ID:MP2K6_HUMAN DESCRIPTION: RecName: Full=Dual specificity mitogen-activated protein kinase kinase 6; Short=MAP kinase kinase 6; Short=MAPKK 6; EC=2.7.12.2; AltName: Full=MAPK/ERK kinase 6; Short=MEK 6; AltName: Full=Stress-activated protein kinase kinase 3; Short=SAPK kinase 3; Short=SAPKK-3; Short=SAPKK3; FUNCTION: Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. With MAP3K3/MKK3, catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in the MAP kinases p38 MAPK11, MAPK12, MAPK13 and MAPK14 and plays an important role in the regulation of cellular responses to cytokines and all kinds of stresses. Especially, MAP2K3/MKK3 and MAP2K6/MKK6 are both essential for the activation of MAPK11 and MAPK13 induced by environmental stress, whereas MAP2K6/MKK6 is the major MAPK11 activator in response to TNF. MAP2K6/MKK6 also phosphorylates and activates PAK6. The p38 MAP kinase signal transduction pathway leads to direct activation of transcription factors. Nuclear targets of p38 MAP kinase include the transcription factors ATF2 and ELK1. Within the p38 MAPK signal transduction pathway, MAP3K6/MKK6 mediates phosphorylation of STAT4 through MAPK14 activation, and is therefore required for STAT4 activation and STAT4-regulated gene expression in response to IL-12 stimulation. The pathway is also crucial for IL-6-induced SOCS3 expression and down-regulation of IL-6-mediated gene induction; and for IFNG- dependent gene transcription. Has a role in osteoclast differentiation through NF-kappa-B transactivation by TNFSF11, and in endochondral ossification and since SOX9 is another likely downstream target of the p38 MAPK pathway. MAP2K6/MKK6 mediates apoptotic cell death in thymocytes. Acts also as a regulator for melanocytes dendricity, through the modulation of Rho family GTPases. CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein. ENZYME REGULATION: Activated by dual phosphorylation on Ser-207 and Thr-211 in response to a variety of cellular stresses, including UV radiation, osmotic shock, hypoxia, inflammatory cytokines, interferon gamma (IFNG), and less often by growth factors. MAP2K6/MKK6 is activated by the majority of M3Ks, such as MAP3K5/ASK1, MAP3K1/MEKK1, MAP3K2/MEKK2, MAP3K3/MEKK3, MAP3K4/MEKK4, MAP3K7/TAK1, MAP3K11/MLK3 and MAP3K17/TAOK2. SUBUNIT: Dimer. Interacts with Yersinia yopJ. Interacts (via its D domain) with its substrates MAPK11, MAPK12, MAPK13 and MAPK14 (By similarity). Interacts (via its DVD domain) with MAP3Ks activators like MAP3K5/ASK1, MAP3K1/MEKK1, MAP3K2/MEKK2, MAP3K3/MEKK3, MAP3K4/MEKK4, MAP3K7/TAK1, MAP3K11/MLK3 and MAP3K17/TAOK2 (By similarity). Interacts with DCTN1. SUBCELLULAR LOCATION: Nucleus. Cytoplasm. Cytoplasm, cytoskeleton. Note=Binds to microtubules. TISSUE SPECIFICITY: Isoform 2 is only expressed in skeletal muscle. Isoform 1 is expressed in skeletal muscle, heart, and in lesser extent in liver or pancreas. INDUCTION: Strongly activated by UV, anisomycin, and osmotic shock but not by phorbol esters, NGF or EGF. DOMAIN: The DVD domain (residues 311-334) contains a conserved docking site and is found in the mammalian MAP kinase kinases (MAP2Ks). The DVD sites bind to their specific upstream MAP kinase kinase kinases (MAP3Ks) and are essential for activation. DOMAIN: The D domain (residues 4-19) contains a conserved docking site and is required for the binding to MAPK substrates (By similarity). PTM: Weakly autophosphorylated. Phosphorylated at Ser-207 and Thr- 211 by the majority of M3Ks, such as MAP3K5/ASK1, MAP3K1/MEKK1, MAP3K2/MEKK2, MAP3K3/MEKK3, MAP3K4/MEKK4, MAP3K7/TAK1, MAP3K11/MLK3 and MAP3K17/TAOK2. PTM: Acetylation of Ser-207 and Thr-211 by Yersinia yopJ prevents phosphorylation and activation, thus blocking the MAPK signaling pathway. SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase subfamily. SIMILARITY: Contains 1 protein kinase domain.
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 P52564
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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.
Biological Process: GO:0000165 MAPK cascade GO:0000187 activation of MAPK activity GO:0001934 positive regulation of protein phosphorylation GO:0002931 response to ischemia GO:0006351 transcription, DNA-templated GO:0006355 regulation of transcription, DNA-templated GO:0006468 protein phosphorylation GO:0006915 apoptotic process GO:0006975 DNA damage induced protein phosphorylation GO:0007050 cell cycle arrest GO:0007165 signal transduction GO:0007346 regulation of mitotic cell cycle GO:0016310 phosphorylation GO:0018108 peptidyl-tyrosine phosphorylation GO:0022602 ovulation cycle process GO:0023014 signal transduction by protein phosphorylation GO:0031098 stress-activated protein kinase signaling cascade GO:0032147 activation of protein kinase activity GO:0032308 positive regulation of prostaglandin secretion GO:0042493 response to drug GO:0042981 regulation of apoptotic process GO:0043065 positive regulation of apoptotic process GO:0051770 positive regulation of nitric-oxide synthase biosynthetic process GO:0060048 cardiac muscle contraction GO:0070423 nucleotide-binding oligomerization domain containing signaling pathway GO:0072709 cellular response to sorbitol
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Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
