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MAPK4 (mitogen-activated protein kinase 4)

Written2008-03Sylvain Meloche
Institut de Recherche en Immunologie et Cancérologie, Université de Montréal, Montréal, Québec H3C 3J7, Canada
Updated2017-03Simon Mathien, Sylvain Meloche
Institute of Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec H3C 3J7, Canada;;

Abstract Review on MAPK4, with data on DNA, on the protein encoded, and where the gene is implicated.

Keywords MAPK4; ERK4; Kinase; signaling pathway; RAS-RAF-MAPK pathway

(Note : for Links provided by Atlas : click)


Alias_symbol (synonym)Erk3-related
Other aliasextracellular signal-regulated kinase 4
LocusID (NCBI) 5596
Atlas_Id 41293
Location 18q21.1  [Link to chromosome band 18q21]
Location_base_pair Starts at 50560087 and ends at 50731826 bp from pter ( according to hg19-Feb_2009)  [Mapping MAPK4.png]
Local_order The MAPK4 gene is located between the genes SKA1 (C18orf24) and MRO on chromosome 18
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
RTTN (18q22.2) / MAPK4 (18q21.1)


  Figure 1. Genomic organization of the MAPK4 gene on chromosome 18.
Description The MAPK4 gene spans 171.7 kb on the long arm of chromosome 18 and is transcribed in the centromere-to-telomere orientation. The gene is composed of 6 exons with the translation initiation codon located in exon 2. The first two exons are separated by a long intron of 102.8 kb.
Transcription The MAPK4 transcribed mRNA has 4,736 bp. No splice variants have been reported.
Pseudogene None.


  Figure 2. Schematic representation of the ERK4 protein structure. Kinase, catalytic kinase domain; C34 conserved region in ERK3 and ERK4; SEG, activation loop motif containing the regulatory phosphorylation residue Ser186.
Description Extracellular signal-regulated kinase 4 (ERK4) is an atypical member of the mitogen-activated protein (MAP) kinase family of serine/threonine kinases. The human ERK4 protein is made of 587 amino acids and contains a typical kinase domain located at the N-terminal extremity. Another region with homology to the MAP kinase ERK3 (C34 domain) has been identified after the kinase domain. The function of the C34 domain is unknown.
Expression MAPK4 mRNA is expressed to the highest level in the brain. Other sites of expression include the heart, lung, kidney, intestine, pancreas, parathyroid gland, prostate, thymus, ovary, eye and ear.
Localisation ERK4 localizes to the cytoplasm and nucleus of a variety of cultured cells.
Function Little is known about the regulation and functions of ERK4. The only known substrate of ERK4 is the protein kinase MAPKAPK5 (MK5).
Homology ERK4 display 73% amino acid identity with ERK3 in the kinase domain. ERK4 and ERK3 define a distinct subfamily of MAP kinases.


Note The R114C/H mutation has been reported in several types of cancer (colorectal adenocarcinoma, diffuse glioma, non-small cell lung cancer, cutaneous melanoma, stomach adenocarcinoma, uterine carcinosarcoma). The functional impact of this mutation on the expression or activity of ERK4 is not known.

Implicated in

Entity Cancer
Note Analysis of copy number alterations (CNAs) from TCGA datasets show that MAPK4 gene is deleted in several adenocarcinomas, includingprostate, esophageal, stomach and lung adenocarcinomas. Also, a chromosomal subregion containing the MAPK4 gene is deleted with high frequency (23%) in pancreatic adenocarcinoma. On the other hand, MAPK4 is amplified with low frequency in neuroendocrine prostate cancer, diffuse large B-cell lymphoma and sarcomas. Interrogation of the Oncomine database reveals that expression of MAPK4 mRNA is downregulated in breast and prostate cancer. Consistent with CNA analysis, MAPK4 mRNA is upregulated in diffuse large B-cell lymphoma.


