Information on EC 2.7.12.2 - mitogen-activated protein kinase kinase and Organism(s) Mus musculus and UniProt Accession O09110

for references in articles please use BRENDA:EC2.7.12.2
Word Map on EC 2.7.12.2
Please wait a moment until all data is loaded. This message will disappear when all data is loaded.
Specify your search results
Select one or more organisms in this record:
This record set is specific for:
Mus musculus
UNIPROT: O09110
Show additional data
Do not include text mining results
Include (text mining) results
Include results (AMENDA + additional results, but less precise)


The taxonomic range for the selected organisms is: Mus musculus

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
malfunction
metabolism
-
signal transduction pathways are integral components of the developmental regulatory network that guides progressive cell fate determination. Essential enzymes MKK4 and MKK7 are upstream kinases of the mitogen-activated protein kinases (MAPKs), responsible for channeling physiological and environmental signals to their cellular responses. In vitro, MKK4 and MKK7 are dispensable for in embryonic stem cell self-renewal and pluripotency maintenance, but they exhibit unique signaling and functional properties in differentiation. MKK4 and MKK7 complemented each other in activation of the JNK-c-Jun cascades and loss of both leads to senescence upon cell differentiation.On the other hand, MKK4 and MKK7 have opposite effects on activation of the p38 cascades during differentiation, MKK4 is required for cardiomyocyte differentiation, while MKK7 represses it
physiological function
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
-
enzyme is the major activator for p38
-
-
?
ATP + c-Jun N-terminal kinase
ADP + phosphorylated c-Jun N-terminal kinase
show the reaction diagram
-
JNK activation
-
-
?
ATP + ERK
ADP + phosphorylated ERK
show the reaction diagram
ATP + Erk-1 gene product
ADP + phosphorylated Erk-1 gene product
show the reaction diagram
phosphorylation primarily on a tyrosine residue and, to a lesser extent, on a threonine
-
?
ATP + JNK
ADP + phopsho-JNK
show the reaction diagram
the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer acting as a metastasis suppressor, overview
-
-
?
ATP + JNK
ADP + phospho-JNK
show the reaction diagram
ATP + JNK
ADP + phosphorylated JNK
show the reaction diagram
ATP + myelin basic protein kinase
ADP + phosphorylated myelin basic protein kinase
show the reaction diagram
-
-
-
?
ATP + p38
ADP + phospho-p38
show the reaction diagram
ATP + protein
ADP + phosphoprotein
show the reaction diagram
ATP + [ERK2 substrate peptide]
ADP + [ERK2 substrate peptide] phosphate
show the reaction diagram
-
MEK1
-
-
?
ATP + [myelin basic protein substrate peptide]
ADP + [myelin basic protein substrate peptide] phosphate
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 + protein
ADP + phosphoprotein
show the reaction diagram
-
enzyme is the major activator for p38
-
-
?
ATP + c-Jun N-terminal kinase
ADP + phosphorylated c-Jun N-terminal kinase
show the reaction diagram
-
JNK activation
-
-
?
ATP + ERK
ADP + phosphorylated ERK
show the reaction diagram
-
phosphorylation by MEK activates ERK, which plays a role in pain induction modulating the A-type currents of potassium channels in neurons, ERK plays a central role in nocireceptive sensitization in the spinal cord
-
-
?
ATP + JNK
ADP + phopsho-JNK
show the reaction diagram
P47809, Q8CE90
the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer acting as a metastasis suppressor, overview
-
-
?
ATP + JNK
ADP + phospho-JNK
show the reaction diagram
P47809, Q8CE90
the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer acting as a metastasis suppressor, overview
-
-
?
ATP + JNK
ADP + phosphorylated JNK
show the reaction diagram
ATP + p38
ADP + phospho-p38
show the reaction diagram
P47809, Q8CE90
the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer acting as a metastasis suppressor, overview
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
additional information
?
