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J. Biol. Chem., Vol. 279, Issue 35, 37153-37162, August 27, 2004

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c-Cbl-mediated Ubiquitinylation Is Required for Epidermal Growth Factor Receptor Exit from the Early Endosomes^*

Tommer Ravid, Jill M. Heidinger, Peter Gee, Elaine M. Khan, and Tzipora Goldkorn

From the Signal Transduction, Department of Internal Medicine, University of California, School of Medicine, Davis, California 95616

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 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.

Received for publication, March 23, 2004 , and in revised form, June 7, 2004.

^* This work was supported by National Institutes of Health Grants HL66189 and HL71871 (to T. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

To whom correspondence should be addressed: Dept. of Signal Transduction, School of Medicine, TB 149, Davis Campus, University of California, Davis, CA 95616. Tel.: 530-752-2988; Fax: 530-752-2949; E-mail: ttgoldkorn{at}ucdavis.edu.

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