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Literature summary extracted from

  • Whitmarsh, A.J.; Davis, R.J.
    Role of mitogen-activated protein kinase kinase 4 in cancer (2007), Oncogene, 26, 3172-3184.
    View publication on PubMed

Activating Compound

EC Number Activating Compound Comment Organism Structure
2.7.12.2 additional information MKKs are activated by phopshorylation through MKKKs, activation mechanism of MKK4 involving MEKK1, overview Drosophila melanogaster
2.7.12.2 additional information MKKs are activated by phopshorylation through MKKKs, activation mechanism of MKK4 involving MEKK1, overview Rattus norvegicus
2.7.12.2 additional information MKKs are activated by phopshorylation through MKKKs, activation mechanism of MKK4 involving MEKK1, overview Xenopus laevis
2.7.12.2 additional information MKKs are activated by phopshorylation through MKKKs, activation mechanism of MKK4 involving MEKK1, overview Homo sapiens
2.7.12.2 additional information MKKs are activated by phopshorylation through MKKKs, activation mechanism of MKK4 involving MEKK1, overview Mus musculus
2.7.12.2 additional information MKKs are activated by phopshorylation through MKKKs, overview Homo sapiens
2.7.12.2 additional information MKKs are activated by phopshorylation through MKKKs, overview Mus musculus

Application

EC Number Application Comment Organism
2.7.12.2 medicine acts as tumor suppressor, but can also promote tumor growth, plays a role in liver formation, the immune system and cardiac hypertrophy, contributes to optimal c-Jun N-terminal kinase activation Mus musculus
2.7.12.2 medicine important role for MKK4 pathways in controlling cancer development, has a tumor suppression function, the MKK4 gene is mutated at a frequency of 5% in a number of cancer types. In contrast, studies in other cell types suggest that MKK4 and c-Jun N-terminal kinase participate in tumor promotion Homo sapiens
2.7.12.2 medicine targets c-Jun N-terminal kinase but not p38 Drosophila melanogaster

Cloned(Commentary)

EC Number Cloned (Comment) Organism
2.7.12.2
-
 Drosophila melanogaster
2.7.12.2
-
 Mus musculus
2.7.12.2
-
 Homo sapiens
2.7.12.2
-
 Rattus norvegicus
2.7.12.2 DMKK4, DNA and amino acid sequence determination Drosophila melanogaster
2.7.12.2 gene Mkk4, expression in ovarian cancer cell line SKOV3ip.1, that lacks endogenous MKK4, leading to a decrease in overt metastatic implants on several tissues and organs Mus musculus
2.7.12.2 MKK4 or XMEK2, DNA and amino acid sequence determination Xenopus laevis
2.7.12.2 MKK4, DNA and amino acid sequence determination, the gene is located on chromosome 17 Homo sapiens

Protein Variants

EC Number Protein Variants Comment Organism
2.7.12.2 additional information overexpression of a constitutively active mutant of MKK4 in bronchial epithelial cell lines increases their proliferation and invasive properties Homo sapiens
2.7.12.2 additional information targeted deletion of the Mkk4 gene, results in early embryonic lethality, anemia, severe hemorrhaging in the liver, impaired liver formation and abnormal hepatogenesis, which correlates with significant apoptosis of liver cells, and greatly reduced thymus size. In Mkk4-/- embryonic stem cells there is no defect in p38 activation in response to a number of stresses Mus musculus
2.7.12.2 additional information construction of MKK4-deficient mutant mice, phenotype, overview Mus musculus
2.7.12.2 additional information overexpression in rat highly metastatic prostate cancer cell line AT6.1 significantly reduces the metastatic ability, overexpression of an inactive MKK4 in the cells leads to reduced lung metastatses and longer survival time in injected mice, overview Rattus norvegicus

Localization

EC Number Localization Comment Organism GeneOntology No. Textmining
2.7.12.2 cytoplasm MKK4, mainly Rattus norvegicus 5737
-
2.7.12.2 cytoplasm MKK4, mainly Homo sapiens 5737
-
2.7.12.2 cytoplasm MKK4, mainly Mus musculus 5737
-

Metals/Ions

EC Number Metals/Ions Comment Organism Structure
2.7.12.2 Mg2+
-
 Drosophila melanogaster
2.7.12.2 Mg2+
-
 Rattus norvegicus
2.7.12.2 Mg2+
-
 Xenopus laevis
2.7.12.2 Mg2+
-
 Homo sapiens
2.7.12.2 Mg2+
-
 Mus musculus

