Prostaglandin E₂ selectively antagonizes prostaglandin F _2α-stimulated T-cell factor/β-catenin signaling pathway by the FP_B prostanoid receptor

FP prostanoid receptors are G-protein-coupled receptors that consist of two isoforms named FP_A and FP_B. Both isoforms activate inositol phosphate second messenger signaling pathways by their endogenous ligand prostaglandin F_2α (PGF_2α). Previously we have shown that both isoforms undergo Rho-mediated cell rounding following treatment with PGF_2α. Following the removal of PGF _2α, however, FP_A-expressing cells return to their original morphology, whereas FP_B-expressing cells do not. It was also found that PGF_2α-could activate T-cell factor (Tcf)/β-catenin signaling in cells expressing the FP_B isoform but not in cells expressing the FP_A isoform. We now show that prostaglandin E₂ (PGE₂) can induce cell rounding and stimulate the formation of inositol phosphates to the same extent as PGF _2α in cells expressing either the FP_A or FP _B isoforms. However, PGE₂ has much lower efficacy as compared with PGF_2α for the activation of Tcf/β-catenin signaling in FP_B-expressing cells, and the cell rounding is reversible. Interestingly, pretreatment of FP_B-expressing cells with PGE₂-attenuated PGF_2α-stimulated Tcf/β-catenin signaling in a dose-dependent manner while having no effect on PGF _2α-stimulated inositol phosphates formation. Thus, the ratio of endogenous PGE₂ and PGF_2α has the potential to selectively regulate one signaling pathway over another. This represents a novel mechanism for the regulation of cell signaling that is distinct from regulation occurring at the level of the receptor and its effector pathways.