title: Nuclear EGFR shuttling induced by ionizing radiation is regulated by phosphorylation at residue Thr654.
abstract: Nuclear localisation of EGFR is associated with treatment resistance of tumor cells. The aim of this study was to identify molecular targets to block nuclear shuttling of EGFR. Mutation of Thr654, located within the putative EGFR NLS demonstrated that phosphorylation of this residue is essential for nuclear EGFR shuttling following irradiation. Deletion of Thr654 blocked nuclear transport of EGFR, whereas mutation to Glu increased shuttling. Treatment with a peptide, corresponding to the phosphorylated NLS, abolished nuclear EGFR transport and reduced radiation-induced activation of DNA-PK, essential for DNA-repair. In accordance with that, lack of nuclear EGFR increased residual DNA damage in tumor cells and reduced cellular survival following irradiation. Blockage of nuclear EGFR shuttling may be a new strategy to fight treatment resistance.
authors.affiliation: Division of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, University of Tübingen, Tübingen, Germany. Klaus.dittmann@uni-tuebingen.de
authors.forename: Klaus
authors.initials: K
authors.lastname: Dittmann
authors.forename: Claus
authors.initials: C
authors.lastname: Mayer
authors.forename: Birgit
authors.initials: B
authors.lastname: Fehrenbacher
authors.forename: Martin
authors.initials: M
authors.lastname: Schaller
authors.forename: Rainer
authors.initials: R
authors.lastname: Kehlbach
authors.forename: H Peter
authors.initials: HP
authors.lastname: Rodemann
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics / Q000528:radiation effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000201:enzymology*; D003600:Cytosol / Q000201:enzymology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019913:Nuclear Localization Signals / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011839:Radiation, Ionizing; D013912:Threonine / Q000378:metabolism
chemical_list: D019913:Nuclear Localization Signals; D013912:Threonine; C512478:EGFR protein, human; D066246:ErbB Receptors