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Information on EC 2.7.12.2 - mitogen-activated protein kinase kinase and Organism(s) Homo sapiens and UniProt Accession P45985

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IUBMB Comments
This enzyme is a dual-specific protein kinase and requires mitogen-activated protein kinase kinase kinase (MAPKKK) for activation. It is required for activation of EC 2.7.11.24, mitogen-activated protein kinase. Phosphorylation of MEK1 by Raf involves phosphorylation of two serine residues . Mitogen-activated protein kinase (MAPK) signal transduction pathways are among the most widespread mechanisms of cellular regulation. Mammalian MAPK pathways can be recruited by a wide variety of stimuli including hormones (e.g. insulin and growth hormone), mitogens (e.g. epidermal growth factor and platelet-derived growth factor), vasoactive peptides (e.g. angiotensin-II and endothelin), inflammatory cytokines of the tumour necrosis factor (TNF) family and environmental stresses such as osmotic shock, ionizing radiation and ischaemic injury.
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Homo sapiens
UNIPROT: P45985
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Word Map
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea
Reaction Schemes
+
a [protein]-(L-serine/L-threonine)
=
+
a [protein]-(L-serine/L-threonine) phosphate
Synonyms
mek/erk, mitogen-activated protein kinase kinase, map kinase kinase, mapkk, mek-1, extracellular-signal-regulated kinase, mapk/erk kinase, map2k4, erk 1, mitogen-activated protein kinase kinase 1, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
dual specificity mitogen-activated protein kinase kinase 4
-
MAP kinase kinase 4
-
mitogen-activated protein kinase kinase 4
-
dual specificity mitogen-activated protein kinase kinase 1
-
dual specificity mitogen-activated protein kinase kinase 2
-
dual specificity mitogen-activated protein kinase kinase 3
-
dual specificity mitogen-activated protein kinase kinase 5
-
dual specificity mitogen-activated protein kinase kinase 6
-
dual specificity mitogen-activated protein kinase kinase 7
-
MAPK kinase
MAPK kinase 1
-
-
MAPK kinase 2
-
-
MAPK kinase 3
-
MAPK kinase 6
-
MAPK kinase kinase-1
-
-
MAPK/ERK kinase 1
-
MAPK/ERK kinase 5
-
MEK 1
-
-
MEK 2
-
-
MEK kinase 2
-
MEK1/2
-
-
MEKK-1
-
-
mitogen activated kinase kinase
-
-
mitogen-activated protein kinase kinase
-
-
mitogen-activated protein kinase kinase 1
mitogen-activated protein kinase kinase 2
mitogen-activated protein kinase kinase 3
mitogen-activated protein kinase kinase 4
-
-
mitogen-activated protein kinase kinase 6
-
-
mitogen-activated protein kinase kinase 7gamma1
-
mitogen-activated protein kinase kinase kinase 2
-
mitogen-activated protein kinase kinase kinase 3
-
mitogen-activated protein kinase kinase kinase 4
-
mitogen-activated protein kinase kinase kinase 5
-
mitogen-activated protein kinase kinase-1
-
-
mitogen-activated protein kinase/ERK kinase kinase 3
-
mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1
-
mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 2
-
MKK7gamma1
-
serine/threonine-protein kinase PAK 7
-
stress kinase mitogen-activated protein kinase kinase 7
-
additional information
SYSTEMATIC NAME
IUBMB Comments
ATP:protein phosphotransferase (MAPKKK-activated)
This enzyme is a dual-specific protein kinase and requires mitogen-activated protein kinase kinase kinase (MAPKKK) for activation. It is required for activation of EC 2.7.11.24, mitogen-activated protein kinase. Phosphorylation of MEK1 by Raf involves phosphorylation of two serine residues [5]. Mitogen-activated protein kinase (MAPK) signal transduction pathways are among the most widespread mechanisms of cellular regulation. Mammalian MAPK pathways can be recruited by a wide variety of stimuli including hormones (e.g. insulin and growth hormone), mitogens (e.g. epidermal growth factor and platelet-derived growth factor), vasoactive peptides (e.g. angiotensin-II and endothelin), inflammatory cytokines of the tumour necrosis factor (TNF) family and environmental stresses such as osmotic shock, ionizing radiation and ischaemic injury.
CAS REGISTRY NUMBER
COMMENTARY hide
142805-58-1
-
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
ATP + JNK
ADP + phospho-JNK
show the reaction diagram
ATP + p38
ADP + phospho-p38
show the reaction diagram
ATP + protein
ADP + phosphoprotein
show the reaction diagram
ATP + a protein
ADP + a phosphoprotein
show the reaction diagram
ATP + c-Jun N-terminal kinase
ADP + phosphorylated c-Jun N-terminal kinase
show the reaction diagram
JNK activation
-
-
?
ATP + ERK
ADP + phospho-ERK
show the reaction diagram
-
-
-
-
?
ATP + ERK
ADP + phosphorylated ERK
show the reaction diagram
-
ERK phosphorylation by MEK1/2
-
-
?
ATP + ERK1
ADP + phosphorylated ERK1
show the reaction diagram
ATP + ERK1/2
ADP + phosphorylated ERK1/2
show the reaction diagram
-
-
-
-
?
ATP + ERK2
ADP + phosphorylated ERK2
show the reaction diagram
ATP + JNK
ADP + JNK phosphate
show the reaction diagram
ATP + JNK
ADP + phosphorylated JNK
show the reaction diagram
-
-
-
?
ATP + JNK1
ADP + phosphorylated JNK1
show the reaction diagram
ATP + K52R-[ERK2]
ADP + phospho-K52R-[ERK2]
show the reaction diagram
catalytically inactive ERK2 in which lysine-52 is substituted with arginine
-
-
?
