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
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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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SwissProt
Manually annotated by BRENDA team
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SwissProt
Manually annotated by BRENDA team
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-
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Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
physiological function
MEKK3 is a central intermediate signaling component in lysophosphatidic acid-induced activation of the nuclear factor-kappa B
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 + 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 + F-kappaB luciferase
ADP + phosphorylated F-kappaB luciferase
show the reaction diagram
-
Ser526 and Thr530 are required for MEKK3-dependent activity
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-
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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 + 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 + 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 + 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
-
-
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
ATP + Rac
ADP + phosphorylated Rac
show the reaction diagram
-
-
-
-
?
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 + 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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-
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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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-
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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 + 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
-
-
?
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
-
-
?
ATP + MEK
ADP + phosphorylated MEK
show the reaction diagram
ATP + MEK1
ADP + phosphorylated MEK1
show the reaction diagram
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
-
activated MEK5 activates ERK5
-
-
?
ATP + MKK
ADP + phosphorylated MKK
show the reaction diagram
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induction of the JNK pathway activation
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-
?
ATP + MKK1
ADP + phosphorylated MKK1
show the reaction diagram
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MKK1 activates the ERK2 signaling pathway
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-
?
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 + p42 MAPK
ADP + phosphorylated p42 MAPK
show the reaction diagram
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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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-
?
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
-
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
?
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Mn2+
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preferred divalent cation as ATP metal cofactor
additional information
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no or nearly no activity with Ni2+, Zn2+, Co2+, and Cu2+
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
BAY 43-9006
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c-Raf inhibitor, shows promising response rate in patients with primary renal cell carcinomas
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 Parkinson´s 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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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
p105
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p38
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negatively regulates tAK1 activation
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PD98059
Protein phosphatase 2A
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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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
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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 MEKK4’s 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
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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
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ASK1, TPL-2, TAK1, MEKK1 and MEKK3
methylglyoxal
N-ethylmaleimide
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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
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induces c-Mos expression
protein CD40
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TPL-2
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protein PGN
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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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TNF-alpha
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Wnt3a
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additional information
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.02 - 0.394
ATP
0.00016 - 0.00036
MEK
-
additional information
additional information
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kinetics of binding between wild-type and mutant Ste11 and wild-type and mutant Ste50, overview
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.005 - 0.26
ATP
0.005 - 0.26
MEK
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
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large scale activity assay with recombinant enzyme in a protein chip consisting of a microwell array with protein covalently attached to the wells via a 3-glycidoxypropyltrimethoxysilane crosslinker, overview
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.3
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assay at
7.4 - 7.5
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assay at
7.6
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assay at
7.9
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assay at
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
25
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assay at
TEMPERATURE RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
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bronchial epithelial cell line
Manually annotated by BRENDA team
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TPL-2, TAK1
Manually annotated by BRENDA team
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high expression level of MEKK3
Manually annotated by BRENDA team
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A-Raf is rarely mutated in human cancers
Manually annotated by BRENDA team
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MLK2 expression correlates with cell elongation and the onset of an apoptotic phase
Manually annotated by BRENDA team
preferential expression of MEKK1 in the vasculature
Manually annotated by BRENDA team
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no changes in B-Raf activity after fertilization
Manually annotated by BRENDA team
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bronchial
Manually annotated by BRENDA team
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of skin
Manually annotated by BRENDA team
-
-
Manually annotated by BRENDA team
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highly expressed
Manually annotated by BRENDA team
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choroidal cancer cell line, expresses V599E mutant enzyme
Manually annotated by BRENDA team
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mutated A-Raf
Manually annotated by BRENDA team
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choroidal cancer cell line, expresses V599E mutant enzyme
Manually annotated by BRENDA team
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highly expressed
Manually annotated by BRENDA team
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high expression level of MEKK3
Manually annotated by BRENDA team
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embryo, MLK2 expression correlates with the differentiation and opening of the nephritic tubules, but not with apoptosis
Manually annotated by BRENDA team
constitutive expression
Manually annotated by BRENDA team
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choroidal cancer cell line, expresses V599E mutant enzyme
Manually annotated by BRENDA team
prior to fertilization, strongest FRK2 mRNA accumulation
Manually annotated by BRENDA team
prior to fertilization, strongest FRK2 mRNA accumulation
Manually annotated by BRENDA team
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overxpressed
Manually annotated by BRENDA team
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Tpl-2 isolated from Moloney leukemia virus-induced thymoma cells
Manually annotated by BRENDA team
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highly expressed
Manually annotated by BRENDA team
basal level of FRK2 mRNA
Manually annotated by BRENDA team
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TAK1
Manually annotated by BRENDA team
predominant expression of MEKK1
Manually annotated by BRENDA team
additional information
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
-
activation of MEK1 by C-Raf
Manually annotated by BRENDA team
-
activation of p42 MAPK
Manually annotated by BRENDA team
-
MEKK1/WRKY53 complexes are predominantly localized in the nucleus
Manually annotated by BRENDA team
additional information
PDB
SCOP
CATH
ORGANISM
UNIPROT
Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
Schizosaccharomyces pombe (strain 972 / ATCC 24843)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
34300
RNA gel blot analysis
36200
Northern blot analysis
45000
-
recombinant single COT30-397, gel filtration
180000
195000
-
SDS-PAGE
200000
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about, recombinant aggregated COT30-397, gel filtration
600000
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about, recombinant aggregated, p105DELTAN-complexed COT30-467
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
dimer
-
dimerization through the catalytic domain is essential for MEKK2 activation, the dimerization motif is in the catalytic domain, the N-terminal domain is not required for dimerization, overview
monomer
-
in solution, NMR spectroscopy
additional information
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
phosphoprotein
proteolytic modification
-
cleavage by caspase-3 at a specific C-terminal cleavage site generates a 91 kDa, catalytically active enzyme fragment
additional information
-
the active MEKK1 stimulates its own ubiquitinylation in vivo which has a negatively regulating function
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
binding of p105 increases the solubility and stability of COT, but decreases catalytic activity
-
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-80°C
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
by centrifugation and on Ni2+-NTA resin
-
by gel filtration
-
partial purification of Mos and B-Raf from egg extracts by heparin affinity chromatography and/or ion exchange chromatography, and GST-MEK1 affinity chromatography, recombinant His6-tagged B-Raf by nickel affinity chromatography
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purification of recombinant MEKK1 and ASK1 by chitin affinity chromatography, endogenous MEKK1 by protein A affinity chromatography
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purification of recombinant wild-type and mutant COT30-397s, free or complexed to p105DELTAN, and of p105DELTAN-complexed recombinant COT30-467 from Sf9 insect cells by anti-Flag immunoaffinity chromatography, the purification of free COT30-467 is not possible due to its extremely low expression level in absence of p105DELTAN
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recombinant His6- and GST-tagged wild-type and mutants enzymes from Escherichia coli by affinity chromatography and gel filtration, the tags are cleaved off
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recombinant protein by tandem affinity purification
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Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
amplified MEKK3 PB1 DNA fragments inserted between NdeI/XhoI sites of pET22b and wild-type MEKK3 PB1 with a C-terminal His tag expressed in Escherichia coli BL21 (DE3) cells, MEKK3 PB1 mutants expressed in Escherichia coli Rosetta cells
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B-RAf, DNA and amino acid sequence determination and analysis, expression of His6-tagged B-Raf in bacteria, expression of His6-tagged and FLAG-tagged C-Raf in insect cells
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co-expression of FLAG-tagged MTK1 and wild-type and mutant HA-tagged MKK6 in COS-7 cells, direct and immunoprecipitation study
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DNA and amino acid sequence determination and analysis, overexpression of the enzyme can complement the defective mutant and results in increase crippled growth after infection
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DNA and amino acid sequence determination and analysis, sequence comparisons, overview
DNA and amino acid sequence determination and analysis, sequence comparisons, overview, MAPKKKalpha overexpression in leaves using the Agrobacterium tumefaciens transfection system
expressed as native and mutant FLAG-tag/HA-tag fusion protein in HEK293T cells, coexpression expreiments with TAK1; expressed together with or without MEKK3 in HEK293T cells
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expressed in COS-7 cells and in yeast
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expression in embryos by microinjection in the two-cell stage, overexpression of MLK2 in COS-7 cells leading to a SEK1/MKK4-dependent hyperactivation of Jun N-terminal kinase
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expression of a MEKK1 promoter-driven beta-Gal fusion protein in Mekk1deltaKD/deltaKD mice
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expression of DLK in cultured keratinocytes using the adenovirus transfection method
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expression of FLAG-tagged