MAP3K4

MAP3K4
Identifiers
Aliases	MAP3K4 , MAPKKK4, MEKK 4, MEKK4, MTK1, PRO0412, mitogen-activated protein kinase kinase kinase 4
External IDs	OMIM: 602425 MGI: 1346875 HomoloGene: 31346 GeneCards: MAP3K4
Gene location (Human)
Chr.	Chromosome 6 (human)
End	161,117,385 bp
Gene location (Mouse)
Chr.	Chromosome 17 (mouse)
End	12,537,683 bp
RNA expression pattern
	Top expressed in
	middle temporal gyrus; ; secondary oocyte; ; Brodmann area 23; ; sural nerve; ; Achilles tendon; ; cavity of mouth; ; pancreatic ductal cell; ; right uterine tube; ; amniotic fluid; ; bronchial epithelial cell;
	Top expressed in
	fossa; ; condyle; ; substantia nigra; ; medullary collecting duct; ; facial motor nucleus; ; Paneth cell; ; vas deferens; ; iris; ; primitive streak; ; ciliary body;
	More reference expression data
	; ;
	More reference expression data
Gene ontology
Molecular function	protein serine/threonine kinase activity ; ATP binding ; protein kinase activity ; protein binding ; MAP kinase kinase kinase activity ; kinase activity ; metal ion binding ; nucleotide binding ; transferase activity ;
Cellular component	perinuclear region of cytoplasm ; cytoplasm ;
Biological process	positive regulation of JUN kinase activity ; intracellular signal transduction ; protein phosphorylation ; placenta development ; positive regulation of telomerase activity ; positive regulation of p38MAPK cascade ; positive regulation of telomere maintenance via telomerase ; regulation of gene expression ; positive regulation of telomere capping ; response to UV-C ; phosphorylation ; male germ-line sex determination ; chorionic trophoblast cell differentiation ; MAPK cascade ; regulation of mitotic cell cycle ; regulation of apoptotic process ; signal transduction ; stress-activated protein kinase signaling cascade ; activation of protein kinase activity ;
	Sources:Amigo / QuickGO
Orthologs
	4216
	26407
	ENSG00000085511
	ENSMUSG00000014426
	Q9Y6R4
	O08648
	NM_001291958 ; NM_001301072 ; NM_005922 ; NM_006724 ; NM_001363582 Contents Interactions ; References ; Further reading ;
	NM_011948 ; NM_001357722
	NP_001278887 ; NP_001288001 ; NP_005913 ; NP_006715 ; NP_001350511
	NP_036078 ; NP_001344651
	Wikidata
View/Edit Human	View/Edit Mouse

Last updated March 04, 2023

Mitogen-activated protein kinase kinase kinase 4 is an enzyme that in humans is encoded by the MAP3K4 gene.^[5]^[6]

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.^[6]

Interactions

MAP3K4 has been shown to interact with GADD45G,^[7] GADD45B ^[7] and GADD45A.^[7]

Related Research Articles

A mitogen-activated protein kinase is a type of protein kinase that is specific to the amino acids serine and threonine. MAPKs are involved in directing cellular responses to a diverse array of stimuli, such as mitogens, osmotic stress, heat shock and proinflammatory cytokines. They regulate cell functions including proliferation, gene expression, differentiation, mitosis, cell survival, and apoptosis.

Mitogen Activated Protein (MAP) kinase kinase kinase, MAPKKK is a serine/threonine-specific protein kinase which acts upon MAP kinase kinase. Subsequently, MAP kinase kinase activates MAP kinase. Several types of MAPKKK can exist but are mainly characterized by the MAP kinases they activate. MAPKKKs are stimulated by a large range of stimuli, primarily environmental and intracellular stressors. MAPKKK is responsible for various cell functions such as cell proliferation, cell differentiation, and apoptosis. The duration and intensity of signals determine which pathway ensues. Additionally, the use of protein scaffolds helps to place the MAPKKK in close proximity with its substrate to allow for a reaction. Lastly, because MAPKKK is involved in a series of several pathways, it has been used as a therapeutic target for cancer, amyloidosis, and neurodegenerative diseases. In humans, there are at least 19 genes which encode MAP kinase kinase kinases:

Apoptosis signal-regulating kinase 1 (ASK1) also known as mitogen-activated protein kinase 5 (MAP3K5) is a member of MAP kinase family and as such a part of mitogen-activated protein kinase pathway. It activates c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases in a Raf-independent fashion in response to an array of stresses such as oxidative stress, endoplasmic reticulum stress and calcium influx. ASK1 has been found to be involved in cancer, diabetes, rheumatoid arthritis, cardiovascular and neurodegenerative diseases.

