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PI4K2β/AP-1-based TGN-endosomal sorting regulates Wnt signaling

Item Type:Article
Title:PI4K2β/AP-1-based TGN-endosomal sorting regulates Wnt signaling
Creators Name:Wieffer, M., Cibrian Uhalte, E., Posor, Y., Otten, C., Branz, K., Schuetz, I., Moessinger, J., Schu, P., Abdelilah-Seyfried, S., Krauss, M. and Haucke, V.
Abstract:Endosomal membrane traffic serves crucial roles in cell physiology, signaling, and development. Sorting between endosomes and the trans-Golgi network (TGN) is regulated among other factors by the adaptor AP-1, an essential component of multicellular organisms. Membrane recruitment of AP-1 requires phosphatidylinositol 4-phosphate [PI(4)P], though the precise mechanisms and PI4 kinase isozyme (or isozymes) involved in generation of this PI(4)P pool remain unclear. The Wnt pathway is a major developmental signaling cascade and depends on endosomal sorting in Wnt-sending cells. Whether TGN/endosomal sorting modulates signaling downstream of Frizzled (Fz) receptors in Wnt-receiving cells is unknown. Here, we identify PI4-kinase type 2{beta} (PI4K2{beta}) as a regulator of TGN/endosomal sorting and Wnt signaling. PI4K2{beta} and AP-1 interact directly and are required for efficient sorting between endosomes and the TGN. Zebrafish embryos depleted of PI4K2{beta} or AP-1 lack pectoral fins due to defective Wnt signaling. Rescue experiments demonstrate requirements for PI4K2{beta}-AP-1 complex formation and PI4K2{beta}-mediated PI(4)P synthesis. Furthermore, PI4K2{beta} binds to the Fz-associated component Dishevelled (Dvl) and regulates endosomal recycling of Fz receptors and Wnt target gene expression. These data reveal an evolutionarily conserved role for PI4K2{beta} and AP-1 in coupling phosphoinositide metabolism to AP-1-mediated sorting and Wnt signaling.
Keywords:Cell Line, Endosomes, Frizzled Receptors, Phosphatidylinositol Phosphates, Phosphotransferases (Alcohol Group Acceptor), Protein Transport, Transcription Factor AP-1, trans-Golgi Network, Wnt Signaling Pathway, Animals, Mice, Rats, Zebrafish
Source:Current Biology
Publisher:Cell Press
Page Range:2185-2190
Date:4 November 2013
Official Publication:https://doi.org/10.1016/j.cub.2013.09.017
PubMed:View item in PubMed

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