BIRB796 inhibits all p38 MAPK isoforms in vitro and in vivo.
The compound BIRB796 inhibits the stress-activated protein kinases p38alpha and p38beta and is undergoing clinical trials for the treatment of inflammatory diseases. Here we report that BIRB796 also inhibits the activity and the activation of SAPK3/p38gamma. This occurs at higher concentrations of BIRB796 than those that inhibit p38alpha and p38beta and at lower concentrations than those that inhibit the activation of JNK isoforms. We also show that at these concentrations, BIRB796 blocks the stress-induced phosphorylation of the scaffold protein SAP97, further establishing that this is a physiological substrate of SAPK3/p38gamma. Our results demonstrate that BIRB796, in combination with SB203580, a compound that inhibits p38alpha and p38beta, but not the other p38 isoforms, can be used to identify physiological substrates of SAPK3/p38gamma as well as those of p38alpha and p38beta.
Kuma
Yvonne
Y
Medical Research Council Protein Phosphorylation Unit, University of Dundee, Scotland, UK.
Sabio
Guadalupe
G
Bain
Jenny
J
Shpiro
Natalia
N
Márquez
Rodolfo
R
Cuenda
Ana
A
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D000074288:Discs Large Homolog 1 Protein; D051528:Guanylate Kinases; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008565:Membrane Proteins; D051379:Mice; D048290:Mitogen-Activated Protein Kinase 11 / Q000037:antagonists & inhibitors; D048291:Mitogen-Activated Protein Kinase 12 / Q000037:antagonists & inhibitors; D048292:Mitogen-Activated Protein Kinase 13 / Q000037:antagonists & inhibitors; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors; D009281:Naphthalenes / Q000494:pharmacology*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D013379:Substrate Specificity; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D010671:Phenylurea Compounds
D048868:Adaptor Proteins, Signal Transducing; D000074288:Discs Large Homolog 1 Protein; D051528:Guanylate Kinases; D008565:Membrane Proteins; D048290:Mitogen-Activated Protein Kinase 11; D048291:Mitogen-Activated Protein Kinase 12; D048292:Mitogen-Activated Protein Kinase 13; D048308:Mitogen-Activated Protein Kinase 14; D009281:Naphthalenes; D047428:Protein Kinase Inhibitors; D011506:Proteins; D011720:Pyrazoles; D048051:p38 Mitogen-Activated Protein Kinases; C513314:DLG1 protein, human; C000614189:Dlg1 protein, mouse; C501119:Dlg1 protein, rat; C452139:doramapimod; D010671:Phenylurea Compounds