Katie Hayward

PhD thesis:

Mechanistic Analysis of Pseudokinase Receptors in Canonical and Non-canonical Wnt Signalling

Wnt signalling comprises ancient, conserved cell-communication pathways that regulate cell fate during embryonic development. Dysregulation of Wnt signalling through aberrant activation or genetic mutation is a major driver of many cancers, as well as rare genetic disorders. All Wnt pathways are initiated when extracellular Wnt ligands bind Frizzled (FZD1–10) receptors and recruit the cytoplasmic hub protein Dishevelled (DVL1–3) to assemble the Wnt signalosome, a multiprotein complex that transduces signals to downstream effectors. To enable Wnts to activate distinct signalling branches, Frizzled receptors partner with various co-receptors. The best characterised are LRP5/6, which are essential for Wnt/β-catenin signalling by inhibiting GSK3. In contrast, the molecular roles of other proposed co-receptors—ROR1, ROR2, RYK and PTK7—remain poorly defined, despite their clear importance in development and disease. Intriguingly, all four are receptor tyrosine pseudokinases, raising the fundamental question of how they influence Wnt signalling without catalytic activity.

Who or what inspired you to pursue your research interests?

My interest in cell signalling pathways stems from a desire to understand the molecular interactions that underpin life itself. During my undergraduate studies, I became fascinated by how cellular proteins sense and respond to their environment, coordinating remarkably rapid and complex responses. This led me to undertake a summer research project at the Babraham Institute, investigating the NF-kB pathway under the guidance of Dr. Simon Cook. This was a hugely inspirational experience that solidified my desire to further pursue a research project that aims to understand how different signalling pathways function, interact and become dysregulated in disease-states.