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Protein

MAP kinase-activated protein kinase 2

Gene

MAPKAPK2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

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-X2-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 RPS6KA3.17 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.2 Publications

Activity regulationi

Activated following phosphorylation by p38-alpha/MAPK14 following various stresses. Inhibited following sumoylation. Specifically inhibited by pyrrolopyridine inhibitors.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei93ATPPROSITE-ProRule annotation1
Active sitei186Proton acceptor1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi70 – 78ATPPROSITE-ProRule annotation9

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionKinase, Serine/threonine-protein kinase, Transferase
Biological processDNA damage
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

BioCyciMetaCyc:HS08751-MONOMER
BRENDAi2.7.11.1 2681
ReactomeiR-HSA-171007 p38MAPK events
R-HSA-199920 CREB phosphorylation
R-HSA-2142691 Synthesis of Leukotrienes (LT) and Eoxins (EX)
R-HSA-2559580 Oxidative Stress Induced Senescence
R-HSA-3371453 Regulation of HSF1-mediated heat shock response
R-HSA-4420097 VEGFA-VEGFR2 Pathway
R-HSA-450302 activated TAK1 mediates p38 MAPK activation
R-HSA-450385 Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA
R-HSA-450513 Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA
SignaLinkiP49137
SIGNORiP49137

Names & Taxonomyi

Protein namesi
Recommended name:
MAP kinase-activated protein kinase 2 (EC:2.7.11.1)
Short name:
MAPK-activated protein kinase 2
Short name:
MAPKAP kinase 2
Short name:
MAPKAP-K2
Short name:
MAPKAPK-2
Short name:
MK-2
Short name:
MK2
Gene namesi
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 1

Organism-specific databases

EuPathDBiHostDB:ENSG00000162889.10
HGNCiHGNC:6887 MAPKAPK2
MIMi602006 gene
neXtProtiNX_P49137

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi93K → R: Kinase defective mutant, abolishes activity. 1 Publication1
Mutagenesisi207D → A: Kinase defective mutant, abolishes activity. 1 Publication1
Mutagenesisi222T → A: Strong decrease in kinase activity. 3 Publications1
Mutagenesisi222T → D: Mimicks phosphorylation state, leading to slight increase of basal kinase activity. 3 Publications1
Mutagenesisi222T → E: Mimicks phosphorylation state and constitutive protein kinase activity; when associated with E-334. 3 Publications1
Mutagenesisi272S → A: Strong decrease in kinase activity. 1 Publication1
Mutagenesisi272S → D: Mimicks phosphorylation state, leading to slight increase of basal kinase activity. 1 Publication1
Mutagenesisi334T → A: Slight decrease in kinase activity. 3 Publications1
Mutagenesisi334T → D or E: Mimicks phosphorylation state, leading to elevated basal kinase activity. 3 Publications1
Mutagenesisi334T → E: Mimicks phosphorylation state and constitutive protein kinase activity; when associated with E-222. 3 Publications1
Mutagenesisi353K → R: Induces decreased sumoylation and increase in protein kinase activity. 1 Publication1

Organism-specific databases

DisGeNETi9261
OpenTargetsiENSG00000162889
PharmGKBiPA30631

Chemistry databases

ChEMBLiCHEMBL2208
DrugBankiDB02010 Staurosporine
GuidetoPHARMACOLOGYi2094

Polymorphism and mutation databases

BioMutaiMAPKAPK2
DMDMi1346538

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000862881 – 400MAP kinase-activated protein kinase 2Add BLAST400

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei9Phosphoserine1 Publication1
Modified residuei25Phosphothreonine1 Publication1
Modified residuei222Phosphothreonine; by MAPK141 Publication1
Modified residuei272Phosphoserine; by MAPK141 Publication1
Modified residuei328Phosphoserine; by autocatalysisBy similarity1
Modified residuei334Phosphothreonine; by MAPK14Combined sources1 Publication1
Cross-linki353Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO)1 Publication

Post-translational modificationi

Sumoylation inhibits the protein kinase activity.1 Publication
Phosphorylated and activated by MAP kinase p38-alpha/MAPK14 at Thr-222, Ser-272 and Thr-334.1 Publication

Keywords - PTMi

Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiP49137
MaxQBiP49137
PaxDbiP49137
PeptideAtlasiP49137
PRIDEiP49137
ProteomicsDBi55964
55965 [P49137-2]

PTM databases

iPTMnetiP49137
PhosphoSitePlusiP49137

Expressioni

Tissue specificityi

Expressed in all tissues examined.

