FP prostanoid receptor activation of a T-cell factor/beta -catenin signaling pathway.
FP prostanoid receptors are G-protein-coupled receptors (GPCR) that consist of two known isoforms, FP(A) and FP(B). These isoforms, which are generated by alternative mRNA splicing, are identical except for their carboxyl-terminal domains. Previously we have shown that stimulation of both isoforms with prostaglandin F(2alpha) (PGF(2alpha)) activates the small G-protein Rho, leading to morphological changes consisting of cell rounding and the formation of cell aggregates. Following the removal of PGF(2alpha), however, FP(A)-expressing cells show rapid reversal of cell rounding, whereas FP(B)-expressing cells do not. We now show that acute treatment of FP(B)-expressing cells with PGF(2alpha) leads to a subcellular reorganization of beta-catenin, a decrease in the phosphorylation of cytoplasmic beta-catenin, and persistent stimulation of Tcf/Lef-mediated transcriptional activation. This does not occur in FP(A)-expressing cells and may underlie the differences between these isoforms with respect to the reversal of cell rounding. The Tcf/beta-catenin signaling pathway is known to mediate the actions of Wnt acting through the heptahelical receptor, Frizzled, and has not been associated previously with GPCR activation. Our findings expand the signaling possibilities for GPCRs and suggest novel roles for FP receptors in normal tissue development and malignant transformation.
Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona 85721-80207, USA.
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Fujino
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JW
Regan
D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000502:physiology*; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D011982:Receptors, Prostaglandin / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D012756:Sheep; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000502:physiology*; D051176:beta Catenin; D020741:rho GTP-Binding Proteins / Q000378:metabolism
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D020033:Protein Isoforms; D011982:Receptors, Prostaglandin; D011994:Recombinant Proteins; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D051176:beta Catenin; C034671:prostaglandin F2alpha receptor; D020741:rho GTP-Binding Proteins