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MAP2K4 (mitogen-activated protein kinase kinase 4)

Written2012-06Kentaro Nakayama, Naomi Nakayama, Kohji Miyazaki
Department of Obstetrics, Gynecology, Shimane University School of Medicine, Shimane, Japan

(Note : for Links provided by Atlas : click)


Alias_symbol (synonym)MEK4
Other aliasJNKK
HGNC (Hugo) MAP2K4
LocusID (NCBI) 6416
Atlas_Id 244
Location 17p12  [Link to chromosome band 17p12]
Location_base_pair Starts at 11924135 and ends at 12047148 bp from pter ( according to hg19-Feb_2009)  [Mapping MAP2K4.png]
Fusion genes
(updated 2016)
MAP2K4 (17p12) / CD79B (17q23.3)MAP2K4 (17p12) / DNAH9 (17p12)SAYSD1 (6p21.2) / MAP2K4 (17p12)
Note Total length: 122917 bp. Strand: plus.


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 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).
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.
Pseudogene Pseudogene is located on Xq13.2.


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.
  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.
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.


Germinal There are no reports regarding the germline.
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 been reported to occur in colorectal, non-small-cell lung, melanoma, and ovarian cancer specimens (Ahn et al., 2011).

Implicated in

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).
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).


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
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
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
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
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
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
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
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
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


This paper should be referenced as such :
Nakayama, K ; Nakayama, N ; Miyazaki, K
MAP2K4 (mitogen-activated protein kinase kinase 4)
Atlas Genet Cytogenet Oncol Haematol. 2012;16(12):898-900.
Free journal version : [ pdf ]   [ DOI ]
On line version :

Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ]
  t(1;9)(p13;p12) PAX5/HIPK1

External links

HGNC (Hugo)MAP2K4   6844
Entrez_Gene (NCBI)MAP2K4  6416  mitogen-activated protein kinase kinase 4
AliasesJNKK; JNKK1; MAPKK4; MEK4; 
GeneCards (Weizmann)MAP2K4
Ensembl hg19 (Hinxton)ENSG00000065559 [Gene_View]  chr17:11924135-12047148 [Contig_View]  MAP2K4 [Vega]
Ensembl hg38 (Hinxton)ENSG00000065559 [Gene_View]  chr17:11924135-12047148 [Contig_View]  MAP2K4 [Vega]
ICGC DataPortalENSG00000065559
TCGA cBioPortalMAP2K4
AceView (NCBI)MAP2K4
Genatlas (Paris)MAP2K4
SOURCE (Princeton)MAP2K4
Genetics Home Reference (NIH)MAP2K4
Genomic and cartography
GoldenPath hg19 (UCSC)MAP2K4  -     chr17:11924135-12047148 +  17p12   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)MAP2K4  -     17p12   [Description]    (hg38-Dec_2013)
EnsemblMAP2K4 - 17p12 [CytoView hg19]  MAP2K4 - 17p12 [CytoView hg38]
Mapping of homologs : NCBIMAP2K4 [Mapview hg19]  MAP2K4 [Mapview hg38]
Gene and transcription
Genbank (Entrez)AA293365 AK122997 AK131544 AK294923 AK313053
RefSeq transcript (Entrez)NM_001281435 NM_003010
RefSeq genomic (Entrez)NC_000017 NC_018928 NG_033952 NT_010718 NW_004929405
Consensus coding sequences : CCDS (NCBI)MAP2K4
Cluster EST : UnigeneHs.514681 [ NCBI ]
CGAP (NCI)Hs.514681
Alternative Splicing GalleryENSG00000065559
Gene ExpressionMAP2K4 [ NCBI-GEO ]   MAP2K4 [ EBI - ARRAY_EXPRESS ]   MAP2K4 [ SEEK ]   MAP2K4 [ MEM ]
Gene Expression Viewer (FireBrowse)MAP2K4 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)6416
GTEX Portal (Tissue expression)MAP2K4
Protein : pattern, domain, 3D structure
UniProt/SwissProtP45985   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP45985  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP45985
Splice isoforms : SwissVarP45985
Catalytic activity : Enzyme2.7.12.2 [ Enzyme-Expasy ] [ IntEnz-EBI ] [ BRENDA ] [ KEGG ]   
Domaine pattern : Prosite (Expaxy)PROTEIN_KINASE_ATP (PS00107)    PROTEIN_KINASE_DOM (PS50011)    PROTEIN_KINASE_ST (PS00108)   
Domains : Interpro (EBI)Kinase-like_dom    Prot_kinase_dom    Protein_kinase_ATP_BS    Ser/Thr_dual-sp_kinase    Ser/Thr_kinase_AS   
Domain families : Pfam (Sanger)Pkinase (PF00069)   
Domain families : Pfam (NCBI)pfam00069   
Domain families : Smart (EMBL)S_TKc (SM00220)  
Conserved Domain (NCBI)MAP2K4
DMDM Disease mutations6416
Blocks (Seattle)MAP2K4
PDB (SRS)3ALN    3ALO    3VUT   
PDB (PDBSum)3ALN    3ALO    3VUT   
PDB (IMB)3ALN    3ALO    3VUT   
PDB (RSDB)3ALN    3ALO    3VUT   
Structural Biology KnowledgeBase3ALN    3ALO    3VUT   
SCOP (Structural Classification of Proteins)3ALN    3ALO    3VUT   
CATH (Classification of proteins structures)3ALN    3ALO    3VUT   
Human Protein AtlasENSG00000065559
Peptide AtlasP45985
Protein Interaction databases
IntAct (EBI)P45985
Ontologies - Pathways
Ontology : AmiGOprotein kinase activity  receptor signaling protein serine/threonine kinase activity  protein tyrosine kinase activity  protein binding  ATP binding  nucleus  cytoplasm  cytosol  apoptotic process  signal transduction  JNK cascade  response to wounding  peptidyl-tyrosine phosphorylation  proteolysis in other organism  Fc-epsilon receptor signaling pathway  cellular response to mechanical stimulus  negative regulation of motor neuron apoptotic process  
Ontology : EGO-EBIprotein kinase activity  receptor signaling protein serine/threonine kinase activity  protein tyrosine kinase activity  protein binding  ATP binding  nucleus  cytoplasm  cytosol  apoptotic process  signal transduction  JNK cascade  response to wounding  peptidyl-tyrosine phosphorylation  proteolysis in other organism  Fc-epsilon receptor signaling pathway  cellular response to mechanical stimulus  negative regulation of motor neuron apoptotic process  
Pathways : BIOCARTAFc Epsilon Receptor I Signaling in Mast Cells [Genes]    T Cell Receptor Signaling Pathway [Genes]    MAPKinase Signaling Pathway [Genes]    TNFR1 Signaling Pathway [Genes]    EGF Signaling Pathway [Genes]    Angiotensin II mediated activation of JNK Pathway via Pyk2 dependent signaling [Genes]    FAS signaling pathway ( CD95 ) [Genes]    Ceramide Signaling Pathway [Genes]    Links between Pyk2 and Map Kinases [Genes]    TNF/Stress Related Signaling [Genes]    Toll-Like Receptor Pathway [Genes]    Inhibition of Cellular Proliferation by Gleevec [Genes]    Keratinocyte Differentiation [Genes]    p38 MAPK Signaling Pathway [Genes]    PDGF Signaling Pathway [Genes]   
Pathways : KEGGMAPK signaling pathway    ErbB signaling pathway    Toll-like receptor signaling pathway    Fc epsilon RI signaling pathway    TNF signaling pathway    GnRH signaling pathway    Epithelial cell signaling in Helicobacter pylori infection    Chagas disease (American trypanosomiasis)    Hepatitis B    Influenza A    HTLV-I infection    Epstein-Barr virus infection   
REACTOMEP45985 [protein]
REACTOME Pathways2559580 [pathway]   2871796 [pathway]   450321 [pathway]   5210891 [pathway]   5684264 [pathway]   
NDEx NetworkMAP2K4
Atlas of Cancer Signalling NetworkMAP2K4
Wikipedia pathwaysMAP2K4
Orthology - Evolution
GeneTree (enSembl)ENSG00000065559
Phylogenetic Trees/Animal Genes : TreeFamMAP2K4
Homologs : HomoloGeneMAP2K4
Homology/Alignments : Family Browser (UCSC)MAP2K4
Gene fusions - Rearrangements
Fusion : MitelmanMAP2K4/CD79B [17p12/17q23.3]  
Fusion: TCGAMAP2K4 17p12 CD79B 17q23.3 BRCA
Fusion: TCGAMAP2K4 17p12 DNAH9 17p12 BRCA
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerMAP2K4 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)MAP2K4
Exome Variant ServerMAP2K4
ExAC (Exome Aggregation Consortium)MAP2K4 (select the gene name)
Genetic variants : HAPMAP6416
Genomic Variants (DGV)MAP2K4 [DGVbeta]
DECIPHER (Syndromes)17:11924135-12047148  ENSG00000065559
CONAN: Copy Number AnalysisMAP2K4 
ICGC Data PortalMAP2K4 
TCGA Data PortalMAP2K4 
Broad Tumor PortalMAP2K4
OASIS PortalMAP2K4 [ Somatic mutations - Copy number]
Cancer Gene: CensusMAP2K4 
Somatic Mutations in Cancer : COSMICMAP2K4  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDMAP2K4
intOGen PortalMAP2K4
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch MAP2K4
DgiDB (Drug Gene Interaction Database)MAP2K4
DoCM (Curated mutations)MAP2K4 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)MAP2K4 (select a term)
NCG5 (London)MAP2K4
Cancer3DMAP2K4(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Genetic Testing Registry MAP2K4
NextProtP45985 [Medical]
Huge Navigator MAP2K4 [HugePedia]
snp3D : Map Gene to Disease6416
BioCentury BCIQMAP2K4
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD6416
Chemical/Pharm GKB GenePA30589
Drug Sensitivity MAP2K4
Clinical trialMAP2K4
canSAR (ICR)MAP2K4 (select the gene name)
Other database
PubMed163 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

Search in all EBI   NCBI

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indexed on : Wed Apr 12 11:34:41 CEST 2017

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