Frizzled receptors signal through G proteins

• Published in: Cellular signalling 2013-06, Vol.25 (6), p.1468-1475
• Main Authors: Nichols, Andrea S., Floyd, Desiree H., Bruinsma, Stephen P., Narzinski, Kirk, Baranski, Thomas J.
• Format: Article
• Language: English
• Subjects: Animals; Cellular; Data points; Drosophila - metabolism; Drosophila Proteins - metabolism; Frizzled; Frizzled Receptors - genetics; Frizzled Receptors - metabolism; G protein; GDI; GPCR; GTP-Binding Protein alpha Subunits - metabolism; GTP-Binding Protein alpha Subunits, Gi-Go - metabolism; GTP-Binding Protein alpha Subunits, Gq-G11 - metabolism; GTP-Binding Protein alpha Subunits, Gs - metabolism; Humans; Kinases; Low Density Lipoprotein Receptor-Related Protein-6 - genetics; Low Density Lipoprotein Receptor-Related Protein-6 - metabolism; Mitogen-Activated Protein Kinases - metabolism; Photoreceptors; Planar cell polarity; Proteins; Receptors; Receptors, G-Protein-Coupled - metabolism; Recombinant Fusion Proteins - biosynthesis; Recombinant Fusion Proteins - genetics; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - metabolism; Signal Transduction; Signalling; Surgical implants; Wnt Proteins - genetics; Wnt Proteins - metabolism; Wnt signaling
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2013.03.009

Frizzled receptors have long been thought to couple to G proteins but biochemical evidence supporting such an interaction has been lacking. Here we expressed mammalian Wnt-Frizzled fusion proteins in Saccharomyces cerevisiae and tested the receptors' ability to activate the yeast mitogen-activated protein kinase (MAPK) pathway via heterotrimeric G proteins. Our results show that Frizzled receptors can interact with Gαi, Gαq, and Gαs proteins, thus confirming that Frizzled functions as a G protein coupled receptor (GPCR). However, the activity level of Frizzled-mediated G protein signaling was much lower than that of a typical GPCR and, surprisingly, was highest when coupled to Gαs. The Frizzled/Gαs interaction was further established in vivo as Drosophila expressing a loss-of-function Gαs allele rescued the photoreceptor differentiation phenotype of Frizzled mutant flies. Together, these data point to an important role for Frizzled as a nontraditional GPCR that preferentially couples to Gαs heterotrimeric G proteins. •Frizzled receptors interact with Gαi, Gαq, and Gαs proteins.•Gαs-mediated Frizzled signaling regulates Drosophila eye development.•Frizzled receptors might act as partial GEFs or functional GDIs.