MOLECULAR-CLONING AND CHARACTERIZATION OF A HUMAN PROTEIN-KINASE THATSPECIFICALLY ACTIVATES C-JUN N-TERMINAL KINASE

The c-Jun N-terminal kinases (JNKs), also called stress-activated prot ein kinases (SAPKs), belong to the mitogen-activated protein kinase (M APK) gene super-family. Like all the MAPKs, JNKs are activated through dual phosphorylation of a theronine residue and a tyrosine residue by a dual specificity kinase such as JNKK1/MKK4/SEK1. Here, we report th e molecular cloning and characterization of hJNKK2 alpha, a human homo log of the recently reported murine MKK7 alpha. hJNKK2 alpha belongs t o the MAPK kinase gene family and is expressed in many adult tissues. It is nearly identical to a recently reported human JNKK2 at the kinas e domain but with major differences in both amino- and carboxyl-termin al sequences, suggesting that hJNKK2 alpha may be an alternative splic ed form of this kinase. Expression of hJNKK2 alpha, but not its relate d kinases JNKK1/MKK4/SEK1, MEK1, MKK3, or MKK6, leads to strong activa tion of JNK in several cell lines. No activation of ERK or p38 kinases was observed with this kinase. An in-vitro kinase assay demonstrated that JNK1 activation by hJNKK2 alpha requires phosphorylation of the t heronine and tyrosine residues at positions 183 and 185 in JNK1. Furth ermore, hJNKK2 alpha activated the JNK-dependent signal transduction p athway in vivo by induction of c-Jun- and ATF2-mediated gene transcrip tion. In conclusion, we have cloned the human homolog of murine MKK7 a lpha, which may be an alternative spliced form of human JNKK2 involved in transducing specific upstream signals to regulate JNK activity in vivo. (C) 1998 Elsevier Science B.V. All rights reserved.