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Sci Signal. 2018 Dec 4;11(559). pii: eaar5536. doi: 10.1126/scisignal.aar5536.

FZD5 is a Gαq-coupled receptor that exhibits the functional hallmarks of prototypical GPCRs.

Author information

1
Section of Receptor Biology and Signaling, Department of Physiology and Pharmacology, Karolinska Institutet, S17165 Stockholm, Sweden.
2
Department of Biochemistry and Molecular Medicine, Institute for Research in Immunology and Cancer, University of Montréal, Montréal, QC H3C 3J7, Canada.
3
Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Strasse 9, 97078 Würzburg, Germany.
4
Institute for Molecular Cell Biology, CMB-Center for Molecular Biomedicine, University Hospital Jena, Friedrich-Schiller University Jena, Hans-Knöll-Strasse 2, 07745 Jena, Germany.
5
Institute for Pharmaceutical Biology, University of Bonn, 53115 Bonn, Germany.
6
Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, P.O. Box 596, SE-751 24 Uppsala, Sweden.
7
Department of Medicine, Research Institute of the McGill University Health Center, McGill University, Montréal, QC H4A 3J1, Canada.
8
Department of Pharmacology and Therapeutics, McGill University, Montréal, QC H3G 1Y6, Canada.
9
Section of Receptor Biology and Signaling, Department of Physiology and Pharmacology, Karolinska Institutet, S17165 Stockholm, Sweden. gunnar.schulte@ki.se carsten.hoffmann@uni-jena.de.
10
Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Strasse 9, 97078 Würzburg, Germany. gunnar.schulte@ki.se carsten.hoffmann@uni-jena.de.

Abstract

Frizzleds (FZDs) are a group of seven transmembrane-spanning (7TM) receptors that belong to class F of the G protein-coupled receptor (GPCR) superfamily. FZDs bind WNT proteins to stimulate diverse signaling cascades involved in embryonic development, stem cell regulation, and adult tissue homeostasis. Frizzled 5 (FZD5) is one of the most studied class F GPCRs that promote the functional inactivation of the β-catenin destruction complex in response to WNTs. However, whether FZDs function as prototypical GPCRs has been heavily debated and, in particular, FZD5 has not been shown to activate heterotrimeric G proteins. Here, we show that FZD5 exhibited a conformational change after the addition of WNT-5A, which is reminiscent of class A and class B GPCR activation. In addition, we performed several live-cell imaging and spectrometric-based approaches, such as dual-color fluorescence recovery after photobleaching (dcFRAP) and resonance energy transfer (RET)-based assays that demonstrated that FZD5 activated Gαq and its downstream effectors upon stimulation with WNT-5A. Together, these findings suggest that FZD5 is a 7TM receptor with a bona fide GPCR activation profile and suggest novel targets for drug discovery in WNT-FZD signaling.

PMID:
30514810
DOI:
10.1126/scisignal.aar5536

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