Cloning and characterization of MEK6, a novel member of the mitogen-activated protein kinase kinase cascade.
Mitogen-activated protein kinases are members of a conserved cascade of kinases involved in many signal transduction pathways. They stimulate phosphorylation of transcription factors in response to extracellular signals such as growth factors, cytokines, ultraviolet light, and stress-inducing agents. A novel mitogen-activated protein kinase kinase, MEK6, was cloned and characterized. The complete MEK6 cDNA was isolated by polymerase chain reaction. It encodes a 334-amino acid protein with 82% identity to MKK3. MEK6 is highly expressed in skeletal muscle like many other members of this family, but in contrast to MKK3 its expression in leukocytes is very low. MEK6 is a member of the p38 kinase cascade and efficiently phosphorylates p38 but not c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) family members in direct kinase assays. Coupled kinase assays demonstrated that MEK6 induces phosphorylation of ATF2 by p38 but does not phosphorylate ATF2 directly. MEK6 is strongly activated by UV, anisomycin, and osmotic shock but not by phorbol esters, nerve growth factor, and epidermal growth factor. This separates MEK6 from the ERK subgroup of protein kinases. MEK6 is only a poor substrate for MEKK, a mitogen-activated protein kinase kinase kinase that efficiently phosphorylates the related family member JNKK.
Stein
B
B
Signal Pharmaceuticals Inc., San Diego, California 92121, USA. bstein@signalpharm.com
Brady
H
H
Yang
M X
MX
Young
D B
DB
Barbosa
M S
MS
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000096:biosynthesis / Q000378:metabolism*; D002460:Cell Line; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D017931:DNA Primers; D004307:Dose-Response Relationship, Radiation; D004790:Enzyme Induction / Q000528:radiation effects; D015723:Gene Library; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D048669:MAP Kinase Kinase 6; D020929:Mitogen-Activated Protein Kinase Kinases; D008969:Molecular Sequence Data; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D011494:Protein Kinases / Q000096:biosynthesis / Q000378:metabolism*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D016324:Sequence Tagged Sites; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays
D017931:DNA Primers; D011994:Recombinant Proteins; D011494:Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048669:MAP Kinase Kinase 6; C482566:MAP2K6 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases