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MCL1 is phosphorylated in the PEST region and stabilized upon ERK activation in viable cells, and at additional sites with cytotoxic okadaic acid or taxol

Oncogene volume 23, pages 5301–5315 (2004)Cite this article

Abstract

BCL2 family members are subject to regulation at multiple levels, providing checks on their ability to contribute to tumorigenesis. However, findings on post-translational BCL2 phosphorylation in different systems have been difficult to integrate. Another antiapoptotic family member, MCL1, exhibits a difference in electrophoretic mobility upon phosphorylation induced by an activator of PKC (12-O-tetradecanoylphorbol 13-acetate; TPA) versus agents that act on microtubules or protein phosphatases 1/2A. A multiple pathway model is now presented, which demonstrates that MCL1 can undergo distinct phosphorylation events – mediated through separate signaling processes and involving different target sites – in cells that remain viable in the presence of TPA versus cells destined to die upon exposure to taxol or okadaic acid. Specifically, TPA induces phosphorylation at a conserved extracellular signal-regulated kinase (ERK) site in the PEST region (Thr 163) and slows turnover of the normally rapidly degraded MCL1 protein; however, okadaic acid and taxol induce ERK-independent MCL1 phosphorylation at additional discrete sites. These findings add a new dimension to our understanding of the complex regulation of antiapoptotic BCL2 family members by demonstrating that, in addition to transcriptional and post-transcriptional regulation, MCL1 is subject to multiple, separate, post-translational phosphorylation events, produced in living versus dying cells at ERK-inducible versus ERK-independent sites.

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Acknowledgements

This work was supported by National Cancer Institute Grant R01-CA57359. We thank Ethan Kohn for a very incisive, helpful review of the paper.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, 03755, NH, USA

    Aaron M Domina, Julie A Vrana & Ruth W Craig

  2. Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, 37232, TN, USA

    Mark A Gregory & Stephen R Hann

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Correspondence to Ruth W Craig.

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Domina, A., Vrana, J., Gregory, M. et al. MCL1 is phosphorylated in the PEST region and stabilized upon ERK activation in viable cells, and at additional sites with cytotoxic okadaic acid or taxol. Oncogene 23, 5301–5315 (2004). https://doi.org/10.1038/sj.onc.1207692

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