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IUBMB CommentsThis enzyme phosphorylates and activates its downstream protein kinase, EC 2.7.12.2, mitogen-activated protein kinase kinase (MAPKK) but requires MAPKKKK for activation. Some members of this family can be activated by p21-activated kinases (PAK/STE20) or Ras. While c-Raf and c-Mos activate the classical MAPK/ERK pathway, MEKK1 and MEKK2 preferentially activate the c-Jun N-terminal protein kinase(JNK)/stress-activated protein kinase (SAPK) pathway . Mitogen-activated protein kinase (MAPK) signal transduction pathways are among the most widespread mechanisms of cellular regulation. Mammalian MAPK pathways can be recruited by a wide variety of stimuli including hormones (e.g. insulin and growth hormone), mitogens (e.g. epidermal growth factor and platelet-derived growth factor), vasoactive peptides (e.g. angiotensin-II and endothelin), inflammatory cytokines of the tumour necrosis factor (TNF) family and environmental stresses such as osmotic shock, ionizing radiation and ischaemic injury.
Synonyms
b-raf, c-raf, mekk1, c-mos, apoptosis signal-regulating kinase 1, mixed lineage kinase, ste11, mekk3, map3k1, mapkkk,
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ATP + MKK1
ADP + phosphorylated MKK1
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ATP + MKK2
ADP + phosphorylated MKK2
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ATP + MPK4
ADP + phosphorylated MPK4
MEKK1 is essential for MPK4 activation by flg22
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ATP + myelin basic protein
ADP + phosphorylated myelin basic protein
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ATP + MKK3
ADP + phosphorylated MKK3
ATP + MPK18
ADP + phosphorylated MPK18
ATP + MPK4
ADP + phosphorylated MPK4
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ATP + MPK6
ADP + phosphorylated MPK6
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ATP + myelin basic protein
ADP + phosphorylated myelin basic protein
ATP + PIN1HL
ADP + phosphorylated PIN1HL
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ATP + PIN7HL
ADP + phosphorylated PIN7HL
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ATP + WRKY53
ADP + phosphorylated WRKY53
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phosphorylation increases DNA-binding activity of WRKY53
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additional information
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ATP + MKK3
ADP + phosphorylated MKK3
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ATP + MKK3
ADP + phosphorylated MKK3
the isoform MKKK20 C-terminal region interacts with MKK3
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ATP + MPK18
ADP + phosphorylated MPK18
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ATP + MPK18
ADP + phosphorylated MPK18
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ATP + myelin basic protein
ADP + phosphorylated myelin basic protein
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ATP + myelin basic protein
ADP + phosphorylated myelin basic protein
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ATP + myelin basic protein
ADP + phosphorylated myelin basic protein
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additional information
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MEKK1 is dispensable for MPK3 and MPK6 activation by flg22
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additional information
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MKK1 and MKK2 interact with MEKK1 and MPK4 in vivo, and activation of MPK4 by flg22 requires MEKK1 as well as MKK1 and MKK2, suggesting that MEKK1, MKK1/MKK2, and MPK4 form a MAPK cascade to negatively regulate plant immune responses
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additional information
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MKK1 and MKK2 interact with MEKK1 and MPK4 in vivo, and activation of MPK4 by flg22 requires MEKK1 as well as MKK1 and MKK2, suggesting that MEKK1, MKK1/MKK2, and MPK4 form a MAPK cascade to negatively regulate plant immune responses
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additional information
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MKK1 and MKK2 interact with MEKK1 and MPK4 in vivo, and activation of MPK4 by flg22 requires MEKK1 as well as MKK1 and MKK2, suggesting that MEKK1, MKK1/MKK2, and MPK4 form a MAPK cascade to negatively regulate plant immune responses
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additional information
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stomatal development and pattern is controlled by YODA
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additional information
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activity of MEKK1 may not be required for flg22-induced MPK4, MPK3 or MPK6 activation or for other macroscopic FLS2-mediated responses
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additional information
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MEKK2 interacts with MPK4 and is phosphorylated by MPK4 in vitro
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additional information
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MEKK2 interacts with MPK4 and is phosphorylated by MPK4 in vitro
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additional information
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MEKK2 interacts with MPK4 and is phosphorylated by MPK4 in vitro
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additional information
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Raf10 has autophosphorylation activity
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additional information
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Raf10 has autophosphorylation activity
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additional information
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Raf11 has autophosphorylation activity
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additional information
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Raf11 has autophosphorylation activity
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ATP + MKK1
ADP + phosphorylated MKK1
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ATP + MKK2
ADP + phosphorylated MKK2
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ATP + MKK3
ADP + phosphorylated MKK3
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ATP + MPK18
ADP + phosphorylated MPK18
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ATP + MPK6
ADP + phosphorylated MPK6
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ATP + myelin basic protein
ADP + phosphorylated myelin basic protein
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additional information
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additional information
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MKK1 and MKK2 interact with MEKK1 and MPK4 in vivo, and activation of MPK4 by flg22 requires MEKK1 as well as MKK1 and MKK2, suggesting that MEKK1, MKK1/MKK2, and MPK4 form a MAPK cascade to negatively regulate plant immune responses
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?
additional information
?
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MKK1 and MKK2 interact with MEKK1 and MPK4 in vivo, and activation of MPK4 by flg22 requires MEKK1 as well as MKK1 and MKK2, suggesting that MEKK1, MKK1/MKK2, and MPK4 form a MAPK cascade to negatively regulate plant immune responses
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?
additional information
?
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MKK1 and MKK2 interact with MEKK1 and MPK4 in vivo, and activation of MPK4 by flg22 requires MEKK1 as well as MKK1 and MKK2, suggesting that MEKK1, MKK1/MKK2, and MPK4 form a MAPK cascade to negatively regulate plant immune responses
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?
additional information
?
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stomatal development and pattern is controlled by YODA
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?
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malfunction
analysis of mekk1 sid2 and mkk1 mkk2 sid2 mutant plants reveals that the elevated salicylic acid levels contribute very little to the mutant phenotypes in mekk1 and mkk1 mkk2
metabolism
a MAPK cascade is a signaling module usually consisting of a MAP kinase kinase kinase (MAPKKK), a MAP kinase kinase, and a MAPK. Activation of MAPKKKs by upstream signals results in sequential phosphorylation of their downstream MAPKKs and MAPKs. In Arabidopsis thaliana, the MEKK1-MKK1/MKK2-MPK4 mitogen-activated protein (MAP) kinase cascade represses cell death and immune responses. MEKK1, MKK1/MKK2, and MPK4 negatively regulate cell death and immunity. The MEKK1-MKK1/MKK2-MPK4 kinase cascade negatively regulates MEKK2 and activation of MEKK2 triggers SUMM2-mediated immune responses
physiological function
MEKK1 is involved in negative regulation of cell death and immunity
metabolism
a MAPK cascade is a signaling module usually consisting of a MAP kinase kinase kinase (MAPKKK), a MAP kinase kinase, and a MAPK. Activation of MAPKKKs by upstream signals results in sequential phosphorylation of their downstream MAPKKs and MAPKs. The MEKK1-MKK1/MKK2-MPK4 kinase cascade negatively regulates MEKK2 and activation of MEKK2 triggers SUMM2-mediated immune responses. Mutants summ1-1 mkk1 mkk2 and summ1-2 mkk1 mkk2 exhibit wild type-like morphology
malfunction
mutations in MEKK2 encoding suppressor of mkk1 mkk2 1 (summ1) gene suppress the cell death and defense responses not only in mkk1 mkk2 but also in mekk1 and mpk4. Overexpression of SUMM1 activates cell death and defense responses that are dependent on the nucleotide binding-leucine-rich repeat protein SUMM2. Pathogen resistance in mutants mkk1 mkk2 is affected by the summ1 mutation, e.g. versus oomycete pathogen Hyaloperonospora arabidopsidis Noco2
malfunction
the abscisic acid-insensitive mutant, ais143, located in the coding region of MAP3K gene Raf10, abolishes RAF10 expression in the mutant. ais143 exhibits reduced seed dormancy as well as reduced abscisic acid sensitivity. The phenotypes are complemented by the wild-type Raf10 gene, and the overexpression of Raf10 results in delayed seed germination and enhanced the abscisic acid sensitivity. Raf11 knockout and overexpression lines show that their phenotypes are similar to those of Raf10 knockout and overexpression lines. An ais143 raf11 double mutant exhibits stronger phenotypes than single mutants, indicating the functional redundancy between Raf10 and Raf11. Expression of many abscisic acid-associated genes, including the key regulatory genes ABI3 and ABI5, is altered in the Raf10 and Raf11 overexpressing lines. Reduced seed dormancy of ais143 and raf11, overview. Both germination and cotyledon greening of ais143 and ais143 raf11 plants are less sensitive to high salt compared to wild-type
malfunction
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the double knockout mutant of RAF22 and RAF28 is embryo lethal. Mutant embryos exhibit various defects, including disordered proembryo cell divisions, disruption of the bilaterally symmetrical structure, abnormally formative divisions of hypophysis and exaggerated suspensor growth
physiological function
mitogen-activated protein (MAP) kinase cascades are universal signaling modules in eukaryotes, which relay external or internal upstream signals to downstream targets. Arabidopsis thaliana putative MAP kinase kinase kinases Raf10 and Raf11 are positive regulators of seed dormancy and abscisic acid response
physiological function
mitogen-activated protein (MAP) kinase cascades are universal signaling modules in eukaryotes, which relay external or internal upstream signals to downstream targets. Arabidopsis thaliana putative MAP kinase kinase kinases Raf10 and Raf11 are positive regulators of seed dormancy. Raf11 plays a redundant role in abscisic acid response
physiological function
the autoimmunity phenotypes in mpk4, mekk1, and mkk1 mkk2 mutant plants are caused by activation of defense responses mediated by SUMM1
physiological function
isoform MKKK20 participates in the osmotic stress response through its regulation of MPK6
physiological function
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isoform MKKK7 negatively regulates flagellin-triggered signalling and basal immunity in Arabidopsis. Isoform MKKK7 attenuates MPK6 activity and defense gene expression. Moreover, MKKK7 suppresses the reactive oxygen species burst downstream of flagellin receptor FLS2
physiological function
MKKK20 autophosphorylates and phosphorylates both mitogen-activated protein kinase kinase MKK3 and MPK18. When all three kinases are combined, no synergistic effect is observed on MPK18 phosphorylation. MKKK20 acts upstream of MPK18 and MKK3. MKKK20 and MKK3 mutants are sensitive to microtubule-disrupting drugs
physiological function
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RAF22 and RAF28 are involved in the regulation of embryogenesis
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K361M
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kinase-inactive MEKK1, rescues the mekk1 dwarf penotype. Elevated temperature dramatically improves the growth of mekk1 plants. K361M plants are fully fertile and grow with a morphology closely resembling wild-type plants. When treated with pathogenic bacteria, K361M plants are slightly more susceptible to an avirulent strain of Pseudomonas syringae and show a delayed hypersensitive response
K361M
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mutation of the kinase domain of MEKK1 reduces the relative expression of the WRKY53 promoter driven GUS gene from 200% in the presence of intact MEKK1 to 132% in the presence of the mutated form
additional information
mekk1-1 and mekk1-2 mutants, exhibit dwarfism and lethality, and also showed early senescence in cotyledons, loss of MEKK1 results in tissue-specific cell death, tissue-specific H2O2 accumulation and constitutive defense responses. Little or no suppression of dwarfism in mekk1/edm1 or mekk1/rar1 double mutants compared with mekk1 when grown at 22°C, but dwarf phenotype is highly recovered in mekk1/rar1 at 26°C, whereas mekk1/edm1 plants are only slightly bigger than mekk1. In mekk1/sid2 mutants growth defect, cell death, H2O2 accumulation and callose deposition phenotypes are not suppressed at 22°C. However, similar to rar1, sid2 partially suppresses these mekk1 phenotypes at 26°C, although the suppression effect is not as strong as in rar1
additional information
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YODA null mutation leads to excess stomata, whereas constittive activation of YODA eliminated stomata
additional information
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mekk1 knockout mutants, display a severe dwarf phenotype, constitutive callose deposition, and constitutive expression of pathogen response genes. The dwarf phenotype is largely rescued by introduction into mekk1 knockout plants of either mutant K361M or a nahG transgene that degrades salicylic acid
additional information
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MEKK1-deficient plants, are misregulated in the expression of a number of genes involved in cellular redox control and accumulate reactive oxygen species. Homozygous mekk1 mutant plants exhibit a lethal phenotype when developing true leaves. Mutant plants stay dwarfed and never reach maturity to produce seeds. Mekk1 and mpk4 mutant plants show similarities with respect to both, phenotype and H2O2 accumulation
additional information
generation of summ1 mutants and of summ1-1 mkk1 mkk2 and summ1-2 mkk1 mkk2 triple mutants. To map the summ1-1 mutation, summ1-1 mkk1 mkk2 (in the Columbia background) is crossed with Landsberg erecta (Ler). F2 plants homozygous for mkk1 mkk2 are selected forlinkage analysis. Crude mapping using 48 such plants reveals that summ1-1 is flanked by markers T13D4 and T15F16 on chromosome 4. Constitutive expression of defense marker genes PR1 and PR2 is completely suppressed in the summ1-1 mkk1 mkk2 and summ1-2 mkk1 mkk2 triple mutants. Suppression of mkk1 mkk2 mutant phenotypes by summ1-1 and summ1-2, overview. Mutants summ1-1 mkk1 mkk2 and summ1-2 mkk1 mkk2 exhibit wild type-like morphology
additional information
