Alternative titles; symbols
HGNC Approved Gene Symbol: MAPK6
Cytogenetic location: 15q21.2 Genomic coordinates (GRCh38): 15:51,971,825-52,067,375 (from NCBI)
MAPK6, or ERK3, belongs to the mitogen-activated protein kinase (MAPK) family and shares highest homology with ERK1 (MAPK3; 601795) and ERK2 (MAPK1; 176948). ERK3 is an atypical MAPK because it lacks the conserved thr-xaa-tyr motif in the activation loop and possesses a long C-terminal extension (summary by Sirois et al., 2015).
Boulton et al. (1991) identified 2 rat ERK1-related kinases, Erk2 and Erk3. By RT-PCR of RNA from insulin-sensitive human tissues with primers based on conserved regions within the kinase domains of MAPKs, Zhu et al. (1994) recovered a partial cDNA that was highly homologous to rat Erk3. They then isolated adipose tissue and fetal skeletal muscle cDNAs containing the remainder of the coding region. The in vitro transcription/translation product migrated at 97 kD by SDS-PAGE. The authors designated the gene human ERK3 and the protein p97MAPK. On Western blots, antibodies against the N-terminal region of p97MAPK recognized an additional 62-kD protein, which Zhu et al. (1994) stated might be MAPK4 (176949). In quiescent skin fibroblasts, both phorbol ester and serum stimulated the p97MAPK myelin basic protein and histone H1 kinase activities.
Meloche et al. (1996) also identified cDNAs encoding human ERK3. Northern blot analysis revealed that ERK3 is expressed as a 4.5-kb mRNA in various human tissues, most abundantly in skeletal muscle. The predicted 721-amino acid protein is 92% identical to rat ERK3 over their shared length, and contains a unique 178-amino acid C-terminal extension.
By fluorescence in situ hybridization, Meloche et al. (1996) mapped the MAPK6 gene to 15q21.
Using a knockin mouse model in which the Erk3 coding sequence was replaced by a beta-galactosidase reporter, Sirois et al. (2015) showed that Erk3 was expressed by double-positive thymocytes undergoing positive selection. In Erk3-deficient mice with a polyclonal T-cell receptor (TCR) repertoire, the authors observed decreased positive selection. Backcrossing Erk3-deficient mice to major histocompatibility complex class I- and class II-restricted TCR transgenic mice also resulted in reduced positive selection. Responses of double-positive thymocytes to in vitro stimulation were significantly reduced in Erk3-deficient mice. Sirois et al. (2015) concluded that ERK3 expression following TCR signaling is critical for positive thymocyte selection.
Boulton, T. G., Nye, S. H., Robbins, D. J., Ip, N. Y., Radziejewska, E., Morgenbesser, S. D., DePinho, R. A., Panayotatos, N., Cobb, M. H., Yancopoulos, G. D. ERKs: a family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF. Cell 65: 663-675, 1991. [PubMed: 2032290] [Full Text: https://doi.org/10.1016/0092-8674(91)90098-j]
Meloche, S., Beatty, B. G., Pellerin, J. Primary structure, expression and chromosomal locus of a human homolog of rat ERK3. Oncogene 13: 1575-1579, 1996. [PubMed: 8875998]
Sirois, J., Daudelin, J.-F., Boulet, S., Marquis, M., Meloche, S., Labrecque, N. The atypical MAPK ERK3 controls positive selection of thymocytes. Immunology 145: 161-169, 2015. [PubMed: 25521218] [Full Text: https://doi.org/10.1111/imm.12433]
Zhu, A. X., Zhao, Y., Moller, D. E., Flier, J. S. Cloning and characterization of p97(MAPK), a novel human homolog of rat ERK-3. Molec. Cell. Biol. 14: 8202-8211, 1994. [PubMed: 7969157] [Full Text: https://doi.org/10.1128/mcb.14.12.8202-8211.1994]