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Information on EC 2.7.12.2 - mitogen-activated protein kinase kinase and Organism(s) Homo sapiens and UniProt Accession Q02750

for references in articles please use BRENDA:EC2.7.12.2

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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.

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 1
-
MAPK kinase
-
MAPK/ERK kinase 1
-
mitogen-activated protein kinase kinase 1
-
mitogen-activated protein kinase/extracellular signal-regulated 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 4
-
dual specificity mitogen-activated protein kinase kinase 5
-
dual specificity mitogen-activated protein kinase kinase 6
-
dual specificity mitogen-activated protein kinase kinase 7
-
MAP kinase kinase 4
-
MAPK kinase
MAPK kinase 1
-
-
MAPK kinase 2
-
-
MAPK kinase 3
-
MAPK kinase 6
-
MAPK kinase 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 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
LITERATURE
COMMENTARY hide
Reversibility
r=reversible
ir=irreversible
?=not specified
ATP + a protein
ADP + a phosphoprotein
show the reaction diagram
ATP + ERK1
ADP + phosphorylated ERK1
show the reaction diagram
Substrates: phosphorylation of extracellular signal-regulated kinase 1
Products: -
?
ATP + ERK2
ADP + phosphorylated ERK2
show the reaction diagram
ATP + K52R-[ERK2]
ADP + phospho-K52R-[ERK2]
show the reaction diagram
Substrates: catalytically inactive ERK2 in which lysine-52 is substituted with arginine
Products: -
?
ATP + MyoD
ADP + phospharylated MyoD
show the reaction diagram
ATP + protein
ADP + phosphoprotein
show the reaction diagram
Substrates: enzyme is involved on MAPK signal transduction pathway
Products: -
?
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
Substrates: JNK activation
Products: -
?
ATP + ERK
ADP + phospho-ERK
show the reaction diagram
-
Substrates: -
Products: -
?
ATP + ERK
ADP + phosphorylated ERK
show the reaction diagram
-
Substrates: ERK phosphorylation by MEK1/2
Products: -
?
ATP + ERK1
ADP + phosphorylated ERK1
show the reaction diagram
Substrates: MEK2 protein stimulates Thr and Tyr phosphorylation on ERK1 and concomitantly activates ERK1 kinase activity more than 100-fold
Products: -
?
ATP + ERK1/2
ADP + phosphorylated ERK1/2
show the reaction diagram
-
Substrates: -
Products: -
?
ATP + ERK2
ADP + phosphorylated ERK2
show the reaction diagram
Substrates: phosphorylation of extracellular signal-regulated kinase 2
Products: -
?
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
Substrates: -
Products: -
?
ATP + JNK1
ADP + phosphorylated JNK1
show the reaction diagram
ATP + K53M-[p38alpha]
ADP + phospho-K53M-[p38alpha]
show the reaction diagram
Substrates: catalytically inactive p38alpha in which lysine-53 is substituted with methionine
Products: -
?
ATP + MKK4
ADP + phosphorylated MKK4
show the reaction diagram
Substrates: -
Products: -
?
ATP + p38
ADP + ?
show the reaction diagram
Substrates: -
Products: -
?
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
-
Substrates: -
Products: -
?
ATP + p38 MAP kinase
ADP + ?
show the reaction diagram
Substrates: phosphorylates and activates p38 MAP kinase
Products: -
?
ATP + p38/MPK2 kinase
ADP + ?
show the reaction diagram
Substrates: phosphorylates and specifically activates the p38/MPK2 subgroup of the mitogen-activated protein kinase superfamily
Products: -
?
ATP + p38alpha
ADP + phosphorylated p38alpha
show the reaction diagram
Substrates: MKK6 phosphorylates p38 MAPK on Thr180 and Tyr182, the sites of phosphorylation that activate p38 MAPK
Products: -
?
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
LITERATURE
COMMENTARY hide
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
ATP + a protein
ADP + a phosphoprotein
show the reaction diagram
ATP + ERK1
ADP + phosphorylated ERK1
show the reaction diagram
Substrates: phosphorylation of extracellular signal-regulated kinase 1
Products: -
?
ATP + ERK2
ADP + phosphorylated ERK2
show the reaction diagram
Substrates: -
Products: -
?
ATP + MyoD
ADP + phospharylated MyoD
show the reaction diagram
Substrates: phosphorylation at Tyr156, activated MEK1 associates with MyoD
Products: -
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
Substrates: enzyme is involved on MAPK signal transduction pathway
Products: -
?
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
Substrates: JNK activation
Products: -
?
ATP + ERK
ADP + phospho-ERK
show the reaction diagram
-
Substrates: -
Products: -
?
ATP + ERK
ADP + phosphorylated ERK
show the reaction diagram
-
Substrates: ERK phosphorylation by MEK1/2
Products: -
?
ATP + ERK1/2
ADP + phosphorylated ERK1/2
show the reaction diagram
-
Substrates: -
Products: -
?
ATP + ERK2
ADP + phosphorylated ERK2
show the reaction diagram
Substrates: phosphorylation of extracellular signal-regulated kinase 2
Products: -
?
ATP + JNK
ADP + JNK phosphate
show the reaction diagram
Substrates: the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer, physiologic effects, overview
Products: -
?
ATP + JNK
ADP + phospho-JNK
show the reaction diagram
Substrates: the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer, physiologic effects, overview
Products: -
?
ATP + p38
ADP + p38 phosphate
show the reaction diagram
Substrates: the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer, physiologic effects, overview
Products: -
?
ATP + p38
ADP + phospho-p38
show the reaction diagram
ATP + p38alpha
ADP + phosphorylated p38alpha
show the reaction diagram
Substrates: MKK6 phosphorylates p38 MAPK on Thr180 and Tyr182, the sites of phosphorylation that activate p38 MAPK
Products: -
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
ATP + Smad3
ADP + phosphorylated Smad3
show the reaction diagram
-
Substrates: 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
Products: -
?
additional information
?
-
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
MIIC
i.e. MEK inhibitor I, the MEK1/2 inhibitor causes NAD(H) reduction, heme oxidation, and decreased oxygen consumption
PD184352
a MEK-specific inhibitor
PD198306
an orally active MEK1/2 inhibitor, acting as an uncoupler
PD98059
the MEK1/2 inhibitor causes NAD(H) reduction, heme oxidation, and decreased oxygen consumption
trametinib
a mitogen-activated protein kinase kinase 1 (MEK1)/MEK2 inhibitor with activity against multiple myeloid cell lines at low nanomolar concentrations, preferential activity among RAS-mutated myeloid malignancies. During clinical oral treatment, most commonly reported treatment-related adverse events are diarrhea, rash, nausea, and increased alanine aminotransferase levels, repeated cycles of trametinib are well tolerated with manageable or reversible toxicities, overview
U0126
the MEK1/2 inhibitor causes NAD(H) reduction, heme oxidation, and decreased oxygen consumption
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/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
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
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
-