Activation of apoptosis signal-regulating kinase 1 by reactive oxygen species through dephosphorylation at serine 967 and 14-3-3 dissociation.

Haian Fu,Lei Chen,Erinn H. Goldman

doi:10.1074/jbc.m311129200

Abstract

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.

Highlights

Reactive oxygen species (ROS)1 produced through a variety of cellular processes or derived from exogenous sources play important roles in the regulation of normal physiology, including cell proliferation, survival, senescence, and apoptotic cell death [1]
apoptosis signal-regulating kinase 1 (ASK1) plays an essential role in mediating H2O2-induced activation of the JNK/p38 pathways and subsequent apoptosis [2, 5, 6]
H2O2 action appears to require the stimulation of an okadaic acidsensitive phosphatase(s) that catalyzes the dephosphorylation of ASK1 at Ser-967, which leads to dissociation of an ASK1 inhibitor, 14-3-3, and activation of ASK1 and its downstream effector kinases

Summary

Introduction

Reactive oxygen species (ROS) produced through a variety of cellular processes or derived from exogenous sources play important roles in the regulation of normal physiology, including cell proliferation, survival, senescence, and apoptotic cell death [1]. Mouse embryonic fibroblast cells from ASK1Ϫ/Ϫ mice are resistant to oxidant- and tumor necrosis factor-␣-induced apoptosis and fail to maintain sustained levels of JNK and p38 kinase activity upon treatment with H2O2 or tumor necrosis factor-␣ [12]. These lines of evidence suggest that ASK1 is a key player in apoptotic signaling, and in particular, ASK1 may function as a pivotal mediator of H2O2-induced stress response. Because of its important role in cell death signaling, the activity of ASK1 is tightly regulated by multiple mechanisms, including phosphorylation, oligomerization, and protein-protein interactions. The inhibitory effect of bound thioredoxin on ASK1, may be redox-independent, as shown in an endothelial cell system [23]

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