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Q02750 (MP2K1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 158. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Dual specificity mitogen-activated protein kinase kinase 1

Short name=MAP kinase kinase 1
Short name=MAPKK 1
Short name=MKK1
EC=2.7.12.2
Alternative name(s):
ERK activator kinase 1
MAPK/ERK kinase 1
Short name=MEK 1
Gene names
Name:MAP2K1
Synonyms:MEK1, PRKMK1
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length393 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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. Ref.6 Ref.9

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

Enzyme regulation

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. Many inhibitors have been identified including pyrrole derivatives, TAK-733 (one of a series of 8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione derivatives), CH4987655 and RDEA119/BAY 869766.

Subunit structure

Found in a complex with at least BRAF, HRAS, MAP2K1, MAPK3/ERK1 and RGS14 By similarity. Forms a heterodimer with MAP2K2/MEK2 By similarity. Forms heterodimers with KSR2 which further dimerize to form tetramers By similarity. Interacts with ARBB2, LAMTOR3, MAPK1/ERK2, MORG1 and RAF1 By similarity. Interacts with PPARG and with isoform 1 of VRK2. Interacts with Yersinia yopJ. Interacts with SGK1. Interacts with BIRC6/bruce. Ref.8 Ref.9 Ref.10 Ref.12 Ref.14

Subcellular location

Cytoplasmcytoskeletonmicrotubule organizing centercentrosome. Cytoplasmcytoskeletonmicrotubule organizing centerspindle pole body. Cytoplasm. Nucleus. Note: Localizes at centrosomes during prometaphase, midzone during anaphase and midbody during telophase/cytokinesis. Ref.6 Ref.9

Tissue specificity

Widely expressed, with extremely low levels in brain. Ref.1

Domain

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

Post-translational modification

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. Ref.3 Ref.7

Acetylation by Yersinia yopJ prevents phosphorylation and activation, thus blocking the MAPK signaling pathway. Ref.8

Involvement in disease

Cardiofaciocutaneous syndrome 3 (CFC3) [MIM:615279]: A form of cardiofaciocutaneous syndrome, a multiple congenital anomaly disorder characterized by a distinctive facial appearance, heart defects and mental retardation. Heart defects include pulmonic stenosis, atrial septal defects and hypertrophic cardiomyopathy. Some affected individuals present with ectodermal abnormalities such as sparse, friable hair, hyperkeratotic skin lesions and a generalized ichthyosis-like condition. Typical facial features are similar to Noonan syndrome. They include high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, and posteriorly angulated ears with prominent helices. Distinctive features of CFC3 include macrostomia and horizontal shape of palpebral fissures.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.29 Ref.30

Sequence similarities

Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase subfamily.

Contains 1 protein kinase domain.

Ontologies

Keywords
   Cellular componentCytoplasm
Cytoskeleton
Nucleus
   Coding sequence diversityAlternative splicing
   DiseaseCardiomyopathy
Disease mutation
Ectodermal dysplasia
Mental retardation
   LigandATP-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
Tyrosine-protein kinase
   PTMAcetylation
Phosphoprotein
   Technical term3D-structure
Complete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processFc-epsilon receptor signaling pathway

