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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; simon.mathien@umontreal.ca; sylvain.meloche@umontreal.ca

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)

Identity

Alias_namesPRKM4
Alias_symbol (synonym)Erk3-related
Erk4
Other aliasextracellular signal-regulated kinase 4
ERK4
pP63mapk
ERK3-related
HGNC (Hugo) MAPK4
LocusID (NCBI) 5596
Atlas_Id 41293
Location 18q21.1  [Link to chromosome band 18q21]
Location_base_pair Starts at 48086484 and ends at 48258196 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 2016)
RTTN (18q22.2) / MAPK4 (18q21.1)

DNA/RNA

 
  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.

Protein

 
  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.

Mutations

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

Note
  
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.
  

Bibliography

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
 

Citation

This paper should be referenced as such :
Mathien S, Meloche S
MAPK4 (mitogen-activated protein kinase 4);
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/MAPK4ID41293ch18q21.html
History of this paper:
Meloche, S. MAPK4 (mitogen-activated protein kinase 4). Atlas Genet Cytogenet Oncol Haematol. 2009;13(1):18-19.
http://documents.irevues.inist.fr/bitstream/handle/2042/44379/03-2008-MAPK4ID41293ch18q21.pdf


External links

Nomenclature
HGNC (Hugo)MAPK4   6878
Cards
AtlasMAPK4ID41293ch18q21
Entrez_Gene (NCBI)MAPK4  5596  mitogen-activated protein kinase 4
AliasesERK-4; ERK4; PRKM4; p63-MAPK; 
p63MAPK
GeneCards (Weizmann)MAPK4
Ensembl hg19 (Hinxton)ENSG00000141639 [Gene_View]  chr18:48086484-48258196 [Contig_View]  MAPK4 [Vega]
Ensembl hg38 (Hinxton)ENSG00000141639 [Gene_View]  chr18:48086484-48258196 [Contig_View]  MAPK4 [Vega]
ICGC DataPortalENSG00000141639
TCGA cBioPortalMAPK4
AceView (NCBI)MAPK4
Genatlas (Paris)MAPK4
WikiGenes5596
SOURCE (Princeton)MAPK4
Genetics Home Reference (NIH)MAPK4
Genomic and cartography
GoldenPath hg19 (UCSC)MAPK4  -     chr18:48086484-48258196 +  18q21.1   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)MAPK4  -     18q21.1   [Description]    (hg38-Dec_2013)
EnsemblMAPK4 - 18q21.1 [CytoView hg19]  MAPK4 - 18q21.1 [CytoView hg38]
Mapping of homologs : NCBIMAPK4 [Mapview hg19]  MAPK4 [Mapview hg38]
OMIM176949   
Gene and transcription
Genbank (Entrez)AA771957 AI088913 AK293818 AK295058 AK303601
RefSeq transcript (Entrez)NM_001292039 NM_001292040 NM_002747
RefSeq genomic (Entrez)NC_000018 NC_018929 NT_010966 NW_004929410
Consensus coding sequences : CCDS (NCBI)MAPK4
Cluster EST : UnigeneHs.433728 [ NCBI ]
CGAP (NCI)Hs.433728
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]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)5596
GTEX Portal (Tissue expression)MAPK4
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 ]   2.7.11.242.7.11.24 [ IntEnz-EBI ]   2.7.11.24 [ BRENDA ]   2.7.11.24 [ KEGG ]   
PhosPhoSitePlusP31152
Domaine pattern : Prosite (Expaxy)PROTEIN_KINASE_ATP (PS00107)    PROTEIN_KINASE_DOM (PS50011)    PROTEIN_KINASE_ST (PS00108)   
Domains : Interpro (EBI)Kinase-like_dom    MAPK_ERK3/4    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)MAPK4
DMDM Disease mutations5596
Blocks (Seattle)MAPK4
SuperfamilyP31152
Human Protein AtlasENSG00000141639
Peptide AtlasP31152
HPRD01497
IPIIPI00010156   IPI01012827   
Protein Interaction databases
DIP (DOE-UCLA)P31152
IntAct (EBI)P31152
FunCoupENSG00000141639
BioGRIDMAPK4
STRING (EMBL)MAPK4
ZODIACMAPK4
Ontologies - Pathways
QuickGOP31152
Ontology : AmiGOMAPK cascade  MAPK cascade  protein serine/threonine kinase activity  MAP kinase activity  protein binding  ATP binding  nucleus  nucleoplasm  cytoplasm  cytosol  protein phosphorylation  cell cycle  protein kinase binding  protein homodimerization activity  protein heterodimerization activity  
Ontology : EGO-EBIMAPK cascade  MAPK cascade  protein serine/threonine kinase activity  MAP kinase activity  protein binding  ATP binding  nucleus  nucleoplasm  cytoplasm  cytosol  protein phosphorylation  cell cycle  protein kinase binding  protein homodimerization activity  protein heterodimerization activity  
Pathways : BIOCARTAMAPKinase Signaling Pathway [Genes]   
REACTOMEP31152 [protein]
REACTOME Pathways5687128 [pathway]   
NDEx NetworkMAPK4
Atlas of Cancer Signalling NetworkMAPK4
Wikipedia pathwaysMAPK4
Orthology - Evolution
OrthoDB5596
GeneTree (enSembl)ENSG00000141639
Phylogenetic Trees/Animal Genes : TreeFamMAPK4
HOVERGENP31152
HOGENOMP31152
Homologs : HomoloGeneMAPK4
Homology/Alignments : Family Browser (UCSC)MAPK4
Gene fusions - Rearrangements
Fusion : MitelmanRTTN/MAPK4 [18q22.2/18q21.1]  [t(18;18)(q21;q22)]  
Fusion: TCGARTTN 18q22.2 MAPK4 18q21.1 GBM
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerMAPK4 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)MAPK4
dbVarMAPK4
ClinVarMAPK4
1000_GenomesMAPK4 
Exome Variant ServerMAPK4
ExAC (Exome Aggregation Consortium)MAPK4 (select the gene name)
Genetic variants : HAPMAP5596
Genomic Variants (DGV)MAPK4 [DGVbeta]
DECIPHER (Syndromes)18:48086484-48258196  ENSG00000141639
CONAN: Copy Number AnalysisMAPK4 
Mutations
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]  
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)
intoGenMAPK4
NCG5 (London)MAPK4
Cancer3DMAPK4(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM176949   
Orphanet
MedgenMAPK4
Genetic Testing Registry MAPK4
NextProtP31152 [Medical]
TSGene5596
GENETestsMAPK4
Huge Navigator MAPK4 [HugePedia]
snp3D : Map Gene to Disease5596
BioCentury BCIQMAPK4
ClinGenMAPK4
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD5596
Chemical/Pharm GKB GenePA30623
Clinical trialMAPK4
Miscellaneous
canSAR (ICR)MAPK4 (select the gene name)
Probes
Litterature
PubMed21 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineMAPK4
EVEXMAPK4
GoPubMedMAPK4
iHOPMAPK4
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Tue Apr 25 18:42:35 CEST 2017

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