H₂O₂ activates the mitogen-activated protein kinase (MAPK) family, particularly ERK2, which plays a critical role in cell survival after oxidative stress. ERK2 is rapidly and transiently activated by H₂O₂, with a 10–20-fold increase in activity within 10 minutes, followed by rapid inactivation. H₂O₂ also moderately activates JNK and p38 pathways and increases the expression of MAPK-dependent genes like c-jun, c-fos, and MKP-1. Suramin pretreatment inhibits ERK2 activation, suggesting a role for growth factor receptors. ERK2 activation by H₂O₂ is blocked by N-acetyl-cysteine, o-phenanthroline, or mannitol, indicating that metal-catalyzed free radical formation mediates the signaling. Dominant negative Ras-N-17 expression in PC12 cells reduces ERK2 activation and increases sensitivity to H₂O₂ toxicity, while constitutive active MEK expression in NIH 3T3 cells increases resistance. These findings suggest that ERK signaling is crucial for cell survival following oxidant injury. The study highlights the role of ERK in mediating cellular responses to oxidative stress and shows that ERK activity is regulated by preexisting phosphatases. The results indicate that H₂O₂-induced ERK activation is mediated by free radicals and metal-catalyzed reactions, and that ERK signaling is essential for cell survival after oxidative stress. The study provides insights into the mechanisms of MAPK regulation by H₂O₂ and underscores the importance of ERK in cell survival following oxidant injury.H₂O₂ activates the mitogen-activated protein kinase (MAPK) family, particularly ERK2, which plays a critical role in cell survival after oxidative stress. ERK2 is rapidly and transiently activated by H₂O₂, with a 10–20-fold increase in activity within 10 minutes, followed by rapid inactivation. H₂O₂ also moderately activates JNK and p38 pathways and increases the expression of MAPK-dependent genes like c-jun, c-fos, and MKP-1. Suramin pretreatment inhibits ERK2 activation, suggesting a role for growth factor receptors. ERK2 activation by H₂O₂ is blocked by N-acetyl-cysteine, o-phenanthroline, or mannitol, indicating that metal-catalyzed free radical formation mediates the signaling. Dominant negative Ras-N-17 expression in PC12 cells reduces ERK2 activation and increases sensitivity to H₂O₂ toxicity, while constitutive active MEK expression in NIH 3T3 cells increases resistance. These findings suggest that ERK signaling is crucial for cell survival following oxidant injury. The study highlights the role of ERK in mediating cellular responses to oxidative stress and shows that ERK activity is regulated by preexisting phosphatases. The results indicate that H₂O₂-induced ERK activation is mediated by free radicals and metal-catalyzed reactions, and that ERK signaling is essential for cell survival after oxidative stress. The study provides insights into the mechanisms of MAPK regulation by H₂O₂ and underscores the importance of ERK in cell survival following oxidant injury.