β-Catenin gets an honorable discharge

In Focus • THE JOURNAL OF CELL BIOLOGY ␤-Catenin gets an honorable discharge B eta-catenin binds E-cadherin to facilitate the formation of inter-cellular adhesions, but it's also a central component of the Wnt signaling pathway that controls cell proliferation and differentiation (1). Activation of the Wnt pathway stabilizes ␤-catenin, enabling it to translocate into the nucleus and pair up with transcription factors to induce target gene expression. In the absence of a Wnt signal, ␤-catenin's activity is kept in check by its sequestration at cell junctions and by the kinase GSK-3␤, which phos-phorylates the protein to trigger its ubiquit-ination and degradation by the proteasome. Chairoungdua et al. reveal a new way in which cells restrain ␤-catenin and potentially suppress tumor metastasis: the protein can be ejected from cells in small vesicles called exosomes (2). Michael Caplan's group at Yale University uncovered this process after fi nd-ing that E-cadherin binds to CD82, a member of the tetraspanin family of transmembrane proteins, which are involved in a variety of different cellular processes including cell adhesion and signal transduction (3). Overexpressing CD82 or a related tetraspanin called CD9 suppressed Wnt signal-ing and reduced ␤-catenin protein levels. Surprisingly , this decrease did not involve GSK-3␤ or the proteasome. Nor did it involve protein degradation by lysosomes. " We were sort of stumped, " Caplan admits, " until we saw a talk that mentioned that tetraspanins like CD82 are associated with exosomes. " Exosomes are small vesicles that form inside endosomes by the inward budding of endosomal membranes. The vesicles are then secreted when the endosome fuses with the plasma membrane (4). Chair-oungdua et al. found that CD9 and CD82 boosted the release of exosomes containing ␤-catenin, thereby reducing cellular levels of the protein and inhibiting the Wnt pathway. Cells lacking CD9, on the other hand, produced fewer exosomes and showed higher Wnt signaling activity. " We think that these tetraspanins facilitate exosome biogenesis, " says Caplan. Tetraspanins associate with each other to form patches within cell membranes that, in concert with specific lipids, might induce vesicle budding into the endosomal lumen. ␤-Catenin could be targeted to these vesicles through the interaction of E-cadherin with tetraspa-nins. E-cadherin was also found in exosomes and CD82 didn't affect Wnt signaling when it was overexpressed in cells lacking the adhesion molecule. Caplan and colleagues now want to investigate whether this is how tetraspan-ins target ␤-catenin to exosomes. The …