Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/91266
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Type: Journal article
Title: Molecular mechanism for the control of eukaryotic elongation factor 2 kinase by pH: role in cancer cell survival
Author: Xie, J.
Mikolajek, H.
Pigott, C.
Hooper, K.
Mellows, T.
Moore, C.
Mohammed, H.
Werner, J.
Thomas, G.
Proud, C.
Citation: Molecular and Cellular Biology, 2015; 35(10):1805-1824
Publisher: American Society for Microbiology
Issue Date: 2015
ISSN: 0270-7306
1098-5549
Statement of
Responsibility: 
Jianling Xie, Halina Mikolajek, Craig R. Pigott, Kelly J. Hooper, Toby Mellows, Claire E. Moore, Hafeez Mohammed, Jörn M. Werner, Gareth J. Thomas and Christopher G. Proud
Abstract: Acidification of the extracellular and/or intracellular environment is involved in many aspects of cell physiology and pathology. Eukaryotic elongation factor 2 kinase (eEF2K) is a Ca(2+)/calmodulin-dependent kinase that regulates translation elongation by phosphorylating and inhibiting eEF2. Here we show that extracellular acidosis elicits activation of eEF2K in vivo, leading to enhanced phosphorylation of eEF2. We identify five histidine residues in eEF2K that are crucial for the activation of eEF2K during acidosis. Three of them (H80, H87, and H94) are in its calmodulin-binding site, and their protonation appears to enhance the ability of calmodulin to activate eEF2K. The other two histidines (H227 and H230) lie in the catalytic domain of eEF2K. We also identify His108 in calmodulin as essential for activation of eEF2K. Acidification of cancer cell microenvironments is a hallmark of malignant solid tumors. Knocking down eEF2K in cancer cells attenuated the decrease in global protein synthesis when cells were cultured at acidic pH. Importantly, activation of eEF2K is linked to cancer cell survival under acidic conditions. Inhibition of eEF2K promotes cancer cell death under acidosis.
Keywords: Cell Line; HCT116 Cells; Animals; Humans; Mice; Neoplasms; Histidine; Calmodulin; Cell Survival; Gene Expression Regulation, Neoplastic; Enzyme Activation; Catalytic Domain; Hydrogen-Ion Concentration; Elongation Factor 2 Kinase; HEK293 Cells
Rights: © 2015, American Society for Microbiology. All Rights Reserved.
RMID: 0030028848
DOI: 10.1128/mcb.00012-15
Appears in Collections:Agriculture, Food and Wine publications

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