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 hyperph osphorylation of tau was investigated in SY5Y human neuroblastoma cells. Wo rtmannin, an inhibitor of PI3K, induced transient (after 1 h) activation of glycogen synthase kinase-3 (GSK-3), hyperphosphorylation of 2 and dose-dep endent cytotoxicity. However, continuous inactivation of protein kinase (PK ) B was observed from 1 to 24 h, suggesting the involvement of protein kina se(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 d elta and induced continuous activation of GSK-3. It is suggested that fragm entation of PKC delta during the process of apoptosis results in the phosph orylation and inactivation of GSK-3 and consequently inhibition of the phos phorylation of tau. (C) 2000 Federation of European Biochemical Societies.