Phosphorylation of microtubule-associated protein tau by stress-activated protein kinases in intact cells

FEBS Lett. 2002 Mar 27;515(1-3):151-4. doi: 10.1016/s0014-5793(02)02460-2.

Abstract

Tau is a microtubule-associated protein that is abnormally hyperphosphorylated in the filamentous lesions that define a number of neurodegenerative diseases collectively referred to as tauopathies. We previously showed that stress-activated protein (SAP) kinases phosphorylate tau protein at many of the hyperphosphorylated sites in vitro. Here we have developed a system to study the effects of five SAP kinases (SAPK1c/JNK1, SAPK2a/p38alpha, SAPK2b/p38beta, SAPK3/p38gamma and SAPK4/p38delta) on tau phosphorylation in intact cells. All kinases phosphorylated tau, albeit at different efficiencies. Tau was a good substrate for SAPK3/p38gamma and SAPK4/p38delta, a reasonable substrate for SAPK2b/p38beta and a relatively poor substrate for SAPK2a/p38alpha and SAPK1c/JNK1. These findings indicate that the aberrant activation of SAP kinases, especially SAPK3/p38gamma and SAPK4/p38delta, could play an important role in the abnormal hyperphosphorylation of tau that is an invariant feature of the tauopathies.

MeSH terms

  • Animals
  • COS Cells
  • Calcium-Calmodulin-Dependent Protein Kinases / genetics
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Immunoblotting
  • Kidney / cytology
  • Kidney / metabolism
  • MAP Kinase Kinase 6
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism*
  • Mitogen-Activated Protein Kinase 11
  • Mitogen-Activated Protein Kinase 12
  • Mitogen-Activated Protein Kinase 13
  • Mitogen-Activated Protein Kinase 8
  • Mitogen-Activated Protein Kinase Kinases / genetics
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism*
  • Phosphorylation
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Substrate Specificity
  • Transfection
  • p38 Mitogen-Activated Protein Kinases
  • tau Proteins / genetics
  • tau Proteins / metabolism

Substances

  • Microtubule-Associated Proteins
  • Protein Isoforms
  • tau Proteins
  • Mitogen-Activated Protein Kinase 12
  • Mitogen-Activated Protein Kinase 13
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinase 11
  • Mitogen-Activated Protein Kinase 8
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 6
  • Mitogen-Activated Protein Kinase Kinases