Information on EC 2.7.12.2 - mitogen-activated protein kinase kinase

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The expected taxonomic range for this enzyme is: Eukaryota

EC NUMBER
COMMENTARY
2.7.12.2
-
RECOMMENDED NAME
GeneOntology No.
mitogen-activated protein kinase kinase
-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
ATP + a protein = ADP + a phosphoprotein
show the reaction diagram
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
ATP:protein phosphotransferase (MAPKKK-activated)
This enzyme is a dual-specific protein kinase and requires mitogen-activated protein kinase kinase kinase (MAPKKK) for activation. It is required for activation of EC 2.7.11.24, mitogen-activated protein kinase. Phosphorylation of MEK1 by Raf involves phosphorylation of two serine residues [5]. 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 ACCESSION NO.
COMMENTARY
LITERATURE
apoptosis signal-regulating kinase 1
O35099
-
ASK1
Q99683
-
ASK1
O35099
-
CaSTE7
P0CY25
-
cdc7 protein kinase
P41892
-
Cdc7p kinase
P41892
-
cell division control protein 7
P41892
-
dual specificity mitogen-activated protein kinase kinase 1
Q63980
-
dual specificity mitogen-activated protein kinase kinase 1
Q02750
-
dual specificity mitogen-activated protein kinase kinase 1
P31938
-
dual specificity mitogen-activated protein kinase kinase 1
P29678
-
dual specificity mitogen-activated protein kinase kinase 1
Q01986
-
dual specificity mitogen-activated protein kinase kinase 1
Q05116
-
dual specificity mitogen-activated protein kinase kinase 2
Q90321
-
dual specificity mitogen-activated protein kinase kinase 2
Q90891
-
dual specificity mitogen-activated protein kinase kinase 2
P36507
-
dual specificity mitogen-activated protein kinase kinase 2
Q63932
-
dual specificity mitogen-activated protein kinase kinase 2
P36506
-
dual specificity mitogen-activated protein kinase kinase 3
P46734
-
dual specificity mitogen-activated protein kinase kinase 3
O09110
-
dual specificity mitogen-activated protein kinase kinase 4
P45985
-
dual specificity mitogen-activated protein kinase kinase 4
P47809
-
dual specificity mitogen-activated protein kinase kinase 5
Q13163
-
dual specificity mitogen-activated protein kinase kinase 5
Q62862
-
dual specificity mitogen-activated protein kinase kinase 6
P52564
-
dual specificity mitogen-activated protein kinase kinase 6
P70236
-
dual specificity mitogen-activated protein kinase kinase 7
O14733
-
dual specificity mitogen-activated protein kinase kinase dSOR1
Q24324
-
dual specificity mitogen-activated protein kinase kinase hemipterous
Q23977
-
dual specificity mitogen-activated protein kinase kinase mek-2
Q10664
-
dual specificity protein kinase FUZ7
Q99078
-
extracellular signal-regulated kinase
-
-
extracellular signal-regulated kinase
P31938
-
extracellular-signal-regulated kinase
-
-
extracellular-signal-regulated kinase
-
-
extracellular-signal-regulated kinase 1
-
-
extracellular-signal-regulated kinase 2
-
-
HEP protein
Q23977
-
JNKK2
O14733
-
mammalian MAP kinase kinase
Q63980
-
MAP kinase kinase
A2XE35, A3FK65, Q0MSI2, Q0Z7Z4, Q5QN75
-
MAP kinase kinase 4
-
-
MAP kinase kinase 4
P45985
-
MAP kinase kinase 4
P47809, Q8CE90
-
MAP kinase kinase 4
-
-
MAP kinase kinase homologue
Q9GRT1
-
MAP kinase kinase MKK1/SSP32
P32490
-
MAP kinase kinase MKK2/SSP33
P32491
-
MAP kinase kinase skh1/pek1
Q9Y884
-
MAP3K11
-
-
MAPK kinase
-
-
MAPK kinase
Arabidopsis thaliana Col-0
-
-
-
MAPK kinase
-
-
MAPK kinase
-
-
MAPK kinase 3
-
-
MAPK kinase kinase-1
-
-
MAPK kinase-1
-
-
MAPK/Erk kinase
P31938
-
MAPK/Erk kinase
-
-
MAPK/ERK kinase 5
Q13163
-
MAPKK
Arabidopsis thaliana Col-0
-
-
-
MAPKK
-
-
MAPKK 1
Q5QN75
-
MAPKK 10-2
A2XE35
-
MAPKK 3
A3FK65
-
MAPKK 4
Q0MSI2
-
MAPKK 6
Q0Z7Z4
-
MAPKK1
P31938
-
MAPKK2
P36507
-
MAPKKK5
Q99683
-
MEK
P31938
-
MEK 1
-
-
MEK 2
-
-
MEK kinase 1
Q62925
-
MEK kinase 2
Q9Y2U5
-
MEK/ERK
-
-
MEK1
Q63980
-
MEK1
-
-
MEK1
P31938
-
MEK1
Q01986
-
MEK2
-
-
MEK2
Q90891
-
MEK2
-
-
MEK2
-
-
MEK2
Q63932
-
MEK5
Q13163
-
MEK5
Q62862
-
MEKK 2
Q61083
-
MEKK-1
-
-
MEKK1
O14733
-
MEKK3
Q99759
-
mitogen activated protein kinase kinase 6
A9UK00
-
mitogen-activated protein kinase kinase
-
-
mitogen-activated protein kinase kinase
-
-
mitogen-activated protein kinase kinase
-
-
mitogen-activated protein kinase kinase 1
-
-
mitogen-activated protein kinase kinase 1
-
-
mitogen-activated protein kinase kinase 2
-
-
mitogen-activated protein kinase kinase 2
-
-
mitogen-activated protein kinase kinase 2
-
-
mitogen-activated protein kinase kinase 3
-
-
mitogen-activated protein kinase kinase 4
-
-
mitogen-activated protein kinase kinase 4
-
-
mitogen-activated protein kinase kinase 4
P45985
-
mitogen-activated protein kinase kinase 4
Q9GRT1
-
mitogen-activated protein kinase kinase 4
-, P47809, Q8CE90
-
mitogen-activated protein kinase kinase 4
-
-
mitogen-activated protein kinase kinase 6
-
-
mitogen-activated protein kinase kinase 7gamma1
O14733
-
mitogen-activated protein kinase kinase homologue
Q9GRT1
-
mitogen-activated protein kinase kinase kinase 1
Q62925
-
mitogen-activated protein kinase kinase kinase 11
-
-
mitogen-activated protein kinase kinase kinase 2
Q9Y2U5
-
mitogen-activated protein kinase kinase kinase 2
Q61083
-
mitogen-activated protein kinase kinase kinase 3
Q99759
-
mitogen-activated protein kinase kinase kinase 3
Q61084
-
mitogen-activated protein kinase kinase kinase 4
Q9Y6R4
-
mitogen-activated protein kinase kinase kinase 5
Q99683
-
mitogen-activated protein kinase kinase kinase 5
O35099
-
mitogen-activated protein kinase kinase type 2
Q90891
-
mitogen-activated protein kinase kinase-1
-
-
mitogen-activated protein kinase kinase-4
-
-
mitogen-activated protein kinase kinase/extracellular signal–regulated kinase
-
-
mitogen-activated protein kinase/ERK kinase kinase 3
Q99759
-
mitogen-activated protein/ERK kinase kinases
Q61083
-
MKK homologue
Q9GRT1
-
MKK1
Q02750
-
MKK3
Arabidopsis thaliana Col-0
-
-
-
MKK4
P45985
-
MKK4
-, P47809, Q8CE90
-
MKK4/SEK1
-
-
MKK6
-
-
MKK6
P52564
-
MKK6
A9UK00
-
MKK7
O14733
-
MKK7
Q8CE90
-
p120cdc7 protein kinase
P41892
-
p21cdc42/rac1 binding protein
Q64303
-
polymyxin B resistance protein kinase
P08018
-
protein kinase byr1
P10506
-
protein kinase wis1
P33886
-
SAPK/ERK kinase-1
P47809
-
SAPKK3
P52564
-
serine/threonine protein kinase STE7
P06784
-
serine/threonine protein kinase STE7 homolog
P0CY25
-
serine/threonine-protein kinase PAK 2
Q64303
-
serine/threonine-protein kinase PAK 7
Q9P286
-
stress-activate protein kinase/extracellular signal-regulated protein kinase kinase-1
-
-
wis1 protein kinase
P33886
-
MKK7gamma1
O14733
-
additional information
-
MKK3 is a group B MAPK kinase
additional information
Arabidopsis thaliana Col-0
-
MKK3 is a group B MAPK kinase
-
additional information
-
the enzyme belongs to the MKK familly
additional information
O14733, P45985
the enzyme belongs to the MKK familly
additional information
P47809, Q8CE90
the enzyme belongs to the MKK familly
additional information
-
the enzyme belongs to the MKK familly
CAS REGISTRY NUMBER
COMMENTARY
142805-58-1
-
ORGANISM
COMMENTARY
LITERATURE
SEQUENCE CODE
SEQUENCE DB
SOURCE
Col-0; the genome contains genes encoding 10 MAPK kinases
-
-
Manually annotated by BRENDA team
MKK1; gene mkk1
UniProt
Manually annotated by BRENDA team
MKK2; gene mkk2
UniProt
Manually annotated by BRENDA team
Arabidopsis thaliana Col-0
Col-0
-
-
Manually annotated by BRENDA team
-
SwissProt
Manually annotated by BRENDA team
-
SwissProt
Manually annotated by BRENDA team
-
SwissProt
Manually annotated by BRENDA team
-
SwissProt
Manually annotated by BRENDA team
MKK4
SwissProt
Manually annotated by BRENDA team
MKK7
SwissProt
Manually annotated by BRENDA team
cv. Tainung 57
-
-
Manually annotated by BRENDA team
-
SwissProt
Manually annotated by BRENDA team
-
SwissProt
Manually annotated by BRENDA team
-
SwissProt
Manually annotated by BRENDA team
adult F1 mice and postnatal day-14, -22, -30, and -60 mice
-
-
Manually annotated by BRENDA team
C57B/Ka-Thy1.1 mice at 6-10 weeks of age
-
-
Manually annotated by BRENDA team
MEK1
SwissProt
Manually annotated by BRENDA team
MEK2
SwissProt
Manually annotated by BRENDA team
MKK4
SwissProt
Manually annotated by BRENDA team
MKK7
UniProt
Manually annotated by BRENDA team
MAPKK 10-2; cv. japonica and indica, var. Pusa Basmati 1, MAP kinase kinase isozyme MAPKK 10-2
UniProt
Manually annotated by BRENDA team
MAPKK 1; cv. japonica and indica, var. Pusa Basmati 1, MAP kinase kinase isozyme MAPKK 1
UniProt
Manually annotated by BRENDA team
MAPKK 3; cv. japonica and indica, var. Pusa Basmati 1, MAP kinase kinase isozyme MAPKK 3
UniProt
Manually annotated by BRENDA team
MAPKK 4, fragment; cv. japonica and indica, var. Pusa Basmati 1, MAP kinase kinase isozyme MAPKK 4
UniProt
Manually annotated by BRENDA team
MAPKK 6; cv. japonica and indica, var. Pusa Basmati 1, MAP kinase kinase isozyme MAPKK 6
UniProt
Manually annotated by BRENDA team
adult female Wistar rats
-
-
Manually annotated by BRENDA team
Sprague-Dawley rats
-
-
Manually annotated by BRENDA team
MKK6a; the fish does not possess a MKK3 gene
UniProt
Manually annotated by BRENDA team
SUBSTRATE
PRODUCT                      
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
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
-
MKK1 phosphorylates and activates the MAP kinases ERK1 and ERK2
-
-
?
ATP + ERK
ADP + phosphorylated ERK
show the reaction diagram
-
ERK phosphorylation by MEK1/2
-
-
?
ATP + ERK
ADP + phosphorylated ERK
show the reaction diagram
-
phosphorylation by MEK activates ERK, which plays a role in pain induction modulating the A-type currents of potassium channels in neurons, ERK plays a central role in nocireceptive sensitization in the spinal cord, ERK phosphorylation by MEK
-
-
?
