Downregulation of β-catenin by human Axin and its association with the APC tumor suppressor, β-catenin and GSK3β

Abstract Background: Inactivation of the adenomatous polyposis coli (APC) tumor suppressor protein is responsible for both inherited and sporadic forms of colon cancer. Growth control by APC may relate to its ability to downregulate β -catenin post-translationally. In cancer, mutations in APC ablate its ability to regulate β -catenin, and mutations in β -catenin prevent its downregulation by wild-type APC. Moreover, signaling by the protein product of the wnt -1 proto-oncogene upregulates β -catenin and promotes tumorigenesis in mice. In a Xenopus developmental system, Wnt-1 signaling was inhibited by Axin, the product of the murine fused gene. This suggests a possible link between Axin, the Wnt-1 signaling components β -catenin and glycogen synthase kinase 3 β (GSK3 β ), and APC. Results: Human Axin (hAxin) binds directly to β -catenin, GSK3 β , and APC in vitro , and the endogenous proteins are found in a complex in cells. Binding sites for Axin were mapped to a region of APC that is typically deleted due to cancer-associated mutations in the APC gene. Overexpression of hAxin strongly promoted the downregulation of wild-type β -catenin in colon cancer cells, whereas mutant oncogenic β -catenin was unaffected. The downregulation was increased by deletion of the APC-binding domain from Axin, suggesting that APC may function to derepress Axin activity. In addition, hAxin dramatically facilitated the phosphorylation of APC and β -catenin by GSK3 β in vitro . Conclusions: Axin acts as a scaffold upon which APC, β -catenin and GSK3 β assemble to coordinate the regulation of β -catenin signaling.

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