Radiation-induced Epidermal Growth Factor Receptor Nuclear Import Is Linked to Activation of DNA-dependent Protein Kinase

• Published in: The Journal of biological chemistry 2005-09, Vol.280 (35), p.31182-31189
• Main Authors: Dittmann, Klaus, Mayer, Claus, Fehrenbacher, Birgit, Schaller, Martin, Raju, Uma, Milas, Luka, Chen, David J., Kehlbach, Rainer, Rodemann, H. Peter
• Format: Article
• Language: English
• Subjects: Active Transport, Cell Nucleus - physiology; Active Transport, Cell Nucleus - radiation effects; Animals; Antibodies, Monoclonal - metabolism; Cell Fractionation; Cell Line, Tumor; Cell Nucleus - chemistry; Cell Nucleus - metabolism; Cell Survival; DNA Repair; DNA-Activated Protein Kinase; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Enzyme Activation; ErbB Receptors - metabolism; Humans; Macromolecular Substances; Mice; Nuclear Proteins; Protein Processing, Post-Translational; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Radiation, Ionizing
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M506591200

Ionizing radiation, but not stimulation with epidermal growth factor (EGF), triggers EGF receptor (EGFR) import into the nucleus in a probably karyopherin α-linked manner. An increase in nuclear EGFR is also observed after treatment with H2O2, heat, or cisplatin. During, this process, the proteins Ku70/80 and the protein phosphatase 1 are transported into the nucleus. As a consequence, an increase in the nuclear kinase activity of DNA-dependent kinase (DNA-PK) and increased formation of the DNA end-binding protein complexes containing DNA-PK, essential for repair of DNA-strand breaks, occurred. Blockade of EGFR import by the anti-EGFR monoclonal antibody C225 abolished EGFR import into the nucleus and radiation-induced activation of DNA-PK, inhibited DNA repair, and increased radiosensitivity of treated cells. Our data implicate a novel function of the EGFR during DNA repair processes.