Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The two faces of Hippo: targeting the Hippo pathway for regenerative medicine and cancer treatment

Key Points

  • The Hippo pathway is an emerging tumour suppressor pathway that regulates cell proliferation, stem cell functions and organ size.

  • The Hippo pathway transduces signals from diverse transmembrane inputs such as the cell adhesion and cell polarity receptors E-cadherin, FAT and Crumbs, as well as G protein-coupled receptors (GPCRs), through a kinase cascade that regulates the subcellular localization and activities of the transcriptional co-activators Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ).

  • YAP and TAZ promote cell proliferation and organ growth. Hyperactivation or overexpression of YAP in mouse models causes overgrowth of various organs and can lead to the development of cancer in the liver, skin and intestine.

  • YAP and TAZ act as oncogenes and are hyperactivated or overexpressed with a high frequency in many common human cancers. YAP and TAZ promote multiple cancer cell phenotypes, including proliferation, migration and resistance to apoptosis.

  • Direct or indirect inhibition of YAP and TAZ is a promising novel targeted approach for cancer therapy, and small-molecule modulators of the Hippo pathway have been discovered. Pharmacological modulation of YAP has been shown to be effective for reverting YAP-driven overgrowth phenotypes in mouse models.

  • Further research is required to test whether small molecules targeting YAP and TAZ are active against human cancer cells and in mouse models that more accurately recapitulate the genetic defects of human tumours.

  • By contrast, drugs that stimulate YAP and TAZ activity may be useful for stem cell expansion and tissue repair following injury. YAP is activated during the regeneration of the intestinal epithelium, and experimental activation of YAP promotes the capacity of the mouse heart to regenerate.

Abstract

The Hippo signalling pathway is an emerging growth control and tumour suppressor pathway that regulates cell proliferation and stem cell functions. Defects in Hippo signalling and hyperactivation of its downstream effectors Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) contribute to the development of cancer, which suggests that pharmacological inhibition of YAP and TAZ activity may be an effective anticancer strategy. Conversely, YAP and TAZ can also have beneficial roles in stimulating tissue repair and regeneration following injury, so their activation may be therapeutically useful in these contexts. A complex network of intracellular and extracellular signalling pathways that modulate YAP and TAZ activities have recently been identified. Here, we review the regulation of the Hippo signalling pathway, its functions in normal homeostasis and disease, and recent progress in the identification of small-molecule pathway modulators.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The core of the Hippo signalling pathway and its mode of action.
Figure 2: The Hippo pathway network.
Figure 3: Hippo-mutant phenotypes in fruitflies and mice.
Figure 4: Cellular functions of YAP and TAZ.

Similar content being viewed by others

References

  1. Halder, G. & Johnson, R. L. Hippo signaling: growth control and beyond. Development 138, 9–22 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Staley, B. K. & Irvine, K. D. Hippo signaling in Drosophila: recent advances and insights. Dev. Dyn. 241, 3–15 (2012).

    Article  CAS  PubMed  Google Scholar 

  3. Genevet, A. & Tapon, N. The Hippo pathway and apico-basal cell polarity. Biochem. J. 436, 213–224 (2011).

    Article  CAS  PubMed  Google Scholar 

  4. Ramos, A. & Camargo, F. D. The Hippo signaling pathway and stem cell biology. Trends Cell Biol. 22, 339–346 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Pan, D. The hippo signaling pathway in development and cancer. Dev. Cell 19, 491–505 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Yu, F. X. & Guan, K. L. The Hippo pathway: regulators and regulations. Genes Dev. 27, 355–371 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Harvey, K. F., Zhang, X. & Thomas, D. M. The Hippo pathway and human cancer. Nature Rev. Cancer 13, 246–257 (2013).

    Article  CAS  Google Scholar 

  8. Stanger, B. Z. Quit your YAPing: a new target for cancer therapy. Genes Dev. 26, 1263–1267 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Liu, A. M., Xu, Z. & Luk, J. M. An update on targeting Hippo-YAP signaling in liver cancer. Expert Opin. Ther. Targets 16, 243–247 (2012).

    Article  CAS  PubMed  Google Scholar 

  10. Hong, W. & Guan, K. L. The YAP and TAZ transcription co-activators: key downstream effectors of the mammalian Hippo pathway. Semin. Cell Dev. Biol. 23, 785–793 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Dong, J. et al. Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell 130, 1120–1133 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Camargo, F. D. et al. YAP1 increases organ size and expands undifferentiated progenitor cells. Curr. Biol. 17, 2054–2060 (2007).

    Article  CAS  PubMed  Google Scholar 

  13. Wang, Y. et al. Overexpression of yes-associated protein contributes to progression and poor prognosis of non-small-cell lung cancer. Cancer Sci. 101, 1279–1285 (2010).

    Article  CAS  PubMed  Google Scholar 

  14. Zhou, Z. et al. TAZ is a novel oncogene in non-small cell lung cancer. Oncogene 30, 2181–2186 (2011).

    Article  CAS  PubMed  Google Scholar 

  15. Overholtzer, M. et al. Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon. Proc. Natl Acad. Sci. USA 103, 12405–12410 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zender, L. et al. Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach. Cell 125, 1253–1267 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Steinhardt, A. A. et al. Expression of Yes-associated protein in common solid tumors. Hum. Pathol. 39, 1582–1589 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Chan, S. W. et al. A role for TAZ in migration, invasion, and tumorigenesis of breast cancer cells. Cancer Res. 68, 2592–2598 (2008).

    Article  CAS  PubMed  Google Scholar 

  19. Fernandez, L. A. et al. YAP1 is amplified and up-regulated in hedgehog-associated medulloblastomas and mediates Sonic hedgehog-driven neural precursor proliferation. Genes Dev. 23, 2729–2741 (2009).

    Article  CAS  Google Scholar 

  20. Xu, M. Z. et al. Yes-associated protein is an independent prognostic marker in hepatocellular carcinoma. Cancer 115, 4576–4585 (2009).

    Article  CAS  PubMed  Google Scholar 

  21. Zhao, B. et al. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev. 21, 2747–2761 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Cai, J. et al. The Hippo signaling pathway restricts the oncogenic potential of an intestinal regeneration program. Genes Dev. 24, 2383–2388 (2010). This study shows that YAP levels are elevated during the regeneration of damaged mouse intestinal crypts after injury by DSS and that YAP is essential for crypt regeneration, but its loss causes no obvious defects during normal homeostasis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Grusche, F. A., Degoutin, J. L., Richardson, H. E. & Harvey, K. F. The Salvador/Warts/Hippo pathway controls regenerative tissue growth in Drosophila melanogaster. Dev. Biol. 350, 255–266 (2011).

    Article  CAS  PubMed  Google Scholar 

  24. Staley, B. K. & Irvine, K. D. Warts and Yorkie mediate intestinal regeneration by influencing stem cell proliferation. Curr. Biol. 20, 1580–1587 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Shaw, R. L. et al. The Hippo pathway regulates intestinal stem cell proliferation during Drosophila adult midgut regeneration. Development 137, 4147–4158 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Karpowicz, P., Perez, J. & Perrimon, N. The Hippo tumor suppressor pathway regulates intestinal stem cell regeneration. Development 137, 4135–4145 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ren, F. et al. Hippo signaling regulates Drosophila intestine stem cell proliferation through multiple pathways. Proc. Natl Acad. Sci. USA 107, 21064–21069 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Xin, M. et al. Hippo pathway effector Yap promotes cardiac regeneration. Proc. Natl Acad. Sci. USA 110, 13839–13844 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Heallen, T. et al. Hippo signaling impedes postnatal cardiomyocyte regeneration. Development 140, 4683–4690 (2013). References 28 and 29 show that YAP is required for postnatal cardiac growth and neonatal cardiac regeneration, and that the expression of a constitutively active form of YAP or deletion of Hippo pathway components in the adult heart stimulates cardiac regeneration after myocardial infarction.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sun, G. & Irvine, K. D. Regulation of Hippo signaling by Jun kinase signaling during compensatory cell proliferation and regeneration, and in neoplastic tumors. Dev. Biol. 350, 139–151 (2011).

    Article  CAS  PubMed  Google Scholar 

  31. Schroeder, M. C. & Halder, G. Regulation of the Hippo pathway by cell architecture and mechanical signals. Semin. Cell Dev. Biol. 23, 803–811 (2012).

    Article  CAS  PubMed  Google Scholar 

  32. Udan, R. S., Kango-Singh, M., Nolo, R., Tao, C. & Halder, G. Hippo promotes proliferation arrest and apoptosis in the Salvador/Warts pathway. Nature Cell Biol. 5, 914–920 (2003).

    Article  CAS  PubMed  Google Scholar 

  33. Harvey, K. F., Pfleger, C. M. & Hariharan, I. K. The Drosophila Mst ortholog, hippo, restricts growth and cell proliferation and promotes apoptosis. Cell 114, 457–467 (2003).

    Article  CAS  PubMed  Google Scholar 

  34. Pantalacci, S., Tapon, N. & Leopold, P. The Salvador partner Hippo promotes apoptosis and cell-cycle exit in Drosophila. Nature Cell Biol. 5, 921–927 (2003).

    Article  CAS  PubMed  Google Scholar 

  35. Wu, S., Huang, J., Dong, J. & Pan, D. Hippo encodes a Ste-20 family protein kinase that restricts cell proliferation and promotes apoptosis in conjunction with salvador and warts. Cell 114, 445–456 (2003).

    Article  CAS  PubMed  Google Scholar 

  36. Jia, J., Zhang, W., Wang, B., Trinko, R. & Jiang, J. The Drosophila Ste20 family kinase dMST functions as a tumor suppressor by restricting cell proliferation and promoting apoptosis. Genes Dev. 17, 2514–2519 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Justice, R. W., Zilian, O., Woods, D. F., Noll, M. & Bryant, P. J. The Drosophila tumor suppressor gene warts encodes a homolog of human myotonic dystrophy kinase and is required for the control of cell shape and proliferation. Genes Dev. 9, 534–546 (1995).

    Article  CAS  PubMed  Google Scholar 

  38. Xu, T., Wang, W., Zhang, S., Stewart, R. A. & Yu, W. Identifying tumor suppressors in genetic mosaics: the Drosophila lats gene encodes a putative protein kinase. Development 121, 1053–1063 (1995).

    CAS  PubMed  Google Scholar 

  39. Creasy, C. L. & Chernoff, J. Cloning and characterization of a member of the MST subfamily of Ste20-like kinases. Gene 167, 303–306 (1995).

    Article  CAS  PubMed  Google Scholar 

  40. Creasy, C. L. & Chernoff, J. Cloning and characterization of a human protein kinase with homology to Ste20. J. Biol. Chem. 270, 21695–21700 (1995).

    Article  CAS  PubMed  Google Scholar 

  41. Taylor, L. K., Wang, H. C. & Erikson, R. L. Newly identified stress-responsive protein kinases, Krs-1 and Krs-2. Proc. Natl Acad. Sci. USA 93, 10099–10104 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Tapon, N. et al. Salvador promotes both cell cycle exit and apoptosis in Drosophila and is mutated in human cancer cell lines. Cell 110, 467–478 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Kango-Singh, M. et al. Shar-pei mediates cell proliferation arrest during imaginal disc growth in Drosophila. Development 129, 5719–5730 (2002).

    Article  CAS  PubMed  Google Scholar 

  44. Lai, Z. C. et al. Control of cell proliferation and apoptosis by mob as tumor suppressor, mats. Cell 120, 675–685 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Huang, J., Wu, S., Barrera, J., Matthews, K. & Pan, D. The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila Homolog of YAP. Cell 122, 421–434 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. Goulev, Y. et al. SCALLOPED interacts with YORKIE, the nuclear effector of the hippo tumor-suppressor pathway in Drosophila. Curr. Biol. 18, 435–441 (2008).

    Article  CAS  PubMed  Google Scholar 

  47. Wu, S., Liu, Y., Zheng, Y., Dong, J. & Pan, D. The TEAD/TEF family protein Scalloped mediates transcriptional output of the Hippo growth-regulatory pathway. Dev. Cell 14, 388–398 (2008).

    Article  CAS  PubMed  Google Scholar 

  48. Zhang, L. et al. The TEAD/TEF family of transcription factor Scalloped mediates Hippo signaling in organ size control. Dev. Cell 14, 377–387 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Zhao, B. et al. TEAD mediates YAP-dependent gene induction and growth control. Genes Dev. 22, 1962–1971 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Vassilev, A., Kaneko, K. J., Shu, H., Zhao, Y. & DePamphilis, M. L. TEAD/TEF transcription factors utilize the activation domain of YAP65, a Src/Yes-associated protein localized in the cytoplasm. Genes Dev. 15, 1229–1241 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Alarcon, C. et al. Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-β pathways. Cell 139, 757–769 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Varelas, X. et al. TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal. Nature Cell Biol. 10, 837–848 (2008).

    Article  CAS  PubMed  Google Scholar 

  53. Ferrigno, O. et al. Yes-associated protein (YAP65) interacts with Smad7 and potentiates its inhibitory activity against TGF-β/Smad signaling. Oncogene 21, 4879–4884 (2002).