ATP + ERK
ADP + phospho-ERK
show the reaction diagram
-
-
-
-
?
ATP + Erk-1 gene product
ADP + phosphorylated Erk-1 gene product
show the reaction diagram
Q63932
phosphorylation primarily on a tyrosine residue and, to a lesser extent, on a threonine
-
?
ATP + ERK1
ADP + phosphorylated ERK1
show the reaction diagram
-
MEK2 protein stimulates Thr and Tyr phosphorylation on ERK1 and concomitantly activates ERK1 kinase activity more than 100-fold
-
-
?
ATP + Janus kinase 2
ADP + phospho-Janus kinase 2
show the reaction diagram
-
activation
-
-
?
ATP + JNK
ADP + phosphorylated JNK
show the reaction diagram
O14733
-
-
-
?
ATP + JNK
ADP + JNK phosphate
show the reaction diagram
O14733, P45985
the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer, physiologic effects, overview
-
-
?
ATP + JNK
ADP + JNK phosphate
show the reaction diagram
O14733, P45985
substrate of MKK4 and MKK7 in a synergistic manner
-
-
?
ATP + JNK
ADP + phopsho-JNK
show the reaction diagram
P47809, Q8CE90
the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer acting as a metastasis suppressor, overview
-
-
?
ATP + JNK
ADP + phospho-JNK
show the reaction diagram
-
the enzyme is involved in stress-activated MAP kinase pathways and tumorigenesis, overview
-
-
?
ATP + JNK
ADP + phospho-JNK
show the reaction diagram
P47809, Q8CE90
the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer acting as a metastasis suppressor, overview
-
-
?
ATP + JNK
ADP + phospho-JNK
show the reaction diagram
O14733, P45985
the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer, physiologic effects, overview
-
-
?
ATP + JNK
ADP + phospho-JNK
show the reaction diagram
-
substrate of MKK4 and MKK7 in a synergistic manner
-
-
?
ATP + JNK
ADP + phospho-JNK
show the reaction diagram
O14733, P45985
substrate of MKK4 and MKK7 in a synergistic manner
-
-
?
ATP + JNK
ADP + phospho-JNK
show the reaction diagram
P47809, Q8CE90
substrate of MKK4 and MKK7 in a synergistic manner
-
-
?
ATP + JNK1
ADP + phosphorylated JNK1
show the reaction diagram
-
-
-
-
?
ATP + JNK1
ADP + phosphorylated JNK1
show the reaction diagram
-
slight phosphorylation, JNK1 may not be the optimal substrate for the isoform
-
-
?
ATP + MAP kinase
ADP + phosphorylated MAP kinase
show the reaction diagram
Q05116
-
-
-
?
ATP + MAP kinase
ADP + phosphorylated MAP kinase
show the reaction diagram
-, Q9GRT1
the enzyme is involved in the mitogen-activated protein kinase signaling pathway important for e.g. flagellar length control, the enzyme is involved in differentiation of the parasite and is important for virulence and infection of human peritoneal macrophages
-
-
?
ATP + MAP kinase
ADP + phosphorylated MAP kinase
show the reaction diagram
-, Q9GRT1
docking site for the substrate is located close to the N-terminal Lys4 and consists of 2 basic amino acid residues separated by a spacer of 2-6 variable residues from an L/I/V-X-L/I/V sequence
-
-
?
ATP + MAP kinase ERK1
ADP + ?
show the reaction diagram
Q10664
-
-
-
?
ATP + MAPK
ADP + phosphorylated MAPK
show the reaction diagram
-
-
-
-
?
ATP + MAPK
ADP + phosphorylated MAPK
show the reaction diagram
-
MAPK activation
-
-
?
ATP + MKK4
ADP + phosphorylated MKK4
show the reaction diagram
-
-
-
-
?
ATP + MPK-7
ADP + phospho-MPK-7
show the reaction diagram
-
-, MKK3 interacts with MPK7 in planta
-
-
?
ATP + MPK-7
ADP + phospho-MPK-7
show the reaction diagram
Arabidopsis thaliana Col-0
-
-, MKK3 interacts with MPK7 in planta
-
-
?
ATP + myelin basic protein
ADP + phosphorylated myelin basic protein
show the reaction diagram
-, Q9GRT1
-
-
-
?
ATP + myelin basic protein kinase
ADP + phosphorylated myelin basic protein kinase
show the reaction diagram
Q63932
-
-
-
?
ATP + p38
ADP + ?
show the reaction diagram
-
-
-
-
?
ATP + p38
ADP + phosphorylated p38
show the reaction diagram
-
-
-
-
?
ATP + p38
ADP + p38 phosphate
show the reaction diagram
O14733, P45985
the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer, physiologic effects, overview
-
-
?
ATP + p38
ADP + p38 phosphate
show the reaction diagram
O14733, P45985
substrate of MKK7
-
-
?
ATP + p38
ADP + phospho-p38
show the reaction diagram
-
-
-
-
?
ATP + p38
ADP + phospho-p38
show the reaction diagram
A9UK00, -
activation by phosphorylation
-
-
?
ATP + p38
ADP + phospho-p38
show the reaction diagram
A9UK00, -
signal cascade upstream activation by phosphorylation, sorbitol induced activation of p38 in salmon TO cells does not require MKK6a, b or c
-
-
?
ATP + p38
ADP + phospho-p38
show the reaction diagram
-
the enzyme is involved in stress-activated MAP kinase pathways and tumorigenesis, overview
-
-
?
ATP + p38
ADP + phospho-p38
show the reaction diagram
P47809, Q8CE90
the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer acting as a metastasis suppressor, overview
-
-
?
ATP + p38
ADP + phospho-p38
show the reaction diagram
O14733, P45985
the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer, physiologic effects, overview
-
-
?
ATP + p38
ADP + phospho-p38
show the reaction diagram
O14733, P45985
substrate of MKK4
-
-
?
ATP + p38
ADP + phospho-p38
show the reaction diagram
P47809, Q8CE90
substrate of MKK4
-
-
?
ATP + p38
ADP + phospho-p38
show the reaction diagram
-
substrate of MKK4 and MKK7
-
-
?
ATP + p38
ADP + phospho-p38
show the reaction diagram
P47809, Q8CE90
substrate of MKK7
-
-
?
ATP + p38 MAP kinase
ADP + ?
show the reaction diagram
-
phosphorylates and activates p38 MAP kinase
-
-
?
ATP + p38/MPK2 kinase
ADP + ?
show the reaction diagram
-
phosphorylates and specifically activates the p38/MPK2 subgroup of the mitogen-activated protein kinase superfamily
-
-
?
ATP + p42 MAP kinase
ADP + ?
show the reaction diagram
-
-
-
-
?
ATP + poly-(Tyr-Glu)
ADP + phospho-poly-(Tyr-Glu)
show the reaction diagram
-
tyrosine kinase substrate
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
P45985, P46734
-
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
Q64303
-
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
Q05116
the enzyme undergoes autophosphorylation on Ser, Thr and Tyr
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
-
tyrosine/threonine kinase
-
-
-
ATP + protein
ADP + phosphoprotein
show the reaction diagram
Q63932
phosphorylates kinase-inactive Erk-1 protein primarily on a tyrosine residue and, to a lesser extent, on a threonine
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
-
Pek1, in its unphosphorylated form, acts as a potent negative regulator of Pmk1 MAPK signalling. Mkh1, an upstream MAPKK kinase, converts Pek1 from being an inhibitor to an activator. Pek1 has a dual stimulatory and inhibitory function which depends on its phosphorylation state
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
P45985, P46734
enzyme is involved in independent human MAP-kinase signal transduction pathway
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
P41892
enzyme plays a key role in initiation of septum formation and cytokinesis in fission yeast, p120cdc7 interacts with the cdc11 protein in the control of septation
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
-
the enzyme renders the cell resistant to polymyxin B
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
O35099
possible role for ASK1 in tissue development during embryogenesis as well as cytokine-induced apoptosis
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
-
MKK4 may participate in a tumor suppressive signaling pathway distinct from DPC4, p16, p53, and BRCA2. The enzyme is a component of a stress and cytokine-induced signal transduction pathway involving MAPK proteins, additional role for MKK4 in tumor suppression
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
O14733
the enzyme is an activator of the c-Jun NH2-terminal kinase, the enzyme is a component of the JNK signal transduction pathway
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
-
dosage-dependent regulator of mitosis in Schizosaccharomyces pombe
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
-
Spg1p is a key element in controlling the onset of septum formation that acts through the Cdc7p kinase
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
-
MKK1 and MKK2 function in a signal transduction pathway involving the protein kinases encoded by PKC1, BCK1, and MPK1. The site of action for MKK1 and MKK2 is between BCK1 and MPK1
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
-
enzyme is the major activator for p38
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
-
enzyme is involved on MAPK signal transduction pathway
-
-
-
ATP + protein
ADP + phosphoprotein
show the reaction diagram
-
enzyme is involved on MAPK signal transduction pathway
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
P06784
enzyme is involved in the response of haploid yeast cells to peptide mating pheromones
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
P0CY25
Hst7 activates the mating pathway even in the absence of upstream signaling components including the Ste7 regulator Ste11, elevates the basal level of the pheromone-inducible FUS1 gene, and amplifies the pseudohyphal growth response in diploid cells
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
-
byr1 is an important gene in the sexual differentiation pathway and at least part of ras1 function is to act directly or indirectly through byr1 to modulate protein phosphorylation
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
Q23977
the enzyme functions in a novel Drosophila MAPK pathway, controlling puckered expression and morphogenetic activity of the dorsal epidermis
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
Q61083, Q61084
MEKK 2 preferentially activates JNK
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
Q61083, Q61084
MEKK 3 preferentially activates p42/44MAPK
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
-
the enzyme is the major activator of RK/p38
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
Q10664
mek-2 acts between lin-45 raf and sur-1/mpk-1 in a signal transduction pathway used in the control of vulval differentiation and other developmental events
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
Q90891
the enzyme is involved in the mitogenic growth factor signal transduction pathway in vertebrates
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
-
the enzyme is a component of the mkh1 signaling pathway. Mkh1, Skh1 and Spm1 constitute a MAPK cascade in Schizosaccharomyces pombe
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
Q99759
MEKK3 regulates the SAPK and the ERK pathway directly
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
Q99078, -
the enzyme is required for locus-dependent and locus-independent steps in the fungal life cycle. Necessary for locus-dependent processes, such as conjugation tube formation, filament formation, and maintenance of filamentous growth, and for locus-independent processes, such as tumor induction and teliospore germination
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
-
ASK1 may be a key element in the mechanism of stress-induced and cytokine-induced apoptosis
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
-
MEK6 is a member of the p38 kinase cascade and efficiently phosphorylates p38, induces phosphorylation of ATF2 by p38 but does not phosphorylate ATF2 directly
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
-
MAPKKK5 may be an upstream activator of MKK4 in the c-Jun N-terminal kinase pathway
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
Q05116
the enzyme functions as a direct upstream activator for a presumed MAP kinase homolog in each signal transduction pathway involved in the regulation of cell cycle progression or cellular responses to extracellular signals
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
Q13163
sequences located in the N-terminus of MEK5 may be important in coupling GTPase signaling molecules to the MEK5 protein kinase cascade
-
-
-
ATP + Red1
ADP + phospho-Red1
show the reaction diagram
-
substrate of Mek1
-
-
?
ATP + Smad3
ADP + phosphorylated Smad3
show the reaction diagram
-
-, mitogen-activated protein kinase kinase-1 regulates SMAD3 expression in epithelial and smooth muscle cells, which is stimulated by TGFbeta-1, SMAD3 is a transcription factor that mediates TGF-?1 signaling and is important in many of the cellular processes that regulate fibrosis and inflammation, overview
-
-
?
ATP + [ERK2 substrate peptide]
ADP + [ERK2 substrate peptide] phosphate
show the reaction diagram
-
MEK1
-
-
?
ATP + [myelin basic protein substrate peptide]
ADP + [myelin basic protein substrate peptide] phosphate
show the reaction diagram
-
-
-
-
?
additional information
?
