Nuclear export of human beta-catenin can occur independent of CRM1 and the adenomatous polyposis coli tumor suppressor.
beta-Catenin is a mediator of the Wnt-signaling pathway. In many cancers, beta-catenin is stabilized and accumulates in the nucleus where it associates with lymphoid-enhancing factor 1/ T-cell transcription factors to activate genes involved in cell transformation. Previously, we showed that adenomatous polyposis coli (APC) protein can regulate beta-catenin localization by nuclear export. In this study, we used in vitro transport assays to test whether cellular beta-catenin can exit the nucleus independent of APC and the CRM1 export receptor. In digitonin-permeabilized SW480 (APC(mut/mut)) tumor cells, nuclear beta-catenin decreased >60% in export reactions in the absence of exogenous factors. Under similar conditions, nuclear c-ABL was only exported after the addition of cytosolic extract, and the export was blocked by the CRM1-specific inhibitor, leptomycin B. The nuclear export of beta-catenin was not blocked by leptomycin B treatment, revealing a CRM1- and APC-independent pathway. The export of beta-catenin was sensitive to lower temperatures and the removal of ATP, indicating an active process. Ectopically expressed yellow fluorescent protein-beta-catenin also displayed CRM1-independent export. Conversely, the overexpression of the CRM1 transporter moderately stimulated export of nuclear beta-catenin, confirming that beta-catenin exits the nucleus by at least two distinct pathways. The shuttling ability of tumor cell beta-catenin has implications for its regulation and its role in transferring signals between the nucleus and plasma membrane.
Eleftheriou
A
A
Westmead Institute for Cancer Research, University of Sydney, Westmead Millennium Institute at Westmead Hospital, New South Wales 2145, Australia.
Yoshida
M
M
Henderson
B R
BR
D025601:Adenomatous Polyposis Coli Protein; D002352:Carrier Proteins / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D006801:Humans; D028884:Karyopherins; D021381:Protein Transport; D018160:Receptors, Cytoplasmic and Nuclear; D015398:Signal Transduction; D015534:Trans-Activators; D014407:Tumor Cells, Cultured; D051176:beta Catenin; D000097606:Exportin 1 Protein
D025601:Adenomatous Polyposis Coli Protein; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D028884:Karyopherins; D018160:Receptors, Cytoplasmic and Nuclear; D015534:Trans-Activators; D051176:beta Catenin; D000097606:Exportin 1 Protein; C495270:CTNNB1 protein, human