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Delineation of a Fat tumor suppressor pathway

Nature Genetics volume 38, pages 1142–1150 (2006)Cite this article

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Abstract

Recent studies in Drosophila melanogaster of the protocadherins Dachsous and Fat suggest that they act as ligand and receptor, respectively, for an intercellular signaling pathway that influences tissue polarity, growth and gene expression, but the basis for signaling downstream of Fat has remained unclear. Here, we characterize functional relationships among D. melanogaster tumor suppressors and identify the kinases Discs overgrown and Warts as components of a Fat signaling pathway. fat, discs overgrown and warts regulate a common set of downstream genes in multiple tissues. Genetic experiments position the action of discs overgrown upstream of the Fat pathway component dachs, whereas warts acts downstream of dachs. Warts protein coprecipitates with Dachs, and Warts protein levels are influenced by fat, dachs and discs overgrown in vivo, consistent with its placement as a downstream component of the pathway. The tumor suppressors Merlin, expanded, hippo, salvador and mob as tumor suppressor also share multiple Fat pathway phenotypes but regulate Warts activity independently. Our results functionally link what had been four disparate groups of D. melanogaster tumor suppressors, establish a basic framework for Fat signaling from receptor to transcription factor and implicate Warts as an integrator of multiple growth control signals.

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Figure 1: Influence of D. melanogaster tumor suppressors on proximal Wg expression.
Figure 2: Influence of D. melanogaster tumor suppressors on Ser in the leg.
Figure 3: Influence of D. melanogaster tumor suppressors on Fat pathway targets in the eye.
Figure 4: Ordering Fat pathway genes by genetic epistasis.
Figure 5: Influence of the Fat pathway on Wts levels.
Figure 6: Coprecipitation of Dachs and Wts.
Figure 7: Pathway model schematic of a proposed Fat pathway.

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Change history

  • 16 October 2006

    In the version of this article initially published, one label in Figure 3d ('Mer') was incorrect. The correct label should read 'GFP'. The error has been corrected in the HTML and PDF versions of the article.

References

  1. Watson, K.L., Justice, R.W. & Bryant, P.J. Drosophila in cancer research: the first fifty tumor suppressor genes. J. Cell Sci. Suppl. 18, 19–33 (1994).

    Article  CAS  PubMed  Google Scholar 

  2. Cho, E. & Irvine, K.D. Action of fat, four-jointed, dachsous and dachs in distal-to-proximal wing signaling. Development 131, 4489–4500 (2004).

    Article  CAS  PubMed  Google Scholar 

  3. Clark, H.F. et al. Dachsous encodes a member of the cadherin superfamily that controls imaginal disc morphogenesis in Drosophila. Genes Dev. 9, 1530–1542 (1995).

    Article  CAS  PubMed  Google Scholar 

  4. Ma, D., Yang, C.H., McNeill, H., Simon, M.A. & Axelrod, J.D. Fidelity in planar cell polarity signalling. Nature 421, 543–547 (2003).

    Article  CAS  PubMed  Google Scholar 

  5. Mahoney, P.A. et al. The fat tumor suppressor gene in Drosophila encodes a novel member of the cadherin gene superfamily. Cell 67, 853–868 (1991).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  7. Simon, M.A. Planar cell polarity in the Drosophila eye is directed by graded Four-jointed and Dachsous expression. Development 131, 6175–6184 (2004).

    Article  CAS  PubMed  Google Scholar 

  8. Strutt, H., Mundy, J., Hofstra, K. & Strutt, D. Cleavage and secretion is not required for Four-jointed function in Drosophila patterning. Development 131, 881–890 (2004).

    Article  CAS  PubMed  Google Scholar 

  9. Strutt, H. & Strutt, D. Nonautonomous planar polarity patterning in Drosophila: dishevelled-independent functions of frizzled. Dev. Cell 3, 851–863 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. Yang, C., Axelrod, J.D. & Simon, M.A. Regulation of frizzled by Fat-like cadherins during planar polarity signaling in the Drosophila compound eye. Cell 108, 675–688 (2002).

    Article  CAS  PubMed  Google Scholar 

  11. Casal, J., Struhl, G. & Lawrence, P. Developmental compartments and planar polarity in Drosophila. Curr. Biol. 12, 1189–1198 (2002).

    Article  CAS  PubMed  Google Scholar 

  12. Bryant, P.J., Huettner, B., Held, L.I. Jr, Ryerse, J. & Szidonya, J. Mutations at the fat locus interfere with cell proliferation control and epithelial morphogenesis in Drosophila. Dev. Biol. 129, 541–554 (1988).

    Article  CAS  PubMed  Google Scholar 

  13. Fanto, M. et al. The tumor-suppressor and cell adhesion molecule Fat controls planar polarity via physical interactions with Atrophin, a transcriptional co-repressor. Development 130, 763–774 (2003).

