Protein Kinase A Phosphorylation of the Proteasome: A Contribution to the α-Secretase Pathway in Human Cells |
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Authors: | Philippe Marambaud Sherwin Wilk Frederic Checler |
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Affiliation: | IPMC du CNRS, UPR411, Valbonne, France;and; Mount Sinai School of Medicine, New York, New York, U.S.A. |
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Abstract: | Abstract: The β-amyloid precursor protein undergoes a physiological cleavage by α-secretase that leads to the release of a secreted C-terminally truncated fragment called APPα and likely concomitantly reduces the formation of the amyloidogenic Aβ peptide. Here we demonstrate that APPα secretion is increased by the protein kinase A (PKA) effectors 8-bromo cyclic AMP and forskolin in human embryonic kidney cells (HK293), and that this can be prevented by a proteasome inhibitor. Furthermore, we establish that PKA effectors but not protein kinase C agonists increase the chymotrypsin-like activity and phosphorylation state of the proteasome in vitro and in vivo in HK293 cells. Altogether, this report demonstrates that the α-secretase pathway is under the control of PKA in human cells and that the proteasome likely contributes, either directly or through yet unknown intermediates, to the PKA-stimulated APPα secretion in human cells. |
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Keywords: | Protein kinase A Proteasome β-Amyloid precursor protein APPα fragment α-Secretase Alzheimer's disease HK293 cells |
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