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

Phosphatidylinositol (PI) 4-phosphate (PI(4) P) and its metabolizing enzymes serve important functions in cell signalling and membrane traffic. PI 4-kinase type II alpha (PI4KII alpha) 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 PI4KII alpha function. Itch directly associates with and ubiquitinates PI4KII alpha, and both proteins colocalize on endosomes containing Wnt-activated frizzled 4 (Fz4) receptor. Depletion of PI4KII alpha 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.