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
  • Published:

Integrating developmental signals: a Hippo in the (path)way

Oncogene volume 31, pages 1743–1756 (2012)Cite this article

Abstract

The Hippo pathway, a signaling cascade that controls cell cycle progression, apoptosis and cell differentiation, has emerged as a fundamental regulator of many physiological and pathological processes. Recent studies have revealed a complex network of interactions directing Hippo pathway activity, and have connected this pathway with other key signaling pathways. Such crosstalk has uncovered novel roles for Hippo signaling, including regulation of TGFβ/SMAD and WNT/β-catenin pathways. This review highlights some of the recent findings in the Hippo field with an emphasis on how the Hippo pathway is integrated with other pathways to mediate diverse processes.

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
Figure 2
Figure 3

Similar content being viewed by others

References

  • Affolter M, Basler K . (2007). The Decapentaplegic morphogen gradient: from pattern formation to growth regulation. Nat Rev Genet 8: 663–674.

    Article  CAS  PubMed  Google Scholar 

  • Alarcon C, Zaromytidou AI, Xi Q, Gao S, Yu J, Fujisawa S et al. (2009). Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-beta pathways. Cell 139: 757–769.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aragon E, Goerner N, Zaromytidou AI, Xi Q, Escobedo A, Massague J et al. (2011). A Smad action turnover switch operated by WW domain readers of a phosphoserine code. Genes Dev 25: 1275–1288.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Arnold SJ, Robertson EJ . (2009). Making a commitment: cell lineage allocation and axis patterning in the early mouse embryo. Nat Rev Mol Cell Biol 10: 91–103.

    Article  CAS  PubMed  Google Scholar 

  • Attisano L, Labbe E . (2004). TGFbeta and Wnt pathway cross-talk. Cancer Metastasis Rev 23: 53–61.

    Article  CAS  PubMed  Google Scholar 

  • Aylon Y, Ofir-Rosenfeld Y, Yabuta N, Lapi E, Nojima H, Lu X et al. (2010). The Lats2 tumor suppressor augments p53-mediated apoptosis by promoting the nuclear proapoptotic function of ASPP1. Genes Dev 24: 2420–2429.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baena-Lopez LA, Rodriguez I, Baonza A . (2008). The tumor suppressor genes dachsous and fat modulate different signalling pathways by regulating dally and dally-like. Proc Natl Acad Sci USA 105: 9645–9650.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barrios-Rodiles M, Brown KR, Ozdamar B, Bose R, Liu Z, Donovan RS et al. (2005). High-throughput mapping of a dynamic signaling network in mammalian cells. Science 307: 1621–1625.

    Article  CAS  PubMed  Google Scholar 

  • Basu S, Totty NF, Irwin MS, Sudol M, Downward J . (2003). Akt phosphorylates the Yes-associated protein, YAP, to induce interaction with 14-3-3 and attenuation of p73-mediated apoptosis. Mol Cell 11: 11–23.

    Article  CAS  PubMed  Google Scholar 

  • Baumgartner R, Poernbacher I, Buser N, Hafen E, Stocker H . (2010). The WW domain protein Kibra acts upstream of Hippo in Drosophila. Dev Cell 18: 309–316.

    Article  CAS  PubMed  Google Scholar 

  • Bulgakova NA, Knust E . (2009). The Crumbs complex: from epithelial-cell polarity to retinal degeneration. J Cell Sci 122: 2587–2596.

    Article  CAS  PubMed  Google Scholar 

  • Camargo FD, Gokhale S, Johnnidis JB, Fu D, Bell GW, Jaenisch R et al. (2007). YAP1 increases organ size and expands undifferentiated progenitor cells. Curr Biol 17: 2054–2060.

    Article  CAS  PubMed  Google Scholar 

  • Chan SW, Lim CJ, Chong YF, Pobbati AV, Huang C, Hong W . (2011a). Hippo pathway-independent restriction of TAZ and YAP by angiomotin. J Biol Chem 286: 7018–7026.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chan SW, Lim CJ, Guo K, Ng CP, Lee I, Hunziker W et al. (2008). A role for TAZ in migration, invasion, and tumorigenesis of breast cancer cells. Cancer Res 68: 2592–2598.

    Article  CAS  PubMed  Google Scholar 

  • Chan SW, Lim CJ, Huang C, Chong YF, Gunaratne HJ, Hogue KA et al. (2011). WW domain-mediated interaction with Wbp2 is important for the oncogenic property of TAZ. Oncogene 30: 600–610.

