Eukaryotic elongation factor 2 kinase (eEF2K) is well known as a Ca2+/calmodulin (CaM)-dependent kinase. eEF2K catalyzes the phosphorylation of eEF2 and subsequently inactivates eEF2 by impairing its ability to bind to the ribosome, thereby negatively modulates protein synthesis. The high expression of eEF2K has been found recently in several types of malignancies. As participating in the progress of tumor, eEF2K emerges a potential target for future cancer therapy. The relationship between eEF2K and tumor, and the latest progress of eEF2K inhibitors were summarized in this article.
Elongation Factor 2 Kinase ; antagonists & inhibitors ; metabolism ; Humans ; Neoplasms ; metabolism ; Peptide Elongation Factor 2 ; metabolism ; Phosphorylation

OBJECTIVETo provide a summary of the relationship between the eEF-2/eEF-2 kinase pathway and each phase of malignant neoplasms. The speci?c importance of this relationship in understanding and treating cancer was also explored.

DATA SOURCESThe data used in this review were mainly obtained from the articles listed in HighWire and PubMed in English. The search terms were "eEF-2 kinase", "oncogenesis", and "tumor progression".

STUDY SELECTIONThis review relates the observation that the overexpression of eEF-2 kinase is seen in cancer, and highlights that it has emerged as promoting the development of many malignant phenotypes when unregulated. This includes increasing the replicative potential of cells, angiogenesis, invasion and metastasis, and evasion of apoptosis.

RESULTSeEF-2 kinase is a structurally and functionally unique protein kinase. The increased activity of this protein in cancer cells is a protective mechanism to allow tumor growth and evolution, and resist cell death through the eEF-2/eEF-2 kinase pathway, but it also makes a potential target for therapy.

CONCLUSIONeEF-2 kinase fills critical niches in the life of a cancer cell and the eEF-2/eEF-2 kinase pathway is a key biochemical sensor.

Apoptosis ; genetics ; physiology ; Elongation Factor 2 Kinase ; genetics ; metabolism ; Humans ; Neoplasms ; enzymology ; genetics

Objective: To investigate the effects of glycogen synthase kinase-3β (GSK3β)/eukaryotic extension factor kinase 2 (eEF2K) signaling pathway on the process of pulmonary fibrosis through in vivo experiments, and find new ideas for clinical treatment of pulmonary fibrosis. Methods: The pulmonary fibrosis model of C57BL/6 male mice was induced by bleomycin with intratracheal injection at the dose of 2 mg/kg. After 14 days of modeling, animals were divided into model group, negative inhibition group and inhibition group (n=5 for each group), and control group was not processed. The inhibition group was treated with TDZD-8 (4 mg/kg) after modeling, the negative inhibition group was given DMSO solution after modeling, and the samples were collected after 28 days. Hematoxylin-eosin staining method was used to detect lung fibrosis in mice and scored according to Ashcroft scale. Expression levels of GSK3β, p-GSK3β, eEF2K, p-eEF2K (Ser70, Ser392, Ser470), precursor protein of matrix metalloproteinase-2 (pro-MMP-2), matrix metalloproteinase-2 (MMP-2), collagen I (Col I), collagen Ⅲ (Col Ⅲ) and α-smooth muscle actin (α-SMA) were detected by Western blot. Results: Compared with control group, the fibrosis score was up-regulated, the expression levels of GSK3β, p-GSK3β, p-eEF2K (Ser70, Ser392, Ser470), pro-MMP-2, MMP-2, Col I, Col Ⅲ and α-SMA were increased, while that of eEF2K was decreased in model group (P＜0.05). Compared with model group, the fibrosis score, expression levels of GSK3β, p-GSK3β, p-eEF2K (Ser70, Ser392, Ser470), pro-MMP-2, MMP-2, Col I, Col Ⅲ and α-SMA were decreased, but the expression level of eEF2K was increased in inhibition group (P＜0.05). Conclusion: GSK3β can activate eEF2K by phosphorylation at the sites of Ser70, Ser392 and Ser470, increase the contents of fibrosis indicators, promote the formation of pulmonary fibrosis, and aggravate lung tissue lesions.
Animals ; Collagen ; Collagen Type I ; Elongation Factor 2 Kinase/metabolism* ; Eukaryota/metabolism* ; Fibrosis ; Glycogen Synthase Kinase 3 beta ; Male ; Matrix Metalloproteinase 2/metabolism* ; Mice ; Mice, Inbred C57BL ; Pulmonary Fibrosis/chemically induced* ; Signal Transduction

