title: PI4K2β/AP-1-based TGN-endosomal sorting regulates Wnt signaling.
abstract: Endosomal membrane traffic serves crucial roles in cell physiology, signaling, and development. Sorting between endosomes and the trans-Golgi network (TGN) is regulated among other factors by the adaptor AP-1, an essential component of multicellular organisms. Membrane recruitment of AP-1 requires phosphatidylinositol 4-phosphate [PI(4)P], though the precise mechanisms and PI4 kinase isozyme (or isozymes) involved in generation of this PI(4)P pool remain unclear. The Wnt pathway is a major developmental signaling cascade and depends on endosomal sorting in Wnt-sending cells. Whether TGN/endosomal sorting modulates signaling downstream of Frizzled (Fz) receptors in Wnt-receiving cells is unknown. Here, we identify PI4-kinase type 2β (PI4K2β) as a regulator of TGN/endosomal sorting and Wnt signaling. PI4K2β and AP-1 interact directly and are required for efficient sorting between endosomes and the TGN. Zebrafish embryos depleted of PI4K2β or AP-1 lack pectoral fins due to defective Wnt signaling. Rescue experiments demonstrate requirements for PI4K2β-AP-1 complex formation and PI4K2β-mediated PI(4)P synthesis. Furthermore, PI4K2β binds to the Fz-associated component Dishevelled (Dvl) and regulates endosomal recycling of Fz receptors and Wnt target gene expression. These data reveal an evolutionarily conserved role for PI4K2β and AP-1 in coupling phosphoinositide metabolism to AP-1-mediated sorting and Wnt signaling.
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie (FMP) and Freie Universität Berlin, Robert-Rössle-Strasse 10, 13125 Berlin-Buch, Germany.
authors.forename: Marnix
authors.initials: M
authors.lastname: Wieffer
authors.forename: Elena
authors.initials: E
authors.lastname: Cibrián Uhalte
authors.forename: York
authors.initials: Y
authors.lastname: Posor
authors.forename: Cécile
authors.initials: C
authors.lastname: Otten
authors.forename: Katharina
authors.initials: K
authors.lastname: Branz
authors.forename: Irene
authors.initials: I
authors.lastname: Schütz
authors.forename: Julia
authors.initials: J
authors.lastname: Mössinger
authors.forename: Peter
authors.initials: P
authors.lastname: Schu
authors.forename: Salim
authors.initials: S
authors.lastname: Abdelilah-Seyfried
authors.forename: Michael
authors.initials: M
authors.lastname: Krauß
authors.forename: Volker
authors.initials: V
authors.lastname: Haucke
mesh_terms: D000818:Animals; D002460:Cell Line; D011992:Endosomes / Q000378:metabolism; D051157:Frizzled Receptors / Q000378:metabolism; D006801:Humans; D051379:Mice; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics* / Q000378:metabolism; D021381:Protein Transport; D051381:Rats; D018808:Transcription Factor AP-1 / Q000235:genetics* / Q000378:metabolism; D060449:Wnt Signaling Pathway; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism; D021601:trans-Golgi Network / Q000378:metabolism
chemical_list: D051157:Frizzled Receptors; D018129:Phosphatidylinositol Phosphates; D018808:Transcription Factor AP-1; D029961:Zebrafish Proteins; C037178:phosphatidylinositol 4-phosphate; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase