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 intestinal regeneration and disease

Nature Reviews Gastroenterology & Hepatology volume 13, pages 324–337 (2016)Cite this article

Subjects

Key Points

  • The Hippo pathway plays an important part in intestinal homeostasis and regeneration in both Drosophila melanogaster and mammals, and its dysregulation often leads to uncontrolled tissue growth

  • In general, YAP1 and TAZ activity promotes intestinal stem cell properties, and overexpression of YAP1 induces stem cell expansion

  • YAP1 and TAZ are crucial for intestinal tissue regeneration after injury; YAP1 depletion leads to disturbed tissue formation during regeneration

  • Crosstalk between the Hippo pathway and other signalling pathways, such as Wnt and Notch, regulates intestinal tissue homeostasis and regeneration, although detailed mechanisms have not yet been elucidated

  • Dysregulation of the Hippo pathway leads to tumorigenesis; YAP1 and TAZ are oncogenic in colorectal cancers, as illustrated by data from mouse models and patient specimens

  • The Hippo pathway also has an important role in liver damage repair and tumorigenesis, and dysregulation of the Hippo pathway leads to uncontrolled growth in the liver

Abstract

The Hippo pathway is a signalling cascade conserved from Drosophila melanogaster to mammals. The mammalian core kinase components comprise MST1 and MST2, SAV1, LATS1 and LATS2 and MOB1A and MOB1B. The transcriptional co-activators YAP1 and TAZ are the downstream effectors of the Hippo pathway and regulate target gene expression. Hippo signalling has crucial roles in the control of organ size, tissue homeostasis and regeneration, and dysregulation of the Hippo pathway can lead to uncontrolled cell growth and malignant transformation. Mammalian intestine consists of a stem cell compartment as well as differentiated cells, and its ability to regenerate rapidly after injury makes it an excellent model system to study tissue homeostasis, regeneration and tumorigenesis. Several studies have established the important role of the Hippo pathway in these processes. In addition, crosstalk between Hippo and other signalling pathways provides tight, yet versatile, regulation of tissue homeostasis. In this Review, we summarize studies on the role of the Hippo pathway in the intestine on these physiological processes and the underlying mechanisms responsible, and discuss future research directions and potential therapeutic strategies targeting Hippo signalling in intestinal disease.

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 integrates signals to regulate the activity of YAP1 and TAZ.
Figure 2: The Hippo pathway controls Drosophila midgut homeostasis by restricting Yki activity.
Figure 3: Mammalian intestine cellular structure and cell fate decision.
Figure 4: The Hippo pathway in intestinal homeostasis and injury-induced regeneration.
Figure 5: Crosstalk between the Hippo pathway and Wnt and Notch signalling in the intestine.
Figure 6: Hippo pathway has roles in organ size control and carcinogenesis in different types of liver cells.

Similar content being viewed by others

References

  1. Barry, E. R. & Camargo, F. D. The Hippo superhighway: signaling crossroads converging on the Hippo/Yap pathway in stem cells and development. Curr. Opin. Cell Biol. 25, 247–253 (2013).

    Article  CAS  PubMed  Google Scholar 

  2. Piccolo, S., Dupont, S. & Cordenonsi, M. The biology of YAP/TAZ: hippo signaling and beyond. Physiol. Rev. 94, 1287–1312 (2014).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. Moroishi, T., Hansen, C. G. & Guan, K. L. The emerging roles of YAP and TAZ in cancer. Nat. Rev. Cancer 15, 73–79 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Yu, F. X., Meng, Z., Plouffe, S. W. & Guan, K. L. Hippo pathway regulation of gastrointestinal tissues. Annu. Rev. Physiol. 77, 201–227 (2015).

    Article  CAS  PubMed  Google Scholar 

  6. Bossuyt, W. et al. An evolutionary shift in the regulation of the Hippo pathway between mice and flies. Oncogene 33, 1218–1228 (2014).

