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Updated: May 6, 2026

Identification of Inositol Phosphate or Phosphoinositide Interacting Proteins by Affinity Chromatography Coupled to Western Blot or Mass Spectrometry
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Identification of Inositol Phosphate or Phosphoinositide Interacting Proteins by Affinity Chromatography Coupled to Western Blot or Mass Spectrometry

Published on: July 26, 2019

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Phosphoinositide 3-kinases upregulate system xc(-) via eukaryotic initiation factor 2α and activating transcription

Jan Lewerenz1, Paul Baxter, Rebecca Kassubek

  • 11 Department of Neurology, Ulm University , Ulm, Germany .

Antioxidants & Redox Signaling
|November 14, 2013
PubMed
Abstract

Insights

Growth factor signaling via phosphoinositide 3-kinases (PI3Ks) activates the cystine/glutamate antiporter system xc(-) through GSK-3β inhibition. This pathway enhances neuroprotection and cell growth, and is implicated in epilepsy.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Biochemistry

Background:

  • Phosphoinositide 3-kinases (PI3Ks) are crucial for growth factor signaling, cell growth, and cytoprotection.
  • The cystine/glutamate antiporter system xc(-) imports cystine and exports glutamate, impacting glutathione synthesis and extracellular glutamate levels.

Purpose of the Study:

  • To elucidate the signaling pathway by which growth factors and PI3Ks induce system xc(-).
  • To demonstrate the biological significance of this pathway in neuroprotection, cell growth, and epilepsy.

Main Methods:

  • Investigated the molecular mechanisms linking PI3K signaling to system xc(-) induction.
  • Analyzed the role of glycogen synthase kinase 3β (GSK-3β), eukaryotic initiation factor 2α phosphorylation, and activating transcription factor 4.
  • Examined pathway activity in primary cortical neurons, fibroblasts, glioblastoma cells, and human epileptic hippocampi.

Main Results:

  • PI3Ks induce system xc(-) via GSK-3β inhibition, eIF2α phosphorylation, and ATF4 translation.
  • This pathway is essential for PI3K-mediated oxidative stress resistance in neurons and insulin-induced fibroblast growth.
  • The pathway is active in glioblastoma cells and induced by neuronal activity and in epilepsy.

Conclusions:

  • PI3K-regulated system xc(-) activity supports neuronal stress resistance and cell growth by increasing cysteine and glutathione.
  • This pathway contributes to epilepsy pathophysiology by up-regulating extracellular glutamate in the brain.
  • The findings reveal a novel signaling branch downstream of GSK-3β with implications for neurological disorders.

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