Description: Homo sapiens mitogen-activated protein kinase kinase 4 (MAP2K4), mRNA. RefSeq Summary (NM_003010): This gene encodes a member of the mitogen-activated protein kinase (MAPK) family. Members of this family act as an integration point for multiple biochemical signals and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation, and development. They form a three-tiered signaling module composed of MAPKKKs, MAPKKs, and MAPKs. This protein is phosphorylated at serine and threonine residues by MAPKKKs and subsequently phosphorylates downstream MAPK targets at threonine and tyrosine residues. A similar protein in mouse has been reported to play a role in liver organogenesis. A pseudogene of this gene is located on the long arm of chromosome X. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]. Transcript (Including UTRs) Position: hg19 chr17:11,924,135-12,047,051 Size: 122,917 Total Exon Count: 11 Strand: + Coding Region Position: hg19 chr17:11,924,204-12,044,577 Size: 120,374 Coding Exon Count: 11
ID:MP2K4_HUMAN DESCRIPTION: RecName: Full=Dual specificity mitogen-activated protein kinase kinase 4; Short=MAP kinase kinase 4; Short=MAPKK 4; EC=2.7.12.2; AltName: Full=JNK-activating kinase 1; AltName: Full=MAPK/ERK kinase 4; Short=MEK 4; AltName: Full=SAPK/ERK kinase 1; Short=SEK1; AltName: Full=Stress-activated protein kinase kinase 1; Short=SAPK kinase 1; Short=SAPKK-1; Short=SAPKK1; AltName: Full=c-Jun N-terminal kinase kinase 1; Short=JNKK; FUNCTION: Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Essential component of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. With MAP2K7/MKK7, is the one of the only known kinase to directly activate the stress-activated protein kinase/c-Jun N-terminal kinases MAPK8/JNK1, MAPK9/JNK2 and MAPK10/JNK3. MAP2K4/MKK4 and MAP2K7/MKK7 both activate the JNKs by phosphorylation, but they differ in their preference for the phosphorylation site in the Thr-Pro-Tyr motif. MAP2K4 shows preference for phosphorylation of the Tyr residue and MAP2K7/MKK7 for the Thr residue. The phosphorylation of the Thr residue by MAP2K7/MKK7 seems to be the prerequisite for JNK activation at least in response to proinflammatory cytokines, while other stimuli activate both MAP2K4/MKK4 and MAP2K7/MKK7 which synergistically phosphorylate JNKs. MAP2K4 is required for maintaining peripheral lymphoid homeostasis. The MKK/JNK signaling pathway is also involved in mitochondrial death signaling pathway, including the release cytochrome c, leading to apoptosis. Whereas MAP2K7/MKK7 exclusively activates JNKs, MAP2K4/MKK4 additionally activates the p38 MAPKs MAPK11, MAPK12, MAPK13 and MAPK14. CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein. ENZYME REGULATION: Activated in response to a variety of cellular stresses, including UV and gamma-irradiation, heat shock, hyperosmolarity, T-cell receptor stimulation, peroxide and inflammatory cytokines. Also activated by developmental cues. MAP2K4/MKK4 is activated by the majority of MKKKs, such as MAP3K5/ASK1, MAP3K1/MEKK1, MAP3K7/TAK1, MAP3K10/MLK2, MAP3K11/MLK3, MAP3K12/DLK and MAP3K13/LZK. SUBUNIT: Interacts with SPAG9 (By similarity). Interacts (via its D domain) with its substrates MAPK8/JNK1, MAPK9/JNK2, MAPK10/JNK3, MAPK11 and MAPK14. Interacts (via its DVD domain) with MAP3Ks activators like MAP3K1/MEKK1 and MAP3K11/MLK3. Interacts with ARRB1, ARRB2 and MAPK8IP3/JIP3. INTERACTION: Q13233:MAP3K1; NbExp=3; IntAct=EBI-447868, EBI-49776; SUBCELLULAR LOCATION: Cytoplasm (By similarity). Nucleus (By similarity). TISSUE SPECIFICITY: Abundant expression is seen in the skeletal muscle. It is also widely expressed in other tissues. DOMAIN: The DVD domain (redidues 364-387) 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 (redidues 34-52) contains a conserved docking site and is required for the binding to MAPK substrates. PTM: Activated by phosphorylation on Ser-257 and Thr-261 by MAP kinase kinase kinases (MAP3Ks). 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=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/map2k4/";
Body Mass Index Caroline S Fox et al. BMC medical genetics 2007, Genome-wide association to body mass index and waist circumference: the Framingham Heart Study 100K project., BMC medical genetics.
[PubMed 17903300]
Adiposity traits are associated with SNPs on the Affymetrix 100K SNP GeneChip. Replication of these initial findings is necessary. These data will serve as a resource for replication as more genes become identified with BMI and WC.
Body Weight Caroline S Fox et al. BMC medical genetics 2007, Genome-wide association to body mass index and waist circumference: the Framingham Heart Study 100K project., BMC medical genetics.
[PubMed 17903300]
Adiposity traits are associated with SNPs on the Affymetrix 100K SNP GeneChip. Replication of these initial findings is necessary. These data will serve as a resource for replication as more genes become identified with BMI and WC.
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 P45985
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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:0001934 positive regulation of protein phosphorylation GO:0006468 protein phosphorylation GO:0006915 apoptotic process GO:0007165 signal transduction GO:0007254 JNK cascade GO:0007257 activation of JUN kinase activity GO:0007346 regulation of mitotic cell cycle GO:0009611 response to wounding GO:0016310 phosphorylation GO:0018108 peptidyl-tyrosine phosphorylation GO:0023014 signal transduction by protein phosphorylation GO:0031098 stress-activated protein kinase signaling cascade GO:0032147 activation of protein kinase activity GO:0034393 positive regulation of smooth muscle cell apoptotic process GO:0042981 regulation of apoptotic process GO:0043065 positive regulation of apoptotic process GO:0043525 positive regulation of neuron apoptotic process GO:0045740 positive regulation of DNA replication GO:0051770 positive regulation of nitric-oxide synthase biosynthetic process GO:0061049 cell growth involved in cardiac muscle cell development GO:0071260 cellular response to mechanical stimulus GO:0072709 cellular response to sorbitol GO:2000672 negative regulation of motor neuron apoptotic process
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