The EGF receptor activates ERK but not JNK Ras-dependently in basal conditions but ERK and JNK activation pathways are predominantly Ras-independent during cardiomyocyte stretch.
Myocardial stretch is a major determinant of ventricular hypertrophy, a physiological adaptational process that can be detrimental, leading to heart failure. Therapies aimed to limit the development of cardiac hypertrophy are thus currently evaluated. Among possible targets, the small G protein Ras and the epidermal growth factor receptor (EGFR) have been shown to be involved during stretch but their precise role in the activation of the major actors of hypertrophy, the mitogen activated protein kinases (MAPK) ERK and JNK is not well known. Our goal was thus was to evaluate precisely the activation pathways of ERK and JNK during stretch, with an emphasis on the role of the EGFR. For this purpose, neonatal rat cardiomyocytes in culture were stretched for different time durations. As measured by Western blot of their phosphorylated forms, ERK and JNK were activated by stretch. Ras inhibition decreased basal ERK phosphorylation but had no effect on stretch-induced ERK activation. Under basal conditions, EGFR activated ERK in a classical Ras-dependent manner. Upon stretch, EGFR transactivation activated ERK through both Ras-dependent and Ras-independent pathways. Interestingly, we also show that the Akt pathway participates in stretch-induced ERK activation with an involvement of EGFR. Unlike ERK, JNK activation is independent of either EGFR or PI3 kinase but dependent on other tyrosine kinases. In conclusion these data show different Ras-dependent and Ras-independent pathways in basal conditions and during stretch with a previously unrecognized role of Akt in the activation of ERK.
Duquesnes
Nicolas
N
INSERM, U769, Signalisation et Physiopathologie Cardiaque, Châtenay-Malabry F-92296, France.
Vincent
Fanny
F
Morel
Eric
E
Lezoualc'h
Frank
F
Crozatier
Bertrand
B
D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D011905:Genes, ras; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D032383:Myocytes, Cardiac / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014162:Transfection; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*
D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D018631:ras Proteins