Axin–Glycogen synthase kinase 3 protein–protein interface (Axin–GSK3 PPI)

The Axin–Glycogen synthase kinase 3 (GSK3) protein–protein interface is a fundamental regulatory component of the canonical Wnt/β-catenin signaling pathway. Axin acts as a central scaffold protein that facilitates the assembly of the β-catenin destruction complex, which includes GSK3β, Adenomatous Polyposis Coli (APC), and Casein Kinase 1 (CK1) [1][2]. Within this complex, the interaction between the GSK3-interaction domain (GID) of Axin and the 285-299 loop of GSK3β is essential for the efficient phosphorylation of β-catenin, marking it for subsequent ubiquitination and proteasomal degradation [2][3]. Dysregulation of this interface is frequently implicated in various pathologies; for instance, loss-of-function mutations in Axin or overactivity of Wnt signaling can lead to β-catenin accumulation and oncogenesis, particularly in colorectal and hepatocellular carcinomas [4]. Conversely, pharmacological disruption of the Axin–GSK3 interface is being explored as a strategy to activate Wnt signaling for regenerative medicine applications, such as bone repair and treating neurodegenerative disorders like Alzheimer's disease [5]. Unlike ATP-competitive GSK3 inhibitors, which may affect multiple signaling pathways, targeting this specific protein-protein interface offers a more selective approach to modulating Wnt-specific functions [5][6]. Current therapeutic efforts focus on the development of small molecules and peptidomimetics designed to competitively inhibit the binding of GSK3 to the Axin GID [6].

Other names

Axin-GSK3 interactionAxin-GSK3β complexAxin-GSK3 binding interfaceAxin-GSK3β protein-protein interaction

Competitive inhibition of the GSK3-binding domain (GID) of Axin to disrupt the β-catenin destruction complex, leading to β-catenin stabilization and Wnt pathway activation.