Human Gene MAP2K4 (uc002gnj.3) Description and Page Index
  Description: Homo sapiens mitogen-activated protein kinase kinase 4 (MAP2K4), mRNA.
RefSeq Summary (NM_003010): This gene encodes a member of the mitogen-activated protein kinase (MAPK) family. Members of this family act as an integration point for multiple biochemical signals and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation, and development. They form a three-tiered signaling module composed of MAPKKKs, MAPKKs, and MAPKs. This protein is phosphorylated at serine and threonine residues by MAPKKKs and subsequently phosphorylates downstream MAPK targets at threonine and tyrosine residues. A similar protein in mouse has been reported to play a role in liver organogenesis. A pseudogene of this gene is located on the long arm of chromosome X. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013].
Transcript (Including UTRs)
   Position: hg19 chr17:11,924,135-12,047,051 Size: 122,917 Total Exon Count: 11 Strand: +
Coding Region
   Position: hg19 chr17:11,924,204-12,044,577 Size: 120,374 Coding Exon Count: 11 

Page IndexSequence and LinksUniProtKB CommentsGenetic AssociationsMalaCardsCTD
Gene AllelesRNA-Seq ExpressionMicroarray ExpressionRNA StructureProtein StructureOther Species
GO AnnotationsmRNA DescriptionsPathwaysOther NamesModel InformationMethods
Data last updated: 2013-06-14

-  Sequence and Links to Tools and Databases
Genomic Sequence (chr17:11,924,135-12,047,051)mRNA (may differ from genome)Protein (399 aa)
Gene SorterGenome BrowserOther Species FASTAVisiGeneGene interactionsTable Schema
BioGPSCGAPEnsemblEntrez GeneExonPrimerGeneCards
neXtProtOMIMPubMedReactomeStanford SOURCEUniProtKB

-  Comments and Description Text from UniProtKB
DESCRIPTION: RecName: Full=Dual specificity mitogen-activated protein kinase kinase 4; Short=MAP kinase kinase 4; Short=MAPKK 4; EC=; AltName: Full=JNK-activating kinase 1; AltName: Full=MAPK/ERK kinase 4; Short=MEK 4; AltName: Full=SAPK/ERK kinase 1; Short=SEK1; AltName: Full=Stress-activated protein kinase kinase 1; Short=SAPK kinase 1; Short=SAPKK-1; Short=SAPKK1; AltName: Full=c-Jun N-terminal kinase kinase 1; Short=JNKK;
FUNCTION: Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Essential component of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. With MAP2K7/MKK7, is the one of the only known kinase to directly activate the stress-activated protein kinase/c-Jun N-terminal kinases MAPK8/JNK1, MAPK9/JNK2 and MAPK10/JNK3. MAP2K4/MKK4 and MAP2K7/MKK7 both activate the JNKs by phosphorylation, but they differ in their preference for the phosphorylation site in the Thr-Pro-Tyr motif. MAP2K4 shows preference for phosphorylation of the Tyr residue and MAP2K7/MKK7 for the Thr residue. The phosphorylation of the Thr residue by MAP2K7/MKK7 seems to be the prerequisite for JNK activation at least in response to proinflammatory cytokines, while other stimuli activate both MAP2K4/MKK4 and MAP2K7/MKK7 which synergistically phosphorylate JNKs. MAP2K4 is required for maintaining peripheral lymphoid homeostasis. The MKK/JNK signaling pathway is also involved in mitochondrial death signaling pathway, including the release cytochrome c, leading to apoptosis. Whereas MAP2K7/MKK7 exclusively activates JNKs, MAP2K4/MKK4 additionally activates the p38 MAPKs MAPK11, MAPK12, MAPK13 and MAPK14.
CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
ENZYME REGULATION: Activated in response to a variety of cellular stresses, including UV and gamma-irradiation, heat shock, hyperosmolarity, T-cell receptor stimulation, peroxide and inflammatory cytokines. Also activated by developmental cues. MAP2K4/MKK4 is activated by the majority of MKKKs, such as MAP3K5/ASK1, MAP3K1/MEKK1, MAP3K7/TAK1, MAP3K10/MLK2, MAP3K11/MLK3, MAP3K12/DLK and MAP3K13/LZK.
SUBUNIT: Interacts with SPAG9 (By similarity). Interacts (via its D domain) with its substrates MAPK8/JNK1, MAPK9/JNK2, MAPK10/JNK3, MAPK11 and MAPK14. Interacts (via its DVD domain) with MAP3Ks activators like MAP3K1/MEKK1 and MAP3K11/MLK3. Interacts with ARRB1, ARRB2 and MAPK8IP3/JIP3.
INTERACTION: Q13233:MAP3K1; NbExp=3; IntAct=EBI-447868, EBI-49776;
SUBCELLULAR LOCATION: Cytoplasm (By similarity). Nucleus (By similarity).
TISSUE SPECIFICITY: Abundant expression is seen in the skeletal muscle. It is also widely expressed in other tissues.
DOMAIN: The DVD domain (redidues 364-387) contains a conserved docking site and is found in the mammalian MAP kinase kinases (MAP2Ks). The DVD sites bind to their specific upstream MAP kinase kinase kinases (MAP3Ks) and are essential for activation.
DOMAIN: The D domain (redidues 34-52) contains a conserved docking site and is required for the binding to MAPK substrates.
PTM: Activated by phosphorylation on Ser-257 and Thr-261 by MAP kinase kinase kinases (MAP3Ks).
SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase subfamily.
SIMILARITY: Contains 1 protein kinase domain.

