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Protein

Dual specificity mitogen-activated protein kinase kinase 1

Gene

Map2k1

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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.1 Publication

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Enzyme regulationi

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.

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sitei8 – 92Cleavage; by anthrax lethal factorBy similarity
Binding sitei97 – 971ATPPROSITE-ProRule annotation
Active sitei190 – 1901Proton acceptorPROSITE-ProRule annotation

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi74 – 829ATPPROSITE-ProRule annotation

GO - Molecular functioni

  1. ATP binding Source: UniProtKB-KW
  2. MAP kinase kinase activity Source: MGI
  3. protein C-terminus binding Source: MGI
  4. protein N-terminus binding Source: MGI
  5. protein serine/threonine/tyrosine kinase activity Source: UniProtKB
  6. protein serine/threonine kinase activator activity Source: MGI
  7. protein serine/threonine kinase activity Source: UniProtKB-KW
  8. protein tyrosine kinase activity Source: UniProtKB-KW
  9. receptor signaling protein tyrosine phosphatase activity Source: MGI

GO - Biological processi

  1. activation of MAPK activity Source: UniProtKB
  2. cell cycle arrest Source: MGI
  3. cell motility Source: MGI
  4. cell proliferation Source: Ensembl
  5. cellular senescence Source: MGI
  6. Golgi inheritance Source: Ensembl
  7. keratinocyte differentiation Source: MGI
  8. labyrinthine layer development Source: MGI
  9. melanosome transport Source: Ensembl
  10. mitotic nuclear division Source: Ensembl
  11. negative regulation of cell proliferation Source: MGI
  12. negative regulation of homotypic cell-cell adhesion Source: Ensembl
  13. neuron differentiation Source: MGI
  14. neuron projection morphogenesis Source: Ensembl
  15. placenta blood vessel development Source: MGI
  16. positive regulation of cell differentiation Source: MGI
  17. positive regulation of cell migration Source: Ensembl
  18. positive regulation of gene expression Source: MGI
  19. positive regulation of protein serine/threonine kinase activity Source: MGI
  20. positive regulation of Ras GTPase activity Source: Ensembl
  21. positive regulation of Ras protein signal transduction Source: MGI
  22. positive regulation of transcription elongation from RNA polymerase II promoter Source: Ensembl
  23. protein heterooligomerization Source: Ensembl
  24. protein phosphorylation Source: MGI
  25. regulation of early endosome to late endosome transport Source: UniProtKB
  26. regulation of Golgi inheritance Source: UniProtKB
  27. regulation of stress-activated MAPK cascade Source: UniProtKB
  28. regulation of vascular smooth muscle contraction Source: Ensembl
  29. response to axon injury Source: Ensembl
  30. response to glucocorticoid Source: Ensembl
  31. response to oxidative stress Source: Ensembl
  32. vesicle transport along microtubule Source: Ensembl
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase, Tyrosine-protein kinase

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.12.2. 3474.
ReactomeiREACT_215461. Signal transduction by L1.
REACT_224208. Interleukin-1 signaling.
REACT_242456. Signaling by FGFR.
REACT_247448. ERK1 activation.
REACT_247566. MEK activation.
REACT_257146. RAF phosphorylates MEK.

Names & Taxonomyi

Protein namesi
Recommended name:
Dual specificity mitogen-activated protein kinase kinase 1 (EC:2.7.12.2)
Short name:
MAP kinase kinase 1
Short name:
MAPKK 1
Alternative name(s):
ERK activator kinase 1
MAPK/ERK kinase 1
Short name:
MEK 1
Gene namesi
Name:Map2k1
Synonyms:Mek1, Prkmk1
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589: Chromosome 9

Organism-specific databases

MGIiMGI:1346866. Map2k1.

