| Note | The MKK4 cDNA has 1197 bp open reading frame encoding a predicted polypeptide of 399 amino acids with a predicted molecular mass of 67 kDa. |
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| | MKK4 interacts with the substrates JNK1, JNK2, JNK3, MAPK11, and MAPK14 via the D domain. MKK4 also interacts with the MAP3K activators MEKK1 and MLK3 via the domain for versatile docking (DVD domain). The DVD domain contains a conserved docking site that binds to upstream MAP3Ks and is essential for activation. The D domain contains a conserved docking site that binds to MAPK substrates. MKK4 is activated by the phosphorylation of Ser-257 and Thr-261 by MAP kinase kinase kinases. |
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| Description | The MKK4 gene encodes a dual specificity protein kinase that belongs to the Ser/Thr protein kinase family. This kinase is a direct activator of MAP kinases in response to environmental stress or mitogenic stimuli. MKK4 has been shown to activate MAPK8/JNK1, MAPK9/JNK2, and MAPK14/p38, but not MAPK1/ERK2 or MAPK3/ERK3. This kinase is phosphorylated and activated by MAP3K1/MEKK. |
| Expression | MKK4 is widely expressed in normal tissues, including the thyroid, heart, lymph nodes, trachea, adrenal glands, and ovaries. The expression of MKK4 is lower in neoplastic tissues. |
| Localisation | MKK4 is primarily located in the cytoplasm of the cell. |
| Function | Three mitogen-activated protein kinase (MAPK) cascades occur in mammals. Each of the MAPK cascades consists of a three-kinase module that includes a MAPK, a MAPK kinase (MAPKK), and a MAPKK kinase (MAPKKK). Various cellular stresses, including ultraviolet (UV) and gamma irradiation, heat shock, hyperosmolarity, hydrogen peroxide, and inflammatory cytokines, activate the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signalling pathway. c-Jun N-terminal kinases (JNKs) are MAPKs that stimulate the transcriptional activity of Jun in response to cellular stress. MAP2K4 is a MAPKK that directly activates the JNKs and the related MAPK p38 (Lin et al., 1995).
MKK4 is a dual specificity kinase that activates the Jun kinases MAPK8 (JNK1) and MAPK9 (JNK2) and MAPK14 (p38), but does not activate MAPK1 (ERK2) or MAPK3 (ERK1). |
| Homology | The MAP2K4 gene is conserved in chimpanzee, dog, cow, mouse, rat, chicken, zebrafish, fruit fly, mosquito, C. elegans, S. pombe, S. cerevisiae, K. lactis, E. gossypii, M. grisea, and N. crassa. |
| Entity | Various cancers |
| Note | Genomic studies have identified somatic mutations in the MAP2K4 gene in a total of 11 human cancer tumours (3% of the 356 tumours evaluated). These mutations are located primarily in the kinase domain. The mutations include frameshift, nonsense, and missense mutations and occur in colorectal, non-small-cell lung, melanoma, and ovarian cancer specimens (Ahn et al., 2011).
The frequency of MKK4 homozygous deletions in high-grade ovarian serous carcinomas was reported to be 4,2%, which is similar to the rates observed in pancreatic (2%) and breast (4,5%) carcinomas (Nakayama et al., 2006). Loss of heterozygosity on chromosome 17p occurred in 24 (86%) of 28 high-grade serous carcinomas, including two cases with a homozygous MKK4 deletion. Downregulation of MKK4 expression was reported in 96 (75%) of 128 ovarian serous carcinomas compared to benign ovarian tissues. These findings suggest that homozygous deletions or reduced expression of MKK4 may contribute to the development of ovarian serous carcinomas (Nakayama et al., 2006).
MKK4 expression related to tumour invasion results from an epithelial to mesenchymal transition (EMT)-like morphological change. Yeasmin et al. reported that the downregulation of MKK4 increased the phosphorylation of NF-κB and promoted the overexpression of Twist, resulting in the downregulation of E-cadherin, which induced an EMT in ovarian cancer.