-  Genetic Association Studies of Complex Diseases and Disorders
  Genetic Association Database (archive): MAP2K4
CDC HuGE Published Literature: MAP2K4
Positive Disease Associations: Body Mass Index , Body Weight , Coronary Artery Disease , Hemoglobin A, Glycosylated , Insulin , Neuroblastoma , Stroke
Related Studies:
  1. Body Mass Index
    Caroline S Fox et al. BMC medical genetics 2007, Genome-wide association to body mass index and waist circumference: the Framingham Heart Study 100K project., BMC medical genetics. [PubMed 17903300]
    Adiposity traits are associated with SNPs on the Affymetrix 100K SNP GeneChip. Replication of these initial findings is necessary. These data will serve as a resource for replication as more genes become identified with BMI and WC.
  2. Body Weight
    Caroline S Fox et al. BMC medical genetics 2007, Genome-wide association to body mass index and waist circumference: the Framingham Heart Study 100K project., BMC medical genetics. [PubMed 17903300]
    Adiposity traits are associated with SNPs on the Affymetrix 100K SNP GeneChip. Replication of these initial findings is necessary. These data will serve as a resource for replication as more genes become identified with BMI and WC.
  3. Coronary Artery Disease
    , , . [PubMed 0]
           more ... click here to view the complete list

-  MalaCards Disease Associations
  MalaCards Gene Search: MAP2K4
Diseases sorted by gene-association score: ovarian serous carcinoma (31), cerebral cavernous malformations-2 (4), pancreatic cancer (2), ovarian cancer, somatic (1)

-  Comparative Toxicogenomics Database (CTD)
  The following chemicals interact with this gene
  • D019256 Cadmium Chloride
  • D015123 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide
  • D000082 Acetaminophen
  • D000111 Acetylcysteine
  • D008070 Lipopolysaccharides
  • D011794 Quercetin
  • C057270 cisplatin-DNA adduct
  • C017947 sodium arsenite
  • C439285 (5-fluoro-2-methyl-1-(4-pyridyl)methylene-3-(N-benzyl)-indene)-acetamide hydrochloride
  • C028474 1,4-bis(2-(3,5-dichloropyridyloxy))benzene
          more ... click here to view the complete list

+  Common Gene Haplotype Alleles
  Press "+" in the title bar above to open this section.

-  RNA-Seq Expression Data from GTEx (53 Tissues, 570 Donors)
  Highest median expression: 31.16 RPKM in Brain - Frontal Cortex (BA9)
Total median expression: 543.02 RPKM

View in GTEx track of Genome Browser    View at GTEx portal     View GTEx Body Map

+  Microarray Expression Data
  Press "+" in the title bar above to open this section.

-  mRNA Secondary Structure of 3' and 5' UTRs
RegionFold EnergyBasesEnergy/Base
Display As
5' UTR -32.6069-0.472 Picture PostScript Text
3' UTR -683.182474-0.276 Picture PostScript Text

The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.

