Phosphatidylinositol 4-kinase IIα function at endosomes is regulated by the ubiquitin ligase Itch

• Published in: EMBO reports Vol. 13; no. 12; pp. 1087 - 1094
• Main Authors: Mössinger, Julia, Wieffer, Marnix, Krause, Eberhard, Freund, Christian, Gerth, Fabian, Krauss, Michael, Haucke, Volker
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.12.2012; Nature Publishing Group UK; Nature Publishing Group
• Subjects: Animals; E3 ubiquitin ligase; EMBO20; endosomes; Endosomes - metabolism; Frizzled Receptors - genetics; Frizzled Receptors - metabolism; Golgi Apparatus - metabolism; HEK293 Cells; HeLa Cells; Humans; Itch; Mice; Minor Histocompatibility Antigens; phosphatidylinositol 4-kinase type IIα; Phosphotransferases (Alcohol Group Acceptor) - genetics; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Protein Binding; Protein Transport; Scientific Report; Scientific Reports; trans-Golgi Network - metabolism; Ubiquitin - metabolism; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Wnt Signaling Pathway; Wnt signalling; endosomes; Itch; E3 ubiquitin ligase; Wnt signalling; phosphatidylinositol 4‐kinase type IIα
• ISSN: 1469-221X; 1469-3178
• DOI: 10.1038/embor.2012.164

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. This study identifies a complex between PI4KIIa and the E3 ubiquitin ligase Itch that modulates Wnt signaling by linking PI4P‐mediated endosomal membrane traffic to degradative sorting of Fz receptors.