Mitogen-activated protein kinase kinase kinase 4 is an enzyme that in humans is encoded by the MAP3K4gene.
The central core of each mitogen-activated protein kinase (MAPK) pathway is a conserved cascade of 3 protein kinases: an activated MAPK kinase kinase (MAPKKK) phosphorylates and activates a specific MAPK kinase (MAPKK), which then activates a specific MAPK. While the ERK MAPKs are activated by mitogenic stimulation, the CSBP2 (p38α) and JNK MAPKs are activated by environmental stresses such as osmotic shock, UV irradiation, wound stress, and inflammatory factors. This gene encodes a MAPKKK, the MEKK4 protein, also called MTK1. This protein contains a protein kinase catalytic domain at the C terminus. The N-terminal nonkinase domain may contain a regulatory domain. Expression of MEKK4 in mammalian cells activated the CSBP2 (p38α) and JNK MAPK pathways, but not the ERK pathway. In vitro kinase studies indicated that recombinant MEKK4 can specifically phosphorylate and activate PRKMK6 (MKK6) and SERK1 (MKK4), MAPKKs that activate CSBP2 (p38α) and JNK, respectively but cannot phosphorylate PRKMK1 (MKK1), an MAPKK that activates ERKs. MEKK4 is a major mediator of environmental stresses that activate the p38 MAPK pathway, and a minor mediator of the JNK pathway. Two alternatively spliced transcripts encoding distinct isoforms have been described.
Nagase T, Seki N, Ishikawa K et al. (1997). "Prediction of the coding sequences of unidentified human genes. VI. The coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of cDNA clones from cell line KG-1 and brain". DNA Res.3 (5): 321–9, 341–54. doi:10.1093/dnares/3.5.321. PMID9039502.
Gerwins P, Blank JL, Johnson GL (1997). "Cloning of a novel mitogen-activated protein kinase kinase kinase, MEKK4, that selectively regulates the c-Jun amino terminal kinase pathway". J. Biol. Chem.272 (13): 8288–95. doi:10.1074/jbc.272.13.8288. PMID9079650.
Luo W, Ng WW, Jin LH et al. (2003). "Axin utilizes distinct regions for competitive MEKK1 and MEKK4 binding and JNK activation". J. Biol. Chem.278 (39): 37451–8. doi:10.1074/jbc.M305277200. PMID12878610.
Ota T, Suzuki Y, Nishikawa T et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet.36 (1): 40–5. doi:10.1038/ng1285. PMID14702039.
Wong CK, Luo W, Deng Y et al. (2004). "The DIX domain protein coiled-coil-DIX1 inhibits c-Jun N-terminal kinase activation by Axin and dishevelled through distinct mechanisms". J. Biol. Chem.279 (38): 39366–73. doi:10.1074/jbc.M404598200. PMID15262978.
Takekawa M, Tatebayashi K, Saito H (2005). "Conserved docking site is essential for activation of mammalian MAP kinase kinases by specific MAP kinase kinase kinases". Mol. Cell18 (3): 295–306. doi:10.1016/j.molcel.2005.04.001. PMID15866172.
Derbyshire ZE, Halfter UM, Heimark RL et al. (2005). "Angiotensin II stimulated transcription of cyclooxygenase II is regulated by a novel kinase cascade involving Pyk2, MEKK4 and annexin II". Mol. Cell. Biochem.271 (1–2): 77–90. doi:10.1007/s11010-005-5386-9. PMID15881658.
Aissouni Y, Zapart G, Iovanna JL et al. (2006). "CIN85 regulates the ability of MEKK4 to activate the p38 MAP kinase pathway". Biochem. Biophys. Res. Commun.338 (2): 808–14. doi:10.1016/j.bbrc.2005.10.032. PMID16256071.