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Redox regulation of PI 3-kinase signalling via inactivation of PTEN

Nick R Leslie1, Deborah Bennett, Yvonne E Lindsay

  • 1Division of Cell Signalling, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK. n.r.leslie@dundee.ac.uk

The EMBO Journal
|October 9, 2003
PubMed

Insights

Oxidative stress inactivates the tumor suppressor PTEN (phosphatase and tensin homolog), activating PI 3-kinase signaling. This novel mechanism explains how cellular oxidants regulate crucial pathways, impacting cell growth and survival.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Cancer Research

Background:

  • PTEN (phosphatase and tensin homolog) is a critical tumor suppressor that antagonizes PI 3-kinase signaling by dephosphorylating PtdIns(3,4,5)P(3).
  • Dysregulation of PTEN and PI 3-kinase pathways are implicated in various cellular processes, including cell growth, proliferation, and survival.

Purpose of the Study:

  • To investigate the effect of oxidative stress on PTEN phosphatase activity and its downstream signaling.
  • To elucidate the role of cellular oxidants in regulating PTEN function and PI 3-kinase pathway activation.

Main Methods:

  • Utilized two distinct assay systems to measure cellular PTEN phosphatase activity under oxidative stress conditions (1 mM hydrogen peroxide).
  • Assessed cellular PtdIns(3,4,5)P(3) levels and the activation of downstream targets like PKB/Akt.
  • Investigated PTEN inactivation and downstream signaling activation in RAW264.7 macrophages stimulated with endogenous oxidants.

Main Results:

  • Oxidative stress, induced by hydrogen peroxide, significantly inhibits cellular PTEN phosphatase activity.
  • Inactivated PTEN leads to increased cellular PtdIns(3,4,5)P(3) levels and subsequent activation of PKB/Akt signaling.
  • Endogenous oxidant production in macrophages inactivates PTEN, resulting in oxidant-dependent activation of downstream signaling pathways.

Conclusions:

  • Oxidants, including those endogenously produced, can activate PI 3-kinase signaling by inactivating the tumor suppressor PTEN.
  • This study reveals a novel regulatory mechanism for PTEN activity and the signaling pathways it controls.
  • Findings have significant implications for understanding cellular processes where both PtdIns(3,4,5)P(3) and oxidants are concurrently present.

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