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

EMBO Rep. 2012 Dec;13(12):1087-94. doi: 10.1038/embor.2012.164. Epub 2012 Nov 13.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Endosomes / metabolism
  • Frizzled Receptors* / genetics
  • Frizzled Receptors* / metabolism
  • Golgi Apparatus / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Mice
  • Minor Histocompatibility Antigens
  • Phosphotransferases (Alcohol Group Acceptor)* / genetics
  • Phosphotransferases (Alcohol Group Acceptor)* / metabolism
  • Protein Binding
  • Protein Transport
  • Ubiquitin / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Wnt Signaling Pathway
  • trans-Golgi Network / metabolism*

Substances

  • Frizzled Receptors
  • Fzd4 protein, mouse
  • Minor Histocompatibility Antigens
  • Ubiquitin
  • Itch protein, mouse
  • Ubiquitin-Protein Ligases
  • Phosphotransferases (Alcohol Group Acceptor)
  • phosphatidylinositol phosphate 4-kinase