Oxidative stress induces lipid-raft-mediated activation of Src homology 2 domain-containing protein-tyrosine phosphatase 2 in astrocytes

Soo Jung Park, Hee Young Kim, Hyunmi Kim, Sang Myun Park, Eun hye Joe, Ilo Jou, Youn Hee Choi

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

Several protein phosphatases are involved in neuroprotection in response to ischemic brain injury. Here, we report that reactive oxygen species (ROS)-mediated oxidative stress promotes phosphorylation of endogenous SHP-2 through lipid rafts in rat primary astrocytes. SHP-2 was transiently phosphorylated during hypoxia/reoxygenation, an effect abrogated by a ROS scavenger and an NADPH oxidase inhibitor. Additionally, exogenous treatment with hydrogen peroxide (H2O2) triggered SHP-2 phosphorylation in a time- and dose-dependent manner and led to its translocation into lipid rafts. H2O2-mediated SHP-2 phosphorylation and translocation were inhibited by filipin III and methyl-β-cyclodextrin (MCD), lipid-raft-disrupting agents. In the presence of H2O2, SHP-2 formed a complex with STAT-3 and reduced the steady-state STAT-3 phosphorylation level. Interestingly, the effect of H2O2 on SHP-2 phosphorylation was cell-type specific. Remarkably, SHP-2 phosphorylation was induced strongly by H2O2 in astrocytes, but barely detectable in microglia. Our results collectively indicate that SHP-2 is activated by ROS-mediated oxidative stress in astrocytes and functions as a component of the raft-mediated signaling pathway that acts through dephosphorylation and inactivation of other phosphotyrosine proteins, such as STAT-3.

Original languageEnglish
Pages (from-to)1694-1702
Number of pages9
JournalFree Radical Biology and Medicine
Volume46
Issue number12
DOIs
StatePublished - 15 Jun 2009

Keywords

  • Astrocyte
  • Free radicals
  • Hypoxia/reoxygenation
  • Microglia
  • Oxidative stress
  • Phosphorylation
  • Raft
  • Reactive oxygen species
  • SHP-2
  • STAT-3
  • Translocation

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