A new type of ERK1/2 autophosphorylation causes cardiac hypertrophy
K. Lorenz, J. Schmitt, E. Schmitteckert, and M. Lohse. Nat Med, 15 (1):
75-83(January 2009)Lorenz, Kristina Schmitt, Joachim P Schmitteckert, Eva M Lohse, Martin
J Research Support, Non-U.S. Gov't United States Nature medicine
Nat Med. 2009 Jan;15(1):75-83. Epub 2008 Dec 7..
Abstract
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 Schmitt, Joachim P Schmitteckert, Eva M Lohse, Martin
J Research Support, Non-U.S. Gov't United States Nature medicine
Nat Med. 2009 Jan;15(1):75-83. Epub 2008 Dec 7.
%0 Journal Article
%1 Lorenz2009
%A Lorenz, K.
%A Schmitt, J. P.
%A Schmitteckert, E. M.
%A Lohse, M. J.
%D 2009
%J Nat Med
%K 1/genetics/*metabolism/physiology 3/genetics/*metabolism/physiology Acid Amino Animals Binding Biological COS Cardiomegaly/*etiology/genetics/metabolism Cercopithecus Cultured Failure/etiology/metabolism GTP-Binding Heart Humans Kinase MAP Mice Mitogen-Activated Models, Multimerization Phosphorylation/genetics/physiology Protein Signal Signaling Substitution/physiology Subunits/metabolism System/physiology Threonine/genetics/metabolism Transduction/physiology Transgenic aethiops beta gamma Cell
%N 1
%P 75-83
%T A new type of ERK1/2 autophosphorylation causes cardiac hypertrophy
%U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19060905
%V 15
%X 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.
@article{Lorenz2009,
abstract = {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.},
added-at = {2010-12-14T18:12:02.000+0100},
author = {Lorenz, K. and Schmitt, J. P. and Schmitteckert, E. M. and Lohse, M. J.},
biburl = {https://www.bibsonomy.org/bibtex/2c303e8be8f8eb4231315a8c940d2c9d7/pharmawuerz},
endnotereftype = {Journal Article},
interhash = {08b19da1dcb9e862ce1e08a60d1239ff},
intrahash = {c303e8be8f8eb4231315a8c940d2c9d7},
issn = {1546-170X (Electronic) 1546-170X (Linking)},
journal = {Nat Med},
keywords = {1/genetics/*metabolism/physiology 3/genetics/*metabolism/physiology Acid Amino Animals Binding Biological COS Cardiomegaly/*etiology/genetics/metabolism Cercopithecus Cultured Failure/etiology/metabolism GTP-Binding Heart Humans Kinase MAP Mice Mitogen-Activated Models, Multimerization Phosphorylation/genetics/physiology Protein Signal Signaling Substitution/physiology Subunits/metabolism System/physiology Threonine/genetics/metabolism Transduction/physiology Transgenic aethiops beta gamma Cell},
month = Jan,
note = {Lorenz, Kristina Schmitt, Joachim P Schmitteckert, Eva M Lohse, Martin
J Research Support, Non-U.S. Gov't United States Nature medicine
Nat Med. 2009 Jan;15(1):75-83. Epub 2008 Dec 7.},
number = 1,
pages = {75-83},
shorttitle = {A new type of ERK1/2 autophosphorylation causes cardiac hypertrophy},
timestamp = {2010-12-14T18:21:26.000+0100},
title = {A new type of ERK1/2 autophosphorylation causes cardiac hypertrophy},
url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19060905},
volume = 15,
year = 2009
}