Protein phosphatase 2A regulates life and death decisions via Akt in a context-dependent manner

Proc Natl Acad Sci U S A. 2007 Nov 27;104(48):19011-6. doi: 10.1073/pnas.0706696104. Epub 2007 Nov 15.

Abstract

Here, we show how targeting protein phosphatase 2A (PP2A), a key regulator of cellular protein phosphorylation, can either induce or prevent apoptosis depending on what other signals the cell is receiving. The oncoprotein polyoma small T interacts with PP2A to regulate survival. In the presence of growth factors, small T induces apoptosis. Akt activity, which usually promotes survival, is required for this death response, because inhibitors of Akt or PI3 kinase protect cells from death. The activation of Akt under these conditions is partial, characterized by T308 phosphorylation but not S473 phosphorylation. In the absence of growth factors, small T protects from cell death. Here, small T uses PP2A to promote phosphorylation of Akt on both T308 and S473. This effect results in a different pattern of phosphorylation of Akt substrates and shifts Akt from a proapoptotic (presence of growth factors) to an antiapoptotic mode (absence of growth factors). An intriguing possibility is that Akt phosphorylation could be therapeutically disregulated to decrease the survival of cancer cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens, Viral, Tumor / genetics
  • Antigens, Viral, Tumor / physiology*
  • Apoptosis / physiology*
  • Caspase 3 / analysis
  • Culture Media, Serum-Free / pharmacology
  • Mice
  • NIH 3T3 Cells / drug effects
  • NIH 3T3 Cells / metabolism
  • Phosphatidylinositol 3-Kinases / physiology
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation / drug effects
  • Phosphoserine / analysis
  • Phosphotyrosine / analysis
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases / physiology
  • Protein Kinase Inhibitors / pharmacology
  • Protein Phosphatase 2 / physiology*
  • Protein Processing, Post-Translational / drug effects
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / physiology*
  • Recombinant Fusion Proteins / physiology
  • Signal Transduction / physiology
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / physiology

Substances

  • Antigens, Viral, Tumor
  • Culture Media, Serum-Free
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Recombinant Fusion Proteins
  • Phosphoserine
  • Phosphotyrosine
  • Parp1 protein, mouse
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases
  • Akt1 protein, mouse
  • Proto-Oncogene Proteins c-akt
  • p38 Mitogen-Activated Protein Kinases
  • Protein Phosphatase 2
  • Casp3 protein, mouse
  • Caspase 3