Information on EC 2.7.11.20 - elongation factor 2 kinase

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The expected taxonomic range for this enzyme is: Eukaryota

EC NUMBER
COMMENTARY
2.7.11.20
-
RECOMMENDED NAME
GeneOntology No.
elongation factor 2 kinase
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
ATP + [elongation factor 2] = ADP + [elongation factor 2] phosphate
show the reaction diagram
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
phospho group transfer
-
-
-
-
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].
SYNONYMS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
Ca2+/calmodulin-dependent kinase III
-
-
Ca2+/calmodulin–dependent kinase III
-
-
eEF-2 kinase
-
-
eEF-2 kinase
-
-
eEF-2 kinase
-
-
EEF-2K
O00418
-
EEF-2K
-
-
EEF-2K
Q08796
-
eEF2 kinase
-
-
eEF2 kinase
Q00418
-
eEF2 kinase
-
-
eEF2-kinase
-
-
eEF2K
F8S834
-
eEF2K
Q00418
-
EF-2K
O00418
-
eIF2alpha kinase
-
-
elongation factor 2 kinase
O01991
-
elongation factor 2 kinase
O00418
-
elongation factor 2 kinase
O08796
-
elongation factor 2 kinase
P70531
-
elongation factor-2 kinase
-
-
eukaryotic elongation factor 2 kinase
-
-
eukaryotic elongation factor 2 kinase
-
-
eukaryotic elongation factor 2 kinase
-
-
eukaryotic elongation factor-2 kinase
-
-
eukaryotic elongation factor-2 kinase
-
-
eukaryotic translation initiation factor 2alpha kinase
-
-
GCN2
-
-
GCN2
Mus musculus C57BL/6J
-
-
-
GCN2 eIF2alpha kinase
-
-
GCN2 eIF2alpha kinase
Mus musculus C57BL/6J
-
-
-
GCN2 kinase
-
-
GCN2 kinase
Mus musculus C57BL/6J
-
-
-
general control nonderepressible 2 kinase
-
-
general control nonderepressible 2 kinase
Mus musculus C57BL/6J
-
-
-
additional information
-
formerly CaMKIII
additional information
-
MHCKs and eEF-2Ks comprise a distinct subgroup within the alpha kinase famiily
CAS REGISTRY NUMBER
COMMENTARY
116283-83-1
-
ORGANISM
COMMENTARY
LITERATURE
SEQUENCE CODE
SEQUENCE DB
SOURCE
male humans of about 25 years
-
-
Manually annotated by BRENDA team
-
SwissProt
Manually annotated by BRENDA team
; C57BL/6J mice
-
-
Manually annotated by BRENDA team
C57BLKsJ lepr-/-db/db mice, diabetc mice
-
-
Manually annotated by BRENDA team
gene eEF-2K
UniProt
Manually annotated by BRENDA team
Mus musculus C57BL/6J
C57BL/6J mice
-
-
Manually annotated by BRENDA team
male Sprague-Dawley rat
-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
malfunction
-
loss of GCN2 enhances immunosuppression by asparaginase
malfunction
-
in vivo studies with Gcn2 knockout mice show increased susceptibility to both acute or chronic liver damage induced by CCl4, as shown by higher alanine aminotransferase and aspartate aminotransferase activities, increased necrosis and higher inflammatory infiltrates compared with wild-type mice. Chronic CCl4 treatment increases deposition of interstitial collagen type I. Col1a1 and col1a2 mRNA levels also increase in CCl4-treated Gcn2-/- mice compared with wild-type mice
physiological function
-
the eIF2 kinase GCN2 is essential for the murine immune system to adapt to amino acid deprivation by asparaginase
physiological function
-
the enzyme is implicated in induction of apoptosis and endoplasmic reticulum stress-responsive genes by sodium salicylate
physiological function
-
the enzyme has a key role in collagen type I production by hepatic stellate cells
physiological function
-
the enzyme is a key regulator of the fibrogenic response to liver injury
physiological function
-
the enzyme plays an important role in the regulation of genes encoding enzymes of amino acid biosynthesis in wheat. The enzyme is implicated in sulfur signalling
SUBSTRATE
PRODUCT                      
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
ATP + a protein
ADP + a phosphoprotein
show the reaction diagram
O00418
-
-
-
?
ATP + a protein
ADP + a phosphoprotein
show the reaction diagram
O01991
-
-
-
?
