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P49138

- MAPK2_MOUSE

UniProt

P49138 - MAPK2_MOUSE

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Protein

MAP kinase-activated protein kinase 2

Gene

Mapkapk2

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli

Functioni

Stress-activated serine/threonine-protein kinase involved in cytokines 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, ELAVL1, HNRNPA0, HSF1, HSP27/HSPB1, KRT18, KRT20, LIMK1, LSP1, PABPC1, PARN, PDE4A, RCSD1, RPS6KA3, TAB3 and TTP/ZFP36. Mediates phosphorylation of HSP27/HSPB1 in response to stress, leading to dissociate HSP27/HSPB1 from large small heat-shock protein (sHsps) oligomers and impair 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 regulate 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 transcript. 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 stabilize GADD45A mRNA. Involved in toll-like receptor signaling pathway (TLR) in dendritic cells: required for acute TLR-induced macropinocytosis by phosphorylating and activating RPS6KA3.8 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Enzyme regulationi

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

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei79 – 791ATPPROSITE-ProRule annotation
Active sitei172 – 1721Proton acceptorPROSITE-ProRule annotation

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi56 – 649ATPPROSITE-ProRule annotation

GO - Molecular functioni

  1. ATP binding Source: UniProtKB-KW
  2. protein serine/threonine kinase activity Source: UniProtKB

GO - Biological processi

  1. 3'-UTR-mediated mRNA stabilization Source: UniProtKB
  2. cellular response to DNA damage stimulus Source: UniProtKB
  3. cellular response to vascular endothelial growth factor stimulus Source: Ensembl
  4. G2 DNA damage checkpoint Source: UniProtKB
  5. inflammatory response Source: UniProtKB
  6. inner ear development Source: MGI
  7. macropinocytosis Source: UniProtKB
  8. mRNA stabilization Source: MGI
  9. peptidyl-serine phosphorylation Source: Ensembl
  10. protein phosphorylation Source: UniProtKB
  11. regulation of interleukin-6 production Source: UniProtKB
  12. regulation of tumor necrosis factor production Source: UniProtKB
  13. response to cytokine Source: UniProtKB
  14. response to lipopolysaccharide Source: UniProtKB
  15. toll-like receptor signaling pathway Source: UniProtKB
  16. vascular endothelial growth factor receptor signaling pathway Source: Ensembl
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase

Keywords - Biological processi

DNA damage

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

ReactomeiREACT_188970. Oxidative Stress Induced Senescence.
REACT_198689. Tristetraprolin (TTP) destabilizes mRNA.
REACT_198695. Butyrate Response Factor 1 (BRF1) destabilizes mRNA.
REACT_207601. p38MAPK events.
REACT_215561. Synthesis of Leukotrienes (LT) and Eoxins (EX).
REACT_222185. Regulation of HSF1-mediated heat shock response.
REACT_224314. CREB phosphorylation.

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
Name:Mapkapk2
Synonyms:Rps6kc1
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589: Chromosome 1

Organism-specific databases

MGIiMGI:109298. Mapkapk2.

Subcellular locationi

Cytoplasm. Nucleus
Note: Phosphorylation and subsequent activation releases the autoinhibitory helix, resulting in the export from the nucleus into the cytoplasm.

GO - Cellular componenti

  1. centrosome Source: Ensembl
  2. cytoplasm Source: UniProtKB
  3. nucleus Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Disruption phenotypei

No visible phenotype. Mice are fertile and do not exhibit behavioral phenotype. Mice show decreased production of inflammatory cytokines such as TNF and IL6 upon LPS-stimulation. Impaired cytokine production make mice less sensitive to LPS-induced endotoxic shock, but more susceptible to bacterial infection. Moreover, the amount of MAP kinase p38 is significantly reduced in cells and tissues. Mice lacking both Mapkapk2 and Mapkapk3 show further reduction of TNF production.3 Publications

