P49137 (MAPK2_HUMAN) 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

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	400 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.5 Ref.6 Ref.8 Ref.9 Ref.10 Ref.11 Ref.12 Ref.13 Ref.14 Ref.15 Ref.17 Ref.18 Ref.19 Ref.20 Ref.21 Ref.23
Catalytic activity	ATP + a protein = ADP + a phosphoprotein. Ref.8 Ref.27
Enzyme regulation	Activated following phosphorylation by p38-alpha/MAPK14 following various stresses. Inhibited following sumoylation. Specifically inhibited by pyrrolopyridine inhibitors.
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. Ref.16 Ref.30 Ref.34
Subcellular location	Cytoplasm. Nucleus. Note: Phosphorylation and subsequent activation releases the autoinhibitory helix, resulting in the export from the nucleus into the cytoplasm. Ref.23
Tissue specificity	Expressed in all tissues examined.
Post-translational modification	Sumoylation inhibits the protein kinase activity. Ref.25 Phosphorylated and activated by MAP kinase p38-alpha/MAPK14 at Thr-222, Ser-272 and Thr-334. Ref.7
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
Coding sequence diversity	Alternative splicing Polymorphism
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Isopeptide bond Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	3'-UTR-mediated mRNA stabilization Inferred from direct assay Ref.14Ref.15Ref.23. Source: UniProtKB G2 DNA damage checkpoint Inferred from mutant phenotype Ref.23. Source: UniProtKB MyD88-dependent toll-like receptor signaling pathway Traceable author statement. Source: Reactome Ras protein signal transduction Traceable author statement. Source: Reactome TRIF-dependent toll-like receptor signaling pathway Traceable author statement. Source: Reactome Toll signaling pathway Traceable author statement. Source: Reactome activation of MAPK activity Traceable author statement. Source: Reactome cellular response to vascular endothelial growth factor stimulus Inferred from mutant phenotype PubMed 18440775. Source: BHF-UCL gene expression Traceable author statement. Source: Reactome inflammatory response Inferred from sequence or structural similarity. Source: UniProtKB innate immune response Traceable author statement. Source: Reactome inner ear development Inferred from electronic annotation. Source: Compara mRNA metabolic process Traceable author statement. Source: Reactome macropinocytosis Inferred from sequence or structural similarity. Source: UniProtKB nerve growth factor receptor signaling pathway Traceable author statement. Source: Reactome peptidyl-serine phosphorylation Inferred from direct assay PubMed 15850461. Source: BHF-UCL regulation of interleukin-6 production Inferred from sequence or structural similarity. Source: UniProtKB regulation of tumor necrosis factor production Inferred from direct assay Ref.15. Source: UniProtKB response to lipopolysaccharide Inferred from sequence or structural similarity. Source: UniProtKB stress-activated MAPK cascade Traceable author statement. Source: Reactome toll-like receptor 1 signaling pathway Traceable author statement. Source: Reactome toll-like receptor 2 signaling pathway Traceable author statement. Source: Reactome toll-like receptor 3 signaling pathway Traceable author statement. Source: Reactome toll-like receptor 4 signaling pathway Traceable author statement. Source: Reactome vascular endothelial growth factor receptor signaling pathway Inferred from mutant phenotype PubMed 18440775. Source: BHF-UCL
Cellular_component	cytosol Traceable author statement. Source: Reactome nucleoplasm Traceable author statement. Source: Reactome
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW protein serine/threonine kinase activity Inferred from direct assay Ref.14Ref.15Ref.23Ref.8Ref.7. Source: UniProtKB signal transducer activity Traceable author statement Ref.1. Source: ProtInc
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
HSF1	Q00613	5	EBI-993299,EBI-719620
HSPB1	P04792	2	EBI-993299,EBI-352682
MAPK14	Q16539	3	EBI-993299,EBI-73946

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P49137-1)

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.

Note: Has a nuclear localization signal.

Isoform 2 (identifier: P49137-2)

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

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 400

400

MAP kinase-activated protein kinase 2

PRO_0000086288

Regions

Domain

64 – 325

262

Protein kinase

Nucleotide binding

70 – 78

9

ATP By similarity

Region

139 – 141

3

Staurosporine binding

Region

328 – 364

37

Autoinhibitory helix By similarity

Region

366 – 390

25

p38 MAPK-binding site

Motif

356 – 365

10

Nuclear export signal (NES)

Motif

371 – 374

4

Bipartite nuclear localization signal 1

Motif

385 – 389

5

Bipartite nuclear localization signal 2

Compositional bias

10 – 40

31

Pro-rich

Compositional bias

35 – 40

6

Poly-Pro

Sites

Active site

186

1

Proton acceptor

Binding site

93

1

ATP By similarity

Amino acid modifications

Modified residue

9

1

Phosphoserine Ref.7

Modified residue

25

1

Phosphothreonine Ref.7

Modified residue

222

1

Phosphothreonine; by MAPK14 Ref.7

Modified residue

272

1

Phosphoserine; by MAPK14 Ref.7

Modified residue

328

1

Phosphoserine; by autocatalysis By similarity

Modified residue

334

1

Phosphothreonine; by MAPK14 Ref.7

Modified residue

338

1

Phosphothreonine By similarity

Cross-link

353

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO) Ref.25

Natural variations

Alternative sequence

354 – 400

47

EEMTS…AALAH → GCLHDKNSDQATWLTRL in isoform 2.

VSP_004910

Natural variant

173

1

A → G. Ref.35
Corresponds to variant rs35671930 [ dbSNP | Ensembl ].

VAR_040753

Natural variant

361

1

A → S. Ref.35
Corresponds to variant rs55894011 [ dbSNP | Ensembl ].

VAR_040754

Experimental info

Mutagenesis

93

1

K → R: Kinase defective mutant, abolishes activity. Ref.14

Mutagenesis

207

1

D → A: Kinase defective mutant, abolishes activity. Ref.7

Mutagenesis

222

1

T → A: Strong decrease in kinase activity. Ref.7 Ref.14 Ref.15

Mutagenesis

222

1

T → D: Mimicks phosphorylation state, leading to slight increase of basal kinase activity. Ref.7 Ref.14 Ref.15

Mutagenesis

222

1

T → E: Mimicks phosphorylation state and constitutive protein kinase activity; when associated with E-334. Ref.7 Ref.14 Ref.15

Mutagenesis

272

1

S → A: Strong decrease in kinase activity. Ref.7

Mutagenesis

272

1

S → D: Mimicks phosphorylation state, leading to slight increase of basal kinase activity. Ref.7

Mutagenesis

334

1

T → A: Slight decrease in kinase activity. Ref.7 Ref.14 Ref.15

Mutagenesis

334

1

T → D or E: Mimicks phosphorylation state, leading to elevated basal kinase activity. Ref.7 Ref.14 Ref.15

Mutagenesis

334

1

T → E: Mimicks phosphorylation state and constitutive protein kinase activity; when associated with E-222. Ref.7 Ref.14 Ref.15

Mutagenesis

353

1

K → R: Induces decreased sumoylation and increase in protein kinase activity. Ref.25

Sequence conflict

116

1

H → D in CAA53094. Ref.5

Sequence conflict

247 – 248

2

WS → LV in CAA53094. Ref.5

Secondary structure

1

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400

Helix Strand Turn

Details...

