title: Frizzled receptors signal through G proteins.
abstract: 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.
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Andrea S
authors.initials: AS
authors.lastname: Nichols
authors.forename: Desiree H
authors.initials: DH
authors.lastname: Floyd
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Bruinsma
authors.forename: Kirk
authors.initials: K
authors.lastname: Narzinski
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Baranski
mesh_terms: D000818:Animals; D004330:Drosophila / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism; D051157:Frizzled Receptors / Q000235:genetics / Q000378:metabolism*; D044385:GTP-Binding Protein alpha Subunits / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism; D006801:Humans; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D015398:Signal Transduction; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D051157:Frizzled Receptors; D044385:GTP-Binding Protein alpha Subunits; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D043562:Receptors, G-Protein-Coupled; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; D051153:Wnt Proteins; D020928:Mitogen-Activated Protein Kinases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D019205:GTP-Binding Protein alpha Subunits, Gs