Disheveled regulates precoupling of heterotrimeric G proteins to Frizzled 6

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KILLANDER Michaela BC PETERSEN Julian ANDRESSEN Kjetil Wessel GANJI Sri Ranjani LEVY Finn Olav SCHUSTER Jens DAHL Niklas BRYJA Vítězslav SCHULTE Gunnar

Year of publication 2014
Type Article in Periodical
Magazine / Source FASEB JOURNAL
MU Faculty or unit

Faculty of Science

Field Genetics and molecular biology
Keywords GNAI1; GNAQ; GPCR; WNT-5A
Description Frizzleds (FZDs) are classified as G-protein-coupling receptors, but how signals are initiated and specified through heterotrimeric G proteins is unknown. FZD6 regulates convergent extension movements, and its C-terminal Arg511Cys mutation causes nail dysplasia in humans. We investigated the functional relationship between FZD6, Disheveled (DVL), and heterotrimeric G proteins. Live cell imaging combined with fluorescence recovery after photobleaching (FRAP) revealed that inactive human FZD6 precouples to GALPHAi1 and GALPHAq but not to GALPHAoA,GALPHAs, and GALPHA12 proteins. G-protein coupling is measured as a 10-20% reduction in the mobile fraction of fluorescently tagged G proteins on chemical receptor surface cross-linking. The FZD6 Arg511Cys mutation is incapable of G-protein precoupling, even though it still binds DVL. Using both FRAP and Förster resonance energy transfer (FRET) technology, we showed that the FZD6-GALPHAi1 and FZD-GALPHAq complexes dissociate on WNT-5A stimulation. Most important, G-protein precoupling of FZD6 and WNT-5A-induced signaling to extracellular signal-regulated kinase1/2 were impaired by DVL knockdown or overexpression, arguing for a strict dependence of FZD6-G-protein coupling on DVL levels and identifying DVL as a master regulator of FZD/G-protein signaling. In summary, we propose a mechanistic connection between DVL and G proteins integrating WNT, FZD, G-protein, and DVL function.
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