ATP + a protein
ADP + a phosphoprotein
show the reaction diagram
O08796
-
-
-
?
ATP + a protein
ADP + a phosphoprotein
show the reaction diagram
P70531
-
-
-
?
ATP + a protein
ADP + a phosphoprotein
show the reaction diagram
-
-
-
-
?
ATP + acetyl-RKKYKFNEDTERRRFL-amide
ADP + acetyl-RKKYKFNED(phospho)TERRRFL-amide
show the reaction diagram
-
-
-
-
?
ATP + RKKFGESEKTKTKEFL
ADP + ?
show the reaction diagram
-
-
-
-
?
ATP + [elongation factor 2]
ADP + [elongation factor 2]phosphate
show the reaction diagram
-
-
-
-
?
ATP + [elongation factor 2]
ADP + [elongation factor 2]phosphate
show the reaction diagram
-
-
-
-
?
ATP + [elongation factor 2]
ADP + [elongation factor 2]phosphate
show the reaction diagram
-
-
-
-
?
ATP + [elongation factor 2]
ADP + [elongation factor 2]phosphate
show the reaction diagram
-
elongation factor 2 regulates the translation elongation through mTOR, p38, and MEK pathways, and is modulated through protein phosphatase 2A, overview
-
-
?
ATP + [elongation factor 2]
ADP + [elongation factor 2]phosphate
show the reaction diagram
-
enzyme regulation by de-/phosphorylation, overview
-
-
?
ATP + [elongation factor 2]
ADP + [elongation factor 2]phosphate
show the reaction diagram
-
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
show the reaction diagram
-
phosphorylation at Thr56
-
-
?
ATP + [elongation factor 2]
ADP + [elongation factor 2]phosphate
show the reaction diagram
-
phosphorylation at Thr56
-
-
?
ATP + [elongation factor 2]
ADP + [elongation factor 2]phosphate
show the reaction diagram
-
phosphorylation at Thr57 inhibits the elongation factor 2 and blocks translational elongation, enzyme activity is regulated by rampamycin, 5-hydroxytryptamine, and serotonin, regulation mechanism, phosphorylation at Thr57 inhibits the elongation factor 2
-
-
?
ATP + [elongation factor 2]
ADP + [elongation factor 2] phosphate
show the reaction diagram
-
-
-
-
?
ATP + [elongation factor 2]
ADP + [elongation factor 2] phosphate
show the reaction diagram
-
-
-
-
?
ATP + [elongation factor 2]
ADP + [elongation factor 2] phosphate
show the reaction diagram
-
-
-
-
?
ATP + [elongation factor 2]
ADP + [elongation factor 2] phosphate
show the reaction diagram
-
-
-
-
?
ATP + [elongation factor 2]
ADP + [elongation factor 2] phosphate
show the reaction diagram
-
the phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 is a key point of regulation of protein synthesis and amino acid homoeostasis in eukaryotes
-
-
?
ATP + [elongation factor 2]
ADP + [elongation factor 2] phosphate
show the reaction diagram
-
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
show the reaction diagram
-
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
show the reaction diagram
-
the recombinant human enzyme is able to phosphorylate wheat germ elongation factor 2 with kinetic parameters comparable to the mammalian enzyme
-
-
?
ATP + [elongation factor 3]
ADP + [elongation factor 3]phosphate
show the reaction diagram
-
-
-
-
?
ATP + [elongation translation factor 2]
ADP + [elongation translation factor 2]phosphate
show the reaction diagram
-
-
-
-
?
ATP + [eukaryotic translation elongation factor 2]
ADP + [eukaryotic translation elongation factor 2] phosphate
show the reaction diagram
-
-
-
-
?
ATP + [eukaryotic translation elongation factor 2]
ADP + [eukaryotic translation elongation factor 2] phosphate
show the reaction diagram
-
phosphorylation at Thr56
-
-
?
ATP + [eukaryotic translation elongation factor 2]
ADP + [eukaryotic translation elongation factor 2] phosphate
show the reaction diagram
-
phosphorylation at Thr56
-
-
?
ATP + [eukaryotic translation elongation factor 2]
ADP + [eukaryotic translation elongation factor 2] phosphate
show the reaction diagram
Q08796
phosphorylation at Thr56
-
-
?
