MAPK4 (mitogen-activated protein kinase 4)

2017-03-01 Simon Mathien , Sylvain Meloche Affiliation

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

MAPK4

LOCATION

18q21.1

LOCUSID

5596

ALIAS

ERK-4,ERK4,PRKM4,p63-MAPK,p63MAPK

FUSION GENES

Show Gene Fusions

Abstract

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

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.

Proteins

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.

Article Bibliography

Pubmed ID	Last Year	Title	Authors
16971392	2006	Regulation of MAPK-activated protein kinase 5 activity and subcellular localization by the atypical MAPK ERK4/MAPK4.	Aberg E et al
17161475	2007	Atypical mitogen-activated protein kinases: structure, regulation and functions.	Coulombe P et al
1319925	1992	Heterogeneous expression of four MAP kinase isoforms in human tissues.	Gonzalez FA et al
16973613	2006	Characterization of the atypical MAPK ERK4 and its activation of the MAPK-activated protein kinase MK5.	Kant S et al
16080956	2005	Genome-wide aberrations in pancreatic adenocarcinoma.	Nowak NJ et al
12504858	2002	The 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 ID	Transcript ID	Uniprot
ENSG00000141639	ENST00000400384	P31152
ENSG00000141639	ENST00000540640	B4DEW2
ENSG00000141639	ENST00000588540	K7EN18
ENSG00000141639	ENST00000592595	K7ELV1

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Signal Transduction	REACTOME	R-HSA-162582
MAPK family signaling cascades	REACTOME	R-HSA-5683057
MAPK6/MAPK4 signaling	REACTOME	R-HSA-5687128
IL-17 signaling pathway	KEGG	ko04657
IL-17 signaling pathway	KEGG	hsa04657

PharmGKB

Entity ID	Name	Type	Evidence	Association	PMIDs
PA284	MAP2K7	Gene	Pathway	associated	20124951
PA30584	MAP2K1	Gene	Pathway	associated	20124951
PA30587	MAP2K2	Gene	Pathway	associated	20124951
PA30588	MAP2K3	Gene	Pathway	associated	20124951
PA30589	MAP2K4	Gene	Pathway	associated	20124951
PA30590	MAP2K5	Gene	Pathway	associated	20124951
PA30591	MAP2K6	Gene	Pathway	associated	20124951
PA7000	sorafenib	Chemical	Pathway	associated	20124951

References

Pubmed ID	Year	Title	Citations
37494889	2024	Genetic Polymorphisms of rs9949644 in MAPK4 Are Associated with Clinical Response to Methotrexate in Patients with Psoriasis.	0
37494889	2024	Genetic Polymorphisms of rs9949644 in MAPK4 Are Associated with Clinical Response to Methotrexate in Patients with Psoriasis.	0
37531320	2023	Cooperative activation of PDK1 and AKT by MAPK4 enhances cancer growth and resistance to therapy.	0
38279470	2023	LINC00467 enhanced the proliferative, migratory and invasive ability of breast cancer cells by targeting miR-18a/b-5p/MAPK4 axis.	0
37531320	2023	Cooperative activation of PDK1 and AKT by MAPK4 enhances cancer growth and resistance to therapy.	0
38279470	2023	LINC00467 enhanced the proliferative, migratory and invasive ability of breast cancer cells by targeting miR-18a/b-5p/MAPK4 axis.	0
35017531	2022	MAPK4 promotes triple negative breast cancer growth and reduces tumor sensitivity to PI3K blockade.	11
36073321	2022	Promotor methylation status of MAPK4 is a novel epigenetic biomarker for prognosis of recurrence in patients with thymic epithelial tumors.	4
35017531	2022	MAPK4 promotes triple negative breast cancer growth and reduces tumor sensitivity to PI3K blockade.	11
36073321	2022	Promotor methylation status of MAPK4 is a novel epigenetic biomarker for prognosis of recurrence in patients with thymic epithelial tumors.	4
33586682	2021	MAPK4 promotes prostate cancer by concerted activation of androgen receptor and AKT.	26
33586682	2021	MAPK4 promotes prostate cancer by concerted activation of androgen receptor and AKT.	26
32711558	2020	MAPK4 deletion enhances radiation effects and triggers synergistic lethality with simultaneous PARP1 inhibition in cervical cancer.	12
33155194	2020	MiR-127-3p inhibits proliferation of ovarian cancer in rats through down-regulating MAPK4.	6
32711558	2020	MAPK4 deletion enhances radiation effects and triggers synergistic lethality with simultaneous PARP1 inhibition in cervical cancer.	12

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-(mitogen-activated-protein-kinase-4)

Historical Card

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

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