-  Protein Domain and Structure Information
  InterPro Domains: Graphical view of domain structure
IPR011009 - Kinase-like_dom
IPR000719 - Prot_kinase_cat_dom
IPR017441 - Protein_kinase_ATP_BS
IPR002290 - Ser/Thr_dual-sp_kinase_dom
IPR008271 - Ser/Thr_kinase_AS

Pfam Domains:
PF00069 - Protein kinase domain
PF07714 - Protein tyrosine kinase
PF14531 - Kinase-like

SCOP Domains:
56112 - Protein kinase-like (PK-like)

Protein Data Bank (PDB) 3-D Structure
MuPIT help

- X-ray MuPIT

- X-ray MuPIT

- X-ray MuPIT

ModBase Predicted Comparative 3D Structure on P45985
The pictures above may be empty if there is no ModBase structure for the protein. The ModBase structure frequently covers just a fragment of the protein. You may be asked to log onto ModBase the first time you click on the pictures. It is simplest after logging in to just click on the picture again to get to the specific info on that model.

-  Orthologous Genes in Other Species
  Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
MouseRatZebrafishD. melanogasterC. elegansS. cerevisiae
No orthologGenome BrowserNo orthologNo orthologNo orthologNo ortholog
Gene DetailsGene Details    
Gene SorterGene Sorter    
 Protein Sequence    

-  Gene Ontology (GO) Annotations with Structured Vocabulary
  Molecular Function:
GO:0000166 nucleotide binding
GO:0004672 protein kinase activity
GO:0004674 protein serine/threonine kinase activity
GO:0004708 MAP kinase kinase activity
GO:0004713 protein tyrosine kinase activity
GO:0005515 protein binding
GO:0005524 ATP binding
GO:0008545 JUN kinase kinase activity
GO:0016301 kinase activity
GO:0016740 transferase activity
GO:0031435 mitogen-activated protein kinase kinase kinase binding

Biological Process:
GO:0000165 MAPK cascade
GO:0001934 positive regulation of protein phosphorylation
GO:0006468 protein phosphorylation
GO:0006915 apoptotic process
GO:0007165 signal transduction
GO:0007254 JNK cascade
GO:0007257 activation of JUN kinase activity
GO:0007346 regulation of mitotic cell cycle
GO:0009611 response to wounding
GO:0016310 phosphorylation
GO:0018108 peptidyl-tyrosine phosphorylation
GO:0023014 signal transduction by protein phosphorylation
GO:0031098 stress-activated protein kinase signaling cascade
GO:0032147 activation of protein kinase activity
GO:0034393 positive regulation of smooth muscle cell apoptotic process
GO:0042981 regulation of apoptotic process
GO:0043065 positive regulation of apoptotic process
GO:0043525 positive regulation of neuron apoptotic process
GO:0045740 positive regulation of DNA replication
GO:0051770 positive regulation of nitric-oxide synthase biosynthetic process
GO:0061049 cell growth involved in cardiac muscle cell development
GO:0071260 cellular response to mechanical stimulus
GO:0072709 cellular response to sorbitol
GO:2000672 negative regulation of motor neuron apoptotic process

Cellular Component:
GO:0005634 nucleus
GO:0005737 cytoplasm
GO:0005829 cytosol
GO:0030424 axon
GO:0032839 dendrite cytoplasm
GO:0043204 perikaryon

