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

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.

Nuclear accumulation of full-length and truncated adenomatous polyposis coli protein in tumor cells depends on proliferation

“…APC has also been suggested to serve as a chaperone that carries b-catenin out of the nucleus for cytoplasmic degradation (Henderson, 2000;Neufeld et al, 2000b). However, we found no colocalization of b-catenin and APC in the nucleus except in one of the investigated cell lines (SW480).…”

“…Nuclear APC is envisaged a regulatory role in gene expression by sequestering b-catenin and thereby counteracting b-catenin-mediated transactivation of target genes (Henderson, 2000;Neufeld et al, 2000b). APC has also been suggested to serve as a chaperone that carries b-catenin out of the nucleus for cytoplasmic degradation (Henderson, 2000;Neufeld et al, 2000b).…”

“…However, the functional role of APC in the nucleus is still almost unknown and previously reported observations are partly contradicting. For example, nuclear APC has been found to sequester b-catenin and promote its nuclear export (Henderson, 2000;Neufeld et al, 2000b;Rosin-Arbesfeld et al, 2000). On the other hand, b-catenin translocation between cytoplasm and nucleus can occur independently of APC (Fagotto et al, 1998;Eleftheriou et al, 2001;Wiechens and Fagotto, 2001).…”

β-Catenin Shows an Overlapping Sequence Requirement but Distinct Molecular Interactions for Its Bidirectional Passage through Nuclear Pores

“…On the other hand, different groups have proposed different mechanisms for the nuclear export of ␤-catenin. One is an involvement of exportin1 along with adenomatous polyposis coli (APC) protein (28,29), and the other is the Ran-independent receptor-free export (30). Because ␤-catenin binds to many different proteins in both the cytoplasm and the nucleus, and its binding partners differ in different cells or under different cellular conditions, different conclusions have been drawn, depending on the cellular system being studied.…”

Novel Double-negative Feedback Loop between Adenomatous Polyposis Coli and Musashi1 in Colon Epithelia

“…Wnt binding to its cognate receptor or APC loss each lead to ␤-catenin accumulation in the cytoplasm, translocation into the nucleus, and interaction with co-activator TCF/LEF-1, resulting in transcription of Wnt target genes. In addition, there is evidence that nuclear APC also brings the transcriptional repressor C-terminal binding protein to the TCF-␤-catenin complex (13), sequesters ␤-catenin from TCF/LEF-1 (14) and facilitates nuclear export of ␤-catenin (15)(16)(17). Approximately 80% of all colorectal cancers are associated with mutation of both APC alleles, resulting in APC truncation and loss of this tumor suppressor function (18).…”