Association of AXIN1 assemblies with microtubules inhibits Wnt/β-catenin signaling
Year: 2026
Type: article
Abstract: The Wnt/β-catenin pathway is crucially involved in cell proliferation and differentiation. AXIN1, a key inhibitor of the pathway, scaffolds the β-catenin destruction complex in the cytoplasm, and pathway activation requires AXIN1 membrane recruitment and inhibition by DVL. Here, we discover an interplay of Wnt signaling and the cytoskeleton, mediated by direct binding of AXIN1 to microtubules via a positively charged binding site. The microtubule interaction ranges from peripherally attached AXIN1 condensates to tightly-tethered fibrillar assemblies that are inhibited by CK1-dependent phosphorylation. Microtubule binding renders the AXIN1 scaffold polymers more stable and stationary, favoring destruction complex assembly. It also counteracts the inhibition of AXIN1 through DVL, as shown by its impact on AXIN1 protein interactions and membrane recruitment, as well as on β-catenin degradation. Pharmacological or genetic inhibition of microtubule binding by endogenous AXIN1 activates Wnt/β-catenin signaling in several cellular systems. Moreover, a cell-permeable peptide designed to competitively block AXIN1 interaction with microtubules increases Wnt signaling and stimulates Wnt signaling-dependent differentiation of osteoblasts. In conclusion, AXIN1-mediated anchoring of the β-catenin destruction complex to microtubules suppresses Wnt signaling, suggesting a target for pharmacological modulation.
Source: The EMBO Journal
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $7,990
OpenAlex ID: W7225451388