Mitogen-activated protein kinase 14, also called p38-α, is an enzyme that in humans is encoded by the MAPK14 gene.

Mitogen-activated protein kinase 8 is a ubiquitous enzyme that in humans is encoded by the MAPK8 gene.

Dual specificity mitogen-activated protein kinase kinase 1 is an enzyme that in humans is encoded by the MAP2K1 gene.

Dual-specificity mitogen-activated protein kinase kinase 4 is an enzyme that in humans is encoded by the MAP2K4 gene.

Dual specificity mitogen-activated protein kinase kinase 6 also known as MAP kinase kinase 6 or MAPK/ERK kinase 6 is an enzyme that in humans is encoded by the MAP2K6 gene, on chromosome 17.

Dual specificity mitogen-activated protein kinase kinase 3 is an enzyme that in humans is encoded by the MAP2K3 gene.

C-jun-amino-terminal kinase-interacting protein 1 is an enzyme that in humans is encoded by the MAPK8IP1 gene.

Mitogen-activated protein kinase kinase kinase 11 is an enzyme that in humans is encoded by the MAP3K11 gene.

Mitogen-activated protein kinase kinase kinase 1 (MAP3K1) is a signal transduction enzyme that in humans is encoded by the autosomal MAP3K1 gene.

Growth arrest and DNA-damage-inducible protein GADD45 alpha is a protein that in humans is encoded by the GADD45A gene.

Dual specificity mitogen-activated protein kinase kinase 7, also known as MAP kinase kinase 7 or MKK7, is an enzyme that in humans is encoded by the MAP2K7 gene. This protein is a member of the mitogen-activated protein kinase kinase family. The MKK7 protein exists as six different isoforms with three possible N-termini and two possible C-termini.

Growth arrest and DNA-damage-inducible, beta, also known as GADD45B, is a protein which in humans is encoded by the GADD45B gene.

Mitogen-activated protein kinase kinase kinase 7-interacting protein 1 is an enzyme that in humans is encoded by the TAB1 gene.

C-jun-amino-terminal kinase-interacting protein 3 is an enzyme that in humans is encoded by the MAPK8IP3 gene.

Mitogen-Activated Protein Kinase Kinase Kinase 2 also known as MEKK2 is an enzyme that in humans is encoded by the MAP3K2 gene.

Mitogen-activated protein kinase 11 is an enzyme that in humans is encoded by the MAPK11 gene.

Mitogen-activated protein kinase 10 also known as c-Jun N-terminal kinase 3 (JNK3) is an enzyme that in humans is encoded by the MAPK10 gene.

References

1 2 3 GRCh38: Ensembl release 89: ENSG00000085511 - Ensembl, May 2017
1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000014426 - Ensembl, May 2017
↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
↑ 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.
1 2 "Entrez Gene: MAP3K4 mitogen-activated protein kinase kinase kinase 4".
1 2 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. 95 (4): 521–30. doi: 10.1016/S0092-8674(00)81619-0 . ISSN 0092-8674. PMID 9827804.

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. Bibcode:2002PNAS...9916899M. 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. S2CID 12481185.
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.

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[refGRCh38Ensembl-1] 1 2 3 GRCh38: Ensembl release 89: ENSG00000085511 - Ensembl, May 2017

[refGRCm38Ensembl-2] 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000014426 - Ensembl, May 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[pmid9305639-5] 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.

[entrez-6] 1 2 "Entrez Gene: MAP3K4 mitogen-activated protein kinase kinase kinase 4".

[pmid9827804-7] 1 2 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. 95 (4): 521–30. doi: 10.1016/S0092-8674(00)81619-0 . ISSN 0092-8674. PMID 9827804.

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v t e Enzymes
Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Diffusion-limited enzyme Coenzyme Cofactor Enzyme catalysis
Regulation	Allosteric regulation Cooperativity Enzyme inhibitor Enzyme activator
Classification	EC number Enzyme superfamily Enzyme family List of enzymes
Kinetics	Enzyme kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics
Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list) EC7 Translocases (list)

MAP3K4

Contents

Interactions

Related Research Articles

References

Further reading