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi208 – 2081T → A: Strong decrease in kinase activity; when associated with A-320. 1 Publication
Mutagenesisi208 – 2081T → E: Mimicks phosphorylation state and constitutive protein kinase activity; when associated with E-320. 1 Publication
Mutagenesisi320 – 3201T → A: Strong decrease in kinase activity; when associated with A-208. 1 Publication
Mutagenesisi320 – 3201T → E: Mimicks phosphorylation state and constitutive protein kinase activity; when associated with E-208. 1 Publication
Mutagenesisi329 – 3291K → R: Leads to constitutive protein kinase activity. 1 Publication
Mutagenesisi335 – 3351W → A: Leads to constitutive protein kinase activity. 1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 386386MAP kinase-activated protein kinase 2PRO_0000086289Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei208 – 2081Phosphothreonine; by MAPK142 Publications
Modified residuei258 – 2581Phosphoserine; by MAPK14By similarity
Modified residuei314 – 3141Phosphoserine; by autocatalysisBy similarity
Modified residuei320 – 3201Phosphothreonine; by MAPK142 Publications
Cross-linki339 – 339Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO)By similarity

Post-translational modificationi

Sumoylation inhibits the protein kinase activity.By similarity
Phosphorylated and activated by MAP kinase p38-alpha/MAPK14 at Thr-208; Ser-258 and Thr-320.2 Publications

Keywords - PTMi

Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

MaxQBiP49138.
PaxDbiP49138.
PRIDEiP49138.

PTM databases

PhosphoSiteiP49138.

Expressioni

Tissue specificityi

Ubiquitously expressed (at protein level).1 Publication

Gene expression databases

BgeeiP49138.
CleanExiMM_MAPKAPK2.
MM_RPS6KC1.
ExpressionAtlasiP49138. baseline and differential.
GenevestigatoriP49138.

Interactioni

Subunit structurei

Heterodimer with p38-alpha/MAPK14. The heterodimer with p38-alpha/MAPK14 forms a stable complex: molecules are positioned 'face to face' so that the ATP-binding sites of both kinases are at the heterodimer interface. Interacts with PHC2 (By similarity).By similarity

Binary interactionsi

WithEntry#Exp.IntActNotes
Mapk14P478112EBI-298776,EBI-298727
Phc1Q640282EBI-298776,EBI-927346
Phc2Q9QWH15EBI-298776,EBI-642357

Protein-protein interaction databases

BioGridi201308. 8 interactions.
IntActiP49138. 7 interactions.
MINTiMINT-4101209.

Structurei

3D structure databases

ProteinModelPortaliP49138.
SMRiP49138. Positions 37-376.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini50 – 311262Protein kinasePROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni125 – 1273Staurosporine bindingBy similarity
Regioni314 – 35037Autoinhibitory helixAdd
BLAST
Regioni331 – 35424Nuclear export signal (NES)Add
BLAST
Regioni352 – 37625p38 MAPK-binding siteBy similarityAdd
BLAST

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi342 – 35110Nuclear export signal (NES)By similarity
Motifi357 – 3604Bipartite nuclear localization signal 1
Motifi371 – 3755Bipartite nuclear localization signal 2

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi6 – 3025Pro-richAdd
BLAST
Compositional biasi13 – 2210Poly-Pro
Compositional biasi25 – 306Poly-Pro

Sequence similaritiesi

Contains 1 protein kinase domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiCOG0515.
HOGENOMiHOG000233031.
HOVERGENiHBG106948.
InParanoidiP49138.
KOiK04443.
OMAiLQMLQDC.
OrthoDBiEOG786H3M.
PhylomeDBiP49138.
TreeFamiTF312891.

Family and domain databases

Gene3Di4.10.1170.10. 1 hit.
InterProiIPR011009. Kinase-like_dom.
IPR027442. MAPKAPK_C.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

P49138-1 [UniParc]FASTAAdd to Basket

« Hide

        10         20         30         40         50
MLSGSPGQTP PAPFPSPPPP APAQPPPPFP QFHVKSGLQI RKNAITDDYK
60 70 80 90 100
VTSQVLGLGI NGKVLRIFDK RTQQKFALKM LQDCPKARRE VELHWRASQC
110 120 130 140 150
PHIVHIVDVY ENLYAGRKCL LIVMECLDGG ELFSRIQDRG DQAFTEREAS
160 170 180 190 200
EIMKSIGEAI QYLHSINIAH RDVKPENLLY TSKRPNAILK LTDFGFAKET
210 220 230 240 250
TSHNSLTTPC YTPYYVAPEV LGPEKYDKSC DMWSLGVIMY ILLCGYPPFY
260 270 280 290 300
SNHGLAISPG MKTRIRMGQY EFPNPEWSEV SEEVKMLIRN LLKTEPTQRM
310 320 330 340 350
TITEFMNHPW IMQSTKVPQT PLHTSRVLKE DKERWEDVKE EMTSALATMR
360 370 380
VDYEQIKIKK IEDASNPLLL KRRKKARAVE DAALAH
Length:386
Mass (Da):44,050
Last modified:January 4, 2005 - v2
Checksum:iED7827641A826BF3
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti2 – 32LS → IR in CAA54183. (PubMed:8262198)Curated

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
X76850 mRNA. Translation: CAA54183.1.
BC063064 mRNA. Translation: AAH63064.1.
CCDSiCCDS15266.1.
PIRiS78100.
RefSeqiNP_032577.1. NM_008551.1.
UniGeneiMm.221235.
Mm.490983.

