Hippo Growth Control Pathway and Organ Size


In multicellular organisms, regulation of growth control occurs because of the concerted action of multiple growth‐regulatory and patterning pathways. Among these, the Hippo (Hpo) pathway gained notoriety for its unique ability to simultaneously regulate cell proliferation and apoptosis to achieve the correct organ size. Initially discovered in Drosophila, this pathway is evolutionarily conserved, and acts as a universal regulator of organ size in metazoa. A complete pathway that integrates signals from the cell membrane to the nucleus has emerged, and multiple modes of Hpo pathway regulation have been elucidated. When the Hpo pathway is active, it acts as a brake on growth – cell proliferation is suppressed and apoptosis is promoted, whereas when the Hpo pathway is inactive, growth occurs – cell proliferation is promoted and apoptosis is suppressed. While the initial discovery of the pathway established its role in regulation of organ size and development, the focus has shifted considerably towards understanding its role in other biological processes such as maintaining tissue homeostasis, stem cell and tissue differentiation, cancer and regeneration. The Hpo signalling pathway functions in organ size control, and understanding its physiological functions will provide insights on its tissue‐ and cell‐type‐specific functions, and its involvement in diseases such as cancer.

Key Concepts

  • Cell proliferation and cell death must be regulated for balanced growth.
  • The regulation of Hippo pathway activity is key to regulating cell number to achieve the correct organ size and growth during normal development.
  • Hippo pathway activation promotes apoptosis and suppresses cell proliferation, whereas Hippo pathway inactivation promotes cell proliferation and suppresses apoptosis.
  • The Hippo pathway is a network of tumour suppressor genes, and genes regulating cell‐ and planar‐polarity.
  • Signalling interactions in the Hippo pathway ultimately converge on the regulation of the oncogene Yorkie pathway activity.
  • The Hippo pathway is conserved across species.
  • Hippo pathway is dysregulated in human cancer (e.g. loss of tumour suppressor gene neurofibromin 2 (NF2) is causal to schwannomas, and the YAP/TAZ oncoproteins are overexpressed in many human cancers [lung, breast, prostate and liver]).
  • Hippo pathway regulates stem cell renewal, regeneration and differentiation in a tissue‐ and context‐specific manner.

Keywords: Hippo pathway; Drosophila; tumour suppressor genes; oncogene; apoptosis; proliferation

Figure 1. The Drosophila Hippo pathway. Cartoon illustrating the signalling interactions among Hippo pathway genes is shown. Arrows indicate positive interactions, whereas inhibitory interactions are shown by a line.


Azzolin L, Panciera T, Soligo S, et al. (2014) YAP/TAZ incorporation in the beta-catenin destruction complex orchestrates the Wnt response. Cell 158(1): 157–170.

Bao Y, Hata Y, Ikeda M and Withanage K (2011) Mammalian Hippo pathway: from development to cancer and beyond. Journal of Biochemistry 149: 361–379.

Boggiano JC and Fehon RG (2012) Growth control by committee: intercellular junctions, cell polarity, and the cytoskeleton regulate Hippo signaling. Developmental Cell 22: 695–702.

Brittle AL, Repiso A, Casal J, Lawrence PA and Strutt D (2010) Four‐jointed modulates growth and planar polarity by reducing the affinity of dachsous for fat. Current Biology 20: 803–810.

Djiane A, Zaessiner S, Babaoglan AB and Bray J (2014) Notch inhibits Yorkie activity in Drosophila wing discs. PLos One 9 (8): e106211.

Dong J, Feldmann G, Huang J, et al. (2007) Elucidation of a universal size‐control mechanism in Drosophila and mammals. Cell 130: 1120–1133.

Fan R, Kim NG and Gumbiner BM (2013) Regulation of Hippo pathway by mitogenic growth factors via phosphoinositide 3‐kinase and phosphoinositide‐dependent kinase‐1. Proc Natl Acad Sci USA 110 (7): 2569–2574.

Feng Y and Irvine KD (2009) Processing and phosphorylation of the Fat receptor. Proceedings of the National Academy of Sciences of the United States of America 106: 11989–11994.

Gilbert MM, Tipping M, Veraksa A and Moberg KH (2011) A screen for conditional growth suppressor genes identifies the Drosophila homolog of HD‐PTP as a regulator of the oncoprotein Yorkie. Developmental Cell 20: 700–712.

Goulev Y, Fauny JD, Gonzalez‐Marti B, et al. (2008) SCALLOPED interacts with YORKIE, the nuclear effector of the hippo tumor‐suppressor pathway in Drosophila. Current Biology 18: 435–441.

Grijalva JL, Huizenga M, Mueller K, et al. (2014) Dynamic alterations in Hippo signaling pathway and YAP activation during liver regeneration. American Journal of Physiology. Gastrointestinal and Liver Physiology 307: G196–G204.

Grusche FA, Richardson HE and Harvey KF (2010) Upstream regulation of the hippo size control pathway. Current Biology 20: R574–R582.

Gumbiner BM and Kim NG (2014) The Hippo‐YAP signaling pathway and contact inhibition of growth. J Cell Sci 127 (Pt 4): 709–717.

Halder G and Johnson RL (2011) Hippo signaling: growth control and beyond. Development 138: 9–22.

Halder G, Dupont S and Piccolo S (2012) Transduction of mechanical and cytoskeletal cues by YAP and TAZ. Nature Reviews Molecular Cell Biology 13: 591–600.

Harvey KF, Zhang X and Thomas DM (2013) The Hippo pathway and human cancer. Nat Rev Cancer 13 (4): 246–257.

Hayashi S, Ochi H, Ogino H, et al. (2014a) Transcriptional regulators in the Hippo signaling pathway control organ growth in Xenopus tadpole tail regeneration. Developmental Biology 396: 31–41.

Hayashi S, Tamura K and Yokoyama H (2014b) Yap1, transcription regulator in the Hippo signaling pathway, is required for Xenopus limb bud regeneration. Developmental Biology 388: 57–67.

Hergovich A (2012) Mammalian Hippo signalling: a kinase network regulated by protein‐protein interactions. Biochemical Society Transactions 40: 124–128.

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

Johnson R and Halder G (2014) The two faces of Hippo: targeting the Hippo pathway for regenerative medicine and cancer treatment. Nature Reviews Drug Discovery 13: 63–79.

Kango‐Singh M and Singh A (2009) Regulation of organ size: insights from the Drosophila Hippo signaling pathway. Developmental Dynamics 238: 1627–1637.

Koontz LM, Liu‐Chittenden Y, Yin F, et al. (2013) The Hippo effector Yorkie controls normal tissue growth by antagonizing scalloped‐mediated default repression. Dev Cell 25 (4): 388–401.

Kwon HJ, Waghmare I, Verghese S, et al. (2015) Drosophila C‐terminal Src kinase regulates growth via the Hippo signaling pathway. Dev Biol 397 (1): 67–76.

Lai ZC, Wei X, Shimizu T, et al. (2005) Control of cell proliferation and apoptosis by mob as tumor suppressor, mats. Cell 120: 675–685.

Lin Z and Pu WT (2014) Harnessing Hippo in the heart: Hippo/Yap signaling and applications to heart regeneration and rejuvenation. Stem Cell Research 13 (3): 571–581.

Matakatsu H and Blair SS (2004) Interactions between Fat and Dachsous and the regulation of planar cell polarity in the Drosophila wing. Development 131: 3785–3794.

Matakatsu H and Blair SS (2006) Separating the adhesive and signaling functions of the Fat and Dachsous protocadherins. Development 133: 2315–2324.

O'Neill E and Kolch W (2005) Taming the Hippo: Raf‐1 controls apoptosis by suppressing MST2/Hippo. Cell Cycle 4: 365–367.

Oh H and Irvine KD (2010) Yorkie: the final destination of Hippo signaling. Trends in Cell Biology 20: 410–417.

Overholtzer M, Zhang G, Smolen GA, et al. (2006) Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon. Proc Natl Acad Sci USA 103 (33): 12405–12410.

Pan D (2007) Hippo signaling in organ size control. Genes and Development 21: 886–897.

Peng HW, Slattery M and Mann RS (2009) Transcription factor choice in the Hippo signaling pathway: homothorax and yorkie regulation of the microRNA bantam in the progenitor domain of the Drosophila eye imaginal disc. Genes and Development 23: 2307–2319.

Piccolo S, Dupont S and Cordenonsi M (2014) The biology of YAP/TAZ: hippo signaling and beyond. Physiol Rev 94 (4): 1287–1312.

Polesello C, Huelsmann S, Brown NH and Tapon N (2006) The Drosophila RASSF homolog antagonizes the hippo pathway. Current Biology 16: 2459–2465.

Rauskolb C, Pan G, Reddy BV, Oh H and Irvine KD (2011) Zyxin links fat signaling to the hippo pathway. PLoS Biology 9: e1000624.

Rauskolb C, Sun S, Sun G, Pan Y and Irvine KD (2014) Cytoskeletal tension inhibits Hippo signaling through an Ajuba‐Warts complex. Cell 158: 143–156.

Ribeiro PS, Josue F, Wepf A, et al. (2010) Combined functional genomic and proteomic approaches identify a PP2A complex as a negative regulator of Hippo signaling. Molecular Cell 39: 521–534.

Rogulja D, Rauskolb C and Irvine KD (2008) Morphogen control of wing growth through the Fat signaling pathway. Developmental Cell 15: 309–321.

