14-3-3 and β-catenin are secreted on extracellular vesicles to activate the oncogenic Wnt pathway

Aberrant activation of the canonical Wnt signal transduction pathway is involved in a large number of human diseases. beta-catenin, the key effector protein of the canonical Wnt pathway, functions in the nucleus with T-cell factor/lymphoid enhancer factor (TCF/LEF) to activate expression of Wnt target genes. Here we show that members of the 14-3-3 protein family bind disheveled-2 (Dvl-2) and glycogen synthase-3 beta (GSK-3 beta) to attenuate the interaction between GSK-3 beta and beta-catenin. Importantly, 14-3-3 and beta-catenin form bleb-like structures and are secreted via extracellular vesicles to induce Wnt signaling activity in target cells. Our data suggest a novel way of transducing the oncogenic Wnt signal in which beta-catenin is regulated by 14-3-3 zeta through the formation of oncosomes that contain both the 14-3-3 and beta-catenin proteins. (C) 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.