SHIP2 controls PtdIns(3,4,5)P(3) levels and PKB activity in response to oxidative stress

Cell Signal. 2007 Oct;19(10):2194-200. doi: 10.1016/j.cellsig.2007.06.022. Epub 2007 Jun 30.

Abstract

Reactive oxygen species (ROS) are known to be involved in redox signalling pathways that may contribute to normal cell function as well as disease progression. The tumour suppressor PTEN and the inositol 5-phosphatase SHIP2 are critical enzymes in the control of PtdIns(3,4,5)P(3) level. It has been reported that oxidants, including those produced in cells such as macrophages, can activate downstream signalling via the inactivation of PTEN. The present study evaluates the potential impact of SHIP2 on phosphoinositides in cells exposed to sodium peroxide. We used a model of SHIP2 deficient mouse embryonic fibroblasts (MEFs) stimulated by H(2)O(2): at 15 min, PtdIns(3,4,5)P(3) was markedly increased in SHIP2 -/- cells as compared to +/+ cells. In contrast, no significant increase in PtdIns(3,4)P(2) could be detected at 15 or 120 min incubation of the cells with H(2)O(2) (0.6 mM). PKB activity was also upregulated in SHIP2 -/- cells as compared to +/+ cells in response to H(2)O(2). SHIP2 add back experiments in SHIP2 -/- cells confirm its critical role as a lipid phosphatase in the control of PtdIns(3,4,5)P(3) level in response to H(2)O(2). We conclude that SHIP2 lipid phosphatase activity plays an important role in the metabolism PtdIns(3,4,5)P(3) which is demonstrated in oxygen stressed cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Fibroblasts / drug effects
  • Fibroblasts / enzymology
  • Homeodomain Proteins / metabolism
  • Hydrogen Peroxide / pharmacology
  • Inositol Polyphosphate 5-Phosphatases
  • Mice
  • Mice, Knockout
  • Oxidative Stress*
  • Phosphatidylinositol Phosphates / metabolism*
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
  • Phosphoric Monoester Hydrolases / genetics
  • Phosphoric Monoester Hydrolases / physiology*
  • Proto-Oncogene Proteins c-akt / metabolism*

Substances

  • Homeodomain Proteins
  • Phosphatidylinositol Phosphates
  • Phox2a protein, mouse
  • phosphatidylinositol 3,4,5-triphosphate
  • Hydrogen Peroxide
  • Proto-Oncogene Proteins c-akt
  • Phosphoric Monoester Hydrolases
  • Inositol Polyphosphate 5-Phosphatases
  • Inppl1 protein, mouse
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases