Alternative titles; symbols
HGNC Approved Gene Symbol: MAPK7
Cytogenetic location: 17p11.2 Genomic coordinates (GRCh38): 17:19,377,750-19,383,544 (from NCBI)
Mitogen-activated protein kinases (MAPKs, or PRKMs) are activated by an upstream cascade of kinases in response to a wide variety of extracellular stimuli. Specific PRKM kinases (MAPKKs, or PRKMKs) have been shown to phosphorylate and activate specific PRKMs in a given signaling pathway. Using the yeast 2-hybrid system with mutant forms of PRKMK5 (602520) as baits, Zhou et al. (1995) identified a cDNA encoding MAPK7, called ERK5 by them. They demonstrated that MAPK7 interacts specifically with PRKMK5, but not with PRKMK1 (176872) or PRKMK2 (601263), suggesting that the PRKMK5/MAPK7 protein cascade is a novel signaling pathway. The 815-amino acid MAPK7 contains the conserved thr-glu-tyr activation motif of ERK-type MAPKs. MAPK7 has an uncharacteristic 400-amino acid C-terminal domain with sequences indicating that it may be targeted to the cytoskeleton. Zhou et al. (1995) found that full-length MAPK7 has no detectable kinase activity in vitro, whereas removal of the C terminus results in autophosphorylation, suggesting that the C terminus may play a role in regulating MAPK7. Northern blot analysis detected a 3.1-kb transcript in a number of human tissues, with the highest levels in heart and skeletal muscle.
By degenerate PCR, Lee et al. (1995) isolated a cDNA encoding a PRKM which they named BMK1. BMK1 shows 98% amino acid identity to ERK5; they differ in a short span of residues at the N terminus. Lee et al. (1995) speculated that these kinases are derived from the same gene, possibly via differential mRNA splicing.
By PCR analysis of a somatic cell hybrid panel, Purandare et al. (1998) mapped the MAPK7 gene to human chromosome 17p11.2.
Thymocyte emigration after positive selection requires KLF2 (602016) expression. Although KLF2 expression by endothelial cells requires ERK5, which is phosphorylated in response to IL7 (146660), Weinreich et al. (2011) found that Erk5-deficient mouse T cells underwent normal development and had no Klf2 deficiency. They concluded that IL7 and ERK5 do not control KLF2 or the semimature to mature single-positive thymocyte transition.
To assess the biologic role of MAPK7 (called ERK5 by them), Regan et al. (2002) deleted the gene in mice. Inactivation of the gene resulted in defective blood vessel and cardiac development leading to embryonic lethality around embryonic day 9.5 to 10.5. Cardiac development was retarded, and the heart failed to undergo normal looping. Endothelial cells that line the developing myocardium of erk5 -/- embryos displayed a disorganized, rounded morphology. Vasculogenesis occurred, but extraembryonic and embryonic blood vessels were disorganized and failed to mature. Furthermore, the investment of embryonic blood vessels with smooth muscle cells was attenuated.
Hayashi et al. (2004) found that targeted ablation of MAPK7 using the Mx1-Cre transgene in adult mice led to lethality within 2 to 4 weeks after the induction of Cre recombinase. Physiologic analysis showed that blood vessels became abnormally leaky after deletion of the MAPK7 gene; histologically, the endothelial cells lining the leaky blood vessels were round, irregularly aligned, and ultimately apoptotic. In vitro removal of MAPK7 also led to the death of endothelial cells, partially due to the downregulation of transcriptional factor MEF2C (600662), which is a direct substrate of MAPK7. In addition, endothelial-specific Mapk7 knockout led to cardiovascular defects identical to that of global Mapk7 -/- mice, but mice lacking Mapk7 only in cardiomyocytes developed to term with no apparent defects. Hayashi et al. (2004) concluded that the MAPK7 pathway is critical for endothelial function and maintenance of blood vessel integrity.
Hayashi, M., Kim, S.-W., Imanaka-Yoshida, K., Yoshida, T., Abel, E. D., Eliceiri, B., Yang, Y., Ulevitch, R. J., Lee, J.-D. Targeted deletion of BMK1/ERK5 in adult mice perturbs vascular integrity and leads to endothelial failure. J. Clin. Invest. 113: 1138-1148, 2004. [PubMed: 15085193] [Full Text: https://doi.org/10.1172/JCI19890]
Lee, J.-D., Ulevitch, R. J., Han, J. Primary structure of BMK1: a new mammalian MAP kinase. Biochem. Biophys. Res. Commun. 213: 715-724, 1995. [PubMed: 7646528] [Full Text: https://doi.org/10.1006/bbrc.1995.2189]
Purandare, S. M., Lee, J.-D., Patel, P. I. Assignment of big MAP kinase (PRKM7) to human chromosome 17 band p11.2 with somatic cell hybrids. Cytogenet. Cell Genet. 83: 258-259, 1998. [PubMed: 10072598] [Full Text: https://doi.org/10.1159/000015199]
Regan, C. P., Li, W., Boucher, D. M., Spatz, S., Su, M. S., Kuida, K. Erk5 null mice display multiple extraembryonic vascular and embryonic cardiovascular defects. Proc. Nat. Acad. Sci. 99: 9248-9253, 2002. [PubMed: 12093914] [Full Text: https://doi.org/10.1073/pnas.142293999]
Weinreich, M. A., Jameson, S. C., Hogquist, K. A. Postselection thymocyte maturation and emigration are independent of IL-7 and ERK5. J. Immun. 186: 1343-1347, 2011. [PubMed: 21187442] [Full Text: https://doi.org/10.4049/jimmunol.1002238]
Zhou, G., Bao, Z. Q., Dixon, J. E. Components of a new human protein kinase signal transduction pathway. J. Biol. Chem. 270: 12665-12669, 1995. [PubMed: 7759517] [Full Text: https://doi.org/10.1074/jbc.270.21.12665]