In most reports, MKK4 is defined as a tumour suppressor gene. However, Finegan and Tournier evaluated the role of MKK4 in skin tumourigenesis and reported that skin-specific MKK4-deficient mice are resistant to carcinogen-induced tumourigenesis. MKK4 is essential for mediating the oncogenic effects of Ras in vivo (Finegan and Tournier, 2010). |
| Prognosis | A decreased expression of MKK4 based on immunointensity scores was observed in 63,2% (55/87) of endometrioid adenocarcinomas analysed. Patients with decreased MKK4 expression in endometrial cancer tissues tended to have a shorter overall rate of survival (p = 0,197) (Ishikawa et al., 2010). |
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| Entity | Embryogenesis |
| Note | MKK4 has diverse physiological functions during embryogenesis. JNK activation by MKK4 and MKK7 is utilised in parallel morphogenetic events in widely divergent species. In vertebrates and invertebrates, MKK4/MKK7-JNK signalling regulates the expression of secreted signalling molecules that are capable of promoting the movements of neighbouring cells that are required for dorsal closure and gastrulation (Asaoka and Nishina, 2010). |
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| Novel members of the mitogen-activated protein kinase activator family in Xenopus laevis. |
| Yashar BM, Kelley C, Yee K, Errede B, Zon LI. |
| Mol Cell Biol. 1993 Sep;13(9):5738-48. |
| PMID 8395011 |
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| Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms. |
| Derijard B, Raingeaud J, Barrett T, Wu IH, Han J, Ulevitch RJ, Davis RJ. |
| Science. 1995 Feb 3;267(5198):682-5. |
| PMID 7839144 |
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| Identification of a dual specificity kinase that activates the Jun kinases and p38-Mpk2. |
| Lin A, Minden A, Martinetto H, Claret FX, Lange-Carter C, Mercurio F, Johnson GL, Karin M. |
| Science. 1995 Apr 14;268(5208):286-90. |
| PMID 7716521 |
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| Homozygous deletion of MKK4 in ovarian serous carcinoma. |
| Nakayama K, Nakayama N, Davidson B, Katabuchi H, Kurman RJ, Velculescu VE, Shih IeM, Wang TL. |
| Cancer Biol Ther. 2006 Jun;5(6):630-4. Epub 2006 Jun 9. |
| PMID 16627982 |
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| Diverse physiological functions of MKK4 and MKK7 during early embryogenesis. |
| Asaoka Y, Nishina H. |
| J Biochem. 2010 Oct;148(4):393-401. Epub 2010 Aug 27. (REVIEW) |
| PMID 20801953 |
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| The mitogen-activated protein kinase kinase 4 has a pro-oncogenic role in skin cancer. |
| Finegan KG, Tournier C. |
| Cancer Res. 2010 Jul 15;70(14):5797-806. Epub 2010 Jul 7. |
| PMID 20610622 |
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| Functional and clinicopathological analysis of loss of MKK4 expression in endometrial cancer. |
| Ishikawa M, Nakayama K, Rahman MT, Rahman M, Katagiri A, Iida K, Miyazaki K. |
| Oncology. 2010;79(3-4):238-46. Epub 2011 Mar 3. |
| PMID 21372598 |
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| Map2k4 functions as a tumor suppressor in lung adenocarcinoma and inhibits tumor cell invasion by decreasing peroxisome proliferator-activated receptor gamma2 expression. |
| Ahn YH, Yang Y, Gibbons DL, Creighton CJ, Yang F, Wistuba II, Lin W, Thilaganathan N, Alvarez CA, Roybal J, Goldsmith EJ, Tournier C, Kurie JM. |
| Mol Cell Biol. 2011 Nov;31(21):4270-85. doi: 10.1128/MCB.05562-11. Epub 2011 Sep 6. |
| PMID 21896780 |
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| Loss of MKK4 expression in ovarian cancer: a potential role for the epithelial to mesenchymal transition. |
| Yeasmin S, Nakayama K, Rahman MT, Rahman M, Ishikawa M, Katagiri A, Iida K, Nakayama N, Miyazaki K. |
| Int J Cancer. 2011 Jan 1;128(1):94-104. doi: 10.1002/ijc.25332. |
| PMID 20309881 |
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