Alternative titles; symbols
HGNC Approved Gene Symbol: MAP2K7
Cytogenetic location: 19p13.2 Genomic coordinates (GRCh38): 19:7,903,877-7,914,478 (from NCBI)
The general function of mitogen-activated protein kinase (MAPK) cascades is to relay environmental signals to the transcriptional machinery in the nucleus and thus modulate gene expression. MAPK cascades consist of a 3-kinase module composed of an MAPK, an MAPK kinase (MAPKK), and an MAPKK kinase (MAPKKK). At least 3 distinct MAPK cascades exist in mammals: one leads to the activation of the extracellular signal-regulated kinases (ERKs; e.g., 601795); another leads to the activation of the p38s (e.g., 602898); and a third leads to the activation of the c-jun N-terminal kinases (JNKs; e.g., JNK1, 601158). JNKs stimulate the transcriptional activity of c-jun (JUN; 165160) in response to growth factors, proinflammatory cytokines, and certain environmental stresses, such as short wavelength UV light and osmotic shock (summary by Wu et al., 1997).
By searching an expressed sequence tag (EST) database with a sequence motif characteristic of MAPKK proteins, Wu et al. (1997) identified a human EST encoding a portion of MAP2K7, which they called JNKK2. They isolated a full-length human JNKK2 cDNA by screening a human skeletal muscle cDNA library with this EST. Northern blot analysis of human tissue RNAs detected a 3.8-kb JNKK2 transcript that was ubiquitously expressed, with the highest level of expression in skeletal muscle. The predicted 419-amino acid JNKK2 protein has 62% sequence identity with the Drosophila JNKK 'hemipterous' (hep) and 52% identity with human JNKK1 (SERK1; 601335).
Independently, Lu et al. (1997) cloned a human JNKK2 cDNA by screening a HeLa cell cDNA library with a human JNKK1 cDNA. They showed that JNKK2 can be activated by MEKK1, RAC (e.g., 602048), and CDC42 (116952).
Foltz et al. (1998) isolated 2 forms of human MAP2K7 cDNA: one encodes a predicted 419-amino acid protein, and the other contains a 126-bp insertion within the coding sequence that results in an additional 42 amino acids. The authors demonstrated that MAP2K7 is activated in response to various environmental and physiologic stimuli, and by constitutively active mutants of RAS (e.g., 139150), RAC, and CDC42.
Wu et al. (1997) showed that JNKK2 is a specific activator of JNK1 and JNK2 (602896), but not of p38 or ERK2 (176948). Among MEKK1 (600982), MEKK2 (MAP3K2; 609487), GCK, and ASK (MEKK5; 602448), MEKK1 is the most potent activator of JNKK2, while the other MAPKKKs efficiently stimulated JNKK2 comparably.
Schramek et al. (2011) showed that the doxorubicin-mediated DNA damage response in human A549 lung carcinoma cells caused rapid phosphorylation and upregulation of p53 (TP53; 191170). MKK7 knockdown reduced p53 phosphorylation, delayed p53 upregulation, and interfered with cell cycle arrest at G2/M. MKK7 was activated in primary lung tumors, and tumors with a p53 mutation showed even higher MKK7 phosphorylation. Schramek et al. (2011) concluded that MKK7 exerts its tumor suppressive function through p53.
Schramek et al. (2011) found that mice with a conditional Map2k7 allele were viable and fertile with no detectable phenotype. Conditional deletion of Map2k7 in epidermis resulted in an 'eye open at birth' phenotype. Inactivation of Map2k7 in lung carcinomas driven by oncogenic Kras (190070) or in mammary tumors driven by transgenic overexpression of activated Neu (ERBB2; 164870) resulted in accelerated tumor onset, failure of G2/M checkpoint, impaired p53 protein expression, and reduced overall survival.
Foltz, I. N., Gerl, R. E., Wieler, J. S., Luckach, M., Salmon, R. A., Schrader, J. W. Human mitogen-activated protein kinase kinase 7 (MKK7) is a highly conserved c-jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) activated by environmental stresses and physiological stimuli. J. Biol. Chem. 273: 9344-9351, 1998. [PubMed: 9535930] [Full Text: https://doi.org/10.1074/jbc.273.15.9344]
Lu, X., Nemoto, S., Lin, A. Identification of c-jun NH(2)-terminal protein kinase (JNK)-activating kinase 2 as an activator of JNK but not p38. J. Biol. Chem. 272: 24751-24754, 1997. [PubMed: 9312068] [Full Text: https://doi.org/10.1074/jbc.272.40.24751]
Schramek, D., Kotsinas, A., Meixner, A., Wada, T., Elling, U., Pospisilik, J. A., Neely, G. G., Zwick, R.-H., Sigl, V., Forni, G., Serrano, M., Gorgoulis, V. G., Penninger, J. M. The stress kinase MKK7 couples oncogenic stress to p53 stability and tumor suppression. Nature Genet. 43: 212-219, 2011. Note: Erratum: Nature Genet. 55: 891-893, 2023. [PubMed: 21317887] [Full Text: https://doi.org/10.1038/ng.767]
Wu, Z., Wu, J., Jacinto, E., Karin, M. Molecular cloning and characterization of human JNKK2, a novel jun NH(2)-terminal kinase-specific kinase. Molec. Cell. Biol. 17: 7407-7416, 1997. [PubMed: 9372971] [Full Text: https://doi.org/10.1128/MCB.17.12.7407]