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Q01986 (MP2K1_RAT) Reviewed, UniProtKB/Swiss-Prot

Last modified March 19, 2014. Version 129. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (1) | 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
OrganismRattus norvegicus (Rat) [Reference proteome]
Taxonomic identifier10116 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus

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 Ref.12

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.6 Ref.7 Ref.10 Ref.11

Subunit structure

Forms a heterodimer with MAP2K2/MEK2 By similarity. Forms heterodimers with KSR2 which further dimerize to form tetramers By similarity. Interacts with MORG1 and VRK2 By similarity. Found in a complex with at least BRAF, HRAS, MAP2K1, MAPK3/ERK1 and RGS14. Interacts with ARRB2, LAMTOR3, MAPK1/ERK2, and RAF1 (via the proline-rich domain). Interacts with SGK1 By similarity. Interacts with BIRC6/bruce By similarity. Ref.6 Ref.7 Ref.9 Ref.11 Ref.13

Subcellular location

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

Domain

The proline-rich region localized between residues 270 and 307 is important for binding to RAF1 and activation of MAP2K1/MEK1. Ref.6

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.8 Ref.10 Ref.11

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 mutant phenotype PubMed 9458043. Source: RGD

cell cycle arrest

Inferred from electronic annotation. Source: Ensembl

cell motility

Inferred from electronic annotation. Source: Ensembl

cell proliferation

Inferred from direct assay PubMed 16481589. Source: RGD

cellular senescence

Inferred from electronic annotation. Source: Ensembl

keratinocyte differentiation

Inferred from electronic annotation. Source: Ensembl

labyrinthine layer development

Inferred from electronic annotation. Source: Ensembl

melanosome transport

Inferred from direct assay PubMed 15753041. Source: RGD

mitosis

Inferred from direct assay PubMed 12695496. Source: RGD

negative regulation of cell proliferation

Inferred from electronic annotation. Source: Ensembl

negative regulation of homotypic cell-cell adhesion

Inferred from mutant phenotype PubMed 17183546. Source: RGD

neuron projection morphogenesis

Inferred from mutant phenotype PubMed 17202850. Source: RGD

peptidyl-tyrosine dephosphorylation

Inferred from electronic annotation. Source: GOC

peptidyl-tyrosine phosphorylation

Inferred from electronic annotation. Source: GOC

placenta blood vessel development

Inferred from electronic annotation. Source: Ensembl

positive regulation of Ras GTPase activity

Inferred from mutant phenotype PubMed 17183546. Source: RGD

positive regulation of Ras protein signal transduction

Inferred from mutant phenotype PubMed 19029245. Source: MGI

positive regulation of cell differentiation

Inferred from electronic annotation. Source: Ensembl

positive regulation of cell migration

Inferred from mutant phenotype PubMed 17183546. Source: RGD

positive regulation of transcription elongation from RNA polymerase II promoter

Inferred from mutant phenotype PubMed 18086894. Source: RGD

protein heterooligomerization

Inferred from physical interaction PubMed 15917294. Source: RGD

regulation of Golgi inheritance

Traceable author statement Ref.16. Source: UniProtKB

regulation of early endosome to late endosome transport

Traceable author statement Ref.16. Source: UniProtKB

regulation of stress-activated MAPK cascade

Traceable author statement Ref.16. Source: UniProtKB

regulation of vascular smooth muscle contraction

Inferred from mutant phenotype PubMed 10198244. Source: RGD

response to axon injury

Inferred from mutant phenotype PubMed 15737734. Source: RGD

response to glucocorticoid

Inferred from direct assay PubMed 11872750. Source: RGD

response to oxidative stress

Inferred from direct assay PubMed 16481589. Source: RGD

vesicle transport along microtubule

Inferred from direct assay PubMed 15753041. Source: RGD

   Cellular_componentGolgi apparatus

Traceable author statement Ref.16. Source: UniProtKB

axon

Inferred from direct assay PubMed 9714150. Source: RGD

cell cortex

Inferred from direct assay PubMed 16272159. Source: RGD

cytosol

Traceable author statement Ref.16. Source: UniProtKB

dendrite cytoplasm

Inferred from direct assay PubMed 9714150. Source: RGD

early endosome

Traceable author statement Ref.16. Source: UniProtKB

focal adhesion

Traceable author statement Ref.16. Source: UniProtKB

late endosome

Traceable author statement Ref.16. Source: UniProtKB

mitochondrion

Traceable author statement Ref.16. Source: UniProtKB

nucleus

Traceable author statement Ref.16. Source: UniProtKB

perikaryon

Inferred from direct assay PubMed 10465442PubMed 9714150. Source: RGD

perinuclear region of cytoplasm

Inferred from direct assay Ref.10. Source: RGD

plasma membrane

Inferred from direct assay Ref.10. Source: RGD

spindle pole body

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular_functionATP binding

Inferred from direct assay PubMed 7611406. Source: RGD

MAP kinase kinase activity

Inferred from direct assay PubMed 7611406PubMed 7624324PubMed 7935430PubMed 8393135. Source: RGD

mitogen-activated protein kinase kinase kinase binding

Inferred from direct assay Ref.6. Source: RGD

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 tyrosine kinase activity

Inferred from electronic annotation. Source: UniProtKB-KW

receptor signaling protein tyrosine phosphatase activity

Inferred from electronic annotation. Source: Ensembl

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_0000086369

Regions

Domain68 – 361294Protein kinase
Nucleotide binding74 – 829ATP By similarity
Region270 – 30738RAF1-binding
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 Ref.11
Modified residue2981Phosphoserine; by PAK Ref.10 Ref.11

Sequences

Sequence LengthMass (Da)Tools
Q01986 [UniParc].

