Skip Header

You are using a version of browser that may not display all the features of this website. Please consider upgrading your browser.
Protein

Dual specificity mitogen-activated protein kinase kinase 1

Gene

Map2k1

Organism
Rattus norvegicus (Rat)
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.2 Publications

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.4 Publications

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

  • ATP binding Source: RGD
  • MAP kinase kinase activity Source: RGD
  • mitogen-activated protein kinase kinase kinase binding Source: RGD
  • protein kinase binding Source: RGD
  • protein serine/threonine/tyrosine kinase activity Source: UniProtKB
  • protein serine/threonine kinase activator activity Source: Ensembl
  • protein serine/threonine kinase activity Source: UniProtKB-KW
  • protein tyrosine kinase activity Source: UniProtKB-KW
  • Ras GTPase binding Source: RGD
  • receptor signaling protein tyrosine phosphatase activity Source: Ensembl

GO - Biological processi

  • activation of MAPK activity Source: UniProtKB
  • cell cycle arrest Source: Ensembl
  • cell motility Source: Ensembl
  • cell proliferation Source: RGD
  • cellular senescence Source: Ensembl
  • Golgi inheritance Source: RGD
  • intracellular signal transduction Source: RGD
  • keratinocyte differentiation Source: Ensembl
  • labyrinthine layer development Source: Ensembl
  • MAPK cascade Source: RGD
  • melanosome transport Source: RGD
  • mitotic nuclear division Source: RGD
  • negative regulation of cell proliferation Source: Ensembl
  • negative regulation of homotypic cell-cell adhesion Source: RGD
  • neuron differentiation Source: RGD
  • neuron projection morphogenesis Source: RGD
  • placenta blood vessel development Source: Ensembl
  • positive regulation of cell differentiation Source: Ensembl
  • positive regulation of cell migration Source: RGD
  • positive regulation of GTPase activity Source: RGD
  • positive regulation of Ras protein signal transduction Source: MGI
  • positive regulation of transcription elongation from RNA polymerase II promoter Source: RGD
  • protein heterooligomerization Source: RGD
  • protein phosphorylation Source: RGD
  • regulation of early endosome to late endosome transport Source: UniProtKB
  • regulation of Golgi inheritance Source: UniProtKB
  • regulation of stress-activated MAPK cascade Source: UniProtKB
  • regulation of vascular smooth muscle contraction Source: RGD
  • response to axon injury Source: RGD
  • response to glucocorticoid Source: RGD
  • response to oxidative stress Source: RGD
  • vesicle transport along microtubule Source: RGD
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. 5301.
ReactomeiREACT_272389. RAF phosphorylates MEK.
REACT_289590. ERK1 activation.
REACT_296554. Signal transduction by L1.
REACT_301510. Interleukin-1 signaling.
REACT_311446. MEK activation.
REACT_357224. Signaling by FGFR1.
REACT_358312. Signaling by FGFR2.
REACT_360381. Signaling by FGFR4.
REACT_362367. Signaling by FGFR3.

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
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
ProteomesiUP000002494 Componenti: Chromosome 8

Organism-specific databases

RGDi70495. Map2k1.

Subcellular locationi

GO - Cellular componenti

  • axon Source: RGD
  • cell cortex Source: RGD
  • cytosol Source: UniProtKB
  • dendrite Source: RGD
  • dendrite cytoplasm Source: RGD
  • early endosome Source: UniProtKB
  • endoplasmic reticulum Source: Ensembl
  • extracellular exosome Source: Ensembl
  • focal adhesion Source: UniProtKB
  • Golgi apparatus Source: UniProtKB
  • intracellular Source: GO_Central
  • late endosome Source: UniProtKB
  • microtubule organizing center Source: UniProtKB-SubCell
  • mitochondrion Source: UniProtKB
  • nucleus Source: UniProtKB
  • perikaryon Source: RGD
  • perinuclear region of cytoplasm Source: RGD
  • plasma membrane Source: RGD
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Cytoskeleton, Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Initiator methioninei1 – 11RemovedBy similarity
Chaini2 – 393392Dual specificity mitogen-activated protein kinase kinase 1PRO_0000086369Add
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 MAPK11 Publication
Modified residuei298 – 2981Phosphoserine; by PAK2 Publications

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.3 Publications

Keywords - PTMi

Phosphoprotein

Proteomic databases

PaxDbiQ01986.
PRIDEiQ01986.

