MAP2K4 (mitogen-activated protein kinase kinase 4)

2012-06-01   Kentaro Nakayama , Naomi Nakayama , Kohji Miyazaki 

Department of Obstetrics, Gynecology, Shimane University School of Medicine, Shimane, Japan





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 stress-activated protein kinase/extracellular signal-related protein kinase kinase 1 (SEK1) and c-Jun N-terminal kinase kinase 1 (JNKK1) (Dérijard et al., 1995).
Atlas Image


MKK4 gene is encoded by 11 exons located on chromosome 17p12. The genomic size is 122917 bp.


mRNA size: 3752 bp; coding sequence from 1 bp-3743 bp.


Pseudogene is located on Xq13.2.



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.
Atlas Image
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.


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.


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.


MKK4 is primarily located in the cytoplasm of the cell.


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).


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.



There are no reports regarding the germline.


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 been reported to occur in colorectal, non-small-cell lung, melanoma, and ovarian cancer specimens (Ahn et al., 2011).

Implicated in

Entity name
Various cancers
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).
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).
Entity name
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).


Pubmed IDLast YearTitleAuthors
218967802011Map2k4 functions as a tumor suppressor in lung adenocarcinoma and inhibits tumor cell invasion by decreasing peroxisome proliferator-activated receptor γ2 expression.Ahn YH et al
208019532010Diverse physiological functions of MKK4 and MKK7 during early embryogenesis.Asaoka Y et al
78391441995Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms.Dérijard B et al
206106222010The mitogen-activated protein kinase kinase 4 has a pro-oncogenic role in skin cancer.Finegan KG et al
213725982010Functional and clinicopathological analysis of loss of MKK4 expression in endometrial cancer.Ishikawa M et al
77165211995Identification of a dual specificity kinase that activates the Jun kinases and p38-Mpk2.Lin A et al
166279822006Homozygous deletion of MKK4 in ovarian serous carcinoma.Nakayama K et al
83950111993Novel members of the mitogen-activated protein kinase activator family in Xenopus laevis.Yashar BM et al
203098812011Loss of MKK4 expression in ovarian cancer: a potential role for the epithelial to mesenchymal transition.Yeasmin S et al

Other Information

Locus ID:

NCBI: 6416
MIM: 601335
HGNC: 6844
Ensembl: ENSG00000065559


dbSNP: 6416
ClinVar: 6416
TCGA: ENSG00000065559


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
MAPK signaling pathwayKEGGko04010
ErbB signaling pathwayKEGGko04012
Toll-like receptor signaling pathwayKEGGko04620
Fc epsilon RI signaling pathwayKEGGko04664
GnRH signaling pathwayKEGGko04912
Epithelial cell signaling in Helicobacter pylori infectionKEGGko05120
MAPK signaling pathwayKEGGhsa04010
ErbB signaling pathwayKEGGhsa04012
Toll-like receptor signaling pathwayKEGGhsa04620
Fc epsilon RI signaling pathwayKEGGhsa04664
GnRH signaling pathwayKEGGhsa04912
Epithelial cell signaling in Helicobacter pylori infectionKEGGhsa05120
Chagas disease (American trypanosomiasis)KEGGko05142
Chagas disease (American trypanosomiasis)KEGGhsa05142
Influenza AKEGGko05164
Influenza AKEGGhsa05164
HTLV-I infectionKEGGko05166
HTLV-I infectionKEGGhsa05166
Epstein-Barr virus infectionKEGGhsa05169
Epstein-Barr virus infectionKEGGko05169
Hepatitis BKEGGhsa05161
TNF signaling pathwayKEGGhsa04668
TNF signaling pathwayKEGGko04668
MAPK (JNK) signalingKEGGhsa_M00688
MAPK (JNK) signalingKEGGM00688
Infectious diseaseREACTOMER-HSA-5663205
Uptake and actions of bacterial toxinsREACTOMER-HSA-5339562
Uptake and function of anthrax toxinsREACTOMER-HSA-5210891
Immune SystemREACTOMER-HSA-168256
Innate Immune SystemREACTOMER-HSA-168249
Toll-Like Receptors CascadesREACTOMER-HSA-168898
Toll Like Receptor 10 (TLR10) CascadeREACTOMER-HSA-168142
MyD88 cascade initiated on plasma membraneREACTOMER-HSA-975871
MAP kinase activation in TLR cascadeREACTOMER-HSA-450294
JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1REACTOMER-HSA-450321
Toll Like Receptor 3 (TLR3) CascadeREACTOMER-HSA-168164
MyD88-independent TLR3/TLR4 cascadeREACTOMER-HSA-166166
TRIF-mediated TLR3/TLR4 signalingREACTOMER-HSA-937061
Toll Like Receptor 5 (TLR5) CascadeREACTOMER-HSA-168176
Toll Like Receptor 7/8 (TLR7/8) CascadeREACTOMER-HSA-168181
MyD88 dependent cascade initiated on endosomeREACTOMER-HSA-975155
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activationREACTOMER-HSA-975138
Toll Like Receptor 9 (TLR9) CascadeREACTOMER-HSA-168138
Toll Like Receptor 4 (TLR4) CascadeREACTOMER-HSA-166016
Activated TLR4 signallingREACTOMER-HSA-166054
MyD88:Mal cascade initiated on plasma membraneREACTOMER-HSA-166058
Toll Like Receptor 2 (TLR2) CascadeREACTOMER-HSA-181438
Toll Like Receptor TLR1:TLR2 CascadeREACTOMER-HSA-168179
Toll Like Receptor TLR6:TLR2 CascadeREACTOMER-HSA-168188
Fc epsilon receptor (FCERI) signalingREACTOMER-HSA-2454202
FCERI mediated MAPK activationREACTOMER-HSA-2871796
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
Interleukin-1 signalingREACTOMER-HSA-446652
Cellular responses to stressREACTOMER-HSA-2262752
Cellular SenescenceREACTOMER-HSA-2559583
Oxidative Stress Induced SenescenceREACTOMER-HSA-2559580
MAP3K8 (TPL2)-dependent MAPK1/3 activationREACTOMER-HSA-5684264
Fluid shear stress and atherosclerosisKEGGko05418
Fluid shear stress and atherosclerosisKEGGhsa05418

Protein levels (Protein atlas)

Not detected


Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA283MAPK8GenePathwayassociated20124951, 23922006
PA447197Attention Deficit Disorder with HyperactivityDiseaseClinicalAnnotationassociatedPD


Pubmed IDYearTitleCitations
167095742006JNK- and p38 kinase-mediated phosphorylation of Bax leads to its activation and mitochondrial translocation and to apoptosis of human hepatoma HepG2 cells.146
171788612006Activation of DNA methyltransferase 1 by EBV LMP1 Involves c-Jun NH(2)-terminal kinase signaling.73
190013752009How does arrestin assemble MAPKs into a signaling complex?68
122234902002Phosphorylation and inactivation of myeloid cell leukemia 1 by JNK in response to oxidative stress.64
152629612004Tobacco smoke control of mucin production in lung cells requires oxygen radicals AP-1 and JNK.56
154964002004Negative regulation of JNK signaling by the tumor suppressor CYLD.56
155926842005Reduced metastasis-suppressor gene mRNA-expression in breast cancer brain metastases.46
153283432004Ser/Thr protein phosphatase 5 inactivates hypoxia-induced activation of an apoptosis signal-regulating kinase 1/MKK-4/JNK signaling cascade.43
196385052009MEK4 function, genistein treatment, and invasion of human prostate cancer cells.43
152564842004Curcumin induces c-jun N-terminal kinase-dependent apoptosis in HCT116 human colon cancer cells.42


Kentaro Nakayama ; Naomi Nakayama ; Kohji Miyazaki

MAP2K4 (mitogen-activated protein kinase kinase 4)

Atlas Genet Cytogenet Oncol Haematol. 2012-06-01

Online version: