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Information on EC 2.7.11.25 - mitogen-activated protein kinase kinase kinase and Organism(s) Homo sapiens and UniProt Accession O95382

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IUBMB Comments
This enzyme phosphorylates and activates its downstream protein kinase, EC 2.7.12.2, mitogen-activated protein kinase kinase (MAPKK) but requires MAPKKKK for activation. Some members of this family can be activated by p21-activated kinases (PAK/STE20) or Ras. While c-Raf and c-Mos activate the classical MAPK/ERK pathway, MEKK1 and MEKK2 preferentially activate the c-Jun N-terminal protein kinase(JNK)/stress-activated protein kinase (SAPK) pathway . 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: O95382
Word Map
  • 2.7.11.25
  • pregnancy
  • melanoma
  • amniotic
  • proto-oncogene
  • cirrhosis
  • nf-kappab
  • radioimmunoassay
  • chorionic
  • yolk
  • amniocentesis
  • oocyte
  • domain-like
  • necroptosis
  • ultrasound
  • gonadotropin
  • fetuses
  • dominant-negative
  • trimester
  • mating
  • receptor-interacting
  • pheromone
  • sorafenib
  • ultrasonography
  • ikappab
  • endoderm
  • singleton
  • carcinoembryonic
  • trisomy
  • serine-threonine
  • spina
  • culinaris
  • teratoma
  • bifida
  • vemurafenib
  • antenatal
  • multikinase
  • estriol
  • ha-ras
  • ras-induced
  • seminoma
  • ikkbeta
  • pik3ca
  • kinase-inactive
  • ras-dependent
  • oncofetal
  • brafv600e
  • p38alpha
  • analysis
  • immunosensors
  • medicine
  • chemoembolization
  • beta-hcg
The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
Synonyms
b-raf, c-raf, mekk1, c-mos, ste11, apoptosis signal-regulating kinase 1, mekk3, mapkkk, mekk2, a-raf, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
apoptosis signal-regulating kinase 1
247
-
apoptosis signal-regulating kinase 2
247
-
ASK2
247
-
B-Raf
247
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B-Raf kinase
247
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BRAF
247
-
BRAF protein serine/threonine kinase
247
-
c-mos
-
-
-
-
C-Raf
247
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cancer osaka thyroid
247
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COT30-397
247
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COT30-467
247
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Dual leucine zipper bearing kinase
-
-
-
-
dual leucine zipper-bearing kinase
247
-
extracellular signal-regulated kinase kinase kinase-1
247
-
GCKR
247
-
germinal center kinase-related enzyme
247
-
HsNIK
-
-
-
-
Leucine-zipper protein kinase
-
-
-
-
MAP 3-kinase
MAP kinase kinase kinase
247
-
MAP kinase kinase kinase 1
247
-
MAP kinase kinase kinase 3
278344
-
MAP/ERK kinase kinase 1
247
-
MAP3K
MAP3K7
247
-
MAPK kinase kinase
247
-
MAPK-upstream kinase
-
-
-
-
MAPKKK
MAPKKK6
MEK kinase 1
247
-
MEKK1
MEKK3
MEKK4
mitogen-activated protein kinase kinase kinase
247
-
mitogen-activated protein kinase kinase kinase 1
247
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mitogen-activated protein kinase kinase kinase 3
266365
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mitogen-activated protein kinase kinase kinase 6
266308
-
mitogen-activated protein kinase kinase kinase kinase
247
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mitogen-activated protein kinase kinase kinase-1
247
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mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 1
307496
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mitogen-activated protein kinase/extracellular-regulated kinase kinase kinase-3
247
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mixed lineage kinase 4
308606
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MKKK
247
-
MLK-like mitogen-activated protein triple kinase
247
-
MLK3
247
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MLK4
308606
-
MLTKalpha
247
-
Mos
247
-
MTK1
247
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MUK
-
-
-
-
NF-kappa beta-inducing kinase
-
-
-
-
Raf
247
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Serine/threonine protein kinase NIK
-
-
-
-
TAO
247
-
TAO2-1
247
-
TGFbeta-activated kinase 1
247
-
TPL-2
247
-
transforming growth factor beta-activated kinase 1
247
-
TTP kinase
307496
-
ZPK
-
-
-
-
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
ATP + a protein = ADP + a phosphoprotein
show the reaction diagram
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
phospho group transfer
-
-
SYSTEMATIC NAME
IUBMB Comments
ATP:protein phosphotransferase (MAPKKKK-activated)
This enzyme phosphorylates and activates its downstream protein kinase, EC 2.7.12.2, mitogen-activated protein kinase kinase (MAPKK) but requires MAPKKKK for activation. Some members of this family can be activated by p21-activated kinases (PAK/STE20) or Ras. While c-Raf and c-Mos activate the classical MAPK/ERK pathway, MEKK1 and MEKK2 preferentially activate the c-Jun N-terminal protein kinase(JNK)/stress-activated protein kinase (SAPK) pathway [2]. 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
146702-84-3
-
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 + ASK1
ADP + phosphorylated ASK1
show the reaction diagram
-
ASK2 activates ASK1 by direct phosphorylation
-
-
?
