Epidermal growth factor receptor activation under oxidative stress fails to promote c-Cbl mediated down-regulation

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)31214-31219
Number of pages6
JournalJournal of Biological Chemistry
Volume277
Issue number34
DOIs
StatePublished - Aug 23 2002

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Oxidative stress
Epidermal Growth Factor Receptor
Phosphorylation
Oxidative Stress
Down-Regulation
Chemical activation
Epidermal Growth Factor
Ligands
Ubiquitination
Ligases
Ubiquitin
Endocytosis
Oxidants
Hydrogen Peroxide
Tyrosine
Carcinogenesis
Degradation

ASJC Scopus subject areas

  • Biochemistry

Cite this

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title = "Epidermal growth factor receptor activation under oxidative stress fails to promote c-Cbl mediated down-regulation",
abstract = "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.",
author = "Tommer Ravid and Sweeney, {Colleen A} and Peter Gee and Carraway, {Kermit L} and Tzipora Goldkorn",
year = "2002",
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T1 - Epidermal growth factor receptor activation under oxidative stress fails to promote c-Cbl mediated down-regulation

AU - Ravid, Tommer

AU - Sweeney, Colleen A

AU - Gee, Peter

AU - Carraway, Kermit L

AU - Goldkorn, Tzipora

PY - 2002/8/23

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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.

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