MEKK1/MEKK4 are responsible for TRAIL-induced JNK/p38 phosphorylation

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Authors: Bo K Sun ; Joo-Hang Kim ; Hoan N. Nguyen ; Seeun Oh ; So Y. Kim ; Hye J. ; Hye J. Choi ; Yong J. Lee ; Jae J. Song

MeSH: 14-3-3 Proteins/metabolism ; Antibodies/pharmacology ; Cell Line, Tumor ; Enzyme Activation/drug effects ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism* ; MAP Kinase Kinase 4/antagonists & inhibitors ; MAP Kinase Kinase 4/genetics ; MAP Kinase Kinase Kinase 1/antagonists & inhibitors ; MAP Kinase Kinase Kinase 1/immunology ; MAP Kinase Kinase Kinase 1/metabolism ; MAP Kinase Kinase Kinase 1/physiology* ; MAP Kinase Kinase Kinase 4/antagonists & inhibitors ; MAP Kinase Kinase Kinase 4/immunology ; MAP Kinase Kinase Kinase 4/metabolism ; MAP Kinase Kinase Kinase 4/physiology* ; Phosphorylation/drug effects ; Protein Binding/drug effects ; Protein Binding/physiology ; RNA, Small Interfering/pharmacology ; TNF-Related Apoptosis-Inducing Ligand/pharmacology* ; p38 Mitogen-Activated Protein Kinases/metabolism*

Abstract: The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to activate mitogen-activated protein kinases (MAPKs) depending on caspase and mammalian sterile 20-like kinase 1 activations. However, the upstream molecule of MAPKs has not yet been identified. The mitogen-activated protein kinase kinase 1 (MEKK1) and the apoptosis signal-regulating kinase 1 (ASK1) are considered to be possible candidates for the action of MAPKKKs induced by TRAIL and the possibility of reactive oxygen species involvement has also been investigated. We found that MEKK1/MEKK4 as opposed to ASK1, are responsible for TRAIL-induced c-Jun NH2-terminal kinase (JNK) or p38 activation, and that their catalytic activity is repressed by the caspase-8 inhibitor, suggesting that the caspase-8 activation induced by TRAIL is indispensible for MEKK activation. The 14-3-3 θ was also shown to interact with and to dissociate from MEKK1 by TRAIL treatment, thus implicating the 14-3-3 protein as a negative regulator of MEKK1 activation. Taken together, we show herein that the upstream molecule of the TRAIL-induced MAPK activation is MEKK, as opposed to ASK1, via the mediation of its signal through JNK/p38 in a caspase-8-dependent manner.