Dual specificity mitogen-activated protein kinase kinase 1

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Reviewed, UniProtKB/Swiss-Prot Q02750 (MP2K1_HUMAN)

Last modified June 16, 2009. Version 103. History...

Clusters with 100%, 90%, 50% identity |

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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 1
      Short name=MAP kinase kinase 1
      Short name=MAPKK 1
    EC=2.7.12.2
Alternative name(s):
    ERK activator kinase 1
    MAPK/ERK kinase 1
      Short name=MEK1

Gene names

Name:	MAP2K1
Synonyms:	MEK1, PRKMK1

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	393 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
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 ERK1 and ERK2 MAP kinases.
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Enzyme regulation	Activated by phosphorylation.
Subunit structure	Interacts with MORG1 By similarity. Interacts with Yersinia yopJ.
Post-translational modification	Phosphorylation on Ser/Thr by MAP kinase kinase kinases (RAF or MEKK1) regulates positively the kinase activity. Acetylation by Yersinia yopJ prevents phosphorylation and activation, thus blocking the MAPK signaling pathway.
Involvement in disease	Defects in MAP2K1 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	Acetylation Phosphoprotein
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological process	Ras protein signal transduction Inferred from Experiment. Source: Reactome cell motion Traceable author statement. Source: ProtInc chemotaxis Traceable author statement. Source: ProtInc
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW MAP kinase kinase activity Ref.2 Traceable author statement. Source: ProtInc protein binding Inferred from physical interaction. Source: UniProtKB protein serine/threonine kinase activity Inferred from electronic annotation. Source: UniProtKB-KW protein tyrosine kinase activity Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

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Binary interactions

With	Entry	#Exp.	IntAct
BIRC6	Q9NR09	1	EBI-492564,EBI-1765160
RAF1	P04049	1	EBI-492564,EBI-365996
TRIB1	Q96RU8	1	EBI-492564,EBI-492555
TRIB3	Q96RU7	1	EBI-492564,EBI-492476

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Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

Removed By similarity

Chain

2 – 393

392

Dual specificity mitogen-activated protein kinase kinase 1

PRO_0000086365

Regions

Domain

68 – 361

294

Protein kinase

Nucleotide binding

74 – 82

ATP By similarity

Compositional bias

262 – 307

Pro-rich

Sites

Active site

190

Proton acceptor By similarity

Binding site

ATP

Site

8 – 9

Cleavage; by anthrax lethal factor

Amino acid modifications

Modified residue

218

Phosphoserine; by RAF Ref.3

Modified residue

222

Phosphoserine; by RAF Ref.3 Ref.7

Modified residue

231

Phosphoserine Ref.8

Modified residue

286

Phosphothreonine Ref.8

Modified residue

386

Phosphothreonine Ref.8

Natural variations

Natural variant

F → S in CFC syndrome.

VAR_035093

Natural variant

130

Y → C in CFC syndrome.

VAR_035094

Experimental info

Mutagenesis

K → R: Inactivation.

Mutagenesis

150

S → A: No loss of activity.

Mutagenesis

212

S → A: No loss of activity.

Mutagenesis

218

S → A: Inactivation.

Mutagenesis

222

S → A: Inactivation.

Secondary structure

393

Helix Strand Turn

Details...

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Sequences

Sequence

Length

Mass (Da)

Tools

Q02750-1 [UniParc].

Last modified January 23, 2007. Version 2.
Checksum: 0344118FFC842D51
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FASTA

393

43,439

        10         20         30         40         50         60 
MPKKKPTPIQ LNPAPDGSAV NGTSSAETNL EALQKKLEEL ELDEQQRKRL EAFLTQKQKV 

        70         80         90        100        110        120 
GELKDDDFEK ISELGAGNGG VVFKVSHKPS GLVMARKLIH LEIKPAIRNQ IIRELQVLHE 

       130        140        150        160        170        180 
CNSPYIVGFY GAFYSDGEIS ICMEHMDGGS LDQVLKKAGR IPEQILGKVS IAVIKGLTYL 

       190        200        210        220        230        240 
REKHKIMHRD VKPSNILVNS RGEIKLCDFG VSGQLIDSMA NSFVGTRSYM SPERLQGTHY 

       250        260        270        280        290        300 
SVQSDIWSMG LSLVEMAVGR YPIPPPDAKE LELMFGCQVE GDAAETPPRP RTPGRPLSSY 

       310        320        330        340        350        360 
GMDSRPPMAI FELLDYIVNE PPPKLPSGVF SLEFQDFVNK CLIKNPAERA DLKQLMVHAF 

