Nuclear EGFR shuttling induced by ionizing radiation is regulated by phosphorylation at residue Thr654.
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.
Dittmann
Klaus
K
Division of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, University of Tübingen, Tübingen, Germany. Klaus.dittmann@uni-tuebingen.de
Mayer
Claus
C
Fehrenbacher
Birgit
B
Schaller
Martin
M
Kehlbach
Rainer
R
Rodemann
H Peter
HP
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
D019913:Nuclear Localization Signals; D013912:Threonine; C512478:EGFR protein, human; D066246:ErbB Receptors