Mixed lineage kinase LZK and antioxidant protein-1 activate NF-kappaB synergistically.

European journal of biochemistry / FEBS

PubMedID: 12492477

Masaki M, Ikeda A, Shiraki E, Oka S, Kawasaki T. Mixed lineage kinase LZK and antioxidant protein-1 activate NF-kappaB synergistically. Eur J Biochem. 2003;270(1):76-83.
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.