Gene expression databases

BgeeiENSG00000162889 Expressed in 233 organ(s), highest expression level in apex of heart
CleanExiHS_MAPKAPK2
GenevisibleiP49137 HS

Organism-specific databases

HPAiCAB010297
HPA045556
HPA063708
HPA064435

Interactioni

Subunit structurei

Heterodimer with p38-alpha/MAPK14; this heterodimer forms a stable complex: molecules are positioned 'face to face' so that the ATP-binding sites of both kinases are at the heterodimer interface (PubMed:12171911, PubMed:17576063, PubMed:17255097, PubMed:17480064, PubMed:17449059, PubMed:17395714). Interacts with PHC2 (PubMed:15094067). Interacts with HSF1 (PubMed:16278218).8 Publications

Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

BioGridi114683, 63 interactors
DIPiDIP-35671N
ELMiP49137
IntActiP49137, 15 interactors
MINTiP49137
STRINGi9606.ENSP00000356070

Chemistry databases

BindingDBiP49137

Structurei

Secondary structure

1400
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliP49137
SMRiP49137
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP49137

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini64 – 325Protein kinasePROSITE-ProRule annotationAdd BLAST262

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni139 – 141Staurosporine binding3
Regioni328 – 364Autoinhibitory helixBy similarityAdd BLAST37
Regioni366 – 390p38 MAPK-binding siteAdd BLAST25

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi356 – 365Nuclear export signal (NES)10
Motifi371 – 374Bipartite nuclear localization signal 14
Motifi385 – 389Bipartite nuclear localization signal 25

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi10 – 40Pro-richAdd BLAST31
Compositional biasi35 – 40Poly-Pro6

Sequence similaritiesi

Phylogenomic databases

eggNOGiKOG0604 Eukaryota
ENOG410XP8F LUCA
GeneTreeiENSGT00900000140876
HOGENOMiHOG000233031
HOVERGENiHBG106948
InParanoidiP49137
KOiK04443
OMAiCRHIVNI
OrthoDBiEOG091G14PL
PhylomeDBiP49137
TreeFamiTF312891

Family and domain databases

Gene3Di4.10.1170.10, 1 hit
InterProiView protein in InterPro
IPR011009 Kinase-like_dom_sf
IPR027442 MAPKAPK_C
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR008271 Ser/Thr_kinase_AS
PfamiView protein in Pfam
PF00069 Pkinase, 1 hit
SMARTiView protein in SMART
SM00220 S_TKc, 1 hit
SUPFAMiSSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00108 PROTEIN_KINASE_ST, 1 hit

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket
Isoform 1 (identifier: P49137-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide
        10         20         30         40         50
MLSNSQGQSP PVPFPAPAPP PQPPTPALPH PPAQPPPPPP QQFPQFHVKS
60 70 80 90 100
GLQIKKNAII DDYKVTSQVL GLGINGKVLQ IFNKRTQEKF ALKMLQDCPK
110 120 130 140 150
ARREVELHWR ASQCPHIVRI VDVYENLYAG RKCLLIVMEC LDGGELFSRI
160 170 180 190 200
QDRGDQAFTE REASEIMKSI GEAIQYLHSI NIAHRDVKPE NLLYTSKRPN
210 220 230 240 250
AILKLTDFGF AKETTSHNSL TTPCYTPYYV APEVLGPEKY DKSCDMWSLG
260 270 280 290 300
VIMYILLCGY PPFYSNHGLA ISPGMKTRIR MGQYEFPNPE WSEVSEEVKM
310 320 330 340 350
LIRNLLKTEP TQRMTITEFM NHPWIMQSTK VPQTPLHTSR VLKEDKERWE
360 370 380 390 400
DVKEEMTSAL ATMRVDYEQI KIKKIEDASN PLLLKRRKKA RALEAAALAH
Note: Has a nuclear localization signal.
Length:400
Mass (Da):45,568
Last modified:February 1, 1996 - v1
Checksum:iE4EFFF11CCF288DC
GO
Isoform 2 (identifier: P49137-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     354-400: EEMTSALATMRVDYEQIKIKKIEDASNPLLLKRRKKARALEAAALAH → GCLHDKNSDQATWLTRL

