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Enzyme Nomenclature
Information on EC 2.7.12.2 - mitogen-activated protein kinase kinase
for references in articles please use BRENDA:EC2.7.12.2
Word Map on EC 2.7.12.2
- 2.7.12.2
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mapks
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3-kinase
- phosphatidylinositol
- carcinoma
- endothelial
- injury
- arrest
- leukemia
- breast
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dominant-negative
- inflammation
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phorbol
- camp
- metastasis
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stress-activated
- caspase-3
- melanoma
- wortmannin
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cyclins
- phosphoinositide
- rapamycin
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blockade
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nf-kappab
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erk-dependent
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signal-related
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kinase-dependent
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neurotrophic
- pertussis
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platelet-derived
- medicine
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phospho-erk1/2
- herbimycin
- drug development
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ras-induced
- anisomycin
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kinase-inactive
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vemurafenib
- p38mapk
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dual-specificity
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ras-mediated
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extracellular-regulated
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egf-induced
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phospho-erk
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erk-mediated
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p21ras
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ras-dependent
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p38alpha
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mek-erk
- pp2
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p90rsk
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braf-mutant
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brafv600e
- analysis
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The enzyme appears in viruses and cellular organisms
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EC NUMBER 
COMMENTARY 
2.7.12.2
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RECOMMENDED NAME
GeneOntology No.
mitogen-activated protein kinase kinase
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
ATP + a protein = ADP + a phosphoprotein
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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.
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CAS REGISTRY NUMBER
COMMENTARY
142805-58-1
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
isolated from a smoke tree, Cotinuscoggygria in Fragrant Hills Park,Beijing
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isolated from a smoke tree, Cotinuscoggygria in Fragrant Hills Park,Beijing
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663773, 665489, 665990, 679010, 679032, 679153, 681836, 682214, 686415, 688931, 689072, 703169, 705707, 740338, 740419
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MAPKK 10-2; cv. japonica and indica, var. Pusa Basmati 1, MAP kinase kinase isozyme MAPKK 10-2
UniProt
MAPKK 1; cv. japonica and indica, var. Pusa Basmati 1, MAP kinase kinase isozyme MAPKK 1
UniProt
MAPKK 3; cv. japonica and indica, var. Pusa Basmati 1, MAP kinase kinase isozyme MAPKK 3
UniProt
MAPKK 4, fragment; cv. japonica and indica, var. Pusa Basmati 1, MAP kinase kinase isozyme MAPKK 4
UniProt
MAPKK 6; cv. japonica and indica, var. Pusa Basmati 1, MAP kinase kinase isozyme MAPKK 6
UniProt
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
malfunction
metabolism
physiological function
additional information
evolution
the protozoan pathogen, Trypanosoma brucei brucei, possesses many protein kinases which show high homology to the catalytic domains of mitogen activated protein kinases (MAPKs) and their upstream regulators. The close relationship of MKK and MKKK kinase domains combined with the phylogenetic distance between trypanosomatids and model organisms makes direct experimentation required to delineate functional attributes of the parasite kinases
evolution
bos5 from Botrytis cinerea, a gene that encodes a mitogen-activated protein kinase kinase (MAPKK), is homologous to OS-5 of Neurospora crassa
evolution
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bos5 from Botrytis cinerea, a gene that encodes a mitogen-activated protein kinase kinase (MAPKK), is homologous to OS-5 of Neurospora crassa
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evolution
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the protozoan pathogen, Trypanosoma brucei brucei, possesses many protein kinases which show high homology to the catalytic domains of mitogen activated protein kinases (MAPKs) and their upstream regulators. The close relationship of MKK and MKKK kinase domains combined with the phylogenetic distance between trypanosomatids and model organisms makes direct experimentation required to delineate functional attributes of the parasite kinases
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malfunction
bloodstream forms lacking MKK1 show decreased growth at 39°C as compared to the parental line, enzyme knockout phenotype, overview. The two mkk1 knockout clones are moderately more sensitive to temperature stress than the wild-type; enzyme knockout phenotype, overview
malfunction
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VdPbs2 deletion strains exhibit delayed melanin synthesis and reduced formation of microsclerotia, similar to a VdHog1 deletion mutant. When exposed to stresses, VdPbs2 mutants are more sensitive than the wild-type to osmotic agents and peroxide, but more resistant to inhibitors of cell wall synthesis and some fungicides. VdPbs2 deletion mutants exhibit reduced virulence on smoke tree and tobacco seedlings. Transcript analysis revealed“s that three genes(VDAG_08724, VDAG_03661,and VDAG_06340) are consistently downregulated in the 1VdPbs2 mutant compared to that of the wild-type after treated with 1 mM H2O2 for 30 min. Phentypes, overview
malfunction
the bos5 gene deletion mutant exhibits reduced vegetative growth and strongly impaired conidiation. The mutant also exhibits increased sensitivity to the dicarboximide fungicide iprodione and to osmotic stress mediated by NaCl or KCl. The BcSAK1 protein, the putative downstream component of BOS5, is not phosphorylated in the mutant. Plant inoculation tests show that the mutants are unable to infect cucumber leaves. All of these defects are restored by genetic complementation of the DELTAbcos5-21 mutant with the wild-type bos5 gene
malfunction
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enzyme mutants show embryonic lethality. Mkk4 knockout embryonic stem cells exhibit diminished p-ATF2 and MEF2C expression, resulting in impaired MHC induction and defective cardiomyocyte differdifferentiation. Loss of MKK4 significantly blocks the induction of Mhca and Mhcb, but had no effect on expression of Mlc. Exogenous MKK4 expression partially restores the ability of Mkk4-/- embryonic stem cells to differentiate into cardiomyocytes. Mice lacking either MKK4 or MKK7 display an analogous embryonic lethal phenotype that may be attributed, at least in part, to insufficient JNK activation; enzyme mutants show embryonic lethality. Mkk7 knockout embryonic stem cells show elevated phosphorylation of MKK4, p38, and ATF2, and increased MEF2C expression. The mutant cells show higher expression of MHC and MLC and enhanced formation of contractile cardiomyocytes. Mice lacking either MKK4 or MKK7 display an analogous embryonic lethal phenotype that may be attributed, at least in part, to insufficient JNK activation
malfunction
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genetic inactivation of the Mkk7 gene alters circadian gene expression
malfunction
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genetic inactivation of MKK7 results in an extended period of oscillation in circadian gene expression in mouse embryonic fibroblasts, genetic inactivation of the Mkk7 gene alters circadian gene expression
malfunction
expression of iron superoxide dismutases FSD2 and FSD3 is significantly increased in Arabidopsis in response to NaCl treatment but blocked in transgenic MKK5-RNAi plant, mkk5. Overexpression of MKK5 in wild-type plants enhances their tolerance to salt treatments, while the mkk5 mutant exhibits hypersensitivity to salt stress in germination on salt-containing media. The kinase activity of MPK6 is totally turned off in mkk5, whereas the activity of MPK3 is only partially blocked. MKK5-overexpressing plants exhibit salt tolerance phenotypes
malfunction
enzyme ZmMKK1 overexpression in Arabidopsis thaliana plants enhances the tolerance to salt and drought stresses, and the expression of ROS scavenging enzyme- and ABA-related genes, such as POD, CAT, RAB18 and RD29A under salt and drought conditions. ZmMKK1-overexpressing Arabidopsis plants show enhanced sensitivity to abscisic acid in seed germination, root length and stomata aperture
malfunction
overexpression of MEK2 significantly promotes the replication of classical swine fever virus,CSFV, whereas knockdown of MEK2 by lentivirus-mediated small hairpin RNAs dramatically inhibits CSFV replication
malfunction
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MKK4 is highly mutated and has a pro-oncogenic role in cancers of pancreatic, breast, colon, prostate, skin, and laryngeal squamous cell. Strong association between -1304T>G (rs3826392) polymorphism in the promoter of MKK4 gene and a decreased risk of sporadic colorectal cancer in a southern Chinese population, overview
malfunction
an mkk3 mutant shows both a hypersensitive response in plant hormone gibberellin and a less sensitive response in red light signaling. Light-induced MAPK activation in wild-type seedlings and constitutive MAPK phosphorylation in dark-grown mkk3 mutant seedlings are found, respectively. The mkk3-1 mutant displays a gibberellic acid-hypersensitive phenotype in hypocotyl elongation, with an additiona long petiole phenotype
