Tissue kallikreins: new players in normal and abnormal cell growth?

Summary

Serine proteases are proteolytic enzymes with an active serine residue in their catalytic site. Kallikreins are a subgroup of the serine protease family and are known to have diverse physiological functions. The human tissue kallikrein gene family has now been fully characterized and includes 15 members, clustered in a 300 kb region on chromosome 19q13.4. In this review, we discuss the common structural features of kallik-reins at the DNA, mRNA and protein levels. Kallikreins are secreted as inactive zymogens and are activated by cleavage of an N-terminal peptide. Some kallikreins can undergo autoactivation while others may be activated by other kallikreins or other proteases. Most kallikreins are predicted to have trypsin-like enzymatic activity except for three members which may have chymotrypsin-like activity. Circumstantial evidence suggests that at least some kallikreins may be part of an enzymatic cascade pathway which is activated in aggressive forms of ovarian and probably other cancers. Accumulating evidence suggests potential diagnostic and/or prognostic roles of kallikreins in diverse malignancies. In addition to PSA, many other kallik-reins show differential expression in malignancy. For example, hK6, 10 and 11 are promising serological markers for ovarian cancer diagnosis. KLK10 may act as a tumor suppressor. In addition to their diagnostic and prognostic values, kallikreins may also be good therapeutic targets.

Part of this paper was originally presented at the joint meetings of the 16th International Congress of the International Society of Fibrinolysis and Proteolysis (ISFP) and the 17th International Fibrinogen Workshop of the International Fibrinogen Research Society (IFRS) held in Munich, Germany, September, 2002.

Keywords

Kallikreins - tumor markers - prostate cancer - breast cancer - ovarian cancer - serine proteases - prognostic and predictive markers

• References

• 1 Rawlings ND, Barrett AJ. Evolutionary families of peptidases. Biochem J 1993; 290: 205-18.
• 2 Schultz RM, Liebman MN. Structure-function relationship in protein families. Devlin TM. (ed.), Textbook of biochemistry with clinical correlations., Fourth Edition. edition. New York: Wiley-liss, Inc; 1997: 1-2. -116.
• 3 Horl WH. Proteinases: potential role in health and disease. Sandler M, Smith HJ (eds.), Design of enzyme inhibitors as drugs. Oxford Oxford university press 1989; pp. 573-81.
• 4 Froelich CJ, Zhang X, Turbov J. et al. Human granzyme B degrades aggrecan proteoglycan in matrix synthesized by chondrocytes. J Immunol 1993; 151: 7161-71.
• 5 Henderson BR, Tansey WP, Phillips SM. et al. Transcriptional and posttranscriptional activation of urokinase plasminogen activator gene expression in metastatic tumor cells. Cancer Res 1992; 52: 2489-96.
• 6 Yousef GM, Diamandis EP. Expanded human tissue kallikrein family – a novel panel of cancer biomarkers. Tumour Biol 2002; 23: 185-92.
• 7 Lesk AM, Fordham WD. Conservation and variability in the structures of serine proteinas-es of the chymotrypsin family. J Mol Biol 1996; 258: 501-37.
• 8 Stryer L. Biochemistry, 4th edition. New York: WH. Freeman and Company; 1995
• 9 van Leeuwen BH, Evans BA, Tregear GW. et al. Mouse glandular kallikrein genes. Identification, structure, and expression of the renal kallikrein gene. J Biol Chem 1986; 261: 5529-35.
• 10 Asakai R, Davie EW, Chung DW. Organization of the gene for human factor XI. Biochemistry 1987; 26: 7221-8.
• 11 Yousef GM, Diamandis EP. The new human tissue kallikrein gene family: structure, function, and association to disease. Endocr Rev 2001; 22: 184-204.
• 12 Yousef GM, Diamandis EP. Human kallik-reins: common structural features, sequence analysis and evolution. Current Genomics 2003; 4: 147-65.
• 13 Yousef GM, Chang A, Scorilas A. et al. Genomic organization of the human kallikrein gene family on chromosome 19q13.3-q13.4. Biochem Biophys Res Commun 2000; 276: 125-33.
