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FZD(5) is a G alpha(q)-coupled receptor that exhibits the functional hallmarks of prototypical GPCRs
Karolinska Inst, Sect Receptor Biol & Signaling, Dept Physiol & Pharmacol, S-17165 Stockholm, Sweden;Univ Montreal, Inst Res Immunol & Canc, Dept Biochem & Mol Med, Montreal, PQ H3C 3J7, Canada.
Univ Wurzburg, Inst Pharmacol & Toxicol, Versbacher Str 9, D-97078 Wurzburg, Germany;Friedrich Schiller Univ Jena, Univ Hosp Jena, Inst Mol Cell Biol, Ctr Mol Biomed, Hans Knoll Str 2, D-07745 Jena, Germany.
Univ Bonn, Inst Pharmaceut Biol, D-53115 Bonn, Germany.
Univ Bonn, Inst Pharmaceut Biol, D-53115 Bonn, Germany.
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2018 (English)In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 11, no 559, article id eaar5536Article in journal (Refereed) Published
Abstract [en]

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 (FZD(5)) is one of the most studied class F GPCRs that promote the functional inactivation of the beta-catenin destruction complex in response to WNTs. However, whether FZDs function as prototypical GPCRs has been heavily debated and, in particular, FZD(5) has not been shown to activate heterotrimeric G proteins. Here, we show that FZD(5) 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 FZD(5) activated G alpha(q) and its downstream effectors upon stimulation with WNT-5A. Together, these findings suggest that FZD(5) is a 7TM receptor with a bona fide GPCR activation profile and suggest novel targets for drug discovery in WNT-FZD signaling.

Place, publisher, year, edition, pages
AMER ASSOC ADVANCEMENT SCIENCE , 2018. Vol. 11, no 559, article id eaar5536
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Cell Biology
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URN: urn:nbn:se:uu:diva-373003DOI: 10.1126/scisignal.aar5536ISI: 000452741000001PubMedID: 30514810OAI: oai:DiVA.org:uu-373003DiVA, id: diva2:1278259
Funder
Swedish Research Council, 2015-02899Swedish Research Council, 2013-5708Knut and Alice Wallenberg Foundation, KAW2008.0149Knut and Alice Wallenberg Foundation, 2008.0139The Karolinska Institutet's Research FoundationSwedish Cancer Society, CAN2014/659Swedish Cancer Society, CAN2017/561Novo Nordisk, NNF17OC0026940Swedish Society for Medical Research (SSMF)Science for Life Laboratory - a national resource center for high-throughput molecular bioscienceGerman Research Foundation (DFG), TRR166German Research Foundation (DFG), FOR2372German Research Foundation (DFG), RTG1873Available from: 2019-01-14 Created: 2019-01-14 Last updated: 2019-01-14Bibliographically approved

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Matricon, PierreCarlsson, Jens

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