Axin cancer mutants form nanoaggregates to rewire the Wnt signaling network

Zeinab Anvarian, Hisashi Nojima, Eline C. Van Kappel, Tobias Madl, Maureen Spit, Martin Viertler, Ingrid Jordens, Low Teck Yew, Revina C. Van Scherpenzeel, Ineke Kuper, Klaus Richter, Albert J.R. Heck, Rolf Boelens, Jean Paul Vincent, Stefan G.D. Rüdiger, Madelon M. Maurice

Research output: Contribution to journalArticle

9 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)324-332
Number of pages9
JournalNature Structural and Molecular Biology
Volume23
Issue number4
DOIs
Publication statusPublished - 5 Apr 2016
Externally publishedYes

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Neoplasms
Axin Protein
Multiprotein Complexes
Missense Mutation
Point Mutation
Human Activities
Drosophila
Proteins
Growth

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Cite this

Anvarian, Z., Nojima, H., Van Kappel, E. C., Madl, T., Spit, M., Viertler, M., ... Maurice, M. M. (2016). Axin cancer mutants form nanoaggregates to rewire the Wnt signaling network. Nature Structural and Molecular Biology, 23(4), 324-332. https://doi.org/10.1038/nsmb.3191

Axin cancer mutants form nanoaggregates to rewire the Wnt signaling network. / Anvarian, Zeinab; Nojima, Hisashi; Van Kappel, Eline C.; Madl, Tobias; Spit, Maureen; Viertler, Martin; Jordens, Ingrid; Teck Yew, Low; Van Scherpenzeel, Revina C.; Kuper, Ineke; Richter, Klaus; Heck, Albert J.R.; Boelens, Rolf; Vincent, Jean Paul; Rüdiger, Stefan G.D.; Maurice, Madelon M.

In: Nature Structural and Molecular Biology, Vol. 23, No. 4, 05.04.2016, p. 324-332.

Research output: Contribution to journalArticle

Anvarian, Z, Nojima, H, Van Kappel, EC, Madl, T, Spit, M, Viertler, M, Jordens, I, Teck Yew, L, Van Scherpenzeel, RC, Kuper, I, Richter, K, Heck, AJR, Boelens, R, Vincent, JP, Rüdiger, SGD & Maurice, MM 2016, 'Axin cancer mutants form nanoaggregates to rewire the Wnt signaling network', Nature Structural and Molecular Biology, vol. 23, no. 4, pp. 324-332. https://doi.org/10.1038/nsmb.3191
Anvarian Z, Nojima H, Van Kappel EC, Madl T, Spit M, Viertler M et al. Axin cancer mutants form nanoaggregates to rewire the Wnt signaling network. Nature Structural and Molecular Biology. 2016 Apr 5;23(4):324-332. https://doi.org/10.1038/nsmb.3191
Anvarian, Zeinab ; Nojima, Hisashi ; Van Kappel, Eline C. ; Madl, Tobias ; Spit, Maureen ; Viertler, Martin ; Jordens, Ingrid ; Teck Yew, Low ; Van Scherpenzeel, Revina C. ; Kuper, Ineke ; Richter, Klaus ; Heck, Albert J.R. ; Boelens, Rolf ; Vincent, Jean Paul ; Rüdiger, Stefan G.D. ; Maurice, Madelon M. / Axin cancer mutants form nanoaggregates to rewire the Wnt signaling network. In: Nature Structural and Molecular Biology. 2016 ; Vol. 23, No. 4. pp. 324-332.
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