Reviewed, UniProtKB/Swiss-Prot P36507 (MP2K2_HUMAN)

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) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › 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.
Post-translational modification	MAPKK is itself dependent on Ser/Thr phosphorylation for activity catalyzed by MAP kinase kinase kinases (RAF or MEKK1).
Involvement in disease	Defects in MAP2K2 are a cause of cardiofaciocutaneous syndrome (CFC syndrome) [MIM:115150]; also known as cardio-facio-cutaneous syndrome. CFC syndrome is 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.
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
Gene Ontology (GO)
Biological process	Ras protein signal transduction Inferred from Experiment. Source: Reactome protein amino acid phosphorylation Non-traceable author statement. Source: UniProtKB
Cellular component	cytosol Ref.1 Inferred from Experiment. Source: Reactome extracellular region Ref.1 Non-traceable author statement. Source: UniProtKB
Molecular function	ATP binding Non-traceable author statement. Source: UniProtKB protein binding Inferred from physical interaction. Source: IntAct protein serine/threonine kinase activity Ref.1 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	3	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

1

1

N-acetylmethionine Ref.15

Modified residue

23

1

Phosphoserine Ref.7 Ref.12

Modified residue

222

1

Phosphoserine; by RAF Ref.13

Modified residue

226

1

Phosphoserine Ref.13 Ref.9

Modified residue

293

1

Phosphoserine Ref.12

Modified residue

295

1

Phosphoserine Ref.12

Modified residue

394

1

Phosphothreonine Ref.15 Ref.7 Ref.13 Ref.9 Ref.3 Ref.6 Ref.11 Ref.17

Modified residue

396

1

Phosphothreonine Ref.12 Ref.13 Ref.11 Ref.8 Ref.10

Natural variations

Natural variant

57

1

F → C in CFC syndrome. Ref.18

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)
	P36507-1 [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: 8388392] [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: 15489334] [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]	"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: 9563949] [Abstract] Cited for: CLEAVAGE BY ANTHRAX LETHAL FACTOR.
[5]	"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: 11104681] [Abstract] Cited for: CLEAVAGE BY ANTHRAX LETHAL FACTOR.
[6]	"Large-scale characterization of HeLa cell nuclear phosphoproteins." Beausoleil S.A., Jedrychowski M., Schwartz D., Elias J.E., Villen J., Li J., Cohn M.A., Cantley L.C., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 101:12130-12135(2004) [PubMed: 15302935] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-394, MASS SPECTROMETRY. Tissue: Epithelium.
[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: 17081983] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-23 AND THR-394, MASS SPECTROMETRY. Tissue: Epithelium.
[8]	"A probability-based approach for high-throughput protein phosphorylation analysis and site localization." Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P. Nat. Biotechnol. 24:1285-1292(2006) [PubMed: 16964243] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-396, MASS SPECTROMETRY. Tissue: Epithelium.
[9]	"Proteomics analysis of protein kinases by target class-selective prefractionation and tandem mass spectrometry." Wissing J., Jaensch L., Nimtz M., Dieterich G., Hornberger R., Keri G., Wehland J., Daub H. Mol. Cell. Proteomics 6:537-547(2007) [PubMed: 17192257] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-226 AND THR-394, MASS SPECTROMETRY.
[10]	"Automated phosphoproteome analysis for cultured cancer cells by two-dimensional nanoLC-MS using a calcined titania/C18 biphasic column." Imami K., Sugiyama N., Kyono Y., Tomita M., Ishihama Y. Anal. Sci. 24:161-166(2008) [PubMed: 18187866] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-396, MASS SPECTROMETRY.
[11]	"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: 18088087] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-394 AND THR-396, MASS SPECTROMETRY. Tissue: Platelet.
[12]	"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: 18691976] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-23; SER-293; SER-295 AND THR-396, MASS SPECTROMETRY.
[13]	"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: 18669648] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-222; SER-226; THR-394 AND THR-396, MASS SPECTROMETRY.
[14]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[15]	"Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach." Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S. Anal. Chem. 81:4493-4501(2009) [PubMed: 19413330] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-394, MASS SPECTROMETRY.
[16]	"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: 19369195] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-23; SER-222; SER-226; SER-293; SER-295 AND THR-396, MASS SPECTROMETRY.
[17]	"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: 19690332] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-394, MASS SPECTROMETRY. Tissue: T-cell.
[18]	"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: 16439621] [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.

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	[»]

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-29119N.

IntAct

P36507. 11 interactions.

STRING

P36507.

PTM databases

PhosphoSite

P36507.

2-D gel databases

REPRODUCTION-2DPAGE

IPI00003783.

Proteomic databases

PeptideAtlas

P36507.

PRIDE

P36507.

Genome annotation databases

Ensembl

ENST00000262948; ENSP00000262948; ENSG00000126934; Homo sapiens. [Genome view]

GeneID

5605.

KEGG

hsa:5605.

UCSC

uc002lzk.1. human.

Organism-specific databases

CTD

5605.

GeneCards

GC19M004041.

H-InvDB

HIX0014653.
HIX0033655.

HGNC

HGNC:6842. MAP2K2.

HPA

CAB003835.

MIM

115150. phenotype.
601263. gene.

Orphanet

1340. Cardiofaciocutaneous syndrome.

PharmGKB

PA30587.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG06383.

HOGENOM

HBG755340.

HOVERGEN

HBG108518.

InParanoid

P36507.

OMA

FEPICEL.

PhylomeDB

P36507.

Enzyme and pathway databases

BRENDA

2.7.12.2. 247.

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_11061. Signalling by NGF.
REACT_16888. Signaling by PDGF.
REACT_18266. Axon guidance.
REACT_498. Signaling by Insulin receptor.
REACT_9417. Signaling by EGFR.

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.
IPR017442. Se/Thr_prot_kinase-like_dom.
IPR008271. Ser/Thr_prot_kinase_AS.
IPR002290. Ser/Thr_prot_kinase_dom.
[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 Resources

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:	March 2, 2010
This is version 122 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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.