ERK1/2 activation in heart is controlled by melusin, focal adhesion kinase and the scaffold protein IQGAP1.
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.
Dipartimento di Genetica, Biologia e Biochimica, Università di Torino, Molecular Biotechnology Center, via Nizza, 52, 10126 Torino,  Italy.
Mauro
M
Sbroggiò
Alessandro
A
Bertero
Silvia
S
Velasco
Federica
F
Fusella
Emanuele
E
De Blasio
Wadie F
WF
Bahou
Lorenzo
L
Silengo
Emilia
E
Turco
Mara
M
Brancaccio
Guido
G
Tarone
D000494:Allosteric Regulation; D000818:Animals; D002312:Cardiomyopathy, Hypertrophic / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D006321:Heart / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D013312:Stress, Physiological; D020703:ras GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*
D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; C101203:IQ motif containing GTPase activating protein 1; C122158:Itgb1bp2 protein, mouse; D018832:Molecular Chaperones; D009097:Multienzyme Complexes; D009124:Muscle Proteins; D020703:ras GTPase-Activating Proteins; D051416:Focal Adhesion Protein-Tyrosine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases