title: SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin-1.
abstract: A class of pyridinyl imidazoles inhibit the MAP kinase homologue, termed here reactivating kinase (RK) [Lee et al. (1994) Nature 372, 739-746]. We now show that one of these compounds (SB 203580) inhibits RK in vitro (IC50 = 0.6 microM), suppresses the activation of MAPKAP kinase-2 and prevents the phosphorylation of heat shock protein (HSP) 27 in response to interleukin-1, cellular stresses and bacterial endotoxin in vivo. These results establish that MAPKAP kinase-2 is a physiological RK substrate, and that HSP27 is phosphorylated by MAPKAP kinase-2 in vivo. The specificity of SB 203580 was indicated by its failure to inhibit 12 other protein kinases in vitro, and by its lack of effect on the activation of RK kinase and other MAP kinase cascades in vivo. We suggest that SB 203580 will be useful for identifying other physiological roles and targets of RK and MAPKAP kinase-2.
authors.affiliation: Department of Biochemistry, University of Dundee, Scotland, UK.
authors.forename: A
authors.initials: A
authors.lastname: Cuenda
authors.forename: J
authors.initials: J
authors.lastname: Rouse
authors.forename: Y N
authors.initials: YN
authors.lastname: Doza
authors.forename: R
authors.initials: R
authors.lastname: Meier
authors.forename: P
authors.initials: P
authors.lastname: Cohen
authors.forename: T F
authors.initials: TF
authors.lastname: Gallagher
authors.forename: P R
authors.initials: PR
authors.lastname: Young
authors.forename: J C
authors.initials: JC
authors.lastname: Lee
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D008969:Molecular Sequence Data; D009414:Nerve Growth Factors / Q000494:pharmacology; D016716:PC12 Cells; D010766:Phosphorylation; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D015398:Signal Transduction; D013312:Stress, Physiological / Q000201:enzymology; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D006360:Heat-Shock Proteins; D007093:Imidazoles; D007375:Interleukin-1; D047908:Intracellular Signaling Peptides and Proteins; D009414:Nerve Growth Factors; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011725:Pyridines; D000099190:MAP-Kinase-Activated Kinase 2; C093642:SB 203580