Dvl3 translocates IPMK to the cell membrane in response to Wnt

Cell Signal. 2012 Dec;24(12):2389-95. doi: 10.1016/j.cellsig.2012.08.009. Epub 2012 Aug 30.

Abstract

Wnt3a binds Frizzled-1 and the LRP5/6 co-receptors, ultimately activating Lef/Tcf-sensitive gene transcription in development. Inositol polyphosphate multikinase, IPMK, which possesses inositol phosphate kinase and lipid inositol kinase activities, is essential in Wnt3a regulation of its canonical pathway as well as physiologically in AMPK signaling. In the current report we show that translocation of IPMK to the cell membrane, where its substrates exist in high abundance, is obligate to its function in Wnt signaling. Translocation of IPMK to the cell membrane occurs within 5 min after Wnt3a stimulation. IPMK ducking onto Dishevelled-3 (Dvl3) requires a PDZ domain and the COOH-terminal prolyly-rich tail of Dvl3. Wnt3a-stimulates mobilization of Dvl3 to the cell membrane, translocating IPMK to the cell membrane also, to facilitate downstream signaling of Frizzled1. Deletion mutant of IPMK lacking the NH2-terminal variable region, IPMKΔN, fails to translocate to the cell membrane and to propagate canonical signaling. Targeting the IPMKΔN back to the cell membrane by addition of an isoprenylated CAAX box rescues its function in Wnt3a downstream signaling.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cell Line, Tumor
  • Cell Membrane / metabolism
  • Dishevelled Proteins
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Mutation
  • PDZ Domains
  • Phosphoproteins / antagonists & inhibitors
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors
  • Phosphotransferases (Alcohol Group Acceptor) / genetics
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Protein Binding
  • Proteins / metabolism
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Rats
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Signal Transduction
  • Wnt3 Protein / genetics
  • Wnt3 Protein / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Dishevelled Proteins
  • Dvl3 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Phosphoproteins
  • Proteins
  • RNA, Small Interfering
  • Recombinant Proteins
  • WD repeat containing planar cell polarity effector
  • Wnt3 Protein
  • Phosphotransferases (Alcohol Group Acceptor)
  • inositol polyphosphate multikinase