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.
journal_name
Sci Signaljournal_title
Science signalingauthors
Wright SC,Cañizal MCA,Benkel T,Simon K,Le Gouill C,Matricon P,Namkung Y,Lukasheva V,König GM,Laporte SA,Carlsson J,Kostenis E,Bouvier M,Schulte G,Hoffmann Cdoi
10.1126/scisignal.aar5536subject
Has Abstractpub_date
2018-12-04 00:00:00issue
559eissn
1945-0877issn
1937-9145pii
11/559/eaar5536journal_volume
11pub_type
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