Any feedback?
Information on EC 2.7.11.20 - elongation factor 2 kinase and Organism(s) Homo sapiens
for references in articles please use BRENDA:EC2.7.11.20Please wait a moment until all data is loaded. This message will disappear when all data is loaded.
EC Tree
2.7.11.20 elongation factor 2 kinaseIUBMB Comments
Requires Ca2+ and calmodulin for activity. The enzyme can also be phosphorylated by the catalytic subunit of EC 2.7.11.11, cAMP-dependent protein kinase. Elongation factor 2 is phosphorylated in several cell types in response to various growth factors, hormones and other stimuli that raise intracellular Ca2+ [1,2].
Specify your search results
Word Map
- 2.7.11.20
- rapamycin
-
perk
- starvation
- mtor
- synaptic
-
heme-regulated
- autophosphorylation
-
uncharged
- eif4e
-
pkr-like
-
ido
-
autokinase
-
alpha-kinase
-
acid-starved
-
cam-dependent
- rottlerin
- medicine
-
histidyl-trna
- pharmacology
- agriculture
The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Synonyms
eef2k, eef-2k, eif2alpha kinase, eef-2 kinase, eef2 kinase, eukaryotic elongation factor 2 kinase, gcn2 kinase, eukaryotic elongation factor-2 kinase, elongation factor-2 kinase, elongation factor 2 kinase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
eEF-2 kinase
EEF-2K
eEF2 kinase
eEF2K
elongation factor-2 kinase
eukaryotic elongation factor 2 kinase
eukaryotic elongation factor-2 kinase
eEF2K
-
eukaryotic elongation factor 2 kinase
-
-
eukaryotic elongation factor 2 kinase
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phospho group transfer
phospho group transfer
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
ATP:[elongation factor 2] phosphotransferase
Requires Ca2+ and calmodulin for activity. The enzyme can also be phosphorylated by the catalytic subunit of EC 2.7.11.11, cAMP-dependent protein kinase. Elongation factor 2 is phosphorylated in several cell types in response to various growth factors, hormones and other stimuli that raise intracellular Ca2+ [1,2].
CAS REGISTRY NUMBER
COMMENTARY
116283-83-1
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ATP + acetyl-RKKYKFNEDTERRRFL-amide
ADP + acetyl-RKKYKFNED(phospho)TERRRFL-amide
-
-
-
?
ATP + cortactin
ADP + phosphorylated cortactin
i.e. SRC8, an Src substrate, phosphorylation peptide sequence is EYQGK-T-EKHAS
-
-
?
ATP + heat shock protein 60
ADP + phosphorylated heat shock protein 60
i.e. HSPD1, phosphorylation peptide sequence is TKDGV-T-VAKSI
-
-
?
ATP + hematological and neurological expressed 1-like protein
ADP + phosphorylated hematological and neurological expressed 1-like protein
i.e. HN1L, phosphorylation peptide sequence is FGSPV-T-ATSRL
-
-
?
ATP + heterogeneous nuclear ribonucleoprotein A1
ADP + phosphorylated heterogeneous nuclear ribonucleoprotein A1
i.e. HNRNPA1, phosphorylation peptide sequence is VSRED-S-QRPGA
-
-
?
ATP + immunoglobulin-binding protein 1
ADP + phosphorylated immunoglobulin-binding protein 1
i.e. IGBP1, phosphorylation peptide sequence is EDDEQ-T-LHRAR
-
-
?
ATP + microtubule-associated protein 4
ADP + phosphorylated microtubule-associated protein 4
i.e. MAP4, phosphorylation peptide sequence is TEAAA-T-TRKPE
-
-
?
ATP + N-myc downstream-regulated gene 1 protein
ADP + phosphorylated N-myc downstream-regulated gene 1 protein
i.e. NDRG1, phosphorylation peptide sequence is TSLDG-T-RSRSH
-
-
?
ATP + PEST proteolytic signal-containing nuclear protein
ADP + phosphorylated PEST proteolytic signal-containing nuclear protein
i.e. PCNP, phosphorylation peptide sequence is AIGSQ-T-TKKAS
-
-
?
ATP + prothymosin alpha
ADP + phosphorylated prothymosin alpha
i.e. PTMA, phosphorylation peptide sequence is TSSEI-T-TKDLK
-
-
?
ATP + SAP domain-containing ribonucleoprotein
ADP + phosphorylated SAP domain-containing ribonucleoprotein
i.e. SARNP, phosphorylation peptide sequence is GTTED-T-EAKKR
-
-
?
ATP + scaffold attachment factor B2
ADP + phosphorylated scaffold attachment factor B2
i.e. SAFB2, phosphorylation peptide sequence is VISVK-T-TSRSK
-
-
?
ATP + U4/U6 small nuclear ribonucleoprotein Prp31
ADP + phosphorylated U4/U6 small nuclear ribonucleoprotein Prp31
i.e. PRP31, phosphorylation peptide sequence is ERLGL-T-EIRKQ
-
-
?
ATP + [elongation translation factor 2]
ADP + [elongation translation factor 2]phosphate
-
-
-
-
?
ATP + MH-1 peptide
ADP + phosphorylated MH-1 peptide
-
the MH-1 peptide amino acid sequence is RKKFGESEKTKTKEFL
-
-
?
ATP + [elongation factor 2]
ADP + [elongation factor 2] phosphate
-
-
-
-
?
ATP + [elongation factor 2]
ADP + [elongation factor 2] phosphate
-
-
-
?
ATP + [elongation factor 2]
ADP + [elongation factor 2] phosphate
-
-
-
?
ATP + [elongation factor 2]
ADP + [elongation factor 2] phosphate
-
Thr348, and presumably its autophosphorylation, are critical for the ability of the enzyme to phosphorylate substrates in trans
-
-
?
ATP + [elongation factor 2]
ADP + [elongation factor 2] phosphate
-
the calmodulin-binding/alpha-kinase domain of the enzyme itself possesses autokinase activity, but is unable to phosphorylate substrates in trans. The phosphorylation of substrates in trans requires the SEL1-like domains of eEF2K
-
-
?
ATP + [elongation factor 2]
ADP + [elongation factor 2] phosphate
the recombinant human enzyme is able to phosphorylate wheat germ elongation factor 2 with kinetic parameters comparable to the mammalian enzyme
-
-
?
ATP + [elongation factor 2]
ADP + [elongation factor 2] phosphate
the enzyme phosphorylates elongation factor 2 at Ser56 and Thr58
-
-
?
ATP + [elongation factor 2]
ADP + [elongation factor 2]phosphate
-
-
-
-
?
ATP + [elongation factor 2]
ADP + [elongation factor 2]phosphate
-
enzyme regulation by de-/phosphorylation, overview
-
-
?
ATP + [elongation factor 2]
ADP + [elongation factor 2]phosphate
-
enzyme regulation via de-/phosphorylations, especially at Ser78, involving several kinases is dependent on the cellular amino acid status, enzyme regulation, overview
-
-
?
ATP + [elongation factor 2]
ADP + [elongation factor 2]phosphate
-
phosphorylation at Thr56
-
-
?
ATP + [eukaryotic elongation factor 2]
ADP + [eukaryotic elongation factor 2] phosphate
-
-
-
?
ATP + [eukaryotic elongation factor 2]
ADP + [eukaryotic elongation factor 2] phosphate
eukaryotic elongation factor 2 is inactivated when it is phosphorylated on Thr56 by the enzyme
-
-
?
additional information
?
-
-
SCH66336, a farnesyltransferase inhibitor, induces rapid phosphorylation and inhibition of eukaryotic translation elongation factor 2 in head and squamous cell carcinoma cells leading to growth inhibition in the cancer cells, the inhibitor functions independently of the signaling cascade involving the eEF2 kinase and its activators phosphorylated p70S6K and phosphorylated MEK
-
-
?
additional information
?
-
-
the enzyme expression and activity is increased in several forms of malignancy and human cancer, non-specific inhibitors of the enzyme cause cell death
-
-
?
additional information
?
-
-
the enzyme regulates protein synthesis in skeletal muscle
-
-
?
additional information
?
-
-
unphosphorylated elongation factor 2 promotes translational elongation, phosphorylation by the eEF2-kinase inhibits it, eEF2-kinase phosphorylated elongation factor 2 is further phosphorylated by cAMP-dependent protein kinase, EC 2.7.11.11, upon forskolin treatment leading to inhibition of elongation of cyclin D3 in T-lymphocytes, overview
-
-
?
additional information
?
