Phosphorylation of axin within biomolecular condensates counteracts its tankyrase-mediated degradation

Axin (also known as AXIN1) is a central negative regulator of the protooncogenic Wnt/ft-catenin signaling pathway, as axin condensates provide a scaffold for the assembly of a multiprotein complex degrading ft-catenin. Axin, in turn, is degraded through tankyrase. Consequently, tankyrase small-molecule inhibitors block Wnt signaling by stabilizing axin, revealing potential for cancer therapy. Here, we discovered that axin is phosphorylated by casein kinase 1 alpha 1 (CSNK1A1, also known as CK1a) at an N-terminal casein kinase 1 consensus motif, and that this phosphorylation is antagonized by the catalytic subunit alpha of protein phosphatase 1 (PPP1CA, hereafter referred to as PP1). Axin condensates promoted phosphorylation by enriching CK1a over PP1. Importantly, the phosphorylation took place within the tankyrase-binding site, electrostatically and/or sterically hindering axin-tankyrase interaction, and counteracting tankyrasemediated degradation of axin. Thus, the presented data propose a novel mechanism regulating axin stability, with implications for Wnt signaling, cancer therapy and self-organization of biomolecular condensates.

Automated summary

Axin serves as a negative regulator of the Wnt/β-catenin signaling pathway, and its stability is regulated by phosphorylation and degradation. Understanding the mechanisms of Axin regulation has implications for cancer therapy and biomolecular condensate organization.