The tyrosine Y250 2.39 in Frizzled 4 defines a conserved motif important for structural integrity of the receptor and recruitment of Disheveled.

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Authors

STRAKOVÁ Kateřina MATRICON Pierre YOKOTA Chika ARTHOFER Elisa BERNATÍK Ondřej RODRIGUEZ David ARENAS CASES Ernesto CARLSSON Jens BRYJA Vítězslav SCHULTE Gunnar

Year of publication 2017
Type Article in Periodical
Magazine / Source Cellular Signalling
MU Faculty or unit

Faculty of Science

Citation
Web http://www.sciencedirect.com/science/article/pii/S0898656817301766?via%3Dihub
Doi http://dx.doi.org/10.1016/j.cellsig.2017.06.018
Field Physiology
Keywords Disheveled; DVL2; Frizzled; FZD(4); GNA12; GNA13
Description 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 beta-catenin-dependent and beta-catenin-independent WNT signaling induced in Xenopus laevis embryos. The same mutant maintained interaction with the heterotrimeric G proteins Galfa12 and Galfa13 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.
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