malfunction
virulence on chestnut and the developmental steps essential for mating are not affected in the DELTAcpkk3 strain. No alterations are reported in DELTAcpkk3, except under hyperosmotic conditions and in the presence of fludioxonil. Phenotype, overview; virulence on chestnut is affected in the DELTAcpkk1 strain which is also unable to complete the developmental steps essential for mating. Phenotype, overview; virulence on chestnut is affected in the DELTAcpkk2 strain which is also unable to complete the developmental steps essential for mating. DELTAcpkk2 mutants show higher sensitivity during growth in medium containing the antibiotic G418, i.e. geneticin. Phenotype, overview
malfunction
knockdown expression of SIP2 via RNA interference (RNAi) results in drastic reduction of nodules formed in transgenic hairy roots. In these roots, the expression levels of SIP2 and three marker genes for infection thread and nodule primordium formation are downregulated drastically, while the expression of two other MAPKK genes are not altered
malfunction
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D-domain mutant CAMKK7DELTAD is inactive toward MPK6 but the activity toward MPK3 is maintained, and the CAMKK7DELTAD mutant loses stomatal cluster-promoting activity; in both CAMKK4 and CAMKK5, removal of the entire N terminus (CAMKK4/5DELTANextDNint) renders the kinases incapable of inhibiting development during the SPCH and MUTE stages. As with CAMKK4/5 variants lacking D-domains, CAMKK7/9DD variants are generally unable to inhibit stomatal development in the SPCH and MUTE stages
malfunction
small grain 1, smg1, mutants exhibit small and light grains, dense and erect panicles and comparatively slightly shorter plants. The short grain and panicle phenotypes of smg1 mutants are caused by a defect in cell proliferation. Mutant smg1 forms dense and erect panicles. Mutant phenotype, overview
malfunction
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the bos5 gene deletion mutant exhibits reduced vegetative growth and strongly impaired conidiation. The mutant also exhibits increased sensitivity to the dicarboximide fungicide iprodione and to osmotic stress mediated by NaCl or KCl. The BcSAK1 protein, the putative downstream component of BOS5, is not phosphorylated in the mutant. Plant inoculation tests show that the mutants are unable to infect cucumber leaves. All of these defects are restored by genetic complementation of the DELTAbcos5-21 mutant with the wild-type bos5 gene
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malfunction
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bloodstream forms lacking MKK1 show decreased growth at 39°C as compared to the parental line, enzyme knockout phenotype, overview. The two mkk1 knockout clones are moderately more sensitive to temperature stress than the wild-type; enzyme knockout phenotype, overview
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malfunction
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VdPbs2 deletion strains exhibit delayed melanin synthesis and reduced formation of microsclerotia, similar to a VdHog1 deletion mutant. When exposed to stresses, VdPbs2 mutants are more sensitive than the wild-type to osmotic agents and peroxide, but more resistant to inhibitors of cell wall synthesis and some fungicides. VdPbs2 deletion mutants exhibit reduced virulence on smoke tree and tobacco seedlings. Transcript analysis revealed“s that three genes(VDAG_08724, VDAG_03661,and VDAG_06340) are consistently downregulated in the 1VdPbs2 mutant compared to that of the wild-type after treated with 1 mM H2O2 for 30 min. Phentypes, overview
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metabolism
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MEK1 activates the prototypic MAPK pathway by activating enzyme ERK1; the p38 pathway is activated by MKK3, MKK4, and MKK6
metabolism
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MAPK forms the backbone of four primary signal transduction cascades leading to the phosphorylation and activation of extracellular signal-regulated kinases 1 and 2 (ERK1-2), JNK, p38 and ERK5. The RAS-RAF-MEK-ERK pathway acts as a conduit to transduce signals from receptor tyrosine kinases (RTKs) to the nucleus. This pathway is intimately tied to intracellular machinery involved in cell proliferation, survival and cell migration, overview
metabolism
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signal transduction pathways are integral components of the developmental regulatory network that guides progressive cell fate determination. Essential enzymes MKK4 and MKK7 are upstream kinases of the mitogen-activated protein kinases (MAPKs), responsible for channeling physiological and environmental signals to their cellular responses. In vitro, MKK4 and MKK7 are dispensable for in embryonic stem cell self-renewal and pluripotency maintenance, but they exhibit unique signaling and functional properties in differentiation. MKK4 and MKK7 complemented each other in activation of the JNK-c-Jun cascades and loss of both leads to senescence upon cell differentiation.On the other hand, MKK4 and MKK7 have opposite effects on activation of the p38 cascades during differentiation, MKK4 is required for cardiomyocyte differentiation, while MKK7 represses it; signal transduction pathways are integral components of the developmental regulatory network that guides progressive cell fate determination. Essential enzymes MKK4 and MKK7 are upstream kinases of the mitogen-activated protein kinases (MAPKs), responsible for channeling physiological and environmental signals to their cellular responses. In vitro, MKK4 and MKK7 are dispensable for in embryonic stem cell self-renewal and pluripotency maintenance, but they exhibit unique signaling and functional properties in differentiation. MKK4 and MKK7 complemented each other in activation of the JNK-c-Jun cascades and loss of both leads to senescence upon cell differentiation.On the other hand, MKK4 and MKK7 have opposite effects on activation of the p38 cascades during differentiation, MKK4 is required for cardiomyocyte differentiation, while MKK7 represses it
metabolism
te enzyme MKK5 is part of the MAP kinase cascade, including MEKK1, MKK5, and MPK6, that mediates the salt-induced expression of iron superoxide dismutases. MKK5 interactes with the MEKK1 protein that is also involved in the salt-induced FSD signalling pathway. Salt-induced iron superoxide dismutases FSD2 and FSD3 expressions are influenced by MEKK1 via MKK5-MPK6-coupled signalling. MPK6 is also involved in the MKK5-mediated iron superoxide dismutase signalling pathway in salt stress. The MKK5-MPK3/MPK6 pathway is similar to the flagellin-induced MAPK signalling pathway, MKK4/MKK5-MPK3/MPK6
metabolism
mitogen-activated protein kinase kinase 2 (MEK2) is a kinase that operates immediately upstream of extracellular regulated kinase 1/2 (ERK1/2) and links to Raf and ERK via phosphorylation. The mitogen-activated protein kinase kinase/extracellular regulated kinase (MEK1/2/ERK1/2) cascade is involved in the replication of several members of the Flaviviridae family, including hepatitis C virus and dengue virus, or of classical swine fever virus, a psetivirus in swine
metabolism
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MKK4 belongs to MAPK pathways known to have involvement in the regulation of apoptosis, inflammation, and tumorigenesis
metabolism
the mitogen-activated protein kinase (MAPK) cascade usually functions as an important signaling network involved in physiological and developmental processes in eukaryotes. The MAPK cascade is usually composed of sequential activations of three classes of Ser/Thr protein kinases: MAPK (MPK), MAPK kinase (MKK), and MAPK kinase kinase (MKKK). The MAPK kinase (MKK) gene family has relatively few members in canonical MAPK cascade gene families, which are classified into four groups (A to D) based on the sequence similarities
metabolism
Cpkk1, the Mkk1 orthologue, acts in a phosphorylation cascade essential for cell integrity; Cpkk2 is the Ste7 orthologue involved in the pheromone response pathway; Cpkk3 is the Pbs2 orthologue, the MAP2K activates during the high-osmolarity response
metabolism
mitogen-activated protein kinase (MAPK) cascades play critical roles in signal transduction processes in eukaryotes. The MAPK kinases (MAPKKs) that link MAPKK kinases (MAPKKKs) and MAPKs are key components of MAPK cascades
metabolism
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the mitogen activated protein kinase kinase (MAPKK) is the central module of MAPK cascade and also a point of signal integration and divergence
metabolism
the enzyme is involved in the MAPK signalling network in Oryza sativa; the enzyme is involved in the MAPK signalling network in Oryza sativa; the enzyme is involved in the MAPK signalling network in Oryza sativa; the enzyme is involved in the MAPK signalling network in Oryza sativa; the enzyme is involved in the MAPK signalling network in Oryza sativa
metabolism
the mitogen activated protein kinase (MAPK) kinase (MKK) is a key component of MAPK cascade that plays important roles in intra and extra cellular signaling in plants
physiological function
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mitogen-activated protein kinase kinase 4 (MAP2K4) plays a crucial role in the stress-activated signal cascade and is enzymatically regulated by ligand or substrate binding, and/or post-translational modification
physiological function
mitogen activated kinase kinase gene MKK1 is not essential in the pathogenic bloodstream stage of Trypanosoma brucei, no effcts on growth and virulence either in vitro or in vivo. Trypanosoma brucei MKK1 does not appear to play a significant role in flagellar biogenesis; mitogen activated kinase kinase gene MKK5 is not essential in the pathogenic bloodstream stage of Trypanosoma brucei, no effcts on growth and virulence either in vitro or in vivo
physiological function
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MEK signaling directly impacts both the expression of these cytokines and their downstream activation pathways
physiological function
