Alternative titles; symbols
HGNC Approved Gene Symbol: MAP3K12
Cytogenetic location: 12q13.13 Genomic coordinates (GRCh38): 12:53,479,669-53,501,539 (from NCBI)
Using subtractive hybridization to enrich for cDNAs specific to human teratocarcinoma cells and the differentiated neuronal cells derived from them, Reddy and Pleasure (1994) performed PCR with degenerate oligonucleotide primers corresponding to the catalytic domains of protein kinases and identified several novel genes. One of these was MAP3K12, also called ZPK, a putative protein kinase that encodes an 859-amino acid polypeptide with a serine/threonine protein kinase domain and a leucine zipper domain. The authors found that the gene is expressed in fetal and adult brain, as well as adult kidney, skeletal muscle, and lung.
Holzman et al. (1994) used degenerate oligonucleotide-based PCR to identify novel protein kinase genes expressed in the embryonic mouse kidney. One of these, designated Dlk, represents the mouse homolog of ZPK. Holzman et al. (1994) found that Dlk encodes an 888-amino acid protein and produces a 3.6-kb transcript that was most abundant in brain. Sequence analysis revealed a kinase catalytic domain, 2 putative leucine zipper motifs, and COOH-terminal and NH2-terminal proline-rich domains suggestive of src homology-3 (SH3) domain binding regions. Transfection of COS-7 cells and Western blotting revealed a 130-kD protein that became autophosphorylated on serine and threonine in an in vitro kinase assay.
Hirai et al. (1996) identified a rat protein kinase, designated Muk, which represents the rat homolog of ZPK and is a member of the mixed lineage kinase (MLK) family.
Hirai et al. (1996) identified rat Muk as an activator of the Jnk pathway. Overexpression of Muk resulted in activation of Jnk1 and the accumulation of a hyperphosphorylated form of c-Jun.
Mata et al. (1996) examined the localization and biochemistry of Dlk in rodent brain. Using in situ hybridization they found that Dlk showed neuron-specific hybridization within all regions of the central nervous system examined. Mata et al. (1996) performed subcellular fractionation of rat cerebral cortex and showed that Dlk was enriched in the nerve terminal plasma membrane fraction and was present in the nerve terminal cytosolic fraction in a phosphorylated state. Mata et al. (1996) presented evidence of homodimerization and autophosphorylation of Dlk and suggested that it may be a component of a calcineurin-regulated signal transduction pathway.
Hammarlund et al. (2009) demonstrated that the Dlk1 MAP kinase pathway is essential for regeneration in C. elegans motor neurons. Loss of this pathway eliminates regeneration, whereas activating it improves regeneration. Further, these proteins also regulate the later step of growth cone migration. Hammarlund et al. (2009) concluded that after axon injury, activation of this MAP kinase cascade is required to switch the mature neuron from an aplastic state to a state capable of growth.
By fluorescence in situ hybridization and somatic cell hybrid analysis, Reddy et al. (1995) mapped the human MAP3K12 gene to chromosome 12q13.
Hammarlund, M., Nix, P., Hauth, L., Jorgensen, E. M., Bastiani, M. Axon regeneration requires a conserved MAP kinase pathway. Science 323: 802-806, 2009. [PubMed: 19164707] [Full Text: https://doi.org/10.1126/science.1165527]
Hirai, S., Izawa, M., Osada, S., Spyrou, G., Ohno, S. Activation of the JNK pathway by distantly related protein kinases, MEKK and MUK. Oncogene 12: 641-650, 1996. [PubMed: 8637721]
Holzman, L. B., Merritt, S. E., Fan, G. Identification, molecular cloning, and characterization of dual leucine zipper bearing kinase. A novel serine/threonine protein kinase that defines a second subfamily of mixed lineage kinases. J. Biol. Chem. 269: 30808-30817, 1994. [PubMed: 7983011]
Mata, M., Merritt, S. E., Fan, G., Yu, G. G., Holzman, L. B. Characterization of dual leucine zipper-bearing kinase, a mixed lineage kinase present in synaptic terminals whose phosphorylation state is regulated by membrane depolarization via calcineurin. J. Biol. Chem. 271: 16888-16896, 1996. [PubMed: 8663324] [Full Text: https://doi.org/10.1074/jbc.271.28.16888]
Reddy, U. R., Nycum, L., Slavc, I., Biegel, J. A. Localization of the human zipper protein kinase gene (ZPK) to chromosome 12q13 by fluorescence in situ hybridization and somatic cell hybrid analysis. Genomics 25: 597-598, 1995. [PubMed: 7790002] [Full Text: https://doi.org/10.1016/0888-7543(95)80069-x]
Reddy, U. R., Pleasure, D. Cloning of a novel putative protein kinase having a leucine zipper domain from human brain. Biochem. Biophys. Res. Commun. 202: 613-620, 1994. Note: Erratum: Biochem. Biophys. Res. Commun. 205: 1494-1495, 1994. [PubMed: 8037767] [Full Text: https://doi.org/10.1006/bbrc.1994.1972]