Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Anvarian, Z; Nojima, H; van Kappel, EC; Madl, T; Spit, M; Viertler, M; Jordens, I; Low, TY; van Scherpenzeel, RC; Kuper, I; Richter, K; Heck, AJ; Boelens, R; Vincent, JP; Rüdiger, SG; Maurice, MM.
Axin cancer mutants form nanoaggregates to rewire the Wnt signaling network.
Nat Struct Mol Biol. 2016; 23(4):324-332
Doi: 10.1038/nsmb.3191
Web of Science
PubMed
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- Co-Autor*innen der Med Uni Graz
- Madl Tobias
- Viertler Martin
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- 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Amino Acid Sequence -
- Animals -
- Axin Protein - analysis
- Axin Protein - genetics
- Axin Protein - metabolism
- Axin Protein - ultrastructure
- Cell Line -
- Drosophila - chemistry
- Drosophila - genetics
- Drosophila - metabolism
- Drosophila - ultrastructure
- Drosophila Proteins - analysis
- Drosophila Proteins - genetics
- Drosophila Proteins - metabolism
- HEK293 Cells -
- Humans -
- Mice -
- Models, Molecular -
- Molecular Sequence Data -
- Mutation, Missense -
- Neoplasms - genetics
- Neoplasms - metabolism
- Neoplasms - pathology
- Point Mutation -
- Protein Aggregates -
- Protein Conformation -
- Protein Interaction Maps -
- Scattering, Small Angle -
- Sequence Alignment -
- Wnt Signaling Pathway -
- X-Ray Diffraction -