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mitogen-activated protein kinase kinase VdPbs2 is a key regulator of microsclerotia formation, oxidative stress and fungicide response and plant virulence in Verticillium dahliae via regulating the activity of VdHog1, a mitogen-activated protein kinase, MAPK. VdPbs2 and VdHog1 function in a cascade that regulates microsclerotia formation and virulence, but not all VdHog1 dependent functions are VdPbs2 regulated. VdPbs2 is essential for the oxidative stress response and is required for plant infection, VdPbs2 may be involved in the penetration process during plant infection
physiological function
the mitogen-activated protein kinase kinase BOS5 is involved in regulating vegetative differentiation and virulence in Botrytis cinerea
physiological function
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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
physiological function
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MKK4 regulates Jun N-terminal kinase (JNK) and differentiating cell survival. And MKK4 is required for p38 activation and cardiomyocyte differentiation. Enzymes MKK4 and MKK7 have complementary and distinct roles in embryonic stem cell differentiation; MKK7 regulates Jun N-terminal kinase (JNK) and differentiating cell survival. Enzymes MKK4 and MKK7 have complementary and distinct roles in embryonic stem cell differentiation. MKK7 reduces p38 activation
physiological function
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the stress kinase mitogen-activated protein kinase kinase 7 (MKK7) is a specific activator of c-Jun N-terminal kinase (JNK), which controls various physiological processes, such as cell proliferation, apoptosis, differentiation, and migration. Involvement of stress kinase mitogen-activated protein kinase kinase 7 in regulation of mammalian circadian clock, overview. JNK interacts with PER2 at both the exogenous and endogenous levels, and MKK7-mediated JNK activation increases the half-life of PER2 protein by inhibiting its ubiquitination. The PER2 protein stabilization induced by MKK7-JNK fusion protein reduces the degradation of PER2 induced by casein kinase 1epsilon. MKK7 controls circadian gene expression in cultured cells
physiological function
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the stress kinase mitogen-activated protein kinase kinase 7 (MKK7) is a specific activator of c-Jun N-terminal kinase (JNK), which controls various physiological processes, such as cell proliferation, apoptosis, differentiation, and migration. Involvement of stress kinase mitogen-activated protein kinase kinase 7 in regulation of mammalian circadian clock, overview. JNK interacts with PER2 at both the exogenous and endogenous levels, and MKK7-mediated JNK activation increases the half-life of PER2 protein by inhibiting its ubiquitination. The PER2 protein stabilization induced by MKK7-JNK fusion protein reduces the degradation of PER2 induced by casein kinase 1epsilon. MKK7 controls circadian gene expression in cultured cells
physiological function
the enzyme plays a role in MAPK signalling cascades involved in salt stress responses
physiological function
enzyme ZmMKK1 might act as an ABA- and ROS-dependent protein kinase in positive modulation of salt and drought tolerance. ZmMKK1 prevents chlorophylls degradation to maintain plants photosynthesis under salt stress, and ZmMKK1 enhances the drought tolerance of transgenic plants
physiological function
mitogen-activated protein kinase kinase 2, a novel E2-interacting protein, promotes the growth of classical swine fever virus, CSFV, via attenuation of the JAK-STAT signaling pathway. The MEK2-E2 interaction occurs during the late stage of CSFV replication and requires the C-termini of MEK2, residues 266 to 400, and E2
physiological function
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the enzyme plays a key role in multiple physiologic and pathophysiologic processes such as inflammation and tumor suppression
physiological function
MKK3 acts in negative regulation in darkness and in light-induced MAPK activation during darklight transition
physiological function
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mitogen-activated protein kinase kinase 3, MKK3, overexpression induces cell cycle arrest via p38 activation mediated Bmi-1 downregulation in hepatocellular carcinoma. MKK3 as a tumor suppressor. MKK3 overexpression suppresses HepG2 and PLC-PRF-5 cell proliferation and induces cell cycle arrest in the two cell lines. In addition, MKK3 overexpression upregulates the cyclin-dependent kinase inhibitors, p16 INK4A and p15 INK4B in hepatocellular carcinoma cells. Their negative regulator, Bim?1, is downregulated following MKK3 overexpression. MKK3 activates p38 in hepatocellular carcinoma cells and SB203580, a p38 inhibitor, reverses the tumor suppressive effect of MKK3
physiological function
GhMKK3 plays an important role in drought tolerance in cotton. Expression of GhPIP1 and GhMPK7 is induced in a MKK3-dependent manner by abscisic acid and drought
physiological function
SIP2 represents a typical plant mitogen-activated protein kinase kinase (MAPKK) and exhibits autophosphorylation and transphosphorylation activities. SymRK may serve as a negative regulator of the SIP2 signaling pathway. SymRK and SIP2 interaqct and are both protein kinases. The kinase domain of SIP2 is responsible for its interaction with SymRK. Essential role of SIP2 in the early symbiosis signaling and nodule organogenesis
physiological function
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isozymes MKK4/5/7/9 affect stomatal development, the D-domains of MKK7/9 are important in regulating subcellular localization of the kinases and this localization is necessary for stomatal promoting activity, overview. Additional regions of MKK4/5 function as MKK specificity determinants in vivo. A 14-3-3 binding site in the D-domain of MKK4 contributes to MKK4 function. When rendered constitutively active, four MAPK kinases (MKKs), MKK4/5/7/9, are capable of perturbing stomatal development, the kinases comprise two pairs, MKK4/5 and MKK7/9, with both overlapping and divergent functions. The behavior of MKK4 mirrors that of MKK5 and MKK7 mirrors that of MKK9 in the stomatal lineage; isozymes MKK4/5/7/9 affect stomatal development, the D-domains of MKK7/9 are important in regulating subcellular localization of the kinases and this localization is necessary for stomatal promoting activity, overview. Additional regions of MKK4/5 function as MKK specificity determinants in vivo. When rendered constitutively active, four MAPK kinases (MKKs), MKK4/5/7/9, are capable of perturbing stomatal development, the kinases comprise two pairs, MKK4/5 and MKK7/9, with both overlapping and divergent functions. The behavior of MKK4 mirrors that of MKK5 and MKK7 mirrors that of MKK9 in the stomatal lineage; isozymes MKK4/5/7/9 affect stomatal development, the D-domains of MKK7/9 are important in regulating subcellular localization of the kinases and this localization is necessary for stomatal promoting activity, overview. When rendered constitutively active, four MAPK kinases (MKKs), MKK4/5/7/9, are capable of perturbing stomatal development, the kinases comprise two pairs, MKK4/5 and MKK7/9, with both overlapping and divergent functions. The behavior of MKK4 mirrors that of MKK5 and MKK7 mirrors that of MKK9 in the stomatal lineage
physiological function
gene SMG1 encodes enzyme MKK4 (OsMKK4), which influences grain size by promoting cell proliferation, SMG1 influences panicle size and shape. OsMKK4 influences brassinosteroid (BR) responses and the expression of BR-related genes. Enzyme OsMKK4 is a factor for grain size, and links the MAPK pathways and brassinosteroids in grain growth
physiological function
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regulatory role of gene OsMKK6 on its regulon of genes, possible physiological role of OsMKK6 in modulating gene expression and signaling pathways during different stresses
physiological function
identification and analysis of the interaction network between members of Oryza sativa mitogen activated protein kinase kinase (MAPKK) and mitogen activated protein kinase (MAPK) overview; identification and analysis of the interaction network between members of Oryza sativa mitogen activated protein kinase kinase (MAPKK) and mitogen activated protein kinase (MAPK) overview; identification and analysis of the interaction network between members of Oryza sativa mitogen activated protein kinase kinase (MAPKK) and mitogen activated protein kinase (MAPK) overview; identification and analysis of the interaction network between members of Oryza sativa mitogen activated protein kinase kinase (MAPKK) and mitogen activated protein kinase (MAPK) overview; identification and analysis of the interaction network between members of Oryza sativa mitogen activated protein kinase kinase (MAPKK) and mitogen activated protein kinase (MAPK) overview
physiological function
role of OsMKK6 gene in salt stress signaling in rice. Constitutively active OsMKK6 overexpressing rice plants exhibit higher salt stress tolerance, overview
physiological function
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the mitogen-activated protein kinase kinase BOS5 is involved in regulating vegetative differentiation and virulence in Botrytis cinerea
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physiological function
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mitogen activated kinase kinase gene MKK1 is not essential in the pathogenic bloodstream stage of Trypanosoma brucei, no effcts on growth and virulence either in vitro or in vivo. Trypanosoma brucei MKK1 does not appear to play a significant role in flagellar biogenesis; mitogen activated kinase kinase gene MKK5 is not essential in the pathogenic bloodstream stage of Trypanosoma brucei, no effcts on growth and virulence either in vitro or in vivo
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physiological function
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mitogen-activated protein kinase kinase VdPbs2 is a key regulator of microsclerotia formation, oxidative stress and fungicide response and plant virulence in Verticillium dahliae via regulating the activity of VdHog1, a mitogen-activated protein kinase, MAPK. VdPbs2 and VdHog1 function in a cascade that regulates microsclerotia formation and virulence, but not all VdHog1 dependent functions are VdPbs2 regulated. VdPbs2 is essential for the oxidative stress response and is required for plant infection, VdPbs2 may be involved in the penetration process during plant infection
