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Updated: Jul 2, 2026
10:12
Protein Misfolding Cyclic Amplification of Prions
Published on: November 7, 2012
Isoform-specific contribution of protein kinase C to prion processing
Moustapha Alfa Cissé1, Krystel Louis, Uschi Braun
1Institut de Pharmacologie Moléculaire et Cellulaire du CNRS, UMR6097, UNSA, Equipe labellisée Fondation pour la Recherche Médicale, Sophia-Antipolis, Valbonne, France.
Molecular and Cellular Neurosciences
|August 30, 2008
Summary
Protein kinase C (PKC) isoforms alpha, delta, and epsilon activate ADAM17, increasing cellular prion protein (PrP(c)) cleavage and N1 fragment secretion. This pathway is crucial for muscarinic receptor-controlled PrP(c) processing.
Area of Science:
- Molecular and Cellular Biology
- Neuroscience
- Biochemistry
Background:
- Cellular prion protein (PrP(c)) undergoes physiological cleavage, releasing an N1 fragment.
- This cleavage is mediated by ADAM metalloproteinases and can be regulated by protein kinase C (PKC).
Purpose of the Study:
- To investigate the specific roles of different PKC isoforms in the regulated processing of PrP(c).
- To elucidate the mechanism by which PKC isoforms influence ADAM17 activity and PrP(c) cleavage.
Main Methods:
- Utilized HEK293 and rhabdomyosarcoma cells over-expressing various PKC isoforms (constitutively active and dominant-negative).
- Assessed N1 fragment secretion and ADAM17 activity using fluorimetric substrates.
- Investigated the phosphorylation status of ADAM17 and the effect of specific mutations (T735A) and ADAM17 deficiency.
Main Results:
- PKC isoforms alpha, delta, and epsilon, but not zeta, significantly increased N1 secretion and ADAM17 activity.
- Over-expression of active PKC isoforms led to ADAM17 phosphorylation at threonine residues, which was reversed by T735A mutation.
- PKCepsilon-dependent N1 production was abolished in ADAM17-deficient cells, confirming ADAM17's essential role.
Conclusions:
- Activation of PKC alpha, delta, and epsilon isoforms promotes PrP(c) cleavage and N1 secretion through phosphorylation and activation of ADAM17.
- This PKC-ADAM17 pathway is a key mechanism underlying M1/M3 muscarinic receptor-mediated control of PrP(c) processing.
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