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The Power of Drosophila Genetics: The Discovery of the Hippo Pathway

  • Rewatee Gokhale
  • Cathie M. PflegerEmail author
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1893)

Abstract

The Hippo Pathway comprises a vast network of components that integrate diverse signals including mechanical cues and cell surface or cell-surface-associated molecules to define cellular outputs of growth, proliferation, cell fate, and cell survival on both the cellular and tissue level. Because of the importance of the regulators, core components, and targets of this pathway in human health and disease, individual components were often identified by efforts in mammalian models or for a role in a specific process such as stress response or cell death. However, multiple components were originally discovered in the Drosophila system, and the breakthrough of conceiving that these components worked together in a signaling pathway came from a series of Drosophila genetic screens and fundamental genetic and phenotypic characterization efforts. In this chapter, we will review the original discoveries leading to the conceptual framework of these components as a tumor suppressor network. We will review chronologically the early efforts that established our initial understanding of the core machinery that then launched the growing and vibrant field to be discussed throughout later chapters of this book.

Key words

Hippo Warts Sav Mats Yorkie Drosophila Signaling Genetics 

Notes

Acknowledgments

We would like to thank the Drosophila community and the broader Hippo Pathway field. We also apologize that we could not cover every advance in the field in this chapter. This review chapter was meant to review the early events in the conception of the field.

