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The tyrosine Y250(2.39) in Frizzled 4 defines a conserved motif important for structural integrity of the receptor and recruitment of Disheveled
Masaryk Univ, Fac Sci, Inst Expt Biol, Lab WNT Signaling, Kotiarska 2, Brno 61137, Czech Republic.;Karolinska Inst, Dept Physiol & Pharmacol, Lab Receptor Biol & Signaling, Nanna Svartz Vag 2, S-17177 Stockholm, Sweden..
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
Karolinska Inst, Dept Med Biochem & Biophys, Lab Mol Neurobiol, Scheelevag 2, S-17177 Stockholm, Sweden..
Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Signal Transduct, NIH, 35A Convent Dr,MSC 3752, Bethesda, MD 20892 USA..
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2017 (English)In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 38, 85-96 p.Article in journal (Refereed) Published
Abstract [en]

Frizzleds (FZDs) are unconventional G protein-coupled receptors, which activate diverse intracellular signaling pathways via the phosphoprotein Disheveled (DVL) and heterotrimeric G proteins. The Interaction interplay of FZDs with DVL and G proteins is complex, involves different regions of FZD and the potential dynamics are poorly understood. In the present study, we aimed to characterize the function of a highly conserved tyrosine (Y250(2.39)) in the intracellular loop 1 (ILl) of human FZD(4). We have found Y250(2.39) to be crucial for DVL2 interaction and DVL2 translocation to the plasma membrane. Mutant FZD4-Y250(2.39)F, impaired in DVL2 binding, was defective in both beta-catenin-dependent and beta-catenin-independent WNT signaling induced in Xenopus laevis embryos. The same mutant maintained interaction with the heterotrimeric G proteins Gan and G alpha(13) and was able to mediate WNT-induced G protein dissociation and G protein-dependent YAP/TAZ signaling. We conclude from modeling and dynamics simulation efforts that Y250(2.39) is important for the structural integrity of the FZD-DVL, but not for the FZD-G protein interface and hypothesize that the interaction network of Y250(2.39) and H348(4.46) plays a role in specifying downstream signaling pathways induced by the receptor.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE INC , 2017. Vol. 38, 85-96 p.
Keyword [en]
Disheveled, DVL2, Frizzled, FZD(4), GNA12, GNA13
National Category
Cell Biology
Identifiers
URN: urn:nbn:se:uu:diva-334748DOI: 10.1016/j.cellsig.2017.06.018ISI: 000408788800009PubMedID: 28668722OAI: oai:DiVA.org:uu-334748DiVA: diva2:1161662
Funder
Swedish Research Council, 2011-2435, 2013-5708, 2015-02899Science for Life Laboratory - a national resource center for high-throughput molecular bioscienceSwedish Cancer Society, CAN2011/690, 2014/659Knut and Alice Wallenberg Foundation, KAW2008.0149Stiftelsen Olle Engkvist ByggmästareLars Hierta Memorial FoundationThe Royal Swedish Academy of Sciences
Available from: 2017-11-30 Created: 2017-11-30 Last updated: 2017-11-30Bibliographically approved

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Matricon, PierreCarlsson, Jens

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