Last modified January 23, 2007. Version 2.
Checksum: A1C8D18FFC852D51

FASTA39343,465
        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 LELLFGCQVE 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]"Molecular structure of a protein-tyrosine/threonine kinase activating p42 mitogen-activated protein (MAP) kinase: MAP kinase kinase."
Wu J., Harrison J.K., Vincent L.A., Haystead C., Haystead T.A.J., Michel H., Hunt D.F., Lynch K.R., Sturgill T.W.
Proc. Natl. Acad. Sci. U.S.A. 90:173-177(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Strain: Sprague-Dawley.
Tissue: Kidney.
[2]"Isolation of two members of the rat MAP kinase kinase gene family."
Otsu M., Terada Y., Okayama H.
FEBS Lett. 320:246-250(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]"Cloning and sequencing of a cDNA encoding rat brain mitogen-activated protein (MAP) kinase activator."
Doering F., Drewes G., Berling B., Mandelkow E.M.
Gene 131:303-304(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE.
Strain: Sprague-Dawley.
[4]"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: Thymus.
[5]Lubec G., Chen W.-Q.
Submitted (APR-2007) to UniProtKB
Cited for: PROTEIN SEQUENCE OF 206-227; 270-291 AND 325-340, MASS SPECTROMETRY.
Strain: Sprague-Dawley.
Tissue: Hippocampus.
[6]"A proline-rich sequence unique to MEK1 and MEK2 is required for raf binding and regulates MEK function."
Catling A.D., Schaeffer H.J., Reuter C.W., Reddy G.R., Weber M.J.
Mol. Cell. Biol. 15:5214-5225(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: DOMAIN, INTERACTION WITH RAF1, ENZYME REGULATION.
[7]"MP1: a MEK binding partner that enhances enzymatic activation of the MAP kinase cascade."
Schaeffer H.J., Catling A.D., Eblen S.T., Collier L.S., Krauss A., Weber M.J.
Science 281:1668-1671(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH LAMTOR3, ENZYME REGULATION.
[8]"A specific activation of the mitogen-activated protein kinase kinase 1 (MEK1) is required for Golgi fragmentation during mitosis."
Colanzi A., Deerinck T.J., Ellisman M.H., Malhotra V.
J. Cell Biol. 149:331-339(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION, FUNCTION.
[9]"Activation and targeting of extracellular signal-regulated kinases by beta-arrestin scaffolds."
Luttrell L.M., Roudabush F.L., Choy E.W., Miller W.E., Field M.E., Pierce K.L., Lefkowitz R.J.
Proc. Natl. Acad. Sci. U.S.A. 98:2449-2454(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH ARRB2.
[10]"PAK1 phosphorylation of MEK1 regulates fibronectin-stimulated MAPK activation."
Slack-Davis J.K., Eblen S.T., Zecevic M., Boerner S.A., Tarcsafalvi A., Diaz H.B., Marshall M.S., Weber M.J., Parsons J.T., Catling A.D.
J. Cell Biol. 162:281-291(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT SER-298, ENZYME REGULATION.
