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External IDsGeneCards: [1]
RefSeq (mRNA)



RefSeq (protein)



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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]


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


  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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  2. 2.0 2.1 "Entrez Gene: MAP3K4 mitogen-activated protein kinase kinase kinase 4".<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  3. 3.0 3.1 3.2 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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>

Further reading

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