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

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The expected taxonomic range for this enzyme is: Eukaryota

EC NUMBER
COMMENTARY
2.7.11.25
-
RECOMMENDED NAME
GeneOntology No.
mitogen-activated protein kinase kinase kinase
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
ATP + a protein = ADP + a phosphoprotein
show the reaction diagram
-
-
-
-
ATP + a protein = ADP + a phosphoprotein
show the reaction diagram
Lys391 is the catalytic residue
-
ATP + a protein = ADP + a phosphoprotein
show the reaction diagram
mechanism of ASK1
-
ATP + a protein = ADP + a phosphoprotein
show the reaction diagram
molecular mechanism of MEKK2 and MEKK3
-
ATP + a protein = ADP + a phosphoprotein
show the reaction diagram
structure-function relationship of MAPKKKs and MAPKKs, K1371 is the catalytic residue of MTK1, MTK1, TAK1, and MEKK1 also possess lysine as catalytic residues
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phospho group transfer
Q99759
-
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.
SYNONYMS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
(JNK)/stress-activated protein kinase-associated protein 1
P53349
-
apoptosis signal-regulated kinase 1
-
-
apoptosis signal-regulating kinase
-
-
apoptosis signal-regulating kinase 1
-
-
apoptosis signal-regulating kinase 1
-
-
apoptosis signal-regulating kinase 2
-
-
B-Raf
-
-
B-Raf kinase
-
-
c-mos
-
-
-
-
C-Raf
-
-
cancer osaka thyroid
-
-
COT
Q6VAB6
-
COT30-397
-
-
COT30-467
-
-
DLK
-
-
-
-
Dual leucine zipper bearing kinase
-
-
-
-
Dual leucine zipper bearing kinase
-
-
dual leucine zipper-bearing kinase
-
-
extracellular signal-regulated kinase kinase kinase-1
-
-
fertilization-related kinase 1
Q6EE09
-
fertilization-related kinase 2
Q6EE08
-
Frk1
Q6EE09
-
Frk2
Q6EE08
-
GCKR
Mus musculus C57BL/6
-
-
-
germinal center kinase-related enzyme
-
-
germinal center kinase-related enzyme
Mus musculus C57BL/6
-
-
-
HsNIK
-
-
-
-
JSAP1
P53349
-
Jun N-terminal kinase kinase kinase
-
-
Jun N-terminal protein kinase
P53349
-
Leucine-zipper protein kinase
-
-
-
-
M3Kalpha
Q75PK5
-
MAP kinase kinase kinase
-
-
MAP kinase kinase kinase
-
-
MAP kinase kinase kinase
Q75PK5
-
MAP kinase kinase kinase
-
-
MAP kinase kinase kinase
-
-
MAP kinase kinase kinase
synthetic construct
-
-
MAP kinase kinase kinase
-
-
MAP kinase kinase kinase 1
-
-
MAP kinase kinase kinase 3
Q6VAB6
-
MAP kinase kinase kinase mkh1
Q10407
-
MAP kinase kinase kinase SSK2
P53599
-
MAP kinase kinase kinase win1
O74304
-
MAP kinase kinase kinase wis4
O14299
-
MAP/ERK kinase kinase 1
Homo sapiens, Mus musculus, synthetic construct
-
-
MAP3K
Q6VAB6
-
MAP3K
Q62073
-
MAP3K
synthetic construct
-
-
MAP3K1
-
-
MAP3K6
-
-
MAP3Ka
Q6RFY4
-
MAP3Ka
Q6RFY3
-
MAPK kinase kinase
-
-
MAPK kinase kinase
synthetic construct
-
-
MAPK-upstream kinase
-
-
-
-
MAPK/ERK kinase kinase 1
-
-
MAPK/ERKkinase kinase 3
Mus musculus, synthetic construct
-
-
MAPKK kinase
-
-
MAPKKK
-
-
MAPKKK
Q6VAB6
-
MAPKKK
Q75PK5
-
MAPKKK
Q7XTK4
-
MAPKKK
Q6EE08, Q6EE09
-
MAPKKK
synthetic construct
-
-
MAPKKK6
-
-
MAPKKK6
O95382
-
MAPKKK6
-
-
MAPKKKalpha
Q6RFY4
-
MAPKKKalpha
Q6RFY3
-
MEK kinase 1
-
-
MEK kinase 1
-
-
MEK kinase 3
-
-
MEKK1
Q39008
-
MEKK1
Q7XTK4
-
MEKK1
synthetic construct
-
-
MEKK3
Q6VAB6
-
MEKK3
Q99759
-
MEKK3
-
belongs to the family of serine/threonine kinases
MEKK3
synthetic construct
-
-
MEKK4
Q6VAB6
-
MEKK5
-
-
MEKK8
-
-
mitogen activated protein kinase kinase kinase
-
-
mitogen-activated protein kinase kinase kinase
-
-
mitogen-activated protein kinase kinase kinase
-
-
mitogen-activated protein kinase kinase kinase
-
-
mitogen-activated protein kinase kinase kinase
-
-
mitogen-activated protein kinase kinase kinase
synthetic construct
-
-
mitogen-activated protein kinase kinase kinase
-
-
mitogen-activated protein kinase kinase kinase 1
-
-
mitogen-activated protein kinase kinase kinase 1
-
-
mitogen-activated protein kinase kinase kinase 1
P53349
-
mitogen-activated protein kinase kinase kinase 1
synthetic construct
-
-
mitogen-activated protein kinase kinase kinase 3
Q99759
-
mitogen-activated protein kinase kinase kinase 4
O08648
-
mitogen-activated protein kinase kinase kinase 6
O95382
-
mitogen-activated protein kinase kinase kinase kinase
-
-
mitogen-activated protein kinase kinase kinase kinase
Mus musculus C57BL/6
-
-
-
mitogen-activated protein kinase kinase kinase-1
-
-
mitogen-activated protein kinase/extracellular-regulated kinase kinase kinase-3
-
-
mitogen-activated protein kinase/extracellular-signal-regulated kinase kinase kinase 1
-
-
mitogen-activated protein/ERK kinase kinase 3
-
-
Mixed Lineage Kinase
-
five characterized forms
MKL3
-
-
MLK
-
five characterized forms termed MLK1, 2, 3, 4 or 7
MLK-like mitogen-activated protein triple kinase
-
-
MLK1
-
-
MLK2
-
-
MLK4
-
-
MTK1
-
-
MUK
-
-
-
-
NF-kappa beta-inducing kinase
-
-
-
-
OMTK1
Q7XTK4
-
oxidative stress-activated MAP triple-kinase 1
Q7XTK4
-
protein kinase byr2
P28829
-
putative mitogen-activated protein kinase 1
Q7XTK4
-
Serine/threonine protein kinase NIK
-
-
-
-
serine/threonine-protein kinase STE11
P23561
-
SSk2 MAPK kinase kinase
-
-
TAK1
Q6VAB6
-
TAK1
-
belongs to the family of serine/threonine kinases
TAK1
Q62073
-
TAK1 (three isoforms termed A,B and C)
-
-
TAO kinase
-
three different forms
TAO1-2
-
-
TAO2-1
-
-
TGF-beta-activated kinase-1
Q62073
-
TGFalpha activated kinase
-
-
TGFbeta activated kinase 1
-
-
Thousand And One kinase
-
-
Tlp2
-
-
TPL-2
-
-
transforming growth factor beta-activated kinase 1
-
-
tumor progression locus-2
-
-
tumour progression locus 2
-
-
ZPK
-
-
-
-
MLTKalpha
-
-
additional information
-
MEKK2 and MEKK3 belong to the MEKK/Ste11 subfamily of the MAP3K family of enzymes
additional information
-
MAP kinase cascade is homologous to the Saccharomyces cerevisiae Slt2p pathway
additional information
Q6RFY4
MAPKKKalpha belongs to the A2 subgroup of the MEKK enzyme family
additional information
-
the enzyme belongs to the MEK family
additional information
Q6RFY3
MAPKKKalpha belongs to the A2 subgroup of the MEKK enzyme family
additional information
-
the enzyme belongs to the MLK family of mitogen activated protein kinase kinase kinases
CAS REGISTRY NUMBER
COMMENTARY
146702-84-3
-
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
Col ecotype
Swissprot
Manually annotated by BRENDA team
Col-0 ecotype
-
-
Manually annotated by BRENDA team
Columbia ecotype
-
-
Manually annotated by BRENDA team
ecotype Columbia
-
-
Manually annotated by BRENDA team
-
SwissProt
Manually annotated by BRENDA team
gene BRAF
-
-
Manually annotated by BRENDA team
MEKK3 isozyme 1
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
-
-
Manually annotated by BRENDA team
; activity requires TAB1 (TAK1 binding protein), binding of TAB1 promotes autophosphorylation of TAK1
-
-
Manually annotated by BRENDA team
; native and mutant mice, mutant embryos are growth retarded and die in utero; normal and mutant mice, mutant mice appear normal at birth but die 7-21 days postpartum due to neurological and intestinal problems; normal and mutant mice, mutant mice die in utero due to severe vascular abnormalities
-
-
Manually annotated by BRENDA team
C57BL/6 mice
-
-
Manually annotated by BRENDA team
wild type embryonic fibroblast and cells with a MAP3K deletion used for experiments
-
-
Manually annotated by BRENDA team
Mus musculus C57BL/6
C57BL/6 mice
-
-
Manually annotated by BRENDA team
strains ORS-SL6a and 74-OR23-IVA and deletion mutants
-
-
Manually annotated by BRENDA team
single copy gene MAPKKKalpha
SwissProt
Manually annotated by BRENDA team
synthetic construct
-
-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
physiological function
Q99759
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)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
ATP + a protein
ADP + a phosphoprotein
show the reaction diagram
-
-
-
-
?
ATP + a protein
ADP + a phosphoprotein
show the reaction diagram
-
-
-
-
?
ATP + a protein
ADP + a phosphoprotein
show the reaction diagram
Q99759
-
-
-
?
ATP + ASK1
ADP + phosphorylated ASK1
show the reaction diagram
Q9WTR2
ASK2 activates ASK1 by direct phosphorylation
-
-
?
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 + ERK
ADP + phosphorylated ERK
show the reaction diagram
-
-
-
-
?
ATP + ERK
ADP + phosphorylated ERK
show the reaction diagram
-
-
-
-
?
ATP + ERK
ADP + phosphorylated ERK
show the reaction diagram
-
i.e. extracellular signal-regulated kinase
-
-
?
ATP + ERK
ADP + phosphorylated ERK
show the reaction diagram
-
PI3K/PKC/Raf-1-independent activation of the MEK/ERK signaling pathway
-
-
?
ATP + ERK
ADP + phosphorylated ERK
show the reaction diagram
synthetic construct
-
MEKK3-dependent activation correlates with a requirement for serine at position 526
-
-
-
ATP + ERK
ADP + phosphorylated ERK
show the reaction diagram
-
TPL-2, TAK1, MEKK3
-
-
?
ATP + ERK5
ADP + phosphorylated ERK5
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, substrate of MEKK2 and MEKK3, no substrate of TAO2-1
-
-
?
ATP + F-kappaB luciferase
ADP + phosphorylated F-kappaB luciferase
show the reaction diagram
synthetic construct
-
Ser526 and Thr530 are required for MEKK3-dependent activity
-
-
-
ATP + GSK3beta
ADP + phosphorylated GSK3beta
show the reaction diagram
Mus musculus, Homo sapiens, Mus musculus C57BL/6
-
regulates phosphorylation at serine 9
-
-
?
ATP + histone H1
ADP + phosphorylated histone H1
show the reaction diagram
-
-
-
-
?
ATP + JNK
ADP + phosphorylated JNK
show the reaction diagram
-
-
-
-
?
ATP + JNK
ADP + phosphorylated JNK
show the reaction diagram
-
-
-
-
?
ATP + JNK
ADP + phosphorylated JNK
show the reaction diagram
-
-
-
-
?
ATP + JNK
ADP + phosphorylated JNK
show the reaction diagram
-
i.e. Jun amino terminal kinase
-
-
?
ATP + JNK
ADP + phosphorylated JNK
show the reaction diagram
-
activated by ASK2 in complex with ASK1
-
-
?