       370        380        390 
IKRSDAEEVD FAGWLCSTIG LNQPSTPTHA AGV

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References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Human T-cell mitogen-activated protein kinase kinases are related to yeast signal transduction kinases." Seger R., Seger D., Lozeman F.J., Ahn N.G., Graves L.M., Campbell J.S., Ericsson L., Harrylock M., Jensen A.M., Krebs E.G. J. Biol. Chem. 267:25628-25631(1992) [PubMed: 1281467] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"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].
[3]	"Activation of MEK family kinases requires phosphorylation of two conserved Ser/Thr residues." Zheng C.-F., Guan K.-L. EMBO J. 13:1123-1131(1994) [PubMed: 8131746] [Abstract] Cited for: PHOSPHORYLATION AT SER-218 AND SER-222, MUTAGENESIS.
[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, PROTEIN SEQUENCE OF 9-17.
[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]	"Yersinia YopJ acetylates and inhibits kinase activation by blocking phosphorylation." Mukherjee S., Keitany G., Li Y., Wang Y., Ball H.L., Goldsmith E.J., Orth K. Science 312:1211-1214(2006) [PubMed: 16728640] [Abstract] Cited for: INTERACTION WITH YOPJ, ACETYLATION.
[7]	"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-222, MASS SPECTROMETRY.
[8]	"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-231; THR-286 AND THR-386, MASS SPECTROMETRY.
[9]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[10]	"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: VARIANTS CFC SYNDROME SER-53 AND CYS-130.
+	Additional computationally mapped references.

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Web resources

GeneReviews

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Cross-references

Sequence databases

L05624 mRNA. Translation: AAA36318.1.
L11284 mRNA. No translation available.

IPI

IPI00219604.

PIR

A45100.

RefSeq

NP_002746.1.

UniGene

Hs.145442

3D structure databases

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1S9J	X-ray	2.40	A	62-392	[»]
2P55	X-ray	2.80	A	62-393	[»]
3EQB	X-ray	2.62	A	62-393	[»]
3EQC	X-ray	1.80	A	35-393	[»]
3EQD	X-ray	2.10	A	35-393	[»]
3EQF	X-ray	2.70	A	35-393	[»]
3EQG	X-ray	2.50	A	35-393	[»]
3EQH	X-ray	2.00	A	35-393	[»]
3EQI	X-ray	1.90	A	35-393	[»]

ModBase

Search...

Protein-protein interaction databases

DIP

DIP:201N.

IntAct

Q02750. 16 interactions.

PTM databases

PhosphoSite

Q02750.

Proteomic databases

PeptideAtlas

Q02750.

PRIDE

Q02750.

Genome annotation databases

Ensembl

ENSG00000169032. Homo sapiens. [Contig view]

GeneID

5604.

KEGG

hsa:5604.

Organism-specific databases

GeneCards

GC15P064466.

H-InvDB

HIX0038157.

HGNC

HGNC:6840. MAP2K1.

HPA

CAB003834.

MIM

115150. phenotype.
176872. gene.

Orphanet

1340. Cardiofaciocutaneous syndrome.

PharmGKB

PA30584.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

Q02750.

HOVERGEN

Q02750.

OMA

Q02750. MQKRRKP.

Enzyme and pathway databases

BRENDA

2.7.12.2. 247.

Pathway_Interaction_DB

bcr_5pathway. BCR signaling pathway.
anthraxpathway. Cellular roles of Anthrax toxin.
ceramidepathway. Ceramide signaling pathway.
pi3kcibpathway. Class IB PI3K non-lipid kinase events.
cd8tcrdownstreampathway. Downstream signaling in naive CD8+ T cells.
endothelinpathway. Endothelins.
ephbfwdpathway. EPHB forward signaling.
fcer1pathway. Fc-epsilon receptor I signaling in mast cells.
foxm1pathway. FOXM1 transcription factor network.
hedgehog_glipathway. Hedgehog signaling events mediated by Gli proteins.
ifngpathway. IFN-gamma pathway.
il2_1pathway. IL2-mediated signaling events.
trkrpathway. Neurotrophic factor-mediated Trk receptor signaling.
tcrraspathway. Ras signaling in the CD4+ TCR pathway.
met_pathway. Signaling events activated by Hepatocyte Growth Factor Receptor (c-Met).
kitpathway. Signaling events mediated by Stem cell factor receptor (c-Kit).
mapktrkpathway. Trk receptor signaling mediated by the MAPK pathway.

Reactome

REACT_11061. Signalling by NGF.
REACT_498. Signaling by Insulin receptor.

Gene expression databases

ArrayExpress

Q02750.

Bgee

Q02750.

CleanEx

HS_MAP2K1.

GermOnline

ENSG00000169032. 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

21776.

PMAP-CutDB

Q02750.

SOURCE

Search...

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Entry information

Entry name

MP2K1_HUMAN

Accession

Primary (citable) accession number: Q02750

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 1, 1993
Last sequence update:	January 23, 2007
Last modified:	June 16, 2009
This is version 103 of the entry and version 2 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 15

Human chromosome 15: 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

Experimental info

Secondary structure

Sequences

References

Web resources

Cross-references

Sequence databases

3D structure databases

Protein-protein interaction databases

PTM 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