    Article  CAS  PubMed  Google Scholar 

  7. Meng, Z., Moroishi, T. & Guan, K. L. Mechanisms of Hippo pathway regulation. Genes Dev. 30, 1–17 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 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 

  9. 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 

  10. 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 

  11. 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 

  12. 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 

  13. 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 

  14. 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 

  15. 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 

  16. 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 

  17. 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 

  18. 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 

  19. 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 

  20. 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 

  21. 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 

  22. Zheng, Y. et al. Identification of Happyhour/MAP4K as alternative Hpo/Mst-like kinases in the Hippo kinase cascade. Dev. Cell 34, 642–655 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Li, Q. et al. The conserved misshapen–warts–Yorkie pathway acts in enteroblasts to regulate intestinal stem cells in Drosophila. Dev. Cell 31, 291–304 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Meng, Z. et al. MAP4K family kinases act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway. Nat. Commun. 6, 8357 (2015).

    Article  CAS  PubMed  Google Scholar 

  25. 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 

  26. 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 

  27. 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 

  28. Varelas, X. The Hippo pathway effectors TAZ and YAP in development, homeostasis and disease. Development 141, 1614–1626 (2014).

    Article  CAS  PubMed  Google Scholar 

  29. Glantschnig, H., Rodan, G. A. & Reszka, A. A. Mapping of MST1 kinase sites of phosphorylation. Activation and autophosphorylation. J. Biol. Chem. 277, 42987–42996 (2002).

    Article  CAS  PubMed  Google Scholar 

  30. Lee, K. K. & Yonehara, S. Phosphorylation and dimerization regulate nucleocytoplasmic shuttling of mammalian STE20-like kinase (MST). J. Biol. Chem. 277, 12351–12358 (2002).

    Article  CAS  PubMed  Google Scholar 

  31. Creasy, C. L., Ambrose, D. M. & Chernoff, J. The Ste20-like protein kinase, Mst1, dimerizes and contains an inhibitory domain. J. Biol. Chem. 271, 21049–21053 (1996).

    Article  CAS  PubMed  Google Scholar 

  32. Hwang, E. et al. Structural insight into dimeric interaction of the SARAH domains from Mst1 and RASSF family proteins in the apoptosis pathway. Proc. Natl Acad. Sci. USA 104, 9236–9241 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ni, L., Zheng, Y., Hara, M., Pan, D. & Luo, X. Structural basis for Mob1-dependent activation of the core Mst–Lats kinase cascade in Hippo signaling. Genes Dev. 29, 1416–1431 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 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 

  35. 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 

  36. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 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 

  38. 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 

  39. 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 

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

    Article  CAS  PubMed  Google Scholar 

  41. Plouffe, S. W., Hong, A. W. & Guan, K. L. Disease implications of the Hippo/YAP pathway. Trends Mol. Med. 21, 212–222 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 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).

    Article  CAS  PubMed  Google Scholar 

  43. Schulzke, J. D. et al. Epithelial tight junctions in intestinal inflammation. Ann. NY Acad. Sci. 1165, 294–300 (2009).

    Article  PubMed  Google Scholar 

  44. Paramasivam, M., Sarkeshik, A., Yates, J. R. 3rd, 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 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. 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 

  47. 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 

  48. 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 

  49. Mohseni, M. et al. A genetic screen identifies an LKB1–MARK signalling axis controlling the Hippo–YAP pathway. Nat. Cell Biol. 16, 108–117 (2014).

