Protein kinase A phosphorylation of the proteasome: a contribution to the alpha-secretase pathway in human cells.
The beta-amyloid precursor protein undergoes a physiological cleavage by alpha-secretase that leads to the release of a secreted C-terminally truncated fragment called APP alpha and likely concomitantly reduces the formation of the amyloidogenic A beta peptide. Here we demonstrate that APP alpha 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 alpha-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 APP alpha secretion in human cells.
Marambaud
P
P
IPMC du CNRS, UPR411, Valbonne, France.
Wilk
S
S
Checler
F
F
D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D002417:Cattle; D002460:Cell Line / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000166:cytology; D009097:Multienzyme Complexes / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex
D016564:Amyloid beta-Protein Precursor; D009097:Multienzyme Complexes; D010446:Peptide Fragments; D005576:Colforsin; D017868:Cyclic AMP-Dependent Protein Kinases; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D046988:Proteasome Endopeptidase Complex