Nuclear EGFR as novel therapeutic target: insights into nuclear translocation and function.
Emerging evidence suggests the existence of a new mode of epidermal growth factor receptor (EGFR) signaling in which activated EGFR undergoes nuclear translocation following treatment with ionizing radiation. The authors provide evidence that the nuclear EGFR transport is a stress-specific cellular reaction, which is linked to src-dependent EGFR internalization into caveolae. These flask-shaped pits can fuse with endoplasmic reticulum and the EGFR is sorted into a perinuclear localization. This compartment may serve as a reservoir for nuclear EGFR transport which is regulated by PKCepsilon (protein kinase Cepsilon). Nuclear EGFR is able to induce transcription of genes essential for cell proliferation and cell-cycle regulation. Moreover, nuclear EGFR has physical contact with compounds of the DNA repair machinery and is involved in removal of DNA damage. Anti-EGFR strategies target radiation-associated EGFR nuclear translocation in different manners. EGFR-inhibitory antibodies, i.e., cetuximab (Erbitux((R))), can block nuclear translocation by EGFR immobilization within the cytosol in responder cell lines, whereas tyrosine kinase inhibitors rather target nuclear kinase activity of EGFR linked with cytosolic or nuclear functions. However, both strategies can inhibit DNA repair following irradiation.
Dittmann
Klaus
K
Division of Radiobiology and Molecular Environmental Research, Department of Radiooncology, University of Tübingen, Tübingen, Germany. klaus.dittmann@uni-tuebingen.de.|Division of Radiobiology and Molecular Environmental Research, Department of Radiooncology, Eberhard Karls University, Röntgenweg 11, 72076, Tübingen, Germany. klaus.dittmann@uni-tuebingen.de.
Mayer
Claus
C
Division of Radiobiology and Molecular Environmental Research, Department of Radiooncology, University of Tübingen, Tübingen, Germany.
Rodemann
H Peter
HP
Division of Radiobiology and Molecular Environmental Research, Department of Radiooncology, University of Tübingen, Tübingen, Germany.
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology; D021941:Caveolae / Q000528:radiation effects; D002453:Cell Cycle / Q000235:genetics / Q000528:radiation effects; D002455:Cell Division / Q000235:genetics / Q000528:radiation effects; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects*; D000068818:Cetuximab; D004249:DNA Damage / Q000235:genetics / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000528:radiation effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D016391:Genes, src / Q000528:radiation effects; D006801:Humans; D051744:Protein Kinase C-epsilon / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects*; D014158:Transcription, Genetic / Q000235:genetics / Q000528:radiation effects; D014178:Translocation, Genetic / Q000187:drug effects / Q000528:radiation effects*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C512478:EGFR protein, human; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D051744:Protein Kinase C-epsilon; D000068818:Cetuximab