APC‐mediated downregulation of β‐catenin activity involves nuclear sequestration and nuclear export

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Abstract
Mutational inactivation of adenomatous polyposis coli (APC) initiates most colon carcinomas. APC functions include targeting cytoplasmic β‐catenin, a Wnt pathway mediator, for proteolysis. Although APC shuttles between cytoplasm and nucleus, the role of nuclear APC protein, particularly with respect to nuclear β‐catenin levels and activity, remains unclear. Here, we demonstrate that APC lacking functional nuclear localization signals (NLSs) or nuclear export signals (NESs) does not effectively downregulate nuclear β‐catenin levels; neither does wild‐type APC when nuclear export is blocked. While APC bearing mutated NLSs could not downregulate β‐catenin‐mediated transcriptional activation, APC lacking NESs remained active. Consistent with the hypothesis that nuclear APC lacking NESs can inhibit β‐catenin function by sequestration, we show that endogenous APC and β‐catenin proteins interact within the nucleus. These data demonstrate that nuclear APC binding to β‐catenin, and then inducing its nuclear export, plays a critical role in the control of nuclear β‐catenin levels and activity.