title: Integration of apoptosis signal-regulating kinase 1-mediated stress signaling with the Akt/protein kinase B-IκB kinase cascade.
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.
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Mary C
authors.initials: MC
authors.lastname: Puckett
authors.forename: Erinn H
authors.initials: EH
authors.lastname: Goldman
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Cockrell
authors.forename: Bei
authors.initials: B
authors.lastname: Huang
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Kasinski
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Du
authors.forename: Cun-Yu
authors.initials: CY
authors.lastname: Wang
authors.forename: Anning
authors.initials: A
authors.lastname: Lin
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ichijo
authors.forename: Fadlo
authors.initials: F
authors.lastname: Khuri
authors.forename: Haian
authors.initials: H
authors.lastname: Fu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D019556:COS Cells / Q000187:drug effects / Q000378:metabolism; D002522:Chlorocebus aethiops; D002867:Chromones / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D016501:Neurites / Q000502:physiology; D016716:PC12 Cells; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D002867:Chromones; D009025:Morpholines; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D012694:Serine; D006861:Hydrogen Peroxide; D051057:Proto-Oncogene Proteins c-akt; D051550:I-kappa B Kinase; D048848:MAP Kinase Kinase Kinase 5