    Article  CAS  PubMed  Google Scholar 

  50. Mo, J. S. et al. Cellular energy stress induces AMPK-mediated regulation of YAP and the Hippo pathway. Nat. Cell Biol. 17, 500–510 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Wang, W. et al. AMPK modulates Hippo pathway activity to regulate energy homeostasis. Nat. Cell Biol. 17, 490–499 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. DeRan, M. et al. Energy stress regulates hippo–YAP signaling involving AMPK-mediated regulation of angiomotin-like 1 protein. Cell Rep. 9, 495–503 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. 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 

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

    Article  CAS  PubMed  Google Scholar 

  55. 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 

  56. 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 

  57. 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  CAS  PubMed  PubMed Central  Google Scholar 

  58. Mori, M. et al. Hippo signaling regulates microprocessor and links cell-density-dependent miRNA biogenesis to cancer. Cell 156, 893–906 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Chaulk, S. G., Lattanzi, V. J., Hiemer, S. E., Fahlman, R. P. & Varelas, X. The Hippo pathway effectors TAZ/YAP regulate dicer expression and microRNA biogenesis through Let-7. J. Biol. Chem. 289, 1886–1891 (2014).

    Article  CAS  PubMed  Google Scholar 

  60. Shao, D. et al. A functional interaction between Hippo-YAP signalling and FoxO1 mediates the oxidative stress response. Nat. Commun. 5, 3315 (2014).

    Article  PubMed  CAS  Google Scholar 

  61. Wu, H. et al. Integration of Hippo signalling and the unfolded protein response to restrain liver overgrowth and tumorigenesis. Nat. Commun. 6, 6239 (2015).

    Article  CAS  PubMed  Google Scholar 

  62. Ma, B. et al. Hypoxia regulates Hippo signalling through the SIAH2 ubiquitin E3 ligase. Nat. Cell Biol. 17, 95–103 (2015).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Rauskolb, C., Sun, S., Sun, G., Pan, Y. & Irvine, K. D. Cytoskeletal tension inhibits Hippo signaling through an Ajuba–Warts complex. Cell 158, 143–156 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Codelia, V. A., Sun, G. & Irvine, K. D. Regulation of YAP by mechanical strain through Jnk and Hippo signaling. Curr. Biol. 24, 2012–2017 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Gayer, C. P. & Basson, M. D. The effects of mechanical forces on intestinal physiology and pathology. Cell. Signal. 21, 1237–1244 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. 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 

  69. 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 

  70. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. O'Hayre, M. et al. The emerging mutational landscape of G proteins and G-protein-coupled receptors in cancer. Nat. Rev. Cancer 13, 412–424 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Liu, G. et al. Kaposi sarcoma-associated herpesvirus promotes tumorigenesis by modulating the Hippo pathway. Oncogene 34, 3536–3546 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Feng, X. et al. Hippo-independent activation of YAP by the GNAQ uveal melanoma oncogene through a trio-regulated rho GTPase signaling circuitry. Cancer Cell 25, 831–845 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Yu, F. X. et al. Mutant Gq/11 promote uveal melanoma tumorigenesis by activating YAP. Cancer Cell 25, 822–830 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. 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).

    Article  CAS  PubMed  Google Scholar 

  76. Iglesias-Bartolome, R. et al. Inactivation of a Gαs-PKA tumour suppressor pathway in skin stem cells initiates basal-cell carcinogenesis. Nat. Cell Biol. 17, 793–803 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Reimann, F., Tolhurst, G. & Gribble, F. M. G-protein-coupled receptors in intestinal chemosensation. Cell Metab. 15, 421–431 (2012).

    Article  CAS  PubMed  Google Scholar 

  78. Pasco, M. Y., Loudhaief, R. & Gallet, A. The cellular homeostasis of the gut: what the Drosophila model points out. Histol. Histopathol. 30, 277–292 (2015).

    CAS  PubMed  Google Scholar 

  79. Buchon, N., Broderick, N. A. & Lemaitre, B. Gut homeostasis in a microbial world: insights from Drosophila melanogaster. Nat. Rev. Microbiol. 11, 615–626 (2013).

    Article  CAS  PubMed  Google Scholar 

  80. Sun, G. & Irvine, K. D. Ajuba family proteins link JNK to Hippo signaling. Sci. Signal. 6, ra81 (2013).

    Article  PubMed  CAS  Google Scholar 

  81. 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 

  82. 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 

  83. 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 

  84. Huang, H. et al. Bantam is essential for Drosophila intestinal stem cell proliferation in response to Hippo signaling. Dev. Biol. 385, 211–219 (2014).