ATP + K53M-[p38alpha]
ADP + phospho-K53M-[p38alpha]
show the reaction diagram
catalytically inactive p38alpha in which lysine-53 is substituted with methionine
-
-
?
ATP + MKK4
ADP + phosphorylated MKK4
show the reaction diagram
-
-
-
?
ATP + MyoD
ADP + phospharylated MyoD
show the reaction diagram
ATP + p38
ADP + ?
show the reaction diagram
-
-
-
?
ATP + p38
ADP + p38 phosphate
show the reaction diagram
ATP + p38
ADP + phospho-p38
show the reaction diagram
-
-
-
-
?
ATP + p38
ADP + phosphorylated p38
show the reaction diagram
-
-
-
-
?
ATP + p38 MAP kinase
ADP + ?
show the reaction diagram
phosphorylates and activates p38 MAP kinase
-
-
?
ATP + p38/MPK2 kinase
ADP + ?
show the reaction diagram
phosphorylates and specifically activates the p38/MPK2 subgroup of the mitogen-activated protein kinase superfamily
-
-
?
ATP + p38alpha
ADP + phosphorylated p38alpha
show the reaction diagram
MKK6 phosphorylates p38 MAPK on Thr180 and Tyr182, the sites of phosphorylation that activate p38 MAPK
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
ATP + Smad3
ADP + phosphorylated Smad3
show the reaction diagram
additional information
?
-
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
ATP + JNK
ADP + phospho-JNK
show the reaction diagram
the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer, physiologic effects, overview
-
-
?
ATP + p38
ADP + phospho-p38
show the reaction diagram
the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer, physiologic effects, overview
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
ATP + a protein
ADP + a phosphoprotein
show the reaction diagram
ATP + c-Jun N-terminal kinase
ADP + phosphorylated c-Jun N-terminal kinase
show the reaction diagram
JNK activation
-
-
?
ATP + ERK
ADP + phospho-ERK
show the reaction diagram
-
-
-
-
?
ATP + ERK
ADP + phosphorylated ERK
show the reaction diagram
-
ERK phosphorylation by MEK1/2
-
-
?
ATP + ERK1
ADP + phosphorylated ERK1
show the reaction diagram
phosphorylation of extracellular signal-regulated kinase 1
-
-
?
ATP + ERK1/2
ADP + phosphorylated ERK1/2
show the reaction diagram
-
-
-
-
?
ATP + ERK2
ADP + phosphorylated ERK2
show the reaction diagram
ATP + JNK
ADP + JNK phosphate
show the reaction diagram
the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer, physiologic effects, overview
-
-
?
ATP + MyoD
ADP + phospharylated MyoD
show the reaction diagram
phosphorylation at Tyr156, activated MEK1 associates with MyoD
-
-
?
ATP + p38
ADP + p38 phosphate
show the reaction diagram
the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer, physiologic effects, overview
-
-
?
ATP + p38
ADP + phospho-p38
show the reaction diagram
-
-
-
-
?
ATP + p38alpha
ADP + phosphorylated p38alpha
show the reaction diagram
MKK6 phosphorylates p38 MAPK on Thr180 and Tyr182, the sites of phosphorylation that activate p38 MAPK
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
ATP + Smad3
ADP + phosphorylated Smad3
show the reaction diagram
-
mitogen-activated protein kinase kinase-1 regulates SMAD3 expression in epithelial and smooth muscle cells, which is stimulated by TGFbeta-1, SMAD3 is a transcription factor that mediates TGF-?1 signaling and is important in many of the cellular processes that regulate fibrosis and inflammation, overview
-
-
?
additional information
?
-
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
ZINC00142380
i.e. 1-methyl-1H-indole-2-carboxylic acid, inhibitor obtained from virtual screening
ZINC00167997
i.e. 2-[(2-carboxyethyl)amino]benzoic acid, inhibitor obtained from virtual screening
ZINC00388545
i.e. 2,6-dihydroxybenzoic acid, inhibitor obtained from virtual screening
ZINC00389778
i.e. 2,4,6-trihydroxybenzoic acid, inhibitor obtained from virtual screening
ZINC00391412
i.e. 2,6-dihydroxy-4-methylbenzoic acid, inhibitor obtained from virtual screening
ZINC01641166
i.e. 2,4,5-trihydroxybenzoic acid, inhibitor obtained from virtual screening
ZINC02349698
i.e. 7-chloro-1H-indole-2-carboxylic acid, inhibitor obtained from virtual screening
ZINC06091752
i.e. 2,3,6-trihydroxybenzoic acid, inhibitor obtained from virtual screening
ZINC13526482
i.e. 2,5-dihydroxy-4-methylbenzoic acid, inhibitor obtained from virtual screening
ZINC14817730
i.e. (2,4,6-trihydroxyphenyl)acetic acid, inhibitor obtained from virtual screening
3,4-difluoro-N-(3-{5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3-phenyl-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)-5-hydroxybenzamide
-
-
3,4-difluoro-N-{3-[3-(3-fluoro-4-hydroxyphenyl)-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl]phenyl}-5-hydroxybenzamide
-
-
3,4-difluoro-N-{3-[5-({2-fluoro-4-[(hydroxymethyl)amino]phenyl}amino)-3-(3-fluoro-4-hydroxyphenyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl]phenyl}-5-hydroxybenzamide
-
-
3,4-difluoro-N-{3-[5-{[2-fluoro-4-(formylamino)phenyl]amino}-3-(3-fluoro-4-hydroxyphenyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl]phenyl}-5-hydroxybenzamide
-
-
4-(4-bromo-2-fluorophenylamino)-1-methylpyridin-2(1H)-one
-
selective anthranilic acid type inhibitors, residues K97, I141, M143, F129, V127, I126, L118, F209, V211, and S212 of MEK1/2 are important for interaction with the inhibitor, noncompetitive to ATP, inhibition of ERK phosphorylation by MEK1/2 by the derivatives with IC50 values of 6.8-124 nM, low cytotoxic effects, overview
anthrax lethal toxin
-
i.e. LeTx, inactivates MKKs, LeTx treatment reduces the levels of phosphorylated extracellular signal-regulated kinase and p38 MAPK in vitro, short treatments with LeTx only modestly affects cell proliferation, sustained treatment markedly reduces cell numbers, LeTx also substantially inhibits the extracellular release of angioproliferative factors including vascular endothelial growth factor, interleukin-8, and basic fibroblast growth factor, overview
-
AS-703026
-
a MEK1–2 inhibitor, binds in the allosteric site of MEK1. For A-375 cells, AS-703026 has a growth IC50 of 4 nM
AS703026
-
-
AZD8330
BAY 869766
-
i.e. RDEA119
capecitabine
-
-
CH-4987655/RO4987655
-
a MEK1/2 inhibitor
CH4987655
CI-1040
-
-
E6201
-
