MAP3K4

Mitogen-activated protein kinase kinase kinase 4
Identifiers
Symbols	MAP3K4 ; MAPKKK4; MEKK 4; MEKK4; MTK1; PRO0412
External IDs	OMIM: 602425 MGI: 1346875 HomoloGene: 31346 ChEMBL: 4853 GeneCards: MAP3K4 Gene
EC number	2.7.11.25
Gene ontology Molecular function • MAP kinase kinase activity • MAP kinase kinase kinase activity • protein binding • ATP binding • metal ion binding Cellular component • intracellular • cytoplasm • perinuclear region of cytoplasm Biological process • MAPK cascade • activation of MAPKK activity • activation of MAPK activity • placenta development • response to UV-C • regulation of gene expression • male germ-line sex determination • intracellular signal transduction • positive regulation of JUN kinase activity • chorionic trophoblast cell differentiation • positive regulation of p38MAPK cascade Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	4216	26407
Ensembl	ENSG00000085511	ENSMUSG00000014426
UniProt	Q9Y6R4	O08648
RefSeq (mRNA)	NM_001291958	NM_011948
RefSeq (protein)	NP_001278887	NP_036078
Location (UCSC)	Chr 6: 160.99 – 161.12 Mb	Chr 17: 12.23 – 12.32 Mb
PubMed search

Mitogen-activated protein kinase kinase kinase 4 is an enzyme that in humans is encoded by the MAP3K4 gene.^[1][2]

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.^[2]

Interactions

MAP3K4 has been shown to interact with GADD45G,^[3] GADD45B^[3] and GADD45A.^[3]

References

1. Takekawa M, Posas F, Saito H (Oct 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. PMC 1170132. PMID 9305639.
2. "Entrez Gene: MAP3K4 mitogen-activated protein kinase kinase kinase 4".
3. Takekawa, M; Saito H (Nov 1998). "A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK". Cell (UNITED STATES) 95 (4): 521–30. doi:10.1016/S0092-8674(00)81619-0. ISSN 0092-8674. PMID 9827804.

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" (PDF). Nature 377 (6547 Suppl): 3–174. PMID 7566098.
• 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.
• 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. PMID 9079650.
• 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. PMC 1170131. PMID 9305638.
• 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. PMC 1170486. 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. doi:10.1016/S0092-8674(00)81619-0. 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. doi:10.1042/bj3360599. PMC 1219910. 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.
• 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. PMC 133894. 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. PMC 139241. PMID 12477932.
• 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.
• Halfter UM, Derbyshire ZE, Vaillancourt RR (2005). "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. doi:10.1042/BJ20041236. PMC 1186689. PMID 15601262.
• 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.
• 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.
• 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.