ATP + [eukaryotic translation elongation factor 2]
ADP + [eukaryotic translation elongation factor 2] phosphate
show the reaction diagram
-
eEF2 is involved in eEF2 in neurite outgrowth regulation mechanism, since phosphorylated eEF2 inhibits mRNA translation via inhibition of eEF2-ribosome binding, calcium elevation appears to inhibit mRNA translation in growth cones by a synergistic mechanism involving regulation of EF2K, S6K, and eEF2 itself, overview
-
-
?
ATP + [eukaryotic translation elongation factor 2]
ADP + [eukaryotic translation elongation factor 2] phosphate
show the reaction diagram
-
eEF2 is involved in eEF2 in neurite outgrowth regulation mechanism, since phosphorylated eEF2 inhibits mRNA translation via inhibition of eEF2-ribosome binding, calcium elevation appears to inhibit mRNA translation in growth cones by a synergistic mechanism involving regulation of EF2K, S6K, and eEF2 itself, overview
-
-
?
ATP + [eukaryotic translation elongation factor 2]
ADP + [eukaryotic translation elongation factor 2] phosphate
show the reaction diagram
-
high glucose and high insulin regulate phosphorylation of eEF2 and eEF2 kinase by rapidly increasing activating Thr56 dephosphorylation of eEF2 and inactivating Ser366 phosphorylation of eEF2 kinase, events that facilitate elongation, overview
-
-
?
ATP + [eukaryotic translation elongation factor 2]
ADP + [eukaryotic translation elongation factor 2] phosphate
show the reaction diagram
-
inhibition of eEF2 phosphorylation leads to increased activity of its upstream regulators AMP-activated protein kinase, AMPK, and eEF2 kinase, eEF2K, regulation, overview
-
-
?
ATP + [eukaryotic translation elongation factor 2]
ADP + [eukaryotic translation elongation factor 2] phosphate
show the reaction diagram
Q08796
the enzyme is involved in eukaryotic elongation factor 2 kinase in ER stress-induced signaling and cell death by inducing stress factors, regulation cascade, overview
-
-
?
ATP + [eukaryotic translation elongation factor 2]
ADP + [eukaryotic translation elongation factor 2] phosphate
show the reaction diagram
-
the reaction leads to derepression of transcription factor GCN4
-
-
?
ATP + [eukaryotic translation elongation factor 2]
ADP + [eukaryotic translation elongation factor 2] phosphate
show the reaction diagram
-
i.e. eEF2, both AMP-activated protein kinase, AMPK, and eEF2 kinase, eEF2K, phosphorylate eEF2, thus two distinct paths lead to eEF2 phosphorylation, overview
-
-
?
ATP + [eukaryotic translation elongation factor 2]
ADP + [eukaryotic translation elongation factor 2] phosphate
show the reaction diagram
-
the enzyme exhibits strong preference for threonine as the phosphoacceptor amino acid, substrate specificity and phosphoacceptor amino acid specificity, overview
-
-
?
ATP + [eukaryotic translation elongation factor 2]
ADP + [eukaryotic translation elongation factor 2] phosphate
show the reaction diagram
Mus musculus C57BL/6J
-
-, the reaction leads to derepression of transcription factor GCN4
-
-
?
ATP + [eukaryotic translation initiation factor 2alpha]
ADP + [eukaryotic translation initiation factor 2alpha]phosphate
show the reaction diagram
-
-, GCN2 mediates translational control of gene expressionin amino acid-starved cells by phosphorylation of the eukaryotic translation initiation factor 2alpha associated to polyribosome and the regulatory GCN1-GCN20 complex, overview
-
-
?
ATP + [MHCK A peptide substrate]
ADP + [MHCK A peptide substrate] phosphate
show the reaction diagram
-
i.e. YAYDTRYRR
-
-
?
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
?
-
-
translation regulation mechanism
-
-
-
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
?
-
-
rottlerin suppresses eEF2K, but not eEF2 phosphorylation in myocytes
-
-
-
additional information
?
-
Q00418
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 cdc2–cyclin B complexe, inactivates the enzyme occuring early in mitosis probably to keep the elongation factor 2 active during mitosis, overview
-
-
-
additional information
?
-
-
the GCN2 eIF2alpha kinase regulates fatty-acid homeostasis in the liver during deprivation of the essential amino acid leucine, thus, the enzyme acts as sensor for amino acid deficiency, overview
-
-
-
additional information
?
-
-
a lysine or arginine in the P+1 position on the C-terminal side of the phosphoacceptor threonine, P site, is critical for peptide substrate recognition by eEF-2K, eEF-2K requires basic residues in both the P+1 and P+3 positions to recognize peptide substrates, overview
-
-
-
additional information
?
