Axin cancer mutants form nanoaggregates to rewire the Wnt signaling network

作者：Anvarian Zeinab; Nojima Hisashi; van Kappel Eline C; Madl Tobias; Spit Maureen; Viertler Martin; Jordens Ingrid; Low Teck Y; van Scherpenzeel Revina C; Kuper Ineke; Richter Klaus; Heck Albert J R; Boelens Rolf; Vincent Jean Paul; Rudiger Stefan G D^*; Maurice Madelon M^*

来源：Nature Structural & Molecular Biology, 2016, 23(4): 324-332.

DOI：10.1038/nsmb.3191

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.

• 出版日期2016-4