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Human Tissue Kallikreins: Physiologic Roles and Applications in Cancer

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Human Tissue Kallikreins: Physiologic Roles and Applications in Cancer Subject Review Human Tissue Kallikreins: Physiologic Roles and Applications in Cancer Carla A. Borgon˜ o, Iacovos P. Michael, and Eleftherios P. Diamandis Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada Abstract The human genome contains at least 553 protease genes and Tissue kallikreins are members of the S1 family (clan SA) counting (4). Protease action is always irreversible and can of trypsin-like serine proteases and are present in at involve either indiscriminant and non-specific degradation of least six mammalian orders. In humans, tissue kallikreins protein substrates, as in apoptosis, or highly specific proteolytic (hK) are encoded by 15 structurally similar, steroid processing or limited hydrolysis of selected target proteins, hormone–regulated genes (KLK ) that colocalize to resulting in a functional change, as in prohormone activation. chromosome 19q13.4, representing the largest cluster Proteases are classified according to three major criteria: of contiguous protease genes in the entire genome. hKs location of the scissile peptide bond within the substrate are widely expressed in diverse tissues and implicated (terminal or internal), catalytic mechanism, and evolutionary in a range of normal physiologic functions from the relationships, as revealed by structure. On the basis of the first regulation of blood pressure and electrolyte balance to criterion, proteases are broadly categorized as either exo- or tissue remodeling, prohormone processing, neural endopeptidases, respectively. According to the second criterion, plasticity, and skin desquamation. Several lines of endopeptidases are divided into the well-known cysteine, serine, evidence suggest that hKs may be involved in cascade threonine, aspartic, and metalloprotease subgroups. Consistent reactions and that cross-talk may exist with proteases with the third criterion, proteases of each catalytic class are of other catalytic classes. The proteolytic activity of clustered into several ‘‘clans,’’ which in turn include many hKs is regulated in several ways including zymogen ‘‘families’’ containing proteases that share significant sequence activation, endogenous inhibitors, such as serpins, similarities (5, 6). and via internal (auto)cleavage leading to inactivation. Serine proteases were among the first enzymes to be studied Dysregulated hK expression is associated with multiple extensively (7). Their structural characteristics, catalytic mecha- diseases, primarily cancer. As a consequence, many nism, and roles in normal physiologic processes (e.g., digestion, kallikreins, in addition to hK3/PSA, have been identified coagulation, and cellular and humoral immunity) and in the as promising diagnostic and/or prognostic biomarkers pathology of many diseases (e.g., cancer, neurodegenerative for several cancer types, including ovarian, breast, and disorders) have been previously reviewed (5, 8-12). With the prostate. Recent data also suggest that hKs may be exception of a small class of membrane-bound serine proteases, causally involved in carcinogenesis, particularly in tumor the vast majority are secreted. Furthermore, serine proteases have metastasis and invasion, and, thus, may represent been organized into 11 evolutionary clans, most of which reside attractive drug targets to consider for therapeutic in clan SA of trypsin/chymotrypsin-like serine proteases (6). intervention. (Mol Cancer Res 2004;2(5):257–80) Tissue kallikreins (EC 3.4.21) form a subgroup of secreted serine proteases within the S1 family of clan SA. To date, tissue Introduction kallikreins have been identified in a variety of species from Proteases/peptidases, defined as enzymes that catalyze pep- six mammalian orders including tide bond hydrolysis, perform fundamental functions in all living organisms (1, 2). The ‘‘degradome’’ or complete set of 1. Primates (e.g., human, chimpanzee, baboon, cynomolgus proteases expressed at a given time within a cell, tissue, or monkey, rhesus monkey, orangutan, gorilla); organism (3) comprises f2% of all genes in many organisms. 2. Rodentia (e.g., mouse, rat, guinea pig, mastomys); 3. Carnivora (e.g., dog, cat); 4. Proboscidea (e.g., elephant); 5. Perissodactyla (e.g., horse); and Received 3/11/04; accepted 4/20/04. 6. Artiodactyla (e.g., pig, cow) (13-15). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in The number of kallikreins varies among species from 2 in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: Eleftherios P. Diamandis, Department of Pathology and the dog (16) to more than 25 in rodents (15, 17). For a more Laboratory Medicine, Mount Sinai Hospital, 600 University Avenue, Toronto, thorough discussion of kallikreins in non-human species, please Ontario, M5G 1X5 Canada. Phone: (416) 586-8443; Fax: (416) 586-8628. E-mail: [email protected] refer to our recent review (14). In humans, the tissue kallikrein Copyright D 2004 American Association for Cancer Research. (hK) family consists of 15 structurally homologous serine Mol Cancer Res 2004;2(5). May 2004 257 Downloaded from mcr.aacrjournals.org on September 27, 2021. © 2004 American Association for Cancer Research. 