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Abstract
Reactive oxygen species (ROS) regulate diverse cellular functions by triggering signal transduction events, such as Src and mitogen-activated protein (MAP) kinases. Here, we report the role of caveolin-1 and Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP-2) in H2O2-induced signaling pathway in brain astrocytes. H2O2-mediated oxidative stress induced phosphorylation of caveolin-1 and association between p-caveolin-1 and SHP-2. SHP-2 specifically bound to wild-type caveolin-1 similarly to c-Src tyrosine kinase (CSK), but not to phosphorylation-deficient mutant of caveolin-1 (Y14A), and interfered with complex formation between caveolin-1 and CSK. In the presence of CSK siRNA, binding between caveolin-1 and SHP-2 was enhanced by H2O2 treatment, which led to reduced Src phosphorylation at tyrosine (Tyr) 530 and enhanced Src phosphorylation at Tyr 419. In contrast, siRNA targeting of SHP-2 facilitated H2O2-mediated interaction between caveolin-1 and CSK and enhanced Src phosphorylation at Tyr 530, leading to subsequent decrease in Src downstream signaling, such as focal adhesion kinase (FAK) and extracellular signal-related kinase (ERK). Our results collectively indicate that SHP-2 alters Src kinase activity by interfering with the complex formation between CSK and phosphotyrosine caveolin-1 in the presence of H2O2, thus functions as a positive regulator in Src signaling under oxidative stress in brain astrocytes.
Highlights
Reactive oxygen species (ROS), such as hydrogen peroxide (H2O2), superoxide (O22), and hydroxyl radicals (OH?), are wellknown regulatory signal molecules in the brain [1,2]
SHP-2 interacted with WT caveolin1, but not mutant caveolin-1, and only in the presence of H2O2. These results indicate that SHP-2 forms a complex with caveolin-1 in response to H2O2 in brain astrocytes and that H2O2-induced caveolin-1 and SHP-2 complex formation is dependent on the Tyr 14 residue of caveolin-1
We have investigated the molecular mechanism for the positive role of SHP-2 in regulating Src activity in response to H2O2-mediated oxidative stress in brain astrocytes
Summary
Reactive oxygen species (ROS), such as hydrogen peroxide (H2O2), superoxide (O22), and hydroxyl radicals (OH?), are wellknown regulatory signal molecules in the brain [1,2]. Since auto-oxidation of neurotransmitters and secretion of excitotoxic glutamate continuously occur, significant amounts of ROS are produced in the brain compared to in other organs. Due to the anatomic structure of brain cells, the extended axonal morphology, and the nonreplicating nature of neurons, the brain is more vulnerable to free radical attacks than other organs [7]. How brain cells survive the continuous high ROS and oxidative stress-vulnerable environment, and whether the brain has specific defense mechanisms against ROS or oxygen species are poorly understood
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