generation of summ1 mutants and of summ1-1 mkk1 mkk2 and summ1-2 mkk1 mkk2 triple mutants. To map the summ1-1 mutation, summ1-1 mkk1 mkk2 (in the Columbia background) is crossed with Landsberg erecta (Ler). F2 plants homozygous for mkk1 mkk2 are selected forlinkage analysis. Crude mapping using 48 such plants reveals that summ1-1 is flanked by markers T13D4 and T15F16 on chromosome 4. Constitutive expression of defense marker genes PR1 and PR2 is completely suppressed in the summ1-1 mkk1 mkk2 and summ1-2 mkk1 mkk2 triple mutants. Suppression of mkk1 mkk2 mutant phenotypes by summ1-1 and summ1-2, overview. Mutants summ1-1 mkk1 mkk2 and summ1-2 mkk1 mkk2 exhibit wild type-like morphology
additional information
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generation of summ1 mutants and of summ1-1 mkk1 mkk2 and summ1-2 mkk1 mkk2 triple mutants. To map the summ1-1 mutation, summ1-1 mkk1 mkk2 (in the Columbia background) is crossed with Landsberg erecta (Ler). F2 plants homozygous for mkk1 mkk2 are selected forlinkage analysis. Crude mapping using 48 such plants reveals that summ1-1 is flanked by markers T13D4 and T15F16 on chromosome 4. Constitutive expression of defense marker genes PR1 and PR2 is completely suppressed in the summ1-1 mkk1 mkk2 and summ1-2 mkk1 mkk2 triple mutants. Suppression of mkk1 mkk2 mutant phenotypes by summ1-1 and summ1-2, overview. Mutants summ1-1 mkk1 mkk2 and summ1-2 mkk1 mkk2 exhibit wild type-like morphology
additional information
identification of a Raf11 knockout mutant, raf11 (SALK_047070), the T-DNA is located in the ninth exon of the Raf11 gene, and Raf11 expression is abolished completely. Contruction of a Raf10 and Raf11 double knockout mutant line, ais143 raf11, by crossing ais143 with raf11, phenotypes, overview
additional information
identification of a Raf11 knockout mutant, raf11 (SALK_047070), the T-DNA is located in the ninth exon of the Raf11 gene, and Raf11 expression is abolished completely. Contruction of a Raf10 and Raf11 double knockout mutant line, ais143 raf11, by crossing ais143 with raf11, phenotypes, overview
additional information
isolation of the abscisic acid-insensitive mutant, ais143, by activation tagging screen. The T-DNA is located in one of the exons (8/13) of the coding region of putative mitogen-activated protein (MAP) kinase kinase kinase (MAP3K) gene, Raf10, thereby abolishing its expression in the mutant. ais143 exhibits reduced seed dormancy as well as reduced abscisic acid sensitivity. The phenotypes are complemented by the wild-type Raf10 gene, and the overexpression of Raf10 results in delayed seed germination and enhanced the abscisic acid sensitivity
additional information
isolation of the abscisic acid-insensitive mutant, ais143, by activation tagging screen. The T-DNA is located in one of the exons (8/13) of the coding region of putative mitogen-activated protein (MAP) kinase kinase kinase (MAP3K) gene, Raf10, thereby abolishing its expression in the mutant. ais143 exhibits reduced seed dormancy as well as reduced abscisic acid sensitivity. The phenotypes are complemented by the wild-type Raf10 gene, and the overexpression of Raf10 results in delayed seed germination and enhanced the abscisic acid sensitivity
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additional information
MEKK1 negatively regulates temperature-sensitive and tissue-specific cell death and H2O2 accumulation that are partly dependent on both RAR1, a key component in resistance protein function, and SID2, an isochorismate synthase required for salicylic acid production upon pathogen infection
additional information
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may play a structural role in signaling, independent of its protein kinase activity, MEKK1 kinase activity may not be required to activate FLS2-mediated defense responses in Arabidopsis. MEKK1 acts upstream of MPK4 as a negative regulator of pathogen response pathways, a function that may not require MEKK1's full kinase activity
additional information
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MEKK1 has a dual function, it can bind to the promoter of WRKY53 and it can interact with the WRKY53 on the protein level and can phosphorylate WRKY53 in vitro thereby increasing its DNA-binding activity. MEKK1 may be able to take a very direct short cut in MAPK signalling by directly phosphorylating a transcription factor
additional information
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MEKK1 regulates multiple processes during vegetative development, accumulation of reactive oxygen species and redox homeostasis
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Bergmann, D.C.; Lukowitz, W.; Somerville, C.R.