Helix

45 – 47

3

Beta strand

48 – 50

3

Helix

59 – 61

3

Beta strand

63 – 73

11

Beta strand

76 – 83

8

Turn

84 – 86

3

Beta strand

89 – 96

8

Helix

99 – 111

13

Beta strand

114 – 117

4

Beta strand

120 – 128

9

Beta strand

131 – 138

8

Beta strand

143 – 145

3

Helix

146 – 152

7

Helix

160 – 179

20

Helix

189 – 191

3

Beta strand

192 – 198

7

Beta strand

203 – 205

3

Beta strand

228 – 230

3

Helix

232 – 234

3

Helix

239 – 242

4

Helix

243 – 258

16

Beta strand

267 – 269

3

Helix

275 – 281

7

Beta strand

283 – 285

3

Helix

288 – 291

4

Helix

296 – 305

10

Turn

310 – 312

3

Helix

316 – 320

5

Helix

323 – 326

4

Helix

328 – 330

3

Beta strand

335 – 337

3

Helix

338 – 344

7

Helix

346 – 348

3

Helix

349 – 363

15

Turn

375 – 377

3

Helix

381 – 389

9

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified February 1, 1996. Version 1. Checksum: E4EFFF11CCF288DC	FASTA	400	45,568
	10 20 30 40 50 60 MLSNSQGQSP PVPFPAPAPP PQPPTPALPH PPAQPPPPPP QQFPQFHVKS GLQIKKNAII 70 80 90 100 110 120 DDYKVTSQVL GLGINGKVLQ IFNKRTQEKF ALKMLQDCPK ARREVELHWR ASQCPHIVRI 130 140 150 160 170 180 VDVYENLYAG RKCLLIVMEC LDGGELFSRI QDRGDQAFTE REASEIMKSI GEAIQYLHSI 190 200 210 220 230 240 NIAHRDVKPE NLLYTSKRPN AILKLTDFGF AKETTSHNSL TTPCYTPYYV APEVLGPEKY 250 260 270 280 290 300 DKSCDMWSLG VIMYILLCGY PPFYSNHGLA ISPGMKTRIR MGQYEFPNPE WSEVSEEVKM 310 320 330 340 350 360 LIRNLLKTEP TQRMTITEFM NHPWIMQSTK VPQTPLHTSR VLKEDKERWE DVKEEMTSAL 370 380 390 400 ATMRVDYEQI KIKKIEDASN PLLLKRRKKA RALEAAALAH
	Isoform 2 [UniParc]. Checksum: FF09AD93D4F73BDB	FASTA	370	42,203
	10 20 30 40 50 60 MLSNSQGQSP PVPFPAPAPP PQPPTPALPH PPAQPPPPPP QQFPQFHVKS GLQIKKNAII 70 80 90 100 110 120 DDYKVTSQVL GLGINGKVLQ IFNKRTQEKF ALKMLQDCPK ARREVELHWR ASQCPHIVRI 130 140 150 160 170 180 VDVYENLYAG RKCLLIVMEC LDGGELFSRI QDRGDQAFTE REASEIMKSI GEAIQYLHSI 190 200 210 220 230 240 NIAHRDVKPE NLLYTSKRPN AILKLTDFGF AKETTSHNSL TTPCYTPYYV APEVLGPEKY 250 260 270 280 290 300 DKSCDMWSLG VIMYILLCGY PPFYSNHGLA ISPGMKTRIR MGQYEFPNPE WSEVSEEVKM 310 320 330 340 350 360 LIRNLLKTEP TQRMTITEFM NHPWIMQSTK VPQTPLHTSR VLKEDKERWE DVKGCLHDKN 370 SDQATWLTRL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The primary structure of a human MAP kinase activated protein kinase 2." Zu Y.-L., Wu F., Gilchrist A., Ai Y., Labadia M.E., Huang C.K. Biochem. Biophys. Res. Commun. 200:1118-1124(1994) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
[2]	"The DNA sequence and biological annotation of human chromosome 1." Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R. Nature 441:315-321(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	"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] (ISOFORM 1). Tissue: Skin and Testis.
[5]	"The substrate specificity and structure of mitogen-activated protein (MAP) kinase-activated protein kinase-2." Stokoe D., Caudwell B., Cohen P.T.W., Cohen P. Biochem. J. 296:843-849(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 5-400 (ISOFORM 1), FUNCTION.
[6]	"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.
[7]	"Identification of novel phosphorylation sites required for activation of MAPKAP kinase-2." Ben-Levy R., Leighton I.A., Doza Y.N., Attwood P., Morrice N., Marshall C.J., Cohen P. EMBO J. 14:5920-5930(1995) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT SER-9; THR-25; THR-222; SER-272 AND THR-334, MUTAGENESIS OF ASP-207; THR-222; SER-272 AND THR-334.
[8]	"A comparison of the substrate specificity of MAPKAP kinase-2 and MAPKAP kinase-3 and their activation by cytokines and cellular stress." Clifton A.D., Young P.R., Cohen P. FEBS Lett. 392:209-214(1996) [PubMed] [Europe PMC] [Abstract] Cited for: CATALYTIC ACTIVITY, FUNCTION IN PHOSPHORYLATION OF HSPB1.