-
the calcium/calmodulin-dependent kinase phosphorylates and inactivates eukaryotic elongation factor 2 and is subject to multisite phosphorylation, which regulates its activity. Phosphorylation at Ser359 by cyclin-dependent kinase 1, as cdc2cyclin B complexe, inactivates the enzyme occuring early in mitosis probably to keep the elongation factor 2 active during mitosis, overview
-
-
?
additional information
?
-
mammalian enzyme elongation factor-2 kinase (eEF2K) a requirement for threonine residues as the target of phosphorylation
-
-
?
additional information
?
-
the enzyme performs autophosphorylation at Thr57. Additional enzyme protein substrates show a strong sequence motif consisting of acidic residues in the -2 position and basic residues in the +3 position and almost exclusively threonine as the phosphorylated residue, peptide mapping and mass spectrometry analysis, overview
-
-
?
additional information
?
-
the enzyme performs autophosphorylation on residue Thr348
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ATP + [elongation translation factor 2]
ADP + [elongation translation factor 2]phosphate
-
-
-
-
?
ATP + [elongation factor 2]
ADP + [elongation factor 2] phosphate
-
-
-
-
?
ATP + [elongation factor 2]
ADP + [elongation factor 2] phosphate
-
-
-
?
ATP + [elongation factor 2]
ADP + [elongation factor 2] phosphate
-
-
-
?
ATP + [elongation factor 2]
ADP + [elongation factor 2] phosphate
the enzyme phosphorylates elongation factor 2 at Ser56 and Thr58
-
-
?
ATP + [elongation factor 2]
ADP + [elongation factor 2]phosphate
-
-
-
-
?
ATP + [elongation factor 2]
ADP + [elongation factor 2]phosphate
-
enzyme regulation by de-/phosphorylation, overview
-
-
?
ATP + [elongation factor 2]
ADP + [elongation factor 2]phosphate
-
enzyme regulation via de-/phosphorylations, especially at Ser78, involving several kinases is dependent on the cellular amino acid status, enzyme regulation, overview
-
-
?
ATP + [elongation factor 2]
ADP + [elongation factor 2]phosphate
-
phosphorylation at Thr56
-
-
?
ATP + [eukaryotic elongation factor 2]
ADP + [eukaryotic elongation factor 2] phosphate
-
-
-
?
ATP + [eukaryotic elongation factor 2]
ADP + [eukaryotic elongation factor 2] phosphate
eukaryotic elongation factor 2 is inactivated when it is phosphorylated on Thr56 by the enzyme
-
-
?
additional information
?
-
-
SCH66336, a farnesyltransferase inhibitor, induces rapid phosphorylation and inhibition of eukaryotic translation elongation factor 2 in head and squamous cell carcinoma cells leading to growth inhibition in the cancer cells, the inhibitor functions independently of the signaling cascade involving the eEF2 kinase and its activators phosphorylated p70S6K and phosphorylated MEK
-
-
?
additional information
?
-
-
the enzyme expression and activity is increased in several forms of malignancy and human cancer, non-specific inhibitors of the enzyme cause cell death
-
-
?
additional information
?
-
-
the enzyme regulates protein synthesis in skeletal muscle
-
-
?
additional information
?
-
-
unphosphorylated elongation factor 2 promotes translational elongation, phosphorylation by the eEF2-kinase inhibits it, eEF2-kinase phosphorylated elongation factor 2 is further phosphorylated by cAMP-dependent protein kinase, EC 2.7.11.11, upon forskolin treatment leading to inhibition of elongation of cyclin D3 in T-lymphocytes, overview
-
-
?
additional information
?
-
the calcium/calmodulin-dependent kinase phosphorylates and inactivates eukaryotic elongation factor 2 and is subject to multisite phosphorylation, which regulates its activity. Phosphorylation at Ser359 by cyclin-dependent kinase 1, as cdc2cyclin B complexe, inactivates the enzyme occuring early in mitosis probably to keep the elongation factor 2 active during mitosis, overview
-
-
?
additional information
?
-
mammalian enzyme elongation factor-2 kinase (eEF2K) a requirement for threonine residues as the target of phosphorylation
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Ca2+
Mg2+
Ca2+
Ca2+/calmodulin stimulates the autophosphorylation of elongation factor 2 kinase on Thr348 and Ser500 to regulate its activity and calcium dependence. Half-maximal activity at 140 nM Ca2+. Maximal activity 0.003 mM Ca2+
Ca2+
-
Ca2+/calmodulin-dependent enzyme. Ca2+/calmodulin enhance the ability of the enzyme to bind to ATP
Ca2+
Ca2+ enhances the affinity of calmodulin toward the enzyme, 0.15 mM Ca2+ is used in assay conditions
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(4-[[4-(1H-benzimidazol-5-ylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzene-1,2-diyl)dicyanamide
-
1-[3-[(5,6,7-trimethyl-2-phenyl-7H-cyclopenta[d]pyrimidin-4-yl)amino]propyl]pyrrolidin-2-one
-
2-chloro-4-hydroxy-5-(3-phenoxyphenyl)-7,7a-dihydrothieno[2,3-b]pyridin-6(3aH)-one
21% inhibition at 0.05 mM
3-([4-[(5-methoxy-2-methylphenyl)amino]pyrimidin-2-yl]amino)benzamide
36% inhibition at 0.05 mM
3-amino-4-(furan-2-yl)-6,7,8,9,10,11-hexahydro-5H-cyclonona[b]thieno[3,2-e]pyridine-2-carboxamide
3-[4-(pyridin-4-yl)-1,3-thiazol-2-yl]-3,4-dihydroquinazolin-2(1H)-one
48% inhibition at 0.05 mM
4-(4-amino-2-methylphenyl)-N-methylpyridin-2-amine
75% inhibition at 0.05 mM
7-amino-1-cyclopropyl-3-ethyl-1,2,3,4-tetrahydro-2,4-dioxopyrido[2,3-d]pyrimidine-6-carboxamide
-
A-484954, highly selective inhibitor
7-amino-1-cyclopropyl-3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d] pyrimidine-6-carboxamide
i.e. A-484954, a pyrido-pyrimidinedione derivative that inhibits eEF2K in an ATP-competitive but CaM-independent manner
7-amino-1-cyclopropyl-3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-6-carboxamide
-
inhibits eEF2 phosphorylation in cells as well as in vitro
N-(2,6-dimethylphenyl)-N'-[4-[2-(ethylamino)pyridin-4-yl]-3-methoxyphenyl]urea
-
N-(2,6-dimethylphenyl)-N'-[4-[2-(ethylamino)pyridin-4-yl]-3-methylphenyl]urea
8.7% inhibition at 0.02 mM
N-(2-chlorophenyl)-N'-[4-[2-(ethylamino)pyridin-4-yl]-3-(trifluoromethyl)phenyl]urea
53.6% inhibition at 0.02 mM
N-(2-chlorophenyl)-N'-[4-[2-(ethylamino)pyridin-4-yl]-3-methoxyphenyl]urea
6.4% inhibition at 0.02 mM
N-(2-chlorophenyl)-N'-[4-[2-(ethylamino)pyridin-4-yl]-3-methylphenyl]urea
21.7% inhibition at 0.02 mM
N-(2-hydroxyethyl)-1-(4-[(E)-[(7-hydroxy-6H-[1,3]thiazolo[5,4-e]indol-8-yl)methylidene]amino]phenyl)methanesulfonamide
-
N-(3-chlorophenyl)-N'-[4-[2-(ethylamino)pyridin-4-yl]-3-(trifluoromethyl)phenyl]urea
82.7% inhibition at 0.02 mM
N-(3-chlorophenyl)-N'-[4-[2-(ethylamino)pyridin-4-yl]-3-fluorophenyl]urea
52.5% inhibition at 0.02 mM
N-(3-chlorophenyl)-N'-[4-[2-(ethylamino)pyridin-4-yl]-3-methoxyphenyl]urea
30.6% inhibition at 0.02 mM
N-(3-chlorophenyl)-N'-[4-[2-(ethylamino)pyridin-4-yl]-3-methylphenyl]urea
73.4% inhibition at 0.02 mM
N-(3-chlorophenyl)-N'-[4-[2-(propylamino)pyridin-4-yl]-3-(trifluoromethyl)phenyl]urea
38.2% inhibition at 0.02 mM
N-(3-chlorophenyl)-N'-[4-[2-[(cyclopropylmethyl)amino]pyridin-4-yl]-3-(trifluoromethyl)phenyl]urea
27.8% inhibition at 0.02 mM
N-[3,5-bis(trifluoromethyl)phenyl]-N'-[4-[2-(ethylamino)pyridin-4-yl]-3-(trifluoromethyl)phenyl]urea
37.2% inhibition at 0.02 mM
N-[4-([4-(azetidin-1-yl)-6-[(3-methyl-1H-pyrazol-5-yl)amino]pyrimidin-2-yl]sulfanyl)phenyl]propanamide
-
N-[4-[2-(ethylamino)pyridin-4-yl]-3-(trifluoromethyl)phenyl]-N'-(4-methoxyphenyl)urea
51.3% inhibition at 0.02 mM
N-[4-[2-(ethylamino)pyridin-4-yl]-3-(trifluoromethyl)phenyl]-N'-(4-methylphenyl)urea
37.9% inhibition at 0.02 mM
N-[4-[2-(ethylamino)pyridin-4-yl]-3-(trifluoromethyl)phenyl]-N'-[4-(naphthalen-2-yl)phenyl]urea
44% inhibition at 0.02 mM
N-[4-[2-(ethylamino)pyridin-4-yl]-3-(trifluoromethyl)phenyl]-N'-[4-(trifluoromethyl)phenyl]urea
76.3% inhibition at 0.02 mM
N-[4-[2-(ethylamino)pyridin-4-yl]-3-fluorophenyl]-N'-(4-methoxyphenyl)urea
34.4% inhibition at 0.02 mM
N-[4-[2-(ethylamino)pyridin-4-yl]-3-fluorophenyl]-N'-[4-(trifluoromethyl)phenyl]urea
41.2% inhibition at 0.02 mM
N-[4-[2-(ethylamino)pyridin-4-yl]-3-methoxyphenyl]-N'-(4-methoxyphenyl)urea
9.0% inhibition at 0.02 mM
N-[4-[2-(ethylamino)pyridin-4-yl]-3-methoxyphenyl]-N'-[4-(trifluoromethyl)phenyl]urea
34.6% inhibition at 0.02 mM
N-[4-[2-(ethylamino)pyridin-4-yl]-3-methylphenyl]-N'-(4-methoxyphenyl)urea
33.4% inhibition at 0.02 mM
N-[4-[2-(ethylamino)pyridin-4-yl]-3-methylphenyl]-N'-(4-methylphenyl)urea
35.4% inhibition at 0.02 mM
N-[4-[2-(ethylamino)pyridin-4-yl]-3-methylphenyl]-N'-[4-(naphthalen-2-yl)phenyl]urea
-
N-[4-[2-(ethylamino)pyridin-4-yl]-3-methylphenyl]-N'-[4-(trifluoromethyl)phenyl]urea
55.3% inhibition at 0.02 mM
N-[4-[2-(propylamino)pyridin-4-yl]-3-(trifluoromethyl)phenyl]-N'-[4-(trifluoromethyl)phenyl]urea
33.3% inhibition at 0.02 mM
N-[4-[2-[(cyclopropylmethyl)amino]pyridin-4-yl]-3-(trifluoromethyl)phenyl]-N'-[4-(trifluoromethyl)phenyl]urea
15.1% inhibition at 0.02 mM
N2,N2-dimethyl-6-[[(2-phenoxyethyl)amino]methyl]-N4-[(1S)-1-phenylethyl]-1,3,5-triazine-2,4-diamine
-
TX-1123
-
inhibits eEF2K, but also affects the activity of tyrosine kinases and exhibits mitochondrial toxicity
TX1918
i.e. 2-((3,5-dimethyl-4-hydroxyphenyl)-methylene)-4-cyclopentene-1,3-dione
-
1-benzyl-3-cetyl-2-methylimidazolium iodide
-
i.e. NH125, inhibits in vitro, but is not a cellular inhibitor elongation factor 2 kinase
1-benzyl-3-cetyl-2-methylimidazolium iodide
i.e. NH125, inhibits eEF2K activity via inhibition of alpha-kinase, a catalytic domain of eEF2K
2-((3-cyano-4-(4-methoxyphenyl)pyridine-2-ylthio)-2-phenylacetic)acid
-
-
3-amino-4-(furan-2-yl)-6,7,8,9,10,11-hexahydro-5H-cyclonona[b]thieno[3,2-e]pyridine-2-carboxamide
-
-
3-amino-4-(furan-2-yl)-6,7,8,9,10,11-hexahydro-5H-cyclonona[b]thieno[3,2-e]pyridine-2-carboxamide
-
A484954
highly selective inhibitor, i.e. 7-amino-1-cyclopropyl-3-ethyl-1,2,3,4-tetrahydro-2,4-dioxopyrido[2,3-d]pyrimidine-6-carboxamide
-
NH125
-
an imidazolium histidine kinase inhibitor also inhibits the eukaryotic eEF-2 kinase enzyme in vitro and in vivo, IC50 is 60 nM, decreases viability of cancer cell lines with IC50S of 0.0007 to 0.0048 mM, overview
rottlerin
-
i.e. 1-[6-[(3-acetyl-2,4,6-trihydroxy-5-methylphenyl)methyl]-5,7-dihydroxy-2,2-dimethyl-2H-1-benzopyran-8-yl]-3-phenyl-2-propen-1-one, mallotoxin
rottlerin
i.e. 1-[6-[(3-acetyl-2,4,6-trihydroxy-5-methylphenyl)methyl]-5,7-dihydroxy-2,2-dimethyl-2H-1-benzopyran-8-yl]-3-phenyl-2-propen-1-one, mallotoxin
siRNA
-
knockdown of eEF-2 kinase and inhibition of autophagy in several cell types
-
siRNA
-
decreases eEF-2 kinase expression by 90%, inhibition of autophagy in several cell types
-
siRNA
-
eEF2K protein levels are decreased ca. 90% in cells transfected with eEF2K siRNA and unaltered by NS siRNA
-
TS4
-
i.e. 4-hydroxy-6-isopropyl-4-methyl-2-p-tolyl-5,6-dihydro-4H-1,3-selenazine
TS4
i.e. 4-hydroxy-6-isopropyl-4-methyl-2-p-tolyl-5,6-dihydro-4H-1,3-selenazine
additional information
-
non-specific inhibitors of the enzyme cause cell death
-
additional information
-
inhibition of elongation factor 2 phosphorylation by the eEF2-kinase prevents the forskolin-induced down-regulation of cyclin D3 elongation
-
additional information
-
eEF2K can be directly inhibited by mTOR phosphorylation and indirectly inhibited by mTOR through p70S6k phosphorylation
-
additional information
phosphorylation at Ser359 by cyclin-dependent kinase 1, as cdc2-cyclin B complex, inhibits eEF2K activity
-
additional information
-
eEF2K activity is also regulated by phosphorylation. Ser366 is phosphorylated by S6 kinases, enzymes which are phosphorylated and activated by mTORC1, phosphorylation at this site desensitizes eEF2K to activation by Ca2+/CaM. Phosphorylation of Ser359, a site whose modification strongly inhibits eEF2K, and Ser78, immediately next to the CaM-binding motif, are also promoted by mTORC1. The latter strongly impairs the interaction of eEF2K with CaM thereby impairing its activation
-
additional information
the C-terminal fragment of the enzyme, eEF-2K562-725, is able to inhibit the phosphorylation of eukaryotic elongation factor 2 by full-length enzyme in trans
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
MG132
-
addition to normoxic MCF10A cells results in a 5- to 10fold increase in eEF2K levels but has no effect on hypoxic MCF10A or HTB20 cells
mTOR
-
mediates the insulin-induced activation of Ser78 phosphorylation, insulin-dependent decrease of eEF2 phosphorylation is blocked by rapamycin
-
Calmodulin
-
strong activation, activation in response to exercise in skeletal muscle
Calmodulin
Ca2+/calmodulin stimulates the autophosphorylation of elongation factor 2 kinase on Thr348 and Ser500 to regulate its activity and calcium dependence. At a calmodulin concentration of 0.002 mM, the enzyme exhibits significant activity
Calmodulin
a central mediator of Ca2+-dependent signaling, the enzyme is dependent on calmodulin
Calmodulin
required, enzyme eEF2K interacts with calmodulin (CaM) through a binding site which lies almost immediately N terminal to its catalytic domain. Comparison of human and murine CaM-binding sites, overview. Hydroxylation of Pro98 impairs binding of eEF2K to calmodulin and its activation by calmodulin
Calmodulin
structural basis for the recognition of calmodulin by eukaryotic elongation factor 2 kinase, NMR spectrometric analysis, overview. The enzyme binds Ca2+-loaded CaM with high affinity largely through the CaM C lobe, but C-lobe-mediated interactions occur in a Ca2+-independent fashion. the lobe lacks bound calcium ions even under high calcium conditions. Conserved eEF-2K residue W85 anchors it to CaM by inserting into a deep hydrophobic cavity within the CaM C lobe. Mutation of residue W85 to S85 substantially weakens interactions between full-length eEF-2K and CaM in vitro and reduces eEF-2 phosphorylation in cells
additional information
-
90 min continuous exercise rapidly increases eukaryotic elongation factor 2 phosphorylation 5-7fold within 1 minute in skeletal muscle of male humans, activation does not function by covalent mechanisms but by allosteric mechanisms involving Ca2+ signaling via calmodulin
-
additional information
-
increased eEF2 phosphorylation in hypoxic MCF10A cells is associated with a 5- to 10fold increase in eEF2K protein levels without an increase in eEF2K mRNA levels
-
additional information
-
AMP-activated protein kinase, AMPK, a major sensor of (low) cellular energy status stimulates the activity of eEF2K via phosphorylation of Ser500
-
additional information
AMPK activates eEF2K via phosphorylation, which is not involved in enzyme activation in hypoxia conditions. Hypoxia or DMOG treatment enhance eEF2 phosphorylation without increasing the levels of the eEF2K protein.
