Off-target effects of MEK inhibitors

Biochemistry. 2013 Aug 6;52(31):5164-6. doi: 10.1021/bi4007644. Epub 2013 Jul 22.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzamides / pharmacology
  • Butadienes / pharmacology
  • Calcium / metabolism
  • Cell Line
  • Chromaffin Cells / drug effects*
  • Chromaffin Cells / metabolism
  • Diphenylamine / analogs & derivatives
  • Diphenylamine / pharmacology
  • Epinephrine / metabolism
  • Flavonoids / pharmacology
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / metabolism
  • MAP Kinase Kinase 1 / antagonists & inhibitors*
  • MAP Kinase Kinase 1 / metabolism
  • MAP Kinase Kinase 2 / antagonists & inhibitors*
  • MAP Kinase Kinase 2 / metabolism
  • Mice
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Nitriles / pharmacology
  • Protein Kinase Inhibitors / pharmacology*

Substances

  • Benzamides
  • Butadienes
  • Flavonoids
  • Insulin
  • Nitriles
  • Protein Kinase Inhibitors
  • U 0126
  • mirdametinib
  • Diphenylamine
  • Mitogen-Activated Protein Kinase 3
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 2
  • Map2k1 protein, mouse
  • Map2k2 protein, mouse
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
  • Calcium
  • Epinephrine