References

  1. 1.
    Rubin GM, Yandell MD, Wortman JR, Gabor Miklos GL, Nelson CR, Hariharan IK et al (2004) Comparative genomics of the eukaryotes. Science 287:2204–2215CrossRefGoogle Scholar
  2. 2.
    Brand AH, Perrimon N (1993) Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118:401–415PubMedPubMedCentralGoogle Scholar
  3. 3.
    Dang DT, Perrimon N (1992) Use of a yeast site-specific recombinase to generate embryonic mosaics in Drosophila. Dev Genet 13:367–375PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Harrison DA, Perrimon N (1993) Simple and efficient generation of marked clones in Drosophila. Curr Biol 3:424–433PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Nüsslein-Volhard C, Wieschaus E (1980) Mutations affecting segment number and polarity in Drosophila. Nature 287:795–801PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Moberg KH, Bell DW, Wahrer DC, Haber DA, Hariharan IK (2001) Archipelago regulates Cyclin E levels in Drosophila and is mutated in human cancer cell lines. Nature 413:311–316PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Moberg KH, Mukherjee A, Veraksa A, Artavanis-Tsakonas S, Hariharan IK (2004) The Drosophila F box protein archipelago regulates dMyc protein levels in vivo. Curr Biol 14:965–974PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Mills K, Daish T, Harvey KF, Pfleger CM, Hariharan IK, Kumar S (2006) The Drosophila melanogaster Apaf-1 homologue ARK is required for most, but not all, programmed cell death. J Cell Biol 172:809–815PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Tapon N, Ito N, Dickson BJ, Treisman JE, Hariharan IK (2001) The Drosophila tuberous sclerosis complex gene homologs restrict cell growth and cell proliferation. Cell 105:345–355PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Tapon N, Harvey KF, Bell DW, Wahrer DC, Schiripo TA, Haber D et al (2002) Salvador promotes both cell cycle exit and apoptosis in Drosophila and is mutated in human cancer cell lines. Cell 110:467–478PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    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 129:5719–5730PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Xu T, Wang W, Zhang S, Stewart RA, Yu W (1995) Identifying tumor suppressors in genetic mosaics: the Drosophila lats gene encodes a putative protein kinase. Development 121:1053–1063PubMedPubMedCentralGoogle Scholar
  13. 13.
    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 9:534–546PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Harvey KF, Pfleger CM, Hariharan IK (2003) The Drosophila Mst ortholog, Hippo, restricts growth and cell proliferation and promotes apoptosis. Cell 114:457–467PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    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 114:445–456PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Pantalacci S, Tapon N, Léopold P (2003) The Salvador partner Hippo promotes apoptosis and cell-cycle exit in Drosophila. Nat Cell Biol 5:921–927PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    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 5:914–920PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    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 17:2514–2519PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    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 120:675–685PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Huang J, Wu S, Barrera J, Matthews K, Pan D (2005) The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila Homolog of YAP. Cell 122:421–434PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Hamaratoglu F, Willecke M, Kango-Singh M, Nolo R, Hyun E, Tao C et al (2006) The tumour-suppressor genes NF2/Merlin and Expanded act through Hippo signalling to regulate cell proliferation and apoptosis. Nat Cell Biol 8:27–36PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Cho E, Feng Y, Rauskolb C, Maitra S, Fehon R, Irvine KD (2006) Delineation of a fat tumor suppressor pathway. Nat Genet 38:1142–1150PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Willecke M, Hamaratoglu F, Kango-Singh M, Udan R, Chen CL, Tao C et al (2006) The fat cadherin acts through the Hippo tumor-suppressor pathway to regulate tissue size. Curr Biol 16:2090–2100PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Silva E, Tsatskis Y, Gardano L, Tapon N, McNeill H (2006) The tumor-suppressor gene fat controls tissue growth upstream of expanded in the Hippo signaling pathway. Curr Biol 16:2081–2089PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Bennett FC, Harvey KF (2006) Fat cadherin modulates organ size in Drosophila via the Salvador/Warts/Hippo signaling pathway. Curr Biol 16:2101–2110PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Zhang L, Ren F, Zhang Q, Chen Y, Wang B, Jiang J (2008) The TEAD/TEF family of transcription factor scalloped mediates Hippo signaling in organ size control. Dev Cell 14:377–387PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Wu S, Liu Y, Zheng Y, Do J, Pan D (2008) The TEAD/TEF family protein scalloped mediates transcriptional output of the Hippo growth-regulatory pathway. Dev Cell 14:388–398PubMedCrossRefGoogle Scholar
  28. 28.
    Goulev Y, Fauny JD, Gonzalez-Marti B, Flagiello D, Silber J, Zider A (2008) SCALLOPED interacts with YORKIE, the nuclear effector of the Hippo tumor-suppressor pathway in Drosophila. Curr Biol 18:435–441PubMedCrossRefGoogle Scholar
  29. 29.
    Leevers SJ, McNeill H (2005) Controlling the size of organs and organisms. Curr Opin Cell Biol 17:604–609PubMedCrossRefGoogle Scholar
  30. 30.
    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 11:11–23CrossRefGoogle Scholar
  31. 31.
    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 130:1120–1133PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Oh H, Irvine KD (2008) In vivo regulation of Yorkie phosphorylation and localization. Development 135:1081–1088PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Ren F, Zhang L, Jiang J (2010) Hippo signaling regulates Yorkie nuclear localization and activity through 14-3-3 dependent and independent mechanisms. Dev Biol 337:303–312PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Bossuyt W, Chen CL, Chen Q, Sudol M, McNeill H, Pan D et al (2014) An evolutionary shift in the regulation of the Hippo pathway between mice and flies. Oncogene 33:1218–1228PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Staley BK, Irvine KD (2010) Warts and Yorkie mediate intestinal regeneration by influencing stem cell proliferation. Curr Biol 20:1580–1587PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    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 U S A 107:21064–21069PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Karpowicz P, Perez J, Perrimon N (2010) The Hippo tumor suppressor pathway regulates intestinal stem cell regeneration. Development 137:4135–4145PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    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 137:4147–4158PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Ding R, Weynans K, Bossing T, Barros CS, Berger C (2016) The Hippo signalling pathway maintains quiescence in Drosophila neural stem cells. Nat Commun 7:10510PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Keder A, Rives-Quinto N, Aerne BL, Franco M, Tapon N, Carmena A (2015) The hippo pathway core cassette regulates asymmetric cell division. Curr Biol 25:2739–2750PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Dewey EB, Sanchez D, Johnston CA (2015) Warts phosphorylates mud to promote pins-mediated mitotic spindle orientation in Drosophila, independent of Yorkie. Curr Biol 25:2751–2762PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Lucas EP, Khanal I, Gaspar P, Fletcher GC, Polesello C, Tapon N et al (2013) The Hippo pathway polarizes the actin cytoskeleton during collective migration of Drosophila border cells. J Cell Biol 201:875–885PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Dutta S, Baehrecke EH (2008) Warts is required for PI3K-regulated growth arrest, autophagy, and autophagic cell death in Drosophila. Curr Biol 18:1466–1475PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Fernández BG, Gaspar P, Brás-Pereira C, Jezowska B, Rebelo SR, Janody F (2011) Actin-capping protein and the Hippo pathway regulate F-actin and tissue growth in Drosophila. Development 138:2237–2246CrossRefGoogle Scholar
  45. 45.
    Marcinkevicius E, Zallen JA (2013) Regulation of cytoskeletal organization and junctional remodeling by the atypical cadherin fat. Development 140:433–443PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Ilanges A, Jahanshahi M, Balobin DM, Pfleger CM (2013) Alcohol interacts with genetic alteration of the Hippo tumor suppressor pathway to modulate tissue growth in drosophila. PLoS One 8:e78880PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Emoto K, Parrish JZ, Jan LY, Jan YN (2006) The tumour suppressor Hippo acts with the NDR kinases in dendritic tiling and maintenance. Nature 443:210–213PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Jahanshahi M, Hsiao K, Jenny A, Pfleger CM (2016) The Hippo pathway targets Rae1 to regulate mitosis and organ size and to feed back to regulate upstream components Merlin, Hippo, and Warts. PLoS Genet 12:e1006198PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Genevet A, Polesello C, Blight K, Robertson F, Collinson LM, Pichaud F et al (2009) The Hippo pathway regulates apical-domain size independently of its growth-control function. J Cell Sci 122:2360–2370PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Verghese S, Waghmare I, Kwon H, Hanes K, Kango-Singh M (2012) Scribble acts in the Drosophila fat-hippo pathway to regulate warts activity. PLoS One 7:e47173PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Sansores-Garcia L, Bossuyt W, Wada K, Yonemura S, Tao C, Sasaki et al (2011) Modulating F-actin organization induces organ growth by affecting the Hippo pathway. EMBO J 30:2325–2335PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Rauskolb C, Pan G, Reddy BV, Oh H, Irvine KD (2011) Zyxin links fat signaling to the hippo pathway. PLoS Biol 9:e1000624PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Rauskolb C, Sun S, Sun G, Pan Y, Irvine KD (2014) Cytoskeletal tension inhibits Hippo signaling through an Ajuba-Warts complex. Cell 158:143–156PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Gaspar P, Holder MV, Aerne BL, Janody F, Tapon N (2015) Zyxin antagonizes the FERM protein expanded to couple F-actin and Yorkie-dependent organ growth. Curr Biol 25:679–689PubMedCrossRefGoogle Scholar
  55. 55.
    Deng H, Wang W, Yu J, Zheng Y, Qing Y, Pan D (2015) Spectrin regulates Hippo signaling by modulating cortical actomyosin activity. elife 4:e06567PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Fletcher GC, Elbediwy A, Khanal I, Ribeiro PS, Tapon N, Thompson BJ (2015) The Spectrin cytoskeleton regulates the Hippo signalling pathway. EMBO J 34:940–954PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Wong KK, Li W, An Y, Duan Y, Li Z, Kang Y et al (2015) β-Spectrin regulates the hippo signaling pathway and modulates the basal actin network. J Biol Chem 290:6397–6407PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Wehr MC, Holder MV, Gailite I, Saunders RE, Maile TM, Ciirdaeva E et al (2013) Salt-inducible kinases regulate growth through the Hippo signalling pathway in Drosophila. Nat Cell Biol 15:61–71PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Aerne BL, Gailite I, Sims D, Tapon N (2015) Hippo stabilises its adaptor Salvador by antagonising the HECT ubiquitin ligase Herc4. PLoS One 