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bioRxiv · 10.1101/2021.05.05.442673

The self-regulated response of the Wnt pathway to an oncogenic mutation in β-catenin

Moshkovsky, A. R.·Ma, W.·Kirschner, M. W.
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Abstract

Oncogenic mutations in {beta}-catenin can inhibit degradation of {beta}-catenin by preventing phosphorylation of its degron. Degron phosphorylation is mediated by the Axin scaffold, Casein Kinase 1 (CK1) and Glycogen Synthase Kinase 3 (GSK3). We studied an oncogenic form of {beta}-catenin with a deletion of serine 45 (S45), a site that is phosphorylated by the kinase CK1. When the S45 site is phosphorylated, it promotes the GSK3-mediated phosphorylations of the {beta}-catenin degron. Deletion of S45 would be expected to prevent GSK3-mediated phosphorylation of the mutant protein and thus block degradation. We found that the S45 mutant was still phosphorylatable by GSK3, and its expression increased the concentration of Axin, restoring the rate of GSK3-mediated phosphorylation to levels comparable to those observed for the wild-type {beta}-catenin. We conclude that there is one core mechanism for creating the phosphodegron for both primed and unprimed {beta}-catenin, which involves the generation of an Axin-GSK3 complex. SIGNIFICANCEUnderstanding how the Wnt pathway responds to mutations in {beta}-catenin phosphodegron can reveal important properties of the pathway in normal and cancer cells and is valuable for the design of more effective therapeutic strategies.

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Moshkovsky, A. R., Ma, W., Kirschner, M. W.. 2021-05-05. The self-regulated response of the Wnt pathway to an oncogenic mutation in β-catenin. https://doi.org/10.1101/2021.05.05.442673

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