Glycans that regulate development and notch signaling
Pamela Stanley obtained her Ph.D. in the laboratory of Prof. David White, Department of Microbiology, University of Melbourne, Australia. She was subsequently a postdoctoral fellow of the Medical Research Council of Canada in the laboratory of Dr. Louis Siminovitch where she began her work on somatic cell glycosylation mutants. She was appointed Assistant Professor in Cell Biology at Albert Einstein in New York in 1977, and became a full Professor in 1986. She was Program Leader of the Molecular Membrane Biology program of the Albert Einstein Cancer Center from 1988 to 2012. She has been Associate Director for Laboratory Research of the Albert Einstein Cancer Center since 2002. She currently holds the Horace W. Goldstein Foundation Chair and is Professor of Cell Biology at Albert Einstein.
Notch signaling occurs when cell surface Notch receptors are stimulated by Notch ligands on an apposing cell. This interaction leads to release of the Notch receptor intracellular domain which complexes with several factors in the nucleus to induce the expression of Notch target genes. A large variety of cell fate decisions depend on regulated Notch signaling during development and differentiation in mammals. Thus, several human diseases and cancers arise from the malfunctioning of Notch signaling pathways. Diseases range from skeletal deformities to heart disease to a variety of cancers. The O-fucose glycans attached to the extracellular domain of Notch receptors play critical but ill-defined roles in the regulation of Notch signaling. In their absence, mouse embryos die at mid-gestation with defects typical of a loss of signaling through all four Notch receptors. O-fucose on Notch receptors is elongated by the addition of another sugar GlcNAc by one of three Fringe GlcNAc-transferases. Dysregulation of Notch signaling by altered glycosyltransferase gene expression has been associated with developmental defects and cancer prognosis. My lab is working to understand molecular mechanisms by which O-fucose glycans and the different Fringe activities regulate Notch signaling. A particular challenge is that there are three Fringe genes, often expressed together in a given tissue. My lab has used genetic strategies to generate cultured cells and mice with Notch receptors that carry no fucose, or only O-fucose, or O-fucose with GlcNAc transferred by a single Fringe enzyme, to identify roles for O-fucose and each Fringe glycosyltransferase in embryonic development and in T and B cell development.
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