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Hippo–YAP/TAZ signalling in organ regeneration and regenerative medicine

Nature Reviews Molecular Cell Biology volume 20, pages 211–226 (2019)Cite this article

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Abstract

The Hippo pathway and its downstream effectors, the transcriptional co-activators Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), regulate organ growth and cell plasticity during animal development and regeneration. Remarkably, experimental activation of YAP/TAZ in the mouse can promote regeneration in organs with poor or compromised regenerative capacity, such as the adult heart and the liver and intestine of old or diseased mice. However, therapeutic YAP/TAZ activation may cause serious side effects. Most notably, YAP/TAZ are hyperactivated in human cancers, and prolonged activation of YAP/TAZ triggers cancer development in mice. Thus, can the power of YAP/TAZ to promote regeneration be harnessed in a safe way? Here, we review the role of Hippo signalling in animal regeneration, examine the promises and risks of YAP/TAZ activation for regenerative medicine and discuss strategies to activate YAP/TAZ for regenerative therapy while minimizing adverse side effects.

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Fig. 1: Hippo signalling pathway components and regulation.
Fig. 2: YAP-mediated heart regeneration.
Fig. 3: Effects of YAP hyperactivation on regeneration and homeostasis of the intestine and skin.
Fig. 4: Effects and benefits of YAP/TAZ activation in different organs.
Fig. 5: Adverse effects of YAP activation in different organs.

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References

  1. Baddour, J. A., Sousounis, K. & Tsonis, P. A. Organ repair and regeneration: an overview. Birth Defects Res. C Embryo Today 96, 1–29 (2012).

    CAS  PubMed  Google Scholar 

  2. Muneoka, K., Allan, C. H., Yang, X., Lee, J. & Han, M. Mammalian regeneration and regenerative medicine. Birth Defects Res. C Embryo Today 84, 265–280 (2008).

    CAS  PubMed  Google Scholar 

  3. Mao, A. S. & Mooney, D. J. Regenerative medicine: Current therapies and future directions. Proc. Natl Acad. Sci. USA 112, 14452–14459 (2015).

    CAS  PubMed  Google Scholar 

  4. Pasumarthi, K. B., Nakajima, H., Nakajima, H. O., Soonpaa, M. H. & Field, L. J. Targeted expression of cyclin D2 results in cardiomyocyte DNA synthesis and infarct regression in transgenic mice. Circ. Res. 96, 110–118 (2005).

    CAS  PubMed  Google Scholar 

  5. Hassink, R. J. et al. Cardiomyocyte cell cycle activation improves cardiac function after myocardial infarction. Cardiovasc. Res. 78, 18–25 (2008).

    CAS  PubMed  Google Scholar 

  6. Kuhn, B. et al. Periostin induces proliferation of differentiated cardiomyocytes and promotes cardiac repair. Nat. Med. 13, 962–969 (2007).

    PubMed  Google Scholar 

  7. Engel, F. B., Hsieh, P. C., Lee, R. T. & Keating, M. T. FGF1/p38 MAP kinase inhibitor therapy induces cardiomyocyte mitosis, reduces scarring, and rescues function after myocardial infarction. Proc. Natl Acad. Sci. USA 103, 15546–15551 (2006).

    CAS  PubMed  Google Scholar 

  8. Trounson, A. & McDonald, C. Stem cell therapies in clinical trials: progress and challenges. Cell Stem Cell 17, 11–22 (2015).

  9. Juan, W. C. & Hong, W. Targeting the Hippo signaling pathway for tissue regeneration and cancer therapy. Genes 7, 55 (2016).

    PubMed Central  Google Scholar 

  10. Patel, S. H., Camargo, F. D. & Yimlamai, D. Hippo signaling in the liver regulates organ size, cell fate, and carcinogenesis. Gastroenterology 152, 533–545 (2017).

    CAS  PubMed  Google Scholar 

  11. Moya, I. M. & Halder, G. The Hippo pathway in cellular reprogramming and regeneration of different organs. Curr. Opin. Cell Biol. 43, 62–68 (2016).

