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EGFR signaling attenuates Groucho-dependent repression to antagonize Notch transcriptional output

Nature Genetics volume 37, pages 101–105 (2005)Cite this article

Abstract

Crosstalk between signaling pathways is crucial for the generation of complex and varied transcriptional networks. Antagonism between the EGF-receptor (EGFR) and Notch pathways in particular is well documented, although the underlying mechanism is poorly understood. The global corepressor Groucho (Gro) and its transducin-like Enhancer-of-split (TLE) mammalian homologs mediate repression by a myriad of repressors, including effectors of the Notch, Wnt (Wg) and TGF-β (Dpp) signaling cascades1,2,3,4,5,6,7,8. Given that there are genetic interactions between gro and components of the EGFR pathway9 (ref. 9 and P.H. et al., unpublished results), we tested whether Gro is at a crossroad between this and other pathways. Here we show that phosphorylation of Gro in response to MAPK activation weakens its repressor capacity, attenuating Gro-dependent transcriptional silencing by the Enhancer-of-split proteins, effectors of the Notch cascade. Thus, Gro is a new junction between signaling pathways, enabling EGFR signaling to antagonize transcriptional output by Notch and potentially other Gro-dependent pathways.

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Figure 1: Gro undergoes phosphorylation in response to RTK signaling.
Figure 2: The repressor capacity of wild-type Gro, but not that of GroAA, is attenuated by MAPK activation.
Figure 3: Ras1 activity in the wing pouch relieves repression by endogenous Gro.
Figure 4: GroDD and GroAA have opposing effects on E(spl)mβ-induced repression of wing veins.
Figure 5: GroAA renders E(spl)m7-mediated repression refractory to EGFR signaling.
Figure 6

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References

  1. Paroush, Z. et al. Groucho is required for Drosophila neurogenesis, segmentation, and sex determination and interacts directly with hairy-related bHLH proteins. Cell 79, 805–815 (1994).

    Article  CAS  Google Scholar 

  2. Giagtzoglou, N., Alifragis, P., Koumbanakis, K.A. & Delidakis, C. Two modes of recruitment of E(spl) repressors onto target genes. Development 130, 259–270 (2003).

    Article  CAS  Google Scholar 

  3. Cavallo, R.A. et al. Drosophila Tcf and Groucho interact to repress Wingless signalling activity. Nature 395, 604–608 (1998).

    Article  CAS  Google Scholar 

  4. Roose, J. et al. The Xenopus Wnt effector XTcf-3 interacts with Groucho-related transcriptional repressors. Nature 395, 608–612 (1998).

    Article  CAS  Google Scholar 

  5. Hasson, P., Muller, B., Basler, K. & Paroush, Z. Brinker requires two corepressors for maximal and versatile repression in Dpp signalling. EMBO J. 20, 5725–5736 (2001).

    Article  CAS  Google Scholar 

  6. Zhang, H., Levine, M. & Ashe, H. Brinker is a sequence-specific transcriptional repressor in the Drosophila embryo. Genes Dev. 15, 261–266 (2001).

    Article  CAS  Google Scholar 

  7. Chen, G. & Courey, A.J. Groucho/TLE family proteins and transcriptional repression. Gene 249, 1–16 (2000).

    Article  CAS  Google Scholar 

  8. Levanon, D. et al. Transcriptional repression by AML1 and LEF-1 is mediated by the TLE/Groucho corepressors. Proc. Natl. Acad. Sci. USA 95, 11590–11595 (1998).

    Article  CAS  Google Scholar 

  9. Price, J.V., Savenye, E.D., Lum, D. & Breitkreutz, A. Dominant enhancers of Egfr in Drosophila melanogaster: genetic links between the Notch and Egfr signaling pathways. Genetics 147, 1139–1153 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Queenan, A.M., Ghabrial, A. & Schupbach, T. Ectopic activation of torpedo/Egfr, a Drosophila receptor tyrosine kinase, dorsalizes both the eggshell and the embryo. Development 124, 3871–3880 (1997).

    CAS  PubMed  Google Scholar 

  11. Brunner, D. et al. A gain-of-function mutation in Drosophila MAP kinase activates multiple receptor tyrosine kinase signaling pathways. Cell 76, 875–888 (1994).

    Article  CAS  Google Scholar 

  12. Zecca, M., Basler, K. & Struhl, G. Direct and long-range action of a wingless morphogen gradient. Cell 87, 833–844 (1996).

    Article  CAS  Google Scholar 

  13. Schweitzer, R., Shaharabany, M., Seger, R. & Shilo, B.Z. Secreted Spitz triggers the DER signaling pathway and is a limiting component in embryonic ventral ectoderm determination. Genes Dev. 9, 1518–1529 (1995).

    Article  CAS  Google Scholar 

  14. Zecca, M. & Struhl, G. Subdivision of the Drosophila wing imaginal disc by EGFR-mediated signaling. Development 129, 1357–1368 (2002).

    CAS  PubMed  Google Scholar 

  15. Wessells, R.J., Grumbling, G., Donaldson, T., Wang, S.H. & Simcox, A. Tissue-specific regulation of vein/EGF receptor signaling in Drosophila. Dev. Biol. 216, 243–259 (1999).

    Article  CAS  Google Scholar 

  16. Wang, S.H., Simcox, A. & Campbell, G. Dual role for Drosophila epidermal growth factor receptor signaling in early wing disc development. Genes Dev. 14, 2271–2276 (2000).

    Article  CAS  Google Scholar 

  17. de Celis, J.F. & Bray, S. Garcia-Bellido, A. Notch signalling regulates veinlet expression and establishes boundaries between veins and interveins in the Drosophila wing. Development 124, 1919–1928 (1997).

    CAS  PubMed  Google Scholar 

  18. zur Lage, P. & Jarman, A.P. Antagonism of EGFR and notch signalling in the reiterative recruitment of Drosophila adult chordotonal sense organ precursors. Development 126, 3149–3157 (1999).

    CAS  PubMed  Google Scholar 

  19. Culi, J., Martin-Blanco, E. & Modolell, J. The EGF receptor and N signalling pathways act antagonistically in Drosophila mesothorax bristle patterning. Development 128, 299–308 (2001).

    CAS  PubMed  Google Scholar 

  20. Shaye, D.D. & Greenwald, I. Endocytosis-mediated downregulation of LIN-12/Notch upon Ras activation in Caenorhabditis elegans. Nature 420, 686–690 (2002).

    Article  CAS  Google Scholar 

  21. de Celis, J.F. & Ruiz Gomez, M. groucho and hedgehog regulate engrailed expression in the anterior compartment of the Drosophila wing. Development 121, 3467–3476 (1995).

    CAS  PubMed  Google Scholar 

  22. Rohrbaugh, M. et al. Notch activation of yan expression is antagonized by RTK/pointed signaling in the Drosophila eye. Curr. Biol. 12, 576–581 (2002).

    Article  CAS  Google Scholar 

  23. Nuthall, H.N., Joachim, K., Palaparti, A. & Stifani, S. A role for cell cycle-regulated phosphorylation in Groucho-mediated transcriptional repression. J. Biol. Chem. 277, 51049–51057 (2002).

    Article  CAS  Google Scholar 

  24. Parkhurst, S.M. Groucho: making its Marx as a transcriptional co-repressor. Trends Genet. 14, 130–132 (1998).

    Article  CAS  Google Scholar 

  25. Simon, M.A. Receptor tyrosine kinases: specific outcomes from general signals. Cell 103, 13–15 (2000).

    Article  CAS  Google Scholar 

  26. Zhang, H. & Levine, M. Groucho and dCtBP mediate separate pathways of transcriptional repression in the Drosophila embryo. Proc. Natl. Acad. Sci. USA 96, 535–540 (1999).

    Article  CAS  Google Scholar 

  27. Courey, A.J. & Jia, S. Transcriptional repression: the long and the short of it. Genes Dev. 15, 2786–2796 (2001).

    CAS  PubMed  Google Scholar 

  28. Bianchi-Frias, D. et al. Hairy transcriptional repression targets and cofactor recruitment in Drosophila. PLoS Biol. 2, E178 (2004).

    Article  Google Scholar 

  29. Barolo, S., Stone, T., Bang, A.G. & Posakony, J.W. Default repression and Notch signaling: Hairless acts as an adaptor to recruit the corepressors Groucho and dCtBP to Suppressor of Hairless. Genes Dev. 16, 1964–1976 (2002).

    Article  CAS  Google Scholar 

  30. Simpson, P. Notch signalling in development: on equivalence groups and asymmetric developmental potential. Curr. Opin. Genet. Dev. 7, 537–542 (1997).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank K. Basler, H. Bellen, S. Bray, S. Cohen, C. Delidakis, O. Gerlitz, E. Hafen, Y. Hiromi, F. Laski, E. Martin-Blanco, J. Modolell, D. Montell, G. Morata, A. Salzberg, T. Schupbach, B. Shilo, G. Struhl, the Bloomington Stock Centre and the Developmental Studies Hybridoma Bank for fly stocks, reagents and antibodies; S. Katzav, C. Levy and R. Grossman for technical assistance; and Y. Bergman, D. Ish-Horowicz, G. Jiménez, B. Shilo and J. Yisraeli for comments on the manuscript. This work was supported by grants from the Israel Science Foundation, Israel Cancer Research Fund, Lejwa Fund for Biochemistry and the Król Charitable Foundation to Z.P., and by a grant from the US National Institutes of Health to A.J.C. P.H. acknowledges a Clore Foundation PhD Scholarship, and C.W. acknowledges a USPHS National Research Service Training Award. Z.P. is a Braun Lecturer.

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Author notes

  1. Peleg Hasson and Nirit Egoz: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry, Faculty of Medicine, The Hebrew University, PO Box 12272, Jerusalem, 91120, Israel

    Peleg Hasson, Nirit Egoz, Tama Dinur & Ze'ev Paroush

  2. Department of Chemistry and Biochemistry, University of California Los Angeles, Box 951569, Los Angeles, 90095-1569, California, USA

    Clint Winkler, Songtao Jia & Albert J Courey

  3. Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, 76100, Israel

    Gloria Volohonsky & Talila Volk

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Correspondence to Ze'ev Paroush.

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Supplementary information

Supplementary Fig. 1

Differential repression of Spalt expression brought about by distinct Groucho derivatives. (PDF 37 kb)

Supplementary Fig. 2

Activated MAPK attenuates Groucho-mediated repression of a Dorsal responsive reporter in Drosophila S2 cells. (PDF 99 kb)

Supplementary Fig. 3

Groucho levels are unaffected by alterations in MAPK activity levels. (PDF 98 kb)

Supplementary Fig. 4

Groucho is an anti-vein determinant. (PDF 73 kb)

Supplementary Methods (PDF 21 kb)

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Hasson, P., Egoz, N., Winkler, C. et al. EGFR signaling attenuates Groucho-dependent repression to antagonize Notch transcriptional output. Nat Genet 37, 101–105 (2005). https://doi.org/10.1038/ng1486

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