Regulation of cell death protease caspase-9 by phosphorylation

Science. 1998 Nov 13;282(5392):1318-21. doi: 10.1126/science.282.5392.1318.

Abstract

Caspases are intracellular proteases that function as initiators and effectors of apoptosis. The kinase Akt and p21-Ras, an Akt activator, induced phosphorylation of pro-caspase-9 (pro-Casp9) in cells. Cytochrome c-induced proteolytic processing of pro-Casp9 was defective in cytosolic extracts from cells expressing either active Ras or Akt. Akt phosphorylated recombinant Casp9 in vitro on serine-196 and inhibited its protease activity. Mutant pro-Casp9(Ser196Ala) was resistant to Akt-mediated phosphorylation and inhibition in vitro and in cells, resulting in Akt-resistant induction of apoptosis. Thus, caspases can be directly regulated by protein phosphorylation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apoptosis*
  • Caspase 9
  • Caspase Inhibitors
  • Caspases / metabolism*
  • Cell Line
  • Cytochrome c Group / pharmacology
  • Enzyme Precursors / metabolism
  • Humans
  • Mass Spectrometry
  • Mutation
  • Peptide Fragments / metabolism
  • Phosphorylation
  • Phosphoserine / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Recombinant Fusion Proteins / metabolism
  • Transfection

Substances

  • Caspase Inhibitors
  • Cytochrome c Group
  • Enzyme Precursors
  • Peptide Fragments
  • Proto-Oncogene Proteins
  • Recombinant Fusion Proteins
  • Phosphoserine
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • CASP9 protein, human
  • Caspase 9
  • Caspases
  • HRAS protein, human
  • Proto-Oncogene Proteins p21(ras)