Mixed lineage kinase LZK and antioxidant protein-1 activate NF-kappaB synergistically.
Leucine zipper-bearing kinase (LZK) is a novel member of the mixed lineage kinase (MLK) family [Sakuma, H., Ikeda, A., Oka, S., Kozutsumi, Y., Zanetta, J. P., and Kawasaki, T. (1997) J. Biol. Chem.272, 28622-28629]. We have previously shown that LZK activates the c-Jun-NH2 terminal kinase (JNK) pathway, but not the extracellular signal-related kinase (ERK) pathway, by acting as a mitogen-activated protein kinase kinase kinase (MAPKKK) [Ikeda, A., Hasegawa, K., Masaki, M., Moriguchi, T., Nishida, E., Kozutsumi, Y., Oka, S., and Kawasaki, T. (2001) J. Biochem.130, 773-781]. However, the mode of activation of LZK remains largely unknown. By means of a yeast two-hybrid screening system, we have identified a molecule localized to mitochondria, antioxidant protein-1 (AOP-1), that binds to LZK and which acts as a modulator of LZK activity. Recently, several MAPKKKs involved in the JNK pathway, such as MEKK1, TAK1 and MLK3, were shown, using over-expression assay systems, to activate a transcription factor, NF-kappaB, through activation of the IKK complex. Using similar assay systems, we demonstrated that LZK activated NF-kappaB-dependent transcription through IKK activation only weakly, but this was reproducible, and that AOP-1 enhanced the LZK-induced NF-kappaB activation. We also provided evidence that LZK was associated directly with the IKK complex through the kinase domain, and that AOP-1 was recruited to the IKK complex through the binding to LZK.
Masaki
Megumi
M
Department of Biological Chemistry and CREST (Core Research for Educational Science and Technology) Project, Japan Science and Technology Corporation, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
Ikeda
Atsushi
A
Shiraki
Eriko
E
Oka
Shogo
S
Kawasaki
Toshisuke
T
D000818:Animals; D002478:Cells, Cultured; D004789:Enzyme Activation; D006801:Humans; D051550:I-kappa B Kinase; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010544:Peroxidases; D061105:Peroxiredoxin III; D054464:Peroxiredoxins; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D020798:Two-Hybrid System Techniques
D016328:NF-kappa B; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; D010544:Peroxidases; C516115:PRDX3 protein, human; D061105:Peroxiredoxin III; D054464:Peroxiredoxins; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; C109162:MAP3K13 protein, human