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P31938 (MP2K1_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 143. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended 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=MEK 1
Gene names
Name:Map2k1
Synonyms:Mek1, Prkmk1
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length393 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Binding of extracellular ligands such as growth factors, cytokines and hormones to their cell-surface receptors activates RAS and this initiates RAF1 activation. RAF1 then further activates the dual-specificity protein kinases MAP2K1/MEK1 and MAP2K2/MEK2. Both MAP2K1/MEK1 and MAP2K2/MEK2 function specifically in the MAPK/ERK cascade, and catalyze the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in the extracellular signal-regulated kinases MAPK3/ERK1 and MAPK1/ERK2, leading to their activation and further transduction of the signal within the MAPK/ERK cascade. Depending on the cellular context, this pathway mediates diverse biological functions such as cell growth, adhesion, survival and differentiation, predominantly through the regulation of transcription, metabolism and cytoskeletal rearrangements. One target of the MAPK/ERK cascade is peroxisome proliferator-activated receptor gamma (PPARG), a nuclear receptor that promotes differentiation and apoptosis. MAP2K1/MEK1 has been shown to export PPARG from the nucleus. The MAPK/ERK cascade is also involved in the regulation of endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC), as well as in the fragmentation of the Golgi apparatus during mitosis. Ref.8

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

Enzyme regulation

Ras proteins such as HRAS mediate the activation of RAF proteins such as RAF1 or BRAF which in turn activate extracellular signal-regulated kinases (ERK) through MAPK (mitogen-activated protein kinases) and ERK kinases MAP2K1/MEK1 and MAP2K2/MEK2. Activation occurs through phosphorylation of Ser-218 and Ser-222. MAP2K1/MEK1 is also the target of negative feed-back regulation by its substrate kinases, such as MAPK1/ERK2. These phosphorylate MAP2K1/MEK1 on Thr-292, thereby facilitating dephosphorylation of the activating residues Ser-218 and Ser-222. Inhibited by serine/threonine phosphatase 2A. Ref.5

Subunit structure

Found in a complex with at least BRAF, HRAS, MAP2K1, MAPK3/ERK1 and RGS14 By similarity. Forms heterodimers with KSR2 which further dimerize to form tetramers By similarity. Interacts with LAMTOR3, MAPK1/ERK2, RAF1, PPARG AND VRK2 By similarity. Interacts with ARRB2 and MORG1. Forms a heterodimer with MAP2K2/MEK2. Interacts with SGK1 By similarity. Interacts with BIRC6/bruce By similarity. Ref.7 Ref.8

Subcellular location

Cytoplasmcytoskeletonmicrotubule organizing centercentrosome By similarity. Cytoplasmcytoskeletonmicrotubule organizing centerspindle pole body By similarity. Cytoplasm By similarity. Nucleus By similarity. Note: Localizes at centrosomes during prometaphase, midzone during anaphase and midbody during telophase/cytokinesis By similarity.

Domain

The proline-rich region localized between residues 270 and 307 is important for binding to RAF1 and activation of MAP2K1/MEK1 By similarity.

Post-translational modification

Phosphorylation at Ser-218 and Ser-222 by MAP kinase kinase kinases (RAF or MEKK1) positively regulates kinase activity. Also phosphorylated at Thr-292 by MAPK1/ERK2 and at Ser-298 by PAK. MAPK1/ERK2 phosphorylation of Thr-292 occurs in response to cellular adhesion and leads to inhibition of Ser-298 phosphorylation by PAK. Ref.5 Ref.8

Disruption phenotype

Affects fibroblast shape and impairs haptotaxis and adhesion-dependent ERK-signaling. Ref.8

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
   Cellular componentCytoplasm
Cytoskeleton
Nucleus
   LigandATP-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
Tyrosine-protein kinase
   PTMPhosphoprotein
   Technical termComplete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processGolgi inheritance