Subcellular locationi

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

GO - Cellular componenti

  1. axon Source: Ensembl
  2. cell cortex Source: Ensembl
  3. cytoplasm Source: MGI
  4. cytosol Source: UniProtKB
  5. dendrite cytoplasm Source: Ensembl
  6. early endosome Source: UniProtKB
  7. endoplasmic reticulum Source: MGI
  8. extracellular vesicular exosome Source: MGI
  9. focal adhesion Source: UniProtKB
  10. Golgi apparatus Source: UniProtKB
  11. late endosome Source: UniProtKB
  12. microtubule Source: Ensembl
  13. mitochondrion Source: UniProtKB
  14. nucleus Source: UniProtKB
  15. perikaryon Source: Ensembl
  16. perinuclear region of cytoplasm Source: Ensembl
  17. plasma membrane Source: MGI
  18. spindle pole body Source: UniProtKB-SubCell
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Cytoskeleton, Nucleus

Pathology & Biotechi

Disruption phenotypei

Affects fibroblast shape and impairs haptotaxis and adhesion-dependent ERK-signaling.1 Publication

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi78 – 781N → G: Impairs interaction with MAP2K2/MEK2. 1 Publication
Mutagenesisi292 – 2921T → A: Results in hyperphosphorylation of the RAF-dependent sites and prolonged ERK phosphorylation. 1 Publication
Mutagenesisi292 – 2921T → D: Results in hypophosphorylation of the RAF-dependent sites and faster ERK inactivation. 1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Initiator methioninei1 – 11RemovedBy similarity
Chaini2 – 393392Dual specificity mitogen-activated protein kinase kinase 1PRO_0000086366Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei218 – 2181Phosphoserine; by RAFBy similarity
Modified residuei222 – 2221Phosphoserine; by RAFBy similarity
Modified residuei286 – 2861PhosphothreonineBy similarity
Modified residuei292 – 2921Phosphothreonine; by MAPK1By similarity
Modified residuei298 – 2981Phosphoserine; by PAKBy similarity

Post-translational modificationi

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.2 Publications

Keywords - PTMi

Phosphoprotein

Proteomic databases

MaxQBiP31938.
PaxDbiP31938.
PRIDEiP31938.

2D gel databases

UCD-2DPAGEP31938.

PTM databases

PhosphoSiteiP31938.

Expressioni

Gene expression databases

BgeeiP31938.
CleanExiMM_MAP2K1.
ExpressionAtlasiP31938. baseline and differential.
GenevestigatoriP31938.

Interactioni

Subunit structurei

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).By similarity

Binary interactionsi

WithEntry#Exp.IntActNotes
Dnajc27Q8CFP63EBI-298860,EBI-9548773
Mapk8ip3Q9ESN9-23EBI-298860,EBI-9549291
PIN1Q135264EBI-298860,EBI-714158From a different organism.

Protein-protein interaction databases

BioGridi204949. 13 interactions.
DIPiDIP-467N.
IntActiP31938. 7 interactions.
MINTiMINT-1518233.
STRINGi10090.ENSMUSP00000005066.

Structurei

3D structure databases

ProteinModelPortaliP31938.
SMRiP31938. Positions 29-382.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini68 – 361294Protein kinasePROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni270 – 30738RAF1-bindingBy similarityAdd
BLAST

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi262 – 30746Pro-richAdd
BLAST

Domaini

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

Sequence similaritiesi

Contains 1 protein kinase domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiCOG0515.
HOGENOMiHOG000234206.
HOVERGENiHBG108518.
InParanoidiP31938.
KOiK04368.
OMAiRDKHAIM.
OrthoDBiEOG7HF1KZ.
PhylomeDBiP31938.
TreeFamiTF105137.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