Genome annotation databases

EnsembliENSMUST00000016672; ENSMUSP00000016672; ENSMUSG00000016528.
GeneIDi17164.
KEGGimmu:17164.
UCSCiuc007cmv.1. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
X76850 mRNA. Translation: CAA54183.1 .
BC063064 mRNA. Translation: AAH63064.1 .
CCDSi CCDS15266.1.
PIRi S78100.
RefSeqi NP_032577.1. NM_008551.1.
UniGenei Mm.221235.
Mm.490983.

3D structure databases

ProteinModelPortali P49138.
SMRi P49138. Positions 37-376.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 201308. 8 interactions.
IntActi P49138. 7 interactions.
MINTi MINT-4101209.

Chemistry

ChEMBLi CHEMBL4990.

PTM databases

PhosphoSitei P49138.

Proteomic databases

MaxQBi P49138.
PaxDbi P49138.
PRIDEi P49138.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENSMUST00000016672 ; ENSMUSP00000016672 ; ENSMUSG00000016528 .
GeneIDi 17164.
KEGGi mmu:17164.
UCSCi uc007cmv.1. mouse.

Organism-specific databases

CTDi 9261.
MGIi MGI:109298. Mapkapk2.

Phylogenomic databases

eggNOGi COG0515.
HOGENOMi HOG000233031.
HOVERGENi HBG106948.
InParanoidi P49138.
KOi K04443.
OMAi LQMLQDC.
OrthoDBi EOG786H3M.
PhylomeDBi P49138.
TreeFami TF312891.

Enzyme and pathway databases

Reactomei REACT_188970. Oxidative Stress Induced Senescence.
REACT_198689. Tristetraprolin (TTP) destabilizes mRNA.
REACT_198695. Butyrate Response Factor 1 (BRF1) destabilizes mRNA.
REACT_207601. p38MAPK events.
REACT_215561. Synthesis of Leukotrienes (LT) and Eoxins (EX).
REACT_222185. Regulation of HSF1-mediated heat shock response.
REACT_224314. CREB phosphorylation.

Miscellaneous databases

ChiTaRSi MAPKAPK2. mouse.
NextBioi 291442.
PROi P49138.
SOURCEi Search...

Gene expression databases

Bgeei P49138.
CleanExi MM_MAPKAPK2.
MM_RPS6KC1.
ExpressionAtlasi P49138. baseline and differential.
Genevestigatori P49138.

