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

Matthew J. Hart, Rico De Los Santos, Iris N. Albert, Bonnee Rubinfeld, Paul Polakis

Research output: Contribution to journalArticlepeer-review

699 Scopus citations

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 3β (GSK3β), and APC. Results: Human Axin (hAxin) binds directly to β-catenin, GSK3β, 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 GSK3β in vitro. Conclusions: Axin acts as a scaffold upon which APC, β-catenin and GSK3β assemble to coordinate the regulation of β-catenin signaling.

Original languageEnglish (US)
Pages (from-to)573-581
Number of pages9
JournalCurrent Biology
Volume8
Issue number10
DOIs
StatePublished - May 7 1998

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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