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 phosphorylate c-Jun protein in response to several cellular stimuli including ultraviolet irradiation, TNF and osmotic shock. We have identified a protein kinase, MUK, as an activator of the JNK-pathway, whose kinase domain shows significant homology to MAPKKK-related proteins such as c-Raf and MEKK. The over-expression of MUK or MEK kinase (MEKK) in NIH3T3 or COS1 cells results in the activation of JNK1 and the accumulation of a hyper-phosphorylated form of c-Jun. While MEKK also activates the ERK pathway, MUK is a rather selective activator of the JNK pathway. On the other hand, c-Raf activates the JNK pathway only slightly despite its remarkable ability to activate the ERK pathway. Even though we originally identified MUK as a MAPKKK-related protein kinase, a greater similarity to mixed lineage kinase (MLK) is found not only in the catalytic domain but also in the 'leucine-zipper'-like motifs located at the C-terminal side of the catalytic domain. The structural divergence between MUK and MEKK reveals the multiplicity of signaling pathways that activate JNK/SAPKs.
Hirai
S
S
Department of Molecular Biology, Yokohama City University School of Medicine, Japan.
Izawa
M
M
Osada
S
S
Spyrou
G
G
Ohno
S
S
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002460:Cell Line; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D017931:DNA Primers; D018076:DNA, Complementary; D048031:JNK Mitogen-Activated Protein Kinases; D016350:Leucine Zippers; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases; D051379:Mice; D020928:Mitogen-Activated Protein Kinases; D008969:Molecular Sequence Data; D011494:Protein Kinases / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D051381:Rats; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014162:Transfection
D017931:DNA Primers; D018076:DNA, Complementary; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D011994:Recombinant Proteins; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases; C482578:Map3k1 protein, mouse; C090757:mitogen-activated protein kinase kinase kinase 12