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EEF2K (eukaryotic elongation factor 2 kinase)

Written2016-01Bulent 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.

(Note : for Links provided by Atlas : click)

Identity

Other namesHSU93850
eEF-2K
HGNC (Hugo) EEF2K
LocusID (NCBI) 29904
Atlas_Id 40411
Location 16p12.2
Location_base_pair Starts at 22217592 and ends at 22300066 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Fusion genes
(updated 2016)
EEF2K (16p12.2) / C10orf35 (10q22.1)EEF2K 16p12.2) / UQCRC2 (16p12.2)EEF2K (16p12.2) / VWA3A (16p12.2)

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

 
  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 A highly specific down-regulation of EEF2K by siRNA in reduces cell proliferation and colony formation of breast and pancreatic cancer cells and inhibits growth of breast tumor, suggesting its role in tumorigenesis (Tekedereli et al., 2012; Ashour et al., 2014a; Ashour et al., 2014b). Also, EEF2K induces expression of MYC , CCND1 (cyclin D1) and VEGFA supresses CDKN1B (p27kip1) expression. eEF-2K promotes the G1/S transition of the cell cycle in breast cancer cells (Tekedereli et al., 2012) and epithelium mesenchimal transtion (EMT) and Transglutaminase 2 (TG2) (Ashour et al., 2014b). EE2K expression induces activity of protumorigenic and inflammatory pathways, including PI3K/Akt, mTOR, IGFR and NF-Kb signaling (Tekedereli et al., 2012; Ashour et al., 2014a; Ashour et al., 2014b).
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

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
 
Ca2+/calmodulin-dependent phosphorylation of elongation factor 2
Ryazanov AG
FEBS Lett 1987 Apr 20;214(2):331-4
PMID 3569528
 
Purification and characterization of calmodulin-dependent protein kinase III from rabbit reticulocytes and rat pancreas
Mitsui K, Brady M, Palfrey HC, Nairn AC
J Biol Chem 1993 Jun 25;268(18):13422-33
PMID 8514778
 
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
 
Identification of a new class of protein kinases represented by eukaryotic elongation factor-2 kinase
Ryazanov AG, Ward MD, Mendola CE, Pavur KS, Dorovkov MV, Wiedmann M, Erdjument-Bromage H, Tempst P, Parmer TG, Prostko CR, Germino FJ, Hait WN
Proc Natl Acad Sci U S A 1997 May 13;94(10):4884-9
PMID 9144159
 
Alpha-kinases: a new class of protein kinases with a novel catalytic domain
Ryazanov AG, Pavur KS, Dorovkov MV
Curr Biol 1999 Jan 28;9(2):R43-5
PMID 10021370
 
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
 
Functional properties of phosphorylated elongation factor 2
Carlberg U, Nilsson A, Nygård O
Eur J Biochem 1990 Aug 17;191(3):639-45
PMID 2390990
 
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
Protein Expr Purif 2011 Oct;79(2):237-44
PMID 21605678
 
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, Finn SG, Proud CG
J Biol Chem 2004 Mar 26;279(13):12220-31
PMID 14709557
 
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
Biochemistry 2012 Mar 20;51(11):2232-45
PMID 22329831
 
Regulation of intracellular levels of calmodulin and tubulin in normal and transformed cells
Chafouleas JG, Pardue RL, Brinkley BR, Dedman JR, Means AR
Proc Natl Acad Sci U S A 1981 Feb;78(2):996-1000
PMID 6262788
 
The eEF2 kinase confers resistance to nutrient deprivation by blocking translation elongation
Leprivier G, Remke M, Rotblat B, Dubuc A, Mateo AR, Kool M, Agnihotri S, El-Naggar A, Yu B, Somasekharan SP, Faubert B, Bridon G, Tognon CE, Mathers J, Thomas R, Li A, Barokas A, Kwok B, Bowden M, Smith S, Wu X, Korshunov A, Hielscher T, Northcott PA, Galpin JD, Ahern CA, Wang Y, McCabe MG, Collins VP, Jones RG, Pollak M, Delattre O, Gleave ME, Jan E, Pfister SM, Proud CG, Derry WB, Taylor MD, Sorensen PH
Cell 2013 May 23;153(5):1064-79
PMID 23706743
 
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
PLoS One 2012;7(7):e41171
PMID 22911754
 