Traceable author statement. Source: Reactome

Golgi inheritance

Inferred from electronic annotation. Source: Ensembl

MAPK cascade

Traceable author statement. Source: Reactome

MyD88-dependent toll-like receptor signaling pathway

Traceable author statement. Source: Reactome

MyD88-independent toll-like receptor signaling pathway

Traceable author statement. Source: Reactome

Ras protein signal transduction

Traceable author statement. Source: Reactome

TRIF-dependent toll-like receptor signaling pathway

Traceable author statement. Source: Reactome

activation of MAPK activity

Traceable author statement Ref.17. Source: UniProtKB

activation of MAPKK activity

Traceable author statement. Source: Reactome

axon guidance

Traceable author statement. Source: Reactome

cell cycle arrest

Inferred from mutant phenotype PubMed 9765203. Source: BHF-UCL

cell motility

Inferred from electronic annotation. Source: Ensembl

cell proliferation

Inferred from electronic annotation. Source: Ensembl

cellular component movement

Traceable author statement PubMed 10912793. Source: ProtInc

cellular senescence

Inferred from mutant phenotype PubMed 9765203. Source: BHF-UCL

chemotaxis

Traceable author statement PubMed 10570282. Source: ProtInc

epidermal growth factor receptor signaling pathway

Traceable author statement. Source: Reactome

fibroblast growth factor receptor signaling pathway

Traceable author statement. Source: Reactome

innate immune response

Traceable author statement. Source: Reactome

insulin receptor signaling pathway

Traceable author statement. Source: Reactome

keratinocyte differentiation

Inferred from electronic annotation. Source: Ensembl

labyrinthine layer development

Inferred from electronic annotation. Source: Ensembl

melanosome transport

Inferred from electronic annotation. Source: Ensembl

mitosis

Inferred from electronic annotation. Source: Ensembl

negative regulation of cell proliferation

Inferred from direct assay PubMed 9765203. Source: BHF-UCL

negative regulation of homotypic cell-cell adhesion

Inferred from electronic annotation. Source: Ensembl

neurotrophin TRK receptor signaling pathway

Traceable author statement. Source: Reactome

placenta blood vessel development

Inferred from electronic annotation. Source: Ensembl

positive regulation of Ras GTPase activity

Inferred from electronic annotation. Source: Ensembl

positive regulation of Ras protein signal transduction

Inferred from electronic annotation. Source: Ensembl

positive regulation of cell differentiation

Inferred from electronic annotation. Source: Ensembl

positive regulation of cell migration

Inferred from electronic annotation. Source: Ensembl

positive regulation of gene expression

Inferred from mutant phenotype PubMed 15155804. Source: UniProt

positive regulation of protein serine/threonine kinase activity

Inferred from direct assay Ref.2. Source: UniProtKB

positive regulation of transcription elongation from RNA polymerase II promoter

Inferred from electronic annotation. Source: Ensembl

protein heterooligomerization

Inferred from electronic annotation. Source: Ensembl

regulation of Golgi inheritance

Traceable author statement Ref.17. Source: UniProtKB

regulation of early endosome to late endosome transport

Traceable author statement Ref.17. Source: UniProtKB

regulation of stress-activated MAPK cascade

Traceable author statement Ref.17. Source: UniProtKB

regulation of vascular smooth muscle contraction

Inferred from electronic annotation. Source: Ensembl

response to axon injury

Inferred from electronic annotation. Source: Ensembl

response to glucocorticoid

Inferred from electronic annotation. Source: Ensembl

response to oxidative stress

Inferred from electronic annotation. Source: Ensembl

signal transduction

Traceable author statement PubMed 10570282. Source: ProtInc

small GTPase mediated signal transduction

Traceable author statement. Source: Reactome

stress-activated MAPK cascade

Traceable author statement. Source: Reactome

toll-like receptor 10 signaling pathway

Traceable author statement. Source: Reactome

toll-like receptor 2 signaling pathway

Traceable author statement. Source: Reactome

toll-like receptor 3 signaling pathway

Traceable author statement. Source: Reactome

toll-like receptor 4 signaling pathway

