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 o f kinases involved in many signal transduction pathways. They stimulat e phosphorylation of transcription factors in response to extracellula r signals such as growth factors, cytokines, ultraviolet light, and st ress-inducing agents. A novel mitogen-activated protein kinase kinase, MEK6, was cloned and characterized. The complete MEK6 cDNA was isolat ed by polymerase chain reaction. It encodes a 334-amino acid protein w ith 82% identity to MKK3. MEK6 is highly expressed in skeletal muscle like many other members of this family, but in contrast to MKK3 its ex pression in leukocytes is very low. MEK6 is a member of the p38 kinase cascade and efficiently phosphorylates p38 but not c-Jun N-terminal k inase (JNK) and extracellular signal-regulated kinase (ERK) family mem bers 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 osmo tic shock but not by phorbol esters, nerve growth factor, and epiderma l growth factor. This separates MEK6 from the ERK subgroup of protein kinases. MEK6 is only a poor substrate for MEKK, a mitogen-activated p rotein kinase kinase kinase that efficiently phosphorylates the relate d family member JNKK.