RanBP3 enhances nuclear export of active (beta)-catenin independently of CRM1.
beta-Catenin is the nuclear effector of the Wnt signaling cascade. The mechanism by which nuclear activity of beta-catenin is regulated is not well defined. Therefore, we used the nuclear marker RanGTP to screen for novel nuclear beta-catenin binding proteins. We identified a cofactor of chromosome region maintenance 1 (CRM1)-mediated nuclear export, Ran binding protein 3 (RanBP3), as a novel beta-catenin-interacting protein that binds directly to beta-catenin in a RanGTP-stimulated manner. RanBP3 inhibits beta-catenin-mediated transcriptional activation in both Wnt1- and beta-catenin-stimulated human cells. In Xenopus laevis embryos, RanBP3 interferes with beta-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 beta-catenin in the nucleus. Conversely, overexpression of RanBP3 leads to a shift of active beta-catenin toward the cytoplasm. Modulation of beta-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 beta-catenin, independent of its role as a CRM1-associated nuclear export cofactor.
Hendriksen
Jolita
J
Department of Tumor Biology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
Fagotto
Francois
F
van der Velde
Hella
H
van Schie
Martijn
M
Noordermeer
Jasprien
J
Fornerod
Maarten
M
D021581:Active Transport, Cell Nucleus; D025601:Adenomatous Polyposis Coli Protein / Q000502:physiology; D000818:Animals; D019521:Body Patterning; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D029721:Drosophila Proteins; D004331:Drosophila melanogaster; D004625:Embryo, Nonmammalian / Q000196:embryology / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology; D006801:Humans; D028884:Karyopherins / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D029543:Nucleocytoplasmic Transport Proteins / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology; D015533:Transcriptional Activation; D051153:Wnt Proteins / Q000502:physiology*; D014982:Xenopus laevis; D051176:beta Catenin / Q000378:metabolism*; D000097606:Exportin 1 Protein
D025601:Adenomatous Polyposis Coli Protein; D029721:Drosophila Proteins; D018398:Homeodomain Proteins; D028884:Karyopherins; D009687:Nuclear Proteins; D029543:Nucleocytoplasmic Transport Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; D000097606:Exportin 1 Protein; C063459:En protein, Drosophila; C112820:RANBP3 protein, human