ATP + cdc42
ADP + phosphorylated cdc42
show the reaction diagram
-
-
-
-
?
ATP + ERK
ADP + phosphorylated ERK
show the reaction diagram
ATP + ERK5
ADP + phosphorylated ERK5
show the reaction diagram
ATP + GSK3beta
ADP + phosphorylated GSK3beta
show the reaction diagram
-
regulates phosphorylation at serine 9
-
-
?
ATP + IKKalpha
ADP + phospho-IKKalpha
show the reaction diagram
-
-
-
?
ATP + JNK
ADP + phosphorylated JNK
show the reaction diagram
ATP + MEK
ADP + phosphorylated MEK
show the reaction diagram
ATP + Mek1
ADP + phospho-Mek1
show the reaction diagram
-
activation
-
-
?
ATP + MEK1
ADP + phosphorylated MEK1
show the reaction diagram
ATP + MEK2
ADP + phospho-MEK2
show the reaction diagram
-
activation
-
-
?
ATP + MEK2
ADP + phosphorylated MEK2
show the reaction diagram
ATP + MEK5
ADP + phosphorylated MEK5
show the reaction diagram
-
MEKK3 and MEK5 form a heterodimer via PB1-PB1 domain interaction, residues Lys 7 and Arg 5 play important roles in the interaction with MEK5 PB1, MEKK3 PB1 binds MEK5 PB1 tightly with a Kd of about 10-8 M
-
-
?
ATP + MKK3
ADP + phosphorylated MKK3
show the reaction diagram
ATP + MKK4
ADP + phosphorylated MKK4
show the reaction diagram
ATP + MKK6
ADP + phosphorylated MKK6
show the reaction diagram
ATP + MKK7
ADP + phosphorylated MKK7
show the reaction diagram
ATP + myelin basic protein
ADP + phosphorylated myelin basic protein
show the reaction diagram
-
-
-
-
?
ATP + p38
ADP + phosphorylated p38
show the reaction diagram
ATP + Rac
ADP + phosphorylated Rac
show the reaction diagram
-
-
-
-
?
ATP + tristetraprolin
ADP + phosphorylated tristetraprolin
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 + a protein
ADP + a phosphoprotein
show the reaction diagram
Q99759
-
-
-
?
ATP + ERK
ADP + phosphorylated ERK
show the reaction diagram
ATP + ERK5
ADP + phosphorylated ERK5
show the reaction diagram
-
substrate of MEKK2 and MEKK3, activation of the ERK-dependent signaling pathway
-
-
?
ATP + IKKalpha
ADP + phospho-IKKalpha
show the reaction diagram
Q5TCX8
-
-
-
?
ATP + JNK
ADP + phosphorylated JNK
show the reaction diagram
-
i.e. Jun amino terminal kinase
-
-
?
ATP + MEK
ADP + phosphorylated MEK
show the reaction diagram
ATP + Mek1
ADP + phospho-Mek1
show the reaction diagram
-
activation
-
-
?
ATP + MEK1
ADP + phosphorylated MEK1
show the reaction diagram
Q6VAB6
activation by MEKK3 of MAPK signaling pathways
-
-
?
ATP + MEK2
ADP + phospho-MEK2
show the reaction diagram
-
activation
-
-
?
ATP + MEK2
ADP + phosphorylated MEK2
show the reaction diagram
Q6VAB6
activation by MEKK3 of MAPK signaling pathways
-
-
?
ATP + MKK3
ADP + phosphorylated MKK3
show the reaction diagram
ATP + MKK4
ADP + phosphorylated MKK4
show the reaction diagram
-
activation of the Jun N-terminal kinase, JNK, pathway leading to apoptosis
-
-
?
ATP + MKK6
ADP + phosphorylated MKK6
show the reaction diagram
ATP + MKK7
ADP + phosphorylated MKK7
show the reaction diagram
ATP + tristetraprolin
ADP + phosphorylated tristetraprolin
show the reaction diagram
Q13233
-
-
-
?
additional information
?
-
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Mn2+
-
preferred divalent cation as ATP metal cofactor
Zn2+
-
2 Zn2+ are bound at region CR1
additional information
-
no or nearly no activity with Ni2+, Zn2+, Co2+, and Cu2+
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
(E)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)-phenyl)-3-(2-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)vinyl)-4-methylbenzamide
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88,5% inhibition of TAK1 at 500 nM
14-3-3
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the binding site is on the CR2 domain of the enzyme
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2-amino-1-{4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}-2-[4-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]ethanone
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3-((1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide
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a type II inhibitor, 97.1% inhibition of TAK1 at 500 nM
3-[(6,7-dimethoxyquinazolin-4-yl)oxy]-N-{4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}-4-methylbenzamide
-
83.7% inhibition of TAK1 at 0.001 mM
4-methyl-3-{[6-(methylamino)pyrimidin-4-yl]oxy}-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]benzamide
-
selectivity analysis with diverse enzymes, overview. 29.3% Inhibition of TAK1 at 0.001 mM
4-methyl-3-{[6-(methylamino)pyrimidin-4-yl]oxy}-N-[3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl]benzamide
-
selectivity analysis with diverse enzymes, overview. 7.0% Inhibition of TAK1 at 0.001 mM
4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)benzamide
-
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4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[2-(1H-pyrrolo[2,3-b]pyridin-4-yl)ethyl]benzamide
-
-
4-methyl-N-[3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl]-3-(7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)benzamide
-
29.3% inhibition of TAK1 at 0.001 mM
4-methyl-N-{4-[(1-methylpiperidin-4-yl)oxy]-3-(trifluoromethyl)phenyl}-3-[(E)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)ethenyl]benzamide
-
-
4-[(4-ethylpiperazin-1-yl)methyl]-N-{3-[2-(1H-pyrrolo[2,3-b]pyridin-4-yl)ethyl]phenyl}-3-(trifluoromethyl)benzamide
-
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4-[5-({4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}carbamoyl)-2-methylphenoxy]-N-methylpyridine-2-carboxamide
-
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BAY 43-9006
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c-Raf inhibitor, shows promising response rate in patients with primary renal cell carcinomas
BIRB796
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CEP-1347
-
inhibits MLKs and is well tolerated in human trials, does not perform in trials for neurodegenerative disorders such as Parkinson´s disease
EGTA
-
negative regulation of COT
farnesylthiosalicylic acid
-
a Ras antagonist, inhibits the wild-type and V599E mutant enzyme in vivo and in vitro
hKSR-2
i.e. human kinase suppressor of ras 2, selectively inhibits MEKK3-activated MAP kinase and NF-kappaB pathways in inflammation, selectively inhibits Cot, no inhibition of MEKK4, TAK1, and Ras-Raf
-
imatinib
-
-
N-[3-(2-cyanopropan-2-yl)phenyl]-4-methyl-3-[(E)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)ethenyl]benzamide
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N-[3-(2-cyanopropan-2-yl)phenyl]-4-methyl-3-[2-(1H-pyrrolo[2,3-b]pyridin-4-yl)ethyl]benzamide