    Article  CAS  PubMed  Google Scholar 

  54. Murakami, M., Nakagawa, M., Olson, E. N. & Nakagawa, O. A. WW domain protein TAZ is a critical coactivator for TBX5, a transcription factor implicated in Holt-Oram syndrome. Proc. Natl Acad. Sci. USA 102, 18034–18039 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Rosenbluh, J. et al. β-catenin-driven cancers require a YAP1 transcriptional complex for survival and tumorigenesis. Cell 151, 1457–1473 (2012). This paper shows that YAP forms a complex with β-catenin and the transcription factor TBX5 in β-catenin-dependent cancer cell lines. The formation of this complex requires phosphorylation of YAP by YES1; dasatinib inhibits YES1 function and impedes the proliferation of β-catenin-dependent cancers in cell lines and animal models.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Yagi, R., Chen, L. F., Shigesada, K., Murakami, Y. & Ito, Y. A. WW domain-containing yes-associated protein (YAP) is a novel transcriptional co-activator. EMBO J. 18, 2551–2562 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Strano, S. et al. Physical interaction with Yes-associated protein enhances p73 transcriptional activity. J. Biol. Chem. 276, 15164–15173 (2001).

    Article  CAS  PubMed  Google Scholar 

  58. Callus, B. A., Verhagen, A. M. & Vaux, D. L. Association of mammalian sterile twenty kinases, Mst1 and Mst2, with hSalvador via C-terminal coiled-coil domains, leads to its stabilization and phosphorylation. FEBS J. 273, 4264–4276 (2006).

    Article  CAS  PubMed  Google Scholar 

  59. Praskova, M., Xia, F. & Avruch, J. MOBKL1A/MOBKL1B phosphorylation by MST1 and MST2 inhibits cell proliferation. Curr. Biol. 18, 311–321 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Chan, E. H. et al. The Ste20-like kinase Mst2 activates the human large tumor suppressor kinase Lats1. Oncogene 24, 2076–2086 (2005).

    Article  CAS  PubMed  Google Scholar 

  61. Wei, X., Shimizu, T. & Lai, Z. C. Mob as tumor suppressor is activated by Hippo kinase for growth inhibition in Drosophila. EMBO J. 26, 1772–1781 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Lei, Q. Y. et al. TAZ promotes cell proliferation and epithelial-mesenchymal transition and is inhibited by the hippo pathway. Mol. Cell. Biol. 28, 2426–2436 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Oh, H. & Irvine, K. D. In vivo regulation of Yorkie phosphorylation and localization. Development 135, 1081–1088 (2008).

    Article  CAS  PubMed  Google Scholar 

  64. Hao, Y., Chun, A., Cheung, K., Rashidi, B. & Yang, X. Tumor suppressor LATS1 is a negative regulator of oncogene YAP. J. Biol. Chem. 283, 5496–5509 (2008).

    Article  CAS  PubMed  Google Scholar 

  65. Oka, T., Mazack, V. & Sudol, M. Mst2 and Lats kinases regulate apoptotic function of Yes kinase-associated protein (YAP). J. Biol. Chem. 283, 27534–27546 (2008).

    Article  CAS  PubMed  Google Scholar 

  66. Kanai, F. et al. TAZ: a novel transcriptional co-activator regulated by interactions with 14-3-3 and PDZ domain proteins. EMBO J. 19, 6778–6791 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Ren, F., Zhang, L. & Jiang, J. Hippo signaling regulates Yorkie nuclear localization and activity through 14-3-3 dependent and independent mechanisms. Dev. Biol. 337, 303–312 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Liu, C. Y. et al. The Hippo tumor pathway promotes TAZ degradation by phosphorylating a phosphodegron and recruiting the SCFβ-TrCP E3 ligase. J. Biol. Chem. 285, 37159–37169 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Zhao, B., Li, L., Tumaneng, K., Wang, C. Y. & Guan, K. L. A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCFβ-TRCP. Genes Dev. 24, 72–85 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Koontz, L. M. et al. The Hippo effector Yorkie controls normal tissue growth by antagonizing scalloped-mediated default repression. Dev. Cell 25, 388–401 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Guo, T. et al. A novel partner of Scalloped regulates Hippo signaling via antagonizing Scalloped-Yorkie activity. Cell Res. 23, 1201–1214 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Ota, M. & Sasaki, H. Mammalian Tead proteins regulate cell proliferation and contact inhibition as transcriptional mediators of Hippo signaling. Development 135, 4059–4069 (2008).

    Article  CAS  PubMed  Google Scholar 

  73. Chan, S. W. et al. TEADs mediate nuclear retention of TAZ to promote oncogenic transformation. J. Biol. Chem. 284, 14347–14358 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Peng, H. W., Slattery, M. & Mann, R. S. 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, 2307–2319 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Zhang, H. et al. TEAD transcription factors mediate the function of TAZ in cell growth and epithelial-mesenchymal transition. J. Biol. Chem. 284, 13355–13362 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Oh, H. & Irvine, K. D. Cooperative regulation of growth by Yorkie and Mad through bantam. Dev. Cell 20, 109–122 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Bazellieres, E., Assemat, E., Arsanto, J. P., Le Bivic, A. & Massey-Harroche, D. Crumbs proteins in epithelial morphogenesis. Front. Biosci. 14, 2149–2169 (2009).

    Article  CAS  Google Scholar 

  78. Varelas, X. et al. The Crumbs complex couples cell density sensing to Hippo-dependent control of the TGF-β-SMAD pathway. Dev. Cell 19, 831–844 (2010).

    Article  CAS  PubMed  Google Scholar 

  79. Chen, C. L. et al. The apical-basal cell polarity determinant Crumbs regulates Hippo signaling in Drosophila. Proc. Natl Acad. Sci. USA 107, 15810–15815 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Robinson, B. S., Huang, J., Hong, Y. & Moberg, K. H. Crumbs regulates Salvador/Warts/Hippo signaling in Drosophila via the FERM-domain protein expanded. Curr. Biol. 20, 582–590 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Grzeschik, N. A., Parsons, L. M., Allott, M. L., Harvey, K. F. & Richardson, H. E. Lgl, aPKC, and Crumbs regulate the Salvador/Warts/Hippo pathway through two distinct mechanisms. Curr. Biol. 20, 573–581 (2010).

    Article  CAS  PubMed  Google Scholar 

  82. Ling, C. et al. The apical transmembrane protein Crumbs functions as a tumor suppressor that regulates Hippo signaling by binding to Expanded. Proc. Natl Acad. Sci. USA 107, 10532–10537 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Chan, S. W. et al. Hippo pathway-independent restriction of TAZ and YAP by angiomotin. J. Biol. Chem. 286, 7018–7026 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Hirate, Y. et al. Polarity-dependent distribution of angiomotin localizes Hippo signaling in preimplantation embryos. Curr. Biol. 23, 1181–1194 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Zhao, B. et al. Angiomotin is a novel Hippo pathway component that inhibits YAP oncoprotein. Genes Dev. 25, 51–63 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Wang, W., Huang, J. & Chen, J. Angiomotin-like proteins associate with and negatively regulate YAP1. J. Biol. Chem. 286, 4364–4370 (2011).

