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. doi: 10.1083/jcb.201805155. Epub 2019 May 22.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytokinesis / genetics
  • Disease Models, Animal
  • Drosophila Proteins / genetics*
  • Drosophila melanogaster / genetics
  • Endosomes / genetics
  • Endosomes / metabolism
  • Gene Expression Regulation / genetics
  • Humans
  • Oculocerebrorenal Syndrome / genetics*
  • Oculocerebrorenal Syndrome / metabolism
  • Oculocerebrorenal Syndrome / pathology
  • PTEN Phosphohydrolase / genetics*
  • Phosphatidylinositol 4,5-Diphosphate / genetics
  • Phosphatidylinositol 4,5-Diphosphate / metabolism
  • Phosphatidylinositol Phosphates / genetics
  • Phosphatidylinositol Phosphates / metabolism
  • Phosphoric Monoester Hydrolases / genetics*
  • Signal Transduction
  • Type C Phospholipases / genetics*

Substances

  • Drosophila Proteins
  • Phosphatidylinositol 4,5-Diphosphate
  • Phosphatidylinositol Phosphates
  • phosphatidylinositol 3,4,5-triphosphate
  • Phosphoric Monoester Hydrolases
  • OCRL protein, human
  • PTEN Phosphohydrolase
  • PTEN protein, Drosophila
  • Type C Phospholipases

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