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Information on EC 2.7.11.25 - mitogen-activated protein kinase kinase kinase and Organism(s) Saccharomyces cerevisiae and UniProt Accession P23561
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2.7.11.25 mitogen-activated protein kinase kinase kinaseIUBMB Comments
This enzyme phosphorylates and activates its downstream protein kinase, EC 2.7.12.2, mitogen-activated protein kinase kinase (MAPKK) but requires MAPKKKK for activation. Some members of this family can be activated by p21-activated kinases (PAK/STE20) or Ras. While c-Raf and c-Mos activate the classical MAPK/ERK pathway, MEKK1 and MEKK2 preferentially activate the c-Jun N-terminal protein kinase(JNK)/stress-activated protein kinase (SAPK) pathway . 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.
Specify your search results
Word Map
- 2.7.11.25
- mapks
- c-jun
- ask1
- necrosis
- melanoma
- proto-oncogene
-
necroptosis
-
domain-like
- mlkl
- tnf
- raf-1
-
receptor-interacting
- oocyte
- nf-kappab
- c-myc
- ripk1
-
dominant-negative
-
meiotic
- sorafenib
- pheromone
- cyclins
-
pseudokinase
- vemurafenib
- ikappab
- pik3ca
- traf2
- n-ras
-
receptor-associated
-
serine-threonine
- analysis
- dabrafenib
- erk5
- mek-1
-
p21-activated
-
kirsten
-
ras-dependent
- p38alpha
-
jnk-dependent
-
kinase-inactive
-
mixed-lineage
-
necrostatin-1s
-
mek-erk
- medicine
-
jnk-mediated
-
braf-mutant
- ikkalpha
-
kinase-dead
-
multikinase
-
ras-induced
- trametinib
-
brafv600e
- ikkbeta
The taxonomic range for the selected organisms is: Saccharomyces cerevisiae
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
+
a [protein]-(L-serine/L-threonine)
=
+
a [protein]-(L-serine/L-threonine) phosphate
Synonyms
b-raf, c-raf, mekk1, c-mos, apoptosis signal-regulating kinase 1, mixed lineage kinase, ste11, mekk3, map3k1, mapkkk, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
c-mos
-
-
-
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DLK
-
-
-
-
Dual leucine zipper bearing kinase
-
-
-
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HsNIK
-
-
-
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Leucine-zipper protein kinase
-
-
-
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MAPK-upstream kinase
-
-
-
-
MUK
-
-
-
-
NF-kappa beta-inducing kinase
-
-
-
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Serine/threonine protein kinase NIK
-
-
-
-
ZPK
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
ATP:protein phosphotransferase (MAPKKKK-activated)
This enzyme phosphorylates and activates its downstream protein kinase, EC 2.7.12.2, mitogen-activated protein kinase kinase (MAPKK) but requires MAPKKKK for activation. Some members of this family can be activated by p21-activated kinases (PAK/STE20) or Ras. While c-Raf and c-Mos activate the classical MAPK/ERK pathway, MEKK1 and MEKK2 preferentially activate the c-Jun N-terminal protein kinase(JNK)/stress-activated protein kinase (SAPK) pathway [2]. Mitogen-activated protein kinase (MAPK) signal transduction pathways are among the most widespread mechanisms of cellular regulation. Mammalian MAPK pathways can be recruited by a wide variety of stimuli including hormones (e.g. insulin and growth hormone), mitogens (e.g. epidermal growth factor and platelet-derived growth factor), vasoactive peptides (e.g. angiotensin-II and endothelin), inflammatory cytokines of the tumour necrosis factor (TNF) family and environmental stresses such as osmotic shock, ionizing radiation and ischaemic injury.
CAS REGISTRY NUMBER
COMMENTARY
146702-84-3
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ATP + protein
ADP + phosphoprotein
enzyme is involved in the response of haploid yeast cells to peptide mating pheromones
-
-
?
ATP + protein
ADP + phosphoprotein
the enzyme is required for cell-type-specific transcription and signal transduction
-
-
?
additional information
?
-
-
Ste11 is involved in MAPK pathway signal transduction governing mating, osmoregulation, and nitrogen starvation by direct interaction with the sterile alpha motif domains, SAM, of Ste50 and Ste11
-
-
?
additional information
?
-
-
Ste50 binds the MAPKKK Ste11 through a head-to-tail sterile interaction via both alpha motif SAM domains, NMR binding study, very tight and stable binding between the two mutants Ste50 L69R and Ste11 L72R, overview
-
-
?
additional information
?
-
-
activator of the Pbs2 MAPKK in the SLN1 branch of the Hog1 MAPK cascade, involved in osmoregulation
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ATP + protein
ADP + phosphoprotein
enzyme is involved in the response of haploid yeast cells to peptide mating pheromones
-
-
?
ATP + protein
ADP + phosphoprotein
the enzyme is required for cell-type-specific transcription and signal transduction
-
-
?
additional information
?
-
-
Ste11 is involved in MAPK pathway signal transduction governing mating, osmoregulation, and nitrogen starvation by direct interaction with the sterile alpha motif domains, SAM, of Ste50 and Ste11
-
-
?
additional information
?