ATP + JNK
ADP + phosphorylated JNK
show the reaction diagram
-
ASK1, TPL-2, TAK1, MLK3, MEKK3
-
-
?
ATP + JNK
ADP + phosphorylated JNK
show the reaction diagram
synthetic construct
-
MEKK3-dependent activation correlates with a requirement for serine at position 526
-
-
-
ATP + JNK
ADP + phosphorylated JNK
show the reaction diagram
Mus musculus, Homo sapiens, Mus musculus C57BL/6
-
required for Wnt-mediated JNK activation in B cells
-
-
?
ATP + MAPKK
ADP + phosphorylated MAPKK
show the reaction diagram
-
MAPKK activation
-
-
?
ATP + MEK
ADP + phosphorylated MEK
show the reaction diagram
-
-
-
-
?
ATP + MEK
ADP + phosphorylated MEK
show the reaction diagram
-
-
-
-
?
ATP + MEK
ADP + phosphorylated MEK
show the reaction diagram
-
PI3K/PKC/Raf-1-independent activation of the MEK/ERK signaling pathway
-
-
?
ATP + MEK
ADP + phosphorylated MEK
show the reaction diagram
-
substrate is a MAPKK, usage of inactivated GST-tagged mutant MEK
-
-
?
ATP + Mek1
ADP + phospho-Mek1
show the reaction diagram
-
-
-
-
?
ATP + MEK1
ADP + phosphorylated MEk1
show the reaction diagram
Q6VAB6
activation by MEKK3 of MAPK signaling pathways
-
-
?
ATP + MEK1
ADP + phosphorylated MEk1
show the reaction diagram
-
MEK1 activates the ERK2 signaling pathway
-
-
?
ATP + MEK1
ADP + phosphorylated MEk1
show the reaction diagram
-
Ras-induced activation of the MAPK signaling cascade
-
-
?
ATP + MEK1
ADP + phosphorylated MEk1
show the reaction diagram
-
substrate is a MAPKK
-
-
?
ATP + MEK1
ADP + phosphorylated MEk1
show the reaction diagram
Q6VAB6
substrate is a MAPKK
-
-
?
ATP + MEK1
ADP + phosphorylated MEk1
show the reaction diagram
-
the substrate of B-Raf and C-Raf is a MAPKK, no substrate of Mos, recombinant GST-MEK1 substrate
-
-
?
ATP + MEK2
ADP + phosphorylated MEK2
show the reaction diagram
Q6VAB6
activation by MEKK3 of MAPK signaling pathways, substrate is a MAPKK
-
-
?
ATP + MEK4
ADP + phosphorylated MEK4
show the reaction diagram
synthetic construct
-
-
-
-
?
ATP + MEK5
ADP + phosphorylated MEK5
show the reaction diagram
-
a MAPKK, activated MEK5 activates ERK5
-
-
?
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 + MKK
ADP + phosphorylated MKK
show the reaction diagram
-
a MAPKK, induction of the JNK pathway activation
-
-
?
ATP + MKK1
ADP + phosphorylated MKK1
show the reaction diagram
-
MKK1 activates the ERK2 signaling pathway, a MAPKK, recombinant GST-tagged MKK1
-
-
?
ATP + MKK3
ADP + phosphorylated MKK3
show the reaction diagram
-
-
-
-
?
ATP + MKK3
ADP + phosphorylated MKK3
show the reaction diagram
-
-
-
-
?
ATP + MKK3
ADP + phosphorylated MKK3
show the reaction diagram
-
a MAPKK
-
-
?
ATP + MKK3
ADP + phosphorylated MKK3
show the reaction diagram
-
a MAPKK
-
-
?
ATP + MKK3
ADP + phosphorylated MKK3
show the reaction diagram
Q7XTK4
a MAPKK, a MAPKK, OMTK1 channels oxidative stress signaling through direct interaction with MAPK MMK3 increasing the cell death rate, OMTK1 and MMK3 form a complex in vivo
-
-
?
ATP + MKK3
ADP + phosphorylated MKK3
show the reaction diagram
-
activation of the p38 MAP kinase signaling pathway
-
-
?
ATP + MKK3
ADP + phosphorylated MKK3
show the reaction diagram
-
activation of the p38 MAP kinase signaling pathway leading to apoptosis
-
-
?
ATP + MKK3
ADP + phosphorylated MKK3
show the reaction diagram
-
ASK1
-
-
?
ATP + MKK4
ADP + phosphorylated MKK4
show the reaction diagram
-
-
-
-
?
ATP + MKK4
ADP + phosphorylated MKK4
show the reaction diagram
-
a MAPKK
-
-
?
ATP + MKK4
ADP + phosphorylated MKK4
show the reaction diagram
-
a MAPKK
-
-
?
ATP + MKK4
ADP + phosphorylated MKK4
show the reaction diagram
-
activation of the Jun N-terminal kinase, JNK, pathway leading to apoptosis
-
-
?
ATP + MKK4
ADP + phosphorylated MKK4
show the reaction diagram
-
MKK4 activates the JNK signaling pathway
-
-
?
ATP + MKK4
ADP + phosphorylated MKK4
show the reaction diagram
-
a MAPKK, activity of wild-type and mutant MEKK1 with wild-type and mutant MKK4, determination of the MKK4 binding site of MEKK1, overview
-
-
?
ATP + MKK4
ADP + phosphorylated MKK4
show the reaction diagram
-
a MAPKK, recombinant GST-tagged MKK4
-
-
?
ATP + MKK4
ADP + phosphorylated MKK4
show the reaction diagram
-
i.e. SEK1, a MAPKK
-
-
?
ATP + MKK4
ADP + phosphorylated MKK4
show the reaction diagram
-
substrate is a MAPKK
-
-
?
ATP + MKK4
ADP + phosphorylated MKK4
show the reaction diagram
-
substrate of MEKK1 mutant Q1254E and of MTK1 mutant E1372Q
-
-
?
ATP + MKK4
ADP + phosphorylated MKK4
show the reaction diagram
-
activated by ASK2 in complex with ASK1
-
-
?
ATP + MKK4
ADP + phosphorylated MKK4
show the reaction diagram
-
ASK1
-
-
?
ATP + MKK6
ADP + phosphorylated MKK6
show the reaction diagram
-
-
-
-
?
ATP + MKK6
ADP + phosphorylated MKK6
show the reaction diagram
-
-
-
-
?
ATP + MKK6
ADP + phosphorylated MKK6
show the reaction diagram
-
-
-
-
?
ATP + MKK6
ADP + phosphorylated MKK6
show the reaction diagram
-
a MAPKK
-
-
?
ATP + MKK6
ADP + phosphorylated MKK6
show the reaction diagram
-
a MAPKK
-
-
?
ATP + MKK6
ADP + phosphorylated MKK6
show the reaction diagram
Q6VAB6
activation by MEKK3 of MAPK signaling pathways
-
-
?
ATP + MKK6
ADP + phosphorylated MKK6
show the reaction diagram
-
activation of the p38 MAP kinase signaling pathway
-
-
?
ATP + MKK6
ADP + phosphorylated MKK6
show the reaction diagram
-
activation of the p38 MAP kinase signaling pathway leading to apoptosis
-
-
?
ATP + MKK6
ADP + phosphorylated MKK6
show the reaction diagram
-
substrate of stress-activated MAPKKKs ASK1 and MTK1, phosphorylation in the activation loop, substrate of stress-activated MAPKKKs ASK1 and MTK1, no activity with MKK6 mutants E318P, F327D, I331D, and V328G, but reduced activity with MKK6 mutants V324G and V328A
-
-
?
ATP + MKK6
ADP + phosphorylated MKK6
show the reaction diagram
Q6VAB6
substrate is a MAPKK
-
-
?
ATP + MKK6
ADP + phosphorylated MKK6
show the reaction diagram
-
activated by ASK2 in complex with ASK1
-
-
?
ATP + MKK6
ADP + phosphorylated MKK6
show the reaction diagram
-
ASK1, TAK1
-
-
?
ATP + MKK6
ADP + phosphorylated MKK6
show the reaction diagram
synthetic construct
-
phosphorylation of Ser526 is required for MKK6 phosphorylation in vitro
-
-
-
ATP + MKK7
ADP + phosphorylated MKK7
show the reaction diagram
-
a MAPKK
-
-
?
ATP + MKK7
ADP + phosphorylated MKK7
show the reaction diagram
Q6VAB6
activation by MEKK3 of MAPK signaling pathways
-
-
?
ATP + MKK7
ADP + phosphorylated MKK7
show the reaction diagram
-
activation of the Jun N-terminal kinase, JNK, signaling pathway leading to apoptosis
-
-
?
ATP + MKK7
ADP + phosphorylated MKK7
show the reaction diagram
Q6VAB6
substrate is a MAPKK
-
-
?
ATP + MPK4
ADP + phosphorylated MPK4
show the reaction diagram
-
-
-
-
?
ATP + MPK4
ADP + phosphorylated MPK4
show the reaction diagram
Q39008
MEKK1 is essential for MPK4 activation by flg22
-
-
?
ATP + myelin basic protein
ADP + phosphorylated myelin basic protein
show the reaction diagram
-
-
-
-
?
ATP + myelin basic protein
ADP + phosphorylated myelin basic protein
show the reaction diagram
-
-
-
-
?
ATP + myelin basic protein
ADP + phosphorylated myelin basic protein
show the reaction diagram
Q39008
-
-
-
?
ATP + p38
ADP + phosphorylated p38
show the reaction diagram
-
-
-
-
?
ATP + p38
ADP + phosphorylated p38
show the reaction diagram
-
activated by ASK2 in complex with ASK1
-
-
?
ATP + p38
ADP + phosphorylated p38
show the reaction diagram
-
ASK1, TAK1
-
-
?
ATP + p38
ADP + phosphorylated p38
show the reaction diagram
synthetic construct
-
MEKK3-dependent activation correlates with a requirement for serine at position 526
-
-
-
ATP + p42 MAPK
ADP + phosphorylated p42 MAPK
show the reaction diagram
-
Ras-induced activation of the MAPK signaling cascade, the substrate of B-Raf and C-Raf, no substrate of Mos, recombinant His6-p42 MAPK substrate
-
-
?
ATP + Pbs2p
ADP + phosphorylated Pbs2p
show the reaction diagram
-
-
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
-
required for activation of the MAPK homologue Spc1, and integrity of the Wis1-Spc1 pathway is required for survival in extreme conditions of heat, osmolarity, oxidation or limited nutrition. Phosphorylates Wis1 in vitro and activates it in vivo
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
-
capable of partial suppression of the ras1 mutant phenotype
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
O08648
selectively regulates the c-Jun amino terminal kinase pathway
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
P23561
enzyme is involved in the response of haploid yeast cells to peptide mating pheromones
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
-
phosphorylates and activates Wis1 MAP kinase kinase in response to high osmolarity
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
-
ste8 gene product functions in the signal transduction pathway
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
-
the enzyme is required for cell-type-specific transcription and signal transduction
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
-
Mkh1 regulates cell morphology, cell wall integrity, salt resistance, cell cycle reentry from stationary-phase arrest, and filamentous growth in response to stress
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
P53349
JSAP1 functions as a scaffold protein in the JNK3 cascade
-
-
?
ATP + Rac
ADP + phosphorylated Rac
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, TAK1 phosphorylates Ror2, a receptor tyrosine kinase, at multiple sites, activity of TAK1 with Ror2 phosphorylation site mutants, overview
-
-
?
ATP + SEK
ADP + phosphorylated SEK
show the reaction diagram
-
recombinant GST-tagged inactive KR-mutant SEK, i.e. SAPK/ERK or stress-activated protein kinase/extracellular-signal-regulated kinase, substrate
-
-
?
ATP + SMRT
ADP + phosphorylated SMRT
show the reaction diagram
synthetic construct
-
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
-
-
?
ATP + Wis1
ADP + phosphorylated Wis1
show the reaction diagram
-
-
-
-
?
ATP + Wis1
ADP + phosphorylated Wis1
show the reaction diagram
-
-
-
?
