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Protein

Dual specificity mitogen-activated protein kinase kinase 1

Gene

MAP2K1

Organism
Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus)
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)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

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. 1309.

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
OrganismiCricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus)
Taxonomic identifieri10029 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaCricetidaeCricetinaeCricetulus

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

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi208 – 2081D → N: No loss of activity. 1 Publication
Mutagenesisi222 – 2221S → A: Inactivation and reduced phosphorylation. 1 Publication
Mutagenesisi222 – 2221S → D: No loss of activity. 1 Publication
Mutagenesisi228 – 2281S → A: No loss of activity. 1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Initiator methionineiRemovedBy similarity
Chaini2 – 393392Dual specificity mitogen-activated protein kinase kinase 1PRO_0000086364Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei218 – 2181Phosphoserine; by RAFBy similarity
Modified residuei222 – 2221Phosphoserine; by RAFCurated
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) 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
Activated by phosphorylation on Ser/Thr catalyzed by MAP kinase kinase kinases (RAF or MEKK1).By similarity

Keywords - PTMi

Phosphoprotein

Interactioni

Subunit structurei

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

Structurei

3D structure databases

ProteinModelPortaliQ63980.
SMRiQ63980. 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-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 the binding to RAF1 and activation of MAP2K1/MEK1.By similarity

Sequence similaritiesi

Contains 1 protein kinase domain.PROSITE-ProRule annotation

Phylogenomic databases

HOVERGENiHBG108518.
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.

Q63980-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MPKKKPTPIQ LNPTPDGSAV NGTSSAETNL EALQKKLEEL ELEEQQRNRL
60 70 80 90 100
EAFLTQKQKV GELKDDDFEK ISELGAGNGG VVFKVSHKPS GLVMARKLIH
110 120 130 140 150
LEIKPAIRNQ IIRELQVLHE CNSPYIVGFY GVFYSDGEIS 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 PPAKLPSGVF SLEFQDFVNK CLIKNPAERA
360 370 380 390
DLKQLLVHAF IKRSDAEEVD FAGWLCSTIG LNQPSTPTHA ASI
Length:393
Mass (Da):43,479
Last modified:November 1, 1996 - v1
Checksum:i35E82B0E416A7167
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
S70933 mRNA. Translation: AAB31379.1.
PIRiS46361.
RefSeqiNP_001233756.1. NM_001246827.1.

Genome annotation databases

GeneIDi100689403.
KEGGicge:100689403.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
S70933 mRNA. Translation: AAB31379.1.
PIRiS46361.
RefSeqiNP_001233756.1. NM_001246827.1.

3D structure databases

ProteinModelPortaliQ63980.
SMRiQ63980. Positions 62-382.
ModBaseiSearch...
MobiDBiSearch...

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

GeneIDi100689403.
KEGGicge:100689403.

Organism-specific databases

CTDi5604.

Phylogenomic databases

HOVERGENiHBG108518.
KOiK04368.

Enzyme and pathway databases

BRENDAi2.7.12.2. 1309.

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

  1. "Constitutive mutant and putative regulatory serine phosphorylation site of mammalian MAP kinase kinase (MEK1)."
    Pages G., Brunet A., L'Allemain G., Pouyssegur J.
    EMBO J. 13:3003-3010(1994) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA], MUTAGENESIS.
    Tissue: Lung fibroblast.

Entry informationi

Entry nameiMP2K1_CRIGR
AccessioniPrimary (citable) accession number: Q63980
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: November 1, 1996
Last modified: May 11, 2016
This is version 93 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Documents

  1. 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.