A new type of ERK1/2 autophosphorylation causes cardiac hypertrophy.
The extracellular-regulated kinases ERK1 and ERK2 (commonly referred to as ERK1/2) have a crucial role in cardiac hypertrophy. ERK1/2 is activated by mitogen-activated protein kinase kinase-1 (MEK1) and MEK2 (commonly referred to as MEK1/2)-dependent phosphorylation in the TEY motif of the activation loop, but how ERK1/2 is targeted toward specific substrates is not well understood. Here we show that autophosphorylation of ERK1/2 on Thr188 directs ERK1/2 to phosphorylate nuclear targets known to cause cardiac hypertrophy. Thr188 autophosphorylation requires the activation and assembly of the entire Raf-MEK-ERK kinase cascade, phosphorylation of the TEY motif, dimerization of ERK1/2 and binding to G protein betagamma subunits released from activated G(q). Thr188 phosphorylation of ERK1/2 was observed in isolated cardiomyocytes induced to undergo hypertrophic growth, in mice upon stimulation of G(q)-coupled receptors or after aortic banding and in failing human hearts. Experiments using transgenic mouse models carrying mutations at the Thr188 phosphorylation site of ERK2 suggested a causal relationship to cardiac hypertrophy. We propose that specific phosphorylation events on ERK1/2 integrate differing upstream signals (Raf1-MEK1/2 or G protein-coupled receptor-G(q)) to induce cardiac hypertrophy.
Lorenz
Kristina
K
Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Strasse 9, Würzburg, Germany. lorenz@toxi.uni-wuerzburg.de
Schmitt
Joachim P
JP
Schmitteckert
Eva M
EM
Lohse
Martin J
MJ
D019943:Amino Acid Substitution / Q000502:physiology; D000818:Animals; D019556:COS Cells; D006332:Cardiomegaly / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D044387:GTP-Binding Protein beta Subunits / Q000378:metabolism; D044388:GTP-Binding Protein gamma Subunits / Q000378:metabolism; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D008954:Models, Biological; D010766:Phosphorylation / Q000235:genetics / Q000502:physiology; D011485:Protein Binding; D055503:Protein Multimerization; D015398:Signal Transduction / Q000502:physiology; D013912:Threonine / Q000235:genetics / Q000378:metabolism
D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D013912:Threonine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3