ATP + WRKY53
ADP + phosphorylated WRKY53
show the reaction diagram
-
phosphorylation increases DNA-binding activity of WRKY53
-
-
?
BAD + ATP
BAD-phosphate + ADP
show the reaction diagram
-
activation of the proapoptotic protein BAD
-
-
-
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
-
-
?
additional information
?
-
O08648
MEKK4 binds to Cdc42 and Rac
-
-
-
additional information
?
-
-
enzyme is part of mitogen-activated protein kinase pathways, crosstalk and regulation mechanism, overview
-
-
-
additional information
?
-
-
activation mechanism of ASK1, overview, ASK1 is involved in oxidative stress-induced cell death and adaptation processes to various stresses, the enzyme is required for induction of apoptosis by e.g. Fas or TNF-alpha, or by the endoplasmic reticulum, mechanism
-
-
-
additional information
?
-
-
activation mechanism of ASK1, overview, ASK1 is involved in oxidative stress-induced cell death and adaptation processes to various stresses, the enzyme is required for induction of apoptosis by e.g. Fas or TNF-alpha, or by the endoplasmic reticulum, mechanism, ASK1 plays an important role in neuropathological alterations in polyQ diseases
-
-
-
additional information
?
-
-
alterations of the intracellular milieu induced by methylglyoxal through a MEKK1-mediated and PI3K/PKC/Raf-1-independent pathway results in the modification of cell response to IGF-I for the cyclin-dependent kinase inibitor p21Waf1/Cip1-mediated growth arrest
-
-
-
additional information
?
-
-
alterations of the intracellular milieu induced by methylglyoxal through a MEKK1-mediated and PI3K/PKC/Raf-1-independent pathway results in the modification of cell response to IGF-I for the cyclin-dependent kinase inibitor p21_Waf1/Cip1-mediated growth arrest, which may be one of the crucial mechanisms for methylglyoxal to promote the development of chronic clinical complications in diabetes in humans
-
-
-
additional information
?
-
-
B-Raf and C-Raf, but not Mos, are required for Ras-induced MEK1 and p42 MAPK activation
-
-
-
additional information
?
-
-
COT is a proto-oncogene, the enzyme is essential for the lipopolysaccharide activation of the ERK MAPK cascade in macrophages
-
-
-
additional information
?
-
Q6VAB6
Cot plays an important role in inflammation and oncogenesis, MEKK3 mediates the activation of JNK and ERK in the MAP kinase pathway and of the NF-kappaB pathway and mediates the interleukin-8 production, MEKK3 and Cot are negatively regulated by hKSR-2
-
-
-
additional information
?
-
-
DLK acts as a key regulator of keratinocyte terminal differentiation, and is involved in activation of the JNK signaling pathway, DLK activity is required for transglutaminase activation and induction of keratinocyte cornification
-
-
-
additional information
?
-
Q6RFY3
MAPKKKalpha is responsible for hypersensitive response and resistance to pathogen infection, the enzyme also regulates cell death in susceptible leaves after infection, overview
-
-
-
additional information
?
-
Q6RFY4
MAPKKKalpha is responsible for hypersensitive response and resistance to Pseudomonas syringae infection, the enzyme also regulates cell death in susceptible, infected leaves, identification of MAPKKKalpha-induced signal cascades, regulation, overview
-
-
-
additional information
?
-
-
MEKK1 and ASK1 might play opposing roles in oxidative stress-induced activation of apoptosis
-
-
-
additional information
?
-
-
MEKK2 and MEKK3 are involved in activation of signal transduction pathways via toll-like receptor TLR, mitogen-activated protein kinases MAPK, and NF-kappaB, overview
-
-
-
additional information
?
-
-
MEKK2 induces the JNK signaling pathway, overview
-
-
-
additional information
?
-
-
MEKK3 is involved in activation of MAPKs e.g. p38 and JNK
-
-
-
additional information
?
-
-
MEKK3 is involved in activation of NF-kappaB and increased expression of cell survival factors which confers resistance to apoptosis
-
-
-
additional information
?
-
-
MLK2 plays a tissue specific role and is required for cement gland development and nephritic tubule formation, MLK2 mediates the response of Jun N-terminal kinase JNK, i.e. stress-activated protein kinase 1 SAPK1, to UV irradiation
-
-
-
additional information
?
-
-
MLTKalpha activates the p38gamma MAPK-dependent signaling pathway, which is regulated by the serine/threonine kinase PKNalpha
-
-
-
additional information
?
-
-
NSY-1 functions in the control of asymmetric expression of odor receptor gene str-2, odor discrimination, and odor chemotaxis, thus possibly in functional differentiation of the nervous system, the enzyme functions downstream of UNC-43 CaMKII
-
-
-
additional information
?
-
-
regulation, overview, Ras and mitogen-activated protein kinase kinase kinase-1 coregulate activator protein-1- and nuclear factor-kappaB-mediated gene expression in airway epithelial cells, the enzyme is involved in activation of the signaling cascades via activator protein AP-1 and NF-kappaB
-
-
-
additional information
?
-
-
Ste11 is involved in MAPK pathway signal transduction governing mating, osmoregulation, and nitrogen starvation by direct interaction with the sterile alpha motif domains, SAM, of Ste50 and Ste11
-
-
-
additional information
?
-
-
stomatal development and pattern is controlled by YODA
-
-
-
additional information
?
-
-
the enzyme is involved in cell signaling and controls cell degeneration and cell differentiation and thus regulating development and pathogenicity sensing the external conditions
-
-
-
additional information
?
-
-
the enzyme is part of the MAPK signaling cascades, overview
-
-
-
additional information
?
-
-
the MAPKKKs are part of the MAPK signaling cascade, overview, MEKK1 regulates calpain-dependent cell migration via regulation of th ERK2-dependent signaling pathway and binding to focal adhesions, actinin, and FAK, overview
-
-
-
additional information
?
-
-
the MAPKKKs are part of the MAPK signaling cascade, several structurally diverse MAPKKK families exist, overview
-
-
-
additional information
?
-
-
the natural enzyme mutant V599E induces cell transformation in NIH3T3 cells, the B-Raf/MEK/ERK pathway regulates cell cycle proteins, overview
-
-
-
additional information
?
-
Q7XTK4
the OMTK1 kinase domain is involved in activation of signaling pathways in case of oxidative stress to induce cell death playing a MAPK scaffolding role, OMTK1 shows low constitutive activity
-
-
-
additional information
?
-
-
no phosphorylation/activation of IkappaB kinase
-
-
-
additional information
?
-
-
Ste50 binds the MAPKKK Ste11 through a head-to-tail sterile interaction via both alpha motif SAM domains, NMR binding study, very tight and stable binding between the two mutants Ste50 L69R and Ste11 L72R, overview
-
-
-
additional information
?
-
-
substrate specificities of MAPKKKs with wild-type and mutant MAPKKs, overview, no activity with MKK7 by MEKK1 mutant Q1254E, wild-type MTK1, and MTK1 mutant E1372Q, the enzyme docks at the DVD docking site of MAPKK, a stretch of about 20 amino acids immediately on the C-terminal side of the catalytic domain, MAPKK with mutated DVD docking sites are inhibitory for the MAPKKK, overview
-
-
-
additional information
?
-
-
the enzyme docks at the DVD docking site of MAPKK, a stretch of about 20 amino acids immediately on the C-terminal side of the catalytic domain, MAPKK with mutated DVD docking sites are inhibitory for the MAPKKK
-
-
-
additional information
?
-
-
endogenous MEKK3 is phosphorylated on Ser526 in the response to exogenous stimuli like osmotic stress
-
-
-
additional information
?
-
-
activity of MEKK1 may not be required for flg22-induced MPK4, MPK3 or MPK6 activation or for other macroscopic FLS2-mediated responses
-
-
-
additional information
?
-
Q39008
MEKK1 is dispensable for MPK3 and MPK6 activation by flg22
-
-
-
additional information
?
-
-
MEKK1-induced MMP-1promoter-driven luciferase activity is largely dependent on a c/EBPbeta-NF-kappaB-like enhancer site at -2008 to -1972 bp
-
-
-
additional information
?
-
-
MEKK3 is required for IL-1R and LPS-induced IL-6 production in fibroblasts
-
-
-
additional information
?
-
-
MEKK4 is a signaling protein of the p38 MAPK pathway
-
-
-
additional information
?
-
synthetic construct
-
N-CoR is refractory to MAPKKK signaling, alternative splicing of N-CoR has only minimal effects on the resistance of this corepressor to MAPKKK inhibition
-
-
-
additional information
?
-
-
activator of the Pbs2 MAPKK in the SLN1 branch of the Hog1 MAPK cascade, involved in osmoregulation
-
-
-
additional information
?
-
-
induces activation of NF-kappaB reporter activity, deficiency cells show defects in TNFalpha signalling
-
-
-
additional information
?
-
-
involved in maintaining cell wall integrity, remodeling of the cell wall in response to host environments is essential for fungal pathogenesis
-
-
-
additional information
?
-
-
involved in the activation of NF-kappaB, negatively regulates MEKK3-induced activation of NF-kappaB reporter activity, able to autophosphorylate at multiple sites when bound to TAB1, deficiency cells show defects in TNFalpha signalling
-
-
-
additional information
?
-
-
involved in the regulation of development and secondary metabolism, deficiency mutant forms short aerial hyphae, show reduced formation of asexual macroconidia, and reduced growth
-
-
-
additional information
?
-
-
phosphorylates and activates MAP kinase kinase, activates ERK and JNK pathways in cells of the imune system in response to inflammatory mediators, knockout mice show normal development but defects in inflammatory response, involved in T-cell proliferation, probably involved in cardiac myocyte differentiation, phosphorylates and activates MAP kinase kinase, activates ERK1/2 and possibly also ERK3, important function in vascular development, important physiological role in cell growth and development, related to oncogenesis, phosphorylates and activates MAP kinase kinase, activates JNK and p38MAP kinases in response to stress stimuli, knockout mice usually dying shortly after birth due to neural tube and skeletal malformations, functions in regulation of apoptosis and cell migration, possibly acts as central regulator of calcium-mediated signaling, phosphorylates and activates MAP kinase kinase, activates JNK during neuronal migration in cerebal cortex development, phosphorylates and activates MAP kinase kinase, activates the p38 pathway in response to stress and DNA damage, phosphorylates and activates MAP kinase kinase, appears to transduce signals for JNK and ERK1/2 activation by pro-inflammatory stimuli and growth factors, key regulator of cell migration, deletion mutants are viable and fertile but display altered migration of epithelial cells resulting in defective eyelid closure, enzyme interacts directly with MEK1, MEK2 and c-Raf, involved in oxidative stress induced apoptosis in cardiac myocytes, enzyme deficiency individuals have diminished B-cell numbers, directly and indirectly involved in cell migration, phosphorylates and activates MAP kinase kinase, important for the transduction of survival signals, involved in the regulation of apoptosis, important for TGFbeta signalling, deletion mutation in adult mice results in bone marrow and liver failure due to increased apoptosis of hematopoetic cells and hepatocytes, embryonic deletion is lethal due to severe vascular defects and delayed growth, phosphorylates and activates MAP kinase kinase, induces the activation of the MEK/ERK pathway, important physiological role in cell growth and development, related to oncogenesis, phosphorylates and activates MAP kinase kinase, involved in cellular stress response and JNK and p38 pathway activation, MLK1, 2 and 3 knockout mice show no obvious abnormalities, MLK 7 is activated in response to stressors like anisomycin and UV radiation and activates pro-apoptotic pathways through p38 and JNK, phosphorylates and activates MAP kinase kinase, regulates apoptosis in response to stress stimuli, knockout mice do not exhibit developmental defects, activates p38 and JNK pathways, phosphorylates and activates MAP kinase kinase, regulates p38,ERK1/2 and JNK, knockout embryos dying in utero due to abnormalities in vessel development and heart development, key regulator of cardiovascular and nervous system formation, phosphorylates and activates MAP kinase kinase, regulation of apoptosis, induction of the MEK/ERK pathway, promotes cell survival in the heart through modulation of MEKK5 activity, important physiological role in cell growth and development, related to oncogenesis, phosphorylates and activates MAP kinase kinase, selctive for the activation of JNK and ERK5, knockout mutants are viable and fertile without apparent malformations, involved in T-cell receptor modulation and cytokine production in response to IgE
-
-
-
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
ATP + a protein
ADP + a phosphoprotein
show the reaction diagram
-
-
-
-
?
ATP + a protein
ADP + a phosphoprotein
show the reaction diagram
-
-
-
-
?
ATP + a protein
ADP + a phosphoprotein
show the reaction diagram
Q99759
-
-
-
?
ATP + ERK
ADP + phosphorylated ERK
show the reaction diagram
-
i.e. extracellular signal-regulated kinase
-
-
?
ATP + ERK
ADP + phosphorylated ERK
show the reaction diagram
-
PI3K/PKC/Raf-1-independent activation of the MEK/ERK signaling pathway
-
-
?
ATP + ERK5
ADP + phosphorylated ERK5
show the reaction diagram
-
substrate of MEKK2 and MEKK3, activation of the ERK-dependent signaling pathway
-
-
?
ATP + JNK
ADP + phosphorylated JNK
show the reaction diagram
-
i.e. Jun amino terminal kinase
-
-
?
ATP + MAPKK
ADP + phosphorylated MAPKK
show the reaction diagram
-
MAPKK activation
-
-
?
ATP + MEK
ADP + phosphorylated MEK
show the reaction diagram
-
-
-
-
?
ATP + MEK
ADP + phosphorylated MEK
show the reaction diagram
-
PI3K/PKC/Raf-1-independent activation of the MEK/ERK signaling pathway
-
-
?
ATP + MEK1
ADP + phosphorylated MEk1
show the reaction diagram
Q6VAB6
activation by MEKK3 of MAPK signaling pathways
-
-
?
ATP + MEK1
ADP + phosphorylated MEk1
show the reaction diagram
-
MEK1 activates the ERK2 signaling pathway
-
-
?
ATP + MEK1
ADP + phosphorylated MEk1
show the reaction diagram
-
Ras-induced activation of the MAPK signaling cascade
-
-
?
ATP + MEK2
ADP + phosphorylated MEK2
show the reaction diagram
Q6VAB6
activation by MEKK3 of MAPK signaling pathways
-
-
?
ATP + MEK5
ADP + phosphorylated MEK5
show the reaction diagram
-
activated MEK5 activates ERK5
-
-
?
ATP + MKK
ADP + phosphorylated MKK
show the reaction diagram
-
induction of the JNK pathway activation
-
-
?
ATP + MKK1
ADP + phosphorylated MKK1
show the reaction diagram
-
MKK1 activates the ERK2 signaling pathway
-
-
?
ATP + MKK3
ADP + phosphorylated MKK3
show the reaction diagram
Q7XTK4
a MAPKK, OMTK1 channels oxidative stress signaling through direct interaction with MAPK MMK3 increasing the cell death rate, OMTK1 and MMK3 form a complex in vivo
-
-
?
ATP + MKK3
ADP + phosphorylated MKK3
show the reaction diagram
-
activation of the p38 MAP kinase signaling pathway
-
-
?
ATP + MKK3
ADP + phosphorylated MKK3
show the reaction diagram
-
activation of the p38 MAP kinase signaling pathway leading to apoptosis
-
-
?
ATP + MKK4
ADP + phosphorylated MKK4
show the reaction diagram
-
a MAPKK
-
-
?
ATP + MKK4
ADP + phosphorylated MKK4
show the reaction diagram
-
activation of the Jun N-terminal kinase, JNK, pathway leading to apoptosis
-
-
?
ATP + MKK4
ADP + phosphorylated MKK4
show the reaction diagram
-
MKK4 activates the JNK signaling pathway
-
-
?
ATP + MKK6
ADP + phosphorylated MKK6
show the reaction diagram
-
-
-
-
?
ATP + MKK6
ADP + phosphorylated MKK6
show the reaction diagram
Q6VAB6
activation by MEKK3 of MAPK signaling pathways
-
-
?
ATP + MKK6
ADP + phosphorylated MKK6
show the reaction diagram
-
activation of the p38 MAP kinase signaling pathway
-
-
?
ATP + MKK6
ADP + phosphorylated MKK6
show the reaction diagram
-
activation of the p38 MAP kinase signaling pathway leading to apoptosis
-
-
?
ATP + MKK6
ADP + phosphorylated MKK6
show the reaction diagram
-
substrate of stress-activated MAPKKKs ASK1 and MTK1
-
-
?
ATP + MKK7
ADP + phosphorylated MKK7
show the reaction diagram
Q6VAB6
activation by MEKK3 of MAPK signaling pathways
-
-
?
ATP + MKK7
ADP + phosphorylated MKK7
show the reaction diagram
-
activation of the Jun N-terminal kinase, JNK, signaling pathway leading to apoptosis
-
-
?
ATP + p42 MAPK
ADP + phosphorylated p42 MAPK
show the reaction diagram
-
Ras-induced activation of the MAPK signaling cascade
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
-
required for activation of the MAPK homologue Spc1, and integrity of the Wis1-Spc1 pathway is required for survival in extreme conditions of heat, osmolarity, oxidation or limited nutrition. Phosphorylates Wis1 in vitro and activates it in vivo
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
-
capable of partial suppression of the ras1 mutant phenotype
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
O08648
selectively regulates the c-Jun amino terminal kinase pathway
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
P23561
enzyme is involved in the response of haploid yeast cells to peptide mating pheromones
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
-
phosphorylates and activates Wis1 MAP kinase kinase in response to high osmolarity
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
-
ste8 gene product functions in the signal transduction pathway
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
-
the enzyme is required for cell-type-specific transcription and signal transduction
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
-
Mkh1 regulates cell morphology, cell wall integrity, salt resistance, cell cycle reentry from stationary-phase arrest, and filamentous growth in response to stress
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
P53349
JSAP1 functions as a scaffold protein in the JNK3 cascade
-
-
?
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
-
-
?
BAD + ATP
BAD-phosphate + ADP
show the reaction diagram
-
activation of the proapoptotic protein BAD
-
-
-
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
-
-
?
additional information
?
-
-
enzyme is part of mitogen-activated protein kinase pathways, crosstalk and regulation mechanism, overview
-
-
-
additional information
?
-
-
activation mechanism of ASK1, overview, ASK1 is involved in oxidative stress-induced cell death and adaptation processes to various stresses, the enzyme is required for induction of apoptosis by e.g. Fas or TNF-alpha, or by the endoplasmic reticulum, mechanism
-
-
-
additional information
?
-
-
activation mechanism of ASK1, overview, ASK1 is involved in oxidative stress-induced cell death and adaptation processes to various stresses, the enzyme is required for induction of apoptosis by e.g. Fas or TNF-alpha, or by the endoplasmic reticulum, mechanism, ASK1 plays an important role in neuropathological alterations in polyQ diseases
-
-
-
additional information
?
-
-
alterations of the intracellular milieu induced by methylglyoxal through a MEKK1-mediated and PI3K/PKC/Raf-1-independent pathway results in the modification of cell response to IGF-I for the cyclin-dependent kinase inibitor p21Waf1/Cip1-mediated growth arrest
-
-
-
additional information
?
-
-
alterations of the intracellular milieu induced by methylglyoxal through a MEKK1-mediated and PI3K/PKC/Raf-1-independent pathway results in the modification of cell response to IGF-I for the cyclin-dependent kinase inibitor p21_Waf1/Cip1-mediated growth arrest, which may be one of the crucial mechanisms for methylglyoxal to promote the development of chronic clinical complications in diabetes in humans
-
-
-
additional information
?
-
-
B-Raf and C-Raf, but not Mos, are required for Ras-induced MEK1 and p42 MAPK activation
-
-
-
additional information
?
-
-
COT is a proto-oncogene, the enzyme is essential for the lipopolysaccharide activation of the ERK MAPK cascade in macrophages
-
-
-
additional information
?
-
Q6VAB6
Cot plays an important role in inflammation and oncogenesis, MEKK3 mediates the activation of JNK and ERK in the MAP kinase pathway and of the NF-kappaB pathway and mediates the interleukin-8 production, MEKK3 and Cot are negatively regulated by hKSR-2
-
-
-
additional information
?
-
-
DLK acts as a key regulator of keratinocyte terminal differentiation, and is involved in activation of the JNK signaling pathway, DLK activity is required for transglutaminase activation and induction of keratinocyte cornification
-
-
-
additional information
?
-
Q6RFY3
MAPKKKalpha is responsible for hypersensitive response and resistance to pathogen infection, the enzyme also regulates cell death in susceptible leaves after infection, overview
-
-
-
additional information
?
-
Q6RFY4
MAPKKKalpha is responsible for hypersensitive response and resistance to Pseudomonas syringae infection, the enzyme also regulates cell death in susceptible, infected leaves, identification of MAPKKKalpha-induced signal cascades, regulation, overview
-
-
-
additional information
?
-
-
MEKK1 and ASK1 might play opposing roles in oxidative stress-induced activation of apoptosis
-
-
-
additional information
?
-
-
MEKK2 and MEKK3 are involved in activation of signal transduction pathways via toll-like receptor TLR, mitogen-activated protein kinases MAPK, and NF-kappaB, overview
-
-
-
additional information
?
-
-
MEKK2 induces the JNK signaling pathway, overview
-
-
-
additional information
?
-
-
MEKK3 is involved in activation of MAPKs e.g. p38 and JNK
-
-
-
additional information
?
-
-
MEKK3 is involved in activation of NF-kappaB and increased expression of cell survival factors which confers resistance to apoptosis
-
-
-
additional information
?
-
-
MLK2 plays a tissue specific role and is required for cement gland development and nephritic tubule formation, MLK2 mediates the response of Jun N-terminal kinase JNK, i.e. stress-activated protein kinase 1 SAPK1, to UV irradiation
-
-
-
additional information
?
-
-
MLTKalpha activates the p38gamma MAPK-dependent signaling pathway, which is regulated by the serine/threonine kinase PKNalpha
-
-
-
additional information
?
-
-
NSY-1 functions in the control of asymmetric expression of odor receptor gene str-2, odor discrimination, and odor chemotaxis, thus possibly in functional differentiation of the nervous system, the enzyme functions downstream of UNC-43 CaMKII
-
-
-
additional information
?
-
-
regulation, overview, Ras and mitogen-activated protein kinase kinase kinase-1 coregulate activator protein-1- and nuclear factor-kappaB-mediated gene expression in airway epithelial cells, the enzyme is involved in activation of the signaling cascades via activator protein AP-1 and NF-kappaB
-
-
-
additional information
?
-
-
Ste11 is involved in MAPK pathway signal transduction governing mating, osmoregulation, and nitrogen starvation by direct interaction with the sterile alpha motif domains, SAM, of Ste50 and Ste11
-
-
-
additional information
?
-
-
stomatal development and pattern is controlled by YODA
-
-
-
additional information
?
-
-
the enzyme is involved in cell signaling and controls cell degeneration and cell differentiation and thus regulating development and pathogenicity sensing the external conditions
-
-
-
additional information
?
-
-
the enzyme is part of the MAPK signaling cascades, overview
-
-
-
additional information
?
-
-
the MAPKKKs are part of the MAPK signaling cascade, overview, MEKK1 regulates calpain-dependent cell migration via regulation of th ERK2-dependent signaling pathway and binding to focal adhesions, actinin, and FAK, overview
-
-
-
additional information
?
-
-
the MAPKKKs are part of the MAPK signaling cascade, several structurally diverse MAPKKK families exist, overview
-
-
-
additional information
?
-
-
the natural enzyme mutant V599E induces cell transformation in NIH3T3 cells, the B-Raf/MEK/ERK pathway regulates cell cycle proteins, overview
-
-
-
additional information
?
-
Q7XTK4
the OMTK1 kinase domain is involved in activation of signaling pathways in case of oxidative stress to induce cell death playing a MAPK scaffolding role, OMTK1 shows low constitutive activity
-
-
-
additional information
?
-
-
endogenous MEKK3 is phosphorylated on Ser526 in the response to exogenous stimuli like osmotic stress
-
-
-
additional information
?
