title: MEKK1/MEKK4 are responsible for TRAIL-induced JNK/p38 phosphorylation.
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.
authors.affiliation: Institute for Cancer Research, Yonsei Cancer Center, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Bo K
authors.initials: BK
authors.lastname: Sun
authors.forename: Joo-Hang
authors.initials: JH
authors.lastname: Kim
authors.forename: Hoan N
authors.initials: HN
authors.lastname: Nguyen
authors.forename: Seeun
authors.initials: S
authors.lastname: Oh
authors.forename: So Y
authors.initials: SY
authors.lastname: Kim
authors.forename: Soojin
authors.initials: S
authors.lastname: Choi
authors.forename: Hye J
authors.initials: HJ
authors.lastname: Choi
authors.forename: Yong J
authors.initials: YJ
authors.lastname: Lee
authors.forename: Jae J
authors.initials: JJ
authors.lastname: Song
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D000906:Antibodies / Q000494:pharmacology; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000235:genetics; D048728:MAP Kinase Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D048768:MAP Kinase Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D048948:14-3-3 Proteins; D000906:Antibodies; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; D048768:MAP Kinase Kinase Kinase 4; D048670:MAP Kinase Kinase 4