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@article{1179560,
author = {Killander, Michaela BC and Petersen, Julian and Andressen, Kjetil Wessel and Ganji, Sri Ranjani and Levy, Finn Olav and Schuster, Jens and Dahl, Niklas and Bryja, Vítězslav and Schulte, Gunnar},
article_number = {5},
doi = {http://dx.doi.org/10.1096/fj.13-246363},
keywords = {GNAI1; GNAQ; GPCR; WNT-5A},
language = {eng},
issn = {0892-6638},
journal = {FASEB JOURNAL},
title = {Disheveled regulates precoupling of heterotrimeric G proteins to Frizzled 6},
volume = {28},
year = {2014}
}
TY - JOUR
ID - 1179560
AU - Killander, Michaela BC - Petersen, Julian - Andressen, Kjetil Wessel - Ganji, Sri Ranjani - Levy, Finn Olav - Schuster, Jens - Dahl, Niklas - Bryja, Vítězslav - Schulte, Gunnar
PY - 2014
TI - Disheveled regulates precoupling of heterotrimeric G proteins to Frizzled 6
JF - FASEB JOURNAL
VL - 28
IS - 5
SP - 2293-2305
EP - 2293-2305
SN - 08926638
KW - GNAI1
KW - GNAQ
KW - GPCR
KW - WNT-5A
N2 - 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.
ER -
KILLANDER, Michaela BC, Julian PETERSEN, Kjetil Wessel ANDRESSEN, Sri Ranjani GANJI, Finn Olav LEVY, Jens SCHUSTER, Niklas DAHL, Vítězslav BRYJA and Gunnar SCHULTE. Disheveled regulates precoupling of heterotrimeric G proteins to Frizzled 6. \textit{FASEB JOURNAL}. 2014, vol.~28, No~5, p.~2293-2305. ISSN~0892-6638. Available from: https://dx.doi.org/10.1096/fj.13-246363.
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