EEF2K (eukaryotic elongation factor 2 kinase)
2016-01-01 Bulent Ozpolat , Ozgur Ozkayar AffiliationUniversity of Texas-Houston-MD Anderson Cancer Center, Department of Experimental Therapeutics, 1515 Holcombe Boulevard, Unit 422, Houston, TX7730; [email protected]
Abstract
Eukaryotic elongation factor 2 kinase (eEF-2K) (also known as Calmodulin (CaM)-dependent elongation factor 2 kinase,CaMKIII) is an unusual calcium\/calmodulin (Ca2+<\/sup>\/CaM)-dependent Threonin kinase that controls the rate of the elongation phase of protein synthesis through phosphorylating elongation factor 2 (eEF2) (Nairn et al., 1985; Ryazanov 1987; Mitsui et al., 1993; Redpath et al., 1993). Phosphorylation of eEF2 on Thr-56 disrupts the interaction between eEF-2 and the ribosome, leading to reduced protein synthesis. eEF-2K is regulated by phosphorylation by multiple signaling pathways and kinases at 11 different phosphorylation sides (Ryazanov et al., 1988; Carlberg et al., 1990; Abramczyk et al., 2011; Browne et al., 2004; Marshall et al., 2012; Chafouleas et al., 1981; Bowden et al., 2013). Hypoxia, nutrient deprivation and metabolic stress are all known to stimulate eEF-2K through activation of AMPK (Chafouleas et al., 1981).The activity of eEF-2K is increased in rapidly proliferating malignant cells and in cancer specimens, but is absent in normal adjacent tissues (Ashour et al., 2014b). eEF-2K promotes cell proliferation, invasion and tumorigenesis of some cancers. eEF-2K expression (mRNA) correlates with poor patient survival and prognosis (outcome) in some solid tumors, including breast , pancreatic cancer and glioblastoma (Meric-Bernstam et al., 2012). The activity of this kinase is increased in many cancers and may be a potential therapeutic target in some cancers.
DNA/RNA
Note
EEF2K gene encodes a Ca2+/calmodulin-dependent kinase known as eukaryotic elongation factor-2 kinase (EEF2K).
Description
The EEF2K gene is composed of 18 exons. It spans approximately 80.35 kb of genomic DNA.
Transcription
This gene encodes 5 transcripts and protein coding transcript (EEF2K-001) has 7388 bp length and this is composed of 725 aa residues. EEF2K-002 is a non sense mediated decay. Other three transcripts (EEF2K-003, -004, -005) do not give rise to proteins.
Pseudogene
No pseudogene reported.
Proteins
Structure of eukaryotic elongation factor-2 kinase (EF2K) protein. CaM: Calmoduline.
Description
Human eukaryotic elongation factor-2 kinase is composed of 725 amino acids (105 KDa) alfa-kinase catalytic domain of this protein is located at the section of 76-356. Calmoduline (CaM) binding domain is located close to N-terminal and next to the catalytic domain. The function of the region located N-terminal of the CaM-binding site is not well understood but removal of this segment leads to intrinsic autophosphorylation and activity; cause inhibitory effect on the EF2K activity. Contain 18 phosphorylation sites. Autophosphorylated at multiple residues, Thr-348 is the major site. Towards the C-terminal region, there are four predicted alfa-helical regions, and these resemble SEL-1-type repeats. The region lies between SEL-1 type repeats and the C-terminus contains higly reserved sequences. The extreme C terminus is known to be essential for the phosphorylation of eukaryotic elongation factor-2 (eEF2).
Expression
Ubiquitosly expressed in nomal tissues. Activity is increased in some tumors.
Localisation
Cytoplasmic.
Function
EEF2K protein belongs to alfa-kinases family of protein kinases. Its activity is dependent to Ca2+/calmodulin kinase and phosphorilates eukaryotic elongation factor-2 (eEF2) at Thr56 and inhibits it association/binding with ribosomes, thus regulates the elongation phase of translation.
Mutations
Note
No mutations identified other than SNPs repsesenting normal variations (http://www.hgmd.cf.ac.uk/ac/gene.php?gene=EEF2K)
Implicated in
Entity name
Breast Cancer
Note
eEF-2K protein expression promotes in breast cancer cell survival, invasion, migration and tumorigenesis (Tekedereli et al., 2012). eEF-2k highly expressed lines compared with normal non-tumorigenic breast epithelium and ist expression is associated with poor patient survival and prognosis (Meric-Bernstam et al., 2012).
Prognosis
Overexpression of eEF-2k is associated with shorter survival and poor prognosis (outcome) in Estrogen receptor (ER) positive (Tekedereli et al., 2012) and triple negative or ER (-) breast cancer patients (Ozpolat et al in press).
Entity name
Pancreatic cancer
Note
eEF-2K protein is significantly overexpressed in pancreatic cancer cell lines and its inhibition lead to inhibition of cell proliferation, in invasion and migration and induces apoptosis (Ashour et al., 2014a; Ashour et al., 2014b).
Entity name
Glioblastome multiforme (GBM)
Note
): eEF-2K protects cells from nutrient deprivation and in conferring tumor cell adaptation to nutrient deprivation and metabolic stress by blocking translation elongation (Bowden et al., 2013).
Entity name
Azheimer disease (AD)
Note
Levels of p-eEF2K were found to be significantly increased, and total eEF2 significantly decreased in AD, when compared to controls in the brain tissue. levels of p-MTOR (Ser2481), and EIF4EBP1 (p-4E-BP1) (Thr70 and Ser65) dramatically increase in AD, and are positively significantly correlated with total tau and p-tau proteins.
Entity name
Hypertension
Note
eEF2K protein increases in mesenteric artery from spontaneously hypertensive rats (SHR). eEF2K mediates TNF-?-induced vascular inflammation via ROS-dependent mechanism, which is at least partly responsible for the development of hypertension in SHR (Usui et al., 2013).
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 21605678 | 2011 | Purification and characterization of tagless recombinant human elongation factor 2 kinase (eEF-2K) expressed in Escherichia coli. | Abramczyk O et al |
| 25215932 | 2014 | Elongation factor-2 kinase regulates TG2/β1 integrin/Src/uPAR pathway and epithelial-mesenchymal transition mediating pancreatic cancer cells invasion. | Ashour AA et al |
| 14709557 | 2004 | Stimulation of the AMP-activated protein kinase leads to activation of eukaryotic elongation factor 2 kinase and to its phosphorylation at a novel site, serine 398. | Browne GJ et al |
| 2390990 | 1990 | Functional properties of phosphorylated elongation factor 2. | Carlberg U et al |
| 6262788 | 1981 | Regulation of intracellular levels of calmodulin and tubulin in normal and transformed cells. | Chafouleas JG et al |
| 4193916 | 1970 | [Nissl staining with cresyl violet]. | Krutsay M et al |
| 23706743 | 2013 | The eEF2 kinase confers resistance to nutrient deprivation by blocking translation elongation. | Leprivier G et al |
| 23102376 | 2012 | Aberrations in translational regulation are associated with poor prognosis in hormone receptor-positive breast cancer. | Meric-Bernstam F et al |
| 8514778 | 1993 | Purification and characterization of calmodulin-dependent protein kinase III from rabbit reticulocytes and rat pancreas. | Mitsui K et al |
| 3906654 | 1985 | Identification of calmodulin-dependent protein kinase III and its major Mr 100,000 substrate in mammalian tissues. | Nairn AC et al |
| 8328970 | 1993 | Cyclic AMP-dependent protein kinase phosphorylates rabbit reticulocyte elongation factor-2 kinase and induces calcium-independent activity. | Redpath NT et al |