    Article  CAS  PubMed  Google Scholar 

  • Chan SW, Lim CJ, Loo LS, Chong YF, Huang C, Hong W . (2009). TEADs mediate nuclear retention of TAZ to promote oncogenic transformation. J Biol Chem 284: 14347–14358.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cho E, Feng Y, Rauskolb C, Maitra S, Fehon R, Irvine KD . (2006). Delineation of a Fat tumor suppressor pathway. Nat Genet 38: 1142–1150.

    Article  CAS  PubMed  Google Scholar 

  • Clevers H . (2006). Wnt/beta-catenin signaling in development and disease. Cell 127: 469–480.

    Article  CAS  PubMed  Google Scholar 

  • Corbit KC, Shyer AE, Dowdle WE, Gaulden J, Singla V, Chen MH et al. (2008). Kif3a constrains beta-catenin-dependent Wnt signalling through dual ciliary and non-ciliary mechanisms. Nat Cell Biol 10: 70–76.

    Article  CAS  PubMed  Google Scholar 

  • Cui CB, Cooper LF, Yang X, Karsenty G, Aukhil I . (2003). Transcriptional coactivation of bone-specific transcription factor Cbfa1 by TAZ. Mol Cell Biol 23: 1004–1013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dai F, Duan X, Liang YY, Lin X, Feng XH . (2010). Coupling of dephosphorylation and nuclear export of Smads in TGF-beta signaling. Methods Mol Biol 647: 125–137.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Di Guglielmo GM, Le Roy C, Goodfellow AF, Wrana JL . (2003). Distinct endocytic pathways regulate TGF-beta receptor signalling and turnover. Nat Cell Biol 5: 410–421.

    Article  CAS  PubMed  Google Scholar 

  • Di Palma T, D'Andrea B, Liguori GL, Liguoro A, de Cristofaro T, Del Prete D et al. (2009). TAZ is a coactivator for Pax8 and TTF-1, two transcription factors involved in thyroid differentiation. Exp Cell Res 315: 162–175.

    Article  CAS  PubMed  Google Scholar 

  • Dong J, Feldmann G, Huang J, Wu S, Zhang N, Comerford SA et al. (2007). Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell 130: 1120–1133.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Duning K, Rosenbusch D, Schluter MA, Tian Y, Kunzelmann K, Meyer N et al. (2010). Polycystin-2 activity is controlled by transcriptional coactivator with PDZ binding motif and PALS1-associated tight junction protein. J Biol Chem 285: 33584–33588.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dupont S, Morsut L, Aragona M, Enzo E, Giulitti S, Cordenonsi M et al. (2011). Role of YAP/TAZ in mechanotransduction. Nature 474: 179–183.

    Article  CAS  PubMed  Google Scholar 

  • Ebisawa T, Fukuchi M, Murakami G, Chiba T, Tanaka K, Imamura T et al. (2001). Smurf1 interacts with transforming growth factor-beta type I receptor through Smad7 and induces receptor degradation. J Biol Chem 276: 12477–12480.

    Article  CAS  PubMed  Google Scholar 

  • Espanel X, Sudol M . (2001). Yes-associated protein and p53-binding protein-2 interact through their WW and SH3 domains. J Biol Chem 276: 14514–14523.

    Article  CAS  PubMed  Google Scholar 

  • Fernandez LA, Northcott PA, Dalton J, Fraga C, Ellison D, Angers S et al. (2009). YAP1 is amplified and up-regulated in hedgehog-associated medulloblastomas and mediates Sonic hedgehog-driven neural precursor proliferation. Genes Dev 23: 2729–2741.

    Article  CAS  Google Scholar 

  • Ferrigno O, Lallemand F, Verrecchia F, L'Hoste S, Camonis J, Atfi A et al. (2002). Yes-associated protein (YAP65) interacts with Smad7 and potentiates its inhibitory activity against TGF-beta/Smad signaling. Oncogene 21: 4879–4884.

    Article  CAS  PubMed  Google Scholar 

  • Genevet A, Wehr MC, Brain R, Thompson BJ, Tapon N . (2010). Kibra is a regulator of the Salvador/Warts/Hippo signaling network. Dev Cell 18: 300–308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Graves JD, Gotoh Y, Draves KE, Ambrose D, Han DK, Wright M et al. (1998). Caspase-mediated activation and induction of apoptosis by the mammalian Ste20-like kinase Mst1. Embo J 17: 2224–2234.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grzeschik NA, Parsons LM, Allott ML, Harvey KF, Richardson HE . (2010). Lgl, aPKC, and Crumbs regulate the Salvador/Warts/Hippo pathway through two distinct mechanisms. Curr Biol 20: 573–581.

    Article  CAS  PubMed  Google Scholar 

  • Habbig S, Bartram MP, Muller RU, Schwarz R, Andriopoulos N, Chen S et al. (2011). NPHP4, a cilia-associated protein, negatively regulates the Hippo pathway. J Cell Biol 193: 633–642.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harvey KF, Pfleger CM, Hariharan IK . (2003). The Drosophila Mst ortholog, Hippo, restricts growth and cell proliferation and promotes apoptosis. Cell 114: 457–467.

    Article  CAS  PubMed  Google Scholar 

  • Hata A, Lagna G, Massagué J, Hemmati-Brivanlou A . (1998). Smad6 inhibits BMP/Smad1 signaling by specifically competing with the Smad4 tumor suppressor. Genes Dev 12: 186–197.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hayashi H, Abdollah S, Qiu Y, Cai J, Xu YY, Grinnell BW et al. (1997). The MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling. Cell 89: 1165–1173.

    Article  CAS  PubMed  Google Scholar 

  • Heallen T, Zhang M, Wang J, Bonilla-Claudio M, Klysik E, Johnson RL et al. (2011). Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size. Science 332: 458–461.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hong JH, Hwang ES, McManus MT, Amsterdam A, Tian Y, Kalmukova R et al. (2005). TAZ, a transcriptional modulator of mesenchymal stem cell differentiation. Science 309: 1074–1078.

    Article  CAS  PubMed  Google Scholar 

  • Hong JH, Yaffe MB . (2006). TAZ: a beta-catenin-like molecule that regulates mesenchymal stem cell differentiation. Cell Cycle 5: 176–179.

    Article  CAS  PubMed  Google Scholar 

  • Hori T, Takaori-Kondo A, Kamikubo Y, Uchiyama T . (2000). Molecular cloning of a novel human protein kinase, kpm, that is homologous to warts/lats, a Drosophila tumor suppressor. Oncogene 19: 3101–3109.

    Article  CAS  PubMed  Google Scholar 

  • Hossain Z, Ali SM, Ko HL, Xu J, Ng CP, Guo K et al. (2007). Glomerulocystic kidney disease in mice with a targeted inactivation of Wwtr1. Proc Natl Acad Sci USA 104: 1631–1636.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Imamura T, Takase M, Nishihara A, Oeda E, Hanai J, Kawabata M et al. (1997). Smad6 inhibits signalling by the TGF-beta superfamily. Nature 389: 622–626.

    Article  CAS  PubMed  Google Scholar 

  • Islas S, Vega J, Ponce L, Gonzalez-Mariscal L . (2002). Nuclear localization of the tight junction protein ZO-2 in epithelial cells. Exp Cell Res 274: 138–148.

    Article  CAS  PubMed  Google Scholar 

  • Jang SW, Yang SJ, Srinivasan S, Ye K . (2007). Akt phosphorylates MstI and prevents its proteolytic activation, blocking FOXO3 phosphorylation and nuclear translocation. J Biol Chem 282: 30836–30844.

    Article  CAS  PubMed  Google Scholar 

  • Javelaud D, Mauviel A . (2004). Mammalian transforming growth factor-betas: Smad signaling and physio-pathological roles. Int J Biochem Cell Biol 36: 1161–1165.

    Article  CAS  PubMed  Google Scholar 

  • Jia J, Zhang W, Wang B, Trinko R, Jiang J . (2003). The Drosophila Ste20 family kinase dMST functions as a tumor suppressor by restricting cell proliferation and promoting apoptosis. Genes Dev 17: 2514–2519.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang Z, Li X, Hu J, Zhou W, Jiang Y, Li G et al. (2006). Promoter hypermethylation-mediated down-regulation of LATS1 and LATS2 in human astrocytoma. Neurosci Res 56: 450–458.

    Article  CAS  PubMed  Google Scholar 

  • Jimenez-Velasco A, Roman-Gomez J, Agirre X, Barrios M, Navarro G, Vazquez I et al. (2005). Downregulation of the large tumor suppressor 2 (LATS2/KPM) gene is associated with poor prognosis in acute lymphoblastic leukemia. Leukemia 19: 2347–2350.

    Article  CAS  PubMed  Google Scholar 

  • Justice RW, Zilian O, Woods DF, Noll M, Bryant PJ . (1995). 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.

    Article  CAS  PubMed  Google Scholar 

  • Kanai F, Marignani PA, Sarbassova D, Yagi R, Hall RA, Donowitz M et al. (2000). TAZ: a novel transcriptional co-activator regulated by interactions with 14-3-3 and PDZ domain proteins. Embo J 19: 6778–6791.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kango-Singh M, Nolo R, Tao C, Verstreken P, Hiesinger PR, Bellen HJ et al. (2002). Shar-pei mediates cell proliferation arrest during imaginal disc growth in Drosophila. Development 129: 5719–5730.

    Article  CAS  PubMed  Google Scholar 

  • Karpowicz P, Perez J, Perrimon N . (2010). The Hippo tumor suppressor pathway regulates intestinal stem cell regeneration. Development 137: 4135–4145.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kato Y, Habas R, Katsuyama Y, Naar AM, He X . (2002). A component of the ARC/Mediator complex required for TGFbeta/Nodal signalling. Nature 418: 641–646.

    Article  CAS  PubMed  Google Scholar 

  • Kavsak P, Rasmussen RK, Causing CG, Bonni S, Zhu H, Thomsen GH et al. (2000). Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation. Mol Cell 6: 1365–1375.

    Article  CAS  PubMed  Google Scholar 

  • Kim D, Shu S, Coppola MD, Kaneko S, Yuan ZQ, Cheng JQ . (2010). Regulation of proapoptotic mammalian ste20-like kinase MST2 by the IGF1-Akt pathway. PLoS One 5: e9616.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kimelman D, Xu W . (2006). beta-catenin destruction complex: insights and questions from a structural perspective. Oncogene 25: 7482–7491.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Lee KK, Ohyama T, Yajima N, Tsubuki S, Yonehara S . (2001). MST, a physiological caspase substrate, highly sensitizes apoptosis both upstream and downstream of caspase activation. J Biol Chem 276: 19276–19285.

    Article  CAS  PubMed  Google Scholar 

  • Lei QY, Zhang H, Zhao B, Zha ZY, Bai F, Pei XH et al. (2008). TAZ promotes cell proliferation and epithelial-mesenchymal transition and is inhibited by the Hippo pathway. Mol Cell Biol 28: 2426–2436.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lian I, Kim J, Okazawa H, Zhao J, Zhao B, Yu J et al. (2010). The role of YAP transcription coactivator in regulating stem cell self-renewal and differentiation. Genes Dev 24: 1106–1118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ling C, Zheng Y, Yin F, Yu J, Huang J, Hong Y et al. (2010). 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu CY, Lv X, Li T, Xu Y, Zhou X, Zhao S et al. (2011). PP1 cooperates with ASPP2 to dephosphorylate and activate TAZ. J Biol Chem 286: 5558–5566.

    Article  CAS  PubMed  Google Scholar 

  • Liu CY, Zha ZY, Zhou X, Zhang H, Huang W, Zhao D et al. (2010). The Hippo tumor pathway promotes TAZ degradation by phosphory. J Biol Chem 285: 37159–37169.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu L, Li Y, Kim SM, Bossuyt W, Liu P, Qiu Q et al. (2010). Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver. Proc Natl Acad Sci USA 107: 1437–1442.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • MacDonald BT, Tamai K, He X . (2009). Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell 17: 9–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Makita R, Uchijima Y, Nishiyama K, Amano T, Chen Q, Takeuchi T et al. (2008). Multiple renal cysts, urinary concentration defects, and pulmonary emphysematous changes in mice lacking TAZ. Am J Physiol Renal Physiol 294: F542–F553.

    Article  CAS  PubMed  Google Scholar 

  • Massague J, Seoane J, Wotton D . (2005). Smad transcription factors. Genes Dev 19: 2783–2810.

    Article  CAS  PubMed  Google Scholar 

  • Matallanas D, Romano D, Yee K, Meissl K, Kucerova L, Piazzolla D et al. (2007). RASSF1A elicits apoptosis through an MST2 pathway directing proapoptotic transcription by the p73 tumor suppressor protein. Mol Cell 27: 962–975.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meignin C, Alvarez-Garcia I, Davis I, Palacios IM . (2007). The Salvador-Warts-Hippo pathway is required for epithelial proliferation and axis specification in Drosophila. Curr Biol 17: 1871–1878.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Miller BW, Lau G, Grouios C, Mollica E, Barrios-Rodiles M, Liu Y et al. (2009). Application of an integrated physical and functional screening approach to identify inhibitors of the Wnt pathway. Mol Syst Biol 5: 315.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Morin-Kensicki EM, Boone BN, Howell M, Stonebraker JR, Teed J, Alb JG et al. (2006). Defects in yolk sac vasculogenesis, chorioallantoic fusion, and embryonic axis elongation in mice with targeted disruption of Yap65. Mol Cell Biol 26: 77–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Murakami M, Nakagawa M, Olson EN, Nakagawa O . (2005). 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Murakami M, Tominaga J, Makita R, Uchijima Y, Kurihara Y, Nakagawa O et al (2006). Transcriptional activity of Pax3 is co-activated by TAZ. Biochem Biophys Res Commun 339: 533–539.

    Article  CAS  PubMed  Google Scholar 

  • Nicolas FJ, De Bosscher K, Schmierer B, Hill CS . (2004). Analysis of Smad nucleocytoplasmic shuttling in living cells. J Cell Sci 117: 4113–4125.

    Article  CAS  PubMed  Google Scholar 

  • Nishioka N, Inoue K, Adachi K, Kiyonari H, Ota M, Ralston A et al. (2009). The Hippo signaling pathway components Lats and Yap pattern Tead4 activity to distinguish mouse trophectoderm from inner cell mass. Dev Cell 16: 398–410.

    Article  CAS  PubMed  Google Scholar 

  • Nusse R . (2005). Wnt signaling in disease and in development. Cell Res 15: 28–32.

    Article  CAS  PubMed  Google Scholar 

  • Oh H, Irvine KD . (2011). Cooperative regulation of growth by Yorkie and Mad through bantam. Dev Cell 20: 109–122.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Oka T, Remue E, Meerschaert K, Vanloo B, Boucherie C, Gfeller D et al. (2010). Functional complexes between YAP2 and ZO-2 are PDZ domain-dependent, and regulate YAP2 nuclear localization and signalling. Biochem J 432: 461–472.

    Article  CAS  PubMed  Google Scholar 

  • Oka T, Schmitt AP, Sudol M . (2011). Opposing roles of angiomotin like 1 and zona occludens-2 on proapoptotic function of YAP. Oncogene (e-pub ahead of print 20 June 2011; doi:10.1038/onc.2011.216).

    Article  PubMed  CAS  Google Scholar 

  • Overholtzer M, Zhang J, Smolen GA, Muir B, Li W, Sgroi DC et al. (2006). Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon. Proc Natl Acad Sci USA 103: 12405–12410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Park KS, Whitsett JA, Di Palma T, Hong JH, Yaffe MB, Zannini M . (2004). TAZ interacts with TTF-1 and regulates expression of surfactant protein-C. J Biol Chem 279: 17384–17390.

    Article  CAS  PubMed  Google Scholar 

  • Penheiter SG, Mitchell H, Garamszegi N, Edens M, Dore Jr JJ, Leof EB . (2002). Internalization-dependent and -independent requirements for transforming growth factor beta receptor signaling via the Smad pathway. Mol Cell Biol 22: 4750–4759.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Polesello C, Tapon N . (2007). Salvador-Warts-Hippo signaling promotes Drosophila posterior follicle cell maturation downstream of notch. Curr Biol 17: 1864–1870.

    Article  CAS  PubMed  Google Scholar 

  • Reddy BV, Rauskolb C, Irvine KD . (2010). Influence of fat-Hippo and notch signaling on the proliferation and differentiation of Drosophila optic neuroepithelia. Development 137: 2397–2408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Remue E, Meerschaert K, Oka T, Boucherie C, Vandekerckhove J, Sudol M et al. (2010). TAZ interacts with zonula occludens-1 and -2 proteins in a PDZ-1 dependent manner. FEBS Lett 584: 4175–4180.

    Article  CAS  PubMed  Google Scholar 

  • Ren F, Wang B, Yue T, Yun EY, Ip YT, Jiang J . (2010). Hippo signaling regulates Drosophila intestine stem cell proliferation through multiple pathways. Proc Natl Acad Sci USA 107: 21064–21069.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Robinson BS, Huang J, Hong Y, Moberg KH . (2010). Crumbs regulates Salvador/Warts/Hippo signaling in Drosophila via the FERM-domain protein Expanded. Curr Biol 20: 582–590.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rotin D . (1998). WW (WWP) domains: from structure to function. Curr Top Microbiol Immunol 228: 115–133.

    CAS  PubMed  Google Scholar 

  • Saadi-Kheddouci S, Berrebi D, Romagnolo B, Cluzeaud F, Peuchmaur M, Kahn A et al. (2001). Early development of polycystic kidney disease in transgenic mice expressing an activated mutant of the beta-catenin gene. Oncogene 20: 5972–5981.

    Article  CAS  PubMed  Google Scholar 

  • Sansom OJ, Griffiths DF, Reed KR, Winton DJ, Clarke AR . (2005). Apc deficiency predisposes to renal carcinoma in the mouse. Oncogene 24: 8205–8210.

    Article  CAS  PubMed  Google Scholar 

  • Santos-Rosa H, Schneider R, Bannister AJ, Sherriff J, Bernstein BE, Emre NC et al. (2002). Active genes are tri-methylated at K4 of histone H3. Nature 419: 407–411.

    Article  CAS  PubMed  Google Scholar 

  • Schlegelmilch K, Mohseni M, Kirak O, Pruszak J, Rodriguez JR, Zhou D et al. (2011). Yap1 acts downstream of alpha-catenin to control epidermal proliferation. Cell 144: 782–795.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schneider R, Bannister AJ, Myers FA, Thorne AW, Crane-Robinson C, Kouzarides T . (2004). Histone H3 lysine 4 methylation patterns in higher eukaryotic genes. Nat Cell Biol 6: 73–77.

    Article  CAS  PubMed  Google Scholar 

  • Seidel C, Schagdarsurengin U, Blumke K, Wurl P, Pfeifer GP, Hauptmann S et al. (2007). Frequent hypermethylation of MST1 and MST2 in soft tissue sarcoma. Mol Carcinog 46: 865–871.

    Article  CAS  PubMed  Google Scholar 

  • Shaw RL, Kohlmaier A, Polesello C, Veelken C, Edgar BA, Tapon N . (2010). The Hippo pathway regulates intestinal stem cell proliferation during Drosophila adult midgut regeneration. Development 137: 4147–4158.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shi Y, Massague J . (2003). Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113: 685–700.

    Article  CAS  PubMed  Google Scholar 

  • Silvis MR, Kreger BT, Lien WH, Klezovitch O, Rudakova GM, Camargo FD et al. (2011). \{alpha\}-Catenin is a tumor suppressor that controls cell accumul. Sci Signal 4: ra33.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Song H, Mak KK, Topol L, Yun K, Hu J, Garrett L et al. (2010). Mammalian Mst1 and Mst2 kinases play essential roles in organ size control and tumor suppression. Proc Natl Acad Sci USA 107: 1431–1436.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • St John MA, Tao W, Fei X, Fukumoto R, Carcangiu ML, Brownstein DG et al. (1999). Mice deficient of Lats1 develop soft-tissue sarcomas, ovarian tumours and pituitary dysfunction. Nat Genet 21: 182–186.

    Article  CAS  PubMed  Google Scholar 

  • Staley BK, Irvine KD . (2010). Warts and Yorkie mediate intestinal regeneration by influencing stem cell proliferation. Curr Biol 20: 1580–1587.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Steinmann K, Sandner A, Schagdarsurengin U, Dammann RH . (2009). Frequent promoter hypermethylation of tumor-related genes in head and neck squamous cell carcinoma. Oncol Rep 22: 1519–1526.

    CAS  PubMed  Google Scholar 

  • Strano S, Munarriz E, Rossi M, Castagnoli L, Shaul Y, Sacchi A et al. (2001). Physical interaction with Yes-associated protein enhances p73 transcriptional activity. J Biol Chem 276: 15164–15173.

    Article  CAS  PubMed  Google Scholar 

  • Sudol M . (1994). Yes-associated protein (YAP65) is a proline-rich phosphoprotein that binds to the SH3 domain of the Yes proto-oncogene product. Oncogene 9: 2145–2152.

    CAS  PubMed  Google Scholar 

  • Sudol M . (2011). Newcomers to the WW domain—mediated network of the Hippo tumor suppressor pathway. Genes Cancer 1: 1115–1118.

    Article  CAS  Google Scholar 

  • Sudol M, Bork P, Einbond A, Kastury K, Druck T, Negrini M et al. (1995). Characterization of the mammalian YAP (Yes-associated protein) gene and its role in defining a novel protein module, the WW domain. J Biol Chem 270: 14733–14741.

    Article  CAS  PubMed  Google Scholar 

  • Sudol M, Sliwa K, Russo T . (2001). Functions of WW domains in the nucleus. FEBS Lett 490: 190–195.

