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Prostatic Trypsin-Like Kallikrein-Related Peptidases

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Prostatic Trypsin-Like Kallikrein-Related Peptidases Article in press - uncorrected proof Biol. Chem., Vol. 389, pp. 653–668, June 2008 • Copyright ᮊ by Walter de Gruyter • Berlin • New York. DOI 10.1515/BC.2008.078 Review Prostatic trypsin-like kallikrein-related peptidases (KLKs) and other prostate-expressed tryptic proteinases as regulators of signalling via proteinase-activated receptors (PARs) Andrew J. Ramsay1, Janet C. Reid1, Mark N. cesses by selective cleavage of specific substrates to Adams1, Hemamali Samaratunga2, Ying Dong1, influence cell behaviour (Turk, 2006). Well known physio- Judith A. Clements1 and John D. Hooper1,* logical examples include the proteinases of the blood coagulation (e.g., thrombin) (Davie et al., 1991), digestive 1 Institute of Health and Biomedical Innovation, (e.g., trypsin) (Yamashina, 1956) and wound healing (e.g., Queensland University of Technology, 6 Musk Avenue, plasmin) (Castellino and Ploplis, 2005) cascades. It is Kelvin Grove, Queensland 4059, Australia also clear that dysregulated serine proteinase activity 2 Department of Anatomical Pathology, Sullivan facilitates progression of various diseases including can- Nicolaides Pathology, Taringa 4068, Australia cer (Dano et al., 2005; Turk, 2006; Szabo and Bugge, * Corresponding author 2008). The cleavage site specificity of these enzymes is e-mail: [email protected] indicated by the residue six amino acids before the cat- alytic serine. In the active conformation of the proteinase, this residue is located at the bottom of a pocket in which Abstract the side-chain of the scissile bond of the substrate is inserted. An aspartate or, rarely, a glutamate at this site The prostate is a site of high expression of serine pro- indicates that the serine proteinase will preferentially teinases including members of the kallikrein-related cleave after substrate arginine or lysine residues (trypsin- peptidase (KLK) family, as well as other secreted and like or tryptic substrate specificity); a small hydrophobic membrane-anchored serine proteinases. It has been residue in this position specifies preferential cleavage known for some time that members of this enzyme family after large hydrophobic amino acids (chymotrypsin-like elicit cellular responses by acting directly on cells. More substrate specificity); and larger, usually non-polar resi- recently, it has been recognised that for serine protein- dues at this site specify preferential proteolysis following ases with specificity for cleavage after arginine and lysine small hydrophobic amino acids (elastase-like substrate residues (trypsin-like or tryptic enzymes) these cellular specificity) (Perona and Craik, 1995, 1997). responses are often mediated by cleavage of members The largest contiguous collection of S1A serine pro- of the proteinase-activated receptor (PAR) family – a four teinase encoding genes is located within the kallikrein- member sub-family of G protein-coupled receptors. related peptidase (KLK) locus at chromosome Here, we review the expression of PARs in prostate, the 19q13.3–13.4 (Gan et al., 2000; Harvey et al., 2000; You- ability of prostatic trypsin-like KLKs and other prostate- sef et al., 2000) which consists of 15 genes, 12 of which expressed tryptic enzymes to cleave PARs, as well as the encode tryptic serine proteinases: KLK1–2, KLK4–6, prostate cancer-associated consequences of PAR acti- KLK8, KLK10–15 (Borgono and Diamandis, 2004; Cle- vation. In addition, we explore the dysregulation of tryp- ments et al., 2004). A common site of expression for the sin-like serine proteinase activity through the loss of KLKs is the prostate with this tissue a predominant site normal inhibitory mechanisms and potential interactions of mRNA expression for KLK2, KLK3 (also known as between these dysregulated enzymes leading to aberrant prostate-specific antigen or PSA), KLK4, KLK11, KLK14 PAR activation, intracellular signalling and cancer-pro- and KLK15 (Clements et al., 2004; Shaw and Diamandis, moting cellular changes. 2007). In addition, mRNA of KLK6, KLK9, KLK12 and Keywords: cancer; kallikrein-related peptidase; KLK13 is highly expressed in this tissue, while low or very prostate; proteinase-activated receptor; serine low prostatic mRNA expression has been reported for proteinase. each of the remaining KLKs (Clements et al., 2004; Shaw and Diamandis, 2007). In summary, as listed in Table 1 (and described in the references cited therein), tran- Introduction scripts of each KLK are expressed in prostate and all family members, except KLK8, have been detected at the Serine proteinases of the S1A sub-family are characte- protein level in normal or cancerous prostate. rised by a triad of amino acids consisting of histidine, Over the last 15 years, it has been increasingly recog- aspartate and serine residues in highly conserved nised that many of the cellular effects elicited by trypsin- sequence motifs, which are essential for catalytic