ID:MP2K1_HUMAN DESCRIPTION: RecName: Full=Dual specificity mitogen-activated protein kinase kinase 1; Short=MAP kinase kinase 1; Short=MAPKK 1; Short=MKK1; EC=2.7.12.2; AltName: Full=ERK activator kinase 1; AltName: Full=MAPK/ERK kinase 1; Short=MEK 1; 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. 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: Found in a complex with at least BRAF, HRAS1, 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. INTERACTION: Q9NR09:BIRC6; NbExp=2; IntAct=EBI-492564, EBI-1765160; P04049:RAF1; NbExp=2; IntAct=EBI-492564, EBI-365996; Q86Y07:VRK2; NbExp=2; IntAct=EBI-492564, EBI-1207615; Q86Y07-1:VRK2; NbExp=2; IntAct=EBI-492564, EBI-1207633; SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton, centrosome. Cytoplasm, cytoskeleton, spindle pole body. Cytoplasm. Nucleus. Note=Localizes at centrosomes during prometaphase, midzone during anaphase and midbody during telophase/cytokinesis. TISSUE SPECIFICITY: Widely expressed, with extremely low levels in brain. DOMAIN: The proline-rich region localized between residues 270 and 307 is important for binding to RAF1 and activation of MAP2K1/MEK1 (By similarity). PTM: 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. PTM: Acetylation by Yersinia yopJ prevents phosphorylation and activation, thus blocking the MAPK signaling pathway. DISEASE: Defects in MAP2K1 are a cause of cardiofaciocutaneous syndrome (CFC syndrome) [MIM:115150]; also known as cardio-facio- cutaneous syndrome. CFC syndrome is 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. The inheritance of CFC syndrome is autosomal dominant. SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase subfamily. SIMILARITY: Contains 1 protein kinase domain. WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/MAP2K1";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on Q02750
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Gene Ontology (GO) Annotations with Structured Vocabulary
Molecular Function: GO:0000166 nucleotide binding GO:0004672 protein kinase activity GO:0004674 protein serine/threonine kinase activity GO:0004708 MAP kinase kinase activity GO:0004712 protein serine/threonine/tyrosine kinase activity GO:0004713 protein tyrosine kinase activity GO:0004728 signal transducer, downstream of receptor, with protein tyrosine phosphatase activity GO:0005515 protein binding GO:0005524 ATP binding GO:0008022 protein C-terminus binding GO:0016301 kinase activity GO:0016740 transferase activity GO:0043539 protein serine/threonine kinase activator activity GO:0047485 protein N-terminus binding GO:0097110 scaffold protein binding
Biological Process: GO:0000165 MAPK cascade GO:0000187 activation of MAPK activity GO:0001932 regulation of protein phosphorylation GO:0006468 protein phosphorylation GO:0006935 chemotaxis GO:0007050 cell cycle arrest GO:0007165 signal transduction GO:0007346 regulation of mitotic cell cycle GO:0007507 heart development GO:0008285 negative regulation of cell proliferation GO:0010628 positive regulation of gene expression GO:0010629 negative regulation of gene expression GO:0016310 phosphorylation GO:0018107 peptidyl-threonine phosphorylation GO:0018108 peptidyl-tyrosine phosphorylation GO:0021697 cerebellar cortex formation GO:0030182 neuron differentiation GO:0030216 keratinocyte differentiation GO:0030878 thyroid gland development GO:0032872 regulation of stress-activated MAPK cascade GO:0042981 regulation of apoptotic process GO:0045597 positive regulation of cell differentiation GO:0045893 positive regulation of transcription, DNA-templated GO:0048538 thymus development GO:0048679 regulation of axon regeneration GO:0048870 cell motility GO:0050772 positive regulation of axonogenesis GO:0060020 Bergmann glial cell differentiation GO:0060324 face development GO:0060425 lung morphogenesis GO:0060440 trachea formation GO:0060502 epithelial cell proliferation involved in lung morphogenesis GO:0060674 placenta blood vessel development GO:0060711 labyrinthine layer development GO:0070371 ERK1 and ERK2 cascade GO:0070374 positive regulation of ERK1 and ERK2 cascade GO:0071902 positive regulation of protein serine/threonine kinase activity GO:0090170 regulation of Golgi inheritance GO:0090398 cellular senescence GO:1903800 positive regulation of production of miRNAs involved in gene silencing by miRNA GO:2000641 regulation of early endosome to late endosome transport
US Server
Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
