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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: Q02750
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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 1
-
MAPK kinase
-
MAPK/ERK kinase 1
-
mitogen-activated protein kinase kinase 1
-
mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1
-
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 + ERK1
ADP + phosphorylated ERK1
show the reaction diagram
phosphorylation of extracellular signal-regulated kinase 1
-
-
?
ATP + ERK2
ADP + phosphorylated ERK2
show the reaction diagram
ATP + K52R-[ERK2]
ADP + phospho-K52R-[ERK2]
show the reaction diagram
catalytically inactive ERK2 in which lysine-52 is substituted with arginine
-
-
?
ATP + MyoD
ADP + phospharylated MyoD
show the reaction diagram
ATP + protein
ADP + phosphoprotein
show the reaction diagram
enzyme is involved on MAPK signal transduction pathway
-
-
?
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 + ERK1
ADP + phosphorylated ERK1
show the reaction diagram
phosphorylation of extracellular signal-regulated kinase 1
-
-
?
ATP + ERK2
ADP + phosphorylated ERK2
show the reaction diagram
-
-
-
?
ATP + MyoD
ADP + phospharylated MyoD
show the reaction diagram
phosphorylation at Tyr156, activated MEK1 associates with MyoD
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
enzyme is involved on MAPK signal transduction pathway
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
MIIC
i.e. MEK inhibitor I, the MEK1/2 inhibitor causes NAD(H) reduction, heme oxidation, and decreased oxygen consumption
PD184352
a MEK-specific inhibitor
PD198306
an orally active MEK1/2 inhibitor, acting as an uncoupler
PD98059
the MEK1/2 inhibitor causes NAD(H) reduction, heme oxidation, and decreased oxygen consumption
trametinib
a mitogen-activated protein kinase kinase 1 (MEK1)/MEK2 inhibitor with activity against multiple myeloid cell lines at low nanomolar concentrations, preferential activity among RAS-mutated myeloid malignancies. During clinical oral treatment, most commonly reported treatment-related adverse events are diarrhea, rash, nausea, and increased alanine aminotransferase levels, repeated cycles of trametinib are well tolerated with manageable or reversible toxicities, overview
U0126
the MEK1/2 inhibitor causes NAD(H) reduction, heme oxidation, and decreased oxygen consumption
additional information
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0533
ATP
pH 7.0, 25°C
0.000184
ERK2
pH 7.0, 25°C
-
0.000129
K52R-[ERK2]
pH 7.0, 25°C
-
additional information
additional information
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.085
ATP
pH 7.0, 25°C
0.503
ERK2
pH 7.0, 25°C
-
0.074
K52R-[ERK2]
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
activated MEK1 associates with MyoD in the nucleus of differentiating myoblasts
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
activated MEK1 associates with MyoD in the nucleus of differentiating myoblasts
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
metabolism
MEK1 activates the prototypic MAPK pathway by activating enzyme ERK1
physiological function
transcriptional activity of MyoD is critical in understanding skeletal muscle development and regeneration. Mitogen-activated protein kinase kinase 1 (MEK1) stabilizes MyoD through direct phosphorylation at tyrosine 156 during myogenic differentiation. The amount of MyoD co-precipitated with MAFbx/AT-1 is reduced in the presence of active MEK1. The phosphorylation probably interrupts the binding of MAFbx/AT-1 to MyoD and thereby increases its stability. The MEK1-induced phosphorylation of MyoD enhances heterodimerization with E proteins
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
MP2K1_HUMAN
393
0
43439
Swiss-Prot
other Location (Reliability: 2)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
40745
x * 40745, MKK1b an alternatively spliced form of the MKK1a gene, calculation from nucleotide sequence
43439
x * 43439, MKK1a, calculation from nucleotide sequence
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
phosphoprotein
Ser218 and Ser222 are the primary sites for phosphorylation
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
S218E/S222E
site-directed mutagenesis, a constitutively active MEK1 mutant, i.e. MEK1EE
Y156F
site-directed mutagenesis, catalytically inactive mutant. The protein level of mutant MyoD-Y156F decreases compared with that of wild type but is recovered in the presence of lactacystin, a proteasome inhibitor. The low protein level of MyoD-Y156F is recovered over that of wild-type by an additional mutation at Leu164, a critical binding residue of MAFbx/AT-1, a Skp, Cullin, F-box (SCF) E3-ubiquitin ligase
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
proteolytic inactivation by anthrax lethal factor
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
overexpression in COS cells
recombinant coexpression of His6-tagged constitutively active MEK1 mutant S218E/S222E and GST-MyoD protein
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
Zheng, C.F.; Guan, K.L.
Activation of MEK family kinases requires phosphorylation of two conserved Ser/Thr residues
EMBO J.
13
1123-1131
1994
Saccharomyces cerevisiae (P06784), Homo sapiens (Q02750)
Manually annotated by BRENDA team
Duesbery, N.S.; Webb, C.P.; Leppla, S.H.; Gordon, V.M.; Klimpel, K.R.; Copeland, T.D.; Ahn, N.G.; Oskarsson, M.K.; Fukasawa, K.; Paull, K.D.; Vande Woude, G.F.
Proteolytic inactivation of MAP-kinase-kinase by anthrax lethal factor
Science
280
734-737
1998
Mus musculus (P31938), Homo sapiens (P36507), Homo sapiens (Q02750)
Manually annotated by BRENDA team
Zheng, C.F.; Guan, K.L.
Cloning and characterization of two distinct human extracellular signal-regulated kinase activator kinases, MEK1 and MEK2
J. Biol. Chem.
268
11435-11439
1993
Homo sapiens (P36507), Homo sapiens (Q02750)
Manually annotated by BRENDA team
Seger, R.; Seger, D.; Lozeman, F.J.; Ahn, N.G.; Graves, L.M.; Campbell, J.S.; Ericsson, L.; Harrylock, M.; Jensen, A.M.; Krebs, E.G.
Human T-cell mitogen-activated protein kinase kinases are related to yeast signal transduction kinases
J. Biol. Chem.
267
25628-25631
1992
Homo sapiens (Q02750), Homo sapiens
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
Borthakur, G.; Popplewell, L.; Boyiadzis, M.; Foran, J.; Platzbecker, U.; Vey, N.; Walter, R.B.; Olin, R.; Raza, A.; Giagounidis, A.; Al-Kali, A.; Jabbour, E.; Kadia, T.; Garcia-Manero, G.; Bauman, J.W.; Wu, Y.; Liu, Y.; Schramek, D.; Cox, D.S.; Wissel, P.; Kantarjian, H.
Activity of the oral mitogen-activated protein kinase kinase inhibitor trametinib in RAS-mutant relapsed or refractory myeloid malignancies
Cancer
122
1871-1879
2016
Homo sapiens (P36507), Homo sapiens (Q02750), Homo sapiens
Manually annotated by BRENDA team
Jo, C.; Cho, S.J.; Jo, S.A.
Mitogen-activated protein kinase kinase 1 (MEK1) stabilizes MyoD through direct phosphorylation at tyrosine 156 during myogenic differentiation
J. Biol. Chem.
286
18903-18913
2011
Homo sapiens (Q02750)
Manually annotated by BRENDA team
Ripple, M.; Kim, N.; Springett, R.
Acute mitochondrial inhibition by mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) 1/2 inhibitors regulates proliferation
J. Biol. Chem.
288
2933-2940
2013
Homo sapiens (P36507), Homo sapiens (Q02750)
Manually annotated by BRENDA team