Interaction of Wnt and a Frizzled homologue triggers G-protein-linked phosphatidylinositol signalling.
In Drosophila, members of the frizzled family of tissue-polarity genes encode proteins that are likely to function as cell-surface receptors of the type known as Wnt receptors, and to initiate signal transduction across the cell membrane, although how they do this is unclear. We show here that the rat protein Frizzled-2 causes an increase in the release of intracellular calcium which is enhanced by Xwnt-5a, a member of the Wnt family. This release of intracellular calcium is suppressed by an inhibitor of the enzyme inositol monophosphatase and hence of the phosphatidylinositol signalling pathway; this suppression can be rescued by injection of the compound myo-inositol, which overcomes the decrease in this intermediate caused by the inhibitor. Agents that inhibit specific G-protein subunits, pertussis toxin, GDP-beta-S and alpha-transducin also inhibit the calcium release triggered by Xwnt-5a and rat Frizzled-2. Our results indicate that some Wnt proteins work through specific Frizzled homologues to stimulate the phosphatidylinositol signalling pathway via heterotrimeric G-protein subunits.
Slusarski
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Department of Biology, The Johns Hopkins University, Baltimore, Maryland 21218, USA.
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D000818:Animals; D002118:Calcium / Q000378:metabolism; D004164:Diphosphonates / Q000494:pharmacology; D004625:Embryo, Nonmammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051157:Frizzled Receptors; D019204:GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D006153:Guanosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D037342:Pertussis Toxin; D010716:Phosphatidylinositols / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D043562:Receptors, G-Protein-Coupled; D017981:Receptors, Neurotransmitter / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013873:Thionucleotides / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D029867:Xenopus Proteins; D015027:Zebrafish
D004164:Diphosphonates; D004791:Enzyme Inhibitors; C489741:FZD1 protein, Xenopus; C489740:FZD1 protein, human; C489744:FZD2 protein, Xenopus; C489742:FZD2 protein, human; D051157:Frizzled Receptors; D010716:Phosphatidylinositols; D011506:Proteins; D043562:Receptors, G-Protein-Coupled; D017981:Receptors, Neurotransmitter; D011994:Recombinant Proteins; D013873:Thionucleotides; D010566:Virulence Factors, Bordetella; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C085096:Wnt5a protein, Xenopus; D029867:Xenopus Proteins; C079103:L 690330; D006153:Guanosine Diphosphate; C078603:Fzd1 protein, rat; C078604:Fzd2 protein, rat; C023427:guanosine 5'-O-(2-thiodiphosphate); D037342:Pertussis Toxin; D010744:Phosphoric Monoester Hydrolases; C021822:myo-inositol-1 (or 4)-monophosphatase; D019204:GTP-Binding Proteins; D002118:Calcium