-
-
activator of the Pbs2 MAPKK in the SLN1 branch of the Hog1 MAPK cascade, involved in osmoregulation
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
-
inhibitory function within the N-terminal domain
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
osomolarity two-component system protein SSK1
-
non-phosphorylated dimer, binding of Ssk1 seems to be necessary for Ssk2 activation
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Ste50
-
Ste50 binding of the MAPKKK Ste11 through a head-to-tail sterile interaction via both alpha motif SAM domains is required for Ste11 activity and cell viability, NMR binding study, very tight and stable binding between the two mutants Ste50 L69R and Ste11 L72R, molecular modeling, overview
-
additional information
-
Ssk1p binds and activates the MEKK kinases Ssk2p and Ssk22p, de-phosphorylated Ssk1p binds to the N-terminal auto-inhibitory domain of Ssk2p and Ssk22p, activating their auto-phosphorylation on a conserved threonine residue
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
-
kinetics of binding between wild-type and mutant Ste11 and wild-type and mutant Ste50, overview
-
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
-
large scale activity assay with recombinant enzyme in a protein chip consisting of a microwell array with protein covalently attached to the wells via a 3-glycidoxypropyltrimethoxysilane crosslinker, overview
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
-
structural analysis of the sterile alpha motif, SAM, domain of Ste11 MAPKKK and of Ste50 effector, several hydrophobic secondary structures and amino acids are required for effective binding, overview
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
DELTA381-400
-
defective in osmotic induction of the 8xCRE-lacZ reporter, mutant is osmosensitive
DELTA401-420
-
defective in osmotic induction of the 8xCRE-lacZ reporter, mutant is osmosensitive
DELTA421-440
-
defective in osmotic induction of the 8xCRE-lacZ reporter, mutant is osmosensitive
L72R
-
site-directed mutagenesis, highly increased tight binding of Ste50 wild-type compared to the Ste11 wild-type enzyme
additional information
additional information
-
inhibition of heterodimeric association of Ste11 and Ste50 in yeast strains leads to defects in mating and activation of high-osmolarity growth pathways
additional information
-
ssk2delta/ssk22delta/ste11delta strain, complementation of the osmo-sensitive phenotype, deletion of the LD domain of Ssk2p results in a serious localization defect when yeast cells are exposed to osmotic stress as well as an inability to facilitate the actin specific functions of Ssk2p
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant His6- and GST-tagged wild-type and mutants enzymes from Escherichia coli by affinity chromatography and gel filtration, the tags are cleaved off
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
overexpression of His6- and GST-tagged wild-type and mutants enzymes in Escherichia coli
-
phylogenetic tree of kinases derived from the kinase core sequence, overview, overexpression as GST-fusion protein under control of the galactose-inducible GAL1 promotor in Escherichia coli, determination of 5'-end sequences
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
analysis
-
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
-
Ssk2p is one of the three MEKK kinases in the HOG pathway, the other two being Ste11p and Ssk22p, Ssk2p is homologous to MEKK4, monitors the integrity of the actin cytoskeleton and regulates its recovery from osmotic stress
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Cairns, B.R.; Ramer, S.W.; Kornberg, R.D.
Order of action of components in the yeast pheromone response pathway revealed with a dominant allele of the STE11 kinase and the multiple phosphorylation of the STE7 kinase
Genes Dev.
6
1305-1318
1992
Saccharomyces cerevisiae (P23561), Saccharomyces cerevisiae
Maeda, T.; Takekawa, M.; Saito, H.
Activation of yeast PBS2 MAPKK by MAPKKKs or by binding of an SH3-containing osmosensor
Science
269
554-558
1995
Saccharomyces cerevisiae (P53599), Saccharomyces cerevisiae
Rhodes, N.; Connell, L.; Errede, B.
STE11 is a protein kinase required for cell-type-specific transcription and signal transduction in yeast
Genes Dev.
4
1862-1874
1990
Saccharomyces cerevisiae (P23561), Saccharomyces cerevisiae
Zhu, H.; Klemic, J.F.; Chang, S.; Bertone, P.; Casamayor, A.; Klemic, K.G.; Smith, D.; Gerstein, M.; Reed, M.A.; Snyder, M.
Analysis of yeast protein kinases using protein chips
Nat. Genet.
26
283-289
2000
Saccharomyces cerevisiae
Kwan, J.J.; Warner, N.; Maini, J.; Chan Tung, K.W.; Zakaria, H.; Pawson, T.; Donaldson, L.W.
Saccharomyces cerevisiae Ste50 binds the MAPKKK Ste11 through a head-to-tail SAM domain interaction
J. Mol. Biol.
356
142-154
2006
Saccharomyces cerevisiae
Bettinger, B.T.; Amberg, D.C.
The MEK kinases MEKK4/Ssk2p facilitate complexity in the stress signaling responses of diverse systems
J. Cell. Biochem.
101
34-43
2007
Saccharomyces cerevisiae, Drosophila melanogaster, Homo sapiens, Mus musculus
Horie, T.; Tatebayashi, K.; Yamada, R.; Saito, H.
Phosphorylated Ssk1 prevents unphosphorylated Ssk1 from activating the Ssk2 mitogen-activated protein kinase kinase kinase in the yeast high-osmolarity glycerol osmoregulatory pathway
Mol. Cell. Biol.
28
5172-5183
2008
Saccharomyces cerevisiae
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