HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

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

This Article Full Text Full Text (PDF) All Versions of this Article: 280/37/32133    most recent M506104200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rampal, R. Articles by Haltiwanger, R. S. Search for Related Content PubMed PubMed Citation Articles by Rampal, R. Articles by Haltiwanger, R. S. Related Collections Papers Of The Week Social Bookmarking                      What's this?

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.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				L. Zhou, L. W. Li, Q. Yan, B. Petryniak, Y. Man, C. Su, J. Shim, S. Chervin, and J. B. Lowe Notch-dependent control of myelopoiesis is regulated by fucosylation Blood, July 15, 2008; 112(2): 308 - 319. [Abstract] [Full Text] [PDF]

				T. Okajima, A. Matsuura, and T. Matsuda Biological Functions of Glycosyltransferase Genes Involved in O-fucose Glycan Synthesis J. Biochem., July 1, 2008; 144(1): 1 - 6. [Abstract] [Full Text] [PDF]

				C. Ge and P. Stanley The O-fucose glycan in the ligand-binding domain of Notch1 regulates embryogenesis and T cell development PNAS, February 5, 2008; 105(5): 1539 - 1544. [Abstract] [Full Text] [PDF]

				S. Shi, C. Ge, Y. Luo, X. Hou, R. S. Haltiwanger, and P. Stanley The Threonine That Carries Fucose, but Not Fucose, Is Required for Cripto to Facilitate Nodal Signaling J. Biol. Chem., July 13, 2007; 282(28): 20133 - 20141. [Abstract] [Full Text] [PDF]

				L. M. Ricketts, M. Dlugosz, K. B. Luther, R. S. Haltiwanger, and E. M. Majerus O-Fucosylation Is Required for ADAMTS13 Secretion J. Biol. Chem., June 8, 2007; 282(23): 17014 - 17023. [Abstract] [Full Text] [PDF]

				L. W. Wang, M. Dlugosz, R. P. T. Somerville, M. Raed, R. S. Haltiwanger, and S. S. Apte O-Fucosylation of Thrombospondin Type 1 Repeats in ADAMTS-like-1/Punctin-1 Regulates Secretion: IMPLICATIONS FOR THE ADAMTS SUPERFAMILY J. Biol. Chem., June 8, 2007; 282(23): 17024 - 17031. [Abstract] [Full Text] [PDF]

				N. Sasaki, T. Sasamura, H. O. Ishikawa, M. Kanai, R. Ueda, K. Saigo, and K. Matsuno Polarized exocytosis and transcytosis of Notch during its apical localization in Drosophila epithelial cells. Genes Cells, January 1, 2007; 12(1): 89 - 103. [Abstract] [Full Text] [PDF]

				K. Kozma, J. J. Keusch, B. Hegemann, K. B. Luther, D. Klein, D. Hess, R. S. Haltiwanger, and J. Hofsteenge Identification and Characterization of abeta1,3-Glucosyltransferase That Synthesizes the Glc-beta1,3-Fuc Disaccharide on Thrombospondin Type 1 Repeats J. Biol. Chem., December 1, 2006; 281(48): 36742 - 36751. [Abstract] [Full Text] [PDF]

				Y. Luo, A. Nita-Lazar, and R. S. Haltiwanger Two Distinct Pathways for O-Fucosylation of Epidermal Growth Factor-like or Thrombospondin Type 1 Repeats J. Biol. Chem., April 7, 2006; 281(14): 9385 - 9392. [Abstract] [Full Text] [PDF]

				R. Rampal, A. S. Y. Li, D. J. Moloney, S. A. Georgiou, K. B. Luther, A. Nita-Lazar, and R. S. Haltiwanger Lunatic Fringe, Manic Fringe, and Radical Fringe Recognize Similar Specificity Determinants in O-Fucosylated Epidermal Growth Factor-like Repeats J. Biol. Chem., December 23, 2005; 280(51): 42454 - 42463. [Abstract] [Full Text] [PDF]