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Phosphorylation of Bim-EL by Erk1/2 on serine 69 promotes its degradation via the proteasome pathway and regulates its proapoptotic function

Oncogene volume 22, pages 6785–6793 (2003)Cite this article

Abstract

Bim is a proapoptotic member of the Bcl-2 family that shares only the BH3 domain with this family. Three Bim proteins Bim-EL, Bim-L and Bim-S are synthesized from the same transcript. We report here that Bim-EL when phosphorylated by Erk1/2 is rapidly degraded via the proteasome pathway. Using different cellular models we evidence that serine 69 is both necessary and sufficient for Erk1/2-mediated phosphorylation and degradation of Bim-EL. In K562 cells, Phorbol 12-myristate 13-acetate activates Erk1/2 and consequently increases Bim-EL phosphorylation and degradation by the proteasome, resulting in cell survival, while the Bcr-Abl inhibitor imatinib abrogates Bim-EL phosphorylation and degradation and induces caspase activation and apoptosis. We also show that Bim-EL(S69G) promotes apoptosis more efficiently than Bim-EL-WT in K562 cells. Altogether, our findings demonstrate that phosphorylation of Bim-EL by Erk1/2 on serine 69 selectively leads to its proteasomal degradation and therefore represents a new and important mechanism of Bim regulation.

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Acknowledgements

This work was supported by INSERM, The Ligue Nationale contre le Cancer (LNC, Equipe labellisée). We are undebted to Dr David Huang and Dr Andreas Strasser (WEHI, Melbourne, Australia) for the kind gift of Bim constructs. FL is a fellowship from the LNC.

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  1. INSERM Unit 526, LNC Label, Faculté de Médecine, 28 Avenue de Valombrose, Nice, Cedex 02, 06107, France

    Frederic Luciano, Arnaud Jacquel, Pascal Colosetti, Magali Herrant, Sebastien Cagnol & Patrick Auberger

  2. UMR CNRS 6547, Centre Antoine Lacassagne, Avenue de valombrose, Nice, Cedex 02, 06100, France

    Gilles Pages

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  1. Frederic Luciano
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Correspondence to Patrick Auberger.

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Luciano, F., Jacquel, A., Colosetti, P. et al. Phosphorylation of Bim-EL by Erk1/2 on serine 69 promotes its degradation via the proteasome pathway and regulates its proapoptotic function. Oncogene 22, 6785–6793 (2003). https://doi.org/10.1038/sj.onc.1206792

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