title: Off-target effects of MEK inhibitors.
abstract: The mitogen-activated protein kinases (MAPKs) ERK1/2 regulate numerous cellular processes, including gene transcription, proliferation, and differentiation. The only known substrates of the MAP2Ks MEK1/2 are ERK1/2; thus, MEK inhibitors PD98059, U0126, and PD0325901 have been important tools in determining the functions of ERK1/2. By using these inhibitors and genetically manipulating MEK, we found that ERK1/2 activation is neither sufficient nor necessary for regulated secretion of insulin from pancreatic β cells or secretion of epinephrine from chromaffin cells. We show that both PD98059 and U0126 reduce agonist-induced entry of calcium into cells in a manner independent of their ability to inhibit ERK1/2. Caution should be used when interpreting results from experiments using these compounds.
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center , Dallas, Texas 75390-9041, United States.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Wauson
authors.forename: Marcy L
authors.initials: ML
authors.lastname: Guerra
authors.forename: Barbara
authors.initials: B
authors.lastname: Barylko
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Albanesi
authors.forename: Melanie H
authors.initials: MH
authors.lastname: Cobb
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D019439:Chromaffin Cells / Q000187:drug effects* / Q000378:metabolism; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D004837:Epinephrine / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*
chemical_list: D001549:Benzamides; D002070:Butadienes; D005419:Flavonoids; D007328:Insulin; D009570:Nitriles; D047428:Protein Kinase Inhibitors; C113580:U 0126; C506614:mirdametinib; D004159:Diphenylamine; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482127:Map2k1 protein, mouse; C482129:Map2k2 protein, mouse; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D002118:Calcium; D004837:Epinephrine