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J Cell Biol. 2019 Jul 1;218(7):2198-2214. doi: 10.1083/jcb.201805155. Epub 2019 May 22.

PTEN reduces endosomal PtdIns(4,5)P2 in a phosphatase-independent manner via a PLC pathway.

Author information

1
Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Canada.
2
Membrane Traffic and Cell Division Lab, Institut Pasteur, UMR3691, Centre National de la Recherche Scientifique, Paris, France.
3
Sorbonne Université, Collège Doctoral, Paris, France.
4
Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
5
Institut des Maladies Génétiques Imagine, Hôpital Necker-Enfants Malades, Université Paris Descartes, Paris, France.
6
Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK martin.p.lowe@manchester.ac.uk.
7
Membrane Traffic and Cell Division Lab, Institut Pasteur, UMR3691, Centre National de la Recherche Scientifique, Paris, France arnaud.echard@pasteur.fr.
8
Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Canada sebastien.carreno@umontreal.ca.
9
Université de Montréal, Département de Pathologie et de Biologie Cellulaire, Montreal, Canada.
#
Contributed equally

Abstract

The tumor suppressor PTEN dephosphorylates PtdIns(3,4,5)P3 into PtdIns(4,5)P2 Here, we make the unexpected discovery that in Drosophila melanogaster PTEN reduces PtdIns(4,5)P2 levels on endosomes, independently of its phosphatase activity. This new PTEN function requires the enzymatic action of dPLCXD, an atypical phospholipase C. Importantly, we discovered that this novel PTEN/dPLCXD pathway can compensate for depletion of dOCRL, a PtdIns(4,5)P2 phosphatase. Mutation of OCRL1, the human orthologue of dOCRL, causes oculocerebrorenal Lowe syndrome, a rare multisystemic genetic disease. Both OCRL1 and dOCRL loss have been shown to promote accumulation of PtdIns(4,5)P2 on endosomes and cytokinesis defects. Here, we show that PTEN or dPLCXD overexpression prevents these defects. In addition, we found that chemical activation of this pathway restores normal cytokinesis in human Lowe syndrome cells and rescues OCRL phenotypes in a zebrafish Lowe syndrome model. Our findings identify a novel PTEN/dPLCXD pathway that controls PtdIns(4,5)P2 levels on endosomes. They also point to a potential new strategy for the treatment of Lowe syndrome.

PMID:
31118240
PMCID:
PMC6605811
[Available on 2020-01-01]
DOI:
10.1083/jcb.201805155

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