Written | 2016-01 | Bulent Ozpolat, Ozgur Ozkayar |
University of Texas-Houston-MD Anderson Cancer Center, Department of Experimental Therapeutics, 1515 Holcombe Boulevard, Unit 422, Houston, TX7730; Bozpolat@mdanderson.org |
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+/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. |
Keywords | Elongation, protein translation, proliferation, invasion, prognosis, survival, cancer |
Identity |
Alias (NCBI) | Calcium/Calmodulin-dependent protein kinase III (CaMK-III) | eEF-2K | HSU93850 |
HGNC (Hugo) | EEF2K |
HGNC Alias symb | eEF-2K | CaMKIII |
LocusID (NCBI) | 29904 |
Atlas_Id | 40411 |
Location | 16p12.2 [Link to chromosome band 16p12] |
Location_base_pair | Starts at 22206278 and ends at 22288738 bp from pter ( according to GRCh38/hg38-Dec_2013) [Mapping EEF2K.png] |
Fusion genes (updated 2017) | Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands) |
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. |
Protein |
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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 |
Note | |
Entity | 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 | 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 | 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 | 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 | 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). |
Bibliography |
Purification and characterization of tagless recombinant human elongation factor 2 kinase (eEF-2K) expressed in Escherichia coli |
Abramczyk O, Tavares CD, Devkota AK, Ryazanov AG, Turk BE, Riggs AF, Ozpolat B, Dalby KN |
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PMID 21605678 |
Elongation factor-2 kinase regulates TG2/β1 integrin/Src/uPAR pathway and epithelial-mesenchymal transition mediating pancreatic cancer cells invasion |
Ashour AA, Gurbuz N, Alpay SN, Abdel-Aziz AA, Mansour AM, Huo L, Ozpolat B |
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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 |
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[Nissl staining with cresyl violet] |
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PMID 23102376 |
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Mitsui K, Brady M, Palfrey HC, Nairn AC |
J Biol Chem 1993 Jun 25;268(18):13422-33 |
PMID 8514778 |
Identification of calmodulin-dependent protein kinase III and its major Mr 100,000 substrate in mammalian tissues |
Nairn AC, Bhagat B, Palfrey HC |
Proc Natl Acad Sci U S A 1985 Dec;82(23):7939-43 |
PMID 3906654 |
Cyclic AMP-dependent protein kinase phosphorylates rabbit reticulocyte elongation factor-2 kinase and induces calcium-independent activity |
Redpath NT, Proud CG |
Biochem J 1993 Jul 1;293 ( Pt 1):31-4 |
PMID 8328970 |
Ca2+/calmodulin-dependent phosphorylation of elongation factor 2 |
Ryazanov AG |
FEBS Lett 1987 Apr 20;214(2):331-4 |
PMID 3569528 |
Phosphorylation of elongation factor 2 by EF-2 kinase affects rate of translation |
Ryazanov AG, Shestakova EA, Natapov PG |
Nature 1988 Jul 14;334(6178):170-3 |
PMID 3386756 |
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, O'Brien JP, Abramczyk O, Devkota AK, Shores KS, Ferguson SB, Kaoud TS, Warthaka M, Marshall KD, Keller KM, Zhang Y, Brodbelt JS, Ozpolat B, Dalby KN |
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PMID 22329831 |
Targeted silencing of elongation factor 2 kinase suppresses growth and sensitizes tumors to doxorubicin in an orthotopic model of breast cancer |
Tekedereli I, Alpay SN, Tavares CD, Cobanoglu ZE, Kaoud TS, Sahin I, Sood AK, Lopez-Berestein G, Dalby KN, Ozpolat B |
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PMID 22911754 |
Eukaryotic elongation factor 2 kinase regulates the development of hypertension through oxidative stress-dependent vascular inflammation |
Usui T, Okada M, Hara Y, Yamawaki H |
Am J Physiol Heart Circ Physiol 2013 Sep 1;305(5):H756-68 |
PMID 23812389 |
Citation |
This paper should be referenced as such : |
Bulent Ozpolat, Ozgur Ozkayar |
EEF2K (eukaryotic elongation factor 2 kinase) |
Atlas Genet Cytogenet Oncol Haematol. 2016;20(9):478-480. |
Free journal version : [ pdf ] [ DOI ] |
Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 2 ] |
EEF2K/UQCRC2 (16p12)
EEF2K/VWA3A (16p12) |
External links |
REVIEW articles | automatic search in PubMed |
Last year publications | automatic search in PubMed |
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