Activation of apoptosis signal-regulating kinase 1 by reactive oxygen species through dephosphorylation at serine 967 and 14-3-3 dissociation.
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 (H(2)O(2)) would have significant therapeutic implications. Recent genetic studies have placed apoptosis signal-regulating kinase 1 (ASK1) in a pivotal position in transmitting H(2)O(2)-initiated signals. How ASK1 is activated by H(2)O(2), though, remains a subject of intense investigation. Here we report a mechanism by which H(2)O(2) induces ASK1 activation through dynamic control of its phosphorylation at serine 967. We found that treatment of COS7 cells with H(2)O(2) 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 ASK1-mediated activation of JNK and p38 pathways.
Goldman
Erinn H
EH
Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Chen
Lei
L
Fu
Haian
H
D048948:14-3-3 Proteins; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D002384:Catalysis; D004789:Enzyme Activation; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D018384:Oxidative Stress; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D017382:Reactive Oxygen Species; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D014446:Tyrosine 3-Monooxygenase / Q000737:chemistry*; D048051:p38 Mitogen-Activated Protein Kinases
D048948:14-3-3 Proteins; D017382:Reactive Oxygen Species; D012694:Serine; D006861:Hydrogen Peroxide; D014446:Tyrosine 3-Monooxygenase; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases; C482858:MAP3K5 protein, human; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases