Molecular Oncology
Volume 3, Issue 4 , Pages 354-365 , August 2009

At the crossroads of polarity, proliferation and apoptosis: The use of Drosophila to unravel the multifaceted role of endocytosis in tumor suppression

  • Thomas Vaccari

      Affiliations

    • Corresponding Author InformationCorresponding authors. Tel.: +39 02 57430 3823; fax: +39 02 57430 3231 (T. Vaccari), Tel.: +1 510 642 8605; fax: +1 510 643 7440 (D. Bilder).
    • Present address: IFOM, Istituto FIRC di Oncologia Molecolare, Milano, Italy.
    • ,
  • David Bilder

      Affiliations

    • Corresponding Author InformationCorresponding authors. Tel.: +39 02 57430 3823; fax: +39 02 57430 3231 (T. Vaccari), Tel.: +1 510 642 8605; fax: +1 510 643 7440 (D. Bilder).

Received 5 May 2009 ,Accepted 25 May 2009.

References 

  1. Adachi-Yamada T, Fujimura-Kamada K, Nishida Y, Matsumoto K. Distortion of proximodistal information causes JNK-dependent apoptosis in Drosophila wing. Nature. 1999;400:166–169
  2. Adachi-Yamada T, O'Connor MB. Morphogenetic apoptosis: a mechanism for correcting discontinuities in morphogen gradients. Dev. Biol. 2002;251:74–90
  3. Bache KG, Slagsvold T, Cabezas A, Rosendal KR, Raiborg C, Stenmark H. The growth-regulatory protein HCRP1/hVps37A is a subunit of mammalian ESCRT-I and mediates receptor down-regulation. Mol. Biol. Cell. 2004;15:4337–4346
  4. Balklava Z, Pant S, Fares H, Grant BD. Genome-wide analysis identifies a general requirement for polarity proteins in endocytic traffic. Nat. Cell Biol. 2007;9:1066–1073
  5. Bernards A, Hariharan IK. Of flies and men – studying human disease in Drosophila. Curr. Opin. Genet. Dev. 2001;11:274–278
  6. Bilder D, Li M, Perrimon N. Cooperative regulation of cell polarity and growth by Drosophila tumor suppressors. Science. 2000;289:113–116
  7. Bilder D. Epithelial polarity and growth control: links from the Drosophila neoplastic tumor suppressors. Genes Dev. 2004;18:1909–1925
  8. Bissell MJ, Radisky D. Putting tumours in context. Nat. Rev. Cancer. 2001;1:46–54
  9. Bökel C, Schwabedissen A, Entchev E, Renaud O, González-Gaitán M. Sara endosomes and the maintenance of Dpp signaling levels across mitosis. Science. 2006;314:1135–1139
  10. Brown S, Hu N, Hombría JC. Identification of the first invertebrate interleukin JAK/STAT receptor, the Drosophila gene domeless. Curr. Biol. 2001;11:1700–1705
  11. Brumby AM, Richardson HE. Scribble mutants cooperate with oncogenic Ras or Notch to cause neoplastic overgrowth in Drosophila. EMBO J. 2003;22:5769–5779
  12. Brumby AM, Richardson HE. Using Drosophila melanogaster to map human cancer pathways. Nat. Rev. Cancer. 2005;5:626–639
  13. Bryant PJ, Schubiger G. Giant and duplicated imaginal discs in a new lethal mutant of Drosophila melanogaster. Dev. Biol. 1971;24:233–263
  14. Chao JL, Tsai YC, Chiu SJ, Sun YH. Localized notch signal acts through eyg and upd to promote global growth in Drosophila eye. Development. 2004;131:3839–3847
  15. Cheng KW, Lahad JP, Kuo WL, Lapuk A, Yamada K, Auersperg N, et al The RAB25 small GTPase determines aggressiveness of ovarian and breast cancers. Nat. Med. 2004;10:1251–1256
  16. Childress JL, Acar M, Tao C, Halder G. Lethal giant discs, a novel C2-domain protein, restricts notch activation during endocytosis. Curr. Biol. 2006;16:2228–2233
  17. Coumailleau F, Fürthauer M, Knoblich JA, González-Gaitán M. Directional delta and notch trafficking in Sara endosomes during asymmetric cell division. Nature. 2009;
  18. Curto M, Cole BK, Lallemand D, Liu CH, McClatchey AI. Contact-dependent inhibition of EGFR signaling by Nf2/Merlin. J. Cell Biol. 2007;177:893–903
  19. Devergne O, Ghiglione C, Noselli S. The endocytic control of JAK/STAT signalling in Drosophila. J. Cell Sci. 2007;120:3457–3464
