title: A selective PIKfyve inhibitor blocks PtdIns(3,5)P(2) production and disrupts endomembrane transport and retroviral budding.
abstract: Phosphoinositides have crucial roles in cellular controls, many of which have been established through the use of small-molecule inhibitors. Here, we describe YM201636, a potent inhibitor of the mammalian class III phosphatidylinositol phosphate kinase PIKfyve, which synthesizes phosphatidylinositol 3,5-bisphosphate. Acute treatment of cells with YM201636 shows that the PIKfyve pathway is involved in the sorting of endosomal transport, with inhibition leading to the accumulation of a late endosomal compartment and blockade of retroviral exit. Inhibitor specificity is shown by the use of short interfering RNA against the target, as well as by rescue with the drug-resistant yeast orthologue Fab1. We concluded that the phosphatidylinositol 3,5-bisphosphate pathway is integral to endosome formation, determining morphology and cargo flux.
authors.affiliation: London Research Institute Cancer Research UK, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
authors.forename: Harold B J
authors.initials: HB
authors.lastname: Jefferies
authors.forename: Frank T
authors.initials: FT
authors.lastname: Cooke
authors.forename: Parmjit
authors.initials: P
authors.lastname: Jat
authors.forename: Christine
authors.initials: C
authors.lastname: Boucheron
authors.forename: Tomonobu
authors.initials: T
authors.lastname: Koizumi
authors.forename: Masahiko
authors.initials: M
authors.lastname: Hayakawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kaizawa
authors.forename: Takahide
authors.initials: T
authors.lastname: Ohishi
authors.forename: Paul
authors.initials: P
authors.lastname: Workman
authors.forename: Michael D
authors.initials: MD
authors.lastname: Waterfield
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Parker
mesh_terms: D000631:Aminopyridines / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism*; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry / Q000494:pharmacology*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D018129:Phosphatidylinositol Phosphates / Q000096:biosynthesis*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D012190:Retroviridae / Q000187:drug effects* / Q000378:metabolism*
chemical_list: C540576:6-amino-N-(3-(4-(4-morpholinyl)pyrido(3',2'-4,5)furo(3,2-d)pyrimidin-2-yl)phenyl)-3-pyridinecarboxamide; D000631:Aminopyridines; D015415:Biomarkers; D004791:Enzyme Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D018129:Phosphatidylinositol Phosphates; C106336:phosphatidylinositol 3,5-diphosphate; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase