Phosphorylation-driven Targeted Protein Degradation of Oncogenic β-catenin

Authors

Wolf, L. M., Poirson, J., Macleod, G., Lin, S., Kim, Y. H., Almeida, M. P., Taipale, M., Angers, S.

Abstract

Therapeutic strategies to inhibit the Wnt signalling pathway for cancer treatment have, so far, failed to advance to the clinic. Induced-proximity drugs are revolutionizing our ability to tackle targets previously considered undruggable. Here, we used an unbiased genome-scale approach to identify induced-proximity protein candidates that inhibit the central Wnt signalling effector {beta}-catenin in colorectal cancer cells. While the identification of several E3 ubiquitin ligases validated our approach, we uncovered that inducing proximity to members of the Casein kinase I (CSNK1) family leads to {beta}-catenin degradation and inhibits the growth of colorectal cancer cells harbouring Wnt pathway mutations. We show that {beta}-catenin degradation induced by CSNK1 proximity is kinase activity- and proteasome-dependent. We propose that the formation of a neo-degron, through kinase recruitment, can expand induced-proximity drug targeting strategies.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 19 Mar 2026.

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