Downregulation 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 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 beta-catenin post-translationally. In cancer, mutations in APC ablate its ability to regulate beta-catenin, and mutations in beta-catenin prevent its downregulation by wild-type APC. Moreover, signaling by the protein product of the wnt-1 proto-oncogene upregulates beta-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 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 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 beta-catenin in colon cancer cells, whereas mutant oncogenic beta-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 beta-catenin by GSK3 beta in vitro.


CONCLUSIONS
Axin acts as a scaffold upon which APC, beta-catenin and GSK3 beta assemble to coordinate the regulation of beta-catenin signaling.
Hart
M J
MJ
Onyx Pharmaceuticals, Richmond, California 94806, USA.
de los Santos
R
R
Albert
I N
IN
Rubinfeld
B
B
Polakis
P
P
D011125:Adenomatous Polyposis Coli; D025601:Adenomatous Polyposis Coli Protein; D060466:Axin Protein; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D006801:Humans; D010766:Phosphorylation; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D012097:Repressor Proteins; D015534:Trans-Activators; D014407:Tumor Cells, Cultured; D029867:Xenopus Proteins; D051176:beta Catenin
D025601:Adenomatous Polyposis Coli Protein; D060466:Axin Protein; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; C000715470:MAS1 protein, human; D011506:Proteins; D000090063:Proto-Oncogene Mas; D012097:Repressor Proteins; D015534:Trans-Activators; D029867:Xenopus Proteins; C555454:axin1 protein, Xenopus; D051176:beta Catenin; D038341:Glycogen Synthase Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3