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Open Access Gold as soon as Publ. Version/Full Text is submitted to ZB.
Axin cancer mutants form nanoaggregates to rewire the Wnt signaling network.
Nat. Struct. Mol. Biol. 23, 324-332 (2016)
Signaling cascades depend on scaffold proteins that regulate the assembly of multiprotein complexes. Missense mutations in scaffold proteins are frequent in human cancer, but their relevance and mode of action are poorly understood. Here we show that cancer point mutations in the scaffold protein Axin derail Wnt signaling and promote tumor growth in vivo through a gain-of-function mechanism. The effect is conserved for both the human and Drosophila proteins. Mutated Axin forms nonamyloid nanometer-scale aggregates decorated with disordered tentacles, which 'rewire' the Axin interactome. Importantly, the tumor-suppressor activity of both the human and Drosophila Axin cancer mutants is rescued by preventing aggregation of a single nonconserved segment. Our findings establish a new paradigm for misregulation of signaling in cancer and show that targeting aggregation-prone stretches in mutated scaffolds holds attractive potential for cancer treatment.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Beta-catenin; Tumor-suppressor; Missense Mutations; Colorectal-cancer; Scaffold Proteins; Complex; Brca1; P53; Aggregation; Drosophila
ISSN (print) / ISBN
1545-9993
e-ISSN
1545-9985
Quellenangaben
Volume: 23,
Issue: 4,
Pages: 324-332
Publisher
Nature Publishing Group
Publishing Place
New York, NY
Reviewing status
Peer reviewed
Institute(s)
Institute of Structural Biology (STB)