  20. Doherty GJ, McMahon HT. Mechanisms of endocytosis. Annu. Rev. Biochem. 2009;
  21. Dong J, Feldmann G, Huang J, Wu S, Zhang N, Comerford SA, et al. Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell. 2007;130:1120–1133
  22. Doyotte A, Russell MR, Hopkins CR, Woodman PG. Depletion of TSG101 forms a mammalian “Class E” compartment: a multicisternal early endosome with multiple sorting defects. J. Cell Sci. 2005;118:3003–3017
  23. Dubois L, Lecourtois M, Alexandre C, Hirst E, Vincent JP. Regulated endocytic routing modulates wingless signaling in Drosophila embryos. Cell. 2001;105:613–624
  24. Edgar BA. From cell structure to transcription: Hippo forges a new path. Cell. 2006;124:267–273
  25. Fortini ME, Skupski MP, Boguski MS, Hariharan IK. A survey of human disease gene counterparts in the Drosophila genome. J. Cell Biol. 2000;150:F23–F30
  26. Fortini, M.E., Bilder, D. Endocytic regulation of notch signaling. Curr Opin Genet Dev., in press (2009 May 15 e-pub ahead of print).
  27. Franz DN, Leonard J, Tudor C, Chuck G, Care M, Sethuraman G, et al. Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Ann. Neurol. 2006;59:490–498
  28. Fuwa TJ, Hori K, Sasamura T, Higgs J, Baron M, Matsuno K. The first deltex null mutant indicates tissue-specific deltex-dependent notch signaling in Drosophila. Mol. Genet. Genomics. 2006;275:251–263
  29. Gallagher CM, Knoblich JA. The conserved c2 domain protein lethal (2) giant discs regulates protein trafficking in Drosophila. Dev. Cell. 2006;11:641–653
  30. Garcia MJ, Pole JC, Chin SF, Teschendorff A, Naderi A, Ozdag H, et al A 1Mb minimal amplicon at 8p11-12 in breast cancer identifies new candidate oncogenes. Oncogene. 2005;24:5235–5245
  31. Gateff E, Schneiderman H. Developmental studies of a new mutant of Drosophila melanogaster: lethal malignant brain tumor (l(2)gl 4). Am. Zool. 1967;7:760
  32. Gateff E. Malignant neoplasms of genetic origin in Drosophila melanogaster. Science. 1978;200:1448–1459
  33. Georgiou M, Marinari E, Burden J, Baum B. Cdc42, Par6, and aPKC regulate Arp2/3-mediated endocytosis to control local adherens junction stability. Curr. Biol. 2008;18:1631–1638
  34. Gould G, Lippincott-Schwartz J. New roles for endosomes: from vesicular carriers to multi-purpose platforms. Nat. Rev. Mol. Cell Biol. 2009;10:287–292
  35. Grabher C, von Boehmer H, Look AT. Notch 1 activation in the molecular pathogenesis of T-cell acute lymphoblastic leukaemia. Nat. Rev. Cancer. 2006;6:347–359
  36. Hagemann T, Wilson J, Kulbe H, Li NF, Leinster DA, Charles K, et al. Macrophages induce invasiveness of epithelial cancer cells via NF-kappa B and JNK. J. Immunol. 2005;175:1197–1205
  37. Hamaratoglu F, Willecke M, Kango-Singh M, Nolo R, Hyun E, Tao C, 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
  38. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70
  39. Hariharan IK, Bilder D. Regulation of imaginal disc growth by tumor-suppressor genes in Drosophila. Annu. Rev. Genet. 2006;40:335–361
  40. Harris KP, Tepass U. Cdc42 and Par proteins stabilize dynamic adherens junctions in the Drosophila neuroectoderm through regulation of apical endocytosis. J. Cell Biol. 2008;183:1129–1143
  41. Herz HM, Chen Z, Scherr H, Lackey M, Bolduc C, Bergmann A. vps25 mosaics display non-autonomous cell survival and overgrowth, and autonomous apoptosis. Development. 2006;133:1871–1880
  42. Hori K, Fostier M, Ito M, Fuwa TJ, Go MJ, Okano H, et al. Drosophila deltex mediates suppressor of hairless-independent and late-endosomal activation of notch signaling. Development. 2004;131:5527–5537
  43. Huang S, Shu L, Dilling MB, Easton J, Harwood FC, Ichijo H, et al. Sustained activation of the JNK cascade and rapamycin-induced apoptosis are suppressed by p53/p21(Cip1). Mol. Cell. 2003;11:1491–1501
