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First published online 28 February 2007
doi: 10.1242/dev.02811
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1 Precursory Research for Embryonic Science and Technology (PRESTO), Japan
Science and Technology Agency, 4-1-8 Honcho Kawaguchi, Saitama, Japan.
2 Department of Biological Science and Technology, Tokyo University of Science,
Chiba 278-8510, Japan.
3 Genome and Drug Research Center, Tokyo University of Science, Chiba 278-8510,
Japan.
4 Department of Biological Sciences, Tokyo Metropolitan University, Tokyo
192-0397, Japan.
5 Department of Biochemistry, Osaka University, Graduate School of Medicine,
Osaka 565-0871, Japan.
* Author for correspondence (e-mail: matsuno{at}rs.noda.tus.ac.jp)
Accepted 17 January 2007
Notch is a transmembrane receptor that mediates the cell-cell interactions necessary for many cell-fate decisions. Endocytic trafficking of Notch plays important roles in the activation and downregulation of this receptor. A Drosophila O-FucT-1 homolog, encoded by O-fut1, catalyzes the O-fucosylation of Notch, a modification essential for Notch signaling and ligand binding. It was recently proposed that O-fut1 acts as a chaperon for Notch in the endoplasmic reticulum and is required for Notch to exit the endoplasmic reticulum. Here, we report that O-fut1 has additional functions in the endocytic transportation of Notch. O-fut1 was indispensable for the constitutive transportation of Notch from the plasma membrane to the early endosome, which we show was independent of the O-fucosyltransferase activity of O-fut1. We also found that O-fut1 promoted the turnover of Notch, which consequently downregulated Notch signaling. O-fut1 formed a stable complex with the extracellular domain of Notch. In addition, O-fut1 protein added to conditioned medium and endocytosed was sufficient to rescue normal Notch transportation to the early endosome in O-fut1 knockdown cells. Thus, an extracellular interaction between Notch and O-fut1 is essential for the normal endocytic transportation of Notch. We propose that O-fut1 is the first example, except for ligands, of a molecule that is required extracellularly for receptor transportation by endocytosis.
Key words: Notch, O-fucosyltransferase, O-fut1, Endocytosis, Drosophila
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