title: Axin cancer mutants form nanoaggregates to rewire the Wnt signaling network.
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.
authors.affiliation: Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Zeinab
authors.initials: Z
authors.lastname: Anvarian
authors.affiliation: The Francis Crick Institute, Mill Hill, London, UK.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Nojima
authors.affiliation: Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Eline C
authors.initials: EC
authors.lastname: van Kappel
authors.affiliation: NMR Spectroscopy Research Group, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, the Netherlands.|Institute of Structural Biology, Helmholtz Zentrum München, Neuherberg, Germany and Biomolecular NMR spectroscopy, Technische Universität München, Garching, Germany.|Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.|Omics Center Graz, BioTechMed Graz, Graz, Austria.
authors.forename: Tobias
authors.initials: T
authors.lastname: Madl
authors.affiliation: Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Maureen
authors.initials: M
authors.lastname: Spit
authors.affiliation: Institute of Structural Biology, Helmholtz Zentrum München, Neuherberg, Germany and Biomolecular NMR spectroscopy, Technische Universität München, Garching, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Viertler
authors.affiliation: Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Jordens
authors.affiliation: Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.|The Netherlands Proteomics Center, Utrecht, the Netherlands.
authors.forename: Teck Y
authors.identifier: http://orcid.org/0000-0001-7878-7534
authors.initials: TY
authors.lastname: Low
authors.affiliation: Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Revina C
authors.initials: RC
authors.lastname: van Scherpenzeel
authors.affiliation: Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Ineke
authors.initials: I
authors.lastname: Kuper
authors.affiliation: Department of Chemistry, Technische Universität München, Garching, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Richter
authors.affiliation: Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.|The Netherlands Proteomics Center, Utrecht, the Netherlands.
authors.forename: Albert J R
authors.identifier: http://orcid.org/0000-0002-2405-4404
authors.initials: AJ
authors.lastname: Heck
authors.affiliation: NMR Spectroscopy Research Group, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, the Netherlands.
authors.forename: Rolf
authors.identifier: http://orcid.org/0000-0002-6939-8913
authors.initials: R
authors.lastname: Boelens
authors.affiliation: The Francis Crick Institute, Mill Hill, London, UK.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Vincent
authors.affiliation: Cellular Protein Chemistry, Bijvoet Centre for Biomolecular Research, Utrecht University, Utrecht, the Netherlands.
authors.forename: Stefan G D
authors.identifier: http://orcid.org/0000-0002-1807-2972
authors.initials: SG
authors.lastname: Rüdiger
authors.affiliation: Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Madelon M
authors.initials: MM
authors.lastname: Maurice
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D060466:Axin Protein / Q000032:analysis / Q000235:genetics* / Q000378:metabolism* / Q000648:ultrastructure; D002460:Cell Line; D004330:Drosophila / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D029721:Drosophila Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017354:Point Mutation; D066329:Protein Aggregates; D011487:Protein Conformation; D060066:Protein Interaction Maps; D053838:Scattering, Small Angle; D016415:Sequence Alignment; D060449:Wnt Signaling Pathway; D014961:X-Ray Diffraction
chemical_list: D060466:Axin Protein; D029721:Drosophila Proteins; D066329:Protein Aggregates