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Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Gene Section
Short Communication
MAP2K4 (mitogen-activated protein kinase kinase 4)
Kentaro Nakayama, Naomi Nakayama, Kohji Miyazaki
Department of Obstetrics and Gynecology, Shimane University School of Medicine, Shimane, Japan (KN,
NN, KM)
Published in Atlas Database: June 2012
Online updated version : http://AtlasGeneticsOncology.org/Genes/MAP2K4ID244ch17p12.html
DOI: 10.4267/2042/48361
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
kinase/extracellular signal-related protein kinase kinase
1 (SEK1) and c-Jun N-terminal kinase kinase 1
(JNKK1) (Dérijard et al., 1995).
Identity
Other names: JNKK, JNKK1, MAPKK4, MEK4,
MKK4, PRKMK4, SAPKK-1, SAPKK1, SEK1,
SERK1
HGNC (Hugo): MAP2K4
Location: 17p12
Note
Total length: 122917 bp. Strand: plus.
Description
MKK4 gene is encoded by 11 exons located on
chromosome 17p12. The genomic size is 122917 bp.
Transcription
mRNA size: 3752 bp; coding sequence from 1 bp-3743
bp.
DNA/RNA
Pseudogene
Pseudogene is located on Xq13.2.
Note
Mitogen-activated protein kinase kinase 4 (MKK4) was
first identified in a cDNA library from Xenopus laevis
embryos using a PCR-based screen and was initially
referred to as XMEK2 (Yashar et al., 1993).
Drosophila, mouse, rat, and human homologues were
subsequently cloned. MKK4 is also known as stressactivated protein
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(12)
Protein
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.
898
MAP2K4 (mitogen-activated protein kinase kinase 4)
Nakayama K, et al.
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.
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).
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.
Homology
Expression
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.
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.
Mutations
Localisation
MKK4 is primarily located in the cytoplasm of the cell.
Germinal
Function
There are no reports regarding the germline.
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
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(12)
Somatic
Genomic studies identified a total of 11 tumours from
human cancer samples (3% of the 356 tumours
evaluated) with somatic mutations in the MAP2K4
(MKK4) gene. These mutations are primarily located in
the kinase domain of MAP2K4. The mutations include
frameshift, nonsense, and missense mutations and have
899
MAP2K4 (mitogen-activated protein kinase kinase 4)
Nakayama K, et al.
been reported to occur in colorectal, non-small-cell
lung, melanoma, and ovarian cancer specimens (Ahn et
al., 2011).
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).
Implicated in
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, nonsmall-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 highgrade 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).
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(12)
References
Yashar BM, Kelley C, Yee K, Errede B, Zon LI. Novel members
of the mitogen-activated protein kinase activator family in
Xenopus laevis. Mol Cell Biol. 1993 Sep;13(9):5738-48
Dérijard B, Raingeaud J, Barrett T, Wu IH, Han J, Ulevitch RJ,
Davis RJ. Independent human MAP-kinase signal transduction
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Feb 3;267(5198):682-5
Lin A, Minden A, Martinetto H, Claret FX, Lange-Carter C,
Mercurio F, Johnson GL, Karin M. Identification of a dual
specificity kinase that activates the Jun kinases and p38-Mpk2.
Science. 1995 Apr 14;268(5208):286-90
Nakayama K, Nakayama N, Davidson B, Katabuchi H, Kurman
RJ, Velculescu VE, Shih IeM, Wang TL. Homozygous deletion
of MKK4 in ovarian serous carcinoma. Cancer Biol Ther. 2006
Jun;5(6):630-4
Asaoka Y, Nishina H. Diverse physiological functions of MKK4
and MKK7 during early embryogenesis. J Biochem. 2010
Oct;148(4):393-401
Finegan KG, Tournier C. The mitogen-activated protein kinase
kinase 4 has a pro-oncogenic role in skin cancer. Cancer Res.
2010 Jul 15;70(14):5797-806
Ishikawa M, Nakayama K, Rahman MT, Rahman M, Katagiri A,
Iida K, Miyazaki K. Functional and clinicopathological analysis
of loss of MKK4 expression in endometrial cancer. Oncology.
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II, Lin W, Thilaganathan N, Alvarez CA, Roybal J, Goldsmith
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suppressor in lung adenocarcinoma and inhibits tumor cell
invasion by decreasing peroxisome proliferator-activated
receptor γ2 expression. Mol Cell Biol. 2011 Nov;31(21):427085
Yeasmin S, Nakayama K, Rahman MT, Rahman M, Ishikawa
M, Katagiri A, Iida K, Nakayama N, Miyazaki K. Loss of MKK4
expression in ovarian cancer: a potential role for the epithelial
to mesenchymal transition. Int J Cancer. 2011 Jan 1;128(1):94104
This article should be referenced as such:
Nakayama K, Nakayama N, Miyazaki K. MAP2K4 (mitogenactivated protein kinase kinase 4). Atlas Genet Cytogenet
Oncol Haematol. 2012; 16(12):898-900.
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