P31938-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MPKKKPTPIQ LNPAPDGSAV NGTSSAETNL EALQKKLEEL ELDEQQRKRL
60 70 80 90 100
EAFLTQKQKV GELKDDDFEK ISELGAGNGG VVFKVSHKPS GLVMARKLIH
110 120 130 140 150
LEIKPAIRNQ IIRELQVLHE CNSPYIVGFY GAFYSDGEIS ICMEHMDGGS
160 170 180 190 200
LDQVLKKAGR IPEQILGKVS IAVIKGLTYL REKHKIMHRD VKPSNILVNS
210 220 230 240 250
RGEIKLCDFG VSGQLIDSMA NSFVGTRSYM SPERLQGTHY SVQSDIWSMG
260 270 280 290 300
LSLVEMAVGR YPIPPPDAKE LELLFGCHVE GDAAETPPRP RTPGRPLSSY
310 320 330 340 350
GMDSRPPMAI FELLDYIVNE PPPKLPSGVF SLEFQDFVNK CLIKNPAERA
360 370 380 390
DLKQLMVHAF IKRSDAEEVD FAGWLCSTIG LNQPSTPTHA ASI
Length:393
Mass (Da):43,474
Last modified:January 23, 2007 - v2
Checksum:i01D1D18572AE40E7
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti374 – 3741W → Q AA sequence (PubMed:1381507).Curated

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L02526 mRNA. Translation: AAA39523.1.
BC054754 mRNA. Translation: AAH54754.1.
CCDSiCCDS23277.1.
PIRiI59571.
RefSeqiNP_032953.1. NM_008927.3.
UniGeneiMm.248907.

Genome annotation databases

EnsembliENSMUST00000005066; ENSMUSP00000005066; ENSMUSG00000004936.
GeneIDi26395.
KEGGimmu:26395.
UCSCiuc009qbp.1. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L02526 mRNA. Translation: AAA39523.1.
BC054754 mRNA. Translation: AAH54754.1.
CCDSiCCDS23277.1.
PIRiI59571.
RefSeqiNP_032953.1. NM_008927.3.
UniGeneiMm.248907.

3D structure databases

ProteinModelPortaliP31938.
SMRiP31938. Positions 29-382.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi204949. 13 interactions.
DIPiDIP-467N.
IntActiP31938. 7 interactions.
MINTiMINT-1518233.
STRINGi10090.ENSMUSP00000005066.

Chemistry

BindingDBiP31938.
ChEMBLiCHEMBL5860.

PTM databases

PhosphoSiteiP31938.

2D gel databases

UCD-2DPAGEP31938.

Proteomic databases

MaxQBiP31938.
PaxDbiP31938.
PRIDEiP31938.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000005066; ENSMUSP00000005066; ENSMUSG00000004936.
GeneIDi26395.
KEGGimmu:26395.
UCSCiuc009qbp.1. mouse.

Organism-specific databases

CTDi5604.
MGIiMGI:1346866. Map2k1.

Phylogenomic databases

eggNOGiCOG0515.
HOGENOMiHOG000234206.
HOVERGENiHBG108518.
InParanoidiP31938.
KOiK04368.
OMAiRDKHAIM.
OrthoDBiEOG7HF1KZ.
PhylomeDBiP31938.
TreeFamiTF105137.

Enzyme and pathway databases

BRENDAi2.7.12.2. 3474.
ReactomeiREACT_215461. Signal transduction by L1.
REACT_224208. Interleukin-1 signaling.
REACT_242456. Signaling by FGFR.
REACT_247448. ERK1 activation.
REACT_247566. MEK activation.
REACT_257146. RAF phosphorylates MEK.

Miscellaneous databases

ChiTaRSiMap2k1. mouse.
NextBioi304339.
PROiP31938.
SOURCEiSearch...

Gene expression databases

BgeeiP31938.
CleanExiMM_MAP2K1.
ExpressionAtlasiP31938. baseline and differential.
GenevestigatoriP31938.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  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. 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. Cited for: DISRUPTION PHENOTYPE, FUNCTION, INTERACTION WITH MAP2K2/MEK2, PHOSPHORYLATION AT THR-292, MUTAGENESIS OF ASN-78 AND THR-292.
  9. Cited for: REVIEW ON FUNCTION.
  10. 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.

Entry informationi

Entry nameiMP2K1_MOUSE
AccessioniPrimary (citable) accession number: P31938
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 1, 1993
Last sequence update: January 23, 2007
Last modified: March 4, 2015
This is version 153 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  3. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.