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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 RIS Download

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

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