P36507 (MP2K2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Dual specificity mitogen-activated protein kinase kinase 2
Short name=MAP kinase kinase 2
Short name=MAPKK 2
EC=2.7.12.2

Alternative name(s):
ERK activator kinase 2
MAPK/ERK kinase 2
Short name=MEK 2

Gene names

Name:	MAP2K2
Synonyms:	MEK2, MKK2, PRKMK2

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	Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. Activates the ERK1 and ERK2 MAP kinases By similarity.
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Subunit structure	Interacts with MORG1 By similarity. Interacts with SGK1. Ref.11
Post-translational modification	MAPKK is itself dependent on Ser/Thr phosphorylation for activity catalyzed by MAP kinase kinase kinases (RAF or MEKK1). Phosphorylated by MAP2K1/MEK1 By similarity. Ref.3 Ref.4 Acetylation of Ser-222 and Ser-226 by Yersinia yopJ prevents phosphorylation and activation, thus blocking the MAPK signaling pathway.
Involvement in disease	Cardiofaciocutaneous syndrome (CFC syndrome) [MIM:115150]: Characterized by a distinctive facial appearance, heart defects and mental retardation. Heart defects include pulmonic stenosis, atrial septal defects and hypertrophic cardiomyopathy. Some affected individuals present with ectodermal abnormalities such as sparse, friable hair, hyperkeratotic skin lesions and a generalized ichthyosis-like condition. Typical facial features are similar to Noonan syndrome. They include high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, and posteriorly angulated ears with prominent helices. The inheritance of CFC syndrome is autosomal dominant. Note: The disease is caused by mutations affecting the gene represented in this entry.
Sequence similarities	Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase subfamily. Contains 1 protein kinase domain.

Ontologies

Keywords
Disease	Disease mutation
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase Tyrosine-protein kinase
PTM	Acetylation Phosphoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	ERK1 and ERK2 cascade Traceable author statement. Source: Reactome 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 MAPKK activity Traceable author statement. Source: Reactome axon guidance Traceable author statement. Source: Reactome epidermal growth factor receptor signaling pathway Traceable author statement. Source: Reactome fibroblast growth factor receptor signaling pathway Traceable author statement. Source: Reactome innate immune response Traceable author statement. Source: Reactome insulin receptor signaling pathway Traceable author statement. Source: Reactome nerve growth factor receptor signaling pathway Traceable author statement. Source: Reactome peptidyl-serine autophosphorylation Inferred from direct assay Ref.1. Source: UniProtKB positive regulation of cell motility Inferred from electronic annotation. Source: Compara regulation of Golgi inheritance Traceable author statement PubMed 19565474. Source: UniProtKB regulation of early endosome to late endosome transport Traceable author statement PubMed 19565474. Source: UniProtKB regulation of stress-activated MAPK cascade Traceable author statement PubMed 19565474. 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
Cellular_component	Golgi apparatus Inferred from direct assay PubMed 21615688. Source: UniProtKB cell cortex Inferred from electronic annotation. Source: Compara cell-cell junction Inferred from direct assay PubMed 21615688. Source: UniProtKB cytosol Traceable author statement PubMed 19565474. Source: UniProtKB early endosome Traceable author statement PubMed 19565474. Source: UniProtKB endoplasmic reticulum Inferred from direct assay PubMed 21615688. Source: UniProtKB extracellular region Non-traceable author statement Ref.1. Source: UniProtKB focal adhesion Traceable author statement PubMed 19565474. Source: UniProtKB internal side of plasma membrane Inferred from direct assay PubMed 21615688. Source: UniProtKB late endosome Traceable author statement PubMed 19565474. Source: UniProtKB microtubule Inferred from direct assay PubMed 21615688. Source: UniProtKB mitochondrion Traceable author statement PubMed 19565474. Source: UniProtKB nucleus Traceable author statement PubMed 19565474. Source: UniProtKB perinuclear region of cytoplasm Inferred from direct assay PubMed 21615688. Source: UniProtKB peroxisomal membrane Inferred from direct assay PubMed 21525035. Source: UniProtKB
Molecular_function	ATP binding Non-traceable author statement. Source: UniProtKB MAP kinase kinase activity Inferred from direct assay Ref.1. Source: UniProtKB PDZ domain binding Inferred from direct assay PubMed 21615688. Source: UniProtKB protein serine/threonine kinase activator activity Inferred from direct assay Ref.1. Source: UniProtKB protein serine/threonine kinase activity Non-traceable author statement. Source: UniProtKB protein tyrosine kinase activity Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
ARAF	P10398	4	EBI-1056930,EBI-365961

