Potentiation of GSK-3-catalyzed Alzheimer-like phosphorylation of human tau by cdk5

Mol Cell Biochem. 1997 Feb;167(1-2):99-105. doi: 10.1023/a:1006883924775.

Abstract

Tau protein from Alzheimer disease (AD) brain is hyperphosphorylated by both proline-dependent protein kinases (PDPKs) and non-PDPKs. It is presently unclear how PDPKs and non-PDPKs interact in tau hyperphosphorylation. Previously we have shown that non-PDPKs can positively modulate the activity of a PDPK (GSK-3) in tau phosphorylation (Singh et al. (1995) FEBS Lett. 358, 267-272). In this study we have investigated whether (A) non-PDPKs can also modulate the activity of the PDPK, cdk5, (B) a PDPK can modulate the activities of another PDPK, as well as non-PDPKs. We found that, like GSK-3, the activity of cdk5 is stimulated if tau were first prephosphorylated by any of several non-PDPKs (A-kinase, C-kinase, CK-1, CaM-kinase II). Prephosphorylation of tau by cdk5 stimulated both the rate and extent of a subsequent phosphorylation catalyzed by GSK-3. Under these conditions thr 231 phosphorylation was especially enhanced (9-fold). No significant stimulation of phosphorylation was observed when the order of these kinases was reversed (i.e. GSK-3 followed by cdk5). By contrast, prephosphorylation of tau by cdk5 served to inhibit subsequent phosphorylation catalyzed by C-kinase and CK-1, but not by A-kinase or CaM-kinase II. Our results suggest that in tau hyperphosphorylation in AD brain, cdk5-catalyzed phosphorylation may serve to upregulate the activity of GSK-3 and down-regulate the activities of C-kinase and CK-1.

Publication types

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

MeSH terms

  • Alzheimer Disease / metabolism*
  • Antibodies / metabolism
  • Binding Sites
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Casein Kinases
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Cyclin-Dependent Kinase 5
  • Cyclin-Dependent Kinases*
  • Epitopes
  • Glycogen Synthase Kinase 3
  • Humans
  • Phosphorylation
  • Protein Kinases / metabolism
  • Protein-Serine-Threonine Kinases / metabolism*
  • tau Proteins / immunology
  • tau Proteins / metabolism*

Substances

  • Antibodies
  • Epitopes
  • tau Proteins
  • Protein Kinases
  • calcium-dependent protein kinase
  • Casein Kinases
  • Cyclin-Dependent Kinase 5
  • Protein-Serine-Threonine Kinases
  • Cyclic AMP-Dependent Protein Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • CDK5 protein, human
  • Cyclin-Dependent Kinases
  • Glycogen Synthase Kinase 3