Modulation of signal transduction through the cellular prion protein is linked to its incorporation in lipid rafts

Because expressed at a significant level at the membrane of human T cells, we made the hypothesis that the cellular prion protein (PrP^c) could behave as a receptor, and be responsible for signal transduction. PrP^c engagement by specific antibodies was observed to induce an increase in cytosolic calcium concentration and led to enhanced activity of Src protein tyrosine kinases. Antibodies to CD4 and CD59 did not influence calcium fluxes or signaling. The effect was maximal after the formation of a network involving avidin and biotinylated antibody to PrP^c and was inhibited after raft disruption. PrP^c localization was not restricted to rafts in resting cells but engagement was a prerequisite for signaling induction, with concomitant PrP^c recruitment into rafts. These results suggest a role for PrP^c in signaling pathways, and show that lateral redistribution of the protein into rafts is important for subsequent signal transduction.Received 22 July 2004; received after revision 10 September 2004; accepted 7 October 2004