title: Dvl3 translocates IPMK to the cell membrane in response to Wnt.
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.
authors.affiliation: Department of Physiology & Biophysics, School of Medicine, Health Sciences Center, State University of New York at Stony Brook, Stony Brook, NY 11794-8661 USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Hsien-yu
authors.initials: HY
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D000072261:Dishevelled Proteins; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D009154:Mutation; D054731:PDZ Domains; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D060508:Wnt3 Protein / Q000235:genetics / Q000378:metabolism*; D000099274:Frizzled-Related Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000072261:Dishevelled Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D017853:Phosphotransferases (Alcohol Group Acceptor); D011506:Proteins; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D060508:Wnt3 Protein; D000099274:Frizzled-Related Proteins; C000606585:Dvl3 protein, mouse; C434257:inositol polyphosphate multikinase