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

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 ß-catenin-mediated Wnt signaling activity and induces a significant decrease in ß-catenin protein levels. Inhibition of Wnt/ß-catenin signaling is independent of glycogen synthase kinase-3ß and of the proteasome- and lysosome-mediated protein degradation pathways. CD82 and CD9 expression induces ß-catenin export via exosomes, which is blocked by a sphingomyelinase inhibitor, GW4869. CD82 fails to induce exosome release of ß-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 ß-catenin. Thus, exosomal packaging and release of cytosolic proteins can modulate the activity of cellular signaling pathways.