    CAS  PubMed  Google Scholar 

  12. 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).

    CAS  PubMed  Google Scholar 

  13. Heallen, T. et al. Hippo signaling impedes adult heart regeneration. Development 140, 4683–4690 (2013). This paper shows that Hippo signalling is an endogenous repressor of adult cardiomyocyte renewal and regeneration and that Hippo deficiency enhances cardiomyocyte regeneration after adult myocardial infarction.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Xin, M. et al. Hippo pathway effector Yap promotes cardiac regeneration. Proc. Natl Acad. Sci. USA 110, 13839–13844 (2013). This paper demonstrates that forced expression of constitutively active YAP-1SA stimulates cardiac regeneration in the adult heart through the activation of embryonic and proliferative gene programmes in cardiomyocytes.

    CAS  PubMed  Google Scholar 

  15. Lin, Z. et al. Cardiac-specific YAP activation improves cardiac function and survival in an experimental murine MI model. Circ. Res. 115, 354–363 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Morikawa, Y., Heallen, T., Leach, J., Xiao, Y. & Martin, J. F. Dystrophin-glycoprotein complex sequesters Yap to inhibit cardiomyocyte proliferation. Nature 547, 227–231 (2017). This paper demonstrates that the dystrophin–glycoprotein complex component dystroglycan 1 directly binds to the Hippo pathway effector YAP to inhibit cardiomyocyte proliferation in mice.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 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). In this study, fetal activation of YAP1 is shown to stimulate cardiomyocyte proliferation in postnatal hearts.

    Google Scholar 

  18. Loforese, G. et al. Impaired liver regeneration in aged mice can be rescued by silencing Hippo core kinases MST1 and MST2. EMBO Mol. Med. 9, 46–60 (2017).

    CAS  PubMed  Google Scholar 

  19. Lu, L., Finegold, M. J. & Johnson, R. L. Hippo pathway coactivators Yap and Taz are required to coordinate mammalian liver regeneration. Exp. Mol. Med. 50, e423 (2018).

    PubMed  PubMed Central  Google Scholar 

  20. Zanconato, F., Cordenonsi, M. & Piccolo, S. YAP/TAZ at the roots of cancer. Cancer Cell 29, 783–803 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  22. 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).

    CAS  PubMed  Google Scholar 

  23. 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).

    CAS  PubMed  Google Scholar 

  24. 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).

    CAS  PubMed  Google Scholar 

  25. 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).

    CAS  PubMed  Google Scholar 

  26. 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).

    CAS  PubMed  Google Scholar 

  27. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  29. 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 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 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).

    CAS  PubMed  Google Scholar 

  34. 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).

    CAS  PubMed  Google Scholar 

  35. 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).

    CAS  PubMed  Google Scholar 

  36. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Ikmi, A. et al. Molecular evolution of the Yap/Yorkie proto-oncogene and elucidation of its core transcriptional program. Mol. Biol. Evol. 31, 1375–1390 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Galli, G. G. et al. YAP drives growth by controlling transcriptional pause release from dynamic enhancers. Mol. Cell 60, 328–337 (2015). This study shows that YAP modulates transcription from superenhancer elements predominantly by regulating promoter-proximal Pol II pause release.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Qing, Y. et al. The Hippo effector Yorkie activates transcription by interacting with a histone methyltransferase complex through Ncoa6. Elife 3, e02564 (2014).

    PubMed Central  Google Scholar 

  45. Zanconato, F. et al. Genome-wide association between YAP/TAZ/TEAD and AP-1 at enhancers drives oncogenic growth. Nat. Cell Biol. 17, 1218–1227 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Stein, C. et al. YAP1 exerts its transcriptional control via TEAD-mediated activation of enhancers. PLOS Genet. 11, e1005465 (2015). This study shows that YAP/TAZ–TEAD and AP-1 form a complex that synergistically activates target genes directly involved in the control of S phase entry and mitosis.

    PubMed  PubMed Central  Google Scholar 

  48. Mudryj, M. et al. Cell cycle regulation of the E2F transcription factor involves an interaction with cyclin A. Cell 65, 1243–1253 (1991).