-
-
activator of the Pbs2 MAPKK in the SLN1 branch of the Hog1 MAPK cascade, involved in osmoregulation
-
-
-
additional information
?
-
-
induces activation of NF-kappaB reporter activity, deficiency cells show defects in TNFalpha signalling
-
-
-
additional information
?
-
-
involved in maintaining cell wall integrity, remodeling of the cell wall in response to host environments is essential for fungal pathogenesis
-
-
-
additional information
?
-
-
involved in the activation of NF-kappaB, negatively regulates MEKK3-induced activation of NF-kappaB reporter activity, able to autophosphorylate at multiple sites when bound to TAB1, deficiency cells show defects in TNFalpha signalling
-
-
-
additional information
?
-
-
involved in the regulation of development and secondary metabolism, deficiency mutant forms short aerial hyphae, show reduced formation of asexual macroconidia, and reduced growth
-
-
-
additional information
?
-
-
phosphorylates and activates MAP kinase kinase, activates ERK and JNK pathways in cells of the imune system in response to inflammatory mediators, knockout mice show normal development but defects in inflammatory response, involved in T-cell proliferation, probably involved in cardiac myocyte differentiation, phosphorylates and activates MAP kinase kinase, activates ERK1/2 and possibly also ERK3, important function in vascular development, important physiological role in cell growth and development, related to oncogenesis, phosphorylates and activates MAP kinase kinase, activates JNK and p38MAP kinases in response to stress stimuli, knockout mice usually dying shortly after birth due to neural tube and skeletal malformations, functions in regulation of apoptosis and cell migration, possibly acts as central regulator of calcium-mediated signaling, phosphorylates and activates MAP kinase kinase, activates JNK during neuronal migration in cerebal cortex development, phosphorylates and activates MAP kinase kinase, activates the p38 pathway in response to stress and DNA damage, phosphorylates and activates MAP kinase kinase, appears to transduce signals for JNK and ERK1/2 activation by pro-inflammatory stimuli and growth factors, key regulator of cell migration, deletion mutants are viable and fertile but display altered migration of epithelial cells resulting in defective eyelid closure, enzyme interacts directly with MEK1, MEK2 and c-Raf, involved in oxidative stress induced apoptosis in cardiac myocytes, enzyme deficiency individuals have diminished B-cell numbers, directly and indirectly involved in cell migration, phosphorylates and activates MAP kinase kinase, important for the transduction of survival signals, involved in the regulation of apoptosis, important for TGFbeta signalling, deletion mutation in adult mice results in bone marrow and liver failure due to increased apoptosis of hematopoetic cells and hepatocytes, embryonic deletion is lethal due to severe vascular defects and delayed growth, phosphorylates and activates MAP kinase kinase, induces the activation of the MEK/ERK pathway, important physiological role in cell growth and development, related to oncogenesis, phosphorylates and activates MAP kinase kinase, involved in cellular stress response and JNK and p38 pathway activation, MLK1, 2 and 3 knockout mice show no obvious abnormalities, MLK 7 is activated in response to stressors like anisomycin and UV radiation and activates pro-apoptotic pathways through p38 and JNK, phosphorylates and activates MAP kinase kinase, regulates apoptosis in response to stress stimuli, knockout mice do not exhibit developmental defects, activates p38 and JNK pathways, phosphorylates and activates MAP kinase kinase, regulates p38,ERK1/2 and JNK, knockout embryos dying in utero due to abnormalities in vessel development and heart development, key regulator of cardiovascular and nervous system formation, phosphorylates and activates MAP kinase kinase, regulation of apoptosis, induction of the MEK/ERK pathway, promotes cell survival in the heart through modulation of MEKK5 activity, important physiological role in cell growth and development, related to oncogenesis, phosphorylates and activates MAP kinase kinase, selctive for the activation of JNK and ERK5, knockout mutants are viable and fertile without apparent malformations, involved in T-cell receptor modulation and cytokine production in response to IgE
-
-
-
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Mg2+
-
-
Mg2+
Q7XTK4
-
Mn2+
-
preferred divalent cation as ATP metal cofactor
additional information
-
no or nearly no activity with Ni2+, Zn2+, Co2+, and Cu2+
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
BAY 43-9006
-
c-Raf inhibitor, shows promising response rate in patients with primary renal cell carcinomas
CEP-1347
-
inhibits MLKs and is well tolerated in human trials, does not perform in trials for neurodegenerative disorders such as Parkinsons disease
EGTA
-
negative regulation of COT
farnesylthiosalicylic acid
-
a Ras antagonist, inhibits the wild-type and V599E mutant enzyme in vivo and in vitro
glutathione
-
binding to glutathione inhibits MEKK1 in vitro
hKSR-2
Q6VAB6
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
-
N-ethylmaleimide
-
MEKK1 inhibition through Cys1238 alkylation, Cys1238 is located in the ATP binding domain, no inhibition of MEKK1 mutant C1238V
p105
-
inhibition of COT activity, but binding of p105 increases the solubility and stability of COT
-
p105
-
blocks the ability of TPL-2 to interact with and phosphorylate MEk
-
p38
-
negatively regulates tAK1 activation
-
Protein phosphatase 2A
Q99759
PP2A, dephosphorylates and inactivates MEKK3
-
RNAi
-
-
-
RNAi
-
knockdown of TAK1 impairs p38 and JNK activation by IL-1 and TNF
-
SB203580
synthetic construct
-
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
-
silences GCKR expression
-
siRNA
Q9WTR2
transfection of siRNA for ASK1 into cells reduces expression of not only ASK1 but also ASK2
-
siRNA
-
MEKK1-specific siRNA inhibits with adenovirus-mediated overexpression of melanoma differentiation-associated gene-7-mediated MEKK1 cleavage
-
SP600125
synthetic construct
-
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
-
the reduced form binds to the N-terminus
thioredoxin
-
ASK1
U0126
-
inhibits MEKK2/MEKK3-dependent ERK5 phosphorylation/activation in vitro and in vivo
U0126
synthetic construct
-
does not relieve the inhibitory effect of MEKK1 on insulin gene transcription, although it effectively decreases phosphorylation of JNK, SAPK/p38 or ERK, respectively
menadione
-
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
additional information
-
no interaction with Cdc42 and RhoA by MLK2
-
additional information
-
MAPKK with mutated DVD docking sites are inhibitory for the MAPKKK, as well as synthetic DVD sequence oligopeptides in vitro and in vivo, overview
-
additional information
-
ubiquitinylation of MEKK1 inhibits the enzyme in vitro and in vivo
-
additional information
-
no inhibition by LY294002 or bisindolylmaleimide
-
additional information
-
MAPKK with mutated DVD docking sites are inhibitory for the MAPKKK, as well as synthetic DVD sequence oligopeptides of e.g. MKK6, in vitro and in vivo, overview
-
additional information
-
prostaglandin E2, wild-type p53 expression in the presence of prostaglandin E2, and p53S15E suppress steady-state levels of MEKK1-induced interstitial collagenase MMP-1 mRNA, effects nullified with co-transfection of p53 dnm or p53S15A. Prostaglandin E2, overexpression of p53wt with prostaglandin E2, or p53S15E abolish MEKK1-induced MMP-1 promoter luciferase activity
-
additional information
Q39008
suppression of mekk1 phenotypes at high temperature
-
additional information
-
inhibitory function within the N-terminal domain
-
additional information
synthetic construct
-
incubation of MEKK1 with phosphoprotein phosphatases 2A dephosphorylates the protein, significantly reducing the basal activity of MEKK1 generated from insect cells
-
additional information
-
MEKK1 down-regulation by interfering RNA significantly delays skin wound closure and impairs activation of Jun NH2-terminal kinases, induction of plasminogen activator inhibitor 1, and restoration of cell-cell junctions of the wounded epidermis
-
additional information
-
sFRP-1 significantly impairs Wnt3a-conditioned-media-induced activation of GCKR
-
additional information
-
inactive in vivo when bound to MEKK3; inactive in vivo when bound to TAK1
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
CpG
-
ASK1, TAK1, MEKK3
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
-
GTPAse Rac1
-
interacts with MLK2, the enzyme contains a G-protein binding domain, i.e. a CRIB domain
-
H2O2
Q7XTK4
oxidative stress activates OMTK1
H2O2
-
activates, MEKK1 kinase activity and protein stability is regulated by H2O2 in a proteasome-dependent manner
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
H2O2
-
ASK1
interleukin 1
-
TPL-2, TAK1, MEKK1 and MEKK3
-
lipopolysaccharide
-
ASK1, TPL-2, TAK1, MEKK1 and MEKK3
N-ethylmaleimide
-
ASK1 activation at lower concentrations
NaCl
Q7XTK4
-
osomolarity two-component system protein SSK1
-
non-phosphorylated dimer, binding of Ssk1 seems to be necessary for Ssk2 activation
-
progesterone
-
induces c-Mos expression
protein CD40
-
TPL-2
-
protein PGN
-
ASK1
-
protein pI:C
-
ASK1
-
protein TAB1
-
positively regulates TAK1 activity
-
protein TAB2
-
positively regulates TAK1 activity
-
protein TNF
-
ASK1, TPL-2, MLK3, TAK1, MEKK1 and MEKK3
-
Ras
-
required for maximal activity in ERK and JNK phosphorylation/activation and for activation of AP-1 pathway
-
Ras
-
activates C-Raf and B-Raf
-
reactive oxygene species
-
the enzyme is oxidative stress-induced
-
sorbitol
-
induces phosphorylation of Ser526, response to osmotic stress
Ste50
-
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
-
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
-
methylglyoxal
-
induces the PI3K/PKC/Raf-1-independent MEK/ERK signaling pathway by activation of MEKK1, accumulates in case of diabetes
additional information
-
TNF-alpha induces MEKK1 and Ras activation
-
additional information
-
polymerization and phosphorylation activates the enzyme after dissociation of thioredoxin due to TNF-alpha treatment
-
additional information
-
UV irradiation increases the enzyme activity, no interaction with Cdc42 and RhoA by MLK2
-
additional information
-
MEKK1 forms complexes with FAK involved in regulation of cell migration, overview
-
additional information
-
MLTKalpha is activated by phosphorylation through PKNalpha
-
additional information
Q7XTK4
MG115 induces OMTK1
-
additional information
-
MEKK2 and MEKK3 are phosphorylated and thereby activated by kinase WNK1
-
additional information
-
dimerization through the catalytic domain is essential for MEKK2 activation
-
additional information
-
phosphorylation at Ser526 and Thr530 in the activation loop is required for MEKK3 activation, dephosphorylation is blocked by binding to protein 14-3-3
-
additional information
-
no change in phosphorylation of Ser526 in the presence or absence of okadaic acid
-
additional information
-
no effect on enzyme activity by RAF-1
-
additional information
-
a functional DVD docking site of MAPKK substrates is absolutely required for activity
-
additional information
-
Ssk1p binds and activates the MEKK kinases Ssk2p and Ssk22p, de-phosphorylated Ssk1p binds to the N-terminal auto-inhibitory domain of Ssk2p and Ssk22p, activating their auto-phosphorylation on a conserved threonine residue
-
additional information
-
RhoA L63, the active mutant of RhoA, dramatically stimulates the activity of endogenous MEKK1, whereas RhoA wild-type and RhoA N19, a dominant negative mutant of RhoA, show little activation effect
-
additional information
-
MEKK1 containing residues 1-719 interacts with wild-type RhoA. MEKK1 (149-636) also associates with wild-type RhoA in yeast. The constitutively active mutant of RhoA, RhoAL63, also binds to residues 149-636, whereas the inactive mutant RhoAN19 fails to bind any of the MEKK1 fragments. Interaction between RhoA and MEKK1 seems to be activation-dependent (GTP-binding dependent) in yeast
-
additional information
synthetic construct
-
stimulation of MEKK1 kinase activity by RhoA in vitro
-
additional information
-
full-thickness skin injury markedly stimulates MEKK1 expression and activity
-
additional information
-