-
-
-
-
-
-
additional information
?
-
-
Pek1, in its unphosphorylated form, acts as a potent negative regulator of Pmk1 MAPK signalling. Mkh1, an upstream MAPKK kinase, converts Pek1 from being an inhibitor to an activator. Pek1 has a dual stimulatory and inhibitory function which depends on its phosphorylation state
-
-
-
additional information
?
-
Q99759
MEKK3 activates SEK and MEK, the known kinases targeting SAPK and ERK respectively
-
-
-
additional information
?
-
-
enzyme is part of mitogen-activated protein kinase pathways, crosstalk and regulation mechanism, overview
-
-
-
additional information
?
-
-, Q9GRT1
the enzyme performs autophosphorylation
-
-
-
additional information
?
-
-
MEK1/2 are involved in the mitogen-activated protein kinase signaling pathway and in cancer tumorigenesis
-
-
-
additional information
?
-
-
the enzyme is involved in the mitogen-activated protein kinase signaling pathway
-
-
-
additional information
?
-
-
the enzyme is involved in the mitogen-activated protein kinase signaling pathway regulating cell dissociation of cancer cells, MEK2 is an invasion-metastasis related factor between highly and weakly invasive cells, occludin acts as antagonist
-
-
-
additional information
?
-
-
the enzyme is involved in the mitogen-activated protein kinase signaling pathway, pathway induction by neurotrophin stabilizes the axonal growth cone, pathway inhibitor semaphorin 3F induces growth cone collaps in sympathetic neurons and reduction of axonal growth
-
-
-
additional information
?
-
-
the enzyme is involved in the mitogen-activated protein kinase signaling pathway, which is involved in e.g. activation of Egr-1 and subsequently of c-Fos and cyclin D1 after mechanic injury for induction/regulation of regrowth of smooth vascular cells, vascular smooth muscle cell proliferation plays an important role in pathogenesis of atherosclerosis and post-angioplasty restenosis, overview
-
-
-
additional information
?
-
-
the enzyme is involved in the mitogen-activated protein kinase signaling pathway, which is involved in e.g. formalin-induced inflammatory pain and thermal hyperalgesia, overview
-
-
-
additional information
?
-
-
the enzyme is involved in the mitogen-activated protein kinase signaling pathway, which is linked to the cell cycle machinery, constitutive phosphorylation and activation of the enzyme leads to cell proliferation in choroidal melanoma cells
-
-
-
additional information
?
-
-
MKK7gamma1 is unable to phosphorylate p38
-
-
-
additional information
?
-
-
adenosine-stimulated adrenal steroidogenesis involves the adenosine A2A and A2B receptors and the Janus kinase 2-mitogen-activated protein kinase kinase-extracellular signal-regulated kinase signaling pathway, overview
-
-
-
additional information
?
-
Q94A06, Q957U9
Arabidopsis thaliana mitogen-activated protein kinase kinase MKK1 is implicated in biotic and abiotic stress responses as part of a signaling cascade including MEKK1 and MPK4, MKK1 and MKK2 function upstream of MPK4, overview. The mkk1/2 double mutant is similar to the mpk4 mutant, as both: (1) are dark green dwarves with curled leaves, (2) constitutively overproduce salicylic acid and exhibit enhanced resistance to biotrophic pathogens and insensitivity to JA, and (3) have enhanced basal expression of PR1 and other SA-dependent defense genes
-
-
-
additional information
?
-
Q94A06, Q957U9
Arabidopsis thaliana mitogen-activated protein kinase kinase MKK2 is implicated in biotic and abiotic stress responses as part of a signaling cascade including MEKK1 and MPK4, MKK1 and MKK2 function upstream of MPK4, overview. mkk2 single mutants appear morphologically normal, the mkk1/2 double mutant is similar to the mpk4 mutant, as both: (1) are dark green dwarves with curled leaves, (2) constitutively overproduce salicylic acid and exhibit enhanced resistance to biotrophic pathogens and insensitivity to JA, and (3) have enhanced basal expression of PR1 and other SA-dependent defense genes
-
-
-
additional information
?
-
-
lithium protection of phencyclidine-induced neurotoxicity and cell death in developing brain: the role of phosphatidylinositol-3 kinase/Akt and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase signaling pathways, overview
-
-
-
additional information
?
-
A2XE35, A3FK65, Q0MSI2, Q0Z7Z4, Q5QN75
MAP kinase kinase 1 is regulated by salt and drought stresses, differential expression, overview
-
-
-
additional information
?
-
A2XE35, A3FK65, Q0MSI2, Q0Z7Z4, Q5QN75
MAP kinase kinase 10-2 is regulated only by cold stress, differential expression, overview
-
-
-
additional information
?
-
A2XE35, A3FK65, Q0MSI2, Q0Z7Z4, Q5QN75
MAP kinase kinase 6 is strongly regulated by cold and salt stresses, differential expression, overview
-
-
-
additional information
?
-
A2XE35, A3FK65, Q0MSI2, Q0Z7Z4, Q5QN75
MAP kinase kinases 4 is strongly regulated by cold and salt stresses, differential expression, overview
-
-
-
additional information
?
-
-
mitogen-activated protein kinase kinase signaling promotes growth and vascularization of fibrosarcoma it is required for growth of fibrosarcoma-derived xenografts, to maintain tumor blood flow, and for vascularization of fibrosarcoma-derived xenografts, and MKK signaling is required for the release of proangiogenic factors from other sarcoma-derived cell lines, overview
-
-
-
additional information
?
-
-
MKK3 positively regulates PR gene expression and plays a role in defense against Pst DC3000. MKK3 is an upstream activator of the group C MAPKs MPK1, MPK2, MPK7, and MPK14, overview
-
-
-
additional information
?
-
O14733, P45985
pro-oncogenic role of mitogen-activated protein kinase kinase 4 in cancer, overview
-
-
-
additional information
?
-
P47809, Q8CE90
pro-oncogenic role of mitogen-activated protein kinase kinase 4 in cancer, overview. MKK4 is also involved in the immune system and development of B- and T-cells, as well as in cardiac hypertrophy, overview
-
-
-
additional information
?
-
A2XE35, A3FK65, Q0MSI2, Q0Z7Z4, Q5QN75
regulation and differential expression, overview
-
-
-
additional information
?
-
-
role of mitogen-activated protein kinase kinase 4 in cancer, overview. MKK4 is also involved in the immune system and development of B- and T-cells, as well as in cardiac hypertrophy, overview
-
-
-
additional information
?
-
-
the MEKK-1 is involved in stress-induced cell death of insulin-producing cells and essential in JNK activation, overview
-
-
-
additional information
?
-
-
TNF-alpha receptor signaling regulates epithelial cell secretion of inflammation and invasion mediators involving signaling through IkappaB kinase complex 2, IKB, nuclear factor kappaB, extracellular signal-regulated kinase, mitogen-activated protein kinase kinase, p38, and phosphatidylinositol 3-kinase, and Akt1/2. MEK, p38, and IKK inhibitors block TNF-alpha-induced IL-8, IL-6, and GM-CSF secretion and 12z invasion, whereas the PI3K inhibitors do not, overview
-
-
-
additional information
?
-
-
MKK signaling is required for cell proliferation and for cytokine release in vitro
-
-
-
additional information
?
-
-
substrate binding via the D-domain of the MKK
-
-
-
additional information
?
-
O14733, P45985
substrate binding via the D-domain of the MKK
-
-
-
additional information
?
-
P47809, Q8CE90
substrate binding via the D-domain of the MKK
-
-
-
additional information
?
-
Arabidopsis thaliana Col-0
-
MKK3 positively regulates PR gene expression and plays a role in defense against Pst DC3000. MKK3 is an upstream activator of the group C MAPKs MPK1, MPK2, MPK7, and MPK14, overview
-
-
-
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
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 + ERK
ADP + phosphorylated ERK
show the reaction diagram
-
ERK phosphorylation by MEK1/2
-
-
?
ATP + ERK
ADP + phosphorylated ERK
show the reaction diagram
-
phosphorylation by MEK activates ERK, which plays a role in pain induction modulating the A-type currents of potassium channels in neurons, ERK plays a central role in nocireceptive sensitization in the spinal cord
-
-
?
ATP + ERK
ADP + phospho-ERK
show the reaction diagram
-
-
-
-
?
ATP + Janus kinase 2
ADP + phospho-Janus kinase 2
show the reaction diagram
-
activation
-
-
?
ATP + JNK
ADP + JNK phosphate
show the reaction diagram
O14733, P45985
the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer, physiologic effects, overview
-
-
?
ATP + JNK
ADP + phopsho-JNK
show the reaction diagram
P47809, Q8CE90
the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer acting as a metastasis suppressor, overview
-
-
?
ATP + JNK
ADP + phospho-JNK
show the reaction diagram
-
the enzyme is involved in stress-activated MAP kinase pathways and tumorigenesis, overview
-
-
?
ATP + JNK
ADP + phospho-JNK
show the reaction diagram
P47809, Q8CE90
the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer acting as a metastasis suppressor, overview
-
-
?
ATP + JNK
ADP + phospho-JNK
show the reaction diagram
O14733, P45985
the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer, physiologic effects, overview
-
-
?
ATP + MAP kinase
ADP + phosphorylated MAP kinase
show the reaction diagram
-, Q9GRT1
the enzyme is involved in the mitogen-activated protein kinase signaling pathway important for e.g. flagellar length control, the enzyme is involved in differentiation of the parasite and is important for virulence and infection of human peritoneal macrophages
-
-
?
ATP + MAPK
ADP + phosphorylated MAPK
show the reaction diagram
-
-
-
-
?
ATP + MAPK
ADP + phosphorylated MAPK
show the reaction diagram
-
MAPK activation
-
-
?
ATP + MPK-7
ADP + phospho-MPK-7
show the reaction diagram
Arabidopsis thaliana, Arabidopsis thaliana Col-0
-
MKK3 interacts with MPK7 in planta
-
-
?
ATP + p38
ADP + p38 phosphate
show the reaction diagram
O14733, P45985
the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer, physiologic effects, overview
-
-
?
ATP + p38
ADP + phospho-p38
show the reaction diagram
-
-
-
-
?
ATP + p38
ADP + phospho-p38
show the reaction diagram
A9UK00, -
signal cascade upstream activation by phosphorylation, sorbitol induced activation of p38 in salmon TO cells does not require MKK6a, b or c
-
-
?
ATP + p38
ADP + phospho-p38
show the reaction diagram
-
the enzyme is involved in stress-activated MAP kinase pathways and tumorigenesis, overview
-
-
?
ATP + p38
ADP + phospho-p38
show the reaction diagram
P47809, Q8CE90
the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer acting as a metastasis suppressor, overview
-
-
?