[9]	"Regulation of Hsp27 oligomerization, chaperone function, and protective activity against oxidative stress/tumor necrosis factor alpha by phosphorylation." Rogalla T., Ehrnsperger M., Preville X., Kotlyarov A., Lutsch G., Ducasse C., Paul C., Wieske M., Arrigo A.P., Buchner J., Gaestel M. J. Biol. Chem. 274:18947-18956(1999) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF HSPB1.
[10]	"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.
[11]	"Arachidonic acid promotes phosphorylation of 5-lipoxygenase at Ser-271 by MAPK-activated protein kinase 2 (MK2)." Werz O., Szellas D., Steinhilber D., Radmark O. J. Biol. Chem. 277:14793-14800(2002) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF LOX5.
[12]	"Affinity purification of ARE-binding proteins identifies polyA-binding protein 1 as a potential substrate in MK2-induced mRNA stabilization." Bollig F., Winzen R., Gaestel M., Kostka S., Resch K., Holtmann H. Biochem. Biophys. Res. Commun. 301:665-670(2003) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF PABPC1.
[13]	"MAPK-activated protein kinase-2 participates in p38 MAPK-dependent and ERK-dependent functions in human neutrophils." Coxon P.Y., Rane M.J., Uriarte S., Powell D.W., Singh S., Butt W., Chen Q., McLeish K.R. Cell. Signal. 15:993-1001(2003) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[14]	"Stabilization of urokinase and urokinase receptor mRNAs by HuR is linked to its cytoplasmic accumulation induced by activated mitogen-activated protein kinase-activated protein kinase 2." Tran H., Maurer F., Nagamine Y. Mol. Cell. Biol. 23:7177-7188(2003) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF ELAVL1, MUTAGENESIS OF LYS-93; THR-222 AND THR-334.
[15]	"MK2-induced tristetraprolin:14-3-3 complexes prevent stress granule association and ARE-mRNA decay." Stoecklin G., Stubbs T., Kedersha N., Wax S., Rigby W.F., Blackwell T.K., Anderson P. EMBO J. 23:1313-1324(2004) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF ZFP36, MUTAGENESIS OF THR-222 AND THR-334.
[16]	"P66(ShcA) interacts with MAPKAP kinase 2 and regulates its activity." Yannoni Y.M., Gaestel M., Lin L.L. FEBS Lett. 564:205-211(2004) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH PHC2.
[17]	"MAPKAP kinase-2 is a cell cycle checkpoint kinase that regulates the G2/M transition and S phase progression in response to UV irradiation." Manke I.A., Nguyen A., Lim D., Stewart M.Q., Elia A.E., Yaffe M.B. Mol. Cell 17:37-48(2005) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF CDC25B AND CDC25C.
[18]	"MAPKAPK-2-mediated LIM-kinase activation is critical for VEGF-induced actin remodeling and cell migration." Kobayashi M., Nishita M., Mishima T., Ohashi K., Mizuno K. EMBO J. 25:713-726(2006) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF LIMK1.
[19]	"Phosphorylation of HSF1 by MAPK-activated protein kinase 2 on serine 121, inhibits transcriptional activity and promotes HSP90 binding." Wang X., Khaleque M.A., Zhao M.J., Zhong R., Gaestel M., Calderwood S.K. J. Biol. Chem. 281:782-791(2006) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF HSF1.
[20]	"MAPKAPK2-mediated LSP1 phosphorylation and FMLP-induced neutrophil polarization." Wu Y., Zhan L., Ai Y., Hannigan M., Gaestel M., Huang C.-K., Madri J.A. Biochem. Biophys. Res. Commun. 358:170-175(2007) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF LSP1.
[21]	"Roles for TAB1 in regulating the IL-1-dependent phosphorylation of the TAB3 regulatory subunit and activity of the TAK1 complex." Mendoza H., Campbell D.G., Burness K., Hastie J., Ronkina N., Shim J.H., Arthur J.S., Davis R.J., Gaestel M., Johnson G.L., Ghosh S., Cohen P. Biochem. J. 409:711-722(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF TAB3.
[22]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Cervix carcinoma.
