A selective PIKfyve inhibitor blocks PtdIns(3,5)P(2) production and disrupts endomembrane transport and retroviral budding.
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.
Jefferies
Harold B J
HB
London Research Institute Cancer Research UK, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
Cooke
Frank T
FT
Jat
Parmjit
P
Boucheron
Christine
C
Koizumi
Tomonobu
T
Hayakawa
Masahiko
M
Kaizawa
Hiroyuki
H
Ohishi
Takahide
T
Workman
Paul
P
Waterfield
Michael D
MD
Parker
Peter J
PJ
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*
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