c-Cbl-mediated Ubiquitinylation Is Required for Epidermal Growth Factor Receptor Exit from the Early Endosomes
Epidermal growth factor receptor (EGFR) controls cell growth and has a key role in tumorigenic processes. The extent of EGFR signaling is tightly regulated by post-transcriptional modifications leading to down-regulation of the levels of the receptor. Previous studies from our laboratory demonstrate...
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Published in | The Journal of biological chemistry Vol. 279; no. 35; pp. 37153 - 37162 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Biochemistry and Molecular Biology
27.08.2004
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Subjects | |
Online Access | Get full text |
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Summary: | Epidermal growth factor receptor (EGFR) controls cell growth and has a key role in tumorigenic processes. The extent of EGFR
signaling is tightly regulated by post-transcriptional modifications leading to down-regulation of the levels of the receptor.
Previous studies from our laboratory demonstrated that the reactive oxidant hydrogen peroxide activates the EGFR, yet, without
down-regulation of the receptor levels, which results in prolonged receptor signaling. In the present study we examined the
role of the E3 ligase c-Cbl, as a possible link between oxidative stress, EGFR signaling, and tumorigenic responses. First,
we ectopically expressed a mutant EGFR (Tyr-1045 â Phe) in cells lacking endogenous receptor, to determine whether the lack
of phosphorylation at this site is the cause for EGFR retention at the membrane under oxidative stress, as we have previously
suggested. Our findings suggest that abrogation of tyrosine 1045 phosphorylation alone is not enough to retain the EGFR at
the plasma membrane under oxidative stress. Second, through the use of the Src inhibitor PP1, our findings establish EGFR
movement out of the early endosomes as the exact location where c-Cbl-mediated ubiquitinylation is essential for EGFR trafficking.
Finally, our studies substantiate the findings that c-Cbl-mediated ubiquitinylation is needed for degradation, but not for
internalization of the EGFR in both transfection-dependent Chinese hamster ovary cells and transfection-independent A549 lung
epithelial cells. These findings only begin to explain the features seen under oxidative stress, but they yield a greater
understanding of the role of c-Cbl in EGFR trafficking. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M403210200 |