Cisplatin-induced activation of the EGF receptor

Benhar, Moran; Engelberg, David; Levitzki, Alexander

doi:10.1038/sj.onc.1205980

Cited by 125 publications

(113 citation statements)

References 43 publications

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“…Ultraviolet irradiation of cells can induce ERK activation, which serves as a survival signal: in this case, ERK activation occurs via SFK-dependent phosphorylation of EGF-R and subsequent downstream signaling (Kitagawa et al, 2002). Similarly, cisplatin-induced activation of EGF-R occurs via SFKs and results in protection (Benhar et al, 2002). These data suggest that DNA-damaging agents can generate survival signals that may be dependent on the regulation of RTKs by SFKs.…”

Section: Ubiquitinationmentioning

confidence: 84%

The interplay between Src family kinases and receptor tyrosine kinases

2004

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Src family tyrosine kinases (SFKs) are involved in a diverse array of physiological processes, as highlighted in this review. An overview of how SFKs interact with, and participate in signaling from, receptor tyrosine kinases (RTKs) is discussed. And also, how SFKs are activated by RTKs, and how SFKs, in turn, can activate RTKs, as well as how SFKs can promote signaling from growth factor receptors in a number of ways including participation in signaling pathways required for DNA synthesis, control of receptor turnover, actin cytoskeleton rearrangements and motility, and survival are discussed.

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Section: Ubiquitinationmentioning

confidence: 84%

The interplay between Src family kinases and receptor tyrosine kinases

2004

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“…One possibility is that gemcitabine-mediated EGFR phosphorylation might be due to activation of c-Src, as gemcitabine induced EGFR phosphorylation at tyrosine 845, which is a known c-Src kinase target (Sato et al, 1995). This pathway of EGFR activation has been implicated previously in response to cisplatin (Benhar et al, 2002). On the other hand, it has been shown that phosphorylation of Y1045, which is a cbl binding site, is necessary for ubiquitination of EGFR.…”

Section: Figurementioning

confidence: 98%

Role of epidermal growth factor receptor degradation in gemcitabine-mediated cytotoxicity

et al. 2006

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We have recently reported that treatment with gemcitabine, a potent chemotherapeutic agent and radiation sensitizer, stimulates phosphorylation of the epidermal growth factor receptor (EGFR). Because phosphorylation of EGFR is known to precede receptor degradation, we hypothesized that gemcitabine treatment may also result in EGFR degradation. In two human head and neck cancer cell lines, UMSCC-1 and UMSCC-6, we demonstrated an approximately 80% decrease in total EGFR levels at 72 h after a 2-h treatment with 1 lM gemcitabine. Neither cisplatin nor 5-fluorouracil, which are used to treat head and neck cancer, caused EGFR degradation. EGFR downregulation did not occur at the level of transcription, as assessed by reverse transcription-polymerase chain reaction (RT-PCR), but instead occurred via phosphorylation and ubiquitination of the receptor along a proteosome/lysosome-mediated pathway. Inhibition of EGFR degradation, by either pretreatment with the EGFR tyrosine kinase inhibitor gefitinib or by exposure to the proteosome/lysosome inhibitor MG132, significantly reduced gemcitabine-induced cell death. These results suggest that EGFR degradation may be a novel mechanism for gemcitabine-mediated cell death. These findings also indicate that caution should be exercised when combining gemcitabine with agents that may prevent EGFR degradation, such as EGFR tyrosine kinase inhibitors administered in a suboptimal sequence or proteosome inhibitors.

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“…Such stimuli include several different reactive oxygen and nitrogen species, such as hydrogen peroxide (21) or peroxynitrite (28), as well as heavy metal ions (29) or anticancer agents such as cisplatin (30).…”

Section: Discussionmentioning

confidence: 99%

Epidermal Growth Factor Receptor Is a Common Mediator of Quinone-induced Signaling Leading to Phosphorylation of Connexin-43

Abdelmohsen¹,

Gerber

Montfort

et al. 2003

Journal of Biological Chemistry

103

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Rat liver epithelial cells were exposed to three quinones with different properties: menadione (2-methyl-1,4-naphthoquinone, vitamin K 3 ), an alkylating as well as redox-cycling quinone, the strongly alkylating p-benzoquinone (BQ), and the non-arylating redox-cycler, 2,3-dimethoxy-1,4-naphthoquinone (DMNQ). All three quinones induced the activation of extracellular signalregulated kinase (ERK) 1 and ERK 2 via the activation of epidermal growth factor receptor (EGFR) and MAPK/ ERK kinases (MEK) 1/2. ERK activation resulted in phosphorylation at Ser-279 and Ser-282 of the gap junctional protein, connexin-43, known to result in the loss of gap junctional intercellular communication. Another EGFRdependent pathway was stimulated, leading to the activation of the antiapoptotic kinase Akt via phosphoinositide 3-kinase. The activation of EGFR-dependent signaling by these quinones was by different mechanisms: (i) menadione, but not BQ or DMNQ, inhibited a protein-tyrosine phosphatase regulating the EGFR, as concluded from an EGFR dephosphorylation assay; (ii) although menadione-induced activation of ERK was unimpaired by pretreatment of cells with N-acetyl cysteine, activation by BQ and DMNQ was prevented; (iii) cellular glutathione (GSH) levels were strongly depleted by BQ. The mere depletion of GSH by application of diethyl maleate EGFR-dependently activated ERK and Akt, thus mimicking BQ effects. GSH levels were only moderately decreased by menadione and not affected by DMNQ. In summary, EGFR-dependent signaling was mediated by protein-tyrosine phosphatase inactivation (menadione), GSH depletion (BQ), and redox-cycling (DMNQ), funneling into the same signaling pathway.

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Cisplatin-induced activation of the EGF receptor

Cited by 125 publications

References 43 publications

The interplay between Src family kinases and receptor tyrosine kinases

The interplay between Src family kinases and receptor tyrosine kinases

Role of epidermal growth factor receptor degradation in gemcitabine-mediated cytotoxicity

Epidermal Growth Factor Receptor Is a Common Mediator of Quinone-induced Signaling Leading to Phosphorylation of Connexin-43

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