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 Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal

Nature Cell Biology volume 13, pages 877–883 (2011)Cite this article

Subjects

Abstract

Precise control of organ size is crucial during animal development and regeneration. In Drosophila and mammals, studies over the past decade have uncovered a critical role for the Hippo tumour-suppressor pathway in the regulation of organ size. Dysregulation of this pathway leads to massive overgrowth of tissue. The Hippo signalling pathway is highly conserved and limits organ size by phosphorylating and inhibiting the transcription co-activators YAP and TAZ in mammals and Yki in Drosophila, key regulators of proliferation and apoptosis. The Hippo pathway also has a critical role in the self-renewal and expansion of stem cells and tissue-specific progenitor cells, and has important functions in tissue regeneration. Emerging evidence shows that the Hippo pathway is regulated by cell polarity, cell adhesion and cell junction proteins. In this review we summarize current understanding of the composition and regulation of the Hippo pathway, and discuss how cell polarity and cell adhesion proteins inform the role of this pathway in organ size control and regeneration.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: The Hippo pathway in Drosophila and mammals.
Figure 2: Mechanisms of YAP/TAZ/Yki inhibition by the Hippo pathway.
Figure 3: Mechanisms of the Hippo pathway in regulation of organ size and regeneration.

Similar content being viewed by others

References

  1. Stanger, B. Z. Organ size determination and the limits of regulation. Cell Cycle 7, 318–324 (2008).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Leevers, S. J. & McNeill, H. Controlling the size of organs and organisms. Curr. Opin. Cell Biol. 17, 604–609 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. 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 

  6. 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 (2010).

    Article  PubMed  CAS  Google Scholar 

  7. Cai, J. et al. The Hippo signaling pathway restricts the oncogenic potential of an intestinal regeneration program. Genes Dev. 24, 2383–2388 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 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 

  9. 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 

  10. 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 

  11. 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  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. Cao, X., Pfaff, S. L. & Gage, F. H. YAP regulates neural progenitor cell number via the TEA domain transcription factor. Genes Dev. 22, 3320–3334 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. 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 

  15. 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).

    Article  CAS  PubMed  Google Scholar 

  16. 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 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  19. 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 

  20. 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 

  21. 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 

  22. 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 

  23. 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 

  24. 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 

  25. 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 

  26. 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 

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

    Article  CAS  PubMed  Google Scholar 

  28. 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 

  29. 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 

  30. 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 

  31. Tyler, D. M. & Baker, N. E. Expanded and Fat regulate growth and differentiation in the Drosophila eye through multiple signaling pathways. Dev. Biol 305, 187–201 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 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 

  33. 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 

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

    Article  CAS  PubMed  Google Scholar 

  35. 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 

  36. Matakatsu, H. & Blair, S. S. Separating the adhesive and signaling functions of the Fat and Dachsous protocadherins. Development 133, 2315–2324 (2006).

    Article  CAS  PubMed  Google Scholar 

  37. Sopko, R. et al. Phosphorylation of the tumor suppressor Fat is regulated by its ligand Dachsous and the kinase discs overgrown. Curr. Biol. 19, 1112–1117 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Feng, Y. & Irvine, K. D. Processing and phosphorylation of the Fat receptor. Proc. Natl Acad. Sci. USA 106, 11989–11994 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Simon, M. A., Xu, A., Ishikawa, H. O. & Irvine, K. D. Modulation of Fat:Dachsous binding by the cadherin domain kinase Four-jointed. Curr Biol 20, 811–817 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Rogulja, D., Rauskolb, C. & Irvine, K. D. Morphogen control of wing growth through the Fat signaling pathway. Dev. Cell 15, 309–321 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Willecke, M., Hamaratoglu, F., Sansores-Garcia, L., Tao, C. & Halder, G. Boundaries of Dachsous cadherin activity modulate the Hippo signaling pathway to induce cell proliferation. Proc. Natl Acad. Sci. USA 105, 14897–14902 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Mao, Y., Kucuk, B. & Irvine, K. D. Drosophila lowfat, a novel modulator of Fat signaling. Development 136, 3223–3233 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zecca, M. & Struhl, G. A feed-forward circuit linking wingless, Fat–Dachsous signaling, and the Warts-Hippo pathway to Drosophila wing growth. PLoS Biol. 8, e1000386 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Feng, Y. & Irvine, K. D. Fat and expanded act in parallel to regulate growth through warts. Proc. Natl Acad. Sci. USA 104, 20362–20367 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 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 

  46. 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 

  47. 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 

  48. 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  CAS  PubMed  PubMed Central  Google Scholar 

  49. 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 

  50. Tao, W. et al. Human homologue of the Drosophila melanogaster lats tumour suppressor modulates CDC2 activity. Nat. Genet. 21, 177–181 (1999).