    Article  CAS  PubMed  Google Scholar 

  87. Paramasivam, M., Sarkeshik, A., Yates, J. R., Fernandes, M. J. & McCollum, D. Angiomotin family proteins are novel activators of the LATS2 kinase tumor suppressor. Mol. Biol. Cell 22, 3725–3733 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Yi, C. et al. A tight junction-associated Merlin-angiomotin complex mediates Merlin's regulation of mitogenic signaling and tumor suppressive functions. Cancer Cell 19, 527–540 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Yi, C. et al. The p130 isoform of angiomotin is required for Yap-mediated hepatic epithelial cell proliferation and tumorigenesis. Sci. Signal. 6, ra77 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Boggiano, J. C., Vanderzalm, P. J. & Fehon, R. G. Tao-1 phosphorylates Hippo/MST kinases to regulate the Hippo-Salvador-Warts tumor suppressor pathway. Dev. Cell 21, 888–895 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Poon, C. L., Lin, J. I., Zhang, X. & Harvey, K. F. The sterile 20-like kinase Tao-1 controls tissue growth by regulating the Salvador-Warts-Hippo pathway. Dev. Cell 21, 896–906 (2011).

    Article  CAS  PubMed  Google Scholar 

  92. Huang, H. L. et al. Par-1 regulates tissue growth by influencing Hippo phosphorylation status and Hippo-salvador association. PLoS Biol. 11, e1001620 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Genevet, A., Wehr, M. C., Brain, R., Thompson, B. J. & Tapon, N. Kibra is a regulator of the Salvador/Warts/Hippo signaling network. Dev. Cell 18, 300–308 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Yu, J. et al. Kibra functions as a tumor suppressor protein that regulates Hippo signaling in conjunction with Merlin and Expanded. Dev. Cell 18, 288–299 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Baumgartner, R., Poernbacher, I., Buser, N., Hafen, E. & Stocker, H. The WW domain protein Kibra acts upstream of Hippo in Drosophila. Dev. Cell 18, 309–316 (2010).

    Article  CAS  PubMed  Google Scholar 

  96. Hamaratoglu, F. et al. The tumour-suppressor genes NF2/Merlin and Expanded act through Hippo signalling to regulate cell proliferation and apoptosis. Nature Cell Biol. 8, 27–36 (2006).

    Article  CAS  PubMed  Google Scholar 

  97. Sansores-Garcia, L. et al. Modulating F-actin organization induces organ growth by affecting the Hippo pathway. EMBO J. 30, 2325–2335 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Fernandez, B. G. et al. Actin-capping protein and the Hippo pathway regulate F-actin and tissue growth in Drosophila. Development 138, 2337–2346 (2011).

    Article  CAS  PubMed  Google Scholar 

  99. Dupont, S. et al. Role of YAP/TAZ in mechanotransduction. Nature 474, 179–183 (2011).

    Article  CAS  PubMed  Google Scholar 

  100. Wada, K., Itoga, K., Okano, T., Yonemura, S. & Sasaki, H. Hippo pathway regulation by cell morphology and stress fibers. Development 138, 3907–3914 (2011). References 96–100 show that YAP activity is regulated by the amount of F-actin stress fibres, by the mechanical properties of the extracellular matrix and by cell geometry. Disruption of F-actin stress fibres or of actin contractility by small-molecule inhibitors suppresses the nuclear localization and activity of YAP.

    Article  CAS  PubMed  Google Scholar 

  101. Zhao, B. et al. Cell detachment activates the Hippo pathway via cytoskeleton reorganization to induce anoikis. Genes Dev. 26, 54–68 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Yu, F. X. et al. Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling. Cell 150, 780–791 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Miller, E. et al. Identification of serum-derived sphingosine-1-phosphate as a small molecule regulator of YAP. Chem. Biol. 19, 955–962 (2012).

    Article  CAS  PubMed  Google Scholar 

  104. Mo, J. S., Yu, F. X., Gong, R., Brown, J. H. & Guan, K. L. Regulation of the Hippo-YAP pathway by protease-activated receptors (PARs). Genes Dev. 26, 2138–2143 (2012). References 101–103 show that GPCRs regulate the activity of the Hippo pathway, and that compounds and ligands that modulate GPCR activity affect YAP activity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Aragona, M. et al. A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factors. Cell 154, 1047–1059 (2013).

    Article  CAS  PubMed  Google Scholar 

  106. Kim, N. G., Koh, E., Chen, X. & Gumbiner, B. M. E-cadherin mediates contact inhibition of proliferation through Hippo signaling-pathway components. Proc. Natl Acad. Sci. USA 108, 11930–11935 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Schlegelmilch, K. et al. Yap1 acts downstream of α-catenin to control epidermal proliferation. Cell 144, 782–795 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Silvis, M. R. et al. α-catenin is a tumor suppressor that controls cell accumulation by regulating the localization and activity of the transcriptional coactivator Yap1. Sci. Signal. 4, ra33 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Das Thakur, M. et al. Ajuba LIM proteins are negative regulators of the Hippo signaling pathway. Curr. Biol. 20, 657–662 (2010).

    Article  CAS  PubMed  Google Scholar 

  110. Rauskolb, C., Pan, G., Reddy, B. V., Oh, H. & Irvine, K. D. Zyxin links fat signaling to the Hippo pathway. PLoS Biol. 9, e1000624 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Tepass, U. The apical polarity protein network in Drosophila epithelial cells: regulation of polarity, junctions, morphogenesis, cell growth, and survival. Annu. Rev. Cell Dev. Biol. 28, 655–685 (2012).

    Article  CAS  PubMed  Google Scholar 

  112. Muthuswamy, S. K. & Xue, B. Cell polarity as a regulator of cancer cell behavior plasticity. Annu. Rev. Cell Dev. Biol. 28, 599–625 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Brieher, W. M. & Yap, A. S. Cadherin junctions and their cytoskeleton(s). Curr. Opin. Cell Biol. 25, 39–46 (2013).

    Article  CAS  PubMed  Google Scholar 

  114. Twiss, F. & de Rooij, J. Cadherin mechanotransduction in tissue remodeling. Cell. Mol. Life Sci. (2013).

  115. Zhang, X., Milton, C. C., Poon, C. L., Hong, W. & Harvey, K. F. Wbp2 cooperates with Yorkie to drive tissue growth downstream of the Salvador-Warts-Hippo pathway. Cell Death Differ. 18, 1346–1355 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Chan, S. W. et al. WW domain-mediated interaction with Wbp2 is important for the oncogenic property of TAZ. Oncogene 30, 600–610 (2011).

    Article  CAS  PubMed  Google Scholar 

  117. Chen, H. I. et al. Characterization of the WW domain of human yes-associated protein and its polyproline-containing ligands. J. Biol. Chem. 272, 17070–17077 (1997).

    Article  CAS  PubMed  Google Scholar 

  118. Sidor, C. M., Brain, R. & Thompson, B. J. Mask proteins are cofactors of Yorkie/YAP in the Hippo pathway. Curr. Biol. 23, 223–228 (2013).

    Article  CAS  PubMed  Google Scholar 

  119. Sansores-Garcia, L. et al. Mask is required for the activity of the Hippo pathway effector Yki/YAP. Curr. Biol. 23, 229–235 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Remue, E. et al. TAZ interacts with zonula occludens-1 and -2 proteins in a PDZ-1 dependent manner. FEBS Lett. 584, 4175–4180 (2010).

    Article  CAS  PubMed  Google Scholar 

  121. Oka, T. et al. Functional complexes between YAP2 and ZO-2 are PDZ domain-dependent, and regulate YAP2 nuclear localization and signalling. Biochem. J. 432, 461–472 (2010).

    Article  CAS  PubMed  Google Scholar 

  122. Poon, C. L., Zhang, X., Lin, J. I., Manning, S. A. & Harvey, K. F. Homeodomain-interacting protein kinase regulates Hippo pathway-dependent tissue growth. Curr. Biol. 22, 1587–1594 (2012).

    Article  CAS  PubMed  Google Scholar 

  123. Chen, J. & Verheyen, E. M. Homeodomain-interacting protein kinase regulates Yorkie activity to promote tissue growth. Curr. Biol. 22, 1582–1586 (2012).

    Article  CAS  PubMed  Google Scholar 

  124. Liu, X. et al. PTPN14 interacts with and negatively regulates the oncogenic function of YAP. Oncogene 32, 1266–1273 (2013).

    Article  CAS  PubMed  Google Scholar 

  125. Wang, W. et al. PTPN14 is required for the density-dependent control of YAP1. Genes Dev. 26, 1959–1971 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Michaloglou, C. et al. The tyrosine phosphatase PTPN14 is a negative regulator of YAP activity. PLoS ONE 8, e61916 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Huang, J. M. et al. 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, 2220–2229 (2013).

    Article  CAS  PubMed  Google Scholar 

  128. Poernbacher, I., Baumgartner, R., Marada, S. K., Edwards, K. & Stocker, H. Drosophila Pez acts in Hippo signaling to restrict intestinal stem cell proliferation. Curr. Biol. 22, 389–396 (2012).

    Article  CAS  PubMed  Google Scholar 

  129. Polesello, C., Huelsmann, S., Brown, N. H. & Tapon, N. The Drosophila RASSF homolog antagonizes the Hippo pathway. Curr. Biol. 16, 2459–2465 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Praskova, M., Khoklatchev, A., Ortiz-Vega, S. & Avruch, J. Regulation of the MST1 kinase by autophosphorylation, by the growth inhibitory proteins, RASSF1 and NORE1, and by Ras. Biochem. J. 381, 453–462 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Ikeda, M. et al. Hippo pathway-dependent and -independent roles of RASSF6. Sci. Signal. 2, ra59 (2009).

    Article  PubMed  Google Scholar 

  132. Ribeiro, P. S. et al. Combined functional genomic and proteomic approaches identify a PP2A complex as a negative regulator of Hippo signaling. Mol. Cell 39, 521–534 (2010).

    Article  CAS  PubMed  Google Scholar 

  133. Wehr, M. C. et al. Salt-inducible kinases regulate growth through the Hippo signalling pathway in Drosophila. Nature Cell Biol. 15, 61–71 (2013).

    Article  CAS  PubMed  Google Scholar 

  134. Yin, F. et al. Spatial organization of Hippo signaling at the plasma membrane mediated by the tumor suppressor Merlin/NF2. Cell 154, 1342–1355 (2013).

    Article  CAS  PubMed  Google Scholar 

  135. Chen, C. L., Schroeder, M. C., Kango-Singh, M., Tao, C. & Halder, G. Tumor suppression by cell competition through regulation of the Hippo pathway. Proc. Natl Acad. Sci. USA 109, 484–489 (2012).

    Article  PubMed  Google Scholar 

  136. Menendez, J., Perez-Garijo, A., Calleja, M. & Morata, G. A tumor-suppressing mechanism in Drosophila involving cell competition and the Hippo pathway. Proc. Natl Acad. Sci. USA 107, 14651–14656 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  137. Cordenonsi, M. et al. The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells. Cell 147, 759–772 (2011).

    Article  CAS  PubMed  Google Scholar 

  138. Zhao, M., Szafranski, P., Hall, C. A. & Goode, S. Basolateral junctions utilize warts signaling to control epithelial-mesenchymal transition and proliferation crucial for migration and invasion of Drosophila ovarian epithelial cells. Genetics 178, 1947–1971 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Bossuyt, W. et al. An evolutionary shift in the regulation of the Hippo pathway between mice and flies. Oncogene http://dx.doi.org/10.1038/onc.2013.82 (2013).

  140. Zhou, D. et al. Mst1 and Mst2 maintain hepatocyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yap1 oncogene. Cancer Cell 16, 425–438 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Lu, L. et al. Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver. Proc. Natl Acad. Sci. USA 107, 1437–1442 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  142. Song, H. et al. Mammalian Mst1 and Mst2 kinases play essential roles in organ size control and tumor suppression. Proc. Natl Acad. Sci. USA 107, 1431–1436 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  143. Lee, K. P. et al. The Hippo-Salvador pathway restrains hepatic oval cell proliferation, liver size, and liver tumorigenesis. Proc. Natl Acad. Sci. USA 107, 8248–8253 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Zhou, D. et al. 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, E1312–1320 (2011). Using mouse models, this paper reports that inactivation of a single YAP allele reverses hyperproliferation and expansion of the stem cell compartment as well as the loss of differentiated cell types in Mst1/Mst2 -null intestinal epithelia.

    Article  PubMed  PubMed Central  Google Scholar 

  145. George, N. M., Day, C. E., Boerner, B. P., Johnson, R. L. & Sarvetnick, N. E. Hippo signaling regulates pancreas development through inactivation of Yap. Mol. Cell. Biol. 32, 5116–5128 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Gao, T. et al. Hippo signaling regulates differentiation and maintenance in the exocrine pancreas. Gastroenterology 144, 1543–1553 (2013).