    Article  CAS  PubMed  Google Scholar 

  85. 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 

  86. Wang, C. et al. Suppressor of Deltex mediates Pez degradation and modulates Drosophila midgut homeostasis. Nat. Commun. 6, 6607 (2015).

    Article  CAS  PubMed  Google Scholar 

  87. Wang, Z. et al. Mutational analysis of the tyrosine phosphatome in colorectal cancers. Science 304, 1164–1166 (2004).

    Article  CAS  PubMed  Google Scholar 

  88. Huang, X. et al. The sterile 20-like kinase tao controls tissue homeostasis by regulating the hippo pathway in Drosophila adult midgut. J. Genet. Genomics 41, 429–438 (2014).

    Article  PubMed  Google Scholar 

  89. Ren, F. et al. Drosophila Myc integrates multiple signaling pathways to regulate intestinal stem cell proliferation during midgut regeneration. Cell Res. 23, 1133–1146 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Jin, Y. et al. Brahma is essential for Drosophila intestinal stem cell proliferation and regulated by Hippo signaling. eLife 2, e00999 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  91. Barker, N. Adult intestinal stem cells: critical drivers of epithelial homeostasis and regeneration. Nat. Rev. Mol. Cell Biol. 15, 19–33 (2014).

    Article  CAS  PubMed  Google Scholar 

  92. Sato, T. et al. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature 469, 415–418 (2011).

    Article  CAS  PubMed  Google Scholar 

  93. van der Flier, L. G. & Clevers, H. Stem cells, self-renewal, and differentiation in the intestinal epithelium. Annu. Rev. Physiol. 71, 241–260 (2009).

    Article  CAS  PubMed  Google Scholar 

  94. Barker, N. et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003–1007 (2007).

    Article  CAS  PubMed  Google Scholar 

  95. Munoz, J. et al. The Lgr5 intestinal stem cell signature: robust expression of proposed quiescent '+4' cell markers. EMBO J. 31, 3079–3091 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Tian, H. et al. A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable. Nature 478, 255–259 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Mo, J. S., Park, H. W. & Guan, K. L. The Hippo signaling pathway in stem cell biology and cancer. EMBO Rep. 15, 642–656 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. 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 

  99. Azzolin, L. et al. YAP/TAZ incorporation in the β-catenin destruction complex orchestrates the Wnt response. Cell 158, 157–170 (2014).

    Article  CAS  PubMed  Google Scholar 

  100. 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 

  101. 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–E1320 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Imajo, M., Ebisuya, M. & Nishida, E. Dual role of YAP and TAZ in renewal of the intestinal epithelium. Nat. Cell Biol. 17, 7–19 (2015).

    Article  CAS  PubMed  Google Scholar 

  103. Llado, V. et al. Repression of intestinal stem cell function and tumorigenesis through direct phosphorylation of β-catenin and Yap by PKCζ. Cell Rep. 10, 740–754 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Barry, E. R. et al. Restriction of intestinal stem cell expansion and the regenerative response by YAP. Nature 493, 106–110 (2013).

    Article  PubMed  CAS  Google Scholar 

  105. Moroishi, T. et al. A YAP/TAZ-induced feedback mechanism regulates Hippo pathway homeostasis. Genes Dev. 29, 1271–1284 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Chen, Q. et al. Homeostatic control of Hippo signaling activity revealed by an endogenous activating mutation in YAP. Genes Dev. 29, 1285–1297 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Dai, X. et al. YAP activates the Hippo pathway in a negative feedback loop. Cell Res. 25, 1175–1178 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Taniguchi, K. et al. A gp130–Src–YAP module links inflammation to epithelial regeneration. Nature 519, 57–U107 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Gregorieff, A., Liu, Y., Inanlou, M. R., Khomchuk, Y. & Wrana, J. L. Yap-dependent reprogramming of Lgr5+ stem cells drives intestinal regeneration and cancer. Nature 526, 715–718 (2015).

