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Endothelin-stimulated ERK activation in airway smooth-muscle cells requires calcium influx and Raf activation.
Vichi P, Whelchel A, Knot H, Nelson MT, Kolch W, Posada J
American Journal of Respiratory Cell & Molecular Biology. 1999;20( 1):99-105.
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Abstract
Endothelin (ET)-1 is a 21-amino-acid peptide that is a potent vasoconstrictor and mitogen. By binding to its G-protein coupled receptor, ET-1 stimulates the proliferation of airway smooth-muscle (ASM) cells, which may be involved in the pathogenesis of asthma. The ETB receptor stimulates activation of the extracellular regulated kinase 2 (ERK2), which is thought to be required for proliferation of ASM cells. Our findings reveal that ET rapidly activates Raf, and that dominant-negative Raf interferes with ET-induced ERK activation in ASM cells. Expression of the amino-terminal Ras-binding domain of Raf inhibited ET-induced ERK activation, suggesting that ET-stimulated Raf activation is a Ras-dependent process. Furthermore, ET-stimulated ERK and Raf activation in ASM cells require calcium influx; chelating extracellular calcium or preventing calcium influx through calcium channels inhibited ET-stimulated, but not phorbol ester-stimulated, ERK and Raf activation.
Keyword(s)
Animals; COS Cells; Enzyme Activation; Mitogen-Activated Protein Kinase 1; Rats; Receptor, Endothelin B; Signal Transduction; Transfection; enzymology: Muscle, Smooth; enzymology: Respiratory System; genetics: Proto-Oncogene Proteins c-raf; genetics: Receptors, Endothelin; metabolism: Ca(2+)-Calmodulin Dependent Protein Kinase; metabolism: Calcium; pharmacology: Endothelin-1