-
-
non-muscle myosin II is a poor substrate for eEF-2 kinase, while eukaryotic elongation factor 2 is no substrate of kinase TRPM7
-
-
-
additional information
?
-
Mus musculus C57BL/6J
-
the GCN2 eIF2alpha kinase regulates fatty-acid homeostasis in the liver during deprivation of the essential amino acid leucine, thus, the enzyme acts as sensor for amino acid deficiency, overview
-
-
-
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
ATP + [elongation factor 2]
ADP + [elongation factor 2]phosphate
show the reaction diagram
-
-
-
-
?
ATP + [elongation factor 2]
ADP + [elongation factor 2]phosphate
show the reaction diagram
-
-
-
-
?
ATP + [elongation factor 2]
ADP + [elongation factor 2]phosphate
show the reaction diagram
-
elongation factor 2 regulates the translation elongation through mTOR, p38, and MEK pathways, and is modulated through protein phosphatase 2A, overview
-
-
?
ATP + [elongation factor 2]
ADP + [elongation factor 2]phosphate
show the reaction diagram
-
enzyme regulation by de-/phosphorylation, overview
-
-
?
ATP + [elongation factor 2]
ADP + [elongation factor 2]phosphate
show the reaction diagram
-
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
show the reaction diagram
-
phosphorylation at Thr56
-
-
?
ATP + [elongation factor 2]
ADP + [elongation factor 2]phosphate
show the reaction diagram
-
phosphorylation at Thr57 inhibits the elongation factor 2 and blocks translational elongation, enzyme activity is regulated by rampamycin, 5-hydroxytryptamine, and serotonin, regulation mechanism
-
-
?
ATP + [elongation factor 2]
ADP + [elongation factor 2] phosphate
show the reaction diagram
-
-
-
-
?
ATP + [elongation factor 2]
ADP + [elongation factor 2] phosphate
show the reaction diagram
-
-
-
-
?
ATP + [elongation factor 2]
ADP + [elongation factor 2] phosphate
show the reaction diagram
-
-
-
-
?
ATP + [elongation factor 2]
ADP + [elongation factor 2] phosphate
show the reaction diagram
-
the phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 is a key point of regulation of protein synthesis and amino acid homoeostasis in eukaryotes
-
-
?
ATP + [elongation factor 3]
ADP + [elongation factor 3]phosphate
show the reaction diagram
-
-
-
-
?
ATP + [elongation translation factor 2]
ADP + [elongation translation factor 2]phosphate
show the reaction diagram
-
-
-
-
?
ATP + [eukaryotic translation elongation factor 2]
ADP + [eukaryotic translation elongation factor 2] phosphate
show the reaction diagram
-
-
-
-
?
ATP + [eukaryotic translation elongation factor 2]
ADP + [eukaryotic translation elongation factor 2] phosphate
show the reaction diagram
-
eEF2 is involved in eEF2 in neurite outgrowth regulation mechanism, since phosphorylated eEF2 inhibits mRNA translation via inhibition of eEF2-ribosome binding, calcium elevation appears to inhibit mRNA translation in growth cones by a synergistic mechanism involving regulation of EF2K, S6K, and eEF2 itself, overview
-
-
?
ATP + [eukaryotic translation elongation factor 2]
ADP + [eukaryotic translation elongation factor 2] phosphate
show the reaction diagram
-
eEF2 is involved in eEF2 in neurite outgrowth regulation mechanism, since phosphorylated eEF2 inhibits mRNA translation via inhibition of eEF2-ribosome binding, calcium elevation appears to inhibit mRNA translation in growth cones by a synergistic mechanism involving regulation of EF2K, S6K, and eEF2 itself, overview
-
-
?
ATP + [eukaryotic translation elongation factor 2]
ADP + [eukaryotic translation elongation factor 2] phosphate
show the reaction diagram
-
high glucose and high insulin regulate phosphorylation of eEF2 and eEF2 kinase by rapidly increasing activating Thr56 dephosphorylation of eEF2 and inactivating Ser366 phosphorylation of eEF2 kinase, events that facilitate elongation, overview
-
-
?
ATP + [eukaryotic translation elongation factor 2]
ADP + [eukaryotic translation elongation factor 2] phosphate
show the reaction diagram
-
inhibition of eEF2 phosphorylation leads to increased activity of its upstream regulators AMP-activated protein kinase, AMPK, and eEF2 kinase, eEF2K, regulation, overview
-
-
?