    CAS  PubMed  Google Scholar 

  49. Ehmer, U. et al. Organ size control is dominant over Rb family inactivation to restrict proliferation in vivo. Cell Rep. 8, 371–381 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Verfaillie, A. et al. Decoding the regulatory landscape of melanoma reveals TEADS as regulators of the invasive cell state. Nat. Commun. 6, 6683 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Liu, X. et al. Tead and AP1 coordinate transcription and motility. Cell Rep. 14, 1169–1180 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Strano, S. et al. The transcriptional coactivator Yes-associated protein drives p73 gene-target specificity in response to DNA Damage. Mol. Cell 18, 447–459 (2005).

    CAS  PubMed  Google Scholar 

  53. 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).

    CAS  PubMed  PubMed Central  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).

    CAS  PubMed  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 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).

    CAS  PubMed  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).

    CAS  PubMed  Google Scholar 

  58. Hergovich, A., Schmitz, D. & Hemmings, B. A. The human tumour suppressor LATS1 is activated by human MOB1 at the membrane. Biochem. Biophys. Res. Commun. 345, 50–58 (2006).

    CAS  PubMed  Google Scholar 

  59. 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).

    CAS  PubMed  Google Scholar 

  60. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 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).

    PubMed  PubMed Central  Google Scholar 

  63. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 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).

    CAS  PubMed  Google Scholar 

  66. 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 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Kim, N. G. & Gumbiner, B. M. Adhesion to fibronectin regulates Hippo signaling via the FAK-Src-PI3K pathway. J. Cell Biol. 210, 503–515 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 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).

    PubMed  PubMed Central  Google Scholar 

  74. 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).

    CAS  PubMed  Google Scholar 

  75. Wada, K.-I., Itoga, K., Okano, T., Yonemura, S. & Sasaki, H. Hippo pathway regulation by cell morphology and stress fibers. Development 138, 3907–3914 (2011).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  78. 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).

    CAS  PubMed  Google Scholar 

  79. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  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).

    CAS  PubMed  Google Scholar 

  82. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 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).

    CAS  PubMed  Google Scholar 

  85. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 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).

    CAS  PubMed  Google Scholar 

  87. 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).

    CAS  PubMed  Google Scholar 

  88. 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).

    CAS  PubMed  Google Scholar 

  89. 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).

    CAS  PubMed  Google Scholar 

  90. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Hong, A. W. et al. Osmotic stress-induced phosphorylation by NLK at Ser128 activates YAP. EMBO Rep. 18, 72–86 (2017).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  94. Sun, S., Reddy, B. V. V. G. & Irvine, K. D. Localization of Hippo signalling complexes and Warts activation in vivo. Nat. Commun. 6, 8402 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  97. Karaman, R. & Halder, G. Cell junctions in Hippo signaling. Cold Spring Harb. Perspect Biol. 10, a028753 (2018).

    PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  100. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Wang, K. C. et al. Flow-dependent YAP/TAZ activities regulate endothelial phenotypes and atherosclerosis. Proc. Natl Acad. Sci. USA 113, 11525–11530 (2016).

    CAS  PubMed  Google Scholar 

  102. Wang, L. et al. Integrin-YAP/TAZ-JNK cascade mediates atheroprotective effect of unidirectional shear flow. Nature 540, 579–582 (2016).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 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).

    CAS  PubMed  Google Scholar 

  105. Elosegui-Artola, A. et al. Force triggers YAP nuclear entry by regulating transport across nuclear pores. Cell 171, 1397–1410 (2017).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Levy, D., Adamovich, Y., Reuven, N. & Shaul, Y. Yap1 phosphorylation by c-Abl is a critical step in selective activation of proapoptotic genes in response to DNA damage. Mol. Cell 29, 350–361 (2008).

    CAS  PubMed  Google Scholar 

  112. Taniguchi, K. et al. A gp130-Src-YAP module links inflammation to epithelial regeneration. Nature 519, 57–62 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 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 demonstrates that treatment with the reversible MST1/MST2 inhibitor XMU-MP-1 can promote mouse intestinal and liver regeneration by hyperactivating YAP.

    CAS  PubMed  Google Scholar 

  114. Hong, A. W., Meng, Z. & Guan, K. L. The Hippo pathway in intestinal regeneration and disease. Nat. Rev. Gastroenterol. Hepatol. 13, 324–337 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Xiao, Y., Leach, J., Wang, J. & Martin, J. F. Hippo/Yap signaling in cardiac development and regeneration. Curr. Treat. Options Cardiovasc. Med. 18, 38 (2016).

    PubMed  Google Scholar 

  116. Zhang, Y. & Del, Re,D. P. A growing role for the Hippo signaling pathway in the heart. J. Mol. Med. 95, 465–472 (2017).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Heallen, T. et al. Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size. Science 332, 458–461 (2011). In this study, embryonic deletion of Hippo core kinases is shown to induce cardiomyocyte proliferation and heart overgrowth by interaction of the Hippo effector YAP with β-catenin on Sox2 and Snai2 genes.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Zhao, R. et al. Yap tunes airway epithelial size and architecture by regulating the identity, maintenance, and self-renewal of stem cells. Dev. Cell 30, 151–165 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 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).

    CAS  PubMed  Google Scholar 

  122. 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  Google Scholar 

  123. Morin-Kensicki, E. M. et al. Defects in yolk sac vasculogenesis, chorioallantoic fusion, and embryonic axis elongation in mice with targeted disruption of Yap65. Mol. Cell. Biol. 26, 77–87 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Makita, R. et al. Multiple renal cysts, urinary concentration defects, and pulmonary emphysematous changes in mice lacking TAZ. Am. J. Physiol. Renal Physiol. 294, F542–F553 (2008).

    CAS  PubMed  Google Scholar 

  125. Mitani, A. et al. Transcriptional coactivator with PDZ-binding motif is essential for normal alveolarization in mice. Am. J. Respir. Crit. Care Med. 180, 326–338 (2009).

    CAS  PubMed  Google Scholar 

  126. Hossain, Z. et al. Glomerulocystic kidney disease in mice with a targeted inactivation of Wwtr1. Proc. Natl Acad. Sci. USA 104, 1631–1636 (2007).

    CAS  PubMed  Google Scholar 

  127. 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).

    CAS  PubMed  Google Scholar 

  128. 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).

    PubMed  PubMed Central  Google Scholar 

  129. Wang, X. et al. YAP/TAZ orchestrate VEGF signaling during developmental angiogenesis. Dev. Cell 42, 462–478 (2017).

    CAS  PubMed  Google Scholar 

  130. Kim, J. et al. YAP/TAZ regulates sprouting angiogenesis and vascular barrier maturation. J. Clin. Invest. 127, 3441–3461 (2017).

    PubMed  PubMed Central  Google Scholar 

  131. Mahoney, J. E., Mori, M., Szymaniak, A. D., Varelas, X. & Cardoso, W. V. The hippo pathway effector Yap controls patterning and differentiation of airway epithelial progenitors. Dev. Cell 30, 137–150 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Reginensi, A. et al. A critical role for NF2 and the Hippo pathway in branching morphogenesis. Nat. Commun. 7, 12309 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Yui, S. et al. YAP/TAZ-dependent reprogramming of colonic epithelium links ECM remodeling to tissue regeneration. Cell Stem Cell 22, 35–49 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Shen, Z. & Stanger, B. Z. YAP regulates S-phase entry in endothelial cells. PLOS ONE 10, e0117522 (2015).

    PubMed  PubMed Central  Google Scholar 

  137. Mizuno, T. et al. YAP induces malignant mesothelioma cell proliferation by upregulating transcription of cell cycle-promoting genes. Oncogene 31, 5117–5122 (2012).

    CAS  PubMed  Google Scholar 

  138. Kapoor, A. et al. Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer. Cell 158, 185–197 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Lian, I. et al. The role of YAP transcription coactivator in regulating stem cell self-renewal and differentiation. Genes Dev. 24, 1106–1118 (2010). This study shows that YAP is inactivated during ES cell differentiation and elevated during iPS cell reprogramming.

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Qin, H. et al. YAP induces human naive pluripotency. Cell Rep. 14, 2301–2312 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Quinn, J., Kunath, T. & Rossant, J. Mouse trophoblast stem cells. Methods Mol. Med. 121, 125–148 (2006).

    PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Chung, H. et al. Yap1 is dispensable for self-renewal but required for proper differentiation of mouse embryonic stem (ES) cells. EMBO Rep. 17, 519–529 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Li, P. et al. Functional role of Mst1/Mst2 in embryonic stem cell differentiation. PLOS ONE 8, e79867 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Panciera, T. et al. Induction of expandable tissue-specific stem/progenitor cells through transient expression of YAP/TAZ. Cell Stem Cell 19, 725–737 (2016). This study demonstrates that transient expression of exogenous YAP or TAZ in primary differentiated mouse cells can induce conversion to a tissue-specific stem or progenitor cell state in mammary gland, neuronal and pancreatic exocrine cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Totaro, A. et al. YAP/TAZ link cell mechanics to Notch signalling to control epidermal stem cell fate. Nat. Commun. 8, 15206 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Lee, M.-J., Byun, M. R., Furutani-Seiki, M., Hong, J.-H. & Jung, H.-S. YAP and TAZ regulate skin wound healing. J. Invest. Dermatol. 134, 518–525 (2014).

    CAS  PubMed  Google Scholar 

  148. Hu, J. K.-H. et al. An FAK-YAP-mTOR signaling axis regulates stem cell-based tissue renewal in mice. Cell Stem Cell 21, 91–106 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Han, D. et al. YAP/TAZ enhance mammalian embryonic neural stem cell characteristics in a Tead-dependent manner. Biochem. Biophys. Res. Commun. 458, 110–116 (2015).

    CAS  PubMed  Google Scholar 

  150. Volckaert, T. et al. Fgf10-Hippo epithelial-mesenchymal crosstalk maintains and recruits lung basal stem cells. Dev. Cell 43, 48–59 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 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).

    CAS  PubMed  Google Scholar 

  153. Bai, H. et al. Yes-associated protein regulates the hepatic response after bile duct ligation. Hepatology 56, 1097–1107 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. 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). This study provides evidence that YAP transiently reprogrammes LGR-positive intestinal stem cells by suppressing WNT signalling while promoting an intestine regeneration programme that includes EGF pathway activation.

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  156. Elbediwy, A. et al. Integrin signalling regulates YAP and TAZ to control skin homeostasis. Development 143, 1674–1687 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Mosqueira, D. et al. Hippo pathway effectors control cardiac progenitor cell fate by acting as dynamic sensors of substrate mechanics and nanostructure. ACS Nano 8, 2033–2047 (2014).

    CAS  PubMed  Google Scholar 

  158. Ramjee, V. et al. Epicardial YAP/TAZ orchestrate an immunosuppressive response following myocardial infarction. J. Clin. Invest. 127, 899–911 (2017).

    PubMed  PubMed Central  Google Scholar 

  159. Porrello, E. R. et al. Transient regenerative potential of the neonatal mouse heart. Science 331, 1078–1080 (2011). This paper demonstrates that hearts of 1-day-old neonatal mice can regenerate after partial surgical resection, but this capacity is lost by 7 days of age.

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Leach, J. P. & Martin, J. F. Cardiomyocyte proliferation for therapeutic regeneration. Curr. Cardiol. Rep. 20, 63 (2018).

    PubMed  Google Scholar 

  161. Schmucker, D. L. & Sanchez, H. Liver regeneration and aging: a current perspective. Curr. Gerontol. Geriatr. Res. 2011, 8 (2011).

    Google Scholar 

  162. Horiguchi, N., Ishac, E. J. N. & Gao, B. Liver regeneration is suppressed in alcoholic cirrhosis: correlation with decreased STAT3 activation. Alcohol 41, 271–280 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Yokoyama, Y., Nagino, M. & Nimura, Y. Mechanism of impaired hepatic regeneration in cholestatic liver. J. Hepatobiliary Pancreat. Surg. 14, 159–166 (2007).

    PubMed  Google Scholar 

  164. Ananthakrishnan, A., Gogineni, V. & Saeian, K. Epidemiology of primary and secondary liver cancers. Semin. Intervent. Radiol. 23, 47–63 (2006).

    PubMed  PubMed Central  Google Scholar 

  165. Fan, F. et al. Pharmacological targeting of kinases MST1 and MST2 augments tissue repair and regeneration. Sci. Transl Med. 8, 352ra108 (2016).

    PubMed  Google Scholar 

  166. Fausto, N. & Campbell, J. S. The role of hepatocytes and oval cells in liver regeneration and repopulation. Mech. Dev. 120, 117–130 (2003).

    CAS  PubMed  Google Scholar 

  167. Okamoto, R. Epithelial regeneration in inflammatory bowel diseases. Inflamm. Regen. 31, 275–281 (2011).

    CAS  Google Scholar 

  168. Fuchs, E. & Chen, T. A matter of life and death: self-renewal in stem cells. EMBO Rep. 14, 39–48 (2013).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  170. Chen, Q. et al. A temporal requirement for Hippo signaling in mammary gland differentiation, growth, and tumorigenesis. Genes Dev. 28, 432–437 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Lin, C., Yao, E. & Chuang, P. T. A conserved MST1/2-YAP axis mediates Hippo signaling during lung growth. Dev. Biol. 403, 101–113 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Guo, Y. et al. Functional and clinical evidence that TAZ is a candidate oncogene in hepatocellular carcinoma. J. Cell. Biochem. 116, 2465–2475 (2015).

    CAS  PubMed  Google Scholar 

  175. Han, S. X. et al. Expression and clinical significance of YAP, TAZ, and AREG in hepatocellular carcinoma. J. Immunol. Res. 2014, 261365 (2014).

    PubMed  PubMed Central  Google Scholar 

  176. Kim, G. J., Kim, H. & Park, Y. N. Increased expression of Yes-associated protein 1 in hepatocellular carcinoma with stemness and combined hepatocellular-cholangiocarcinoma. PLOS ONE 8, e75449 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Xiao, H., Jiang, N., Zhou, B., Liu, Q. & Du, C. TAZ regulates cell proliferation and epithelial-mesenchymal transition of human hepatocellular carcinoma. Cancer Sci. 106, 151–159 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  179. Cheng, H. et al. Functional genomics screen identifies YAP1 as a key determinant to enhance treatment sensitivity in lung cancer cells. Oncotarget 7, 28976–28988 (2016).

    PubMed  Google Scholar 

  180. Lau, A. N. et al. Tumor-propagating cells and Yap/Taz activity contribute to lung tumor progression and metastasis. EMBO J. 33, 468–481 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Noguchi, S. et al. An integrative analysis of the tumorigenic role of TAZ in human non-small cell lung cancer. Clin. Cancer Res. 20, 4660–4672 (2014).

    CAS  PubMed  Google Scholar 

  182. Su, L. L. et al. Expression of Yes-associated protein in non-small cell lung cancer and its relationship with clinical pathological factors. Chinese Med. J. 125, 4003–4008 (2012).

    CAS  Google Scholar 

  183. 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).

    CAS  PubMed  Google Scholar 

  184. Xie, M. et al. Prognostic significance of TAZ expression in resected non-small cell lung cancer. J. Thorac. Oncol. 7, 799–807 (2012).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  186. Bartucci, M. et al. TAZ is required for metastatic activity and chemoresistance of breast cancer stem cells. Oncogene 34, 681–690 (2015).

    CAS  PubMed  Google Scholar 

  187. Lee, K. W. et al. Significant association of oncogene YAP1 with poor prognosis and cetuximab resistance in colorectal cancer patients. Clin. Cancer Res. 21, 357–364 (2015).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  190. 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 

  191. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. Menzel, M. et al. In melanoma, Hippo signaling is affected by copy number alterations and YAP1 overexpression impairs patient survival. Pigment Cell Melanoma Res. 27, 671–673 (2014).

