Molecular Mechanism for the Control of Eukaryotic Elongation Factor 2 Kinase by pH: Role in Cancer Cell Survival

Molecular and Cellular Biology
Jianling XieC 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.

References

Feb 1, 1991·The American Journal of Physiology·B K EnglandW E Mitch
Aug 17, 1990·European Journal of Biochemistry·U CarlbergO Nygård
Nov 15, 1995·The Biochemical Journal·F Buttgereit, M D Brand
Jan 1, 1994·Physiological Reviews·R H Fitts
Nov 1, 1995·Molecular Biology of the Cell·Y IshizakiM C Raff
Oct 4, 2000·Biochemistry·K S PavurA G Ryazanov
Nov 6, 2002·Biochemistry·Maxim V DorovkovAlexey G Ryazanov
Dec 9, 2003·Journal of Inorganic Biochemistry·Artur Krezel, Wojciech Bal
Jul 29, 2004·Cell Cycle·Karim MekhailStephen Lee
Nov 2, 2004·Nature Reviews. Cancer·Robert A Gatenby, Robert J Gillies
Feb 19, 2005·Science·D D SarbassovDavid M Sabatini
Aug 17, 2005·Genes & Development·Aurelio A TelemanStephen M Cohen
Oct 4, 2007·The Journal of Craniofacial Surgery·Roberto BecelliFabio Altieri
Mar 2, 2010·Seminars in Cancer Biology·Andrés CastellanosIsidro Sánchez-García
Mar 24, 2010·Nature Reviews. Nephrology·Jeffrey A Kraut, Nicolaos E Madias
Jul 28, 2010·Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine·Xiaomeng ZhangRobert J Gillies
Jul 9, 2011·PloS One·Aruna D BalgiMichel Roberge
Sep 17, 2011·Nature Reviews. Drug Discovery·Dario Neri, Claudiu T Supuran
Nov 26, 2011·The Biochemical Journal·Craig R PigottChristopher G Proud
Jan 6, 2012·The Biochemical Journal·Sébastien Pyr Dit RuysChristopher G Proud
Jan 5, 2013·Cancer Research·Veronica EstrellaRobert J Gillies
Jan 2, 2014·Frontiers in Physiology·Mehdi DamaghiRobert J Gillies
Sep 4, 2014·Molecular and Cellular Biology·Xuemin WangChristopher G Proud
Mar 11, 2015·Molecular and Cellular Biology·Claire E J MooreChristopher G Proud
Jan 1, 2014·Translation·Jianling Xie, Chris G Proud

❮ Previous
Next ❯

Citations

Jul 30, 2016·International Journal of Developmental Neuroscience : the Official Journal of the International Society for Developmental Neuroscience·Wenru PanSimon A Koblar
Jan 11, 2017·Molecular and Cellular Biology·Stephen FitterAndrew C W Zannettino
Jul 10, 2019·International Journal of Cancer. Journal International Du Cancer·Ying ZhouKaikai Shen
May 8, 2020·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Didem Karakas, Bulent Ozpolat
Sep 10, 2020·Signal Transduction and Targeted Therapy·Pei-Shan HuRui-Hua Xu
Dec 14, 2017·International Journal of Cancer. Journal International Du Cancer·Jianling XieChristopher G Proud
Dec 14, 2016·The Journal of Biological Chemistry·Clint D J TavaresKevin N Dalby
Jul 14, 2017·Reproduction, Fertility, and Development·Stella Liong, Martha Lappas
Jul 1, 2018·Cold Spring Harbor Perspectives in Biology·Christopher G Proud
Apr 17, 2020·Disease Models & Mechanisms·John R P KnightAnne E Willis
Mar 15, 2020·Cellular and Molecular Life Sciences : CMLS·Jianling XieChristopher G Proud
Oct 24, 2020·The Biochemical Journal·Yu WuChristopher G Proud
Mar 30, 2021·The Biochemical Journal·Roman V LenchineChristopher G Proud

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.