Institute of Chemistry and Biochemistry, Freie Universität Berlin, Takustraße 6, 14195 Berlin, Germany.
EMBO Rep. 2012 Dec;13(12):1087-94. doi: 10.1038/embor.2012.164. Epub 2012 Nov 13.
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.
磷脂酰肌醇 4-磷酸(PI(4)P)及其代谢酶在细胞信号转导和膜运输中发挥着重要作用。PI 4-激酶 IIα(PI4KIIα)调节 Wnt 信号转导、信号受体的内体分选,并促进衔接蛋白募集到内体和高尔基体。在这里,我们确定 E3 泛素连接酶 Itch 是 PI4KIIα 功能的结合伴侣和调节剂。Itch 直接与 PI4KIIα 结合并泛素化 PI4KIIα,并且这两种蛋白质都在含有 Wnt 激活的卷曲蛋白 4(Fz4)受体的内体上共定位。PI4KIIα 或 Itch 的耗竭调节 Wnt 信号转导,伴随 Fz4 内化和降解分选的相应变化。这些发现揭示了磷酸肌醇调节的内体膜运输、泛素和 Wnt 信号转导调节之间的新分子联系。