(Mitogen-Activated Protein Kinase Kinase Kinase 4 (MAP3K4))
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. [provided by RefSeq, Jul 2008].
Wong, Luo, Deng, Zou, Ye, Lin: "The DIX domain protein coiled-coil-DIX1 inhibits c-Jun N-terminal kinase activation by Axin and dishevelled through distinct mechanisms." in: The Journal of biological chemistry, Vol. 279, Issue 38, pp. 39366-73, (2004) (PubMed).
Luo, Ng, Jin, Ye, Han, Lin: "Axin utilizes distinct regions for competitive MEKK1 and MEKK4 binding and JNK activation." in: The Journal of biological chemistry, Vol. 278, Issue 39, pp. 37451-8, (2003) (PubMed).
Kovalsky, Lung, Roller, Fornace: "Oligomerization of human Gadd45a protein." in: The Journal of biological chemistry, Vol. 276, Issue 42, pp. 39330-9, (2001) (PubMed).