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Sci. Signal., 20 December 2011
Vol. 4, Issue 204, p. ra89
[DOI: 10.1126/scisignal.2002335]

RESEARCH ARTICLES

Protein O-GlcNAcylation Is Required for Fibroblast Growth Factor Signaling in Drosophila

Daniel Mariappa1, Kathrin Sauert2*, Karina Mariño3{dagger}, Daniel Turnock3{ddagger}, Ryan Webster1, Daan M. F. van Aalten4, Michael A. J. Ferguson3, and H.-Arno J. Müller1§

1 Division of Cell and Developmental Biology, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
2 Institut für Genetik, Heinrich-Heine Universität, 40225 Düsseldorf, Germany.
3 Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
4 Division of Cell Signalling and Immunology, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.

* Present address: AG Entwicklungsbiologie, Universitätsklinikum Essen, Institut für Zellbiologie (Tumorforschung), Hufelandstrasse 55, 45122 Essen, Germany.

{dagger} Present address: National Institute for Bioprocessing Research and Training, Dublin-Oxford Glycobiology Laboratory, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.

{ddagger} Present address: Clinical Biochemistry Laboratory, Salford Royal Foundation Hospital, Salford M6 8HD, UK.

Abstract: Glycosylation is essential for growth factor signaling through N-glycosylation of ligands and receptors and the biosynthesis of proteoglycans as co-receptors. Here, we show that protein O-GlcNAcylation is crucial for fibroblast growth factor (FGF) signaling in Drosophila. We found that nesthocker (nst) encodes a phosphoacetylglucosamine mutase and that nst mutant embryos exhibited low amounts of intracellular uridine 5'-diphosphate–N-acetylglucosamine (UDP-GlcNAc), which disrupted protein O-GlcNAcylation. Nst was required for mitogen-activated protein kinase (MAPK) signaling downstream of FGF but not MAPK signaling activated by epidermal growth factor. nst was dispensable for the function of the FGF ligands and the FGF receptor’s extracellular domain but was essential in the signal-receiving cells downstream of the FGF receptor. We identified the adaptor protein Downstream of FGF receptor (Dof), which interacts with the FGF receptor, as the relevant target for O-GlcNAcylation in the FGF pathway, suggesting that protein O-GlcNAcylation of the activated receptor complex is essential for FGF signal transduction.

§ To whom correspondence should be addressed. E-mail: h.j.muller{at}dundee.ac.uk

Citation: D. Mariappa, K. Sauert, K. Mariño, D. Turnock, R. Webster, D. M. F. van Aalten, M. A. J. Ferguson, H.- A. J. Müller, Protein O-GlcNAcylation Is Required for Fibroblast Growth Factor Signaling in Drosophila. Sci. Signal. 4, ra89 (2011).

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