Protein arginine methylation is important for a variety of cellular processes including transcriptional regulation, mRNA splicing, DNA repair, nuclear/cytoplasmic shuttling and various signal transduction pathways. However, the role of arginine methylation in protein biosynthesis and the extracellular signals that control arginine methylation are not fully understood. Basic fibroblast growth factor (bFGF) has been identified as a potent stimulator of myofibroblast dedifferentiation into fibroblasts. We demonstrated that symmetric arginine dimethylation of eukaryotic elongation factor 2 (eEF2) is induced by bFGF without the change in the expression level of eEF2 in mouse embryo fibroblast NIH3T3 cells. The eEF2 methylation is preceded by ras-raf-mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK1/2)-p21(Cip/WAF1) activation, and suppressed by the mitogen-activated protein kinase (MAPK) inhibitor PD98059 and p21(Cip/WAF1) short interfering RNA (siRNA). We determined that protein arginine methyltransferase 7 (PRMT7) is responsible for the methylation, and that PRMT5 acts as a coordinator. Collectively, we demonstrated that eEF2, a key factor involved in protein translational elongation is symmetrically arginine-methylated in a reversible manner, being regulated by bFGF through MAPK signaling pathway.
Animals ; Arginine ; Cell Dedifferentiation ; Cyclin-Dependent Kinase Inhibitor p21/genetics/metabolism ; Elongation Factor 2 Kinase/*metabolism ; Fibroblast Growth Factor 2/*metabolism ; Fibroblasts/*metabolism/pathology ; Flavonoids/pharmacology ; MAP Kinase Signaling System/drug effects/genetics ; Methylation ; Mice ; Mitogen-Activated Protein Kinases/antagonists & inhibitors ; Myofibroblasts/pathology ; NIH 3T3 Cells ; Protein Methyltransferases/*metabolism ; Protein-Arginine N-Methyltransferases/*metabolism ; RNA, Small Interfering/genetics

Protein arginine methylation is important for a variety of cellular processes including transcriptional regulation, mRNA splicing, DNA repair, nuclear/cytoplasmic shuttling and various signal transduction pathways. However, the role of arginine methylation in protein biosynthesis and the extracellular signals that control arginine methylation are not fully understood. Basic fibroblast growth factor (bFGF) has been identified as a potent stimulator of myofibroblast dedifferentiation into fibroblasts. We demonstrated that symmetric arginine dimethylation of eukaryotic elongation factor 2 (eEF2) is induced by bFGF without the change in the expression level of eEF2 in mouse embryo fibroblast NIH3T3 cells. The eEF2 methylation is preceded by ras-raf-mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK1/2)-p21(Cip/WAF1) activation, and suppressed by the mitogen-activated protein kinase (MAPK) inhibitor PD98059 and p21(Cip/WAF1) short interfering RNA (siRNA). We determined that protein arginine methyltransferase 7 (PRMT7) is responsible for the methylation, and that PRMT5 acts as a coordinator. Collectively, we demonstrated that eEF2, a key factor involved in protein translational elongation is symmetrically arginine-methylated in a reversible manner, being regulated by bFGF through MAPK signaling pathway.
Animals ; Arginine ; Cell Dedifferentiation ; Cyclin-Dependent Kinase Inhibitor p21/genetics/metabolism ; Elongation Factor 2 Kinase/*metabolism ; Fibroblast Growth Factor 2/*metabolism ; Fibroblasts/*metabolism/pathology ; Flavonoids/pharmacology ; MAP Kinase Signaling System/drug effects/genetics ; Methylation ; Mice ; Mitogen-Activated Protein Kinases/antagonists & inhibitors ; Myofibroblasts/pathology ; NIH 3T3 Cells ; Protein Methyltransferases/*metabolism ; Protein-Arginine N-Methyltransferases/*metabolism ; RNA, Small Interfering/genetics