ATP + [eukaryotic translation elongation factor 2]
ADP + [eukaryotic translation elongation factor 2] phosphate
show the reaction diagram
Q08796
the enzyme is involved in eukaryotic elongation factor 2 kinase in ER stress-induced signaling and cell death by inducing stress factors, regulation cascade, overview
-
-
?
ATP + [eukaryotic translation elongation factor 2]
ADP + [eukaryotic translation elongation factor 2] phosphate
show the reaction diagram
Mus musculus, Mus musculus C57BL/6J
-
the reaction leads to derepression of transcription factor GCN4
-
-
?
ATP + [eukaryotic translation initiation factor 2alpha]
ADP + [eukaryotic translation initiation factor 2alpha]phosphate
show the reaction diagram
-
GCN2 mediates translational control of gene expressionin amino acid-starved cells by phosphorylation of the eukaryotic translation initiation factor 2alpha associated to polyribosome and the regulatory GCN1-GCN20 complex, overview
-
-
?
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
?
-
-
translation regulation mechanism
-
-
-
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
?
-
-
rottlerin suppresses eEF2K, but not eEF2 phosphorylation in myocytes
-
-
-
additional information
?
-
Q00418
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 cdc2–cyclin B complexe, inactivates the enzyme occuring early in mitosis probably to keep the elongation factor 2 active during mitosis, overview
-
-
-
additional information
?
-
Mus musculus, Mus musculus C57BL/6J
-
the GCN2 eIF2alpha kinase regulates fatty-acid homeostasis in the liver during deprivation of the essential amino acid leucine, thus, the enzyme acts as sensor for amino acid deficiency, overview
-
-
-
METALS and IONS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
Ca2+
-
-
Ca2+
-
completely dependent on, activates
Ca2+
-
dependent on, activates
Ca2+
-
Ca2+-dependent elongation factor 2 phosphorylation and inhibition blocks the elongation in translation, rapamycin/5-hydroxytryptamine increase the dephosphorylation
Ca2+
-
strong activation, activation in response to exercise in skeletal muscle
Ca2+
-
dependent on
Ca2+
-
calcium-calmodulin-dependent enzyme, calcium also decreases the level of phosphorylated p70-S6 kinase, a kinase known to inhibit EF2K
Ca2+
-
required
Ca2+
-
activates
Ca2+
-
Ca2+/calmodulin-dependent enzyme. Ca2+/calmodulin enhance the ability of the enzyme to bind to ATP
Ca2+
-
Ca2+/calmodulin-dependent enzyme
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+
calcium/calmodulin
Q00418
dependent on
Mg2+
-
required
INHIBITORS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
1-benzyl-3-cetyl-2-methylimidazolium iodide
-
NH125
-
1-benzyl-3-cetyl-2-methylimidazolium iodide
-
i.e. NH125, inhibits in vitro, but is not a cellular inhibitor elongation factor 2 kinase
-
2-((3,5-di-tert-butyl-4-hydroxyphenyl)-methylene)-4-cyclopentene-1,3-dione
-
TX-1123
-
bombesin
-
a secretagogue, increases elongation rates, and decreases elongation factor 2 phosphorylation
Carbachol
-
a secretagogue, increases elongation rates, and decreases elongation factor 2 phosphorylation
Cholecystokinin
-
a secretagogue, increases elongation rates, increases phosphorylation of eEF2 kinase, and decreases elongation factor 2 phosphorylation reversed by rapamycin, PD98059, calyculin, or SB202190
compound C
-
AMPK inhibitor compound C blocks eEF2K and eEF2 phosphorylation
ethanol
-
decreases phosphorylation of eEF2K, whereas elongation factor 2 phosphorylation increases, but this response is not mediated by eEF2K
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
phorbol ester PMA
-
-
rottlerin
-
blocks the effects of stimulators AICAR and FBS
serotonin
-
inhibits the enzyme in synaptosomes and in isolated neurites, antagonizes rapamycin/5-hydroxytryptamine, mechanism
shRNA
-
decreases eEF-2 kinase expression by 90%
-
shRNA
-
eEF2K protein levels are 8fold reduced
-
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
-
TS2
-
1,3-selenazine derivative
TS4
-
1,3-selenazine derivative
lopinavir
-
i.e. LPV, increases the phosphorylation of eEF2 kinase on Ser366 reducing its activity, LPV affects eEF2 activity via an AMPK-eEF2K dependent pathway, overview
additional information
-
no effect by CPT-cAMP and A23187
-
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 by p70-S6 kinase inhibits EF2K, Ca2+ decreases the phosphorylation of the enzyme
-
additional information
Q00418
phosphorylation at Ser359 by cyclin-dependent kinase 1, as cdc2-cyclin B complex, inhibits eEF2K activity
-
additional information
-
rottlerin suppresses eEF2K, but not eEF2 phosphorylation in myocytes
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
5-amino-4-imidazolecarboxyamide riboside
-
-
AICAR
-
increases the levels of eEF2K phosphorylation more than 2fold
calcium/calmodulin
Q00418
dependent on
-
Calmodulin
-
-
Calmodulin
-
completely dependent on
Calmodulin
-
dependent on
Calmodulin
-
strong activation, activation in response to exercise in skeletal muscle
Calmodulin
-
dependent on
Calmodulin
-
calcium-calmodulin-dependent enzyme
Calmodulin
-
required
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
calyculin
-
reverses activation of the elongation factor 2 by dephosphorylation through cholecystokinin
carbonyl cyanide 3-chlorophenylhydrazone
-
-
D-glucose
-
high glucose or high insulin rapidly increase inactivating Ser366 phosphorylation of eEF2 kinase
FBS protein
-
increases the levels of eEF2K phosphorylation more than 2fold
-
GCN1-GCN20
-
positive effectors, uncharged tRNAs activate GCN2 requiring direct interaction with both the GCN1-GCN20 regulatory complex and ribosomes
-
Insulin
-
high glucose or high insulin rapidly increase inactivating Ser366 phosphorylation of eEF2 kinase
-
mTOR
-
mediates the insulin-induced activation of Ser78 phosphorylation, insulin-dependent decrease of eEF2 phosphorylation is blocked by rapamycin
-
PD98059
-
reverses activation of the elongation factor 2 by dephosphorylation through cholecystokinin
phosphorylated MEK
-
activates the enzyme
-
phosphorylated p70S6K
-
activates the enzyme
-
Rapamycin
-
reverses activation of the elongation factor 2 by dephosphorylation through cholecystokinin
Rapamycin
-
increases the binding of calmodulin to the enzyme
rapamycin/5-hydroxytryptamine
-
rapamycin activates the enzyme in neuron and antagonizes serotonin mediated by 5-hydroxytryptamine, rapamycin alone has no effect, but increases with 5-hydroxytryptamine the dephosphorylation of the eukaryotic elongation factor 2, 5-hydroxytryptamine decreases the phosphorylation of the eukaryotic elongation factor 2 at Thr57 in a rapamycin-sensitive manner, mechanism
-
SB202190
-
reverses activation of the elongation factor 2 by dephosphorylation through cholecystokinin
uncharged tRNAs
-
activate GCN2 requiring direct interaction with both the GCN1-GCN20 regulatory complex and ribosomes
-
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
additional information
-
no effect by CPT-cAMP and A23187
-
additional information
-
ATP depletion activates the enzyme
-
additional information
-
ATP depletion activates the enzyme in cardiomyocytes
-
additional information
-
the eEF3-like domain has an effector function in GCN2 activation
-
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
-
the enzyme is activated by uncharged tRNA-dependent mechanisms
-
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
-
high potassium-evoked Ca2+ elevation enhances phosphorylation of eEF2 in growth cones, overview
-
additional information
-
inhibition of eEF2 phosphorylation leads to increased activity of its upstream regulators AMP-activated protein kinase and eEF2 kinase, overview
-
additional information
-
activated by incubation with histidine-free medium
-
IC50 VALUE [mM]
IC50 VALUE [mM] Maximum
INHIBITOR
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
6e-05
-
1-benzyl-3-cetyl-2-methylimidazolium iodide
-
pH 7.5, 30°C
-
6e-05
-
NH125
-
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
-
decreases viability of cancer cell lines with IC50S of 0.0007 to 0.0048 mM, overview
SPECIFIC ACTIVITY [µmol/min/mg]
SPECIFIC ACTIVITY MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
0.536
-
-
30°C, pH 7.5
additional information
-
-
-
pH OPTIMUM
pH MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
7
-
-
assay at
7
-
-
assay at
7.5
-
-
assay at
pH RANGE
pH RANGE MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
TEMPERATURE OPTIMUM MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
25
-
-
assay at
30
-
-
assay at
30
-
-
assay at
30
-
-
assay at
30
-
-
assay at
30
-
-
activity assay
30
-
-
assay at
SOURCE TISSUE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
SOURCE
-
glioblastoma cell line
Manually annotated by BRENDA team
-
ovarian carcinoma cell line
Manually annotated by BRENDA team
-
murine myoblasts
Manually annotated by BRENDA team
-
phosphorylated or dephosphorylated enzyme
