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@article{1356016,
author = {Arthofer, E. and Hot, B. and Petersen, J. and Straková, Kateřina and Jager, S. and Grundmann, M. and Kostenis, E. and Gutkind, JS and Schulte, Gunnar},
article_location = {Baltimore, USA},
article_number = {4},
doi = {http://dx.doi.org/10.1124/mol.116.104919},
keywords = {FZD4; WNT; G protein; GNA12; GNA13; p115-RHOGEF},
language = {eng},
issn = {0026-895X},
journal = {Molecular Pharmacology},
title = {WNT Stimulation Dissociates a Frizzled 4 Inactive-State Complex with G alpha(12/13)},
url = {http://molpharm.aspetjournals.org/content/90/4/447},
volume = {90},
year = {2016}
}
TY - JOUR
ID - 1356016
AU - Arthofer, E. - Hot, B. - Petersen, J. - Straková, Kateřina - Jager, S. - Grundmann, M. - Kostenis, E. - Gutkind, JS - Schulte, Gunnar
PY - 2016
TI - WNT Stimulation Dissociates a Frizzled 4 Inactive-State Complex with G alpha(12/13)
JF - Molecular Pharmacology
VL - 90
IS - 4
SP - 447-459
EP - 447-459
PB - Williams and Wilkins
SN - 0026895X
KW - FZD4
KW - WNT
KW - G protein
KW - GNA12
KW - GNA13
KW - p115-RHOGEF
UR - http://molpharm.aspetjournals.org/content/90/4/447
N2 - Frizzleds (FZDs) are unconventional G protein-coupled receptors that belong to the class Frizzled. They are bound and activated by the Wingless/Int-1 lipoglycoprotein (WNT) family of secreted lipoglycoproteins. To date, mechanisms of signal initiation and FZD-G protein coupling remain poorly understood. Previously, we showed that FZD(6) assembles withG alpha(i1)/G alpha(q) (but not withG alpha(s), G alpha(o) and G alpha(12/13)), and that these inactive-state complexes are dissociated by WNTs and regulated by the phosphoprotein Dishevelled (DVL). Here, we investigated the inactive-state assembly of heterotrimeric G proteins with FZD(4), a receptor important in retinal vascular development and frequently mutated in Norrie disease or familial exudative vitreoretinopathy. Live-cell imaging experiments using fluorescence recovery after photobleaching show that human FZD(4) assembles-in a DVL-independent manner-with G alpha(12/13) but not representatives of other heterotrimeric G protein subfamilies, such as G alpha(i1), G alpha(o), G alpha(s), andG alpha(q). The FZD(4)-Gprotein complex dissociates upon stimulation with WNT-3A, WNT-5A, WNT-7A, and WNT-10B. In addition, WNT-induced dynamic mass redistribution changes in untransfected and, even more so, in FZD(4) green fluorescent protein-transfected cells depend on G alpha(12/13). Furthermore, expression of FZD(4) and G alpha(12) or G alpha(13) in human embryonic kidney 293 cells induces WNT-dependent membrane recruitment of p115-RHOGEF (RHO guanine nucleotide exchange factor, molecular weight 115 kDa), a direct target of G alpha(12/13) signaling, underlining the functionality of an FZD(4)-G alpha(12/13)-RHO signaling axis. In summary, G alpha(12/13)-mediatedWNT/FZD(4) signaling through p115-RHOGEF offers an intriguing and previously unappreciated mechanistic link of FZD(4) signaling to cytoskeletal rearrangements and RHO signaling with implications for the regulation of angiogenesis during embryonic and tumor development.
ER -
ARTHOFER, E., B. HOT, J. PETERSEN, Kateřina STRAKOVÁ, S. JAGER, M. GRUNDMANN, E. KOSTENIS, JS GUTKIND and Gunnar SCHULTE. WNT Stimulation Dissociates a Frizzled 4 Inactive-State Complex with G alpha(12/13). \textit{Molecular Pharmacology}. Baltimore, USA: Williams and Wilkins, vol.~90, No~4, p.~447-459. ISSN~0026-895X. doi:10.1124/mol.116.104919. 2016.
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