ATP + p38
ADP + phospho-p38
show the reaction diagram
O14733, P45985
the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer, physiologic effects, overview
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
P45985, P46734
-
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
Q64303
-
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
-
Pek1, in its unphosphorylated form, acts as a potent negative regulator of Pmk1 MAPK signalling. Mkh1, an upstream MAPKK kinase, converts Pek1 from being an inhibitor to an activator. Pek1 has a dual stimulatory and inhibitory function which depends on its phosphorylation state
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
P45985, P46734
enzyme is involved in independent human MAP-kinase signal transduction pathway
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
P41892
enzyme plays a key role in initiation of septum formation and cytokinesis in fission yeast, p120cdc7 interacts with the cdc11 protein in the control of septation
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
-
the enzyme renders the cell resistant to polymyxin B
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
O35099
possible role for ASK1 in tissue development during embryogenesis as well as cytokine-induced apoptosis
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
-
MKK4 may participate in a tumor suppressive signaling pathway distinct from DPC4, p16, p53, and BRCA2. The enzyme is a component of a stress and cytokine-induced signal transduction pathway involving MAPK proteins, additional role for MKK4 in tumor suppression
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
O14733
the enzyme is an activator of the c-Jun NH2-terminal kinase, the enzyme is a component of the JNK signal transduction pathway
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
-
dosage-dependent regulator of mitosis in Schizosaccharomyces pombe
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
-
Spg1p is a key element in controlling the onset of septum formation that acts through the Cdc7p kinase
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
-
MKK1 and MKK2 function in a signal transduction pathway involving the protein kinases encoded by PKC1, BCK1, and MPK1. The site of action for MKK1 and MKK2 is between BCK1 and MPK1
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
-
enzyme is the major activator for p38
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
-
enzyme is involved on MAPK signal transduction pathway
-
-
-
ATP + protein
ADP + phosphoprotein
show the reaction diagram
-
enzyme is involved on MAPK signal transduction pathway
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
P06784
enzyme is involved in the response of haploid yeast cells to peptide mating pheromones
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
P0CY25
Hst7 activates the mating pathway even in the absence of upstream signaling components including the Ste7 regulator Ste11, elevates the basal level of the pheromone-inducible FUS1 gene, and amplifies the pseudohyphal growth response in diploid cells
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
-
byr1 is an important gene in the sexual differentiation pathway and at least part of ras1 function is to act directly or indirectly through byr1 to modulate protein phosphorylation
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
Q23977
the enzyme functions in a novel Drosophila MAPK pathway, controlling puckered expression and morphogenetic activity of the dorsal epidermis
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
Q61083, Q61084
MEKK 2 preferentially activates JNK
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
Q61083, Q61084
MEKK 3 preferentially activates p42/44MAPK
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
-
the enzyme is the major activator of RK/p38
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
Q10664
mek-2 acts between lin-45 raf and sur-1/mpk-1 in a signal transduction pathway used in the control of vulval differentiation and other developmental events
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
Q90891
the enzyme is involved in the mitogenic growth factor signal transduction pathway in vertebrates
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
-
the enzyme is a component of the mkh1 signaling pathway. Mkh1, Skh1 and Spm1 constitute a MAPK cascade in Schizosaccharomyces pombe
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
Q99759
MEKK3 regulates the SAPK and the ERK pathway directly
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
Q99078, -
the enzyme is required for locus-dependent and locus-independent steps in the fungal life cycle. Necessary for locus-dependent processes, such as conjugation tube formation, filament formation, and maintenance of filamentous growth, and for locus-independent processes, such as tumor induction and teliospore germination
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
-
ASK1 may be a key element in the mechanism of stress-induced and cytokine-induced apoptosis
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
-
MEK6 is a member of the p38 kinase cascade and efficiently phosphorylates p38, induces phosphorylation of ATF2 by p38 but does not phosphorylate ATF2 directly
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
-
MAPKKK5 may be an upstream activator of MKK4 in the c-Jun N-terminal kinase pathway
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
Q05116
the enzyme functions as a direct upstream activator for a presumed MAP kinase homolog in each signal transduction pathway involved in the regulation of cell cycle progression or cellular responses to extracellular signals
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
Q13163
sequences located in the N-terminus of MEK5 may be important in coupling GTPase signaling molecules to the MEK5 protein kinase cascade
-
-
-
ATP + Smad3
ADP + phosphorylated Smad3
show the reaction diagram
-
mitogen-activated protein kinase kinase-1 regulates SMAD3 expression in epithelial and smooth muscle cells, which is stimulated by TGFbeta-1, SMAD3 is a transcription factor that mediates TGF-?1 signaling and is important in many of the cellular processes that regulate fibrosis and inflammation, overview
-
-
?
additional information
?
-
-
enzyme is part of mitogen-activated protein kinase pathways, crosstalk and regulation mechanism, overview
-
-
-
additional information
?
-
-
MEK1/2 are involved in the mitogen-activated protein kinase signaling pathway and in cancer tumorigenesis
-
-
-
additional information
?
-
-
the enzyme is involved in the mitogen-activated protein kinase signaling pathway
-
-
-
additional information
?
-
-
the enzyme is involved in the mitogen-activated protein kinase signaling pathway regulating cell dissociation of cancer cells, MEK2 is an invasion-metastasis related factor between highly and weakly invasive cells, occludin acts as antagonist
-
-
-
additional information
?
-
-
the enzyme is involved in the mitogen-activated protein kinase signaling pathway, pathway induction by neurotrophin stabilizes the axonal growth cone, pathway inhibitor semaphorin 3F induces growth cone collaps in sympathetic neurons and reduction of axonal growth
-
-
-
additional information
?
-
-
the enzyme is involved in the mitogen-activated protein kinase signaling pathway, which is involved in e.g. activation of Egr-1 and subsequently of c-Fos and cyclin D1 after mechanic injury for induction/regulation of regrowth of smooth vascular cells, vascular smooth muscle cell proliferation plays an important role in pathogenesis of atherosclerosis and post-angioplasty restenosis, overview
-
-
-
additional information
?
-
-
the enzyme is involved in the mitogen-activated protein kinase signaling pathway, which is involved in e.g. formalin-induced inflammatory pain and thermal hyperalgesia, overview
-
-
-
additional information
?
-
-
the enzyme is involved in the mitogen-activated protein kinase signaling pathway, which is linked to the cell cycle machinery, constitutive phosphorylation and activation of the enzyme leads to cell proliferation in choroidal melanoma cells
-
-
-
additional information
?
-
-
adenosine-stimulated adrenal steroidogenesis involves the adenosine A2A and A2B receptors and the Janus kinase 2-mitogen-activated protein kinase kinase-extracellular signal-regulated kinase signaling pathway, overview
-
-
-
additional information
?
-
Q94A06, Q957U9
Arabidopsis thaliana mitogen-activated protein kinase kinase MKK1 is implicated in biotic and abiotic stress responses as part of a signaling cascade including MEKK1 and MPK4, MKK1 and MKK2 function upstream of MPK4, overview. The mkk1/2 double mutant is similar to the mpk4 mutant, as both: (1) are dark green dwarves with curled leaves, (2) constitutively overproduce salicylic acid and exhibit enhanced resistance to biotrophic pathogens and insensitivity to JA, and (3) have enhanced basal expression of PR1 and other SA-dependent defense genes
-
-
-
additional information
?
-
Q94A06, Q957U9
Arabidopsis thaliana mitogen-activated protein kinase kinase MKK2 is implicated in biotic and abiotic stress responses as part of a signaling cascade including MEKK1 and MPK4, MKK1 and MKK2 function upstream of MPK4, overview. mkk2 single mutants appear morphologically normal, the mkk1/2 double mutant is similar to the mpk4 mutant, as both: (1) are dark green dwarves with curled leaves, (2) constitutively overproduce salicylic acid and exhibit enhanced resistance to biotrophic pathogens and insensitivity to JA, and (3) have enhanced basal expression of PR1 and other SA-dependent defense genes
-
-
-
additional information
?
-
-
lithium protection of phencyclidine-induced neurotoxicity and cell death in developing brain: the role of phosphatidylinositol-3 kinase/Akt and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase signaling pathways, overview
-
-
-
additional information
?
-
A2XE35, A3FK65, Q0MSI2, Q0Z7Z4, Q5QN75
MAP kinase kinase 1 is regulated by salt and drought stresses, differential expression, overview
-
-
-
additional information
?
-
A2XE35, A3FK65, Q0MSI2, Q0Z7Z4, Q5QN75
MAP kinase kinase 10-2 is regulated only by cold stress, differential expression, overview
-
-
-
additional information
?
-
A2XE35, A3FK65, Q0MSI2, Q0Z7Z4, Q5QN75
MAP kinase kinase 6 is strongly regulated by cold and salt stresses, differential expression, overview
-
-
-
additional information
?
-
A2XE35, A3FK65, Q0MSI2, Q0Z7Z4, Q5QN75
MAP kinase kinases 4 is strongly regulated by cold and salt stresses, differential expression, overview
-
-
-
additional information
?
-
-
mitogen-activated protein kinase kinase signaling promotes growth and vascularization of fibrosarcoma it is required for growth of fibrosarcoma-derived xenografts, to maintain tumor blood flow, and for vascularization of fibrosarcoma-derived xenografts, and MKK signaling is required for the release of proangiogenic factors from other sarcoma-derived cell lines, overview
-
-
-
additional information
?
-
-
MKK3 positively regulates PR gene expression and plays a role in defense against Pst DC3000. MKK3 is an upstream activator of the group C MAPKs MPK1, MPK2, MPK7, and MPK14, overview
-
-
-
additional information
?
-
O14733, P45985
pro-oncogenic role of mitogen-activated protein kinase kinase 4 in cancer, overview
-
-
-
additional information
?
-
P47809, Q8CE90
pro-oncogenic role of mitogen-activated protein kinase kinase 4 in cancer, overview. MKK4 is also involved in the immune system and development of B- and T-cells, as well as in cardiac hypertrophy, overview
-
-
-
additional information
?
-
A2XE35, A3FK65, Q0MSI2, Q0Z7Z4, Q5QN75
regulation and differential expression, overview
-
-
-
additional information
?
-
-
role of mitogen-activated protein kinase kinase 4 in cancer, overview. MKK4 is also involved in the immune system and development of B- and T-cells, as well as in cardiac hypertrophy, overview
-
-
-
additional information
?
-
-
the MEKK-1 is involved in stress-induced cell death of insulin-producing cells and essential in JNK activation, overview
-
-
-
additional information
?
-
-
TNF-alpha receptor signaling regulates epithelial cell secretion of inflammation and invasion mediators involving signaling through IkappaB kinase complex 2, IKB, nuclear factor kappaB, extracellular signal-regulated kinase, mitogen-activated protein kinase kinase, p38, and phosphatidylinositol 3-kinase, and Akt1/2. MEK, p38, and IKK inhibitors block TNF-alpha-induced IL-8, IL-6, and GM-CSF secretion and 12z invasion, whereas the PI3K inhibitors do not, overview
-
-
-
additional information
?
