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Shiyi Xi – ACRF Chemical Biology division

30/10/2024 12:00 pm - 30/10/2024 1:00 pm
Location
Davis Auditorium

WEHI Wednesday Seminar hosted by Professor Ethan Goddard
 

Shiyi Xi
PhD Student – Goddard Laboratory, ACRF Chemical Biology division – New Medicines & Advanced Technologies Theme, WEHI

(this is a PhD Completion seminar)
 

Mechanisms orchestrating the activity of tumour-suppressive A4GNT

 

Davis Auditorium

Join via SLIDO enter code #WEHIWednesday

Including Q&A session
 

 

Mucins are glycoproteins that play important roles in health and disease. The 21 canonical human mucins include cell surface transmembrane proteins involved in signalling, such as MUC1, and the extracellular soluble mucins constituting the mucus gel, such as MUC5AC. Moreover, mucin-like domains also exist in other glycoproteins, including signalling proteins like the adhesion receptor CD44, the phosphatidyl-serine receptor TIM-1, and the P selectin ligand PSGL-1. This expanded human ‘mucinome’ is comprised of around 350 proteins, which accounts for ~2% of the proteome.

All proteins of the ‘mucinome’ bear densely O-glycosylated regions. The nature of this characteristic glycosylation is functionally important. Interactions between glycans and lectins within the extracellular milieu govern the physical properties of mucus but also drive the formation of signalling complexes. A classic example of the latter phenomenon is how changes in MUC1 glycosylation facilitate galectin-mediated MUC1-EGFR association/activation to drive epithelial cancer cell proliferation.

My PhD studies have focused on the understudied mucin domain-modifying glycosyltransferase A4GNT. The glycans produced by A4GNT are recognised by the extracellular trefoil factor (TFF) lectins. This interaction between A4GNT-modified mucin and TFF lectin plays important roles in tumour suppression: disruption of A4GNT or TFF leads to spontaneous adenocarcinoma formation in mice. This is mirrored in humans, where the evolution of gastric, pancreatic, and cervical cancer often features loss of A4GNT and/or TFF expression.

This seminar will detail my efforts to delineate the details of A4GNT activity using biochemical, structural, proteomic, and cell-based approaches. My findings help determine exactly which proteins are modified by A4GNT, where they are modified, and how/why this protein modification occurs on a focussed subset of glycoproteins. This has important ramifications for understanding the tumour-suppressive roles of A4GNT and the TFFs.

 

All welcome!

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