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Regulation of the phosphorylation and nuclear import and export of &bgr;-catenin by APC and its cancer-related truncated form

ABSTRACT We report the first direct analysis of the endogenous &bgr;-catenin phosphorylation activity in colon cancer SW480 cells. By comparing parental SW480 cells that harbor a typical truncated adenomatous polyposis coli (APC) form, cells expressing full-length APC and APC-depleted cells, we provide the formal demonstration that APC is necessary for &bgr;-catenin phosphorylation, both for priming of the protein at residue serine 45 and for the subsequent phosphorylation of residues 33, 37 and 41. Truncated APC still sustains a surprisingly high phosphorylation activity, which requires the protein to bind to &bgr;-catenin through the APC 20-amino-acid (20AA) repeats, thus providing a biochemical explanation for the precise truncations found in cancer cells. We also show that most of the &bgr;-catenin phosphorylation activity is associated with a dense insoluble fraction. We finally examine the impact of full-length and truncated APC on &bgr;-catenin nuclear transport. We observe that &bgr;-catenin is transported much faster than previously thought. Although this fast translocation is largely insensitive to the presence of wild-type or truncated APC, the two forms appear to limit the pool of &bgr;-catenin that is available for transport, which could have an impact on &bgr;-catenin nuclear activities in normal and cancer cells.