad.294348.116

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  149. Wang G, Lu X, Dey P, Deng P, Wu CC, Jiang S, Fang Z, Zhao K, Konaparthi R, Hua S, Zhang J, Li-Ning-Tapia EM, Kapoor A, Wu CJ, Patel NB, Guo Z, Ramamoorthy V, Tieu TN, Heffernan T, Zhao D, Shang X, Khadka S, Hou P, Hu B, Jin EJ, Yao W, Pan X, Ding Z, Shi Y, Li L, Chang Q, Troncoso P, Logothetis CJ, McArthur MJ, Chin L, Wang YA, DePinho RA (2016) Targeting YAP-dependent MDSC infiltration impairs tumor progression. Cancer Discov 6(1):80–95. https://doi.org/10.1158/2159-8290.CD-15-0224

    Article  PubMed  CAS  Google Scholar 

  150. Liu B, Zheng Y, Yin F, Yu J, Silverman N, Pan D (2016) Toll receptor-mediated Hippo signaling controls innate immunity in Drosophila. Cell 164(3):406–419. https://doi.org/10.1016/j.cell.2015.12.029

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  151. Moroishi T, Hayashi T, Pan WW, Fujita Y, Holt MV, Qin J, Carson DA, Guan KL (2016) The Hippo pathway kinases LATS1/2 suppress cancer immunity. Cell 167(6):1525–1539 e1517. https://doi.org/10.1016/j.cell.2016.11.005

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Meng F, Zhou R, Wu S, Zhang Q, Jin Q, Zhou Y, Plouffe SW, Liu S, Song H, Xia Z, Zhao B, Ye S, Feng XH, Guan KL, Zou J, Xu P (2016) Mst1 shuts off cytosolic antiviral defense through IRF3 phosphorylation. Genes Dev 30(9):1086–1100. https://doi.org/10.1101/gad.277533.116

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  153. Zhang Q, Meng F, Chen S, Plouffe SW, Wu S, Liu S, Li X, Zhou R, Wang J, Zhao B, Liu J, Qin J, Zou J, Feng XH, Guan KL, Xu P (2017) Hippo signalling governs cytosolic nucleic acid sensing through YAP/TAZ-mediated TBK1 blockade. Nat Cell Biol 19(4):362–374. https://doi.org/10.1038/ncb3496

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  154. Lee BS, Park DI, Lee DH, Lee JE, Yeo MK, Park YH, Lim DS, Choi W, Lee DH, Yoo G, Kim HB, Kang D, Moon JY, Jung SS, Kim JO, Cho SY, Park HS, Chung C (2017) Hippo effector YAP directly regulates the expression of PD-L1 transcripts in EGFR-TKI-resistant lung adenocarcinoma. Biochem Biophys Res Commun 491(2):493–499. https://doi.org/10.1016/j.bbrc.2017.07.007

    Article  PubMed  CAS  Google Scholar 

  155. Feng J, Yang H, Zhang Y, Wei H, Zhu Z, Zhu B, Yang M, Cao W, Wang L, Wu Z (2017) Tumor cell-derived lactate induces TAZ-dependent upregulation of PD-L1 through GPR81 in human lung cancer cells. Oncogene 36(42):5829–5839. https://doi.org/10.1038/onc.2017.188

    Article  PubMed  CAS  Google Scholar 

  156. Thaventhiran JE, Hoffmann A, Magiera L, de la Roche M, Lingel H, Brunner-Weinzierl M, Fearon DT (2012) Activation of the Hippo pathway by CTLA-4 regulates the expression of Blimp-1 in the CD8+ T cell. Proc Natl Acad Sci USA 109(33):E2223–2229. https://doi.org/10.1073/pnas.1209115109

    Article  PubMed  PubMed Central  Google Scholar 

  157. Geng J, Yu S, Zhao H, Sun X, Li X, Wang P, Xiong X, Hong L, Xie C, Gao J, Shi Y, Peng J, Johnson RL, Xiao N, Lu L, Han J, Zhou D, Chen L (2017) The transcriptional coactivator TAZ regulates reciprocal differentiation of TH17 cells and Treg cells. Nat Immunol 18(7):800–812. https://doi.org/10.1038/ni.3748

