INTERACTION OF WNT AND A FRIZZLED HOMOLOG TRIGGERS G-PROTEIN-LINKED PHOSPHATIDYLINOSITOL SIGNALING

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 transducti on across the cell membrane(1,2), although how they do this is unclear . We show here that the rat protein Frizzled-2 causes an increase in t he release of intracellular calcium which is enhanced by Xwnt-5a, a me mber of the Wnt family. This release of intracellular calcium is suppr essed 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 phosphatidylinos itol signalling pathway via heterotrimeric G-protein subunits.