Show »
Length:370
Mass (Da):42,203
Checksum:iFF09AD93D4F73BDB
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti116H → D in CAA53094 (PubMed:8280084).Curated1
Sequence conflicti247 – 248WS → LV in CAA53094 (PubMed:8280084).Curated2

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_040753173A → G1 PublicationCorresponds to variant dbSNP:rs35671930Ensembl.1
Natural variantiVAR_040754361A → S1 PublicationCorresponds to variant dbSNP:rs55894011Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_004910354 – 400EEMTS…AALAH → GCLHDKNSDQATWLTRL in isoform 2. 1 PublicationAdd BLAST47

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U12779 mRNA Translation: AAA20851.1
AL591846 Genomic DNA No translation available.
CH471100 Genomic DNA Translation: EAW93526.1
CH471100 Genomic DNA Translation: EAW93529.1
BC036060 mRNA Translation: AAH36060.2
BC052584 mRNA Translation: AAH52584.1
X75346 mRNA Translation: CAA53094.1
CCDSiCCDS1466.1 [P49137-2]
CCDS31001.1 [P49137-1]
PIRiJC2204
S39793
RefSeqiNP_004750.1, NM_004759.4 [P49137-2]
NP_116584.2, NM_032960.3 [P49137-1]
UniGeneiHs.643566
Hs.713747

Genome annotation databases

EnsembliENST00000294981; ENSP00000294981; ENSG00000162889 [P49137-2]
ENST00000367103; ENSP00000356070; ENSG00000162889 [P49137-1]
GeneIDi9261
KEGGihsa:9261
UCSCiuc001hel.3 human [P49137-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Cross-referencesi

Web resourcesi

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U12779 mRNA Translation: AAA20851.1
AL591846 Genomic DNA No translation available.
CH471100 Genomic DNA Translation: EAW93526.1
CH471100 Genomic DNA Translation: EAW93529.1
BC036060 mRNA Translation: AAH36060.2
BC052584 mRNA Translation: AAH52584.1
X75346 mRNA Translation: CAA53094.1
CCDSiCCDS1466.1 [P49137-2]
CCDS31001.1 [P49137-1]
PIRiJC2204
S39793
RefSeqiNP_004750.1, NM_004759.4 [P49137-2]
NP_116584.2, NM_032960.3 [P49137-1]
UniGeneiHs.643566
Hs.713747

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1KWPX-ray2.80A/B1-400[»]
1NXKX-ray2.70A/B/C/D1-400[»]
1NY3X-ray3.00A1-400[»]
2JBOX-ray3.10A41-364[»]
2JBPX-ray3.31A/B/C/D/E/F/G/H/I/J/K/L41-364[»]
2OKRX-ray2.00C/F370-393[»]
2ONLX-ray4.00C/D1-400[»]
2OZAX-ray2.70A47-400[»]
2P3GX-ray3.80X45-371[»]
2PZYX-ray2.90A/B/C/D41-364[»]
3A2CX-ray2.90A/B/C/D/E/F/G/H/I/J/K/L41-364[»]
3FPMX-ray3.30A41-364[»]
3FYJX-ray3.80X45-371[»]
3FYKX-ray3.50X45-371[»]
3GOKX-ray3.20A/B/C/D/E/F/G/H/I/J/K/L41-364[»]
3KA0X-ray2.90A47-366[»]
3KC3X-ray2.90A/B/C/D/E/F/G/H/I/J/K/L41-364[»]
3KGAX-ray2.55A47-364[»]
3M2WX-ray2.41A47-364[»]
3M42X-ray2.68A47-364[»]
3R2BX-ray2.90A/B/C/D/E/F/G/H/I/J/K/L47-364[»]
3R2YX-ray3.00A46-364[»]
3R30X-ray3.20A46-364[»]
3WI6X-ray2.99A/B/C/D/E/F41-364[»]
4TYHX-ray3.00A51-400[»]
ProteinModelPortaliP49137
SMRiP49137
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi114683, 63 interactors
DIPiDIP-35671N
ELMiP49137
IntActiP49137, 15 interactors
MINTiP49137
STRINGi9606.ENSP00000356070

