P31938 (MP2K1_MOUSE) Reviewed, UniProtKB/Swiss-Prot
Last modified February 19, 2014. Version 141. History...
Names and origin
|Protein names||Recommended name:|
Dual specificity mitogen-activated protein kinase kinase 1
Short name=MAP kinase kinase 1
Short name=MAPKK 1
ERK activator kinase 1
MAPK/ERK kinase 1
Short name=MEK 1
|Organism||Mus musculus (Mouse) [Reference proteome]|
|Taxonomic identifier||10090 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus|
|Sequence length||393 AA.|
|Sequence processing||The displayed sequence is further processed into a mature form.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
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.8
ATP + a protein = ADP + a phosphoprotein.
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. Ref.5
Found in a complex with at least BRAF, HRAS, MAP2K1, MAPK3/ERK1 and RGS14 By similarity. Forms heterodimers with KSR2 which further dimerize to form tetramers By similarity. Interacts with LAMTOR3, MAPK1/ERK2, RAF1, PPARG AND VRK2 By similarity. Interacts with ARRB2 and MORG1. Forms a heterodimer with MAP2K2/MEK2. Interacts with SGK1 By similarity. Interacts with BIRC6/bruce By similarity.
Cytoplasm › cytoskeleton › microtubule organizing center › centrosome By similarity. Cytoplasm › cytoskeleton › microtubule organizing center › spindle 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.
The proline-rich region localized between residues 270 and 307 is important for binding to RAF1 and activation of MAP2K1/MEK1 By similarity.
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.5 Ref.8
Affects fibroblast shape and impairs haptotaxis and adhesion-dependent ERK-signaling. Ref.8
Contains 1 protein kinase domain.
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Initiator methionine||1||1||Removed By similarity|
|Chain||2 – 393||392||Dual specificity mitogen-activated protein kinase kinase 1||PRO_0000086366|
|Domain||68 – 361||294||Protein kinase|
|Nucleotide binding||74 – 82||9||ATP By similarity|
|Region||270 – 307||38||RAF1-binding By similarity|
|Compositional bias||262 – 307||46||Pro-rich|
|Active site||190||1||Proton acceptor By similarity|
|Binding site||97||1||ATP By similarity|
|Site||8 – 9||2||Cleavage; by anthrax lethal factor By similarity|
Amino acid modifications
|Modified residue||218||1||Phosphoserine; by RAF By similarity|
|Modified residue||222||1||Phosphoserine; by RAF By similarity|
|Modified residue||286||1||Phosphothreonine By similarity|
|Modified residue||292||1||Phosphothreonine; by MAPK1 By similarity|
|Modified residue||298||1||Phosphoserine; by PAK By similarity|
|Mutagenesis||78||1||N → G: Impairs interaction with MAP2K2/MEK2. Ref.8|
|Mutagenesis||292||1||T → A: Results in hyperphosphorylation of the RAF-dependent sites and prolonged ERK phosphorylation. Ref.8|
|Mutagenesis||292||1||T → D: Results in hypophosphorylation of the RAF-dependent sites and faster ERK inactivation. Ref.8|
|Sequence conflict||374||1||W → Q AA sequence Ref.3|
|||"The primary structure of MEK, a protein kinase that phosphorylates the ERK gene product."|
Crews C.M., Alessandrini A., Erikson R.L.
Science 258:478-480(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE.
|||"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].
|||"Purification of a murine protein-tyrosine/threonine kinase that phosphorylates and activates the Erk-1 gene product: relationship to the fission yeast byr1 gene product."|
Crews C.M., Erikson R.L.
Proc. Natl. Acad. Sci. U.S.A. 89:8205-8209(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEIN SEQUENCE OF 4-20; 71-84; 114-136; 206-234 AND 363-384.
|||Lubec G., Klug S.|
Submitted (MAR-2007) to UniProtKB
Cited for: PROTEIN SEQUENCE OF 206-227; 270-291 AND 325-340, MASS SPECTROMETRY.
|||"A divergence in the MAP kinase regulatory network defined by MEK kinase and Raf."|
Lange-Carter C.A., Pleiman C.M., Gardner A.M., Blumer K.J., Johnson G.L.
Science 260:315-319(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AND ENZYME REGULATION.
|||"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.
|||"Modular construction of a signaling scaffold: MORG1 interacts with components of the ERK cascade and links ERK signaling to specific agonists."|
Vomastek T., Schaeffer H.-J., Tarcsafalvi A., Smolkin M.E., Bissonette E.A., Weber M.J.
Proc. Natl. Acad. Sci. U.S.A. 101:6981-6986(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH MORG1.
|||"A Mek1-Mek2 heterodimer determines the strength and duration of the Erk signal."|
Catalanotti F., Reyes G., Jesenberger V., Galabova-Kovacs G., de Matos Simoes R., Carugo O., Baccarini M.
Nat. Struct. Mol. Biol. 16:294-303(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: DISRUPTION PHENOTYPE, FUNCTION, INTERACTION WITH MAP2K2/MEK2, PHOSPHORYLATION AT THR-292, MUTAGENESIS OF ASN-78 AND THR-292.
|||"Signaling by dual specificity kinases."|
Dhanasekaran N., Premkumar Reddy E.
Oncogene 17:1447-1455(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON FUNCTION.
|||"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.
|||"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.
|||"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.
|+||Additional computationally mapped references.|
|L02526 mRNA. Translation: AAA39523.1.|
BC054754 mRNA. Translation: AAH54754.1.
|RefSeq||NP_032953.1. NM_008927.3. |
3D structure databases
|SMR||P31938. Positions 39-381. |
Protein-protein interaction databases
|BioGrid||204949. 12 interactions.|
|IntAct||P31938. 4 interactions.|
2D gel databases
Protocols and materials databases
Genome annotation databases
|Ensembl||ENSMUST00000005066; ENSMUSP00000005066; ENSMUSG00000004936. |
|UCSC||uc009qbp.1. mouse. |
|MGI||MGI:1346866. Map2k1. |
Enzyme and pathway databases
|BRENDA||220.127.116.11. 3474. |
|Reactome||REACT_107772. Immune System. |
Gene expression databases
Family and domain databases
|InterPro||IPR011009. Kinase-like_dom. |
|Pfam||PF00069. Pkinase. 1 hit. |
|SMART||SM00220. S_TKc. 1 hit. |
|SUPFAM||SSF56112. SSF56112. 1 hit. |
|PROSITE||PS00107. PROTEIN_KINASE_ATP. 1 hit. |
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
|ChiTaRS||MAP2K1. mouse. |
|Accession||Primary (citable) accession number: P31938|
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|