[23]	"DNA damage activates a spatially distinct late cytoplasmic cell-cycle checkpoint network controlled by MK2-mediated RNA stabilization." Reinhardt H.C., Hasskamp P., Schmedding I., Morandell S., van Vugt M.A., Wang X., Linding R., Ong S.E., Weaver D., Carr S.A., Yaffe M.B. Mol. Cell 40:34-49(2010) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF HNRNPA0 AND PARN, SUBCELLULAR LOCATION.
[24]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[25]	"MK2 SUMOylation regulates actin filament remodeling and subsequent migration in endothelial cells by inhibiting MK2 kinase and HSP27 phosphorylation." Chang E., Heo K.S., Woo C.H., Lee H., Le N.T., Thomas T.N., Fujiwara K., Abe J. Blood 117:2527-2537(2011) [PubMed] [Europe PMC] [Abstract] Cited for: SUMOYLATION AT LYS-353, MUTAGENESIS OF LYS-353.
[26]	"MK2 and MK3--a pair of isoenzymes?" Ronkina N., Kotlyarov A., Gaestel M. Front. Biosci. 13:5511-5521(2008) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW.
[27]	"Structure of mitogen-activated protein kinase-activated protein (MAPKAP) kinase 2 suggests a bifunctional switch that couples kinase activation with nuclear export." Meng W., Swenson L.L., Fitzgibbon M.J., Hayakawa K., Ter Haar E., Behrens A.E., Fulghum J.R., Lippke J.A. J. Biol. Chem. 277:37401-37405(2002) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) IN COMPLEX WITH ADP AND STAUROSPORINE, CATALYTIC ACTIVITY.
[28]	"Catalytically active MAP KAP kinase 2 structures in complex with staurosporine and ADP reveal differences with the autoinhibited enzyme." Underwood K.W., Parris K.D., Federico E., Mosyak L., Czerwinski R.M., Shane T., Taylor M., Svenson K., Liu Y., Hsiao C.L., Wolfrom S., Maguire M., Malakian K., Telliez J.B., Lin L.L., Kriz R.W., Seehra J., Somers W.S., Stahl M.L. Structure 11:627-636(2003) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS).
[29]	"The discovery of carboline analogs as potent MAPKAP-K2 inhibitors." Wu J.P., Wang J., Abeywardane A., Andersen D., Emmanuel M., Gautschi E., Goldberg D.R., Kashem M.A., Lukas S., Mao W., Martin L., Morwick T., Moss N., Pargellis C., Patel U.R., Patnaude L., Peet G.W., Skow D. , Snow R.J., Ward Y., Werneburg B., White A. Bioorg. Med. Chem. Lett. 17:4664-4669(2007) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 41-364 IN COMPLEX WITH CARBOLINE-BASED INHIBITORS.
[30]	"Crystal structure of the p38 alpha-MAPKAP kinase 2 heterodimer." ter Haar E., Prabhakar P., Liu X., Lepre C. J. Biol. Chem. 282:9733-9739(2007) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (4.0 ANGSTROMS) IN COMPLEX WITH MAPK14, INTERACTION WITH MAPK14.
[31]	Erratum ter Haar E., Prabhakar P., Liu X., Lepre C. J. Biol. Chem. 282:14684-14684(2007)
[32]	"Pyrrolopyridine inhibitors of mitogen-activated protein kinase-activated protein kinase 2 (MK-2)." Anderson D.R., Meyers M.J., Vernier W.F., Mahoney M.W., Kurumbail R.G., Caspers N., Poda G.I., Schindler J.F., Reitz D.B., Mourey R.J. J. Med. Chem. 50:2647-2654(2007) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (3.8 ANGSTROMS) OF 45-371 IN COMPLEX WITH PYRROLOPYRIDINE INHIBITORS.
[33]	"Structural basis for a high affinity inhibitor bound to protein kinase MK2." Hillig R.C., Eberspaecher U., Monteclaro F., Huber M., Nguyen D., Mengel A., Muller-Tiemann B., Egner U. J. Mol. Biol. 369:735-745(2007) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (3.1 ANGSTROMS) OF 41-364 IN COMPLEX WITH PYRROLOPYRIDINE INHIBITOR.
[34]	"Molecular basis of MAPK-activated protein kinase 2:p38 assembly." White A., Pargellis C.A., Studts J.M., Werneburg B.G., Farmer B.T. II Proc. Natl. Acad. Sci. U.S.A. 104:6353-6358(2007) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 47-400 IN COMPLEX WITH MAPK14, INTERACTION WITH MAPK14.
[35]	"Patterns of somatic mutation in human cancer genomes." Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R. Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] GLY-173 AND SER-361.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

