Editors' ChoiceCell Biology

Exit by Exosome

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Science Signaling  28 Sep 2010:
Vol. 3, Issue 141, pp. ec294
DOI: 10.1126/scisignal.3141ec294

Tetraspanins are transmembrane proteins that show decreased abundance in various tumors. In contrast, increased abundance of β-catenin is associated with colon cancer. Basal phosphorylation by glycogen synthase 3β (GSK-3β) targets β-catenin for proteosomal degradation; signals that prevent GSK-3β phosphorylation enable the nuclear translocation of stabilized β-catenin and initiation of gene transcription. Previous microarray analysis suggested that the tetraspanin CD9 may inhibit Wnt signaling, leading Chairoungdua et al. to investigate a possible link. In cells expressing β-catenin, cotransfection of the tetraspanins CD9 or CD82, but not CD63, decreased the cytoplasmic and nuclear abundance of β-catenin and the activity of a β-catenin transcriptional reporter. The decrease in β-catenin abundance did not occur through degradation by proteasomal or lysosomal pathways and did not require GSK-3β. Instead, the localization of β-catenin changed from nuclear (when a control plasmid or CD63 was cotransfected) to punctate and membrane-associated (when CD9 or CD82 was cotransfected). Electron microscopy revealed that β-catenin was released in exosomes. Besides coexpression of CD9 and CD82, exosomal release of β-catenin required E-cadherin, and CD82 coimmunoprecipitated with β-catenin and E-cadherin in transfected cells. Bone marrow–derived dendritic cells from Cd9–/– knockout mice released fewer exosomes than those from wild-type mice, suggesting a functional role for CD9 in exosome formation. Thus, CD9 and CD82 antagonize β-catenin–dependent signaling by promoting the extracellular release of β-catenin in exosomes.

A. Chairoungdua, D. L. Smith, P. Pochard, M. Hull, M. J. Caplan, Exosome release of β-catenin: A novel mechanism that antagonizes Wnt signaling. J. Cell Biol. 190, 1079–1091 (2010). [Abstract] [Full Text]

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