MAP3K4

Mitogen-activated protein kinase kinase kinase 4
Identifiers
Symbols	MAP3K4 ; FLJ42439; KIAA0213; MAPKKK4; MEKK4; MTK1; PRO0412
External IDs	Template:OMIM5 Template:MGI HomoloGene: 31346
Gene ontology Molecular function Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Biological process Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO
RNA expression pattern
File:PBB GE MAP3K4 216199 s at tn.png
File:PBB GE MAP3K4 204089 x at tn.png
More reference expression data
Orthologs
Template:GNF Ortholog box
Species	Human	Mouse
Entrez	n/a	n/a
Ensembl	n/a	n/a
UniProt	n/a	n/a
RefSeq (mRNA)	n/a	n/a
RefSeq (protein)	n/a	n/a
Location (UCSC)	n/a	n/a
PubMed search	n/a	n/a

Mitogen-activated protein kinase kinase kinase 4, also known as MAP3K4, is a human 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 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 and JNK MAPK pathways, but not the ERK pathway. In vitro kinase studies indicated that recombinant MEKK4 can specifically phosphorylate and activate PRKMK6 and SERK1, MAPKKs that activate CSBP2 and JNK, respectively but cannot phosphorylate PRKMK1, an MAPKK that activates ERKs. MEKK4 is a major mediator of environmental stresses that activate the CSBP2 MAPK pathway, and a minor mediator of the JNK pathway. Two alternatively spliced transcripts encoding distinct isoforms have been described.

Further reading

• Whitmarsh AJ, Davis RJ (2007). "Role of mitogen-activated protein kinase kinase 4 in cancer". Oncogene. 26 (22): 3172–84. 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.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• 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. PMID 9039502.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• 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. PMID 9079650.CS1 maint: Multiple names: authors list (link)
• Fanger GR, Johnson NL, Johnson GL (1997). "MEK kinases are regulated by EGF and selectively interact with Rac/Cdc42". EMBO J. 16 (16): 4961–72. doi:10.1093/emboj/16.16.4961. PMID 9305638.CS1 maint: Multiple names: authors list (link)
• Takekawa M, Posas F, Saito H (1997). "A human homolog of the yeast Ssk2/Ssk22 MAP kinase kinase kinases, MTK1, mediates stress-induced activation of the p38 and JNK pathways". EMBO J. 16 (16): 4973–82. doi:10.1093/emboj/16.16.4973. PMID 9305639.CS1 maint: Multiple names: authors list (link)
• Posas F, Saito H (1998). "Activation of the yeast SSK2 MAP kinase kinase kinase by the SSK1 two-component response regulator". EMBO J. 17 (5): 1385–94. doi:10.1093/emboj/17.5.1385. PMID 9482735.
• Takekawa M, Saito H (1998). "A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK". Cell. 95 (4): 521–30. PMID 9827804.
• Chan-Hui PY, Weaver R (1999). "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. PMID 9841871.
• Kovalsky O, Lung FD, Roller PP, Fornace AJ (2001). "Oligomerization of human Gadd45a protein". J. Biol. Chem. 276 (42): 39330–9. doi:10.1074/jbc.M105115200. PMID 11498536.CS1 maint: Multiple names: authors list (link)
• 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. PMID 12052864.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• 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.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• 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.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• 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.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• 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.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• Halfter UM, Derbyshire ZE, Vaillancourt RR. "Interferon-gamma-dependent tyrosine phosphorylation of MEKK4 via Pyk2 is regulated by annexin II and SHP2 in keratinocytes". Biochem. J. 388 (Pt 1): 17–28. doi:10.1042/BJ20041236. PMID 15601262.CS1 maint: Multiple names: authors list (link)
• 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. Cell. 18 (3): 295–306. doi:10.1016/j.molcel.2005.04.001. PMID 15866172.CS1 maint: Multiple names: authors list (link)
• 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. PMID 15881658.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• Abell AN, Johnson GL (2006). "MEKK4 is an effector of the embryonic TRAF4 for JNK activation". J. Biol. Chem. 280 (43): 35793–6. 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.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)