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
2.7.12.2 ATP + JNK Homo sapiens the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer, physiologic effects, overview ADP + JNK phosphate
-
 ?
2.7.12.2 ATP + JNK Mus musculus the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer acting as a metastasis suppressor, overview ADP + phopsho-JNK
-
 ?
2.7.12.2 ATP + JNK Rattus norvegicus the enzyme is involved in stress-activated MAP kinase pathways and tumorigenesis, overview ADP + phospho-JNK
-
 ?
2.7.12.2 ATP + JNK Mus musculus the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer acting as a metastasis suppressor, overview ADP + phospho-JNK
-
 ?
2.7.12.2 ATP + JNK Homo sapiens the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer, physiologic effects, overview ADP + phospho-JNK
-
 ?
2.7.12.2 ATP + p38 Homo sapiens the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer, physiologic effects, overview ADP + p38 phosphate
-
 ?
2.7.12.2 ATP + p38 Rattus norvegicus the enzyme is involved in stress-activated MAP kinase pathways and tumorigenesis, overview ADP + phospho-p38
-
 ?
2.7.12.2 ATP + p38 Mus musculus the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer acting as a metastasis suppressor, overview ADP + phospho-p38
-
 ?
2.7.12.2 ATP + p38 Homo sapiens the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer, physiologic effects, overview ADP + phospho-p38
-
 ?
2.7.12.2 additional information Homo sapiens pro-oncogenic role of mitogen-activated protein kinase kinase 4 in cancer, overview ?
-
 ?
2.7.12.2 additional information Mus musculus 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 ?
-
 ?
2.7.12.2 additional information Rattus norvegicus 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 ?
-
 ?

Organism

EC Number Organism UniProt Comment Textmining
2.7.12.2 Drosophila melanogaster
-
-
-
2.7.12.2 Homo sapiens
-
-
-
2.7.12.2 Homo sapiens O14733 MKK7
-
2.7.12.2 Homo sapiens P45985 MKK4
-
2.7.12.2 Mus musculus
-
-
-
2.7.12.2 Mus musculus P47809 MKK4
-
2.7.12.2 Mus musculus Q8CE90 MKK7
-
2.7.12.2 Rattus norvegicus
-
-
-
2.7.12.2 Xenopus laevis
-
-
-

Posttranslational Modification

EC Number Posttranslational Modification Comment Organism
2.7.12.2 phosphoprotein MKKs are activated by phopshorylation through MKKKs, e.g. MEKK, MLK, TAK1, Ask1, or TPL2 Homo sapiens
2.7.12.2 phosphoprotein MKKs are activated by phopshorylation through MKKKs, e.g. MEKK, MLK, TAK1, Ask1, or TPL2 Mus musculus
2.7.12.2 phosphoprotein MKKs are activated by phopshorylation through MKKKs, e.g. MEKK, MLK, TAK1, Ask1, or TPL2, MKK4 is phopshorylated at serine and threonine residues in the SIAKT motif Drosophila melanogaster
2.7.12.2 phosphoprotein MKKs are activated by phopshorylation through MKKKs, e.g. MEKK, MLK, TAK1, Ask1, or TPL2, MKK4 is phopshorylated at serine and threonine residues in the SIAKT motif Rattus norvegicus
2.7.12.2 phosphoprotein MKKs are activated by phopshorylation through MKKKs, e.g. MEKK, MLK, TAK1, Ask1, or TPL2, MKK4 is phopshorylated at serine and threonine residues in the SIAKT motif Xenopus laevis
2.7.12.2 phosphoprotein MKKs are activated by phopshorylation through MKKKs, e.g. MEKK, MLK, TAK1, Ask1, or TPL2, MKK4 is phopshorylated at serine and threonine residues in the SIAKT motif Homo sapiens
2.7.12.2 phosphoprotein MKKs are activated by phopshorylation through MKKKs, e.g. MEKK, MLK, TAK1, Ask1, or TPL2, MKK4 is phopshorylated at serine and threonine residues in the SIAKT motif Mus musculus

