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Epidermal growth factor (EGF) activates nuclear factor-κB through IκBα kinase-independent but EGF receptor-kinase dependent tyrosine 42 phosphorylation of IκBα

Oncogene volume 26, pages 7324–7332 (2007)Cite this article

A Corrigendum to this article was published on 16 October 2015

Abstract

Overexpression of epidermal growth factor (EGF) receptor and constitutive activation of nuclear factor-κB (NF-κB) are frequently encountered in tumor cells. Although EGF has been shown to induce NF-κB activation, the mechanism is poorly understood. EGF activated NF-κB DNA binding, induced NF-κB reporter activity and the expression of antiapoptotic and cell-proliferative gene products. Interestingly, non-small cell lung adenocarcinoma cell lines (HCC827 and H3255), which exhibit EGFR amplification, showed ligand-independent activation of NF-κB. Unlike tumor-necrosis factor (TNF), however, EGF failed to induce IκBα phosphorylation and ubiquitination and the activation of IκBα kinase (IKK). Although DN-IKKβ inhibited TNF-induced NF-κB activity, DN-IKKβ had no effect on EGF-induced NF-κB activation, suggesting that EGF-induced NF-κB activation is IKK independent. Using dominant-negative plasmids, we also demonstrated the role of TRADD, TRAF2, NIK and Ras in EGF-induced NF-κB activation. By using specific antibodies and IκBα plasmid, which is mutated at tyrosine 42 to phenylalanine, we show that EGF induced the tyrosine phosphorylation of IκBα at residue 42. Furthermore, EGF receptor kinase inhibitor blocked IκBα phosphorylation and consequent NF-κB activation. Overall, our results indicate that tyrosine phosphorylation of IκBα at residue 42 is critical for EGF-induced NF-κB activation pathway.

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Abbreviations

EGF:

epidermal growth factor

EGFR:

epidermal growth factor receptor

EMSA:

electrophoretic mobility shift assay

IκB:

inhibitory subunit of NF-κB

NF-κB:

nuclear factor-κB

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Acknowledgements

We thank Dawn Chalaire for providing valuable comments. Dr Aggarwal is the Ransom Horne Jr, Professor of Cancer Research. This work was supported by a grant from the Clayton Foundation for Research (to BBA) and National Institutes of Health PO1 grant CA91844 on lung chemoprevention (to BBA).

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  1. M M Chaturvedi

    Present address: 2Current address: Dr MM Chaturvedi, The Department of Zoology, University of Delhi, Delhi 110007, India.,

Authors and Affiliations

  1. Department of Experimental Therapeutics, Cytokine Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    G Sethi, K S Ahn, M M Chaturvedi & B B Aggarwal

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  1. G Sethi
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Correspondence to B B Aggarwal.

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Sethi, G., Ahn, K., Chaturvedi, M. et al. Epidermal growth factor (EGF) activates nuclear factor-κB through IκBα kinase-independent but EGF receptor-kinase dependent tyrosine 42 phosphorylation of IκBα. Oncogene 26, 7324–7332 (2007). https://doi.org/10.1038/sj.onc.1210544

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