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We showed previously that activation of the thromboxane prostanoid (TP) receptor causes human airway smooth muscle (HASM) cells to proliferate, suggesting a role in airway remodeling. This study aimed at determining the molecular mechanisms underlying this mitogenic action. We found that the MEK inhibitor PD98059 significantly affected agonist-induced DNA synthesis of HASM cells, which suggests that extracellular signal-regulated kinases (ERK) are involved. ERK activation by the agonist U46619 was rapid, sensitive to pertussis toxin, and significantly abrogated by the tyrosine kinase inhibitors genistein and PP1. Stimulation of the TP receptor was also found to translocate phosphorylated ERK into the nucleus. TP receptor was found to activate Ras, as demonstrated by inhibition of ERK activation and DNA synthesis by Clostridium sordellii lethal toxin, and by the ability of U46619 to increase RasGTP. Finally, [3H]thymidine incorporation and ERK phosphorylation were also affected by prior treatment with protein kinase C inhibitor GF109203X, although to different extents. In conclusion, in HASM cells TP receptor, predominantly coupled to Gi/o proteins, activates the Ras/ERK pathway to induce mitogenesis, probably with the involvement of nonreceptor tyrosine kinases and protein kinase C.