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

Authors
Park, SJ; Kim, HY; Kim, H; Park, SM; Joe, EH; Jou, I; Choi, YH
Citation
Free radical biology & medicine, 46(12):1694-1702, 2009
Journal Title
Free radical biology & medicine
ISSN
0891-58491873-4596
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 (H(2)O(2)) triggered SHP-2 phosphorylation in a time- and dose-dependent manner and led to its translocation into lipid rafts. H(2)O(2)-mediated SHP-2 phosphorylation and translocation were inhibited by filipin III and methyl-beta-cyclodextrin (MCD), lipid-raft-disrupting agents. In the presence of H(2)O(2), SHP-2 formed a complex with STAT-3 and reduced the steady-state STAT-3 phosphorylation level. Interestingly, the effect of H(2)O(2) on SHP-2 phosphorylation was cell-type specific. Remarkably, SHP-2 phosphorylation was induced strongly by H(2)O(2) 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.
MeSH terms
AnimalsAstrocytes/metabolism*Cells, CulturedDose-Response Relationship, DrugEnzyme Inhibitors/pharmacologyFilipin/pharmacologyFree Radical Scavengers/pharmacologyHydrogen Peroxide/pharmacologyMembrane Microdomains/metabolism*Oxidative Stress/physiology*PhosphorylationProtein Tyrosine Phosphatase, Non-Receptor Type 11/antagonists & inhibitorsProtein Tyrosine Phosphatase, Non-Receptor Type 11/metabolism*RatsRats, Sprague-DawleyReactive Oxygen Species/metabolismSTAT3 Transcription Factor/metabolismSignal Transduction/physiologyTime Factorsbeta-Cyclodextrins/pharmacology
DOI
10.1016/j.freeradbiomed.2009.03.026
PMID
19348936
Appears in Collections:
Journal Papers > Research Organization > Chronic Inflammatory Disease Research Center
Journal Papers > School of Medicine / Graduate School of Medicine > Pharmacology
AJOU Authors
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