P49138 (MAPK2_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	386 AA.
Sequence status	Complete.
Protein existence	Evidence 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 process	DNA damage
Cellular component	Cytoplasm Nucleus
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Isopeptide bond Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	3'-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 vascular endothelial growth factor stimulus Inferred from electronic annotation. Source: Compara inflammatory response Inferred from mutant phenotype Ref.5. Source: UniProtKB inner ear development Inferred from direct assay PubMed 21795542. Source: MGI macropinocytosis Inferred from mutant phenotype Ref.12. Source: UniProtKB peptidyl-serine phosphorylation Inferred from electronic annotation. Source: Compara 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 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: Compara
Cellular_component	cytoplasm Inferred from direct assay Ref.6. Source: UniProtKB nucleus Inferred from direct assay Ref.6. Source: UniProtKB
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW protein serine/threonine kinase activity Inferred from direct assay Ref.7Ref.12Ref.6. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 386	386	MAP kinase-activated protein kinase 2		PRO_0000086289
Regions
	Domain	50 – 311	262	Protein kinase
	Nucleotide binding	56 – 64	9	ATP By similarity
	Region	125 – 127	3	Staurosporine binding By similarity
	Region	314 – 350	37	Autoinhibitory helix
	Region	331 – 354	24	Nuclear export signal (NES)
	Region	352 – 376	25	p38 MAPK-binding site By similarity
	Motif	342 – 351	10	Nuclear export signal (NES) By similarity
	Motif	357 – 360	4	Bipartite nuclear localization signal 1
	Motif	371 – 375	5	Bipartite nuclear localization signal 2
	Compositional bias	6 – 30	25	Pro-rich
	Compositional bias	13 – 22	10	Poly-Pro
	Compositional bias	25 – 30	6	Poly-Pro
Sites
	Active site	172	1	Proton acceptor By similarity
	Binding site	79	1	ATP By similarity
Amino acid modifications
	Modified residue	208	1	Phosphothreonine; by MAPK14 Ref.4 Ref.6 Ref.13
	Modified residue	258	1	Phosphoserine; by MAPK14 By similarity
	Modified residue	314	1	Phosphoserine; by autocatalysis By similarity
	Modified residue	320	1	Phosphothreonine; by MAPK14 Ref.4 Ref.6 Ref.13
	Modified residue	324	1	Phosphothreonine Ref.13
	Cross-link	339		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO) By similarity
Experimental info
	Mutagenesis	208	1	T → A: Strong decrease in kinase activity; when associated with A-320. Ref.4
	Mutagenesis	208	1	T → E: Mimicks phosphorylation state and constitutive protein kinase activity; when associated with E-320. Ref.4
	Mutagenesis	320	1	T → A: Strong decrease in kinase activity; when associated with A-208. Ref.4
	Mutagenesis	320	1	T → E: Mimicks phosphorylation state and constitutive protein kinase activity; when associated with E-208. Ref.4
	Mutagenesis	329	1	K → R: Leads to constitutive protein kinase activity. Ref.4
	Mutagenesis	335	1	W → A: Leads to constitutive protein kinase activity. Ref.4
	Sequence conflict	2 – 3	2	LS → IR in CAA54183. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	P49138 [UniParc]. Last modified January 4, 2005. Version 2. Checksum: ED7827641A826BF3	FASTA	386	44,050
	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

References

	« Hide 'large scale' referencesShow '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: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-208; THR-320 AND THR-324, MASS SPECTROMETRY. 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.
IPI	IPI00113079.
PIR	S78100.
RefSeq	NP_032577.1. NM_008551.1.
UniGene	Mm.221235. Mm.490983.
3D structure databases
ProteinModelPortal	P49138.
SMR	P49138. Positions 37-376.
ModBase	Search...
Protein-protein interaction databases
IntAct	P49138. 1 interaction.
PTM databases
PhosphoSite	P49138.
Proteomic databases
PaxDb	P49138.
PRIDE	P49138.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000016672; ENSMUSP00000016672; ENSMUSG00000016528.
GeneID	17164.
KEGG	mmu:17164.
Organism-specific databases
CTD	9261.
MGI	MGI:109298. Mapkapk2.
Phylogenomic databases
eggNOG	COG0515.
HOGENOM	HOG000233031.
HOVERGEN	HBG106948.
InParanoid	P49138.
KO	K04443.
OMA	FQRIQDK.
OrthoDB	EOG4HQDJP.
Gene expression databases
ArrayExpress	P49138.
Bgee	P49138.
CleanEx	MM_MAPKAPK2. MM_RPS6KC1.
Genevestigator	P49138.
GermOnline	ENSMUSG00000016528. Mus musculus.
Family and domain databases
InterPro	IPR011009. Kinase-like_dom. IPR000719. Prot_kinase_cat_dom. IPR017441. Protein_kinase_ATP_BS. IPR002290. Ser/Thr_dual-sp_kinase_dom. IPR008271. Ser/Thr_kinase_AS. [Graphical view]
Pfam	PF00069. Pkinase. 1 hit. [Graphical view]
SMART	SM00220. S_TKc. 1 hit. [Graphical view]
SUPFAM	SSF56112. Kinase_like. 1 hit.
PROSITE	PS00107. PROTEIN_KINASE_ATP. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00108. PROTEIN_KINASE_ST. 1 hit. [Graphical view]
ProtoNet	Search...
Other
ChEMBL	CHEMBL4990.
ChiTaRS	MAPKAPK2. mouse.
NextBio	291442.
SOURCE	Search...

Entry information

Entry name

MAPK2_MOUSE

Accession

Primary (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:	May 1, 2013
This is version 114 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program