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

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The enzyme appears in selected viruses and cellular organisms

EC NUMBER
COMMENTARY hide
2.7.11.25
-
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
-
-
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
-
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
evolution
-
the enzyme belongs to the RAF (rapidly accelerated fibrosarcoma) kinase family
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
-
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 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
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
?
-
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
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+
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
-
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
-
-
3-((1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide
-
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
-
-
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
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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
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
-
-
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
-
-
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
-
-
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
-
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
-
inhibition of COT activity, but binding of p105 increases the solubility and stability of COT
-
PD98059
-
-
Protein phosphatase 2A
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PP2A, dephosphorylates and inactivates MEKK3
-
RNAi
-
-
-
shRNA
-
silences GCKR expression
-
siRNA
-
MEKK1-specific siRNA inhibits with adenovirus-mediated overexpression of melanoma differentiation-associated gene-7-mediated MEKK1 cleavage
-
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 MEKK4s 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
reactive oxygene species
-
the enzyme is oxidative stress-induced
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TGFbeta
-
TGFbeta-activated kinase 1
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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
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.02 - 0.394
ATP
0.00016 - 0.00036
MEK
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.005 - 0.26
ATP
0.005 - 0.26
MEK
-
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.4
-
assay at
7.4 - 7.5
-
assay at
7.5
-
assay at
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
22
-
assay at room temperature
25
-
assay at
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
-
bronchial epithelial cell line
Manually annotated by BRENDA team
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high expression level of MEKK3
Manually annotated by BRENDA team
-
A-Raf is rarely mutated in human cancers
Manually annotated by BRENDA team
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bronchial
Manually annotated by BRENDA team
-
of skin
Manually annotated by BRENDA team
gene MLK4 is significantly upregulated in mesenchymal glioma spheres by 4fold or more compared with proneural spheres and/or somatic cell types including normal neural progenitors and astrocytes. MLK4 expression is enriched in the stemness-associated ALDEFLUOR-positive subpopulations in MES 83 glioma spheres
Manually annotated by BRENDA team
-
choroidal cancer cell line, expresses V599E mutant enzyme
Manually annotated by BRENDA team
-
mutated A-Raf
Manually annotated by BRENDA team
-
choroidal cancer cell line, expresses V599E mutant enzyme
Manually annotated by BRENDA team
-
high expression level of MEKK3
Manually annotated by BRENDA team
-
-
Manually annotated by BRENDA team
-
choroidal cancer cell line, expresses V599E mutant enzyme
Manually annotated by BRENDA team
additional information
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
-
to a lesser degree
Manually annotated by BRENDA team
additional information
-
ectopic expression of B-Raf in cutaneous melanoma cells
-
Manually annotated by BRENDA team
PDB
SCOP
CATH
UNIPROT
ORGANISM
Homo sapiens;
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
45000
-
recombinant single COT30-397, gel filtration
200000
-
about, recombinant aggregated COT30-397, gel filtration
600000
-
about, recombinant aggregated, p105DELTAN-complexed COT30-467
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
monomer
-
in solution, NMR spectroscopy
additional information
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
phosphoprotein
ubiquitination
the PHD domain of MEKK1 mediates its Lys63-linked autoubiquitination, leading to a stabilized interaction with other proteins. Autoubiquitination of MEKK1 strongly depends on its kinase activity, as well as the presence of TRAF2
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
10 mg/ml TAK1-TAB1 by hanging-drop method at 20C, mixing of 0.004 ml of protein solution with 0004 ml of reservoir solution containing 0.65-0.75 M sodium citrate, 0.2 M NaCl, 0.1 M Tris, pH 7.0, and 5 mM adenosine, X-ray diffraction structure determination and analysis, molecular replacement with inactive TAK1-TAB1 structure, PDB cID 2YIY, as search model
-
purified recombinant RAS-binding domain (RBD) from human B-RAF kinase, by microbatch-under-oil crystallization method at 18C, X-ray diffraction structure determination and analysis at 2.0 A resolution
-
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
binding of p105 increases the solubility and stability of COT, but decreases catalytic activity
-
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
by gel filtration
-
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
-
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
-
co-expression of FLAG-tagged MTK1 and wild-type and mutant HA-tagged MKK6 in COS-7 cells, direct and immunoprecipitation study
-
expressed in COS-7 cells and in yeast
-
expression of DLK in cultured keratinocytes using the adenovirus transfection method
-
expression of FLAG-tagged COT30-467 and COT30-397 in a stable and soluble form when co-expressed with the C-terminal part of p105, complex formation with p105 reduces the kcat value of COT30-397 but increases the expression level, expression of wild-type and mutant COT30-397s in Spodoptera frugiperda Sf9 cells using the baculovirus infection system
-
expression of FLAG-tagged MEKK3 in HEK293T and HeLa cells, co-expression of NF-kappaB
expression of His- or FLAG-tagged wild-type and mutant MEKK3s in HEK293 EBNA cells, co-expression of substrate GST-HA-tagged MKK6 substrate
-
expression of wild-type and inactive mutant enzymes in HEK293T cells and in COS-7 cells as HA-tagged proteins
-
expression of wild-type and mutant MAP3Ks, MEKK1-4 and TAO2-1, in HEK293 cells, co-expression of ERK5 and WNK1
-
overexpression of the mutant enzyme V599E in COS cells leading to 10.7fold increased activity
-
stable expression of HA-tagged MEKK3 in HEK293, U373, and Hep3B cells, the expression of MEKK3 blocks the TRAIL-mediated activation of the apoptosis pathway and increases cell resistance to cytotoxic agents such as doxorubicin, daunorubicin, camptothecin, and paclitaxel, overview, TRAIL is a TNF-related apoptosis-inducing ligand
-
subcloned into the HA-tagged mammalian expression vector pcDNA3.1
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
mixed lineage kinase 4 (MLK4) is overexpressed in mesenchymal but not proneural glioma stem cells. gene MLK4 is significantly upregulated in mesenchymal glioma spheres by 4fold or more compared with proneural spheres and/or somatic cell types including normal neural progenitors and astrocytes. MLK4 expression is enriched in the stemness-associated ALDEFLUOR-positive subpopulations in MES 83 glioma spheres
the MLK4 promoter is hypermethylated in proneural tumors with isocitrate dehydrogenase 1 (IDH1) mutation, suggesting that epigenetic silencing is one mechanism by which MLK4 is expressed at lower levels in proneural gliobalstomas
ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
D13A
-
site-directed mutagenesis, the mutation of the conserved Asp13 of MEKK3 to Ala completely abolishes the binding between CCM2ct and MEKK3nt
D169A
-
site-directed mutagenesis, the kinase-dead mutation of TAO2-1 does not influence the ERK5 activation level
D270A
-
site-directed mutagenesis of COT30-397, inactive mutant
E1372Q
-
site-directed mutagenesis, the MTK1 mutant shows altered substrate specificity comapred to the wild-type enzyme
E3A
-
site-directed mutagenesis, the mutation of the nonconserved Glu3 of MEKK3 to Ala causes a 2fold reduction of the binding affinity between CCM2ct and MEKK3nt
I10D
-
site-directed mutagenesis, the mutation completely abolishes the binding between CCM2ct and MEKK3nt
K1371D
-
site-directed mutagenesis, MTK1 mutant catalytic site mutant, inactive mutant, no interaction with substrate MKK6 docking site mutants
K1371E
-
site-directed mutagenesis, MTK1 mutant catalytic site mutant, inactive mutant, no interaction with substrate MKK6 docking site mutants
K1371G
-
site-directed mutagenesis, MTK1 mutant catalytic site mutant, inactive mutant, no interaction with substrate MKK6 docking site mutants
K1371R
-
site-directed mutagenesis, MTK1 mutant catalytic site mutant, inactive mutant, no interaction with substrate MKK6 docking site mutants
K14D
-
site-directed mutagenesis, the mutation completely abolishes the binding between CCM2ct and MEKK3nt
K17D
-
site-directed mutagenesis, the mutation completely abolishes the binding between CCM2ct and MEKK3nt
K385M
-
site-directed mutagenesis of MEKK2, inactive mutant enzyme
K391A
-
site-directed mutagenesis of MEKK3, the mutant shows highly reduced activity compared to the wild-type enzyme
K391M
-
site-directed mutagenesis of MEKK3, inactive mutant enzyme
K7A
-
considerably weakens the affinity with MEK5 PB1, dilution is endothermal
K7D
-
site-directed mutagenesis, the mutation completely abolishes the binding between CCM2ct and MEKK3nt
K7R
-
sustains the strong binding affinity, Kd is 0.37 micromol, dilution is exothermal like with wild-type
Q1254E
-
site-directed mutagenesis, the MEKK1 mutant shows altered substrate specificity comapred to the wild-type enzyme
R14A
-
binds to MEK5 PB1 with binding affinity of Kd 0.5 micromol, comparable to that of wild-type, dilution is endothermal
R5A
-
binding affinity decreases greatly to 1.6 micromol, dilution is endothermal
R76A
-
binds to MEK5 PB1 with binding affinity of Kd 0.22 micromol comparable to that of wild-type, dilution is endothermal
S526A
-
site-directed mutagenesis of MEKK3, the mutant shows highly reduced activity compared to the wild-type enzyme
S526D
-
site-directed mutagenesis of MEKK3, the mutant shows reduced activity compared to the wild-type enzyme
S526E
-
site-directed mutagenesis of MEKK3, the mutant shows reduced activity compared to the wild-type enzyme
T516A/S520A
-
MEKK3 with double alanine mutations can not bind the catalytic subunit of protein phosphatase 2a
T516E/S520D
-
double mutant, MEKK3 is phosphorylated at Thr-516 and Ser-520 within the kinase activation loop by protein phosphatase 2a
T530A
-
site-directed mutagenesis of MEKK3, the mutant shows highly reduced activity compared to the wild-type enzyme
T530D
-
site-directed mutagenesis of MEKK3, the mutant shows highly reduced activity compared to the wild-type enzyme
T530E
-
site-directed mutagenesis of MEKK3, the mutant shows highly reduced activity compared to the wild-type enzyme
V599E
-
naturally occurring mutation of cancer cells, the mutation leads to 10fold increased enzyme activity compared to the wild-type enzyme, and constitutive, Ras-independent activation, siRNA-mediated depletion of the mutant enzyme diminishes the enzyme activity and also cell proliferation
additional information
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
analysis
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proline cis-trans isomerization of MEKK3 PB1 of the Gln38-Pro39 bond, first case of structural heterogeneity within PB1 domains, major difference between both isomers in the Pro39 region. Residues Gly37-Leu40 form a type VIb beta-turn in the cis conformation, whereas no obvious character of beta-turn is observed in the trans conformation. Internal motions in the beta3/beta4-turn on a microsecond-millisecond time scale
medicine
additional information