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. β-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-3β (GSK-3β) to attenuate the interaction between GSK-3β and β-catenin. Importantly, 14-3-3 and β-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 β-catenin is regulated by 14-3-3ζ through the formation of "oncosomes" that contain both the 14-3-3 and β-catenin proteins.
Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Shiri
S
Dovrat
Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Michal
M
Caspi
Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Alona
A
Zilberberg
Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Lital
L
Lahav
Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Anastasia
A
Firsow
Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Hila
H
Gur
Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: arina@post.tau.ac.il.
Rina
R
Rosin-Arbesfeld
D048948:14-3-3 Proteins / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D000072261:Dishevelled Proteins; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D009369:Neoplasms / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D021381:Protein Transport; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*
D048948:14-3-3 Proteins; D048868:Adaptor Proteins, Signal Transducing; C000606581:DVL2 protein, human; D000072261:Dishevelled Proteins; D010750:Phosphoproteins; D051153:Wnt Proteins; D051176:beta Catenin; D038362:Glycogen Synthase Kinase 3
14-3-3; Exosomes; Extracellular vesicles; Wnt signaling; β-catenin