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J. Cell Biol. 190 (6): 1079-1091

Copyright © 2010 by the Rockefeller University Press.

Article

Exosome release of β-catenin: a novel mechanism that antagonizes Wnt signaling

Arthit Chairoungdua1,2, Danielle L. Smith1, Pierre Pochard1, Michael Hull1, , and Michael J. Caplan1

1 Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510
2 Department of Physiology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand

Correspondence to Michael J. Caplan: michael.caplan{at}yale.edu

Abstract: CD82 and CD9 are tetraspanin membrane proteins that can function as suppressors of tumor metastasis. Expression of CD9 and CD82 in transfected cells strongly suppresses β-catenin–mediated Wnt signaling activity and induces a significant decrease in β-catenin protein levels. Inhibition of Wnt/β-catenin signaling is independent of glycogen synthase kinase-3β and of the proteasome- and lysosome-mediated protein degradation pathways. CD82 and CD9 expression induces β-catenin export via exosomes, which is blocked by a sphingomyelinase inhibitor, GW4869. CD82 fails to induce exosome release of β-catenin in cells that express low levels of E-cadherin. Exosome release from dendritic cells generated from CD9 knockout mice is reduced compared with that from wild-type dendritic cells. These results suggest that CD82 and CD9 down-regulate the Wnt signaling pathway through the exosomal discharge of β-catenin. Thus, exosomal packaging and release of cytosolic proteins can modulate the activity of cellular signaling pathways.

Abbreviations: BMDC, bone marrow dendritic cell • ESCRT, endosomal sorting complex required for transport • GSK-3β, glycogen synthase kinase-3β • MVB, multivesicular body

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