Article

The Frizzled family of unconventional G-protein-coupled receptors

Section of Receptor Biology and Signaling, Department of Physiology and Pharmacology, Karolinska Institutet, S-171 77 Stockholm, Sweden.
Trends in Pharmacological Sciences (Impact Factor: 9.99). 11/2007; 28(10):518-25. DOI: 10.1016/j.tips.2007.09.001
Source: PubMed

ABSTRACT The Frizzled (FZD) family of receptors is critically involved in embryogenesis, and there is substantial evidence that members of this family also regulate tissue homeostasis in many different organs in the adult. FZD receptors have seven transmembrane-spanning domains and are activated by the WNT family of lipoglycoproteins. Many aspects of FZD signal transduction and pharmacology are still unclear. In this review, we summarize recent advances and some of the key questions about the molecular pharmacology of FZDs, FZD-associated proteins and signal transduction. We also discuss what little is known about the pharmacological binding profiles and the degree of selectivity of WNTs and other extracellular ligands for FZDs. Finally, we focus on signaling events that occur as a direct consequence of FZD activation, signaling via the central phosphoprotein Dishevelled (DVL) and FZD coupling to heterotrimeric G proteins. Here, we outline the current state of knowledge on FZDs and FZD signal transduction and pinpoint aspects of debate and future directions.

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Available from: Gunnar Schulte, Aug 28, 2015
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    • "Frizzled4 (Fz4) belongs to the family of Frizzled cell surface receptors that are involved in a variety of biological processes during development as well as in adult life1112. Fz4 displays the structural landmarks observed in G protein-coupled receptors1112: an ectosolic N-Terminus, seven hydrophobic transmembrane segments, three intracellular and extracellular loops and a cytosolic C-terminal tail13. Two PDZ binding motives are located one internally and one at the C-terminus of Fz4. "
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    ABSTRACT: Frizzled 4 belongs to the superfamily of G protein coupled receptors. The unstructured cytosolic tail of the receptor is essential for its activity. The mutation L501fsX533 in the fz4 gene results in a new COOH-tail of the receptor and causes a form of Familial exudative vitreoretinopathy. Here we show that the mutated tail is structured. Two amphipathic helices, displaying affinity for membranes and resembling the structure of Influenza Hemagglutinin fusion peptide, constitute the new fold. This tail induces the aggregation of the receptor in the Endoplasmic Reticulum and it is sufficient to block the export to the Golgi of a chimeric VSVG protein containing the mutated tail. Affecting the tail's structure, net charge or amphipathicity relocates the mutated Fz4 receptor to the Plasma Membrane. Such disorder-to-order structural transition was never described in GPCRs and opens a new scenario on the possible effect of mutations on unstructured regions of proteins.
    Scientific Reports 09/2013; 3:2659. DOI:10.1038/srep02659 · 5.58 Impact Factor
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    • "Dfz2 groups closely with FZD5/8 and fz/Dfz1 with FZD3/6. The Hedgehog (another family of secreted signaling protein) pathway protein Smoothened (SMO) is distantly related to FZD (Schulte and Bryja 2007 "
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    ABSTRACT: Frizzled and LRP5/6 are Wnt receptors that upon activation lead to stabilization of cytoplasmic β-catenin. In this study, we review the current knowledge of these two families of receptors, including their structures and interactions with Wnt proteins, and signaling mechanisms from receptor activation to the engagement of intracellular partners Dishevelled and Axin, and finally to the inhibition of β-catenin phosphorylation and ensuing β-catenin stabilization.
    Cold Spring Harbor perspectives in biology 12/2012; 4(12). DOI:10.1101/cshperspect.a007880 · 8.23 Impact Factor
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    • "In various cell systems it was shown that WNT-5A activates WNT/Ca2+ signaling, the WNT/RAC1 and WNT/RHO pathway [11] involving the phosphoproteins disheveled 1, 2, 3 (DVL1, 2, 3), which are viewed as a signaling hub relaying many WNT signaling routes [12]. Further, heterotrimeric G proteins have been implicated in WNT/FZD signal transduction [13-16] and, indeed, recent studies confirmed a previous supposition that WNTs can induce the activation of heterotrimeric G proteins [17-19]. Among classical downstream targets of GPCR signaling are the mitogen-activated protein kinases (MAPK) and especially the extracellular signal-regulated kinases ERK1/2 [20], which can be activated by many GPCRs irrespective of which G protein family the receptors associate with [21,22]. "
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    ABSTRACT: WNT-5A signaling in the central nervous system is important for morphogenesis, neurogenesis and establishment of functional connectivity; the source of WNT-5A and its importance for cellular communication in the adult brain, however, are mainly unknown. We have previously investigated the inflammatory effects of WNT/β-catenin signaling in microglia in Alzheimer's disease. WNT-5A, however, generally recruits β-catenin-independent signaling. Thus, we aim here to characterize the role of WNT-5A and downstream signaling pathways for the inflammatory transformation of the brain's macrophages, the microglia. Mouse brain sections were used for immunohistochemistry. Primary isolated microglia and astrocytes were employed to characterize the WNT-induced inflammatory transformation and underlying intracellular signaling pathways by immunoblotting, quantitative mRNA analysis, proliferation and invasion assays. Further, measurements of G protein activation by [γ-35 S]GTP binding, examination of calcium fluxes and cyclic AMP production were used to define intracellular signaling pathways. Astrocytes in the adult mouse brain express high levels of WNT-5A, which could serve as a novel astroglia-microglia communication pathway. The WNT-5A-induced proinflammatory microglia response is characterized by increased expression of inducible nitric oxide synthase, cyclooxygenase-2, cytokines, chemokines, enhanced invasive capacity and proliferation. Mapping of intracellular transduction pathways reveals that WNT-5A activates heterotrimeric Gi/o proteins to reduce cyclic AMP levels and to activate a Gi/o protein/phospholipase C/calcium-dependent protein kinase/extracellular signal-regulated kinase 1/2 (ERK1/2) axis. We show further that WNT-5A-induced ERK1/2 signaling is responsible for distinct aspects of the proinflammatory transformation, such as matrix metalloprotease 9/13 expression, invasion and proliferation. Thus, WNT-5A-induced and G protein-dependent signaling to ERK1/2 is important for the regulation of proinflammatory responses in mouse primary microglia cells. We show for the first time that WNT-5A/G protein signaling mediates physiologically important processes in primary mammalian cells with natural receptor and G protein stochiometry. Consequently, WNT-5A emerges as an important means of astrocyte-microglia communication and we, therefore, suggest WNT-5A as a new player in neuroinflammatory conditions, such as neurodegenerative disease, hypoxia, stroke, injury and infection.
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