• 14 Harvey TJ, Hooper JD, Myers SA. et al. Tissue-specific expression patterns and fine mapping of the human kallikrein (KLK) locus on proximal 19q13.4. J Biol Chem 2000; 275: 37397-406.
• 15 Diamandis EP, Yousef GM, Clements J. et al. New nomenclature for the human tissue kallikrein gene family. Clin Chem 2000; 46: 1855-8.
• 16 Diamandis EP, Yousef GM. Human tissue kallikreins: a family of new cancer biomarkers. Clin Chem 2002; 48: 1198-205.
• 17 Katz BA, Liu B, Barnes M. et al. Crystal structure of recombinant human tissue kallikrein at 2.0 A resolution. Protein Sci 1998; 7: 875-85.
• 18 Gomis-Ruth FX, Bayes A, Sotiropoulou G. et al. The structure of human prokallikrein 6 reveals a novel activation mechanism for the kallikrein family. J Biol Chem 2002; 277: 27273-81.
• 19 Yousef GM, Scorilas A, Jung K. et al. Molecular cloning of the human kallikrein 15 gene (KLK15). Up-regulation in prostate cancer. J Biol Chem 2001; 276: 53-61.
• 20 Brattsand M, Egelrud T. Purification, molecular cloning, and expression of a human stratum corneum trypsin-like serine protease with possible function in desquamation. J Biol Chem 1999; 274: 30033-40.
• 21 Hansson L, Stromqvist M, Backman A. et al. Cloning, expression, and characterization of stratum corneum chymotryptic enzyme. A skin-specific human serine proteinase. J Biol Chem 1994; 269: 19420-6.
• 22 Rittenhouse HG, Finlay JA, Mikolajczyk SD. et al. Human Kallikrein 2 (hK2) and prostate-specific antigen (PSA): two closely related, but distinct, kallikreins in the prostate. Crit Rev Clin Lab Sci 1998; 35: 275-368.
• 23 Macfarlane SR, Seatter MJ, Kanke T. et al. Proteinase-activated receptors. Pharmacol Rev 2001; 53: 245-82.
• 24 Akiyama K, Nakamura T, Iwanaga S. et al. The chymotrypsin-like activity of human prostate-specific antigen, gamma-seminoprotein. FEBS Lett 1987; 225: 168-72.
• 25 Robert M, Gibbs BF, Jacobson E. et al. Characterization of prostate-specific antigen proteolytic activity on its major physiological substrate, the sperm motility inhibitor precursor/ semenogelin I. Biochemistry 1997; 36: 3811-9.
• 26 Lovgren J, Airas K, Lilja H. Enzymatic action of human glandular kallikrein 2 (hK2). Substrate specificity and regulation by Zn2+ and extracellular protease inhibitors. Eur J Biochem 1999; 262: 781-9.
• 27 Halprin KM. Epidermal turnover time are-examination. Br J Dermatol 1972; 86: 14-9.
• 28 Takayama TK, McMullen BA, Nelson PS. et al. Characterization of hK4 (Prostase), a prostate-specific serine protease: activation of the precursor of prostate specific antigen (pro-PSA) and single-chain urokinase-type plasminogen activator and degradation of prostatic acid phosphatase. Biochemistry 2001; 40: 15341-8.
• 29 Takayama TK, Carter CA, Deng T. Activation of prostate-specific antigen precursor (pro-PSA) by prostin, a novel human prostatic serine protease identified by degenerate PCR. Biochemistry 2001; 40: 1679-87.
• 30 Mitsui S, Yamada T, Okui A. et al. A novel iso-form of a kallikrein-like protease, TLSP/hip-postasin, (PRSS20), is expressed in the human brain and prostate. Biochem Biophys Res Commun 2000; 272: 205-11.
• 31 Brillard-Bourdet M, Moreau T, Gauthier F. Substrate specificity of tissue kallikreins: importance of an extended interaction site. Biochim Biophys Acta 1995; 1246: 47-52.
