THE 7-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 OFMITOGEN-ACTIVATED PROTEIN-KINASES

In airway smooth muscle cells ligand binding to the seven-transmembran e endothelin and thrombin receptors stimulates cell growth. Rapid acti vation 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 recep tor signaling involving activation of the Jun kinase pathway. Receptor coupling to Jun kinase activation may involve heterotrimeric G protei ns since the kinase was enzymatically activated in cells treated with aluminum fluoride. The activity of Raf-1, measured by immune complex k inase 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 significan tly inhibited by ac tivation of cyclic AMP-dependent protein kinase by forskolin. Proliferation of airway smooth muscle cells, measured by i ncorporation of [H-3]thymidine into DNA, was also greatly attenuated b y forskolin.