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additional information
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the transient state of apo npMAP2K4 exists between the canonical kinase fold and the aggregation state. The ATP molecule under physiological conditions allows the transient conformation to rapidly assume the canonical kinase fold but the depletion of ATP under conditions of low levels of bioactivity perhaps enhances the transition to the aggregation state
additional information
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Pfnek3 is a novel dual-specificity kinase of the malarial parasite, displaying both serine/threonine and tyrosine kinase activities, even though it has a HGDLKSTN motif in the catalytic loop that resembles the consensus HRDLKxxN signature found in the serine/threonine kinases. Tyrosine phosphorylation is involved in regulation of the serine/threonine and tyrosine kinase activities of Pfnek3
additional information
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anaphylatoxins (mainly C5a) are key players in the initiation of arthritis and utilize the MEK kinase cascade to initiate the disease process
additional information
MEK2 does not affect CSFV replication after blocking the interferon-induced Janus kinase signal transducer and activator of transcription (JAK-STAT) signaling pathway by ruxolitinib, a JAK-STAT-specific inhibitor. U0126 but not PD98059 inhibits CSFV replication
additional information
the interaction between SymRK and SIP2 is conserved among legumes, interaction analysis of SIP2 and SymRK from different legume species, overview
additional information
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the interaction between SymRK and SIP2 is conserved among legumes, interaction analysis of SIP2 and SymRK from different legume species, overview
additional information
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installation of a cell type-specific expression system, unique in that it allows activation of MKK signaling in cells exhibiting important generalizable behaviors (e.g., cell division and fate acquisition) without the induction of cell death or additional deleterious phenotypes commonly associated with broad activation of MKKs. Determination of influence of functional docking domains of MKKs on MAPK signal output, overview; installation of a cell type-specific expression system, unique in that it allows activation of MKK signaling in cells exhibiting important generalizable behaviors (e.g., cell division and fate acquisition) without the induction of cell death or additional deleterious phenotypes commonly associated with broad activation of MKKs. Determination of influence of functional docking domains of MKKs on MAPK signal output, overview. The D-domains of MKK7 regulate the subcellular localization of the kinase, overview; installation of a cell type-specific expression system, unique in that it allows activation of MKK signaling in cells exhibiting important generalizable behaviors (e.g., cell division and fate acquisition) without the induction of cell death or additional deleterious phenotypes commonly associated with broad activation of MKKs. Determination of influence of functional docking domains of MKKs on MAPK signal output, overview. The D-domains of MKK9 regulate the subcellular localization of the kinase, overview
additional information
determination of the three-dimensional structure of rice MAPKKs and MAPKs by a homology modelling approach, protein-protein docking to predict MAPKK-MAPK interactions; determination of the three-dimensional structure of rice MAPKKs and MAPKs by a homology modelling approach, protein-protein docking to predict MAPKK-MAPK interactions; determination of the three-dimensional structure of rice MAPKKs and MAPKs by a homology modelling approach, protein-protein docking to predict MAPKK-MAPK interactions; determination of the three-dimensional structure of rice MAPKKs and MAPKs by a homology modelling approach, protein-protein docking to predict MAPKK-MAPK interactions; determination of the three-dimensional structure of rice MAPKKs and MAPKs by a homology modelling approach, protein-protein docking to predict MAPKK-MAPK interactions
additional information
determination of the three-dimensional structure of rice MAPKKs and MAPKs by a homology modelling approach, protein-protein docking to predict MAPKK-MAPK interactions; determination of the three-dimensional structure of rice MAPKKs and MAPKs by a homology modelling approach, protein-protein docking to predict MAPKK-MAPK interactions; determination of the three-dimensional structure of rice MAPKKs and MAPKs by a homology modelling approach, protein-protein docking to predict MAPKK-MAPK interactions; determination of the three-dimensional structure of rice MAPKKs and MAPKs by a homology modelling approach, protein-protein docking to predict MAPKK-MAPK interactions; determination of the three-dimensional structure of rice MAPKKs and MAPKs by a homology modelling approach, protein-protein docking to predict MAPKK-MAPK interactions
additional information
determination of the three-dimensional structure of rice MAPKKs and MAPKs by a homology modelling approach, protein-protein docking to predict MAPKK-MAPK interactions; determination of the three-dimensional structure of rice MAPKKs and MAPKs by a homology modelling approach, protein-protein docking to predict MAPKK-MAPK interactions; determination of the three-dimensional structure of rice MAPKKs and MAPKs by a homology modelling approach, protein-protein docking to predict MAPKK-MAPK interactions; determination of the three-dimensional structure of rice MAPKKs and MAPKs by a homology modelling approach, protein-protein docking to predict MAPKK-MAPK interactions; determination of the three-dimensional structure of rice MAPKKs and MAPKs by a homology modelling approach, protein-protein docking to predict MAPKK-MAPK interactions
additional information
determination of the three-dimensional structure of rice MAPKKs and MAPKs by a homology modelling approach, protein-protein docking to predict MAPKK-MAPK interactions; determination of the three-dimensional structure of rice MAPKKs and MAPKs by a homology modelling approach, protein-protein docking to predict MAPKK-MAPK interactions; determination of the three-dimensional structure of rice MAPKKs and MAPKs by a homology modelling approach, protein-protein docking to predict MAPKK-MAPK interactions; determination of the three-dimensional structure of rice MAPKKs and MAPKs by a homology modelling approach, protein-protein docking to predict MAPKK-MAPK interactions; determination of the three-dimensional structure of rice MAPKKs and MAPKs by a homology modelling approach, protein-protein docking to predict MAPKK-MAPK interactions
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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 + Erk-1 gene product
ADP + phosphorylated Erk-1 gene product
phosphorylation primarily on a tyrosine residue and, to a lesser extent, on a threonine
-
?
ATP + extracellular regulated kinase 1
ADP + phosphorylated extracellular regulated kinase 1
-
-
-
?
ATP + extracellular regulated kinase 2
ADP + phosphorylated extracellular regulated kinase 2
-
-
-
?
ATP + JNK
ADP + phopsho-JNK
the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer acting as a metastasis suppressor, overview
-
-
?
ATP + K52R-[ERK2]
ADP + phospho-K52R-[ERK2]
-
catalytically inactive ERK2 in which lysine-52 is substituted with arginine
-
-
?
ATP + K53M-[p38alpha]
ADP + phospho-K53M-[p38alpha]
-
catalytically inactive p38alpha in which lysine-53 is substituted with methionine
-
-
?
ATP + MAP kinase 6
ADP + phosphorylated Map kinase 6
Arabidopsis thaliana MAP kinase MPK6
-
-
?
ATP + myelin basic protein
ADP + phoshorylated myelin basic protein
-
-
-
?
ATP + myelin basic protein kinase
ADP + phosphorylated myelin basic protein kinase
-
-
-
?
ATP + p38 MAP kinase
ADP + ?
-
phosphorylates and activates p38 MAP kinase
-
-
?
ATP + p38/MPK2 kinase
ADP + ?
-
phosphorylates and specifically activates the p38/MPK2 subgroup of the mitogen-activated protein kinase superfamily
-
-
?
ATP + p38alpha
ADP + phosphorylated p38alpha
-
MKK6 phosphorylates p38 MAPK on Thr180 and Tyr182, the sites of phosphorylation that activate p38 MAPK
-
-
?
ATP + Pfmap2
ADP + phosphorylated Pfmap2
-
the enzyme phosphorylates its potential in vivo Pfmap2 substrate largely on Thr290
-
-
?
ATP + poly-(Tyr-Glu)
ADP + phospho-poly-(Tyr-Glu)
-
tyrosine kinase substrate
-
-
?
ATP + [ERK2 substrate peptide]
ADP + [ERK2 substrate peptide] phosphate
-
MEK1
-
-
?
ATP + [myelin basic protein substrate peptide]
ADP + [myelin basic protein substrate peptide] phosphate
-
-
-
-
?
ATP + a protein
ADP + a phosphoprotein
-
MKK1 phosphorylates and activates the MAP kinases ERK1 and ERK2
-
-
?
ATP + BcSak1
ADP + phosphorylated BcSak1
protei BcSAK1 is the putative downstream component of BOS5
-
-
?
ATP + BcSak1
ADP + phosphorylated BcSak1
protei BcSAK1 is the putative downstream component of BOS5
-
-
?
ATP + c-Jun N-terminal kinase
ADP + phosphorylated c-Jun N-terminal kinase
-
JNK activation
-
-
?
ATP + c-Jun N-terminal kinase
ADP + phosphorylated c-Jun N-terminal kinase
-
JNK activation
-
-
?
ATP + ERK
ADP + phosphorylated ERK
-
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 + ERK1
ADP + phosphorylated ERK1
-
MEK2 protein stimulates Thr and Tyr phosphorylation on ERK1 and concomitantly activates ERK1 kinase activity more than 100-fold
-
-
?
ATP + ERK1
ADP + phosphorylated ERK1
-
phosphorylation of extracellular signal-regulated kinase 1
-
-
?
ATP + ERK2
ADP + phosphorylated ERK2
-
phosphorylation of extracellular signal-regulated kinase 2
-
-
?
ATP + ERK2
ADP + phosphorylated ERK2
-
MEK1 is able to effectively phosphorylate Thr183 and Tyr185 in the activation loop of ERK2
-
-
?
ATP + JNK
ADP + JNK phosphate
the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer, physiologic effects, overview
-
-
?
ATP + JNK
ADP + JNK phosphate
substrate of MKK4 and MKK7 in a synergistic manner
-
-
?
ATP + JNK
ADP + phospho-JNK
the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer, physiologic effects, overview
-
-
?
ATP + JNK
ADP + phospho-JNK
substrate of MKK4 and MKK7 in a synergistic manner
-
-
?
