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HGNC Approved Gene Symbol: KLK8
Cytogenetic location: 19q13.41 Genomic coordinates (GRCh38) : 19:50,996,008-51,001,604 (from NCBI)
KLK8 belongs to the kallikrein subgroup of serine proteases, which have diverse physiologic functions in many tissues. For background information on kallikreins, see 147960.
By searching an EST database, followed by PCR on hippocampus and keratinocyte cDNA and RACE, Yoshida et al. (1998) isolated a cDNA encoding KLK8, the human homolog of mouse neuropsin. The deduced 260-amino acid protein, 72% identical to the mouse sequence, has an N-terminal signal peptide, conserved residues for protease activity, an N-linked glycosylation site, and 13 cys residues. Northern blot analysis detected a 0.9-kb transcript in keratinocytes.
Using a similar strategy, Mitsui et al. (1999) obtained cDNAs encoding 260- and 305-amino acid KLK8 isoforms, which they termed type-1 and type-2 neuropsin, respectively. Sequence analysis determined that type 2 has a 45-residue leucine- and proline-rich insert at the C terminus of the putative leader sequence of type 1. Mouse and human genomic sequence analysis indicated that type 2 is a species-specific splice variant for humans. Northern blot analysis revealed that type 1 is most intensely expressed in pancreas, with lower expression in placenta, whereas type 2 is expressed in brain, suggesting organ-specific alternative splicing. RT-PCR analysis detected type 2 expression in hippocampus. Dot blot hybridization demonstrated expression of type 2 in all investigated areas of the brain. Western blot analysis showed that type-1 and type-2 neuropsin are secreted as 35- and 38-kD proteins, respectively, from insect cells.
By RT-PCR analysis using degenerate primers for serine proteases in normal ovary and ovarian carcinoma, Underwood et al. (1999) identified a cDNA encoding KLK8, which they called TADG14. Database searching showed that TADG14 is identical to the 280-amino acid human neuropsin at the protein but not the cDNA level. Northern blot analysis detected a 1.4-kb transcript that was highly overexpressed in 20 of 30 ovarian carcinomas studied. Western blot analysis detected a 30-kD protein in tumor cell lines. Immunohistochemical analysis detected KLK8 in carcinoma but not normal ovarian tissue. Underwood et al. (1999) suggested that circulating KLK8 may be a useful marker for early detection of ovarian carcinoma.
By RT-PCR of 35 adult and fetal tissues, Gan et al. (2000) detected highest KLK8 expression in adult skin. Most other tissues showed weak KLK8 expression.
Kishi et al. (2003) demonstrated K8 protein in ovarian cancer tissue extracts, serum, and ascites fluid, suggesting that it may serve as a new ovarian cancer marker.
By genomic sequence analysis, Yoshida et al. (1998) determined that KLK8 is a single-copy gene that contains 6 exons and spans 5.4 kb. Promoter analysis revealed atypical TATA and CCAAT box sequences.
Attwood et al. (2011) demonstrated in mice that the serine protease neuropsin is critical for stress-related plasticity in the amygdala by regulating the dynamics of the EphB2-NMDA receptor interaction, the expression of Fkbp5 (602623), and anxiety-like behavior. Stress results in neuropsin-dependent cleavage of EphB2 in the amygdala, causing dissociation of EphB2 from the NR1 (138249) subunit of the NMDA receptor and promoting membrane turnover of EphB2 receptors. Dynamic EphB2-NR1 interaction enhances NMDA receptor current, induces Fkpb5 gene expression, and enhances behavioral signatures of anxiety. On stress, neuropsin-deficient mice do not show EphB2 cleavage and its dissociation from NR1, resulting in a static EphB2-NR1 interaction, attenuated induction of the Fkbp5 gene, and low anxiety. The behavioral response to stress can be restored by intraamygdala injection of neuropsin into neuropsin-deficient mice and disrupted by the injection of either anti-EphB2 antibodies or silencing the Fkbp5 gene in the amygdala of wildtype mice. Attwood et al. (2011) concluded that their findings established a novel neuronal pathway linking stress-induced proteolysis of EphB2 in the amygdala to anxiety.
Harvey et al. (2000) mapped the KLK8 gene to chromosome 19q13.4 in the KLK gene cluster between KLK7 (604438) and KLK9 (605504). They noted that KLK5 (605643) to KLK14 are transcribed telomere to centromere.
Lu et al. (2007) demonstrated that type-2 KLK8 is absent from nonhuman primates, indicating that it is human specific. In vitro splicing assays revealed a human-specific mutation that triggers the change in splicing pattern, and mutation assays showed that this mutation is necessary and sufficient for type-2 KLK8 expression.
Attwood, B. K., Bourgognon, J.-M., Patel, S., Mucha, M., Schiavon, E., Skrzypiec, A. E., Young, K. W., Shiosaka, S., Korostynski, M., Piechota, M., Przewlocki, R., Pawlak, R. Neuropsin cleaves EphB2 in the amygdala to control anxiety. Nature 473: 372-375, 2011. [PubMed: 21508957] [Full Text: https://doi.org/10.1038/nature09938]
Gan, L., Lee, I., Smith, R., Argonza-Barrett, R., Lei, H., McCuaig, J., Moss, P., Paeper, B., Wang, K. Sequencing and expression analysis of the serine protease gene cluster located in chromosome 19q13 region. Gene 257: 119-130, 2000. [PubMed: 11054574] [Full Text: https://doi.org/10.1016/s0378-1119(00)00382-6]
Harvey, T. J., Hooper, J. D., Myers, S. A., Stephenson, S.-A., Ashworth, L. K., Clements, J. A. Tissue-specific expression patterns and fine mapping of the human kallikrein (KLK) locus on proximal 19q13.4. J. Biol. Chem. 275: 37397-37406, 2000. [PubMed: 10969073] [Full Text: https://doi.org/10.1074/jbc.M004525200]
Kishi, T., Grass, L., Soosaipillai, A., Scorilas, A., Harbeck, N., Schmalfeldt, B., Dorn, J., Mysliwiec, M., Schmitt, M., Diamandis, E. P. Human kallikrein 8, a novel biomarker for ovarian carcinoma. Cancer Res. 63: 2771-2774, 2003. [PubMed: 12782581]
Lu, Z., Peng, J., Su, B. A human-specific mutation leads to the origin of a novel splice form of neuropsin (KLK8), a gene involved in learning and memory. Hum. Mutat. 28: 978-984, 2007. [PubMed: 17487847] [Full Text: https://doi.org/10.1002/humu.20547]
Mitsui, S., Tsuruoka, N., Yamashiro, K., Nakazato, H., Yamaguchi, N. A novel form of human neuropsin, a brain-related serine protease, is generated by alternative splicing and is expressed preferentially in human adult brain. Europ. J. Biochem. 260: 627-634, 1999. [PubMed: 10102990] [Full Text: https://doi.org/10.1046/j.1432-1327.1999.00213.x]
Underwood, L. J, Tanimoto, H., Wang, Y., Shigemasa, K., Parmley, T. H., O'Brien, T. J. Cloning of tumor-associated differentially expressed gene-14, a novel serine protease overexpressed by ovarian carcinoma. Cancer Res. 59: 4435-4439, 1999. [PubMed: 10485494]
Yoshida, S., Taniguchi, M., Hirata, A., Shiosaka, S. Sequence analysis and expression of human neuropsin cDNA and gene. Gene 213: 9-16, 1998. [PubMed: 9714609] [Full Text: https://doi.org/10.1016/s0378-1119(98)00232-7]