APC-mediated downregulation of beta-catenin activity involves nuclear sequestration and nuclear export

Mutational inactivation of adenomatous polyposis coli (APC) initiates most colon carcinomas. APC functions include targeting cytoplasmic beta -catenin , a Wnt pathway mediator, for proteolysis. Although APC shuttles between cy toplasm and nucleus, the role of nuclear APC protein, particularly with res pect to nuclear beta -catenin levels and activity, remains unclear. Here, w e demonstrate that APC lacking functional nuclear localization signals (NLS s) or nuclear export signals (NESs) does not effectively downregulate nucle ar beta -catenin levels; neither does wild-type APC when nuclear export is blocked. While APC bearing mutated NLSs could not downregulate beta -cateni n-mediated transcriptional activation, APC lacking NESs remained active. Co nsistent with the hypothesis that nuclear APC lacking NESs can inhibit beta -catenin function by sequestration, we show that endogenous APC and beta - catenin proteins interact within the nucleus. These data demonstrate that n uclear APC binding to beta -catenin, and then inducing its nuclear export, plays a critical role in the control of nuclear beta -catenin levels and ac tivity.