Glycobiology: The role of glycosylation in signal transduction and development

Ph.D., Duke University
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Our laboratory is studying the structure and function of complex carbohydrates in biological systems. This relatively new field, termed "Glycobiology", has grown rapidly with the realization that glycoconjugates play important roles in nearly all aspects of metazoan biology. The fundamental question being addressed in our laboratory is: What are the functional consequences of covalently modifying proteins with sugars, especially as related to signal transduction events in cells?

Recent work in our laboratory has demonstrated that signal transduction pathways, such as that controlled by the Notch receptor, can be regulated by altering the structure of the carbohydrate modifications on the receptor. Notch is a cell surface receptor that plays a key role in numerous phases of development and differentiation. It participates in cell-to-cell signaling, becoming activated upon binding to its ligands, which are transmembrane proteins on adjacent cells. Defects in Notch signaling can cause numerous developmental deformities in organisms from Drosophila to mammals, including human diseases such as T cell leukemias, a type of cerebral arteriopathy (CADASIL), Alagille syndrome, and a common form of congenital heart disease (Tetrology of Fallot). We have recently shown that Notch is modified with two unusual forms of O-linked glycosylation, O-fucose and O-glucose, on the epidermal growth factor-like (EGF) repeats in its extracellular domain (see Moloney et al., 2000, J. Biol. Chem. 275, 9604-9611 for more details). Over half of Notch's 36 tandem EGF repeats contain putative consensus sequences for the addition of these sugars, and most of these sites are evolutionary conserved. Even more significantly, we have recently discovered a biological role for the O-fucose modifications by showing that the Fringe protein, a known modulator of Notch function, is an O-fucose specific ß1,3 N-acetylglucosaminyltransferase (see Moloney et al., 2000 Nature 406, 369-375 for more details). These results demonstrate that Fringe mediates its affects on Notch function by altering the O-fucose structures on Notch. The modulation of Notch signaling by elongation of O-fucose provides a new paradigm for the involvement of glycosylation in signal transduction events.

Selected Publications

• Wang, Y., Shao, L., Shi, S., Harris, R.J., Spellman, M.W., Stanley, P. and Haltiwanger, R.S. (2001) Modification of Epidermal Growth Factor-Like Repeats with O-Fucose: Molecular Cloning and Expression of a Novel GDP-Fucose: Polypeptide O-Fucosyltransferase. J. Biol. Chem. 276, 40338-40345.
  
  
• Moloney, D.J., Panin, V.M., Johnston, S.J., Chen, J., Shao, L., Wilson, R., Wang, Y., Stanley, P., Irvine, K.D., Haltiwanger, R.S. and Vogt, T.F. (2000) Fringe is a Glycosyltransferase that Modifies Notch.  Nature 406, 369-375.
  
  
• Moloney, D., Shair, L.H., Lu, F., Xia, J., Locke, R., Matta, K.L. and Haltiwanger, R.S. (2000) Mammalian Notch 1 is modified with two unusual forms of O-linked glycosylation found on Epidermal Growth Factor-like modules.   J. Biol. Chem. 275, 9604-9611.
  
  
• Moloney, D. and Haltiwanger, R.S. (1999) The O-linked fucose glycosylation pathway:  Identification and characterization of a UDP-glucose: O-fucose ß1,3glucosyltransferase. Glycobiology 9, 679-687.
  
  
• Moloney, D., Lin, A.I., and Haltiwanger, R.S. (1997) The O-Linked Fucose Glycosylation Pathway:  Evidence for Protein-Specific Elongation of O-Linked Fucose in Chinese Hamster Ovary Cells.  J. Biol. Chem. 272, 19046-19050.