    Article  CAS  PubMed  Google Scholar 

  110. Stroncek, J. D. & Reichert, W. M. Indwelling Neural Implants: Strategies for Contending with the In Vivo Environment (CRC Press, 2008).

    Google Scholar 

  111. Vanuytsel, T., Senger, S., Fasano, A. & Shea-Donohue, T. Major signaling pathways in intestinal stem cells. Biochim. Biophys. Acta 1830, 2410–2426 (2013).

    Article  CAS  PubMed  Google Scholar 

  112. Pinto, D., Gregorieff, A., Begthel, H. & Clevers, H. Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. Genes Dev. 17, 1709–1713 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Batlle, E. et al. β-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB. Cell 111, 251–263 (2002).

    Article  CAS  PubMed  Google Scholar 

  114. Korinek, V. et al. Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nat. Genet. 19, 379–383 (1998).

    Article  CAS  PubMed  Google Scholar 

  115. Varelas, X. et al. The Hippo pathway regulates Wnt/β-catenin signaling. Dev. Cell 18, 579–591 (2010).

    Article  CAS  PubMed  Google Scholar 

  116. Imajo, M., Miyatake, K., Iimura, A., Miyamoto, A. & Nishida, E. A molecular mechanism that links Hippo signalling to the inhibition of Wnt/β-catenin signalling. EMBO J. 31, 1109–1122 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Azzolin, L. et al. Role of TAZ as mediator of Wnt signaling. Cell 151, 1443–1456 (2012).

    Article  CAS  PubMed  Google Scholar 

  118. 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 

  119. Miyoshi, H., Ajima, R., Luo, C. T., Yamaguchi, T. P. & Stappenbeck, T. S. Wnt5a potentiates TGF-β signaling to promote colonic crypt regeneration after tissue injury. Science 338, 108–113 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Park, H. W. et al. Alternative Wnt signaling activates YAP/TAZ. Cell 162, 780–794 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Kopan, R. & Ilagan, M. X. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 137, 216–233 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. VanDussen, K. L. et al. Notch signaling modulates proliferation and differentiation of intestinal crypt base columnar stem cells. Development 139, 488–497 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Sancho, R., Cremona, C. A. & Behrens, A. Stem cell and progenitor fate in the mammalian intestine: Notch and lateral inhibition in homeostasis and disease. EMBO Rep. 16, 571–581 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. van Es, J. H. et al. Notch/γ-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 435, 959–963 (2005).

    Article  CAS  PubMed  Google Scholar 

  125. Yimlamai, D. et al. Hippo pathway activity influences liver cell fate. Cell 157, 1324–1338 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Wang, R. N. et al. Bone Morphogenetic Protein (BMP) signaling in development and human diseases. Genes Dis. 1, 87–105 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Haramis, A. P. et al. De novo crypt formation and juvenile polyposis on BMP inhibition in mouse intestine. Science 303, 1684–1686 (2004).

    Article  CAS  PubMed  Google Scholar 

  128. He, X. C. et al. BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-β-catenin signaling. Nat. Genet. 36, 1117–1121 (2004).

    Article  CAS  PubMed  Google Scholar 

  129. 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 

  130. Batts, L. E., Polk, D. B., Dubois, R. N. & Kulessa, H. Bmp signaling is required for intestinal growth and morphogenesis. Dev. Dyn. 235, 1563–1570 (2006).

    Article  CAS  PubMed  Google Scholar 

  131. Kosinski, C. et al. Indian hedgehog regulates intestinal stem cell fate through epithelial-mesenchymal interactions during development. Gastroenterology 139, 893–903 (2010).

