Syndecan-2 expression increases serum-withdrawal-induced apoptosis, mediated by re-distribution of Fas into lipid rafts, in stably transfected Swiss 3T3 cells.

To examine the function of syndecan-2, one of the most abundant heparan sulfate proteoglycans in fibroblasts, we obtained stably transfected Swiss 3T3 clones. We examined the effects of stable syndecan-2 overexpression on programmed cell death, finding that syndecan-2 transfected cells were more sensitive to apoptosis induced by serum-withdrawal than control cells. In addition, overexpression of syndecan-2 correlates with increased membrane levels of the Fas/CD95 receptor, suggesting that the increased serum-withdrawal apoptosis observed in Swiss 3T3 cells might be Fas receptor-dependent. Differences in Fas membrane levels between both control and syndecan-2 transfected cells result from a redistribution of the Fas receptor. Our data clearly demonstrate that increased Fas levels are primarily related to lipid rafts and that this increase is a key factor in Fas/CD95-mediated apoptosis. Moreover, disruption of lipid rafts with methyl-beta-cyclodextrin or filipin significantly reduced apoptosis in response to serum withdrawal. The differences in Fas/CD95 membrane distribution could explain why syndecan-2 transfected cells have a higher susceptibility to serum-withdrawal-induced apoptosis.