DNA-dependent protein kinase-mediated phosphorylation of protein kinase B requires a specific recognition sequence in the C-terminal hydrophobic motif

Jongsun Park, Jianhua Feng, Yuwen Li, Ola Hammarsten, Derek P. Brazil, Brian A. Hemmings*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

44 Citations (Scopus)

Abstract

DNA-dependent protein kinase (DNA-PK) has been implicated in a variety of nuclear processes including DNA double strand break repair, V(D)J recombination, and transcription. A recent study showed that DNA-PK is responsible for Ser-473 phosphorylation in the hydrophobic motif of protein kinase B (PKB/Akt) in genotoxic-stressed cells, suggesting a novel role for DNA-PK in cell signaling. Here, we report that DNA-PK activity toward PKB peptides is impaired in DNA-PK knock-out mouse embryonic fibroblast cells when compared with wild type. In addition, human glioblastoma cells expressing a mutant form of DNA-PK (M059J) displayed a lower DNA-PK activity when compared with glioblastoma cells expressing wild-type DNA-PK (M059K) when PKB peptide substrates were tested. DNA-PK preferentially phosphorylated PKB on Ser-473 when compared with its known in vitro substrate, p53. A consensus hydrophobic amino acid surrounding the Ser-473 phospho-acceptor site in PKB containing amino acids Phe at position +1 and +4 and Tyr at position - 1 are critical for DNA-PK activity. Thus, these data define the specificity of DNA-PK action as a Ser-473 kinase for PKB in DNA repair signaling.

Original languageEnglish
Pages (from-to)6169-6174
Number of pages6
JournalJournal of Biological Chemistry
Volume284
Issue number10
DOIs
Publication statusPublished - 06 Mar 2009

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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