NIH Research Festival
Mucin-type glycosylation, otherwise known as O-GalNAc glycosylation, is the most common form of O-linked glycosylation in mammalian cells. Mucins are a family of ~20 secreted and/or membrane bound high molecular weight proteins and contain long stretches of tandem repeat (TR) peptide sequences with N-acetylgalactosamine (GalNAc)-initiated oligosaccharide chains linked to the hydroxyl group of the TR‚Äôs serines or threonines. These glycoproteins are essential for processes including cell-cell communication, cellular protection, and signal transduction. In disease states, they are known to resist apoptosis, initiate immunogenic responses, and enhance metastasis, resulting in their over expression in several cancers. Mucin 4 (MUC4) is specifically known for its over expression in pancreatic ductal adenocarcinoma (PDAC), and lack of expression in healthy pancreas tissue, making it a biomarker for the disease. While the mechanism for glycosylation is well understood- involving the interaction of the mucin with uridinediphospho-GalNAc (UDP-GalNAc) and one of the 20 polypeptide N-acetylgalacosaminyltransferase isoenzymes (GALNTs) within the Golgi body- specific glycosylation selectivity towards TR serines and threonines is not as well-known and needs further exploration. We set out to examine the substrate specificity of various TR sequences from MUC4 by replicating mucin-type glycosylation in vitro, with the goals of identifying primary sites of glycosylation on TR sequences and determining patterns of glycosylation across the isoenzymes. Understanding glycosylation specificity and selectivity will expand our knowledge of cancer generation and aid future development of cancer therapeutics.
Scientific Focus Area: Cancer Biology
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