-
additional information
the enzyme is activated under conditions of stress, such as energy depletion or nutrient deprivation, which can arise in poorly-vascularised tumours
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.000069
1,1'-(cyclopropane-1,1-diyldisulfonyl)bis(4-chlorobenzene)
Homo sapiens
-
at 25°C, pH not specified in the publication
0.00044
2-((3,5-dimethyl-4-hydroxyphenyl)-methylene)-4-cyclopentene-1,3-dione
Homo sapiens
-
at 25°C, pH not specified in the publication
0.00017
3-amino-4-(furan-2-yl)-6,7,8,9,10,11-hexahydro-5H-cyclonona[b]thieno[3,2-e]pyridine-2-carboxamide
Homo sapiens
-
at 25°C, pH not specified in the publication
0.00023
3-phenyl-7-(pyrrolidin-1-yl)-2,3-dihydro-1H-inden-1-one
Homo sapiens
-
at 25°C, pH not specified in the publication
0.0323
3-[[(6-bromonaphthalen-1-yl)oxy]methyl]-1-methyl-4-phenylpiperidine
Homo sapiens
-
at 25°C, pH not specified in the publication
0.000032
4-benzyl-N-(2,4-difluorophenyl)-1,4-diazepane-1-carboxamide
Homo sapiens
-
at 25°C, pH not specified in the publication
0.00023
7-amino-1-cyclopropyl-3-ethyl-1,2,3,4-tetrahydro-2,4-dioxopyrido[2,3-d]pyrimidine-6-carboxamide
Homo sapiens
-
at 25°C, pH not specified in the publication
0.01327
N-dodecyl-N,N-dimethyl-9H-fluoren-9-aminium bromide
Homo sapiens
-
at 25°C, pH not specified in the publication
0.00006
NH125
Homo sapiens
-
an imidazolium histidine kinase inhibitor also inhibits the eukaryotic eEF-2 kinase enzyme in vitro and in vivo, IC50 is 60 nM
0.0007 - 0.0048
NH125
Homo sapiens
-
decreases viability of cancer cell lines with IC50S of 0.0007 to 0.0048 mM, overview
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7.5
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
30
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
additional information
-
when deprived of nutrients, the activity of eEF-2 kinase is rapidly increased
-
when deprived of nutrients, the activity of eEF-2 kinase is rapidly increased
additional information
-
the enzyme expression and activity is increased in several forms of malignancy
additional information
activity of eEF2K is selectively increased in proliferating cells
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
malfunction
metabolism
physiological function
additional information
evolution
eEF2K is a calcium/calmodulin dependent kinase that belongs to the alpha kinase family, which has negligible sequence identity to the conventional protein kinase family
evolution
-
eukaryotic elongation factor 2 kinase (eEF2K) is a member of the small group of atypical alpha-kinases, eEF2K is not a member of the main kinase superfamily. alpha-Kinases show no sequence similarity to the main protein kinase superfamily, although they do display limited three-dimensional structural similarity
evolution
eukaryotic elongation factor 2 kinase is a member of the atypical alpha-kinase family
malfunction
eEF2K gene knockdown on TNF-alpha-induced inflammatory responses in HUVECs
malfunction
kinase-dead and other activity-deficient mutants of eEF2K are stabilized, as is a mutant lacking a critical autophosphorylation site (Thr348 in eEF2K), which is thought to be required for eEF2K and other alpha-kinases to achieve their active conformations. In contrast, application of small-molecule eEF2K inhibitors does not stabilize the protein. Achieving an active conformation, rather than eEF2K activity per se, is required for its susceptibility to degradation
malfunction
knockdown of eEF-2K expression leads to a significant increase in phosphatase 2A-A (PP2A-A) protein synthesis and remarkable downregulation of c-Myc and pyruvate kinase M2 isoform, the key glycolytic enzyme transcriptionally activated by c-Myc. In addition, depletion of eEF-2K reduces the ability of the transformed cells to proliferate and enhance the sensitivity of tumor cells to chemotherapy both in vitro and in vivo. The glucose level is significantly higher in the conditioned medium of the cells with eEF-2K knockdown than that of the control cells. Activation of adenosine monophosphate-activated protein kinase, which increases phosphorylation of AMPK at Thr172, is observed in the cells subjected to silencing of eEF-2K expression. Downregulation of PKM2 mRNA and protein in the cells deficient in eEF-2K, but Overexpression of c-Myc reverses the eEF-2K-mediated downregulation of PKM2 mRNA expression. Silencing of eEF-2K expression blunts the hypoxia-stimulated glycolysis and reduces survival of hypoxic tumor cells. Phenotype, overview
malfunction
-
knocking down eEF2K in hippocampal neurons inhibits synaptic activity induced increases in BDNF production and decreases the stability of dendritic spines
malfunction
mutation of the hydrophobic CaM anchor on eEF-2K disrupts its cellular activity. Mutation of residue W85 to S85 substantially weakens interactions between full-length eEF-2K and CaM in vitro and reduces eEF-2 phosphorylation in cells
malfunction
enzyme silencing blunts autophagic responses, but promotes doxorubicin-induced pyroptotic cell death in melanoma cells. Enzyme suppressionresults in inhibiting autophagy and augmenting pyroptosis, thus modulating the sensitivity of melanoma cells to doxorubicin
malfunction
inhibiting the enzyme or knocking down its expression renders cancer cells sensitive to death under nutrient-starved conditions
malfunction
-
inhibition of the enzyme markedly augments cell proliferation and differentiation, suppresses apoptosis and autophagy, and reverses the anti-fibrotic effects of a p38 MAPK inhibitor. Enzyme inhibition induces resistance to apoptosis in MRC-5 cells treated with transforming growth factor beta 1
malfunction
knocking down or inhibiting the enzyme in cancer cells impairs migration and invasion of cancer cells
malfunction
-
pharmacological inhibition or knockdown of the enzyme in highly metastatic liver cancer cells inhibits their colony forming and migratory capacities, as well as reducing their invasiveness. Knocking down the enzyme reduces the expression of angiogenesis-related growth factors in liver cancer cells and the expression of growth factor receptors on HUVEC cells, and thus restricts signalling crosstalk that promotes angiogenesis between hepatocellular carcinoma cells and endothelial cells
metabolism
eEF2K is degraded by a proteasome-dependent pathway in response to genotoxic stress requiring a phosphodegron that includes an autophosphorylation site. The enzyme is also degraded under stress like including acidosis or treatment of cells with 2-deoxyglucose not requiring a phosphodegron
metabolism
-
the eEF2K protein is degraded via a proteasome-dependent pathway, e.g., during normoxia in breast cancer cells or in response to inhibition of hsp90, which acts as a chaperone for eEF2K. Degradation of eEF2K requires the autophosphorylation site at Ser445, which forms part of a typical bTrCP-binding motif or phosphodegron
physiological function
-
the enzyme has a key role in collagen type I production by hepatic stellate cells
physiological function
-
eEF2K phosphorylates and inhibits eukaryotic elongation factor 2, to slow down the elongation stage of protein synthesis, which normally consumes a great deal of energy and amino acids.. eEF2K is dependent on Ca2+ and calmodulin, and is also regulated by a plethora of other inputs, including inhibition by signalling downstream of anabolic signalling pathways such as the mammalian target of rapamycin complex 1. Enzyme eEF2K helps to protect cancer cells against nutrient starvation and is also cytoprotective in other settings, including hypoxia. Roles for eEF2K in neurological processes such as learning and memory and perhaps in depression. Regulation by phosphorylation of eukaryotic elongation factor 2 (eEF2), overview. In addition to being dependent upon Ca2+/calmodulin, eEF2K activity is also regulated by phosphorylation, which occurs at several sites downstream of various signalling pathways. eEF2K activity is negatively regulated by signalling through the mammalian target of rapamycin complex 1 (mTORC1). Consequence of increasing eEF2K activity in the brain may be to regulate the synthesis of specific proteins. Increases in eEF2K activity are important for the synthesis of Arc, an immediate-early gene involved in the trafficking of glutamate receptors and cytoskeletal rearrangement that is implicated in various types of synaptic plasticity and memory. Stimulation of metabotropic glutamate receptors (mGluRs) results in an eEF2Kdependent increase in Arc synthesis
