DOWN-REGULATION OF BETA-CATENIN BY HUMAN AXIN AND ITS ASSOCIATION WITH THE APC TUMOR-SUPPRESSOR, BETA-CATENIN AND GSK3-BETA

Background: Inactivation of the adenomatous polyposis coil (APC) tumor suppressor protein is responsible for both inherited and sporadic for ms of colon cancer. Growth control by APC may relate to its ability to downregulate beta-catenin post-translationally. In cancer, mutations in APC ablate its ability to regulate beta-catenin, and mutations in b eta-catenin prevent its downregulation by wild-type APC. Moreover, sig naling by the protein product of the wnt-1 proto-oncogene upregulates beta-catenin and promotes tumorigenesis in mice. In a Xenopus developm ental system, Wnt-1 signaling was inhibited by Axin, the product of th e murine fused gene. This suggests a possible link between Axin, the W nt-1 signaling components beta-catenin and glycogen synthase kinase 3 beta (GSK3 beta), and APC. Results: Human Axin (hAxin) binds directly to beta-catenin, GSK3 beta, and APC in vitro, and the endogenous prote ins are found in a complex in cells. Binding sites for Axin were mappe d to a region of APC that is typically deleted due to cancer-associate d mutations in the APC gene. Overexpression of hAxin strongly promoted the downregulation of wild-type beta-catenin in colon cancer cells, w hereas mutant oncogenic beta-catenin was unaffected. The downregulatio n was increased by deletion of the APC-binding domain from Axin, sugge sting that APC may function to derepress Axin activity. In addition, h Axin dramatically facilitated the phosphorylation of APC and beta-cate nin by GSK3 beta in vitro. Conclusions: Axin acts as a scaffold upon w hich APC, beta-catenin and GSK3 beta assemble to coordinate the regula tion of beta-catenin signaling. (C) Current Biology Ltd ISSN 0960-9822 .