Source Tissue

EC Number Source Tissue Comment Organism Textmining
2.7.12.2 brain highest levels of expression Mus musculus
-
2.7.12.2 brain highest levels of expression Homo sapiens
-
2.7.12.2 brain high expression level of MKK4, expression in adult and fetal brain Homo sapiens
-
2.7.12.2 brain high expression level of MKK4, expression in adult and fetal brain Mus musculus
-
2.7.12.2 brain cancer cell impaired expression of MKK4 Homo sapiens
-
2.7.12.2 breast cancer cell impaired expression of MKK4 Homo sapiens
-
2.7.12.2 bronchial epithelial cell
-
 Homo sapiens
-
2.7.12.2 central nervous system Mkk4 transcripts confined to the central nervous system in early embryogenesis, up to embryonic day 10 Mus musculus
-
2.7.12.2 cerebellum highest levels of expression Mus musculus
-
2.7.12.2 cerebellum highest levels of expression Homo sapiens
-
2.7.12.2 cerebellum high expression level of MKK4 Homo sapiens
-
2.7.12.2 cerebellum high expression level of MKK4 Mus musculus
-
2.7.12.2 cerebral cortex highest levels of expression Mus musculus
-
2.7.12.2 cerebral cortex highest levels of expression Homo sapiens
-
2.7.12.2 cerebral cortex high expression level of MKK4 Homo sapiens
-
2.7.12.2 cerebral cortex high expression level of MKK4 Mus musculus
-
2.7.12.2 embryonic stem cell
-
 Mus musculus
-
2.7.12.2 fibroblast
-
 Mus musculus
-
2.7.12.2 heart
-
 Mus musculus
-
2.7.12.2 hippocampus highest levels of expression Mus musculus
-
2.7.12.2 hippocampus highest levels of expression Homo sapiens
-
2.7.12.2 hippocampus high expression level of MKK4 Homo sapiens
-
2.7.12.2 hippocampus high expression level of MKK4 Mus musculus
-
2.7.12.2 hypothalamus highest levels of expression Mus musculus
-
2.7.12.2 hypothalamus highest levels of expression Homo sapiens
-
2.7.12.2 hypothalamus high expression level of MKK4 Homo sapiens
-
2.7.12.2 hypothalamus high expression level of MKK4 Mus musculus
-
2.7.12.2 liver in later embryogenesis, starting at day 12, Mkk4 becomes highly expressed in the developing liver coincident with a period of active differentiation and an increase in liver size Mus musculus
-
2.7.12.2 liver high expression level of MKK4, expression in adult and fetal liver Homo sapiens
-
2.7.12.2 liver high expression level of MKK4, expression in adult and fetal liver Mus musculus
-
2.7.12.2 additional information AT6.1 cell, lacks MKK4 expression, overexpression of MKK4 significantly reduces its metastatic ability Rattus norvegicus
-
2.7.12.2 additional information ubiquitous expression of MKK4 in adult tissues Rattus norvegicus
-
2.7.12.2 additional information ubiquitous expression of MKK4 in adult tissues Homo sapiens
-
2.7.12.2 additional information ubiquitous expression of MKK4 in adult tissues Mus musculus
-
2.7.12.2 ovary cancer cell impaired expression of MKK4 Homo sapiens
-
2.7.12.2 prostate high expression of MKK4 in the epithelium but not in the stromal compartment Mus musculus
-
2.7.12.2 prostate cancer cell impaired expression of MKK4 Homo sapiens
-
2.7.12.2 prostate cancer cell line
-
 Rattus norvegicus
-

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
2.7.12.2 ATP + JNK the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer, physiologic effects, overview Homo sapiens ADP + JNK phosphate
-
 ?
2.7.12.2 ATP + JNK substrate of MKK4 and MKK7 in a synergistic manner Homo sapiens ADP + JNK phosphate
-
 ?
2.7.12.2 ATP + JNK the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer acting as a metastasis suppressor, overview Mus musculus ADP + phopsho-JNK
-
 ?
2.7.12.2 ATP + JNK the enzyme is involved in stress-activated MAP kinase pathways and tumorigenesis, overview Rattus norvegicus ADP + phospho-JNK
-
 ?
2.7.12.2 ATP + JNK the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer acting as a metastasis suppressor, overview Mus musculus ADP + phospho-JNK
-
 ?
2.7.12.2 ATP + JNK the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer, physiologic effects, overview Homo sapiens ADP + phospho-JNK
-
 ?
2.7.12.2 ATP + JNK substrate of MKK4 and MKK7 in a synergistic manner Rattus norvegicus ADP + phospho-JNK
-
 ?
2.7.12.2 ATP + JNK substrate of MKK4 and MKK7 in a synergistic manner Homo sapiens ADP + phospho-JNK
-
 ?
2.7.12.2 ATP + JNK substrate of MKK4 and MKK7 in a synergistic manner Mus musculus ADP + phospho-JNK
-
 ?
2.7.12.2 ATP + p38 the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer, physiologic effects, overview Homo sapiens ADP + p38 phosphate
-
 ?
2.7.12.2 ATP + p38 substrate of MKK7 Homo sapiens ADP + p38 phosphate
-
 ?
2.7.12.2 ATP + p38 the enzyme is involved in stress-activated MAP kinase pathways and tumorigenesis, overview Rattus norvegicus ADP + phospho-p38
-
 ?
2.7.12.2 ATP + p38 the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer acting as a metastasis suppressor, overview Mus musculus ADP + phospho-p38
-
 ?
2.7.12.2 ATP + p38 the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer, physiologic effects, overview Homo sapiens ADP + phospho-p38
-
 ?
2.7.12.2 ATP + p38 substrate of MKK4 Homo sapiens ADP + phospho-p38
-
 ?
2.7.12.2 ATP + p38 substrate of MKK4 Mus musculus ADP + phospho-p38
-
 ?
2.7.12.2 ATP + p38 substrate of MKK4 and MKK7 Rattus norvegicus ADP + phospho-p38
-
 ?
2.7.12.2 ATP + p38 substrate of MKK7 Mus musculus ADP + phospho-p38
-
 ?
2.7.12.2 additional information pro-oncogenic role of mitogen-activated protein kinase kinase 4 in cancer, overview Homo sapiens ?
-
 ?
2.7.12.2 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 Mus musculus ?
-
 ?
2.7.12.2 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 Rattus norvegicus ?
-
 ?
2.7.12.2 additional information substrate binding via the D-domain of the MKK Drosophila melanogaster ?
-
 ?
2.7.12.2 additional information substrate binding via the D-domain of the MKK Rattus norvegicus ?
-
 ?
2.7.12.2 additional information substrate binding via the D-domain of the MKK Xenopus laevis ?
-
 ?
2.7.12.2 additional information substrate binding via the D-domain of the MKK Homo sapiens ?
-
 ?
2.7.12.2 additional information substrate binding via the D-domain of the MKK Mus musculus ?
-
 ?

Subunits

EC Number Subunits Comment Organism
2.7.12.2 More the catalytic domain contains 11 subdomains Homo sapiens

Synonyms

EC Number Synonyms Comment Organism
2.7.12.2 DMKK4
-
 Drosophila melanogaster
2.7.12.2 MAP kinase kinase 4
-
 Drosophila melanogaster
2.7.12.2 MAP kinase kinase 4
-
 Rattus norvegicus
2.7.12.2 MAP kinase kinase 4
-
 Xenopus laevis
2.7.12.2 MAP kinase kinase 4
-
 Homo sapiens
2.7.12.2 MAP kinase kinase 4
-
 Mus musculus
2.7.12.2 mitogen-activated protein kinase kinase 4
-
 Drosophila melanogaster
2.7.12.2 mitogen-activated protein kinase kinase 4
-
 Mus musculus
2.7.12.2 mitogen-activated protein kinase kinase 4
-
 Homo sapiens
2.7.12.2 mitogen-activated protein kinase kinase 4
-
 Rattus norvegicus
2.7.12.2 mitogen-activated protein kinase kinase 4
-
 Xenopus laevis
2.7.12.2 MKK4
-
 Drosophila melanogaster
2.7.12.2 MKK4
-
 Mus musculus
2.7.12.2 MKK4
-
 Homo sapiens
2.7.12.2 MKK4
-
 Rattus norvegicus
2.7.12.2 MKK4
-
 Xenopus laevis
2.7.12.2 MKK7
-
 Rattus norvegicus
2.7.12.2 MKK7
-
 Homo sapiens
2.7.12.2 MKK7
-
 Mus musculus
2.7.12.2 More the enzyme belongs to the MKK familly Drosophila melanogaster
2.7.12.2 More the enzyme belongs to the MKK familly Rattus norvegicus
2.7.12.2 More the enzyme belongs to the MKK familly Xenopus laevis
2.7.12.2 More the enzyme belongs to the MKK familly Homo sapiens
2.7.12.2 More the enzyme belongs to the MKK familly Mus musculus
2.7.12.2 stress-activate protein kinase/extracellular signal-regulated protein kinase kinase-1
-
 Mus musculus
2.7.12.2 XMEK2
-
 Xenopus laevis

Cofactor

EC Number Cofactor Comment Organism Structure
2.7.12.2 ATP
-
 Drosophila melanogaster
2.7.12.2 ATP
-
 Rattus norvegicus
2.7.12.2 ATP
-
 Xenopus laevis
2.7.12.2 ATP
-
 Homo sapiens
2.7.12.2 ATP
-
 Mus musculus