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P49138 (MAPK2_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 126. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
MAP kinase-activated protein kinase 2

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
EC=2.7.11.1
Gene names
Name:Mapkapk2
Synonyms:Rps6kc1
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length386 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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. Ref.3 Ref.5 Ref.7 Ref.9 Ref.10 Ref.12 Ref.14 Ref.15

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

Enzyme regulation

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

Subunit structure

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.

Subcellular location

Cytoplasm. Nucleus. Note: Phosphorylation and subsequent activation releases the autoinhibitory helix, resulting in the export from the nucleus into the cytoplasm. Ref.4 Ref.6

Tissue specificity

Ubiquitously expressed (at protein level). Ref.11

Post-translational modification

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. Ref.4 Ref.6

Disruption phenotype

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. Ref.5 Ref.8 Ref.11

Sequence similarities

Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family.

Contains 1 protein kinase domain.

Ontologies

Keywords
   Biological processDNA damage
   Cellular componentCytoplasm
Nucleus
   LigandATP-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
   PTMIsopeptide bond
Phosphoprotein
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_process3'-UTR-mediated mRNA stabilization

Inferred from sequence or structural similarity. Source: UniProtKB

G2 DNA damage checkpoint

Inferred from sequence or structural similarity. Source: UniProtKB

cellular response to DNA damage stimulus

Inferred from sequence or structural similarity. Source: UniProtKB

cellular response to vascular endothelial growth factor stimulus

Inferred from electronic annotation. Source: Ensembl

inflammatory response

Inferred from mutant phenotype Ref.5. Source: UniProtKB

inner ear development

Inferred from direct assay PubMed 21795542. Source: MGI

mRNA stabilization

Inferred from mutant phenotype PubMed 11741878. Source: MGI

macropinocytosis

Inferred from mutant phenotype Ref.12. Source: UniProtKB

peptidyl-serine phosphorylation

Inferred from electronic annotation. Source: Ensembl

protein phosphorylation

Inferred from direct assay Ref.6. Source: UniProtKB

regulation of interleukin-6 production

Inferred from mutant phenotype Ref.5. Source: UniProtKB

regulation of tumor necrosis factor production

Inferred from mutant phenotype Ref.5. Source: UniProtKB

response to cytokine

Inferred from sequence or structural similarity. Source: UniProtKB

response to lipopolysaccharide

Inferred from mutant phenotype Ref.5Ref.12. Source: UniProtKB

toll-like receptor signaling pathway

Inferred from mutant phenotype Ref.12. Source: UniProtKB

vascular endothelial growth factor receptor signaling pathway

Inferred from electronic annotation. Source: Ensembl

   Cellular_componentcytoplasm

Inferred from direct assay Ref.6. Source: UniProtKB

nucleus

Inferred from direct assay Ref.6. Source: UniProtKB

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

protein binding

Inferred from physical interaction Ref.12. Source: UniProtKB

protein serine/threonine kinase activity

Inferred from direct assay Ref.7Ref.12Ref.6. Source: UniProtKB

Complete GO annotation...

Binary interactions

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 386386MAP kinase-activated protein kinase 2
PRO_0000086289

Regions

Domain50 – 311262Protein kinase
Nucleotide binding56 – 649ATP By similarity
Region125 – 1273Staurosporine binding By similarity
Region314 – 35037Autoinhibitory helix
Region331 – 35424Nuclear export signal (NES)
Region352 – 37625p38 MAPK-binding site By similarity
Motif342 – 35110Nuclear export signal (NES) By similarity
Motif357 – 3604Bipartite nuclear localization signal 1
Motif371 – 3755Bipartite nuclear localization signal 2
Compositional bias6 – 3025Pro-rich
Compositional bias13 – 2210Poly-Pro
Compositional bias25 – 306Poly-Pro

Sites

Active site1721Proton acceptor By similarity
Binding site791ATP By similarity

Amino acid modifications

Modified residue2081Phosphothreonine; by MAPK14 Ref.4 Ref.6
Modified residue2581Phosphoserine; by MAPK14 By similarity
Modified residue3141Phosphoserine; by autocatalysis By similarity
Modified residue3201Phosphothreonine; by MAPK14 Ref.4 Ref.6
Cross-link339Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO) By similarity

Experimental info

Mutagenesis2081T → A: Strong decrease in kinase activity; when associated with A-320. Ref.4
Mutagenesis2081T → E: Mimicks phosphorylation state and constitutive protein kinase activity; when associated with E-320. Ref.4
Mutagenesis3201T → A: Strong decrease in kinase activity; when associated with A-208. Ref.4
Mutagenesis3201T → E: Mimicks phosphorylation state and constitutive protein kinase activity; when associated with E-208. Ref.4
Mutagenesis3291K → R: Leads to constitutive protein kinase activity. Ref.4
Mutagenesis3351W → A: Leads to constitutive protein kinase activity. Ref.4
Sequence conflict2 – 32LS → IR in CAA54183. Ref.1

Sequences

Sequence LengthMass (Da)Tools
P49138 [UniParc].

