Molecular mechanisms of the β-catenin destruction complex in health and disease

Wnt/β-catenin signalling comprises a fundamental cell-to-cell communication pathway that governs cellular growth and differentiation in complex organisms. Central to this pathway is the transcriptional co-regulator β-catenin. In the absence of Wnt signals, β-catenin is continuously targeted for degradation by a destruction complex, thereby preventing β-catenin-mediated gene expression.

In this thesis, we investigate how AXIN1, the central scaffold of the β-catenin destruction complex, regulates assembly and function of this complex in healthy cells, and how disease-related mutations affect this regulation.
We identify novel interactions within and between AXIN1 proteins that are critical for their polymerization. These interactions stabilize destruction complex assemblies and promote their ability to degrade β-catenin efficiently. Interestingly, we show that reinforcing these interactions can reduce the detrimental effects of cancer mutations that disrupt Wnt signalling.

In addition, we examine the roles of AXIN1 and β-catenin mutations in liver cancer. While AXIN1 mutations generally lead to milder Wnt signalling activation than β-catenin mutations, they still provide sufficient levels of signalling to support Wnt-independent growth. In addition, we uncover a previously unknown subset of AXIN1 cancer mutations that are truncated at their N-terminus. Finally, we identify a new class of AXIN1 mutations found in patients with bone disorders. These mutations hyperactivate Wnt signalling by disrupting AXIN1 polymerization and reducing its stability.

Together, our findings highlight the key regulatory role of AXIN1 in the β-catenin destruction complex and provide insight into how AXIN1 mutations alter destruction complex assembly and function to contribute to disease.