blocks proliferation of many of the cell lines typically used in testing MEK inhibitors, such as Colo205 and MiaPaca-2
GDC0973
-
-
GSK1120212
-
-
LL-Z1640-2
-
a MEK1 inhibitor, which shows reasonable MEK inhibition but a very short half-life
MEK162
-
-
MIIC
i.e. MEK inhibitor I, the MEK1/2 inhibitor causes NAD(H) reduction, heme oxidation, and decreased oxygen consumption
N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)-3,4-difluoro-5-hydroxybenzamide
-
-
N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)benzamide
-
-
N-(3-{3-cyclopropyl-5-[(4-cyclopropyl-2-fluorophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)-2-oxopropanamide
-
-
N-(3-{5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3-phenyl-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)-2-oxopropanamide
-
-
N-(3-{5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3-phenyl-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)benzamide
-
-
N-{3-[3-(3-fluoro-4-hydroxyphenyl)-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl]phenyl}-2-oxopropanamide
-
-
N-{3-[5-(cyclopropylmethyl)-3-(3-fluoro-4-hydroxyphenyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl]phenyl}-3,4-difluoro-5-hydroxybenzamide
-
-
N-{3-[5-(cyclopropylmethyl)-3-(4-hydroxy-3-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl]phenyl}-3,4-difluoro-5-hydroxybenzamide
-
-
N-{3-[5-(cyclopropylmethyl)-3-(4-hydroxyphenyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl]phenyl}-3,4-difluoro-5-hydroxybenzamide
-
-
PD0325901
-
-
PD184352
a MEK-specific inhibitor
PD184352/CI-1040
-
a allosteric, non-ATP competitive MEK inhibitor
PD198306
an orally active MEK1/2 inhibitor, acting as an uncoupler
PD318088
-
-
PD98059
pemetrexed
-
-
RDEA119
-
-
RDEA436
-
-
-
refametinib
-
-
RO4987655
-
-
RO5126766
-
-
selumetinib
siRNA
-
TAK733
-
-
temozolomide
-
-
trametinib
U0126
XL-518/GDC-0973
-
selective for MEK1 relative to MEK2
additional information
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
anisomycin
activates
CD40
activated by ligation of CD40, the B-cell antigen receptor
-
doxycycline
-
induces expression of HA-MEK1
growth factor interleukin-3
activates
-
additional information
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0533
ATP
pH 7.0, 25°C
0.000184
ERK2
pH 7.0, 25°C
-
0.000129
K52R-[ERK2]
pH 7.0, 25°C
-
0.00016
K53M-[p38alpha]
pH 7.0, 25°C
-
0.000205
p38alpha
pH 7.0, 25°C
-
additional information
additional information
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.085
ATP
pH 7.0, 25°C
0.503
ERK2
pH 7.0, 25°C
-
0.074
K52R-[ERK2]
pH 7.0, 25°C
-
0.152
K53M-[p38alpha]
pH 7.0, 25°C
-
0.243
p38alpha
pH 7.0, 25°C
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0000068 - 0.000124
4-(4-bromo-2-fluorophenylamino)-1-methylpyridin-2(1H)-one
Homo sapiens
-
selective anthranilic acid type inhibitors, residues K97, I141, M143, F129, V127, I126, L118, F209, V211, and S212 of MEK1/2 are important for interaction with the inhibitor, noncompetitive to ATP, inhibition of ERK phosphorylation by MEK1/2 by the deriva
0.000052
AS-703026
Homo sapiens
-
inhibition of MEK1, pH and temperature not specified in the publication
0.000019 - 0.000047
BAY 869766
0.0000052
CH4987655
Homo sapiens
-
inhibition of MEK1, pH and temperature not specified in the publication
0.000046
LL-Z1640-2
Homo sapiens
-
inhibition of MEK1, pH and temperature not specified in the publication
0.000014
selumetinib
Homo sapiens
-
inhibition of MEK1 phosphorylation of ERK2, pH and temperature not specified in the publication
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
high expression level of MKK4, expression in adult and fetal brain
Manually annotated by BRENDA team
high expression level of MKK4
Manually annotated by BRENDA team
high expression level of MKK4
Manually annotated by BRENDA team
colorectal cancer cell line
Manually annotated by BRENDA team
high expression level of MKK4
Manually annotated by BRENDA team
high expression level of MKK4
Manually annotated by BRENDA team
high expression level of MKK4, expression in adult and fetal liver
Manually annotated by BRENDA team
human pancreatic, lung, breast, testicle, and colorectal cancer cell lines
Manually annotated by BRENDA team
MKK3 is a prognostic marker in malignant astrocytomas
Manually annotated by BRENDA team
impaired expression of MKK4
Manually annotated by BRENDA team
impaired expression of MKK4
Manually annotated by BRENDA team
strong expression
Manually annotated by BRENDA team
highest levels of expression
Manually annotated by BRENDA team
highest levels of expression
Manually annotated by BRENDA team
medium expression
Manually annotated by BRENDA team
MKK3 i s upregulated and activated in invasive glioma cells in vitro, overexpression and phosphorylation of MKK3 are linked to glioma invasion, MKK3 is overexpressed in invasive glioma cells in situ and correlates with active p38
Manually annotated by BRENDA team
highest levels of expression
Manually annotated by BRENDA team
highest levels of expression
Manually annotated by BRENDA team
strongest expression in the human tissue panel
Manually annotated by BRENDA team
weak expression
Manually annotated by BRENDA team
LX-1 cell, strong expression
Manually annotated by BRENDA team
strongest expression in human immune panel
Manually annotated by BRENDA team
peripheral blood, weak expression
Manually annotated by BRENDA team
activated MEK1 associates with MyoD in the nucleus of differentiating myoblasts
Manually annotated by BRENDA team
-
choroidal melanoma cell line
Manually annotated by BRENDA team
weak expression
Manually annotated by BRENDA team
impaired expression of MKK4
Manually annotated by BRENDA team
weak expression
Manually annotated by BRENDA team
-
only 8% of normal tissues show MKK4 immunolabeling
Manually annotated by BRENDA team
isolated from osteoarthritis and rheumatoid arthritis patients
Manually annotated by BRENDA team
lowest expression in human immune panel
Manually annotated by BRENDA team
additional information
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
evolution
the enzyme is a member of the MAP kinase family
malfunction
