Biology:MAP3K4

Short description: Protein-coding gene in the species Homo sapiens

Generic protein structure example

Mitogen-activated protein kinase kinase kinase 4 is an enzyme that in humans is encoded by the MAP3K4 gene.

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.

Interactions

MAP3K4 has been shown to interact with GADD45G, GADD45B and GADD45A.

Further reading

• "Role of mitogen-activated protein kinase kinase 4 in cancer". Oncogene 26 (22): 3172–84. 2007. doi:10.1038/sj.onc.1210410. PMID 17496914. 
• Adams MD; Kerlavage AR; Fleischmann RD et al. (1995). "Initial assessment of human gene diversity and expression patterns based upon 83 million nucleotides of cDNA sequence". Nature 377 (6547 Suppl): 3–174. PMID 7566098. http://www.columbia.edu/itc/biology/pollack/w4065/client_edit/readings/nature377_3.pdf. 
• 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. PMID 9039502. 
• "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. 1997. doi:10.1074/jbc.272.13.8288. PMID 9079650. 
• "MEK kinases are regulated by EGF and selectively interact with Rac/Cdc42". EMBO J. 16 (16): 4961–72. 1997. doi:10.1093/emboj/16.16.4961. PMID 9305638. 
• "Activation of the yeast SSK2 MAP kinase kinase kinase by the SSK1 two-component response regulator". EMBO J. 17 (5): 1385–94. 1998. doi:10.1093/emboj/17.5.1385. PMID 9482735. 
• "A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK". Cell 95 (4): 521–30. 1998. doi:10.1016/S0092-8674(00)81619-0. PMID 9827804. 
• "Human mitogen-activated protein kinase kinase kinase mediates the stress-induced activation of mitogen-activated protein kinase cascades". Biochem. J. 336 (Pt 3): 599–609. 1999. doi:10.1042/bj3360599. PMID 9841871. 
• "Oligomerization of human Gadd45a protein". J. Biol. Chem. 276 (42): 39330–9. 2001. doi:10.1074/jbc.M105115200. PMID 11498536. 
• Mita H; Tsutsui J; Takekawa M et al. (2002). "Regulation of MTK1/MEKK4 Kinase Activity by Its N-Terminal Autoinhibitory Domain and GADD45 Binding". Mol. Cell. Biol. 22 (13): 4544–55. doi:10.1128/MCB.22.13.4544-4555.2002. PMID 12052864. 
• Strausberg RL; Feingold EA; Grouse LH et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMID 12477932. Bibcode: 2002PNAS...9916899M. 
• 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. PMID 12878610. 
• 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. PMID 14702039. 
• 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. PMID 15262978. 
• "Interferon-γ-dependent tyrosine phosphorylation of MEKK4 via Pyk2 is regulated by annexin II and SHP2 in keratinocytes". Biochem. J. 388 (Pt 1): 17–28. 2005. doi:10.1042/BJ20041236. PMID 15601262. 
• "Conserved docking site is essential for activation of mammalian MAP kinase kinases by specific MAP kinase kinase kinases". Mol. Cell 18 (3): 295–306. 2005. doi:10.1016/j.molcel.2005.04.001. PMID 15866172. 
• 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. PMID 15881658. 
• "MEKK4 is an effector of the embryonic TRAF4 for JNK activation". J. Biol. Chem. 280 (43): 35793–6. 2006. doi:10.1074/jbc.C500260200. PMID 16157600. 
• 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. PMID 16256071.