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Cell Signal. 2017 Oct;38:85-96. doi: 10.1016/j.cellsig.2017.06.018. Epub 2017 Jun 29.

The tyrosine Y2502.39 in Frizzled 4 defines a conserved motif important for structural integrity of the receptor and recruitment of Disheveled.

Author information

1
Laboratory of WNT Signaling, Institute of Experimental Biology, Faculty of Science, Masaryk University, Kotlarska 2, 61137 Brno, Czech Republic; Laboratory of Receptor Biology and Signaling, Department of Physiology and Pharmacology, Karolinska Institutet, Nanna Svartz väg 2, 17177, Stockholm, Sweden.
2
Department of Cell and Molecular Biology, Science for Life Laboratory, Uppsala University, SE-75124 Uppsala, Sweden.
3
Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheeleväg 2, 17177 Stockholm, Sweden.
4
Section on Molecular Signal Transduction Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 35A Convent Drive, MSC 3752, Bethesda, MD 20892-3752, USA.
5
Laboratory of WNT Signaling, Institute of Experimental Biology, Faculty of Science, Masaryk University, Kotlarska 2, 61137 Brno, Czech Republic.
6
Department of Biochemistry and Biophysics and Center for Biomembrane Research, Stockholm University, SE-10691 Stockholm, Sweden.
7
Laboratory of WNT Signaling, Institute of Experimental Biology, Faculty of Science, Masaryk University, Kotlarska 2, 61137 Brno, Czech Republic; Laboratory of Receptor Biology and Signaling, Department of Physiology and Pharmacology, Karolinska Institutet, Nanna Svartz väg 2, 17177, Stockholm, Sweden. Electronic address: gunnar.schulte@ki.se.

Abstract

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 (Y2502.39) in the intracellular loop 1 (IL1) of human FZD4. We have found Y2502.39 to be crucial for DVL2 interaction and DVL2 translocation to the plasma membrane. Mutant FZD4-Y2502.39F, impaired in DVL2 binding, was defective in both β-catenin-dependent and β-catenin-independent WNT signaling induced in Xenopus laevis embryos. The same mutant maintained interaction with the heterotrimeric G proteins Gα12 and Gα13 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 Y2502.39 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 Y2502.39 and H3484.46 plays a role in specifying downstream signaling pathways induced by the receptor.

KEYWORDS:

DVL2; Disheveled; FZD(4); Frizzled; GNA12; GNA13

PMID:
28668722
DOI:
10.1016/j.cellsig.2017.06.018
[Indexed for MEDLINE]

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