Stress-activated protein kinase/c-jun N-terminal kinase phosphorylates tau protein

J Neurochem. 1997 Apr;68(4):1736-44. doi: 10.1046/j.1471-4159.1997.68041736.x.

Abstract

A proportion of the neuronal microtubule-associated protein (MAP) tau is highly phosphorylated in foetal and adult brain, whereas the majority of tau in the neurofibrillary tangles of Alzheimer's patients is hyperphosphorylated; many of the phosphorylation sites are serines or threonines followed by prolines. Several kinases phosphorylate tau at such sites in vitro. We have now shown that purified recombinant stress-activated protein kinase/c-Jun N-terminal kinase, a proline-directed kinase of the MAP kinase extended family, phosphorylates recombinant tau in vitro on threonine and serine residues. Western blots using antibodies to phosphorylation-dependent tau epitopes demonstrated that phosphorylation occurs in both of the main phosphorylated regions of tau protein. Unlike glycogen synthase kinase-3, the c-Jun N-terminal kinase readily phosphorylates Thr205 and Ser422, which are more highly phosphorylated in Alzheimer tau than in foetal or adult tau. Glycogen synthase kinase-3 may preferentially phosphorylate the sites found physiologically, in foetal and to a smaller extent in adult tau, whereas stress-activated/c-Jun N-terminal kinase and/or other members of the extended MAP kinase family may be responsible for pathological proline-directed phosphorylations. Inflammatory processes in Alzheimer brain might therefore contribute directly to the pathological formation of the hyperphosphorylated tau found in neurofibrillary tangles.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibody Specificity
  • Blotting, Western
  • Brain Chemistry / physiology
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Epitopes / metabolism
  • Humans
  • JNK Mitogen-Activated Protein Kinases*
  • MAP Kinase Kinase 4
  • Mitogen-Activated Protein Kinase Kinases*
  • Phosphoproteins / analysis
  • Phosphoproteins / immunology
  • Phosphorylation
  • Protein Kinase C / metabolism*
  • Protein Kinases / metabolism*
  • Serine / metabolism
  • Stress, Physiological / metabolism*
  • Threonine / metabolism
  • tau Proteins / analysis
  • tau Proteins / immunology
  • tau Proteins / metabolism*

Substances

  • Epitopes
  • Phosphoproteins
  • tau Proteins
  • Threonine
  • Serine
  • Protein Kinases
  • Cyclic AMP-Dependent Protein Kinases
  • Protein Kinase C
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4
  • Mitogen-Activated Protein Kinase Kinases