Family and domain databases

Gene3Di 4.10.1170.10. 1 hit.
InterProi IPR011009. Kinase-like_dom.
IPR027442. MAPKAPK_C.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view ]
Pfami PF00069. Pkinase. 1 hit.
[Graphical view ]
SMARTi SM00220. S_TKc. 1 hit.
[Graphical view ]
SUPFAMi SSF56112. SSF56112. 1 hit.
PROSITEi PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  1. "The MAP kinase-activated protein kinase 2 contains a proline-rich SH3-binding domain."
    Engel K., Plath K., Gaestel M.
    FEBS Lett. 336:143-147(1993) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 2-386.
    Tissue: Lung.
  2. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Strain: C57BL/6.
    Tissue: Brain.
  3. "Small heat shock proteins are molecular chaperones."
    Jakob U., Gaestel M., Engel K., Buchner J.
    J. Biol. Chem. 268:1517-1520(1993) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN PHOSPHORYLATION OF HSPB1.
  4. "Constitutive activation of mitogen-activated protein kinase-activated protein kinase 2 by mutation of phosphorylation sites and an A-helix motif."
    Engel K., Schultz H., Martin F., Kotlyarov A., Plath K., Hahn M., Heinemann U., Gaestel M.
    J. Biol. Chem. 270:27213-27221(1995) [PubMed] [Europe PMC] [Abstract]
    Cited for: SUBCELLULAR LOCATION, PHOSPHORYLATION AT THR-208 AND THR-320, MUTAGENESIS OF THR-208; THR-320; LYS-329 AND TRP-335.
  5. "MAPKAP kinase 2 is essential for LPS-induced TNF-alpha biosynthesis."
    Kotlyarov A., Neininger A., Schubert C., Eckert R., Birchmeier C., Volk H.D., Gaestel M.
    Nat. Cell Biol. 1:94-97(1999) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, DISRUPTION PHENOTYPE.
  6. "Leptomycin B-sensitive nuclear export of MAPKAP kinase 2 is regulated by phosphorylation."
    Engel K., Kotlyarov A., Gaestel M.
    EMBO J. 17:3363-3371(1998) [PubMed] [Europe PMC] [Abstract]
    Cited for: SUBCELLULAR LOCATION, PHOSPHORYLATION AT THR-208 AND THR-320, NUCLEAR EXPORT SIGNAL (NES).
  7. "Inhibition of SAPK2a/p38 prevents hnRNP A0 phosphorylation by MAPKAP-K2 and its interaction with cytokine mRNAs."
    Rousseau S., Morrice N., Peggie M., Campbell D.G., Gaestel M., Cohen P.
    EMBO J. 21:6505-6514(2002) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN PHOSPHORYLATION OF HNRNPA0.
  8. Cited for: DISRUPTION PHENOTYPE.
  9. "MAPKAP kinase 2 phosphorylates tristetraprolin on in vivo sites including Ser178, a site required for 14-3-3 binding."
    Chrestensen C.A., Schroeder M.J., Shabanowitz J., Hunt D.F., Pelo J.W., Worthington M.T., Sturgill T.W.
    J. Biol. Chem. 279:10176-10184(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN PHOSPHORYLATION OF ZFP36.
  10. "The phosphorylation of CapZ-interacting protein (CapZIP) by stress-activated protein kinases triggers its dissociation from CapZ."
    Eyers C.E., McNeill H., Knebel A., Morrice N., Arthur S.J.C., Cuenda A., Cohen P.
    Biochem. J. 389:127-135(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN PHOSPHORYLATION OF RCSD1.
  11. "The mitogen-activated protein kinase (MAPK)-activated protein kinases MK2 and MK3 cooperate in stimulation of tumor necrosis factor biosynthesis and stabilization of p38 MAPK."
    Ronkina N., Kotlyarov A., Dittrich-Breiholz O., Kracht M., Hitti E., Milarski K., Askew R., Marusic S., Lin L.L., Gaestel M., Telliez J.B.
    Mol. Cell. Biol. 27:170-181(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: DISRUPTION PHENOTYPE, TISSUE SPECIFICITY.
  12. "The MAPK-activated kinase Rsk controls an acute Toll-like receptor signaling response in dendritic cells and is activated through two distinct pathways."
    Zaru R., Ronkina N., Gaestel M., Arthur J.S., Watts C.
    Nat. Immunol. 8:1227-1235(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN PHOSPHORYLATION OF RPS6KA3.
  13. Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Liver.
  14. "p38 MAP kinase and MAPKAP kinases MK2/3 cooperatively phosphorylate epithelial keratins."
    Menon M.B., Schwermann J., Singh A.K., Franz-Wachtel M., Pabst O., Seidler U., Omary M.B., Kotlyarov A., Gaestel M.
    J. Biol. Chem. 285:33242-33251(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN PHOSPHORYLATION OF KRT18 AND KRT20.
  15. "Phosphorylation of cAMP-specific PDE4A5 (phosphodiesterase-4A5) by MK2 (MAPKAPK2) attenuates its activation through protein kinase A phosphorylation."
    MacKenzie K.F., Wallace D.A., Hill E.V., Anthony D.F., Henderson D.J., Houslay D.M., Arthur J.S., Baillie G.S., Houslay M.D.
    Biochem. J. 435:755-769(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN PHOSPHORYLATION OF PDE4A.

Entry informationi

Entry nameiMAPK2_MOUSE
AccessioniPrimary (citable) accession number: P49138
Secondary accession number(s): Q6P561
Entry historyi
Integrated into UniProtKB/Swiss-Prot: February 1, 1996
Last sequence update: January 4, 2005
Last modified: October 29, 2014
This is version 129 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  3. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3