[Nissl staining with cresyl violet]
Krutsay M
Z Med Labortech 1970;11(2):75-6
PMID 4193916
 
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
J Cell Mol Med 2014 Nov;18(11):2235-51
PMID 25215932
 
Aberrations in translational regulation are associated with poor prognosis in hormone receptor-positive breast cancer
Meric-Bernstam F, Chen H, Akcakanat A, Do KA, Lluch A, Hennessy BT, Hortobagyi GN, Mills GB, Gonzalez-Angulo A
Breast Cancer Res 2012 Oct 26;14(5):R138
PMID 23102376
 
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 :
Ozpolat B, Ozkayar O
EEF2K (eukaryotic elongation factor 2 kinase);
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/EEF2KID40411ch16p12.html


External links

Nomenclature
HGNC (Hugo)EEF2K   24615
Cards
AtlasEEF2KID40411ch16p12.txt
Entrez_Gene (NCBI)EEF2K  29904  eukaryotic elongation factor 2 kinase
GeneCards (Weizmann)EEF2K
Ensembl hg19 (Hinxton)ENSG00000103319 [Gene_View]  chr16:22217592-22300066 [Contig_View]  EEF2K [Vega]
Ensembl hg38 (Hinxton)ENSG00000103319 [Gene_View]  chr16:22217592-22300066 [Contig_View]  EEF2K [Vega]
ICGC DataPortalENSG00000103319
TCGA cBioPortalEEF2K
AceView (NCBI)EEF2K
Genatlas (Paris)EEF2K
WikiGenes29904
SOURCE (Princeton)EEF2K
Genomic and cartography
GoldenPath hg19 (UCSC)EEF2K  -     chr16:22217592-22300066 +  16p12   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)EEF2K  -     16p12   [Description]    (hg38-Dec_2013)
EnsemblEEF2K - 16p12 [CytoView hg19]  EEF2K - 16p12 [CytoView hg38]
Mapping of homologs : NCBIEEF2K [Mapview hg19]  EEF2K [Mapview hg38]
OMIM606968   
Gene and transcription
Genbank (Entrez)AK022569 AK308757 AW675420 BC032665 CA397138
RefSeq transcript (Entrez)NM_013302
RefSeq genomic (Entrez)NC_000016 NC_018927 NT_187260 NW_004929400
Consensus coding sequences : CCDS (NCBI)EEF2K
Cluster EST : UnigeneHs.498892 [ NCBI ]
CGAP (NCI)Hs.498892
Alternative Splicing GalleryENSG00000103319
Gene ExpressionEEF2K [ NCBI-GEO ]   EEF2K [ EBI - ARRAY_EXPRESS ]   EEF2K [ SEEK ]   EEF2K [ MEM ]
Gene Expression Viewer (FireBrowse)EEF2K [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)29904
GTEX Portal (Tissue expression)EEF2K
Protein : pattern, domain, 3D structure
UniProt/SwissProtO00418 (Uniprot)
NextProtO00418  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProO00418
Splice isoforms : SwissVarO00418 (Swissvar)
Catalytic activity : Enzyme2.7.11.20 [ Enzyme-Expasy ]   2.7.11.202.7.11.20 [ IntEnz-EBI ]   2.7.11.20 [ BRENDA ]   2.7.11.20 [ KEGG ]   
PhosPhoSitePlusO00418
Domaine pattern : Prosite (Expaxy)ALPHA_KINASE (PS51158)   
Domains : Interpro (EBI)eEF-2K    Kinase-like_dom    MHCK_EF2_kinase    Sel1-like    TPR-like_helical_dom   
Domain families : Pfam (Sanger)Alpha_kinase (PF02816)    Sel1 (PF08238)   
Domain families : Pfam (NCBI)pfam02816    pfam08238   
Domain families : Smart (EMBL)Alpha_kinase (SM00811)  
DMDM Disease mutations29904
Blocks (Seattle)EEF2K
SuperfamilyO00418
Human Protein AtlasENSG00000103319
Peptide AtlasO00418
HPRD07369
IPIIPI00011689   
Protein Interaction databases
DIP (DOE-UCLA)O00418
IntAct (EBI)O00418
FunCoupENSG00000103319
BioGRIDEEF2K
STRING (EMBL)EEF2K
ZODIACEEF2K
Ontologies - Pathways
QuickGOO00418
Ontology : AmiGOresponse to ischemia  protein kinase activity  elongation factor-2 kinase activity  calcium ion binding  calmodulin binding  ATP binding  cytoplasm  cytosol  translational elongation  translation factor activity, RNA binding  postsynaptic density  regulation of protein autophosphorylation  cellular response to insulin stimulus  negative regulation of apoptotic process  positive regulation of endocytosis  protein autophosphorylation  positive regulation of synapse assembly  positive regulation of dendritic spine morphogenesis  cellular response to calcium ion  cellular response to cAMP  cellular response to anoxia  cellular response to brain-derived neurotrophic factor stimulus  response to prolactin  
Ontology : EGO-EBIresponse to ischemia  protein kinase activity  elongation factor-2 kinase activity  calcium ion binding  calmodulin binding  ATP binding  cytoplasm  cytosol  translational elongation  translation factor activity, RNA binding  postsynaptic density  regulation of protein autophosphorylation  cellular response to insulin stimulus  negative regulation of apoptotic process  positive regulation of endocytosis  protein autophosphorylation  positive regulation of synapse assembly  positive regulation of dendritic spine morphogenesis  cellular response to calcium ion  cellular response to cAMP  cellular response to anoxia  cellular response to brain-derived neurotrophic factor stimulus  response to prolactin  
Pathways : BIOCARTAEukaryotic protein translation [Genes]   
REACTOMEO00418 [protein]
REACTOME PathwaysR-HSA-166208 mTORC1-mediated signalling [pathway]
NDEx Network
Atlas of Cancer Signalling NetworkEEF2K
Wikipedia pathwaysEEF2K
Orthology - Evolution
OrthoDB29904
GeneTree (enSembl)ENSG00000103319
Phylogenetic Trees/Animal Genes : TreeFamEEF2K
Homologs : HomoloGeneEEF2K
Homology/Alignments : Family Browser (UCSC)EEF2K
Gene fusions - Rearrangements
Fusion : MitelmanEEF2K/C10orf35 [16p12.2/10q22.1]  
Fusion : MitelmanEEF2K/UQCRC2 [16p12.2/16p12.2]  [t(16;16)(p12;p12)]  
Fusion : MitelmanEEF2K/VWA3A [16p12.2/16p12.2]  [t(16;16)(p12;p12)]  
Fusion: TCGAEEF2K 16p12.2 C10orf35 10q22.1 LUSC
Fusion: TCGAEEF2K 16p12.2 UQCRC2 16p12.2 BRCA
Fusion: TCGAEEF2K 16p12.2 VWA3A 16p12.2 BRCA
Polymorphisms : SNP, variants
NCBI Variation ViewerEEF2K [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)EEF2K
dbVarEEF2K
ClinVarEEF2K
1000_GenomesEEF2K 
Exome Variant ServerEEF2K
ExAC (Exome Aggregation Consortium)EEF2K (select the gene name)
Genetic variants : HAPMAP29904
Genomic Variants (DGV)EEF2K [DGVbeta]
Mutations
ICGC Data PortalEEF2K 
TCGA Data PortalEEF2K 
Broad Tumor PortalEEF2K
OASIS PortalEEF2K [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICEEF2K 
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch EEF2K
DgiDB (Drug Gene Interaction Database)EEF2K
DoCM (Curated mutations)EEF2K (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)EEF2K (select a term)
intoGenEEF2K
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] 
Diseases
DECIPHER (Syndromes)16:22217592-22300066  ENSG00000103319
CONAN: Copy Number AnalysisEEF2K 
Mutations and Diseases : HGMDEEF2K
OMIM606968   
MedgenEEF2K
Genetic Testing Registry EEF2K
NextProtO00418 [Medical]
TSGene29904
GENETestsEEF2K
Huge Navigator EEF2K [HugePedia]
snp3D : Map Gene to Disease29904
BioCentury BCIQEEF2K
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD29904
Chemical/Pharm GKB GenePA134992891
Clinical trialEEF2K
Miscellaneous
canSAR (ICR)EEF2K (select the gene name)
Probes
Litterature
PubMed58 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineEEF2K
EVEXEEF2K
GoPubMedEEF2K
iHOPEEF2K
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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