Unravelling the Interaction between Dishevelled and Axin: A Key to Wnt/β-Catenin Signalling in Health and Disease

Summary

Wnt/β-catenin signaling is a highly conserved pathway crucial for cell fate determination during embryonic development and tissue homeostasis. Dysregulation of this pathway is implicated as an early driver in various cancers, particularly colorectal cancer (CRC). In the absence of Wnt ligands, a destruction complex comprising Axin targets β-catenin for proteasomal degradation.

Upon Wnt stimulation, Axin is recruited to the plasma membrane by Dishevelled, leading to the inactivation of the destruction complex, stabilization of β-catenin, and subsequent transcriptional activation of Wnt target genes. The interaction between Dishevelled and Axin occurs through dynamic and reversible head-to-tail heteropolymerisation of their respective DIX domains.

Surprisingly, genetic deletion of Dishevelled's DIX domain does not abolish Dishevelled-dependent Axin recruitment to the plasma membrane and Wnt/β-catenin signaling in Drosophila, suggesting an additional interaction surface between Dishevelled and Axin.

Project aims

This PhD studentship will delineate the precise interaction between Dishevelled and Axin using cell-based and in vitro biophysical and structural assays. This research aims to provide insights into the molecular mechanisms underlying Wnt signaling and therefore has implications for understanding Wnt-related pathologies and identifying potential novel therapeutic interventions.

Contact details

Dr Melissa Gammons - mg2128@cam.ac.uk

Opportunities

This project is open to applicants who want to do a:

• PhD