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Literature summary for 2.7.12.2 extracted from
- Role of mitogen-activated protein kinase kinase 4 in cancer (2007), Oncogene, 26, 3172-3184.
Activating Compound
| Activating Compound | Comment | Organism | Structure |
|---|---|---|---|
| additional information | MKKs are activated by phopshorylation through MKKKs, activation mechanism of MKK4 involving MEKK1, overview | Drosophila melanogaster | |
| additional information | MKKs are activated by phopshorylation through MKKKs, activation mechanism of MKK4 involving MEKK1, overview | Rattus norvegicus | |
| additional information | MKKs are activated by phopshorylation through MKKKs, activation mechanism of MKK4 involving MEKK1, overview | Xenopus laevis | |
| additional information | MKKs are activated by phopshorylation through MKKKs, activation mechanism of MKK4 involving MEKK1, overview | Homo sapiens | |
| additional information | MKKs are activated by phopshorylation through MKKKs, activation mechanism of MKK4 involving MEKK1, overview | Mus musculus | |
| additional information | MKKs are activated by phopshorylation through MKKKs, overview | Homo sapiens | |
| additional information | MKKs are activated by phopshorylation through MKKKs, overview | Mus musculus |
Application
| Application | Comment | Organism |
|---|---|---|
| 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 |
| 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 |
| medicine | targets c-Jun N-terminal kinase but not p38 | Drosophila melanogaster |
Cloned(Commentary)
| Cloned (Comment) | Organism |
|---|---|
- |
Drosophila melanogaster |
- |
Mus musculus |
- |
Homo sapiens |
- |
Rattus norvegicus |
| DMKK4, DNA and amino acid sequence determination | Drosophila melanogaster |
| 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 |
| MKK4 or XMEK2, DNA and amino acid sequence determination | Xenopus laevis |
| MKK4, DNA and amino acid sequence determination, the gene is located on chromosome 17 | Homo sapiens |
Protein Variants
| Protein Variants | Comment | Organism |
|---|---|---|
| additional information | overexpression of a constitutively active mutant of MKK4 in bronchial epithelial cell lines increases their proliferation and invasive properties | Homo sapiens |
| 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 |
| additional information | construction of MKK4-deficient mutant mice, phenotype, overview | Mus musculus |
| 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
| Localization | Comment | Organism | GeneOntology No. | Textmining |
|---|---|---|---|---|
| cytoplasm | MKK4, mainly | Rattus norvegicus | 5737 | - |
| cytoplasm | MKK4, mainly | Homo sapiens | 5737 | - |
| cytoplasm | MKK4, mainly | Mus musculus | 5737 | - |
Metals/Ions
| Metals/Ions | Comment | Organism | Structure |
|---|---|---|---|
| Mg2+ | - |
Drosophila melanogaster |  |
| Mg2+ | - |
Rattus norvegicus | |
| Mg2+ | - |
Xenopus laevis | |
| Mg2+ | - |
Homo sapiens | |
| Mg2+ | - |
Mus musculus | |
Natural Substrates/ Products (Substrates)
| Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| ATP + JNK | Homo sapiens | the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer, physiologic effects, overview | ADP + JNK phosphate | - |
? | |
| 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 | - |
? | |
| ATP + JNK | Rattus norvegicus | the enzyme is involved in stress-activated MAP kinase pathways and tumorigenesis, overview | ADP + phospho-JNK | - |
? | |
| 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 | - |
? | |
| ATP + JNK | Homo sapiens | the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer, physiologic effects, overview | ADP + phospho-JNK | - |
? | |
| ATP + p38 | Homo sapiens | the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer, physiologic effects, overview | ADP + p38 phosphate | - |
? | |
| ATP + p38 | Rattus norvegicus | the enzyme is involved in stress-activated MAP kinase pathways and tumorigenesis, overview | ADP + phospho-p38 | - |
? | |
| 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 | - |
? | |
| ATP + p38 | Homo sapiens | the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer, physiologic effects, overview | ADP + phospho-p38 | - |
? | |
| additional information | Homo sapiens | pro-oncogenic role of mitogen-activated protein kinase kinase 4 in cancer, overview | ? | - |
? | |
