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

• DOI: 10.1038/sj.cdd.4401238
• Publication Date: 2003-06-18T14:37:21Z
• Authors: W Liu; A A Akhand; K Takeda; Y Kawamoto; M Itoigawa; M Kato; H Suzuki; N Ishikawa; I Nakashima
• Keywords: Feedback, Physiological; 0301 basic medicine; Aldehydes; Caspase 3; Down-Regulation; Apoptosis; Protein Serine-Threonine Kinases; Caspase Inhibitors; Jurkat Cells; 03 medical and health sciences; Caspases; Proto-Oncogene Proteins; Okadaic Acid; Phosphoprotein Phosphatases; Serine; Humans; Protein Phosphatase 2; Enzyme Inhibitors; Phosphorylation; Oligopeptides; Proto-Oncogene Proteins c-akt; Signal Transduction

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.