TY - JOUR
T1 - Epidermal growth factor receptor activation under oxidative stress fails to promote c-Cbl mediated down-regulation
AU - Ravid, Tommer
AU - Sweeney, Colleen
AU - Gee, Peter
AU - Carraway, Kermit L.
AU - Goldkorn, Tzipora
PY - 2002/8/23
Y1 - 2002/8/23
N2 - 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 (H2O2) 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 H2O2 differs from that induced by its ligand, EGF. Importantly, H2O2 generates a receptor with negligible phosphorylation at tyrosine 1045, the major docking site for the ubiquitin ligase c-Cbl. As a result, H2O2-activated receptors fail to recruit c-Cbl and do not undergo ubiquitination and endocytosis. In summary, H2O2 stimulation results in an activated receptor uncoupled from normal down-regulation, a process that may contribute to oxidant-mediated tumorigenesis.
AB - 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 (H2O2) 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 H2O2 differs from that induced by its ligand, EGF. Importantly, H2O2 generates a receptor with negligible phosphorylation at tyrosine 1045, the major docking site for the ubiquitin ligase c-Cbl. As a result, H2O2-activated receptors fail to recruit c-Cbl and do not undergo ubiquitination and endocytosis. In summary, H2O2 stimulation results in an activated receptor uncoupled from normal down-regulation, a process that may contribute to oxidant-mediated tumorigenesis.
UR - http://www.scopus.com/inward/record.url?scp=0037163042&partnerID=8YFLogxK
U2 - 10.1074/jbc.M204677200
DO - 10.1074/jbc.M204677200
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C2 - 12063263
AN - SCOPUS:0037163042
SN - 0021-9258
VL - 277
SP - 31214
EP - 31219
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 34
ER -