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

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 beta -catenin. The molecular mechanism by which APC regulates the stability of beta -catenin was investigated. The central region of APC, APC-(1211-2075), has the beta -catenin- and Axin-binding sites and down-regulates beta -catenin. Glycogen synthase kinase-3 beta (GSK-3 beta) phosphorylated beta -catenin slightly in the presence of either APC-(1211-2075) or Axin(Delta beta -catenin) in which the beta -catenin-binding site is deleted, and greatly in the presence of both proteins. The enhancement of the GSK-3 beta -dependent phosphorylation of beta -catenin was eliminated by the APC-binding site of Axin. Axin down-regulated beta -catenin in SW480 cells, but not Axin(Delta beta -catenin). I, L cells where APC is intact, Axin(Delta beta -catenin) inhibited Wnt-dependent accumulation of beta -catenin but not Axin-(298-832)(Delta beta -catenin) in which the APC- and beta -catenin-binding sites are deleted. These results indicate that the complex formation of APC and Axin enhances the phosphorylation of beta -catenin by GSK-3 beta, leading to the down-regulation of beta -catenin.