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MGP002808

UniProt Annotations

Entry Information
Gene Namemitogen-activated protein kinase kinase 4
Protein EntryMP2K4_HUMAN
UniProt IDP45985
SpeciesHuman
Comments
Comment typeDescription
Alternative ProductsEvent=Alternative splicing; Named isoforms=2; Name=1; IsoId=P45985-1; Sequence=Displayed; Name=2; IsoId=P45985-2; Sequence=VSP_038838; Note=No experimental confirmation available.;
Catalytic ActivityATP + a protein = ADP + a phosphoprotein.
DomainThe D domain (residues 34-52) contains a conserved docking site and is required for the binding to MAPK substrates.
DomainThe DVD domain (residues 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.
Enzyme RegulationActivated 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. {ECO:0000269|PubMed:9003778}.
FunctionDual 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. {ECO:0000269|PubMed:7716521}.
InteractionQ13233:MAP3K1; NbExp=3; IntAct=EBI-447868, EBI-49776;
PtmActivated by phosphorylation on Ser-257 and Thr-261 by MAP kinase kinase kinases (MAP3Ks). {ECO:0000269|PubMed:18669648, ECO:0000269|PubMed:19369195, ECO:0000269|PubMed:9003778}.
SimilarityBelongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase subfamily. {ECO:0000305}.
SimilarityContains 1 protein kinase domain. {ECO:0000255|PROSITE-ProRule:PRU00159}.
Subcellular LocationCytoplasm {ECO:0000250}. Nucleus {ECO:0000250}.
SubunitInteracts 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. {ECO:0000250, ECO:0000269|PubMed:11090355, ECO:0000269|PubMed:12189133, ECO:0000269|PubMed:12788955, ECO:0000269|PubMed:19782076, ECO:0000269|PubMed:9003778}.
Tissue SpecificityAbundant expression is seen in the skeletal muscle. It is also widely expressed in other tissues.
Web ResourceName=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/MAP2K4ID244ch17p12.html";
Web ResourceName=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/map2k4/";
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