Traceable author statement. Source: Reactome

toll-like receptor 5 signaling pathway

Traceable author statement. Source: Reactome

toll-like receptor 9 signaling pathway

Traceable author statement. Source: Reactome

toll-like receptor TLR1:TLR2 signaling pathway

Traceable author statement. Source: Reactome

toll-like receptor TLR6:TLR2 signaling pathway

Traceable author statement. Source: Reactome

toll-like receptor signaling pathway

Traceable author statement. Source: Reactome

vesicle transport along microtubule

Inferred from electronic annotation. Source: Ensembl

   Cellular_componentGolgi apparatus

Traceable author statement Ref.17. Source: UniProtKB

cell cortex

Inferred from electronic annotation. Source: Ensembl

cytoplasm

Inferred from direct assay. Source: HPA

cytosol

Traceable author statement Ref.17. Source: UniProtKB

dendrite cytoplasm

Inferred from electronic annotation. Source: Ensembl

early endosome

Traceable author statement Ref.17. Source: UniProtKB

focal adhesion

Traceable author statement Ref.17. Source: UniProtKB

late endosome

Traceable author statement Ref.17. Source: UniProtKB

mitochondrion

Traceable author statement Ref.17. Source: UniProtKB

nucleus

Traceable author statement Ref.17. Source: UniProtKB

perikaryon

Inferred from electronic annotation. Source: Ensembl

perinuclear region of cytoplasm

Inferred from electronic annotation. Source: Ensembl

plasma membrane

Inferred from direct assay. Source: HPA

spindle pole body

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

MAP kinase kinase activity

Inferred from direct assay Ref.2. Source: UniProtKB

protein kinase activity

Traceable author statement PubMed 10570282. Source: ProtInc

protein serine/threonine kinase activator activity

Inferred from direct assay Ref.2. Source: UniProtKB

protein serine/threonine kinase activity

Traceable author statement. Source: Reactome

protein serine/threonine/tyrosine kinase activity

Traceable author statement Ref.17. Source: UniProtKB

protein tyrosine kinase activity

Inferred from electronic annotation. Source: UniProtKB-KW

receptor signaling protein tyrosine phosphatase activity

Inferred from electronic annotation. Source: Ensembl

Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q02750-1)

Also known as: MKK1a;

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: Q02750-2)

Also known as: MKK1b;

The sequence of this isoform differs from the canonical sequence as follows:
     147-172: Missing.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Initiator methionine11Removed By similarity
Chain2 – 393392Dual specificity mitogen-activated protein kinase kinase 1
PRO_0000086365

Regions

Domain68 – 361294Protein kinase
Nucleotide binding74 – 829ATP
Nucleotide binding143 – 1464ATP
Nucleotide binding150 – 1534ATP
Nucleotide binding192 – 1954ATP
Region77 – 782Inhibitor binding
Region144 – 1463Inhibitor binding
Region208 – 2125Inhibitor binding
Region270 – 30738RAF1-binding By similarity
Compositional bias262 – 30746Pro-rich

Sites

Active site1901Proton acceptor By similarity
Binding site771Inhibitor; via carbonyl oxygen
Binding site781Inhibitor; via amide nitrogen and carbonyl oxygen
Binding site971ATP
Binding site971Inhibitor
Binding site1901Inhibitor
Binding site1941Inhibitor; via carbonyl oxygen
Binding site2081ATP
Binding site2081Inhibitor
Binding site2121Inhibitor; via amide nitrogen
Site8 – 92Cleavage; by anthrax lethal factor

Amino acid modifications

Modified residue2181Phosphoserine; by RAF Ref.3
Modified residue2221Phosphoserine; by RAF Ref.3
Modified residue2861Phosphothreonine Ref.11
Modified residue2921Phosphothreonine; by MAPK1 By similarity
Modified residue2981Phosphoserine; by PAK Ref.7

Natural variations

Alternative sequence147 – 17226Missing in isoform 2.
VSP_040500
Natural variant531F → S in CFC3. Ref.29
VAR_035093
Natural variant1281G → V in CFC3. Ref.30
VAR_069780
Natural variant1301Y → C in CFC3. Ref.29
VAR_035094

Experimental info

Mutagenesis971K → R: Inactivation.
Mutagenesis1501S → A: No loss of activity.
Mutagenesis2121S → A: No loss of activity.
Mutagenesis2181S → A: Inactivation.
Mutagenesis2221S → A: Inactivation.

Secondary structure

....................................................... 393
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 (MKK1a) [UniParc].

