Protein phosphatase 2A-linked and -unlinked caspase-dependent pathways for downregulation of Akt kinase triggered by 4-hydroxynonenal

Cell Death Differ. 2003 Jul;10(7):772-81. doi: 10.1038/sj.cdd.4401238.

Abstract

We studied the signal pathways for regulation of serine/threonine protein kinase Akt in Jurkat cells that had been treated with 4-hydroxynonenal (HNE) for caspase-dependent apoptosis induction. Treatment of cells with HNE led to a decrease in the level of Akt activity due to the dephosphorylation at Ser473, a major regulatory phosphorylation site. HNE-mediated dephosphorylation of Akt was prevented by a protein phosphatase 2A (PP2A) inhibitor, okadaic acid, and by a caspase-3 inhibitor, DEVD-CHO. HNE treatment resulted in an increase in the total level of PP2A activity, release of active tyrosine-dephosphorylated PP2A from the cytoskeleton and PP2A-Akt association, which were all dependent on caspase-3 activation. These results suggest that the level of PP2A activity is at least in part determined by its tyrosine phosphorylation, which is dually controlled by okadaic acid-sensitive phosphatases and protein-tyrosine kinases. Possibly underlying the mechanism of caspase-mediated activation of PP2A, HNE treatment resulted in downregulation of the activity of Src kinase, as a representative caspase-sensitive kinase to phosphorylate PP2A at tyrosine. In addition, activated caspase-3 partially cleaved Akt at a late stage of the apoptosis. These results indicate the existence of two distinct caspase-dependent signal pathways for downregulation of Akt that works as a mechanism of positive feedback regulation for HNE-triggered apoptotic signals.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehydes / pharmacology*
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Caspase 3
  • Caspase Inhibitors
  • Caspases / metabolism*
  • Down-Regulation / drug effects
  • Down-Regulation / physiology
  • Enzyme Inhibitors / pharmacology
  • Feedback, Physiological / drug effects
  • Feedback, Physiological / physiology
  • Humans
  • Jurkat Cells
  • Okadaic Acid / pharmacology
  • Oligopeptides / pharmacology
  • Phosphoprotein Phosphatases / antagonists & inhibitors
  • Phosphoprotein Phosphatases / metabolism*
  • Phosphorylation / drug effects
  • Protein Phosphatase 2
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Serine / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • src-Family Kinases / drug effects
  • src-Family Kinases / metabolism

Substances

  • Aldehydes
  • Caspase Inhibitors
  • Enzyme Inhibitors
  • Oligopeptides
  • Proto-Oncogene Proteins
  • aspartyl-glutamyl-valyl-aspartal
  • Okadaic Acid
  • Serine
  • src-Family Kinases
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 2
  • CASP3 protein, human
  • Caspase 3
  • Caspases
  • 4-hydroxy-2-nonenal