Last modified January 4, 2005. Version 2.
Checksum: ED7827641A826BF3

FASTA38644,050
        10         20         30         40         50         60 
MLSGSPGQTP PAPFPSPPPP APAQPPPPFP QFHVKSGLQI RKNAITDDYK VTSQVLGLGI 

        70         80         90        100        110        120 
NGKVLRIFDK RTQQKFALKM LQDCPKARRE VELHWRASQC PHIVHIVDVY ENLYAGRKCL 

       130        140        150        160        170        180 
LIVMECLDGG ELFSRIQDRG DQAFTEREAS EIMKSIGEAI QYLHSINIAH RDVKPENLLY 

       190        200        210        220        230        240 
TSKRPNAILK LTDFGFAKET TSHNSLTTPC YTPYYVAPEV LGPEKYDKSC DMWSLGVIMY 

       250        260        270        280        290        300 
ILLCGYPPFY SNHGLAISPG MKTRIRMGQY EFPNPEWSEV SEEVKMLIRN LLKTEPTQRM 

       310        320        330        340        350        360 
TITEFMNHPW IMQSTKVPQT PLHTSRVLKE DKERWEDVKE EMTSALATMR VDYEQIKIKK 

       370        380 
IEDASNPLLL KRRKKARAVE DAALAH 

« Hide

References

« Hide 'large scale' references
[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]"Distinct cellular functions of MK2."
Kotlyarov A., Yannoni Y., Fritz S., Laass K., Telliez J.B., Pitman D., Lin L.L., Gaestel M.
Mol. Cell. Biol. 22:4827-4835(2002) [PubMed] [Europe PMC] [Abstract]
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]"Large-scale phosphorylation analysis of mouse liver."
Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.
Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007) [PubMed] [Europe PMC] [Abstract]
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.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
X76850 mRNA. Translation: CAA54183.1.
BC063064 mRNA. Translation: AAH63064.1.
CCDSCCDS15266.1.
PIRS78100.
RefSeqNP_032577.1. NM_008551.1.
UniGeneMm.221235.
Mm.490983.

3D structure databases

ProteinModelPortalP49138.
SMRP49138. Positions 37-376.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid201308. 8 interactions.
IntActP49138. 7 interactions.
MINTMINT-4101209.

Chemistry

ChEMBLCHEMBL4990.

PTM databases

PhosphoSiteP49138.

Proteomic databases

MaxQBP49138.
PaxDbP49138.
PRIDEP49138.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000016672; ENSMUSP00000016672; ENSMUSG00000016528.
GeneID17164.
KEGGmmu:17164.
UCSCuc007cmv.1. mouse.

Organism-specific databases

CTD9261.
MGIMGI:109298. Mapkapk2.

Phylogenomic databases

eggNOGCOG0515.
HOGENOMHOG000233031.
HOVERGENHBG106948.
InParanoidP49138.
KOK04443.
OMALQMLQDC.
OrthoDBEOG786H3M.
PhylomeDBP49138.
TreeFamTF312891.

Gene expression databases

ArrayExpressP49138.
BgeeP49138.
CleanExMM_MAPKAPK2.
MM_RPS6KC1.
GenevestigatorP49138.

Family and domain databases

Gene3D4.10.1170.10. 1 hit.
InterProIPR011009. Kinase-like_dom.
IPR027442. MAPKAPK_C.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMSSF56112. SSF56112. 1 hit.
PROSITEPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSMAPKAPK2. mouse.
NextBio291442.
PROP49138.
SOURCESearch...

Entry information

Entry nameMAPK2_MOUSE
AccessionPrimary (citable) accession number: P49138
Secondary accession number(s): Q6P561
Entry history
Integrated into UniProtKB/Swiss-Prot: February 1, 1996
Last sequence update: January 4, 2005
Last modified: July 9, 2014
This is version 126 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot