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

Area of Science:

• Molecular Biology
• Cell Signaling
• Biochemistry

Background:

• Axin (AXIN1) is a key negative regulator of Wnt/β-catenin signaling, forming condensates that degrade β-catenin.
• Axin degradation is mediated by tankyrase, and its inhibition shows cancer therapeutic potential by stabilizing axin.

Purpose of the Study:

• To investigate the regulatory mechanism of axin stability.
• To identify kinases and phosphatases involved in axin regulation.
• To understand the role of axin condensates in this regulation.

Main Methods:

• Investigated axin phosphorylation by casein kinase 1 alpha 1 (CSNK1A1/CK1α).
• Examined the antagonistic role of protein phosphatase 1 catalytic subunit alpha (PPP1CA/PP1).
• Analyzed the effect of axin condensates on CK1α and PP1 enrichment.

Main Results:

• Discovered axin phosphorylation by CK1α at an N-terminal motif.
• Identified PP1 as an antagonist to CK1α-mediated axin phosphorylation.
• Showed axin condensates enrich CK1α over PP1, promoting phosphorylation.
• Demonstrated that phosphorylation occurs at the tankyrase-binding site, hindering axin-tankyrase interaction and counteracting tankyrase-mediated degradation.

Conclusions:

• Proposed a novel mechanism for axin stability regulation via CK1α phosphorylation and PP1 antagonism.
• Highlighted the role of axin condensates in modulating this phosphorylation.
• Suggested implications for Wnt signaling, cancer therapy, and biomolecular condensate self-organization.