| 3569528 | 1987 | Ca2+/calmodulin-dependent phosphorylation of elongation factor 2. | Ryazanov AG et al |
| 3386756 | 1988 | Phosphorylation of elongation factor 2 by EF-2 kinase affects rate of translation. | Ryazanov AG et al |
| 22329831 | 2012 | Calcium/calmodulin stimulates the autophosphorylation of elongation factor 2 kinase on Thr-348 and Ser-500 to regulate its activity and calcium dependence. | Tavares CD et al |
| 22911754 | 2012 | Targeted silencing of elongation factor 2 kinase suppresses growth and sensitizes tumors to doxorubicin in an orthotopic model of breast cancer. | Tekedereli I et al |
| 23812389 | 2013 | Eukaryotic elongation factor 2 kinase regulates the development of hypertension through oxidative stress-dependent vascular inflammation. | Usui T et al |
Other Information
Locus ID:
NCBI: 29904
MIM: 606968
HGNC: 24615
Ensembl: ENSG00000103319
Variants:
dbSNP: 29904
ClinVar: 29904
TCGA: ENSG00000103319
COSMIC: EEF2K
RNA/Proteins
| Gene ID | Transcript ID | Uniprot |
|---|---|---|
| ENSG00000103319 | ENST00000263026 | O00418 |
| ENSG00000103319 | ENST00000568269 | H3BRH4 |
Expression (GTEx)
Pathways
Protein levels (Protein atlas)
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 34796967 | 2023 | Roles of eukaryotic elongation factor 2 kinase (eEF2K) in neuronal plasticity, cognition, and Alzheimer disease. | 6 |
| 37172726 | 2023 | Structure of the complex between calmodulin and a functional construct of eukaryotic elongation factor 2 kinase bound to an ATP-competitive inhibitor. | 2 |
| 34796967 | 2023 | Roles of eukaryotic elongation factor 2 kinase (eEF2K) in neuronal plasticity, cognition, and Alzheimer disease. | 6 |
| 37172726 | 2023 | Structure of the complex between calmodulin and a functional construct of eukaryotic elongation factor 2 kinase bound to an ATP-competitive inhibitor. | 2 |
| 35347072 | 2022 | eEF2K promotes PD-L1 stabilization through inactivating GSK3β in melanoma. | 11 |
| 35718922 | 2022 | miRNA-193b-5p Suppresses Pancreatic Cancer Cell Proliferation, Invasion, Epithelial Mesenchymal Transition, and Tumor Growth by Inhibiting eEF2K. | 1 |
| 35347072 | 2022 | eEF2K promotes PD-L1 stabilization through inactivating GSK3β in melanoma. | 11 |
| 35718922 | 2022 | miRNA-193b-5p Suppresses Pancreatic Cancer Cell Proliferation, Invasion, Epithelial Mesenchymal Transition, and Tumor Growth by Inhibiting eEF2K. | 1 |
| 33539938 | 2021 | Targeting eukaryotic elongation factor-2 kinase suppresses the growth and peritoneal metastasis of ovarian cancer. | 7 |
| 33734395 | 2021 | Novel regulation of the eEF2K/eEF2 pathway: prospects of 'PQBP1 promotes translational elongation and regulates hippocampal mGluR-LTD by suppressing eEF2 phosphorylation'. | 1 |
| 33779695 | 2021 | Elongation factor eEF2 kinase and autophagy jointly promote survival of cancer cells. | 1 |
| 33890716 | 2021 | Structural dynamics of the complex of calmodulin with a minimal functional construct of eukaryotic elongation factor 2 kinase and the role of Thr348 autophosphorylation. | 6 |
| 34352439 | 2021 | eEF2K as a novel metastatic and prognostic biomarker in gastric cancer patients. | 5 |
| 33539938 | 2021 | Targeting eukaryotic elongation factor-2 kinase suppresses the growth and peritoneal metastasis of ovarian cancer. | 7 |
| 33734395 | 2021 | Novel regulation of the eEF2K/eEF2 pathway: prospects of 'PQBP1 promotes translational elongation and regulates hippocampal mGluR-LTD by suppressing eEF2 phosphorylation'. | 1 |
Citation
Bulent Ozpolat ; Ozgur Ozkayar
EEF2K (eukaryotic elongation factor 2 kinase)
Atlas Genet Cytogenet Oncol Haematol. 2016-01-01
Online version: http://atlasgeneticsoncology.org/gene/40411/eef2k-(eukaryotic-elongation-factor-2-kinase)
