Epidermal Growth Factor Receptor Activation under Oxidative Stress Fails to Promote c-Cbl Mediated Down-regulation

Ravid, Tommer; Sweeney, Colleen; Gee, Peter; Carraway, Kermit L.; Goldkorn, Tzipora

doi:10.1074/jbc.m204677200

Cited by 98 publications

(111 citation statements)

References 30 publications

(43 reference statements)

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“…Fig. 9 also depicts that Egfr activity can be potentiated by H 2 O 2 (69,70) and c-Src (71,72), both of which inhibit the function of c-Cbl. Overexpression of c-Src induces c-Cbl turnover resulting in increased EGFR activity (71,72).…”

Section: Discussionmentioning

confidence: 99%

Apc Deficiency Is Associated with Increased Egfr Activity in the Intestinal Enterocytes and Adenomas of C57BL/6J-Min/+ Mice

Moran¹,

Hunt

Javid³

et al. 2004

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Apc Deficiency Is Associated with Increased Egfr Activity in the Intestinal Enterocytes and Adenomas of C57BL/6J-Min/+ Mice

Moran¹,

Hunt

Javid³

et al. 2004

Journal of Biological Chemistry

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“…EGFR endocytosis has been shown previously to be regulated by tyrosine phosphorylation in the cytoplasmic tail of the EGFR (7,14,43,44). Oncogenic EGFR mutants such as the EGFRvIII show increased levels of tyrosine 1173 phosphorylation (35,45).…”

Section: Discussionmentioning

confidence: 99%

Abl Tyrosine Kinase Regulates Endocytosis of the Epidermal Growth Factor Receptor

Tanos

Pendergast

2006

Journal of Biological Chemistry

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Signal attenuation from ligand-activated epidermal growth factor receptor (EGFR) is mediated in part by receptor endocytosis and trafficking to the lysosomal degradative compartment. Uncoupling the activated EGFR from endocytosis and degradation has emerged as a mechanism for oncogenic activation of the EGFR. The Abl nonreceptor tyrosine kinase is activated by ligand-stimulated EGFR, but the role of Abl in EGFR signaling has not been defined. Here we uncovered a novel role for the activated Abl kinase in the regulation of EGFR endocytosis. We show that activated Abl impairs EGFR internalization. Moreover, we show that activated Abl phosphorylates the EGFR primarily on tyrosine 1173, and that mutation of this site to phenylalanine restores ligand-dependent endocytosis of the EGFR in the presence of activated Abl. Furthermore, we show that activated Abl allows the ligand-activated EGFR to escape Cbl-dependent down-regulation by inhibiting the accumulation of Cbl at the plasma membrane in response to epidermal growth factor stimulation and disrupting the formation of the EGFR⅐Cbl complex without affecting Cbl protein stability. These findings reveal a novel role for Abl in promoting increased cell-surface expression of the EGFR and suggest that Abl/EGFR signaling may cooperate in human tumors.

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“…Secondly, ROS have been reported to stimulate Src (43)(44)(45), which has been shown to stimulate JNK through Cas (34). Available evidence suggests that ROS stimulate Src indirectly, i.e.…”

Section: Discussionmentioning

confidence: 99%

Tobacco Smoke Control of Mucin Production in Lung Cells Requires Oxygen Radicals AP-1 and JNK

Gensch

Gallup

Sucher

et al. 2004

Journal of Biological Chemistry

142

120

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In smokers' lungs, excessive mucus clogs small airways, impairing respiration and promoting recurrent infection. A breakthrough in understanding this pathology was the realization that smoke could directly stimulate mucin synthesis in lung epithelial cells and that this phenomenon was dependent on the cell surface receptor for epidermal growth factor, EGFR. Distal steps in the smoke-triggered pathway have not yet been determined. We report here that the predominant airway mucin (MUC5AC) undergoes transcriptional up-regulation in response to tobacco smoke; this is mediated by an AP-1-containing response element, which binds JunD and Fra-2. These transcription factors require phosphorylation by upstream kinases JNK and ERK, respectively. Whereas ERK activation results from the upstream activation of EGFR, JNK activation is chiefly EGFR-independent. Our experiments demonstrated that smoke activates JNK via a Src-dependent, EGFRindependent signaling cascade initiated by smoke-induced reactive oxygen species. Taken together with our earlier results, these data indicate that the induction of mucin by smoke is the combined effect of mutually independent, reactive oxygen species activation of both EGFR and JNK.The primary cause of morbidity in chronic bronchitis is mucin overproduction, a phenomenon for which the molecular pathogenesis is unknown. Inflammatory cells are abundant in smokers' airways (1-3) and are capable of stimulating mucin production (4 -7), suggesting that at least some of the excessive mucin in smokers' lungs is secondary to inflammation.In addition, however, smoke itself can induce mucin synthesis in lung cells (8,9). The question of how this occurs is complex in that smoke, a composite of irritant molecules including acetaldehyde, hydroquinone, formaldehyde, benzo-[a]pyrene, cresol, nicotine, catechol, acrolein, coumarin, anthracene, nitrogen oxides, and heavy metals (10, 11) may act on lung epithelial cells in diverse ways. For example, the induction of cytochrome P450 by tobacco smoke (12) is mediated by binding of the aryl hydrocarbon nuclear receptor to a dioxin response element in the 5Ј-flank of the gene, but the induction of the ␥-glutamylcysteine synthetase heavy subunit (␥-GCS-HS) gene is mediated by the binding of a c-Jun/c-Jun homodimer to an AP-1-like response element (13).Previous reports have implicated the receptor for epidermal growth factor (EGFR) 1 in the induction of mucin gene MUC5AC by smoke (9). Consistent with a role for EGFR in mucin induction, an EGF response element has been identified 200 bp upstream of the MUC5AC gene (14). The response of this element to EGFR ligands EGF and transforming growth factor-␣ is mediated by Sp1. One might predict from these data that the induction of MUC5AC by smoke would depend on interaction between the EGF response element at Ϫ200 bp and Sp1.In contrast, in the present study we show that MUC5AC is controlled principally by a smoke response element ϳ3 kb upstream of the EGF response element. This element is AP-1-dependent and is bound by Ju...

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Epidermal Growth Factor Receptor Activation under Oxidative Stress Fails to Promote c-Cbl Mediated Down-regulation

Cited by 98 publications

References 30 publications

Apc Deficiency Is Associated with Increased Egfr Activity in the Intestinal Enterocytes and Adenomas of C57BL/6J-Min/+ Mice

Apc Deficiency Is Associated with Increased Egfr Activity in the Intestinal Enterocytes and Adenomas of C57BL/6J-Min/+ Mice

Abl Tyrosine Kinase Regulates Endocytosis of the Epidermal Growth Factor Receptor

Tobacco Smoke Control of Mucin Production in Lung Cells Requires Oxygen Radicals AP-1 and JNK

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