Manually annotated by BRENDA team
-
C-6 cell, half-life of the enzyme is 6 h
Manually annotated by BRENDA team
-
cervical carcinoma cell line
Manually annotated by BRENDA team
-
gastric epithelial cell
Manually annotated by BRENDA team
-
oral epidermoid carcinoma cell line
Manually annotated by BRENDA team
-
; expression of lipogenic genes and the activity of fatty acid synthase in the liver are repressed and lipid stores in adipose tissue are mobilized in GCN2 wild-type mice upon leucine deprivation
Manually annotated by BRENDA team
Mus musculus C57BL/6J
-
; expression of lipogenic genes and the activity of fatty acid synthase in the liver are repressed and lipid stores in adipose tissue are mobilized in GCN2 wild-type mice upon leucine deprivation
-
Manually annotated by BRENDA team
-
breast carcinoma cell line
Manually annotated by BRENDA team
-
breastcancer cell line
Manually annotated by BRENDA team
-
when deprived of nutrients, the activity of eEF-2 kinase is rapidly increased
Manually annotated by BRENDA team
-
cancer cell line
Manually annotated by BRENDA team
-
cancer cell line
Manually annotated by BRENDA team
-
DRG neurons
Manually annotated by BRENDA team
-
ovarian carcinoma cell line
Manually annotated by BRENDA team
-
prostate carcinoma cell line
Manually annotated by BRENDA team
F8S834
the enzyme is differentially regulated in separate compartments
Manually annotated by BRENDA team
-
cell lines of head and neck cancer
Manually annotated by BRENDA team
-
glioblastoma cell line
Manually annotated by BRENDA team
-
glioma cell line
Manually annotated by BRENDA team
-
when deprived of nutrients, the activity of eEF-2 kinase is rapidly increased
Manually annotated by BRENDA team
-
at the level of elongation
Manually annotated by BRENDA team
-
cancer cell line
Manually annotated by BRENDA team
-
glioblastoma cell line
Manually annotated by BRENDA team
-
glioblastoma cell line
Manually annotated by BRENDA team
-
cancer cell line
Manually annotated by BRENDA team
-
cancer cell line
Manually annotated by BRENDA team
-
cancer cell line
Manually annotated by BRENDA team
-
cancer cell line
Manually annotated by BRENDA team
-
cancer cell line
Manually annotated by BRENDA team
Q08796
primary mouse embryonic fibroblasts
Manually annotated by BRENDA team
additional information
-
the enzyme expression and activity is increased in several forms of malignancy
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
MOLECULAR WEIGHT
MOLECULAR WEIGHT MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
90000
-
-
extracted from gastric epithelial cells, determined by SDS-PAGE and Western blot analysis
100000
-
-
recombinant protein, determined by SDS-PAGE
160000
-
-
gel filtration
SUBUNITS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
?
-
x * 81499, calculation from nucleotide sequence
?
-
x * 82000, light scattering analysis, calculated from sequence; x * 95000, SDS-PAGE
additional information
-
recombinant GST-tagged enzyme peptide mapping
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
phosphoprotein
F8S834
-
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 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
Q00418
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
-
phosphorylated GCN2 is the active form of the enzyme
phosphoprotein
-
inactivating Ser366 phosphorylation of eEF2 kinase
phosphoprotein
-
phosphorylation by p70-S6 kinase inhibits EF2K, Ca2+ decreases the phosphorylation of the enzyme
phosphoprotein
-
phosphorylation at Ser366 inhibits the enzyme, mediated by cholecystokinin
phosphoprotein
-
the enzyme performs autophosphorylation, stimulation of AMP-activated protein kinase, EC 2.7.11.11, by AMP leads to activation of the enzyme and to its phosphorylation at Ser398 in the regulatory domain, other phosphorylation sites of the enzyme are Ser78, Ser359, Ser377, and Ser366
phosphoprotein
-
phosphorylation by p70-S6 kinase inhibits EF2K, Ca2+ decreases the phosphorylation of the enzyme
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
-
phosphorylation of eEF2K can either inhibit or enhance the activity of its downstream substrate, depending on the site of phosphorylation and the type of stimul, lopinavir increases the phosphorylation of eEF2 kinase on Ser366 reducing its activity, LPV affects eEF2 activity via an AMPK-eEF2K dependent pathway, overview
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
GENERAL STABILITY
ORGANISM
UNIPROT ACCESSION NO.
