Wnt3a stimulation elicits G-protein-coupled receptor properties of mammalian frizzled proteins

Abstract

Receptors of the Fz (Frizzled) family initiate Wnt liganddependent signalling controlling multiple steps in organism development and carcinogenesis. Fz proteins possess seven transmembrane domains, and their signalling depends on heterotrimeric G-proteins in various organisms; however, Fz proteins constitute a distinct group within the GPCR (G-proteincoupled receptor) superfamily, and Fz signalling can be G-proteinindependent in some experimental setups, leading to concerns about the GPCR nature of these proteins. In the present study, we demonstrate that mammalian Fz proteins act as GPCRs on heterotrimeric Go/i proteins. Addition of the Wnt3a ligand to rat brain membranes or cultured cells elicits Fz-dependent guanine-nucleotide exchange on Go/i proteins. These responses were sensitive to a Wnt antagonist and to pertussis toxin, which decouples the Go/i proteins from their receptors through covalent modification. The results of the present study provide the longawaited biochemical proof of the GPCR nature of Fz receptors.