    Article  CAS  PubMed  Google Scholar 

  147. Heallen, T. et al. Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size. Science 332, 458–461 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Yabuta, N. et al. N-terminal truncation of Lats1 causes abnormal cell growth control and chromosomal instability. J. Cell Sci. 126, 508–520 (2013).

    Article  CAS  PubMed  Google Scholar 

  149. Polesello, C. & Tapon, N. Salvador-warts-hippo signaling promotes Drosophila posterior follicle cell maturation downstream of notch. Curr. Biol. 17, 1864–1870 (2007).

    Article  CAS  PubMed  Google Scholar 

  150. Meignin, C., Alvarez-Garcia, I., Davis, I. & Palacios, I. M. The Salvador-Warts-Hippo pathway is required for epithelial proliferation and axis specification in Drosophila. Curr. Biol. 17, 1871–1878 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Bennett, F. C. & Harvey, K. F. Fat cadherin modulates organ size in Drosophila via the Salvador/Warts/Hippo signaling pathway. Curr. Biol. 16, 2101–2110 (2006).

    Article  CAS  PubMed  Google Scholar 

  152. Bryant, P. J. et al. Mutations at the fat locus interfere with cell proliferation control and epithelial morphogenesis in Drosophila. Dev. Biol. 129, 541–554 (1988).

    Article  CAS  PubMed  Google Scholar 

  153. Cho, E. et al. Delineation of a Fat tumor suppressor pathway. Nature Genet. 38, 1142–1150 (2006).

    Article  CAS  PubMed  Google Scholar 

  154. Silva, E., Tsatskis, Y., Gardano, L., Tapon, N. & McNeill, H. The tumor-suppressor gene fat controls tissue growth upstream of expanded in the Hippo signaling pathway. Curr. Biol. 16, 2081–2089 (2006).

    Article  CAS  PubMed  Google Scholar 

  155. Willecke, M. et al. The fat cadherin acts through the Hippo tumor-suppressor pathway to regulate tissue size. Curr. Biol. 16, 2090–2100 (2006).

    Article  CAS  PubMed  Google Scholar 

  156. MacDougall, N. et al. Merlin, the Drosophila homologue of neurofibromatosis-2, is specifically required in posterior follicle cells for axis formation in the oocyte. Development 128, 665–673 (2001).

    CAS  PubMed  Google Scholar 

  157. Milton, C. C., Zhang, X., Albanese, N. O. & Harvey, K. F. Differential requirement of Salvador-Warts-Hippo pathway members for organ size control in Drosophila melanogaster. Development 137, 735–743 (2010).

    Article  CAS  PubMed  Google Scholar 

  158. Pellock, B. J., Buff, E., White, K. & Hariharan, I. K. The Drosophila tumor suppressors Expanded and Merlin differentially regulate cell cycle exit, apoptosis, and Wingless signaling. Dev. Biol. 304, 102–115 (2007).

    Article  CAS  PubMed  Google Scholar 

  159. Yu, J., Poulton, J., Huang, Y. C. & Deng, W. M. The Hippo pathway promotes Notch signaling in regulation of cell differentiation, proliferation, and oocyte polarity. PLoS ONE 3, e1761 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. McCartney, B. M., Kulikauskas, R. M., LaJeunesse, D. R. & Fehon, R. G. The neurofibromatosis-2 homologue, Merlin, and the tumor suppressor Expanded function together in Drosophila to regulate cell proliferation and differentiation. Development 127, 1315–1324 (2000).

    CAS  PubMed  Google Scholar 

  161. von Gise, A. et al. YAP1, the nuclear target of Hippo signaling, stimulates heart growth through cardiomyocyte proliferation but not hypertrophy. Proc. Natl Acad. Sci. USA 109, 2394–2399 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  162. Xin, M. et al. Regulation of insulin-like growth factor signaling by Yap governs cardiomyocyte proliferation and embryonic heart size. Sci. Signal. 4, ra70 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Zhang, H., Pasolli, H. A. & Fuchs, E. Yes-associated protein (YAP) transcriptional coactivator functions in balancing growth and differentiation in skin. Proc. Natl Acad. Sci. USA 108, 2270–2275 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  164. Mikeladze-Dvali, T. et al. The growth regulators Warts/Lats and Melted interact in a bistable loop to specify opposite fates in Drosophila R8 photoreceptors. Cell 122, 775–787 (2005).

    Article  CAS  PubMed  Google Scholar 

  165. Nishioka, N. et al. The Hippo signaling pathway components Lats and Yap pattern Tead4 activity to distinguish mouse trophectoderm from inner cell mass. Dev. Cell 16, 398–410 (2009).

    Article  CAS  PubMed  Google Scholar 

  166. Oh, H. et al. Genome-wide association of Yorkie with chromatin and chromatin-remodeling complexes. Cell Rep. 3, 309–318 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Nagaraj, R. et al. Control of mitochondrial structure and function by the Yorkie/YAP oncogenic pathway. Genes Dev. 26, 2027–2037 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Kaneko, K. J. & Depamphilis, M. L. TEAD4 establishes the energy homeostasis essential for blastocoel formation. Development 140, 3680–3690 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Bhat, K. P. et al. The transcriptional coactivator TAZ regulates mesenchymal differentiation in malignant glioma. Genes Dev. 25, 2594–2609 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Imanaka, Y. et al. MicroRNA-141 confers resistance to cisplatin-induced apoptosis by targeting YAP1 in human esophageal squamous cell carcinoma. J. Hum. Genet. 56, 270–276 (2011).

    Article  CAS  PubMed  Google Scholar 

  171. Kawahara, M. et al. Kpm/Lats2 is linked to chemosensitivity of leukemic cells through the stabilization of p73. Blood 112, 3856–3866 (2008).

    Article  CAS  PubMed  Google Scholar 

  172. Lai, D., Ho, K. C., Hao, Y. & Yang, X. 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, 2728–2738 (2011).

    Article  CAS  PubMed  Google Scholar 

  173. Huo, X. et al. Overexpression of Yes-associated protein confers doxorubicin resistance in hepatocellullar carcinoma. Oncol. Rep. 29, 840–846 (2013).

    Article  CAS  PubMed  Google Scholar 

  174. Urtasun, R. et al. Connective tissue growth factor autocriny in human hepatocellular carcinoma: oncogenic role and regulation by epidermal growth factor receptor/Yes-associated protein-mediated activation. Hepatology 54, 2149–2158 (2011).

    Article  CAS  PubMed  Google Scholar 

  175. Juric, V., Chen, C. C. & Lau, L. F. Fas-mediated apoptosis is regulated by the extracellular matrix protein CCN1 (CYR61) in vitro and in vivo. Mol. Cell. Biol. 29, 3266–3279 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Piccolo, S., Cordenonsi, M. & Dupont, S. Molecular pathways: YAP & TAZ take the centerstage in organ growth and tumorigenesis. Clin. Cancer Res. 19, 4925–4930 (2013).

