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

Abstract

g 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 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-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.

DKK3 expression in hepatocytes defines susceptibility to liver steatosis and obesity

“…Moreover, the interaction between IKK and ASK1 [46], as well as the regulation of IRS1 by IKKβ [47], have been suggested to play a role in this process. Thus, these diverse signaling pathways, including the IKKβ/NF-кB and IRS1/AKT pathways are interconnected.…”

Structural Basis for Small Molecule NDB (N-Benzyl-N-(3-(tert-butyl)-4-hydroxyphenyl)-2,6-dichloro-4-(dimethylamino) Benzamide) as a Selective Antagonist of Farnesoid X Receptor α (FXRα) in Stabilizing the Homodimerization of the Receptor

“…Assay-TR-FRET assay was performed according to the published approach (25). HEK293T cells were plated in a 6-well plate and cultured overnight in DMEM.…”

Pharmacological Inhibition of NOS Activates ASK1/JNK Pathway Augmenting Docetaxel-Mediated Apoptosis in Triple-Negative Breast Cancer

“…ASK1 activates c-Jun N-terminal kinase (JNK) in response to a variety of stress stimuli (21). ASK1 serves as a central signaling hub that mediates EnR stress response and apoptosis (22). Therefore, ASK1's activity is tightly regulated via phosphorylation sites (22).…”

“…ASK1 serves as a central signaling hub that mediates EnR stress response and apoptosis (22). Therefore, ASK1's activity is tightly regulated via phosphorylation sites (22). For instance, phosphorylation of Thr845 ASK1 is essential for ASK1 activation, which promotes apoptotic cell death (23).…”

“…Ser83 remains phosphorylated under low-stress conditions, keeping ASK1 inactive (24,25). Ser967 serves as a sensor that mediates the physical interaction of 14-3-3 with ASK1, which suppresses ASK1-mediated apoptosis (22,26). Because of this, ASK1 has been described as a mediator of the apoptotic cell death resulting from chemotherapy (27).…”