Hippo Signaling and Stem Cells

  • Kriti Shrestha
  • Fernando D. CamargoEmail author


The normal growth and development of an organ is dependent on the precise balance of stem cell self-renewal and differentiation. Slightest aberrations in signals stem cells receive can cause growth abnormalities and cancer. Emerging data suggest that the highly conserved Hippo signaling pathway can directly regulate stem cell proliferation and maintenance to control organ size. Furthermore, deregulation of the pathway promotes cancer stem cell-like properties and leads to tumor formation. Together, these findings implicate that the Hippo pathway modulates the dynamic activity of stem cells in tissue repair, regeneration, and development. Here, we summarize the latest findings that establish the role of Hippo pathway in stem cell biology.


Stem cell Cancer Hippo pathway Organ size Cancer stem cell 



We apologize to those investigators whose work we could not cite due to limited space. We thank Annie M. Tremblay, Evan Barry, and Morvarid Mohseni for providing feedback and proofreading this manuscript. Fernando D. Camargo is a Pew Scholar and is supported by grants from the National Institutes of Health, the Stand Up to Cancer Foundation and the Department of Defense.


  1. Depaepe V, et al. Ephrin signalling controls brain size by regulating apoptosis of neural progenitors. Nature. 2005;435:1244–50.PubMedCrossRefGoogle Scholar
  2. Stanger BZ, Tanaka AJ, Melton DA. Organ size is limited by the number of embryonic progenitor cells in the pancreas but not the liver. Nature. 2007;445:886–91.PubMedCrossRefGoogle Scholar
  3. Justice RW, Zilian O, Woods DF, Noll M, Bryant PJ. 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. 1995;9:534–46.PubMedCrossRefGoogle Scholar
  4. Pan D. The Hippo signaling pathway in development and cancer. Dev Cell. 2010;19:491–505.PubMedCrossRefGoogle Scholar
  5. Zhao B, Tumaneng K, Guan KL. The Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal. Nat Cell Biol. 2011;13:877–83.PubMedCrossRefGoogle Scholar
  6. Khokhlatchev A, et al. Identification of a novel Ras-regulated proapoptotic pathway. Curr Biol. 2002;12:253–65.PubMedCrossRefGoogle Scholar
  7. Oh HJ, et al. Role of the tumor suppressor RASSF1A in Mst1-mediated apoptosis. Cancer Res. 2006;66:2562–9.PubMedCrossRefGoogle Scholar
  8. Dong J, et al. Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell. 2007;130:1120–33.PubMedCrossRefGoogle Scholar
  9. Chan EH, et al. The Ste20-like kinase Mst2 activates the human large tumor suppressor kinase Lats1. Oncogene. 2005;24:2076–86.PubMedCrossRefGoogle Scholar
  10. Hirabayashi S, et al. Threonine 74 of MOB1 is a putative key phosphorylation site by MST2 to form the scaffold to activate nuclear Dbf2-related kinase 1. Oncogene. 2008;27:4281–92.PubMedCrossRefGoogle Scholar
  11. Praskova M, Xia F, Avruch J. MOBKL1A/MOBKL1B phosphorylation by MST1 and MST2 inhibits cell proliferation. Curr Biol. 2008;18:311–21.PubMedCrossRefGoogle Scholar
  12. Hao Y, Chun A, Cheung K, Rashidi B, Yang X. Tumor suppressor LATS1 is a negative regulator of oncogene YAP. J Biol Chem. 2008;283:5496–509.PubMedCrossRefGoogle Scholar
  13. Oh H, Irvine KD. In vivo regulation of Yorkie phosphorylation and localization. Development. 2008;135:1081–8.PubMedCrossRefGoogle Scholar
  14. Zhao B, et al. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev. 2007;21:2747–61.PubMedCrossRefGoogle Scholar
  15. Lei QY, et al. TAZ promotes cell proliferation and epithelial-mesenchymal transition and is inhibited by the Hippo pathway. Mol Cell Biol. 2008;28:2426–36.PubMedCrossRefGoogle Scholar
  16. Oka T, Mazack V, Sudol M. Mst2 and Lats kinases regulate apoptotic function of Yes kinase-associated protein (YAP). J Biol Chem. 2008;283:27534–46.PubMedCrossRefGoogle Scholar
  17. Kanai F, et al. TAZ: a novel transcriptional co-activator regulated by interactions with 14-3-3 and PDZ domain proteins. EMBO J. 2000;19:6778–91.PubMedCrossRefGoogle Scholar
  18. Basu S, Totty NF, Irwin MS, Sudol M, Downward J. Akt phosphorylates the Yes-associated protein, YAP, to induce interaction with 14-3-3 and attenuation of p73-mediated apoptosis. Mol Cell. 2003;11:11–23.PubMedCrossRefGoogle Scholar
  19. Mauviel A, Nallet-Staub F, Varelas X. Integrating developmental signals: a Hippo in the (path)way. Oncogene. 2012;31:1743–56.PubMedCrossRefGoogle Scholar
  20. Sudol M, Harvey KF. Modularity in the Hippo signaling pathway. Trends Biochem Sci. 2010;35:627–33.PubMedCrossRefGoogle Scholar
  21. Zhao B, et al. TEAD mediates YAP-dependent gene induction and growth control. Genes Dev. 2008;22:1962–71.PubMedCrossRefGoogle Scholar
  22. Schlegelmilch K, et al. Yap1 acts downstream of alpha-catenin to control epidermal proliferation. Cell. 2011;144:782–95.PubMedCrossRefGoogle Scholar
  23. Kaneko KJ, DePamphilis ML. Regulation of gene expression at the beginning of mammalian development and the TEAD family of transcription factors. Dev Genet. 1998;22:43–55.PubMedCrossRefGoogle Scholar
  24. Jacquemin P, et al. Differential expression of the TEF family of transcription factors in the murine placenta and during differentiation of primary human trophoblasts in vitro. Dev Dyn. 1998;212:423–36.PubMedCrossRefGoogle Scholar
  25. Kaneko KJ, Cullinan EB, Latham KE, DePamphilis ML. Transcription factor mTEAD-2 is selectively expressed at the beginning of zygotic gene expression in the mouse. Development. 1997;124:1963–73.PubMedGoogle Scholar
  26. 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. 2006;8:27–36.PubMedCrossRefGoogle Scholar
  27. Zhang N, et al. The Merlin/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals. Dev Cell. 2010;19:27–38.PubMedCrossRefGoogle Scholar
  28. Camargo FD, et al. YAP1 increases organ size and expands undifferentiated progenitor cells. Curr Biol. 2007;17:2054–60.PubMedCrossRefGoogle Scholar
  29. Avruch J, Zhou D, Fitamant J, Bardeesy N. Mst1/2 signalling to Yap: gatekeeper for liver size and tumour development. Br J Cancer. 2011;104:24–32.PubMedCrossRefGoogle Scholar
  30. Liu-Chittenden Y, et al. Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP. Genes Dev. 2012;26:1300–5.PubMedCrossRefGoogle Scholar
  31. Zhou D, et al. Mst1 and Mst2 maintain hepatocyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yap1 oncogene. Cancer Cell. 2009;16:425–38.PubMedCrossRefGoogle Scholar
  32. Song H, et al. Mammalian Mst1 and Mst2 kinases play essential roles in organ size control and tumor suppression. Proc Natl Acad Sci U S A. 2010;107:1431–6.PubMedCrossRefGoogle Scholar
  33. Lee KP, et al. The Hippo-Salvador pathway restrains hepatic oval cell proliferation, liver size, and liver tumorigenesis. Proc Natl Acad Sci U S A. 2010;107:8248–53.PubMedCrossRefGoogle 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 U S A. 2010;107:1437–42.PubMedCrossRefGoogle Scholar
  35. Benhamouche S, et al. Nf2/Merlin controls progenitor homeostasis and tumorigenesis in the liver. Genes Dev. 2010;24:1718–30.PubMedCrossRefGoogle Scholar
  36. 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 U S A. 2011;108:E1312–20.PubMedCrossRefGoogle Scholar
  37. Fre S, et al. Notch and Wnt signals cooperatively control cell proliferation and tumorigenesis in the intestine. Proc Natl Acad Sci U S A. 2009;106:6309–14.PubMedCrossRefGoogle Scholar
  38. Varelas X, et al. The Hippo pathway regulates Wnt/beta-catenin signaling. Dev Cell. 2010a;18:579–91.PubMedCrossRefGoogle Scholar
  39. Clevers H. Wnt/beta-catenin signaling in development and disease. Cell. 2006;127:469–80.PubMedCrossRefGoogle Scholar
  40. Nusse R. Wnt signaling in disease and in development. Cell Res. 2005;15:28–32.PubMedCrossRefGoogle Scholar
  41. Imajo M, Miyatake K, Iimura A, Miyamoto A, Nishida E. A molecular mechanism that links Hippo signalling to the inhibition of Wnt/beta-catenin signalling. EMBO J. 2012;31:1109–22.PubMedCrossRefGoogle Scholar
  42. Merkle FT, Alvarez-Buylla A. Neural stem cells in mammalian development. Curr Opin Cell Biol. 2006;18:704–9.PubMedCrossRefGoogle Scholar
  43. Cao X, Pfaff SL, Gage FH. YAP regulates neural progenitor cell number via the TEA domain transcription factor. Genes Dev. 2008;22:3320–34.PubMedCrossRefGoogle Scholar
  44. Provias JP, Becker LE. Cellular and molecular pathology of medulloblastoma. J Neurooncol. 1996;29:35–43.PubMedCrossRefGoogle Scholar
  45. Dahmane N, Ruiz i Altaba A. Sonic hedgehog regulates the growth and patterning of the cerebellum. Development. 1999;126:3089–100.PubMedGoogle Scholar
  46. Raffel C, et al. Sporadic medulloblastomas contain PTCH mutations. Cancer Res. 1997;57:842–5.PubMedGoogle Scholar
  47. 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. 1998;58:1798–803.PubMedGoogle Scholar
  48. Fernandez LA, et al. YAP1 is amplified and up-regulated in hedgehog-associated medulloblastomas and mediates Sonic hedgehog-driven neural precursor proliferation. Genes Dev. 2009;23:2729–41.CrossRefGoogle Scholar
  49. Li Y, Hibbs MA, Gard AL, Shylo NA, Yun K. Genome-wide analysis of N1ICD/RBPJ targets in vivo reveals direct transcriptional regulation of Wnt, SHH, and Hippo pathway effectors by Notch1. Stem Cells. 2012;30:741–52.PubMedCrossRefGoogle Scholar
  50. Fuchs E. Scratching the surface of skin development. Nature. 2007;445:834–42.PubMedCrossRefGoogle Scholar
  51. Zhang H, Pasolli HA, Fuchs E. Yes-associated protein (YAP) transcriptional coactivator functions in balancing growth and differentiation in skin. Proc Natl Acad Sci U S A. 2011;108:2270–5.PubMedCrossRefGoogle Scholar
  52. Lee JH et al. A crucial role of WW45 in developing epithelial tissues in the mouse. EMBO J. 2008;27.Google Scholar
  53. Silvis MR et al. alpha-catenin is a tumor suppressor that controls cell accumulation by regulating the localization and activity of the transcriptional coactivator Yap1. Sci Signal. 2011;4:ra33.Google Scholar
  54. Lien WH, Klezovitch O, Fernandez TE, Delrow J, Vasioukhin V. alphaE-catenin controls cerebral cortical size by regulating the hedgehog signaling pathway. Science. 2006a;311:1609–12.PubMedCrossRefGoogle Scholar
  55. Lien WH, Klezovitch O, Vasioukhin V. Cadherin-catenin proteins in vertebrate development. Curr Opin Cell Biol. 2006b;18:499–506.PubMedCrossRefGoogle Scholar
  56. Robinson BS, Huang J, Hong Y, Moberg KH. Crumbs regulates Salvador/Warts/Hippo signaling in Drosophila via the FERM-domain protein Expanded. Curr Biol. 2010;20:582–90.PubMedCrossRefGoogle Scholar
  57. 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 U S A. 2010;107:10532–7.PubMedCrossRefGoogle Scholar
  58. Chen CL, et al. The apical-basal cell polarity determinant Crumbs regulates Hippo signaling in Drosophila. Proc Natl Acad Sci U S A. 2010;107:15810–5.PubMedCrossRefGoogle Scholar
  59. Grzeschik NA, Parsons LM, Allott ML, Harvey KF, Richardson HE. Lgl, aPKC, and Crumbs regulate the Salvador/Warts/Hippo pathway through two distinct mechanisms. Curr Biol. 2010;20:573–81.PubMedCrossRefGoogle Scholar
  60. Skouloudaki K, et al. Scribble participates in Hippo signaling and is required for normal zebrafish pronephros development. Proc Natl Acad Sci U S A. 2009;106:8579–84.PubMedCrossRefGoogle Scholar
  61. Varelas X, et al. The Crumbs complex couples cell density sensing to Hippo-dependent control of the TGF-beta-SMAD pathway. Dev Cell. 2010b;19:831–44.PubMedCrossRefGoogle Scholar
  62. Doggett K, Grusche FA, Richardson HE, Brumby AM. Loss of the Drosophila cell polarity regulator Scribbled promotes epithelial tissue overgrowth and cooperation with oncogenic Ras-Raf through impaired Hippo pathway signaling. BMC Dev Biol. 2011;11:57.PubMedCrossRefGoogle Scholar
  63. Kim NG, Koh E, Chen X, Gumbiner BM. E-cadherin mediates contact inhibition of proliferation through Hippo signaling-pathway components. Proc Natl Acad Sci U S A. 2011;108:11930–5.PubMedCrossRefGoogle Scholar
  64. Heallen T, et al. Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size. Science. 2011;332:458–61.PubMedCrossRefGoogle Scholar
  65. Xin M et al. Regulation of insulin-like growth factor signaling by Yap governs cardiomyocyte proliferation and embryonic heart size. Sci Signal. 2011;4:ra70.Google Scholar
  66. 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 U S A. 2012;109:2394–9.CrossRefGoogle Scholar
  67. Shiojima I, Walsh K. Regulation of cardiac growth and coronary angiogenesis by the Akt/PKB signaling pathway. Genes Dev. 2006;20:3347–65.PubMedCrossRefGoogle Scholar
  68. Matsui Y, et al. Lats2 is a negative regulator of myocyte size in the heart. Circ Res. 2008;103:1309–18.PubMedCrossRefGoogle Scholar
  69. Watt KI, et al. Yap is a novel regulator of C2C12 myogenesis. Biochem Biophys Res Commun. 2010;393:619–24.PubMedCrossRefGoogle Scholar
  70. Judson RN, Tremblay, Annie M, Knopp, Paul, White, Robert, Urcia, Roby, De Bari, Cosimo., Zammit, Peter S, Camargo, Fernando D, Wackerhage, Henning. The Hippo pathway member Yap plays a key role in influencing fate decisions in muscle satellite cells. J Cell Sci. 2012.Google Scholar
  71. Jeong H, et al. TAZ as a novel enhancer of MyoD-mediated myogenic differentiation. FASEB J. 2010;24:3310–20.PubMedCrossRefGoogle Scholar
  72. 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. 2009;16:398–410.PubMedCrossRefGoogle Scholar
  73. Biswas A, Hutchins R. Embryonic stem cells. Stem Cells Dev. 2007;16:213–22.PubMedCrossRefGoogle Scholar
  74. Darr H, Benvenisty N. Human embryonic stem cells: the battle between self-renewal and differentiation. Regen Med. 2006;1:317–25.PubMedCrossRefGoogle Scholar
  75. Xiao L, Yuan X, Sharkis SJ. Activin A maintains self-renewal and regulates fibroblast growth factor, Wnt, and bone morphogenic protein pathways in human embryonic stem cells. Stem Cells. 2006;24:1476–86.PubMedCrossRefGoogle Scholar
  76. James D, Levine AJ, Besser D, Hemmati-Brivanlou A. TGFbeta/activin/nodal signaling is necessary for the maintenance of pluripotency in human embryonic stem cells. Development. 2005;132:1273–82.PubMedCrossRefGoogle Scholar
  77. Vallier L, Alexander M, Pedersen RA. Activin/Nodal and FGF pathways cooperate to maintain pluripotency of human embryonic stem cells. J Cell Sci. 2005;118:4495–509.PubMedCrossRefGoogle Scholar
  78. Varelas X, et al. TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal. Nat Cell Biol. 2008;10:837–48.PubMedCrossRefGoogle Scholar
  79. Evans M. Discovering pluripotency: 30 years of mouse embryonic stem cells. Nat Rev Mol Cell Biol. 2011;12:680–6.PubMedCrossRefGoogle Scholar
  80. Chambers I, Smith A. Self-renewal of teratocarcinoma and embryonic stem cells. Oncogene. 2004;23:7150–60.PubMedCrossRefGoogle Scholar
  81. Ying QL, Nichols J, Chambers I, Smith A. BMP induction of Id proteins suppresses differentiation and sustains embryonic stem cell self-renewal in collaboration with STAT3. Cell. 2003;115:281–92.PubMedCrossRefGoogle Scholar
  82. Alarcon C, et al. Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-beta pathways. Cell. 2009;139:757–69.PubMedCrossRefGoogle Scholar
  83. Tamm C, Bower N, Anneren C. Regulation of mouse embryonic stem cell self-renewal by a Yes-YAP-TEAD2 signaling pathway downstream of LIF. J Cell Sci. 124:1136–44.Google Scholar
  84. Lian I, et al. The role of YAP transcription coactivator in regulating stem cell self-renewal and differentiation. Genes Dev. 2010;24:1106–18.PubMedCrossRefGoogle Scholar
  85. Visvader JE, Lindeman GJ. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer. 2008;8:755–68.PubMedCrossRefGoogle Scholar
  86. Pece S, et al. Biological and molecular heterogeneity of breast cancers correlates with their cancer stem cell content. Cell. 2010;140:62–73.PubMedCrossRefGoogle Scholar
  87. Cordenonsi M, et al. The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells. Cell. 2011;147:759–72.PubMedCrossRefGoogle Scholar
  88. Bhat KP, et al. The transcriptional coactivator TAZ regulates mesenchymal differentiation in malignant glioma. Genes Dev. 2011;25:2594–609.PubMedCrossRefGoogle Scholar
  89. Jansson L, Larsson J. Normal hematopoietic stem cell function in mice with enforced expression of the Hippo signaling effector YAP1. PLoS One. 2012;7:e32013.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Stem Cell ProgramChildren’s HospitalBostonUSA
  2. 2.Department of Stem Cell and Regenerative BiologyHarvard UniversityCambridgeUSA
  3. 3.Harvard Stem Cell InstituteCambridgeUSA

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