Inactivation of glycogen synthase kinase-3 by protein kinase C delta: implications for regulation of tau phosphorylation.
The role of the phosphatidylinositol 3-kinase (PI3K) pathway in the hyperphosphorylation of tau was investigated in SY5Y human neuroblastoma cells. Wortmannin, an inhibitor of PI3K, induced transient (after 1 h) activation of glycogen synthase kinase-3 (GSK-3), hyperphosphorylation of tau and dose-dependent cytotoxicity. However, continuous inactivation of protein kinase (PK) B was observed from 1 to 24 h, suggesting the involvement of protein kinase(s) other than PKB in the phosphorylation and inactivation of GSK-3 after 3 h. In cells treated with wortmannin, PKC delta fragments were observed, and the PKC activity increased after 3 h, whereas treatment of cells with z-DEVD-fmk, an inhibitor of caspase 3, also inhibited fragmentation of PKC delta and induced continuous activation of GSK-3. It is suggested that fragmentation of PKC delta during the process of apoptosis results in the phosphorylation and inactivation of GSK-3 and consequently inhibition of the phosphorylation of tau.
Tsujio
I
I
Department of Clinical Neuroscience, Psychiatry, Osaka University, Graduate School of Medicine, D-3, 2-2 Yamadaoka, Suita, Osaka, Japan.
Tanaka
T
T
Kudo
T
T
Nishikawa
T
T
Shinozaki
K
K
Grundke-Iqbal
I
I
Iqbal
K
K
Takeda
M
M
D000544:Alzheimer Disease / Q000378:metabolism; D000730:Androstadienes / Q000494:pharmacology; D017209:Apoptosis; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053148:Caspase 3; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D006801:Humans; D007527:Isoenzymes / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011493:Protein Kinase C / Q000494:pharmacology*; D051745:Protein Kinase C-delta; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D000077191:Wortmannin; D016875:tau Proteins / Q000378:metabolism*
D000730:Androstadienes; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D009842:Oligopeptides; D000081082:Phosphoinositide-3 Kinase Inhibitors; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; D016875:tau Proteins; D038341:Glycogen Synthase Kinases; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; C505407:CASP3 protein, human; D053148:Caspase 3; D000077191:Wortmannin