    Article  CAS  PubMed  Google Scholar 

  177. Scheel, C. & Weinberg, R. A. Cancer stem cells and epithelial-mesenchymal transition: concepts and molecular links. Semin. Cancer Biol. 22, 396–403 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Zhang, N. et al. The Merlin/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals. Dev. Cell 19, 27–38 (2010). This study shows that heterozygous deletion of YAP significantly suppresses the overproliferation phenotypes resulting from loss of NF2 , which suggests that YAP is a potential drug target in cancers associated with NF2 inactivation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Asthagiri, A. R. et al. Neurofibromatosis type 2. Lancet 373, 1974–1986 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Hanemann, C. O. Magic but treatable? Tumours due to loss of merlin. Brain 131, 606–615 (2008).

    Article  CAS  PubMed  Google Scholar 

  181. Murakami, H. et al. LATS2 is a tumor suppressor gene of malignant mesothelioma. Cancer Res. 71, 873–883 (2011).

    Article  CAS  PubMed  Google Scholar 

  182. Hall, C. A. et al. Hippo pathway effector Yap is an ovarian cancer oncogene. Cancer Res. 70, 8517–8525 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Baldwin, C., Garnis, C., Zhang, L., Rosin, M. P. & Lam, W. L. Multiple microalterations detected at high frequency in oral cancer. Cancer Res. 65, 7561–7567 (2005).

    Article  CAS  PubMed  Google Scholar 

  184. Snijders, A. M. et al. Rare amplicons implicate frequent deregulation of cell fate specification pathways in oral squamous cell carcinoma. Oncogene 24, 4232–4242 (2005).

    Article  CAS  PubMed  Google Scholar 

  185. Modena, P. et al. Identification of tumor-specific molecular signatures in intracranial ependymoma and association with clinical characteristics. J. Clin. Oncol. 24, 5223–5233 (2006).

    Article  CAS  PubMed  Google Scholar 

  186. Jiang, Z. et al. Promoter hypermethylation-mediated down-regulation of LATS1 and LATS2 in human astrocytoma. Neurosci. Res. 56, 450–458 (2006).

    Article  CAS  PubMed  Google Scholar 

  187. Takahashi, Y. et al. Down-regulation of LATS1 and LATS2 mRNA expression by promoter hypermethylation and its association with biologically aggressive phenotype in human breast cancers. Clin. Cancer Res. 11, 1380–1385 (2005).

    Article  CAS  PubMed  Google Scholar 

  188. Seidel, C. et al. Frequent hypermethylation of MST1 and MST2 in soft tissue sarcoma. Mol. Carcinog. 46, 865–871 (2007).

    Article  CAS  PubMed  Google Scholar 

  189. Li, H. et al. Deregulation of Hippo kinase signalling in human hepatic malignancies. Liver Int. 32, 38–47 (2012).

    Article  CAS  PubMed  Google Scholar 

  190. Zhang, T. et al. Hepatitis B virus X protein modulates oncogene Yes-associated protein by CREB to promote growth of hepatoma cells. Hepatology 56, 2051–2059 (2012).

    Article  CAS  PubMed  Google Scholar 

  191. Wu, H. et al. The Ets transcription factor GABP is a component of the Hippo pathway essential for growth and antioxidant defense. Cell Rep. 3, 1663–1677 (2013).

    Article  CAS  PubMed  Google Scholar 

  192. Wang, J. et al. TRIB2 acts downstream of Wnt/TCF in liver cancer cells to regulate YAP and C/EBPα function. Mol. Cell 51, 211–225 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Konsavage, W. M. et al. Wnt/β-catenin signaling regulates Yes-associated protein (YAP) gene expression in colorectal carcinoma cells. J. Biol. Chem. 287, 11730–11739 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Liu-Chittenden, Y. et al. Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP. Genes Dev. 26, 1300–1305 (2012). This paper shows that the expression of a dominant negative version of TEAD2 suppresses the overproliferation and tumorigenesis caused by YAP overexpression or inactivation of NF2, but it does not affect normal liver development. Furthermore, the authors identify the porphyrin family — particularly verteporfin — as inhibitors of the YAP–TEAD interaction and activity. Treatment of mice using verteporfin prevented liver overgrowth owing to YAP overexpression or to the activation of endogenous YAP in Nf2 -mutant livers.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Barry, E. R. et al. Restriction of intestinal stem cell expansion and the regenerative response by YAP. Nature 493, 106–110 (2013). This paper reports the surprising finding that in transgenic mice the overexpression of YAP in the colon reduces WNT expression and intestinal stem cell proliferation; conversely, loss of YAP results in WNT hypersensitivity during regeneration, possibly through a mechanism that involves sequestration of the WNT pathway component DVL by YAP in the cytoplasm.

    Article  CAS  PubMed  Google Scholar 

  196. Li, V. S. & Clevers, H. Intestinal regeneration: YAP-tumor suppressor and oncoprotein? Curr. Biol. 23, R110–R112 (2013).

    Article  CAS  PubMed  Google Scholar 

  197. Diep, C. H. et al. Down-regulation of Yes associated protein 1 expression reduces cell proliferation and clonogenicity of pancreatic cancer cells. PLoS ONE 7, e32783 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Lamar, J. M. et al. The Hippo pathway target, YAP, promotes metastasis through its TEAD-interaction domain. Proc. Natl Acad. Sci. USA 109, E2441–E2450 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  199. Zhou, Z., Zhu, J. S., Xu, Z. P. & Zhang, Q. Lentiviral vector-mediated siRNA knockdown of the YAP gene inhibits growth and induces apoptosis in the SGC7901 gastric cancer cell line. Mol. Med. Rep. 4, 1075–1082 (2011).

    CAS  PubMed  Google Scholar 

  200. Wang, X., Su, L. & Ou, Q. Yes-associated protein promotes tumour development in luminal epithelial derived breast cancer. Eur. J. Cancer 48, 1227–1234 (2012).

    Article  CAS  PubMed  Google Scholar 

  201. Chen, D. et al. LIFR is a breast cancer metastasis suppressor upstream of the Hippo-YAP pathway and a prognostic marker. Nature Med. 18, 1511–1517 (2012).

    Article  CAS  PubMed  Google Scholar 

  202. Lavado, A. et al. Tumor suppressor Nf2 limits expansion of the neural progenitor pool by inhibiting Yap/Taz transcriptional coactivators. Development 140, 3323–3334 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Lian, I. et al. The role of YAP transcription coactivator in regulating stem cell self-renewal and differentiation. Genes Dev. 24, 1106–1118 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Qin, H. et al. Transcriptional analysis of pluripotency reveals the Hippo pathway as a barrier to reprogramming. Hum. Mol. Genet. 21, 2054–2067 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Fellous, T. G. et al. Locating the stem cell niche and tracing hepatocyte lineages in human liver. Hepatology 49, 1655–1663 (2009).