-
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
1-(2,3-dihydroxypropyl)-4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
-
1-(3-cyanopropyl)-4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
-
1-allyl-4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
-
1-ethyl-4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
-
1-methyl-4-(2-naphthylamino)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
-
3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzamide
-
4-(2-fluoro-4-iodoanilino)-1-(2-hydroxyethyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
-
4-(2-fluoro-4-iodoanilino)-1-(3-hydroxypropyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
-
4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
-
4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid
-
4-(2-fluoro-4-iodoanilino)-1-[2-(2-methoxyethoxy)ethyl]-6-oxo-1,6-dihydro-3-pyridinecarboxamide
-
4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
-
4-(2-fluoro-4-iodoanilino)-6-oxo-1-propyl-1,6-dihydro-3-pyridinecarboxamide
-
4-(2-fluoro-4-iodoanilino)-N,1-dimethyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
-
4-(2-fluoro-4-iodoanilino)-N,N,1-trimethyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
-
4-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
-
4-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
-
4-(2-fluoro-4-iodoanilino)-N-(3-hydroxypropyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
-
4-(2-fluoro-4-methylanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
-
4-(2-fluoro-4-methylsulfanylphenylamino)-1-methyl-6-oxo-1,6-dihydro-3 -pyridinecarboxamide
-
4-(3,4-dichlorophenylamino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
-
4-(4-bromo-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
-
4-(4-bromo-2-fluoroanilino)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
-
4-(4-cyano-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
-
4-(4-ethyl-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
-
4-(4-ethynyl-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
-
4-amino-1-[3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl]-2-hydroxybutan-1-one
-
4-[2-fluoro-4-(1,1,2,2,3,3,4,4,4-nonafluorobutyl)anilino]-1-methyl-6-oxo-1,6 -dihydro-3-pyridinecarboxamide
-
4-[2-fluoro-4-(3-hydroxypropyl)anilino]-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
-
4-[3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl]-3-hydroxy-4-oxobutanamide
-
Cocoa procyanidin B2
-
procyanidin B2 suppresses TPA-induced phosphorylation of MEK, ERK, and p90RSK in JB6 P+ cells, suppresses JB6 P+ cell transformation by inhibiting mitogen-activated protein kinase kinase, molecular mechanism, overview
Cocoa procyanidins
-
suppresses JB6 P+ cell transformation by inhibiting mitogen-activated protein kinase kinase, molecular mechanisms of the chemopreventive potential of cocoa and its active ingredients, overview
-
ethyl 4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate
-
PD098059
-
MEK1 inhibitor
PD98059
-
inhibitor specific for MEK/ERK activation, granulocyte/macrophage colony number is decreased by ca. 60%
siRNA
-
knockdown of MEK, HSCs give rise to Mac-1+ myeloid cells less efficiently than control HSCs
-
tert-butyl [5-(aminocarbonyl)-4-(2-fluoro-4-iodoanilino)-2-oxo-1(2H)-pyridinyl]acetate
-
U0126
[5-(aminocarbonyl)-4-(2-fluoro-4-iodoanilino)-2-oxo-1(2H)-pyridinyl]acetic acid
-
additional information
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
additional information
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.01
1-(2,3-dihydroxypropyl)-4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
Mus musculus;
P31938, Q63932
above, cascade IC50
0.00489 - 0.0049
1-(3-cyanopropyl)-4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
0.000091 - 0.01
1-allyl-4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
0.001
1-ethyl-4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
0.003
1-methyl-4-(2-naphthylamino)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
0.0000174
3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzamide
Mus musculus;
P31938, Q63932
cascade IC50
0.00254 - 0.005
4-(2-fluoro-4-iodoanilino)-1-(2-hydroxyethyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
0.003
4-(2-fluoro-4-iodoanilino)-1-(3-hydroxypropyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
0.000004 - 0.000023
4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
0.000425 - 0.005
4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid
0.00113
4-(2-fluoro-4-iodoanilino)-1-[2-(2-methoxyethoxy)ethyl]-6-oxo-1,6-dihydro-3-pyridinecarboxamide
0.0001 - 0.00063
4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
0.00043 - 0.00254
4-(2-fluoro-4-iodoanilino)-6-oxo-1-propyl-1,6-dihydro-3-pyridinecarboxamide
0.000195
4-(2-fluoro-4-iodoanilino)-N,1-dimethyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
0.000627 - 1.2
