MAPK4 (mitogen-activated protein kinase 4)

2017-03-01   Simon 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

Identity

HGNC
LOCATION
18q21.1
LOCUSID
ALIAS
ERK-4,ERK4,PRKM4,p63-MAPK,p63MAPK
FUSION GENES

Abstract

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

DNA/RNA

Atlas Image
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.

Proteins

Atlas Image
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

Entity name
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

Pubmed IDLast YearTitleAuthors
169713922006Regulation of MAPK-activated protein kinase 5 activity and subcellular localization by the atypical MAPK ERK4/MAPK4.Aberg E et al
171614752007Atypical mitogen-activated protein kinases: structure, regulation and functions.Coulombe P et al
13199251992Heterogeneous expression of four MAP kinase isoforms in human tissues.Gonzalez FA et al
169736132006Characterization of the atypical MAPK ERK4 and its activation of the MAPK-activated protein kinase MK5.Kant S et al
160809562005Genome-wide aberrations in pancreatic adenocarcinoma.Nowak NJ et al
125048582002The protein kinase ERK3 is encoded by a single functional gene: genomic analysis of the ERK3 gene family.Turgeon B et al

Other Information

Locus ID:

NCBI: 5596
MIM: 176949
HGNC: 6878
Ensembl: ENSG00000141639

Variants:

dbSNP: 5596
ClinVar: 5596
TCGA: ENSG00000141639
COSMIC: MAPK4

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000141639ENST00000400384P31152
ENSG00000141639ENST00000540640B4DEW2
ENSG00000141639ENST00000588540K7EN18
ENSG00000141639ENST00000592595K7ELV1

Expression (GTEx)

0
10
20
30
40
50
60

Pathways

PathwaySourceExternal ID
Signal TransductionREACTOMER-HSA-162582
MAPK family signaling cascadesREACTOMER-HSA-5683057
MAPK6/MAPK4 signalingREACTOMER-HSA-5687128
IL-17 signaling pathwayKEGGko04657
IL-17 signaling pathwayKEGGhsa04657

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA284MAP2K7GenePathwayassociated20124951
PA30584MAP2K1GenePathwayassociated20124951
PA30587MAP2K2GenePathwayassociated20124951
PA30588MAP2K3GenePathwayassociated20124951
PA30589MAP2K4GenePathwayassociated20124951
PA30590MAP2K5GenePathwayassociated20124951
PA30591MAP2K6GenePathwayassociated20124951
PA7000sorafenibChemicalPathwayassociated20124951

References

Pubmed IDYearTitleCitations
169736132006Characterization of the atypical MAPK ERK4 and its activation of the MAPK-activated protein kinase MK5.33
211778702011Activation loop phosphorylation of ERK3/ERK4 by group I p21-activated kinases (PAKs) defines a novel PAK-ERK3/4-MAPK-activated protein kinase 5 signaling pathway.26
194739792009Docking of PRAK/MK5 to the atypical MAPKs ERK3 and ERK4 defines a novel MAPK interaction motif.19
306886592019MAPK4 overexpression promotes tumor progression via noncanonical activation of AKT/mTOR signaling.6

Citation

Simon Mathien ; Sylvain Meloche

MAPK4 (mitogen-activated protein kinase 4)

Atlas Genet Cytogenet Oncol Haematol. 2017-03-01

Online version: http://atlasgeneticsoncology.org/gene/41293/mapk4

Historical Card

2008-03-01 MAPK4 (mitogen-activated protein kinase 4) by  Sylvain Meloche 

Institut de Recherche en Immunologie et Cancérologie, Université de Montréal, Montréal, Québec H3C 3J7, Canada