Dual specificity mitogen-activated protein kinase kinase 2

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Reviewed, UniProtKB/Swiss-Prot P36507 (MP2K2_HUMAN)

Last modified June 16, 2009. Version 112. History...

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Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents

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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=MEK2

Gene names

Name:	MAP2K2
Synonyms:	MEK2, MKK2, PRKMK2

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

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Protein attributes

Sequence length	400 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

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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.

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Ontologies

Keywords
Disease	Disease mutation
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase Tyrosine-protein kinase
PTM	Phosphoprotein
Technical term	3D-structure 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	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 Non-traceable author statement. Source: UniProtKB protein tyrosine kinase activity Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

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Binary interactions

With	Entry	#Exp.	IntAct	Notes
ARAF	P10398	3	EBI-1056930,EBI-365961

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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

ATP By similarity

Compositional bias

266 – 315

Pro-rich

Sites

Active site

194

Proton acceptor By similarity

Binding site

101

ATP By similarity

Site

10 – 11

Cleavage; by anthrax lethal factor

Amino acid modifications

Modified residue

Phosphoserine Ref.7 Ref.12

Modified residue

222

Phosphoserine; by RAF Ref.13

Modified residue

226

Phosphoserine Ref.13 Ref.9

Modified residue

293

Phosphoserine Ref.12

Modified residue

295

Phosphoserine Ref.12

Modified residue

394

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

Modified residue

396

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

Natural variations

Natural variant

F → C in CFC syndrome.

VAR_035095

Secondary structure

400

Helix Strand Turn

Details...

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Sequences

Sequence

Length

Mass (Da)

Tools

P36507-1 [UniParc].

Last modified June 1, 1994. Version 1.
Checksum: 3401D522515C30A5
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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

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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]	"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.

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Web resources

GeneReviews

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Cross-references

Sequence databases

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

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

ModBase

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Protein-protein interaction databases

DIP

DIP:29119N.

IntAct

P36507. 11 interactions.

PTM databases

PhosphoSite

P36507.

2-D gel databases

REPRODUCTION-2DPAGE

IPI00003783.

Proteomic databases

PeptideAtlas

P36507.

PRIDE

P36507.

Genome annotation databases

Ensembl

ENSG00000126934. Homo sapiens. [Contig view]

GeneID

5605.

KEGG

hsa:5605.

Organism-specific databases

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

HOGENOM

P36507.

HOVERGEN

P36507.

OMA

P36507. FEPICEL.

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_498. Signaling by Insulin receptor.

Gene expression databases

ArrayExpress

P36507.

Bgee

P36507.

CleanEx

HS_MAP2K2.

GermOnline

ENSG00000126934. Homo sapiens.

Family and domain databases

InterPro

IPR000719. Prot_kinase_core.
IPR017441. Protein_kinase_ATP_BS.
IPR017442. Se/Thr_pkinase-rel.
IPR008271. Ser_thr_pkin_AS.
IPR002290. Ser_thr_pkinase.
[Graphical view]

Pfam

PF00069. Pkinase. 1 hit.
[Graphical view]

ProDom

PD000001. Prot_kinase. 1 hit.
[Graphical view] [Entries sharing at least one domain]

SMART

SM00220. S_TKc. 1 hit.
[Graphical view]

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...

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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:	June 16, 2009
This is version 112 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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Relevant documents

Human chromosome 19

Human chromosome 19: entries, gene names and cross-references to MIM

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

SIMILARITY comments

Index of protein domains and families

Names and origin

Protein attributes

General annotation (Comments)

Ontologies

Binary interactions

With

Entry

#Exp.

IntAct

Notes

Sequence annotation (Features)

Molecule processing

Regions

Sites

Amino acid modifications

Natural variations

Secondary structure

Sequences

References

Web resources

Cross-references

Sequence databases

3D structure databases

Protein-protein interaction databases

PTM databases

2-D gel databases

Proteomic databases

Genome annotation databases

Organism-specific databases

Phylogenomic databases

Enzyme and pathway databases

Gene expression databases

Family and domain databases

Other Resources

Entry information

Relevant documents