ATP + JNK
ADP + phospho-JNK
the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer acting as a metastasis suppressor, overview
-
-
?
ATP + JNK
ADP + phospho-JNK
substrate of MKK4 and MKK7 in a synergistic manner
-
-
?
ATP + JNK
ADP + phospho-JNK
-
the enzyme is involved in stress-activated MAP kinase pathways and tumorigenesis, overview
-
-
?
ATP + JNK
ADP + phospho-JNK
-
substrate of MKK4 and MKK7 in a synergistic manner
-
-
?
ATP + JNK
ADP + phosphorylated JNK
phosphorylation of JNK at the Thr residue located in the activation loop
-
-
?
ATP + JNK
ADP + phosphorylated JNK
phosphorylation of JNK at the Tyr residue located in the activation loop
-
-
?
ATP + JNK1
ADP + phosphorylated JNK1
-
slight phosphorylation, JNK1 may not be the optimal substrate for the isoform
-
-
?
ATP + MAP kinase
ADP + phosphorylated MAP kinase
activation of MAP kinase
-
-
?
ATP + MAP kinase
ADP + phosphorylated MAP kinase
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
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 + MPK-7
ADP + phospho-MPK-7
-
MKK3 interacts with MPK7 in planta
-
-
?
ATP + MPK-7
ADP + phospho-MPK-7
-
MKK3 interacts with MPK7 in planta
-
-
?
ATP + myelin basic protein
ADP + phosphorylated myelin basic protein
-
-
-
?
ATP + myelin basic protein
ADP + phosphorylated myelin basic protein
-
Pfnek3 phosphorylates MBP on threonine, but not serine residues
-
-
?
ATP + MyoD
ADP + phospharylated MyoD
-
phosphorylation at Tyr156, activated MEK1 associates with MyoD
-
-
?
ATP + MyoD
ADP + phospharylated MyoD
-
phosphorylation at Tyr156 recombinant GST-tagged MyoD substrate. Mutational analysis of phosphorylation sites using MyoD Tyr mutants, overview
-
-
?
ATP + p38
ADP + p38 phosphate
the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer, physiologic effects, overview
-
-
?
ATP + p38
ADP + phospho-p38
the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer, physiologic effects, overview
-
-
?
ATP + p38
ADP + phospho-p38
the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer acting as a metastasis suppressor, overview
-
-
?
ATP + p38
ADP + phospho-p38
-
the enzyme is involved in stress-activated MAP kinase pathways and tumorigenesis, overview
-
-
?
ATP + p38
ADP + phospho-p38
signal cascade upstream activation by phosphorylation, sorbitol induced activation of p38 in salmon TO cells does not require MKK6a, b or c
-
-
?
ATP + protein
ADP + phosphoprotein
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
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
the enzyme functions in a novel Drosophila MAPK pathway, controlling puckered expression and morphogenetic activity of the dorsal epidermis
-
-
?
ATP + protein
ADP + phosphoprotein
the enzyme is involved in the mitogenic growth factor signal transduction pathway in vertebrates
-
-
?
ATP + protein
ADP + phosphoprotein
enzyme is involved in independent human MAP-kinase signal transduction pathway
-
-
?
ATP + protein
ADP + phosphoprotein
-
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
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
-
enzyme is the major activator for p38
-
-
?
ATP + protein
ADP + phosphoprotein
-
enzyme is involved on MAPK signal transduction pathway
-
-
?
ATP + protein
ADP + phosphoprotein
-
the enzyme is the major activator of RK/p38
-
-
?
ATP + protein
ADP + phosphoprotein
MEKK3 regulates the SAPK and the ERK pathway directly
-
-
?
ATP + protein
ADP + phosphoprotein
-
ASK1 may be a key element in the mechanism of stress-induced and cytokine-induced apoptosis
-
-
?
ATP + protein
ADP + phosphoprotein
-
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
-
MAPKKK5 may be an upstream activator of MKK4 in the c-Jun N-terminal kinase pathway
-
-
?
ATP + protein
ADP + phosphoprotein
sequences located in the N-terminus of MEK5 may be important in coupling GTPase signaling molecules to the MEK5 protein kinase cascade
-
-
-
ATP + protein
ADP + phosphoprotein
phosphorylates kinase-inactive Erk-1 protein primarily on a tyrosine residue and, to a lesser extent, on a threonine
-
-
?
ATP + protein
ADP + phosphoprotein
possible role for ASK1 in tissue development during embryogenesis as well as cytokine-induced apoptosis
-
-
?
ATP + protein
ADP + phosphoprotein
-
enzyme is the major activator for p38
-
-
?
ATP + protein
ADP + phosphoprotein
-
enzyme is involved on MAPK signal transduction pathway
-
-
-
ATP + protein
ADP + phosphoprotein
MEKK 2 preferentially activates JNK
-
-
?
ATP + protein
ADP + phosphoprotein
MEKK 3 preferentially activates p42/44MAPK
-
-
?
ATP + protein
ADP + phosphoprotein
-
the enzyme renders the cell resistant to polymyxin B
-
-
?
ATP + protein
ADP + phosphoprotein
-
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
enzyme is involved in the response of haploid yeast cells to peptide mating pheromones
-
-
?
ATP + protein
ADP + phosphoprotein
-
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
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
-
dosage-dependent regulator of mitosis in Schizosaccharomyces pombe
-
-
?
ATP + protein
ADP + phosphoprotein
-
Spg1p is a key element in controlling the onset of septum formation that acts through the Cdc7p kinase
-
-
?
ATP + protein
ADP + phosphoprotein
-
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
-
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
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
the enzyme undergoes autophosphorylation on Ser, Thr and Tyr
-
-
?
ATP + protein
ADP + phosphoprotein
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 + Smad3
ADP + phosphorylated Smad3
-
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 + VdHog1
ADP + phosphorylated VdHog1
-
VdHog1 is a mitogen-activated protein kinase, MAPK
-
-
?
ATP + VdHog1
ADP + phosphorylated VdHog1
-
VdHog1 is a mitogen-activated protein kinase, MAPK
-
-
?
additional information
?
-
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
?
-
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
?
-
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
?
-
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
?
-
-
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
?
-
-
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
?
-
-
substrate binding via the D-domain of the MKK
-
-
-
additional information
?
-
-
enzyme is part of mitogen-activated protein kinase pathways, crosstalk and regulation mechanism, overview
-
-
-
additional information
?
-
-
GhMKK3 interacts with GhMPK7, a typical C group MAPK member, and GhPIP1 potein. GhMPK7 is phosphorylated by GhMKK3 in protoplasts
-
-
-
additional information
?
-
GhMKK3 interacts with GhMPK7, a typical C group MAPK member, and GhPIP1 potein. GhMPK7 is phosphorylated by GhMKK3 in protoplasts
-
-
-
additional information
?
-
MEKK3 activates SEK and MEK, the known kinases targeting SAPK and ERK respectively
-
-
-
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, 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
?
-
-
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
?
-
pro-oncogenic role of mitogen-activated protein kinase kinase 4 in cancer, overview
-
-
-
additional information
?
-
pro-oncogenic role of mitogen-activated protein kinase kinase 4 in cancer, 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
?
-
substrate binding via the D-domain of the MKK
-
-
-
additional information
?
-
-
development of a continuous spectrophotometric assay for mitogen-activated protein kinase kinases. The assay relies on the measurement of phosphoprotein product generated in the first step of the MAPK kinase reaction. Dephosphorylation of the phosphoprotein is coupled to a MAPK phosphatase, MKP3, to generate phosphate, which is then used as the substrate of purine nucleoside phosphorylase to catalyze the N-glycosidic cleavage of 2-amino 6-mercapto 7-methyl purine ribonucleoside. Of the reaction products ribose 1-phosphate and 2-amino 6-mercapto 7-methylpurine, the latter has a high absorbance at 360 nm relative to the nucleoside and, hence, provides a spectrophotometric signal that can be continuously followed. In the presence of excess phosphatase, the phosphorylated protein substrate molecules undergo dephosphorylation almost immediately after their formation. The steady-state use of the resultant inorganic phosphate is a reflection of the constant initial velocity of the exchange reaction. Method development and evaluation, overview
-
-
-
additional information
?
-
-
development of a continuous spectrophotometric assay for mitogen-activated protein kinase kinases. The assay relies on the measurement of phosphoprotein product generated in the first step of the MAPK kinase reaction. Dephosphorylation of the phosphoprotein is coupled to a MAPK phosphatase, MKP5, to generate phosphate, which is then used as the substrate of purine nucleoside phosphorylase to catalyze the N-glycosidic cleavage of 2-amino 6-mercapto 7-methyl purine ribonucleoside. Of the reaction products ribose 1-phosphate and 2-amino 6-mercapto 7-methylpurine, the latter has a high absorbance at 360 nm relative to the nucleoside and, hence, provides a spectrophotometric signal that can be continuously followed. In the presence of excess phosphatase, the phosphorylated protein substrate molecules undergo dephosphorylation almost immediately after their formation. The steady-state use of the resultant inorganic phosphate is a reflection of the constant initial velocity of the exchange reaction. Method development and evaluation, overview
-
-
-
additional information
?