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 400

400

Dual specificity mitogen-activated protein kinase kinase 2

PRO_0000086372

Regions

Domain

72 – 369

298

Protein kinase

Nucleotide binding

78 – 86

9

ATP By similarity

Compositional bias

266 – 315

50

Pro-rich

Sites

Active site

194

1

Proton acceptor By similarity

Binding site

101

1

ATP By similarity

Site

10 – 11

2

Cleavage; by anthrax lethal factor

Amino acid modifications

Modified residue

222

1

O-acetylserine; by Yersinia yopJ; alternate

Modified residue

222

1

Phosphoserine; by RAF; alternate Ref.4

Modified residue

226

1

O-acetylserine; by Yersinia yopJ; alternate

Modified residue

226

1

Phosphoserine; alternate Ref.4

Modified residue

293

1

Phosphoserine Ref.9

Modified residue

295

1

Phosphoserine Ref.9 Ref.14

Modified residue

394

1

Phosphothreonine Ref.3 Ref.10 Ref.14 Ref.16

Modified residue

396

1

Phosphothreonine Ref.10 Ref.16

Natural variations

Natural variant

57

1

F → C in CFC syndrome. Ref.17

VAR_035095

Secondary structure

1

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400

Helix Strand Turn

Details...

Helix

69 – 71

3

Beta strand

72 – 80

9

Beta strand

85 – 91

7

Turn

92 – 94

3

Beta strand

97 – 103

7

Helix

110 – 119

10

Helix

120 – 122

3

Beta strand

133 – 148

16

Helix

155 – 161

7

Beta strand

162 – 164

3

Helix

167 – 186

20

Helix

197 – 199

3

Beta strand

200 – 202

3

Beta strand

208 – 210

3

Helix

217 – 222

6

Helix

236 – 239

4

Helix

246 – 262

17

Helix

272 – 279

8

Helix

318 – 327

10

Turn

335 – 337

3

Helix

340 – 349

10

Turn

354 – 356

3

Helix

360 – 364

5

Helix

367 – 374

8

Helix

379 – 386

8

Sequences

	Sequence		Length	Mass (Da)
	P36507 [UniParc]. Last modified June 1, 1994. Version 1. Checksum: 3401D522515C30A5	FASTA	400	44,424
	10 20 30 40 50 60 MLARRKPVLP ALTINPTIAE GPSPTSEGAS EANLVDLQKK LEELELDEQQ KKRLEAFLTQ 70 80 90 100 110 120 KAKVGELKDD DFERISELGA GNGGVVTKVQ HRPSGLIMAR KLIHLEIKPA IRNQIIRELQ 130 140 150 160 170 180 VLHECNSPYI VGFYGAFYSD GEISICMEHM DGGSLDQVLK EAKRIPEEIL GKVSIAVLRG 190 200 210 220 230 240 LAYLREKHQI MHRDVKPSNI LVNSRGEIKL CDFGVSGQLI DSMANSFVGT RSYMAPERLQ 250 260 270 280 290 300 GTHYSVQSDI WSMGLSLVEL AVGRYPIPPP DAKELEAIFG RPVVDGEEGE PHSISPRPRP 310 320 330 340 350 360 PGRPVSGHGM DSRPAMAIFE LLDYIVNEPP PKLPNGVFTP DFQEFVNKCL IKNPAERADL 370 380 390 400 KMLTNHTFIK RSEVEEVDFA GWLCKTLRLN QPGTPTRTAV

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning and characterization of two distinct human extracellular signal-regulated kinase activator kinases, MEK1 and MEK2." Zheng C.-F., Guan K.-L. J. Biol. Chem. 268:11435-11439(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[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]. Tissue: Muscle and Skin.
[3]	Bienvenut W.V., Zebisch A., Kolch W. Submitted (DEC-2008) to UniProtKB Cited for: PROTEIN SEQUENCE OF 40-51; 53-61; 64-100; 102-112; 164-172; 194-205; 265-297; 362-371 AND 389-397, PHOSPHORYLATION AT THR-394, MASS SPECTROMETRY. Tissue: Colon carcinoma.
[4]	"Acetylation of MEK2 and I kappa B kinase (IKK) activation loop residues by YopJ inhibits signaling." Mittal R., Peak-Chew S.Y., McMahon H.T. Proc. Natl. Acad. Sci. U.S.A. 103:18574-18579(2006) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 210-231, INACTIVATION BY YERSINIA YOPJ, PHOSPHORYLATION AT SER-222 AND SER-226, ACETYLATION AT SER-222 AND SER-226, MASS SPECTROMETRY.
[5]	"Proteolytic inactivation of MAP-kinase-kinase by anthrax lethal factor." Duesbery N.S., Webb C.P., Leppla S.H., Gordon V.M., Klimpel K.R., Copeland T.D., Ahn N.G., Oskarsson M.K., Fukasawa K., Paull K.D., Vande Woude G.F. Science 280:734-737(1998) [PubMed] [Europe PMC] [Abstract] Cited for: CLEAVAGE BY ANTHRAX LETHAL FACTOR.
[6]	"Susceptibility of mitogen-activated protein kinase kinase family members to proteolysis by anthrax lethal factor." Vitale G., Bernardi L., Napolitani G., Mock M., Montecucco C. Biochem. J. 352:739-745(2000) [PubMed] [Europe PMC] [Abstract] Cited for: CLEAVAGE BY ANTHRAX LETHAL FACTOR.
[7]	"Global, in vivo, and site-specific phosphorylation dynamics in signaling networks." Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M. Cell 127:635-648(2006) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Cervix carcinoma.
[8]	"Phosphoproteome of resting human platelets." Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J., Schuetz C., Walter U., Gambaryan S., Sickmann A. J. Proteome Res. 7:526-534(2008) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Platelet.
[9]	"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle." Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M. Mol. Cell 31:438-448(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-293 AND SER-295, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[10]	"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: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-394 AND THR-396, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[11]	"Protein kinase SGK1 enhances MEK/ERK complex formation through the phosphorylation of ERK2: implication for the positive regulatory role of SGK1 on the ERK function during liver regeneration." Won M., Park K.A., Byun H.S., Kim Y.R., Choi B.L., Hong J.H., Park J., Seok J.H., Lee Y.H., Cho C.H., Song I.S., Kim Y.K., Shen H.M., Hur G.M. J. Hepatol. 51:67-76(2009) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH SGK1.
[12]	"Large-scale proteomics analysis of the human kinome." Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., Mann M., Daub H. Mol. Cell. Proteomics 8:1751-1764(2009) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[13]	"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions." Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K. Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Leukemic T-cell.
[14]	"Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis." Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M. Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-295 AND THR-394, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[15]	"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].
[16]	"System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation." Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B. Sci. Signal. 4:RS3-RS3(2011) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-394 AND THR-396, MASS SPECTROMETRY.
[17]	"Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome." Rodriguez-Viciana P., Tetsu O., Tidyman W.E., Estep A.L., Conger B.A., Cruz M.S., McCormick F., Rauen K.A. Science 311:1287-1290(2006) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT CFC SYNDROME CYS-57.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

