MAPK6 (mitogen-activated protein kinase 6)

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
15q21.2
LOCUSID
ALIAS
ERK3,HsT17250,PRKM6,p97MAPK
FUSION GENES

Abstract

Review on MAPK6, with data on DNA, on the protein encoded, and where the gene is implicated.

DNA/RNA

Atlas Image
Genomic organization of the MAPK6 gene on chromosome 15.

Description

The MAPK6 gene spans 47.01 kb on the long arm of chromosome 15 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 26.45 kb.

Transcription

The MAPK6 transcribed mRNA has 4,186 bp. No splice variants have been reported.

Pseudogene

Database analysis reveals the presence of six MAPK6 pseudogenes localized on four different chromosomes: MAPK6PS1 (8q11.23), MAPK6PS2 (21q21.1), MAPK6PS3 (13q14.13), MAPK6PS4 (8q11.1), MAPK6PS5 (8q23.1) and MAPK6PS6 (10q11.23). All six loci contain intronless copies of MAPK6 and display the features of processed pseudogenes.

Proteins

Atlas Image
Schematic representation of the ERK3 protein structure. Kinase, catalytic kinase domain; C34 conserved region in ERK3 and ERK4; SEG, activation loop motif containing the regulatory phosphorylation residue Ser189.

Description

Extracellular signal-regulated kinase 3 (ERK3) is an atypical member of the mitogen-activated protein (MAP) kinase family of serine/threonine kinases. The human ERK3 protein is made of 721 amino acids and contains a typical kinase domain located at the N-terminal extremity. Another region with homology to the MAP kinase ERK4 (C34 domain) has been identified after the kinase domain. The function of the C34 domain is unknown.

Expression

MAPK6 mRNA is expressed ubiquitously. The highest levels of expression are observed in the skeletal muscle and brain. ERK3 is a highly unstable protein, with a half-life of less than one hour, that is constitutively degraded by the ubiquitin-proteasome pathway.

Localisation

ERK3 localizes to the cytoplasm and nucleus of a variety of cultured cells.

Function

Little is known about the regulation and functions of ERK3. Recent studies suggest a potential involvement of the kinase in the control of cell differentiation, cytoskeletal remodelling, cell migration and invasion, DNA repair, and immune response. The best-characterized and validated substrate of ERK3 is the protein kinase MAPKAPK5 (MK5).

Homology

ERK3 display 73% amino acid identity with ERK4 in the kinase domain. ERK4 and ERK3 define a distinct subfamily of MAP kinases.

Mutations

Note

No recurrent mutation in the MAPK6 gene has been reported in cancer.

Implicated in

Entity name
Cancer
Note
Studies have documented the upregulation of MAPK6 mRNA in squamous cell carcinomas of the skin, squamous cell lung carcinoma, and tongue squamous cell carcinoma. Expression of MAPK6 mRNA is also increased in salivary adenoid cystic carcinoma, adrenocortical carcinoma, T-cell acute lymphoblastic leukemia, and acute myeloid leukemia. In lymphomas, reports have suggested an increase of MAPK6 expression in Burkitts lymphoma and a decrease in Hodgkins lymphoma. Downregulation of MAPK6 mRNA level has also been observed in cutaneous melanoma, (colorectal adenocarcinomaand esophageal adenocarcinoma. The significance of these changes remains to be investigated.

Bibliography

Pubmed IDLast YearTitleAuthors
20322901991ERKs: a family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF.Boulton TG et al
225089862012The extracellular signal-regulated kinase 3 (mitogen-activated protein kinase 6 [MAPK6])-MAPK-activated protein kinase 5 signaling complex regulates septin function and dendrite morphology.Brand F et al
171614752007Atypical mitogen-activated protein kinases: structure, regulation and functions.Coulombe P et al
150673372004Induction of p97MAPK expression regulates collagen mediated inhibition of proliferation and migration in human squamous cell carcinoma lines.Crowe DL et al
225054542012ERK3 signals through SRC-3 coactivator to promote human lung cancer cell invasion.Long W et al
250025292014The catalytic activity of the mitogen-activated protein kinase extracellular signal-regulated kinase 3 is required to sustain CD4+ CD8+ thymocyte survival.Marquis M et al
88759981996Primary structure, expression and chromosomal locus of a human homolog of rat ERK3.Meloche S et al
155383862004Scaffolding by ERK3 regulates MK5 in development.Schumacher S et al
155779432004Activation of MK5/PRAK by the atypical MAP kinase ERK3 defines a novel signal transduction pathway.Seternes OM et al
125048582002The protein kinase ERK3 is encoded by a single functional gene: genomic analysis of the ERK3 gene family.Turgeon B et al
106572542000Cloning and characterization of mouse extracellular-signal-regulated protein kinase 3 as a unique gene product of 100 kDa.Turgeon B et al
245856352014ERK3 promotes endothelial cell functions by upregulating SRC-3/SP1-mediated VEGFR2 expression.Wang W et al
79691571994Cloning and characterization of p97MAPK, a novel human homolog of rat ERK-3.Zhu AX et al

Other Information

Locus ID:

NCBI: 5597
MIM: 602904
HGNC: 6879
Ensembl: ENSG00000069956

Variants:

dbSNP: 5597
ClinVar: 5597
TCGA: ENSG00000069956
COSMIC: MAPK6

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000069956ENST00000261845Q16659

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

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA284MAP2K7GenePathwayassociated20124951
PA30584MAP2K1GenePathwayassociated20124951
PA30587MAP2K2GenePathwayassociated20124951
PA30588MAP2K3GenePathwayassociated20124951
PA30589MAP2K4GenePathwayassociated20124951
PA30590MAP2K5GenePathwayassociated20124951
PA30591MAP2K6GenePathwayassociated20124951
PA7000sorafenibChemicalPathwayassociated20124951

References

Pubmed IDYearTitleCitations
152264182004N-Terminal ubiquitination of extracellular signal-regulated kinase 3 and p21 directs their degradation by the proteasome.46
128080962003Rapid turnover of extracellular signal-regulated kinase 3 by the ubiquitin-proteasome pathway defines a novel paradigm of mitogen-activated protein kinase regulation during cellular differentiation.44
225054542012ERK3 signals through SRC-3 coactivator to promote human lung cancer cell invasion.39
213172882011Identification of the atypical MAPK Erk3 as a novel substrate for p21-activated kinase (Pak) activity.27
182352252008A functional link between the human cell cycle-regulatory phosphatase Cdc14A and the atypical mitogen-activated kinase Erk3.23
282418492017Metformin potentiates the effect of arsenic trioxide suppressing intrahepatic cholangiocarcinoma: roles of p38 MAPK, ERK3, and mTORC1.15
267017252016ERK3 regulates TDP2-mediated DNA damage response and chemoresistance in lung cancer cells.12
245856352014ERK3 promotes endothelial cell functions by upregulating SRC-3/SP1-mediated VEGFR2 expression.11
290955262019NEAT1/hsa-mir-98-5p/MAPK6 axis is involved in non-small-cell lung cancer development.11
169643792006Regulation of ERK3/MAPK6 expression by BRAF.8

Citation

Simon Mathien ; Sylvain Meloche

MAPK6 (mitogen-activated protein kinase 6)

Atlas Genet Cytogenet Oncol Haematol. 2017-03-01

Online version: http://atlasgeneticsoncology.org/gene/43349/mapk6

Historical Card

2008-08-01 MAPK6 (mitogen-activated protein kinase 6) by  Sylvain Meloche 

Institut de Recherche en Immunologie et Cancerologie, Universite de Montreal, Montreal, Quebec H3C 3J7, Canada