physiological function
eukaryotic elongation factor 2 kinase (eEF-2K) phosphorylates eEF-2 leading to a decrease in global protein synthesis
physiological function
eukaryotic elongation factor 2 kinase (eEF2K) is an atypical protein kinase which negatively regulates protein synthesis, is activated under stress conditions and plays a role in cytoprotection, e.g. in cancer cells
physiological function
eukaryotic elongation factor 2 kinase (eEF2K) prevents binding of eEF to the ribosome via phosphorylation of eEF and thus prevents further translation. The enzyme regulates the development of hypertension through oxidative stress-dependent vascular inflammation
physiological function
phosphorylation of eEF-2 by eEF-2K is an essential system in regulation of global protein synthesis. Cancer cells predominantly metabolize glucose by glycolysis to produce energy in order to meet their metabolic requirement, a phenomenon known as Warburg effect. Enzyme eEF-2 kinase is a critical regulator of Warburg effect through controlling synthesis of protein phosphatase 2A-A (PP2A-A), a key factor that facilitates the ubiquitin-proteasomal degradation of c-Myc protein. Eukaryotic elongation factor-2 kinase (eEF-2K) has a negative regulator of protein synthesis, has a critical role in promoting glycolysis in cancer cells. eEF-2K is required for the hypoxia-stimulated glycolysis and promotes survival of hypoxic tumor cells. Enzyme eEF-2K activates PKM2 through stabilizing c-Myc protein, MG132, a proteasome inhibitor, can rescue the downregulation of c-Myc in the cells with knockdown of eEF-2K expression. eEF-2K is supportive to growth and proliferation of tumor cells
physiological function
the phosphorylation of eEF2 through eEF2 kinase blocks translation elongation, which is thought to be critical to regulating cellular energy usage. eEF2K has a role in regulating cellular energy usage that involves multiple pathways and regulatory feedback
physiological function
transcription elongation is controlled by phosphorylation of eukaryotic elongation factor 2 (eEF2), which inhibits its activity and is catalyzed by eEF2 kinase (eEF2K), a calcium/calmodulin-dependent alpha-kinase. eEF2K activity is regulated through several signaling pathways linked, e.g., to nutrient availability. Hypoxia causes the activation of eEF2K and induces eEF2 phosphorylation. eEF2K is subject to hydroxylation on proline 98. Proline hydroxylation is catalyzed by proline hydroxylases, oxygen-dependent enzymes which are inactivated during hypoxia. Hypoxia-induced eEF2 phosphorylation requires eEF2K and is not catalyzed by AMPK, it does also not require signaling via AMPK or mTORC1. Pharmacological inhibition of proline hydroxylases, e.g. by DMOG treatment, also stimulates eEF2 phosphorylation. Pro98 lies in a universally conserved linker between the calmodulin-binding and catalytic domains of eEF2K. Its hydroxylation partially impairs the binding of calmodulin to eEF2K and markedly limits the calmodulin-stimulated activity of eEF2K. Neuronal cells depend on oxygen, and eEF2K helps to protect them from hypoxia. eEF2K is cytoprotective during hypoxia and other conditions of nutrient insufficiency, it aids the survival of neuronal cells during hypoxia and has a key role in helping cells withstand nutrient deficiency
physiological function
In many types of tumour cells, and likely in more advanced solid tumours, the enzyme helps protect cells against nutrient depletion and other stresses by slowing down protein synthesis (thereby conserving resources) and/or altering the translation rates of specific mRNAs and thus the levels of the corresponding proteins. The enzyme aids the growth of solid tumours in vivo and aids cell migration. The enzyme is required for the resistance of tumors to caloric restriction-induced cell death. The enzyme plays a role in protecting breast cancer cells against endoplasmic reticulum stress, apparently by activating autophagy
physiological function
-
the enzyme acts downstream of p38 MAPK to regulate proliferation, apoptosis and autophagy in human lung fibroblasts. The enzyme might inhibit transforming growth factor beta 1-induced NHLF proliferation and differentiation and activates normal lung fibroblast cell apoptosis and autophagy through p38 MAPK signaling, which might ameliorate lung fibroblast-to-myofibroblast differentiation
physiological function
-
the enzyme contributes to angiogenesis and tumor progression in hepatocellular carcinoma via transcription factors SP1/KLF5-mediated endothelial growth factor expression, as well as the subsequent stimulation of PI3K/Akt and STAT3 signalling
physiological function
the enzyme controls the translation of mRNAs encoding proteins involving in cell migration
physiological function
the enzyme is cytoprotective for cells faced with glucose starvation. The enzyme promotes cell survival by inhibiting protein synthesis without inducing autophagy. The enzyme makes a substantial contribution to the cytoprotective effect of mammalian target of rapamycin complex 1 inhibition
physiological function
the enzyme plays a the regulatory role of in pyroptosis in doxorubicin-treated human melanoma cells. The enzyme dictates the cross-talk between pyroptosis and autophagy in doxorubicin-treated human melanoma cells
physiological function
the enzyme protects cancer cells against acidosis and impedes tumorigenesis
additional information
homology modelling of eEF2K using the structure of myosin heavy chain kinase, EC 2.7.11.7, PDB ID 3LMH. A glutamate might act as gatekeeper and makes likely hydrogen bonds to the adenine in the active site and is essential for activity in the alpha kinase family
additional information
solution structure of the Ca2+-CaM-eEF-2KCBD complex, structure analysis, NMR spectrometric analysis, detailed overview
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). EF2K_HUMAN
725
0
82144
Swiss-Prot
other Location (Reliability: 1)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
90000
extracted from gastric epithelial cells, determined by SDS-PAGE and Western blot analysis
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phosphoprotein
side-chain modification
eEF2K is subject to hydroxylation on proline 98 catalyzed by proline hydroxylases. Hydroxylation of Pro98 impairs binding of eEF2K to calmodulin and its activation by calmodulin
additional information
-
the enzyme is ubiquitinated in vivo, ubiquitination and turnover is increased by inhibition of heat shock protein 90, enzyme degradation involves the proteasome
phosphoprotein
-
the eEF2 kinase is activated by phosphorylation through AMPK, phosphorylation sites of the eEF2 kinase are Ser366, Ser398, and Ser78, the phosphorylation of the latter is regulated by insulin in an mTOR protein-dependent manner, Ser78 is no target for the kinase S6K1
phosphoprotein
-
the enzyme performs autophosphorylation, stimulation of AMP-activated protein kinase, EC 2.7.11.11, by AMP leads to activation of the wild-type and mutant enzyme and to its phosphorylation at Ser398 in the regulatory domain, other phosphorylation sites of the enzyme are Ser78, Ser359, Ser377, and Ser366, the latter is phosphorylated by kinases S6K1 and p90RSK inhibiting the enzyme