    Article  PubMed  CAS  Google Scholar 

  158. Zhou D, Medoff BD, Chen L, Li L, Zhang XF, Praskova M, Liu M, Landry A, Blumberg RS, Boussiotis VA, Xavier R, Avruch J (2008) The Nore1B/Mst1 complex restrains antigen receptor-induced proliferation of naive T cells. Proc Natl Acad Sci USA 105(51):20321–20326. https://doi.org/10.1073/pnas.0810773105

    Article  PubMed  PubMed Central  Google Scholar 

  159. Li C, Bi Y, Li Y, Yang H, Yu Q, Wang J, Wang Y, Su H, Jia A, Hu Y, Han L, Zhang J, Li S, Tao W, Liu G (2017) Dendritic cell MST1 inhibits Th17 differentiation. Nat Commun 8:14275. https://doi.org/10.1038/ncomms14275

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  160. Jansson L, Larsson J (2012) Normal hematopoietic stem cell function in mice with enforced expression of the Hippo signaling effector YAP1. PLoS One 7(2):e32013. https://doi.org/10.1371/journal.pone.0032013

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  161. Liu-Chittenden Y, Huang B, Shim JS, Chen Q, Lee SJ, Anders RA, Liu JO, Pan D (2012) Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP. Genes Dev 26(12):1300–1305. https://doi.org/10.1101/gad.192856.112

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  162. Dasari VR, Mazack V, Feng W, Nash J, Carey DJ, Gogoi R (2017) Verteporfin exhibits YAP-independent anti-proliferative and cytotoxic effects in endometrial cancer cells. Oncotarget 8(17):28628–28640. https://doi.org/10.18632/oncotarget.15614

    Article  PubMed  PubMed Central  Google Scholar 

  163. Chen HH, Mullett SJ, Stewart AF (2004) Vgl-4, a novel member of the vestigial-like family of transcription cofactors, regulates alpha1-adrenergic activation of gene expression in cardiac myocytes. J Biol Chem 279(29):30800–30806. https://doi.org/10.1074/jbc.M400154200

    Article  PubMed  CAS  Google Scholar 

  164. Jiao S, Li C, Hao Q, Miao H, Zhang L, Li L, Zhou Z (2017) VGLL4 targets a TCF4–TEAD4 complex to coregulate Wnt and Hippo signalling in colorectal cancer. Nat Commun 8:14058. https://doi.org/10.1038/ncomms14058

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  165. Zhou Z, Hu T, Xu Z, Lin Z, Zhang Z, Feng T, Zhu L, Rong Y, Shen H, Luk JM, Zhang X, Qin N (2015) Targeting Hippo pathway by specific interruption of YAP–TEAD interaction using cyclic YAP-like peptides. FASEB J 29(2):724–732. https://doi.org/10.1096/fj.14-262980

    Article  PubMed  CAS  Google Scholar 

  166. Pobbati AV, Han X, Hung AW, Weiguang S, Huda N, Chen GY, Kang C, Chia CS, Luo X, Hong W, Poulsen A (2015) Targeting the central pocket in human transcription factor TEAD as a potential cancer therapeutic strategy. Structure 23(11):2076–2086. https://doi.org/10.1016/j.str.2015.09.009

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  167. Chan P, Han X, Zheng B, DeRan M, Yu J, Jarugumilli GK, Deng H, Pan D, Luo X, Wu X (2016) Autopalmitoylation of TEAD proteins regulates transcriptional output of the Hippo pathway. Nat Chem Biol 12(4):282–289. https://doi.org/10.1038/nchembio.2036

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  168. Noland CL, Gierke S, Schnier PD, Murray J, Sandoval WN, Sagolla M, Dey A, Hannoush RN, Fairbrother WJ, Cunningham CN (2016) Palmitoylation of TEAD transcription factors is required for their stability and function in Hippo pathway signaling. Structure 24(1):179–186. https://doi.org/10.1016/j.str.2015.11.005

    Article  PubMed  CAS  Google Scholar 

  169. Rosenbluh J, Nijhawan D, Cox AG, Li X, Neal JT, Schafer EJ, Zack TI, Wang X, Tsherniak A, Schinzel AC, Shao DD, Schumacher SE, Weir BA, Vazquez F, Cowley GS, Root DE, Mesirov JP, Beroukhim R, Kuo CJ, Goessling W, Hahn WC (2012) beta-Catenin-driven cancers require a YAP1 transcriptional complex for survival and tumorigenesis. Cell 151(7):1457–1473. https://doi.org/10.1016/j.cell.2012.11.026

