Tyrosine phosphorylation of HPK1 by activated Src promotes ischemic brain injury in rat hippocampal CA1 region

FEBS Lett. 2008 Jun 11;582(13):1894-900. doi: 10.1016/j.febslet.2008.05.009. Epub 2008 May 20.

Abstract

Hematopoietic progenitor kinase 1 (HPK1) is a hematopoietic cell-restricted member of the Ste20 serine/threonine kinase super family. We recently reported that HPK1 is involved in c-Jun NH2-terminal kinase (JNK) signaling pathway by sequential activation of MLK3-MKK7-JNK3 after cerebral ischemia. Here, we used 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo [3,4-d] pyrimidine (PP2) and MK801 to investigate the events upstream of HPK1 in ischemic brain injury. Immunoprecipitation and immunoblot results showed that PP2 and MK801 significantly decreased the activation of Src, HPK1, MLK3, JNK3 and c-Jun, respectively, during ischemia/reperfusion. Histology and TUNEL staining showed PP2 or MK801 protects against neuron death after brain ischemia. We speculate that this unique signaling pathway through the tyrosine phosphorylation of HPK1 promotes ischemic brain injury by activated Src via N-methyl-d-aspartate receptor and, ultimately, the activation of the MLK3-MKK7-JNK3 pathway after cerebral ischemia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Ischemia / drug therapy
  • Brain Ischemia / enzymology*
  • Brain Ischemia / pathology
  • Cytoprotection
  • Dizocilpine Maleate / pharmacology
  • Hippocampus / drug effects
  • Hippocampus / enzymology*
  • Hippocampus / pathology
  • MAP Kinase Kinase Kinases / antagonists & inhibitors
  • MAP Kinase Kinase Kinases / metabolism
  • Male
  • Mitogen-Activated Protein Kinase 10 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 10 / metabolism
  • Mitogen-Activated Protein Kinase Kinase Kinase 11
  • Neuroprotective Agents / pharmacology
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • Protein Serine-Threonine Kinases / metabolism*
  • Pyrimidines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Reperfusion Injury / enzymology
  • Reperfusion Injury / pathology
  • Signal Transduction
  • Tyrosine / metabolism*
  • src-Family Kinases / antagonists & inhibitors
  • src-Family Kinases / metabolism*

Substances

  • AG 1879
  • Neuroprotective Agents
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Tyrosine
  • Dizocilpine Maleate
  • Mitogen-Activated Protein Kinase 10
  • hematopoietic progenitor kinase 1
  • src-Family Kinases
  • Protein Serine-Threonine Kinases
  • MAP Kinase Kinase Kinases