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J. Biol. Chem., Vol. 280, Issue 35, 31182-31189, September 2, 2005

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

Klaus Dittmann, Claus Mayer, Birgit Fehrenbacher¶, Martin Schaller¶, Uma Raju||, Luka Milas||, David J. Chen**, Rainer Kehlbach, and H. Peter Rodemann

From the Division of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, University of Tübingen, 72076 Tübingen, ^¶Department of Dermatology, University of Tübingen, 72076 Tübingen, Germany, ^||Department of Experimental Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, ^**Division of Molecular Radiation Biology, Department of Radiation Oncology, Utah Southwestern Medical Center, Dallas, Texas 75390-9187, and Department of Radiology, University of Tübingen, 72076 Tübingen, Germany

Ionizing radiation, but not stimulation with epidermal growth factor (EGF), triggers EGF receptor (EGFR) import into the nucleus in a probably karyopherin -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.

Received for publication, June 17, 2005

^* The work was supported by the Fortüne Program Nr. 1022 and 1399-0-0 and BMBF-IZKF-project B6 (01KS9602), Deutsche Krebshilfe Grant 106401, National Institutes of Health Grant CA06294, and NCI, National Institutes of Health Cancer Center Core Grant CA16672. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Division of Radiobiology and Molecular Environmental Research, Dept. of Radiation Oncology, Eberhard-Karls-University, Röntgenweg 11, 72076 Tübingen, Germany. Tel.: 49-7071-2987465; Fax: 49-7071-295900; E-mail: klaus.dittmann{at}uni-tuebingen.de.

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