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Interaction of Wnt and a Frizzled homologue triggers G-protein-linked phosphatidylinositol signalling

Abstract

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 membrane1,2, 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-β-S and α-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.

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Figure 1: Differential calcium transient activity in zebrafish embryos induced by expression of Rfz-2 , Rfz-1 or globin RNA.
Figure 2: Induction of intracellular Ca2+ transients by Rfz-2 in the presence of Wnt proteins.
Figure 3: Pertussis toxin (PTX), the A-promoter of PTX, GDP-β-S, and α-transducin inhibit Rfz-2 -induced release of intracellular.
Figure 4: The IMPase inhibitor L-690,330 suppresses Rfz-2 -induced intracellular Ca2+ release and is rescued by addition of myo -inositol.

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Acknowledgements

We thank W. B. Busa for advice on calcium imaging and for discussion; N. Nathanson for comments on the manuscript, and J. Hurley for transducin cDNA. This work was supported by the HHMI (R.T.M.) and grants from the NIH (V.G.C.); D.C.S. was supported by an NRSA fellowship from the NIH.

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Correspondence to Randall T. Moon.

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Slusarski, D., Corces, V. & Moon, R. Interaction of Wnt and a Frizzled homologue triggers G-protein-linked phosphatidylinositol signalling. Nature 390, 410–413 (1997). https://doi.org/10.1038/37138

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