New Nomenclature for the Human Tissue Kallikrein Gene Family

The human kallikrein gene family is important to the discipline of clinical chemistry because it contains genes that encode for valuable cancer biomarkers, including the best tumor marker available today, prostate-specific antigen (PSA). Despite reports of numerous kallikrein-like genes in the mouse (1), until 2–3 years ago, only three human kallikrein genes were recognized: pancreatic/renal kallikrein (KLK1), human glandular kallikrein 2 (KLK2), and prostate-specific antigen (KLK3) (1)(2). The proteins encoded by the three kallikrein genes are now known as hK1, hK2, and hK3 (PSA). These three genes encode for serine proteases with either trypsin-like (hK1, hK2) or chymotrypsin-like (hK3) activity. Traditionally, kallikreins have been defined as enzymes that can act on high-molecular weight substrates and release bioactive peptides, known as kinins (3). Among the known kallikrein enzymes, only plasma kallikrein (encoded by a single gene localized on human chromosome 4q35; official symbol KLKB1) and pancreatic/renal kallikrein (hK1) have significant kininogenase activity. The proteins encoded by the KLK2 and the KLK3 genes have minimal or no kininogenase activity (4)(5). Why then are the KLK1, KLK2, and KLK3 genes classified together into one gene family (tissue kallikrein gene family), when two of the three enzymes have no significant kallikrein enzymatic activity? This grouping is justified, based on the extensive homologies between the three genes at both the DNA and protein levels [reviewed in Ref. (2)] as well as their clustering in a 60-kb region on human chromosome 19q13.3-q13.4 (6). It should then be emphasized that the term “kallikrein” does not necessarily imply that the gene product has kininogenase activity. Rittenhouse et al. (2) have recently published a revised nomenclature for the three classical kallikrein genes. More recently, it has become apparent that several other kallikrein-like genes, encoding for serine proteases, are clustered in the same chromosomal locus along with the three classical kallikreins. We now know that there are at least 14 different genes exhibiting significant homologies and other similarities between them that are clustered within a 300-kb region on human chromosome 19q13.3-q13.4 (7). The similarities between these 14 genes are summarized below [for more details, see Diamandis et al. (7)]: All genes localize to the same chromosomal region (19q13.3-q13.4), starting at ∼55.6 Mb on the metric physical map of the chromosome (8). All genes encode for putative serine proteases with a conserved catalytic triad (histidine, aspartic acid, and serine in the appropriate positions). All genes have five coding exons (some members contain one or more 5′ untranslated exons). Coding exon sizes are similar or identical. Intron phases are fully conserved among all 14 human members and among members of the rodent kallikrein gene families. Intron phase refers to the location of the intron within the codon. Intron phase I means that the intron occurs after the first nucleotide of the codon; phase II means that the intron occurs after the second nucleotide; phase 0 means that the intron occurs between codons. All genes have significant sequence homologies at the DNA and amino acid levels (40–80%). Many of these genes are regulated by steroid hormones. Because many of these new genes were cloned independently by different investigators, various empirical names were initially used for their description. The three classical human kallikrein genes as well as the rodent kallikrein genes have a loop region designated the “kallikrein loop”, which is thought to be important for substrate specificity of these enzymes (1). Given the diversity of substrates identified for the rodent families, the presence of the loop does not imply that all kallikreins have kininogenase activity but merely that this region, which is one of the most divergent regions in these enzymes, is important for a particular substrate specificity of each enzyme. The 11 new members of this family do not have the kallikrein loop, suggesting that this family has diverged further in humans than in rodents. The Human Genome Organization (HUGO) recently proposed guidelines for human gene nomenclature. Initially, some members of the new kallikrein gene family were classified by HUGO, along with other serine proteases, under the prefix “PRSS”, which stands for protease serine. It is now clear that this designation does not serve well the needs of the future because members of this multigene family are classified together with other serine proteases that map in different locations of the genome. The