• 32 Khan AR, James MN. Molecular mechanisms for the conversion of zymogens to active proteolytic enzymes. Protein Sci 1998; 7: 815-36.
• 33 Denmeade SR, Lovgren J, Khan SR. et al. Activation of latent protease function of pro-hK2, but not pro-PSA, involves autoprocessing. Prostate 2001; 48: 122-6.
• 34 Little SP, Dixon EP, Norris F. et al. A novel and potentially amyloidogenic enzyme cDNA isolated from Alzheimer’s disease brain. J Biol Chem 1997; 272: 25135-42.
• 35 Christensson A, Bjork T, Nilsson O. et al. Serum prostate specific antigen complexed to alpha 1-antichymotrypsin as an indicator of prostate cancer. J Urol 1993; 150: 100-5.
• 36 Christensson A, Lilja H. Complex formation between protein C inhibitor and prostate-specific antigen in vitro and in human semen. Eur J Biochem 1994; 220: 45-53.
• 37 Stephan C, Jung K, Lein M. et al. Molecular forms of prostate-specific antigen and human kallikrein 2 as promising tools for early diagnosis of prostate cancer. Cancer Epidemiol Biomarkers Prev 2000; 9: 1133-47.
• 38 Christensson A, Laurell CB, Lilja H. Enzymatic activity of prostate-specific antigen and its reactions with extracellular serine pro-teinase inhibitors. Eur J Biochem 1990; 194: 755-63.
• 39 Lovgren J, Rajakoski K, Karp M. et al. Activation of the zymogen form of prostate-specific antigen by human glandular kallikrein2. Biochem Biophys Res Commun 1997; 238: 549-55.
• 40 Silverthorn DU. Human physiology. An integrated aproach. New Jersy: Prentice Hall; 1995
• 41 Yousef GM, Diamandis EP. Human tissue kallikreins: a new enzymatic cascade pathway?. Biol Chem 2002; 383: 1045-57.
• 42 Takayama TK, Fujikawa K, Davie EW. Characterization of the precursor of prostate-specific antigen. Activation by trypsin and by human glandular kallikrein. J Biol Chem 1997; 272: 21582-8.
• 43 Bhoola K, Ramsaroop R, Plendl J. et al. Kallikrein and kinin receptor expression in inflammation and cancer. Biol Chem 2001; 382: 77-89.
• 44 Bhoola KD, Figueroa CD, Worthy K. Bioregulation of kinins: kallikreins, kinino-gens, and kininases. Pharmacol Rev 1992; 44: 1-80.
• 45 Meneton P, Bloch-Faure M, Hagege AA. et al. Cardiovascular abnormalitis with normal blood pressure in tissue kallikrein-deficient mice. Proc Natl Acad Sci USA 2001; 98: 2634-9.
• 46 Sharma JN, Uma K, Noor AR. et al. Blood pressure regulation by the kallikrein-kinin system. Gen Pharmacol 1996; 27: 55-63.
• 47 Kumar A, Mikolajczyk SD, Goel AS. et al. Expression of pro form of prostate-specific antigen by mammalian cells and its conversion to mature, active form by human kallik-rein 2. Cancer Res 1997; 57: 3111-4.
• 48 Deperthes D, Frenette G, Brillard-Bourdet M. et al. Potential involvement of kallikrein hK2 in the hydrolysis of the human seminal vesicle proteins after ejaculation. J Androl 1996; 17: 659-65.
• 49 Lilja H. A kallikrein-like serine protease in prostatic fluid cleaves the predominant seminal vesicle protein. J Clin Invest 1985; 76: 1899-903.
• 50 Heidtmann HH, Nettelbeck DM, Mingels A. et al. Generation of angiostatin-like fragments from plasminogen by prostate-specific antigen. Br J Cancer 1999; 81: 1269-73.
• 51 Hu JC, Zhang C, Sun X. et al. Characterization of the mouse and human PRSS17 genes, their relationship to other serine proteases, and the expression of PRSS17 in developing mouse incisors. Gene 2000; 251: 1-8.
