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.
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