MKK4 is highly mutated and has a pro-oncogenic role in cancers of pancreatic, breast, colon, prostate, skin, and laryngeal squamous cell. Strong association between -1304T>G (rs3826392) polymorphism in the promoter of MKK4 gene and a decreased risk of sporadic colorectal cancer in a southern Chinese population, overview
metabolism
MKK4 belongs to MAPK pathways known to have involvement in the regulation of apoptosis, inflammation, and tumorigenesis
physiological function
malfunction
genetic inactivation of the Mkk7 gene alters circadian gene expression
metabolism
physiological function
additional information
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
MP2K4_HUMAN
399
0
44288
Swiss-Prot
other Location (Reliability: 2)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
37000
x * 37000, calculation from nucleotide sequence
40745
x * 40745, MKK1b an alternatively spliced form of the MKK1a gene, calculation from nucleotide sequence
43439
x * 43439, MKK1a, calculation from nucleotide sequence
47940
sequence analysis
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
?
x * 37419 , apo npMAP2K4, sequence calculation, x * 37950, npMAP2K4/ANP complex, sequence calculation, x * 39000 , apo npMAP2K4, light scattering, x * 40000, npMAP2K4/ANP complex, light scattering
additional information
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
phosphoprotein
MKKs are activated by phopshorylation through MKKKs, e.g. MEKK, MLK, TAK1, Ask1, or TPL2, MKK4 is phopshorylated at serine and threonine residues in the SIAKT motif
phosphoprotein
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
molecular dynamics simulation of inhibitors ZINC06091752-MKK4 and ZINC00391412-MKK4 complexes reveals stable and potential binding modes. Residues Lys 231 and Ser 233 show hydrogen bonding between ligand and receptor whereas Lys 131 and Lys 231 making ionic interactions between ligand and MKK4
purified recombinant apo MAP2K4-KD or in complex with ANP, 15 mg/ml protein in a solution containing 20 mM Tris-HCl, pH 7.5, 100 mM NaCl, 10% glycerol and 10 mM DTT for the apoenzyme, and 2 mM ANP and MgCl2 additional for the npMAP2K4/ANP complex, mixing with reservoir solution containing 0.2 M ammonium acetate, 22-25% w/v PEG 3350 and 0.1 M HEPES–NaOH, pH 7.0, 20°C, X-ray diffraction structure determination and analysis at 3.5 A resolution
mutant C218S, to 1.3 A resolution. The C-terminal region connecting to the DVD domain fits into the elongated groove in the N-lobe of the adjacent molecule and works as a negative regulator, fixing the open-type auto-inhibition form
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
C147S
90% of wild-type activity
C218S
84% of wild-type activity, mutation drastically augments the protein production and crystallographic resolution. C218S crystals grown under microgravity in a space environment yield a 1.3 A resolution structure
C218S/C276S
40% of wild-type activity
C218S/C276S/C147S
40% of wild-type activity
C218S/C276S/C147S/C296S
20% of wild-type activity
C276S
98% of wild-type activity, mutation maintains the specific activity and increases the protein yield
C296S
79% of wild-type activity, mutation maintains the specific activity and increases the protein yield
S207E/T211E
a constitutively active MKK6 mutant
S218E/S222E
site-directed mutagenesis, a constitutively active MEK1 mutant, i.e. MEK1EE
Y156F
site-directed mutagenesis, catalytically inactive mutant. The protein level of mutant MyoD-Y156F decreases compared with that of wild type but is recovered in the presence of lactacystin, a proteasome inhibitor. The low protein level of MyoD-Y156F is recovered over that of wild-type by an additional mutation at Leu164, a critical binding residue of MAFbx/AT-1, a Skp, Cullin, F-box (SCF) E3-ubiquitin ligase
additional information
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
40.8
melting temperature, wild-type
41.4
melting temperature, mutant C218S
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
proteolytic inactivation by anthrax lethal factor
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene MKK4, maps to chromosome 17p11.2 and encodes a 399-amino acid protein in humans spans over 120 kb and consists of 11 exons, for identification of the genetic effects of the -1304T>G polymorphism on cancer risk, a meta-analysis composed of the publications evaluating the association between the -1304T>G polymorphism and risk of cancer is performed, overview
MKK4, DNA and amino acid sequence determination, the gene is located on chromosome 17
A549 cells transfected with wild-type or constitutively active MEK1 cDNA, both MEK1 expressions lead to increased SMAD3 expression and ERK phosphorylation
-
expressed in COS7 cells
expression in COS and 293 cells
expression in Escherichia coli
HA-MEK1 cloned into pRevTRE, HA-tagged MEK1 expressed in HeLa cells
-
isolation of cDNA
MEK1, sequence comparison
-
overexpression in COS cells
recombinant coexpression of His6-tagged constitutively active MEK1 mutant S218E/S222E and GST-MyoD protein
subcloned into the pET28b bacterial expression vector and expressed with a 6 x N-terminal His tag, also subcloned into pGEX 4T-3 for bacterial expression as a GST-fusion protein
transient overexpression of MEKK-1 in insulin-producing cell lines RIN-5AH and betaTC-6
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
tert-butyl hydroperoxide induces the expression of MAP kinase (mainly JNK and ERK) in QZG cells
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
analysis
development of a continuous spectrophotometric assay for mitogen-activated protein kinase kinases
drug development
-
because of their importance in cell proliferation and signaling, MAPK pathways are being targeted for drugs for oncology, inflammation and other conditions. MEK inhibitors may be beneficial for cancer therapy. MEK inhibition is likely to be of particular importance in specific tumors where the MEK pathway is highly and directly activated
medicine
additional information
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Derijard, B.; Raingeaud, J.; Barrett, T.; Wu, I.H.; Han, J.; Ulevitch, R.J.; Davis, R.J.
Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms
Science
267
682-685
1995
Homo sapiens (P45985), Homo sapiens (P46734)
Manually annotated by BRENDA team
Zhou, G.; Bao, Z.Q.; Dixon, J.E.
Components of a new human protein kinase signal transduction pathway
J. Biol. Chem.
270
12665-12669
1995
Homo sapiens (Q13163), Homo sapiens
Manually annotated by BRENDA team
Tournier, C.; Whitmarsh, A.J.; Cavanagh, J.; Barrett, T.; Davis, R.J.
Mitogen-activated protein kinase kinase 7 is an activator of the c-Jun NH2-terminal kinase
Proc. Natl. Acad. Sci. USA
94
7337-7342
1997
Homo sapiens (O14733)
Manually annotated by BRENDA team
Moriguchi, T.; Toyoshima, F.; Gotoh, Y.; Iwamatsu, A.; et al.
Purification and identification of a major activator for p38 from osmotically shocked cells. Activation of mitogen-activated protein kinase kinase 6 by osmotic shock, tumor necrosis factor-alpha, and H2O2
J. Biol. Chem.
271
26981-26988
1996
Mus musculus (O09110), Mus musculus, Homo sapiens (P46734)
Manually annotated by BRENDA team
Foltz, I.N.; Gerl, R.E.; Wieler, J.S.; Luckach, M.; Salmon, R.A.; Schrader, J.W.
Human mitogen-activated protein kinase kinase 7 (MKK7) is a highly conserved c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) activated by environmental stresses and physiological stimuli
J. Biol. Chem.
273
9344-9351
1998
Homo sapiens (O14733), Homo sapiens
Manually annotated by BRENDA team
Lu, X.; Nemoto, S.; Lin, A.
Identification of c-Jun NH2-terminal protein kinase (JNK)-activating kinase 2 as an activator of JNK but not p38
J. Biol. Chem.
272
24751-24754
1997
Homo sapiens (O14733)
Manually annotated by BRENDA team
Vitale, G.; Bernardi, L.; Napolitani, G.; Mock, M.; Montecucco, C.
Susceptibility of mitogen-activated protein kinase kinase family members to proteolysis by anthrax lethal factor
Biochem. J.
352
739-745
2000
Homo sapiens (O14733), Homo sapiens (P36507), Homo sapiens (P45985), Homo sapiens (P52564), Homo sapiens (Q02750)
Manually annotated by BRENDA team
Wu, Z.; Wu, J.; Jacinto, E.; Karin, M.
Molecular cloning and characterization of human JNKK2, a novel Jun NH2-terminal kinase-specific kinase
Mol. Cell. Biol.
17
7407-7416
1997
Homo sapiens (O14733), Homo sapiens
Manually annotated by BRENDA team
Zheng, C.F.; Guan, K.L.
Activation of MEK family kinases requires phosphorylation of two conserved Ser/Thr residues
EMBO J.
13
1123-1131
1994
Saccharomyces cerevisiae (P06784), Homo sapiens (Q02750)
Manually annotated by BRENDA team
Duesbery, N.S.; Webb, C.P.; Leppla, S.H.; Gordon, V.M.; Klimpel, K.R.; Copeland, T.D.; Ahn, N.G.; Oskarsson, M.K.; Fukasawa, K.; Paull, K.D.; Vande Woude, G.F.
Proteolytic inactivation of MAP-kinase-kinase by anthrax lethal factor
Science
280
734-737
1998
Mus musculus (P31938), Homo sapiens (P36507), Homo sapiens (Q02750)
Manually annotated by BRENDA team
Zheng, C.F.; Guan, K.L.
Cloning and characterization of two distinct human extracellular signal-regulated kinase activator kinases, MEK1 and MEK2
J. Biol. Chem.
268
11435-11439
1993
Homo sapiens (P36507), Homo sapiens (Q02750)
Manually annotated by BRENDA team
Lin, A.; Minden, A.; Martinetto, H.; Claret, F.X.; Lange-Carter, C.; Mercurio, F.; Johnson, G.L.; Karin, M.
Identification of a dual specificity kinase that activates the Jun kinases and p38-Mpk2
Science
268
286-290
1995
Homo sapiens (P45985)
Manually annotated by BRENDA team
Su, G.H.; Hilgers, W.; Shekher, M.C.; Tang, D.J.; Yeo, C.J.; Hruban, R.H.; Kern, S.E.