phosphoprotein
the calcium/calmodulin-dependent kinase, that phosphorylates and inactivates eukaryotic elongation factor 2, is subject to multisite phosphorylation, which regulates its activity, overview
phosphoprotein
-
phosphorylation of the enzyme differentially affects the turnover of the enzyme under both normal and stress conditions. Phosphorylation control of the enzyme is a complex process, with a variety of signaling pathways converging on eEF-2K. The mTOR pathway deactivates the enzyme by phosphorylating the enzyme at Ser78 and Ser366, while the AMPK pathway activates eEF-2K through phosphorylation at Ser398 during cellular stress
phosphoprotein
-
phosphorylation sites: Ser61, Ser66, Ser78, Ser366, Ser445, Ser474, Ser491, Thr348, Thr353. The autophosphorylation sites Thr348, Thr353, Ser366 and Ser445 are are highly conserved among vertebrate elongation factor 2 kinases. None of the sites lies in the catalytic domain. Ser366 is phosphorylated not only autocatalytically but also in trans by other kinases. Thr348 appears to be constitutively autophosphorylated in vitro. Thr348, and presumably its autophosphorylation, are critical for the ability of the enzyme to phosphorylate substrates in trans
phosphoprotein
upon incubation with Ca2+ and calmodulin, the enzyme undergoes rapid autophosphorylation. Identification of five major autophosphorylation sites: Thr348, Thr353, Ser445, Ser474, and Ser500. Phosphorylation of Thr348 is required for substrate phosphorylation, but not selfphosphorylation
phosphoprotein
AMPK activates eEF2K via phosphorylation. Inhibition of proline hydroxylases, e.g. by DMOG, induces the phosphorylation of eEF2 independently of altered mTORC1 or AMPK signaling
phosphoprotein
-
eEF2K activity is also regulated by phosphorylation. Ser366 is phosphorylated by S6 kinases, enzymes which are phosphorylated and activated by mTORC1, phosphorylation at this site desensitizes eEF2K to activation by Ca2+/CaM. Phosphorylation of Ser359, a site whose modification strongly inhibits eEF2K, and Ser78, immediately next to the CaM-binding motif, are also promoted by mTORC1. The latter strongly impairs the interaction of eEF2K with CaM thereby impairing its activation. For eEF2K stimulation, cAMP, a catabolic signal which inhibits protein synthesis, stimulates cAMP-dependent protein kinase, PKA, which phosphorylates eEF2K at Ser500. Degradation of eEF2K requires the autophosphorylation site at Ser445, which forms part of a typical bTrCP-binding motif or phosphodegron. eEF2K is also phosphorylated at several sites in response to activation of stress-stimulated MAP kinase cascades, either directly by MAPKs or by their downstream effectors. Phosphorylation of eEF2 at Thr56 impairs its binding to the ribosome. The enzyme is regulated by its phosphorylation status, overview
phosphoprotein
the enzyme autophosphorylates at Thr-348. Phosphorylation of Ser-500 integrates with Ca2+ and calmodulin to regulate the enzyme activity. Phosphorylation of Thr-348 and Ser-500 regulates the Ca2+/calmodulin-dependent activity of the enzyme
phosphoprotein
the enzyme autophosphorylates on Thr348. The enzyme is extensively regulated by phosphorylation. S6 kinase phosphorylates the enzyme on Ser366 and impairs its activation by Ca2+/calmodulin. Mammalian target of rapamycin complex 1 directly phosphorylates the enzyme on Ser78/Ser396 thereby negatively regulating the enzyme activity
phosphoprotein
the enzyme undergoes autophosphorylation, with a major site being Thr348. The phosphorylation of Thr348 enhances the enzyme activity by increasing its affinity for a (peptide) substrate and its intrinsic catalytic activity. The 70 kDa ribosomal protein S6 kinase phosphorylates the enzyme at Ser366, inactivating it. Ser78 of the enzyme is also phosphorylated in an mTORC1-dependent manner. This phosphorylation impairs calmodulin binding, and thus, the activation of the enzyme. The Ras/Raf/MEK/ERK pathway also makes direct inputs into the inactivation of the enzyme via direct phosphorylation of the enzyme by ERK (at Ser359). Enzyme phosphorylation increases during hypoxia
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
E717A
the mutation in the C-terminal fragment of the enzyme reduces elongation factor 2 phosphorylation activity
S366A
-
activity with RKKFGESEKTKTKEFL is decreased approximately 90% compared to wild-type activity after preincubation for 60 min with MgATP2-
S398A
S445A
no difference in activity compared to wild-type enzyme with respect to the ability to phosphorylate a peptide substrate
S445D
no difference in activity compared to wild-type enzyme with respect to the ability to phosphorylate a peptide substrate
S474A
no difference in activity compared to wild-type enzyme with respect to the ability to phosphorylate a peptide substrate
S474D
no difference in activity compared to wild-type enzyme with respect to the ability to phosphorylate a peptide substrate
S500A
no difference in activity compared to wild-type enzyme with respect to the ability to phosphorylate a peptide substrate
S500D
S78A
S78A/S366A
-
phosphorylation-defective mutant, mutation results in an increased stability under normal culture conditions, t1/2 is above 24 h
T348A
T348D
T348E
-
the mutant enzyme phosphorylates purified elongation factor 2 poorly compared with wild-type
T353A
no difference in activity compared to wild-type enzyme with respect to the ability to phosphorylate a peptide substrate
T353D
no difference in activity compared to wild-type enzyme with respect to the ability to phosphorylate a peptide substrate
W85S
site-directed mutagenesis, Mutation of residue W85 to S85 substantially weakens interactions between full-length eEF-2K and CaM in vitro and reduces eEF-2 phosphorylation in cells
Y712A
the mutation in the C-terminal fragment of the enzyme reduces elongation factor 2 phosphorylation activity
Y712A/Y713A
the mutations in the C-terminal fragment of the enzyme abolish elongation factor 2 phosphorylation activity
Y713A
the mutation in the C-terminal fragment of the enzyme reduces elongation factor 2 phosphorylation activity
additional information
S398A
-
site-directed mutagenesis, mutation of a phosphorylation site, no phosphorylation by AMPK, altered regulation by phosphorylation compared to the wild-type enzyme
S398A
-
phosphorylation-defective mutant, mutation results in an increased stability under normal culture conditions, t1/2 is above 24 h
S500D
no difference in activity compared to wild-type enzyme with respect to the ability to phosphorylate a peptide substrate. The mutation renders the enzyme Ca2+-independent
S500D
the mutation enhances the rate of activation (Thr-348 autophosphorylation) by 6fold and lowers the EC50 for Ca2+/calmpdulin binding to activated enzyme (Thr-348 phosphorylated) by 20fold as compared to the wild type
S78A
-
site-directed mutagenesis, mutation of a phosphorylation site, altered regulation by phosphorylation compared to the wild-type enzyme, but the mutation does not influence AMPK
S78A
-
activity with RKKFGESEKTKTKEFL is decreased approximately 50% compared to wild-type activity after preincubation for 60 min with MgATP2-
T348A
-
activity with RKKFGESEKTKTKEFL is decreased approximately 90% compared to wild-type activity after preincubation for 60 min with MgATP2-. The mutant enzyme phosphorylates purified elongation factor 2 poorly compared with wild-type
T348D
-
the mutant enzyme phosphorylates purified elongation factor 2 poorly compared with wild-type
additional information
-
the eEF2 kinase level is higher in PDK1-lacking cells, constitutive phosphorylation at Ser78 of the eEF2 kinase occurs in TSC2-deficient cells
additional information
knockdown of eEF2K gene by small interfering RNA (siRNA)
