Information on EC 2.7.12.2 - mitogen-activated protein kinase kinase and Organism(s) Homo sapiens and UniProt Accession Q9P286

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Homo sapiens
UNIPROT: Q9P286


The taxonomic range for the selected organisms is: Homo sapiens

The enzyme appears in selected viruses and cellular organisms

EC NUMBER
COMMENTARY hide
2.7.12.2
-
RECOMMENDED NAME
GeneOntology No.
mitogen-activated protein kinase kinase
-
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
-
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
SwissProt
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
evolution
-
the enzyme is a member of the MAP kinase family
malfunction
metabolism
physiological function
additional information
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
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 + phospho-JNK
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 SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
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
O14733, P45985
the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer, physiologic effects, overview
-
-
?
ATP + JNK
ADP + phospho-JNK
show the reaction diagram
O14733, P45985
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
O14733, P45985
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
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
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
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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
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AS-703026
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a MEK1–2 inhibitor, binds in the allosteric site of MEK1. For A-375 cells, AS-703026 has a growth IC50 of 4 nM
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AS703026
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AZD8330
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BAY 869766
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i.e. RDEA119
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capecitabine
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CH-498755/RO498755
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a MEK1/2 inhibitor
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CH4987655
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CI-1040
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E6201
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blocks proliferation of many of the cell lines typically used in testing MEK inhibitors, such as Colo205 and MiaPaca-2
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GDC0973
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-
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GSK1120212
-
-
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LL-Z1640-2
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a MEK1 inhibitor, which shows reasonable MEK inhibition but a very short half-life
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MEK162
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-
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MIIC
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i.e. MEK inhibitor I, the MEK1/2 inhibitor causes NAD(H) reduction, heme oxidation, and decreased oxygen consumption
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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
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a MEK-specific inhibitor
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PD184352/CI-1040
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a allosteric, non-ATP competitive MEK inhibitor
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PD198306
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an orally active MEK1/2 inhibitor, acting as an uncoupler
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PD318088
-
-
PD98059
pemetrexed
-
-
RDEA119
-
-
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RDEA436
-
-
-
refametinib
-
-
-
RO4987655
-
-
-
RO5126766
-
-
-
selumetinib
-
siRNA
-
TAK733
-
-
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temozolomide
-
-
trametinib
-
U0126
XL-518/GDC-0973
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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
-
Michaelis-Menten kinetics
-
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
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0.000019 - 0.000047
BAY 869766
-
0.0000052
CH4987655
Homo sapiens
-
inhibition of MEK1, pH and temperature not specified in the publication
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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
7
-
assay at
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
25
-
assay at
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
-
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
-
colorectal cancer cell line
Manually annotated by BRENDA team
-
medium expression
Manually annotated by BRENDA team
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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
-
strongest expression in the human tissue panel
Manually annotated by BRENDA team
-
weak 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
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activated MEK1 associates with MyoD in the nucleus of differentiating myoblasts
Manually annotated by BRENDA team
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choroidal melanoma cell line
Manually annotated by BRENDA team
-
weak expression
Manually annotated by BRENDA team
-
weak expression
Manually annotated by BRENDA team
-
airway; bronchial airway
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
-
human pancreatic, lung, breast, testicle, and colorectal cancer cell lines
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
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
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
phosphoprotein
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
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
-
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
proteolytic inactivation by anthrax lethal factor
-
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
A549 cells transfected with wild-type or constitutively active MEK1 cDNA, both MEK1 expressions lead to increased SMAD3 expression and ERK phosphorylation; MEK1, sequence comparison
-
expressed in COS7 cells
-
expression in COS and 293 cells
-
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
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HA-MEK1 cloned into pRevTRE, HA-tagged MEK1 expressed in HeLa cells
-
isolation of cDNA
MKK4, DNA and amino acid sequence determination, the gene is located on chromosome 17
overexpression in COS cells
-
recombinant coexpression of His6-tagged constitutively active MEK1 mutant S218E/S222E and GST-MyoD protein
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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
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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
-
ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
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
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