Alterations in pancreatic, biliary, and breast carcinomas support MKK4 as a genetically targeted tumor suppressor gene
Cancer Res.
58
2339-2342
1998
Homo sapiens (P45985)
Manually annotated by BRENDA team
Raingeaud, J.; Whitmarsh, A.J.; Barrett, T.; Derijard, B.; Davis, R.J.
MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway
Mol. Cell. Biol.
16
1247-1255
1996
Homo sapiens (P46734), Homo sapiens (P52564)
Manually annotated by BRENDA team
Teng, D.H.; Chen, Y.; Lian, L.; Ha, P.C.; Tavtigian, S.V.; Wong, A.K.
Mutation analyses of 268 candidate genes in human tumor cell lines
Genomics
74
352-364
2001
Homo sapiens (P46734), Homo sapiens
Manually annotated by BRENDA team
Cuenda, A.; Alonso, G.; Morrice, N.; Jones, M.; Meier, R.; Cohen, P.; Nebreda, A.R.
Purification and cDNA cloning of SAPKK3, the major activator of RK/p38 in stress- and cytokine-stimulated monocytes and epithelial cells
EMBO J.
15
4156-4164
1996
Homo sapiens (P52564), Homo sapiens, Mus musculus (P70236), Mus musculus
Manually annotated by BRENDA team
Han, J.; Lee, J.D.; Jiang, Y.; Li, Z.; Feng, L.; Ulevitch, R.J.
Characterization of the structure and function of a novel MAP kinase kinase (MKK6)
J. Biol. Chem.
271
2886-2891
1996
Homo sapiens (P52564), Homo sapiens
Manually annotated by BRENDA team
Moriguchi, T.; Kuroyanagi, N.; Yamaguchi, K.; Gotoh, Y.; Irie, K.; Kano, T.; Shirakabe, K.; Muro, Y.; Shibuya, H.; Matsumoto, K.; Nishida, E.; Hagiwara, M.
A novel kinase cascade mediated by mitogen-activated protein kinase kinase 6 and MKK3
J. Biol. Chem.
271
13675-13679
1996
Homo sapiens (P52564)
Manually annotated by BRENDA team
Stein, B.; Brady, H.; Yang, M.X.; Young, D.B.; Barbosa, M.S.
Cloning and characterization of MEK6, a novel member of the mitogen-activated protein kinase kinase cascade
J. Biol. Chem.
271
11427-11433
1996
Homo sapiens (P52564)
Manually annotated by BRENDA team
Seger, R.; Seger, D.; Lozeman, F.J.; Ahn, N.G.; Graves, L.M.; Campbell, J.S.; Ericsson, L.; Harrylock, M.; Jensen, A.M.; Krebs, E.G.
Human T-cell mitogen-activated protein kinase kinases are related to yeast signal transduction kinases
J. Biol. Chem.
267
25628-25631
1992
Homo sapiens (Q02750), Homo sapiens
Manually annotated by BRENDA team
Chang, H.Y.; Nishitoh, H.; Yang, X.; Ichijo, H.; Baltimore, D.
Activation of apoptosis signal-regulating kinase 1 (ASK1) by the adapter protein Daxx
Science
281
1860-1863
1998
Homo sapiens (Q99683)
Manually annotated by BRENDA team
Ichijo, H.; Nishida, E.; Irie, K.; ten Dijke, P.; Saitoh, M.; Moriguchi, T.; Takagi, M.; Matsumoto, K.; Miyazono, K.; Gotoh, Y.
Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways
Science
275
90-94
1997
Homo sapiens (Q99683)
Manually annotated by BRENDA team
Wang, X.S.; Diener, K.; Jannuzzi, D.; Trollinger, D.; Tan, T.H.; Lichenstein, H.; Zukowski, M.; Yao, Z.
Molecular cloning and characterization of a novel protein kinase with a catalytic domain homologous to mitogen-activated protein kinase kinase kinase
J. Biol. Chem.
271
31607-31611
1996
Homo sapiens (Q99683), Homo sapiens
Manually annotated by BRENDA team
Ellinger-Ziegelbauer, H.; Brown, K.; Kelly, K.; Siebenlist, U.
Direct activation of the stress-activated protein kinase (SAPK) and extracellular signal-regulated protein kinase (ERK) pathways by an inducible mitogen-activated protein Kinase/ERK kinase kinase 3 (MEKK) derivative
J. Biol. Chem.
272
2668-2674
1997
Homo sapiens (Q99759), Homo sapiens
Manually annotated by BRENDA team
Nagase, T.; Ishikawa, K.; Kikuno, R.; Hirosawa, M.; Nomura, N.; Ohara, O.
Prediction of the coding sequences of unidentified human genes. XV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro
DNA Res.
6
337-345
1999
Homo sapiens (Q9P286)
Manually annotated by BRENDA team
Cheng, J.; Yang, J.; Xia, Y.; Karin, M.; Su, B.
Synergistic interaction of MEK kinase 2, c-Jun N-terminal kinase (JNK) kinase 2, and JNK1 results in efficient and specific JNK1 activation
Mol. Cell. Biol.
20
2334-2342
2000
Homo sapiens (Q9Y2U5)
Manually annotated by BRENDA team
Nagase, T.; Seki, N.; Ishikawa, K.; Ohira, M.; Kawarabayasi, Y.; Ohara, O.; Tanaka, A.; Kotani, H.; Miyajima, N.; Nomura, N.
Prediction of the coding sequences of unidentified human genes. VI. The coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of cDNA clones from cell line KG-1 and brain
DNA Res.
3; 321-329
341-354
1996
Homo sapiens (Q9Y6R4)
-
Manually annotated by BRENDA team
Takekawa, M.; Posas, F.; Saito, H.
A human homolog of the yeast Ssk2/Ssk22 MAP kinase kinase kinases, MTK1, mediates stress-induced activation of the p38 and JNK pathways
EMBO J.
