title: A novel GSK3-regulated APC:Axin interaction regulates Wnt signaling by driving a catalytic cycle of efficient βcatenin destruction.
abstract: APC, a key negative regulator of Wnt signaling in development and oncogenesis, acts in the destruction complex with the scaffold Axin and the kinases GSK3 and CK1 to target βcatenin for destruction. Despite 20 years of research, APC's mechanistic function remains mysterious. We used FRAP, super-resolution microscopy, functional tests in mammalian cells and flies, and other approaches to define APC's mechanistic role in the active destruction complex when Wnt signaling is off. Our data suggest APC plays two roles: (1) APC promotes efficient Axin multimerization through one known and one novel APC:Axin interaction site, and (2) GSK3 acts through APC motifs R2 and B to regulate APC:Axin interactions, promoting high-throughput of βcatenin to destruction. We propose a new dynamic model of how the destruction complex regulates Wnt signaling and how this goes wrong in cancer, providing insights into how this multiprotein signaling complex is assembled and functions via multivalent interactions.
authors.affiliation: Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, United States.
authors.forename: Mira I
authors.initials: MI
authors.lastname: Pronobis
authors.affiliation: Cell Biology and Physiology Center, National Heart, Lung, and Blood Institute, Bethesda, United States.
authors.forename: Nasser M
authors.initials: NM
authors.lastname: Rusan
authors.affiliation: Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Peifer
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism*; D000818:Animals; D060466:Axin Protein / Q000378:metabolism*; D002460:Cell Line; D004330:Drosophila; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D006801:Humans; D008856:Microscopy, Fluorescence; D025941:Protein Interaction Mapping; D055503:Protein Multimerization; D059748:Proteolysis; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D060466:Axin Protein; D051176:beta Catenin; D038362:Glycogen Synthase Kinase 3
keywords: APC; Axin; D. melanogaster; Wnt signaling; beta-catenin; cell biology; human; human biology; medicine