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Disheveled regulates precoupling of heterotrimeric G proteins to Frizzled 6
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2014 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 28, no 5, 2293-2305 p.Article in journal (Refereed) Published
Abstract [en]

Frizzleds (FZDs) are classified as G-protein-coupling receptors, but how signals are initiated and specified through heterotrimeric G proteins is unknown. FZD(6) regulates convergent extension movements, and its C-terminal Arg511Cys mutation causes nail dysplasia in humans. We investigated the functional relationship between FZD(6), Disheveled (DVL), and heterotrimeric G proteins. Live cell imaging combined with fluorescence recovery after photobleaching (FRAP) revealed that inactive human FZD(6) precouples to G(i1) and G(q) but not to G(oA),G(s), and G(12) 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 FZD(6) Arg511Cys mutation is incapable of G-protein precoupling, even though it still binds DVL. Using both FRAP and Forster resonance energy transfer (FRET) technology, we showed that the FZD(6)-G(i1) and FZD-G(q) complexes dissociate on WNT-5A stimulation. Most important, G-protein precoupling of FZD(6) and WNT-5A-induced signaling to extracellular signal-regulated kinase1/2 were impaired by DVL knockdown or overexpression, arguing for a strict dependence of FZD(6)-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.Kilander, M. B. C., Petersen, J., Andressen, K. W., Ganji, R. S. Levy, F. O., Schuster, J., Dahl N., Bryja, V., Schulte, G. Disheveled regulates precoupling of heterotrimeric G proteins to Frizzled 6.

Place, publisher, year, edition, pages
2014. Vol. 28, no 5, 2293-2305 p.
Keyword [en]
GPCR, WNT-5A, GNAI1, GNAQ
National Category
Basic Medicine
Identifiers
URN: urn:nbn:se:uu:diva-227186DOI: 10.1096/fj.13-246363ISI: 000335336000031OAI: oai:DiVA.org:uu-227186DiVA: diva2:729905
Available from: 2014-06-26 Created: 2014-06-24 Last updated: 2017-12-05Bibliographically approved

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Schuster, JensDahl, Niklas

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