ACTIVATION OF THE JNK PATHWAY BY DISTANTLY RELATED PROTEIN-KINASES, MEKK AND MUK

JNK/SAPKs are identified as new members of the MAPK family; they phosp horylate c-Jun protein in response to several cellular stimuli includi ng ultraviolet irradiation, TNF and osmotic shock. We have identified a protein kinase, MUK, as an activator of the JNK-pathway, whose kinas e domain shows significant homology to MAPKKK-related proteins such as c-Raf and MEKK. The over-expression of MUK or MEK kinase (MEKK) in NI H3T3 or COS1 cells results in the activation of JNK1 and the accumulat ion of a hyper-phosphorylated form of c-Jun. While MEKK also activates the ERK pathway, MUK is a rather selective activator of the JNK pathw ay, On the other hand, c-Raf activates the JNK pathway only slightly d espite its remarkable ability to activate the ERK pathway. Even though we originally identified MUK as a MAPKKK-related protein kinase, a gr eater similarity to mixed lineage kinase (MLK) is found not only in th e catalytic domain but also in the 'leucine-zipper'-like motifs locate d at the C-terminal side of the catalytic domain. The structural diver gence between MUK and MEKK reveals the multiplicity of signaling pathw ays that activate JNK/SAPKs.