ACTIVATION OF STRESS-ACTIVATED PROTEIN-KINASES C-JUN N-TERMINAL PROTEIN-KINASES (SAPKS JNKS) BY A NOVEL MITOGEN-ACTIVATED PROTEIN-KINASE KINASE (MKK7)/

Mitogen-activated protein kinase (MAPK) kinases (MKKs) are dual-specif icity protein kinases that phosphorylate and activate MAPK. We have is olated a cDNA encoding a novel protein kinase that has significant hom ology to MKKs. The novel kinase MKK7 has a nucleotide sequence that en codes an open reading frame of 347 amino acids with 11 kinase subdomai ns. MKK7 is ubiquitously expressed in all adult and embryonic organs b ut displays high expression in epithelial tissues at later stages of f etal development. When transiently expressed in 293 cells, MKK7 specif ically activated stress-activated protein kinases (SAPKs)/c-Jun N-term inal protein kinases (JNKs) but not extracellular-regulated kinase or p38 kinase. A kinase-negative mutant of MKK7 inhibits interleukin-1 be ta, lipopolysaccharide, and MEKK1-induced SAPK/JNH activation. Thus, M KK7 is a new member of the MAPK kinase family that functions upstream of SAPK/JNK in the SAPK/JNK signaling pathway.