FIG. 8.

Hypothetical model of axin complex formation. In the unstimulated state (top), axin forms a complex with itself (blue), GSK-3β (green), β-catenin (red), APC (brown), and protein phosphatase 2A (not shown). In this model, APC (and/or other proteins that bind to the RGS domain) blocks access of a GSK-3β inhibitor (black box). GSK-3β remains active, phosphorylating β-catenin, which is then degraded. Wnt signaling (bottom right) would cause a conformational change in the axin complex (this could be a reversible conformational change or proteolytic cleavage) that now allows access of the GSK-3β inhibitor. The ΔRGS mutant (bottom left) mimics this conformational change, allowing constitutive access of the GSK-3β inhibitor. In both cases, inhibition of GSK-3β leads to stabilization of β-catenin, which then translocates to the nucleus, binds to LEF-1, and activates transcription of Wnt-responsive genes. Alternative models are discussed in the text.