Inferred from electronic annotation. Source: Ensembl

activation of MAPK activity

Traceable author statement Ref.11. Source: UniProtKB

cell cycle arrest

Inferred from electronic annotation. Source: Ensembl

cell motility

Inferred from mutant phenotype PubMed 10209122. Source: MGI

cell proliferation

Inferred from electronic annotation. Source: Ensembl

cellular senescence

Inferred from electronic annotation. Source: Ensembl

keratinocyte differentiation

Inferred from mutant phenotype PubMed 11841548. Source: MGI

labyrinthine layer development

Inferred from mutant phenotype PubMed 10209122. Source: MGI

melanosome transport

Inferred from electronic annotation. Source: Ensembl

mitosis

Inferred from electronic annotation. Source: Ensembl

negative regulation of cell proliferation

Inferred from electronic annotation. Source: Ensembl

negative regulation of homotypic cell-cell adhesion

Inferred from electronic annotation. Source: Ensembl

neuron differentiation

Inferred from mutant phenotype PubMed 15145949. Source: MGI

neuron projection morphogenesis

Inferred from electronic annotation. Source: Ensembl

placenta blood vessel development

Inferred from mutant phenotype PubMed 10209122. Source: MGI

positive regulation of Ras GTPase activity

Inferred from electronic annotation. Source: Ensembl

positive regulation of Ras protein signal transduction

Inferred from sequence orthology PubMed 19029245. Source: MGI

positive regulation of cell differentiation

Inferred from direct assay PubMed 16908534. Source: MGI

positive regulation of cell migration

Inferred from electronic annotation. Source: Ensembl

positive regulation of transcription elongation from RNA polymerase II promoter

Inferred from electronic annotation. Source: Ensembl

protein heterooligomerization

Inferred from electronic annotation. Source: Ensembl

protein phosphorylation

Inferred from mutant phenotype PubMed 15896720. Source: MGI

regulation of Golgi inheritance

Traceable author statement Ref.11. Source: UniProtKB

regulation of early endosome to late endosome transport

Traceable author statement Ref.11. Source: UniProtKB

regulation of stress-activated MAPK cascade

Traceable author statement Ref.11. Source: UniProtKB

regulation of vascular smooth muscle contraction

Inferred from electronic annotation. Source: Ensembl

response to axon injury

Inferred from electronic annotation. Source: Ensembl

response to glucocorticoid

Inferred from electronic annotation. Source: Ensembl

response to oxidative stress

Inferred from electronic annotation. Source: Ensembl

vesicle transport along microtubule

Inferred from electronic annotation. Source: Ensembl

   Cellular_componentGolgi apparatus

Traceable author statement Ref.11. Source: UniProtKB

cell cortex

Inferred from electronic annotation. Source: Ensembl

cytosol

Traceable author statement Ref.11. Source: UniProtKB

dendrite cytoplasm

Inferred from electronic annotation. Source: Ensembl

early endosome

Traceable author statement Ref.11. Source: UniProtKB

focal adhesion

Traceable author statement Ref.11. Source: UniProtKB

late endosome

Traceable author statement Ref.11. Source: UniProtKB

mitochondrion

Traceable author statement Ref.11. Source: UniProtKB

nucleus

Traceable author statement Ref.11. Source: UniProtKB

perikaryon

Inferred from electronic annotation. Source: Ensembl

perinuclear region of cytoplasm

Inferred from electronic annotation. Source: Ensembl

plasma membrane

Inferred from electronic annotation. Source: Ensembl

spindle pole body

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

MAP kinase kinase activity

Inferred from mutant phenotype PubMed 11841548. Source: MGI

protein serine/threonine kinase activator activity

Inferred from electronic annotation. Source: Ensembl

protein serine/threonine kinase activity

Inferred from electronic annotation. Source: UniProtKB-KW

protein serine/threonine/tyrosine kinase activity

Traceable author statement Ref.11. Source: UniProtKB

protein tyrosine kinase activity

Inferred from electronic annotation. Source: UniProtKB-KW

receptor signaling protein tyrosine phosphatase activity

Inferred from mutant phenotype PubMed 15896720. Source: MGI

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Initiator methionine11Removed By similarity
Chain2 – 393392Dual specificity mitogen-activated protein kinase kinase 1
PRO_0000086366

Regions

Domain68 – 361294Protein kinase
Nucleotide binding74 – 829ATP By similarity
Region270 – 30738RAF1-binding By similarity
Compositional bias262 – 30746Pro-rich

Sites

Active site1901Proton acceptor By similarity
Binding site971ATP By similarity
Site8 – 92Cleavage; by anthrax lethal factor By similarity

Amino acid modifications

Modified residue2181Phosphoserine; by RAF By similarity
Modified residue2221Phosphoserine; by RAF By similarity
Modified residue2861Phosphothreonine By similarity
Modified residue2921Phosphothreonine; by MAPK1 By similarity
Modified residue2981Phosphoserine; by PAK By similarity

Experimental info

Mutagenesis781N → G: Impairs interaction with MAP2K2/MEK2. Ref.8
Mutagenesis2921T → A: Results in hyperphosphorylation of the RAF-dependent sites and prolonged ERK phosphorylation. Ref.8
Mutagenesis2921T → D: Results in hypophosphorylation of the RAF-dependent sites and faster ERK inactivation. Ref.8
Sequence conflict3741W → Q AA sequence Ref.3

Sequences

Sequence LengthMass (Da)Tools
P31938 [UniParc].