    Article  CAS  PubMed  Google Scholar 

  • Takahashi Y, Miyoshi Y, Takahata C, Irahara N, Taguchi T, Tamaki Y et al. (2005). Down-regulation of LATS1 and LATS2 mRNA expression by promoter hypermethylation and its association with biologically aggressive phenotype in human breast cancers. Clin Cancer Res 11: 1380–1385.

    Article  CAS  PubMed  Google Scholar 

  • Tao W, Zhang S, Turenchalk GS, Stewart RA, St John MA, Chen W et al. (1999). Human homologue of the Drosophila melanogaster lats tumour suppressor modulates CDC2 activity. Nat Genet 21: 177–181.

    Article  CAS  PubMed  Google Scholar 

  • Tapon N, Harvey KF, Bell DW, Wahrer DC, Schiripo TA, Haber DA et al. (2002). Salvador promotes both cell cycle exit and apoptosis in Drosophila and is mutated in human cancer cell lines. Cell 110: 467–478.

    Article  CAS  PubMed  Google Scholar 

  • Thiery JP, Acloque H, Huang RY, Nieto MA . (2009). Epithelial-mesenchymal transitions in development and disease. Cell 139: 871–890.

    Article  CAS  PubMed  Google Scholar 

  • Tian Y, Kolb R, Hong JH, Carroll J, Li D, You J et al. (2007). TAZ promotes PC2 degradation through a SCFbeta-Trcp E3 ligase complex. Mol Cell Biol 27: 6383–6395.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tyler DM, Baker NE . (2007). Expanded and fat regulate growth and differentiation in the Drosophila eye through multiple signaling pathways. Dev Biol 305: 187–201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Varelas X, Sakuma R, Samavarchi-Tehrani P, Peerani R, Rao BM, Dembowy J et al. (2008). TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal. Nat Cell Biol 10: 837–848.

    Article  CAS  PubMed  Google Scholar 

  • Varelas X, Miller BW, Sopko R, Song S, Gregorieff A, Fellouse FA et al. (2010a). The Hippo pathway regulates Wnt/beta-catenin signaling. Dev Cell 18: 579–591.

    Article  CAS  PubMed  Google Scholar 

  • Varelas X, Samavarchi-Tehrani P, Narimatsu M, Weiss A, Cockburn K, Larsen BG et al. (2010b). The Crumbs complex couples cell density sensing to Hippo-dependent control of the TGF-beta-SMAD pathway. Dev Cell 19: 831–844.

    Article  CAS  PubMed  Google Scholar 

  • Vassilev A, Kaneko KJ, Shu H, Zhao Y, DePamphilis ML . (2001). TEAD/TEF transcription factors utilize the activation domain of YAP65, a Src/Yes-associated protein localized in the cytoplasm. Genes Dev 15: 1229–1241.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vigneron AM, Ludwig RL, Vousden KH . (2010). Cytoplasmic ASPP1 inhibits apoptosis through the control of YAP. Genes Dev 24: 2430–2439.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang T . (2003). The 26S proteasome system in the signaling pathways of TGF-beta superfamily. Front Biosci 8: d1109–d1127.

    Article  CAS  PubMed  Google Scholar 

  • Webb C, Upadhyay A, Giuntini F, Eggleston I, Furutani-Seiki M, Ishima R et al. (2011). Structural features and ligand binding properties of tandem WW domains from YAP and TAZ, nuclear effectors of the Hippo pathway. Biochemistry 50: 3300–3309.

    Article  CAS  PubMed  Google Scholar 

  • Wrana JL . (2000). Regulation of Smad activity. Cell 100: 189–192.

    Article  CAS  PubMed  Google Scholar 

  • Wu S, Huang J, Dong J, 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.

    Article  CAS  PubMed  Google Scholar 

  • Xiao L, Chen Y, Ji M, Dong J . (2011). KIBRA regulates Hippo signaling activity via interactions with large tumor suppressor kinases. J Biol Chem 286: 7788–7796.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xiao Z, Watson N, Rodriguez C, Lodish HF . (2001). Nucleocytoplasmic shuttling of smad1 conferred by its nuclear localization and nuclear export signals. J Biol Chem 276: 39404–39410.

