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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
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

GO - Biological processi

  • activation of MAPK activity Source: UniProtKB
  • Bergmann glial cell differentiation Source: MGI
  • cell cycle arrest Source: MGI
  • cell motility Source: MGI
  • cellular senescence Source: MGI
  • cerebellar cortex formation Source: MGI
  • epithelial cell proliferation involved in lung morphogenesis Source: MGI
  • ERK1 and ERK2 cascade Source: MGI
  • face development Source: MGI
  • heart development Source: MGI
  • keratinocyte differentiation Source: MGI
  • labyrinthine layer development Source: MGI
  • lung morphogenesis Source: MGI
  • mitophagy in response to mitochondrial depolarization Source: MGI
  • negative regulation of cell proliferation Source: MGI
  • negative regulation of gene expression Source: MGI
  • neuron differentiation Source: MGI
  • placenta blood vessel development Source: MGI
  • positive regulation of axonogenesis Source: MGI
  • positive regulation of cell differentiation Source: MGI
  • positive regulation of gene expression Source: MGI
  • positive regulation of protein serine/threonine kinase activity Source: MGI
  • positive regulation of Ras protein signal transduction Source: MGI
  • protein phosphorylation Source: MGI
  • regulation of axon regeneration Source: MGI
  • regulation of early endosome to late endosome transport Source: UniProtKB
  • regulation of Golgi inheritance Source: UniProtKB
  • regulation of protein phosphorylation Source: MGI
  • regulation of stress-activated MAPK cascade Source: UniProtKB
  • thymus development Source: MGI
  • thyroid gland development Source: MGI
  • trachea formation Source: MGI
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.
ReactomeiR-MMU-110056. MAPK3 (ERK1) activation.
R-MMU-445144. Signal transduction by L1.
R-MMU-5673000. RAF activation.
R-MMU-5674135. MAP2K and MAPK activation.
R-MMU-5674499. Negative feedback regulation of MAPK pathway.

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
Proteomesi
  • UP000000589 Componenti: Chromosome 9

Organism-specific databases

MGIiMGI:1346866. Map2k1.

Subcellular locationi

  • Cytoplasmcytoskeletonmicrotubule organizing centercentrosome By similarity
  • Cytoplasmcytoskeletonmicrotubule organizing centerspindle pole body By similarity
  • Cytoplasm 1 Publication
  • Nucleus By similarity
  • Membrane 1 Publication; Peripheral membrane protein 1 Publication

  • Note: Localizes at centrosomes during prometaphase, midzone during anaphase and midbody during telophase/cytokinesis (By similarity). Membrane localization is probably regulated by its interaction with KSR1 (PubMed:10409742).By similarity1 Publication

GO - Cellular componenti

  • cytoplasm Source: MGI
  • cytosol Source: UniProtKB
  • early endosome Source: UniProtKB
  • endoplasmic reticulum Source: MGI
  • extracellular exosome Source: MGI
  • focal adhesion Source: UniProtKB
  • Golgi apparatus Source: UniProtKB
  • late endosome Source: UniProtKB
  • microtubule organizing center Source: UniProtKB-SubCell
  • mitochondrion Source: UniProtKB
  • nucleus Source: UniProtKB
  • plasma membrane Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Cytoskeleton, Membrane, 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

Chemistry

ChEMBLiCHEMBL5860.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Initiator methionineiRemovedBy 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 RAF1 Publication
Modified residuei222 – 2221Phosphoserine; by RAFBy similarity
Modified residuei286 – 2861PhosphothreonineCombined sources
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

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sitei8 – 92Cleavage; by anthrax lethal factorBy similarity

Keywords - PTMi

Phosphoprotein

Proteomic databases

EPDiP31938.
PaxDbiP31938.
PRIDEiP31938.

2D gel databases

UCD-2DPAGEP31938.

PTM databases

iPTMnetiP31938.
PhosphoSiteiP31938.

Expressioni

Gene expression databases

BgeeiP31938.
CleanExiMM_MAP2K1.
ExpressionAtlasiP31938. baseline and differential.
GenevisibleiP31938. MM.

Interactioni

Subunit structurei

Found in a complex with at least BRAF, HRAS, MAP2K1, MAPK3/ERK1 and RGS14. Forms heterodimers with KSR2 which further dimerize to form tetramers. Interacts with ARRB2, LAMTOR3, MAPK1/ERK2, RAF1, PPARG AND VRK2. Interacts with SGK1, BIRC6/bruce (By similarity). Interacts with KSR-1 (PubMed:10409742). Interacts with MORG1 (PubMed:15118098). Forms a heterodimer with MAP2K2/MEK2 (PubMed:19219045).By similarity3 Publications

Binary interactionsi

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

GO - Molecular functioni

Protein-protein interaction databases

BioGridi204949. 16 interactions.
DIPiDIP-467N.
IntActiP31938. 7 interactions.
MINTiMINT-1518233.
STRINGi10090.ENSMUSP00000005066.

Chemistry

BindingDBiP31938.

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

eggNOGiKOG0581. Eukaryota.
ENOG410XQ5A. LUCA.
HOGENOMiHOG000234206.
HOVERGENiHBG108518.
InParanoidiP31938.
KOiK04368.
OMAiELMFGCP.
OrthoDBiEOG7HF1KZ.
PhylomeDBiP31938.
TreeFamiTF105137.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
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. 16 interactions.
DIPiDIP-467N.
IntActiP31938. 7 interactions.
MINTiMINT-1518233.
STRINGi10090.ENSMUSP00000005066.

Chemistry

BindingDBiP31938.
ChEMBLiCHEMBL5860.

PTM databases

iPTMnetiP31938.
PhosphoSiteiP31938.

2D gel databases

UCD-2DPAGEP31938.

Proteomic databases

EPDiP31938.
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

eggNOGiKOG0581. Eukaryota.
ENOG410XQ5A. LUCA.
HOGENOMiHOG000234206.
HOVERGENiHBG108518.
InParanoidiP31938.
KOiK04368.
OMAiELMFGCP.
OrthoDBiEOG7HF1KZ.
PhylomeDBiP31938.
TreeFamiTF105137.

Enzyme and pathway databases

BRENDAi2.7.12.2. 3474.
ReactomeiR-MMU-110056. MAPK3 (ERK1) activation.
R-MMU-445144. Signal transduction by L1.
R-MMU-5673000. RAF activation.
R-MMU-5674135. MAP2K and MAPK activation.
R-MMU-5674499. Negative feedback regulation of MAPK pathway.

Miscellaneous databases

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

Gene expression databases

BgeeiP31938.
CleanExiMM_MAP2K1.
ExpressionAtlasiP31938. baseline and differential.
GenevisibleiP31938. MM.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
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/6J.
    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. "Kinase suppressor of Ras forms a multiprotein signaling complex and modulates MEK localization."
    Stewart S., Sundaram M., Zhang Y., Lee J., Han M., Guan K.L.
    Mol. Cell. Biol. 19:5523-5534(1999) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH KSR1, SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-218.
  8. "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.
  9. Cited for: DISRUPTION PHENOTYPE, FUNCTION, INTERACTION WITH MAP2K2/MEK2, PHOSPHORYLATION AT THR-292, MUTAGENESIS OF ASN-78 AND THR-292.
  10. Cited for: REVIEW ON FUNCTION.
  11. Cited for: REVIEW ON ENZYME REGULATION.
  12. "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.
  13. Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-286, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Brain, Brown adipose tissue, Heart, Kidney, Liver, Lung, Pancreas and Spleen.
  14. "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: May 11, 2016
This is version 166 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

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 one 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.