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  170. Mi W, Lin Q, Childress C, Sudol M, Robishaw J, Berlot CH, Shabahang M, Yang W (2015) Geranylgeranylation signals to the Hippo pathway for breast cancer cell proliferation and migration. Oncogene 34(24):3095–3106. https://doi.org/10.1038/onc.2014.251

    Article  PubMed  CAS  Google Scholar 

  171. Mo JS, Yu FX, Gong R, Brown JH, Guan KL (2012) Regulation of the Hippo-YAP pathway by protease-activated receptors (PARs). Genes Dev 26(19):2138–2143. https://doi.org/10.1101/gad.197582.112

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  172. Kim NG, Gumbiner BM (2015) Adhesion to fibronectin regulates Hippo signaling via the FAK-Src-PI3K pathway. J Cell Biol 210(3):503–515. https://doi.org/10.1083/jcb.201501025

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  173. Huang SM, Mishina YM, Liu S, Cheung A, Stegmeier F, Michaud GA, Charlat O, Wiellette E, Zhang Y, Wiessner S, Hild M, Shi X, Wilson CJ, Mickanin C, Myer V, Fazal A, Tomlinson R, Serluca F, Shao W, Cheng H, Shultz M, Rau C, Schirle M, Schlegl J, Ghidelli S, Fawell S, Lu C, Curtis D, Kirschner MW, Lengauer C, Finan PM, Tallarico JA, Bouwmeester T, Porter JA, Bauer A, Cong F (2009) Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 461(7264):614–620. https://doi.org/10.1038/nature08356

    Article  PubMed  CAS  Google Scholar 

  174. Troilo A, Benson EK, Esposito D, Garibsingh RA, Reddy EP, Mungamuri SK, Aaronson SA (2016) Angiomotin stabilization by tankyrase inhibitors antagonizes constitutive TEAD-dependent transcription and proliferation of human tumor cells with Hippo pathway core component mutations. Oncotarget 7(20):28765–28782. https://doi.org/10.18632/oncotarget.9117

    Article  PubMed  PubMed Central  Google Scholar 

  175. 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(3):524–532. https://doi.org/10.1016/j.celrep.2015.09.014

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  176. 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. https://doi.org/10.1038/ncomms3976

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  177. Bao Y, Nakagawa K, Yang Z, Ikeda M, Withanage K, Ishigami-Yuasa M, Okuno Y, Hata S, Nishina H, Hata Y (2011) A cell-based assay to screen stimulators of the Hippo pathway reveals the inhibitory effect of dobutamine on the YAP-dependent gene transcription. J Biochem 150(2):199–208. https://doi.org/10.1093/jb/mvr063

    Article  PubMed  CAS  Google Scholar 

  178. Fan F, He Z, Kong LL, Chen Q, Yuan Q, Zhang S, Ye J, Liu H, Sun X, Geng J, Yuan L, Hong L, Xiao C, Zhang W, Sun X, Li Y, Wang P, Huang L, Wu X, Ji Z, Wu Q, Xia NS, Gray NS, Chen L, Yun CH, Deng X, Zhou D (2016) Pharmacological targeting of kinases MST1 and MST2 augments tissue repair and regeneration. Sci Transl Med 8(352):352ra108. https://doi.org/10.1126/scitranslmed.aaf2304

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We apologize to those colleagues, whose work has not been cited because of space limitations. This work was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare, Republic of Korea (Grant Number: HI17C1560), and the National Research Foundation of Korea (NRF) Grant funded by the Korea government (2017R1A4A1015328 and 2018R1C1B6004301), and funded by the Yonsei University Future-leading Research Initiative of 2017 (2017-22-0071) to H.W.P. In addition, S.H.M and S.Y.P were supported by the Brain Korea (BK21) PLUS Program.

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Moon, S., Yeon Park, S. & Woo Park, H. Regulation of the Hippo pathway in cancer biology. Cell. Mol. Life Sci. 75, 2303–2319 (2018). https://doi.org/10.1007/s00018-018-2804-1

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