Inactivation of glycogen synthase kinase-3 by protein kinase C delta: implications for regulation of tau phosphorylation |
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Authors: | Tsujio I Tanaka T Kudo T Nishikawa T Shinozaki K Grundke-Iqbal I Iqbal K Takeda M |
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Institution: | Department of Clinical Neuroscience, Psychiatry, Osaka University, Graduate School of Medicine, D-3, 2-2 Yamadaoka, Suita, Osaka, Japan. |
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Abstract: | 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. |
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