Robert S. Haltiwanger, Ph.D. Professor and Interim Chair Department of Biochemistry and Cell Biology Life Sciences Building Stony Brook University Stony Brook, NY 11794-5215 Office telephone: 631-632-7336 E-mail: Robert.Haltiwanger@SUNYSB.EDU
Research Description

Glycobiology: Our laboratory is studying the structure and function of complex carbohydrates in biological systems. This relatively new field, recently 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?

Role of O-glycosylation in the Notch signaling pathway.

Recent work in our laboratory has demonstrated that signal transduction pathways, such as that controlled by the Notch receptor, can be regulated by changing 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 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 many of these sites are evolutionary conserved. Even more significantly, we have 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 strongly suggest 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. We are currently examining the mechanism by which the O-fucose glycans affect Notch activity (see "Recent Publications" for more details).

O-Fucose modifications on Thrombospondin type 1 Repeats.

O-Fucose modifications are known to exist in the context of a different cysteine-knot motif, that of thrombospondin type 1 repeats (TSRs). We have recently demonstrated that the O-fucosylation of TSRs is mediated by a distinct set of enzymes than those that modify EGF repeats (see Luo et al., 2006, J. Biol. Chem. IN PRESS, for more details). We have also identified the enzyme responsible for addition of O-fucose to TSRs, protein O-fucosyltransferase 2 (POFUT2) (see Luo et al., 2006, J. Biol. Chem. IN PRESS, for more details). We are currently examining biological functions for O-fucosylation of TSRs.

Top of Page