Last modified January 23, 2007. Version 2.
Checksum: 01D1D18572AE40E7

FASTA39343,474
        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 LELLFGCHVE GDAAETPPRP RTPGRPLSSY 

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

       370        380        390 
IKRSDAEEVD FAGWLCSTIG LNQPSTPTHA ASI 

« Hide

References

« Hide 'large scale' references
[1]"The primary structure of MEK, a protein kinase that phosphorylates the ERK gene product."
Crews C.M., Alessandrini A., Erikson R.L.
Science 258:478-480(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE.
[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].
Strain: C57BL/6.
Tissue: Brain.
[3]"Purification of a murine protein-tyrosine/threonine kinase that phosphorylates and activates the Erk-1 gene product: relationship to the fission yeast byr1 gene product."
Crews C.M., Erikson R.L.
Proc. Natl. Acad. Sci. U.S.A. 89:8205-8209(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEIN SEQUENCE OF 4-20; 71-84; 114-136; 206-234 AND 363-384.
Tissue: T-cell.
[4]Lubec G., Klug S.
Submitted (MAR-2007) to UniProtKB
Cited for: PROTEIN SEQUENCE OF 206-227; 270-291 AND 325-340, IDENTIFICATION BY MASS SPECTROMETRY.
Tissue: Hippocampus.
[5]"A divergence in the MAP kinase regulatory network defined by MEK kinase and Raf."
Lange-Carter C.A., Pleiman C.M., Gardner A.M., Blumer K.J., Johnson G.L.
Science 260:315-319(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AND ENZYME REGULATION.
[6]"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.
[7]"Modular construction of a signaling scaffold: MORG1 interacts with components of the ERK cascade and links ERK signaling to specific agonists."
Vomastek T., Schaeffer H.-J., Tarcsafalvi A., Smolkin M.E., Bissonette E.A., Weber M.J.
Proc. Natl. Acad. Sci. U.S.A. 101:6981-6986(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH MORG1.
[8]"A Mek1-Mek2 heterodimer determines the strength and duration of the Erk signal."
Catalanotti F., Reyes G., Jesenberger V., Galabova-Kovacs G., de Matos Simoes R., Carugo O., Baccarini M.
Nat. Struct. Mol. Biol. 16:294-303(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: DISRUPTION PHENOTYPE, FUNCTION, INTERACTION WITH MAP2K2/MEK2, PHOSPHORYLATION AT THR-292, MUTAGENESIS OF ASN-78 AND THR-292.
[9]"Signaling by dual specificity kinases."
Dhanasekaran N., Premkumar Reddy E.
Oncogene 17:1447-1455(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON FUNCTION.
[10]"The RAF proteins take centre stage."
Wellbrock C., Karasarides M., Marais R.
Nat. Rev. Mol. Cell Biol. 5:875-885(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON ENZYME REGULATION.
[11]"The ERK signaling cascade--views from different subcellular compartments."
Yao Z., Seger R.
BioFactors 35:407-416(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON FUNCTION.
[12]"The ERK cascade: distinct functions within various subcellular organelles."
Wortzel I., Seger R.
Genes Cancer 2:195-209(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON FUNCTION.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
L02526 mRNA. Translation: AAA39523.1.
BC054754 mRNA. Translation: AAH54754.1.
PIRI59571.
RefSeqNP_032953.1. NM_008927.3.
UniGeneMm.248907.

3D structure databases

ProteinModelPortalP31938.
SMRP31938. Positions 39-381.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid204949. 12 interactions.
DIPDIP-467N.
IntActP31938. 4 interactions.
MINTMINT-1518233.
STRING10090.ENSMUSP00000005066.

Chemistry

BindingDBP31938.
ChEMBLCHEMBL5860.

PTM databases

PhosphoSiteP31938.

2D gel databases

UCD-2DPAGEP31938.

Proteomic databases

PaxDbP31938.
PRIDEP31938.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000005066; ENSMUSP00000005066; ENSMUSG00000004936.
GeneID26395.
KEGGmmu:26395.
UCSCuc009qbp.1. mouse.

Organism-specific databases

CTD5604.
MGIMGI:1346866. Map2k1.

Phylogenomic databases

eggNOGCOG0515.
HOGENOMHOG000234206.
HOVERGENHBG108518.
InParanoidP31938.
KOK04368.
OMARDKHAIM.
OrthoDBEOG7HF1KZ.
PhylomeDBP31938.
TreeFamTF105137.

Enzyme and pathway databases

BRENDA2.7.12.2. 3474.
ReactomeREACT_98458. Immune System.

Gene expression databases

ArrayExpressP31938.
BgeeP31938.
CleanExMM_MAP2K1.
GenevestigatorP31938.

Family and domain databases

InterProIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMSSF56112. SSF56112. 1 hit.
PROSITEPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSMAP2K1. mouse.
NextBio304339.
PROP31938.
SOURCESearch...

Entry information

Entry nameMP2K1_MOUSE
AccessionPrimary (citable) accession number: P31938
Entry history
Integrated into UniProtKB/Swiss-Prot: July 1, 1993
Last sequence update: January 23, 2007
Last modified: April 16, 2014
This is version 143 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot