Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 33, Issue 11, Pages 2252-2259Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00047-13
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Funding
- U.S. National Institutes of Health [P01 CA116676]
- Georgia Cancer Coalition
- Georgia Research Alliance
- PhRMA Foundation Predoctoral Fellowship in Pharmacology/Toxicology
- Grants-in-Aid for Scientific Research [25650061, 20229004] Funding Source: KAKEN
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Cellular processes are tightly controlled through well-coordinated signaling networks that respond to conflicting cues, such as reactive oxygen species (ROS), endoplasmic reticulum (ER) stress signals, and survival factors to ensure proper cell function. We report here a direct interaction between inhibitor of kappa B kinase (IKK) and apoptosis signal-regulating kinase 1 (ASK1), unveiling a critical node at the junction of survival, inflammation, and stress signaling networks. IKK can be activated by growth factor stimulation or tumor necrosis factor alpha engagement. IKK forms a complex with and phosphorylates ASK1 at a sensor site, Ser967, leading to the recruitment of 14-3-3, counteracts stress signal-triggered ASK1 activation, and suppresses ASK1-mediated functions. An inhibitory role of IKK in JNK signaling has been previously reported to depend on NF-kappa B-mediated gene expression. Our data suggest that IKK has a dual role: a transcription-dependent and a transcription-independent action in controlling the ASK1-JNK axis, coupling IKK to ROS and ER stress response. Direct phosphorylation of ASK1 by IKK also defines a novel IKK phosphorylation motif. Because of the intimate involvement of ASK1 in diverse diseases, the IKK/ASK1 interface offers a promising target for therapeutic development.
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