Regulation of MAPK-activated protein kinase 5 activity and subcellular localization by the atypical MAPK ERK4/MAPK4.
Aberg E, Perander M, Johansen B, Julien C, Meloche S, Keyse SM, Seternes OM.
J Biol Chem. 2006 Nov 17;281(46):35499-510.
PMID 16971392
Atypical mitogen-activated protein kinases: structure, regulation and functions.
Coulombe P, Meloche S.
Biochim Biophys Acta. 2007 Aug;1773(8):1376-87. (REVIEW)
PMID 17161475
Heterogeneous expression of four MAP kinase isoforms in human tissues.
Gonzalez FA, Raden DL, Rigby MR, Davis RJ.
FEBS Lett. 1992 Jun 15;304(2-3):170-8.
PMID 1319925
Characterization of the atypical MAPK ERK4 and its activation of the MAPK-activated protein kinase MK5.
Kant S, Schumacher S, Singh MK, Kispert A, Kotlyarov A, Gaestel M.
J Biol Chem. 2006 Nov 17;281(46):35511-9.
PMID 16973613
Genome-wide aberrations in pancreatic adenocarcinoma.
Nowak NJ, Gaile D, Conroy JM, McQuaid D, Cowell J, Carter R, Goggins MG, Hruban RH, Maitra A.
Cancer Genet Cytogenet. 2005 Aug;161(1):36-50.
PMID 16080956
The protein kinase ERK3 is encoded by a single functional gene: genomic analysis of the ERK3 gene family.
Turgeon B, Lang BF, Meloche S.
Genomics. 2002 Dec;80(6):673-80.
PMID 12504858


This paper should be referenced as such :
Simon Mathien, Sylvain Meloche
MAPK4 (mitogen-activated protein kinase 4)
Atlas Genet Cytogenet Oncol Haematol. 2017;21(12):441-442.
Free journal version : [ pdf ]   [ DOI ]
On line version :
History of this paper:
Meloche, S. MAPK4 (mitogen-activated protein kinase 4). Atlas Genet Cytogenet Oncol Haematol. 2009;13(1):18-19.

Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ]
  t(18;18)(q21;q22) RTTN/MAPK4

