Epidermal growth factor receptor exposed to oxidative stress undergoes Src- and caveolin-1-dependent perinuclear trafficking.
The epidermal growth factor (EGF) receptor (EGFR) has been found to be overexpressed in several types of cancer cells, and the regulation of its oncogenic potential has been widely studied. The paradigm for EGFR down-regulation involves the trafficking of activated receptor molecules from the plasma membrane, through clathrin-coated pits, and into the cell for lysosomal degradation. We have previously shown that oxidative stress generated by H2O2 results in aberrant phosphorylation of the EGFR. This leads to the loss of c-Cbl-mediated ubiquitination of the EGFR and, consequently, prevents its degradation. However, we have found that c-Cbl-mediated ubiquitination is required solely for degradation but not for internalization of the EGFR under oxidative stress. To further examine the fate of the EGFR under oxidative stress, we used confocal analysis to show that the receptor not only remains co-localized with caveolin-1 at the plasma membrane, but at longer time points, is also sorted to a perinuclear compartment via a clathrin-independent, caveolae-mediated pathway. Our findings indicate that although the EGFR associates with caveolin-1 constitutively, caveolin-1 is hyperphosphorylated only under oxidative stress, which is essential in transporting the EGFR to a perinuclear location, where it is not degraded and remains active. Thus, oxidative stress may have a role in tumorigenesis by not only activating the EGFR but also by promoting prolonged activation of the receptor both at the plasma membrane and within the cell.
Khan
Elaine M
EM
Signal Transduction Laboratory, Department of Internal Medicine, University of California, School of Medicine, Davis, California 95616, USA.
Heidinger
Jill M
JM
Levy
Michal
M
Lisanti
Michael P
MP
Ravid
Tommer
T
Goldkorn
Tzipora
T
D021581:Active Transport, Cell Nucleus; D051242:Caveolin 1 / Q000378:metabolism*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D002966:Clathrin / Q000378:metabolism; D015536:Down-Regulation; D066246:ErbB Receptors / Q000502:physiology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008954:Models, Biological; D018384:Oxidative Stress; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism*
D051242:Caveolin 1; D002966:Clathrin; D006861:Hydrogen Peroxide; D066246:ErbB Receptors; D019061:src-Family Kinases