| 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 | ? | - |
? | |
| 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
| Organism | UniProt | Comment | Textmining |
|---|---|---|---|
| Drosophila melanogaster | - |
- |
- |
| Homo sapiens | - |
- |
- |
| Homo sapiens | O14733 | MKK7 | - |
| Homo sapiens | P45985 | MKK4 | - |
| Mus musculus | - |
- |
- |
| Mus musculus | P47809 | MKK4 | - |
| Mus musculus | Q8CE90 | MKK7 | - |
| Rattus norvegicus | - |
- |
- |
| Xenopus laevis | - |
- |
- |
Posttranslational Modification
| Posttranslational Modification | Comment | Organism |
|---|---|---|
| phosphoprotein | MKKs are activated by phopshorylation through MKKKs, e.g. MEKK, MLK, TAK1, Ask1, or TPL2 | Homo sapiens |
| phosphoprotein | MKKs are activated by phopshorylation through MKKKs, e.g. MEKK, MLK, TAK1, Ask1, or TPL2 | Mus musculus |
| 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 |
| 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 |
| 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 |
| 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 |
| 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
| Source Tissue | Comment | Organism | Textmining |
|---|---|---|---|
| brain | highest levels of expression | Mus musculus | - |
| brain | highest levels of expression | Homo sapiens | - |
| brain | high expression level of MKK4, expression in adult and fetal brain | Homo sapiens | - |
| brain | high expression level of MKK4, expression in adult and fetal brain | Mus musculus | - |
| brain cancer cell | impaired expression of MKK4 | Homo sapiens | - |
| breast cancer cell | impaired expression of MKK4 | Homo sapiens | - |
| bronchial epithelial cell | - |
Homo sapiens | - |
| central nervous system | Mkk4 transcripts confined to the central nervous system in early embryogenesis, up to embryonic day 10 | Mus musculus | - |
| cerebellum | highest levels of expression | Mus musculus | - |
| cerebellum | highest levels of expression | Homo sapiens | - |
| cerebellum | high expression level of MKK4 | Homo sapiens | - |
| cerebellum | high expression level of MKK4 | Mus musculus | - |
| cerebral cortex | highest levels of expression | Mus musculus | - |
| cerebral cortex | highest levels of expression | Homo sapiens | - |
| cerebral cortex | high expression level of MKK4 | Homo sapiens | - |
| cerebral cortex | high expression level of MKK4 | Mus musculus | - |
| embryonic stem cell | - |
Mus musculus | - |
| fibroblast | - |
Mus musculus | - |
| heart | - |
Mus musculus | - |
| hippocampus | highest levels of expression | Mus musculus | - |
| hippocampus | highest levels of expression | Homo sapiens | - |
| hippocampus | high expression level of MKK4 | Homo sapiens | - |
| hippocampus | high expression level of MKK4 | Mus musculus | - |
| hypothalamus | highest levels of expression | Mus musculus | - |
| hypothalamus | highest levels of expression | Homo sapiens | - |
| hypothalamus | high expression level of MKK4 | Homo sapiens | - |
| hypothalamus | high expression level of MKK4 | Mus musculus | - |
| 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 | - |
| liver | high expression level of MKK4, expression in adult and fetal liver | Homo sapiens | - |
| liver | high expression level of MKK4, expression in adult and fetal liver | Mus musculus | - |
| additional information | AT6.1 cell, lacks MKK4 expression, overexpression of MKK4 significantly reduces its metastatic ability | Rattus norvegicus | - |
| additional information | ubiquitous expression of MKK4 in adult tissues | Rattus norvegicus | - |
| additional information | ubiquitous expression of MKK4 in adult tissues | Homo sapiens | - |
| additional information | ubiquitous expression of MKK4 in adult tissues | Mus musculus | - |
| ovary cancer cell | impaired expression of MKK4 | Homo sapiens | - |
| prostate | high expression of MKK4 in the epithelium but not in the stromal compartment | Mus musculus | - |
| prostate cancer cell | impaired expression of MKK4 | Homo sapiens | - |
| prostate cancer cell line | - |
Rattus norvegicus | - |
Substrates and Products (Substrate)
| Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| ATP + JNK | the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer, physiologic effects, overview | Homo sapiens | ADP + JNK phosphate | - |
? | |
| ATP + JNK | substrate of MKK4 and MKK7 in a synergistic manner | Homo sapiens | ADP + JNK phosphate | - |
? | |
| 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 | - |
? | |
| ATP + JNK | the enzyme is involved in stress-activated MAP kinase pathways and tumorigenesis, overview | Rattus norvegicus | ADP + phospho-JNK | - |
? | |
| 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 | - |
? | |
| ATP + JNK | the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer, physiologic effects, overview | Homo sapiens | ADP + phospho-JNK | - |
? | |
| ATP + JNK | substrate of MKK4 and MKK7 in a synergistic manner | Rattus norvegicus | ADP + phospho-JNK | - |
? | |
| ATP + JNK | substrate of MKK4 and MKK7 in a synergistic manner | Homo sapiens | ADP + phospho-JNK | - |
? | |
| ATP + JNK | substrate of MKK4 and MKK7 in a synergistic manner | Mus musculus | ADP + phospho-JNK | - |
? | |
| ATP + p38 | the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer, physiologic effects, overview | Homo sapiens | ADP + p38 phosphate | - |
? | |
| ATP + p38 | substrate of MKK7 | Homo sapiens | ADP + p38 phosphate | - |
? | |
| ATP + p38 | the enzyme is involved in stress-activated MAP kinase pathways and tumorigenesis, overview | Rattus norvegicus | ADP + phospho-p38 | - |
? | |
| 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 | - |
? | |
| ATP + p38 | the enzyme is involved in stress-activated MAP kinase pathways, tumorigenesis, and cancer, physiologic effects, overview | Homo sapiens | ADP + phospho-p38 | - |
? | |
| ATP + p38 | substrate of MKK4 | Homo sapiens | ADP + phospho-p38 | - |
? | |
| ATP + p38 | substrate of MKK4 | Mus musculus | ADP + phospho-p38 | - |
? | |
| ATP + p38 | substrate of MKK4 and MKK7 | Rattus norvegicus | ADP + phospho-p38 | - |
? | |
| ATP + p38 | substrate of MKK7 | Mus musculus | ADP + phospho-p38 | - |
? | |
| additional information | pro-oncogenic role of mitogen-activated protein kinase kinase 4 in cancer, overview | Homo sapiens | ? | - |
? | |
| 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 | ? | - |
? | |
| 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 | ? | - |
? | |
| additional information | substrate binding via the D-domain of the MKK | Drosophila melanogaster | ? | - |
? | |
| additional information | substrate binding via the D-domain of the MKK | Rattus norvegicus | ? | - |
? | |
| additional information | substrate binding via the D-domain of the MKK | Xenopus laevis | ? | - |
? | |
| additional information | substrate binding via the D-domain of the MKK | Homo sapiens | ? | - |
? | |
| additional information | substrate binding via the D-domain of the MKK | Mus musculus | ? | - |
? | |
Subunits
| Subunits | Comment | Organism |
|---|---|---|
| More | the catalytic domain contains 11 subdomains | Homo sapiens |
Synonyms
| Synonyms | Comment | Organism |
|---|---|---|
| DMKK4 | - |
Drosophila melanogaster |
| MAP kinase kinase 4 | - |
Drosophila melanogaster |
| MAP kinase kinase 4 | - |
Rattus norvegicus |
| MAP kinase kinase 4 | - |
Xenopus laevis |
| MAP kinase kinase 4 | - |
Homo sapiens |
| MAP kinase kinase 4 | - |
Mus musculus |
| mitogen-activated protein kinase kinase 4 | - |
Drosophila melanogaster |
| mitogen-activated protein kinase kinase 4 | - |
Mus musculus |
| mitogen-activated protein kinase kinase 4 | - |
Homo sapiens |
| mitogen-activated protein kinase kinase 4 | - |
Rattus norvegicus |
| mitogen-activated protein kinase kinase 4 | - |
Xenopus laevis |
| MKK4 | - |
Drosophila melanogaster |
| MKK4 | - |
Mus musculus |
| MKK4 | - |
Homo sapiens |
| MKK4 | - |
Rattus norvegicus |
| MKK4 | - |
Xenopus laevis |
| MKK7 | - |
Rattus norvegicus |
| MKK7 | - |
Homo sapiens |
| MKK7 | - |
Mus musculus |
| More | the enzyme belongs to the MKK familly | Drosophila melanogaster |
| More | the enzyme belongs to the MKK familly | Rattus norvegicus |
| More | the enzyme belongs to the MKK familly | Xenopus laevis |
| More | the enzyme belongs to the MKK familly | Homo sapiens |
| More | the enzyme belongs to the MKK familly | Mus musculus |
| stress-activate protein kinase/extracellular signal-regulated protein kinase kinase-1 | - |
Mus musculus |
| XMEK2 | - |
Xenopus laevis |
Cofactor
| Cofactor | Comment | Organism | Structure |
|---|---|---|---|
| ATP | - |
Drosophila melanogaster | |
| ATP | - |
Rattus norvegicus | |
| ATP | - |
Xenopus laevis | |
| ATP | - |
Homo sapiens | |
| ATP | - |
Mus musculus | |
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