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Mol. Cell. Biol., 08 1996, 4088-4094, Vol 16, No. 8
Copyright © 1996, American Society for Microbiology

Deletion of an amino-terminal sequence beta-catenin in vivo and promotes hyperphosporylation of the adenomatous polyposis coli tumor suppressor protein

S Munemitsu, I Albert, B Rubinfeld and P Polakis
Onyx Pharmaceuticals, Richmond, California 94806, USA.

Regulation of cell adhesion and cell signaling by beta-catenin occurs through a mechanism likely involving the targeted degradation of the protein. Deletional analysis was used to generate a beta-catenin refractory to rapid turnover and to examine its effects on complexes containing either cadherin or the adenomatous polyposis coli (APC) protein. The results show that amino-terminal deletion of beta-catenin results in a protein with increased stability that acts in a dominant fashion with respect to wild-type beta-catenin. Constitutive expression in AtT20 cells of a beta-catenin lacking 89 N-terminal amino acids (deltaN89beta-catenin) resulted in severely reduced levels of the more labile wild-type beta-catenin. The mutant beta-catenin was expressed at endogenous levels but displaced the vast majority of wild-type beta- catenin associated with N-cadherin. The deltaN89beta-catenin accumulated on the APC protein to a level 10-fold over that of wild- type beta-catenin and recruited a kinase into the APC complex. The kinase was highly active toward APC in vitro and promoted a sodium dodecyl sulfate gel band shift that was also evident for endogenous APC from cells expressing the mutant beta-catenin. Unlike wild-type beta- catenin, which partitions solely as part of a high-molecular-weight complex, the deltaN89 mutant protein also fractionated as a stable monomer, indicating that it had escaped the requirement to associate with other proteins. That similar N-terminal mutants of beta-catenin have been implicated in cellular transformation suggests that their abnormal association with APC may, in part, be responsible for this phenotype.


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