title: Exosome release of β-catenin: a novel mechanism that antagonizes Wnt signaling.
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.
authors.affiliation: Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Arthit
authors.initials: A
authors.lastname: Chairoungdua
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Smith
authors.forename: Pierre
authors.initials: P
authors.lastname: Pochard
authors.forename: Michael
authors.initials: M
authors.lastname: Hull
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Caplan
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002460:Cell Line; D055354:Exosomes / Q000378:metabolism* / Q000648:ultrastructure; D055785:Gene Knockdown Techniques; D017930:Genes, Reporter / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051861:Kangai-1 Protein / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D021381:Protein Transport; D015398:Signal Transduction; D060245:Tetraspanin 29; D014162:Transfection; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; C497688:CD82 protein, human; C554869:CD9 protein, human; D015820:Cadherins; C554870:Cd9 protein, mouse; D051861:Kangai-1 Protein; D008562:Membrane Glycoproteins; D060245:Tetraspanin 29; D051153:Wnt Proteins; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D046988:Proteasome Endopeptidase Complex