G Protein Signaling from Activated Rat Frizzled-1 to the β-Catenin-Lef-Tcf Pathway

Liu, Tong
DeCostanzo, Anthony J.
Liu, Xunxian
Wang, Hsien-yu
Hallagan, Sarah
Moon, Randall T.
Malbon, Craig C.

¹Department of Molecular Pharmacology and ²Department of Physiology, Diabetes and Metabolic Diseases Research Center, University Medical Center, State University of New York at Stony Brook, Stony Brook, NY 11794-8651, USA. ³Howard Hughes Medical Institute, Department of Pharmacology and Center for Developmental Biology, University of Washington School of Medicine, Seattle, WA 98195, USA.

*To whom correspondence should be addressed. E-mail: [email protected]

22 February 2001; accepted 23 April 2001

Science 292(5522):p 1718-1722, June 1, 2001.

The frizzled receptors, which mediate development and display seven hydrophobic, membrane-spanning segments, are cell membrane-localized. We constructed a chimeric receptor with the ligand-binding and transmembrane segments from the β₂-adrenergic receptor (β₂AR) and the cytoplasmic domains from rat Frizzled-1 (Rfz1). Stimulation of mouse F9 clones expressing the chimera (β₂AR-Rfz1) with the β-adrenergic agonist isoproterenol stimulated stabilization of β-catenin, activation of a β-catenin-sensitive promoter, and formation of primitive endoderm. The response was blocked by inactivation of pertussis toxin-sensitive, heterotrimeric guanine nucleotide-binding proteins (G proteins) and by depletion of Gαq and Gαo. Thus, G proteins are elements of Wnt/Frizzled-1 signaling to the β-catenin-lymphoid-enhancer factor (LEF)-T cell factor (Tcf) pathway.