construction of the first detailed map of the human kallikrein gene locus (7)(9) allows for a more rational assignment of official gene symbols. Because the tissue kallikrein multigene families of rodents and other animal species were known before 1992, an international working party had reached agreement in 1992 on uniform nomenclature of the animal kallikreins (10). On the basis of this paradigm and the guidelines of HUGO (details available at the HUGO Gene Nomenclature Committee Website at: http://www.gene.ucl.ac.uk/nomenclature/), an international group of scientists working in the field agreed to adopt the new human kallikrein gene nomenclature, as shown in Table 1 . Also included in Table 1 are previous symbols, based on the PRSS system as well as names originally proposed by the discoverers of these genes. Gene numbering starts from centromere to telomere on chromosome 19q13.3-q13.4 with the exception of the three classical kallikreins, for which the existing nomenclature was retained. It is possible that in the future, new members of this gene family may be identified, either centromeric to KLK1 or telomeric to KLK14. If new kallikrein genes are identified in this locus, they will be numbered sequentially, starting with KLK15. No other kallikrein-like or other genes map between the 14 kallikrein genes described by Diamandis et al. (7). Recent developments related to the new human kallikrein gene family, including structure, function, and association of the various kallikreins with human diseases, have recently been reviewed (7). It is possible that some new kallikrein genes and their products may be used in the future as valuable biomarkers for various cancers and other chronic diseases. We hope that expansion of the new human kallikrein gene family, identification of new members, and the new nomenclature presented here will facilitate progress in this field and improve our understanding of the physiological functions and the connections of the new kallikrein genes to various human diseases. As with everything else in science, this newly proposed nomenclature should not be written in stone. As more developments become available, we will consider modifying this proposal to reflect the “state-of-the-art” knowledge and to fulfill the needs of easy communication in this field of investigation. New nomenclature for human kallikreins. Genes are presented in their order on chromosome 19q13.3-q13.4 from centromere to telomere. Full gene names are as follows: hPRK, human pancreatic/renal kallikrein; hGK-1, human glandular kallikrein-1; KLK-L, kallikrein-like; EMSP1, enamel matrix serine proteinase 1; HSCTE, human stratum corneum tryptic enzyme; HSCCE, human stratum corneum chymotryptic enzyme; TADG-14, tumor-associated, differentially expressed gene-14; NES1, normal epithelial cell-specific 1 gene; TLSP, trypsin-like serine protease; PRSS, protease serine; PRSSL, protease serine-like. The Online Mendelian Inheritance in Man (OMIM) Website is http://www.ncbi.nlm.nih.gov/omim/. Yousef GM, Magklara A, Diamandis EP. KLK-L5 is a novel serine protease and a new member of the human kallikrein gene family—differential expression in breast cancer. Submitted for publication. Yousef GM, Magklara A, Chang A, Diamandis EP. Cloning of a new member of the human kallikrein gene family, KLK14, which appears to be down-regulated in breast cancer. Submitted for publication. New nomenclature for human kallikreins. Genes are presented in their order on chromosome 19q13.3-q13.4 from centromere to telomere. Full gene names are as follows: hPRK, human pancreatic/renal kallikrein; hGK-1, human glandular kallikrein-1; KLK-L, kallikrein-like; EMSP1, enamel matrix serine proteinase 1; HSCTE, human stratum corneum tryptic enzyme; HSCCE, human stratum corneum chymotryptic enzyme; TADG-14, tumor-associated, differentially expressed gene-14; NES1, normal epithelial cell-specific 1 gene; TLSP, trypsin-like serine protease; PRSS, protease serine; PRSSL, protease serine-like. The Online Mendelian Inheritance in Man (OMIM) Website is http://www.ncbi.nlm.nih.gov/omim/. Yousef GM, Magklara A, Diamandis EP. KLK-L5 is a novel serine protease and a new member of the human kallikrein gene family—differential expression in breast cancer. Submitted for publication. Yousef GM, Magklara A, Chang A, Diamandis EP. Cloning of a new member of the human kallikrein gene family, KLK14, which appears to be down-regulated in breast cancer. Submitted for publication. Note Added in Proof: A detailed review on the tissue human kallikrein gene family will appear in Endocrine Reviews[Yousef AM, Diamandis EP. The new human tissue kallikrein gene family: function and association to disease (in press)].