Skip to main content
PMC home page
Genetics logoLink to Genetics
. 2003 May;164(1):247–258. doi: 10.1093/genetics/164.1.247

Drosophila gain-of-function mutant RTK torso triggers ectopic Dpp and STAT signaling.

Jinghong Li 1, Willis X Li 1
PMCID: PMC1462547  PMID: 12750336

Abstract

Overactivation of receptor tyrosine kinases (RTKs) has been linked to tumorigenesis. To understand how a hyperactivated RTK functions differently from wild-type RTK, we conducted a genome-wide systematic survey for genes that are required for signaling by a gain-of-function mutant Drosophila RTK Torso (Tor). We screened chromosomal deficiencies for suppression of a gain-of-function mutation tor (tor(GOF)), which led to the identification of 26 genomic regions that, when in half dosage, suppressed the defects caused by tor(GOF). Testing of candidate genes in these regions revealed many genes known to be involved in Tor signaling (such as those encoding the Ras-MAPK cassette, adaptor and structural molecules of RTK signaling, and downstream target genes of Tor), confirming the specificity of this genetic screen. Importantly, this screen also identified components of the TGFbeta (Dpp) and JAK/STAT pathways as being required for Tor(GOF) signaling. Specifically, we found that reducing the dosage of thickveins (tkv), Mothers against dpp (Mad), or STAT92E (aka marelle), respectively, suppressed tor(GOF) phenotypes. Furthermore, we demonstrate that in tor(GOF) embryos, dpp is ectopically expressed and thus may contribute to the patterning defects. These results demonstrate an essential requirement of noncanonical signaling pathways for a persistently activated RTK to cause pathological defects in an organism.

Full Text

The Full Text of this article is available as a PDF (441.1 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ambrosio L., Mahowald A. P., Perrimon N. Requirement of the Drosophila raf homologue for torso function. Nature. 1989 Nov 16;342(6247):288–291. doi: 10.1038/342288a0. [DOI] [PubMed] [Google Scholar]
  2. Brummel T. J., Twombly V., Marqués G., Wrana J. L., Newfeld S. J., Attisano L., Massagué J., O'Connor M. B., Gelbart W. M. Characterization and relationship of Dpp receptors encoded by the saxophone and thick veins genes in Drosophila. Cell. 1994 Jul 29;78(2):251–261. doi: 10.1016/0092-8674(94)90295-x. [DOI] [PubMed] [Google Scholar]
  3. Brunner D., Oellers N., Szabad J., Biggs W. H., 3rd, Zipursky S. L., Hafen E. A gain-of-function mutation in Drosophila MAP kinase activates multiple receptor tyrosine kinase signaling pathways. Cell. 1994 Mar 11;76(5):875–888. doi: 10.1016/0092-8674(94)90362-x. [DOI] [PubMed] [Google Scholar]
  4. Brönner G., Jäckle H. Control and function of terminal gap gene activity in the posterior pole region of the Drosophila embryo. Mech Dev. 1991 Nov;35(3):205–211. doi: 10.1016/0925-4773(91)90019-3. [DOI] [PubMed] [Google Scholar]
  5. Casanova J., Llimargas M., Greenwood S., Struhl G. An oncogenic form of human raf can specify terminal body pattern in Drosophila. Mech Dev. 1994 Oct;48(1):59–64. doi: 10.1016/0925-4773(94)90006-x. [DOI] [PubMed] [Google Scholar]
  6. Casanova J., Struhl G. The torso receptor localizes as well as transduces the spatial signal specifying terminal body pattern in Drosophila. Nature. 1993 Mar 11;362(6416):152–155. doi: 10.1038/362152a0. [DOI] [PubMed] [Google Scholar]
  7. Chang H. C., Rubin G. M. 14-3-3 epsilon positively regulates Ras-mediated signaling in Drosophila. Genes Dev. 1997 May 1;11(9):1132–1139. doi: 10.1101/gad.11.9.1132. [DOI] [PubMed] [Google Scholar]
  8. Dickson B. J., van der Straten A., Dominguez M., Hafen E. Mutations Modulating Raf signaling in Drosophila eye development. Genetics. 1996 Jan;142(1):163–171. doi: 10.1093/genetics/142.1.163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Doyle H. J., Bishop J. M. Torso, a receptor tyrosine kinase required for embryonic pattern formation, shares substrates with the sevenless and EGF-R pathways in Drosophila. Genes Dev. 1993 Apr;7(4):633–646. doi: 10.1101/gad.7.4.633. [DOI] [PubMed] [Google Scholar]
  10. Duffy J. B., Perrimon N. The torso pathway in Drosophila: lessons on receptor tyrosine kinase signaling and pattern formation. Dev Biol. 1994 Dec;166(2):380–395. doi: 10.1006/dbio.1994.1324. [DOI] [PubMed] [Google Scholar]
  11. Ghiglione C., Perrimon N., Perkins L. A. Quantitative variations in the level of MAPK activity control patterning of the embryonic termini in Drosophila. Dev Biol. 1999 Jan 1;205(1):181–193. doi: 10.1006/dbio.1998.9102. [DOI] [PubMed] [Google Scholar]
  12. Greenwood S., Struhl G. Different levels of Ras activity can specify distinct transcriptional and morphological consequences in early Drosophila embryos. Development. 1997 Dec;124(23):4879–4886. doi: 10.1242/dev.124.23.4879. [DOI] [PubMed] [Google Scholar]
  13. Hou X. S., Melnick M. B., Perrimon N. Marelle acts downstream of the Drosophila HOP/JAK kinase and encodes a protein similar to the mammalian STATs. Cell. 1996 Feb 9;84(3):411–419. doi: 10.1016/s0092-8674(00)81286-6. [DOI] [PubMed] [Google Scholar]
  14. Häder T., Wainwright D., Shandala T., Saint R., Taubert H., Brönner G., Jäckle H. Receptor tyrosine kinase signaling regulates different modes of Groucho-dependent control of Dorsal. Curr Biol. 2000 Jan 13;10(1):51–54. doi: 10.1016/s0960-9822(99)00265-1. [DOI] [PubMed] [Google Scholar]
  15. Karim F. D., Chang H. C., Therrien M., Wassarman D. A., Laverty T., Rubin G. M. A screen for genes that function downstream of Ras1 during Drosophila eye development. Genetics. 1996 May;143(1):315–329. doi: 10.1093/genetics/143.1.315. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Klingler M., Erdélyi M., Szabad J., Nüsslein-Volhard C. Function of torso in determining the terminal anlagen of the Drosophila embryo. Nature. 1988 Sep 15;335(6187):275–277. doi: 10.1038/335275a0. [DOI] [PubMed] [Google Scholar]
  17. Kockel L., Vorbrüggen G., Jäckle H., Mlodzik M., Bohmann D. Requirement for Drosophila 14-3-3 zeta in Raf-dependent photoreceptor development. Genes Dev. 1997 May 1;11(9):1140–1147. doi: 10.1101/gad.11.9.1140. [DOI] [PubMed] [Google Scholar]
  18. Li W., Noll E., Perrimon N. Identification of autosomal regions involved in Drosophila Raf function. Genetics. 2000 Oct;156(2):763–774. doi: 10.1093/genetics/156.2.763. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Li W., Skoulakis E. M., Davis R. L., Perrimon N. The Drosophila 14-3-3 protein Leonardo enhances Torso signaling through D-Raf in a Ras 1-dependent manner. Development. 1997 Oct;124(20):4163–4171. doi: 10.1242/dev.124.20.4163. [DOI] [PubMed] [Google Scholar]
  20. Li Willis X., Agaisse Herve, Mathey-Prevot Bernard, Perrimon Norbert. Differential requirement for STAT by gain-of-function and wild-type receptor tyrosine kinase Torso in Drosophila. Development. 2002 Sep;129(18):4241–4248. doi: 10.1242/dev.129.18.4241. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Liaw G. J., Rudolph K. M., Huang J. D., Dubnicoff T., Courey A. J., Lengyel J. A. The torso response element binds GAGA and NTF-1/Elf-1, and regulates tailless by relief of repression. Genes Dev. 1995 Dec 15;9(24):3163–3176. doi: 10.1101/gad.9.24.3163. [DOI] [PubMed] [Google Scholar]
  22. Lu X., Chou T. B., Williams N. G., Roberts T., Perrimon N. Control of cell fate determination by p21ras/Ras1, an essential component of torso signaling in Drosophila. Genes Dev. 1993 Apr;7(4):621–632. doi: 10.1101/gad.7.4.621. [DOI] [PubMed] [Google Scholar]
  23. Marshall C. J. Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell. 1995 Jan 27;80(2):179–185. doi: 10.1016/0092-8674(95)90401-8. [DOI] [PubMed] [Google Scholar]
  24. Melnick M. B., Perkins L. A., Lee M., Ambrosio L., Perrimon N. Developmental and molecular characterization of mutations in the Drosophila-raf serine/threonine protein kinase. Development. 1993 May;118(1):127–138. doi: 10.1242/dev.118.1.127. [DOI] [PubMed] [Google Scholar]
  25. Nellen D., Affolter M., Basler K. Receptor serine/threonine kinases implicated in the control of Drosophila body pattern by decapentaplegic. Cell. 1994 Jul 29;78(2):225–237. doi: 10.1016/0092-8674(94)90293-3. [DOI] [PubMed] [Google Scholar]
  26. Newfeld S. J., Chartoff E. H., Graff J. M., Melton D. A., Gelbart W. M. Mothers against dpp encodes a conserved cytoplasmic protein required in DPP/TGF-beta responsive cells. Development. 1996 Jul;122(7):2099–2108. doi: 10.1242/dev.122.7.2099. [DOI] [PubMed] [Google Scholar]
  27. Penton A., Chen Y., Staehling-Hampton K., Wrana J. L., Attisano L., Szidonya J., Cassill J. A., Massagué J., Hoffmann F. M. Identification of two bone morphogenetic protein type I receptors in Drosophila and evidence that Brk25D is a decapentaplegic receptor. Cell. 1994 Jul 29;78(2):239–250. doi: 10.1016/0092-8674(94)90294-1. [DOI] [PubMed] [Google Scholar]
  28. Pignoni F., Baldarelli R. M., Steingrímsson E., Diaz R. J., Patapoutian A., Merriam J. R., Lengyel J. A. The Drosophila gene tailless is expressed at the embryonic termini and is a member of the steroid receptor superfamily. Cell. 1990 Jul 13;62(1):151–163. doi: 10.1016/0092-8674(90)90249-e. [DOI] [PubMed] [Google Scholar]
  29. Pignoni F., Steingrímsson E., Lengyel J. A. bicoid and the terminal system activate tailless expression in the early Drosophila embryo. Development. 1992 May;115(1):239–251. doi: 10.1242/dev.115.1.239. [DOI] [PubMed] [Google Scholar]
  30. Ray R. P., Arora K., Nüsslein-Volhard C., Gelbart W. M. The control of cell fate along the dorsal-ventral axis of the Drosophila embryo. Development. 1991 Sep;113(1):35–54. doi: 10.1242/dev.113.1.35. [DOI] [PubMed] [Google Scholar]
  31. Robertson SC, Tynan J, Donoghue DJ. RTK mutations and human syndromes: when good receptors turn bad. Trends Genet. 2000 Aug;16(8):368–368. doi: 10.1016/s0168-9525(00)02077-1. [DOI] [PubMed] [Google Scholar]
  32. Roth S., Stein D., Nüsslein-Volhard C. A gradient of nuclear localization of the dorsal protein determines dorsoventral pattern in the Drosophila embryo. Cell. 1989 Dec 22;59(6):1189–1202. doi: 10.1016/0092-8674(89)90774-5. [DOI] [PubMed] [Google Scholar]
  33. Rusch J., Levine M. Regulation of the dorsal morphogen by the Toll and torso signaling pathways: a receptor tyrosine kinase selectively masks transcriptional repression. Genes Dev. 1994 Jun 1;8(11):1247–1257. doi: 10.1101/gad.8.11.1247. [DOI] [PubMed] [Google Scholar]
  34. Rushlow C. A., Han K., Manley J. L., Levine M. The graded distribution of the dorsal morphogen is initiated by selective nuclear transport in Drosophila. Cell. 1989 Dec 22;59(6):1165–1177. doi: 10.1016/0092-8674(89)90772-1. [DOI] [PubMed] [Google Scholar]
  35. Sewing A., Wiseman B., Lloyd A. C., Land H. High-intensity Raf signal causes cell cycle arrest mediated by p21Cip1. Mol Cell Biol. 1997 Sep;17(9):5588–5597. doi: 10.1128/mcb.17.9.5588. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Simon M. A., Bowtell D. D., Dodson G. S., Laverty T. R., Rubin G. M. Ras1 and a putative guanine nucleotide exchange factor perform crucial steps in signaling by the sevenless protein tyrosine kinase. Cell. 1991 Nov 15;67(4):701–716. doi: 10.1016/0092-8674(91)90065-7. [DOI] [PubMed] [Google Scholar]
  37. Singer J. B., Harbecke R., Kusch T., Reuter R., Lengyel J. A. Drosophila brachyenteron regulates gene activity and morphogenesis in the gut. Development. 1996 Dec;122(12):3707–3718. doi: 10.1242/dev.122.12.3707. [DOI] [PubMed] [Google Scholar]
  38. Sprenger F., Nüsslein-Volhard C. Torso receptor activity is regulated by a diffusible ligand produced at the extracellular terminal regions of the Drosophila egg. Cell. 1992 Dec 11;71(6):987–1001. doi: 10.1016/0092-8674(92)90394-r. [DOI] [PubMed] [Google Scholar]
  39. Steingrímsson E., Pignoni F., Liaw G. J., Lengyel J. A. Dual role of the Drosophila pattern gene tailless in embryonic termini. Science. 1991 Oct 18;254(5030):418–421. doi: 10.1126/science.1925599. [DOI] [PubMed] [Google Scholar]
  40. Strecker T. R., Halsell S. R., Fisher W. W., Lipshitz H. D. Reciprocal effects of hyper- and hypoactivity mutations in the Drosophila pattern gene torso. Science. 1989 Feb 24;243(4894 Pt 1):1062–1066. doi: 10.1126/science.2922596. [DOI] [PubMed] [Google Scholar]
  41. Strecker T. R., Yip M. L., Lipshitz H. D. Zygotic genes that mediate torso receptor tyrosine kinase functions in the Drosophila melanogaster embryo. Proc Natl Acad Sci U S A. 1991 Jul 1;88(13):5824–5828. doi: 10.1073/pnas.88.13.5824. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Tang A. H., Neufeld T. P., Rubin G. M., Müller H. A. Transcriptional regulation of cytoskeletal functions and segmentation by a novel maternal pair-rule gene, lilliputian. Development. 2001 Mar;128(5):801–813. doi: 10.1242/dev.128.5.801. [DOI] [PubMed] [Google Scholar]
  43. Tsuda L., Inoue Y. H., Yoo M. A., Mizuno M., Hata M., Lim Y. M., Adachi-Yamada T., Ryo H., Masamune Y., Nishida Y. A protein kinase similar to MAP kinase activator acts downstream of the raf kinase in Drosophila. Cell. 1993 Feb 12;72(3):407–414. doi: 10.1016/0092-8674(93)90117-9. [DOI] [PubMed] [Google Scholar]
  44. Weigel D., Jürgens G., Klingler M., Jäckle H. Two gap genes mediate maternal terminal pattern information in Drosophila. Science. 1990 Apr 27;248(4954):495–498. doi: 10.1126/science.2158673. [DOI] [PubMed] [Google Scholar]
  45. Wharton K. A., Ray R. P., Gelbart W. M. An activity gradient of decapentaplegic is necessary for the specification of dorsal pattern elements in the Drosophila embryo. Development. 1993 Feb;117(2):807–822. doi: 10.1242/dev.117.2.807. [DOI] [PubMed] [Google Scholar]
  46. Wittwer F., van der Straten A., Keleman K., Dickson B. J., Hafen E. Lilliputian: an AF4/FMR2-related protein that controls cell identity and cell growth. Development. 2001 Mar;128(5):791–800. doi: 10.1242/dev.128.5.791. [DOI] [PubMed] [Google Scholar]
  47. Woods D., Parry D., Cherwinski H., Bosch E., Lees E., McMahon M. Raf-induced proliferation or cell cycle arrest is determined by the level of Raf activity with arrest mediated by p21Cip1. Mol Cell Biol. 1997 Sep;17(9):5598–5611. doi: 10.1128/mcb.17.9.5598. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Yan R., Small S., Desplan C., Dearolf C. R., Darnell J. E., Jr Identification of a Stat gene that functions in Drosophila development. Cell. 1996 Feb 9;84(3):421–430. doi: 10.1016/s0092-8674(00)81287-8. [DOI] [PubMed] [Google Scholar]
  49. van der Straten A., Rommel C., Dickson B., Hafen E. The heat shock protein 83 (Hsp83) is required for Raf-mediated signalling in Drosophila. EMBO J. 1997 Apr 15;16(8):1961–1969. doi: 10.1093/emboj/16.8.1961. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Genetics are provided here courtesy of Oxford University Press

RESOURCES