-
Arabidopsis thaliana Col-0
-
MKK3 positively regulates PR gene expression and plays a role in defense against Pst DC3000. MKK3 is an upstream activator of the group C MAPKs MPK1, MPK2, MPK7, and MPK14, overview
-
-
-
COFACTOR
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
ATP
-
dependent on
ATP
-, Q9GRT1
subdomain II with an invariable lysine residue is responsible for ATP binding
ATP
O14733, P45985
;
ATP
P47809, Q8CE90
;
ATP
A9UK00, -
-
METALS and IONS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
Ca2+
-
elevation of cytosolic Ca2+ by ethylene may stimulate protein phosphatase and MAPKK, which finally activates IPO expression
Cd2+
-
can partially substitue Mg2+
Co2+
-
can partially substitue Mg2+
Mg2+
-
-
Mg2+
-
dependent on, Mg2+ is the physiologic metal ion, other divalent cations are able to support nucleotide binding, but only Mn2+, Co2+, and Cd2+ can substitute Mg2+ in supporting the catalytic activity
Mg2+
O14733, P45985
;
Mg2+
P47809, Q8CE90
;
Mg2+
A9UK00, -
-
Mg2+
-
-
Mn2+
-
can partially substitue Mg2+
INHIBITORS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
1-(2,3-dihydroxypropyl)-4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
-
1-(3-cyanopropyl)-4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
;
1-allyl-4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
;
1-ethyl-4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
;
1-methyl-4-(2-naphthylamino)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
;
3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzamide
P31938, Q63932
-
4-(2-fluoro-4-iodoanilino)-1-(2-hydroxyethyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
;
4-(2-fluoro-4-iodoanilino)-1-(3-hydroxypropyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
;
4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
;
4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid
P31938, Q63932
;
4-(2-fluoro-4-iodoanilino)-1-[2-(2-methoxyethoxy)ethyl]-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
;
4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
;
4-(2-fluoro-4-iodoanilino)-6-oxo-1-propyl-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
;
4-(2-fluoro-4-iodoanilino)-N,1-dimethyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
;
4-(2-fluoro-4-iodoanilino)-N,N,1-trimethyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
;
4-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
-
4-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
;
4-(2-fluoro-4-iodoanilino)-N-(3-hydroxypropyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
;
4-(2-fluoro-4-methylanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
;
4-(2-fluoro-4-methylsulfanylphenylamino)-1-methyl-6-oxo-1,6-dihydro-3 -pyridinecarboxamide
P31938, Q63932
;
4-(3,4-dichlorophenylamino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
;
4-(4-bromo-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
;
4-(4-bromo-2-fluoroanilino)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
;
4-(4-bromo-2-fluorophenylamino)-1-methylpyridin-2(1H)-ones
-
selective anthranilic acid type inhibitors, residues K97, I141, M143, F129, V127, I126, L118, F209, V211, and S212 of MEK1/2 are important for interaction with the inhibitor, noncompetitive to ATP, inhibition of ERK phosphorylation by MEK1/2 by the derivatives with IC50 values of 6.8-124 nM, low cytotoxic effects, overview
4-(4-cyano-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
;
4-(4-ethyl-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
;
4-(4-ethynyl-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
;
4-amino-1-[3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl]-2-hydroxybutan-1-one
P31938, Q63932
-
4-[2-fluoro-4-(1,1,2,2,3,3,4,4,4-nonafluorobutyl)anilino]-1-methyl-6-oxo-1,6 -dihydro-3-pyridinecarboxamide
P31938, Q63932
;
4-[2-fluoro-4-(3-hydroxypropyl)anilino]-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
;
4-[3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl]-3-hydroxy-4-oxobutanamide
P31938, Q63932
-
anthrax lethal toxin
-
i.e. LeTx, inactivates MKKs, LeTx treatment reduces the levels of phosphorylated extracellular signal-regulated kinase and p38 MAPK in vitro, short treatments with LeTx only modestly affects cell proliferation, sustained treatment markedly reduces cell numbers, LeTx also substantially inhibits the extracellular release of angioproliferative factors including vascular endothelial growth factor, interleukin-8, and basic fibroblast growth factor, overview
-
Berberine
-
suppresses MEK/ERK-dependent Egr-1 signaling pathway and inhibits vascular smooth muscle cell regrowth after mechanical injury in vitro
CI-1040
P31938, Q63932
-
Cocoa procyanidin B2
-
procyanidin B2 suppresses TPA-induced phosphorylation of MEK, ERK, and p90RSK in JB6 P+ cells, suppresses JB6 P+ cell transformation by inhibiting mitogen-activated protein kinase kinase, molecular mechanism, overview
Cocoa procyanidins
-
suppresses JB6 P+ cell transformation by inhibiting mitogen-activated protein kinase kinase, molecular mechanisms of the chemopreventive potential of cocoa and its active ingredients, overview
-
PD098059
-
MEK1 inhibitor
PD318088
P31938, Q63932
-
PD334581
P31938, Q63932
-
PD98059
-
inhibitor specific for MEK/ERK activation, granulocyte/macrophage colony number is decreased by ca. 60%
PD98059
-
MEK-specific inhibitor, enhances antileukemia activity of Mdm2 antagonists in AML cells and p53-mediated transcription-dependent apoptosis. MEK inhibition accumulates p53 into the nucleus in OCIAML-3 cells, but does not affect the nucleoplasmic localization of Mdm2. The inhibitor restricts p21-mediated antiapoptotic mechanisms by repressing p53-dependent induction of p21, which enables Nutlin-3a to induce sufficient apoptosis in G1-phase cells
PD98059
-
inhibition of MEK1 with either PD98059 results in a substantial dose-dependent inhibition of SMAD3 promoter activity, reduced SMAD3 protein expression in A549 cells and airway smooth muscle cells after treatment with MEK1 inhibitors; substantial dose-dependent inhibition of SMAD3 promoter activity, 5.8fold reduction, MEK1 inhibition of SMAD3 promoter function is primarily mediated through an Sp1-dependent mechanism
PD98059
-
MAPKK inhibitor, inhibits IPO expression stimulated by staurosporine
PD98059
-
the MEK inhibitor completely blocks adenosine-stimulated corticosterone production
PD98059
-
MEK inhibitor, effective dose of 0.05 mM
phencyclidine
-
a N-methyl-D-aspartate receptor antagonist, it is neurotoxic to developing brains and results in schizophrenia-like behaviors later in development, it elicites time-dependent inhibition of the MEK/ERK and PI-3K/Akt pathways, overview
siRNA
-
knockdown of MEK, HSCs give rise to Mac-1+ myeloid cells less efficiently than control HSCs
-
siRNA
-
MEK1/2-specific inhibitor, delays, but does not block the passage of synchronized HeLa cells into M phase
-
siRNA
-
cells transiently transfected with two independent sets of siRNAs show significant down-regulation of MKK3 and phosphorylated MKK3
-
tert-butyl [5-(aminocarbonyl)-4-(2-fluoro-4-iodoanilino)-2-oxo-1(2H)-pyridinyl]acetate
P31938, Q63932
-
U0126
-
specific MEK inhibitor
U0126
-
MEK inhibitor
U0126
-
MEK inhibitor
U0126
-
inhibitor specific for MEK/ERK activation, granulocyte/macrophage colony number is decreased by ca. 60%
U0126
-
inhibition of MEK1 with either UO126 results in a substantial dose-dependent inhibition of SMAD3 promoter activity, reduced SMAD3 protein expression in A549 cells and airway smooth muscle cells after treatment with MEK1 inhibitors; substantial dose-dependent inhibition of SMAD3 promoter activity, 2.3fold reduction, MEK1 inhibition of SMAD3 promoter function is primarily mediated through an Sp1-dependent mechanism
U0126
-
potent MEK-1/2 inhibitor, cellular size, DNA fragmentation, nuclear condensation, and the phosphorylated ERK-1 protein products of H9c2 cells treated with Porphyromonas gingivalis medium, are all significantly reduced after pre-administration of U0126
U0126
-
MEK1/2-specific inhibitor, delays, but does not block the passage of synchronized HeLa cells into M phase
U0126
-
the MEK inhibitor completely blocks adenosine-stimulated corticosterone production
U0126
-
MEK inhibitor, effective dose at 0.1 mM
[5-(aminocarbonyl)-4-(2-fluoro-4-iodoanilino)-2-oxo-1(2H)-pyridinyl]acetic acid
P31938, Q63932
-
ethyl 4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate
P31938, Q63932
;
additional information
-
inactivated by the serine/threonine phosphatase 2A but not by the protein-tyrosine phosphatase 1B
-
additional information
-
occludin acts as antagonist of the MEK and ERK signaling pathway inducing cell aggregation of pancreatic cancer cells
-
additional information
-
treatment with LY294002, paclitaxel, or serum starvation does not induce apoptosis of wild-type MEF cells
-
additional information
P31938, Q63932
design and synthesis of 4-anilino-5-carboxamido-2-pyridone MEK1 inhibitors using a combination of medicinal chemistry, computational chemistry, and structural elucidation, overview. Binding structure analysis, overview
-
additional information
-
no MEK inhibition by theobromine
-
additional information
-
MEK, p38, and IKK inhibitors block TNF-alpha-induced IL-8, IL-6, and GM-CSF secretion and 12z invasion, whereas the PI3K inhibitors do not
-
additional information
-
stress-induced target of rapamycin complex 1 activation can be blocked by RNAi against mitogen-activated protein kinase kinase 3 and 6
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
anisomycin
-
activates
CD40
-
activated by ligation of CD40, the B-cell antigen receptor
-
doxycycline
-
induces expression of HA-MEK1
growth factor interleukin-3
-
activates
-
additional information
-
activation is induced by epidermal growth factor tyrosine protein kinase and nucelar growth factor tyrosine protein kinase
-
additional information
-
enzyme is activated by environmental stress and physiological stimuli. In hematopoietic cells, endogenous MKK7 is activated by treatment with the growth factor interleukin-3, or by ligation of CD40, the B-cell antigen receptor, or the receptor for the Fc fragment of immunoglobulin. MKK7 is also activated when cells are exposed to heat, UV irradiation, anisomycin, hyperosmolarity or the pro-inflammatory cytokine tumor necrosis factor-alpha
-
additional information
-
Pbs2p is activated by MAP kinase kinase kinases Ssk2p and Ssk22p that are under the control of the SLN1-SSK1 two-component osmosensor. Alternatively, Pbs2p is activated by a mechanism that involves the binding of its amino terminal proline-rich motif to the Src homology 3 domain of a putative transmembrane osmosensor Sho1p
-
additional information
-
activation in vivo in response to serum, phosphorylation and activation by the v-Raf protein in vitro
-
additional information
-
MEK6 is strongly activated by UV, anisomycin, and osmotic shock
-
additional information
Q64303
activated by GTP-Cdc42 or GTP-Rac1 in vitro
-
additional information
-
the enzyme is activated in cells treated with tumor necrosis factor-alpha
-
additional information
-
MEK, ERK-1 and ERK-2 are activated by phosphorylation, tetanus toxin or the C-terminal part of the heavy chain induce phosphorylation of ERK-1 and ERK-2 at Thr202 and Tyr204
-
additional information
-
MEK and ERK are activated by phosphorylation
-
additional information
-
MEK, ERK-1 and ERK-2 are activated by phosphorylation by B-Raf, the B-Raf mutant V590E activates the enzymes constitutively and independently of Ras, which leads to melanoma cell proliferation
-
additional information
-
neurotrophin induces mitogen-activated protein kinase kinase signaling, which is antagonized by semaphorin 3F, Gab-1, an adaptor protein, is recruited by the TrkA kinase to activate MEK in sympathetic neurons, Gab-1 can reverse semaphorin 3F inhibition of the MEK activation
-
additional information
-
ERK and MEK are activated by phosphorylation, ERK is induced by formalin
-
additional information
-
dissociation factor DF induces MEK1/2 and ERK1/2 expression
-
additional information
-
MKKs are activated by phopshorylation through MKKKs, activation mechanism of MKK4 involving MEKK1, overview
-
additional information
O14733, P45985
MKKs are activated by phopshorylation through MKKKs, activation mechanism of MKK4 involving MEKK1, overview; MKKs are activated by phopshorylation through MKKKs, overview
-
additional information
P47809, Q8CE90
MKKs are activated by phopshorylation through MKKKs, activation mechanism of MKK4 involving MEKK1, overview; MKKs are activated by phopshorylation through MKKKs, overview
-
additional information
-
MKKs are activated by phopshorylation through MKKKs, activation mechanism of MKK4 involving MEKK1, overview
-
additional information
-
MKK3 expression is induced upon Pseudomonas syringae infection
-
IC50 VALUE [mM]
IC50 VALUE [mM] Maximum
INHIBITOR
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.01
-
1-(2,3-dihydroxypropyl)-4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
above, cascade IC50
0.00489
-
1-(3-cyanopropyl)-4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
inhibition of the Raf-MEK-ERK cascade in an isolated enzyme assay
0.0049
-
1-(3-cyanopropyl)-4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
cascade IC50
0.000091
-
1-allyl-4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
inhibition of the Raf-MEK-ERK cascade in an isolated enzyme assay
0.00601
-
1-allyl-4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
cascade IC50
0.01
-
1-allyl-4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
inhibition of the Raf-MEK-ERK cascade in an isolated enzyme assay
0.001
-
1-ethyl-4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
cascade IC50; inhibition of the Raf-MEK-ERK cascade in an isolated enzyme assay
0.003
-
1-methyl-4-(2-naphthylamino)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
cascade IC50; inhibition of the Raf-MEK-ERK cascade in an isolated enzyme assay
0.0000174
-
3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzamide
P31938, Q63932
cascade IC50
0.00254
-
4-(2-fluoro-4-iodoanilino)-1-(2-hydroxyethyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
inhibition of the Raf-MEK-ERK cascade in an isolated enzyme assay
0.005
-
4-(2-fluoro-4-iodoanilino)-1-(2-hydroxyethyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
above cascade IC50; colon26 cellular assay
0.003
-
4-(2-fluoro-4-iodoanilino)-1-(3-hydroxypropyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
above, cascade IC50; inhibition of the Raf-MEK-ERK cascade in an isolated enzyme assay
0.000004
-
4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
colon26 cellular assay
0.000023
-
4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
cascade IC50; inhibition of the Raf-MEK-ERK cascade in an isolated enzyme assay
0.000425
-
4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid
P31938, Q63932
cascade IC50; inhibition of the Raf-MEK-ERK cascade in an isolated enzyme assay
0.005
-
4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid
P31938, Q63932
colon26 cellular assay
0.00113
-
4-(2-fluoro-4-iodoanilino)-1-[2-(2-methoxyethoxy)ethyl]-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
cascade IC50; inhibition of the Raf-MEK-ERK cascade in an isolated enzyme assay
0.0001
-
4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
cascade IC50; inhibition of the Raf-MEK-ERK cascade in an isolated enzyme assay
0.00063
-
4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
colon26 cellular assay
0.00043
-
4-(2-fluoro-4-iodoanilino)-6-oxo-1-propyl-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
colon26 cellular assay
0.00254
-
4-(2-fluoro-4-iodoanilino)-6-oxo-1-propyl-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
cascade IC50; inhibition of the Raf-MEK-ERK cascade in an isolated enzyme assay
0.000195
-
4-(2-fluoro-4-iodoanilino)-N,1-dimethyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
cascade IC50; inhibition of the Raf-MEK-ERK cascade in an isolated enzyme assay
0.000627
-
4-(2-fluoro-4-iodoanilino)-N,N,1-trimethyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
inhibition of the Raf-MEK-ERK cascade in an isolated enzyme assay
1.2
-
4-(2-fluoro-4-iodoanilino)-N,N,1-trimethyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
cascade IC50
0.000005
-
4-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
colon26 cellular assay
0.000018
-
4-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
cascade IC50; inhibition of the Raf-MEK-ERK cascade in an isolated enzyme assay
0.00018
-
4-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
colon26 cellular assay
0.000206
-
4-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
inhibition of the Raf-MEK-ERK cascade in an isolated enzyme assay
0.00021
-
4-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
cascade IC50
0.000061
-
4-(2-fluoro-4-iodoanilino)-N-(3-hydroxypropyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
cascade IC50; inhibition of the Raf-MEK-ERK cascade in an isolated enzyme assay
0.000095
-
4-(2-fluoro-4-iodoanilino)-N-(3-hydroxypropyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
colon26 cellular assayy
0.00297
-
4-(2-fluoro-4-methylanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
cascade IC50; inhibition of the Raf-MEK-ERK cascade in an isolated enzyme assay
0.00015
-
4-(2-fluoro-4-methylsulfanylphenylamino)-1-methyl-6-oxo-1,6-dihydro-3 -pyridinecarboxamide
P31938, Q63932
colon26 cellular assay
0.000356
-
4-(2-fluoro-4-methylsulfanylphenylamino)-1-methyl-6-oxo-1,6-dihydro-3 -pyridinecarboxamide
P31938, Q63932
inhibition of the Raf-MEK-ERK cascade in an isolated enzyme assay
0.00036
-
4-(2-fluoro-4-methylsulfanylphenylamino)-1-methyl-6-oxo-1,6-dihydro-3 -pyridinecarboxamide
P31938, Q63932
cascade IC50
0.0039
-
4-(3,4-dichlorophenylamino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
colon26 cellular assay
0.0057
-
4-(3,4-dichlorophenylamino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
cascade IC50
0.00572
-
4-(3,4-dichlorophenylamino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
inhibition of the Raf-MEK-ERK cascade in an isolated enzyme assay
0.000093
-
4-(4-bromo-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
colon26 cellular assay
0.0019
-
4-(4-bromo-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
cascade IC50
0.00191
-
4-(4-bromo-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
inhibition of the Raf-MEK-ERK cascade in an isolated enzyme assay
0.00012
-
4-(4-bromo-2-fluoroanilino)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
colon26 cellular assay
0.00363
-
4-(4-bromo-2-fluoroanilino)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
cascade IC50; inhibition of the Raf-MEK-ERK cascade in an isolated enzyme assay
0.0000068
0.000124
4-(4-bromo-2-fluorophenylamino)-1-methylpyridin-2(1H)-ones
-
selective anthranilic acid type inhibitors, residues K97, I141, M143, F129, V127, I126, L118, F209, V211, and S212 of MEK1/2 are important for interaction with the inhibitor, noncompetitive to ATP, inhibition of ERK phosphorylation by MEK1/2 by the deriva
0.01
-
4-(4-cyano-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
above, cascade IC50; inhibition of the Raf-MEK-ERK cascade in an isolated enzyme assay
0.00011
-
4-(4-ethyl-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
colon26 cellular assay
0.00262
-
4-(4-ethyl-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
cascade IC50; inhibition of the Raf-MEK-ERK cascade in an isolated enzyme assay
0.000021
-
4-(4-ethynyl-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
colon26 cellular assay
0.0001
-
4-(4-ethynyl-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
cascade IC50; inhibition of the Raf-MEK-ERK cascade in an isolated enzyme assay
0.0000842
-
4-amino-1-[3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl]-2-hydroxybutan-1-one
P31938, Q63932
cascade IC50
0.01
-
4-[2-fluoro-4-(1,1,2,2,3,3,4,4,4-nonafluorobutyl)anilino]-1-methyl-6-oxo-1,6 -dihydro-3-pyridinecarboxamide
P31938, Q63932
above, cascade IC50; inhibition of the Raf-MEK-ERK cascade in an isolated enzyme assay
0.01
-
4-[2-fluoro-4-(3-hydroxypropyl)anilino]-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
P31938, Q63932
above, cascade IC50; inhibition of the Raf-MEK-ERK cascade in an isolated enzyme assay
0.0000012
-
4-[3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl]-3-hydroxy-4-oxobutanamide
P31938, Q63932
cascade IC50
0.000016
-
CI-1040
P31938, Q63932
clinical candidate, inhibition of the Raf-MEK-ERK cascade in an isolated enzyme assay
0.000046
-
CI-1040
P31938, Q63932
clinical candidate, colon26 cellular assay
0.000063
-
ethyl 4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate
P31938, Q63932
colon26 cellular assay
0.000669
-
ethyl 4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate
P31938, Q63932
inhibition of the Raf-MEK-ERK cascade in an isolated enzyme assay
0.00067
-
ethyl 4-(2-fuoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate
P31938, Q63932
cascade IC50
-
0.01
-
tert-butyl [5-(aminocarbonyl)-4-(2-fluoro-4-iodoanilino)-2-oxo-1(2H)-pyridinyl]acetate
P31938, Q63932
inhibition of the Raf-MEK-ERK cascade in an isolated enzyme assay
0.01
-
[5-(aminocarbonyl)-4-(2-fluoro-4-iodoanilino)-2-oxo-1(2H)-pyridinyl]acetic acid
P31938, Q63932
above, cascade IC50
SPECIFIC ACTIVITY [µmol/min/mg]
SPECIFIC ACTIVITY MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
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
pH MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
7.2
-
-
assay at
7.4
-
P31938, Q63932
assay at
TEMPERATURE OPTIMUM
TEMPERATURE OPTIMUM MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
30
-
-
assay at
37
-
-
in vivo assay at
37
-
P31938, Q63932
assay at
40
-
-, Q9GRT1
-
pI VALUE
pI VALUE MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
7.4
-
-, Q9GRT1
sequence calculation
SOURCE TISSUE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
SOURCE
-
human alveolar Type II epithelial adenocarcinoma cell line
Manually annotated by BRENDA team
-
MKK3 is a prognostic marker in malignant astrocytomas
Manually annotated by BRENDA team
-
expression at low levels
Manually annotated by BRENDA team
Q62862
isoenzyme MEK5 beta
Manually annotated by BRENDA team
-
weak expression
Manually annotated by BRENDA team
-
93000 Da form
Manually annotated by BRENDA team
P47809, Q8CE90
highest levels of expression
Manually annotated by BRENDA team
O14733, P45985
highest levels of expression
Manually annotated by BRENDA team
O14733, P45985
high expression level of MKK4, expression in adult and fetal brain
Manually annotated by BRENDA team
P47809, Q8CE90
high expression level of MKK4, expression in adult and fetal brain
Manually annotated by BRENDA team
O14733, P45985
impaired expression of MKK4
Manually annotated by BRENDA team
O14733, P45985
impaired expression of MKK4
Manually annotated by BRENDA team
-
from superior cervical ganglia
Manually annotated by BRENDA team
P47809, Q8CE90
Mkk4 transcripts confined to the central nervous system in early embryogenesis, up to embryonic day 10
Manually annotated by BRENDA team
P47809, Q8CE90
highest levels of expression
Manually annotated by BRENDA team
O14733, P45985
highest levels of expression
Manually annotated by BRENDA team
O14733, P45985
high expression level of MKK4
Manually annotated by BRENDA team
P47809, Q8CE90
high expression level of MKK4
Manually annotated by BRENDA team
P47809, Q8CE90
highest levels of expression
Manually annotated by BRENDA team
O14733, P45985
highest levels of expression
Manually annotated by BRENDA team
O14733, P45985
high expression level of MKK4
Manually annotated by BRENDA team
P47809, Q8CE90
high expression level of MKK4
Manually annotated by BRENDA team
-
colorectal cancer cell line
Manually annotated by BRENDA team
-
medium expression
Manually annotated by BRENDA team
O35099
17 days post coitum, expression of ASK1 in developing skin, cartilage and bone
Manually annotated by BRENDA team
P47809, Q8CE90
-
Manually annotated by BRENDA team
-
superior cervical
Manually annotated by BRENDA team
-
MKK3 i s upregulated and activated in invasive glioma cells in vitro, overexpression and phosphorylation of MKK3 are linked to glioma invasion, MKK3 is overexpressed in invasive glioma cells in situ and correlates with active p38
Manually annotated by BRENDA team
-
components of Porphyromonas gingivalis spent culture medium not only result in increased total MEK-1 and ERK-1 protein products, but also cause increased cellular size, DNA fragmentation, and nuclear condensation
Manually annotated by BRENDA team
-
expression at low levels in adult brain, expression at high levels in neonatal brain
Manually annotated by BRENDA team
-
weak expression
Manually annotated by BRENDA team
-
93000 Da form
Manually annotated by BRENDA team
P47809, Q8CE90
highest levels of expression
Manually annotated by BRENDA team
O14733, P45985
highest levels of expression
Manually annotated by BRENDA team
O14733, P45985
high expression level of MKK4
Manually annotated by BRENDA team
P47809, Q8CE90
high expression level of MKK4
Manually annotated by BRENDA team
P47809, Q8CE90
highest levels of expression
Manually annotated by BRENDA team
O14733, P45985
highest levels of expression
Manually annotated by BRENDA team
O14733, P45985
high expression level of MKK4
Manually annotated by BRENDA team
P47809, Q8CE90
high expression level of MKK4
Manually annotated by BRENDA team
-
strongest expression in the human tissue panel
Manually annotated by BRENDA team
Q62862
enzyme MEK5 alpha
Manually annotated by BRENDA team
-
44000 Da form
Manually annotated by BRENDA team
P47809, Q8CE90
in later embryogenesis, starting at day 12, Mkk4 becomes highly expressed in the developing liver coincident with a period of active differentiation and an increase in liver size
Manually annotated by BRENDA team
-
weak expression in adult and fetal liver
Manually annotated by BRENDA team
O14733, P45985
high expression level of MKK4, expression in adult and fetal liver
Manually annotated by BRENDA team
P47809, Q8CE90