16
4973-4982
1997
Homo sapiens (Q9Y6R4), Homo sapiens
Manually annotated by BRENDA team
Jia, Y.; Quinn, C.M.; Bump, N.J.; Clark, K.M.; Clabbers, A.; Hardman, J.; Gagnon, A.; Kamens, J.; Tomlinson, M.J.; Wishart, N.; Allen, H.
Purification and kinetic characterization of recombinant human mitogen-activated protein kinase kinase kinase COT and the complexes with its cellular partner NF-kappa B1 p105
Arch. Biochem. Biophys.
441
64-74
2005
Homo sapiens
Manually annotated by BRENDA team
Calipel, A.; Lefevre, G.; Pouponnot, C.; Mouriaux, F.; Eychene, A.; Mascarelli, F.
Mutation of B-Raf in human choroidal melanoma cells mediates cell proliferation and transformation through the MEK/ERK Pathway
J. Biol. Chem.
278
42409-42418
2003
Homo sapiens
Manually annotated by BRENDA team
Wallace, E.M.; Lyssikatos, J.; Blake, J.F.; Seo, J.; Yang, H.W.; Yeh, T.C.; Perrier, M.; Jarski, H.; Marsh, V.; Poch, G.; Livingston, M.G.; Otten, J.; Hingorani, G.; Woessner, R.; Lee, P.; Winkler, J.; Koch, K.
Potent and selective mitogen-activated protein kinase kinase (MEK) 1,2 inhibitors. 4-(4-Bromo-2-fluorophenylamino)-1-methylpyridin-2(1H)-ones
J. Med. Chem.
49
441-444
2006
Homo sapiens
Manually annotated by BRENDA team
Michael, L.; Swantek, J.; Robinson, M.J.
Cloning and expression of human mitogen-activated protein kinase kinase 7gamma1
Biochem. Biophys. Res. Commun.
341
679-683
2006
Homo sapiens (O14733), Homo sapiens
Manually annotated by BRENDA team
Cunningham, S.C.; Kamangar, F.; Kim, M.P.; Hammoud, S.; Haque, R.; Iacobuzio-Donahue, C.A.; Maitra, A.; Ashfaq, R.; Hustinx, S.; Heitmiller, R.E.; Choti, M.A.; Lillemoe, K.D.; Cameron, J.L.; Yeo, C.J.; Schulick, R.D.; Montgomery, E.
Claudin-4, mitogen-activated protein kinase kinase 4, and stratifin are markers of gastric adenocarcinoma precursor lesions
Cancer Epidemiol. Biomarkers Prev.
15
281-287
2006
Homo sapiens
Manually annotated by BRENDA team
Kojima, K.; Konopleva, M.; Samudio, I.J.; Ruvolo, V.; Andreeff, M.
Mitogen-activated protein kinase kinase inhibition enhances nuclear proapoptotic function of p53 in acute myelogenous leukemia cells
Cancer Res.
67
3210-3219
2007
Homo sapiens
Manually annotated by BRENDA team
Ross, K.R.; Corey, D.A.; Dunn, J.M.; Kelley, T.J.
SMAD3 expression is regulated by mitogen-activated protein kinase kinase-1 in epithelial and smooth muscle cells
Cell. Signal.
19
923-931
2007
Homo sapiens
Manually annotated by BRENDA team
Feinstein, T.N.; Linstedt, A.D.
Mitogen-activated protein kinase kinase 1-dependent Golgi unlinking occurs in G2 phase and promotes the G2/M cell cycle transition
Mol. Biol. Cell
18
594-604
2007
Homo sapiens
Manually annotated by BRENDA team
Demuth, T.; Reavie, L.B.; Rennert, J.L.; Nakada, M.; Nakada, S.; Hoelzinger, D.B.; Beaudry, C.E.; Henrichs, A.N.; Anderson, E.M.; Berens, M.E.
MAP-ing glioma invasion: mitogen-activated protein kinase kinase 3 and p38 drive glioma invasion and progression and predict patient survival
Mol. Cancer Ther.
6
1212-1222
2007
Homo sapiens (P46734), Homo sapiens
Manually annotated by BRENDA team
Whitmarsh, A.J.; Davis, R.J.
Role of mitogen-activated protein kinase kinase 4 in cancer
Oncogene
26
3172-3184
2007
Drosophila melanogaster, Homo sapiens, Homo sapiens (O14733), Homo sapiens (P45985), Mus musculus, Mus musculus (P47809), Mus musculus (Q8CE90), Rattus norvegicus, Xenopus laevis
Manually annotated by BRENDA team
Mokhtari, D.; Myers, J.W.; Welsh, N.
The MAPK kinase kinase-1 is essential for stress-induced pancreatic islet cell death
Endocrinology
149
3046-3053
2008
Homo sapiens
Manually annotated by BRENDA team
Ding, Y.; Boguslawski, E.A.; Berghuis, B.D.; Young, J.J.; Zhang, Z.; Hardy, K.; Furge, K.; Kort, E.; Frankel, A.E.; Hay, R.V.; Resau, J.H.; Duesbery, N.S.
Mitogen-activated protein kinase kinase signaling promotes growth and vascularization of fibrosarcoma
Mol. Cancer Ther.
7
648-658
2008
Homo sapiens
Manually annotated by BRENDA team
Grund, E.M.; Kagan, D.; Tran, C.A.; Zeitvogel, A.; Starzinski-Powitz, A.; Nataraja, S.; Palmer, S.S.
Tumor necrosis factor-alpha regulates inflammatory and mesenchymal responses via mitogen-activated protein kinase kinase, p38, and nuclear factor kappaB in human endometriotic epithelial cells
Mol. Pharmacol.