activity like serine proteinases are mediated by activation (Rawlings and Barrett, 1994). These enzymes, which of cell surface proteins known as proteinase activated encompass as many as 140 (Rawlings et al., 2006) of the receptors (PARs). These receptors, which comprise a G total 569 human degradome complement (Lo´ pez-Otı´n protein coupled receptor sub-family consisting of and Matrisian, 2007), modulate a variety of cellular pro- PAR1–PAR4, are irreversibly activated by the action of Brought to you by | University of Queensland - UQ Library 2008/121 Authenticated Download Date | 9/14/15 3:38 AM 654 Table 1 Summary of studies examining proteolytic substrate specificity and prostate expression of kallikrein-related peptidases. A.J. Ramsay et al. KLK Specificity P1 Preference Protein expression in normal and cancerous prostate Expression patterna Cancerb 1 Tryptic Arg, Met, Phe)Lys SF; N ND (Sueiras-Diaz et al., 1994; Chagas et al., 1995; (Geiger and Clausnitzer, 1981; Fink et al., 1985; Bourgeois et al., 1997; Chen et al., 2000; Borgono et al., 2007b) Shaw and Diamandis, 2007) 2 Tryptic Arg SF; N; B; P; C Up (Bourgeois et al., 1997; Mikolajczyk et al., 1998; (Deperthes et al., 1995; Young et al., 1996; Lovgren et al., 1999a; Cloutier et al., 2002) Darson et al., 1997, Darson et al., 1999; Tremblay et al., 1997; Lovgren et al., 1999b; Magklara et al., 2000; Herrala et al., 2001; Brought to youby|University ofQueensland -UQLibrary Veveris-Lowe et al., 2005; Shaw and Diamandis, 2007) 3 Chymotryptic Leu, Tyr, Phe, Gln, His, Asn, Leu, Ser SF; N; B; P; C Down Article in press - uncorrected proof (Akiyama et al., 1987; Christensson et al., 1990; (Darson et al., 1997, 1999; Denmeade et al., 1997; Takayama et al., 1997; Herrala et al., 2001; Ishida et al., 2003; Magklara et al., 2000; Download Date |9/14/15 3:38 AM Coombs et al., 1998; Malm et al., 2000) Shaw and Diamandis, 2007; Simone et al., 2000; Tremblay et al., 1997; Veveris-Lowe et al., 2005) 4 Tryptic Arg)Lys SF; N; B; P; C Up Authenticated (Takayama et al., 2001; Matsumura et al., 2005; (Day et al., 2002; Obiezu et al., 2002, 2005; Dong et al., 2005; Debela et al., 2006a,b; Obiezu et al., 2006; Borgono et al., 2007a) Veveris-Lowe et al., 2005; Klokk et al., 2007; Shaw and Diamandis, 2007) 5 Tryptic Arg)Lys, Phe, Tyr, Gly, Asp SF; N ND (Brattsand et al., 2005; Michael et al., 2005; Debela et al., 2006b; (Shaw and Diamandis, 2007) Oikonomopoulou et al., 2006; Borgono et al., 2007a,b) 6 Tryptic Arg)Lys, Leu, Phe, Tyr, Leu, Gly, Ser, Thr, Pro SF; N; B; C Down (Little et al., 1997; Okui et al., 2001; Bernett et al., 2002; (Diamandis et al., 2000; Petraki et al., 2001, 2003a) Magklara et al., 2003; Debela et al., 2006b; Oikonomopoulou et al., 2006; Borgono et al., 2007b) 7 Chymotryptic Try)Phe, Leu SF; N ND (Egelrud, 1993; Skytt et al., 1995) (Kishi et al., 2004; Shaw and Diamandis, 2007) 8 Tryptic Arg, Lys Not detected ND (Rajapakse et al., 2005; Kishi et al., 2006; Stefansson et al., 2008) 9 Chymotryptic Not done SF; N ND (Shaw and Diamandis, 2007) 10 Tryptic Arg)Lys SF; N; B; C Down (Debela et al., 2006b) (Luo et al., 2001a; Petraki et al., 2002, 2003a; Shaw and Diamandis, 2007) 11 Tryptic Arg SF; N; B Upc (Mitsui et al., 2000; Luo et al., 2006) (Diamandis et al., 2002; Nakamura et al., 2003; Shaw and Diamandis, 2007) Article in press - uncorrected proof Tryptic serine proteinases and PARs in prostate 655 b c proteinases (Vu et al., 1991; Bohm et al., 1996a; Ishihara ND Up et al., 1997; Xu et al., 1998; Boire et al., 2005; Vesey et Cancer al., 2007). In fact, PAR activation is almost exclusively mediated by serine proteinases with trypsin-like sub- strate specificity for cleavage following arginine or lysine residues. As shown in Figure 1A cleavage occurs within the amino-terminal exodomain of the receptor following either an arginine or lysine residue generating a new ami- no-terminal. This neo-epitope serves as a tethered ligand which binds intramolecularly, causing allosteric changes within the PAR, followed by receptor coupling to hete- rotrimeric G proteins and signal transduction (Figure 1B, activation). Importantly, it is also possible for proteinases to cleave downstream of the activation site or within a PAR extracellular loop leading to disarming of the recep- tor (Oikonomopoulou et al., 2006) (Figure 1B, disarming). PARs are involved in a number of physiological process- es, such as cardiovascular responses, neuronal cell sur- vival, platelet aggregation, inflammation and epidermal function, and also mediate disease-associated cellular a changes including those necessary for cancer progres- Protein expression in normal and cancerous prostate sion, such as dysregulated cell proliferation and migra- tion (Macfarlane et al., 2001). Recently, several prostatic KLKs with trypsin-like sub- strate specificity have been shown to cleave PARs lead- ing either to receptor activation or disarming. It is also Expression pattern known that normal and diseased prostate is the site of expression of many other tryptic serine proteinases.
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