• 52 Egelrud T, Lundstrom A. The dependence of detergent-induced cell dissociation in non-palmo-plantar stratum corneum on endogenous proteolysis. J Invest Dermatol 1990; 95: 456-9.
• 53 Black MH, Diamandis EP. The diagnostic and prognostic utility of prostate-specific antigen for diseases of the breast. Breast Cancer Res Treat 2000; 59: 1-14.
• 54 Anisowicz A, Sotiropoulou G, Stenman G. et al. A novel protease homolog differentially expressed in breast and ovarian cancer. Mol Med 1996; 2: 624-36.
• 55 Liu XL, Wazer DE, Watanabe K. et al. Identification of a novel serine protease-like gene, the expression of which is down-regulated during breast cancer progression. Cancer Res 1996; 56: 3371-9.
• 56 Goyal J, Smith KM, Cowan JM. et al. The role for NES1 serine protease as a novel tumor suppressor. Cancer Res 1998; 58: 4782-6.
• 57 Diamandis EP, Yousef GM, Soosaipillai AR. et al. Human kallikrein 6 (zyme/protease M/neurosin): a new serum biomarker of ovarian carcinoma. Clin Biochem 2000; 33: 579-83.
• 58 Diamandis EP, Yousef GM, Soosaipillai AR. et al. Immunofluorometric assay of human kallikrein 6 (zyme/protease M/neurosin) and preliminary clinical applications. Clin Biochem 2000; 33: 369-75.
• 59 Luo LY, Katsaros D, Scorilas A. et al. Prognostic value of human kallikrein 10 expression in epithelial ovarian carcinoma. Clin Cancer Res 2001; 7: 2372-9.
• 60 Luo L, Bunting P, Scorilas A. et al. Human kallikrein 10: a novel tumor marker for ovarian carcinoma?. Clin Chim Acta 2001; 306: 111-8.
• 61 Diamandis EP, Okui A, Mitsui S. et al. Human kallikrein 11: A new biomarker of prostate and ovarian carcinoma. Cancer Res 2002; 62: 295-300.
• 62 Underwood LJ, Tanimoto H, Wang Y. et al. Cloning of tumor-associated differentially expressed gene-14, a novel serine protease overexpressed by ovarian carcinoma. Cancer Res 1999; 59: 4435-9.
• 63 Magklara A, Scorilas A, Katsaros D. et al. The human KLK8 (neuropsin/ovasin) gene: Identification of two novel splice variants and its prognostic value in ovarian cancer. Clin Cancer Res 2001; 7: 806-11.
• 64 Tanimoto H, Underwood LJ, Shigemasa K. et al. The stratum corneum chymotryptic enzyme that mediates shedding and desquamation of skin cells is highly overexpressed in ovarian tumor cells. Cancer 1999; 86: 2074-82.
• 65 Obiezu CV, Scorilas A, Katsaros D. et al. Higher human kallikrein gene 4 (klk4) expression indicates poor prognosis of ovarian cancer patients. Clin Cancer Res 2001; 7: 2380-6.
• 66 Kim H, Scorilas A, Katsaros D. et al. Human kallikrein gene 5 (KLK5) expression is an indicator of poor prognosis in ovarian cancer. Br J Cancer 2001; 84: 643-50.
• 67 Dong Y, Kaushal A, Bui L. et al. Human kallikrein 4 (KLK4) is highly expressed in serous ovarian carcinomas. Clin Cancer Res 2001; 7: 2363-71.
• 68 Yousef GM, Kyriakopoulou LG, Scorilas A. et al. Quantitative expression of the human kallikrein gene 9 (KLK9) in ovarian cancer: a new independent and favorable prognostic marker. Cancer Res 2001; 61: 7811-8.
• 69 Mahabeer R, Bhoola KD. Kallikrein and kinin receptor genes. Pharmacol Ther 2000; 88: 77-89.
• 70 Wolf WC, Evans DM, Chao L. et al. A synthetic tissue kallikrein inhibitor suppresses cancer cell invasiveness. Am J Pathol 2001; 159: 1797-805.