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
in vivo half-life of the enzyme is 6 h, proteasome inhibitor MG132 prolonged the half-life of the enzyme to more than 24 h
-
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant full-length human calmodulin (CaM), the predicted calmodulin-binding segment of human eEF-2K, residues 74-100 (eEF-2KCBD), and full-length eEF-2K
recombinant GST-tagged wild-type and FLAG-tagged mutant enzymes from Escherichia coli
-
recombinant GST-tagged wild-type and mutant eEF2K enzymes from Escherichia coli strain Rosetta(DE3)pLysS
recombinant His-tagged enzyme from Escherichia coli strain BL21 Rosetta 2 by nickel affinity chromatography, ultrafiltration, cleavage of the tag with Sumo protease, and anion exchange chromatography, followed by gel filtration
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression as a GST (glutathione transferase)-fusion protein in Escherichia coli
-
expression in Escherichia coli
expression of GST-tagged wild-type enzyme and of a FLAG-tagged mutant enzyme in Escherichia coli
-
overexpression of the enzyme in glioma T98-G cells causes a 10fold increased resistance to inhibitor NH125
-
recombinant coexpression of full-length human calmodulin (CaM), the predicted calmodulin-binding segment of human eEF-2K, residues 74-100 (eEF-2KCBD), and full-length eEF-2K
recombinant expression of His-tagged enzyme in Escherichia coli strain BL21 Rosetta 2
recombinant overexpression of FLAG-tagged enzyme from pcDNA3.1 vector in HEK-293 cells, recombinant expression of GST-tagged wild-type and mutant eEF2K enzymes in Escherichia coli strain Rosetta(DE3)pLysS
the C-terminal fragment of the enzyme, eEF-2K562 725, is expressed in Escherichia coli BL21(DE3) cells
wild type and mutants Y712A/Y713A and E717A of the C-terminal enzyme fragment eEF-2K627-725 are expressed in Escherichia coli BL21(DE3) cells
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
over-expressed by a stressful, heat-stressed, environment, Helicobacter pylori infection enhances the EF-2K expression in HGC-27 cells as much as heat stress do
the expression of the mRNA for EEF2K is probably regulated in multiple ways, e.g. downstream of AMPK, and in some settings by mTORC1 signaling and HIF1
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
additional information
-
eEF2 kinase is stabilized against decay during hypoxia by phosphorylation
medicine
-
eEF-2 kinase plays a regulatory role in the autophagic process in tumor cells, is a downstream member of the mTOR signaling, may promote cancer cell survival under conditions of nutrient deprivation through regulating autophagy. Therefore, eEF-2 kinase may be a part of a survival mechanism in glioblastoma and targeting this kinase may represent a novel approach to cancer treatment
medicine
-
plays a regulatory role in the autophagic process in tumor cells and may promote cancer cell survival under conditions of nutrient deprivation, eEF-2 kinase activation may be a part of a survival mechanism in glioblastoma
medicine
-
suppressing autophagy and augmenting apoptosis via inhibition of eEF-2 kinase can modulate sensitivity of tumor cells to Akt inhibition, and suggest that eEF-2 kinase may be utilized as an effective target for reinforcing the anti-tumor efficacy of Akt inhibitors such as MK-2206
medicine
the enzyme a possible target for therapeutic intervention in solid tumours
medicine
-
high expression levels of the enzyme are associated with poor prognosis of hepatocellular carcinoma
medicine
high levels of enzyme expression are associated with invasive carcinoma and metastatic tumors. Inhibiting the enzyme may help prevent cancer cell mobility and metastasis. The enzyme is a potential therapeutic target for preventing tumor metastasis
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Ryazanov, A.G.; Ward, M.D.; Mendola, C.E.; Pavur, K.S.; Dorovkov, M.V.; Wiedmann, M.; Erdjument-Bromage, H.; Tempst, P.; Parmer, T.G.; Prostko, C.R.; Germino, F.J.; Hait, W.N.
Identification of a new class of protein kinases represented by eukaryotic elongation factor-2 kinase
Proc. Natl. Acad. Sci. USA
94
4884-4889
1997
Caenorhabditis elegans (O01991), Caenorhabditis elegans, Homo sapiens (O00418), Homo sapiens, Mus musculus (O08796), Mus musculus, Rattus norvegicus (P70531)
Arora, S.; Yang, J.M.; Kinzy, T.G.; Utsumi, R.; Okamoto, T.; Kitayama, T.; Ortiz, P.A.; Hait, W.N.
Identification and characterization of an inhibitor of eukaryotic elongation factor 2 kinase against human cancer cell lines
Cancer Res.
63
6894-6899
2003
Homo sapiens
Arora, S.; Yang, J.M.; Hait, W.N.
Identification of the ubiquitin-proteasome pathway in the regulation of the stability of eukaryotic elongation factor-2 kinase
Cancer Res.
65
3806-3810
2005
Homo sapiens, Rattus norvegicus
Ren, H.; Tai, S.K.; Khuri, F.; Chu, Z.; Mao, L.
Farnesyltransferase inhibitor SCH66336 induces rapid phosphorylation of eukaryotic translation elongation factor 2 in head and neck squamous cell carcinoma cells
Cancer Res.
65
5841-5847
2005
Homo sapiens
Gutzkow, K.B.; Lahne, H.U.; Naderi, S.; Torgersen, K.M.; Skalhegg, B.; Koketsu, M.; Uehara, Y.; Blomhoff, H.K.
Cyclic AMP inhibits translation of cyclin D3 in T lymphocytes at the level of elongation by inducing eEF2-phosphorylation
Cell. Signal.
15
871-881
2003
Homo sapiens
Browne, G.J.; Finn, S.G.; Proud, C.G.
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
J. Biol. Chem.
279
12220-12231
2004
Homo sapiens, Rattus norvegicus
Rose, A.J.; Broholm, C.; Kiillerich, K.; Finn, S.G.; Proud, C.G.; Rider, M.H.; Richter, E.A.; Kiens, B.
Exercise rapidly increases eukaryotic elongation factor 2 phosphorylation in skeletal muscle of men
J. Physiol.
569
223-228
2005
Homo sapiens
Browne, G.J.; Proud, C.G.
A novel mTOR-regulated phosphorylation site in elongation factor 2 kinase modulates the activity of the kinase and its binding to calmodulin
Mol. Cell. Biol.
24
2986-2997
2004
Homo sapiens
Hait, W.N.; Wu, H.; Jin, S.; Yang, J.M.
Elongation factor-2 kinase: its role in protein synthesis and autophagy
Autophagy
2
294-296
2006
Homo sapiens
Wu, H.; Yang, J.M.; Jin, S.; Zhang, H.; Hait, W.N.
Elongation factor-2 kinase regulates autophagy in human glioblastoma cells
Cancer Res.
66
3015-3023
2006
Homo sapiens
Connolly, E.; Braunstein, S.; Formenti, S.; Schneider, R.J.
Hypoxia inhibits protein synthesis through a 4E-BP1 and elongation factor 2 kinase pathway controlled by mTOR and uncoupled in breast cancer cells
Mol. Cell. Biol.
26
3955-3965
2006
Homo sapiens
Smith, E.M.; Proud, C.G.
Cdc2-cyclin B regulates eEF2 kinase activity in a cell cycle- and amino acid-dependent manner
EMBO J.
27
1005-1016
2008
Homo sapiens (O00418)
Ayada, K.; Yokota, K.; Kawahara, Y.; Yamamoto, Y.; Hirai, K.; Inaba, T.; Kita, M.; Okada, H.; Yamamoto, K.; Oguma, K.
Immune reactions against elongation factor 2 kinase: specific pathogenesis of gastric ulcer from Helicobacter pylori infection
Clin. Dev. Immunol.
2009
850623
2009
Homo sapiens (O00418), Homo sapiens
Huber-Keener, K.J.; Evans, B.R.; Ren, X.; Cheng, Y.; Zhang, Y.; Hait, W.N.; Yang, J.M.
Phosphorylation of elongation factor-2 kinase differentially regulates the enzymes stability under stress conditions
Biochem. Biophys. Res. Commun.
424
308-314
2012
Homo sapiens
Pigott, C.R.; Mikolajek, H.; Moore, C.E.; Finn, S.J.; Phippen, C.W.; Werner, J.M.; Proud, C.G.
Insights into the regulation of eukaryotic elongation factor 2 kinase and the interplay between its domains
Biochem. J.
442
105-118
2012
Homo sapiens
Pyr Dit Ruys, S.; Wang, X.; Smith, E.M.; Herinckx, G.; Hussain, N.; Rider, M.H.; Vertommen, D.; Proud, C.G.
Identification of autophosphorylation sites in eukaryotic elongation factor-2 kinase
Biochem. J.
442
681-692
2012
Homo sapiens
Devkota, A.K.; Tavares, C.D.; Warthaka, M.; Abramczyk, O.; Marshall, K.D.; Kaoud, T.S.; Gorgulu, K.; Ozpolat, B.; Dalby, K.N.
