GeneBe

MAPKAPK2

protein-coding

MAPK activated protein kinase 2, the group of MAPK activated protein kinases

Gene summary

This gene encodes a member of the Ser/Thr protein kinase family. This kinase is regulated through direct phosphorylation by p38 MAP kinase. In conjunction with p38 MAP kinase, this kinase is known to be involved in many cellular processes including stress and inflammatory responses, nuclear export, gene expression regulation and cell proliferation. Heat shock protein HSP27 was shown to be one of the substrates of this kinase in vivo. Two transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_032960.4

Inheritance

—

ClinVar variants

U:44B:4

Top phenotype

Neurodevelopmental disorder

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr1:206,684,905-206,734,281

External References & Databases

Ensembl (ENSG00000162889)NCBI Gene (9261)OMIM (602006)HGNC:6887GenCCUniProt (P49137)AlphaFoldClinVar (MAPKAPK2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~49.4 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MAPKAPK2 variants in ClinVar

3 Conditions Cataloged
not specifiedTotal: 32
not providedTotal: 6
Neurodevelopmental disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_032960.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
2
clinvar
2
clinvar
1
clinvar
 5
missense
37
clinvar
1
clinvar
 38
nonsense
2
clinvar
 2
start loss
0
frameshift
0
splice donor/acceptor (+/-2bp)
3
clinvar
 3
Total00443148
Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 17 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_032960.4RefSeqNP_116584.210MANE Select
ENST00000367103.4EnsemblENSP00000356070.410MANE Select
NM_004759.5RefSeqNP_004750.110Standard
ENST00000294981.8EnsemblENSP00000294981.410Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
mapkapk2aDanio rerio

Structure: I-YSL

Quality: aggregated

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human)
  • VEGF signaling pathway - Homo sapiens (human)
  • Neurotrophin signaling pathway - Homo sapiens (human)
  • C-type lectin receptor signaling pathway - Homo sapiens (human)
  • MAPK signaling pathway - Homo sapiens (human)

Biological Process

  • MAPK cascade
  • activation of MAPK activity
  • toll-like receptor signaling pathway
  • protein phosphorylation
  • leukotriene metabolic process

Molecular Function

  • protein kinase activity
  • protein serine/threonine kinase activity
  • calmodulin-dependent protein kinase activity
  • protein binding
  • calmodulin binding

Cellular Component

  • nucleus
  • nucleoplasm
  • cytoplasm
  • centrosome
  • cytosol

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000367103
Coding exons
10
Length
49340
Individuals with no LoFs
125742
Homozygous LoFs
0
Heterozygous LoFs
5
Defined
125747
p
0.0000199
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense3.05982270.4310.00001312596
Missense (PolyPhen)1674.5920.2145787
Synonymous-0.6359890.31.090.00000527767
Loss of Function4.37022.30.000.00000120250

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000580.000058rare
Ashkenazi Jewish0.0000990.000099rare
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000190.000018rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Stress-activated serine/threonine-protein kinase involved in cytokine production, endocytosis, reorganization of the cytoskeleton, cell migration, cell cycle control, chromatin remodeling, DNA damage response and transcriptional regulation. Following stress, it is phosphorylated and activated by MAP kinase p38-alpha/MAPK14, leading to phosphorylation of substrates. Phosphorylates serine in the peptide sequence, Hyd-X-R-X(2)-S, where Hyd is a large hydrophobic residue. Phosphorylates ALOX5, CDC25B, CDC25C, CEP131, ELAVL1, HNRNPA0, HSP27/HSPB1, KRT18, KRT20, LIMK1, LSP1, PABPC1, PARN, PDE4A, RCSD1, RPS6KA3, TAB3 and TTP/ZFP36. Phosphorylates HSF1; leading to the interaction with HSP90 proteins and inhibiting HSF1 homotrimerization, DNA-binding and transactivation activities (PubMed:16278218). Mediates phosphorylation of HSP27/HSPB1 in response to stress, leading to the dissociation of HSP27/HSPB1 from large small heat-shock protein (sHsps) oligomers and impairment of their chaperone activities and ability to protect against oxidative stress effectively. Involved in inflammatory response by regulating tumor necrosis factor (TNF) and IL6 production post-transcriptionally: acts by phosphorylating AU-rich elements (AREs)-binding proteins ELAVL1, HNRNPA0, PABPC1 and TTP/ZFP36, leading to the regulation of the stability and translation of TNF and IL6 mRNAs. Phosphorylation of TTP/ZFP36, a major post-transcriptional regulator of TNF, promotes its binding to 14-3-3 proteins and reduces its ARE mRNA affinity, leading to inhibition of dependent degradation of ARE-containing transcripts. Phosphorylates CEP131 in response to cellular stress induced by ultraviolet irradiation which promotes binding of CEP131 to 14-3-3 proteins and inhibits formation of novel centriolar satellites (PubMed:26616734). Also involved in late G2/M checkpoint following DNA damage through a process of post-transcriptional mRNA stabilization: following DNA damage, relocalizes from nucleus to cytoplasm and phosphorylates HNRNPA0 and PARN, leading to stabilization of GADD45A mRNA. Involved in toll-like receptor signaling pathway (TLR) in dendritic cells: required for acute TLR-induced macropinocytosis by phosphorylating and activating RPS6KA3. {ECO:0000269|PubMed:10383393, ECO:0000269|PubMed:11844797, ECO:0000269|PubMed:12456657, ECO:0000269|PubMed:12565831, ECO:0000269|PubMed:14499342, ECO:0000269|PubMed:14517288, ECO:0000269|PubMed:15014438, ECO:0000269|PubMed:15629715, ECO:0000269|PubMed:16278218, ECO:0000269|PubMed:16456544, ECO:0000269|PubMed:17481585, ECO:0000269|PubMed:18021073, ECO:0000269|PubMed:20932473, ECO:0000269|PubMed:26616734, ECO:0000269|PubMed:8093612, ECO:0000269|PubMed:8280084, ECO:0000269|PubMed:8774846}.;

Recessive Scores

pRec
0.182

Intolerance Scores

LoFtool
0.202
RVIS EVS
-0.65
RVIS percentile EVS
16.36

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.990

Gene Damage Prediction

AllRecessiveDominant
MendelianHighMediumMedium
Primary ImmunodeficiencyHighHighHigh
CancerHighHighHigh
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