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Dishevelled enables casein kinase 1-mediated phosphorylation of Frizzled 6 required for cell membrane localization
Masaryk Univ, Fac Sci, Lab WNT Signaling, Inst Expt Biol, Kotlarska 2, CS-61137 Brno, Czech Republic;Karolinska Inst, Biomedicum 6D, Dept Physiol & Pharmacol, Sect Receptor Biol & Signaling, Tomtebodavagen 16, SE-17165 Stockholm, Sweden.
Karolinska Inst, Biomedicum 6D, Dept Physiol & Pharmacol, Sect Receptor Biol & Signaling, Tomtebodavagen 16, SE-17165 Stockholm, Sweden.
Masaryk Univ, Fac Sci, Lab WNT Signaling, Inst Expt Biol, Kotlarska 2, CS-61137 Brno, Czech Republic.
Karolinska Inst, Biomedicum 6D, Dept Physiol & Pharmacol, Sect Receptor Biol & Signaling, Tomtebodavagen 16, SE-17165 Stockholm, Sweden.
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2018 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 293, no 48, p. 18477-18493Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
American Society for Biochemistry and Molecular Biology, 2018. Vol. 293, no 48, p. 18477-18493
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Cell Biology
Identifiers
URN: urn:nbn:se:uu:diva-377983DOI: 10.1074/jbc.RA118.004656ISI: 000458467300006PubMedID: 30309985OAI: oai:DiVA.org:uu-377983DiVA, id: diva2:1293411
Funder
Swedish Research Council, 2013-5708Swedish Research Council, 2015-02899Knut and Alice Wallenberg Foundation, KAW2008.0149Swedish Cancer Society, CAN2014/659, CAN2017/561Stiftelsen Olle Engkvist Byggmästare, 2016/193German Research Foundation (DFG), KO 5463/1-1European Social Fund (ESF)The Karolinska Institutet's Research FoundationScience for Life Laboratory - a national resource center for high-throughput molecular bioscienceAvailable from: 2019-03-04 Created: 2019-03-04 Last updated: 2019-03-04Bibliographically approved

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