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Identification of a PKB/Akt hydrophobic motif Ser-473 kinase as DNA-dependent protein kinase.

Full activation of protein kinase B (PKB)/Akt requires phosphorylation on Thr-308 and Ser-473 by 3-phosphoinositide-dependent kinase-1 (PDK1) and Ser-473 kinase (S473K), respectively. Although PDK1 has been well characterized, the identification of the S473K remains controversial. A major PKB Ser-473 kinase activity was purified from the membrane fraction of HEK293 cells and found to be DNA-dependent protein kinase (DNA-PK). DNA-PK co-localized and associated with PKB at the plasma membrane. In vitro, DNA-PK phosphorylated PKB on Ser-473, resulting in a approximately 10-fold enhancement of PKB activity. Knockdown of DNA-PK by small interfering RNA inhibited Ser-473 phosphorylation induced by insulin and pervanadate. DNA-PK-deficient glioblastoma cells did not respond to insulin at the level of Ser-473 phosphorylation; this effect was restored by complementation with the human PRKDC gene. We conclude that DNA-PK is a long sought after kinase responsible for the Ser-473 phosphorylation step in the activation of PKB.

Pubmed ID: 15262962


  • Feng J
  • Park J
  • Cron P
  • Hess D
  • Hemmings BA


The Journal of biological chemistry

Publication Data

September 24, 2004

Associated Grants


Mesh Terms

  • 3T3-L1 Cells
  • Amino Acid Motifs
  • Animals
  • Cell Line
  • Cell Line, Tumor
  • Cell Membrane
  • Chromatography, Gel
  • DNA, Complementary
  • DNA-Activated Protein Kinase
  • DNA-Binding Proteins
  • Enzyme Activation
  • Genetic Complementation Test
  • Glioblastoma
  • Humans
  • Insulin
  • Mice
  • Microscopy, Fluorescence
  • Models, Biological
  • Nuclear Proteins
  • Phosphorylation
  • Plasmids
  • Precipitin Tests
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-akt
  • Recombinant Proteins
  • Serine
  • Time Factors
  • Transfection
  • Vanadates