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 ACCESSION NO.
LITERATURE
recombinant GST-tagged wild-type and FLAG-tagged mutant enzymes from Escherichia coli
-
with a nickel column by affinity chromatography
-
recombinant GST-tagged enzyme from Escherichia coli strain BL21(DE3) by affinity chromatography
-
Cloned/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
expression as a GST (glutathione transferase)-fusion protein in Escherichia coli
-
expression in Escherichia coli
-
expression of GST-tagged enzyme 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
-
using an EasyXpress Linear Template kit
-
-
O08796
enzyme expression as GST-tagged protein in Escherichia coli strain BL21(DE3)
-
expression in HEK-293 cells
-
overexpression in transgenic wheat results in significant decreases in total free amino acid concentration in the grain, with free asparagine concentration in particular being much lower than in controls
-
EXPRESSION
ORGANISM
UNIPROT ACCESSION NO.
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
-
ENGINEERING
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
S454A
F8S834
neurons injected with mutant enzyme S454A shows significantly more phosphorylation of elongation factor 2 than do neurons injected with wild-type enzyme
C314A
-
complete loss of activity
C318A
-
complete loss of activity
D274A
-
loss of ability to bind ATP
H213A
-
complete loss of activity
H260A
-
complete loss of activity
K170M
-
complete loss of activity, loss of ability to bind ATP
S366A
-
activity with RKKFGESEKTKTKEFL is decreased approximately 90% compared to wild-type activity after preincubation for 60 min with MgATP2-
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
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
-
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
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-
S78A/S366A
-
phosphorylation-defective mutant, mutation results in an increased stability under normal culture conditions, t1/2 is above 24 h
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
T348A
-
about 95% loss of the kinase activity
T348D
-
the mutant enzyme phosphorylates purified elongation factor 2 poorly compared with wild-type
T348D
-
about 93% loss of the kinase activity
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
K170R
-
complete loss of activity, loss of ability to bind ATP
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
T353D
-
no difference in activity compared to wild-type enzyme with respect to the ability to phosphorylate a peptide substrate
additional information
-
construction of Gcn2 knockout mice and effects on enzyme activity and leucine metabolism, phenotype, overview; GCN2-deficient mice fed a leucine-deprived diet, develop liver steatosis, genes related to triglyceride synthesis and expression of SREBP-1c and PPARg are not repressed. Beta-oxidation genes and fatty-acid transport genes are upregulated, mutant exhibits reduced lipid mobilization
additional information
Q08796
construction of gene eEF-2K deletion mutants, phenotype, overview
additional information
Mus musculus C57BL/6J
-
construction of Gcn2 knockout mice and effects on enzyme activity and leucine metabolism, phenotype, overview; GCN2-deficient mice fed a leucine-deprived diet, develop liver steatosis, genes related to triglyceride synthesis and expression of SREBP-1c and PPARg are not repressed. Beta-oxidation genes and fatty-acid transport genes are upregulated, mutant exhibits reduced lipid mobilization
-
additional information
-
construction of GCN1 and GCN2 mutants with mutations in the domain structures that are involved in interaction between the GCNs, the elongation factors, and the polyribosome, overview
APPLICATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
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
-
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
agriculture
-
manipulation of TaGCN2 gene expression can be used to reduce free asparagine accumulation in wheat grain and the risk of acrylamide formation in wheat products
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
additional information
-
eEF2 kinase is stabilized against decay during hypoxia by phosphorylation
pharmacology
-
the enzyme is a target for development of anticancer drugs
additional information
-
novel function of GCN2, regulates lipid metabolism during leucine deprivation in addition to regulating amino acid metabolism
additional information
-
eEF2 kinase does not play a role in regulating elongation factor 2
additional information
Mus musculus C57BL/6J
-
novel function of GCN2, regulates lipid metabolism during leucine deprivation in addition to regulating amino acid metabolism
-