    Article  CAS  PubMed  Google Scholar 

  132. Reifenberger, J. et al. Missense mutations in SMOH in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system. Cancer Res. 58, 1798–1803 (1998).

    CAS  PubMed  Google Scholar 

  133. Wetmore, C. Sonic hedgehog in normal and neoplastic proliferation: insight gained from human tumors and animal models. Curr. Opin. Genet. Dev. 13, 34–42 (2003).

    Article  CAS  PubMed  Google Scholar 

  134. 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 

  135. Terzic, J., Grivennikov, S., Karin, E. & Karin, M. Inflammation and colon cancer. Gastroenterology 138, 2101–2114.e5 (2010).

    Article  CAS  PubMed  Google Scholar 

  136. Zhang, L. et al. NDR functions as a physiological YAP1 kinase in the intestinal epithelium. Curr. Biol. 25, 296–305 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. 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 

  138. Lam-Himlin, D. M. et al. The hippo pathway in human upper gastrointestinal dysplasia and carcinoma: a novel oncogenic pathway. Int. J. Gastrointest. Cancer 37, 103–109 (2006).

    PubMed  Google Scholar 

  139. Wang, L. et al. Overexpression of YAP and TAZ is an independent predictor of prognosis in colorectal cancer and related to the proliferation and metastasis of colon cancer cells. PLoS ONE 8, e65539 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Yuen, H. F. et al. TAZ expression as a prognostic indicator in colorectal cancer. PLoS ONE 8, e54211 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Pan, J. et al. Lentivirus-mediated RNA interference targeting WWTR1 in human colorectal cancer cells inhibits cell proliferation in vitro and tumor growth in vivo. Oncol. Rep. 28, 179–185 (2012).

    CAS  PubMed  Google Scholar 

  142. Powell, S. M. et al. APC mutations occur early during colorectal tumorigenesis. Nature 359, 235–237 (1992).

    Article  CAS  PubMed  Google Scholar 

  143. Bienz, M. & Clevers, H. Linking colorectal cancer to Wnt signaling. Cell 103, 311–320 (2000).

    Article  CAS  PubMed  Google Scholar 

  144. Brabletz, T., Jung, A., Dag, S., Hlubek, F. & Kirchner, T. β-catenin regulates the expression of the matrix metalloproteinase-7 in human colorectal cancer. Am. J. Pathol. 155, 1033–1038 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Crawford, H. C. et al. The metalloproteinase matrilysin is a target of β-catenin transactivation in intestinal tumors. Oncogene 18, 2883–2891 (1999).

    Article  CAS  PubMed  Google Scholar 

  146. He, T. C. et al. Identification of c-MYC as a target of the APC pathway. Science 281, 1509–1512 (1998).

    Article  CAS  PubMed  Google Scholar 

  147. Tetsu, O. & McCormick, F. β-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 398, 422–426 (1999).

    Article  CAS  PubMed  Google Scholar 

  148. He, T. C., Chan, T. A., Vogelstein, B. & Kinzler, K. W. PPARδ is an APC-regulated target of nonsteroidal anti-inflammatory drugs. Cell 99, 335–345 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Cai, J., Maitra, A., Anders, R. A., Taketo, M. M. & Pan, D. β-catenin destruction complex-independent regulation of Hippo-YAP signaling by APC in intestinal tumorigenesis. Genes Dev. 29, 1493–1506 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Rosenbluh, J. et al. β-catenin-driven cancers require a YAP1 transcriptional complex for survival and tumorigenesis. Cell 151, 1457–1473 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Sancho, R. et al. JNK signalling modulates intestinal homeostasis and tumourigenesis in mice. EMBO J. 28, 1843–1854 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Chen, F. JNK-induced apoptosis, compensatory growth, and cancer stem cells. Cancer Res. 72, 379–386 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. 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 

  154. Tomlinson, V. et al. JNK phosphorylates Yes-associated protein (YAP) to regulate apoptosis. Cell Death Dis. 1, e29 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Mehenni, H. et al. Loss of LKB1 kinase activity in Peutz–Jeghers syndrome, and evidence for allelic and locus heterogeneity. Am. J. Hum. Genet. 63, 1641–1650 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Giardiello, F. M. et al. Increased risk of cancer in the Peutz–Jeghers syndrome. N. Engl. J. Med. 316, 1511–1514 (1987).

    Article  CAS  PubMed  Google Scholar 

  157. Sanchez-Cespedes, M. A role for LKB1 gene in human cancer beyond the Peutz–Jeghers syndrome. Oncogene 26, 7825–7832 (2007).

    Article  CAS  PubMed  Google Scholar 

  158. Nguyen, H. B., Babcock, J. T., Wells, C. D. & Quilliam, L. A. LKB1 tumor suppressor regulates AMP kinase/mTOR-independent cell growth and proliferation via the phosphorylation of Yap. Oncogene 32, 4100–4109 (2013).

    Article  CAS  PubMed  Google Scholar 

  159. Grivennikov, S. et al. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 15, 103–113 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Bechmann, L. P. et al. The interaction of hepatic lipid and glucose metabolism in liver diseases. J. Hepatol. 56, 952–964 (2012).

    Article  CAS  PubMed  Google Scholar 

  161. Taub, R. Liver regeneration: from myth to mechanism. Nat. Rev. Mol. Cell Biol. 5, 836–847 (2004).

    Article  CAS  PubMed  Google Scholar 

  162. Fausto, N., Campbell, J. S. & Riehle, K. J. Liver regeneration. Hepatology 43, S45–S53 (2006).

    Article  CAS  PubMed  Google Scholar 

  163. Pan, D. Hippo signaling in organ size control. Genes Dev. 21, 886–897 (2007).

    Article  CAS  PubMed  Google Scholar 

  164. 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 

  165. 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 

  166. 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 

  167. 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 

  168. 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 

  169. 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 

  170. 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 

  171. Nishio, M. et al. Cancer susceptibility and embryonic lethality in Mob1a/1b double-mutant mice. J. Clin. Invest. 122, 4505–4518 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Septer, S. et al. Yes-associated protein is involved in proliferation and differentiation during postnatal liver development. Am. J. Physiol. Gastrointest. Liver Physiol. 302, G493–G503 (2012).

    Article  CAS  PubMed  Google Scholar 

  173. Poncy, A. et al. Transcription factors SOX4 and SOX9 cooperatively control development of bile ducts. Dev. Biol. 404, 136–148 (2015).

    Article  CAS  PubMed  Google Scholar 

  174. Grijalva, J. L. et al. Dynamic alterations in Hippo signaling pathway and YAP activation during liver regeneration. Am. J. Physiol. Gastrointest. Liver Physiol. 307, G196–G204 (2014).

    Article  CAS  PubMed  Google Scholar 

  175. Apte, U. et al. Enhanced liver regeneration following changes induced by hepatocyte-specific genetic ablation of integrin-linked kinase. Hepatology 50, 844–851 (2009).

    Article  CAS  PubMed  Google Scholar 

  176. Herr, K. J. et al. Loss of α-catenin elicits a cholestatic response and impairs liver regeneration. Sci. Rep. 4, 6835 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Su, T. et al. Two-signal requirement for growth-promoting function of Yap in hepatocytes. eLife 4, e02948 (2015).

    Article  PubMed Central  Google Scholar 

  178. Mannaerts, I. et al. The Hippo pathway effector YAP controls mouse hepatic stellate cell activation. J. Hepatol. 63, 679–688 (2015).

    Article  CAS  PubMed  Google Scholar 

  179. Bai, H. et al. Expression of Yes-associated protein modulates Survivin expression in primary liver malignancies. Hum. Pathol. 43, 1376–1385 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Li, X. et al. Co-activation of PIK3CA and Yap promotes development of hepatocellular and cholangiocellular tumors in mouse and human liver. Oncotarget 6, 10102–10115 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  182. Ahn, E. Y., Kim, J. S., Kim, G. J. & Park, Y. N. RASSF1A-mediated regulation of AREG via the Hippo pathway in hepatocellular carcinoma. Mol. Cancer Res. 11, 748–758 (2013).

