Authors and Affiliations
Department of Biology, University of Konstanz, Konstanz, Switzerland
VL Katanaev & S Buestorf
Cell Communication and Signaling volume 7, Article number: A19 (2009)
Receptors of the Frizzled family initiate Wnt ligand-dependent signal transduction cascades controlling multiple steps in organism development and are highly conserved in animal evolution. Misactivation of the Wnt/Frizzled signaling underlies many cases of cancerogenesis. Frizzled receptors possess seven transmembrane domains and their signaling depends on trimeric G proteins in various organisms. However, as Frizzled proteins constitute a distinct group within the superfamily of G protein-coupled receptors (GPCR), and as Frizzled signaling can apparently be G protein-independent in some experimental setups, the GPCR nature of Frizzled receptors has been questioned. Here we demonstrate that human Frizzled receptors can directly bind the trimeric Go protein in a pertussis toxin-sensitive manner. Furthermore, addition of Wnt ligands elicits Frizzled-dependent guanine nucleotide exchange on Go. An excess of secreted Frizzled-related protein, a known antagonist of the Wnt/Frizzled pathways, inhibits Go activation, as does pretreatment of Go with pertussis toxin. These experiments provide a biochemical proof of the GPCR activities of Frizzled receptors. They also establish an in vitro assay of monitoring Frizzled activation by Wnt ligands, applicable for the high-throughput agonist/antagonist screening.
Katanaev, V., Buestorf, S. The G protein-coupled receptor identity of the frizzled proteins. Cell Commun Signal 7 (Suppl 1), A19 (2009). https://doi.org/10.1186/1478-811X-7-S1-A19