External links

HGNC (Hugo)MAPK4   6878
Entrez_Gene (NCBI)MAPK4  5596  mitogen-activated protein kinase 4
AliasesERK-4; ERK4; PRKM4; p63-MAPK; 
GeneCards (Weizmann)MAPK4
Ensembl hg19 (Hinxton)ENSG00000141639 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000141639 [Gene_View]  ENSG00000141639 [Sequence]  chr18:50560087-50731826 [Contig_View]  MAPK4 [Vega]
ICGC DataPortalENSG00000141639
TCGA cBioPortalMAPK4
Genatlas (Paris)MAPK4
SOURCE (Princeton)MAPK4
Genetics Home Reference (NIH)MAPK4
Genomic and cartography
GoldenPath hg38 (UCSC)MAPK4  -     chr18:50560087-50731826 +  18q21.1-q21.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)MAPK4  -     18q21.1-q21.2   [Description]    (hg19-Feb_2009)
GoldenPathMAPK4 - 18q21.1-q21.2 [CytoView hg19]  MAPK4 - 18q21.1-q21.2 [CytoView hg38]
Mapping of homologs : NCBIMAPK4 [Mapview hg19]  MAPK4 [Mapview hg38]
Gene and transcription
Genbank (Entrez)AA771957 AI088913 AK293818 AK295058 AK303601
RefSeq transcript (Entrez)NM_001292039 NM_001292040 NM_002747
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)MAPK4
Alternative Splicing GalleryENSG00000141639
Gene ExpressionMAPK4 [ NCBI-GEO ]   MAPK4 [ EBI - ARRAY_EXPRESS ]   MAPK4 [ SEEK ]   MAPK4 [ MEM ]
Gene Expression Viewer (FireBrowse)MAPK4 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)5596
GTEX Portal (Tissue expression)MAPK4
Human Protein AtlasENSG00000141639-MAPK4 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP31152   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP31152  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP31152
Splice isoforms : SwissVarP31152
Catalytic activity : Enzyme2.7.11.24 [ Enzyme-Expasy ] [ IntEnz-EBI ] [ BRENDA ] [ KEGG ]   [ MEROPS ]
Domaine pattern : Prosite (Expaxy)PROTEIN_KINASE_ATP (PS00107)    PROTEIN_KINASE_DOM (PS50011)    PROTEIN_KINASE_ST (PS00108)   
Domains : Interpro (EBI)Kinase-like_dom_sf    MAPK_ERK3/4    Prot_kinase_dom    Protein_kinase_ATP_BS    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)MAPK4
DMDM Disease mutations5596
Blocks (Seattle)MAPK4
Human Protein Atlas [tissue]ENSG00000141639-MAPK4 [tissue]
Peptide AtlasP31152
IPIIPI00010156   IPI01012827   
Protein Interaction databases
IntAct (EBI)P31152
Ontologies - Pathways
Ontology : AmiGOMAPK cascade  protein serine/threonine kinase activity  MAP kinase activity  protein binding  ATP binding  nucleus  nucleus  nucleoplasm  cytoplasm  cytoplasm  cytosol  protein phosphorylation  cell cycle  regulation of gene expression  protein kinase binding  intracellular signal transduction  protein homodimerization activity  protein heterodimerization activity  
Ontology : EGO-EBIMAPK cascade  protein serine/threonine kinase activity  MAP kinase activity  protein binding  ATP binding  nucleus  nucleus  nucleoplasm  cytoplasm  cytoplasm  cytosol  protein phosphorylation  cell cycle  regulation of gene expression  protein kinase binding  intracellular signal transduction  protein homodimerization activity  protein heterodimerization activity  
REACTOMEP31152 [protein]
REACTOME PathwaysR-HSA-5687128 [pathway]   
NDEx NetworkMAPK4
Atlas of Cancer Signalling NetworkMAPK4
Wikipedia pathwaysMAPK4
Orthology - Evolution
GeneTree (enSembl)ENSG00000141639
Phylogenetic Trees/Animal Genes : TreeFamMAPK4
Homologs : HomoloGeneMAPK4
Homology/Alignments : Family Browser (UCSC)MAPK4
Gene fusions - Rearrangements
Fusion : MitelmanRTTN/MAPK4 [18q22.2/18q21.1]  [t(18;18)(q21;q22)]  
Fusion PortalRTTN 18q22.2 MAPK4 18q21.1 GBM
Fusion : Fusion_HubCNPY1--MAPK4    MAPK4--PARK2    MAPK4--RTTN    MAPK4--SMAD4    ORC4--MAPK4    RTTN--MAPK4   
Fusion : QuiverMAPK4
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerMAPK4 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)MAPK4
Exome Variant ServerMAPK4
ExAC (Exome Aggregation Consortium)ENSG00000141639
GNOMAD BrowserENSG00000141639
Varsome BrowserMAPK4
Genetic variants : HAPMAP5596
Genomic Variants (DGV)MAPK4 [DGVbeta]
DECIPHERMAPK4 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisMAPK4 
ICGC Data PortalMAPK4 
TCGA Data PortalMAPK4 
Broad Tumor PortalMAPK4
OASIS PortalMAPK4 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICMAPK4  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DMAPK4
Mutations and Diseases : HGMDMAPK4
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 MAPK4
DgiDB (Drug Gene Interaction Database)MAPK4
DoCM (Curated mutations)MAPK4 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)MAPK4 (select a term)
NCG5 (London)MAPK4
Cancer3DMAPK4(select the gene name)
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Genetic Testing Registry MAPK4
NextProtP31152 [Medical]
Target ValidationMAPK4
Huge Navigator MAPK4 [HugePedia]
snp3D : Map Gene to Disease5596
BioCentury BCIQMAPK4
Clinical trials, drugs, therapy
Protein Interactions : CTD5596
Pharm GKB GenePA30623
Pharm GKB PathwaysPA2032   
Clinical trialMAPK4
canSAR (ICR)MAPK4 (select the gene name)
DataMed IndexMAPK4
PubMed24 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Tue Jun 30 20:45:30 CEST 2020

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