high expression level of MKK4, expression in adult and fetal liver
Manually annotated by BRENDA team
-
weak expression
Manually annotated by BRENDA team
-
93000 Da form
Manually annotated by BRENDA team
-
LX-1 cell, strong expression
Manually annotated by BRENDA team
-
strongest expression in human immune panel
Manually annotated by BRENDA team
-
peripheral blood, weak expression
Manually annotated by BRENDA team
-
cultured cortical neurons from fetal brain
Manually annotated by BRENDA team
-
choroidal melanoma cell line
Manually annotated by BRENDA team
O14733, P45985
impaired expression of MKK4
Manually annotated by BRENDA team
-
weak expression
Manually annotated by BRENDA team
-
subcutaneous tumor cell line, highly invasive
Manually annotated by BRENDA team
-
weak expression
Manually annotated by BRENDA team
-, Q9GRT1
and during differentiation to amastigote
Manually annotated by BRENDA team
P47809, Q8CE90
high expression of MKK4 in the epithelium but not in the stromal compartment
Manually annotated by BRENDA team
O14733, P45985
impaired expression of MKK4
Manually annotated by BRENDA team
Arabidopsis thaliana Col-0
-
-
-
Manually annotated by BRENDA team
-
weak expression
Manually annotated by BRENDA team
-
airway, bronchial airway
Manually annotated by BRENDA team
-
epididymal spermatozoa, 60000 Da variant of MAP3K11, may be a result of proteolytic cleavage of the longer form
Manually annotated by BRENDA team
-
weak expression
Manually annotated by BRENDA team
-
93000 Da form
Manually annotated by BRENDA team
-
only 8% of normal tissues show MKK4 immunolabeling
Manually annotated by BRENDA team
-
isolated from osteoarthritis and rheumatoid arthritis patients
Manually annotated by BRENDA team
-
human pancreatic, lung, breast, testicle, and colorectal cancer cell lines
Manually annotated by BRENDA team
-
93000, 70000, 40000, 23000 Da forms, first MAP3K11 expression detectable at day-14, higher levels of expression at day-30 and day-36
Manually annotated by BRENDA team
-
lowest expression in human immune panel
Manually annotated by BRENDA team
-
transgenic ProMKK3:GUS lines show basal expression that is strongly induced by Pseudomonas syringae pv tomato strain DC3000 infection but not by abiotic stresses
Manually annotated by BRENDA team
Arabidopsis thaliana Col-0
-
transgenic ProMKK3:GUS lines show basal expression that is strongly induced by Pseudomonas syringae pv tomato strain DC3000 infection but not by abiotic stresses
-
Manually annotated by BRENDA team
-
choroidal from eyes, and cutaneous
Manually annotated by BRENDA team
additional information
Q62862
isoform MEK5 beta is ubiquitously distributed and primarily cytosolic. Isoform MEK5 alpha is expressed most highly in liver and brain and is particulate
Manually annotated by BRENDA team
additional information
-
cancer cell growth patterns, overview
Manually annotated by BRENDA team
additional information
-, Q9GRT1
the enzyme is developmentally regulated expressed, no expression in the amastigote stage in human host cells
Manually annotated by BRENDA team
additional information
-
89% of studied tissues with intestinal metaplasia lesions, 100% with gastric epithelial dysplasia lesions, 93% with primary cancer and 96% with metastatic cancer show positive MKK4 immunolabeling
Manually annotated by BRENDA team
additional information
-
AT6.1 cell, lacks MKK4 expression, overexpression of MKK4 significantly reduces its metastatic ability
Manually annotated by BRENDA team
additional information
-
no expression in thymus, medium expression in GI-112 cell, weak expression in GI-117 cell
Manually annotated by BRENDA team
additional information
-
not in spermatogonia, early primary spermatocytes, Sertoli cells, or peritubular myoid cells
Manually annotated by BRENDA team
additional information
-
NSCLC cell lines H1299, H226B, H226Br, H332, H358, H460, A549, H596, and Calu-6
Manually annotated by BRENDA team
additional information
-
OCI-AML-3 cell and MOLM-13 cell
Manually annotated by BRENDA team
additional information
-
U87 cell, U118 cell, SNB19 cell and U87deltaEGFR cell
Manually annotated by BRENDA team
additional information
-
ubiquitous expression of MKK4 in adult tissues
Manually annotated by BRENDA team
additional information
O14733, P45985
ubiquitous expression of MKK4 in adult tissues
Manually annotated by BRENDA team
additional information
P47809, Q8CE90
ubiquitous expression of MKK4 in adult tissues
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
developing spermatids and epididymal spermatozoa, colocalization of MAP3K11 and CRISP2
-
Manually annotated by BRENDA team
-
late spermatocytes and round spermatids
Manually annotated by BRENDA team
O14733, P45985
MKK4, mainly
Manually annotated by BRENDA team
P47809, Q8CE90
MKK4, mainly
Manually annotated by BRENDA team
Q62862
isoform MEK5 beta is primarily cytosolic
Manually annotated by BRENDA team
-, Q9GRT1
of promastigotes
-
Manually annotated by BRENDA team
Q62925
associated with
Manually annotated by BRENDA team
Q62862
isoform MEK5 alpha
-
Manually annotated by BRENDA team
Arabidopsis thaliana Col-0
-
-
-
-
Manually annotated by BRENDA team
PDB
SCOP
CATH
ORGANISM
Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
MOLECULAR WEIGHT
MOLECULAR WEIGHT MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
23000
-
-
fragment of MAP3K11, Western blot analysis
44000
-
-
fragment of MAP3K11, Western blot analysis
47940
-
-
sequence analysis
60000
-
-
fragment of MAP3K11 in epididymal sperm, Western blot analysis
70000
-
-
fragment of MAP3K11, Western blot analysis
93000
-
-
MAP3K11 in somatic tissue, Western blot analysis
SUBUNITS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
?
Q05116
x * 45000
?
-
x * 37000, calculation from nucleotide sequence
?
Q64303
x * 62000
?
-
x * 66000, calculation from nucleotide sequence
?
Q61083, Q61084
x * 71000
?
Q62925
x * 195000, SDS-PAGE
?
Q61083, Q61084
x * 69200
?
-
x * 45000, calculation from nucleotide sequence
?
-
x * 77500, calculation from nucleotide sequence
?
-
x * 44000, calculation from nucleotide sequence
?
-
x * 43439, MKK1a, calculation from nucleotide sequence
?
-
x * 43330, calculation from nucleotide sequence
?
-
x * 44500
?
-
x * 40745, MKK1b an alternatively spliced form of the MKK1a gene, calculation from nucleotide sequence
?
-, Q9GRT1
x * 38900, sequence calculation, x * 39000, recombinant enzyme, SDS-PAGE
additional information
Q62862
alternative splicing results in a 50000 Da alpha and a 40000 Da beta isoform of MEK5
additional information
-, Q9GRT1
the enzyme contains a protein kinase domain, residues L73-I331, with 11 highly conserved subdomains, and a subdomain II with an invariable lysine residue responsible for ATP binding
additional information
-
domain and sequence motifs of MAPKK isozymes, overview
additional information
-
the catalytic domain contains 11 subdomains
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
phosphoprotein
Q63980
Ser222 represents one key MAPKKK-dependent phosphorylation site switching on and off the activity of MAPKK, an event crucial for growth control
phosphoprotein
-
MKKs are activated by phopshorylation through MKKKs, e.g. MEKK, MLK, TAK1, Ask1, or TPL2, MKK4 is phopshorylated at serine and threonine residues in the SIAKT motif
phosphoprotein
-
activation by phosphorylation
phosphoprotein
-
Ser218 and Ser222 are the primary sites for phosphorylation
phosphoprotein
-
the enzyme is phosphorylated and activated in vitro by TAK1
phosphoprotein
-
MEK and ERK are phosphorylated by B-Raf, a mitogen-activated protein kinase kinase kinase, the B-Raf mutant V590E activates the enzymes constitutively and independently of Ras, which leads to melanoma cell proliferation
phosphoprotein
-
MEK is phosphorylated and activated by the mitogen-activated protein kinase kinase kinase COT, which can be inhibited by p105
phosphoprotein
-
DETA/NO and streptozotocin induce rapid threonine phosphorylation of MEKK-1, overview
phosphoprotein
O14733, P45985
MKKs are activated by phopshorylation through MKKKs, e.g. MEKK, MLK, TAK1, Ask1, or TPL2
phosphoprotein
O14733, P45985
MKKs are activated by phopshorylation through MKKKs, e.g. MEKK, MLK, TAK1, Ask1, or TPL2, MKK4 is phopshorylated at serine and threonine residues in the SIAKT motif
phosphoprotein
-
oleanolic acid increases the phosphorylations of JNK and ERK markedly in a dose-dependent manner, low concentration of tert-butyl hydroperoxide transiently increased the phosphorylation of JNK and high concentration of tert-butyl hydroperoxide decreased the phosphorylation of it
phosphoprotein
-, Q9GRT1
the enzyme performs autophosphorylation
phosphoprotein
-
ERK and MEK are activated by phosphorylation
phosphoprotein
P47809, Q8CE90
MKKs are activated by phopshorylation through MKKKs, e.g. MEKK, MLK, TAK1, Ask1, or TPL2
phosphoprotein
P47809, Q8CE90
MKKs are activated by phopshorylation through MKKKs, e.g. MEKK, MLK, TAK1, Ask1, or TPL2, MKK4 is phopshorylated at serine and threonine residues in the SIAKT motif
phosphoprotein
-
Ser217 and Ser221 are the sites phosphorylated by p74raf-1. Phosphorylation of either residue is sufficient for maximal activation
phosphoprotein
-
phosphorylation and activation by the v-Raf protein in vitro
phosphoprotein
-
MEK and ERK are activated by phosphorylation
phosphoprotein
-
MEK is phosphorylated at Ser217 and Ser221, activating phosphorylation of ERK-1 and ERK-2 at Thr202 and Tyr204 induced by tetanus toxin or the C-terminal part of the heavy chain
phosphoprotein
-
MKKs are activated by phopshorylation through MKKKs, e.g. MEKK, MLK, TAK1, Ask1, or TPL2, MKK4 is phopshorylated at serine and threonine residues in the SIAKT motif
phosphoprotein
-
Ser218 and Ser222 are the primary sites for phosphorylation
phosphoprotein
-
STE7 displays several phosphorylation forms and is multiply phosphorylated in response to either pheromone or coexpression of dominant STE11 protein
phosphoprotein
-
the enzyme performs autophosporylation
phosphoprotein
-
Pek1 has a dual stimulatory and inhibitory function which depends on its phosphorylation state
phosphoprotein
-
MKKs are activated by phopshorylation through MKKKs, e.g. MEKK, MLK, TAK1, Ask1, or TPL2, MKK4 is phopshorylated at serine and threonine residues in the SIAKT motif
Crystallization/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
MEK1, to a resolution of 2.8 A
P31938, Q63932
GENERAL STABILITY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
proteolytic inactivation by anthrax lethal factor
-
proteolytic inactivation by anthrax lethal factor
-
Purification/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
recombinant wild-type and mutant GST-fusion enzymes from Escherichia coli by glutathione affinity chromatography
-, Q9GRT1
Cloned/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
construction of a 35S:MKK3-WT:myc expression cassette, either myc epitope-tagged wild-type MKK3 or constitutively active MKK3 are transiently expressed in Arabidopsis thaliana protoplasts, co-overexpression of MKK3 with MKK7 in ProPR1:GUS transgenic cell line, interaction analysis of MKK3 with group C MAPK kinases by yeast two-hybrid system, MKK3 and MPK7 induce the PR1 promoter, overview; open reading frames of MKK3 cloned into the plant expression vector pRT100 and fused at their C-terminal end to a c-myc epitope. Arabidopsis protoplast transient expression
-
genes mkk1 and mkk2; genes mkk1 and mkk2
Q94A06, Q957U9
; DMKK4, DNA and amino acid sequence determination
-
; MKK4, DNA and amino acid sequence determination, the gene is located on chromosome 17
O14733, P45985
A549 cells transfected with wild-type or constitutively active MEK1 cDNA, both MEK1 expressions lead to increased SMAD3 expression and ERK phosphorylation; MEK1, sequence comparison
-
expressed in COS7 cells
-
expression in COS and 293 cells
-
HA-MEK1 cloned into pRevTRE, HA-tagged MEK1 expressed in HeLa cells
-
isolation of cDNA
-
overexpression in COS cells
-
subcloned into the pET28b bacterial expression vector and expressed with a 6 x N-terminal His tag, also subcloned into pGEX 4T-3 for bacterial expression as a GST-fusion protein
-
transient overexpression of MEKK-1 in insulin-producing cell lines RIN-5AH and betaTC-6
-
DNA and amino acid sequence determination and analysis, expression of wild-type and mutant GST-fusion enzymes in Escherichia coli, expression of a GFP-tagged enzyme in the null mutant strain, complementation of the null mutant strain by expression of the enzyme from plasmid or by reintegration of the wild-type gene into the genomic DNA locus
-, Q9GRT1
; gene Mkk4, expression in ovarian cancer cell line SKOV3ip.1, that lacks endogenous MKK4, leading to a decrease in overt metastatic implants on several tissues and organs
P47809, Q8CE90
constitutive active form of MEK1 and siRNA-targeting MEK1 cloned into MSCV-IRES-GFP vector, retrovirally transduced to HSCs and injected into sublethally irradiated RAG2-/- (CD42.2) mice
-
expressed in COS7 cells
-
expression in HEK293 cells; expression in HEK293 cells