treatment of H1299-dnIkappaBalpha tumors with adenovirus-mediated overexpression of melanoma differentiation-associated gene-7 shows increased MEKK1 cleavage and activation of caspase-3, induces NF-kappaB expression in lung tumor cells in a time-dependent manner. NF-kappaB activation by overexpressed dnIkappaBalpha enhances the antitumor activity of melanoma differentiation-associated gene-7
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.02
ATP
-
recombinant COT30-397, pH 7.5, 22C, with 5 mM Mn2+
0.03
ATP
-
recombinant COT30-397/p105DELTAN and recombinant COT30-467/p105DELTAN, pH 7.5, 22C, with 5 mM Mn2+
0.31
ATP
-
recombinant COT30-397/p105DELTAN, pH 7.5, 22C, with 10 mM Mg2+
0.39
ATP
-
recombinant COT30-397, pH 7.5, 22C, with 10 mM Mn2+
0.394
ATP
-
recombinant COT30-467/p105DELTAN, pH 7.5, 22C, with 10 mM Mg2+
0.00016
MEK
-
recombinant COT30-467/p105DELTAN, pH 7.5, 22C, with 5 mM Mn2+
-
0.00019
MEK
-
recombinant COT30-397, pH 7.5, 22C, with 5 mM Mn2+
-
0.0003
MEK
-
recombinant COT30-397/p105DELTAN, pH 7.5, 22C, with 10 mM Mg2+; recombinant COT30-397/p105DELTAN, pH 7.5, 22C, with 5 mM Mn2+
-
0.00031
MEK
-
recombinant COT30-467/p105DELTAN, pH 7.5, 22C, with 10 mM Mg2+
-
0.00036
MEK
-
recombinant COT30-397, pH 7.5, 22C, with 10 mM Mg2+
-
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
LITERATURE
IMAGE
0.005
ATP
-
recombinant COT30-467/p105DELTAN, pH 7.5, 22C, with 10 mM Mg2+
0.006
ATP
-
recombinant COT30-467/p105DELTAN, pH 7.5, 22C, with 5 mM Mn2+
0.0328
ATP
-
recombinant COT30-397/p105DELTAN, pH 7.5, 22C, with 10 mM Mg2+
0.033
ATP
-
recombinant COT30-397/p105DELTAN, pH 7.5, 22C, with 5 mM Mn2+
0.245
ATP
-
recombinant COT30-397, pH 7.5, 22C, with 10 mM Mn2+
0.26
ATP
-
recombinant COT30-397, pH 7.5, 22C, with 5 mM Mn2+
0.005
MEK
-
recombinant COT30-467/p105DELTAN, pH 7.5, 22C, with 10 mM Mg2+
-
0.006
MEK
-
recombinant COT30-467/p105DELTAN, pH 7.5, 22C, with 5 mM Mn2+
-
0.0328
MEK
-
recombinant COT30-397/p105DELTAN, pH 7.5, 22C, with 10 mM Mg2+
-
0.033
MEK
-
recombinant COT30-397/p105DELTAN, pH 7.5, 22C, with 5 mM Mn2+
-
0.245
MEK
-
recombinant COT30-397, pH 7.5, 22C, with 10 mM Mg2+
-
0.26
MEK
-
recombinant COT30-397, pH 7.5, 22C, with 5 mM Mn2+
-
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
-
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
LITERATURE
7.3
-
assay at
7.4 - 7.5
-
assay at
7.4
-
assay at
7.4
Q7XTK4
assay at
7.4
-
assay at
7.4
-
assay at
7.5
-
assay at
7.6
-
assay at
7.9
-
assay at
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
22
-
assay at room temperature
22
-
assay at room temperature
22
Q7XTK4
assay at room temperature
25
-
assay at
30
-
assay at
30
-
assay at
30
-
assay at
30
-
assay at
TEMPERATURE RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
22 - 28
Q39008
-
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
bronchial epithelial cell line
Manually annotated by BRENDA team
-
TPL-2, TAK1
Manually annotated by BRENDA team
Mus musculus C57BL/6
-
-
-
Manually annotated by BRENDA team
-
high expression level of MEKK3
Manually annotated by BRENDA team
-
A-Raf is rarely mutated in human cancers
Manually annotated by BRENDA team
-
MLK2 expression correlates with cell elongation and the onset of an apoptotic phase
Manually annotated by BRENDA team
Q39008
preferential expression of MEKK1 in the vasculature
Manually annotated by BRENDA team
-
no changes in B-Raf activity after fertilization
Manually annotated by BRENDA team
-
no changes in B-Raf activity in the first embryonic cell cycles
Manually annotated by BRENDA team
-
MEKK4 mRNA is detected from stages embryonic day 8.5 through 14.5 encompassing prelooped, looping, cushion morphogenesis, and completed septation stages of heart development. MEKK4 protein is detected to the developing heart at stages embryonic day 10.5 to 14.5
Manually annotated by BRENDA team
-
gard cells of leaf and shoot epidermis
Manually annotated by BRENDA team
-
constitutive c-Mos expression transforms fibroblasts
Manually annotated by BRENDA team
-
cardiac myocytes
Manually annotated by BRENDA team
-
detection of MEKK4 transcripts to early myocardium, endocardium and to cardiac cushion cells that have executed epithelial to mesenchymal transformation
Manually annotated by BRENDA team
-
highly expressed in myocardium of embryonic heart, MLK3 and MLK7
Manually annotated by BRENDA team
-
embryonic kidney cell line
Manually annotated by BRENDA team
-
DLK acts as a key regulator of keratinocyte terminal differentiation and cornification
Manually annotated by BRENDA team
-
MEKK1 binds to the promoter of the WRKY53 gene regulating the switch from a leaf age dependent to a plant age dependent expression
Manually annotated by BRENDA team
Q39008
preferential expression of MEKK1 in the vasculature
Manually annotated by BRENDA team
-
highly expressed
Manually annotated by BRENDA team
-
TPL-2 and MEKK1
Manually annotated by BRENDA team
-
ASK1, TPL-2, MLK3, TAK1, MEKK1 and MEKK3
Manually annotated by BRENDA team
-
choroidal cancer cell line, expresses V599E mutant enzyme
Manually annotated by BRENDA team
-
fibroblast cell line
Manually annotated by BRENDA team
-
choroidal cancer cell line, expresses V599E mutant enzyme
Manually annotated by BRENDA team
-
highly expressed
Manually annotated by BRENDA team
-
no changes in B-Raf activity during progesterone-induced maturation
Manually annotated by BRENDA team
-
high expression level of MEKK3
Manually annotated by BRENDA team
-
embryo, MLK2 expression correlates with the differentiation and opening of the nephritic tubules, but not with apoptosis
Manually annotated by BRENDA team
Q75PK5
constitutive expression
Manually annotated by BRENDA team
Q6EE08, Q6EE09
basal level of FRK2 mRNA
Manually annotated by BRENDA team
Q75PK5
constitutive expression
Manually annotated by BRENDA team
Q75PK5
constitutive expression
Manually annotated by BRENDA team
-
highly expressed
Manually annotated by BRENDA team
-
choroidal cancer cell line, expresses V599E mutant enzyme
Manually annotated by BRENDA team
-
highly expressed
Manually annotated by BRENDA team
Q6EE08, Q6EE09
prior to fertilization, strongest FRK2 mRNA accumulation
Manually annotated by BRENDA team
Q6EE08, Q6EE09
prior to fertilization, strongest FRK2 mRNA accumulation
Manually annotated by BRENDA team
-
Tpl-2 isolated from Moloney leukemia virus-induced thymoma cells
Manually annotated by BRENDA team
-
highly expressed
Manually annotated by BRENDA team
Q6EE08, Q6EE09
basal level of FRK2 mRNA
Manually annotated by BRENDA team
Q39008
predominant expression of MEKK1
Manually annotated by BRENDA team
Mus musculus C57BL/6
-
-
-
Manually annotated by BRENDA team
-
MLK2 expression from late gastrula stage/early neurula stage on
Manually annotated by BRENDA team
-
mutated A-Raf
Manually annotated by BRENDA team
additional information
-
stomatal development and pattern is controlled by YODA
Manually annotated by BRENDA team
additional information
Q75PK5
the enzyme is ubiquitously expressed
Manually annotated by BRENDA team
additional information
-
tissue-specific expression of MLK2, no or very low expression in liver, lung, heart, muscle, and kidney
Manually annotated by BRENDA team
additional information
-
atrioventricular canal
Manually annotated by BRENDA team
additional information
-
H1299 cell, MRC-9 cell
Manually annotated by BRENDA team
additional information
Q6EE08, Q6EE09
ovule, strong up-regulation of FRK2 after fertilization, FRK2 mRNAs accumulate during early ovule development in the megasporocyte and in the integument of developing ovules
Manually annotated by BRENDA team
additional information
-
not detected in kidney and liver
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
Mus musculus C57BL/6
-
-
-
Manually annotated by BRENDA team
-
activation of MEK1 by C-Raf
Manually annotated by BRENDA team
-
MEKK1/WRKY53 complexes are predominantly localized in the nucleus
Manually annotated by BRENDA team
Mus musculus C57BL/6
-
to a lesser degree
-
Manually annotated by BRENDA team
Q7XTK4
basal activity level of OMTK1
-
Manually annotated by BRENDA team
-
activation of p42 MAPK
Manually annotated by BRENDA team
additional information
-
localized to perinuclear, vesicular compartment similar to the Golgi
-
Manually annotated by BRENDA team
additional information
-
ectopic expression of B-Raf in cutaneous melanoma cells
-
Manually annotated by BRENDA team
additional information
-
the enzyme colocalizes with focal adhesions
-
Manually annotated by BRENDA team
PDB
SCOP
CATH
ORGANISM
Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
Schizosaccharomyces pombe (strain 972 / ATCC 24843)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
34300
Q6EE08, Q6EE09
RNA gel blot analysis
681128
36200
Q6EE08, Q6EE09
Northern blot analysis
681128
45000
-
recombinant single COT30-397, gel filtration
663773
180000
-
-
491819
180000
-
-
491834
195000
synthetic construct
-
SDS-PAGE
681764
200000
-
about, recombinant aggregated COT30-397, gel filtration
663773
600000
-
about, recombinant aggregated, p105DELTAN-complexed COT30-467
663773
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY
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
-
COT30-467 forms very tightly bound complexes with p105DELTAN which remain intact at 2-4 M urea
additional information
-
DLK is a dual leucine zipper-bearing protein
additional information
-
MEKK1 forms complexes with FAK involved in regulation of cell migration, overview
additional information
-
structural analysis of the sterile alpha motif, SAM, domain of Ste11 MAPKKK and of Ste50 effector, several hydrophobic secondary structures and amino acids are required for effective binding, overview
additional information
-
subdomain VIII is a specificity-determining region in MEKK1
additional information
-
the C-terminus contains the kinase domain, two ubiquitin interaction motifs, a region of interaction with small GTPases, and a caspase 3-like cleavage site
additional information
-
the large enzyme possesses several domains including a proline-rich region, indispensable for activity, and a 60-amino acid-long polyglutamine stretch, which is not necessary for full activity
additional information
-
the MLTKalpha C-terminus possesses an alpha-motif in vicinity to the leucine zipper, the alpha-motif is supposed to be a regulatory and phosphorylation site
additional information
-
the subdomain X is required for phosphorylation and activation of MAPKKs in vivo
additional information
Q62073
TAK1 domain structure, overview
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phosphoprotein
-
activation by phosphorylation
phosphoprotein
Q99759
-
phosphoprotein
-
MEKK2 and MEKK3 are phosphorylated at the N-terminus and thereby activated by kinase WNK1, residues K385 and K391, respectively, are involved
phosphoprotein
-
MLTKalpha is phosphorylated by PKNalpha, probably at the C-terminal alpha-motif
phosphoprotein
-
phosphorylation activates the enzyme
phosphoprotein
-
MEKK2 and MEKK3 are activated by phosphorylation, determination of phosphorylation sites, S519 is a key regulator phosphorylation site in MEKK2,other sites are Thr521 and Thr523
phosphoprotein
-
phosphorylation activates the enzyme
proteolytic modification
-
cleavage by caspase-3 at a specific C-terminal cleavage site generates a 91 kDa, catalytically active enzyme fragment
phosphoprotein
-
the enzyme performs autophosporylation
phosphoprotein
-
phosphorylation at Ser526 and Thr530 in the activation loop is required for MEKK3 activation, dephosphorylation is blocked by binding to protein 14-3-3
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
-80C
synthetic construct
-
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
-
recombinant protein by tandem affinity purification
-
purification of recombinant MEKK1 and ASK1 by chitin affinity chromatography, endogenous MEKK1 by protein A affinity chromatography
-
recombinant His6- and GST-tagged wild-type and mutants enzymes from Escherichia coli by affinity chromatography and gel filtration, the tags are cleaved off
-
by centrifugation and on Ni2+-NTA resin
synthetic construct
-
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
-
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
expression of Myc-tagged MEKK1 under the 35 S cauliflower mosaic virus promoter in Arabidopsis protoplasts
-
