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Information on EC 2.7.12.2 - mitogen-activated protein kinase kinase and Organism(s) Homo sapiens and UniProt Accession Q13163

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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: Q13163
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Word Map
The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
Synonyms
mek/erk, map kinase kinase, mapkk, mek-1, extracellular-signal-regulated kinase, mapk/erk kinase, erk 1, map2k4, mitogen-activated protein kinase kinase 1, erk 2, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
ASK1
266364
-
dual specificity mitogen-activated protein kinase kinase 1
266338
-
dual specificity mitogen-activated protein kinase kinase 2
266324
-
dual specificity mitogen-activated protein kinase kinase 3
266328
-
dual specificity mitogen-activated protein kinase kinase 4
266326
-
dual specificity mitogen-activated protein kinase kinase 5
266346
-
dual specificity mitogen-activated protein kinase kinase 6
266332
-
dual specificity mitogen-activated protein kinase kinase 7
266302
-
JNKK1
266326
-
JNKK2
266302
-
MAP kinase kinase 4
266326
-
MAP2K4
266326
-
MAPK kinase
MAPK kinase 1
247
-
MAPK kinase 2
247
-
MAPK kinase 3
247
-
MAPK kinase 6
266332
-
MAPK kinase kinase-1
247
-
MAPK/ERK kinase 1
266338
-
MAPK/ERK kinase 5
266346
-
MAPKK2
266324
-
MAPKKK5
266364
-
MEK 1
247
-
MEK 2
247
-
MEK kinase 2
266368
-
MEK1/2
247
-
MEK4,
266326
-
MEK5
266346
-
MEKK-1
247
-
MEKK1
266302
-
MEKK3
266365
-
mitogen activated kinase kinase
247
-
mitogen-activated protein kinase kinase
247
-
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
247
-
mitogen-activated protein kinase kinase 7gamma1
266302
-
mitogen-activated protein kinase kinase kinase 2
266368
-
mitogen-activated protein kinase kinase kinase 3
266365
-
mitogen-activated protein kinase kinase kinase 4
266369
-
mitogen-activated protein kinase kinase kinase 5
266364
-
mitogen-activated protein kinase kinase-1
247
-
mitogen-activated protein kinase/ERK kinase kinase 3
266365
-
mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1
266338
-
mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 2
266324
-
MKK
247
-
MKK1
266338
-
MKK7gamma1
266302
-
SAPKK3
266332
-
SEK1
266326
-
serine/threonine-protein kinase PAK 7
266366
-
stress kinase mitogen-activated protein kinase kinase 7
266302
-
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 + protein
ADP + phosphoprotein
show the reaction diagram
sequences located in the N-terminus of MEK5 may be important in coupling GTPase signaling molecules to the MEK5 protein kinase cascade
-
-
-
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 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 + protein
ADP + phosphoprotein
show the reaction diagram
Q13163
sequences located in the N-terminus of MEK5 may be important in coupling GTPase signaling molecules to the MEK5 protein kinase cascade
-
-
-
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
INHIBITOR
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
-
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
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doxycycline
-
induces expression of HA-MEK1
growth factor interleukin-3
-
activates
-
additional information
-