The seven-transmembrane-spanning receptors for endothelin and thrombin cause proliferation of airway smooth muscle cells and activation of the extracellular regulated kinase and c-Jun NH2-terminal kinase groups of mitogen-activated protein kinases.
In airway smooth muscle cells ligand binding to the seven-transmembrane endothelin and thrombin receptors stimulates cell growth. Rapid activation of the extracellular regulated kinase 2 and c-Jun NH2-terminal kinase groups of mitogen-activated protein kinases was also observed. The results demonstrate a novel mechanism of seven-transmembrane receptor signaling involving activation of the Jun kinase pathway. Receptor coupling to Jun kinase activation may involve heterotrimeric G proteins since the kinase was enzymatically activated in cells treated with aluminum fluoride. The activity of Raf-1, measured by immune complex kinase assay, revealed that platelet-derived growth factor and phorbol 12-myristate 13-acetate both stimulated Raf-1 activity, while thrombin and endothelin did not appreciably stimulate Raf-1. The data suggest that endothelin and thrombin stimulate Raf-1-independent mechanisms of mitogen-activated protein kinase activation. Endothelin- or thrombin-induced activation of mitogen-activated protein kinases was significantly inhibited by activation of cyclic AMP-dependent protein kinase by forskolin. Proliferation of airway smooth muscle cells, measured by incorporation of [3H]thymidine into DNA, was also greatly attenuated by forskolin.
Shapiro
P S
PS
Department of Molecular Physiology and Biophysics, College of Medicine, University of Vermont, Burlington, Vermont 05405, USA.
Evans
J N
JN
Davis
R J
RJ
Posada
J A
JA
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D016232:Endothelins / Q000494:pharmacology; D004789:Enzyme Activation; D048031:JNK Mitogen-Activated Protein Kinases; D007700:Kinetics; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D009130:Muscle, Smooth / Q000166:cytology* / Q000201:enzymology / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf; D051381:Rats; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000502:physiology*; D017466:Receptors, Endothelin / Q000187:drug effects / Q000502:physiology*; D018179:Receptors, Thrombin / Q000187:drug effects / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism; D014132:Trachea / Q000166:cytology* / Q000201:enzymology / Q000502:physiology*
D016232:Endothelins; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D017466:Receptors, Endothelin; D018179:Receptors, Thrombin; D011993:Recombinant Fusion Proteins; D005576:Colforsin; D004247:DNA; D000242:Cyclic AMP; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D013917:Thrombin; D013755:Tetradecanoylphorbol Acetate; D013936:Thymidine