Sopko R, Silva E, Clayton L, et al. (2009) Phosphorylation of the tumor suppressor fat is regulated by its ligand Dachsous and the kinase discs overgrown. Current Biology 19: 1112–1117.

St Johnston D (2002) The art and design of genetic screens: Drosophila melanogaster. Nature Reviews Genetics 3: 176–188.

Staley BK and Irvine KD (2012) Hippo signaling in Drosophila: recent advances and insights. Developmental Dynamics 241: 3–15.

Sun G and Irvine KD (2011) Regulation of Hippo signaling by Jun kinase signaling during compensatory cell proliferation and regeneration, and in neoplastic tumors. Developmental Biology 350: 139–151.

Tipping M and Perrimon N (2014) Drosophila as a model for context‐dependent tumorigenesis. Journal of Cellular Physiology 229: 27–33.

Udan RS, Kango‐Singh M, Nolo R, Tao C and Halder G (2003) Hippo promotes proliferation arrest and apoptosis in the Salvador/Warts pathway. Nature Cell Biology 5 (10): 914–920.

Varelas X, Miller BW, Sopko R, et al. (2010a) The Hippo pathway regulates Wnt/beta‐catenin signaling. Developmental Cell 18: 579–591.

Varelas X, Samavarchi‐Tehrani P, Narimatsu M, et al. (2010b) The crumbs complex couples cell density sensing to Hippo‐dependent control of the TGF‐beta‐SMAD pathway. Developmental Cell 19: 831–844.

Verghese S, Waghmare I, Kwon H, Hanes K and Kango‐Singh M (2012) Scribble acts in the Drosophila fat‐hippo pathway to regulate warts activity. PLoS One 7: e47173.

Verghese S, Waghmare I, Singh SR and Kango‐Singh M (2013) Molecular Genetics of Axial Patterning, Growth and Disease in the Drosophila Eye, Springer: 229–270.

Waghmare I, Roebke A, Minata M, Kango‐Singh M and Nakano I (2014) Intercellular cooperation and competition in brain cancers: lessons from Drosophila and human studies. Stem Cells Translational Medicine 3: 1262–1268.

Willecke M, Hamaratoglu F, Sansores‐Garcia L, Tao C and Halder G (2008) Boundaries of Dachsous Cadherin activity modulate the Hippo signaling pathway to induce cell proliferation. Proceedings of the National Academy of Sciences of the United States of America 105: 14897–14902.

Wu S, Huang J, Dong J and Pan D (2003) 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.

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

Yu FX and Guan KL (2013) The Hippo pathway: regulators and regulations.. Genes Dev 27(4): 355–371.

Zecca M and Struhl G (2010) A feed‐forward circuit linking wingless, fat‐dachsous signaling, and the warts‐hippo pathway to Drosophila wing growth. PLoS Biology 8: e1000386.

Zeng Q and Hong W (2008) The emerging role of the hippo pathway in cell contact inhibition, organ size control, and cancer development in mammals. Cancer Cell 13: 188–192.

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

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

Zhao B, Li L, Lei Q and Guan KL (2010a) The Hippo‐YAP pathway in organ size control and tumorigenesis: an updated version. Genes and Development 24: 862–874.

Zhao B, Li L, Tumaneng K, Wang CY and Guan KL (2010b) A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta‐TRCP). Genes and Development 24: 72–85.

Zhao B, Tumaneng K and Guan KL (2011) The Hippo pathway in organ size control, tissue regeneration and stem cell self‐renewal. Nature Cell Biology 13: 877–883.

Further Reading

Chaulk SG, Lattanzi VJ, Hiemer SE, Fahlman RP and Varelas X (2014) The Hippo pathway effectors TAZ/YAP regulate dicer expression and microRNA biogenesis through Let‐7. Journal of Biological Chemistry 289: 1886–1891.

Chen Q, Zhang N, Gray RS, et al. (2014) A temporal requirement for Hippo signaling in mammary gland differentiation, growth, and tumorigenesis. Genes and Development 28: 432–437.

Lucas EP, Khanal I, Gaspar P, et al. (2013) The Hippo pathway polarizes the actin cytoskeleton during collective migration of Drosophila border cells. Journal of Cell Biology 201: 875–885.

Manzanares M and Rodriguez TA (2013) Development: Hippo signalling turns the embryo inside out. Current Biology 23: R559–R561.

Waghmare I, Roebke A, Minata M, Kango‐Singh M and Nakano I (2014) Intercellular cooperation and competition in brain cancers: lessons from Drosophila and human studies. Stem Cells Translational Medicine 3: 1262–1268.

Weiss EL (2013) Hippo unleashed! Proteome‐scale analysis reveals new views of Hippo pathway biology. Science Signaling 6: pe36.

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Waghmare, Indrayani, Verghese, Shilpi, and Kango‐Singh, Madhuri(May 2015) Hippo Growth Control Pathway and Organ Size. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0026054]