Abstract
Extracellular signal-regulated kinase 1/2 (ERK1/2) signalling is a key pathway in cardiomyocyte hypertrophy and survival in response to many different stress stimuli. We have previously characterized melusin as a muscle-specific chaperone protein capable of ERK1/2 signalling activation in the heart. Here, we show that in the heart, melusin forms a supramolecular complex with the proto-oncogene c-Raf, MEK1/2 (also known as MAPKK1/2) and ERK1/2 and that melusin-bound mitogen-activated protein kinases (MAPKs) are activated by pressure overload. Moreover, we demonstrate that both focal adhesion kinase (FAK) and IQ motif-containing GTPase activating protein 1 (IQGAP1), a scaffold protein for the ERK1/2 signalling cascade, are part of the melusin complex and are required for ERK1/2 activation in response to pressure overload. Finally, analysis of isolated neonatal cardiomyocytes indicates that both FAK and IQGAP1 regulate melusin-dependent cardiomyocyte hypertrophy and survival through ERK1/2 activation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Allosteric Regulation
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Animals
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Cardiomyopathy, Hypertrophic / drug therapy
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Cardiomyopathy, Hypertrophic / metabolism*
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Cardiomyopathy, Hypertrophic / pathology
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Cardiomyopathy, Hypertrophic / physiopathology
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Cell Survival / drug effects
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Cells, Cultured
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Cytoskeletal Proteins / genetics
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Cytoskeletal Proteins / metabolism*
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Enzyme Activation / drug effects
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Enzyme Activation / genetics
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Enzyme Inhibitors / pharmacology
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Focal Adhesion Protein-Tyrosine Kinases / metabolism*
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Heart / drug effects
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Heart / physiology
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Heart / physiopathology
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / genetics
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Mice
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Mice, Knockout
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Mice, Transgenic
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Molecular Chaperones / genetics
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Molecular Chaperones / metabolism*
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Multienzyme Complexes / metabolism
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Muscle Proteins / genetics
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Muscle Proteins / metabolism*
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Myocytes, Cardiac / drug effects
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Myocytes, Cardiac / metabolism*
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Myocytes, Cardiac / pathology
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Stress, Physiological
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ras GTPase-Activating Proteins / genetics
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ras GTPase-Activating Proteins / metabolism*
Substances
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Cytoskeletal Proteins
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Enzyme Inhibitors
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IQ motif containing GTPase activating protein 1
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Itgb1bp2 protein, mouse
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Molecular Chaperones
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Multienzyme Complexes
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Muscle Proteins
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ras GTPase-Activating Proteins
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Focal Adhesion Protein-Tyrosine Kinases
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Extracellular Signal-Regulated MAP Kinases