title: Phosphatidylinositol 4-kinase IIα function at endosomes is regulated by the ubiquitin ligase Itch.
abstract: Phosphatidylinositol (PI) 4-phosphate (PI(4)P) and its metabolizing enzymes serve important functions in cell signalling and membrane traffic. PI 4-kinase type IIα (PI4KIIα) regulates Wnt signalling, endosomal sorting of signalling receptors, and promotes adaptor protein recruitment to endosomes and the trans-Golgi network. Here we identify the E3 ubiquitin ligase Itch as binding partner and regulator of PI4KIIα function. Itch directly associates with and ubiquitinates PI4KIIα, and both proteins colocalize on endosomes containing Wnt-activated frizzled 4 (Fz4) receptor. Depletion of PI4KIIα or Itch regulates Wnt signalling with corresponding changes in Fz4 internalization and degradative sorting. These findings unravel a new molecular link between phosphoinositide-regulated endosomal membrane traffic, ubiquitin and the modulation of Wnt signalling.
authors.affiliation: Institute of Chemistry and Biochemistry, Freie Universität Berlin, Takustraße 6, 14195 Berlin, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Mössinger
authors.forename: Marnix
authors.initials: M
authors.lastname: Wieffer
authors.forename: Eberhard
authors.initials: E
authors.lastname: Krause
authors.forename: Christian
authors.initials: C
authors.lastname: Freund
authors.forename: Fabian
authors.initials: F
authors.lastname: Gerth
authors.forename: Michael
authors.initials: M
authors.lastname: Krauss
authors.forename: Volker
authors.initials: V
authors.lastname: Haucke
mesh_terms: D000818:Animals; D011992:Endosomes / Q000378:metabolism; D051157:Frizzled Receptors / Q000235:genetics / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D015778:Minor Histocompatibility Antigens; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D021601:trans-Golgi Network / Q000378:metabolism*
chemical_list: D051157:Frizzled Receptors; C498581:Fzd4 protein, mouse; D015778:Minor Histocompatibility Antigens; D025801:Ubiquitin; C471637:Itch protein, mouse; D044767:Ubiquitin-Protein Ligases; D017853:Phosphotransferases (Alcohol Group Acceptor); C402182:phosphatidylinositol phosphate 4-kinase