full-length cDNA inserted into pGBKT7 vector to generate a MEKK1-GBD fusion construct, introduced into yeast strain Y187 containing the LacZ gene under the control of the GAL1 promoter, full-length MEKK1 fragments subcloned into the pQE30 expression vector to create pQE-MEKK1 encoding the 6 x His-tagged protein and expressed in Escherichia coli, full-length MEKK1 cDNA fragment with a HA-tag cloned into the pGFPc155c vector encoding the C-terminal part of the GFP protein and transformed to Agrobacterium tumefaciens strain GV3101/pMP90 and injected to Arabidopsis leaves
-
gene YDA, transcriptome analysis of seedlings with wild-type and altered YODA activity, overview
-
MEKK1 and mutant K361M constructs introduced into Arabidopsis plants via Agrobacterium transformation
-
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
Q6VAB6
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
Q99759
gene M3Kalpha, DNA and amino acid sequence determination and analysis
Q75PK5
OMTK1, DNA and amino acid sequence determination, expression as GST-fusion protein, transient co-expression of Myc-tagged OMTK1 and HA-tagged MMK3 in Arabidopsis thaliana protoplasts, in vitro trabscription and translation of wild-type and mutant OMTK1 by reticulocyte lysate
Q7XTK4
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
-
expression of a MEKK1 promoter-driven beta-Gal fusion protein in Mekk1deltaKD/deltaKD mice
-
expression of GST-tagged full length MEKK2 and MEKK2 C-terminal and N-terminal fragments, i.e. of residues 1-619, 342-619, and 342-424, in COS-1 cells
-
expression of HA-tagged active MEKK2 and inactive S519A MEKK2 mutant catalytic sites, expression of wild-type and mutant full length MEKK2s and of wild-type and mutant MEKK3s
-
expression of His6-tagged MEKK1 subdomain VIII, comprising residues 1174-1493, His6-tagged wild-type, full-length enzyme, and His6-tagged mutant enzymes F1443A, I1394/L1402A, Q1405R/Q1406R, and L1402A/F1443A in HeLa and COS-1 cells
-
full-length ASK2 cDNA inserted in pJG4-5, kinase-negative mutant of ASK1 inserted in pEG202. ASK1 and ASK2 constructs co-transformed along with the reporter plasmid pSH18-34 in EGY48 yeast strains, mutants transfected into HEK293 cells and MEF cells
Q9WTR2
into pBluescript, SF-9 insect cells infected with baculovirus expressing either MEKK4 or the kinase inactive form of MEKK4
-
into PCR3.1 vector and expressed in HEK-293 cells
-
MEKK1 fragments (1-132, 149-347, 149-636, 630-772, 766-1173, 766-1493, 1-719, and 565-1174) incorporated into pAS1CYH2 vector, expressed in Saccharomyces cerevisiae Y190 cells
-
MEKK2, DNA and amino acid sequence determination, expression of wild-type and mutant MEKK2 by reticulocyte lysate TnT T7 mixture, expression of wild-type and mutant MEKK2 and MEKK1 in COS-1 cells and in HeLa cells, coexpression with ERK5 in COS-1 cells
-
TAK1 expressed in HeLa cells
-
TAK1 expression in HEK-293 cells, Ror2-Tak1 interaction analysis by expression in the yeast two-hybrid system
Q62073
transient co-expression of MEKK1 and FAK in HEK293 cells
-
wild-type and mutant enzyme
-
DNA and amino acid sequence determination and analysis, sequence comparisons, overview, MAPKKKalpha overexpression in leaves using the Agrobacterium tumefaciens transfection system
Q6RFY4
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
-
expression of MEKK1 and ASK1 in CV-1 cells using a vaccinia virus transfection system
-
isolation and characterization
-
overexpression of His6- and GST-tagged wild-type and mutants enzymes in Escherichia coli
-
phylogenetic tree of kinases derived from the kinase core sequence, overview, overexpression as GST-fusion protein under control of the galactose-inducible GAL1 promotor in Escherichia coli, determination of 5'-end sequences
-
transgenic plants carrying the sense or antisense construct of FRK2
Q6EE08, Q6EE09
DNA and amino acid sequence determination and analysis, sequence comparisons, overview
Q6RFY3
expression vector for the catalytic domain of MEKK1 expressed in a beta cell line or in primary pancreatic islets from transgenic mice
synthetic construct
-
FLAG-MEKK3 excised from pBTM116 and ligated into the EcoRV site of pcDNA3.1, HEK293 EBNA cells transiently transfected with MEKK3, K391M, or point mutants in the pcDNA3.1 HisA plasmid HisA
synthetic construct
-
MEKK1 cDNA sequence amplified from the pCEP4-HAMEKK1 plasmid and ligated into baculovirus transfer vector pVL1393. Recombinant baculoviruses generated by contransfection with linear wild-type baculoviral DNA into Sf9 cells
synthetic construct
-
MEKK1 construct expressed using CV-1 cells
synthetic construct
-
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
-
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
-
ENGINEERING
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
K361M
-
kinase-inactive MEKK1, rescues the mekk1 dwarf penotype. Elevated temperature dramatically improves the growth of mekk1 plants. K361M plants are fully fertile and grow with a morphology closely resembling wild-type plants. When treated with pathogenic bacteria, K361M plants are slightly more susceptible to an avirulent strain of Pseudomonas syringae and show a delayed hypersensitive response
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
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
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
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
Q99759
MEKK3 with double alanine mutations can not bind the catalytic subunit of protein phosphatase 2a
T516E/S520D
Q99759
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
C433A
-
completely abolishes its interaction with RhoA
C441A
-
site-directed mutagenesis, the mutant enzyme is not ubiquitinylated and thus shows a higher ERK activating activity
F1443A
-
site-directed mutagenesis of MEKK1, the mutation abolishes the in vitro interaction with MKK4, but retains the in vivo activity
F1443A
-
site-directed mutagenesis, subdomain X mutation, the mutant shows reduced activity compared to the wild-type enzyme
F571A
-
site-directed mutagenesis of MEKK2, inactive mutant
G452C/R454C/N455D
-
completely abolishes its interaction with RhoA
I1394/L1402A
-
site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type enzyme
I1445A
-
site-directed mutagenesis of MEKK1, the mutation has a deleterious effect on MEKK1 function
I1454A
-
site-directed mutagenesis of MEKK1, the mutation abolishes the in vitro interaction with MKK4, but retains the in vivo activity
I573A
-
site-directed mutagenesis of MEKK2, inactive mutant
K1361R
-
shows remarkable increase in the number of neural tube defects
L1402A/F1443A
-
site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type enzyme
L1458A
-
site-directed mutagenesis of MEKK1, the mutation has a deleterious effect on MEKK1 function
P1452A
-
site-directed mutagenesis of MEKK1, the mutation has a deleterious effect on MEKK1 function
P1455A
-
site-directed mutagenesis of MEKK1, the mutation has a deleterious effect on MEKK1 function
P580A
-
site-directed mutagenesis of MEKK2, the mutant shows 82% of wild-type activity
P584A
-
site-directed mutagenesis of MEKK2, the mutant shows activity similar to the wild-type enzyme
Q1405R/Q1406R
-
site-directed mutagenesis C-terminal to the subdomain VIII, creation of an optimal recognition site for protease furin, the mutant binds MKK4 more tightly than the wild-type enzyme, MKK4 binding protects the mutant enzyme from proteolytic cleavage
S1459A
-
site-directed mutagenesis of MEKK1, the mutation abolishes the in vitro interaction with MKK4, but retains the in vivo activity
S519A
-
site-directed mutagenesis, MEKK2 phosphorylation site mutant, inactive mutant
S526A
-
site-directed mutagenesis, MEKK3 phosphorylation site mutant, inactive mutant
S526A/K391M
-
critical phosphorylation site and catalytic site
T521A
-
site-directed mutagenesis, MEKK2 phosphorylation site mutant, the mutant shows slightly reduced activity compared to the wild-type enzyme
T523A
-
site-directed mutagenesis, MEKK2 phosphorylation site mutant, the mutant shows slightly reduced activity compared to the wild-type enzyme
T575A/Q576A/P577A
-
site-directed mutagenesis of MEKK2, inactive mutant
A62D
-
site-directed mutagenesis, no binding of Ste50
DELTA321-340
-
practically identical to the wild type
DELTA341-360
-
practically identical to the wild type
DELTA361-380
-
practically identical to the wild type
DELTA381-400
-
defective in osmotic induction of the 8xCRE-lacZ reporter, mutant is osmosensitive
DELTA401-420
-
defective in osmotic induction of the 8xCRE-lacZ reporter, mutant is osmosensitive
DELTA421-440
-
defective in osmotic induction of the 8xCRE-lacZ reporter, mutant is osmosensitive
I59R
-
site-directed mutagenesis, no binding of Ste50
K391M
synthetic construct
-
catalytically inactive mutant of MEKK3, is not phosphorylated at Ser526, abrogates NF-kappaB luciferase activity
S511A
synthetic construct
-
can activate the ERK pathway
S526A
synthetic construct
-
fails to activate the NF-kappaB luciferase reporter gene and is unable to activate the MEK and ERK pathway
S526D
synthetic construct
-
is capable of activating a NF-kappaB luciferase reporter gene as well as ERK and MEK
S526E
synthetic construct
-
is capable of activating a NF-kappaB luciferase reporter gene as well as ERK and MEK
T516A
synthetic construct
-
can activate the ERK pathway
T520A
synthetic construct
-
can activate the ERK pathway
T522A
synthetic construct
-
can activate the ERK pathway
T528A
synthetic construct
-
can activate the ERK pathway
T530A
synthetic construct
-
fails to activate the NF-kappaB luciferase reporter gene and is unable to activate the MEK and ERK pathway
T530D
synthetic construct
-
unable to activate MEKK3-dependent signaling pathways
K361M
-
mutation of the kinase domain of MEKK1 reduces the relative expression of the WRKY53 promoter driven GUS gene from 200% in the presence of intact MEKK1 to 132% in the presence of the mutated form
additional information
-
YODA null mutation leads to excess stomata, whereas constittive activation of YODA eliminated stomata
additional information
-
mekk1 knockout mutants, display a severe dwarf phenotype, constitutive callose deposition, and constitutive expression of pathogen response genes. The dwarf phenotype is largely rescued by introduction into mekk1 knockout plants of either mutant K361M or a nahG transgene that degrades salicylic acid
additional information
Q39008
mekk1-1 and mekk1-2 mutants, exhibit dwarfism and lethality, and also showed early senescence in cotyledons, loss of MEKK1 results in tissue-specific cell death, tissue-specific H2O2 accumulation and constitutive defense responses. Little or no suppression of dwarfism in mekk1/edm1 or mekk1/rar1 double mutants compared with mekk1 when grown at 22C, but dwarf phenotype is highly recovered in mekk1/rar1 at 26C, whereas mekk1/edm1 plants are only slightly bigger than mekk1. In mekk1/sid2 mutants growth defect, cell death, H2O2 accumulation and callose deposition phenotypes are not suppressed at 22C. However, similar to rar1, sid2 partially suppresses these mekk1 phenotypes at 26C, although the suppression effect is not as strong as in rar1
additional information
-
MEKK1-deficient plants, are misregulated in the expression of a number of genes involved in cellular redox control and accumulate reactive oxygen species. Homozygous mekk1 mutant plants exhibit a lethal phenotype when developing true leaves. Mutant plants stay dwarfed and never reach maturity to produce seeds. Mekk1 and mpk4 mutant plants show similarities with respect to both, phenotype and H2O2 accumulation
K7R
-
sustains the strong binding affinity, Kd is 0.37 micromol, dilution is exothermal like with wild-type
additional information
-
construction of a kinase-defective MTLKalpha mutant, expression of a kinase-defective PKNalpha mutant results in inhibition of MLTKalpha activity and p38 kinase induction
additional information
-
MEKK3 overexpression confers resistance to apoptosis through activation of NF-kappaB
additional information
-
overexpression of DLK in cultured keratinocytes results in altered features of the cell concerning suprabasal localization, cell shape, compacted cytoplasm, DNA fragmentation, and regulation of filaggrin expression, which is upregulated, terminally differentiated phenotype, the transglutaminase activity is increased leading to cornified cell envelope formation, overview
additional information
-
overexpression of WNK1 in HEK293 cells leads to increased enzyme activity, a kinase-dead mutation of MEKK1 does not influence the ERK5 activation level
additional information
-
the BRAF gene is mutated in several cancers, especially in cutaneous melanoma
additional information
-
deletion of the CRIB domain of MEKK4 diminishes but does not abolish Cdc42 binding
additional information
-
MEKK1 knockdown in invasive human breast carcinoma cells leads to reduced uPA expression, cell migration, and invasiveness
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
Q7XTK4
an OMTK1 mutant reduced in MMK3 complex formation shows decreased MMK3 and cell death activation
L582A/P583A
-
site-directed mutagenesis of MEKK2, inactive mutant
additional information
-
mutations in the MEKK subdomain X differentially affect MEKK2 and MEKK1 activity, overview
additional information
-
ASK1-/- cells, are resistant to TNF-induced apoptosis, produce low levels of TNF after LPS injection and are resistant to LPS-induced septic shock. In macrophages from TPL-2 deficient mice, activation of ERK is blocked following TLR4, TLR2 or TNFR1 stimulation, whereas activation of p38 and JNK via these receptors is unaffected, LPS upregulation of TNF is reduced, are resistant to endotoxin shock induced by LPS and D-galactosamine. TAK1-/- mice die early in uterus. Mlk3-/- mice are viable. In Mekk1-/- mice, normal or blocked JNK activation induced by TNF and IL-1, discrepancy in two different studies. MEKK3-deficient mice, embryonic lethal, activation of JNK and p38 is blocked, but not of ERK by IL-1 and TLR4
additional information
Q9WTR2
endogenous ASK2 constitutively degraded in ASK1-deficient cells, kinase-negative mutant of ASK1 effectively activates MAP2K and is more competent to respond to oxidative stress than ASK2 alone. Knockdown of ASK2 reveals that ASK2 is required for oxidative stress-induced JNK activation
additional information
-
Gckr-/- cells, have a significant defect in Wnt-mediated JNK activation and in induction of beta-catenin compared to wild-type
additional information
-
kinase inactive form of MEKK4, attenuates mesenchyme production
additional information
-
MEKK1-4 knockout mice, MEKK3 knockout is embryo-lethal, displaying inadequate fetal-maternal vascularization. MEKK4 knockout is largely perinatal lethal, and associated with defective neural tube closure, shows loss of JNK and p38 activation. MEKK1-2 knockouts are associated with impaired tissue remodeling associated with wound healing and homeostasis, expression of JunB and Fra-2 is markedly increased in MEKK1-deficient mouse fibroblasts. MLK3-deficient mice are viable and fertile with only a mild defect in the epidermal tissue of the dorsal midline. Mouse embryos deficient in either B-Raf or C-Raf die before day E12.5. A-Raf deficient mice die perinatally at 1-3 weeks of age. Tpl2-deficient mice are viable and appear indistinguishable from littermates, produce reduced levels of TNFalpha in response to LPS injection, are resistant to LPS/D-galactosamine-induced pathology. TAK1-deficient mouse embryo fibroblasts show decreased IL-1beta-induced IL-6 expression, TAK1-deficient keratinocytes develop a severe postnatal inflammation, loss of MEKK1 does not alter the course of tumorigenesis or inhibit primary tumor growth, intimal hyperplasia is significantly reduced
additional information
-
Mekk1deltaKD/deltaKD mice, MEKK1 ablation significantly delays skin wound closure and impairs activation of Jun NH2-terminal kinases, induction of plasminogen activator inhibitor 1, and restoration of cell-cell junctions of the wounded epidermis. Reconstituting MEKK1 expression with MEKK1 wild-type expression significantly accelerates wound closure
additional information
-
MEKK4-/- mice, protein is not essential for embryonic survival, but more than 80% of mice exhibit neural tube defects and die shortly after birth. Reduced level of IFN-gamma production in response to cytokine treatment. MEKK4-3R mutant, completely abolishes CIN85 interaction and is defective in activating the p38 pathway. Intermediate MKK6 causes reduction in p38 activation in response to both oxidative stress and epidermal growth factor stimulation, less prone to ubiquitination
V586A
-
site-directed mutagenesis of MEKK2, the mutant shows activity similar to the wild-type enzyme
additional information
Mus musculus C57BL/6
-
Gckr-/- cells, have a significant defect in Wnt-mediated JNK activation and in induction of beta-catenin compared to wild-type
-
additional information
Q6RFY4
construction of mutant plants for identification of genes and pathway functioning in hypersensitive response and resistance by MAPKKKalpha silencing, co-expression of tomato resistance R gene Cf9 and the Cladosporium fulvum avirulence gene avr9, a multicomponent transgenic construct, overexpression of the full length Lycopersicon esculentum enzyme or the isolated tomato enzyme kinase domain in leaves leads to pathogen-independent cell death induction, overview
additional information
-
enzyme-defective mutant strains AS4-44 and AS6-5 are impaired in the development of crippled growth after infection causing a cell degenerative process, and are defective in mycelium pigmentation, aerial hyphae differentiation, and making of fruiting bodies showing female sterility, construction of mutants lacking the proline-riche region or the polyglutamine stretch, mutant phenotypes, overview
L72R
-
site-directed mutagenesis, highly increased tight binding of Ste50 wild-type compared to the Ste11 wild-type enzyme
additional information
-
inhibition of heterodimeric association of Ste11 and Ste50 in yeast strains leads to defects in mating and activation of high-osmolarity growth pathways
additional information
-
ssk2delta/ssk22delta/ste11delta strain, complementation of the osmo-sensitive phenotype, deletion of the LD domain of Ssk2p results in a serious localization defect when yeast cells are exposed to osmotic stress as well as an inability to facilitate the actin specific functions of Ssk2p
Y54R
-
site-directed mutagenesis, no binding of Ste50
additional information
Q6EE08, Q6EE09
FRK2-S2, FRK2-S17, FRK2-S5, FRK2-S7, FRK2-S9, and FRK2-11 mutant sense lines reveal that overexpression of FRK2 produces smaller than normal fruits containing fewer seeds, FRK2-S2 and FRK2-S17 mutant sense lines reveal that overexpression of FRK2 leads to transformation of ovules into carpelloid structures, FRK2-S20 mutant sense line shows complete co-suppression for FRK2, plants containing the antisense construct show reduced ScFRK2 mRNA levels compared with the wild-type
additional information
Q6RFY3
overexpression of the full length enzyme or the isolated tomato enzyme kinase domain in Nicotiana benthiana leaves leads to pathogen-independent cell death induction, overview
T530E
synthetic construct
-
unable to activate MEKK3-dependent signaling pathways
additional information
-
enzyme inactivation by antisense expression method and expression of dominant negative MLK2 defective in the ATP binding site, which impairs the UV irradiation sensitivity, overview
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
analysis
-
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
-
cleavage of MEKK1 and caspase-3 is highly increased in adenovirus-mediated overexpression of melanoma differentiation-associated gene-7treated H1299-dnIkappaBalpha tumors than in adenovirus-mediated overexpression of melanoma differentiation-associated gene-7treated H1299-Neo tumors
medicine
-
GCKR facilitates both canonical and noncanonical Wnt signaling in B lymphocytes
medicine
-
gene amplification and corresponding increased Tpl-2 expression in some human breast cancers
medicine
-
GCKR facilitates both canonical and noncanonical Wnt signaling in B lymphocytes
medicine
-
MEKK4 is a critical signaling molecule during cardiovascular development, plays an important role in cardiac cushion morphogenesis, kinase activity of MEKK4 is essential, but not sufficient, to support developmental epithelial to mesenchymal transformation
medicine
Mus musculus C57BL/6
-
GCKR facilitates both canonical and noncanonical Wnt signaling in B lymphocytes
-
additional information
-
may play a structural role in signaling, independent of its protein kinase activity, MEKK1 kinase activity may not be required to activate FLS2-mediated defense responses in Arabidopsis. MEKK1 acts upstream of MPK4 as a negative regulator of pathogen response pathways, a function that may not require MEKK1's full kinase activity
additional information
-
MEKK1 has a dual function, it can bind to the promoter of WRKY53 and it can interact with the WRKY53 on the protein level and can phosphorylate WRKY53 in vitro thereby increasing its DNA-binding activity. MEKK1 may be able to take a very direct short cut in MAPK signalling by directly phosphorylating a transcription factor
additional information
Q39008
MEKK1 negatively regulates temperature-sensitive and tissue-specific cell death and H2O2 accumulation that are partly dependent on both RAR1, a key component in resistance protein function, and SID2, an isochorismate synthase required for salicylic acid production upon pathogen infection
additional information
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MEKK1 regulates multiple processes during vegetative development, accumulation of reactive oxygen species and redox homeostasis
medicine
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stress kinase MEKK1-induced MMP-1 expression in human arthritis-affected synovial cells is mediated, in large part, by c/EBPbeta (NF-kappaBp65) promoter transactivation
additional information
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ASK2, a highly related serine/threonine kinase to ASK1, functions as a MAP3K only in a heteromeric complex with ASK1
additional information
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two isoforms of MEKK4, monitors the integrity of the actin cytoskeleton and regulates its recovery from osmotic stress, MEKK4 and TRAF4 are involved in the process of neurulation
medicine
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role in epithelial wound healing, transmits wound signals, leading to the transcriptional activation of genes involved in ECM homeostasis, epithelial cell migration, and wound reepithelialization
additional information
Q9WTR2
ASK2, a highly related serine/threonine kinase to ASK1, functions as a MAP3K only in a heteromeric complex with ASK1
additional information
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two isoforms of MEKK4, play a role in downregulating apoptosis during neurulation via the p38 MAPK pathway
analysis
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development of a protein chip consisting of a silicone elastomer microwell array with recombinant enzyme covalently attached to the wells via a 3-glycidoxypropyltrimethoxysilane crosslinker for large scale activity assay, overview
additional information
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Ssk2p is one of the three MEKK kinases in the HOG pathway, the other two being Ste11p and Ssk22p, Ssk2p is homologous to MEKK4, monitors the integrity of the actin cytoskeleton and regulates its recovery from osmotic stress
additional information
Q6EE08, Q6EE09
role of FRK2 in pre- and post-fertilization events, overexpression of FRK2 leads to the production of fruits with a severely reduced number of seeds, and leads to changes in the expression of the class D floral homeotic gene ScFBP11, suggesting that FRK2 kinase may interact, directly or indirectly, with the FBP7/11 pathway that directs establishment of ovule identity
medicine
synthetic construct
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IL-1beta through MEKK1 inhibits human insulin gene transcription and does so, at least in part, by decreasing MafA transcriptional activity at the RIPE3b control element. Since inappropriate insulin biosynthesis contributes to beta cell dysfunction, inhibition of MEKK1 may decelerate or prevent progression from a prediabetic state to diabetes mellitus
additional information
synthetic construct
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cells can customize their transcriptional response to MAPKKK cascade signaling by selective expression of the SMRT or N-CoR locus, by selective utilization of a specific corepressor splice variant, and by selective exploitation of specific tiers of the MAPK cascade
additional information
synthetic construct
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the association between MEKK3 and 14-3-3 is dependent on Ser526 and prevents dephosphorylation of Ser526 in HEK293 EBNA cells, Ser526 of MEKK3 is an autophosphorylation site within the T-loop that is regulated by PP2A and 14-3-3 proteins