Recent evidence supports a neuroprotective role of Src homology 2-containing protein tyrosine phosphatase 2 (SHP-2) against ischemic brain injury. However, the molecular mechanisms of SHP-2 activation and those governing how SHP-2 exerts its function under oxidative stress conditions are not well understood. Recently we have reported that reactive oxygen species (ROS)-mediated oxidative stress promotes the phosphorylation of endogenous SHP-2 through lipid rafts, and that this phosphorylation strongly occurs in astrocytes, but not in microglia. To investigate the molecules involved in events leading to phosphorylation of SHP-2, raft proteins were analyzed using astrocytes and microglia. Interestingly, caveolin-1 and -2 were detected only in astrocytes but not in microglia, whereas flotillin-1 was expressed in both cell types. To examine whether the $H_2O_2$-dependent phosphorylation of SHP-2 is mediated by caveolin-1, we used specific small interfering RNA (siRNA) to downregulate caveolin- 1 expression. In the presence of caveolin-1 siRNA, the level of SHP-2 phosphorylation induced by $H_2O_2$ was significantly decreased, compared with in the presence of control siRNA. Overexpression of caveolin- 1 effectively increased $H_2O_2$-induced SHP-2 phosphorylation in microglia. Lastly, $H_2O_2$ induced extracellular signal-regulated kinase (ERK) activation in astrocytes through caveolin-1. Our results suggest that caveolin-1 is involved in astrocyte-specific intra-cellular responses linked to the SHP-2-mediated signaling cascade following ROS-induced oxidative stress.