University of Cambridge > > Babraham Seminar > Explorations of N- and O-linked Glycosylation on Extracellular and Intracellular Cell Surfaces

Explorations of N- and O-linked Glycosylation on Extracellular and Intracellular Cell Surfaces

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  • UserProf. Catherine Costello; William Fairfield Warren Distinguished Professor and Director of the Center for Biomedical Mass Spectrometry, Boston University, Boston, MA World_link
  • ClockWednesday 23 September 2020, 15:00-16:00
  • HouseOnline via zoom.

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N- and O-linked glycosylation is often the key to inter- and intracellular signaling, as well as the entry of pathogens and toxins. Mass spectrometry and complementary approaches are powerful tools for the determination of the locations and specificity of such interactions. This can help to understand normal and aberrant pathways, and guide development of therapeutic interventions. Representative examples, including the following, will be discussed.

Mutation of one N-glycosylation site near the Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) ligand binding site quickly amplified its ligand-dependent phosphorylation (activation) at specific sites, and resulted in higher levels of phospho-Src compared to wild type VEGFR -2, which may have implications for endothelial cell proliferation and migration, whereas mutations at nearby N-glycosylation sites did not appear to impact ligand-mediated activation of VEGFR -2.

At specific N-glycosylation sites, Epidermal Growth Factor Receptor (EGFR) from indolent CAL27 cells had highly fucosylated N-glycans, whereas the corresponding N-linked glycans on EGFR from metastatic HSC -3 cells displayed much lower levels of fucosylation. Our MS/MS data showed that treatment with a drug candidate promoted modification of HSC -3 glycans with terminal fucose, potentially inhibiting EGFR signaling. The results suggest inhibition of β-catenin/CBP signaling as a therapeutic approach to downregulate EGFR pro-tumorigenic activity.

Surprising results obtained during recent studies revealed that highly fucosylated proteins are present adjacent to the nucleus of cells in the pathogens Cryptosporidium and T. gondii and related organisms. These unusual protein modifications, which apparently arose via the kidnapping of plant genes, may represent targets for drug development.

About the speaker:

Catherine E. Costello is a William Fairfield Warren Distinguished Professor at Boston University, with appointments in the Depts. of Biochemistry, Physiology & Biophysics, and Chemistry. She earned her AB at Emmanuel College, Boston, and PhD at Georgetown University, Washington, DC, and was a postdoctoral fellow and Senior Research Scientist at MIT . She founded the BU School of Medicine Center for Biomedical Mass Spectrometry in 1994. Her research centers on development of MS-based methods for biopolymers and their application to study glycobiology, protein post-translational modifications, protein misfolding disorders, cardiovascular and infectious diseases, and bioactive lipids. She has authored nearly 400 research papers. She was President of the American Society for Mass Spectrometry from 2002-2004 and the International Human Proteome Organization in 2011 & 2012, and the International Mass Spectrometry Foundation from 2014-2018. She has received several major national and international recognitions in the fields of MS, glycobiology, proteomics and chemistry and is a Fellow of the ACS and the AAAS .

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