Q61083, Q61084
isozymes MAPKK 10-2, DNA and amino acid sequence determination and analysis, quantitative expression analysis: the rice MAPKK isozymes are differentially regulated by cold, heat, salinity and drought stresses, sequence comparison, phylogenetic tree, overview; isozymes MAPKK 1, DNA and amino acid sequence determination and analysis, quantitative expression analysis: the rice MAPKK isozymes are differentially regulated by cold, heat, salinity and drought stresses, sequence comparison, phylogenetic tree, overview; isozymes MAPKK 3, DNA and amino acid sequence determination and analysis, quantitative expression analysis: the rice MAPKK isozymes are differentially regulated by cold, heat, salinity and drought stresses, sequence comparison, phylogenetic tree, overview; isozymes MAPKK 4, DNA and amino acid sequence determination and analysis, quantitative expression analysis: the rice MAPKK isozymes are differentially regulated by cold, heat, salinity and drought stresses, sequence comparison, phylogenetic tree, overview; isozymes MAPKK 6, DNA and amino acid sequence determination and analysis, quantitative expression analysis: the rice MAPKK isozymes are differentially regulated by cold, heat, salinity and drought stresses, sequence comparison, phylogenetic tree, overview
A2XE35, A3FK65, Q0MSI2, Q0Z7Z4, Q5QN75
expression in COS cells
-
isolation of cDNA; isolation of cDNA
-
phylogenetic tree of kinases derived from the kinase core sequence, overview, expression as GST-fusion protein under control of the galactose-inducible GAL1 promotor in Escherichia coli, determination of 5'-end sequences
-
MKK6, DNA and amino acid sequence determination and analysis, expression analysis and phylogenetic tree, recombinant ectopical expression of c-Myc-tagged MKK6a, b, and c in CHSE-214 cells
A9UK00, -
bacterial expression
Q05116
MKK4 or XMEK2, DNA and amino acid sequence determination
-
EXPRESSION
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
tert-butyl hydroperoxide induces the expression of MAP kinase (mainly JNK and ERK) in QZG cells
-
ENGINEERING
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
S235E/T241E
Arabidopsis thaliana Col-0
-
constitutively active kinase, MKK3-overexpressing plants, show significantly less Pseudomonas syringae growth compared with wild-type plants at 48 and 72 h after inoculation
-
D208N
Q63980
mutation abolishes MAPKK activity
additional information
-
mkk3 knockout plants, growth of virulent Pseudomonas syringae is increased
additional information
Q94A06, Q957U9
mkk1 single mutant appears similar to the wild-type, basal levels of MPK4 activity are not impaired in them, and MKK1 is in part functionally redundant in unchallenged plants, overview, the mkk1/2 double mutant is severely dwarfed, phenotypes of mkk1/2 are due to loss-of-function of both MKK1 and MKK2, overview. Hormone levels and growth phenotypes of mkk1/2/sid2 and mkk1/2/ein2 triple mutants, overview
additional information
Q94A06, Q957U9
mkk2 single mutant appears similar to the wild-type, basal levels of MPK4 activity are not impaired in them, and MKK2 is in part functionally redundant in unchallenged plants, overview, the mkk1/2 double mutant is severely dwarfed, phenotypes of mkk1/2 are due to loss-of-function of both MKK1 and MKK2, overview. Hormone levels and growth phenotypes of mkk1/2/sid2 and mkk1/2/ein2 triple mutants, overview
additional information
-
transgenic ProMKK3:GUS lines show basal expression in vascular tissues that is strongly induced by Pseudomonas syringae pv tomato strain DC3000 infection but not by abiotic stresses. The growth of virulent Pst DC3000 is increased in mkk3 knockout plants and decreased in MKK3-overexpressing plants, MKK3 overexpression lines show increased expression of several PR genes, phenotypes, overview
S235E/T241E
-
constitutively active kinase, MKK3-overexpressing plants, show significantly less Pseudomonas syringae growth compared with wild-type plants at 48 and 72 h after inoculation
additional information
Arabidopsis thaliana Col-0
-
mkk3 knockout plants, growth of virulent Pseudomonas syringae is increased, transgenic ProMKK3:GUS lines show basal expression in vascular tissues that is strongly induced by Pseudomonas syringae pv tomato strain DC3000 infection but not by abiotic stresses. The growth of virulent Pst DC3000 is increased in mkk3 knockout plants and decreased in MKK3-overexpressing plants, MKK3 overexpression lines show increased expression of several PR genes, phenotypes, overview
-
S222A
Q63980
mutation abolishes MAPKK activity, shows a reduction in phosphorylation in response to active MAPKKK and exerts a dominant negative effect on the serum-stimulated endogenous MAPKK
additional information
O14733, P45985
overexpression of a constitutively active mutant of MKK4 in bronchial epithelial cell lines increases their proliferation and invasive properties
additional information
-
positive regulation of SMAD3 expression is demonstrated by expression of a constitutively active ca-MEK1 construct, where the presence of ca-MEK1 results in increased SMAD3 protein expression
additional information
-
silencing of MEKK-1 in betaTC-6 and human dispersed islet cells by siRNA results in protection from DETA/NO, streptozotocin, H2O2, and tunicamycin induced cell death, transient overexpression of MEKK-1 in insulin-producing cell lines RIN-5AH and betaTC-6 leads to increase in c-Jun N-terminal kinase phosphorylation and augmented cell death induced by DETA/NO, streptozotocin, and H2O2, overview
K102R
-, Q9GRT1
site-directed mutagenesis, kinase inactive mutant, but slight autophosphorylation activity, the mutant strain shows a phenotype with a proliferation defect after infection of human macrophages and no or delayed lesion development in mice
additional information
-, Q9GRT1
construction of deletion/disruption, null, or loss-of-function mutants, which all show a phenotype with a proliferation defect after infection of human macrophages and no or delayed lesion development in mice, gene replacement method
additional information
-
expression of the neuron-specific dominant negative mitogen activated protein kinase kinase in mutant mice leads to impaired inflammatory pain and thermal hyperalgesia
additional information
-
MKK4-null MEF cells, are highly susceptible to apoptosis by LY294002, paclitaxel, or serum starvation. MKK4 loss increases PTEN expression and inhibits PI3K-dependent signaling but reveals persistent AKT phosphorylation in serum-starved MKK4-null cells
additional information
P47809, Q8CE90
targeted deletion of the Mkk4 gene, results in early embryonic lethality, anemia, severe hemorrhaging in the liver, impaired liver formation and abnormal hepatogenesis, which correlates with significant apoptosis of liver cells, and greatly reduced thymus size. In Mkk4-/- embryonic stem cells there is no defect in p38 activation in response to a number of stresses
additional information
P47809, Q8CE90
construction of MKK4-deficient mutant mice, phenotype, overview
additional information
-
overexpression of Gab-1 in sympathetic neuronal cells leads to increased MEK and ERK activation
additional information
-
overexpression in rat highly metastatic prostate cancer cell line AT6.1 significantly reduces the metastatic ability, overexpression of an inactive MKK4 in the cells leads to reduced lung metastatses and longer survival time in injected mice, overview
APPLICATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
medicine
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targets c-Jun N-terminal kinase but not p38
medicine
O14733, P45985
important role for MKK4 pathways in controlling cancer development, has a tumor suppression function, the MKK4 gene is mutated at a frequency of 5% in a number of cancer types. In contrast, studies in other cell types suggest that MKK4 and c-Jun N-terminal kinase participate in tumor promotion
medicine
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key activator of p38 MAPK in glioma, MKK3 activation is strongly correlated with p38 activation in vitro and in vivo, strong promoter of tumor invasion, progression, and poor patient survival, interference with MKK3 signaling through a novel treatment combination of p38 inhibitor plus temozolomide heightens the vulnerability of glioma to chemotherapy
medicine
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MKK4 immunolabeling detects precursor lesions of gastric adenocarcinoma that are otherwise clinically, radiographically, and endoscopically inapparent, is useful in the diagnosis and therapeutic targeting of gastric adenocarcinoma precursor lesions
medicine
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novel isoform of human MKK7, is expressed in various normal tissues, tumors, and in synoviocytes from rheumatoid and osteoarthritis patients. Recombinant MKK7gamma1 can be phosphorylated and activated by MEKK1
medicine
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plays a role in acute myelogenous leukemia, Raf/MEK/ERK pathway regulates the subcellular localization of p53 and the relative contribution of transcription-dependent and transcription-independent pathways in p53-mediated apoptosis
drug development
P31938, Q63932
design and synthesis of a new series of MEK1 inhibitors, the 4-anilino-5-carboxamido-2-pyridones
medicine
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Porphyromonas gingivalis-secreted factors may initiate MEK/ERK signal pathways and lead to myocardial cell hypertrophy and apoptosis
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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MKK3 pathway plays a role in pathogen defense, MKK3 is an upstream activator of the group C MAPKs MPK1, MPK2, MPK7, and MPK14. MKK3 shows the strongest interaction with MPK7, it phosphorylates MPK7. H2O2, but not flg22, activates MPK7 in an MKK3-mediated manner, MKK3 and MPK7 are part of a signaling pathway that regulates PR1 expression
additional information
Arabidopsis thaliana Col-0
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MKK3 pathway plays a role in pathogen defense, MKK3 is an upstream activator of the group C MAPKs MPK1, MPK2, MPK7, and MPK14. MKK3 shows the strongest interaction with MPK7, it phosphorylates MPK7. H2O2, but not flg22, activates MPK7 in an MKK3-mediated manner, MKK3 and MPK7 are part of a signaling pathway that regulates PR1 expression
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medicine
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MKK inhibition by anthrax lethal toxin LeTx is a broadly effective strategy for targeting neovascularization in fibrosarcomas and other similar proliferative lesions
additional information
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MEK1 is an important regulator of SMAD3 expression
additional information
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MEK1 plays an in vivo role in Golgi reorganization, which regulates cell cycle progression, MEK signaling promotes G2/M cell cycle transition by unlinking the Golgi, that involves, at least in part, phosphorylation of the putative Golgi structural protein GRASP55
additional information
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MAPKK is involved in IPO expression pathway, but the regulatory role of MAPKK in ethylene transduction pathway is in the downstream of Ca2+ accumulation in cytosol. Position of MAPKK in the signal transduction of ethylene is downstream of the dephosphorylated protein(s). The signal induced by ethylene is transferred to dephosphorylated protein(s) first, and then passes to MAPKK to cause the activation of IPO
medicine
P47809, Q8CE90
acts as tumor suppressor, but can also promote tumor growth, plays a role in liver formation, the immune system and cardiac hypertrophy, contributes to optimal c-Jun N-terminal kinase activation
additional information
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MEK/ERK pathway plays an important role in myeloid differentiation, especially granulocyte/macrophage lineage commitment, not only in ectopic interleukin-2 driven lineage conversion in common lymphoid progenitors but also in physiologic hematopoiesis
additional information
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MKK4 promotes the survival of MEF cells by decreasing the expression of phosphatase and tensin homologue deleted from chromosome 10 PTEN. MKK4 inhibits PTEN transcription by activating NFkappaB, a transcriptional suppressor of PTEN. MKK4 is required for nuclear translocation of RelA/p65 and processing of the NFkappaB2 precursor p100 into the mature form p52. MKK4 promotes cell survival by activating phosphatidylinositol 3-kinase through an NFkappaB/PTEN-dependent pathway
additional information
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the carboxyl-most 20 amino acids of MAP3K11 interact with the CRISP domain of CRISP2. CRISP2 may be a MAP3K11-modifying protein or, alternatively, MAP3K11 acts to phosphorylate CRISP2 during acrosome development