Epidermal growth factor receptor activation under oxidative stress fails to promote c-Cbl mediated down-regulation.
Activation of the epidermal growth factor (EGF) receptor by its ligand, EGF, rapidly enhances receptor internalization and degradation, which desensitizes receptor signaling. In contrast, we have shown previously that exposure to oxidative stress in the form of hydrogen peroxide (H(2)O(2)) activated the EGF receptor but that the levels of activated receptors did not decline, which resulted in prolonged receptor signaling. This study provides mechanistic insights into these different modes of EGF receptor activation. Here we demonstrate that the pattern of receptor tyrosine phosphorylation induced by H(2)O(2) differs from that induced by its ligand, EGF. Importantly, H(2)O(2) generates a receptor with negligible phosphorylation at tyrosine 1045, the major docking site for the ubiquitin ligase c-Cbl. As a result, H(2)O(2)-activated receptors fail to recruit c-Cbl and do not undergo ubiquitination and endocytosis. In summary, H(2)O(2) stimulation results in an activated receptor uncoupled from normal down-regulation, a process that may contribute to oxidant-mediated tumorigenesis.
Ravid
Tommer
T
Signal Transduction, Department of Internal Medicine, Cancer Center, University of California School of Medicine, Davis, CA 95616, USA.
Sweeney
Colleen
C
Gee
Peter
P
Carraway
Kermit L
KL
Goldkorn
Tzipora
T
D015536:Down-Regulation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000032:analysis / Q000378:metabolism*; D005949:Glucose Oxidase / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000494:pharmacology; D018384:Oxidative Stress; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D050721:Proto-Oncogene Proteins c-cbl; D014443:Tyrosine / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
D011518:Proto-Oncogene Proteins; D025801:Ubiquitin; D014443:Tyrosine; D004815:Epidermal Growth Factor; D006861:Hydrogen Peroxide; D005949:Glucose Oxidase; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D066246:ErbB Receptors; C067419:CBL protein, human