Information on EC 2.7.11.25 - mitogen-activated protein kinase kinase kinase

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The enzyme appears in viruses and cellular organisms

EC NUMBER
COMMENTARY hide
2.7.11.25
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RECOMMENDED NAME
GeneOntology No.
mitogen-activated protein kinase kinase kinase
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
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-
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
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ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
i.e. Botryotinia fuckeliana, strain 38B1 is isolated from a grape in California, USA, and deposited to the China Microbiological Culture Collection Center, accession number CGMCC no. 4006
UniProt
Manually annotated by BRENDA team
i.e. Botryotinia fuckeliana, strain 38B1 is isolated from a grape in California, USA, and deposited to the China Microbiological Culture Collection Center, accession number CGMCC no. 4006
UniProt
Manually annotated by BRENDA team
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-
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Manually annotated by BRENDA team
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SwissProt
Manually annotated by BRENDA team
disruption of MCK1 resulted in the fungus undergoing autolysis and showing hypersensitivity to cell-wall-degrading enzyme, mutant strain produces significantly reduced numbers of conidia and developed appressoria in a slightly retarded manner compared with the wild type, mutant is unable to penetrate into plant tissues
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Manually annotated by BRENDA team
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SwissProt
Manually annotated by BRENDA team
C57BL/6 mice
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-
Manually annotated by BRENDA team
strains ORS-SL6a and 74-OR23-IVA and deletion mutants
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Manually annotated by BRENDA team
single copy gene MAPKKKalpha
SwissProt
Manually annotated by BRENDA team
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-
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Manually annotated by BRENDA team
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Manually annotated by BRENDA team
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SwissProt
Manually annotated by BRENDA team
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Manually annotated by BRENDA team
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Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
evolution
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 + ASK1
ADP + phosphorylated ASK1
show the reaction diagram
ATP + Atf1
ADP + phosphorylated Atf1
show the reaction diagram
ATP + BcSak1
ADP + phosphorylated BcSak1
show the reaction diagram
ATP + c-Jun
ADP + phosphorylated c-Jun
show the reaction diagram
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MAP3K1 phosphorylates and activates a JNK-c-Jun module
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-
?
ATP + cdc42
ADP + phosphorylated cdc42
show the reaction diagram
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-
-
-
?
ATP + ERK
ADP + phosphorylated ERK
show the reaction diagram
ATP + ERK5
ADP + phosphorylated ERK5
show the reaction diagram
ATP + F-kappaB luciferase
ADP + phosphorylated F-kappaB luciferase
show the reaction diagram
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Ser526 and Thr530 are required for MEKK3-dependent activity
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-
-
ATP + GSK3beta
ADP + phosphorylated GSK3beta
show the reaction diagram
ATP + histone H1
ADP + phosphorylated histone H1
show the reaction diagram
-
-
-
-
?
ATP + IKKalpha
ADP + phospho-IKKalpha
show the reaction diagram
-
-
-
?
ATP + JNK
ADP + phosphorylated JNK
show the reaction diagram
ATP + MAPKK
ADP + phosphorylated MAPKK
show the reaction diagram
-
MAPKK activation
-
-
?
ATP + MEK
ADP + phosphorylated MEK
show the reaction diagram
ATP + Mek1
ADP + phospho-Mek1
show the reaction diagram
ATP + MEK1
ADP + phosphorylated MEK1
show the reaction diagram
ATP + MEK2
ADP + phospho-MEK2
show the reaction diagram
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activation
-
-
?
ATP + MEK2
ADP + phosphorylated MEK2
show the reaction diagram
ATP + MEK4
ADP + phosphorylated MEK4
show the reaction diagram
-
-
-
-
?
ATP + MEK5
ADP + phosphorylated MEK5
show the reaction diagram
ATP + MKK
ADP + phosphorylated MKK
show the reaction diagram
ATP + MKK1
ADP + phosphorylated MKK1
show the reaction diagram
ATP + MKK2
ADP + phosphorylated MKK2
show the reaction diagram
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 + MPK4
ADP + phosphorylated MPK4
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 + p42 MAPK
ADP + phosphorylated p42 MAPK
show the reaction diagram
ATP + Pbs2p
ADP + phosphorylated Pbs2p
show the reaction diagram
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-
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
ATP + Rac
ADP + phosphorylated Rac
show the reaction diagram
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-
-
-
?
ATP + Ror2
ADP + phospho-Ror2
show the reaction diagram
ATP + SEK
ADP + phosphorylated SEK
show the reaction diagram
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recombinant GST-tagged inactive KR-mutant SEK, i.e. SAPK/ERK or stress-activated protein kinase/extracellular-signal-regulated kinase, substrate
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-
?
