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Axin cancer mutants form nanoaggregates to rewire the Wnt signaling network

2016; Nature Portfolio; Volume: 23; Issue: 4 Linguagem: Inglês

10.1038/nsmb.3191

1545-9993

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

Hippo pathway signaling and YAP/TAZ

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.