-
-
the enzyme performs autophosphorylation
-
-
-
additional information
?
-
the enzyme performs autophosphorylation
-
-
-
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, which is involved in e.g. formalin-induced inflammatory pain and thermal hyperalgesia, overview
-
-
-
additional information
?
-
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
?
-
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
?
-
substrate binding via the D-domain of the MKK
-
-
-
additional information
?
-
substrate binding via the D-domain of the MKK
-
-
-
additional information
?
-
MKK4 phosphorylates JNK on Tyr, while MKK7 phosphorylates Thr, and MKK4 and MKK7 together cause dual phosphorylation of JNK thus, optimal activation
-
-
-
additional information
?
-
MAP kinase kinase 1 is regulated by salt and drought stresses, differential expression, overview
-
-
-
additional information
?
-
MAP kinase kinase 1 is regulated by salt and drought stresses, differential expression, overview
-
-
-
additional information
?
-
MAP kinase kinase 1 is regulated by salt and drought stresses, differential expression, overview
-
-
-
additional information
?
-
MAP kinase kinase 1 is regulated by salt and drought stresses, differential expression, overview
-
-
-
additional information
?
-
MAP kinase kinase 1 is regulated by salt and drought stresses, differential expression, overview
-
-
-
additional information
?
-
MAP kinase kinase 10-2 is regulated only by cold stress, differential expression, overview
-
-
-
additional information
?
-
MAP kinase kinase 10-2 is regulated only by cold stress, differential expression, overview
-
-
-
additional information
?
-
MAP kinase kinase 10-2 is regulated only by cold stress, differential expression, overview
-
-
-
additional information
?
-
MAP kinase kinase 10-2 is regulated only by cold stress, differential expression, overview
-
-
-
additional information
?
-
MAP kinase kinase 10-2 is regulated only by cold stress, differential expression, overview
-
-
-
additional information
?
-
MAP kinase kinase 6 is strongly regulated by cold and salt stresses, differential expression, overview
-
-
-
additional information
?
-
MAP kinase kinase 6 is strongly regulated by cold and salt stresses, differential expression, overview
-
-
-
additional information
?
-
MAP kinase kinase 6 is strongly regulated by cold and salt stresses, differential expression, overview
-
-
-
additional information
?
-
MAP kinase kinase 6 is strongly regulated by cold and salt stresses, differential expression, overview
-
-
-
additional information
?
-
MAP kinase kinase 6 is strongly regulated by cold and salt stresses, differential expression, overview
-
-
-
additional information
?
-
MAP kinase kinases 4 is strongly regulated by cold and salt stresses, differential expression, overview
-
-
-
additional information
?
-
MAP kinase kinases 4 is strongly regulated by cold and salt stresses, differential expression, overview
-
-
-
additional information
?
-
MAP kinase kinases 4 is strongly regulated by cold and salt stresses, differential expression, overview
-
-
-
additional information
?
-
MAP kinase kinases 4 is strongly regulated by cold and salt stresses, differential expression, overview
-
-
-
additional information
?
-
MAP kinase kinases 4 is strongly regulated by cold and salt stresses, differential expression, overview
-
-
-
additional information
?
-
regulation and differential expression, overview
-
-
-
additional information
?
-
regulation and differential expression, overview
-
-
-
additional information
?
-
regulation and differential expression, overview
-
-
-
additional information
?
-
regulation and differential expression, overview
-
-
-
additional information
?
-
regulation and differential expression, overview
-
-
-
additional information
?
-
protein-protein docking of MAPKK and MAPK
-
-
-
additional information
?
-
protein-protein docking of MAPKK and MAPK
-
-
-
additional information
?
-
protein-protein docking of MAPKK and MAPK
-
-
-
additional information
?
-
protein-protein docking of MAPKK and MAPK
-
-
-
additional information
?
-
-
the enzyme displays both serine/threonine and tyrosine kinase activities in autophosphorylation reactions as well as in phosphorylation of the exogenous myelin basic protein substrate. Ability of Pfnek3 to autophosphorylate on both the serine/threonine and the tyrosine residues. The dual-specificity activity of the kinase is distinctly influenced by the type of divalent cation present
-
-
-
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, 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
?
-
-
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
?
-
-
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
?
-
-
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
?
-
-
substrate binding via the D-domain of the MKK
-
-
-
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
?
-
-
substrate binding via the D-domain of the MKK
-
-
-
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
NATURAL SUBSTRATES
NATURAL PRODUCTS
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 + ERK1
ADP + phosphorylated ERK1
-
phosphorylation of extracellular signal-regulated kinase 1
-
-
?
ATP + extracellular regulated kinase 1
ADP + phosphorylated extracellular regulated kinase 1
I3L5D4
-
-
-
?
ATP + extracellular regulated kinase 2
ADP + phosphorylated extracellular regulated kinase 2
I3L5D4
-
-
-
?
ATP + JNK
ADP + JNK phosphate
O14733, P45985
the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer, physiologic effects, overview
-
-
?
ATP + JNK
ADP + phopsho-JNK
P47809, Q8CE90
the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer acting as a metastasis suppressor, overview
-
-
?
ATP + myelin basic protein
ADP + phosphorylated myelin basic protein
-
Pfnek3 phosphorylates MBP on threonine, but not serine residues
-
-
?
ATP + MyoD
ADP + phospharylated MyoD
-
phosphorylation at Tyr156, activated MEK1 associates with MyoD
-
-
?
ATP + p38
ADP + p38 phosphate
O14733, P45985
the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer, physiologic effects, overview
-
-
?
ATP + p38alpha
ADP + phosphorylated p38alpha
-
MKK6 phosphorylates p38 MAPK on Thr180 and Tyr182, the sites of phosphorylation that activate p38 MAPK
-
-
?
ATP + Pfmap2
ADP + phosphorylated Pfmap2
-
the enzyme phosphorylates its potential in vivo Pfmap2 substrate largely on Thr290
-
-
?
ATP + Smad3
ADP + phosphorylated Smad3
-
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 + c-Jun N-terminal kinase
ADP + phosphorylated c-Jun N-terminal kinase
-
JNK activation
-
-
?
ATP + c-Jun N-terminal kinase
ADP + phosphorylated c-Jun N-terminal kinase
-
JNK activation
-
-
?
ATP + ERK
ADP + phosphorylated ERK
-
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 + ERK2
ADP + phosphorylated ERK2
-
phosphorylation of extracellular signal-regulated kinase 2
-
-
?
ATP + JNK
ADP + phospho-JNK
O14733, P45985
the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer, physiologic effects, overview
-
-
?
ATP + JNK
ADP + phospho-JNK
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
-
the enzyme is involved in stress-activated MAP kinase pathways and tumorigenesis, overview
-
-
?
ATP + JNK
ADP + phosphorylated JNK
Q8CE90
phosphorylation of JNK at the Thr residue located in the activation loop
-
-
?
ATP + JNK
ADP + phosphorylated JNK
Q8CE90
phosphorylation of JNK at the Tyr residue located in the activation loop
-
-
?
ATP + MAP kinase
ADP + phosphorylated MAP kinase
O80396
activation of MAP kinase
-
-
?
ATP + MAP kinase
ADP + phosphorylated MAP kinase
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 + MPK-7
ADP + phospho-MPK-7
-
MKK3 interacts with MPK7 in planta
-
-
?
ATP + MPK-7
ADP + phospho-MPK-7
-
MKK3 interacts with MPK7 in planta
-
-
?
ATP + p38
ADP + phospho-p38
O14733, P45985
the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer, physiologic effects, overview
-
-
?
ATP + p38
ADP + phospho-p38
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
-
the enzyme is involved in stress-activated MAP kinase pathways and tumorigenesis, overview
-
-
?
ATP + p38
ADP + phospho-p38
A9UK00
signal cascade upstream activation by phosphorylation, sorbitol induced activation of p38 in salmon TO cells does not require MKK6a, b or c
-
-
?
ATP + protein
ADP + phosphoprotein
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
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
Q23977
the enzyme functions in a novel Drosophila MAPK pathway, controlling puckered expression and morphogenetic activity of the dorsal epidermis
-
-
?
ATP + protein
ADP + phosphoprotein
Q90891
the enzyme is involved in the mitogenic growth factor signal transduction pathway in vertebrates
-
-
?
ATP + protein
ADP + phosphoprotein
P45985, P46734
enzyme is involved in independent human MAP-kinase signal transduction pathway
-
-
?
ATP + protein
ADP + phosphoprotein
-
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
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
-
enzyme is the major activator for p38
-
-
?
ATP + protein
ADP + phosphoprotein
-
enzyme is involved on MAPK signal transduction pathway
-
-
?
ATP + protein
ADP + phosphoprotein
-
the enzyme is the major activator of RK/p38
-
-
?
ATP + protein
ADP + phosphoprotein
Q99759
MEKK3 regulates the SAPK and the ERK pathway directly
-
-
?
ATP + protein
ADP + phosphoprotein
-
ASK1 may be a key element in the mechanism of stress-induced and cytokine-induced apoptosis
-
-
?
ATP + protein
ADP + phosphoprotein
-
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
-
MAPKKK5 may be an upstream activator of MKK4 in the c-Jun N-terminal kinase pathway
-
-
?
ATP + protein
ADP + phosphoprotein
Q13163
sequences located in the N-terminus of MEK5 may be important in coupling GTPase signaling molecules to the MEK5 protein kinase cascade
-
-
-
ATP + protein
ADP + phosphoprotein
O35099
possible role for ASK1 in tissue development during embryogenesis as well as cytokine-induced apoptosis
-
-
?
ATP + protein
ADP + phosphoprotein
-
enzyme is the major activator for p38
-
-
?
ATP + protein
ADP + phosphoprotein
-
enzyme is involved on MAPK signal transduction pathway
-
-
-
ATP + protein
ADP + phosphoprotein
Q61083, Q61084
MEKK 2 preferentially activates JNK
-
-
?
ATP + protein
ADP + phosphoprotein
Q61083, Q61084
MEKK 3 preferentially activates p42/44MAPK
-
-
?
ATP + protein
ADP + phosphoprotein
-
the enzyme renders the cell resistant to polymyxin B
-
-
?
ATP + protein
ADP + phosphoprotein
-
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
P06784
enzyme is involved in the response of haploid yeast cells to peptide mating pheromones
-
-
?
ATP + protein
ADP + phosphoprotein
-
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
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
-
dosage-dependent regulator of mitosis in Schizosaccharomyces pombe
-
-
?
ATP + protein
ADP + phosphoprotein
-
Spg1p is a key element in controlling the onset of septum formation that acts through the Cdc7p kinase
-
-
?
ATP + protein
ADP + phosphoprotein
-
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
-
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
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
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 + VdHog1
ADP + phosphorylated VdHog1
-
VdHog1 is a mitogen-activated protein kinase, MAPK
-
-
?
ATP + VdHog1
ADP + phosphorylated VdHog1
-
VdHog1 is a mitogen-activated protein kinase, MAPK
-
-
?
additional information
?
-
Q94A06
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
?
-
Q9S7U9
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
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
?
-
Q9S7U9
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
?
-
-
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
?
-
-
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
?
-
-
enzyme is part of mitogen-activated protein kinase pathways, crosstalk and regulation mechanism, overview
-
-
-
additional information
?
-
-
GhMKK3 interacts with GhMPK7, a typical C group MAPK member, and GhPIP1 potein. GhMPK7 is phosphorylated by GhMKK3 in protoplasts
-
-
-
additional information
?
-
S4S5K3
GhMKK3 interacts with GhMPK7, a typical C group MAPK member, and GhPIP1 potein. GhMPK7 is phosphorylated by GhMKK3 in protoplasts
-
-
-
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, 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
?
-
-
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
?
-
O14733
pro-oncogenic role of mitogen-activated protein kinase kinase 4 in cancer, overview
-
-
-
additional information
?
-
P45985
pro-oncogenic role of mitogen-activated protein kinase kinase 4 in cancer, 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
?
-
-
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, which is involved in e.g. formalin-induced inflammatory pain and thermal hyperalgesia, overview
-
-
-
additional information
?
-
P47809
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
?
-
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
?
-
Q8CE90
MKK4 phosphorylates JNK on Tyr, while MKK7 phosphorylates Thr, and MKK4 and MKK7 together cause dual phosphorylation of JNK thus, optimal activation
-
-
-
additional information
?
-
A2XE35
MAP kinase kinase 1 is regulated by salt and drought stresses, differential expression, overview
-
-
-
additional information
?
-
A3FK65
MAP kinase kinase 1 is regulated by salt and drought stresses, differential expression, overview
-
-
-
additional information
?
-
Q0MSI2
MAP kinase kinase 1 is regulated by salt and drought stresses, differential expression, overview
-
-
-
additional information
?
-
Q0Z7Z4
MAP kinase kinase 1 is regulated by salt and drought stresses, differential expression, overview
-
-
-
additional information
?
-
Q5QN75
MAP kinase kinase 1 is regulated by salt and drought stresses, differential expression, overview
-
-
-
additional information
?
-
A2XE35
MAP kinase kinase 10-2 is regulated only by cold stress, differential expression, overview
-
-
-
additional information
?
-
A3FK65
MAP kinase kinase 10-2 is regulated only by cold stress, differential expression, overview
-
-
-
additional information
?
-
Q0MSI2
MAP kinase kinase 10-2 is regulated only by cold stress, differential expression, overview
-
-
-
additional information
?
-
Q0Z7Z4
MAP kinase kinase 10-2 is regulated only by cold stress, differential expression, overview
-
-
-
additional information
?
-
Q5QN75
MAP kinase kinase 10-2 is regulated only by cold stress, differential expression, overview
-
-
-
additional information
?
-
A2XE35
MAP kinase kinase 6 is strongly regulated by cold and salt stresses, differential expression, overview
-
-
-
additional information
?
-
A3FK65
MAP kinase kinase 6 is strongly regulated by cold and salt stresses, differential expression, overview
-
-
-
additional information
?
-
Q0MSI2
MAP kinase kinase 6 is strongly regulated by cold and salt stresses, differential expression, overview
-
-
-
additional information
?
-
Q0Z7Z4
MAP kinase kinase 6 is strongly regulated by cold and salt stresses, differential expression, overview
-
-
-
additional information
?
-
Q5QN75
MAP kinase kinase 6 is strongly regulated by cold and salt stresses, differential expression, overview
-
-
-
additional information
?
-
A2XE35
MAP kinase kinases 4 is strongly regulated by cold and salt stresses, differential expression, overview
-
-
-
additional information
?
-
A3FK65
MAP kinase kinases 4 is strongly regulated by cold and salt stresses, differential expression, overview
-
-
-
additional information
?
-
Q0MSI2
MAP kinase kinases 4 is strongly regulated by cold and salt stresses, differential expression, overview
-
-
-
additional information
?
-
Q0Z7Z4
MAP kinase kinases 4 is strongly regulated by cold and salt stresses, differential expression, overview
-
-
-
additional information
?
-
Q5QN75
MAP kinase kinases 4 is strongly regulated by cold and salt stresses, differential expression, overview
-
-
-
additional information
?
-
A2XE35
regulation and differential expression, overview
-
-
-
additional information
?
-
A3FK65
regulation and differential expression, overview
-
-
-
additional information
?
-
Q0MSI2
regulation and differential expression, overview
-
-
-
additional information
?
-
Q0Z7Z4
regulation and differential expression, overview
-
-
-
additional information
?
-
Q5QN75
regulation and differential expression, overview
-
-
-
additional information
?
-
A2XE35
protein-protein docking of MAPKK and MAPK
-
-
-
additional information
?
-
A3FK65
protein-protein docking of MAPKK and MAPK
-
-
-
additional information
?
-
A5A544
protein-protein docking of MAPKK and MAPK
-
-
-
additional information
?
-
I3RJI6
protein-protein docking of MAPKK and MAPK
-
-
-
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, 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
?
-
-
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
?
-
-
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
?