-  Descriptions from all associated GenBank mRNAs
  BC036032 - Homo sapiens mitogen-activated protein kinase kinase 4, mRNA (cDNA clone MGC:33126 IMAGE:5272439), complete cds.
BC060764 - Homo sapiens mitogen-activated protein kinase kinase 4, mRNA (cDNA clone MGC:71508 IMAGE:5294838), complete cds.
AK131544 - Homo sapiens cDNA FLJ16780 fis, clone BRTHA2034874, highly similar to Dual specificity mitogen-activated protein kinase kinase 4 (EC
AK313053 - Homo sapiens cDNA, FLJ93529, highly similar to Homo sapiens mitogen-activated protein kinase kinase 4 (MAP2K4), mRNA.
U17743 - Human JNK activating kinase (JNKK1) mRNA, complete cds.
AK294923 - Homo sapiens cDNA FLJ52538 complete cds, highly similar to Dual specificity mitogen-activated proteinkinase kinase 4 (EC
L36870 - Homo sapiens MAP kinase kinase 4 (MKK4) mRNA, complete cds.
BC050386 - Homo sapiens cDNA clone IMAGE:5764060, containing frame-shift errors.
AB590846 - Synthetic construct DNA, clone: pFN21AB6562, Homo sapiens MAP2K4 gene for mitogen-activated protein kinase kinase 4, without stop codon, in Flexi system.
BT019676 - Homo sapiens mitogen-activated protein kinase kinase 4 mRNA, complete cds.
CR536564 - Homo sapiens full open reading frame cDNA clone RZPDo834E1022D for gene MAP2K4, mitogen-activated protein kinase kinase 4; complete cds, incl. stopcodon.
JD460704 - Sequence 441728 from Patent EP1572962.
JD407797 - Sequence 388821 from Patent EP1572962.
AK316177 - Homo sapiens cDNA, FLJ79076 complete cds, highly similar to Dual specificity mitogen-activated protein kinase kinase 4 (EC
AK316100 - Homo sapiens cDNA, FLJ78999 complete cds, highly similar to Dual specificity mitogen-activated protein kinase kinase 4 (EC
JD113749 - Sequence 94773 from Patent EP1572962.
AK122997 - Homo sapiens cDNA FLJ16771 fis, clone BRAWH3030613, highly similar to Homo sapiens mitogen-activated protein kinase kinase 4 (MAP2K4).
JD522676 - Sequence 503700 from Patent EP1572962.
JD426977 - Sequence 408001 from Patent EP1572962.
JD277098 - Sequence 258122 from Patent EP1572962.
JD241573 - Sequence 222597 from Patent EP1572962.
JD036791 - Sequence 17815 from Patent EP1572962.
JD502176 - Sequence 483200 from Patent EP1572962.
JD436177 - Sequence 417201 from Patent EP1572962.
JD493900 - Sequence 474924 from Patent EP1572962.
JD045984 - Sequence 27008 from Patent EP1572962.
L31902 - Human (clone 1NIB-210) normalized cDNA library sequence.
JD242984 - Sequence 224008 from Patent EP1572962.
JD545540 - Sequence 526564 from Patent EP1572962.
JD147947 - Sequence 128971 from Patent EP1572962.
JD431588 - Sequence 412612 from Patent EP1572962.
JD368087 - Sequence 349111 from Patent EP1572962.
JD516091 - Sequence 497115 from Patent EP1572962.
JD300200 - Sequence 281224 from Patent EP1572962.
JD225768 - Sequence 206792 from Patent EP1572962.
JD185559 - Sequence 166583 from Patent EP1572962.
JD226230 - Sequence 207254 from Patent EP1572962.
JD374152 - Sequence 355176 from Patent EP1572962.
JD449393 - Sequence 430417 from Patent EP1572962.
JD060999 - Sequence 42023 from Patent EP1572962.
JD293775 - Sequence 274799 from Patent EP1572962.
JD297686 - Sequence 278710 from Patent EP1572962.
JD386742 - Sequence 367766 from Patent EP1572962.
JD408722 - Sequence 389746 from Patent EP1572962.
JD419669 - Sequence 400693 from Patent EP1572962.
JD502083 - Sequence 483107 from Patent EP1572962.
JD172789 - Sequence 153813 from Patent EP1572962.
JD093171 - Sequence 74195 from Patent EP1572962.
JD036607 - Sequence 17631 from Patent EP1572962.
JD060282 - Sequence 41306 from Patent EP1572962.
JD235851 - Sequence 216875 from Patent EP1572962.
JD280127 - Sequence 261151 from Patent EP1572962.

-  Biochemical and Signaling Pathways
  KEGG - Kyoto Encyclopedia of Genes and Genomes
hsa04010 - MAPK signaling pathway
hsa04012 - ErbB signaling pathway
hsa04620 - Toll-like receptor signaling pathway
hsa04664 - Fc epsilon RI signaling pathway
hsa04912 - GnRH signaling pathway
hsa05120 - Epithelial cell signaling in Helicobacter pylori infection
hsa05142 - Chagas disease

BioCarta from NCI Cancer Genome Anatomy Project
h_fcer1Pathway - Fc Epsilon Receptor I Signaling in Mast Cells
h_tcrPathway - T Cell Receptor Signaling Pathway
h_mapkPathway - MAPKinase Signaling Pathway
h_tnfr1Pathway - TNFR1 Signaling Pathway
h_egfPathway - EGF Signaling Pathway
h_At1rPathway - Angiotensin II mediated activation of JNK Pathway via Pyk2 dependent signaling
h_fasPathway - FAS signaling pathway ( CD95 )
h_ceramidePathway - Ceramide Signaling Pathway
h_pyk2Pathway - Links between Pyk2 and Map Kinases
h_stressPathway - TNF/Stress Related Signaling
h_tollPathway - Toll-Like Receptor Pathway
h_gleevecpathway - Inhibition of Cellular Proliferation by Gleevec
h_keratinocytePathway - Keratinocyte Differentiation
h_p38mapkPathway - p38 MAPK Signaling Pathway
h_pdgfPathway - PDGF Signaling Pathway

Reactome (by CSHL, EBI, and GO)

Protein P45985 (Reactome details) participates in the following event(s):

R-HSA-2730896 Phosphorylation of MEK4 by MEKK1
R-HSA-3229152 MAP3K5 (ASK1) phosphorylates MAP2K4 (SEK1)
R-HSA-5211391 Anthrax LF cleaves target cell MAP2K4 (MEK4)
R-HSA-450337 Activated TAK1 phosphorylates MKK4/MKK7
R-HSA-451649 TPL2 phosphorylates MEK1, SEK1
R-HSA-168162 Phosphorylation of human JNKs by activated MKK4/MKK7
R-HSA-2871796 FCERI mediated MAPK activation
R-HSA-2559580 Oxidative Stress Induced Senescence
R-HSA-5210891 Uptake and function of anthrax toxins
R-HSA-450321 JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1
R-HSA-5684264 MAP3K8 (TPL2)-dependent MAPK1/3 activation
R-HSA-2454202 Fc epsilon receptor (FCERI) signaling
R-HSA-2559583 Cellular Senescence
R-HSA-5339562 Uptake and actions of bacterial toxins
R-HSA-450294 MAP kinase activation
R-HSA-9020702 Interleukin-1 signaling
R-HSA-168249 Innate Immune System
R-HSA-2262752 Cellular responses to stress
R-HSA-5663205 Infectious disease
R-HSA-166058 MyD88:Mal cascade initiated on plasma membrane
R-HSA-168164 Toll Like Receptor 3 (TLR3) Cascade
R-HSA-448424 Interleukin-17 signaling
R-HSA-937061 TRIF(TICAM1)-mediated TLR4 signaling
R-HSA-975138 TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation
R-HSA-975871 MyD88 cascade initiated on plasma membrane
R-HSA-446652 Interleukin-1 family signaling
R-HSA-168256 Immune System
R-HSA-8953897 Cellular responses to external stimuli
R-HSA-1643685 Disease
R-HSA-166016 Toll Like Receptor 4 (TLR4) Cascade
R-HSA-168179 Toll Like Receptor TLR1:TLR2 Cascade
R-HSA-168188 Toll Like Receptor TLR6:TLR2 Cascade
R-HSA-168898 Toll-Like Receptors Cascades
R-HSA-449147 Signaling by Interleukins
R-HSA-166166 MyD88-independent TLR4 cascade
R-HSA-975155 MyD88 dependent cascade initiated on endosome
R-HSA-168142 Toll Like Receptor 10 (TLR10) Cascade
R-HSA-168176 Toll Like Receptor 5 (TLR5) Cascade
R-HSA-181438 Toll Like Receptor 2 (TLR2) Cascade
R-HSA-1280215 Cytokine Signaling in Immune system
R-HSA-168138 Toll Like Receptor 9 (TLR9) Cascade
R-HSA-168181 Toll Like Receptor 7/8 (TLR7/8) Cascade

-  Other Names for This Gene
  Alternate Gene Symbols: B2R7N7, B3KYB2, D3DTS5, JNKK1, MEK4, MKK4, MP2K4_HUMAN, NM_003010, NP_003001, P45985, PRKMK4, Q5U0B8, Q6FHX4, Q6P9H2, Q6PIE6, SEK1, SERK1, SKK1
UCSC ID: uc002gnj.3
RefSeq Accession: NM_003010
Protein: P45985 (aka MP2K4_HUMAN or MPK4_HUMAN)
CCDS: CCDS11162.1, CCDS62095.1

-  Gene Model Information
category: coding nonsense-mediated-decay: no RNA accession: NM_003010.2
exon count: 11CDS single in 3' UTR: no RNA size: 3752
ORF size: 1200CDS single in intron: no Alignment % ID: 100.00
txCdsPredict score: 2600.00frame shift in genome: no % Coverage: 99.76
has start codon: yes stop codon in genome: no # of Alignments: 1
has end codon: yes retained intron: no # AT/AC introns 0
selenocysteine: no end bleed into intron: 0# strange splices: 0
Click here for a detailed description of the fields of the table above.

-  Methods, Credits, and Use Restrictions
  Click here for details on how this gene model was made and data restrictions if any.