Investigating the kinetic mechanism of inhibition of elongation factor 2 kinase by NH125: evidence of a common in vitro artifact
Biochemistry
51
2100-2112
2012
Homo sapiens
Tavares, C.D.; OBrien, J.P.; Abramczyk, O.; Devkota, A.K.; Shores, K.S.; Ferguson, S.B.; Kaoud, T.S.; Warthaka, M.; Marshall, K.D.; Keller, K.M.; Zhang, Y.; Brodbelt, J.S.; Ozpolat, B.; Dalby, K.N.
Calcium/calmodulin stimulates the autophosphorylation of elongation factor 2 kinase on Thr-348 and Ser-500 to regulate its activity and calcium dependence
Biochemistry
51
2232-2245
2012
Homo sapiens (O00418), Homo sapiens
Cheng, Y.; Ren, X.; Zhang, Y.; Patel, R.; Sharma, A.; Wu, H.; Robertson, G.P.; Yan, L.; Rubin, E.; Yang, J.M.
eEF-2 kinase dictates cross-talk between autophagy and apoptosis induced by Akt Inhibition, thereby modulating cytotoxicity of novel Akt inhibitor MK-2206
Cancer Res.
71
2654-2663
2011
Homo sapiens
Arriazu, E.; Ruiz de Galarreta, M.; Lopez-Zabalza, M.J.; Leung, T.M.; Nieto, N.; Iraburu, M.J.
GCN2 kinase is a key regulator of fibrogenesis and acute and chronic liver injury induced by carbon tetrachloride in mice
Lab. Invest.
93
303-310
2013
Homo sapiens, Mus musculus
Abramczyk, O.; Tavares, C.D.; Devkota, A.K.; Ryazanov, A.G.; Turk, B.E.; Riggs, A.F.; Ozpolat, B.; Dalby, K.N.
Purification and characterization of tagless recombinant human elongation factor 2 kinase (eEF-2K) expressed in Escherichia coli
Protein Expr. Purif.
79
237-244
2011
Homo sapiens (O00418), Homo sapiens
Kenney, J.W.; Moore, C.E.; Wang, X.; Proud, C.G.
Eukaryotic elongation factor 2 kinase, an unusual enzyme with multiple roles
Adv. Biol. Regul.
55
15-27
2014
Homo sapiens, Mus musculus (O08796)
Usui, T.; Okada, M.; Hara, Y.; Yamawaki, H.
Eukaryotic elongation factor 2 kinase regulates the development of hypertension through oxidative stress-dependent vascular inflammation
Am. J. Physiol. Heart Circ. Physiol.
305
H756-H768
2013
Homo sapiens (O00418), Rattus norvegicus (P70531), Rattus norvegicus Wistar (P70531)
Wang, X.; Xie, J.; da Mota, S.R.; Moore, C.E.; Proud, C.G.
Regulated stability of eukaryotic elongation factor 2 kinase requires intrinsic but not ongoing activity
Biochem. J.
467
321-331
2015
Homo sapiens (O00418)
Lazarus, M.; Levin, R.; Shokat, K.
Discovery of new substrates of the elongation factor-2 kinase suggests a broader role in the cellular nutrient response
Cell. Signal.
29
78-83
2017
Homo sapiens (O00418)
Moore, C.E.; Mikolajek, H.; Regufe da Mota, S.; Wang, X.; Kenney, J.W.; Werner, J.M.; Proud, C.G.
Elongation factor 2 kinase is regulated by proline hydroxylation and protects cells during hypoxia
Mol. Cell. Biol.
35
1788-1804
2015
Homo sapiens (O00418), Mus musculus (O08796)
Cheng, Y.; Ren, X.; Yuan, Y.; Shan, Y.; Li, L.; Chen, X.; Zhang, L.; Takahashi, Y.; Yang, J.W.; Han, B.; Liao, J.; Li, Y.; Harvey, H.; Ryazanov, A.; Robertson, G.P.; Wan, G.; Liu, D.; Chen, A.F.; Tao, Y.; Yang, J.M.
eEF-2 kinase is a critical regulator of Warburg effect through controlling PP2A-A synthesis
Oncogene
2016
1-16
2016
Homo sapiens (O00418)
Lee, K.; Alphonse, S.; Piserchio, A.; Tavares, C.D.; Giles, D.H.; Wellmann, R.M.; Dalby, K.N.; Ghose, R.
Structural basis for the recognition of eukaryotic elongation factor 2 kinase by calmodulin
Structure
24
1441-1451
2016
Homo sapiens (O00418)
Xiao, T.; Liu, R.; Proud, C.G.; Wang, M.W.
A high-throughput screening assay for eukaryotic elongation factor 2 kinase inhibitors
Acta Pharm. Sin. B
6
557-563
2016
Homo sapiens
Liu, R.; Proud, C.G.
Eukaryotic elongation factor 2 kinase as a drug target in cancer, and in cardiovascular and neurodegenerative diseases
Acta Pharmacol. Sin.
37
285-294
2016
Homo sapiens (O00418), Homo sapiens
Yu, P.; Wang, H.Y.; Tian, M.; Li, A.X.; Chen, X.S.; Wang, X.L.; Zhang, Y.; Cheng, Y.
Eukaryotic elongation factor-2 kinase regulates the cross-talk between autophagy and pyroptosis in doxorubicin-treated human melanoma cells in vitro
Acta Pharmacol. Sin.
40
1237-1244
2019
Homo sapiens (O00418), Homo sapiens
Will, N.; Piserchio, A.; Snyder, I.; Ferguson, S.B.; Giles, D.H.; Dalby, K.N.; Ghose, R.
Structure of the C-terminal helical repeat domain of eukaryotic elongation factor 2 kinase
Biochemistry
55
5377-5386
2016
Homo sapiens (O00418)
Wang, X.; Xie, J.; Proud, C.G.
Eukaryotic elongation factor 2 kinase (eEF2K) in cancer
Cancers (Basel)
9
162
2017
Homo sapiens (O00418)
Moore, C.E.; Wang, X.; Xie, J.; Pickford, J.; Barron, J.; Regufe da Mota, S.; Versele, M.; Proud, C.G.
Elongation factor 2 kinase promotes cell survival by inhibiting protein synthesis without inducing autophagy
Cell. Signal.
28
284-293
2016
Homo sapiens (O00418)
Pan, Z.; Chen, Y.; Liu, J.; Jiang, Q.; Yang, S.; Guo, L.; He, G.
Design, synthesis, and biological evaluation of polo-like kinase 1/eukaryotic elongation factor 2 kinase (PLK1/EEF2K) dual inhibitors for regulating breast cancer cells apoptosis and autophagy
Eur. J. Med. Chem.
144
517-528
2018
Homo sapiens (O00418)
Wang, Y.; Huang, G.; Wang, Z.; Qin, H.; Mo, B.; Wang, C.
Elongation factor-2 kinase acts downstream of p38 MAPK to regulate proliferation, apoptosis and autophagy in human lung fibroblasts
Exp. Cell Res.
363
291-298
2018
Homo sapiens
Xie, J.; Shen, K.; Lenchine, R.V.; Gethings, L.A.; Trim, P.J.; Snel, M.F.; Zhou, Y.; Kenney, J.W.; Kamei, M.; Kochetkova, M.; Wang, X.; Proud, C.G.
Eukaryotic elongation factor 2 kinase upregulates the expression of proteins implicated in cell migration and cancer cell metastasis
Int. J. Cancer
142
1865-1877
2018
Homo sapiens (O00418)
Zhou, Y.; Li, Y.; Xu, S.; Lu, J.; Zhu, Z.; Chen, S.; Tan, Y.; He, P.; Xu, J.; Proud, C.G.; Xie, J.; Shen, K.
Eukaryotic elongation factor 2 kinase promotes angiogenesis in hepatocellular carcinoma via PI3K/Akt and STAT3
Int. J. Cancer
146
1383-1395
2020
Homo sapiens
Tavares, C.D.; Giles, D.H.; Stancu, G.; Chitjian, C.A.; Ferguson, S.B.; Wellmann, R.M.; Kaoud, T.S.; Ghose, R.; Dalby, K.N.
Signal integration at elongation factor 2 kinase the roles of calcium, calmodulin, and Ser-500 phosphorylation
J. Biol. Chem.
292
2032-2045
2017
Homo sapiens (O00418)
EXTERNAL LINKS (specific for EC-Number 2.7.11.20)
Use of this online version of BRENDA is free under the CC BY 4.0 license. See terms of use for full details.
Release 2023.1 (January 2023)
Legal
Curated at
Member of
