title: Regulation of Wnt signaling by the tumor suppressor adenomatous polyposis coli does not require the ability to enter the nucleus or a particular cytoplasmic localization.
abstract: Wnt signaling plays key roles in development and disease. The tumor suppressor adenomatous polyposis coli (APC) is an essential negative regulator of Wnt signaling. Its best-characterized role is as part of the destruction complex, targeting the Wnt effector β-catenin (βcat) for phosphorylation and ultimate destruction, but several studies suggested APC also may act in the nucleus at promoters of Wnt-responsive genes or to shuttle βcat out for destruction. Even in its role in the destruction complex, APC's mechanism of action remains mysterious. We have suggested APC positions the destruction complex at the appropriate subcellular location, facilitating βcat destruction. In this study, we directly tested APC's proposed roles in the nucleus or in precisely localizing the destruction complex by generating a series of APC2 variants to which we added tags relocalizing otherwise wild-type APC to different cytoplasmic locations. We tested these for function in human colon cancer cells and Drosophila embryos. Strikingly, all rescue Wnt regulation and down-regulate Wnt target genes in colon cancer cells, and most restore Wnt regulation in Drosophila embryos null for both fly APCs. These data suggest that APC2 does not have to shuttle into the nucleus or localize to a particular subcellular location to regulate Wnt signaling.
authors.affiliation: Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3280, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Roberts
authors.forename: Mira I
authors.initials: MI
authors.lastname: Pronobis
authors.forename: John S
authors.initials: JS
authors.lastname: Poulton
authors.forename: Eric G
authors.initials: EG
authors.lastname: Kane
authors.forename: Mark
authors.initials: M
authors.lastname: Peifer
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D051186:Armadillo Domain Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000196:embryology / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000378:metabolism / Q000473:pathology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D019913:Nuclear Localization Signals / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051820:TCF Transcription Factors / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism
chemical_list: C495305:ARM protein, Drosophila; D051186:Armadillo Domain Proteins; D003598:Cytoskeletal Proteins; D029721:Drosophila Proteins; D005231:Fatty Acids, Unsaturated; D050505:Mutant Proteins; D019913:Nuclear Localization Signals; D051820:TCF Transcription Factors; D014157:Transcription Factors; C117846:adenomatous polyposis coli protein 2; D051176:beta Catenin; C038753:leptomycin B