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Cisplatin induces PKB/Akt activation and p38MAPK phosphorylation of the EGF receptor

Oncogene volume 25, pages 7381–7390 (2006)Cite this article

A Corrigendum to this article was published on 01 February 2007

Abstract

Cisplatin is an effective DNA-damaging antitumor agent employed for the treatment of various human cancers. In this study, we report that Cisplatin activates PKB/Akt in several cancer cell lines and that this activation is mediated by EGFR, Src and PI3-kinase. Inhibition of PI3-kinase activity decreases the survival of the cells exposed to Cisplatin, suggesting that Cisplatin-induced PKB/Akt activation may lead to Cisplatin resistance. While investigating the EGFR-dependent PKB/Akt activation in MDA-MB-468 cells, we found that the EGFR receptor undergoes a gel mobility shift upon Cisplatin treatment, which is mediated by p38MAPK. An EGFR, in which threonine 669 was mutated to alanine (A669), is phosphorylated by p38MAPK to a much lesser extent, suggesting that threonine 669 is a p38 phosphorylation site. We found that Cisplatin induces EGFR internalization, which is mediated by p38MAPK-dependent phosphorylation of the receptor on threonine 669. Our results identify the EGFR as a new substrate of p38 and identify threonine 669 as a new phosphorylation site that regulates EGFR internalization. Together, these results suggest that Cisplatin has side effects, which may alter the signaling pattern of cancer cells and modulate the desired effects of Cisplatin treatment.

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Acknowledgements

We thank all the researchers who provided plasmids, cell lines and reagents. We thank Nadav Askary for helping with the p38 kinase assay, to Moran Benhar for fruitful discussions and to Bennjamin Gaiger for the advice and the reagents for the immunofluorescent experiments.

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  1. S E Winograd-Katz

    Present address: Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel

Authors and Affiliations

  1. Department of Biological Chemistry, Unit of Cellular Signaling, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel

    S E Winograd-Katz & A Levitzki

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  2. A Levitzki
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Correspondence to A Levitzki.

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Winograd-Katz, S., Levitzki, A. Cisplatin induces PKB/Akt activation and p38MAPK phosphorylation of the EGF receptor. Oncogene 25, 7381–7390 (2006). https://doi.org/10.1038/sj.onc.1209737

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