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Nat Struct Mol Biol. 2016 Apr;23(4):324-32. doi: 10.1038/nsmb.3191. Epub 2016 Mar 14.

Axin cancer mutants form nanoaggregates to rewire the Wnt signaling network.

Author information

1
Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
2
The Francis Crick Institute, Mill Hill, London, UK.
3
NMR Spectroscopy Research Group, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, the Netherlands.
4
Institute of Structural Biology, Helmholtz Zentrum München, Neuherberg, Germany and Biomolecular NMR spectroscopy, Technische Universität München, Garching, Germany.
5
Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
6
Omics Center Graz, BioTechMed Graz, Graz, Austria.
7
Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.
8
The Netherlands Proteomics Center, Utrecht, the Netherlands.
9
Department of Chemistry, Technische Universität München, Garching, Germany.
10
Cellular Protein Chemistry, Bijvoet Centre for Biomolecular Research, Utrecht University, Utrecht, the Netherlands.

Abstract

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.

PMID:
26974125
DOI:
10.1038/nsmb.3191
[Indexed for MEDLINE]

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