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Protein

Dual specificity mitogen-activated protein kinase kinase 1

Gene

MAP2K1

Organism
Oryctolagus cuniculus (Rabbit)
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 (By similarity).By similarity

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 (By similarity).By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei97ATPPROSITE-ProRule annotation1 Publication1
Active sitei190Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi74 – 82ATPPROSITE-ProRule annotation1 Publication9

GO - Molecular functioni

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. 1749.

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
OrganismiOryctolagus cuniculus (Rabbit)
Taxonomic identifieri9986 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresLagomorphaLeporidaeOryctolagus
Proteomesi
  • UP000001811 Componenti: Unplaced

Subcellular locationi

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

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

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Cytoskeleton, Membrane, Nucleus

Pathology & Biotechi

Chemistry databases

ChEMBLiCHEMBL5740.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemoved1 Publication
ChainiPRO_00000863682 – 393Dual specificity mitogen-activated protein kinase kinase 1Add BLAST392

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei218Phosphoserine; by RAF1 Publication1
Modified residuei222Phosphoserine; by RAF1 Publication1
Modified residuei286PhosphothreonineBy similarity1
Modified residuei292Phosphothreonine; by MAPK1By similarity1
Modified residuei298Phosphoserine; by PAKBy similarity1

Post-translational modificationi

Phosphorylation at Ser-218 and Ser-222 by MAP kinase kinase kinases (RAF or MEKK1) regulates positively the 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.By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei8 – 9Cleavage; by anthrax lethal factorBy similarity2

Keywords - PTMi

Phosphoprotein

Proteomic databases

PRIDEiP29678.

PTM databases

iPTMnetiP29678.

Interactioni

Subunit structurei

Found in a complex with at least BRAF, HRAS, MAP2K1, MAPK3/ERK1 and RGS14. Forms a heterodimer with MAP2K2/MEK2. Interacts with ARRB2, LAMTOR3, MAPK1/ERK2, MORG1, RAF1, PPARG and VRK2. Interacts with SGK1. Interacts with BIRC6/bruce. Interacts with KSR1 (By similarity). Forms heterodimers with KSR2 which further dimerize to form tetramers (PubMed:21441910).By similarity1 Publication

Protein-protein interaction databases

DIPiDIP-40535N.
IntActiP29678. 1 interactor.

Chemistry databases

BindingDBiP29678.

Structurei

Secondary structure

1393
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi44 – 55Combined sources12
Turni56 – 59Combined sources4
Turni65 – 67Combined sources3
Beta strandi73 – 75Combined sources3
Turni88 – 91Combined sources4
Beta strandi95 – 100Combined sources6
Helixi105 – 115Combined sources11
Helixi116 – 120Combined sources5
Beta strandi129 – 133Combined sources5
Beta strandi136 – 143Combined sources8
Helixi151 – 156Combined sources6
Helixi163 – 184Combined sources22
Helixi193 – 195Combined sources3
Beta strandi196 – 198Combined sources3
Beta strandi204 – 206Combined sources3
Helixi213 – 218Combined sources6
Helixi232 – 236Combined sources5
Helixi242 – 258Combined sources17
Helixi271 – 273Combined sources3
Helixi310 – 319Combined sources10
Turni327 – 329Combined sources3
Helixi332 – 341Combined sources10
Turni346 – 348Combined sources3
Helixi352 – 356Combined sources5
Helixi359 – 366Combined sources8
Helixi371 – 375Combined sources5
Turni376 – 378Combined sources3

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2Y4IX-ray3.46C1-393[»]
5KKRX-ray3.51C1-393[»]
ProteinModelPortaliP29678.
SMRiP29678.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini68 – 361Protein kinasePROSITE-ProRule annotationAdd BLAST294

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni270 – 307RAF1-bindingBy similarityAdd BLAST38

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi262 – 307Pro-richAdd BLAST46

Domaini

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

Sequence similaritiesi

Contains 1 protein kinase domain.PROSITE-ProRule annotation

Phylogenomic databases

HOGENOMiHOG000234206.
HOVERGENiHBG108518.
InParanoidiP29678.
KOiK04368.

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.

P29678-1 [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 LELMFGCQVE GDAAETPPRP RTPGRPLSSY
310 320 330 340 350
GMDSRPPMAI FELLDYIVNE PPPKLPSAVF SLEFQDFVNK CLIKNPAERA
360 370 380 390
DLKQLMVHAF IKRSDAEEVD FAGWLCSTIG LNQPSTPTHA AGV
Length:393
Mass (Da):43,453
Last modified:January 23, 2007 - v2
Checksum:i0341B42FF9218D51
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
Z30163 mRNA. Translation: CAA82912.1.
PIRiS42068.
RefSeqiNP_001076098.1. NM_001082629.1.
UniGeneiOcu.3187.

Genome annotation databases

GeneIDi100009316.
KEGGiocu:100009316.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
Z30163 mRNA. Translation: CAA82912.1.
PIRiS42068.
RefSeqiNP_001076098.1. NM_001082629.1.
UniGeneiOcu.3187.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2Y4IX-ray3.46C1-393[»]
5KKRX-ray3.51C1-393[»]
ProteinModelPortaliP29678.
SMRiP29678.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

DIPiDIP-40535N.
IntActiP29678. 1 interactor.

Chemistry databases

BindingDBiP29678.
ChEMBLiCHEMBL5740.

PTM databases

iPTMnetiP29678.

Proteomic databases

PRIDEiP29678.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

GeneIDi100009316.
KEGGiocu:100009316.

Organism-specific databases

CTDi5604.

Phylogenomic databases

HOGENOMiHOG000234206.
HOVERGENiHBG108518.
InParanoidiP29678.
KOiK04368.

Enzyme and pathway databases

BRENDAi2.7.12.2. 1749.

Miscellaneous databases

PROiP29678.

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...

Entry informationi

Entry nameiMP2K1_RABIT
AccessioniPrimary (citable) accession number: P29678
Entry historyi
Integrated into UniProtKB/Swiss-Prot: April 1, 1993
Last sequence update: January 23, 2007
Last modified: November 30, 2016
This is version 129 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

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  2. 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.