Phosphorylation of thr(668) in the cytoplasmic domain of the Alzheimer's disease amyloid precursor protein by stress-activated protein kinase 1b (Jun N-terminal kinase-3)

J Neurochem. 2001 Jan;76(1):316-20. doi: 10.1046/j.1471-4159.2001.00102.x.

Abstract

Threonine(668) (thr(668)) within the carboxy-terminus of the Alzheimer's disease amyloid precursor protein (APP) is a known in vivo phosphorylation site. Phosphorylation of APPthr(668) is believed to regulate APP function and metabolism. Thr(668) precedes a proline, which suggests that it is targeted for phosphorylation by proline-directed kinase(s). We have investigated the ability of four major neuronally active proline-directed kinases, cyclin dependent protein kinase-5, glycogen synthase kinase-3 beta, p42 mitogen-activated protein kinase and stress-activated protein kinase-1b, to phosphorylate APPthr(668) and report here that SAPK1b induces robust phosphorylation of this site both in vitro and in vivo. This finding provides a molecular framework to link cellular stresses with APP metabolism in both normal and disease states.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism*
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Binding Sites / physiology
  • CHO Cells
  • COS Cells
  • Calcium-Calmodulin-Dependent Protein Kinases / genetics
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Cricetinae
  • Cyclin-Dependent Kinase 5
  • Cyclin-Dependent Kinases / genetics
  • Cyclin-Dependent Kinases / metabolism
  • Glycogen Synthase Kinase 3
  • Glycogen Synthase Kinases
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Mitogen-Activated Protein Kinase 1 / genetics
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 10
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism*
  • Neurofilament Proteins / metabolism
  • Phosphorylation
  • Protein Structure, Tertiary
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Threonine / metabolism
  • Transfection

Substances

  • Amyloid beta-Protein Precursor
  • Isoenzymes
  • Neurofilament Proteins
  • Recombinant Fusion Proteins
  • neurofilament protein H
  • Threonine
  • Mitogen-Activated Protein Kinase 10
  • Protein-Tyrosine Kinases
  • Glycogen Synthase Kinases
  • Cyclin-Dependent Kinase 5
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Cyclin-Dependent Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinases
  • Glycogen Synthase Kinase 3