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The tyrosine kinase Lck is a positive regulator of the mitochondrial apoptosis pathway by controlling Bak expression

Oncogene volume 25, pages 186–197 (2006)Cite this article

Abstract

Tyrosine kinases of the Src family have been implicated in key biological processes. Here, we provide evidence that p56Lck, a lymphoid-specific Src kinase, is involved in the activation of the mitochondrial apoptosis pathway. Lck-deficient T cells were completely resistant to anticancer drugs. In contrast, apoptosis sensitivity to death receptors was not altered, indicating a specific interference of Lck with the mitochondrial pathway. Re-expression of Lck restored sensitivity to drug-induced apoptosis and triggered mitochondrial cytochrome c release and caspase activation. Further analysis identified that the sensitization by Lck was independent of classical mediators of T-cell signaling, but essentially involved the Bcl-2 protein Bak. Expression of Bak was completely absent in Lck-deficient cells, while re-expression of Lck transcriptionally triggered Bak expression and conferred sensitivity to apoptosis, associated with a proapoptotic conformational change of Bak. Furthermore, in vitro the truncated fragment of Bid specifically activated Bak and cytochrome c release only from mitochondria of Lck-expressing cells. These results do not only demonstrate a sentinel role of Lck in drug resistance but also delineate a hitherto unknown pathway of Src kinases in regulation of Bcl-2 proteins.

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Acknowledgements

We thank Drs RT Abraham, A Kosugi, I Schmitz and A Weiss for valuable cells and reagents. This work was supported by the Deutsche Krebshilfe.

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  1. A K Samraj and C Stroh: Both these authors contributed equally to this work.

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  1. Institute of Molecular Medicine, University of Düsseldorf, Germany

    A K Samraj, C Stroh, U Fischer & K Schulze-Osthoff

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  1. A K Samraj
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Correspondence to K Schulze-Osthoff.

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Samraj, A., Stroh, C., Fischer, U. et al. The tyrosine kinase Lck is a positive regulator of the mitochondrial apoptosis pathway by controlling Bak expression. Oncogene 25, 186–197 (2006). https://doi.org/10.1038/sj.onc.1209034

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