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P29678

- MP2K1_RABIT

UniProt

P29678 - MP2K1_RABIT

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Protein

Dual specificity mitogen-activated protein kinase kinase 1

Gene

MAP2K1

Organism
Oryctolagus cuniculus (Rabbit)
Status
Reviewed - 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
Sitei8 – 92Cleavage; by anthrax lethal factorBy similarity
Binding sitei97 – 971ATP1 PublicationPROSITE-ProRule annotation
Active sitei190 – 1901Proton acceptorPROSITE-ProRule annotation

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi74 – 829ATP1 PublicationPROSITE-ProRule annotation

GO - Molecular functioni

  1. ATP binding Source: UniProtKB-KW
  2. protein serine/threonine kinase activity Source: UniProtKB-KW
  3. protein tyrosine kinase activity Source: UniProtKB-KW
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
ProteomesiUP000001811: Unplaced

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. cytoplasm Source: UniProtKB-KW
  2. cytoskeleton Source: UniProtKB-KW
  3. nucleus Source: UniProtKB-KW
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Cytoskeleton, Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Initiator methioninei1 – 11Removed1 Publication
Chaini2 – 393392Dual specificity mitogen-activated protein kinase kinase 1PRO_0000086368Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei218 – 2181Phosphoserine; by RAF1 Publication
Modified residuei222 – 2221Phosphoserine; by RAF1 Publication
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

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. Interacts with BIRC6/bruce.By similarity

Protein-protein interaction databases

DIPiDIP-40535N.
IntActiP29678. 1 interaction.
STRINGi9986.ENSOCUP00000007582.

Structurei

Secondary structure

1
393
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Helixi44 – 5512
Turni56 – 594
Turni65 – 673
Beta strandi73 – 753
Turni88 – 914
Beta strandi95 – 1006
Helixi105 – 11511
Helixi116 – 1205
Beta strandi129 – 1335
Beta strandi136 – 1438
Helixi151 – 1566
Helixi163 – 18422
Helixi193 – 1953
Beta strandi196 – 1983
Beta strandi204 – 2063
Helixi213 – 2186
Helixi232 – 2365
Helixi242 – 25817
Helixi271 – 2733
Helixi310 – 31910
Turni327 – 3293
Helixi332 – 34110
Turni346 – 3483
Helixi352 – 3565
Helixi359 – 3668
Helixi371 – 3755
Turni376 – 3783

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
2Y4IX-ray3.46C1-393[»]
ProteinModelPortaliP29678.
SMRiP29678. 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

eggNOGiCOG0515.
HOGENOMiHOG000234206.
HOVERGENiHBG108518.
InParanoidiP29678.

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.

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:
EMBL
GenBank
DDBJ
Links Updated
Z30163 mRNA. Translation: CAA82912.1.
PIRiS42068.
RefSeqiNP_001076098.1. NM_001082629.1.
UniGeneiOcu.3187.

Genome annotation databases

GeneIDi100009316.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
Z30163 mRNA. Translation: CAA82912.1 .
PIRi S42068.
RefSeqi NP_001076098.1. NM_001082629.1.
UniGenei Ocu.3187.

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
Entry Method Resolution (Å) Chain Positions PDBsum
2Y4I X-ray 3.46 C 1-393 [» ]
ProteinModelPortali P29678.
SMRi P29678. Positions 62-382.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

DIPi DIP-40535N.
IntActi P29678. 1 interaction.
STRINGi 9986.ENSOCUP00000007582.

Chemistry

BindingDBi P29678.
ChEMBLi CHEMBL5740.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

GeneIDi 100009316.

Organism-specific databases

CTDi 5604.

Phylogenomic databases

eggNOGi COG0515.
HOGENOMi HOG000234206.
HOVERGENi HBG108518.
InParanoidi P29678.

Enzyme and pathway databases

BRENDAi 2.7.12.2. 1749.

Family and domain databases

InterProi IPR011009. 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 ]
Pfami PF00069. Pkinase. 1 hit.
[Graphical view ]
SMARTi SM00220. S_TKc. 1 hit.
[Graphical view ]
SUPFAMi SSF56112. SSF56112. 1 hit.
PROSITEi PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

  1. "Identification of the sites in MAP kinase kinase-1 phosphorylated by p74raf-1."
    Alessi D.R., Saito Y., Campbell D.G., Cohen P., Sithanadam G., Rapp U., Ashworth A., Marshall C.J., Cowley S.
    EMBO J. 13:1610-1619(1994) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA], PHOSPHORYLATION AT SER-218 AND SER-222 BY RAF.
  2. "The amino acid sequence of a mammalian MAP kinase kinase."
    Ashworth A., Nakielny S., Cohen P., Marshall C.
    Oncogene 7:2555-2556(1992) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 16-393, PARTIAL PROTEIN SEQUENCE.
    Tissue: Brain and Skeletal muscle.
  3. "MAP kinase kinase from rabbit skeletal muscle. A novel dual specificity enzyme showing homology to yeast protein kinases involved in pheromone-dependent signal transduction."
    Nakielny S., Campbell D.G., Cohen P.
    FEBS Lett. 308:183-189(1992) [PubMed] [Europe PMC] [Abstract]
    Cited for: PROTEIN SEQUENCE OF 2-16; 85-96 AND 190-201.
    Tissue: Skeletal muscle.
  4. "Renaturation and partial peptide sequencing of mitogen-activated protein kinase (MAP kinase) activator from rabbit skeletal muscle."
    Wu J., Michel H., Rossomando A., Haystead T., Shabanowitz J., Hunt D.F., Sturgill T.W.
    Biochem. J. 285:701-705(1992) [PubMed] [Europe PMC] [Abstract]
    Cited for: PROTEIN SEQUENCE OF 85-96 AND 190-201.
    Tissue: Skeletal muscle.
  5. "A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK."
    Brennan D.F., Dar A.C., Hertz N.T., Chao W.C., Burlingame A.L., Shokat K.M., Barford D.
    Nature 472:366-369(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: X-RAY CRYSTALLOGRAPHY (3.46 ANGSTROMS) IN COMPLEX WITH ATP AND HUMAN KSR2, PHOSPHORYLATION.

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: October 29, 2014
This is version 112 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

External Data

Dasty 3