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N-[4-{[3-(dimethylamino)pyrrolidin-1-yl]methyl}-3-(trifluoromethyl)phenyl]-4-methyl-3-[(E)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)ethenyl]benzamide
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N-{4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}-3-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)benzamide
-
75.6% inhibition of TAK1 at 0.001 mM
N-{4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}-3-[(E)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)ethenyl]benzamide
-
-
N-{4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}-3-[2-(1H-pyrrolo[2,3-b]pyridin-4-yl)ethyl]benzamide
-
-
N-{4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}-4-methyl-3-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)benzamide
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77.7% inhibition of TAK1 at 0.001 mM; 86.5% inhibition of TAK1 at 0.001 mM
N-{4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}-4-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-ylmethoxy)benzamide
-
59.6% inhibition of TAK1 at 0.001 mM
N-{4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}-4-methyl-3-[(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]benzamide
-
57.7% inhibition of TAK1 at 0.001 mM
N-{4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}-4-methyl-3-[2-(1H-pyrrolo[2,3-b]pyridin-4-yl)ethyl]benzamide
-
74.3% inhibition of TAK1 at 0.001 mM
N-{4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}-4-methyl-3-{[2-(methylamino)pyrimidin-4-yl]oxy}benzamide
-
77.7% inhibition of TAK1 at 0.001 mM
N-{4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}-4-methyl-3-{[6-(methylamino)pyrimidin-4-yl]oxy}benzamide
-
78.5% inhibition of TAK1 at 0.001 mM
N-{4-[(4-ethylpiperazin-1-yl)methyl]phenyl}-4-methyl-3-[(E)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)ethenyl]benzamide
-
-
nilotinib
-
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p105
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inhibition of COT activity, but binding of p105 increases the solubility and stability of COT
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PD98059
-
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Protein phosphatase 2A
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PP2A, dephosphorylates and inactivates MEKK3
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RNAi
-
-
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shRNA
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silences GCKR expression
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siRNA
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MEKK1-specific siRNA inhibits with adenovirus-mediated overexpression of melanoma differentiation-associated gene-7-mediated MEKK1 cleavage
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sorafenib
-
-
thioredoxin
-
the reduced form binds to the N-terminus
U0126
-
inhibits MEKK2/MEKK3-dependent ERK5 phosphorylation/activation in vitro and in vivo
additional information
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
Gadd45alpha
-
causes an increase in the activation of both the p38 and JNK pathways, but not the ERK pathway, upregulates MEKK4’s kinase activity to a lesser degree as compared to Gadd45beta or Gadd45gamma
-
Gadd45beta
-
causes an increase in the activation of both the p38 and JNK pathways, but not the ERK pathway
-
Gadd45gamma
-
causes an increase in the activation of both the p38 and JNK pathways, but not the ERK pathway
-
H2O2
-
phosphorylation of ASK2 at Thr807 increases in response to H2O2 in cells co-expressing ASK2 and a ASK1 kinase-negative mutant, whereas singly expressed ASK2 does not respond to H2O2. ASK2 kinase-negative mutant co-expressed with ASK1 kinase-negative mutant is not phosphorylated at Thr807 irrespective of the H2O2 treatment
methylglyoxal
-
induces the PI3K/PKC/Raf-1-independent MEK/ERK signaling pathway by activation of MEKK1, accumulates in case of diabetes
Ras
-
reactive oxygene species
-
the enzyme is oxidative stress-induced
-
TGFbeta
-
TGFbeta-activated kinase 1
-
TNF-alpha
-
treatment with TNF-alpha dissociates the inhibitor thioredoxin from the enzyme's N-terminus
-
Wnt3a
-
induces GCKR kinase activity. APC, Asef, and Rac are required for Wnt signaling to activate GCKR
-
additional information
-