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EMBO reports 9, 2, 164–170 (2008)
doi:10.1038/sj.embor.7401155
AOP Published online: 11 January 2008
A selective PIKfyve inhibitor blocks PtdIns(3,5)P2 production and disrupts endomembrane transport and retroviral budding
EMBO Open
Harold B J Jefferies1*, Frank T Cooke2*, Parmjit Jat3, Christine Boucheron1†, Tomonobu Koizumi4, Masahiko Hayakawa4, Hiroyuki Kaizawa4, Takahide Ohishi4, Paul Workman5, Michael D Waterfield6 & Peter J Parker1, 7
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1 London Research Institute Cancer Research UK, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London WC2A 3PX, UK
2 Department of Biochemistry and Molecular Biology, University College London, Gower Street, London WC1E 6BT, UK
3 Department of Neurodegenerative Disease, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK
4 Institute for Drug Discovery Research, Astellas Pharma Inc, 21 Miyukigoaka, Tsukuba, Ibaraki 305-8585, Japan
5 Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey SN2 5NG, UK
6 Proteomics Unit, Wolfson Institute for Biomedical Research, University College, Gower Street, London WC1E 6BT, UK
7 The Division of Cancer Studies, King's College School of Medicine, St Thomas Street, London SE1 1UL, UK
To whom correspondence should be addressed
Peter J Parker Tel: +44 20 7269 3513; Fax: +44 20 7269 3094; E-mail: peter.parker@cancer.org.uk
* These authors contributed equally to this work
† Present address: Unilever Corporate Research, Colworth Park, Sharnbrook, Bedfordshire MK44 1LQ, UK
Received 25 September 2007; Accepted 23 November 2007; Published online 11 January 2008.
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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.
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