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Published online 28 November 2005. doi:10.1083/jcb.200502141
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 171, Number 5, 785-797
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Article

RanBP3 enhances nuclear export of active ß-catenin independently of CRM1

Jolita Hendriksen1, Francois Fagotto2, Hella van der Velde1, Martijn van Schie3, Jasprien Noordermeer3, and Maarten Fornerod1

1 Department of Tumor Biology, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands
2 Department of Biology, McGill University, Montreal, Quebec, Canada H3A 2T5
3 Department of Molecular Cell Biology, Leiden University Medical Center, 2333 AL Leiden, Netherlands

Correspondence to Maarten Fornerod: m.fornerod{at}nki.nl

ß-Catenin is the nuclear effector of the Wnt signaling cascade. The mechanism by which nuclear activity of ß-catenin is regulated is not well defined. Therefore, we used the nuclear marker RanGTP to screen for novel nuclear ß-catenin binding proteins. We identified a cofactor of chromosome region maintenance 1 (CRM1)–mediated nuclear export, Ran binding protein 3 (RanBP3), as a novel ß-catenin–interacting protein that binds directly to ß-catenin in a RanGTP-stimulated manner. RanBP3 inhibits ß-catenin–mediated transcriptional activation in both Wnt1- and ß-catenin–stimulated human cells. In Xenopus laevis embryos, RanBP3 interferes with ß-catenin–induced dorsoventral axis formation. Furthermore, RanBP3 depletion stimulates the Wnt pathway in both human cells and Drosophila melanogaster embryos. In human cells, this is accompanied by an increase of dephosphorylated ß-catenin in the nucleus. Conversely, overexpression of RanBP3 leads to a shift of active ß-catenin toward the cytoplasm. Modulation of ß-catenin activity and localization by RanBP3 is independent of adenomatous polyposis coli protein and CRM1. We conclude that RanBP3 is a direct export enhancer for ß-catenin, independent of its role as a CRM1-associated nuclear export cofactor.

Abbreviations used in this paper: APC, adenomatous polyposis coli; ARM, armadillo; CRM1, chromosome region maintenance 1; DAI, dorsoanterior index; dsRNA, double-stranded RNA; FG, phenylalanine glycine; FOP, fake optimal promoter; GSK3ß, glycogen synthase kinase 3ß; HEK, human embryonic kidney; LEF, lymphocyte enhancer binding factor; LMB, leptomycin B; mRFP, monomeric red fluorescent protein; NES, nuclear export signal; RanBP3, Ran binding protein 3; RNAi, RNA interference; shRNA, short hairpin RNA; TCF, T cell factor; TOP, TCF optimal promoter; wt, wild-type.


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