4-(2-fluoro-4-iodoanilino)-N,N,1-trimethyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
0.000005 - 0.000018
4-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
0.00018 - 0.00021
4-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
0.000061 - 0.000095
4-(2-fluoro-4-iodoanilino)-N-(3-hydroxypropyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
0.00297
4-(2-fluoro-4-methylanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
0.00015 - 0.00036
4-(2-fluoro-4-methylsulfanylphenylamino)-1-methyl-6-oxo-1,6-dihydro-3 -pyridinecarboxamide
0.0039 - 0.00572
4-(3,4-dichlorophenylamino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
0.000093 - 0.00191
4-(4-bromo-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
0.00012 - 0.00363
4-(4-bromo-2-fluoroanilino)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
0.01
4-(4-cyano-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
0.00011 - 0.00262
4-(4-ethyl-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
0.000021 - 0.0001
4-(4-ethynyl-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
0.0000842
4-amino-1-[3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl]-2-hydroxybutan-1-one
Mus musculus;
P31938, Q63932
cascade IC50
0.01
4-[2-fluoro-4-(1,1,2,2,3,3,4,4,4-nonafluorobutyl)anilino]-1-methyl-6-oxo-1,6 -dihydro-3-pyridinecarboxamide
0.01
4-[2-fluoro-4-(3-hydroxypropyl)anilino]-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
0.0000012
4-[3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl]-3-hydroxy-4-oxobutanamide
Mus musculus;
P31938, Q63932
cascade IC50
0.000016 - 0.000046
CI-1040
0.000063 - 0.000669
ethyl 4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate
0.00067
ethyl 4-(2-fuoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate
Mus musculus;
P31938, Q63932
cascade IC50
-
0.01
tert-butyl [5-(aminocarbonyl)-4-(2-fluoro-4-iodoanilino)-2-oxo-1(2H)-pyridinyl]acetate
Mus musculus;
P31938, Q63932
inhibition of the Raf-MEK-ERK cascade in an isolated enzyme assay
0.01
[5-(aminocarbonyl)-4-(2-fluoro-4-iodoanilino)-2-oxo-1(2H)-pyridinyl]acetic acid
Mus musculus;
P31938, Q63932
above, cascade IC50
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.2
-
assay at
7.4
assay at
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
30
-
assay at
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
Mkk4 transcripts confined to the central nervous system in early embryogenesis, up to embryonic day 10
Manually annotated by BRENDA team
17 days post coitum, expression of ASK1 in developing skin, cartilage and bone
Manually annotated by BRENDA team
high expression of MKK4 in the epithelium but not in the stromal compartment
Manually annotated by BRENDA team
-
epididymal spermatozoa, 60000 Da variant of MAP3K11, may be a result of proteolytic cleavage of the longer form
Manually annotated by BRENDA team
-
93000 Da form
Manually annotated by BRENDA team
-
93000, 70000, 40000, 23000 Da forms, first MAP3K11 expression detectable at day-14, higher levels of expression at day-30 and day-36
Manually annotated by BRENDA team
additional information
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
-
developing spermatids and epididymal spermatozoa, colocalization of MAP3K11 and CRISP2
-
Manually annotated by BRENDA team
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
23000
-
fragment of MAP3K11, Western blot analysis
44000
-
fragment of MAP3K11, Western blot analysis
44500
-
x * 44500
60000
-
fragment of MAP3K11 in epididymal sperm, Western blot analysis
69200
x * 69200
70000
-
fragment of MAP3K11, Western blot analysis
71000
x * 71000
93000
-
MAP3K11 in somatic tissue, Western blot analysis
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
phosphoprotein
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
MEK1, to a resolution of 2.8 A
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
proteolytic inactivation by anthrax lethal factor
-
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
expressed in COS7 cells
-
constitutive active form of MEK1 and siRNA-targeting MEK1 cloned into MSCV-IRES-GFP vector, retrovirally transduced to HSCs and injected into sublethally irradiated RAG2-/- (CD42.2) mice
-
expression in HEK293 cells
gene Mkk4, expression in ovarian cancer cell line SKOV3ip.1, that lacks endogenous MKK4, leading to a decrease in overt metastatic implants on several tissues and organs
gene MKK4, real-time RT-PCR expression analysis
-
gene MKK7, real-time RT-PCR expression analysis
-
ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
drug development
design and synthesis of a new series of MEK1 inhibitors, the 4-anilino-5-carboxamido-2-pyridones
medicine
acts as tumor suppressor, but can also promote tumor growth, plays a role in liver formation, the immune system and cardiac hypertrophy, contributes to optimal c-Jun N-terminal kinase activation
additional information