PTM databases

PhosphoSiteiQ01986.

Expressioni

Gene expression databases

GenevisibleiQ01986. RN.

Interactioni

Subunit structurei

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).By similarity

Protein-protein interaction databases

BioGridi251005. 5 interactions.
STRINGi10116.ENSRNOP00000013933.

Structurei

3D structure databases

ProteinModelPortaliQ01986.
SMRiQ01986. Positions 62-382.
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-bindingAdd
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/MEK1.1 Publication

Sequence similaritiesi

Contains 1 protein kinase domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiCOG0515.
GeneTreeiENSGT00760000119199.
HOGENOMiHOG000234206.
HOVERGENiHBG108518.
InParanoidiQ01986.
KOiK04368.
OMAiEPPMNIS.
OrthoDBiEOG7HF1KZ.
PhylomeDBiQ01986.
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.

Q01986-1 [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 LELLFGCQVE 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):43,465
Last modified:January 23, 2007 - v2
Checksum:iA1C8D18FFC852D51
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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.
PIRiJN0840.
RefSeqiNP_113831.1. NM_031643.4.
UniGeneiRn.5850.

Genome annotation databases

EnsembliENSRNOT00000013933; ENSRNOP00000013933; ENSRNOG00000010176.
GeneIDi170851.
KEGGirno:170851.
UCSCiRGD:70495. rat.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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.
PIRiJN0840.
RefSeqiNP_113831.1. NM_031643.4.
UniGeneiRn.5850.

3D structure databases

ProteinModelPortaliQ01986.
SMRiQ01986. Positions 62-382.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi251005. 5 interactions.
STRINGi10116.ENSRNOP00000013933.

PTM databases

PhosphoSiteiQ01986.

Proteomic databases

PaxDbiQ01986.
PRIDEiQ01986.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSRNOT00000013933; ENSRNOP00000013933; ENSRNOG00000010176.
GeneIDi170851.
KEGGirno:170851.
UCSCiRGD:70495. rat.

Organism-specific databases

CTDi5604.
RGDi70495. Map2k1.

Phylogenomic databases

eggNOGiCOG0515.
GeneTreeiENSGT00760000119199.
HOGENOMiHOG000234206.
HOVERGENiHBG108518.
InParanoidiQ01986.
KOiK04368.
OMAiEPPMNIS.
OrthoDBiEOG7HF1KZ.
PhylomeDBiQ01986.
TreeFamiTF105137.

Enzyme and pathway databases

BRENDAi2.7.12.2. 5301.
ReactomeiREACT_272389. RAF phosphorylates MEK.
REACT_289590. ERK1 activation.
REACT_296554. Signal transduction by L1.
REACT_301510. Interleukin-1 signaling.
REACT_311446. MEK activation.
REACT_357224. Signaling by FGFR1.
REACT_358312. Signaling by FGFR2.
REACT_360381. Signaling by FGFR4.
REACT_362367. Signaling by FGFR3.

Miscellaneous databases

NextBioi621291.
PROiQ01986.

Gene expression databases

GenevisibleiQ01986. RN.

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. "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, IDENTIFICATION BY 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. 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. Cited for: IDENTIFICATION IN A COMPLEX WITH BRAF; HRAS; MAPK3 AND RGS14.
  14. Cited for: REVIEW ON FUNCTION.
  15. 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.

Entry informationi

Entry nameiMP2K1_RAT
AccessioniPrimary (citable) accession number: Q01986
Secondary accession number(s): Q5EBD5
Entry historyi
Integrated into UniProtKB/Swiss-Prot: April 1, 1993
Last sequence update: January 23, 2007
Last modified: June 24, 2015
This is version 143 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. 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.