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PTEN reduces endosomal PtdIns(4,5)P2 in a phosphatase-independent manner via a PLC pathway.
J Cell Biol 2019; 218(7):2198-2214JC

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.

Authors+Show Affiliations

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

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31118240

Citation

Mondin, Virginie E., et al. "PTEN Reduces Endosomal PtdIns(4,5)P2 in a Phosphatase-independent Manner Via a PLC Pathway." The Journal of Cell Biology, vol. 218, no. 7, 2019, pp. 2198-2214.
Mondin VE, Ben El Kadhi K, Cauvin C, et al. PTEN reduces endosomal PtdIns(4,5)P2 in a phosphatase-independent manner via a PLC pathway. J Cell Biol. 2019;218(7):2198-2214.
Mondin, V. E., Ben El Kadhi, K., Cauvin, C., Jackson-Crawford, A., Bélanger, E., Decelle, B., ... Carréno, S. (2019). PTEN reduces endosomal PtdIns(4,5)P2 in a phosphatase-independent manner via a PLC pathway. The Journal of Cell Biology, 218(7), pp. 2198-2214. doi:10.1083/jcb.201805155.
Mondin VE, et al. PTEN Reduces Endosomal PtdIns(4,5)P2 in a Phosphatase-independent Manner Via a PLC Pathway. J Cell Biol. 2019 Jul 1;218(7):2198-2214. PubMed PMID: 31118240.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - PTEN reduces endosomal PtdIns(4,5)P2 in a phosphatase-independent manner via a PLC pathway. AU - Mondin,Virginie E, AU - Ben El Kadhi,Khaled, AU - Cauvin,Clothilde, AU - Jackson-Crawford,Anthony, AU - Bélanger,Emilie, AU - Decelle,Barbara, AU - Salomon,Rémi, AU - Lowe,Martin, AU - Echard,Arnaud, AU - Carréno,Sébastien, Y1 - 2019/05/22/ PY - 2018/06/01/received PY - 2019/03/15/revised PY - 2019/05/02/accepted PY - 2019/5/24/pubmed PY - 2019/5/24/medline PY - 2019/5/24/entrez SP - 2198 EP - 2214 JF - The Journal of cell biology JO - J. Cell Biol. VL - 218 IS - 7 N2 - 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. SN - 1540-8140 UR - https://www.unboundmedicine.com/medline/citation/31118240/PTEN_reduces_endosomal_PtdIns_45_P2_in_a_phosphatase_independent_manner_via_a_PLC_pathway_ L2 - https://rupress.org/jcb/article-lookup/doi/10.1083/jcb.201805155 DB - PRIME DP - Unbound Medicine ER -