    Article  CAS  PubMed  Google Scholar 

  183. Sohn, B. H. et al. Inactivation of Hippo pathway is significantly associated with poor prognosis in hepatocellular carcinoma. Clin. Cancer Res. 22, 1256–1264 (2016).

    Article  CAS  PubMed  Google Scholar 

  184. 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 

  185. Kowalik, M. A. et al. Yes-associated protein regulation of adaptive liver enlargement and hepatocellular carcinoma development in mice. Hepatology 53, 2086–2096 (2011).

    Article  CAS  PubMed  Google Scholar 

  186. Huang, W. et al. Xenobiotic stress induces hepatomegaly and liver tumors via the nuclear receptor constitutive androstane receptor. Mol. Endocrinol. 19, 1646–1653 (2005).

    Article  CAS  PubMed  Google Scholar 

  187. Dong, B. et al. Activating CAR and β-catenin induces uncontrolled liver growth and tumorigenesis. Nat. Commun. 6, 5944 (2015).

    Article  CAS  PubMed  Google Scholar 

  188. 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 

  189. Liu, P. et al. HBV preS2 promotes the expression of TAZ via miRNA-338-3p to enhance the tumorigenesis of hepatocellular carcinoma. Oncotarget 6, 29048–29059 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  190. Wang, X. et al. Bile acid receptors and liver cancer. Curr. Pathobiol. Rep. 1, 29–35 (2013).

    Article  PubMed  Google Scholar 

  191. Liu, N. et al. Hepatocarcinogenesis in FXR−/− mice mimics human HCC progression that operates through HNF1α regulation of FXR expression. Mol. Endocrinol. 26, 775–785 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Anakk, S. et al. Bile acids activate YAP to promote liver carcinogenesis. Cell Rep. 5, 1060–1069 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Park, Y. Y. et al. Yes-associated protein 1 and transcriptional coactivator with PDZ-binding motif activate the mammalian target of rapamycin complex 1 pathway by regulating amino acid transporters in hepatocellular carcinoma. Hepatology 63, 159–172 (2015).

    Article  PubMed  CAS  Google Scholar 

  194. Tschaharganeh, D. F. et al. Yes-associated protein up-regulates Jagged-1 and activates the Notch pathway in human hepatocellular carcinoma. Gastroenterology 144, 1530–1542.e12 (2013).

    Article  CAS  PubMed  Google Scholar 

  195. Shen, S. et al. A miR-130a-YAP positive feedback loop promotes organ size and tumorigenesis. Cell Res. 25, 997–1012 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Fitamant, J. et al. YAP inhibition restores hepatocyte differentiation in advanced HCC, leading to tumor regression. Cell Rep. 10, 1692–1707 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors apologize to colleagues who have made many important contributions to the Hippo field but whose work could not be cited because of the scope of this Review. We would like to thank K. Lin and T. Moroishi for critical reading of this manuscript. K-L.G. is supported by grants from the NIH (CA132809, EYO226116, and P30CA023100). A.W.H. is supported in part by the T32 GM007752 training grant.

Author information

Authors and Affiliations

  1. Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, 92093, California, USA

    Audrey W. Hong, Zhipeng Meng & Kun-Liang Guan

Authors
  1. Audrey W. Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhipeng Meng
    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

Contributions

All authors contributed equally to the article.

Corresponding author

Correspondence to Kun-Liang Guan.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hong, A., Meng, Z. & Guan, KL. The Hippo pathway in intestinal regeneration and disease. Nat Rev Gastroenterol Hepatol 13, 324–337 (2016). https://doi.org/10.1038/nrgastro.2016.59

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrgastro.2016.59

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