Last modified January 23, 2007. Version 2.
Checksum: 0344118FFC842D51

FASTA39343,439
        10         20         30         40         50         60 
MPKKKPTPIQ LNPAPDGSAV NGTSSAETNL EALQKKLEEL ELDEQQRKRL EAFLTQKQKV 

        70         80         90        100        110        120 
GELKDDDFEK ISELGAGNGG VVFKVSHKPS GLVMARKLIH LEIKPAIRNQ IIRELQVLHE 

       130        140        150        160        170        180 
CNSPYIVGFY GAFYSDGEIS ICMEHMDGGS LDQVLKKAGR IPEQILGKVS IAVIKGLTYL 

       190        200        210        220        230        240 
REKHKIMHRD VKPSNILVNS RGEIKLCDFG VSGQLIDSMA NSFVGTRSYM SPERLQGTHY 

       250        260        270        280        290        300 
SVQSDIWSMG LSLVEMAVGR YPIPPPDAKE LELMFGCQVE GDAAETPPRP RTPGRPLSSY 

       310        320        330        340        350        360 
GMDSRPPMAI FELLDYIVNE PPPKLPSGVF SLEFQDFVNK CLIKNPAERA DLKQLMVHAF 

       370        380        390 
IKRSDAEEVD FAGWLCSTIG LNQPSTPTHA AGV 

« Hide

Isoform 2 (MKK1b) [UniParc].

Checksum: 9944432D8705DEFD
Show »

FASTA36740,764

References

« Hide 'large scale' references
[1]"Human T-cell mitogen-activated protein kinase kinases are related to yeast signal transduction kinases."
Seger R., Seger D., Lozeman F.J., Ahn N.G., Graves L.M., Campbell J.S., Ericsson L., Harrylock M., Jensen A.M., Krebs E.G.
J. Biol. Chem. 267:25628-25631(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), PARTIAL PROTEIN SEQUENCE, TISSUE SPECIFICITY.
Tissue: T-cell.
[2]"Cloning and characterization of two distinct human extracellular signal-regulated kinase activator kinases, MEK1 and MEK2."
Zheng C.-F., Guan K.-L.
J. Biol. Chem. 268:11435-11439(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[3]"Activation of MEK family kinases requires phosphorylation of two conserved Ser/Thr residues."
Zheng C.-F., Guan K.-L.
EMBO J. 13:1123-1131(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT SER-218 AND SER-222, MUTAGENESIS.
[4]"Proteolytic inactivation of MAP-kinase-kinase by anthrax lethal factor."
Duesbery N.S., Webb C.P., Leppla S.H., Gordon V.M., Klimpel K.R., Copeland T.D., Ahn N.G., Oskarsson M.K., Fukasawa K., Paull K.D., Vande Woude G.F.
Science 280:734-737(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: CLEAVAGE BY ANTHRAX LETHAL FACTOR, PROTEIN SEQUENCE OF 9-17.
[5]"Susceptibility of mitogen-activated protein kinase kinase family members to proteolysis by anthrax lethal factor."
Vitale G., Bernardi L., Napolitani G., Mock M., Montecucco C.
Biochem. J. 352:739-745(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: CLEAVAGE BY ANTHRAX LETHAL FACTOR.
[6]"The MAP kinase pathway is required for entry into mitosis and cell survival."
Liu X., Yan S., Zhou T., Terada Y., Erikson R.L.
Oncogene 23:763-776(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION, FUNCTION.
[7]"Role of group A p21-activated kinases in activation of extracellular-regulated kinase by growth factors."
Beeser A., Jaffer Z.M., Hofmann C., Chernoff J.
J. Biol. Chem. 280:36609-36615(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT SER-298.
[8]"Yersinia YopJ acetylates and inhibits kinase activation by blocking phosphorylation."
Mukherjee S., Keitany G., Li Y., Wang Y., Ball H.L., Goldsmith E.J., Orth K.
Science 312:1211-1214(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH YOPJ, ACETYLATION.
[9]"Interaction with MEK causes nuclear export and downregulation of peroxisome proliferator-activated receptor gamma."
Burgermeister E., Chuderland D., Hanoch T., Meyer M., Liscovitch M., Seger R.
Mol. Cell. Biol. 27:803-817(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH PPARG.
[10]"Final stages of cytokinesis and midbody ring formation are controlled by BRUCE."
Pohl C., Jentsch S.
Cell 132:832-845(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH BIRC6/BRUCE.
[11]"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle."
Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M.
Mol. Cell 31:438-448(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-286, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[12]"Protein kinase SGK1 enhances MEK/ERK complex formation through the phosphorylation of ERK2: implication for the positive regulatory role of SGK1 on the ERK function during liver regeneration."
Won M., Park K.A., Byun H.S., Kim Y.R., Choi B.L., Hong J.H., Park J., Seok J.H., Lee Y.H., Cho C.H., Song I.S., Kim Y.K., Shen H.M., Hur G.M.
J. Hepatol. 51:67-76(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH SGK1.
[13]"Large-scale proteomics analysis of the human kinome."
Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., Mann M., Daub H.
Mol. Cell. Proteomics 8:1751-1764(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[14]"VRK2 inhibits mitogen-activated protein kinase signaling and inversely correlates with ErbB2 in human breast cancer."
Fernandez I.F., Blanco S., Lozano J., Lazo P.A.
Mol. Cell. Biol. 30:4687-4697(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH VRK2.
[15]"Signaling by dual specificity kinases."
Dhanasekaran N., Premkumar Reddy E.
Oncogene 17:1447-1455(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON FUNCTION.
[16]"The RAF proteins take centre stage."
Wellbrock C., Karasarides M., Marais R.
Nat. Rev. Mol. Cell Biol. 5:875-885(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON ENZYME REGULATION.
[17]"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.
[18]"Initial characterization of the human central proteome."
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.
BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[19]"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.
[20]"Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition."
