Prostaglandin E2 selectively antagonizes prostaglandin F2alpha-stimulated T-cell factor/beta-catenin signaling pathway by the FPB prostanoid receptor.
FP prostanoid receptors are G-protein-coupled receptors that consist of two isoforms named FPA and FPB. Both isoforms activate inositol phosphate second messenger signaling pathways by their endogenous ligand prostaglandin F2alpha (PGF2alpha). Previously we have shown that both isoforms undergo Rho-mediated cell rounding following treatment with PGF2alpha. Following the removal of PGF2alpha, however, FPA-expressing cells return to their original morphology, whereas FPB-expressing cells do not. It was also found that PGF2alpha-could activate T-cell factor (Tcf)/beta-catenin signaling in cells expressing the FPB isoform but not in cells expressing the FPA isoform. We now show that prostaglandin E2 (PGE2) can induce cell rounding and stimulate the formation of inositol phosphates to the same extent as PGF2alpha in cells expressing either the FPA or FPB isoforms. However, PGE2 has much lower efficacy as compared with PGF2alpha for the activation of Tcf/beta-catenin signaling in FPB-expressing cells, and the cell rounding is reversible. Interestingly, pretreatment of FPB-expressing cells with PGE2-attenuated PGF2alpha-stimulated Tcf/beta-catenin signaling in a dose-dependent manner while having no effect on PGF2alpha-stimulated inositol phosphates formation. Thus, the ratio of endogenous PGE2 and PGF2alpha 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.
Fujino
Hiromichi
H
Department of Pharmacology & Toxicology, College of Pharmacy, The University of Arizona, Tucson 85721-0207, USA.
Vielhauer
George A
GA
Regan
John W
JW
D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D015237:Dinoprost / Q000494:pharmacology*; D015232:Dinoprostone / Q000494:pharmacology*; D017930:Genes, Reporter; D006801:Humans; D007668:Kidney; D021122:Protein Subunits / Q000502:physiology; D011982:Receptors, Prostaglandin / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000502:physiology*; D014162:Transfection; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D021122:Protein Subunits; D011982:Receptors, Prostaglandin; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D051176:beta Catenin; C034671:prostaglandin F2alpha receptor; D015237:Dinoprost; D015232:Dinoprostone