title: Messing up disorder: how do missense mutations in the tumor suppressor protein APC lead to cancer?
abstract: Mutations in the adenomatous polyposis coli (APC) tumor suppressor gene strongly predispose to development of gastro-intestinal tumors. Central to the tumorigenic events in APC mutant cells is the uncontrolled stabilization and transcriptional activation of the protein β-catenin. Many questions remain as to how APC controls β-catenin degradation. Remarkably, the large C-terminal region of APC, which spans over 2000 amino acids and includes critical regions in downregulating β-catenin, is predicted to be natively unfolded. Here we discuss how this uncommonly large disordered region may help to coordinate the multiple cellular functions of APC. Recently, a significant number of germline and somatic missense mutations in the central region of APC were linked to tumorigenesis in the colon as well as extra-intestinal tissues. We classify and localize all currently known missense mutations in the APC structure. The molecular basis by which these mutations interfere with the function of APC remains unresolved. We propose several mechanisms by which cancer-related missense mutations in the large disordered domain of APC may interfere with tumor suppressor activity. Insight in the underlying molecular events will be invaluable in the development of novel strategies to counter dysregulated Wnt signaling by APC mutations in cancer.
authors.affiliation: Cellular Protein Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, Padualaan 8, 3584CH Utrecht, The Netherlands.
authors.forename: David P
authors.initials: DP
authors.lastname: Minde
authors.forename: Zeinab
authors.initials: Z
authors.lastname: Anvarian
authors.forename: Stefan Gd
authors.initials: SG
authors.lastname: Rüdiger
authors.forename: Madelon M
authors.initials: MM
authors.lastname: Maurice
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics / Q000378:metabolism; D025601:Adenomatous Polyposis Coli Protein / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D017491:Genes, APC / Q000502:physiology*; D016147:Genes, Tumor Suppressor; D006801:Humans; D008954:Models, Biological; D020125:Mutation, Missense / Q000502:physiology*; D009369:Neoplasms / Q000235:genetics*; D017510:Protein Folding; D017434:Protein Structure, Tertiary / Q000502:physiology
chemical_list: D025601:Adenomatous Polyposis Coli Protein