Complex formation of adenomatous polyposis coli gene product and axin facilitates glycogen synthase kinase-3β-dependent phosphorylation of β-catenin and down-regulates β-catenin

Abstract

Adenomatous polyposis coli gene product (APC) functions as a tumor suppressor and its mutations in familial adenomatous polyposis and colorectal cancers lead to the accumulation of cytoplasmic β-catenin. The molecular mechanism by which APC regulates the stability of β-catenin was investigated. The central region of APC, APC-(1211-2075), has the β-catenin- and Axin-binding sites and down-regulates β-catenin. Glycogen synthase kinase-3β (GSK-3β) phosphorylated β-catenin slightly in the presence of either APC-(1211-2075) or Axin(Δβ-catenin), in which the β-catenin-binding site is deleted, and greatly in the presence of both proteins. The enhancement of the GSK-3β-dependent phosphorylation of β-catenin was eliminated by the APC-binding site of Axin. Axin down-regulated β-catenin in SW480 cells, but not Axin(Δβ-catenin). In L cells where APC is intact, Axin(Δβ-catenin) inhibited Wnt-dependent accumulation of β-catenin but not Axin-(298-832)(Δβ-catenin) in which the APC- and β-catenin-binding sites are deleted. These results indicate that the complex formation of APC and Axin enhances the phosphorylation of β-catenin by GSK-3β, leading to the down-regulation of β-catenin.