    Article  CAS  PubMed  Google Scholar 

  206. Bergmann, O. et al. Evidence for cardiomyocyte renewal in humans. Science 324, 98–102 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Xu, M. Z. et al. AXL receptor kinase is a mediator of YAP-dependent oncogenic functions in hepatocellular carcinoma. Oncogene 30, 1229–1240 (2011).

    Article  CAS  PubMed  Google Scholar 

  208. Neesse, A. et al. CTGF antagonism with mAb FG-3019 enhances chemotherapy response without increasing drug delivery in murine ductal pancreas cancer. Proc. Natl Acad. Sci. USA 110, 12325–12330 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  209. Zhang, J. et al. YAP-dependent induction of amphiregulin identifies a non-cell-autonomous component of the Hippo pathway. Nature Cell Biol. 11, 1444–1450 (2009).

    Article  CAS  PubMed  Google Scholar 

  210. Yang, N. et al. TAZ induces growth factor-independent proliferation through activation of EGFR ligand amphiregulin. Cell Cycle 11, 2922–2930 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Liu, A. M., Xu, M. Z., Chen, J., Poon, R. T. & Luk, J. M. Targeting YAP and Hippo signaling pathway in liver cancer. Expert Opin. Ther. Targets 14, 855–868 (2010).

    Article  CAS  PubMed  Google Scholar 

  212. Cohen, P. Protein kinases — the major drug targets of the twenty-first century? Nature Rev. Drug Discov. 1, 309–315 (2002).

    Article  CAS  Google Scholar 

  213. Anand, R. et al. Toward the development of a potent and selective organoruthenium mammalian sterile 20 kinase inhibitor. J. Med. Chem. 52, 1602–1611 (2009). This paper reports on the development of a small-molecule inhibitor for the MST1 kinase that has high selectivity and that can serve as a starting point for developing improved MST1 inhibitors.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Ghose, A. K., Herbertz, T., Pippin, D. A., Salvino, J. M. & Mallamo, J. P. Knowledge based prediction of ligand binding modes and rational inhibitor design for kinase drug discovery. J. Med. Chem. 51, 5149–5171 (2008).

    Article  CAS  PubMed  Google Scholar 

  215. Norman, R. A., Toader, D. & Ferguson, A. D. Structural approaches to obtain kinase selectivity. Trends Pharmacol. Sci. 33, 273–278 (2012).

    Article  CAS  PubMed  Google Scholar 

  216. Chen, L. et al. Structural basis of YAP recognition by TEAD4 in the Hippo pathway. Genes Dev. 24, 290–300 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Li, Z. et al. Structural insights into the YAP and TEAD complex. Genes Dev. 24, 235–240 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Tian, W., Yu, J., Tomchick, D. R., Pan, D. & Luo, X. Structural and functional analysis of the YAP-binding domain of human TEAD2. Proc. Natl Acad. Sci. USA 107, 7293–7298 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  219. Fan, R., Kim, N. G. & Gumbiner, B. M. Regulation of Hippo pathway by mitogenic growth factors via phosphoinositide 3-kinase and phosphoinositide-dependent kinase-1. Proc. Natl Acad. Sci. USA 110, 2569–2574 (2013). This study shows that mitogenic growth factors such as EGF stimulate YAP nuclear accumulation and activity through PI3K and phosphoinositide-dependent kinase-1 (PDK1) signalling, which causes dissociation of a Hippo core complex. PI3K and PDK1 inhibitors, but not AKT inhibitors, inhibit YAP nuclear accumulation in several cultured cell lines.

    Article  PubMed  PubMed Central  Google Scholar 

  220. Strassburger, K., Tiebe, M., Pinna, F., Breuhahn, K. & Teleman, A. A. Insulin/IGF signaling drives cell proliferation in part via Yorkie/YAP. Dev. Biol. 367, 187–196 (2012).

    Article  CAS  PubMed  Google Scholar 

  221. Yu, F. X. et al. Protein kinase A activates the Hippo pathway to modulate cell proliferation and differentiation. Genes Dev. 27, 1223–1232 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Bao, Y. et al. 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, 199–208 (2011). Using the intracellular localization of a green fluorescent protein (GFP)–YAP fusion protein in osteosarcoma cells as a read-out, the authors conducted a small-scale screen and identified the G protein-coupled β-adrenergic receptor agonist dobutamine as an inhibitor of YAP nuclear localization and activity.

    Article  CAS  PubMed  Google Scholar 

  223. Oudhoff, M. J. et al. Control of the Hippo pathway by Set7-dependent methylation of Yap. Dev. Cell 26, 188–194 (2013).

    Article  CAS  PubMed  Google Scholar 

  224. Hata, S. et al. A novel acetylation cycle of transcription co-activator Yes-associated protein that is downstream of Hippo pathway is triggered in response to SN2 alkylating agents. J. Biol. Chem. 287, 22089–22098 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Mao, B. et al. SIRT1 regulates YAP2-mediated cell proliferation and chemoresistance in hepatocellular carcinoma. Oncogene http://dx.doi.org/10.1038/onc.2013.88 (2013).

Download references

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Randy Johnson or Georg Halder.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

Malignancies

Invasive neoplasms or tumours. Malignant tumours invade neighbouring tissues and have the potential to spread to other tissues.

Transcriptional co-activators

Proteins that stimulate gene expression but that cannot bind to DNA itself and are instead recruited to DNA by binding to another DNA-binding transcription factor.

Imaginal discs

Disc-like structures of epithelial cells found in insect larvae that proliferate during the larval stages to around 100,000 cells and then differentiate into various adult structures during metamorphosis. The simplicity of their single-cell layered structure and the ease of genetic manipulation and observation made Drosophila melanogaster imaginal discs into a prominent model system to study cell proliferation, growth control, tissue patterning and cell type specification.

Neoplasia

Abnormal growth of tissue that exceeds surrounding tissues and stops responding properly to appropriate growth-inhibitory signals.

Mammospheres

Primary or immortalized mammary epithelial cells that can be grown under anchorage-independent conditions to generate spheres of cells. The mammosphere or related tumoursphere assay is often used to detect stem cells in mixed populations of stem and progenitor cells. Transient amplifying or differentiated cells have a limited ability to form mammospheres, whereas bona fide stem cells can generate spheres that can be passaged beyond ten generations.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Johnson, R., Halder, G. The two faces of Hippo: targeting the Hippo pathway for regenerative medicine and cancer treatment. Nat Rev Drug Discov 13, 63–79 (2014). https://doi.org/10.1038/nrd4161

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd4161

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer