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MAPK6 (mitogen-activated protein kinase 6)

Written2008-08Sylvain Meloche
Institut de Recherche en Immunologie et Cancerologie, Universite de Montreal, Montreal, Quebec 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 MAPK6, with data on DNA, on the protein encoded, and where the gene is implicated.

Keywords MAPK4; ERK3; Kinase; signaling pathway; RAS-RAF-MAPK pathway

(Note : for Links provided by Atlas : click)

Identity

Alias_namesPRKM6
Alias_symbol (synonym)ERK3
p97MAPK
HsT17250
Other alias
HGNC (Hugo) MAPK6
LocusID (NCBI) 5597
Atlas_Id 43349
Location 15q21.2  [Link to chromosome band 15q21]
Location_base_pair Starts at 52019214 and ends at 52066265 bp from pter ( according to hg19-Feb_2009)  [Mapping MAPK6.png]
Local_order The MAPK6 gene is located between the genes LEO1 and BCL2L10 on chromosome 15.
Fusion genes
(updated 2016)
IGF1R (15q26.3) / MAPK6 (15q21.2)MAPK6 (15q21.2) / TMOD3 (15q21.2)MAPK6 (15q21.2) / USO1 (4q21.1)
PYGO1 (15q21.3) / MAPK6 (15q21.2)SYMPK (19q13.32) / MAPK6 (15q21.2)

DNA/RNA

 
  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.

Protein

 
  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

Note
  
Entity 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 Burkitt's lymphoma and a decrease in Hodgkin's 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

ERKs: a family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF.
Boulton TG, Nye SH, Robbins DJ, Ip NY, Radziejewska E, Morgenbesser SD, DePinho RA, Panayotatos N, Cobb MH, Yancopoulos GD.
Cell. 1991 May 17;65(4):663-75.
PMID 2032290
 
The 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, Schumacher S, Kant S, Menon MB, Simon R, Turgeon B, Britsch S, Meloche S, Gaestel M, Kotlyarov A.
Mol Cell Biol 2012; 32: 2467-2478.
PMID 22508986
 
Atypical mitogen-activated protein kinases: structure, regulation and functions.
Coulombe P, Meloche S.
Biochim Biophys Acta. 2007 Aug;1773(8):1376-87. Epub 2006 Nov 7.
PMID 17161475
 
Induction of p97MAPK expression regulates collagen mediated inhibition of proliferation and migration in human squamous cell carcinoma lines.
Crowe DL.
Int J Oncol. 2004 May;24(5):1159-63.
PMID 15067337
 
ERK3 signals through SRC-3 coactivator to promote human lung cancer cell invasion.
Long W, Foulds CE, Qin J, Liu J, Ding C, Lonard DM, Solis LM, Wistuba II, Qin J, Tsai SY, Tsai MJ, O'Malley BW.
J Clin Invest 2012; 122: 1869-1880.
PMID 22505454
 
The catalytic activity of the mitogen-activated protein kinase extracellular signal-regulated kinase 3 is required to sustain CD4+ CD8+ thymocyte survival.
Marquis M, Daudelin JF, Boulet S, Sirois J, Crain K, Mathien S, Turgeon B, Rousseau J, Meloche S, Labrecque N.
Mol Cell Biol 2014; 34: 3374-3387.
PMID 25002529
 
Primary structure, expression and chromosomal locus of a human homolog of rat ERK3.
Meloche S, Beatty BG, Pellerin J.
Oncogene. 1996 Oct 3;13(7):1575-9.
PMID 8875998
 
Scaffolding by ERK3 regulates MK5 in development.
Schumacher S, Laass K, Kant S, Shi Y, Visel A, Gruber AD, Kotlyarov A, Gaestel M.
EMBO J. 2004 Dec 8;23(24):4770-9. Epub 2004 Nov 11.
PMID 15538386
 
Activation of MK5/PRAK by the atypical MAP kinase ERK3 defines a novel signal transduction pathway.
Seternes OM, Mikalsen T, Johansen B, Michaelsen E, Armstrong CG, Morrice NA, Turgeon B, Meloche S, Moens U, Keyse SM.
EMBO J. 2004 Dec 8;23(24):4780-91. Epub 2004 Dec 2.
PMID 15577943
 
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
 
Cloning and characterization of mouse extracellular-signal-regulated protein kinase 3 as a unique gene product of 100 kDa.
Turgeon B, Saba-El-Leil MK, Meloche S.
Biochem J. 2000 Feb 15;346 Pt 1:169-75.
PMID 10657254
 
ERK3 promotes endothelial cell functions by upregulating SRC-3/SP1-mediated VEGFR2 expression.
Wang W, Bian K, Vallabhaneni S, Zhang B, Wu RC, O'Malley BW, Long W.
J Cell Physiol 2014; 229: 1529-1537.
PMID 24585635
 
Cloning and characterization of p97MAPK, a novel human homolog of rat ERK-3.
Zhu AX, Zhao Y, Moller DE, Flier JS.
Mol Cell Biol. 1994 Dec;14(12):8202-11.
PMID 7969157
 

Citation

This paper should be referenced as such :
Mathien S, Meloche S
MAPK6 (mitogen-activated protein kinase 6);
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/MAPK6ID43349ch15q21.html
History of this paper:
Meloche, S. MAPK6 (mitogen-activated protein kinase 6). Atlas Genet Cytogenet Oncol Haematol. 2009;13(7):483-484.
http://documents.irevues.inist.fr/bitstream/handle/2042/44512/08-2008-MAPK6ID43349ch15q21.pdf


External links

Nomenclature
HGNC (Hugo)MAPK6   6879
Cards
AtlasMAPK6ID43349ch15q21
Entrez_Gene (NCBI)MAPK6  5597  mitogen-activated protein kinase 6
AliasesERK3; HsT17250; PRKM6; p97MAPK
GeneCards (Weizmann)MAPK6
Ensembl hg19 (Hinxton)ENSG00000069956 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000069956 [Gene_View]  chr15:52019214-52066265 [Contig_View]  MAPK6 [Vega]
ICGC DataPortalENSG00000069956
TCGA cBioPortalMAPK6
AceView (NCBI)MAPK6
Genatlas (Paris)MAPK6
WikiGenes5597
SOURCE (Princeton)MAPK6
Genetics Home Reference (NIH)MAPK6
Genomic and cartography
GoldenPath hg38 (UCSC)MAPK6  -     chr15:52019214-52066265 +  15q21.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)MAPK6  -     15q21.2   [Description]    (hg19-Feb_2009)
EnsemblMAPK6 - 15q21.2 [CytoView hg19]  MAPK6 - 15q21.2 [CytoView hg38]
Mapping of homologs : NCBIMAPK6 [Mapview hg19]  MAPK6 [Mapview hg38]
OMIM602904   
Gene and transcription
Genbank (Entrez)AB451301 AF420474 AK313633 BC035492 CR749401
RefSeq transcript (Entrez)NM_002748
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)MAPK6
Cluster EST : UnigeneHs.411847 [ NCBI ]
CGAP (NCI)Hs.411847
Alternative Splicing GalleryENSG00000069956
Gene ExpressionMAPK6 [ NCBI-GEO ]   MAPK6 [ EBI - ARRAY_EXPRESS ]   MAPK6 [ SEEK ]   MAPK6 [ MEM ]
Gene Expression Viewer (FireBrowse)MAPK6 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)5597
GTEX Portal (Tissue expression)MAPK6
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ16659   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ16659  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ16659
Splice isoforms : SwissVarQ16659
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 ]   
PhosPhoSitePlusQ16659
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_kinase_AS   
Domain families : Pfam (Sanger)Pkinase (PF00069)   
Domain families : Pfam (NCBI)pfam00069   
Domain families : Smart (EMBL)S_TKc (SM00220)  
Conserved Domain (NCBI)MAPK6
DMDM Disease mutations5597
Blocks (Seattle)MAPK6
PDB (SRS)2I6L   
PDB (PDBSum)2I6L   
PDB (IMB)2I6L   
PDB (RSDB)2I6L   
Structural Biology KnowledgeBase2I6L   
SCOP (Structural Classification of Proteins)2I6L   
CATH (Classification of proteins structures)2I6L   
SuperfamilyQ16659
Human Protein AtlasENSG00000069956
Peptide AtlasQ16659
HPRD04213
IPIIPI00003431   
Protein Interaction databases
DIP (DOE-UCLA)Q16659
IntAct (EBI)Q16659
FunCoupENSG00000069956
BioGRIDMAPK6
STRING (EMBL)MAPK6
ZODIACMAPK6
Ontologies - Pathways
QuickGOQ16659
Ontology : AmiGOMAPK cascade  protein serine/threonine kinase activity  MAP kinase activity  MAP kinase activity  protein binding  ATP binding  nucleus  nucleus  nucleoplasm  cytoplasm  cytoplasm  cytosol  cytosol  protein phosphorylation  cell cycle  signal transduction  regulation of gene expression  protein kinase binding  septin cytoskeleton  intracellular signal transduction  protein complex  protein heterodimerization activity  positive regulation of dendritic spine development  cellular response to organic substance  
Ontology : EGO-EBIMAPK cascade  protein serine/threonine kinase activity  MAP kinase activity  MAP kinase activity  protein binding  ATP binding  nucleus  nucleus  nucleoplasm  cytoplasm  cytoplasm  cytosol  cytosol  protein phosphorylation  cell cycle  signal transduction  regulation of gene expression  protein kinase binding  septin cytoskeleton  intracellular signal transduction  protein complex  protein heterodimerization activity  positive regulation of dendritic spine development  cellular response to organic substance  
Pathways : BIOCARTAMAPKinase Signaling Pathway [Genes]   
REACTOMEQ16659 [protein]
REACTOME PathwaysR-HSA-5687128 [pathway]   
NDEx NetworkMAPK6
Atlas of Cancer Signalling NetworkMAPK6
Wikipedia pathwaysMAPK6
Orthology - Evolution
OrthoDB5597
GeneTree (enSembl)ENSG00000069956
Phylogenetic Trees/Animal Genes : TreeFamMAPK6
HOVERGENQ16659
HOGENOMQ16659
Homologs : HomoloGeneMAPK6
Homology/Alignments : Family Browser (UCSC)MAPK6
Gene fusions - Rearrangements
Fusion : MitelmanMAPK6/TMOD3 [15q21.2/15q21.2]  
Fusion : MitelmanMAPK6/USO1 [15q21.2/4q21.1]  [t(4;15)(q21;q21)]  
Fusion: TCGAMAPK6 15q21.2 TMOD3 15q21.2 LGG
Fusion: TCGAMAPK6 15q21.2 USO1 4q21.1 BRCA
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerMAPK6 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)MAPK6
dbVarMAPK6
ClinVarMAPK6
1000_GenomesMAPK6 
Exome Variant ServerMAPK6
ExAC (Exome Aggregation Consortium)MAPK6 (select the gene name)
Genetic variants : HAPMAP5597
Genomic Variants (DGV)MAPK6 [DGVbeta]
DECIPHERMAPK6 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisMAPK6 
Mutations
ICGC Data PortalMAPK6 
TCGA Data PortalMAPK6 
Broad Tumor PortalMAPK6
OASIS PortalMAPK6 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICMAPK6  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDMAPK6
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch MAPK6
DgiDB (Drug Gene Interaction Database)MAPK6
DoCM (Curated mutations)MAPK6 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)MAPK6 (select a term)
intoGenMAPK6
NCG5 (London)MAPK6
Cancer3DMAPK6(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM602904   
Orphanet
MedgenMAPK6
Genetic Testing Registry MAPK6
NextProtQ16659 [Medical]
TSGene5597
GENETestsMAPK6
Target ValidationMAPK6
Huge Navigator MAPK6 [HugePedia]
snp3D : Map Gene to Disease5597
BioCentury BCIQMAPK6
ClinGenMAPK6
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD5597
Chemical/Pharm GKB GenePA30624
Clinical trialMAPK6
Miscellaneous
canSAR (ICR)MAPK6 (select the gene name)
Probes
Litterature
PubMed35 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineMAPK6
EVEXMAPK6
GoPubMedMAPK6
iHOPMAPK6
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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