    Article  CAS  PubMed  Google Scholar 

  • Yagi R, Chen LF, Shigesada K, Murakami Y, Ito Y . (1999). A WW domain-containing yes-associated protein (YAP) is a novel transcriptional co-activator. Embo J 18: 2551–2562.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yi C, Troutman S, Fera D, Stemmer-Rachamimov A, Avila JL, Christian N et al. (2011). A tight junction-associated Merlin-angiomotin complex mediates Merlin's regulation of mitogenic signaling and tumor suppressive functions. Cancer Cell 19: 527–540.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yim H, Sung CK, You J, Tian Y, Benjamin T . (2011). Nek1 and TAZ interact to maintain normal levels of polycystin 2. J Am Soc Nephrol 22: 832–837.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu J, Poulton J, Huang YC, Deng WM . (2008). The Hippo pathway promotes Notch signaling in regulation of cell differentiation, proliferation, and oocyte polarity. PLoS One 3: e1761.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Yu J, Zheng Y, Dong J, Klusza S, Deng WM, Pan D . (2010). Kibra functions as a tumor suppressor protein that regulates Hippo signaling in conjunction with Merlin and Expanded. Dev Cell 18: 288–299.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yuan Z, Kim D, Shu S, Wu J, Guo J, Xiao L et al. (2010). Phosphoinositide 3-kinase/Akt inhibits MST1-mediated pro-apoptotic signaling through phosphorylation of threonine 120. J Biol Chem 285: 3815–3824.

    Article  CAS  PubMed  Google Scholar 

  • Zhang H, Liu CY, Zha ZY, Zhao B, Yao J, Zhao S et al. (2009a). TEAD transcription factors mediate the function of TAZ in cell growth and epithelial-mesenchymal transition. J Biol Chem 284: 13355–13362.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang H, Pasolli HA, Fuchs E . (2011). Yes-associated protein (YAP) transcriptional coactivator functions in balancing growth and differentiation in skin. Proc Natl Acad Sci USA 108: 2270–2275.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang J, Ji JY, Yu M, Overholtzer M, Smolen GA, Wang R et al. (2009b). YAP-dependent induction of amphiregulin identifies a non-cell-autonomous component of the Hippo pathway. Nat Cell Biol 11: 1444–1450.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang X, Milton CC, Humbert PO, Harvey KF . (2009c). Transcriptional output of the Salvador/Warts/Hippo pathway is controlled in distinct fashions in Drosophila melanogaster and mammalian cell lines. Cancer Res 69: 6033–6041.

    Article  CAS  PubMed  Google Scholar 

  • Zhang Y, Chang C, Gehling DJ, Hemmati-Brivanlou A, Derynck R . (2001). Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase. Proc Natl Acad Sci USA 98: 974–979.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao B, Ye X, Yu J, Li L, Li W, Li S et al. (2008). TEAD mediates YAP-dependent gene induction and growth control. Genes Dev 22: 1962–1971.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao B, Kim J, Ye X, Lai ZC, Guan KL . (2009). Both TEAD-binding and WW domains are required for the growth stimulation and oncogenic transformation activity of yes-associated protein. Cancer Res 69: 1089–1098.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao B, Li L, Lu Q, Wang LH, Liu CY, Lei Q et al. (2011). Angiomotin is a novel Hippo pathway component that inhibits YAP oncoprotein. Genes Dev 25: 51–63.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou D, Conrad C, Xia F, Park JS, Payer B, Yin Y et al. (2009). Mst1 and Mst2 maintain hepatocyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yap1 oncogene. Cancer Cell 16: 425–438.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Supported by the Karin Grunebaum Cancer Foundation (to X.V.), and Donation Henriette et Emile Goutière, Institut National du Cancer (INCa, PLBIO-2008), INSERM, CNRS, Ligue Nationale Contre le Cancer (Equipe Labellisée LIGUE), Université Paris XI (to A.M.). F. N-S. the recipient of a Ligue Nationale Contre le Cancer doctoral studentship.

Author information

Authors and Affiliations

  1. Institut Curie, Centre de Recherche, Orsay, France

    A Mauviel & F Nallet-Staub

  2. INSERM U1021, Orsay, France

    A Mauviel & F Nallet-Staub

  3. CNRS UMR3347, Orsay, France

    A Mauviel & F Nallet-Staub

  4. Université Paris XI, Orsay, France

    A Mauviel & F Nallet-Staub

  5. Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA

    X Varelas

Authors
  1. A Mauviel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. F Nallet-Staub
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. X Varelas
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A Mauviel.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mauviel, A., Nallet-Staub, F. & Varelas, X. Integrating developmental signals: a Hippo in the (path)way. Oncogene 31, 1743–1756 (2012). https://doi.org/10.1038/onc.2011.363

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2011.363

Keywords

This article is cited by

Search

Advanced search

Quick links