  44. Humbert PO, Russell SM, Richardson HE. Dlg, Scribble and Lgl in cell polarity, cell proliferation and cancer. Bioessays. 2003;25:542–553
  45. Igaki T, Pagliarini RA, Xu T. Loss of cell polarity drives tumor growth and invasion through JNK activation in Drosophila. Curr. Biol. 2006;16:1139–1146
  46. Igaki T, Pastor-Pareja JC, Aonuma H, Miura M, Xu T. Intrinsic tumor suppression and epithelial maintenance by endocytic activation of Eiger/TNF signaling in Drosophila. Dev. Cell. 2009;16:458–465
  47. Jaekel R, Klein T. The Drosophila notch inhibitor and tumor suppressor gene lethal (2) giant discs encodes a conserved regulator of endosomal trafficking. Dev. Cell. 2006;11:655–669
  48. Jekely G, Rorth P. Hrs mediates downregulation of multiple signalling receptors in Drosophila. EMBO Rep. 2003;4:1163–1168
  49. Jékely G, Sung HH, Luque CM, Rørth P. Regulators of endocytosis maintain localized receptor tyrosine kinase signaling in guided migration. Dev. Cell. 2005;9:197–207
  50. Johnson KC, Kissil JL, Fry JL, Jacks T. Cellular transformation by a FERM domain mutant of the Nf2 tumor suppressor gene. Oncogene. 2002;21:5990–5997
  51. Kanazawa C, Morita E, Yamada M, Ishii N, Miura S, Asao H, et al. Effects of deficiencies of STAMs and Hrs, mammalian class E Vps proteins, on receptor downregulation. Biochem. Biophys. Res. Commun. 2003;309:848–856
  52. Karp CM, Tan TT, Mathew R, Nelson D, Mukherjee C, Degenhardt K, et al. Role of the polarity determinant crumbs in suppressing mammalian epithelial tumor progression. Cancer Res. 2008;68:4105–4115
  53. Kenerson H, Dundon TA, Yeung RS. Effects of rapamycin in the Eker rat model of tuberous sclerosis complex. Pediatr. Res. 2005;57:67–75
  54. Komada M, Kitamura N. The Hrs/STAM complex in the downregulation of receptor tyrosine kinases. J. Biochem. 2005;137:1–8
  55. Kopan R, Ilagan MX. The canonical notch signaling pathway: unfolding the activation mechanism. Cell. 2009;137:216–233
  56. Kwei KA, Finch JS, Ranger-Moore J, Bowden GT. The role of Rac1 in maintaining malignant phenotype of mouse skin tumor cells. Cancer Lett. 2006;231:326–338
  57. Langevin J, Le Borgne R, Rosenfeld F, Gho M, Schweisguth F, Bellaïche Y. Lethal giant larvae controls the localization of notch-signaling regulators numb, neuralized, and Sanpodo in Drosophila sensory-organ precursor cells. Curr. Biol. 2005;15:955–962
  58. Lee L, Sudentas P, Donohue B, Asrican K, Worku A, Walker V, et al Efficacy of a rapamycin analog (CCI-779) and IFN-gamma in tuberous sclerosis mouse models. Genes Chromosomes Cancer. 2005;42:213–227
  59. Leibfried A, Fricke R, Morgan MJ, Bogdan S, Bellaiche Y. Drosophila Cip4 and WASp define a branch of the Cdc42-Par6-aPKC pathway regulating E-cadherin endocytosis. Curr. Biol. 2008;18:1639–1648
  60. Li L, Cohen SN. Tsg101: a novel tumor susceptibility gene isolated by controlled homozygous functional knockout of allelic loci in mammalian cells. Cell. 1996;85:319–329
  61. Lin WW, Karin M. A cytokine-mediated link between innate immunity, inflammation, and cancer. J. Clin. Invest. 2007;117:1175–1183
  62. Lloyd TE, Atkinson R, Wu M, Zhou Y, Pennetta G, Bellen HJ. Hrs regulates endosome membrane invagination and tyrosine kinase receptor signaling in Drosophila. Cell. 2002;108:261–269
  63. Lu H, Bilder D. Endocytic control of epithelial polarity and proliferation in Drosophila. Nat. Cell Biol. 2005;7:1132–1139
  64. Maitra S, Kulikauskas RM, Gavilan H, Fehon RG. The tumor suppressors Merlin and Expanded function cooperatively to modulate receptor endocytosis and signaling. Curr. Biol. 2006;16:702–709
  65. Marois E, Mahmoud A, Eaton S. The endocytic pathway and formation of the wingless morphogen gradient. Development. 2006;133:307–317