    Article  CAS  PubMed  Google Scholar 

  14. Mao, Y. et al. Dachs, an unconventional myosin that functions downstream of Fat to regulate growth, affinity and gene expression in Drosophila. Development 133, 2539–2551 (2006).

    Article  CAS  PubMed  Google Scholar 

  15. McClatchey, A.I. & Giovannini, M. Membrane organization and tumorigenesis–the NF2 tumor suppressor, Merlin. Genes Dev. 19, 2265–2277 (2005).

    Article  CAS  PubMed  Google Scholar 

  16. McClatchey, A.I. et al. Mice heterozygous for a mutation at the Nf2 tumor suppressor locus develop a range of highly metastatic tumors. Genes Dev. 12, 1121–1133 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Edgar, B.A. From cell structure to transcription: hippo forges a new path. Cell 124, 267–273 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. Harvey, K.F., Pfleger, C.M. & Hariharan, I.K. The Drosophila Mst ortholog, hippo, restricts growth and cell proliferation and promotes apoptosis. Cell 114, 457–467 (2003).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Justice, R.W., Zilian, O., Woods, D.F., Noll, M. & Bryant, P.J. 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 (1995).

    Article  CAS  PubMed  Google Scholar 

  21. Kango-Singh, M. et al. Shar-pei mediates cell proliferation arrest during imaginal disc growth in Drosophila. Development 129, 5719–5730 (2002).

    Article  CAS  PubMed  Google Scholar 

  22. Lai, Z.C. et al. Control of cell proliferation and apoptosis by mob as tumor suppressor, mats. Cell 120, 675–685 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  24. Tapon, N. et al. salvador promotes both cell cycle exit and apoptosis in Drosophila and is mutated in human cancer cell lines. Cell 110, 467–478 (2002).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  27. Xu, T., Wang, W., Zhang, S., Stewart, R.A. & Yu, W. Identifying tumor suppressors in genetic mosaics: the Drosophila lats gene encodes a putative protein kinase. Development 121, 1053–1063 (1995).

    CAS  PubMed  Google Scholar 

  28. Edwards, K.M. & Munger, K. Make WARTS, not cancer!. Oncogene 23, 5263–5265 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. Tao, W. et al. Human homologue of the Drosophila melanogaster lats tumour suppressor modulates CDC2 activity. Nat. Genet. 21, 177–181 (1999).

    Article  CAS  PubMed  Google Scholar 

  30. Zilian, O. et al. double-time is identical to discs overgrown, which is required for cell survival, proliferation and growth arrest in Drosophila imaginal discs. Development 126, 5409–5420 (1999).

    CAS  PubMed  Google Scholar 

  31. Jia, J. et al. Phosphorylation by double-time/CKIepsilon and CKIalpha targets cubitus interruptus for Slimb/beta-TRCP-mediated proteolytic processing. Dev. Cell 9, 819–830 (2005).

    Article  CAS  PubMed  Google Scholar 

  32. Kloss, B. et al. The Drosophila clock gene double-time encodes a protein closely related to human casein kinase Iepsilon. Cell 94, 97–107 (1998).

    Article  CAS  PubMed  Google Scholar 

  33. Price, M.A. & Kalderon, D. Proteolysis of the Hedgehog signaling effector Cubitus interruptus requires phosphorylation by glycogen synthase kinase 3 and casein kinase 1. Cell 108, 823–835 (2002).

    Article  CAS  PubMed  Google Scholar 

  34. Klein, T.J., Jenny, A., Djiane, A. & Mlodzik, M. CKIvarepsilon/discs overgrown promotes both Wnt-Fz/beta-catenin and Fz/PCP signaling in Drosophila. Curr. Biol. 16, 1337–1343 (2006).

    Article  CAS  PubMed  Google Scholar 

  35. Boedigheimer, M. & Laughon, A. Expanded: a gene involved in the control of cell proliferation in imaginal discs. Development 118, 1291–1301 (1993).

    CAS  PubMed  Google Scholar 

  36. McCartney, B.M. & Fehon, R.G. Distinct cellular and subcellular patterns of expression imply distinct functions for the Drosophila homologues of moesin and the neurofibromatosis 2 tumor suppressor, merlin. J. Cell Biol. 133, 843–852 (1996).

    Article  CAS  PubMed  Google Scholar 

  37. McCartney, B.M., Kulikauskas, R.M., LaJeunesse, D.R. & Fehon, R.G. The neurofibromatosis-2 homologue, Merlin, and the tumor suppressor expanded function together in Drosophila to regulate cell proliferation and differentiation. Development 127, 1315–1324 (2000).

    CAS  PubMed  Google Scholar 

  38. Hamaratoglu, F. et al. The tumour-suppressor genes NF2/Merlin and Expanded act through Hippo signalling to regulate cell proliferation and apoptosis. Nat. Cell Biol. 8, 27–36 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Maitra, S., Kulikauskas, R.M., Gavilan, H. & Fehon, R.G. The tumor suppressors Merlin and expanded function cooperatively to modulate receptor endocytosis and signaling. Curr. Biol. 16, 702–709 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Zeidler, M.P., Perrimon, N. & Strutt, D.I. Multiple roles for four-jointed in planar polarity and limb patterning. Dev. Biol. 228, 181–196 (2000).

    Article  CAS  PubMed  Google Scholar 

  41. Buckles, G.R., Rauskolb, C., Villano, J.L. & Katz, F.N. four-jointed interacts with dachs, abelson and enabled and feeds back onto the Notch pathway to affect growth and segmentation in the Drosophila leg. Development 128, 3533–3542 (2001).

    CAS  PubMed  Google Scholar 

  42. Blaumueller, C.M. & Mlodzik, M. The Drosophila tumor suppressor expanded regulates growth, apoptosis, and patterning during development. Mech. Dev. 92, 251–262 (2000).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  44. Matakatsu, H. & Blair, S.S. Separating the adhesive and signaling functions of the Fat and Dachsous protocadherins. Development 133, 2315–2324 (2006).

    Article  CAS  PubMed  Google Scholar 

  45. Jaiswal, M., Agrawal, N. & Sinha, P. Fat and Wingless signaling oppositely regulate epithelial cell-cell adhesion and distal wing development in Drosophila. Development 133, 925–935 (2006)

    Article  CAS  PubMed  Google Scholar 

  46. Garoia, F. et al. The tumor suppressor gene fat modulates the EGFR-mediated proliferation control in the imaginal tissues of Drosophila melanogaster. Mech. Dev. 122, 175–187 (2005).

    Article  CAS  PubMed  Google Scholar 

  47. Zender, L. et al. Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach. Cell 125, 1253–1267 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lee, T. & Luo, L. Mosaic analysis with a repressible cell marker (MARCM) for Drosophila neural development. Trends Neurosci. 24, 251–254 (2001).

    Article  CAS  PubMed  Google Scholar 

  49. Rauskolb, C. & Irvine, K.D. Notch-mediated segmentation and growth control of the Drosophila leg. Dev. Biol. 210, 339–350 (1999).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank S. Blair, P. Bryant, S. Carroll, S. Cohen, B. Hay, G. Halder, I. Hariharan, M. Mlodzik, M. Noll, H. Richardson, A. Laughon, J. Jiang, Z.C. Lai, D.J. Pan, the Developmental Studies Hybridoma Bank and the Bloomington stock center for antibodies and D. melanogaster stocks and B. Kucuk and O. Dunaevsky for technical assistance. This work was supported by US National Institutes of Health grants GM63057 (C.R.) and NS034783 (R.F.) and by the Howard Hughes Medical Institute (K.D.I.).

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Author notes

  1. Eunjoo Cho and Yongqiang Feng: These authors contributed equally to this work.

Authors and Affiliations

  1. Waksman Institute and Department of Molecular Biology and Biochemistry, Howard Hughes Medical Institute, Rutgers, The State University of New Jersey, Piscataway, 08854, New Jersey, USA

    Eunjoo Cho, Yongqiang Feng & Kenneth D Irvine

  2. Waksman Institute, Rutgers, The State University of New Jersey, Piscataway, 08854, New Jersey, USA

    Cordelia Rauskolb

  3. Department of Molecular Genetics and Cell Biology, 920 E. 58th St, University of Chicago, Chicago, 60637, Illinois, USA

    Sushmita Maitra & Rick Fehon

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Contributions

E.C. conducted most of the experiments analyzing gene regulation and genetic epistasis (Figs. 1,2,3,4 and Supplementary Figs. 1,2). Y.F. conducted the experiments analyzing Warts stability and Warts-Dachs binding (Figs. 5and6) and contributed to experiments analyzing gene regulation and genetic epistasis (Fig. 4 and Supplementary Fig. 4). C.R. contributed to experiments analyzing gene regulation and genetic epistasis (Figs. 1,2,3,4 and Supplementary Figs. 1,2,3,4). S.M. and R.F. provided unpublished reagents. K.I. directed the research and wrote the paper.

Note: Supplementary information is available on the Nature Genetics website.

Corresponding author

Correspondence to Kenneth D Irvine.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Additional experiments on the regulation of WG in the proximal wing. (PDF 906 kb)

Supplementary Fig. 2

Additional experiments on the regulation of Fat pathway targets in the eye. (PDF 311 kb)

Supplementary Fig. 3

fat mutant clones are associated with extra interommatidial cells. (PDF 143 kb)

Supplementary Fig. 4

Regulation of ex transcription by Fat signaling. (PDF 353 kb)

Supplementary Table 1

PCR primer sequences. (PDF 41 kb)

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Cho, E., Feng, Y., Rauskolb, C. et al. Delineation of a Fat tumor suppressor pathway. Nat Genet 38, 1142–1150 (2006). https://doi.org/10.1038/ng1887

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