Stomatal development and pattern controlled by a MAPKK kinase
Science
304
1494-1497
2004
Arabidopsis thaliana
brenda
Ichimura, K.; Casais, C.; Peck, S.C.; Shinozaki, K.; Shirasu, K.
MEKK1 is required for MPK4 activation and regulates tissue-specific and temperature-dependent cell death in Arabidopsis
J. Biol. Chem.
281
36969-36976
2006
Arabidopsis thaliana (Q39008)
brenda
Nakagami, H.; Soukupova, H.; Schikora, A.; Zarsky, V.; Hirt, H.
A Mitogen-activated protein kinase kinase kinase mediates reactive oxygen species homeostasis in Arabidopsis
J. Biol. Chem.
281
38697-38704
2006
Arabidopsis thaliana
brenda
Miao, Y.; Laun, T.M.; Smykowski, A.; Zentgraf, U.
Arabidopsis MEKK1 can take a short cut: it can directly interact with senescence-related WRKY53 transcription factor on the protein level and can bind to its promoter
Plant Mol. Biol.
65
63-76
2007
Arabidopsis thaliana
brenda
Suarez-Rodriguez, M.C.; Adams-Phillips, L.; Liu, Y.; Wang, H.; Su, S.H.; Jester, P.J.; Zhang, S.; Bent, A.F.; Krysan, P.J.
MEKK1 is required for flg22-induced MPK4 activation in Arabidopsis plants
Plant Physiol.
143
661-669
2007
Arabidopsis thaliana
brenda
Lee, S.J.; Lee, M.H.; Kim, J.I.; Kim, S.Y.
Arabidopsis putative MAP kinase kinase kinases Raf10 and Raf11 are positive regulators of seed dormancy and ABA response
Plant Cell Physiol.
56
84-97
2015
Arabidopsis thaliana (F4HVH9), Arabidopsis thaliana (F4K645), Arabidopsis thaliana Col-0 (F4HVH9), Arabidopsis thaliana Col-0 (F4K645)
brenda
Kong, Q.; Qu, N.; Gao, M.; Zhang, Z.; Ding, X.; Yang, F.; Li, Y.; Dong, O.X.; Chen, S.; Li, X.; Zhang, Y.
The MEKK1-MKK1/MKK2-MPK4 kinase cascade negatively regulates immunity mediated by a mitogen-activated protein kinase kinase kinase in Arabidopsis
Plant Cell
24
2225-2236
2012
Arabidopsis thaliana (O81472), Arabidopsis thaliana (Q39008), Arabidopsis thaliana, Arabidopsis thaliana Col-0 (O81472), Arabidopsis thaliana Col-0 (Q39008)
brenda
Mithoe, S.; Ludwig, C.; Pel, M.; Cucinotta, M.; Casartelli, A.; Mbengue, M.; Sklenar, J.; Derbyshire, P.; Robatzek, S.; Pieterse, C.; Aebersold, R.; Menke, F.
Attenuation of pattern recognition receptor signaling is mediated by a MAP kinase kinase kinase
EMBO Rep.
17
441-454
2016
Arabidopsis thaliana
brenda
Benhamman, R.; Bai, F.; Drory, S.; Loubert-Hudon, A.; Ellis, B.; Matton, D.
The Arabidopsis mitogen-activated protein kinase kinase kinase 20 (MKKK20) acts upstream of MKK3 and MPK18 in two separate signaling pathways involved in root microtubule functions
Front. Plant Sci.
8
1352
2017
Arabidopsis thaliana, Arabidopsis thaliana (Q9SND6)
brenda
Wang, B.; Liu, G.; Zhang, J.; Li, Y.; Yang, H.; Ren, D.
The RAF-like mitogen-activated protein kinase kinase kinases RAF22 and RAF28 are required for the regulation of embryogenesis in Arabidopsis
Plant J.
96
734-747
2018
Arabidopsis thaliana
brenda
Bai, F.; Matton, D.
The Arabidopsis mitogen-activated protein kinase kinase kinase 20(MKKK20) C-terminal domain interacts with MKK3 and harbors a typical DEF mammalian MAP kinase docking site
Plant Signal. Behav.
13
e1503498
2018
Arabidopsis thaliana (Q9SND6), Arabidopsis thaliana
brenda