• 71 Yousef GM, Diamandis EP. Kallikreins, steroid hormones and ovarian cancer: is there a link?. Minerva Endocrinol 2002; 27: 157-66.
• 72 Yousef GM, Scorilas A, Magklara A. et al. The androgen-regulated gene human kallikrein 15 (KLK15) is an independent and favorable prognostic marker for breast cancer. Br J Cancer 2002; 87: 1294-300.
• 73 Yousef GM, Fracchioli S, Scorilas A. et al. Steroid hormone regulation and prognostic value of the human kallikrein gene 14 (KLK14) in ovarian cancer. Am J Clin Path 2003; 119: 346-55.
• 74 Smyth MJ. Starum corneum chymotryptic enzyme. AJ Barrett, R. N.D, JF. Woessner (eds.), Handbook of proteolytic enzymes. London: Academic Press; 1998: 87-9.
• 75 Sutkowski DM, Goode RL, Baniel J. et al. Growth regulation of prostatic stromal cells by prostate-specific antigen. J Natl Cancer Inst 1999; 91: 1663-9.
• 76 Iwamura M, Hellman J, Cockett AT. et al. Alteration of the hormonal bioactivity of parathyroid hormone-related protein (PTHrP) as a result of limited proteolysis by prostate-specific antigen. Urology 1996; 48: 317-25.
• 77 Matsui H, Takahashi T. Mouse testicular ley-dig cells express klk21, a tissue kallikrein that cleaves fibronectin and igf-binding protein-3. Endocrinology 2001; 142: 4918-29.
• 78 Plendl J, Snyman C, Naidoo S. et al. Expression of tissue kallikrein and kinin receptors in angiogenic microvascular endothelial cells. Biol Chem 2000; 381: 1103-15.
• 79 Magklara A, Scorilas A, Catalona WJ. et al. The combination of human glandular kallik-rein and free prostate-specific antigen (PSA) enhances discrimination between prostate cancer and benign prostatic hyperplasia in patients with moderately increased total PSA. Clin Chem 1999; 45: 1960-6.
• 80 Yousef GM, Scorilas A, Kyriakopoulou LG. et al. Human kallikrein gene 5 (KLK5) expression by quantitative PCR: an independent indicator of poor prognosis in breast cancer. Clin Chem 2002; 48: 1241-50.
• 81 Yousef GM, Scorilas A, Chang A. et al. Down-regulation of the human kallikrein gene 5 (KLK5) in prostate cancer tissues. Prostate 2002; 51: 126-32.
• 82 Yousef GM, Obiezu CV, Jung K. et al. Differential expression of kallikrein gene 5 in cancerous and normal testicular tissues. Urology 2002; 60: 714-8.
• 83 Diamandis EP, Scorilas A, Fracchioli S. et al. Human kallikrein 6 (hK6): A new potential serum biomarker for diagnosis and prognosis of ovarian carcinoma. J Clin Oncol 2003; 21: 1035-43.
• 84 Tanimoto H, Underwood LJ, Shigemasa K. et al. Increased expression of protease M in ovarian tumors. Tumour Biol 2001; 22: 11-8.
• 85 Yousef GM, Scorilas A, Nakamura T. et al. The prognostic value of the human kallikrein gene 9 (KLK9) in breast cancer. Breast Cancer Res Treat 2003; 78: 149-58.
• 86 Yousef GM, Magklara A, Diamandis EP. KLK12 is a novel serine protease and a new member of the human kallikrein gene family-differential expression in breast cancer. Genomics 2000; 69: 331-41.
• 87 Yousef GM, Chang A, Diamandis EP. Identification and characterization of KLK-L4, a new kallikrein-like gene that appears to be down-regulated in breast cancer tissues. J Biol Chem 2000; 275: 11891-8.
• 88 Yousef GM, Magklara A, Chang A. et al. Cloning of a new member of the human kallik-rein gene family, KLK14, which is down-regulated in different malignancies. Cancer Res 2001; 61: 3425-31.