L11285 mRNA. No translation available.
BC000471 mRNA. Translation: AAH00471.1.
BC018645 mRNA. Translation: AAH18645.1.

IPI

IPI00003783.

PIR

A46723.

RefSeq

NP_109587.1. NM_030662.3.

UniGene

Hs.465627.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1S9I	X-ray	3.20	A/B	55-400	[»]
4H3Q	X-ray	2.20	B	4-16	[»]

ProteinModelPortal

P36507.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-29119N.

IntAct

P36507. 10 interactions.

MINT

MINT-99667.

STRING

9606.ENSP00000262948.

PTM databases

PhosphoSite

P36507.

Polymorphism databases

DMDM

547915.

2D gel databases

REPRODUCTION-2DPAGE

IPI00003783.

Proteomic databases

PaxDb

P36507.

PeptideAtlas

P36507.

PRIDE

P36507.

Protocols and materials databases

DNASU

5605.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000262948; ENSP00000262948; ENSG00000126934.

GeneID

5605.

KEGG

hsa:5605.

UCSC

uc002lzj.3. human.

Organism-specific databases

CTD

5605.

GeneCards

GC19M004090.

H-InvDB

HIX0033655.

HGNC

HGNC:6842. MAP2K2.

HPA

CAB003835.

MIM

115150. phenotype.
601263. gene.

neXtProt

NX_P36507.

Orphanet

1340. Cardiofaciocutaneous syndrome.

PharmGKB

PA30587.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0515.

HOGENOM

HOG000234206.

HOVERGEN

HBG108518.

InParanoid

P36507.

KO

K04369.

OMA

SGEIKIC.

OrthoDB

EOG4SF965.

PhylomeDB

P36507.

Enzyme and pathway databases

BRENDA

2.7.12.2. 2681.

Pathway_Interaction_DB

anthraxpathway. Cellular roles of Anthrax toxin.
ceramidepathway. Ceramide signaling pathway.
cd8tcrdownstreampathway. Downstream signaling in naive CD8+ T cells.
endothelinpathway. Endothelins.
fcer1pathway. Fc-epsilon receptor I signaling in mast cells.
il2_1pathway. IL2-mediated signaling events.
met_pathway. Signaling events activated by Hepatocyte Growth Factor Receptor (c-Met).
kitpathway. Signaling events mediated by Stem cell factor receptor (c-Kit).

Reactome

REACT_111045. Developmental Biology.
REACT_111102. Signal Transduction.
REACT_116125. Disease.
REACT_6782. TRAF6 Mediated Induction of proinflammatory cytokines.
REACT_6900. Immune System.

Gene expression databases

ArrayExpress

P36507.

Bgee

P36507.

CleanEx

HS_MAP2K2.

Genevestigator

P36507.

GermOnline

ENSG00000126934. 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

P36507.

ChEMBL

CHEMBL2964.

ChiTaRS

MAP2K2. human.

EvolutionaryTrace

P36507.

GenomeRNAi

5605.

NextBio

21780.

PMAP-CutDB

P36507.

SOURCE

Search...

Entry information

Entry name

MP2K2_HUMAN

Accession

Primary (citable) accession number: P36507

Entry history

Integrated into UniProtKB/Swiss-Prot:	June 1, 1994
Last sequence update:	June 1, 1994
Last modified:	May 1, 2013
This is version 154 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.