Inactivation of glycogen synthase kinase-3 by protein kinase C delta: implications for regulation of tau phosphorylation

FEBS Lett. 2000 Mar 3;469(1):111-7. doi: 10.1016/s0014-5793(00)01234-5.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alzheimer Disease / metabolism
  • Androstadienes / pharmacology
  • Apoptosis
  • Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Caspase 3
  • Caspase Inhibitors
  • Enzyme Inhibitors / pharmacology
  • Glycogen Synthase Kinase 3
  • Glycogen Synthase Kinases
  • Humans
  • Isoenzymes / pharmacology*
  • Oligopeptides / pharmacology
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation
  • Protein Kinase C / pharmacology*
  • Protein Kinase C-delta
  • Signal Transduction / drug effects
  • Tumor Cells, Cultured
  • Wortmannin
  • tau Proteins / metabolism*

Substances

  • Androstadienes
  • Caspase Inhibitors
  • Enzyme Inhibitors
  • Isoenzymes
  • Oligopeptides
  • Phosphoinositide-3 Kinase Inhibitors
  • benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone
  • tau Proteins
  • Glycogen Synthase Kinases
  • PRKCD protein, human
  • Protein Kinase C
  • Protein Kinase C-delta
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Glycogen Synthase Kinase 3
  • CASP3 protein, human
  • Caspase 3
  • Wortmannin