    Article  CAS  PubMed  Google Scholar 

  51. Graves, J. D. et al. Caspase-mediated activation and induction of apoptosis by the mammalian Ste20-like kinase Mst1. EMBO J. 17, 2224–2234 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. 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 

  53. Lee, J. H. et al. A crucial role of WW45 in developing epithelial tissues in the mouse. EMBO J. 27, 1231–1242 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Oh, H. J. et al. Role of the tumor suppressor RASSF1A in Mst1-mediated apoptosis. Cancer Res. 66, 2562–2569 (2006).

    Article  CAS  PubMed  Google Scholar 

  55. Khokhlatchev, A. et al. Identification of a novel Ras-regulated proapoptotic pathway. Curr. Biol. 12, 253–265 (2002).

    Article  CAS  PubMed  Google Scholar 

  56. 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 

  57. 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 

  58. 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 

  59. 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 

  60. 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 

  61. 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 

  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. 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 

  64. 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 

  65. 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 

  66. 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 

  67. 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 

  68. 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 

  69. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Benhamouche, S. et al. Nf2/Merlin controls progenitor homeostasis and tumorigenesis in the liver. Genes Dev. 24, 1718–1730 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. 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 

  72. 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  CAS  PubMed  PubMed Central  Google Scholar 

  73. 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  CAS  PubMed  PubMed Central  Google Scholar 

  74. 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 

  75. 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 

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

    Article  CAS  PubMed  Google Scholar 

  77. 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  PubMed  PubMed Central  CAS  Google Scholar 

  78. 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 

  79. Gilbert, M. M., Tipping, M., Veraksa, A. & Moberg, K. H. A screen for conditional growth suppressor genes identifies the Drosophila homolog of HD-PTP as a regulator of the oncoprotein Yorkie. Dev. Cell 20, 700–712 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Badouel, C. et al. The FERM-domain protein Expanded regulates Hippo pathway activity via direct interactions with the transcriptional activator Yorkie. Dev. Cell 16, 411–420 (2009).

    Article  CAS  PubMed  Google Scholar 

  81. Oh, H., Reddy, B. V. & Irvine, K. D. Phosphorylation-independent repression of Yorkie in Fat-Hippo signaling. Dev. Biol. 335, 188–197 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Zhao, B. et al. Angiomotin is a novel Hippo pathway component that inhibits YAP oncoprotein. Genes Dev. 25, 51–63 (2001).

    Article  CAS  Google Scholar 

  83. Wang, W., Huang, J. & Chen, J. Angiomotin-like proteins associate with and negatively regulate YAP1. J. Biol. Chem. 286, 4364–4370 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. 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 

  85. 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 

  86. 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 

  87. 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 

  88. 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 

  89. 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 

  90. 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 

  91. 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 

  92. 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 

  93. 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 

  94. Kitagawa, M. A Sveinsson's chorioretinal atrophy-associated missense mutation in mouse Tead1 affects its interaction with the co-factors YAP and TAZ. Biochem. Biophys. Res. Commun. 361, 1022–1026 (2007).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Fossdal, R. et al. A novel TEAD1 mutation is the causative allele in Sveinsson's chorioretinal atrophy (helicoid peripapillary chorioretinal degeneration). Hum. Mol. Genet. 13, 975–981 (2004).

    Article  CAS  PubMed  Google Scholar 

  97. 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 

  98. Neto-Silva, R. M., de Beco, S. & Johnston, L. A. Evidence for a growth-stabilizing regulatory feedback mechanism between Myc and Yorkie, the Drosophila homolog of Yap. Dev. Cell 19, 507–520 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Ziosi, M. et al. dMyc functions downstream of Yorkie to promote the supercompetitive behavior of Hippo pathway mutant cells. PLoS Genet. 6, e1001140 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. 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 

  101. 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 

  102. Komuro, A., Nagai, M., Navin, N. E. & Sudol, M. WW domain-containing protein YAP associates with ErbB-4 and acts as a co-transcriptional activator for the carboxyl-terminal fragment of ErbB-4 that translocates to the nucleus. J. Biol. Chem. 278, 33334–33341 (2003).