-
-
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
-
-
-
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
ATP
subdomain II with an invariable lysine residue is responsible for ATP binding
ATP
-
upon ATP-binding, the transient conformation adopted the configuration of typical kinase folding. In the absence of ATP-binding, the transient state of apo npMAP2K4 may shift to a state of aggregation via non-particular hydrophobic interactions as a result of the exposed hydrophobic residues
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Ca2+
-
elevation of cytosolic Ca2+ by ethylene may stimulate protein phosphatase and MAPKK, which finally activates IPO expression
Mg2+
Mn2+
NaCl
mitogen-activated protein kinase kinase 5, MKK5, is activated in response to salt stress
additional information
-
serine/threonine and tyrosine kinase activities are distinctly influenced by Mg2+ and Mn2+ cofactors. Pfnek3 can undergo further tyrosine autophosphorylation in vitro, with Mn2+ as the preferred metal cofactor
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
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INHIBITORS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
1-(2,3-dihydroxypropyl)-4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
-
1-(3-cyanopropyl)-4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
;
1-allyl-4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
;
1-ethyl-4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
;
1-methyl-4-(2-naphthylamino)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
;
3,4-difluoro-N-(3-{5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3-phenyl-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)-5-hydroxybenzamide
-
-
3,4-difluoro-N-{3-[3-(3-fluoro-4-hydroxyphenyl)-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl]phenyl}-5-hydroxybenzamide
-
-
3,4-difluoro-N-{3-[5-({2-fluoro-4-[(hydroxymethyl)amino]phenyl}amino)-3-(3-fluoro-4-hydroxyphenyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl]phenyl}-5-hydroxybenzamide
-
-
3,4-difluoro-N-{3-[5-{[2-fluoro-4-(formylamino)phenyl]amino}-3-(3-fluoro-4-hydroxyphenyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl]phenyl}-5-hydroxybenzamide
-
-
4-(2-fluoro-4-iodoanilino)-1-(2-hydroxyethyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
;
4-(2-fluoro-4-iodoanilino)-1-(3-hydroxypropyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
;
4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
;
4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid
;
4-(2-fluoro-4-iodoanilino)-1-[2-(2-methoxyethoxy)ethyl]-6-oxo-1,6-dihydro-3-pyridinecarboxamide
;
4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
;
4-(2-fluoro-4-iodoanilino)-6-oxo-1-propyl-1,6-dihydro-3-pyridinecarboxamide
;
4-(2-fluoro-4-iodoanilino)-N,1-dimethyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
;
4-(2-fluoro-4-iodoanilino)-N,N,1-trimethyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
;
4-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
-
4-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
;
4-(2-fluoro-4-iodoanilino)-N-(3-hydroxypropyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
;
4-(2-fluoro-4-methylanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
;
4-(2-fluoro-4-methylsulfanylphenylamino)-1-methyl-6-oxo-1,6-dihydro-3 -pyridinecarboxamide
;
4-(3,4-dichlorophenylamino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
;
4-(4-bromo-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
;
4-(4-bromo-2-fluoroanilino)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
;
4-(4-bromo-2-fluorophenylamino)-1-methylpyridin-2(1H)-one
-
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
;
4-(4-ethyl-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
;
4-(4-ethynyl-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
;
4-amino-1-[3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl]-2-hydroxybutan-1-one
-
4-[2-fluoro-4-(1,1,2,2,3,3,4,4,4-nonafluorobutyl)anilino]-1-methyl-6-oxo-1,6 -dihydro-3-pyridinecarboxamide
;
4-[2-fluoro-4-(3-hydroxypropyl)anilino]-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
;
4-[3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl]-3-hydroxy-4-oxobutanamide
-
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
-
AS-703026
-
a MEK12 inhibitor, binds in the allosteric site of MEK1. For A-375 cells, AS-703026 has a growth IC50 of 4 nM
-
Berberine
-
suppresses MEK/ERK-dependent Egr-1 signaling pathway and inhibits vascular smooth muscle cell regrowth after mechanical injury in vitro
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
-
E6201
-
blocks proliferation of many of the cell lines typically used in testing MEK inhibitors, such as Colo205 and MiaPaca-2
-
ethyl 4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate
;
LL-Z1640-2
-
a MEK1 inhibitor, which shows reasonable MEK inhibition but a very short half-life
-
MIIC
-
i.e. MEK inhibitor I, the MEK1/2 inhibitor causes NAD(H) reduction, heme oxidation, and decreased oxygen consumption; i.e. MEK inhibitor I, the MEK1/2 inhibitor causes NAD(H) reduction, heme oxidation, and decreased oxygen consumption
-
N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)-3,4-difluoro-5-hydroxybenzamide
-
-
N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)benzamide
-
-
N-(3-{3-cyclopropyl-5-[(4-cyclopropyl-2-fluorophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)-2-oxopropanamide
-
-
N-(3-{5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3-phenyl-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)-2-oxopropanamide
-
-
N-(3-{5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3-phenyl-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)benzamide
-
-
N-{3-[3-(3-fluoro-4-hydroxyphenyl)-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl]phenyl}-2-oxopropanamide
-
-
N-{3-[5-(cyclopropylmethyl)-3-(3-fluoro-4-hydroxyphenyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl]phenyl}-3,4-difluoro-5-hydroxybenzamide
-
-
N-{3-[5-(cyclopropylmethyl)-3-(4-hydroxy-3-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl]phenyl}-3,4-difluoro-5-hydroxybenzamide
-
-
N-{3-[5-(cyclopropylmethyl)-3-(4-hydroxyphenyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl]phenyl}-3,4-difluoro-5-hydroxybenzamide
-
-
PD198306
-
an orally active MEK1/2 inhibitor, acting as an uncoupler; an orally active MEK1/2 inhibitor, acting as an uncoupler
-
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
tert-butyl [5-(aminocarbonyl)-4-(2-fluoro-4-iodoanilino)-2-oxo-1(2H)-pyridinyl]acetate
-
[5-(aminocarbonyl)-4-(2-fluoro-4-iodoanilino)-2-oxo-1(2H)-pyridinyl]acetic acid
-
CH4987655
-
or RO4987655, a non-ATP competitive inhibitor, highly selective for MEK1
-
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
-
the MEK1/2 inhibitor causes NAD(H) reduction, heme oxidation, and decreased oxygen consumption; the MEK1/2 inhibitor causes NAD(H) reduction, heme oxidation, and decreased oxygen consumption
PD98059
-
MAPKK inhibitor, inhibits IPO expression stimulated by staurosporine
PD98059
-
inhibitor specific for MEK/ERK activation, granulocyte/macrophage colony number is decreased by ca. 60%
PD98059
-
the MEK inhibitor completely blocks adenosine-stimulated corticosterone production
selumetinib
-
i.e. AZD6244, potent and highly selective, non-ATP competitive inhibitor of MEK1/2, MEK1 phosphorylation of ERK2. The compound inhibits growth of cell lines
-
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
-
siRNA
-
knockdown of MEK, HSCs give rise to Mac-1+ myeloid cells less efficiently than control HSCs
-
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; 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
-
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
-
MEK1/2-specific inhibitor, delays, but does not block the passage of synchronized HeLa cells into M phase
U0126
-
the MEK1/2 inhibitor causes NAD(H) reduction, heme oxidation, and decreased oxygen consumption; the MEK1/2 inhibitor causes NAD(H) reduction, heme oxidation, and decreased oxygen consumption
U0126
-
inhibitor specific for MEK/ERK activation, granulocyte/macrophage colony number is decreased by ca. 60%
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
-
the MEK inhibitor completely blocks adenosine-stimulated corticosterone production
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
-
additional information
-
known inhibitor structure screening, and design of specific allosteric MEK1/2 inhibitors with improved pharmacokinetic/pharmacodynamic profiles to be used as alternative cancer medications. Trametinib is used as the lead structure. Molecular docking and binding simulations, thermodynamics, and quantitative structure-activity relationships, allosteric inhibitory site, overview
-
additional information
-
the MEK enzyme contains a hydrophobic allosteric pocket adjacent to the ATP-binding site which allows for the design of highly selective allosteric inhibitors
-
additional information
-
design of small molecule MEK1/2 inhibitors to block ERK1/2-mediated signaling and inhibit proliferation. Four structurally distinct MEK1/2 inhibitors acutely affect mitochondrial bioenergetics. The anti-mitochondrial effects of MEK1/2 inhibitors determine the proliferative potential; design of small molecule MEK1/2 inhibitors to block ERK1/2-mediated signaling and inhibit proliferation. Four structurally distinct MEK1/2 inhibitors acutely affect mitochondrial bioenergetics. The anti-mitochondrial effects of MEK1/2 inhibitors determine the proliferative potential
-
additional information
SymRK acts as an inhibitor of SIP2 kinase activity when MPK6 is used as a substrate, suggesting that SymRK may serve as a negative regulator of the SIP2 signaling pathway. SymRK and SIP2 interact with each other but cannot use one another as a substrate for phosphorylation. SymRK can autophosphorylate itself but fails to phosphorylate the kinase-negative SIP2-KR, suggesting that SymRK is neither a potential phosphorylation target nor a kinase source of SIP2
-
additional information
-
SymRK acts as an inhibitor of SIP2 kinase activity when MPK6 is used as a substrate, suggesting that SymRK may serve as a negative regulator of the SIP2 signaling pathway. SymRK and SIP2 interact with each other but cannot use one another as a substrate for phosphorylation. SymRK can autophosphorylate itself but fails to phosphorylate the kinase-negative SIP2-KR, suggesting that SymRK is neither a potential phosphorylation target nor a kinase source of SIP2
-
additional information
-
occludin acts as antagonist of the MEK and ERK signaling pathway inducing cell aggregation of pancreatic cancer cells
-
additional information
-
inactivated by the serine/threonine phosphatase 2A but not by the protein-tyrosine phosphatase 1B
-
additional information
-
treatment with LY294002, paclitaxel, or serum starvation does not induce apoptosis of wild-type MEF cells
-
additional information
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
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 inhibition of MEK2 by MEK1/ERK1/2-specific inhibitor PD98059
-
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
-
MKK3 expression is induced upon Pseudomonas syringae infection
-
additional information
light signals activate the MAP kinase via phosphorylation through MAP kinase kinase
-
additional information
-
MKKs are activated by phopshorylation through MKKKs, activation mechanism of MKK4 involving MEKK1, overview
-
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
-
MEK6 is strongly activated by UV, anisomycin, and osmotic shock
-
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 by B-Raf, the B-Raf mutant V590E activates the enzymes constitutively and independently of Ras, which leads to melanoma cell proliferation
-
additional information
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; MKKs are activated by phopshorylation through MKKKs, overview
-
additional information
-
dissociation factor DF induces MEK1/2 and ERK1/2 expression
-
additional information
-
ERK and MEK are activated by phosphorylation, ERK is induced by formalin
-
additional information
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; MKKs are activated by phopshorylation through MKKKs, overview
-
additional information
-
the enzyme is activated by phosphorylation through a specific mitogen-activated protein kinase kinase kinase
-