Ohren J.F., Chen H., Pavlovsky A., Whitehead C., Zhang E., Kuffa P., Yan C., McConnell P., Spessard C., Banotai C., Mueller W.T., Delaney A., Omer C., Sebolt-Leopold J., Dudley D.T., Leung I.K., Flamme C., Warmus J. expand/collapse author list , Kaufman M., Barrett S., Tecle H., Hasemann C.A.
Nat. Struct. Mol. Biol. 11:1192-1197(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 62-392 IN COMPLEX WITH ATP AND INHIBITOR.
[21]"4-anilino-5-carboxamido-2-pyridone derivatives as noncompetitive inhibitors of mitogen-activated protein kinase kinase."
Spicer J.A., Rewcastle G.W., Kaufman M.D., Black S.L., Plummer M.S., Denny W.A., Quin J. III, Shahripour A.B., Barrett S.D., Whitehead C.E., Milbank J.B., Ohren J.F., Gowan R.C., Omer C., Camp H.S., Esmaeil N., Moore K., Sebolt-Leopold J.S. expand/collapse author list , Pryzbranowski S., Merriman R.L., Ortwine D.F., Warmus J.S., Flamme C.M., Pavlovsky A.G., Tecle H.
J. Med. Chem. 50:5090-5102(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 62-393 IN COMPLEX WITH ATP AND INHIBITOR.
[22]"2-Alkylamino- and alkoxy-substituted 2-amino-1,3,4-oxadiazoles-O-Alkyl benzohydroxamate esters replacements retain the desired inhibition and selectivity against MEK (MAP ERK kinase)."
Warmus J.S., Flamme C., Zhang L.Y., Barrett S., Bridges A., Chen H., Gowan R., Kaufman M., Sebolt-Leopold J., Leopold W., Merriman R., Ohren J., Pavlovsky A., Przybranowski S., Tecle H., Valik H., Whitehead C., Zhang E.
Bioorg. Med. Chem. Lett. 18:6171-6174(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.62 ANGSTROMS) OF 62-393 IN COMPLEX WITH ATP AND INHIBITOR.
[23]"Crystal structures of MEK1 binary and ternary complexes with nucleotides and inhibitors."
Fischmann T.O., Smith C.K., Mayhood T.W., Myers J.E., Reichert P., Mannarino A., Carr D., Zhu H., Wong J., Yang R.S., Le H.V., Madison V.S.
Biochemistry 48:2661-2674(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 35-393 IN COMPLEX WITH ADP AND INHIBITOR.
[24]"Beyond the MEK-pocket: can current MEK kinase inhibitors be utilized to synthesize novel type III NCKIs? Does the MEK-pocket exist in kinases other than MEK?"
Tecle H., Shao J., Li Y., Kothe M., Kazmirski S., Penzotti J., Ding Y.H., Ohren J., Moshinsky D., Coli R., Jhawar N., Bora E., Jacques-O'Hagan S., Wu J.
Bioorg. Med. Chem. Lett. 19:226-229(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 62-382 IN COMPLEX WITH ATP AND INHIBITOR.
[25]"RDEA119/BAY 869766: a potent, selective, allosteric inhibitor of MEK1/2 for the treatment of cancer."
Iverson C., Larson G., Lai C., Yeh L.T., Dadson C., Weingarten P., Appleby T., Vo T., Maderna A., Vernier J.M., Hamatake R., Miner J.N., Quart B.
Cancer Res. 69:6839-6847(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 62-393 IN COMPLEX WITH ATP AND INHIBITOR.
[26]"Structure-based design and synthesis of pyrrole derivatives as MEK inhibitors."
Wallace M.B., Adams M.E., Kanouni T., Mol C.D., Dougan D.R., Feher V.A., O'Connell S.M., Shi L., Halkowycz P., Dong Q.
Bioorg. Med. Chem. Lett. 20:4156-4158(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 62-382 IN COMPLEX WITH ADP AND INHIBITOR.
[27]"Discovery of TAK-733, a potent and selective MEK allosteric site inhibitor for the treatment of cancer."
Dong Q., Dougan D.R., Gong X., Halkowycz P., Jin B., Kanouni T., O'Connell S.M., Scorah N., Shi L., Wallace M.B., Zhou F.
Bioorg. Med. Chem. Lett. 21:1315-1319(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 62-382 IN COMPLEX WITH ATP AND INHIBITOR.
[28]"Design and synthesis of novel allosteric MEK inhibitor CH4987655 as an orally available anticancer agent."
Isshiki Y., Kohchi Y., Iikura H., Matsubara Y., Asoh K., Murata T., Kohchi M., Mizuguchi E., Tsujii S., Hattori K., Miura T., Yoshimura Y., Aida S., Miwa M., Saitoh R., Murao N., Okabe H., Belunis C. expand/collapse author list , Janson C., Lukacs C., Schuck V., Shimma N.
Bioorg. Med. Chem. Lett. 21:1795-1801(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 62-393.
[29]"Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome."
Rodriguez-Viciana P., Tetsu O., Tidyman W.E., Estep A.L., Conger B.A., Cruz M.S., McCormick F., Rauen K.A.
Science 311:1287-1290(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS CFC3 SER-53 AND CYS-130.
[30]"Mutation and phenotypic spectrum in patients with cardio-facio-cutaneous and Costello syndrome."
Schulz A.L., Albrecht B., Arici C., van der Burgt I., Buske A., Gillessen-Kaesbach G., Heller R., Horn D., Hubner C.A., Korenke G.C., Konig R., Kress W., Kruger G., Meinecke P., Mucke J., Plecko B., Rossier E., Schinzel A. expand/collapse author list , Schulze A., Seemanova E., Seidel H., Spranger S., Tuysuz B., Uhrig S., Wieczorek D., Kutsche K., Zenker M.
Clin. Genet. 73:62-70(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT CFC3 VAL-128.
+Additional computationally mapped references.

Web resources

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
L05624 mRNA. Translation: AAA36318.1.
L11284 mRNA. No translation available.
PIRA45100.
RefSeqNP_002746.1. NM_002755.3.
UniGeneHs.145442.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1S9JX-ray2.40A62-392[»]
2P55X-ray2.80A62-393[»]
3DV3X-ray2.30A62-382[»]
3DY7X-ray2.70A62-393[»]
3E8NX-ray2.50A62-393[»]
3EQBX-ray2.62A62-393[»]
3EQCX-ray1.80A35-393[»]
3EQDX-ray2.10A35-393[»]
3EQFX-ray2.70A35-393[»]
3EQGX-ray2.50A35-393[»]
3EQHX-ray2.00A35-393[»]
3EQIX-ray1.90A35-393[»]
3MBLX-ray2.60A62-382[»]
3ORNX-ray2.80A62-393[»]
3OS3X-ray2.80A62-393[»]
3PP1X-ray2.70A62-382[»]
3SLSX-ray2.30A/B45-383[»]
3V01X-ray2.70A62-393[»]
3V04X-ray2.70A62-393[»]
3VVHX-ray2.00A/B/C62-393[»]
3ZLSX-ray2.50A37-383[»]
3ZLWX-ray2.12A37-383[»]
3ZLXX-ray2.20A37-383[»]
3ZLYX-ray2.11A37-383[»]
3ZM4X-ray2.37A37-383[»]
4AN2X-ray2.50A61-392[»]
4AN3X-ray2.10A61-392[»]
4AN9X-ray2.80A61-392[»]
4ANBX-ray2.20A61-392[»]
4ARKX-ray2.60A62-393[»]
4LMNX-ray2.80A62-393[»]
ProteinModelPortalQ02750.
SMRQ02750. Positions 39-381.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid111590. 42 interactions.
DIPDIP-201N.
IntActQ02750. 26 interactions.
MINTMINT-99632.
STRING9606.ENSP00000302486.

Chemistry

BindingDBQ02750.
ChEMBLCHEMBL2111351.
GuidetoPHARMACOLOGY2062.

PTM databases

PhosphoSiteQ02750.

Polymorphism databases

DMDM400274.

Proteomic databases

PaxDbQ02750.
PeptideAtlasQ02750.
PRIDEQ02750.

Protocols and materials databases

DNASU5604.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000307102; ENSP00000302486; ENSG00000169032. [Q02750-1]
GeneID5604.
KEGGhsa:5604.
UCSCuc010bhq.3. human. [Q02750-1]

Organism-specific databases

CTD5604.
GeneCardsGC15P066679.
HGNCHGNC:6840. MAP2K1.
HPACAB003834.
HPA026430.
MIM176872. gene.
615279. phenotype.
neXtProtNX_Q02750.
Orphanet1340. Cardiofaciocutaneous syndrome.
PharmGKBPA30584.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0515.
HOGENOMHOG000234206.
HOVERGENHBG108518.
InParanoidQ02750.
KOK04368.
OMARDKHAIM.
OrthoDBEOG7HF1KZ.
PhylomeDBQ02750.
TreeFamTF105137.

Enzyme and pathway databases

BRENDA2.7.12.2. 2681.
ReactomeREACT_111045. Developmental Biology.
REACT_111102. Signal Transduction.
REACT_116125. Disease.
REACT_6782. TRAF6 Mediated Induction of proinflammatory cytokines.
REACT_6900. Immune System.
SignaLinkQ02750.

Gene expression databases

ArrayExpressQ02750.
BgeeQ02750.
CleanExHS_MAP2K1.
GenevestigatorQ02750.

Family and domain databases

InterProIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMSSF56112. SSF56112. 1 hit.
PROSITEPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSMAP2K1. human.
EvolutionaryTraceQ02750.
GeneWikiMAP2K1.
GenomeRNAi5604.
NextBio21776.
PMAP-CutDBQ02750.
PROQ02750.
SOURCESearch...

Entry information

Entry nameMP2K1_HUMAN
AccessionPrimary (citable) accession number: Q02750
Entry history
Integrated into UniProtKB/Swiss-Prot: July 1, 1993
Last sequence update: January 23, 2007
Last modified: April 16, 2014
This is version 158 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 15

Human chromosome 15: entries, gene names and cross-references to MIM