    Article  CAS  PubMed  Google Scholar 

  103. Omerovic, J. et al. Ligand-regulated association of ErbB-4 to the transcriptional co-activator YAP65 controls transcription at the nuclear level. Exp. Cell Res. 294, 469–479 (2004).

    Article  CAS  PubMed  Google Scholar 

  104. 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 

  105. Hong, J. H. et al. TAZ, a transcriptional modulator of mesenchymal stem cell differentiation. Science 309, 1074–1078 (2005).

    Article  CAS  PubMed  Google Scholar 

  106. 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 

  107. Cui, C. B., Cooper, L. F., Yang, X., Karsenty, G. & Aukhil, I. Transcriptional coactivation of bone-specific transcription factor Cbfa1 by TAZ. Mol. Cell Biol. 23, 1004–1013 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Park, K. S. et al. TAZ interacts with TTF-1 and regulates expression of surfactant protein-C. J. Biol. Chem. 279, 17384–17390 (2004).

    Article  CAS  PubMed  Google Scholar 

  109. Murakami, M. et al. Transcriptional activity of Pax3 is co-activated by TAZ. Biochem. Biophys. Res. Commun. 339, 533–539 (2006).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  111. Lapi, E. et al. PML, YAP, and p73 are components of a proapoptotic autoregulatory feedback loop. Mol. Cell 32, 803–814 (2008).

    Article  CAS  PubMed  Google Scholar 

  112. Matallanas, D. et al. RASSF1A elicits apoptosis through an MST2 pathway directing proapoptotic transcription by the p73 tumor suppressor protein. Mol. Cell 27, 962–975 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. 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 

  114. Thompson, B. J. & Cohen, S. M. The Hippo pathway regulates the bantam microRNA to control cell proliferation and apoptosis in Drosophila. Cell 126, 767–774 (2006).

    Article  CAS  PubMed  Google Scholar 

  115. Nolo, R., Morrison, C. M., Tao, C., Zhang, X. & Halder, G. The bantam microRNA is a target of the Hippo tumor-suppressor pathway. Curr. Biol. 16, 1895–1904 (2006).

    Article  CAS  PubMed  Google Scholar 

  116. 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 

  117. 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 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Genevet, A. et al. The Hippo pathway regulates apical-domain size independently of its growth-control function. J. Cell Sci. 122, 2360–2370 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Skouloudaki, K. et al. Scribble participates in Hippo signaling and is required for normal zebrafish pronephros development. Proc. Natl Acad. Sci. USA 106, 8579–8584 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Zhan, L. et al. Deregulation of scribble promotes mammary tumorigenesis and reveals a role for cell polarity in carcinoma. Cell 135, 865–878 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Hong, Y., Stronach, B., Perrimon, N., Jan, L. Y. & Jan, Y. N. Drosophila Stardust interacts with Crumbs to control polarity of epithelia but not neuroblasts. Nature 414, 634–638 (2001).

    Article  CAS  PubMed  Google Scholar 

  123. Grzeschik, N. A., Amin, N., Secombe, J., Brumby, A. M. & Richardson, H. E. Abnormalities in cell proliferation and apico-basal cell polarity are separable in Drosophila lgl mutant clones in the developing eye. Dev. Biol. 311, 106–123 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. 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 

  125. 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  PubMed  PubMed Central  CAS  Google Scholar 

  126. 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 

  127. 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  CAS  PubMed  PubMed Central  Google Scholar 

  128. 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 

  129. 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 

  130. Furuyama, K. et al. Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine. Nat. Genet. 43, 34–41 (2010).

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We apologize for those primary works that we could not cite due to space constraints. Research in the lab of K.L.G. is supported by grants from NIH and CIRM.

Author information

Authors and Affiliations

  1. Bin Zhao is at the Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China,

    Bin Zhao

  2. Karen Tumaneng and Kun-Liang Guan are in the Department of Pharmacology and Moores Cancer Center, Bin Zhao, University of California at San Diego, La Jolla, California 92093-0815, USA,

    Bin Zhao, Karen Tumaneng & Kun-Liang Guan

Authors
  1. Bin Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Karen Tumaneng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kun-Liang Guan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kun-Liang Guan.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhao, B., Tumaneng, K. & Guan, KL. The Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal. Nat Cell Biol 13, 877–883 (2011). https://doi.org/10.1038/ncb2303

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb2303

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing