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J. Biol. Chem., Vol. 280, Issue 37, 32133-32140, September 16, 2005

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Highly Conserved O-Fucose Sites Have Distinct Effects on Notch1 Function^*

Raajit Rampal1, Joseph F. Arboleda-Velasquez, Alexandra Nita-Lazar, Kenneth S. Kosik, and Robert S. Haltiwanger2

From the Department of Biochemistry and Cell Biology, Institute for Cell and Developmental Biology, Stony Brook University, Stony Brook, New York 11794-5215 and the Neurology Department, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115

The extracellular domain of mouse Notch1 contains 36 tandem epidermal growth factor-like (EGF) repeats, many of which are modified with O-fucose. Previous work from several laboratories has indicated that O-fucosylation plays an important role in ligand mediated Notch activation. Nonetheless, it is not clear whether all, or a subset, of the EGF repeats need to be O-fucosylated. Three O-fucose sites are invariantly conserved in all Notch homologues with 36 EGF repeats (within EGF repeats 12, 26, and 27). To investigate which O-fucose sites on Notch1 are important for ligand-mediated signaling, we mutated the three invariant O-fucose sites in mouse Notch1, along with several less highly conserved sites, and evaluated their ability to transduce Jagged1- and Delta1-mediated signaling in a cell-based assay. Our analysis revealed that mutation of any of the three invariant O-fucose sites resulted in significant changes in both Delta1 and Jagged1 mediated signaling, but mutations in less highly conserved sites had no detectable effect. Interestingly, mutation of each invariant site gave a distinct effect on Notch function. Mutation of the O-fucose site in EGF repeat 12 resulted in loss of Delta1 and Jagged1 signaling, while mutation of the O-fucose site in EGF repeat 26 resulted in hyperactivation of both Delta1 and Jagged1 signaling. Mutation of the O-fucose site in EGF repeat 27 resulted in faulty trafficking of the Notch receptor to the cell surface and a decreased S1 processing of the receptor. These results indicate that the most highly conserved O-fucose sites in Notch1 are important for both processing and ligand-mediated signaling in the context of a cell-based signaling assay.

Received for publication, June 3, 2005

^* This work was supported in part by National Institutes of Health Grant GM 61126. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

This article was selected as a Paper of the Week.

¹ Supported in part by Medical Scientist Training Program Training Grant T32 GM008444.

² To whom correspondence should be addressed. Tel.: 631-632-7336; Fax: 631-632-8575;E-mail: rhaltiwanger{at}ms.cc.sunysb.edu.

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