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 Given that there are genetic interactions between gro and components of the EGFR pathway9 (ref. 9 and P.H. et al., unpublished results), we tested whether Gro is at a crossroad between this and other pathways.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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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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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)
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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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DOI: https://doi.org/10.1038/ng1486
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