  66. McClatchey AI, Fehon RG. Merlin and the ERM proteins – regulators of receptor distribution and signaling at the cell cortex. Trends Cell Biol. 2009;
  67. Menut L, Vaccari T, Dionne H, Hill J, Wu G, Bilder D. A mosaic genetic screen for Drosophila neoplastic tumor suppressor genes based on defective pupation. Genetics. 2007;177:1667–1677
  68. Miaczynska M, Pelkmans L, Zerial M. Not just a sink: endosomes in control of signal transduction. Curr. Opin. Cell Biol. 2004;16:400–406
  69. Moberg KH, Schelble S, Burdick SK, Hariharan IK. Mutations in erupted, the Drosophila ortholog of mammalian tumor susceptibility gene 101, elicit non-cell-autonomous overgrowth. Dev. Cell. 2005;9:699–710
  70. Morrison HA, Dionne H, Rusten TE, Brech A, Fisher WW, Pfeiffer BD, et al. Regulation of early endosomal entry by the Drosophila tumor suppressors Rabenosyn and Vps45. Mol. Biol. Cell. 2008;
  71. Mosesson Y, Mills G, Yarden Y. Derailed endocytosis: an emerging feature of cancer. Nat. Rev. Cancer. 2008;8:835–850
  72. Mukherjee A, Veraksa A, Bauer A, Rosse C, Camonis J, Artavanis-Tsakonas S. Regulation of notch signalling by non-visual beta-arrestin. Nat. Cell Biol. 2005;7:1191–1201
  73. Oh KB, Stanton MJ, West WW, Todd GL, Wagner KU. Tsg101 is upregulated in a subset of invasive human breast cancers and its targeted overexpression in transgenic mice reveals weak oncogenic properties for mammary cancer initiation. Oncogene. 2007;26:5950–5959
  74. Pagliarini RA, Xu T. A genetic screen in Drosophila for metastatic behavior. Science. 2003;302:1227–1231
  75. Pai LM, Barcelo G, Schüpbach T. D-cbl, a negative regulator of the Egfr pathway, is required for dorsoventral patterning in Drosophila oogenesis. Cell. 2000;103:51–61
  76. Pasternak SH, Bagshaw RD, Guiral M, Zhang S, Ackerley CA, Pak BJ, et al. Presenilin-1, nicastrin, amyloid precursor protein, and gamma-secretase activity are co-localized in the lysosomal membrane. J. Biol. Chem. 2003;278:26687–26694
  77. Piddini E, Marshall F, Dubois L, Hirst E, Vincent JP. Arrow (LRP6) and Frizzled2 cooperate to degrade wingless in Drosophila imaginal discs. Development. 2005;132:5479–5489
  78. Razi M, Futter CE. Distinct roles for Tsg101 and Hrs in multivesicular body formation and inward vesiculation. Mol. Biol. Cell. 2006;17:3469–3483
  79. Rives AF, Rochlin KM, Wehrli M, Schwartz SL, DiNardo S. Endocytic trafficking of wingless and its receptors, Arrow and DFrizzled-2, in the Drosophila wing. Dev. Biol. 2006;293:268–283
  80. Rodahl LM, Haglund K, Sem-Jacobsen C, Wendler F, Vincent JP, Lindmo K, et al. Disruption of Vps4 and JNK function in Drosophila causes tumour growth. PLoS ONE. 2009;4:e4354
  81. Roy M, Pear WS, Aster JC. The multifaceted role of notch in cancer. Curr. Opin. Genet. Dev. 2007;17:52–59
  82. Ruland J, Sirard C, Elia A, MacPherson D, Wakeham A, Li L, et al. p. 53 accumulation, defective cell proliferation, and early embryonic lethality in mice lacking tsg101. Proc. Natl. Acad. Sci. USA. 2001;98:1859–1864
  83. Rusten TE, Rodahl LM, Pattni K, Englund C, Samakovlis C, Dove S, et al. Fab1 phosphatidylinositol 3-phosphate 5-kinase controls trafficking but not silencing of endocytosed receptors. Mol. Biol. Cell. 2006;17:3989–4001
  84. Sakata T, Sakaguchi H, Tsuda L, Higashitani A, Aigaki T, Matsuno K, et al. Drosophila Nedd4 regulates endocytosis of notch and suppresses its ligand-independent activation. Curr. Biol. 2004;14:2228–2236
  85. Saksena S, Sun J, Chu T, Emr SD. ESCRTing proteins in the endocytic pathway. Trends Biochem. Sci. 2007;32:561–573
  86. Seto ES, Bellen HJ. Internalization is required for proper wingless signaling in Drosophila melanogaster. J. Cell Biol. 2006;173:95–106
  87. Shestopal SA, Makunin IV, Belyaeva ES, Ashburner M, Zhimulev IF. Molecular characterization of the deep orange (dor) gene of Drosophila melanogaster. Mol. Gen. Genet. 1997;253:642–648
  88. Sotillos S, Díaz-Meco MT, Moscat J, Castelli-Gair Hombría J. Polarized subcellular localization of Jak/STAT components is required for efficient signaling. Curr. Biol. 2008;18:624–629
  89. Spang A. On the fate of early endosomes. Biol. Chem. 2009;
  90. St Johnston MA. The art and design of genetic screens: Drosophila melanogaster. Nat. Rev. Genet. 2002;3:176–188
  91. Sweeney N, Brenman J, Jan Y, Gao F. The coiled-coil protein shrub controls neuronal morphogenesis in Drosophila. Curr. Biol. 2006;16:1006–1011
  92. Thompson BJ, Mathieu J, Sung HH, Loeser E, Rorth P, Cohen SN. Tumor suppressor properties of the ESCRT-II complex component Vps25 in Drosophila. Dev. Cell. 2005;9:711–720
  93. Tien AC, Rajan A, Bellen HJ. A notch updated. J. Cell Biol. 2009;184:621–629
  94. Tsai YC, Sun YH. Long-range effect of upd, a ligand for Jak/STAT pathway, on cell cycle in Drosophila eye development. Genesis. 2004;39:141–153
  95. Uhlirova M, Bohmann D. JNK- and Fos-regulated Mmp1 expression cooperates with Ras to induce invasive tumors in Drosophila. EMBO J. 2006;25:5294–5304
  96. Vaccari T, Bilder D. The Drosophila tumor suppressor vps25 prevents nonautonomous overproliferation by regulating notch trafficking. Dev. Cell. 2005;9:687–698
  97. Vaccari T, Lu H, Kanwar R, Fortini ME, Bilder D. Endosomal entry regulates notch receptor activation in Drosophila melanogaster. J. Cell Biol. 2008;180:755–762
  98. Vaccari, T., Rusten, T.E., Menut, L., Nezis, I., Brech, A., Stenmark, H., Bilder, D. Comparative analysis of ESCRT -I, -II, -III function in Drosophila by efficient isolation of ESCRT mutants. J. Cell Sci., in press.
  99. Ventura JJ, Cogswell P, Flavell RA, Baldwin AS, Davis RJ. JNK potentiates TNF-stimulated necrosis by increasing the production of cytotoxic reactive oxygen species. Genes Dev. 2004;18:2905–2915
  100. Vidal M, Cagan RL. Drosophila models for cancer research. Curr. Opin. Genet. Dev. 2006;16:10–16
  101. Wagner KU, Krempler A, Qi Y, Park K, Henry MD, Triplett AA, et al. Tsg101 is essential for cell growth, proliferation, and cell survival of embryonic and adult tissues. Mol. Cell. Biol. 2003;23:150–162
  102. Warner TS, Sinclair DA, Fitzpatrick KA, Singh M, Devlin RH, Honda BM. The light gene of Drosophila melanogaster encodes a homologue of VPS41, a yeast gene involved in cellular-protein trafficking. Genome. 1998;41:236–243
  103. Whiteman EL, Liu CJ, Fearon ER, Margolis B. The transcription factor snail represses Crumbs3 expression and disrupts apico-basal polarity complexes. Oncogene. 2008;27:3875–3879
  104. Wilkin M, Tongngok P, Gensch N, Clemence S, Motoki M, Yamada K, et al Drosophila HOPS and AP-3 complex genes are required for a deltex-regulated activation of notch in the endosomal trafficking pathway. Dev. Cell. 2008;15:762–772
  105. Wilkin MB, Carbery AM, Fostier M, Aslam H, Mazaleyrat SL, Higgs J, et al. Regulation of notch endosomal sorting and signaling by Drosophila Nedd4 family proteins. Curr. Biol. 2004;14:2237–2244
  106. Willecke M, Hamaratoglu F, Kango-Singh M, Udan R, Chen CL, Tao C, et al. The fat cadherin acts through the hippo tumor-suppressor pathway to regulate tissue size. Curr. Biol. 2006;16:2090–2100
  107. Xu Z, Liang L, Wang H, Li T, Zhao M. HCRP1, a novel gene that is downregulated in hepatocellular carcinoma, encodes a growth-inhibitory protein. Biochem. Biophys. Res. Commun. 2003;311:1057–1066

PII: S1574-7891(09)00076-3

doi: 10.1016/j.molonc.2009.05.005

Molecular Oncology
Volume 3, Issue 4 , Pages 354-365 , August 2009

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