73
1394-1404
2008
Homo sapiens
Manually annotated by BRENDA team
Wang, X.; Ye, X.L.; Liu, R.; Chen, H.L.; Bai, H.; Liang, X.; Zhang, X.D.; Wang, Z.; Li, W.L.; Hai, C.X.
Antioxidant activities of oleanolic acid in vitro: possible role of Nrf2 and MAP kinases
Chem. Biol. Interact.
184
328-337
2010
Homo sapiens
Manually annotated by BRENDA team
Cully, M.; Genevet, A.; Warne, P.; Treins, C.; Liu, T.; Bastien, J.; Baum, B.; Tapon, N.; Leevers, S.J.; Downward, J.
A role for p38 stress-activated protein kinase in regulation of cell growth via TORC1
Mol. Cell. Biol.
30
481-495
2010
Homo sapiens
Manually annotated by BRENDA team
Zheng, L.S.; Zhang, Y.Y.; Wu, J.W.; Wu, Z.; Zhang, Z.Y.; Wang, Z.X.
A continuous spectrophotometric assay for mitogen-activated protein kinase kinases
Anal. Biochem.
421
191-197
2012
Homo sapiens (P52564), Homo sapiens (Q02750)
Manually annotated by BRENDA team
Matsumoto, T.; Kinoshita, T.; Kirii, Y.; Tada, T.; Yamano, A.
Crystal and solution structures disclose a putative transient state of mitogen-activated protein kinase kinase 4
Biochem. Biophys. Res. Commun.
425
195-200
2012
Homo sapiens (P45985)
Manually annotated by BRENDA team
Borthakur, G.; Popplewell, L.; Boyiadzis, M.; Foran, J.; Platzbecker, U.; Vey, N.; Walter, R.B.; Olin, R.; Raza, A.; Giagounidis, A.; Al-Kali, A.; Jabbour, E.; Kadia, T.; Garcia-Manero, G.; Bauman, J.W.; Wu, Y.; Liu, Y.; Schramek, D.; Cox, D.S.; Wissel, P.; Kantarjian, H.
Activity of the oral mitogen-activated protein kinase kinase inhibitor trametinib in RAS-mutant relapsed or refractory myeloid malignancies
Cancer
122
1871-1879
2016
Homo sapiens (P36507), Homo sapiens (Q02750), Homo sapiens
Manually annotated by BRENDA team
Yari, H.; Ganjalikhany, M.R.; Sadegh, H.
In silico investigation of new binding pocket for mitogen activated kinase kinase (MEK): development of new promising inhibitors
Comput. Biol. Chem.
59 Pt A
185-198
2015
Homo sapiens
Manually annotated by BRENDA team
Chapman, M.S.; Miner, J.N.
Novel mitogen-activated protein kinase kinase inhibitors
Expert Opin. Investig. Drugs
20
209-220
2011
Homo sapiens
Manually annotated by BRENDA team
Jo, C.; Cho, S.J.; Jo, S.A.
Mitogen-activated protein kinase kinase 1 (MEK1) stabilizes MyoD through direct phosphorylation at tyrosine 156 during myogenic differentiation
J. Biol. Chem.
286
18903-18913
2011
Homo sapiens (Q02750)
Manually annotated by BRENDA team
Uchida, Y.; Osaki, T.; Yamasaki, T.; Shimomura, T.; Hata, S.; Horikawa, K.; Shibata, S.; Todo, T.; Hirayama, J.; Nishina, H.
Involvement of stress kinase mitogen-activated protein kinase kinase 7 in regulation of mammalian circadian clock
J. Biol. Chem.
287
8318-8326
2012
Homo sapiens (O14733), Mus musculus (Q8CE90), Mus musculus
Manually annotated by BRENDA team
Ripple, M.; Kim, N.; Springett, R.
Acute mitochondrial inhibition by mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) 1/2 inhibitors regulates proliferation
J. Biol. Chem.
288
2933-2940
2013
Homo sapiens (P36507), Homo sapiens (Q02750)
Manually annotated by BRENDA team
Geng, P.; Ou, J.; Xie, G.; Li, J.; Zhao, X.; Xiang, L.; Liao, Y.; Wang, N.; Liang, H.
Mitogen-activated protein kinase kinase 4 gene polymorphism and cancer risk
Medicine (Baltimore)
94
e0938
2015
Homo sapiens (P45985)
Manually annotated by BRENDA team
Wang, L.; Chen, C.; Feng, S.; Lei, P.; Tian, J.
Mitogen-activated protein kinase kinase 3 induces cell cycle arrest via p38 activation mediated Bmi-1 downregulation in hepatocellular carcinoma
Mol. Med. Rep.
13
243-248
2016
Homo sapiens (P46734)
Manually annotated by BRENDA team
Kinoshita, T.; Hashimoto, T.; Sogabe, Y.; Fukada, H.; Matsumoto, T.; Sawa, M.
High-resolution structure discloses the potential for allosteric regulation of mitogen-activated protein kinase kinase 7
Biochem. Biophys. Res. Commun.
493
313-317
2017
Homo sapiens (O14733)
Manually annotated by BRENDA team
Khanam, U.; Malik, B.; Mathur, P.; Rathi, B.
Identification of novel inhibitors for mitogen-activated protein kinase kinase 4 by virtual screening and molecular dynamics simulation techniques
Int. J. Pharm. Pharm. Sci.
8
262-268
2016
Homo sapiens (P45985)
-
Manually annotated by BRENDA team
Gibson, E.S.; Woolfrey, K.M.; Li, H.; Hogan, P.G.; Nemenoff, R.A.; Heasley, L.E.; DellAcqua, M.L.
Subcellular localization and activity of the mitogen-activated protein kinase kinase 7 (MKK7) gamma isoform are regulated through binding to the phosphatase calcineurin
Mol. Pharmacol.
95
20-32
2019
Homo sapiens (O14733)
Manually annotated by BRENDA team