Integration of Apoptosis Signal-Regulating Kinase 1-Mediated Stress Signaling with the Akt/Protein Kinase B-IκB Kinase Cascade

• Type of Material: Article
• Authors: Mary C. Puckett, Emory University; Erinn H. Goldman, Emory University; Lisa M. Cockrell, Emory University; Bei Huang, Emory University; Andrea L. Kasinski, Emory University; Yuhong Du, Emory University; Cun-Yu Wang, University of California at Los Angeles; Anning Lin, University of Chicago; Hidenori Ichijo, The University of Tokyo; Fadlo Khuri, Emory University; Haian Fu, Emory University
• Language: English
• Date: 2013-06
• Publisher: American Society for Microbiology
• Publication Version: Final Published Version
• Copyright Statement: © 2013, American Society for Microbiology. All Rights Reserved.
• Final Published Version (URL): http://mcb.asm.org/content/33/11/2252
• Title of Journal or Parent Work: Molecular and Cellular Biology
• Volume: 33
• Issue: 11
• Start Page: 2252
• End Page: 2259
• Grant/Funding Information: This study was supported in part by the U.S. National Institutes of Health grants P01 CA116676 (F.R.K. and H.F.), the Georgia Cancer Coalition (F.R.K. and H.F.), the Georgia Research Alliance (H.F.), and a PhRMA Foundation Predoctoral Fellowship in Pharmacology/Toxicology (M.C.P.).
• Research Categories: Biology, Molecular

Abstract

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 κB 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-κB-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.