The APC tumour suppressor has a nuclear export function

The adenomatous polpyposis coli (APC) protein is mutated in most colorectal tumours1. Nearly all APC mutations are truncations, and many of these terminate in the mutation cluster region located halfway through the protein2,3,4. In cancer cells expressing mutant APC, β-catenin is stabilized5,6 and translocates into the nucleus to act as a transcriptional co-activator of T-cell factor7. During normal development, APC also promotes the destabilization of β-catenin and Drosophila Armadillo8,9,10,11. It does so by binding to the Axin complex which earmarks β-catenin/Armadillo for degradation by the proteasome pathway12. APC has a regulatory role in this process13,14, which is poorly understood. Here we show that APC contains highly conserved nuclear export signals 3′ adjacent to the mutation cluster region that enable it to exit from the nucleus. This ability is lost in APC mutant cancer cells, and we provide evidence that β-catenin accumulates in the nucleus as a result. Thus, the ability of APC to exit from the nucleus appears to be critical for its tumour suppressor function.