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Information on EC 2.7.12.2 - mitogen-activated protein kinase kinase

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IUBMB Comments
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 . 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.
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UNIPROT: P52564
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Word Map
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea
Reaction Schemes
+
a [protein]-(L-serine/L-threonine)
=
+
a [protein]-(L-serine/L-threonine) phosphate
Synonyms
mek/erk, mitogen-activated protein kinase kinase, map kinase kinase, mapkk, mek-1, extracellular-signal-regulated kinase, mapk/erk kinase, map2k4, erk 1, mitogen-activated protein kinase kinase 1, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
dual specificity mitogen-activated protein kinase kinase 6
-
MAPK kinase
-
MAPK kinase 6
-
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.
CAS REGISTRY NUMBER
COMMENTARY hide
142805-58-1
-
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
ATP + a protein
ADP + a phosphoprotein
show the reaction diagram
-
-
-
?
ATP + K53M-[p38alpha]
ADP + phospho-K53M-[p38alpha]
show the reaction diagram
catalytically inactive p38alpha in which lysine-53 is substituted with methionine
-
-
?
ATP + p38
ADP + ?
show the reaction diagram
-
-
-
?
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 + p38alpha
ADP + phosphorylated p38alpha
show the reaction diagram
MKK6 phosphorylates p38 MAPK on Thr180 and Tyr182, the sites of phosphorylation that activate p38 MAPK
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
additional information
?
-
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
ATP + a protein
ADP + a phosphoprotein
show the reaction diagram
-
-
-
?
ATP + p38alpha
ADP + phosphorylated p38alpha
show the reaction diagram
MKK6 phosphorylates p38 MAPK on Thr180 and Tyr182, the sites of phosphorylation that activate p38 MAPK
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
anisomycin
activates
additional information
MEK6 is strongly activated by UV, anisomycin, and osmotic shock
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.00016
K53M-[p38alpha]
pH 7.0, 25°C
-
0.000205
p38alpha
pH 7.0, 25°C
-
additional information
additional information
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.152
K53M-[p38alpha]
pH 7.0, 25°C
-
0.243
p38alpha
pH 7.0, 25°C
-
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
metabolism
the p38 pathway is activated by MKK3, MKK4, and MKK6
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
MP2K6_HUMAN
334
0
37492
Swiss-Prot
other Location (Reliability: 2)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
37000
x * 37000, calculation from nucleotide sequence
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
?
x * 37000, calculation from nucleotide sequence
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
phosphoprotein
the enzyme is phosphorylated and activated in vitro by TAK1
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
S207E/T211E
a constitutively active MKK6 mutant
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
isolation of cDNA
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
analysis
development of a continuous spectrophotometric assay for mitogen-activated protein kinase kinases
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Vitale, G.; Bernardi, L.; Napolitani, G.; Mock, M.; Montecucco, C.
Susceptibility of mitogen-activated protein kinase kinase family members to proteolysis by anthrax lethal factor
Biochem. J.
352
739-745
2000
Homo sapiens (O14733), Homo sapiens (P36507), Homo sapiens (P45985), Homo sapiens (P52564), Homo sapiens (Q02750)
Manually annotated by BRENDA team
Raingeaud, J.; Whitmarsh, A.J.; Barrett, T.; Derijard, B.; Davis, R.J.
MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway
Mol. Cell. Biol.
16
1247-1255
1996
Homo sapiens (P46734), Homo sapiens (P52564)
Manually annotated by BRENDA team
Cuenda, A.; Alonso, G.; Morrice, N.; Jones, M.; Meier, R.; Cohen, P.; Nebreda, A.R.
Purification and cDNA cloning of SAPKK3, the major activator of RK/p38 in stress- and cytokine-stimulated monocytes and epithelial cells
EMBO J.
15
4156-4164
1996
Homo sapiens (P52564), Homo sapiens, Mus musculus (P70236), Mus musculus
Manually annotated by BRENDA team
Han, J.; Lee, J.D.; Jiang, Y.; Li, Z.; Feng, L.; Ulevitch, R.J.
Characterization of the structure and function of a novel MAP kinase kinase (MKK6)
J. Biol. Chem.
271
2886-2891
1996
Homo sapiens (P52564), Homo sapiens
Manually annotated by BRENDA team
Moriguchi, T.; Kuroyanagi, N.; Yamaguchi, K.; Gotoh, Y.; Irie, K.; Kano, T.; Shirakabe, K.; Muro, Y.; Shibuya, H.; Matsumoto, K.; Nishida, E.; Hagiwara, M.
A novel kinase cascade mediated by mitogen-activated protein kinase kinase 6 and MKK3
J. Biol. Chem.
271
13675-13679
1996
Homo sapiens (P52564)
Manually annotated by BRENDA team
Stein, B.; Brady, H.; Yang, M.X.; Young, D.B.; Barbosa, M.S.
Cloning and characterization of MEK6, a novel member of the mitogen-activated protein kinase kinase cascade
J. Biol. Chem.
271
11427-11433
1996
Homo sapiens (P52564)
Manually annotated by BRENDA team
Zheng, L.S.; Zhang, Y.Y.; Wu, J.W.; Wu, Z.; Zhang, Z.Y.; Wang, Z.X.
A continuous spectrophotometric assay for mitogen-activated protein kinase kinases
Anal. Biochem.
421
191-197
2012
Homo sapiens (P52564), Homo sapiens (Q02750)
Manually annotated by BRENDA team