258 Borgon˜oetal. protease genes that colocalize in tandem to 19q13.4 (18). Of the pseudogenes, all of which presumably arose due to gene f176 serine protease genes within the human genome, this duplication events. In humans, the KLK locus spans f300 kb family represents the largest contiguous cluster (4, 19). In fact, on the long arm of chromosome 19 in cytogenic region 13.3 the kallikrein gene family is the largest cluster of protease genes to 13.4 and is bound centromerically by the testicular acid of any catalytic class (4, 19). phosphatase gene (ACPT; ref. 60), and telomerically by a The discovery of the complete hK family can be divided into cancer-associated gene (CAG)4 and Siglec-9, a member of the two eras. The first era (1930s to 1980s) witnessed the discovery sialic acid-binding Ig-like lectin (Siglec) family (61) (Fig. 1A). of the ‘‘classical’’ kallikreins. Although originally found in The KLK genes are tightly clustered in a tandem array, and are human urine (20, 21), human kallikrein 1 was subsequently not intervened by any non-KLK genes. The three classical identified at abundant levels in the pancreas (in Greek, the human KLK genes (KLK1, KLK2, and KLK3) are clustered ‘‘kallikreas’’), from which its name was derived (22). However, within a 60-kb region with KLK15, whereas KLK4-KLK14 the gene for this kallikrein, now called KLK1, was not dis- and the WKLK1 pseudogene are all located telomeric to KLK2. covered until 1985 (23, 24). During the late 1980s, two genes The direction of transcription of all genes is from telomere with high structural similarity to KLK1, currently known as to centromere with the exception of KLK3 and KLK2. KLK2 and KLK3/PSA, were cloned and colocalized to the The syntenic relationship of KLK gene organization is same chromosomal region (19q13.4) with KLK1 (25-27). At relatively conserved among human, chimpanzee, and rodent this time, it was concluded that the human kallikrein family genomes. The chimpanzee KLK locus is strikingly similar to had only three members, a statement that would hold for the human locus, spans f350 kb of genomic sequence on f10 years. chromosome 20, and contains orthologs to all 15 human KLK The second era (1994 to 2001) saw the expansion of the genes, which share more than 99% sequence similarity at the kallikrein family to 15 genes and the complete description of DNA and amino acid levels (Fig. 1B). Although the relative the human kallikrein locus. During the mid- to late 1990s, location and direction of transcription of KLK1 and KLK4- independent researchers cloned several novel serine pro- KLK14 is conserved among the human, chimpanzee, mouse, tease genes with significant similarities to the classical kalli- and rat loci, discrepancies exist with respect to locus size and krein genes. These included, human stratum corneum number of KLK1 and KLK15 paralogs and pseudogenes within chymotryptic enzyme (HSCCE)/KLK7 (28), normal epithelial the mouse and rat genomes, due to additional gene duplication cell-specific gene 1 (NES1)/KLK10 (29), protease M/zyme/ events. In the mouse, the KLK locus covers 590 kb within neurosin/KLK6 (30-32), neuropsin/TADG-14/KLK8 (33, 34), cytogenic region B2 on chromosome 7 and comprises 26 genes and trypsin-like serine protease (TLSP)/hippostasin/KLK11 and 11 pseudogenes (Fig. 1C). In contrast to the human and (35, 36) These genes were subsequently recognized as tissue chimp, the mouse lacks KLK2 and KLK3 orthologs but kallikrein genes and mapped to 19q13.4 by Diamandis and contains 23 KLK1 paralogs, 14 of which are functional. The colleagues (37-43). An additional seven kallikrein genes were latter reside between KLK1 and KLK15 in a 290-kb region, an independently cloned by our group and others, namely: prostase/ area that is only 1.5 kb in length within the human locus. KLK-L1/KLK4/ARM1/PRSS17 (44-46), human stratum cor- Generally, mouse and human KLK orthologs share f77% to neum tryptic enzyme (HSCTE)/KLK-L2/KLK5 (47, 48), KLK- 80% sequence similarity (62). The rat KLK locus spans 580 kb L3/KLK9 (40), KLK-L4/KLK13 (49), KLK-L5/KLK12 (50), within cytogenic region q21 on chromosome 1, contains 22 KLK-L6/KLK14 (51, 52), and prostinogen/KLK15 (53, 54), as genes and 19 pseudogenes, and is also devoid of KLK2 and well as the first kallikrein pseudogene, WKLK1.2 According to KLK3 orthologs (Fig. 1D). Interestingly, this locus contains the official nomenclature, kallikrein gene and protein symbols nine duplications of a f30-kb region harboring the KLK1, are currently denoted ‘‘KLK’’ and ‘‘hK,’’ respectively (55). Gene KLK15, and WKLK2 genes between WKLK2 and KLK4, numbering starts from centromere to telomere on chromosome resulting in nine paralogs of each gene. However, only the 19q13.4 with the exception of the three classical kallikreins, KLK1 paralogs are functional.
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