title: Self-association of the APC tumor suppressor is required for the assembly, stability, and activity of the Wnt signaling destruction complex.
abstract: The tumor suppressor adenomatous polyposis coli (APC) is an essential negative regulator of Wnt signaling through its activity in the destruction complex with Axin, GSK3β, and CK1 that targets β-catenin/Armadillo (β-cat/Arm) for proteosomal degradation. The destruction complex forms macromolecular particles we termed the destructosome. Whereas APC functions in the complex through its ability to bind both β-cat and Axin, we hypothesize that APC proteins play an additional role in destructosome assembly through self-association. Here we show that a novel N-terminal coil, the APC self-association domain (ASAD), found in vertebrate and invertebrate APCs, directly mediates self-association of Drosophila APC2 and plays an essential role in the assembly and stability of the destructosome that regulates β-cat degradation in Drosophila and human cells. Consistent with this, removal of the ASAD from the Drosophila embryo results in β-cat/Arm accumulation and aberrant Wnt pathway activation. These results suggest that APC proteins are required not only for the activity of the destructosome, but also for the assembly and stability of this macromolecular machine.
authors.affiliation: Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA 15213.
authors.forename: Ezgi
authors.initials: E
authors.lastname: Kunttas-Tatli
authors.affiliation: Department of Biology, Franklin and Marshall College, Lancaster, PA 17604.
authors.forename: David M
authors.initials: DM
authors.lastname: Roberts
authors.affiliation: Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA 15213 bmccartney@cmu.edu.
authors.forename: Brooke M
authors.initials: BM
authors.lastname: McCartney
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000737:chemistry / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D051186:Armadillo Domain Proteins / Q000235:genetics / Q000378:metabolism; D060466:Axin Protein / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology; D004330:Drosophila / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004625:Embryo, Nonmammalian / Q000166:cytology; D006801:Humans; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: C555337:APC protein, human; C467323:APC2 protein, Drosophila; C495305:ARM protein, Drosophila; D025601:Adenomatous Polyposis Coli Protein; D051186:Armadillo Domain Proteins; D060466:Axin Protein; C118000:Axn protein, Drosophila; D029721:Drosophila Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D051176:beta Catenin