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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aminopyridines / chemistry
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Aminopyridines / pharmacology*
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Animals
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Biological Transport / drug effects
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Biomarkers / metabolism
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Cell Membrane / drug effects*
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Cell Membrane / metabolism*
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Endosomes / drug effects
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Endosomes / metabolism
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Heterocyclic Compounds, 3-Ring / chemistry
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Heterocyclic Compounds, 3-Ring / pharmacology*
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Lysosomes / drug effects
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Lysosomes / metabolism
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Mice
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NIH 3T3 Cells
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Phosphatidylinositol Phosphates / biosynthesis*
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Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors*
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Retroviridae / drug effects*
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Retroviridae / metabolism*
Substances
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6-amino-N-(3-(4-(4-morpholinyl)pyrido(3',2'-4,5)furo(3,2-d)pyrimidin-2-yl)phenyl)-3-pyridinecarboxamide
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Aminopyridines
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Biomarkers
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Enzyme Inhibitors
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Heterocyclic Compounds, 3-Ring
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Phosphatidylinositol Phosphates
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phosphatidylinositol 3,5-diphosphate
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Phosphotransferases (Alcohol Group Acceptor)
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1-phosphatidylinositol-4-phosphate 5-kinase