Signaling through O-GlcNAc
O-linked β-N-acetylglucosamine (O-GlcNAc) has emerged as a major signaling modification in mammalian cells. Like phosphorylation, O-GlcNAc is dynamically added to and removed from thousands of nuclear, cytoplasmic and mitochondrial proteins to control their functions. However, key questions about O-GlcNAc remain, including its upstream regulation and downstream phenotypic effects. We are studying the role of O-GlcNAc in a variety of processes, including mediating protein-protein interactions, regulating cytoskeletal function and vesicle trafficking, and governing growth and stress pathways in cancer cells.
Cell and systems biology of nucleotide-sugar metabolism
Nucleotide-sugars are abundant metabolites important for nearly all aspects of glycobiology, and genetic defects in pathways that maintain nucleotide-sugar pools cause congenital human diseases. Although most enzymes that create or destroy nucleotide-sugars are well understood at the biochemical level, their regulation at the cell biological and systems levels is largely mysterious. We are exploring how nucleotide-sugar pools are synthesized and maintained in healthy cells, and how perturbations to these processes affect cells at the metabolomic and phenotypic levels.
Glycoprotein quality control and ER stress
Mammalian cells use sophisticated quality control machinery to monitor the folding and processing of glycoproteins in the endoplasmic reticulum (ER) and Golgi. When misfolded glycoproteins accumulate due to physiological or pathological stimuli, ER stress pathways are activated to increase the capacity of the organelle to process client proteins, and, if necessary, to initiate apoptosis. ER quality control and stress pathways are required for normal development and are dysregulated in a variety of common diseases, but their mechanisms and regulation are incompletely understood. We are interested in understanding how glycoprotein folding intersects with ER stress pathways in mammalian cells, and how these processes might be manipulated for therapeutic benefit.