ATP + SMRT
ADP + phosphorylated SMRT
show the reaction diagram
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SMRT is regulated by MAPKKK cascades that induce its release from its receptor partners, its export from nucleus to cytoplasm, and derepression of target gene expression. SMRTalpha, SMRTtau, and SMRTsp2 splice variants are released from their nuclear receptor partners in response to MAPKKK activation, the SMRTsp18 variant, which resembles N-CoR in its overall molecular architecture, is relatively refractory to this kinase-induced release
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-
?
ATP + Sty1
ADP + phosphorylated Sty1
show the reaction diagram
ATP + tristetraprolin
ADP + phosphorylated tristetraprolin
show the reaction diagram
ATP + Wis1
ADP + phosphorylated Wis1
show the reaction diagram
ATP + WRKY53
ADP + phosphorylated WRKY53
show the reaction diagram
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phosphorylation increases DNA-binding activity of WRKY53
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-
?
BAD + ATP
BAD-phosphate + ADP
show the reaction diagram
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activation of the proapoptotic protein BAD
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MAP2K + ATP
MAP2K-phosphate + ADP
show the reaction diagram
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involved in reducing c-jun N-terminal kinase (JNK, MAPK8) activation and protecting the mice from nickel-induced acute lung injury
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MEK-1 + ATP
phosphorylated MEK-1 + ADP
show the reaction diagram
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essential step of the MAP-kinase cascade, activation of MEK-1 which is a MAPKK, essential role in vegetative hyphal growth, conidiation and protoperithecial development, as well as a more limited involvement in maintenance of cell wall integrity, not essential for the resistance to osmotic stress, negatively regulates tyrosinase expression
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?
additional information
?
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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 + Atf1
ADP + phosphorylated Atf1
show the reaction diagram
ATP + BcSak1
ADP + phosphorylated BcSak1
show the reaction diagram
ATP + c-Jun
ADP + phosphorylated c-Jun
show the reaction diagram
-
MAP3K1 phosphorylates and activates a JNK-c-Jun module
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-
?
ATP + ERK
ADP + phosphorylated ERK
show the reaction diagram
ATP + ERK5
ADP + phosphorylated ERK5
show the reaction diagram
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substrate of MEKK2 and MEKK3, activation of the ERK-dependent signaling pathway
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-
?
ATP + IKKalpha
ADP + phospho-IKKalpha
show the reaction diagram
Q5TCX8
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-
-
?
ATP + JNK
ADP + phosphorylated JNK
show the reaction diagram
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i.e. Jun amino terminal kinase
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?
ATP + MAPKK
ADP + phosphorylated MAPKK
show the reaction diagram
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MAPKK activation
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-
?
ATP + MEK
ADP + phosphorylated MEK
show the reaction diagram
ATP + Mek1
ADP + phospho-Mek1
show the reaction diagram
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activation
-
-
?
ATP + MEK1
ADP + phosphorylated MEK1
show the reaction diagram
ATP + MEK2
ADP + phospho-MEK2
show the reaction diagram
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activation
-
-
?
ATP + MEK2
ADP + phosphorylated MEK2
show the reaction diagram
Q6VAB6
activation by MEKK3 of MAPK signaling pathways
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?
ATP + MEK5
ADP + phosphorylated MEK5
show the reaction diagram
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activated MEK5 activates ERK5
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-
?
ATP + MKK
ADP + phosphorylated MKK
show the reaction diagram
-
induction of the JNK pathway activation
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-
?
ATP + MKK1
ADP + phosphorylated MKK1
show the reaction diagram
ATP + MKK2
ADP + phosphorylated MKK2
show the reaction diagram
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 + p42 MAPK
ADP + phosphorylated p42 MAPK
show the reaction diagram
-
Ras-induced activation of the MAPK signaling cascade
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-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
ATP + Ror2
ADP + phospho-Ror2
show the reaction diagram
Q62073
TGF-beta activated kinase 1, a MAPKKK, interacts with Ror2 and phosphorylates its intracellular carboxyterminal serine/thronine/proline-rich, STP, domain, Wnt-ligand binding differentially controls the Ror2/TAK1 interaction, Ror2 seems to act as a Wnt co-receptor enhancing Wnt-dependent canonical pathways while Tyr- and Ser/Thr-phosphorylation of Ror2 negatively controls the efficiency of these pathways, overview
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?
ATP + Sty1
ADP + phosphorylated Sty1
show the reaction diagram
ATP + tristetraprolin
ADP + phosphorylated tristetraprolin
show the reaction diagram
Q13233
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-
-
?
BAD + ATP
BAD-phosphate + ADP
show the reaction diagram
-
activation of the proapoptotic protein BAD
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MAP2K + ATP
MAP2K-phosphate + ADP
show the reaction diagram
-
involved in reducing c-jun N-terminal kinase (JNK, MAPK8) activation and protecting the mice from nickel-induced acute lung injury
-
-
-
MEK-1 + ATP
phosphorylated MEK-1 + ADP
show the reaction diagram
-
essential step of the MAP-kinase cascade, activation of MEK-1 which is a MAPKK, essential role in vegetative hyphal growth, conidiation and protoperithecial development, as well as a more limited involvement in maintenance of cell wall integrity, not essential for the resistance to osmotic stress, negatively regulates tyrosinase expression
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-
?
additional information
?
-
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Mn2+
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preferred divalent cation as ATP metal cofactor
Zn2+
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2 Zn2+ are bound at region CR1
additional information
-
no or nearly no activity with Ni2+, Zn2+, Co2+, and Cu2+
INHIBITORS
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
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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
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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
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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
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4-methyl-N-[3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl]-3-(7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)benzamide
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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
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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
BIRB796
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CEP-1347
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inhibits MLKs and is well tolerated in human trials, does not perform in trials for neurodegenerative disorders such as Parkinsons disease
EGTA
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negative regulation of COT
farnesylthiosalicylic acid
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a Ras antagonist, inhibits the wild-type and V599E mutant enzyme in vivo and in vitro
glutathione
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binding to glutathione inhibits MEKK1 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
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imatinib
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menadione
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i.e. 2-methyl-1,4-naphthoquinone, oxidative stress caused by menadione inhibits MEKK1, which can be reversed by DTT and glutathione, inhibition is thus caused by a reversible Cys1238 oxidation mechanism followed by binding to glutathione, no inhibition of MEKK1 mutant C1238V
N-ethylmaleimide
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MEKK1 inhibition through Cys1238 alkylation, Cys1238 is located in the ATP binding domain, no inhibition of MEKK1 mutant C1238V
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
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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
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N-{4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}-3-[2-(1H-pyrrolo[2,3-b]pyridin-4-yl)ethyl]benzamide
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N-{4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}-4-methyl-3-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)benzamide
-
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
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nilotinib
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-
p105
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p38
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negatively regulates tAK1 activation
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PD98059
Protein phosphatase 2A
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PP2A, dephosphorylates and inactivates MEKK3
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RNAi
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SB203580
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does not relieve the inhibitory effect of MEKK1 on insulin gene transcription, although it effectively decreases phosphorylation of JNK, SAPK/p38 or ERK, respectively
shRNA
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siRNA
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sorafenib
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-
SP600125
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does not relieve the inhibitory effect of MEKK1 on insulin gene transcription, although it effectively decreases phosphorylation of JNK, SAPK/p38 or ERK, respectively
thioredoxin
U0126
additional information
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
CpG
-
ASK1, TAK1, MEKK3
Gadd45alpha
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causes an increase in the activation of both the p38 and JNK pathways, but not the ERK pathway, upregulates MEKK4s kinase activity to a lesser degree as compared to Gadd45beta or Gadd45gamma
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Gadd45beta
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causes an increase in the activation of both the p38 and JNK pathways, but not the ERK pathway
-
Gadd45gamma
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causes an increase in the activation of both the p38 and JNK pathways, but not the ERK pathway
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GTPAse Rac1
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interacts with MLK2, the enzyme contains a G-protein binding domain, i.e. a CRIB domain
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interleukin 1
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TPL-2, TAK1, MEKK1 and MEKK3
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lipopolysaccharide
-
ASK1, TPL-2, TAK1, MEKK1 and MEKK3
methylglyoxal
N-ethylmaleimide
-
ASK1 activation at lower concentrations
osomolarity two-component system protein SSK1
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non-phosphorylated dimer, binding of Ssk1 seems to be necessary for Ssk2 activation
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progesterone
-
induces c-Mos expression
protein CD40
-
TPL-2
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protein PGN
-
ASK1
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protein pI:C
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ASK1
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protein TAB1
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positively regulates TAK1 activity
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protein TAB2
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positively regulates TAK1 activity
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protein TNF
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ASK1, TPL-2, MLK3, TAK1, MEKK1 and MEKK3
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reactive oxygene species
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sorbitol
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induces phosphorylation of Ser526, response to osmotic stress
Ste50
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Ste50 binding of the MAPKKK Ste11 through a head-to-tail sterile interaction via both alpha motif SAM domains is required for Ste11 activity and cell viability, NMR binding study, very tight and stable binding between the two mutants Ste50 L69R and Ste11 L72R, molecular modeling, overview
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TGFbeta
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TGFbeta-activated kinase 1
-
TNF-alpha
-
Wnt3a
-
additional information
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.02 - 0.394
ATP
0.00016 - 0.00036
MEK
-
additional information
additional information
-
kinetics of binding between wild-type and mutant Ste11 and wild-type and mutant Ste50, overview
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.005 - 0.26
ATP
0.005 - 0.26
MEK
-