    CAS  PubMed  Google Scholar 

  193. Fujii, M. et al. TGF-beta synergizes with defects in the Hippo pathway to stimulate human malignant mesothelioma growth. J. Exp. Med. 209, 479–494 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  194. Wang, Q. et al. TAZ promotes epithelial to mesenchymal transition via the upregulation of connective tissue growth factor expression in neuroblastoma cells. Mol. Med. Rep. 11, 982–988 (2015).

    CAS  PubMed  Google Scholar 

  195. Mueller, S. et al. Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes. Nature 554, 62–68 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. Snijders-Keilholz, A., Ewing, P., Seynaeve, C. & Burger, C. W. Primitive neuroectodermal tumor of the cervix uteri: a case report — changing concepts in therapy. Gynecol. Oncol. 98, 516–519 (2005).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  198. Zhang, W. et al. YAP promotes malignant progression of Lkb1-deficient lung adenocarcinoma through downstream regulation of survivin. Cancer Res. 75, 4450–4457 (2015).

    CAS  PubMed  Google Scholar 

  199. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  201. Coussens, L. M. & Werb, Z. Inflammation and cancer. Nature 420, 860–867 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    PubMed Central  Google Scholar 

  203. Liu, F. et al. Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis. Am. J. Physiol. Lung Cell. Mol. Physiol. 308, L344–L357 (2015).

    CAS  PubMed  Google Scholar 

  204. Liang, M. et al. Yap/Taz deletion in Gli+ cell-derived myofibroblasts attenuates fibrosis. J. Am. Soc. Nephrol. 28, 3278–3290 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  205. Judson, R. N. et al. Constitutive expression of yes-associated protein (Yap) in adult skeletal muscle fibres induces muscle atrophy and myopathy. PLOS ONE 8, e59622 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  207. Zincarelli, C., Soltys, S., Rengo, G. & Rabinowitz, J. E. Analysis of AAV serotypes 1–9 mediated gene expression and tropism in mice after systemic injection. Mol. Ther. 16, 1073–1080 (2008).

    CAS  PubMed  Google Scholar 

  208. Samulski, R. J. & Muzyczka, N. AAV-mediated gene therapy for research and therapeutic purposes. Annu. Rev. Virol. 1, 427–451 (2014).

    PubMed  Google Scholar 

  209. Naso, M. F., Tomkowicz, B., Perry, W. L. & Strohl, W. R. Adeno-Associated Virus (AAV) as a vector for gene therapy. Biodrugs 31, 317–334 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  210. Vanrell, L. et al. Development of a liver-specific Tet-on inducible system for AAV vectors and its application in the treatment of liver cancer. Mol. Ther. 19, 1245–1253 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  211. Valon, L., Marin-Llaurado, A., Wyatt, T., Charras, G. & Trepat, X. Optogenetic control of cellular forces and mechanotransduction. Nat. Commun. 8, 14396 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  212. Bassat, E. et al. The extracellular matrix protein agrin promotes heart regeneration in mice. Nature 547, 179–184 (2017). This paper shows that agrin, a component of neonatal ECM, promotes cardiac regeneration through disassembly of the dystrophin–glycoprotein complex, which stimulates signalling mediated by YAP and ERK.

    CAS  PubMed  PubMed Central  Google Scholar 

  213. Mokalled, M. H. et al. Injury-induced ctgfa directs glial bridging and spinal cord regeneration in zebrafish. Science 354, 630–634 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  214. Sun, X. et al. The influence of connective tissue growth factor on rabbit ligament injury repair. Bone Joint Res. 6, 399–404 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  215. Zhu, S. et al. Combined effects of connective tissue growth factor-modified bone marrow-derived mesenchymal stem cells and NaOH-treated PLGA scaffolds on the repair of articular cartilage defect in rabbits. Cell Transplant. 23, 715–727 (2014).

