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The role of tyrosine kinase Etk/Bmx in EGF-induced apoptosis of MDA-MB-468 breast cancer cells

Oncogene volume 23, pages 1854–1862 (2004)Cite this article

Abstract

Etk/Bmx, a member of the Tec family of tyrosine kinases, mediates various signaling pathways and confers several cellular functions. In the present study, we have explored the functional role of Etk in mediating EGF-induced apoptosis, using MDA-MB-468 cell line as a model. We first demonstrated that EGF treatment induces Etk tyrosine phosphorylation in both HeLa and MDA-MB-468 cells. Overexpression of Etk by recombinant adenovirus in MDA-MB-468 cells potentiates the extent of EGF-induced cell apoptosis. The observed Etk-enhanced MDA-MB-468 cell apoptosis is associated with the Stat1 activation, as demonstrated by electrophoresis mobility shift assays and reporter gene assays. By contrast, a kinase domain deletion mutant EtkΔK, functioning as a dominant-negative mutant, ameliorates EGF-induced Stat1 activation and apoptosis in MDA-MB-468 cells. To explore whether the activated Etk alone is sufficient for inducing apoptosis, a conditionally activated Etk (ΔEtk-ER), a chimeric fusion protein of PH domain-truncated Etk and ligand-binding domain of estrogen receptor, was introduced into MDA-MB-468 cells. Upon β-estradiol ligand activation, the ΔEtk-ER could stimulate Stat1 activity and confer cell apoptosis independent of EGF treatment. Taken together, our findings indicate that Etk is a downstream signaling molecule of EGF receptor and suggest that Etk activation is essential for transducing the EGF-induced apoptotic signaling.

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Abbreviations

Etk:

epithelial and endothelial tyrosine kinase

EGF:

epidermal growth factor

PI3 kinase:

phosphoinositol-3 kinase

E2:

β-estradiol

ER:

estrogen receptor

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Acknowledgements

This work was supported by the intramural funds of the National Health Research Institutes (to H-MS), and in part by the National Institute of Health Research Grants CA39207 and 91574 (to HJK) and R01 DE 10742 and DE14183 (to DKA).

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Authors and Affiliations

  1. Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, ROC, Taiwan

    Kai-Yun Chen & Hsiu-Ming Shih

  2. Division of Molecular and Genomic Medicine, National Health Research Institutes, Taipei, ROC, Taiwan

    Kai-Yun Chen, Li-Ming Huang & Hsiu-Ming Shih

  3. University of California at Davis Cancer Center, Sacramento, California, 95817, CA, USA

    Hsing-Jien Kung

  4. Department of Molecular Pharmacology and Toxicology, University of Southern California, Los Angeles, 90033, CA, USA

    David K Ann

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Chen, KY., Huang, LM., Kung, HJ. et al. The role of tyrosine kinase Etk/Bmx in EGF-induced apoptosis of MDA-MB-468 breast cancer cells. Oncogene 23, 1854–1862 (2004). https://doi.org/10.1038/sj.onc.1207308

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