U12779 mRNA. Translation: AAA20851.1.
AL591846 Genomic DNA. Translation: CAI13543.1.
AL591846 Genomic DNA. Translation: CAI13544.1.
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.

IPI

IPI00026054.
IPI00215763.

PIR

JC2204.
S39793.

RefSeq

NP_004750.1. NM_004759.4.
NP_116584.2. NM_032960.3.

UniGene

Hs.643566.
Hs.713747.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1KWP	X-ray	2.80	A/B	1-400	[»]
1NXK	X-ray	2.70	A/B/C/D	1-400	[»]
1NY3	X-ray	3.00	A	1-400	[»]
2JBO	X-ray	3.10	A	41-364	[»]
2JBP	X-ray	3.31	A/B/C/D/E/F/G/H/I/J/K/L	41-364	[»]
2OKR	X-ray	2.00	C/F	370-393	[»]
2ONL	X-ray	4.00	C/D	1-400	[»]
2OZA	X-ray	2.70	A	47-400	[»]
2P3G	X-ray	3.80	X	45-371	[»]
2PZY	X-ray	2.90	A/B/C/D	41-364	[»]
3A2C	X-ray	2.90	A/B/C/D/E/F/G/H/I/J/K/L	41-364	[»]
3FPM	X-ray	3.30	A	41-364	[»]
3FYJ	X-ray	3.80	X	45-371	[»]
3FYK	X-ray	3.50	X	45-371	[»]
3GOK	X-ray	3.20	A/B/C/D/E/F/G/H/I/J/K/L	41-364	[»]
3KA0	X-ray	2.90	A	47-366	[»]
3KC3	X-ray	2.90	A/B/C/D/E/F/G/H/I/J/K/L	41-364	[»]
3KGA	X-ray	2.55	A	47-364	[»]
3M2W	X-ray	2.41	A	47-364	[»]
3M42	X-ray	2.68	A	47-364	[»]
3R2B	X-ray	2.90	A/B/C/D/E/F/G/H/I/J/K/L	47-364	[»]
3R2Y	X-ray	3.00	A	46-364	[»]
3R30	X-ray	3.20	A	46-364	[»]

ProteinModelPortal

P49137.

ModBase

Search...

Protein-protein interaction databases

IntAct

P49137. 5 interactions.

MINT

MINT-1539725.

STRING

9606.ENSP00000356070.

PTM databases

PhosphoSite

P49137.

Polymorphism databases

DMDM

1346538.

Proteomic databases

PaxDb

P49137.

PRIDE

P49137.

Protocols and materials databases

DNASU

9261.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000294981; ENSP00000294981; ENSG00000162889.
ENST00000367103; ENSP00000356070; ENSG00000162889.
ENST00000579291; ENSP00000461936; ENSG00000266641.
ENST00000579635; ENSP00000462387; ENSG00000266641.

GeneID

9261.

KEGG

hsa:9261.

UCSC

uc001hel.2. human.
uc001hem.2. human.

Organism-specific databases

CTD

9261.

GeneCards

GC01P206858.

HGNC

HGNC:6887. MAPKAPK2.

HPA

CAB010297.

MIM

602006. gene.

neXtProt

NX_P49137.

PharmGKB

PA30631.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0515.

HOGENOM

HOG000233031.

HOVERGEN

HBG106948.

InParanoid

P49137.

KO

K04443.

OMA

FQRIQDK.

Enzyme and pathway databases

BRENDA

2.7.11.1. 2681.

Pathway_Interaction_DB

il2_1pathway. IL2-mediated signaling events.
p38_mk2pathway. p38 signaling mediated by MAPKAP kinases.
p38alphabetadownstreampathway. Signaling mediated by p38-alpha and p38-beta.
mapktrkpathway. Trk receptor signaling mediated by the MAPK pathway.

Reactome

REACT_111102. Signal Transduction.
REACT_111217. Metabolism.
REACT_21257. Metabolism of RNA.
REACT_6782. TRAF6 Mediated Induction of proinflammatory cytokines.
REACT_6900. Immune System.
REACT_71. Gene Expression.

Gene expression databases

Bgee

P49137.

CleanEx

HS_MAPKAPK2.

Genevestigator

P49137.

GermOnline

ENSG00000162889. Homo sapiens.

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

BindingDB

P49137.

ChEMBL

CHEMBL2208.

ChiTaRS

MAPKAPK2. human.

EvolutionaryTrace

P49137.

GenomeRNAi

9261.

NextBio

34715.

SOURCE

Search...

Entry information

Entry name

MAPK2_HUMAN

Accession

Primary (citable) accession number: P49137
Secondary accession number(s): Q5SY30, Q5SY41, Q8IYD6

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 1, 1996
Last sequence update:	February 1, 1996
Last modified:	May 1, 2013
This is version 137 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.