    PubMed  Google Scholar 

  216. Kim, K. H., Chen, C. C., Monzon, R. I. & Lau, L. F. Matricellular protein CCN1 promotes regression of liver fibrosis through induction of cellular senescence in hepatic myofibroblasts. Mol. Cell. Biol. 33, 2078–2090 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  217. Choi, J. S., Kim, K. H. & Lau, L. F. The matricellular protein CCN1 promotes mucosal healing in murine colitis through IL-6. Mucosal Immunol. 8, 1285–1296 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Facultad de Ingeniería y Ciencias Aplicadas, Universidad de Las Americas, Quito, Ecuador

    Iván M. Moya

  2. VIB Center for Cancer Biology, and KU Leuven Department of Oncology, University of Leuven, Leuven, Belgium

    Iván M. Moya & Georg Halder

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Glossary

β-Catenin destruction complex

A multiprotein complex that includes the tumour suppressors axin and adenomatous polyposis coli (APC), the Ser/Thr kinases GSK3 and casein kinase 1δ /1ε (CK1), protein phosphatase 2 A (PP2A) and the E3-ubiquitin ligase β-TrCP, which is involved in degradation of β-catenin. In the absence of WNT signalling, the complex generates a β-TrCP recognition site by phosphorylation of the β-catenin amino terminus, which targets β-catenin for degradation by the proteasome.

Imaginal discs

A group of undifferentiated cells in an insect larva that will develop into different adult structures such as eyes, antennae and wings.

Trophectoderm

The outer cells of the mammalian blastocyst that eventually form the placental interface between mother and offspring; also known as a trophoblast.

Branching morphogenesis

The growth and branching of epithelial tubules during embryogenesis.

Intestinal crypts

Glands found in the intestinal epithelium lining the small and large intestine, which contain stem cells and Paneth cells; also known as crypts of Lieberkühn.

Polycomb group proteins

A family of chromatin-remodelling proteins that induce epigenetic silencing of genes.

Dystrophin

A cytoplasmic component of the dystrophin-associated protein complex in muscle fibres that connects the cytoskeleton to the extracellular matrix.

Duchenne muscular dystrophy

A genetic disorder caused by an absence of dystrophin and characterized by progressive muscle degeneration and weakness.

Liposomal vesicles

Spherical vesicles composed of a bilayer comprising one or more phospholipids that are used as vehicles for the administration of nutrients or pharmaceutical drugs.

Biliary epithelial cells

Cuboidal epithelial cells that form bile ducts in the liver; also known as cholangiocytes.

Ductular reactions

Reactions associated with a pathologically increased number of ductules or fine ramifications of the biliary tree in the liver that are often associated with a response to injury.

Ulcerative colitis

A chronic bowel disease that causes inflammation in the large intestine or colon.

Crohn’s disease

An inflammatory bowel disease, which can present with inflammation anywhere in the digestive tract, from the mouth to the anus.

Parenchyma

The functional tissue of an organ that does not include any connective or supporting tissue.

Mesotheliomas

Cancers that develop from the mesothelium, which is the thin layer of tissue that covers many internal organs.

Neurofibrosarcomas

Tumours that develop from the cells surrounding the peripheral nerves; also known as peripheral nerve sheath tumours.

Schwannomas

Generally benign tumours derived from Schwann cells, which are cells forming part of the nerve sheath.

Stellate cells

Pericytes found in the perisinusoidal space of the liver, also known as the space of Disse (a small area between the sinusoids and hepatocytes).

Enterocytes

Simple columnar epithelial cells found in the small intestine that fulfil absorptive functions.

Goblet cells

Mucus-producing cells found in the epithelium of the intestinal and respiratory tracts.

Paneth cells

Epithelial cells located at the base of the intestinal crypt that secrete antimicrobial peptides and produce niche factors that modulate and maintain neighbouring stem cells.

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Moya, I.M., Halder, G. Hippo–YAP/TAZ signalling in organ regeneration and regenerative medicine. Nat Rev Mol Cell Biol 20, 211–226 (2019). https://doi.org/10.1038/s41580-018-0086-y

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