Chemistry databases

BindingDBiP49137
ChEMBLiCHEMBL2208
DrugBankiDB02010 Staurosporine
GuidetoPHARMACOLOGYi2094

PTM databases

iPTMnetiP49137
PhosphoSitePlusiP49137

Polymorphism and mutation databases

BioMutaiMAPKAPK2
DMDMi1346538

Proteomic databases

EPDiP49137
MaxQBiP49137
PaxDbiP49137
PeptideAtlasiP49137
PRIDEiP49137
ProteomicsDBi55964
55965 [P49137-2]

Protocols and materials databases

DNASUi9261
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000294981; ENSP00000294981; ENSG00000162889 [P49137-2]
ENST00000367103; ENSP00000356070; ENSG00000162889 [P49137-1]
GeneIDi9261
KEGGihsa:9261
UCSCiuc001hel.3 human [P49137-1]

Organism-specific databases

CTDi9261
DisGeNETi9261
EuPathDBiHostDB:ENSG00000162889.10
GeneCardsiMAPKAPK2
HGNCiHGNC:6887 MAPKAPK2
HPAiCAB010297
HPA045556
HPA063708
HPA064435
MIMi602006 gene
neXtProtiNX_P49137
OpenTargetsiENSG00000162889
PharmGKBiPA30631
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0604 Eukaryota
ENOG410XP8F LUCA
GeneTreeiENSGT00900000140876
HOGENOMiHOG000233031
HOVERGENiHBG106948
InParanoidiP49137
KOiK04443
OMAiCRHIVNI
OrthoDBiEOG091G14PL
PhylomeDBiP49137
TreeFamiTF312891

Enzyme and pathway databases

BioCyciMetaCyc:HS08751-MONOMER
BRENDAi2.7.11.1 2681
ReactomeiR-HSA-171007 p38MAPK events
R-HSA-199920 CREB phosphorylation
R-HSA-2142691 Synthesis of Leukotrienes (LT) and Eoxins (EX)
R-HSA-2559580 Oxidative Stress Induced Senescence
R-HSA-3371453 Regulation of HSF1-mediated heat shock response
R-HSA-4420097 VEGFA-VEGFR2 Pathway
R-HSA-450302 activated TAK1 mediates p38 MAPK activation
R-HSA-450385 Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA
R-HSA-450513 Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA
SignaLinkiP49137
SIGNORiP49137

Miscellaneous databases

ChiTaRSiMAPKAPK2 human
EvolutionaryTraceiP49137
GeneWikiiMAPKAPK2
GenomeRNAii9261
PROiPR:P49137
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000162889 Expressed in 233 organ(s), highest expression level in apex of heart
CleanExiHS_MAPKAPK2
GenevisibleiP49137 HS

Family and domain databases

Gene3Di4.10.1170.10, 1 hit
InterProiView protein in InterPro
IPR011009 Kinase-like_dom_sf
IPR027442 MAPKAPK_C
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR008271 Ser/Thr_kinase_AS
PfamiView protein in Pfam
PF00069 Pkinase, 1 hit
SMARTiView protein in SMART
SM00220 S_TKc, 1 hit
SUPFAMiSSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00108 PROTEIN_KINASE_ST, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiMAPK2_HUMAN
AccessioniPrimary (citable) accession number: P49137
Secondary accession number(s): Q5SY30, Q5SY41, Q8IYD6
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 1, 1996
Last sequence update: February 1, 1996
Last modified: September 12, 2018
This is version 193 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 1
    Human chromosome 1: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  4. SIMILARITY comments
    Index of protein domains and families
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  7. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
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