10:e0131113PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Hirabayashi S, Cagan RL (2015) Salt-inducible kinases mediate nutrient-sensing to link dietary sugar and tumorigenesis in Drosophila. elife 4:e08501PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Yin F, Yu J, Zheng Y, Chen Q, Zhang N, Pan D (2013) Spatial organization of Hippo signaling at the plasma membrane mediated by the tumor suppressor Merlin/NF2. Cell 154:1342–1355PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Sun S, Reddy BVVG, Irvine KD (2015) Localization of Hippo signalling complexes and Warts activation in vivo. Nat Commun 6:8402PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Mikeladze-Dvali T, Wernet MF, Pistillo D, Mazzoni EO, Teleman AA, Chen YW et al (2005) The growth regulators warts/lats and melted interact in a bistable loop to specify opposite fates in Drosophila R8 photoreceptors. Cell 122:775–787PubMedCrossRefGoogle Scholar
  64. 64.
    Jukam D, Desplan C (2011) Binary regulation of Hippo pathway by Merlin/NF2, Kibra, Lgl, and melted specifies and maintains postmitotic neuronal fate. Dev Cell 21:874–887PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Jukam D, Xie B, Rister J, Terrell D, Charlton-Perkins M, Pistillo D et al (2013) Opposite feedbacks in the Hippo pathway for growth control and neural fate. Science 342:1238016PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Neto-Silva RM, de Beco S, Johnston LA (2010) Evidence for a growth-stabilizing regulatory feedback mechanism between Myc and Yorkie, the Drosophila homolog of Yap. Dev Cell 19:507–520PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Ziosi M, Baena-López LA, Grifoni D, Froldi F, Pession A, Garoia F et al (2010) dMyc functions downstream of Yorkie to promote the supercompetitive behavior of hippo pathway mutant cells. PLoS Genet 6:e1001140PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Meng Z, Moroishi T, Guan KL (2006) Mechanisms of Hippo pathway regulation. Genes Dev 30:1–17CrossRefGoogle Scholar
  69. 69.
    Yu FX, Zhao B, Guan KL (2015) Hippo pathway in organ size control, tissue homeostasis, and cancer. Cell 163:811–828PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Watt KI, Harvey KF, Gregorevic P (2017) Regulation of tissue growth by the mammalian Hippo signaling pathway. Front Physiol 8:942PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Milton CC, Grusche FA, Degoutin JL, Yu E, Dai Q, Lai EC et al (2014) The Hippo pathway regulates hematopoiesis in Drosophila melanogaster. Curr Biol 24:2673–2680PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Liu B, Zheng Y, Yin F, Yu J, Silverman N, Pan D (2016) Toll receptor-mediated Hippo signaling controls innate immunity in Drosophila. Cell 164:406–419PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Sing A, Tsatskis Y, Fabian L, Hester I, Rosenfeld R, Serricchio M et al (2014) The atypical cadherin fat directly regulates mitochondrial function and metabolic state. Cell 158:1293–1308PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Colombani J, Polesello C, Josué F, Tapon N (2006) Dmp53 activates the Hippo pathway to promote cell death in response to DNA damage. Curr Biol 16:1453–1458PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Thompson BJ, Cohen SM (2006) The Hippo pathway regulates the bantam microRNA to control cell proliferation and apoptosis in Drosophila. Cell 126:767–774PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Nolo R, Morrison CM, Tao C, Zhang X, Halder G (2006) The bantam microRNA is a target of the hippo tumor-suppressor pathway. Curr Biol 16:1895–1904PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Polesello C, Huelsmann S, Brown NH, Tapon N (2006) The Drosophila RASSF homolog antagonizes the hippo pathway. Curr Biol 16:2459–2465PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Tyler DM, Li W, Zhuo N, Pellock B, Baker NE (2007) Genes affecting cell competition in Drosophila. Genetics 175:643–657PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Wei X, Shimizu T, Lai ZC (2007) Mob as tumor suppressor is activated by Hippo kinase for growth inhibition in Drosophila. EMBO J 26:1772–1781PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Pellock BJ, Buff E, White K, Hariharan IK (2007) The Drosophila tumor suppressors expanded and Merlin differentially regulate cell cycle exit, apoptosis, and wingless signaling. Dev Biol 304:102–115PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Shimizu T, Ho LL, Lai ZC (2008) The mob as tumor suppressor gene is essential for early development and regulates tissue growth in Drosophila. Genetics 178:957–965PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Badouel C, Gardano L, Amin N, Garg A, Rosenfeld R, Le Bihan T et al (2009) The FERM-domain protein expanded regulates Hippo pathway activity via direct interactions with the transcriptional activator Yorkie. Dev Cell 16:411–420PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Oh H, Reddy BV, Irvine KD (2009) Phosphorylation-independent repression of Yorkie in fat-Hippo signaling. Dev Biol 335:188–197PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Peng HW, Slattery M, 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 Dev 23:2307–2319PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Hamaratoglu F, Gajewski K, Sansores-Garcia L, Morrison C, Tao C, Halder G (2009) The Hippo tumor-suppressor pathway regulates apical-domain size in parallel to tissue growth. J Cell Sci 122:2351–2359PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Chen CL, Gajewski KM, Hamaratoglu F, Bossuyt W, Sansores-Garcia L, Tao C et al (2010) The apical-basal cell polarity determinant Crumbs regulates Hippo signaling in Drosophila. Proc Natl Acad Sci USA 107:15810–15815PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    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 20:573–581PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    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 107:10532–10537PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Parsons LM, Grzeschik NA, Allott ML, Richardson HE (2010) Lgl/aPKC and Crb regulate the Salvador/Warts/Hippo pathway. Fly 4:288–293PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    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 20:582–590PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Hafezi Y, Bosch JA, Hariharan IK (2012) Differences in levels of the transmembrane protein Crumbs can influence cell survival at clonal boundaries. Dev Biol 368:358–369PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Baumgartner R, Poernbacher I, Buser N, Hafen E, Stocker H (2010) The WW domain protein Kibra acts upstream of Hippo in Drosophila. Dev Cell 18:309–316PubMedCrossRefPubMedCentralGoogle Scholar
  93. 93.
    Genevet A, Wehr MC, Brain R, Thompson BJ, Tapon N (2010) Kibra is a regulator of the Salvador/Warts/Hippo signaling network. Dev Cell 18:300–308PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    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 18:288–299PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Das Thakur M, Feng Y, Jagannathan R, Seppa MJ, Skeath JB, Longmore GD (2010) Ajuba LIM proteins are negative regulators of the Hippo signaling pathway. Curr Biol 20:657–662PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Ribeiro PS, Josué F, Wepf A, Wehr MC, Rinner O, Kelly G et al (2010) Combined functional genomic and proteomic approaches identify a PP2A complex as a negative regulator of Hippo signaling. Mol Cell 39:521–534PubMedCrossRefPubMedCentralGoogle Scholar
  97. 97.
    Oh H, Irvine KD (2011) Cooperative regulation of growth by Yorkie and Mad through bantam. Dev Cell 20:109–122PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Boggiano JC, Vanderzalm PJ, Fehon RG (2011) Tao-1 phosphorylates Hippo/MST kinases to regulate the Hippo-Salvador-Warts tumor suppressor pathway. Dev Cell 21:888–895PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Poon CL, Lin JI, Zhang X, Harvey KF (2011) The sterile 20-like kinase Tao-1 controls tissue growth by regulating the Salvador-Warts-Hippo pathway. Dev Cell 21:896–906PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    Verghese S, Bedi S, Kango-Singh M (2012) Hippo signalling controls Dronc activity to regulate organ size in Drosophila. Cell Death Differ 19:1664–1676PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Herranz H, Hong X, Cohen SM (2012) Mutual repression by bantam miRNA and Capicua links the EGFR/MAPK and Hippo pathways in growth control. Curr Biol 22:651–657PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    Yue T, Tian A, Jiang J (2012) The cell adhesion molecule echinoid functions as a tumor suppressor and upstream regulator of the Hippo signaling pathway. Dev Cell 22:255–267PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Kagey JD, Brown JA, Moberg KH (2012) Regulation of Yorkie activity in Drosophila imaginal discs by the Hedgehog receptor gene patched. Mech Dev 129:339–349PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Ye X, Deng Y, Lai ZC (2012) Akt is negatively regulated by Hippo signaling for growth inhibition in Drosophila. Dev Biol 369:115–123PubMedCrossRefPubMedCentralGoogle Scholar
  105. 105.
    Sansores-Garcia L, Atkins M, Moya IM, Shahmoradgoli M, Tao C, Mills GB et al (2013) Mask is required for the activity of the Hippo pathway effector Yki/YAP. Curr Biol 23:229–235PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Sidor CM, Brain R, Thompson BJ (2013) Mask proteins are cofactors of Yorkie/YAP in the Hippo pathway. Curr Biol 23:223–238PubMedCrossRefPubMedCentralGoogle Scholar
  107. 107.
    Oh H, Slattery M, Ma L, Crofts A, White KP, Mann RS et al (2013) Genome-wide association of Yorkie with chromatin and chromatin-remodeling complexes. Cell Rep 3:309–318PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Reddy BV, Irvine KD (2013) Regulation of Hippo signaling by EGFR-MAPK signaling through Ajuba family proteins. Dev Cell 24:459–471PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Koontz LM, Liu-Chittenden Y, Yin F, Zheng Y, Yu J, Huang B et al (2013) The Hippo effector Yorkie controls normal tissue growth by antagonizing scalloped-mediated default repression. Dev Cell 25:388–401PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Huang HL, Wang S, Yin MX, Dong L, Wang C, Wu W et al (2013) Par-1 regulates tissue growth by influencing hippo phosphorylation status and hippo-Salvador association. PLoS Biol 11:e1001620PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Sun G, Irvine KD (2013) Ajuba family proteins link JNK to Hippo signaling. Sci Signal 6:ra81PubMedCrossRefPubMedCentralGoogle Scholar
  112. 112.
    Zhang C, Robinson BS, Xu W, Yang L, Yao B, Zhao H et al (2015) The ecdysone receptor coactivator Taiman links Yorkie to transcriptional control of germline stem cell factors in somatic tissue. Dev Cell 34:168–180PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Zheng Y, Wang W, Liu B, Deng H, Uster E, Pan D (2015) Identification of Happyhour/MAP4K as alternative Hpo/Mst-like kinases in the Hippo kinase Cascade. Dev Cell 34:642–655PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Li S, Cho YS, Yue T, Ip YT, Jiang J (2015) Overlapping functions of the MAP4K family kinases Hppy and Msn in Hippo signaling. Cell Discov 1:15038PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Oncological SciencesThe Icahn School of Medicine at Mount SinaiNew YorkUSA
  2. 2.The Graduate School of Biomedical Sciences, The Icahn School of Medicine at Mount SinaiNew YorkUSA
  3. 3.The Tisch Cancer Institute, The Icahn School of Medicine at Mount SinaiNew YorkUSA

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