[11]"Mitogen-activated protein kinase feedback phosphorylation regulates MEK1 complex formation and activation during cellular adhesion."
Eblen S.T., Slack-Davis J.K., Tarcsafalvi A., Parsons J.T., Weber M.J., Catling A.D.
Mol. Cell. Biol. 24:2308-2317(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT THR-292 AND SER-298, INTERACTION WITH MAPK1/ERK2, ENZYME REGULATION.
[12]"The novel lipid raft adaptor p18 controls endosome dynamics by anchoring the MEK-ERK pathway to late endosomes."
Nada S., Hondo A., Kasai A., Koike M., Saito K., Uchiyama Y., Okada M.
EMBO J. 28:477-489(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION OF THE MAPK/ERK PATHWAY.
[13]"Regulator of G-protein signaling 14 (RGS14) is a selective H-Ras effector."
Willard F.S., Willard M.D., Kimple A.J., Soundararajan M., Oestreich E.A., Li X., Sowa N.A., Kimple R.J., Doyle D.A., Der C.J., Zylka M.J., Snider W.D., Siderovski D.P.
PLoS ONE 4:E4884-E4884(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION IN A COMPLEX WITH BRAF; HRAS; MAPK3 AND RGS14.
[14]"Signaling by dual specificity kinases."
Dhanasekaran N., Premkumar Reddy E.
Oncogene 17:1447-1455(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON FUNCTION.
[15]"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.
[16]"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.
[17]"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
Z16415 mRNA. Translation: CAA78905.1.
D13341 mRNA. Translation: BAA02603.1.
D14591 mRNA. Translation: BAA03441.1.
X62313 mRNA. Translation: CAA44192.1.
BC089772 mRNA. Translation: AAH89772.1.
PIRJN0840.
RefSeqNP_113831.1. NM_031643.4.
UniGeneRn.5850.

3D structure databases

ProteinModelPortalQ01986.
SMRQ01986. Positions 62-382.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid251005. 5 interactions.
STRING10116.ENSRNOP00000013933.

PTM databases

PhosphoSiteQ01986.

Proteomic databases

PaxDbQ01986.
PRIDEQ01986.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSRNOT00000013933; ENSRNOP00000013933; ENSRNOG00000010176.
GeneID170851.
KEGGrno:170851.
UCSCRGD:70495. rat.

Organism-specific databases

CTD5604.
RGD70495. Map2k1.

Phylogenomic databases

eggNOGCOG0515.
GeneTreeENSGT00690000101918.
HOGENOMHOG000234206.
HOVERGENHBG108518.
InParanoidQ01986.
KOK04368.
OMAYLESEDQ.
OrthoDBEOG7HF1KZ.
TreeFamTF105137.

Enzyme and pathway databases

BRENDA2.7.12.2. 5301.
ReactomeREACT_195021. Developmental Biology.

Gene expression databases

GenevestigatorQ01986.

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

NextBio621291.
PROQ01986.

Entry information

Entry nameMP2K1_RAT
AccessionPrimary (citable) accession number: Q01986
Secondary accession number(s): Q5EBD5
Entry history
Integrated into UniProtKB/Swiss-Prot: April 1, 1993
Last sequence update: January 23, 2007
Last modified: March 19, 2014
This is version 129 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