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Oxidative stress has been indicated in a variety of pathological processes such as atherosclerosis, diabetes, and neurodegenerative diseases. Understanding how intracellular signaling pathways respond to oxidative insults such as hydrogen peroxide (H2O2) would have significant therapeutic implications. Recent genetic studies have placed apoptosis signal-regulating kinase 1 (ASK1) in a pivotal position in transmitting H2O2-initiated signals. How ASK1 is activated by H2O2, though, remains a subject of intense investigation. Here we report a mechanism by which H2O2 induces ASK1 activation through dynamic control of its phosphorylation at serine 967. We found that treatment of COS7 cells with H2O2 triggers dephosphorylation of Ser-967 through an okadaic acid-sensitive phosphatase, resulting in dissociation of the ASK1·14-3-3 complex with concomitant increase of ASK1 catalytic activity and ASKl-mediated activation of JNK and p38 pathways. [ABSTRACT FROM AUTHOR]