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Sci. Signal., 5 June 2012
Vol. 5, Issue 227, p. ra40
[DOI: 10.1126/scisignal.2002718]


Coupled Activation and Degradation of eEF2K Regulates Protein Synthesis in Response to Genotoxic Stress

Flore Kruiswijk1, Laurensia Yuniati1, Roberto Magliozzi1, Teck Yew Low2,3, Ratna Lim1, Renske Bolder1, Shabaz Mohammed2,3, Christopher G. Proud4, Albert J. R. Heck2,3, Michele Pagano5,6, and Daniele Guardavaccaro1*

1 Hubrecht Institute–KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, Netherlands.
2 Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584 CH Utrecht, Netherlands.
3 Netherlands Proteomics Center, Padualaan 8, 3584 CH Utrecht, Netherlands.
4 School of Biological Sciences, School of Biological Sciences, Life Sciences Building, University of Southampton, Southampton SO17 1BJ, UK.
5 Department of Pathology, NYU Cancer Institute, New York University School of Medicine, 522 First Avenue, SRB1107, New York, NY 10016, USA.
6 Howard Hughes Medical Institute.

Abstract: The kinase eEF2K [eukaryotic elongation factor 2 (eEF2) kinase] controls the rate of peptide chain elongation by phosphorylating eEF2, the protein that mediates the movement of the ribosome along the mRNA by promoting translocation of the transfer RNA from the A to the P site in the ribosome. eEF2K-mediated phosphorylation of eEF2 on threonine 56 (Thr56) decreases its affinity for the ribosome, thereby inhibiting elongation. Here, we show that in response to genotoxic stress, eEF2K was activated by AMPK (adenosine monophosphate–activated protein kinase)–mediated phosphorylation on serine 398. Activated eEF2K phosphorylated eEF2 and induced a temporary ribosomal slowdown at the stage of elongation. Subsequently, during DNA damage checkpoint silencing, a process required to allow cell cycle reentry, eEF2K was degraded by the ubiquitin-proteasome system through the ubiquitin ligase SCFβTrCP (Skp1–Cul1–F-box protein, β-transducin repeat–containing protein) to enable rapid resumption of translation elongation. This event required autophosphorylation of eEF2K on a canonical βTrCP-binding domain. The inability to degrade eEF2K during checkpoint silencing caused sustained phosphorylation of eEF2 on Thr56 and delayed the resumption of translation elongation. Our study therefore establishes a link between DNA damage signaling and translation elongation.

* To whom correspondence should be addressed. E-mail: d.guardavaccaro{at}

Citation: F. Kruiswijk, L. Yuniati, R. Magliozzi, T. Y. Low, R. Lim, R. Bolder, S. Mohammed, C. G. Proud, A. J. R. Heck, M. Pagano, D. Guardavaccaro, Coupled Activation and Degradation of eEF2K Regulates Protein Synthesis in Response to Genotoxic Stress. Sci. Signal. 5, ra40 (2012).

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Proteasome-dependent Degradation of Transcription Factor Activating Enhancer-binding Protein 4 (TFAP4) Controls Mitotic Division.
S. D'Annibale, J. Kim, R. Magliozzi, T. Y. Low, S. Mohammed, A. J. R. Heck, and D. Guardavaccaro (2014)
J. Biol. Chem. 289, 7730-7737
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Proteasomal Degradation of Eukaryotic Elongation Factor-2 Kinase (EF2K) Is Regulated by cAMP-PKA Signaling and the SCF{beta}TRCP Ubiquitin E3 Ligase.
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S. Meloche and P. P. Roux (2012)
Science Signaling 5, pe25
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