Parkin, Edward T. and Watt, Nicole T. and Turner, Anthony J. and Hooper, Nigel M. (2004) Dual Mechanisms for Shedding of the Cellular Prion Protein. Journal of Biological Chemistry, 279 (12). pp. 11170-11178. ISSN 1083-351XFull text not available from this repository.
The cellular prion protein (PrPC) is essential for the pathogenesis and transmission of prion diseases. Whereas the majority of PrPC is bound to the cell membrane via a glycosylphosphatidylinositol (GPI) anchor, a secreted form of the protein has been identified. Here we show that PrPC can be shed into the medium of human neuroblastoma SH-SY5Y cells by both protease- and phospholipase-mediated mechanisms. The constitutive shedding of PrPC was inhibited by a range of hydroxamate-based zinc metalloprotease inhibitors in a manner identical to the -secretase-mediated shedding of the amyloid precursor protein, indicating a proteolytic shedding mechanism. Like amyloid precursor protein, this zinc metalloprotease-mediated shedding of PrPC could be stimulated by phorbol myristate acetate and by copper ions. The lipid raft-disrupting agents filipin and methyl--cyclodextrin promoted the shedding of PrPC via a distinct mechanism that was not inhibited by hydroxamate-based inhibitors. Filipin-mediated shedding of PrPC is likely to occur via phospholipase cleavage of the GPI anchor, since a transmembrane polypeptide-anchored PrP construct was not shed in response to filipin treatment. Collectively, our data indicate that shedding of PrPC can occur via both secretase-like proteolytic cleavage of the protein and phospholipase cleavage of the GPI anchor moiety.
|Journal or Publication Title:||Journal of Biological Chemistry|
|Subjects:||Q Science > QH Natural history > QH301 Biology|
|Departments:||Faculty of Health and Medicine > Biomedical & Life Sciences|
|Deposited By:||Dr Edward Parkin|
|Deposited On:||11 Jun 2008 11:04|
|Last Modified:||25 Mar 2017 02:53|
Actions (login required)