Journal
CELL RESEARCH
Volume 19, Issue 9, Pages 1062-1078Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/cr.2009.86
Keywords
Prion; copper; endoproteolytic cleavage; signal transduction; lipid raft
Categories
Funding
- NHMRC Program [400202, 400183, 454546, 400229]
- University of Melbourne CR Roper Fellowship
- NH&MRC Career Development Award [251745]
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The copper-binding, membrane-anchored, cellular prion protein (PrPC) has two constitutive cleavage sites producing distinct N- and C-terminal fragments (N1/C1 and N2/C2). Using RK13 cells expressing either human PrPC, mouse PrPC or mouse PrPC carrying the 3F4 epitope, this study explored the influence of the PrPC primary sequence on endoproteolytic cleavage and one putative PrPC function, MAP kinase signal transduction, in response to exogenous copper with or without a perturbed membrane environment. PrPC primary sequence, especially that around the N1/C1 cleavage site, appeared to influence basal levels of proteolysis at this location and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, with increased processing demonstrating an inverse relationship with basal ERK1/2 activation. Human PrPC showed increased N1/C1 cleavage in response to copper alone, accompanied by specific p38 and JNK/SAPK phosphorylation. Combined exposure to copper plus the cholesterol-sequestering antibiotic filipin resulted in a mouse PrPC-specific substantial increase in signal protein phosphorylation, accompanied by an increase in N1/C1 cleavage. Mouse PrPC harboring the human N1/C1 cleavage site assumed more human-like profiles basally and in response to copper and altered membrane environments. Our results demonstrate that the PrPC primary sequence around the N1/C1 cleavage site influences endoproteolytic processing at this location, which appears linked to MAP kinase signal transduction both basally and in response to copper. Further, the primary sequence appears to confer a mutual dependence of N1/C1 cleavage and membrane integrity on the fidelity of PrPC-related signal transduction in response to exogenous stimuli.
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