Publication details

Dishevelled enables casein kinase 1-mediated phosphorylation of Frizzled 6 required for cell membrane localization

Authors

STRAKOVÁ Kateřina KOWALSKI-JAHN M. GYBEĽ Tomáš VALNOHOVÁ Jana DHOPLE V.M. HARNOŠ Jakub BERNATÍK Ondřej GANJI Sri Ranjani ZDRÁHAL Zbyněk MULDER J. LINDSKOG C. BRYJA Vítězslav SCHULTE G.

Year of publication 2018
Type Article in Periodical
Magazine / Source Journal of Biological Chemistry
MU Faculty or unit

Faculty of Science

Citation
Doi http://dx.doi.org/10.1074/jbc.RA118.004656
Keywords DEP DOMAIN; FUNCTIONAL-ANALYSIS; PLANAR POLARITY; BETA-ARRESTINS; DIX DOMAIN; I-EPSILON; RECEPTOR; RECRUITMENT; COMPLEX; GROWTH
Description Frizzleds (FZDs) are receptors for secreted lipoglycoproteins of the Wingless/Int-1(WNT) family, initiating an important signal transduction network in multicellular organisms. FZDs are G protein-coupled receptors (GPCRs), which are well known to be regulated by phosphorylation, leading to specific downstream signaling or receptor desensitization. The role and underlying mechanisms of FZD phosphorylation remain largely unexplored. Here, we investigated the phosphorylation of human FZD(6). Using MS analysis and a phospho-state- and -site-specific antibody, we found that Ser-648, located in the FZD(6) C terminus, is efficiently phosphorylated by casein kinase 1 is an element of (CK1 is an element of) and that this phosphorylation requires the scaffolding protein Dishevelled (DVL). In an overexpression system, DVL1, -2, and -3 promoted CK1-mediated FZD(6) phosphorylation on Ser-648. This DVL activity required an intact DEP domain and FZD-mediated recruitment of this domain to the cell membrane. Substitution of the CK1 is an element of-targeted phosphomo-tif reduced FZD(6) surface expression, suggesting that Ser-648 phosphorylation controls membrane trafficking of FZD(6). Phos-pho-Ser-648 FZD(6) immunoreactivity in human fallopian tube epithelium was predominantly apical, associated with cilia in a subset of epithelial cells, compared with the total FZD(6) protein expression, suggesting that FZD(6) phosphorylation contributes to asymmetric localization of receptor function within the cell and to epithelial polarity. Given the key role of FZD(6) in planar cell polarity, our results raise the possibility that asymmetric phosphorylation of FZD(6) rather than asymmetric protein distribution accounts for polarized receptor signaling.
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