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: 11.54). 11/2007; 28(10):518-25. DOI: 10.1016/
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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    • "Nineteen Wnt genes have been identified in the vertebrate genome, all of which signal through the seven-transmembrane-domain Frizzled (FZD) receptors (Schulte et al, 2007). Signaling events occur as the direct consequence of FZD activation, via the phosphoprotein dishevelled (DVL). "
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    ABSTRACT: Hippocampal synapses play a key role in memory and learning processes by inducing long-term potentiation and depression. Wnt signaling is essential in the development and maintenance of synapses via several mechanisms. We have previously found that Wnt5a induces the production of nitric oxide (NO), which modulates NMDA receptor expression in the postsynaptic regions of hippocampal neurons. Here, we report that Wnt5a selectively inhibits a voltage-gated K(+) current (Kv current) and increases synaptic activity in hippocampal slices. Further supporting a specific role for Wnt5a, the soluble Frizzled receptor protein (sFRP-2; a functional Wnt antagonist) fully inhibits the effects of Wnt5a. We additionally show that these responses to Wnt5a are mediated by activation of a ROR2 receptor and increased NO production because they are suppressed by the shRNA-mediated knockdown of ROR2 and by 7-nitroindazole, a specific inhibitor of neuronal NOS. Together, our results show that Wnt5a increases NO production by acting on ROR2 receptors, which in turn inhibit Kv currents. These results reveal a novel mechanism by which Wnt5a may regulate the excitability of hippocampal neurons. Copyright © 2015. Published by Elsevier Inc.
    Molecular and Cellular Neuroscience 08/2015; DOI:10.1016/j.mcn.2015.08.011 · 3.84 Impact Factor
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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 · 8.68 Impact Factor
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