PrPc on the road: trafficking of the cellular prion protein.

The glycosylphosphatidylinositol (GPI)-anchored cellular prion protein (PrP^c) has a fundamental role in prion diseases. Intracellular trafficking of PrP^c is important in the generation of protease resistant PrP species but little is known of how endocytosis affects PrP^c function. Here, we discuss recent experiments that have illuminated how PrP^c is internalized and what are the possible destinations taken by the protein. Contrary to what would be expected for a GPI-anchored protein there is increasing evidence that clathrin-mediated endocytosis and classical endocytic organelles participate in PrP^c trafficking. Moreover, the N-terminal domain of PrP^c may be involved in sorting events that can direct the protein during its intracellular journey. Indeed, the concept that the GPI-anchor determines PrP^c trafficking has been challenged. Cellular signaling can be triggered or be regulated by PrP^c and we suggest that endocytosis of PrP^c may influence signaling in several ways. Definition of the processes that participate in PrP^c endocytosis and intracellular trafficking can have a major impact on our understanding of the mechanisms involved in PrP^c function and conversion to protease resistant conformations. [ABSTRACT FROM AUTHOR]